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The 2020 HIMSS Cybersecurity Survey gathered buy generic zithromax online feedback from 168 US based healthcare contraindications for zithromax cybersecurity professionals – mostly IT and infosec leaders at provider organizations, but also some consultants and vendors – to offer an updated snapshot showing the of the current security landscape. (HIMSS is the parent company of Healthcare IT News.)The big takeaway is buy generic zithromax online that breaches, ransomware and other security incidents are getting bigger and more disruptive at healthcare organizations, with scam artists, cybercriminals and even nation-state actors becoming ever more brazen and persistent.Phishing remains the most common initial vulnerability, allowing bad actors an entry point from which they can exploit hospital IT systems. HIMSS20 Digital Learn on-demand, earn credit, find products and solutions. Get Started buy generic zithromax online >>.

"Phishing is the number one way that attackers are getting into your systems and networks," said HIMSS Director of Privacy buy generic zithromax online and Security Lee Kim."What are attackers after?. Financial and employee information [is] the most prized," she said. "Going after buy generic zithromax online the money is the number one goal. Employee information is also hot, as this information is valuable for both phishers and identity thieves."Interestingly, patient information was only number three on the list.Most of the time, "disruption of information technology operations and business operations are typical outcomes of cyberattacks," according to the report – and most of the time, that disruption is temporary and relatively limited in scope.However, "disruption of clinical care, or damage or destruction of clinical care systems and devices also occurs," the report notes.And, as seen several months ago in Germany, sometimes that disruption can prove fatal for vulnerable patients.Even given the widespread worry that delays in care as in that incident – or attacks on connected medical devices or vulnerable IoT systems – could cause adverse events, "patient safety impacts are likely underreported," according to the report.

"There is buy generic zithromax online a lack of available mechanisms for identifying and detecting patient safety impacts," researchers wrote. "The respondents reporting patient safety impacts were asked if effective mechanisms were in place to detect patient safety issues related to significant security incidents."Sixty-one percent of these respondents indicated that their organizations did not have effective mechanisms in buy generic zithromax online place," they added. "Because of the clear nexus between patient safety and cybersecurity, it is clear that more organizations need to have effective mechanisms for detecting patient safety issues."THE LARGER TRENDThe survey emphasizes that the attacks on the healthcare space are getting bigger, more complex and more damaging in general."Significant security incidents continue to plague healthcare organizations of all types and sizes," the researchers wrote.Moreover, the sheer variety of ways vulnerabilities can be exploited shows the size of the challenge for CISOs, CIOs and other security leaders. According to HIMSS, the most common significant security buy generic zithromax online incidents were:Phishing attacks (reported by 57% of respondents)Credential harvesting attacks (21%)Social engineering attacks other than phishing (20%)Ransomware or other malware (20%)Theft or loss (16%)Website or web application attacks (14%)Negligent insider activity (13%)Breach or data leakage (11%)Malicious insider activity (10%)Despite all this risk, cybersecurity budgets are still not up to where they should be at most healthcare organizations according to the report, with just 6% or less of information technology budgets typically allocated for cybersecurity.And despite the heightened risk – as illustrated most recently by a sobering ransomware warning from the Cybersecurity and Infrastructure Security Agency, the FBI and HHS – "budgets are mainly static," said researchers.

"Cybersecurity budgets generally did not change from the prior year."Even more challenging is the fact that most provider organizations are running on old or even outdated technologies."Legacy systems are the norm [and] are pervasive in healthcare," according to HIMSS. Meanwhile, the buy generic zithromax online "footprint of legacy systems is significantly growing," with Windows Server 2008, Windows 7 and Windows XP still in place.At least health systems are doing adequately with basic controls in place. For instance, the report notes, lukewarmly, "most, but not all, organizations have firewalls and anti-zithromax software in place" by now.At other organizations, "some progress is being made for basic and advanced controls," including system monitoring, patch and vulnerability management tools, and multi-factor authentication.Likewise, "more comprehensive security risk assessments [and] end-to-end security risk assessments are being done," even if there's "room for improvement," according to HIMSS – which also notices that "new or improved security measures are being implemented, and drafting, revising, and/or testing policies, procedures, and documentation are being done as a result of security buy generic zithromax online risk assessments."Still, one ongoing vulnerability is that "business continuity and disaster recovery plans are nonexistent or very weak at many healthcare organizations," according to the report. "Frequently, these plans are not tested until an actual incident occurs.

In the case of a significant security incident, chaos can ensue and enormous costs can mount."Without a doubt, healthcare organizations should be proactive with buy generic zithromax online developing, implementing, testing and training. These actions are necessary for robust business continuity and disaster recovery plans. The plans should also continue to evolve based upon lessons learned."ON THE RECORD"Most buy generic zithromax online healthcare organizations are experiencing disruption of their systems," said Lee Kim of HIMSS. "Some experience disruption buy generic zithromax online of clinical systems.

Do you have a backup plan in case your system goes down?. We’ve already had the buy generic zithromax online first documented case of a patient death due to a ransomware attack. We don’t want the trend to continue. We have to be vigilant with our plans."Read the full 2020 HIMSS Healthcare Cybersecurity Survey.President Donald Trump this week fired Cybersecurity and Infrastructure Security Agency Director Christopher Krebs via Twitter, following CISA's assurances that the presidential election was "the most secure in American history." The buy generic zithromax online firing comes on the heels of a joint warning this past month from CISA, the U.S.

Department of Health and Human Services, and the Federal Bureau of Investigations of an buy generic zithromax online "increased and imminent" cyber threat to hospitals. "The president’s decision to fire Director Krebs makes America less safe," said U.S. House Committee on Homeland buy generic zithromax online Security Chair Rep. Bennie G.

Thompson, D-Miss., and buy generic zithromax online Rep. Lauren Underwood, D-Ill., who chairs the Subcommittee on Cybersecurity, Infrastructure Protection and Innovation, in a joint statement on Tuesday."The president’s unsubstantiated tweets this evening do nothing to defend our state and local governments and critical infrastructure against malicious buy generic zithromax online cyber campaigns," they said. "Anytime the government loses well-respected cyber professionals like Chris Krebs, especially under these political circumstances, there’s bound to be at least a momentary downside impact on CISA’s morale," said Drex DeFord, healthcare executive strategist for CI Security, to Healthcare IT News. DeFord continued, "Healthcare clearly leans on CISA buy generic zithromax online to provide insights to cybersecurity threats, and given the multiple stressors on healthcare organizations today, we can ill-afford any glitches in the capabilities of CISA, or their ability to quickly and effectively coordinate with valued cyber-partners like the FBI, HHS, and Homeland Security."Chris has, by all reports, done a great job building his team at CISA, and I continue to feel hopeful that, while he’ll be missed, his crew will deliver on the same high-quality security mission that healthcare has come to rely on," DeFord added.WHY IT MATTERS CISA Assistant Director Bryan S.

Ware, who helped spearhead the agency's initiatives to protect the health industry from both criminal and state-sponsored hacking, is also out buy generic zithromax online at the U.S. Department of Homeland Security.As CyberScoop reported last week, Ware declined to comment on whether his resignation was prompted by a request from the Trump administration. Ware had buy generic zithromax online been focused on the dangers of ransomware, the vulnerabilities of telehealth and hospital remote-work technology, and the risks that nation-state bad actors posed to life sciences organizations as they worked on a buy antibiotics treatment. "This year, right there with elections infrastructure, healthcare infrastructure is a major priority and a really new priority for us," he said earlier this year.THE LARGER TREND Cyber threats have taken on new danger in the buy antibiotics era, with the rapid scale-up of telehealth, a shift to working from home, and a stretched-thin workforce combining to make hospitals and other health systems especially vulnerable.Several health systems have reported being hit with cyberattacks this fall – most notably Universal Health Services, which experienced a network shutdown throughout its U.S.

Facilities after buy generic zithromax online an apparent ransomware incident in September. ON THE RECORD "We commend Chris Krebs for refusing to cave to political pressure from the White House and instead choosing to uphold his obligations to the American people as director of the Cybersecurity and Infrastructure Security buy generic zithromax online Agency," said Thompson and Underwood in their statement. Kat Jercich is senior editor of Healthcare IT News.Twitter. @kjercichEmail.

Kjercich@himss.orgHealthcare IT News is a HIMSS Media publication.Earlier this year, Geisinger health system based in Danville, Pennsylvania, had full intensive care units at several of its hospitals, leading to higher acuity in the step-down units at those facilities. The ICUs were already supported by Geisinger’s eICU program, and the health system wanted to extend that support on a temporary basis to its step-down units.In addition, all the non-rooms that were converted to negative airflow had solid-wood doors, making it impossible to see the patients. The health system needed a simple, easy and cost-effective way to implement video monitoring for those rooms.PROPOSAL HIMSS20 Digital Learn on-demand, earn credit, find products and solutions. Get Started >>.

Geisinger already was using a telehealth ICU system from vendor Caregility and in-room AV equipment in its ICUs.“The Caregility technology offered a HIPAA-compliant, two-way, audio/video solution,” said Tracey Kopenhaver, RN, eICU and cardiac ICU operations manager at Geisinger. €œThe technology was offered in a mobile app that could be downloaded to any mobile device. The proposal was to put an iPad with the app in each patient room and connect via a second device at the desk to allow visualization of the patient.”"Having people who understand what clinicians do and how we use products and technology to take care of patients is vital to ensuring that solutions make sense and are easy to use."Tracey Kopenhaver, RN, GeisingerIn the case of the step-down units, Geisinger wanted to be able to connect that staff to its eICU nurses and physicians for added support.MARKETPLACEThere are many vendors of telemedicine technology and services on the health IT market today. Healthcare IT News recently compiled a comprehensive list of these vendors with detailed descriptions.

To read this special report, click here.MEETING THE CHALLENGEThe health system deployed an iPad with the Caregility app to each room of the step-down units. At the touch of a button on the app, the nurse in the room with the patient could access an experienced critical care nurse or provider.“We were able to assist the bedside clinical staff with early intervention for patients whose condition was getting worse,” Kopenhaver explained. €œWe also were able to assist with little things like documentation that required two nurses, so that only one bedside nurse needed to go into the room. This allowed us to save PPE such as gowns, gloves and masks, which were in short supply.”RESULTSGeisinger implemented eICU support for more than 60 rooms within a week.“In the units supported by eICU, patients appreciate that there always is somebody in the background helping us make sure they’re not having any problems,” Kopenhaver noted.

€œThe bedside nursing and provider staff appreciate the additional support from the eICU staff.”The health system’s IT staff is appreciative of system-monitoring and smart-alert functionality to make the team aware of any network or device connectivity issues, she added.ADVICE FOR OTHERS“Having people who understand what clinicians do and how we use products and technology to take care of patients is vital to ensuring that solutions make sense and are easy to use,” Kopenhaver advised.Provider organizations should look for a product that offers simple installation, a full telehealth suite, EHR integration and a reporting ability that allows staff to go in and get productivity information, she added.“ASP-based solutions have so many more advantages than an internal desktop client, because you can reach everywhere in the health system very easily,” she concluded. €œOur next focus is looking more at the non-ICU patient population and determining how we can help support those patients who are deteriorating outside of the ICU and hopefully keep them outside of the ICU.”Twitter. @SiwickiHealthITEmail the writer. Bsiwicki@himss.orgHealthcare IT News is a HIMSS Media publication..

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Hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), and familial intestinal gastric cancer (FIGC).7–9 Germline mutations and deletions within the E-cadherin gene (CDH1) are the main cause of HDGC and affect 14%–40% of families.10–12 Additionally, while α-E-catenin gene (CTNNA1) mutations have been proven to cause HDGC, germline variants in homologous recombination DNA repair genes, such as PALB2, await confirmation as potential causes of disease in mutation-negative HDGC families.13–15 Concerning GAPPS, APC promoter 1B point mutations are the underlying useful source cause of this syndrome in several families.16 Unlike HDGC and GAPPS, FIGC remains genetically unexplained, despite the recent report of PALB2 germline mutations in three individuals with intestinal tumours but lacking family history of GC.14 zithromax 500mg pfizer 17FIGC is characterised by an autosomal dominant inheritance pattern of intestinal gastric cancer (IGC), without gastric polyposis, and is defined according to GC incidence, as agreed by the International Gastric Cancer Linkage Consortium.9 Therefore, in high incidence countries, the diagnostic criteria is analogous to the Amsterdam criteria for hereditary non-polyposis colorectal cancer (HNPCC). At least three relatives should have IGC and one of them should be a first-degree relative of the other two. At least two successive generations should be affected.

And in one of the relatives, GC zithromax 500mg pfizer should be diagnosed before the age of 50. In countries with low incidence, the following criteria are used. At least two first-degree relatives (FDR) or second-degree relatives (SDR) affected by IGC, one diagnosed before the age of 50.

Or three or more relatives with zithromax 500mg pfizer IGC at any age.9 Because no novel data exist supporting familial aggregation of IGC, no specific tumour spectrum has been defined, and no data support a particular age of onset. Hence, the above criteria have never been revisited or validated. Therefore, these families are often neglected and rarely followed in oncogenetic consultations.GC also develops in the context of other inherited cancer predisposition syndromes.18 In particular, GC has been identified in the tumour spectrum of Lynch syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, familial adenomatous polyposis, juvenile polyposis, and hereditary breast and ovarian cancer, among others.19–22 Therefore, genes causing hereditary cancer susceptibility syndromes, even if only slightly associated with GC susceptibility, would be good candidates to test as potential FIGC causal genes.Herein, we used a next-generation sequencing approach to interrogate a panel of genes implicated in upper gastrointestinal tract cancer, or in cancer susceptibility syndromes, across 50 probands with familial aggregation of IGC from Tuscany, a region from Italy with high incidence of GC.23 The access to a highly homogeneous FIGC cohort, the largest ever studied, and its comparison with an HDGC series and a cohort of sporadic intestinal gastric cancer (SIGC) allowed us to define three objectives and to extend the current knowledge on FIGC predisposition.

(1) characterise the age of cancer onset and disease zithromax 500mg pfizer spectrum of our FIGC cohort. (2) search for evidence for a Mendelian and monogenic pattern of inheritance. And (3) search for evidence of alternative oligogenic/polygenic modes of inheritance.Herein, we gathered evidence that FIGC is likely a genetically determined, GC-predisposing disease, different at the clinical, germline and somatic levels from SIGC and HDGC.

We further proposed the first testing criteria for FIGC families.MethodsPatient selectionFifty FIGC and 17 HDGC-CDH1 mutation-negative probands were admitted at the Division of General Surgery and Surgical Oncology, University of Siena, zithromax 500mg pfizer Italy. The selection of FIGC families was based on the following criteria. (1) proband presenting with GC of intestinal histology.

(2) familial aggregation of zithromax 500mg pfizer GC. (3) family history of cancer, other than gastric. (4) negative genetic test for germline CDH1 coding sequence mutations (exclusion of HDGC).

And (5) negative zithromax 500mg pfizer genetic test for germline for the promoter 1B of APC (exclusion of GAPPS). The 17 HDGC probands were negative for CDH1 germline coding mutations and selected as a control group. Forty-seven patients with SIGC were collected in Portugal.Multigene panel sequencing, variant calling and filteringDNA from normal gastric mucosa (germline) and tumour tissue from 50 FIGC and 17 HDGC-CDH1 mutation-negative probands were sequenced using three Illumina MiSeq custom panels.

TruSeq Custom Amplicon Assay 1, TruSeq Custom Amplicon Assay 2 and Nextera custom panel (online supplementary table 1) zithromax 500mg pfizer. The selection of genes deposited in each panel was based on their implication in upper gastrointestinal tract cancers or in cancer susceptibility syndromes identified through literature review (online supplementary table 2). FASTQ files were aligned to the RefSeq Human Genome GRCh38 using bwa-mem, and variants were called using Samtools.24 25 Called variants were defined as germline or somatic by normal-tumour pair comparison and annotated with Ensembl and Catalogue Of Somatic Mutations In Cancer (COSMIC (FATHMM- Functional Analysis through Hidden Markov Models).26 27 High-quality (HQ) germline or somatic variants were defined as presenting ≥20 reads per allele and genotype quality ≥90 and call quality ≥100.

Next, all single nucleotide polymorphism database (dbSNP) identifiers available for FIGC germline variants (regardless of quality criteria) were screened in zithromax 500mg pfizer four European populations from 1000 Genomes. (1) 107 normal individuals from Tuscany (Italy, TSI). (2) 91 normal individuals from Great Britain (GBR).

(3) 99 zithromax 500mg pfizer normal individuals from Finland (FIN). And (4) 107 normal individuals from Spain (IBS).28 Germline variants without dbSNP identifiers available in the 1000 Genomes were screened using Ensembl VEP for truncating consequences. Detected truncating variants presented on average less than four reads, that is, were of low quality and discarded.

FIGC germline, rare HQ exclusive variants were selected if they (1) displayed genotypes in FIGCs distinct from GBR, FIN and IBS populations and zithromax 500mg pfizer below 1% in the TSI population. (2) presented ≥20 reads per allele, genotype quality ≥90 and call quality ≥100. (3) displayed genotypes distinct from HDGCs and SIGCs.

And (4) presented allele frequency in ExAC and gnomAD populations below 1%.29Supplemental materialSupplemental materialValidation of FIGC germline, rare zithromax 500mg pfizer HQ exclusive variants by Sanger sequencingTwelve out of 32 FIGC germline, rare HQ exclusive variants were validated by PCR-Sanger sequencing. Briefly, 20–50 ng of DNA from normal and matched tumour was amplified using Multiplex PCR Kit (Qiagen) and custom primers flanking each variant. PCR products were purified with ExoSAP-IT Express (Applied Biosystems) and sequenced on an ABI3100 Genetic Analyzer using BigDye Terminator V.3.1 Cycle Sequencing Kit (Applied Biosystems).Intronic germline variants were analysed using the splice site prediction software NetGene2 V.2.4.30Somatic second-hit analysisLoss of heterozygosity (LOH) and somatic second mutations were determined by calculating the variant allele frequency (VAF) and screening genes with FIGC germline, rare HQ exclusive variants, respectively.

In particular, VAF was calculated by dividing the number of reads for the variant allele by the total number of reads both for the normal and for the zithromax 500mg pfizer corresponding tumour samples. LOH was defined when more than 20% increase of VAF over normal was observed.Germline and somatic landscape analysis of 50 FIGC casesFIGC germline and somatic landscapes were analysed on a per-variant and per-gene basis, considering the number of FIGC germline, rare HQ exclusive variants detected per proband (0, 1 or >1). The similarities/differences for the germline and somatic variant and gene landscapes per FIGC class were analysed using unsupervised hierarchical clustering using R package ggplot2 for heatmap and dendrogram construction.31 For somatic variant/gene landscape analysis, FIGC classes were also divided according to microsatellite instable status and compared using analysis of variance statistics with R.

The number of microsatellite instable (MSI) and microsatellite stable (MSS) tumours per FIGC class was compared using Pearson’s χ2 test.Comparison of germline and somatic landscapes for FIGC, SIGC and HDGCVCF files obtained from whole genome sequencing (Complete Genomics platform) of 47 SIGCs and VCF files of 17 HDGCs were analysed to detect germline zithromax 500mg pfizer and somatic variants, using the same germline/somatic variant definition and sequencing quality criteria previously described for FIGC cases. Of note, due to the differential resolution between whole genome sequencing and targeted sequencing, only variants detected in the 47 SIGCs in the same regions targeted by the custom panels were selected for downstream analysis.Germline and somatic landscapes of FIGC, SIGC and HDGC cases were performed on a per-gene basis. Each gene was classified as presenting 0 or ≥1 germline/somatic variants.

Germline and somatic joint zithromax 500mg pfizer landscape was defined by counting the number of germline and somatic variants for each gene, which was classified as displaying no germline or somatic variants. ‰¥1 germline and 0 somatic variants. 0 germline and ≥1 somatic variants.

Or ≥1 germline and zithromax 500mg pfizer ≥1 somatic variants. Results were plotted in a heatmap and a dendrogram, and principal component analysis was performed using R. The frequency of genes with germline/somatic variants in FIGCs, SIGCs and HDGCs was calculated, and genes with a frequency difference ≥50% were represented in a bar plot and in a heatmap using R.ResultsAge of onset and disease spectrum in FIGCOf the 50 FIGC probands (table 1), 18 were female and 32 were male.

The mean age at diagnosis was zithromax 500mg pfizer 71.8±8.0 years. From the 50 families depicted in table 1, 5 (10%) had >1 FDR with GC (mean age. 68.8±7.5 years).

14 (28%) zithromax 500mg pfizer had concomitantly FDR and SDR or FDR and third-degree relatives with GC (mean age. 68.7±8.4 years). 29 (58%) had a single FDR with GC (mean age.

73.6±7.2 years) zithromax 500mg pfizer. And 2 (4%) had only SDR affected with GC (mean. 74±15.6 years).View this table:Table 1 Clinical characteristics of FIGC probands and their family historyWhen considering the disease spectrum in these FIGC families, 19 different phenotypes have been observed affecting 208 family members (figure 1, table 1).

The most zithromax 500mg pfizer prevalent phenotype was GC, detected in 138 of 208 (66.3%) family members. 50 probands with IGC and 88 additional patients with unknown GC histology. The second and third most prevalent phenotypes were colorectal/colon and breast cancer observed in nine patients from seven families.

Of note, eight patients from six families were affected with gastric ulcer, a non-cancerous lesion, which is the zithromax 500mg pfizer third most common disease phenotype in this cohort. Besides these phenotypes, positive history of lung cancer was observed in six families. Leukaemia in five families.

Laryngotracheal and zithromax 500mg pfizer hepatobiliary cancer in four families. Osteosarcoma in three families. Prostate, liver, melanoma, gynaecological, bladder and brain cancers were detected in two families each.

And thyroid, kidney and oral cancer zithromax 500mg pfizer in one family. Moreover, 11 families had relatives affected by an unidentified type of cancer that often coexisted with other cancer types such as colon, leukaemia, breast, liver and prostate.Disease spectrum of FIGC families. The disease spectrum of FIGC encompassed 19 different phenotypes affecting 208 family members.

The most prevalent phenotype was gastric cancer, detected in 138 of 208, followed by colorectal/colon and breast cancers in zithromax 500mg pfizer 9 of 208. FIGC, familial intestinal gastric cancer." data-icon-position data-hide-link-title="0">Figure 1 Disease spectrum of FIGC families. The disease spectrum of FIGC encompassed 19 different phenotypes affecting 208 family members.

The most zithromax 500mg pfizer prevalent phenotype was gastric cancer, detected in 138 of 208, followed by colorectal/colon and breast cancers in 9 of 208. FIGC, familial intestinal gastric cancer.Germline and somatic variant discovery across FIGC probandsMultigene panel sequencing analysis of normal-tumour DNA of 50 FIGC probands revealed a total of 10 062 variants (≥1 read covering the alternative allele). Of these, 4998 (49.7%) were detected in normal DNA and defined as germline variants.

The remaining 5064 (50.3%) were called as somatic zithromax 500mg pfizer variants due to exclusive presence in tumour DNA. We started by exploring germline variants, focusing on rare variants in single genes (monogenic hypothesis) or variants co-occurring in several genes, regardless of their population frequency (oligogenic/polygenic hypothesis).Monogenic hypothesis. FIGC-associated rare germline variants and somatic second-hitsTo identify rare germline FIGC-predisposing variants, we performed a systematic analysis of all germline variants, focusing on their frequency across normal populations and GC cohorts, and sequencing quality.We identified 4998 germline variants in the 50 patients with FIGC (figure 2A).

From the 4998 FIGC germline variants, the genotype frequency of 1038 (20.8%) was available for four 1000 Genomes European populations.28 From the 79.2% of variants absent from 1000 Genomes, only 1.3% (n=53) presented truncating effects, however supported on average by less than four reads, zithromax 500mg pfizer that is, of very low quality and hence confidently discarded. From the 1038 variants present in 1000 Genomes, 121 (11.7%) presented genotypes absent from the four populations screened. Of these 121 variants, only 60 presented the abovementioned sequencing quality criteria.

From these, 43 variants were exclusively detected in FIGC comparing with HDGC-CDH1 zithromax 500mg pfizer mutation-negative and SIGC cohorts. With regard to the 17 discarded variants, all were found in at least one HDGC proband and none in SIGC.90 and a call quality >100). From these, 43 variants presented the RefSeq genotype in the HDGC-CDH1 mutation-negative and sporadic GC cohorts.

A final set of 32 germline, rare zithromax 500mg pfizer and high-quality FIGC-exclusive variants were selected by screening the allele frequency of these variants in all ExAC and gnomAD populations available. (B) Germline variant burden of FIGC families with 0, 1 or >1 rare germline variants. P value was determined by ANOVA statistics.

(C) Heatmap and dendrogram of 710 HQ FIGC germline variants zithromax 500mg pfizer of FIGC family classes (Z-score normalised expression level. White, no detected variants. Purple, detected variants.

(D) Heatmap and dendrogram of 64 genes zithromax 500mg pfizer with the 710 germline variants of FIGC family classes (Z-score normalised expression levels. White, genes with no detected variants. Light salmon, genes with a single variant.

Pink, gene carrying zithromax 500mg pfizer 2–5 distinct variants. Purple, gene with 6–10 distinct variants. Dark purple, gene with 11–15 distinct variants.

ANOVA, analysis of zithromax 500mg pfizer variance. FIGC, familial intestinal gastric cancer. GC, gastric cancer.

HDGC, hereditary zithromax 500mg pfizer diffuse gastric cancer. HQ, high-quality." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-1819006706" data-figure-caption="Co-occurrence of rare germline variants does not define a specific germline landscape. (A) Discovery of FIGC rare germline predisposition variants.

A total of 4998 germline variants were detected zithromax 500mg pfizer in normal stomach using multigene panel sequencing. From these, 1038 were identified by the 1000 Genomes Project, and 121 were absent from four distinct normal European populations. Of these 121 variants, only 60 were classified as variants of high quality (with at least 20 reads for each allele, a genotype quality >90 and a call quality >100).

From these, 43 variants presented the RefSeq zithromax 500mg pfizer genotype in the HDGC-CDH1 mutation-negative and sporadic GC cohorts. A final set of 32 germline, rare and high-quality FIGC-exclusive variants were selected by screening the allele frequency of these variants in all ExAC and gnomAD populations available. (B) Germline variant burden of FIGC families with 0, 1 or >1 rare germline variants.

P value was determined by zithromax 500mg pfizer ANOVA statistics. (C) Heatmap and dendrogram of 710 HQ FIGC germline variants of FIGC family classes (Z-score normalised expression level. White, no detected variants.

Purple, detected variants zithromax 500mg pfizer. (D) Heatmap and dendrogram of 64 genes with the 710 germline variants of FIGC family classes (Z-score normalised expression levels. White, genes with no detected variants.

Light salmon, genes with a single variant zithromax 500mg pfizer. Pink, gene carrying 2–5 distinct variants. Purple, gene with 6–10 distinct variants.

Dark purple, gene with 11–15 distinct zithromax 500mg pfizer variants. ANOVA, analysis of variance. FIGC, familial intestinal gastric cancer.

GC, gastric zithromax 500mg pfizer cancer. HDGC, hereditary diffuse gastric cancer. HQ, high-quality." data-icon-position data-hide-link-title="0">Figure 2 Co-occurrence of rare germline variants does not define a specific germline landscape.

(A) Discovery of FIGC rare germline predisposition zithromax 500mg pfizer variants. A total of 4998 germline variants were detected in normal stomach using multigene panel sequencing. From these, 1038 were identified by the 1000 Genomes Project, and 121 were absent from four distinct normal European populations.

Of these 121 variants, only 60 were classified as variants of high quality (with at least zithromax 500mg pfizer 20 reads for each allele, a genotype quality >90 and a call quality >100). From these, 43 variants presented the RefSeq genotype in the HDGC-CDH1 mutation-negative and sporadic GC cohorts. A final set of 32 germline, rare and high-quality FIGC-exclusive variants were selected by screening the allele frequency of these variants in all ExAC and gnomAD populations available.

(B) Germline variant burden zithromax 500mg pfizer of FIGC families with 0, 1 or >1 rare germline variants. P value was determined by ANOVA statistics. (C) Heatmap and dendrogram of 710 HQ FIGC germline variants of FIGC family classes (Z-score normalised expression level.

White, no detected variants zithromax 500mg pfizer. Purple, detected variants. (D) Heatmap and dendrogram of 64 genes with the 710 germline variants of FIGC family classes (Z-score normalised expression levels.

White, genes with no zithromax 500mg pfizer detected variants. Light salmon, genes with a single variant. Pink, gene carrying 2–5 distinct variants.

Purple, gene with 6–10 distinct zithromax 500mg pfizer variants. Dark purple, gene with 11–15 distinct variants. ANOVA, analysis of variance.

FIGC, familial intestinal zithromax 500mg pfizer gastric cancer. GC, gastric cancer. HDGC, hereditary diffuse gastric cancer.

HQ, high-quality.From the 43 germline, rare and HQ FIGC-exclusive variants, 31 (72.1%) displayed very low allele frequency in all ExAC and gnomAD populations (figure 2A, online supplementary table 3), and were present in 21 of 50 (42%) FIGC probands (7 zithromax 500mg pfizer missense, 7 3’untranslated (UTR), 2 5’UTR, 12 intronic and 3 synonymous in 18 genes. Online supplementary table 4). Fifteen probands carried a single variant and six exhibited co-occurrence of two or more variants (online supplementary table 5).

After excluding variants classified as benign and predicted as zithromax 500mg pfizer intronic, synonymous or not impacting splicing, 12 variants were validated by Sanger sequencing (table 2).Supplemental materialSupplemental materialSupplemental materialView this table:Table 2 FIGC rare germline variants validated by Sanger sequencingA missense variant in PMS1 (c.224C>T), predicted as pathogenic, deleterious and probably damaging by FATHMM, SIFT and PolyPhen, respectively (table 2, online supplementary table 3), was found in family P1 (table 1, online supplementary table 4). The probands, who developed an MSS IGC at 59 years, had an FDR with GC at 80 and two other FDR and SDR with unidentified cancers at 50 and 75 years, respectively. The only supporting evidence for the role of this variant in FIGC was its COSMIC record as somatic in one GC sample (COSM6198026) (online supplementary table 3).The proband of family P27 presented three germline variants of uncertain significance, two in SMAD4 (c.424+5G>A.

C.454+38G>C) and one in PRSS1 zithromax 500mg pfizer (c.201-99G>C) (online supplementary table 4). Variants c.424+5G>A in SMAD4 and c.201–99G>C in PRSS1 were the only intronic variants predicted to disrupt RNA splicing (table 2, online supplementary tables 3 and 5,). In particular, SMAD4 variant c.424+5G>A decreases the confidence of a donor splice site, which may lead to intron 3 retention, a premature termination codon and generation of a 142 amino acid truncated protein.

On the other hand, PRSS1 variant c.201-99G>C creates a new, high-confidence zithromax 500mg pfizer acceptor splice site within intron 2, which may lead to a truncated 69 amino acid protein. Proband P27 developed an MSS IGC at age 64 and had family history of GC, gastric ulcer, laryngotracheal, gynaecological and hepatobiliary cancers (table 1, online supplementary table 4). The presence of these phenotypes seems to exclude juvenile polyposis and hereditary pancreatitis as underlying syndromes of this family, but could support a potential role for SMAD4 together with PRSS1 in FIGC.We then screened the primary tumours of P1 and P27 FIGC probands for somatic second-hit inactivating mechanisms (LOH, somatic mutation) in germline-affected genes.

None of the two FIGC probands showed evidence of deleterious somatic variants nor LOH zithromax 500mg pfizer of the wild-type allele of the germline targeted genes (data not shown).Although interesting, these findings are insufficient to support the monogenic hypothesis for FIGC and a potentially causal role for the abovementioned affected genes.Oligogenic/polygenic hypothesis. Co-occurrence of rare germline variants determines somatic landscapes of FIGC tumoursWe then proceeded with the oligogenic/polygenic hypothesis, which takes into consideration the co-occurrence of germline variants, regardless of their population frequency, as a risk factor for this disease, which would determine the subsequent somatic events necessary for malignant transformation.We categorised the 50 FIGC probands according to the presence of rare germline variants. Families with no variants (n=30).

Families with zithromax 500mg pfizer a single variant (n=14). And families with multiple variants (n=6). To understand the germline and somatic variant burden for each of these three FIGC classes, we applied the previously described quality criteria obtaining 710 HQ germline variants and 344 HQ somatic variants.

The average number of HQ germline variants was identical zithromax 500mg pfizer across the three classes of FIGC families (75.7, 77.4 and 74.5 for families without (0), with one (1) or more than one (>1) rare germline variants, respectively. Figure 2B). Germline landscape unsupervised hierarchical clustering revealed no associations between variants or variant-bearing genes and a particular FIGC family class (figure 2C,D).Concerning the somatic variant burden, no significant differences were observed across the three FIGC classes (15.0, 13.8 and 11.2 for families with 0, 1 or >1 rare germline variants, respectively.

Figure 3A) zithromax 500mg pfizer. Again, no clustering of specific variants/genes and particular FIGC classes was observed (figure 3B,C).1 rare germline variants. P value was determined by ANOVA statistics.

(B) Heatmap and dendrogram of 344 FIGC somatic variants of zithromax 500mg pfizer FIGC family classes (Z-score normalised expression level. White, no detected variants. Orange, detected variants.

(C) Heatmap zithromax 500mg pfizer and dendrogram of 46 genes with the 344 somatic variants of FIGC family classes (Z-score normalised expression levels. White, gene with no detected variants. Yellow, gene with a single variant.

Orange, gene zithromax 500mg pfizer carrying 2–5 distinct variants. Light brown, gene with 6–10 distinct variants. Brown, gene with 11–15 distinct variants.

(D) Somatic variant burden of FIGC families with 0, 1 or >1 rare germline variants subdivided zithromax 500mg pfizer according to MSI status. P value was determined by ANOVA statistics. ANOVA, analysis of variance.

FIGC, familial intestinal zithromax 500mg pfizer gastric cancer. HQ, high-quality. MSI, microsatellite instable.

MSS, microsatellite stable." class="highwire-fragment fragment-images colorbox-load" zithromax 500mg pfizer rel="gallery-fragment-images-1819006706" data-figure-caption="Rare germline variants are not major determinants of FIGC somatic events. (A) Somatic variant burden of FIGC families with 0, 1 or >1 rare germline variants. P value was determined by ANOVA statistics.

(B) Heatmap and dendrogram of zithromax 500mg pfizer 344 FIGC somatic variants of FIGC family classes (Z-score normalised expression level. White, no detected variants. Orange, detected variants.

(C) Heatmap and dendrogram zithromax 500mg pfizer of 46 genes with the 344 somatic variants of FIGC family classes (Z-score normalised expression levels. White, gene with no detected variants. Yellow, gene with a single variant.

Orange, gene carrying zithromax 500mg pfizer 2–5 distinct variants. Light brown, gene with 6–10 distinct variants. Brown, gene with 11–15 distinct variants.

(D) Somatic variant burden of FIGC families with 0, 1 or >1 rare germline variants zithromax 500mg pfizer subdivided according to MSI status. P value was determined by ANOVA statistics. ANOVA, analysis of variance.

FIGC, familial intestinal zithromax 500mg pfizer gastric cancer. HQ, high-quality. MSI, microsatellite instable.

MSS, microsatellite stable." zithromax 500mg pfizer data-icon-position data-hide-link-title="0">Figure 3 Rare germline variants are not major determinants of FIGC somatic events. (A) Somatic variant burden of FIGC families with 0, 1 or >1 rare germline variants. P value was determined by ANOVA statistics.

(B) Heatmap and dendrogram of 344 FIGC somatic variants of FIGC family zithromax 500mg pfizer classes (Z-score normalised expression level. White, no detected variants. Orange, detected variants.

(C) Heatmap and dendrogram of 46 genes with the 344 zithromax 500mg pfizer somatic variants of FIGC family classes (Z-score normalised expression levels. White, gene with no detected variants. Yellow, gene with a single variant.

Orange, gene carrying 2–5 distinct variants zithromax 500mg pfizer. Light brown, gene with 6–10 distinct variants. Brown, gene with 11–15 distinct variants.

(D) Somatic variant burden of FIGC zithromax 500mg pfizer families with 0, 1 or >1 rare germline variants subdivided according to MSI status. P value was determined by ANOVA statistics. ANOVA, analysis of variance.

FIGC, familial zithromax 500mg pfizer intestinal gastric cancer. HQ, high-quality. MSI, microsatellite instable.

MSS, microsatellite stable.We verified that 38% of the FIGC tumours in our series displayed the MSI phenotype, and further zithromax 500mg pfizer investigated whether MSI could influence the somatic variant burden and landscape in families with 0, 1 or >1 rare germline variants. After subdividing each FIGC class according to its MSI status, no significant differences were observed both in terms of somatic variant burden and landscape between categories (figure 3B–D). Nevertheless, we observed that among FIGC families with multiple rare germline variants (>1), MSI tumours showed an average number of HQ somatic variants twofold higher than that of MSS tumours (17 vs 10 HQ somatic variants per case, respectively.

Figure 3D, online supplementary zithromax 500mg pfizer figure 1A). This observation prompted us to explore the influence of rare germline variants, independently of their number, on tumour instability and consequent somatic variant burden. Despite the lack of statistical significance, we observed an enrichment of MSI tumours in FIGC families carrying rare germline variants comparing with MSI tumours from families lacking rare germline variants (online supplementary figure 1B).

Concerning the zithromax 500mg pfizer average of somatic variants, whereas MSI and MSS tumours from FIGC lacking rare germline variants displayed a similar average number, there was a non-significant trend for higher average number of HQ somatic variants in MSI tumours versus MSS tumours from FIGC families with rare germline variants (≥1. Online supplementary figure 1C).Supplemental materialAlthough our data did not support the hypothesis that co-occurrence of rare germline variants is a major determinant of FIGC-related somatic landscapes, these pinpointed a potential correlation between the coexistence of rare and common germline variants, high average number of somatic variants and MSI phenotype in FIGC.FIGC is genetically distinct from SIGC and from HDGC-CDH1 mutation-negativeSince the late age of onset in FIGC probands and their relatives makes it hard to distinguish bona fide FIGCs from SIGCs, we compared the age of onset of FIGC probands with the age of onset of a series of SIGC cases. We found that FIGC probands developed GC approximately 10 years earlier than patients with SIGC (p=4.5E-03.

Figure 4E).FIGC zithromax 500mg pfizer is a genetic entity distinct from SIGC. (A) Principal component analysis of genes with germline variants. (B) Principal component analysis of genes with somatic variants.

(C) Frequency of genes with germline zithromax 500mg pfizer or somatic variants enriched in FIGC cases in comparison with SIGC cases. Purple for genes with germline events and orange for genes with somatic events. (D) Heatmap and dendrogram of a panel of genes with the highest frequency of germline and/or somatic variants in FIGC (n=50) versus SIGC (n=47).

(E) Age at diagnosis of zithromax 500mg pfizer FIGC (n=50) and SIGC cases (n=47). (F) Average number of somatic variants detected in FIGC (n=50) and SIGC cases (n=47). White, gene with no variants.

Purple, gene with germline variants zithromax 500mg pfizer. Orange, gene with somatic variants. Red, gene with germline and somatic variants.

P values calculated zithromax 500mg pfizer with Wilcoxon signed-rank test. FIGC, familial intestinal gastric cancer. SIGC, sporadic intestinal gastric cancer, PC1, principal component 1.

PC2, principal component 2." data-icon-position data-hide-link-title="0">Figure 4 FIGC is a genetic entity distinct from SIGC zithromax 500mg pfizer. (A) Principal component analysis of genes with germline variants. (B) Principal component analysis of genes with somatic variants.

(C) Frequency of genes with zithromax 500mg pfizer germline or somatic variants enriched in FIGC cases in comparison with SIGC cases. Purple for genes with germline events and orange for genes with somatic events. (D) Heatmap and dendrogram of a panel of genes with the highest frequency of germline and/or somatic variants in FIGC (n=50) versus SIGC (n=47).

(E) Age at diagnosis of FIGC (n=50) and zithromax 500mg pfizer SIGC cases (n=47). (F) Average number of somatic variants detected in FIGC (n=50) and SIGC cases (n=47). White, gene with no variants.

Purple, gene zithromax 500mg pfizer with germline variants. Orange, gene with somatic variants. Red, gene with germline and somatic variants.

P values calculated with zithromax 500mg pfizer Wilcoxon signed-rank test. FIGC, familial intestinal gastric cancer. SIGC, sporadic intestinal gastric cancer, PC1, principal component 1.

PC2, principal component 2.We next explored whether these FIGC and SIGC were also distinct at the germline and/or somatic zithromax 500mg pfizer levels. Principal component analysis revealed that certain genes were differentially associated with FIGCs and SIGCs (figure 4A,B). Specifically, common germline variants in TP53 were present in more than 50% of FIGC probands, while only 11% of SIGC cases presented these germline variants (figure 4A,C).

At the somatic level, the frequency of BRCA2, ATM, FOXF1, FHIT, SDHB, MSH6, CTNNA1 and PXN could distinguish FIGC from SIGC tumours, with more than 50% of FIGC displaying common variants in these genes, as compared with very low frequencies in SIGC (figure 4B,C).By zithromax 500mg pfizer combining all germline and somatic landscapes of 50 FIGCs and 47 SIGCs focusing only on the abovementioned genes, and using unsupervised hierarchical clustering, two main clusters were evidenced separating most FIGCs from SIGCs (figure 4D). Whereas FIGCs carried both germline and somatic variants in TP53, BRCA2, ATM, FOXF1, FHIT, SDHB, MSH6, CTNNA1 and PXN genes, SIGCs lacked TP53 and FHIT germline and somatic variants and mainly presented BRCA2, ATM, FOXF1, SDHB, MSH6, CTNNA1 and PXN somatic variants.Further supporting that FIGC represents a different entity likely evolving for longer than SIGCs is the fact that FIGC tumours presented statistically significantly more somatic common variants than SIGC tumours (p=4.2E-06), even if arising from patients 10 years younger on average (figure 4E,F).To further understand whether FIGC is a genetic entity also distinct from HDGC-CDH1 mutation-negative, we compared the germline and somatic landscapes of 7 FIGCs and 17 HDGCs sequenced with the same Next Generation Sequencing (NGS) panel. We verified that indeed FIGC and HDGC also display considerable differences between germline and somatic landscapes (online supplementary figure 2)().

However, the low number of FIGC cases possible to analyse, which was due to sequencing panel differences, hampers more formal conclusions.Overall, our results suggest that FIGC, rather than a monogenic disease, is likely a polygenic disease with distinctive germline and somatic landscapes from SIGC and HDGC-CDH1-negative.DiscussionFIGC presents an autosomal dominant inheritance pattern of IGC, without gastric polyposis, and has been clinically defined by analogy to the Amsterdam criteria for HNPCC.9 However, lack of novel zithromax 500mg pfizer data supporting familial aggregation of IGC at a given age of onset as well as the non-existence of tumour spectrum descriptions have impeded the redefinition of FIGC testing criteria, useful for identification and management of these families.The primary strength of this study is the use of a large homogeneous cohort of probands with IGC, familial aggregation of GC, detailed personal/family history, age of disease onset and disease spectrum. This series does not present clinical criteria compatible with any other gastrointestinal cancer-associated syndrome, is clearly enriched in GC and mainly of intestinal type, which suggests this is the first data-driven testing criteria for FIGC families. We propose that any family presenting two GC cases, one confirmed of intestinal histology, independently of age, and with or without colorectal cancer, breast cancer or gastric ulcers in other family members, could be considered FIGC.Besides potential testing criteria, our study also reported the first large-scale sequencing analysis of the germline and somatic landscapes of FIGC and respective comparisons with comparable landscapes of SIGC and HDGC-CDH1 mutation-negative.

Among these, only 1%–3% are https://www.nickiandkaren.com/where-can-you-buy-symbicort-over-the-counter/ thought to buy generic zithromax online be hereditary, falling into one of the following syndromes. Hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), and familial intestinal gastric cancer (FIGC).7–9 Germline mutations and deletions within the E-cadherin gene (CDH1) are the main cause of HDGC and affect 14%–40% of families.10–12 Additionally, while α-E-catenin gene (CTNNA1) mutations have been proven to cause HDGC, germline variants in homologous recombination DNA repair genes, such as PALB2, await confirmation as potential causes of disease in mutation-negative HDGC families.13–15 Concerning GAPPS, APC promoter 1B point mutations are the underlying cause of this syndrome in several families.16 Unlike HDGC and GAPPS, FIGC remains genetically unexplained, despite the recent report of PALB2 germline mutations in three individuals with intestinal tumours but lacking family history of GC.14 17FIGC is characterised by an autosomal dominant inheritance pattern of intestinal gastric cancer (IGC), without gastric polyposis, and is defined according to GC incidence, as agreed by the International Gastric Cancer Linkage Consortium.9 Therefore, in high incidence countries, the diagnostic criteria is analogous to the Amsterdam criteria for hereditary non-polyposis colorectal cancer (HNPCC). At least three relatives should have IGC and one of them should be a first-degree relative of the other two.

At least two successive generations should be buy generic zithromax online affected. And in one of the relatives, GC should be diagnosed before the age of 50. In countries with low incidence, the following criteria are used.

At least two first-degree relatives (FDR) or second-degree relatives (SDR) affected by buy generic zithromax online IGC, one diagnosed before the age of 50. Or three or more relatives with IGC at any age.9 Because no novel data exist supporting familial aggregation of IGC, no specific tumour spectrum has been defined, and no data support a particular age of onset. Hence, the above criteria have never been revisited or validated.

Therefore, these families are buy generic zithromax online often neglected and rarely followed in oncogenetic consultations.GC also develops in the context of other inherited cancer predisposition syndromes.18 In particular, GC has been identified in the tumour spectrum of Lynch syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, familial adenomatous polyposis, juvenile polyposis, and hereditary breast and ovarian cancer, among others.19–22 Therefore, genes causing hereditary cancer susceptibility syndromes, even if only slightly associated with GC susceptibility, would be good candidates to test as potential FIGC causal genes.Herein, we used a next-generation sequencing approach to interrogate a panel of genes implicated in upper gastrointestinal tract cancer, or in cancer susceptibility syndromes, across 50 probands with familial aggregation of IGC from Tuscany, a region from Italy with high incidence of GC.23 The access to a highly homogeneous FIGC cohort, the largest ever studied, and its comparison with an HDGC series and a cohort of sporadic intestinal gastric cancer (SIGC) allowed us to define three objectives and to extend the current knowledge on FIGC predisposition. (1) characterise the age of cancer onset and disease spectrum of our FIGC cohort. (2) search for evidence for a Mendelian and monogenic pattern of inheritance.

And (3) buy generic zithromax online search for evidence of alternative oligogenic/polygenic modes of inheritance.Herein, we gathered evidence that FIGC is likely a genetically determined, GC-predisposing disease, different at the clinical, germline and somatic levels from SIGC and HDGC. We further proposed the first testing criteria for FIGC families.MethodsPatient selectionFifty FIGC and 17 HDGC-CDH1 mutation-negative probands were admitted at the Division of General Surgery and Surgical Oncology, University of Siena, Italy. The selection of FIGC families was based on the following criteria.

(1) proband presenting with buy generic zithromax online GC of intestinal histology. (2) familial aggregation of GC. (3) family history of cancer, other than gastric.

(4) negative buy generic zithromax online genetic test for germline CDH1 coding sequence mutations (exclusion of HDGC). And (5) negative genetic test for germline for the promoter 1B of APC (exclusion of GAPPS). The 17 HDGC probands were negative for CDH1 germline coding mutations and selected as a control group.

Forty-seven patients with SIGC were collected in Portugal.Multigene panel sequencing, variant calling and filteringDNA from normal gastric mucosa (germline) and tumour tissue from 50 FIGC buy generic zithromax online and 17 HDGC-CDH1 mutation-negative probands were sequenced using three Illumina MiSeq custom panels. TruSeq Custom Amplicon Assay 1, TruSeq Custom Amplicon Assay 2 and Nextera custom panel (online supplementary table 1). The selection of genes deposited in each panel was based on their implication in upper gastrointestinal tract cancers or in cancer susceptibility syndromes identified through literature review (online supplementary table 2).

FASTQ files were aligned to the RefSeq Human Genome GRCh38 using bwa-mem, and variants were called using Samtools.24 25 Called variants were defined as germline or somatic by normal-tumour pair comparison and annotated with Ensembl and Catalogue buy generic zithromax online Of Somatic Mutations In Cancer (COSMIC (FATHMM- Functional Analysis through Hidden Markov Models).26 27 High-quality (HQ) germline or somatic variants were defined as presenting ≥20 reads per allele and genotype quality ≥90 and call quality ≥100. Next, all single nucleotide polymorphism database (dbSNP) identifiers available for FIGC germline variants (regardless of quality criteria) were screened in four European populations from 1000 Genomes. (1) 107 normal individuals from Tuscany (Italy, TSI).

(2) 91 normal buy generic zithromax online individuals from Great Britain (GBR). (3) 99 normal individuals from Finland (FIN). And (4) 107 normal individuals from Spain (IBS).28 Germline variants without dbSNP identifiers available in the 1000 Genomes were screened using Ensembl VEP for truncating consequences.

Detected truncating variants presented on average less than buy generic zithromax online four reads, that is, were of low quality and discarded. FIGC germline, rare HQ exclusive variants were selected if they (1) displayed genotypes in FIGCs distinct from GBR, FIN and IBS populations and below 1% in the TSI population. (2) presented ≥20 reads per allele, genotype quality ≥90 and call quality ≥100.

(3) displayed genotypes distinct buy generic zithromax online from HDGCs and SIGCs. And (4) presented allele frequency in ExAC and gnomAD populations below 1%.29Supplemental materialSupplemental materialValidation of FIGC germline, rare HQ exclusive variants by Sanger sequencingTwelve out of 32 FIGC germline, rare HQ exclusive variants were validated by PCR-Sanger sequencing. Briefly, 20–50 ng of DNA from normal and matched tumour was amplified using Multiplex PCR Kit (Qiagen) and custom primers flanking each variant.

PCR products were purified with ExoSAP-IT Express (Applied Biosystems) and sequenced on an ABI3100 Genetic Analyzer using BigDye Terminator V.3.1 Cycle Sequencing Kit (Applied Biosystems).Intronic germline variants were analysed using the splice site prediction software NetGene2 V.2.4.30Somatic second-hit analysisLoss of heterozygosity (LOH) and somatic second mutations were determined by calculating buy generic zithromax online the variant allele frequency (VAF) and screening genes with FIGC germline, rare HQ exclusive variants, respectively. In particular, VAF was calculated by dividing the number of reads for the variant allele by the total number of reads both for the normal and for the corresponding tumour samples. LOH was defined when more than 20% increase of VAF over normal was observed.Germline and somatic landscape analysis of 50 FIGC casesFIGC germline and somatic landscapes were analysed on a per-variant and per-gene basis, considering the number of FIGC germline, rare HQ exclusive variants detected per proband (0, 1 or >1).

The similarities/differences for the germline and somatic variant and gene landscapes per FIGC class were analysed using unsupervised hierarchical clustering using R package ggplot2 for heatmap and dendrogram construction.31 For buy generic zithromax online somatic variant/gene landscape analysis, FIGC classes were also divided according to microsatellite instable status and compared using analysis of variance statistics with R. The number of microsatellite instable (MSI) and microsatellite stable (MSS) tumours per FIGC class was compared using Pearson’s χ2 test.Comparison of germline and somatic landscapes for FIGC, SIGC and HDGCVCF files obtained from whole genome sequencing (Complete Genomics platform) of 47 SIGCs and VCF files of 17 HDGCs were analysed to detect germline and somatic variants, using the same germline/somatic variant definition and sequencing quality criteria previously described for FIGC cases. Of note, due to the differential resolution between whole genome sequencing and targeted sequencing, only variants detected in the 47 SIGCs in the same regions targeted by the custom panels were selected for downstream analysis.Germline and somatic landscapes of FIGC, SIGC and HDGC cases were performed on a per-gene basis.

Each gene was classified as presenting 0 or ≥1 germline/somatic buy generic zithromax online variants. Germline and somatic joint landscape was defined by counting the number of germline and somatic variants for each gene, which was classified as displaying no germline or somatic variants. ‰¥1 germline and 0 somatic variants.

0 germline and buy generic zithromax online ≥1 somatic variants. Or ≥1 germline and ≥1 somatic variants. Results were plotted in a heatmap and a dendrogram, and principal component analysis was performed using R.

The frequency of genes with germline/somatic variants in FIGCs, SIGCs and HDGCs was calculated, and genes with a frequency difference ≥50% were represented in a bar plot and in a heatmap using R.ResultsAge of onset and buy generic zithromax online disease spectrum in FIGCOf the 50 FIGC probands (table 1), 18 were female and 32 were male. The mean age at diagnosis was 71.8±8.0 years. From the 50 families depicted in table 1, 5 (10%) had >1 FDR with GC (mean age.

68.8±7.5 years) buy generic zithromax online. 14 (28%) had concomitantly FDR and SDR or FDR and third-degree relatives with GC (mean age. 68.7±8.4 years).

29 (58%) had a single FDR buy generic zithromax online with GC (mean age. 73.6±7.2 years). And 2 (4%) had only SDR affected with GC (mean.

74±15.6 years).View this table:Table 1 Clinical characteristics buy generic zithromax online of FIGC probands and their family historyWhen considering the disease spectrum in these FIGC families, 19 different phenotypes have been observed affecting 208 family members (figure 1, table 1). The most prevalent phenotype was GC, detected in 138 of 208 (66.3%) family members. 50 probands with IGC and 88 additional patients with unknown GC histology.

The second and third most prevalent phenotypes buy generic zithromax online were colorectal/colon and breast cancer observed in nine patients from seven families. Of note, eight patients from six families were affected with gastric ulcer, a non-cancerous lesion, which is the third most common disease phenotype in this cohort. Besides these phenotypes, positive history of lung cancer was observed in six families.

Leukaemia in buy generic zithromax online five families. Laryngotracheal and hepatobiliary cancer in four families. Osteosarcoma in three families.

Prostate, liver, melanoma, gynaecological, bladder buy generic zithromax online and brain cancers were detected in two families each. And thyroid, kidney and oral cancer in one family. Moreover, 11 families had relatives affected by an unidentified type of cancer that often coexisted with other cancer types such as colon, leukaemia, breast, liver and prostate.Disease spectrum of FIGC families.

The disease spectrum of FIGC buy generic zithromax online encompassed 19 different phenotypes affecting 208 family members. The most prevalent phenotype was gastric cancer, detected in 138 of 208, followed by colorectal/colon and breast cancers in 9 of 208. FIGC, familial intestinal gastric cancer." data-icon-position data-hide-link-title="0">Figure 1 Disease spectrum of FIGC families.

The disease spectrum buy generic zithromax online of FIGC encompassed 19 different phenotypes affecting 208 family members. The most prevalent phenotype was gastric cancer, detected in 138 of 208, followed by colorectal/colon and breast cancers in 9 of 208. FIGC, familial intestinal gastric cancer.Germline and somatic variant discovery across FIGC probandsMultigene panel sequencing analysis of normal-tumour DNA of 50 FIGC probands revealed a total of 10 062 variants (≥1 read covering the alternative allele).

Of these, 4998 (49.7%) were detected in normal DNA and buy generic zithromax online defined as germline variants. The remaining 5064 (50.3%) were called as somatic variants due to exclusive presence in tumour DNA. We started by exploring germline variants, focusing on rare variants in single genes (monogenic hypothesis) or variants co-occurring in several genes, regardless of their population frequency (oligogenic/polygenic hypothesis).Monogenic hypothesis.

FIGC-associated rare germline variants and somatic second-hitsTo identify rare germline FIGC-predisposing variants, we performed a systematic analysis of all germline variants, focusing buy generic zithromax online on their frequency across normal populations and GC cohorts, and sequencing quality.We identified 4998 germline variants in the 50 patients with FIGC (figure 2A). From the 4998 FIGC germline variants, the genotype frequency of 1038 (20.8%) was available for four 1000 Genomes European populations.28 From the 79.2% of variants absent from 1000 Genomes, only 1.3% (n=53) presented truncating effects, however supported on average by less than four reads, that is, of very low quality and hence confidently discarded. From the 1038 variants present in 1000 Genomes, 121 (11.7%) presented genotypes absent from the four populations screened.

Of these buy generic zithromax online 121 variants, only 60 presented the abovementioned sequencing quality criteria. From these, 43 variants were exclusively detected in FIGC comparing with HDGC-CDH1 mutation-negative and SIGC cohorts. With regard to the 17 discarded variants, all were found in at least one HDGC proband and none in SIGC.90 and a call quality >100).

From these, 43 variants buy generic zithromax online presented the RefSeq genotype in the HDGC-CDH1 mutation-negative and sporadic GC cohorts. A final set of 32 germline, rare and high-quality FIGC-exclusive variants were selected by screening the allele frequency of these variants in all ExAC and gnomAD populations available. (B) Germline variant burden of FIGC families with 0, 1 or >1 rare germline variants.

P value was determined by ANOVA statistics buy generic zithromax online. (C) Heatmap and dendrogram of 710 HQ FIGC germline variants of FIGC family classes (Z-score normalised expression level. White, no detected variants.

Purple, detected buy generic zithromax online variants. (D) Heatmap and dendrogram of 64 genes with the 710 germline variants of FIGC family classes (Z-score normalised expression levels. White, genes with no detected variants.

Light salmon, buy generic zithromax online genes with a single variant. Pink, gene carrying 2–5 distinct variants. Purple, gene with 6–10 distinct variants.

Dark purple, buy generic zithromax online gene with 11–15 distinct variants. ANOVA, analysis of variance. FIGC, familial intestinal gastric cancer.

GC, gastric cancer buy generic zithromax online. HDGC, hereditary diffuse gastric cancer. HQ, high-quality." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-1819006706" data-figure-caption="Co-occurrence of rare germline variants does not define a specific germline landscape.

(A) Discovery buy generic zithromax online of FIGC rare germline predisposition variants. A total of 4998 germline variants were detected in normal stomach using multigene panel sequencing. From these, 1038 were identified by the 1000 Genomes Project, and 121 were absent from four distinct normal European populations.

Of these 121 variants, only 60 were classified as variants of high quality (with at least 20 reads for each allele, a genotype buy generic zithromax online quality >90 and a call quality >100). From these, 43 variants presented the RefSeq genotype in the HDGC-CDH1 mutation-negative and sporadic GC cohorts. A final set of 32 germline, rare and high-quality FIGC-exclusive variants were selected by screening the allele frequency of these variants in all ExAC and gnomAD populations available.

(B) Germline variant burden of FIGC families with 0, 1 or >1 rare germline variants buy generic zithromax online. P value was determined by ANOVA statistics. (C) Heatmap and dendrogram of 710 HQ FIGC germline variants of FIGC family classes (Z-score normalised expression level.

White, no detected buy generic zithromax online variants. Purple, detected variants. (D) Heatmap and dendrogram of 64 genes with the 710 germline variants of FIGC family classes (Z-score normalised expression levels.

White, genes with buy generic zithromax online no detected variants. Light salmon, genes with a single variant. Pink, gene carrying 2–5 distinct variants.

Purple, gene buy generic zithromax online with 6–10 distinct variants. Dark purple, gene with 11–15 distinct variants. ANOVA, analysis of variance.

FIGC, familial intestinal gastric buy generic zithromax online cancer. GC, gastric cancer. HDGC, hereditary diffuse gastric cancer.

HQ, high-quality." data-icon-position data-hide-link-title="0">Figure 2 Co-occurrence of rare germline variants does not define buy generic zithromax online a specific germline landscape. (A) Discovery of FIGC rare germline predisposition variants. A total of 4998 germline variants were detected in normal stomach using multigene panel sequencing.

From these, 1038 were identified by the 1000 Genomes Project, and 121 were absent from four distinct normal European populations buy generic zithromax online. Of these 121 variants, only 60 were classified as variants of high quality (with at least 20 reads for each allele, a genotype quality >90 and a call quality >100). From these, 43 variants presented the RefSeq genotype in the HDGC-CDH1 mutation-negative and sporadic GC cohorts.

A final set of buy generic zithromax online 32 germline, rare and high-quality FIGC-exclusive variants were selected by screening the allele frequency of these variants in all ExAC and gnomAD populations available. (B) Germline variant burden of FIGC families with 0, 1 or >1 rare germline variants. P value was determined by ANOVA statistics.

(C) Heatmap buy generic zithromax online and dendrogram of 710 HQ FIGC germline variants of FIGC family classes (Z-score normalised expression level. White, no detected variants. Purple, detected variants.

(D) Heatmap buy generic zithromax online and dendrogram of 64 genes with the 710 germline variants of FIGC family classes (Z-score normalised expression levels. White, genes with no detected variants. Light salmon, genes with a single variant.

Pink, gene carrying 2–5 distinct variants buy generic zithromax online. Purple, gene with 6–10 distinct variants. Dark purple, gene with 11–15 distinct variants.

ANOVA, analysis buy generic zithromax online of variance. FIGC, familial intestinal gastric cancer. GC, gastric cancer.

HDGC, hereditary diffuse gastric buy generic zithromax online cancer. HQ, high-quality.From the 43 germline, rare and HQ FIGC-exclusive variants, 31 (72.1%) displayed very low allele frequency in all ExAC and gnomAD populations (figure 2A, online supplementary table 3), and were present in 21 of 50 (42%) FIGC probands (7 missense, 7 3’untranslated (UTR), 2 5’UTR, 12 intronic and 3 synonymous in 18 genes. Online supplementary table 4).

Fifteen probands carried a buy generic zithromax online single variant and six exhibited co-occurrence of two or more variants (online supplementary table 5). After excluding variants classified as benign and predicted as intronic, synonymous or not impacting splicing, 12 variants were validated by Sanger sequencing (table 2).Supplemental materialSupplemental materialSupplemental materialView this table:Table 2 FIGC rare germline variants validated by Sanger sequencingA missense variant in PMS1 (c.224C>T), predicted as pathogenic, deleterious and probably damaging by FATHMM, SIFT and PolyPhen, respectively (table 2, online supplementary table 3), was found in family P1 (table 1, online supplementary table 4). The probands, who developed an MSS IGC at 59 years, had an FDR with GC at 80 and two other FDR and SDR with unidentified cancers at 50 and 75 years, respectively.

The only supporting evidence for the role of this variant in FIGC was its COSMIC record as somatic in one GC sample (COSM6198026) (online supplementary table 3).The proband of family P27 presented three germline buy generic zithromax online variants of uncertain significance, two in SMAD4 (c.424+5G>A. C.454+38G>C) and one in PRSS1 (c.201-99G>C) (online supplementary table 4). Variants c.424+5G>A in SMAD4 and c.201–99G>C in PRSS1 were the only intronic variants predicted to disrupt RNA splicing (table 2, online supplementary tables 3 and 5,).

In particular, SMAD4 variant c.424+5G>A decreases buy generic zithromax online the confidence of a donor splice site, which may lead to intron 3 retention, a premature termination codon and generation of a 142 amino acid truncated protein. On the other hand, PRSS1 variant c.201-99G>C creates a new, high-confidence acceptor splice site within intron 2, which may lead to a truncated 69 amino acid protein. Proband P27 developed an MSS IGC at age 64 and had family history of GC, gastric ulcer, laryngotracheal, gynaecological and hepatobiliary cancers (table 1, online supplementary table 4).

The presence of these phenotypes seems to exclude juvenile polyposis and hereditary buy generic zithromax online pancreatitis as underlying syndromes of this family, but could support a potential role for SMAD4 together with PRSS1 in FIGC.We then screened the primary tumours of P1 and P27 FIGC probands for somatic second-hit inactivating mechanisms (LOH, somatic mutation) in germline-affected genes. None of the two FIGC probands showed evidence of deleterious somatic variants nor LOH of the wild-type allele of the germline targeted genes (data not shown).Although interesting, these findings are insufficient to support the monogenic hypothesis for FIGC and a potentially causal role for the abovementioned affected genes.Oligogenic/polygenic hypothesis. Co-occurrence of rare germline variants determines somatic landscapes of FIGC tumoursWe then proceeded with the oligogenic/polygenic hypothesis, which takes into consideration the co-occurrence of germline variants, regardless of their population frequency, as a risk factor for this disease, which would determine the subsequent somatic events necessary for malignant transformation.We categorised the 50 FIGC probands according to the presence of rare germline variants.

Families with no variants (n=30) buy generic zithromax online. Families with a single variant (n=14). And families with multiple variants (n=6).

To understand the germline and somatic variant burden for each of these three FIGC classes, we applied the previously buy generic zithromax online described quality criteria obtaining 710 HQ germline variants and 344 HQ somatic variants. The average number of HQ germline variants was identical across the three classes of FIGC families (75.7, 77.4 and 74.5 for families without (0), with one (1) or more than one (>1) rare germline variants, respectively. Figure 2B).

Germline landscape unsupervised hierarchical clustering revealed no associations between variants or variant-bearing genes and a particular FIGC family class (figure buy generic zithromax online 2C,D).Concerning the somatic variant burden, no significant differences were observed across the three FIGC classes (15.0, 13.8 and 11.2 for families with 0, 1 or >1 rare germline variants, respectively. Figure 3A). Again, no clustering of specific variants/genes and particular FIGC classes was observed (figure 3B,C).1 rare germline variants.

P value was determined by ANOVA statistics buy generic zithromax online. (B) Heatmap and dendrogram of 344 FIGC somatic variants of FIGC family classes (Z-score normalised expression level. White, no detected variants.

Orange, detected buy generic zithromax online variants. (C) Heatmap and dendrogram of 46 genes with the 344 somatic variants of FIGC family classes (Z-score normalised expression levels. White, gene with no detected variants.

Yellow, gene with a buy generic zithromax online single variant. Orange, gene carrying 2–5 distinct variants. Light brown, gene with 6–10 distinct variants.

Brown, gene buy generic zithromax online with 11–15 distinct variants. (D) Somatic variant burden of FIGC families with 0, 1 or >1 rare germline variants subdivided according to MSI status. P value was determined by ANOVA statistics.

ANOVA, analysis buy generic zithromax online of variance. FIGC, familial intestinal gastric cancer. HQ, high-quality.

MSI, microsatellite instable buy generic zithromax online. MSS, microsatellite stable." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-1819006706" data-figure-caption="Rare germline variants are not major determinants of FIGC somatic events. (A) Somatic variant burden of FIGC families with 0, 1 or >1 rare germline variants.

P value was determined by ANOVA statistics buy generic zithromax online. (B) Heatmap and dendrogram of 344 FIGC somatic variants of FIGC family classes (Z-score normalised expression level. White, no detected variants.

Orange, detected buy generic zithromax online variants. (C) Heatmap and dendrogram of 46 genes with the 344 somatic variants of FIGC family classes (Z-score normalised expression levels. White, gene with no detected variants.

Yellow, gene with a single buy generic zithromax online variant. Orange, gene carrying 2–5 distinct variants. Light brown, gene with 6–10 distinct variants.

Brown, gene buy generic zithromax online with 11–15 distinct variants. (D) Somatic variant burden of FIGC families with 0, 1 or >1 rare germline variants subdivided according to MSI status. P value was determined by ANOVA statistics.

ANOVA, analysis buy generic zithromax online of variance. FIGC, familial intestinal gastric cancer. HQ, high-quality.

MSI, microsatellite buy generic zithromax online instable. MSS, microsatellite stable." data-icon-position data-hide-link-title="0">Figure 3 Rare germline variants are not major determinants of FIGC somatic events. (A) Somatic variant burden of FIGC families with 0, 1 or >1 rare germline variants.

P value was determined by ANOVA buy generic zithromax online statistics. (B) Heatmap and dendrogram of 344 FIGC somatic variants of FIGC family classes (Z-score normalised expression level. White, no detected variants.

Orange, detected buy generic zithromax online variants. (C) Heatmap and dendrogram of 46 genes with the 344 somatic variants of FIGC family classes (Z-score normalised expression levels. White, gene with no detected variants.

Yellow, gene with a single variant buy generic zithromax online. Orange, gene carrying 2–5 distinct variants. Light brown, gene with 6–10 distinct variants.

Brown, gene with 11–15 buy generic zithromax online distinct variants. (D) Somatic variant burden of FIGC families with 0, 1 or >1 rare germline variants subdivided according to MSI status. P value was determined by ANOVA statistics.

ANOVA, analysis buy generic zithromax online of variance. FIGC, familial intestinal gastric cancer. HQ, high-quality.

MSI, microsatellite instable buy generic zithromax online. MSS, microsatellite stable.We verified that 38% of the FIGC tumours in our series displayed the MSI phenotype, and further investigated whether MSI could influence the somatic variant burden and landscape in families with 0, 1 or >1 rare germline variants. After subdividing each FIGC class according to its MSI status, no significant differences were observed both in terms of somatic variant burden and landscape between categories (figure 3B–D).

Nevertheless, we observed that among FIGC families with multiple rare germline variants (>1), MSI tumours showed an average number of HQ somatic variants twofold higher than that buy generic zithromax online of MSS tumours (17 vs 10 HQ somatic variants per case, respectively. Figure 3D, online supplementary figure 1A). This observation prompted us to explore the influence of rare germline variants, independently of their number, on tumour instability and consequent somatic variant burden.

Despite the lack of statistical significance, we observed an enrichment of buy generic zithromax online MSI tumours in FIGC families carrying rare germline variants comparing with MSI tumours from families lacking rare germline variants (online supplementary figure 1B). Concerning the average of somatic variants, whereas MSI and MSS tumours from FIGC lacking rare germline variants displayed a similar average number, there was a non-significant trend for higher average number of HQ somatic variants in MSI tumours versus MSS tumours from FIGC families with rare germline variants (≥1. Online supplementary figure 1C).Supplemental materialAlthough our data did not support the hypothesis that co-occurrence of rare germline variants is a major determinant of FIGC-related somatic landscapes, these pinpointed a potential correlation between the coexistence of rare and common germline variants, high average number of somatic variants and MSI phenotype in FIGC.FIGC is genetically distinct from SIGC and from HDGC-CDH1 mutation-negativeSince the late age of onset in FIGC probands and their relatives makes it hard to distinguish bona fide FIGCs from SIGCs, we compared the age of onset of FIGC probands with the age of onset of a series of SIGC cases.

We found that FIGC probands developed GC approximately 10 years earlier than patients with SIGC buy generic zithromax online (p=4.5E-03. Figure 4E).FIGC is a genetic entity distinct from SIGC. (A) Principal component analysis of genes with germline variants.

(B) Principal component analysis of genes buy generic zithromax online with somatic variants. (C) Frequency of genes with germline or somatic variants enriched in FIGC cases in comparison with SIGC cases. Purple for genes with germline events and orange for genes with somatic events.

(D) Heatmap and dendrogram of a panel of genes with the highest frequency of buy generic zithromax online germline and/or somatic variants in FIGC (n=50) versus SIGC (n=47). (E) Age at diagnosis of FIGC (n=50) and SIGC cases (n=47). (F) Average number of somatic variants detected in FIGC (n=50) and SIGC cases (n=47).

White, gene with buy generic zithromax online no variants. Purple, gene with germline variants. Orange, gene with somatic variants.

Red, gene with germline and somatic buy generic zithromax online variants. P values calculated with Wilcoxon signed-rank test. FIGC, familial intestinal gastric cancer.

SIGC, sporadic intestinal gastric buy generic zithromax online cancer, PC1, principal component 1. PC2, principal component 2." data-icon-position data-hide-link-title="0">Figure 4 FIGC is a genetic entity distinct from SIGC. (A) Principal component analysis of genes with germline variants.

(B) Principal component analysis of genes with buy generic zithromax online somatic variants. (C) Frequency of genes with germline or somatic variants enriched in FIGC cases in comparison with SIGC cases. Purple for genes with germline events and orange for genes with somatic events.

(D) Heatmap and dendrogram of a panel of genes with the highest frequency of germline and/or somatic variants in FIGC (n=50) versus SIGC (n=47) buy generic zithromax online. (E) Age at diagnosis of FIGC (n=50) and SIGC cases (n=47). (F) Average number of somatic variants detected in FIGC (n=50) and SIGC cases (n=47).

White, gene buy generic zithromax online with no variants. Purple, gene with germline variants. Orange, gene with somatic variants.

Red, gene with buy generic zithromax online germline and somatic variants. P values calculated with Wilcoxon signed-rank test. FIGC, familial intestinal gastric cancer.

SIGC, sporadic intestinal gastric buy generic zithromax online cancer, PC1, principal component 1. PC2, principal component 2.We next explored whether these FIGC and SIGC were also distinct at the germline and/or somatic levels. Principal component analysis revealed that certain genes were differentially associated with FIGCs and SIGCs (figure 4A,B).

Specifically, common germline variants in buy generic zithromax online TP53 were present in more than 50% of FIGC probands, while only 11% of SIGC cases presented these germline variants (figure 4A,C). At the somatic level, the frequency of BRCA2, ATM, FOXF1, FHIT, SDHB, MSH6, CTNNA1 and PXN could distinguish FIGC from SIGC tumours, with more than 50% of FIGC displaying common variants in these genes, as compared with very low frequencies in SIGC (figure 4B,C).By combining all germline and somatic landscapes of 50 FIGCs and 47 SIGCs focusing only on the abovementioned genes, and using unsupervised hierarchical clustering, two main clusters were evidenced separating most FIGCs from SIGCs (figure 4D). Whereas FIGCs carried both germline and somatic variants in TP53, BRCA2, ATM, FOXF1, FHIT, SDHB, MSH6, CTNNA1 and PXN genes, SIGCs lacked TP53 and FHIT germline and somatic variants and mainly presented BRCA2, ATM, FOXF1, SDHB, MSH6, CTNNA1 and PXN somatic variants.Further supporting that FIGC represents a different entity likely evolving for longer than SIGCs is the fact that FIGC tumours presented statistically significantly more somatic common variants than SIGC tumours (p=4.2E-06), even if arising from patients 10 years younger on average (figure 4E,F).To further understand whether FIGC is a genetic entity also distinct from HDGC-CDH1 mutation-negative, we compared the germline and somatic landscapes of 7 FIGCs and 17 HDGCs sequenced with the same Next Generation Sequencing (NGS) panel.

We verified that indeed FIGC and HDGC buy generic zithromax online also display considerable differences between germline and somatic landscapes (online supplementary figure 2)(). However, the low number of FIGC cases possible to analyse, which was due to sequencing panel differences, hampers more formal conclusions.Overall, our results suggest that FIGC, rather than a monogenic disease, is likely a polygenic disease with distinctive germline and somatic landscapes from SIGC and HDGC-CDH1-negative.DiscussionFIGC presents an autosomal dominant inheritance pattern of IGC, without gastric polyposis, and has been clinically defined by analogy to the Amsterdam criteria for HNPCC.9 However, lack of novel data supporting familial aggregation of IGC at a given age of onset as well as the non-existence of tumour spectrum descriptions have impeded the redefinition of FIGC testing criteria, useful for identification and management of these families.The primary strength of this study is the use of a large homogeneous cohort of probands with IGC, familial aggregation of GC, detailed personal/family history, age of disease onset and disease spectrum. This series does not present clinical criteria compatible with any other gastrointestinal cancer-associated syndrome, is clearly enriched in GC and mainly of intestinal type, which suggests this is the first data-driven testing criteria for FIGC families.

What may interact with Zithromax?

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In 2019, the Topol review was published on behalf of the allergic reaction to zithromax secretary of state for health and social care in the UK, preparing the healthcare workforce to deliver the digital future.1 A multidisciplinary team of experts, including clinicians, researchers, ethicists, computer scientists, engineers and economists, reviewed the available data and projected into the future (ie, next 20 buy zithromax overnight shipping years) two key questions. What impact technological developments (including genomics, artificial intelligence (AI), digital medicine and robotics) will have on the roles and functions of National Health System clinical staff?. How could this innovation (ie, biosensors, electronic patient record, smartphone apps, digital infrastructure and virtual reality) ensure safer, more productive, more effective and more personalised care for patients?. It is now widely recognised that data science and information technologies enable understanding of the uniqueness of each individual and the ability to deliver healthcare on a far more timely, efficient and tailored basis.Mental health is a top priority in the UK national research agenda2 and presents a unique opportunity because it is in the next wave of adoption of digital health and innovation technologies.3 The Topol review noted that innovation can ‘bring a new emphasis on the nurturing of the precious interhuman bond, based on trust, clinical presence, empathy and communication’.

In 2019, the Topol review was published on behalf of the secretary of state for health buy generic zithromax online and social care in the UK, preparing the healthcare workforce to deliver the digital future.1 A multidisciplinary team of experts, including clinicians, researchers, ethicists, computer scientists, engineers and economists, reviewed the available data and projected into the future (ie, next 20 years) two key questions. What impact technological developments (including genomics, artificial intelligence (AI), digital medicine and robotics) will have on the roles and functions of National Health System clinical staff?. How could this innovation (ie, biosensors, electronic patient record, smartphone apps, digital infrastructure and virtual reality) ensure safer, more productive, more effective and more personalised care for patients?. It is now widely recognised that data science and information technologies enable understanding of the uniqueness of each individual and the ability to deliver healthcare on a far more timely, efficient and tailored basis.Mental health is a top priority in the UK national research agenda2 and presents a unique opportunity because it is in the next wave of adoption of digital health and innovation technologies.3 The Topol review noted that innovation can ‘bring a new emphasis on the nurturing of the precious interhuman bond, based on trust, clinical presence, empathy and communication’.

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Two strains of the bacterium causing tuberculosis have http://2016.swissbiotechday.ch/can-i-buy-lasix-online/ only minor genetic differences but attack the lungs in is zithromax used for uti completely different fashion, according to Rutgers researchers.The findings, published in the journal Nature Communications, could help break the cycle of rapid transmission of TB, the second-leading infectious killer in the world after buy antibiotics, according to the World Health Organization. The disease mechanisms uncovered in the study could also provide answers about why treatments work in some patients but not others."These findings implicate strain differences as having an important effect on the response of lung alveolar macrophages and how tuberculosis manifests itself in the body and how it is transmitted," said study author Padmini Salgame, associate director of the Public Health Research Institute at Rutgers New Jersey Medical School. "We also believe it will inform anyone hoping to devise more effective treatments."To better understand is zithromax used for uti transmission and how it relates to treatment outcomes, the researchers focused on the impact these two strains of Mycobacterium tuberculosis have on the lungs. Though the strains differ slightly in their gene sequences, one is regarded as "high transmission" because it spreads easily and the second as "low transmission" because it does not infect as readily.

TB bacteria are spread through the air when persons with TB disease in their lungs cough, speak or even sing.Using strains identified in a Rutgers collaborative study with researchers at Núcleo de Doenças Infecciosas (NDI)in Brazil comparing "high transmission" and "low transmission" households of people with TB, the scientists studied the immune pathways is zithromax used for uti that the pathogen triggered in the lungs of the infected mice.In mice infected with the high transmission strain, their lungs quickly formed clumps of immune cells known as granulomas that encased the invading bacteria, stopping development of a more virulent disease. In most cases, the granulomas broke down eventually, spilling their contents. Researchers believe that if the escaped bacteria are close enough to the bronchial airway, they could be expelled into the air as infectious aerosols."By inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the is zithromax used for uti airways, high transmission M. Tuberculosis strains are poised for greater transmissibility," said Salgame, who is also a professor in the Department of Medicine.In mice infected with the low transmission strain, the invading bacteria were slow to activate the lung alveolar macrophages and ended up producing patches of inflammation within the lungs that did not allow the bacteria to escape into airways and allowed them to conglomerate and intensify the , Salgame said.The discovery of the different trajectories taken by the strains gives hope to new approaches to stopping transmission and treatment."We have long known that some individuals with TB are more infectious than others," Salgame said.

"However, until now, the mechanisms responsible for this variability in transmission between individuals with TB have not been well understood."Other Rutgers authors included Arianne Lovey, Sheetal Verma, Vaishnavi Kaipilyawar and Jerrold Ellner, all at the Center for Emerging Pathogens, and is zithromax used for uti Seema Husain of The Genomics Center. Story Source. Materials provided by is zithromax used for uti Rutgers University. Original written by Kitta MacPherson.

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Two strains of the bacterium causing tuberculosis buy generic zithromax online have only minor genetic differences but attack the lungs in completely different fashion, according to Rutgers researchers.The findings, published in the journal Nature Can i buy lasix online Communications, could help break the cycle of rapid transmission of TB, the second-leading infectious killer in the world after buy antibiotics, according to the World Health Organization. The disease mechanisms uncovered in the study could also provide answers about why treatments work in some patients but not others."These findings implicate strain differences as having an important effect on the response of lung alveolar macrophages and how tuberculosis manifests itself in the body and how it is transmitted," said study author Padmini Salgame, associate director of the Public Health Research Institute at Rutgers New Jersey Medical School. "We also believe it will inform anyone hoping to devise more effective treatments."To better understand transmission and how it relates to treatment outcomes, the researchers buy generic zithromax online focused on the impact these two strains of Mycobacterium tuberculosis have on the lungs. Though the strains differ slightly in their gene sequences, one is regarded as "high transmission" because it spreads easily and the second as "low transmission" because it does not infect as readily.

TB bacteria are spread through the air when persons with TB disease in their lungs cough, speak or even sing.Using strains identified in a Rutgers collaborative study with researchers at Núcleo de Doenças Infecciosas (NDI)in Brazil comparing "high transmission" and "low transmission" households of people with TB, the scientists studied the immune pathways that the pathogen triggered in buy generic zithromax online the lungs of the infected mice.In mice infected with the high transmission strain, their lungs quickly formed clumps of immune cells known as granulomas that encased the invading bacteria, stopping development of a more virulent disease. In most cases, the granulomas broke down eventually, spilling their contents. Researchers believe that if the escaped bacteria are close enough to the bronchial airway, they could be buy generic zithromax online expelled into the air as infectious aerosols."By inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the airways, high transmission M. Tuberculosis strains are poised for greater transmissibility," said Salgame, who is also a professor in the Department of Medicine.In mice infected with the low transmission strain, the invading bacteria were slow to activate the lung alveolar macrophages and ended up producing patches of inflammation within the lungs that did not allow the bacteria to escape into airways and allowed them to conglomerate and intensify the , Salgame said.The discovery of the different trajectories taken by the strains gives hope to new approaches to stopping transmission and treatment."We have long known that some individuals with TB are more infectious than others," Salgame said.

"However, until now, the mechanisms responsible for this variability in transmission between individuals with TB have not been well understood."Other Rutgers authors included Arianne Lovey, Sheetal Verma, Vaishnavi Kaipilyawar and buy generic zithromax online Jerrold Ellner, all at the Center for Emerging Pathogens, and Seema Husain of The Genomics Center. Story Source. Materials provided by Rutgers University buy generic zithromax online. Original written by Kitta MacPherson.

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Low grade intraventricular zithromax dosage for std haemorrhage and click this over here now cerebral palsyNicky Hollebrandse and colleagues describe the neurodevelopmental outcomes at 8 years of almost 500 extremely preterm infants born before 28 week’s gestation and relate these to the presence and severity of intraventricular haemorrhage (IVH) that was identified in the newborn period. It is particularly valuable that they achieved 91.4% follow-up of so many patients and to an age when assessments can be more detailed. When no IVH was identified, cerebral palsy was observed in 8% of the infants and zithromax dosage for std impaired academic ability in 16%. With grade 1 and 2 IVH, cerebral palsy increased to 15% and 18% respectively, with no increase in the risk of impaired cognitive outcomes. With more severe IVH, risks of cerebral palsy and cognitive impairment increased further.

Around 5% of the infants with grade 1 and 2 zithromax dosage for std IVH developed cystic periventricular leukomalacia (PVL) later. The authors did not control for this and they considered it possible that IVH could be part of the causal pathway for this lesion. The infants did not have MRI scans. Later ultrasound detectable PVL zithromax dosage for std could account for some but not most of the observed cerebral palsy in infants with low grade IVH. Nohaa Gorma and Stephen Miller highlight the prime importance of school age outcomes over earlier measures.

They emphasise the zithromax dosage for std need to investigate interventions during and beyond the neonatal period, including the social environment and support provided to families, if we are to optimise the outcomes for these children. See pages F4 and F2Diffuse excessive high signal intensity (DEHSI) on term equivalent MRI scan is not predictive of later cognitive abnormality or cerebral palsyThere have been a number of papers in the journal recently looking at the relationship between MRI scan findings at term and outcome in preterm infants. Chandra Prakash Rath and colleagues performed a meta-analysis of studies evaluating the significance of DEHSI. They included 1832 preterm infants who had MRI scans at term equivalent age and zithromax dosage for std assessments of cognitive ability and cerebral palsy using validated instruments. At 1 year of age or older.

DEHSI was common and was not a useful predictor of either cognitive outcome or cerebral palsy. See page F9Opaque wraps and pulse oximeter readingsPrakash Kannan Loganathan and colleagues investigated whether the use of an opaque wrap over the pulse oximeter probe affected the performance of zithromax dosage for std the pulse oximeter in 96 clinically stable newborn infants. They were interested in the speed with which the oximeter displayed valid data and the distribution of the SpO2 readings obtained. They evaluated zithromax dosage for std this for Masimo and Nellcor oximeters. The use of the opaque wrap had no important effect on the performance of either oximeter type.

For the study period the infants were monitored simultaneously using both a Nellcor and a Masimo oximter, permitting a comparison of the readings between the two devices as an interesting additional finding. The mean SpO2 obtained with the Masimo oximiter zithromax dosage for std was 2.85% higher than the mean SpO2 simultaneously obtained with the Nellcor oximeter. The infants were clinically stable and this difference was observed when readings were typically in the low to mid 90 s. Both devices are providing an estimate of the arterial oxygen saturation and neither should be considered a gold standard over the other. However a difference in the apparent calibration of the two devices of this magnitude demonstrated in a reasonably large comparison in the key region of zithromax dosage for std clinical interest for newborn infants could have important clinical implications as the devices are used interchangeably for a range of clinical indications related to specific SpO2 ranges.

See page F57Preterm births during lockdownGitte Hedermann and colleagues were among the first to report observational data from the buy antibiotics lockdown period suggesting a reduction in the number of extremely preterm births. In comparison zithromax dosage for std with the same time period during the preceding 5 years there were significantly fewer extremely preterm deliveries in Denmark during lockdown, with no change in total deliveries. Similar observations have been reported from elsewhere and raise questions about the contributing factors, which will be a rich source of new research as larger population datasets become available for analysis. Wouldn’t it be nice if slowing the pace of life for pregnant women is enough to improve pregnancy outcomes?. It is unlikely that the findings will be the same in all zithromax dosage for std datasets because the degree of lockdown will be variable and the extent to which important healthcare delivery is disrupted could have an adverse impact.

See page F93Fetal haemoglobin levels and bronchopulmonary dysplasiaWilliam Hellstrom and colleagues analysed the fetal haemoglobin (HbF) levels on almost 12 000 blood gas samples taken during the first week of life in 452 preterm infants born before 30 week’s gestation. They found that infants whose HbF levels fell the most during week one after birth were at highest risk of bronchopulmonary dysplasia (BPD). They also analysed arterial PO2 levels and these were significantly lower in the infants who zithromax dosage for std developed BPD, suggesting that the observation does not relate to simply to an effect mediated through changes in oxygenation. They hypothesise that the higher falls in HbF reflect sampling losses and replacement by transfusion and that there is a loss of endogenous blood components that are essential for normal organ development, such as insulin-like growth factor 1. The authors are investigating the potential beneficial role of minimising the loss of endogenous zithromax dosage for std blood components in an ongoing multicentre randomised trial using microsampling methods to greatly reduce sampling losses.

See page F88Bowel ultrasound in the management of necrotising enterocolitisKaren Alexander and Colleagues provide a comprehensive overview of the use of bowel ultrasound scanning in the investigation and management of infants with suspected or confirmed necrotising enterocolitis. There are lots of images of key features and the article will be of value to anyone increasing their use of this technique or introducing it. See page F96Despite significant advances in perinatal and neonatal care, intraventricular haemorrhage (IVH)—bleeding from blood vessels within the germinal matrix of the developing brain into the ventricular system—continues to affect 15%–20% of very preterm neonates and 45% of those born extremely preterm (EP).1 More than half of very preterm neonates will exhibit neurodevelopmental challenges as a consequence of IVH that range widely in severity across motor and cognitive zithromax dosage for std domains.2 Such disabilities place a significant toll on affected children and their families, as well as on the education and healthcare system, highlighting the need for timely interventions in the neonatal intensive care unit (NICU) and beyond.The study reported by Hollebrandse et al3 assesses the relationship between IVH and neurodevelopmental outcomes at 8 years of age in children born EP, using a population-based sample of 546 EP neonates and 679 matched term-born controls. This cohort is distinguished by remarkably high follow-up rates from three different timepoints. In their study, Hollebrandse et al raise three critical issues in the investigation of the impact of IVH on neurodevelopmental outcomes.

First is the importance of the zithromax dosage for std age at which neurodevelopmental assessment occurs and its implications to understanding the long-term impacts of IVH. Second is the extent to which different grades of IVH contribute to the spectrum of neurodevelopmental outcomes. Third is identifying interventions within NICU practice and postdischarge that can help mitigate the adverse impacts of IVH with attention to the timepoints at which these therapies are most supportive of neurodevelopmental outcomes.The age at which neurodevelopmental ….

Low grade intraventricular haemorrhage read and cerebral palsyNicky Hollebrandse and buy generic zithromax online colleagues describe the neurodevelopmental outcomes at 8 years of almost 500 extremely preterm infants born before 28 week’s gestation and relate these to the presence and severity of intraventricular haemorrhage (IVH) that was identified in the newborn period. It is particularly valuable that they achieved 91.4% follow-up of so many patients and to an age when assessments can be more detailed. When no IVH was identified, cerebral palsy was observed in 8% of the infants and impaired academic buy generic zithromax online ability in 16%.

With grade 1 and 2 IVH, cerebral palsy increased to 15% and 18% respectively, with no increase in the risk of impaired cognitive outcomes. With more severe IVH, risks of cerebral palsy and cognitive impairment increased further. Around 5% of the infants with grade 1 and 2 IVH developed cystic periventricular buy generic zithromax online leukomalacia (PVL) later.

The authors did not control for this and they considered it possible that IVH could be part of the causal pathway for this lesion. The infants did not have MRI scans. Later ultrasound detectable PVL could account for some but not most of the observed cerebral palsy in infants with low grade IVH buy generic zithromax online.

Nohaa Gorma and Stephen Miller highlight the prime importance of school age outcomes over earlier measures. They emphasise the need to investigate interventions during and beyond the neonatal period, including the social environment and support provided to buy generic zithromax online families, if we are to optimise the outcomes for these children. See pages F4 and F2Diffuse excessive high signal intensity (DEHSI) on term equivalent MRI scan is not predictive of later cognitive abnormality or cerebral palsyThere have been a number of papers in the journal recently looking at the relationship between MRI scan findings at term and outcome in preterm infants.

Chandra Prakash Rath and colleagues performed a meta-analysis of studies evaluating the significance of DEHSI. They included 1832 preterm infants who had MRI scans at term equivalent age buy generic zithromax online and assessments of cognitive ability and cerebral palsy using validated instruments. At 1 year of age or older.

DEHSI was common and was not a useful predictor of either cognitive outcome or cerebral palsy. See page F9Opaque wraps and pulse oximeter readingsPrakash Kannan Loganathan and colleagues investigated buy generic zithromax online whether the use of an opaque wrap over the pulse oximeter probe affected the performance of the pulse oximeter in 96 clinically stable newborn infants. They were interested in the speed with which the oximeter displayed valid data and the distribution of the SpO2 readings obtained.

They evaluated this for Masimo buy generic zithromax online and Nellcor oximeters. The use of the opaque wrap had no important effect on the performance of either oximeter type. For the study period the infants were monitored simultaneously using both a Nellcor and a Masimo oximter, permitting a comparison of the readings between the two devices as an interesting additional finding.

The mean SpO2 obtained with the Masimo oximiter was 2.85% higher than buy generic zithromax online the mean SpO2 simultaneously obtained with the Nellcor oximeter. The infants were clinically stable and this difference was observed when readings were typically in the low to mid 90 s. Both devices are providing an estimate of the arterial oxygen saturation and neither should be considered a gold standard over the other.

However a difference in the apparent calibration of the two devices of this magnitude demonstrated in a reasonably large comparison in the key region of clinical interest for newborn infants could have important clinical implications as the devices are used interchangeably for a range of clinical buy generic zithromax online indications related to specific SpO2 ranges. See page F57Preterm births during lockdownGitte Hedermann and colleagues were among the first to report observational data from the buy antibiotics lockdown period suggesting a reduction in the number of extremely preterm births. In comparison with the same time period during the preceding 5 years there were significantly fewer extremely preterm deliveries in Denmark during lockdown, with no change in buy generic zithromax online total deliveries.

Similar observations have been reported from elsewhere and raise questions about the contributing factors, which will be a rich source of new research as larger population datasets become available for analysis. Wouldn’t it be nice if slowing the pace of life for pregnant women is enough to improve pregnancy outcomes?. It is unlikely that the findings will be the same in all datasets because the degree of lockdown will be variable and the extent to which important buy generic zithromax online healthcare delivery is disrupted could have an adverse impact.

See page F93Fetal haemoglobin levels and bronchopulmonary dysplasiaWilliam Hellstrom and colleagues analysed the fetal haemoglobin (HbF) levels on almost 12 000 blood gas samples taken during the first week of life in 452 preterm infants born before 30 week’s gestation. They found that infants whose HbF levels fell the most during week one after birth were at highest risk of bronchopulmonary dysplasia (BPD). They also analysed arterial PO2 levels and these were significantly lower in the infants who developed BPD, suggesting that buy generic zithromax online the observation does not relate to simply to an effect mediated through changes in oxygenation.

They hypothesise that the higher falls in HbF reflect sampling losses and replacement by transfusion and that there is a loss of endogenous blood components that are essential for normal organ development, such as insulin-like growth factor 1. The authors are buy generic zithromax online investigating the potential beneficial role of minimising the loss of endogenous blood components in an ongoing multicentre randomised trial using microsampling methods to greatly reduce sampling losses. See page F88Bowel ultrasound in the management of necrotising enterocolitisKaren Alexander and Colleagues provide a comprehensive overview of the use of bowel ultrasound scanning in the investigation and management of infants with suspected or confirmed necrotising enterocolitis.

There are lots of images of key features and the article will be of value to anyone increasing their use of this technique or introducing it. See page F96Despite significant advances in perinatal and neonatal care, intraventricular haemorrhage (IVH)—bleeding from blood vessels within the germinal matrix of the developing brain into the ventricular system—continues to affect 15%–20% of very preterm neonates and 45% of those born extremely preterm (EP).1 More than half of very preterm neonates will exhibit neurodevelopmental challenges as a consequence of IVH that range widely in severity across motor and cognitive domains.2 Such disabilities place a significant toll on affected children buy generic zithromax online and their families, as well as on the education and healthcare system, highlighting the need for timely interventions in the neonatal intensive care unit (NICU) and beyond.The study reported by Hollebrandse et al3 assesses the relationship between IVH and neurodevelopmental outcomes at 8 years of age in children born EP, using a population-based sample of 546 EP neonates and 679 matched term-born controls. This cohort is distinguished by remarkably high follow-up rates from three different timepoints.

In their study, Hollebrandse et al raise three critical issues in the investigation of the impact of IVH on neurodevelopmental outcomes. First is the importance of the age at buy generic zithromax online which neurodevelopmental assessment occurs and its implications to understanding the long-term impacts of IVH. Second is the extent to which different grades of IVH contribute to the spectrum of neurodevelopmental outcomes.

Third is identifying interventions within NICU practice and postdischarge that can help mitigate the adverse impacts of IVH with attention to the timepoints at which these therapies are most supportive of neurodevelopmental outcomes.The age at which neurodevelopmental ….

Zithromax walgreens price

IntroductionTracing the implications zithromax walgreens price of developments within genetic science find more information has become a major area of research and debate within medical sociology and allied disciplines (Martin and Dingwall 2010). Sociologists and bioethicists have long argued that technological developments are leading to an increasing ‘geneticisation’ of many aspects of health and healthcare (Lippman 1991). This can particularly be seen in the establishment and adoption of a ‘genomics agenda’ within public zithromax walgreens price health institutions (Mwale and Farsides 2021). Genomics involves the study of all of a person’s genes (the genome) and how genes interact with each other and the environment.

The expansion of this area of medicine has been made possible by technological development, economic investment and the application of political capital. Going beyond the individual gene offers new diagnostic and treatment possibilities—particularly for complex and rare conditions.Alongside these clinical opportunities, there are substantial zithromax walgreens price social implications. As Martin and Dingwall (2010, 514) have noted, one of the distinguishing features of genetics (and now, genomics) is its promissory discourse which relies on a mobilisation of ‘high expectations and social anxieties’. Such can involve a reconfiguring of expectations, zithromax walgreens price hopes and fears about the future (Martin and Dingwall 2010).

As Parker (2012) argues, ethical problems within genetics emerge against, and need to be understood in the context of, a rich background of complex but largely day-to-day practice. This is also true for the experiences of those engaging with genomics as patients or carers. An engagement with genomics is always mediated through, and interpreted zithromax walgreens price against, peoples’ own lived (and everyday) experience (Featherstone et al. 2006).Understanding the perspectives of those who engage with genomic medicine services is (or, should be) an important facet of social scientific enquiry.

Particularly, as previous research has suggested that patients’ expectations and assumptions about ethical practice may not always be the same as those of healthcare professionals (Dheensa, Fenwick, and Lucassen 2016). However, as Lewis et al zithromax walgreens price. (2020) note, there are relatively few qualitative studies that explore the perspectives of parents who have been offered genomic sequencing to diagnose their child’s rare conditions in the UK. As a result, we are less aware of how zithromax walgreens price families see the impact on their lives of the positive imagined futures presented by scientists, clinicians and policy makers.

We might also be prone to reducing the experience of families down to that of travellers on the ‘diagnostic odyssey’ so often referred to in literature (Rosell et al. 2016). Our research aims to collate rich accounts of lived experience in order to make zithromax walgreens price visible the diverse, variable and multilayered everyday lives of patients and families and how these correspond with emerging, rapidly changing, and complex fields such as genomic medicine. While the application of genomic technologies has the potential to transform patients' lives, the excitement (or, ‘genohype’ (Kakuk 2006)) around these technologies mustn't eclipse the everyday experiences of the people who live with, and care for, those with genetic conditions.

As Kerr et al. (2021) have argued, these promissory claims are fragile and contested, particularly when set against everyday encounters.Dealing with the uncertainty that the advent and subsequent mainstreaming of clinical genomics brings requires working in a way that empowers ‘voices at the margins zithromax walgreens price so that they may help craft creative options and [create] opportunities for collective consensual decision-making that are respectful of difference’ (Baylis 2019, 175). This involves finding ways to speak ‘with’ rather than ‘for’, creating a way for the ideas and interests of stakeholder communities to rise to the fore, and hence, our interest in participatory-writing.Writing worldsWriting, as we see it, belongs at the heart of social research. It is part of zithromax walgreens price research.

A research method in its own right. A means of enquiry, exploration and articulation. (Phillips and Kara (2021, 8)Finding ways to understand, evoke and (re)present the experiences of research participants is at the heart of social zithromax walgreens price scientific inquiry. Methodological plurality and creativity is increasingly celebrated as allowing for more nuanced perspectives, different modalities of knowledge and more participatory approaches to doing research with (as opposed to simply, on) participants (DeLyser and Sui 2014).

The challenge, as described by Deacon (2000) is to ‘find ways to make living systems actually come alive’. Given that ‘social researchers work with participants to zithromax walgreens price explore their experiences and perspectives in their own words’ (Phillips and Kara 2021, 105) there are opportunities to think more creatively about how we come to elicit, produce and obtain these words. Written words, not just spoken.As Richardson (2000, 923) argues ‘writing is also a way of 'knowing'—a method of discovery and analysis’. Explorations of using writing as a mode of inquiry zithromax walgreens price have seen experimentation with different written forms (Eshun and Madge 2012.

Lorimer 2018. Phillips and Kara 2021) as well as autobiographical accounts in the style of autoethnographic methods (Bochner and Ellis 2002). However, as Elizabeth (2008, 4) notes, such a use of autobiographical writing as a method remains zithromax walgreens price underused and is ‘is largely confined to those sociologists who choose to write personally. Participants are rarely granted a similar opportunity’.

Certainly, many such examples can be found of this style of zithromax walgreens price academic writing, and obviously, this is not to downplay their contributions and insights, but to draw attention to the potential ways in which such methods can be extended to engage with the knowledges of participants. There is perhaps something troubling about the way that ‘writing’ is something retained as the privileged territory of the researcher.Participatory methods have been invoked to great success across a diverse range of settings. Participatory drawing (Literat 2013), participatory photography (Prins 2010), participatory video (Kindon 2003) to name just a few. Yet there appears zithromax walgreens price to remain a hesitancy to extending these principles of participation to that staple of research.

Writing. Many of the benefits that have been identified as resulting from social researchers using writing as method (Phillips and Kara 2021. Richardson and zithromax walgreens price St. Pierre 2018) can also equally arrive from enabling those we research with to contribute illuminating understandings through the processual experience of writing.

For example, in writing about writing as a method of inquiry, Richardson and St zithromax walgreens price. Pierre (2018, 1428) emphasis original) reflect on the benefits of how ‘thought happened in the writing’. Similarly, Phillips and Kara (2021, 17) explain how ‘writing can help us to explore experiences and identify and express emotions’. Of course, zithromax walgreens price such a generation of new ideas, understandings and connections through writing is not limited to those doing research, but extends to all those who might embrace and engage in the exploratory and expressive acts and processes emerging from an engagement in writing.Asking participants to write is not an unusual method in and of itself.

It is the core thing that we ask people to do when we send them qualitative questionnaires and include room for open-ended responses in our surveys. Diary methods have a rich history as an enlightening form of empirical investigation, capable of offering insights into everyday life (Latham 2003). The Mass Observation Project and Archive similarly relies on participants becoming diarists and writers, responding in a written form and recording zithromax walgreens price their experiences and thoughts (McGlacken and Hobson-West 2022. Smart 2011).

Yet, despite zithromax walgreens price such utilisations of inscription, there still remains something of a sense of impropriety to the notion that research participants may write, rather than speak—one in conflict with, and challenging to, the privileged place which interviewing occupies within qualitative inquiry (Elizabeth 2008). In describing the Mass Observation Project, Smart (2011, 541) describes how, until more recently, sociological engagement with the written narratives produced through the Mass Observation Project has been limited ‘because the free way in which they wrote was not regarded as sufficiently rigorous for sociological analysis’. Attitudes have since changed however, to recognise the richness and depth of the narratives that many Mass Observation panellists produce (Smart 2011).There are substantial benefits in asking participants to write about their lives (Elizabeth 2008). Using writing as a method of inquiry raises the possibility for ‘producing different knowledge and zithromax walgreens price producing knowledge differently’ (St.

Pierre 1997, 175). Writing creates a zithromax walgreens price very different modality of representation. It allows research participants to ‘give the researcher their stories and words in an exact form’ (Deacon 2000). As Penn (2001, 50, emphasis original) argues, to write is an act of agency.

€˜when we write zithromax walgreens price we are no longer being done to. We are doing’. This can be a particularly important mechanism of representation for certain groups and narratives, particularly if writing about events where agency may have been lacking for the author. Writing thus provides a way of transferring a level of control zithromax walgreens price and ownership to participants ‘in a way that traditional interviews cannot’ (Burtt 2020, 7).

This could simply be about enabling participants to take the time to narrate their experiences in their own terms. This ‘giving time’ may be at odds with some forms of social science that prioritise and privilege the immediacy and synchronicity of the research interview as a strategy zithromax walgreens price for overcoming anxieties about ‘premeditation’. Yet for some topics and participants, the opportunity to respond carefully and thoughtfully allows a more sensitive immersion in research. Participants can spend as long as they need to complete their written reflections, considering carefully their responses in an atmosphere less structured by the pressures of direct questioning (Burtt 2020).

Participatory-writing can provide windows on subjects that would otherwise be hard to reach by virtue of their personal or sensitive nature (Phillips zithromax walgreens price and Kara 2021). Writing can afford a level of safety in providing space, time and privacy to consider the framing and language in which disclosures and stories are told, navigating and articulating vulnerability and uncertainty. Participants are able to craft their voice. Such crafting may zithromax walgreens price again be challenged by those concerned about the risks to the generation of ‘truthfulness’, though to assume that only through the imposition of questions on the spot during interviews are authentic and authorative accounts produced is flawed.

To quote Elizabeth (2008, 14):Writing provides researchers with access to the unique, partial and situated perspectives of our participants. We gain insight into the discourses that circulate in their social milieu and zithromax walgreens price the way in which these vie for our participants' subjectivities.Writing can enable people to overcome the effects of self-censorship, allowing self-revelatory forms of expression (Elizabeth 2008). While oral research methods are often based on the dialogue between interviewer and interviewee, writing tasks, as Elizabeth (2008) describes, can put past and present selves into dialogue with each other. Writing brings a level of flexibility that can aid progression beyond fixed questions and rigid categories and vocabularies introduced by the researcher, participants can employ their own concepts and terminology, and even, to certain extents, define the questions they wish to ask and answer (Burtt 2020).

Similarly, participatory-writing as a method is less influenced by the mediating effects of the interviewer (or zithromax walgreens price other focus-group participants). Interjections, perceived cues, puzzled looks or requests to know that one’s narrative is making sense (Burtt 2020. Elizabeth 2008).This is not to claim that writing produces accounts that can be universally representative or the source for generalisations about the social world, rather the impact and intention of writing as a method is to be illustrative (Evans 2021. Phillips and Kara zithromax walgreens price 2021).

By collating multiple autobiographical accounts from participants with a shared connection, social researchers are left with a ‘method through which we might investigate that more conventional social space of the collective’ (Evans 2021, 14). This in itself allows for the inclusion of multiple ‘voices’ within the final written product of research, giving a platform to participants that has the potential to be less directly mediated and subject to academic meddling.This is not to position writing as an epistemologically ‘better’ method of inquiry than more conventional oral research practices, but rather to recognise that zithromax walgreens price writing can allow the production of very different kinds of personal revelations from participants than what may be forthcoming when spoken. That creative or autobiographical written accounts may result in omissions and imperfect interpretations of the self is well recognised (Evans 2021), but such critiques can likewise be applied to the majority of social research methods. The point is to understand how different methods can allow different facets of life and self to arise to the fore.

Like all methods, participatory-writing has its zithromax walgreens price time and place (Phillips and Kara 2021). Elizabeth (2008) suggests that there is great value in using writing exercises in conjunction with interview or focus group discussions.While embracing the ways that participants’ ‘crafted written work stands to provide eloquent answers to research questions and speak to research interests from original angles’ (Phillips and Kara 2021, 114) it is also important to remember that often the additional product of participatory-writing research are the conversations and reflections that occur along the way. Indeed, it is the practice and process of participating that can matter the most, rather than the outputs of words on a page—as useful and illuminating as they may be (Phillips and Kara 2021). The ethical bargain struck with participants may mean that on occasion the primary product (writing) is never seen nor shared, zithromax walgreens price only the experience of producing it.While social science may not have a long tradition of encouraging participants themselves to write as a mode of inquiry, as part of the rise of expressive and arts-based therapies there has been a renewed attention to writing as a therapeutic technique (Elizabeth 2008.

Pennebaker and Chung 2007. Peterkin and zithromax walgreens price Prettyman 2009. Robinson 2000). There are numerous studies that explore forms of expressive writing as a means for coping with a variety of situations (Bolton 2008.

Gebler and Maercker 2007), yet few studies that take up Richardson (2000) challenge of using writing as a way of inquiring, zithromax walgreens price understanding and ‘knowing’ more about such experiences—particularly in a fully participatory vein (though see Phillips and Kara (2021) for an insightful volume that catalogues recent efforts to do just this). It is perhaps such codings of writing as having ‘therapeutic’ applications which has stifled experimentation by qualitative researchers. Similarly, the assumption that writing exercises have a therapeutic component (by design, intention or as a predictable but unintended side effect) zithromax walgreens price may make ethics committees cautious in their policing of such methods. Though again, the ‘research interview’ is often structured by, and experienced as, a confessional (Crowe 1998) and therapeutic opportunity (Birch and Miller 2000).Of course, the open-endedness of writing presents challenges as well as opportunities (Phillips and Kara 2021).

As Phillips and Kara (2021, 76) recognise, we write ‘within the means available to us’, with dominant discourses often infiating work that hopes to be creative, searching and illuminating, becoming more conventional or hegemonic. Writing obviously has the potential to be an exclusionary activity, with the possibilities for participation influenced by numerous factors such as zithromax walgreens price class, gender, health and cultural differences, alongside past educational experiences, language fluency, habit, practice and even time available. Participation can be challenging and uncomfortable, and may be prefigured by pre-existing attitudes and aptitudes to the written form—and the sharing thereof. As Phillips et al.

(2021, 54) poignantly note, ‘creative writing is not for everyone, zithromax walgreens price all of the time’. Rather than acting as a participatory method, instituting writing as the method by which people take part in research can deter participation (Phillips and Kara 2021). However, McMillan and McNicol zithromax walgreens price (2021, 86) suggest rather than an imposition of what writing should be, there are ways of working that can allow ‘a community’s existing ways of writing and knowing to come through’. Such can involve cultivating a sense of inclusion, safety and trust among participants (Phillips et al.

2021)—many of the core values of qualitative research at large, around building rapport and relationships are particularly applicable to using writing as a method of participatory inquiry.It is important to bear in mind that writing is directly affected by the nature of the intended audience, and particularly the levels to which any audience may be imagined to have been conferred with evaluative powers (Elizabeth 2008). Similarly, and as with any form of qualitative research, accounts produced through writing are shaped by the possibilities and desires for levels of anonymity for zithromax walgreens price the authors involved. Further, we must recognise that writing fixes words—and as Elizabeth (2008) notes, hence also fixing constructions of selves and narratives. Though given that most interview research involves a subsequent transcription to an often equally fixed written form, this is perhaps not too dissimilar.

Indeed, the opportunity for a level of zithromax walgreens price editorial oversight of one’s own words and stories is one of the benefits brought about through participatory-writing. However, while writing as a mode of inquiry can be less intrusive and less pressurised, especially when taking place in the writer’s own time and space, this also means there are also fewer opportunities for researchers to provide emotional support, reassurance or to steer questioning away from distressing topics (Burtt 2020). There are thus complex ethical considerations prior to asking participants to write, to sit and mediate on a topic, in ways that—though possibly enjoyable, comforting and self-revelatory, can also be frustrating and saddening zithromax walgreens price (Elizabeth 2008. Phillips and Kara 2021).As well as affecting those doing the writing, writing also has the potential to affect readers in ways that formal academic writing cannot (Phillips and Kara 2021).

Participants’ writings can be well suited to disseminating research, particularly as the expressive nature of a participant’s writing can be seen to be ‘evoking’ emotion rather than just ‘explaining’ emotion. Showing rather than telling (Andrews zithromax walgreens price 2018). Participant-produced stories have an ‘enlivening’ quality, and can have a valuable role to play as communicative resources, building—and bridging—empathy (Parr 2021). Parr's work in particular demonstrates how stories can lead to changes in behaviours and styles of engagement within professional communities (Parr 2021).1Participatory-writing with people affected by rare genetic conditionsThis research is part of a larger participatory study working creatively and collaboratively with families touched by genetic conditions to explore the experiences of patients and participants in genomic medicine and research.

Our aim is to identify the overlaps and gaps between practitioner and patient accounts of ethically relevant issues as zithromax walgreens price they occur in clinical genomics and find ways of supporting people to feel more comfortable when having challenging conversations. Our principal research question is whether accounts of patient experience might contribute to the preparedness of clinicians to deal with the ethical challenges of genomics practice.It was this ambitious research question that piqued our interest in participatory writing, with the hope that such narratives might express and evoke aspects of lived experience in productive and affective ways, beyond what was possible through more conventional social-scientific registers and/or participatory practices of ‘patient engagement’. As Frank (2012) notes, equipping healthcare professionals with a sense of ‘what zithromax walgreens price to listen for’ can enhance ‘professional listening’.Co-production is at the heart of the research project. Our research is directly informed and guided by people with lived experience.

We have a participatory steering group who attend project meetings, share their ideas and experiences, and contribute and comment on the design of research activities. This has allowed us to develop relationships with participants, build trust and confidence, and demonstrate our commitment to confidentiality, giving people zithromax walgreens price a voice, and effecting change. Thus, we see ‘patient and public involvement’ as a constant and continual process, rather than an initial involvement at the outset of the project. Our research involves continued dialogue and input from people with lived experience of genomics and the active enrolment of their expertise, feedback and insights into the design of this project—in all its extents, zithromax walgreens price including research questions, methodology, recruitment and dissemination.

Our participants have acted as peer-researchers and had oversight of the writing of this article.Conversations with members of this steering group indicated an interest in, and encouragement to, explore ways of researching using arts-based methods. Working with an author and life-writing tutor, we designed a participatory-writing programme that would encompass an hour-long online facilitated workshop on a weekly basis for 6 weeks. We were conscious zithromax walgreens price of accommodating the availability of people with often complex caring responsibilities (particularly during buy antibiotics). Finding a mutually acceptable time to run the writing group was one of the largest challenges, although the extent to which individual participants committed to attending despite, and alongside, their commitments of caring and work (exacerbated by buy antibiotics lockdowns) gave some insight into how much potential value people saw in this work.

Aware of the online and disembodied nature of the groups, we sent participants a small ‘care package’ of stationery ahead of the meetings to show our appreciation and to help build a sense of occasion. We were aware that through writing (and reading others’ stories), people would be brushing up against personal and emotional topics, which could cause, or even reveal, a level of upset and anxiety zithromax walgreens price. Our aim was that the writing groups might exist as a ‘safe space’ to explore these narratives. However, while we had hoped participants would find being involved in our research empowering and cathartic, we were keen to zithromax walgreens price stress that our research activities did not constitute a form of ‘art therapy’.

In preparing for the possibility of distress, we appointed a colleague (external to the project) with extensive pastoral experience who could be called on to support participants (and researchers) should the experience become challenging.Initially, we recruited participants through our existing networks and relationships. A ‘purposive sampling’ technique (Sarantakos 2012) with our aim being ‘not to choose a representative sample, rather to select an illustrative one’ (Valentine 1997, 112). These were people who served as ‘patient representatives’ on ethical and governance zithromax walgreens price panels relating to genomics or who were active in patient led organisations. These were people whose voices and expertise had already been sought out in different fora.

Through a level of ‘snowballing’, these initial participants made suggestions for others within their advocacy networks and patient communities who they felt could contribute to—and enjoy taking part in—our research. The participant group was mixed in zithromax walgreens price gender, though with a larger number of women, and ages ranging from mid-30s to early 50s. All of our participants had direct experience of genetic disease within their families, with many having a significant level of caring responsibility as a result. Our participants had experience of participating in large zithromax walgreens price genomic medicine projects, such as the 100 000 Genomes Project and/or the Deciphering Developmental Disorders Study.

Many of the participants we were working with had an active blogging practice, and were keen to take part in research in a way that made use of their skills, interests and communicative strengths—but also to get something out of the research themselves, in learning new ways to hone their writing practice. Others took a little more convincing, and were particularly hesitant about how doing some writing could be scientifically productive or of value.Week by week, each session involved our professional writing tutor introducing different creative writing exercises, designed to enable both novice and experienced writers to begin to express ideas and thoughts with greater fluency. This included being introduced to, and trying zithromax walgreens price out, techniques such as free-writing, narrative-distancing and writing in response to a given prompt (such as telling the story of a cherished object). At the end of each session, participants were given a creative exercise to tackle in their own time.

During the introduction and after each in-session activity participants were invited to reflect directly on their experience and the content of their writing. Participants were invited, but never pressured, to share zithromax walgreens price their writing with the group by reading a short excerpt. Discussion was guided by the facilitator to focus on the experience of the process of writing, and to prompt the group to notice any thematic similarities or differences in written accounts. The emphasis throughout was on building zithromax walgreens price confidence in expressing lived experience.Our first writing group—who affectionately became known as the ‘Thursday Writers’—consisted of five participants, alongside the life-writing tutor, and the first author (RG), who took a participatory role in the group, rather than solely an observational one.2 Our intent was that participants would read extracts from their writing, and hopefully share it with the research team.

However, participants were quickly very vocal about wanting to share their outputs in full among the other members of the group too, and we created a secure online space where people could upload what they had written in the sessions or as part of the ‘homework’. Some participants chose to use word processors, others uploaded photos of their handwritten pages. Reflecting on the impact of reading other people’s writing and noting points of connection became a regular feature of discussions (a point we will return to later on).Our ‘Thursday Writers’ were hugely supportive of the participatory-writing programme, and several participants supported zithromax walgreens price us to recruit for a second 6-week programme with an additional seven participants (which also ended up running on a Thursday). All of the writing group sessions were recorded, with participants’ consent, which has allowed us to revisit and reflect on the types of narratives that were created and shared, alongside those which were uploaded to a ‘sharing folder’ (one for each group—it was key that the ‘safe space’ created for sharing writing was limited to the people who were in the online sessions together).

Participants also consented to their written pieces being used in publications, a question which was revisited in the drafting of this article.After each 6-week programme, we arranged reflective interviews with participants, giving everyone an opportunity zithromax walgreens price to share their thoughts and experiences regarding participating in the writing groups. The written pieces that participants had produced throughout the course also served as an elicitory device during these conversations (Bagnoli 2009), allowing us to delve further into the context, meaning and emotions surrounding the participant’s writing, as well as asking them to reflect on what the piece represented or evoked that may be outside of view to others.We have specifically chosen not to attribute interview quotes nor written pieces to individuals. This is to aid confidentiality, which was an important theme for participants (see later discussion). While we zithromax walgreens price could have chosen to use pseudonyms or participant codes, these can be reductive.

Through not attributing quotes or pieces of writing to individuals, we are able to demonstrate commonalities across different and diverse rare genetic conditions.Engaging with the written pieces produced through participatory-writing involved paying close attention to the stories (and, processes of storying) that were written, aiming to better understand their impact and significance (Phillips et al. 2021). For us, zithromax walgreens price this involved drawing on aspects of dialogical narrative analysis (DNA) (Frank 2010, 2012). Such an analytical approach involves questioning:What is the storyteller’s art, through which she or he represents life in the form of a story?.

And what form of life is reflected in such a representation, including the resources to tell particular kinds of stories, affinities with those who will listen to and understand such stories, vulnerabilities including not being able to tell an adequate story, zithromax walgreens price and contests, including which version of a story trumps which other versions?. (Frank 2012, 33).DNA involves understanding stories as artful representations of lives. It involves considering why someone might choose to tell such a story and exploring how identities are being formed and sustained by the storying process. DNA’s concern is how to speak with a research participant rather than about them, and show what is at stake in a story as a zithromax walgreens price form of response.

A central premise of DNA is that it does not seek to interpret stories or ‘discover truths’ that have ‘escaped the attention of the storytellers’ (Frank 2012), rather the intent is to witness stories, and enable voices to be both heard and evocative—often through positioning them into dialogue with other, but similar, diffuse voices. Thus, the purpose of a dialogical narrative analysis is not to ‘display mastery over the story, but rather to expand the listener’s openness to how much the story is saying’ (Frank 2010, 88).Writing everyday storiesSimilarly to Phillips et al. (2021), our approach zithromax walgreens price was not to extract stories from our participants, but enable them to recount the stories that were of importance to them. Although we were interested in the dawn of genomic medicine and the sociotechnical imaginaries involved (Mwale and Farsides 2021), we were also interested in what everyday life is like for the people who live with, and care for, those with genetic conditions, and how genomics acts to reconfigure (or, perhaps, does not) aspects of people’s lives outside of the clinic.

As Prainsack, Schicktanz, and zithromax walgreens price Werner-Felmayer (2014, 11) argue, genetics takes place ‘outside of the clinic as well as within. It takes place in families, patient groups, state organisations, on the Internet, and on the international market’.The phrase ‘everyday life’ is often associated with the ‘ordinary, routine and repetitive aspects of social life that are pervasive and yet frequently overlooked and taken-for-granted’ (Pinder 2011, 223). Finding significance in the everyday and respect for the ‘mundane’ draws from a feminist commitment to understand the material conditions of people’s lived experience and practices (Hanson 1992). Attending to ‘everyday life’ allows a focus on those practices and zithromax walgreens price aspects of life that are hidden by dominant narratives (Highmore 2002).

An everyday perspective challenges privileging certain spaces, such as ‘the clinic’, as being the locus of how and where people experience genomic medicine, to instead explore that which exceeds these formalised encounters and overflows into other domains of life. For Lefebvre zithromax walgreens price (1991, 97), everyday life is ‘what is left over’. Our participants’ writing provided us with a viewpoint of those things which are ‘left over’ from accounts of genomics. It draws our attention to the way that geneticisation (Lippman 1991) and genohype (Kakuk 2006) infiate everyday life, but also how, frequently, at an everyday level, these new sociotechnical regimes may have little impact.

With genomics being presented as a cornucopia and salve for all manner of health and social challenges, understanding ‘what is left over’ is an important effort in making visible the inconspicuous aspects zithromax walgreens price of living with rare genetic conditions. As Nicholas and Gillett (1997) argue, to begin to appreciate the bioethical issues at stake, we need to fill in the gaps that exist within our understanding, something which cannot be done without narrative insights. Similarly, reflecting on genetics practice at large, Featherstone et al. (2006, xii) zithromax walgreens price argue that ‘a sound appreciation of everyday social reality is of profound importance for professional practice’.

Thus, as Frank (2012, 36) notes, ‘to describe the world may be the most effective way to change it’.Many of the pieces of writing that emerged from the groups touched on these sorts of everyday realities, and hidden complexities, of caring for people affected by rare genetic conditions.With ‘My Day Begins’, I just sat down, and I was typing rather than writing freehand because I’m faster. And yeah, there it was, and I hardly had to change zithromax walgreens price anything, after the first draft. I was really pleased with it, and you know I started off just trying to make it as factual as possible, as matter of fact as possible. And it wasn’t until I shared it with other people that then they went ‘Whoa’.

And I went ‘Whoa? zithromax walgreens price. Really?. This is life.’ And I thought that was very interesting.As one of our participants commented, writing these sorts of creative pieces allowed them to draw attention to the complexities involved in care—practical, emotional and identity-based complexities, not just medicalised complexities. As the author of ‘My Day Begins’ (figure 1) notes,'My Day Begins'—a piece of writing from one of our zithromax walgreens price writing groups.

WAV, wheelchair accessible vehicle." data-icon-position data-hide-link-title="0">Figure 1 'My Day Begins'—a piece of writing from one of our writing groups. WAV, wheelchair accessible vehicle.There’s stuff in there about the complexity of caring for somebody, the practical complexities, and there’s stuff about the emotional complexity of being part of a wider family unit and still having zithromax walgreens price to cope. And there’s this stuff in there about having to put aside your sense of self and be a parent or a carer. And I think a lot of people who don't have caring responsibilities would never think twice about that.Bury (1982, 169) noted how illness can result in ‘biographical disruptions’, where ‘the structures of everyday life and the forms of knowledge which underpin them are disrupted’.

Such was certainly present in the written pieces that our participants zithromax walgreens price produced. Though, rather than a singular disruption, years with no diagnosis, potential misdiagnoses and potentially having to adapt to receiving a diagnosis for a condition different to what had been expected (Dheensa, Lucassen, and Fenwick 2019), means that genomics follows multiple disruptions to both forms of knowledge and everyday life. Figure 2 exemplifies this.'Freewriting, Session #3'—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 2 'Freewriting, Session #3'—a piece of writing from one of our writing groups.Yet even in writing these representations, participants were keen to hold attention to these acts as being specifically everyday. They were aware and quite critical of the possibility for acts of interpretation zithromax walgreens price to render their writing as something very different.

One participant described the challenge of eliciting empathetic responses, rather than just solely sympathetic responses.Sometimes I feel in this juxtaposition about not wanting to be personified as a superhero, because we’re not, we are just doing what the majority of parents would do if they had to do it, that is how it is.As a route to enabling the possibility of empathetic response, many of those who took part in the participatory-writing sessions commented how their pieces perhaps captured aspects of their lives that they felt were outside the view and understanding of medical professionals. The lack of alignment between families and healthcare professionals as to what ethical practice around genomics might mean and require (Dheensa, Fenwick, and Lucassen 2016) can be produced in part by this lack of visibility and knowledge about what is important and what is experienced on an everyday level.‘They [healthcare professionals] tend to have a close in view of it rather than a bird’s eye view of it, in a way all of that stuff zithromax walgreens price and stress is invisible.’‘I think clinic doctors perhaps don't see anything like this side of things.’‘I’ve written quite a lot and I think other people have as well about how it feels to be a family with or without a diagnosis, rather than what the medics or what the team seems to think is important.’Noting things as being exterior to more commonplace comprehensions was not always presented as disenfranchisement or critique of healthcare professionals, but rather a way of drawing attention to the multiple forms of lived expertise that parents were called on to develop and mobilise. One piece, ‘Word Salad Counsellor’ (figure 3), in particular showcased how engagements with genomic medicine required patients and parents to develop new skills and knowledges, specifically in navigating the complex scientific languages through which clinicians enact and practice care.'Word Salad Counsellor'—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 3 'Word Salad Counsellor'—a piece of writing from one of our writing groups.There is much to take away from figure 3. The use of humour to mask painful experiences.

The hyper zithromax walgreens price awareness of space and environment. The use of language, metaphors and similes. The lack of attention zithromax walgreens price to important personal information (e.g. Misgendering the child) in lieu of a focus on complex scientific information.

The unfortunate use of the word ‘exciting’ when attached to what is in fact bad news for this family.In particular, this tongue-in-cheek piece highlights how accessing genomic medicine services can require quickly learning scientific vocabulary in order to interpret clinical communications and be confident in understanding, participating and obtaining, optimum care. The challenges of the technical zithromax walgreens price language surrounding genomics (and health information in general) are well established (Stuckey et al. 2015). The onus is frequently on the patient to acquire the expertise to interpret the information being provided—as described in the quote below from an interview with the author.Yeah, I mean it’s amplified but it’s not amplified by very much at all.

I took your world’s worst zithromax walgreens price plausible genetic counsellor and went from there. The surreal-ness of it actually comes from a lot of the stuff that’s real in a way because I went back to it and thought which bits really chimed?. Of course, it’s all the stuff like, ‘Oh, yes, zithromax walgreens price this is a known variant of not a great deal of significance.’ All those kinds of things. To most people it sounds like Douglas Adams but it’s not, it’s just what arrives in the letter.

Okay, should I worry about this?. Do I need to translate it before I worry about zithromax walgreens price it?. What are we doing here?. … I’ve rapidly built on my A level biology knowledge which was already 30 years out of date.

When I learnt my genetics the human genome hadn’t been sequenced so it’s all happened in my lifetime really and it’s been a bit of zithromax walgreens price a helter-skelter. In a way you’ve got to learn it … it’s all delivered in closed codes and so in order to pick any of the useful information out of that you’ve got to learn it quick.Although not the intended purpose of the writer, the original piece of writing and the follow-up discussion provide invaluable insight into the way theory and practice come together (or do not) in the clinic. The encounter highlights the centrality of what can be described as a ‘diffusion model’ zithromax walgreens price (McNeil 2013) of public engagement efforts around genomics. That is, the aspirations and follow on assumptions that groups will acquire scientific knowledge about new technologies via a ‘trickling down’ or ‘osmosis’ of information.

This is slightly different from—though, entangled with—ideas that suggest a ‘deficit model’ of public engagement, that takes as its starting point a deficiency in understanding that can be solved through more or better education (Marks 2016). A diffusion approach instead zithromax walgreens price assumes that those encountering a new technology will actively seek, access, comprehend and use related information. Institutionally, it is a passive (indeed, neoliberal) approach to public engagement that positions individuals as responsible for their own empowerment. In practice, the prevalence of a diffusion model of public engagement is potentially as equally problematic as the well-critiqued deficit model.

Hoping that those engaging with genomics zithromax walgreens price services will have acquired the confidence, knowledge and skills to equitably participate through a wider diffusion of public understanding of genomics and/or a commitment to self-education is, at best, a sticking plaster. More creative dialogical strategies for developing public engagement around genomics are still very much required (Samuel and Farsides 2018).Participants were keen to use the groups, and their writing, as an opportunity to craft narratives and representations that resisted and challenged what they frequently felt was expected (and indeed, imposed on them) by institutions—whether the wider genomics ‘industry’, or even patient support groups. As such, participants were zithromax walgreens price aware of particular types of writing that would be well received and seen to have extrinsic value, but struggled to square that with the way in which they wanted to tell their own stories and reflect those of their children.We’re thinking more about how our children are represented, and their awareness of themselves. It’s that thing that ‘this child is disabled and they’ve had a horrible life and they’re so sick and blah-blah-blah’, and then people give you funding … And I’ve had conversations with [charity] about it before because they’d written something for a funding bid and it said ‘a lot of these children will die’, and I thought, ‘Do you really need to say that?.

€™, and they were like, ‘Yeah, because that’s what gets people…’. But when you’re thinking about your child and how you want the world to view them and zithromax walgreens price how you want them to view themselves, it’s kind of a different thing I guess.Thus, many of the pieces of writing that participants created aimed to tell positive stories, ‘normal’ stories, that resisted medicalisation and politicisation, even casting it to the margins, such as in ‘My Magical Girl’ (figure 4). As one participant noted, ‘one of the things I really liked, one of the reasons that I write is to share the good stuff that happens’. Intertwined with this, we can witness how participants are keen to reclaim and recentre certain aspects of their identities which perhaps they do not get the opportunity zithromax walgreens price to voice in other (particularly, medical) contexts.

As one participant reflected on their writing. €˜I think there is that bit of still being a mum and not being a carer or a medical secretary’. Parents of children with rare genetic conditions are often implicitly expected to become ‘expert caregivers’—something which healthcare systems rely on, though simultaneously struggle to acknowledge (Baumbusch, Mayer, and Sloan-Yip 2018).‘My Magical Girl’—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 4 ‘My Magical Girl’—a piece of writing from one of our writing groups.Similarly, another participant reflecting on the writing groups explained:We did a narrative piece that I’m just looking at now and I think that does what I zithromax walgreens price like to do, which is just show some of the normal stuff around living with someone with a rare condition. Just trying to show that we do have a normal life and just showing that we do have things in common with other people, we do have things we can talk about and if you come and talk to us or read our writing, it doesn’t have to be about genetics!.

We’ve got other things that are in our lives and are important to us.At first glance, some of the written excerpts appeared to describe aspects of life quite mundane and unremarkable. However, when read through the context of zithromax walgreens price rare genetic conditions, these pieces can draw attention to how such multiple aspects of everyday life are reconfigured and challenged. Indeed, one participant reflected that, ‘I don’t think I wrote particularly much about her condition per se, but then I think things leak out in whatever you’re writing about’. While another noted how ‘no matter what we write about, you can always feel that parenting concern in the back of zithromax walgreens price your mind.

The inability to be completely free of that.’. For example, the written piece ‘My Garden’ (figure 5), touches on the home adaptations and extensions often required to allow domestic spaces to become accessible, the exclusions that can be felt from public spaces lacking specialist play equipment and the vulnerabilities that a rare diagnosis can bring in zithromax times.'My Garden'—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 5 'My Garden'—a piece of writing from one of our writing groups.Many of the pieces written as part of our two writing groups explored some of these other things, whether descriptions of gardens, fond memories or day-to-day conversations. Not all of them were approached through zithromax walgreens price the lens of rare conditions. Instead, caring responsibilities or medical paraphernalia featured as an absent-presence.

Yet, many of these pieces of writing, even when not directly or explicitly mentioning rare disease, carried messages and themes that other participants took to be particularly meaningful when interpreted through their own lived experience of rare genetic conditions, such as ‘The Blanket’ (figure 6).'The Blanket'—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 6 'The Blanket'—a piece of writing from one of our writing groups.The Blanket was amazing because it was that kind of completionist idea, the idea that the caring and dealing with the genetic odyssey is a never-ending saga and so you never get to complete anything because you’ve got to do it again from scratch tomorrow. The blanket zithromax walgreens price more than anything else kind of touched me. It’s the one I really took away with me.Writing in this way gave participants scope and freedom to tell stories that they felt—as one participant described—‘could only happen by metaphor’. It provided a way to represent aspects of their lives and experiences that exceeded what could be conveyed in oral recollections and explanations zithromax walgreens price.

The blank page and freedom to write about anything was an important way of creating a space where people felt comfortable to explore different narratives, centre different identities and challenge assumptions about life with rare conditions. As one participant explained:I was a bit worried that at the beginning, we would be invited to delve into points in our story that we felt were pivotal or particularly strong memories. And I was very glad that [the facilitator] didn't zithromax walgreens price do that. She was very careful to say, this could be any of your experiences, write about any of it.

And then, of course, you can choose how far you tip-toe into that or not. And that was good.With this in mind, we want to briefly turn our attention to reflecting on the value that writing has had here, as a qualitative method, and how it has allowed us as researchers to explore the lifeworlds of families zithromax walgreens price touched by genetic conditions.Reflecting on the value of participatory-writing for social researchParticipatory-writing has enabled us to learn about many of the things that mattered to our participants. It has given us an insight into their everyday lives. The complexities, zithromax walgreens price the challenges, the frustrations.

Writing (and the interlinked processes of sharing and reading) has allowed our participants to voice their narratives and representations in ways that they found to be important and authentic.The written pieces that were created—whether poem or prose—have been immensely evocative. We have included as many as possible, and in full. Particularly as, to quote Frank (2012, 36), ‘each story zithromax walgreens price must be considered as a whole. Methods that fragment stories serve other purposes’.

Herein lies one of the challenges of participatory-writing, in that what is produced does not lend zithromax walgreens price itself well to the demands and constraints of academic publishing!. Though we hope to also demonstrate what is achievable even when time is short. One of the largest challenges of the method that we and our participants reflected on were discussions around privacy and confidentiality.There’s a lot of stuff now that I have to be so careful, because of protecting the kids’ privacy. There’s stuff I’d like to talk about because it affects me, some of the conversations that we’ve had to have, I can’t put those anywhere and it’s not that I want to necessarily share that as such, it’s a difficult one in that sometimes it is zithromax walgreens price just cathartic to get it out and write it out but then I’m always mindful, who is reading this?.

How can this come back in the future?. How would that get back?. How would I feel if my kids, zithromax walgreens price how would they feel if this was out there?. Writing brings with it a greater sense of permeance and mobility.

It produces a record in ways zithromax walgreens price different to that of conversation. In our research, we always ensured that people felt comfortable to not share what they had written—and indeed, some people did not. Throughout the process we stressed the optional nature and modular approach to sharing, allowing people to choose what was shared with us as researchers, what was shared within the group, and what—if anything—could be shared more widely, for example, the pieces of writing featured in this publication. Participants assessed this issue on a piece-by-piece basis and knew that we as researchers wanted them to retain full control over everything they had written.It was encouraging that participants reflected on how writing had, as a method, both encouraged and enabled zithromax walgreens price them to detail aspects of their experience that might not have come to the fore had we relied solely on oral interviews.

Writing, as one of our participants described, ‘really threw a light on those things that it’s really hard to explain under other circumstances’. Another participant described noticing that the written medium had encouraged them to ‘dig a little bit more’ into their feelings:[You] can twiddle with it, so like we might come out of this meeting now and I might think, ‘oh god, I wish I’d said that’. Whereas if you’ve got a week or so to actually play with it and zithromax walgreens price add or take away from it or whatever, because sometimes you write something and it’s done, but then you start typing it up and you’ll just rephrase it in a different way. So, there’s that time to actually consider it.The opportunity to creatively use metaphors, write-between-the-lines, and crucially, take the time to craft and edit narratives gave our participants the opportunity to consider how they responded, and to convey what they felt was an added level of detail.

For some, zithromax walgreens price it was particularly the opportunities that writing offered to make these narratives ‘more lively and interesting’ that was appealing. This liveliness is particularly important if we take seriously Vannini’s claims that social research ought to consider the ‘unique and novel ways it can reverberate with people, what social change or intellectual fascination it can inspire, what impressions it can animate, what surprises it can generate, what expectations it can violate, what new stories it can generate’(Vannini 2015, 12). This involves recognising the performative quality of words themselves and the intersubjective means by which knowledge is co-created by writer and reader (Anderson 2014), a shift from aiming to explain how something might ‘feel’ to instead attempting to expressively evoke how something might ‘feel’.Writing in this way has thus been a valuable method for us. But it zithromax walgreens price was also an approach which our participants valued and embraced.

Participants described the cathartic release of writing something and then ‘letting go of it’, something that also enabled them to have a level of distance from what was produced and represented.I’m usually writing something because I know that I’m going to put it somewhere somebody can read it. But this, I was just writing it. I suppose in some ways that was different […] in terms of the idea of a revelation and feeling zithromax walgreens price things.Writing provided a way for participants to navigate and negotiate vulnerability on their own terms. It produced a level of solidarity and sociality among the groups too, one that acted as a counter to what one participant described as ‘the isolation and loneliness that lots of carers feel’.

We’d—perhaps naively—initiated this research in the hopes of producing material that would be engaging and informative to healthcare professionals, however, it quickly became apparent zithromax walgreens price that reading other people’s writing was powerful and rewarding for other families affected by rare conditions too.I think being able to connect to what other people were saying. I know there was a piece in particular that [participant] wrote, and I felt like that could have been something that I actually could have written myself. The language that she used, the situation that it was about, it was definitely something that I thought, ‘Wow that’s my life, I could have written that.’ That was quite strange actually, it was nice though.This overlapped with what participants felt to be another strand of value in writing about their experiences. Being heard.There’s just something about knowing that zithromax walgreens price people are listening and actually giving you a really nice way to talk about things.

It’s as far away from medicalised as you can get, isn’t it, just doing creative writing.The creativity of the medium, and its differentiation from the language and communication styles associated with more clinical discourse became something that in itself had a generative potential. Participants felt enabled to claim an ownership and validity to their representations of experiences zithromax walgreens price. The written form had an authority and level of definition that empowered people to write about the more-than-medical realities that constitute life with rare genetic conditions. It provided an important outlet for people to voice their narratives—often stories that they felt had no place or might even undermine their expertise.

As one participant commented, ‘nobody asks me this zithromax walgreens price stuff’. Another described how,I think people see you swan-like gliding along, having these silly ideas about how easy you’re making it look. They don’t see any of all of the bits that are going on behind it and writing about nappies and children being resuscitated and all of that kind of thing. I suppose I feel it allows me to tell people what it’s really like.Again, it zithromax walgreens price emphasises the value of taking an everyday approach, and considering what is ‘left over’ (Lefebvre 1991), what exceeds or escapes more formalised representations of life with rare conditions, and what is absent from the genomic imaginaries and promissory discourses that are created and mobilised at a political level.ConclusionIn the spirit of dialogical narrative analysis, our aim has never been to ‘summarise our findings’, but ‘rather to open continuing possibilities of listening and of responding to what is heard’ (Frank 2012, 36).

Stories are integral to medical care, as Nicholas and Gillett (1997, 296) argue, ‘in its representation of subjective experience, narrative gives us access to the perceptions and valuation of other human beings, and thus narrative bioethics is a means of thinking about the meaning of illness in the life of a patient and about the role of the physician in the patient-physician interaction’. The stories produced through our writing groups provide a window into the worlds of genomic medicine, the worlds outside zithromax walgreens price of the clinic. They are powerful, and exist as a reminder of the wider context in which families affected by rare disease are operating—the structural, social, administrative and bureaucratic challenges which must be navigated. Challenges that are compounded by one another.

But also, the joys, the normality, the forgettability, the not-quite-all-consuming nature of rare zithromax walgreens price conditions, and the opportunities that families find to resist a wholescale medicalisation or pathologisation of life. These stories do not provide answers or solutions. Instead, their value lies in helping to unfold the implications of experiences and illuminating what is often submerged or eclipsed by wider sociotechnical frames (Morris 2001). As Featherstone zithromax walgreens price et al.

(2006, 149) argue ‘it is vital for researchers and practitioners alike to ground their work in an understanding of everyday family practices that is sensitive to their complexities’.We know that stories have lives, that stories travel, that stories remain memorable (Parr 2021). We hope that the excerpts we have showcased here, along with those that will be published elsewhere, might prompt greater understanding of the lived experiences of families whose lives have become entwined with the genomics agenda zithromax walgreens price. Narratives can serve as a reminder of how medical practices are experienced by patients, but also how medical encounters are situated within, against and alongside everything else that happens in people’s lives (Nicholas and Gillett 1997). As Morris (2001, 55) has described, this is not a practice of thinking about stories, but rather a process of thinking with stories, ‘allowing narrative to work on us’.Data availability statementNo data are available.

Due to the highly personal, sensitive and emotional nature of the qualitative data generated, and in order to respect participant’s preferences zithromax walgreens price and consent, at this stage data is not being made publicly available beyond what has been published in this article. Interested parties are welcome to contact the corresponding author for further details.Ethics statementsPatient consent for publicationNot applicable.Ethics approvalThis study involves human participants. This project and other elements of the authors' research were granted ethical and research governance approval by The Brighton and Sussex Medical School Research Governance and Ethics Committee (ER/BSMS9KQM/2). Participants gave informed consent to participate in the study before taking part.AcknowledgmentsThe authors thank the peer reviewers and editors, who zithromax walgreens price provided deep engagement with their work and for the generosity, kindness and openness towards this manuscript.Notes1.

There is a long tradition of using stories, narratives and writing as a way to prompt healthcare professionals to reflect on medical ethics (Jones 1999. Nelson 1997) zithromax walgreens price. This often takes literary sources as a starting point, though there is a growing interest in gathering stories from much more diverse places. For example, Gualtieri and Akhtar (2013) describe how blogs written by patients can offer insights and rich narratives, and provide a means to reflect on the psychosocial and emotional consequences of chronic disease.

Using ‘found’ material in this way however can create complexities around zithromax walgreens price consent (Hookway 2008) and thus there are opportunities to think about more equitable and participatory ways of researching and writing with participants.2. RG has lived experience of a rare genetic condition themselves. The decision for RG to be present was discussed with potential participants who suggested they would be keen for them to be there..

IntroductionTracing the implications of developments within genetic science has become a major area of research and debate within medical sociology and buy generic zithromax online allied disciplines (Martin and address Dingwall 2010). Sociologists and bioethicists have long argued that technological developments are leading to an increasing ‘geneticisation’ of many aspects of health and healthcare (Lippman 1991). This can particularly be seen in the establishment and adoption of buy generic zithromax online a ‘genomics agenda’ within public health institutions (Mwale and Farsides 2021). Genomics involves the study of all of a person’s genes (the genome) and how genes interact with each other and the environment.

The expansion of this area of medicine has been made possible by technological development, economic investment and the application of political capital. Going beyond the individual gene offers new diagnostic and treatment possibilities—particularly for complex and buy generic zithromax online rare conditions.Alongside these clinical opportunities, there are substantial social implications. As Martin and Dingwall (2010, 514) have noted, one of the distinguishing features of genetics (and now, genomics) is its promissory discourse which relies on a mobilisation of ‘high expectations and social anxieties’. Such can involve a reconfiguring of expectations, hopes and fears about the future (Martin and buy generic zithromax online Dingwall 2010).

As Parker (2012) argues, ethical problems within genetics emerge against, and need to be understood in the context of, a rich background of complex but largely day-to-day practice. This is also true for the experiences of those engaging with genomics as patients or carers. An engagement with genomics is always mediated through, and buy generic zithromax online interpreted against, peoples’ own lived (and everyday) experience (Featherstone et al. 2006).Understanding the perspectives of those who engage with genomic medicine services is (or, should be) an important facet of social scientific enquiry.

Particularly, as previous research has suggested that patients’ expectations and assumptions about ethical practice may not always be the same as those of healthcare professionals (Dheensa, Fenwick, and Lucassen 2016). However, as Lewis et al buy generic zithromax online. (2020) note, there are relatively few qualitative studies that explore the perspectives of parents who have been offered genomic sequencing to diagnose their child’s rare conditions in the UK. As a result, we are less aware of how families see the impact on their lives of the positive imagined futures presented by scientists, clinicians and policy makers buy generic zithromax online.

We might also be prone to reducing the experience of families down to that of travellers on the ‘diagnostic odyssey’ so often referred to in literature (Rosell et al. 2016). Our research aims to collate rich accounts of lived experience in buy generic zithromax online order to make visible the diverse, variable and multilayered everyday lives of patients and families and how these correspond with emerging, rapidly changing, and complex fields such as genomic medicine. While the application of genomic technologies has the potential to transform patients' lives, the excitement (or, ‘genohype’ (Kakuk 2006)) around these technologies mustn't eclipse the everyday experiences of the people who live with, and care for, those with genetic conditions.

As Kerr et al. (2021) have argued, these promissory claims are fragile and contested, particularly when set against everyday encounters.Dealing buy generic zithromax online with the uncertainty that the advent and subsequent mainstreaming of clinical genomics brings requires working in a way that empowers ‘voices at the margins so that they may help craft creative options and [create] opportunities for collective consensual decision-making that are respectful of difference’ (Baylis 2019, 175). This involves finding ways to speak ‘with’ rather than ‘for’, creating a way for the ideas and interests of stakeholder communities to rise to the fore, and hence, our interest in participatory-writing.Writing worldsWriting, as we see it, belongs at the heart of social research. It is part of buy generic zithromax online research.

A research method in its own right. A means of enquiry, exploration and articulation. (Phillips and Kara (2021, 8)Finding buy generic zithromax online ways to understand, evoke and (re)present the experiences of research participants is at the heart of social scientific inquiry. Methodological plurality and creativity is increasingly celebrated as allowing for more nuanced perspectives, different modalities of knowledge and more participatory approaches to doing research with (as opposed to simply, on) participants (DeLyser and Sui 2014).

The challenge, as described by Deacon (2000) is to ‘find ways to make living systems actually come alive’. Given that ‘social buy generic zithromax online researchers work with participants to explore their experiences and perspectives in their own words’ (Phillips and Kara 2021, 105) there are opportunities to think more creatively about how we come to elicit, produce and obtain these words. Written words, not just spoken.As Richardson (2000, 923) argues ‘writing is also a way of 'knowing'—a method of discovery and analysis’. Explorations of using writing as a mode of inquiry have seen experimentation with different written buy generic zithromax online forms (Eshun and Madge 2012.

Lorimer 2018. Phillips and Kara 2021) as well as autobiographical accounts in the style of autoethnographic methods (Bochner and Ellis 2002). However, as Elizabeth (2008, 4) notes, such a use of autobiographical writing as a method remains underused and buy generic zithromax online is ‘is largely confined to those sociologists who choose to write personally. Participants are rarely granted a similar opportunity’.

Certainly, many such examples can be found of this style of academic writing, and obviously, this buy generic zithromax online is not to downplay their contributions and insights, but to draw attention to the potential ways in which such methods can be extended to engage with the knowledges of participants. There is perhaps something troubling about the way that ‘writing’ is something retained as the privileged territory of the researcher.Participatory methods have been invoked to great success across a diverse range of settings. Participatory drawing (Literat 2013), participatory photography (Prins 2010), participatory video (Kindon 2003) to name just a few. Yet there appears to remain a hesitancy to buy generic zithromax online extending these principles of participation to that staple of research.

Writing. Many of the benefits that have been identified as resulting from social researchers using writing as method (Phillips and Kara 2021. Richardson and buy generic zithromax online St. Pierre 2018) can also equally arrive from enabling those we research with to contribute illuminating understandings through the processual experience of writing.

For example, in writing about writing as a buy generic zithromax online method of inquiry, Richardson and St. Pierre (2018, 1428) emphasis original) reflect on the benefits of how ‘thought happened in the writing’. Similarly, Phillips and Kara (2021, 17) explain how ‘writing can help us to explore experiences and identify and express emotions’. Of course, such a generation of new ideas, understandings and connections through writing is not limited to those doing research, but extends to all those who might embrace and engage buy generic zithromax online in the exploratory and expressive acts and processes emerging from an engagement in writing.Asking participants to write is not an unusual method in and of itself.

It is the core thing that we ask people to do when we send them qualitative questionnaires and include room for open-ended responses in our surveys. Diary methods have a rich history as an enlightening form of empirical investigation, capable of offering insights into everyday life (Latham 2003). The Mass Observation Project and Archive similarly relies on participants becoming buy generic zithromax online diarists and writers, responding in a written form and recording their experiences and thoughts (McGlacken and Hobson-West 2022. Smart 2011).

Yet, despite such utilisations of inscription, there still remains something of a sense of impropriety to the notion that research participants may write, rather than speak—one in buy generic zithromax online conflict with, and challenging to, the privileged place which interviewing occupies within qualitative inquiry (Elizabeth 2008). In describing the Mass Observation Project, Smart (2011, 541) describes how, until more recently, sociological engagement with the written narratives produced through the Mass Observation Project has been limited ‘because the free way in which they wrote was not regarded as sufficiently rigorous for sociological analysis’. Attitudes have since changed however, to recognise the richness and depth of the narratives that many Mass Observation panellists produce (Smart 2011).There are substantial benefits in asking participants to write about their lives (Elizabeth 2008). Using writing as a method of inquiry raises the possibility for ‘producing different knowledge and buy generic zithromax online producing knowledge differently’ (St.

Pierre 1997, 175). Writing creates a very buy generic zithromax online different modality of representation. It allows research participants to ‘give the researcher their stories and words in an exact form’ (Deacon 2000). As Penn (2001, 50, emphasis original) argues, to write is an act of agency.

€˜when we write we are buy generic zithromax online no longer being done to. We are doing’. This can be a particularly important mechanism of representation for certain groups and narratives, particularly if writing about events where agency may have been lacking for the author. Writing thus provides a way of transferring a level of control and ownership to buy generic zithromax online participants ‘in a way that traditional interviews cannot’ (Burtt 2020, 7).

This could simply be about enabling participants to take the time to narrate their experiences in their own terms. This ‘giving time’ may be at odds with some forms buy generic zithromax online of social science that prioritise and privilege the immediacy and synchronicity of the research interview as a strategy for overcoming anxieties about ‘premeditation’. Yet for some topics and participants, the opportunity to respond carefully and thoughtfully allows a more sensitive immersion in research. Participants can spend as long as they need to complete their written reflections, considering carefully their responses in an atmosphere less structured by the pressures of direct questioning (Burtt 2020).

Participatory-writing can provide windows on subjects that would otherwise be hard to reach by virtue of their personal or sensitive nature buy generic zithromax online (Phillips and Kara 2021). Writing can afford a level of safety in providing space, time and privacy to consider the framing and language in which disclosures and stories are told, navigating and articulating vulnerability and uncertainty. Participants are able to craft their voice. Such crafting may again be challenged by those concerned about the risks to the generation of ‘truthfulness’, though to assume that only through the imposition of questions on the buy generic zithromax online spot during interviews are authentic and authorative accounts produced is flawed.

To quote Elizabeth (2008, 14):Writing provides researchers with access to the unique, partial and situated perspectives of our participants. We gain insight into the discourses that circulate in their social milieu and the way buy generic zithromax online in which these vie for our participants' subjectivities.Writing can enable people to overcome the effects of self-censorship, allowing self-revelatory forms of expression (Elizabeth 2008). While oral research methods are often based on the dialogue between interviewer and interviewee, writing tasks, as Elizabeth (2008) describes, can put past and present selves into dialogue with each other. Writing brings a level of flexibility that can aid progression beyond fixed questions and rigid categories and vocabularies introduced by the researcher, participants can employ their own concepts and terminology, and even, to certain extents, define the questions they wish to ask and answer (Burtt 2020).

Similarly, participatory-writing as a method is less influenced by the mediating effects of the interviewer (or buy generic zithromax online other focus-group participants). Interjections, perceived cues, puzzled looks or requests to know that one’s narrative is making sense (Burtt 2020. Elizabeth 2008).This is not to claim that writing produces accounts that can be universally representative or the source for generalisations about the social world, rather the impact and intention of writing as a method is to be illustrative (Evans 2021. Phillips and Kara buy generic zithromax online 2021).

By collating multiple autobiographical accounts from participants with a shared connection, social researchers are left with a ‘method through which we might investigate that more conventional social space of the collective’ (Evans 2021, 14). This in itself allows for the inclusion of multiple ‘voices’ within the final written product of research, giving a platform to participants that has the potential to be less directly mediated and subject to academic meddling.This is not to position writing as an epistemologically ‘better’ method of inquiry than more conventional oral research practices, but rather to recognise that writing can allow the production of very different kinds of personal revelations from buy generic zithromax online participants than what may be forthcoming when spoken. That creative or autobiographical written accounts may result in omissions and imperfect interpretations of the self is well recognised (Evans 2021), but such critiques can likewise be applied to the majority of social research methods. The point is to understand how different methods can allow different facets of life and self to arise to the fore.

Like all methods, participatory-writing has its time and place (Phillips and Kara 2021) buy generic zithromax online. Elizabeth (2008) suggests that there is great value in using writing exercises in conjunction with interview or focus group discussions.While embracing the ways that participants’ ‘crafted written work stands to provide eloquent answers to research questions and speak to research interests from original angles’ (Phillips and Kara 2021, 114) it is also important to remember that often the additional product of participatory-writing research are the conversations and reflections that occur along the way. Indeed, it is the practice and process of participating that can matter the most, rather than the outputs of words on a page—as useful and illuminating as they may be (Phillips and Kara 2021). The ethical bargain struck with participants may mean that on occasion the primary product (writing) is never seen nor shared, only the experience of producing it.While social science may not have a long tradition buy generic zithromax online of encouraging participants themselves to write as a mode of inquiry, as part of the rise of expressive and arts-based therapies there has been a renewed attention to writing as a therapeutic technique (Elizabeth 2008.

Pennebaker and Chung 2007. Peterkin and buy generic zithromax online Prettyman 2009. Robinson 2000). There are numerous studies that explore forms of expressive writing as a means for coping with a variety of situations (Bolton 2008.

Gebler and Maercker 2007), buy generic zithromax online yet few studies that take up Richardson (2000) challenge of using writing as a way of inquiring, understanding and ‘knowing’ more about such experiences—particularly in a fully participatory vein (though see Phillips and Kara (2021) for an insightful volume that catalogues recent efforts to do just this). It is perhaps such codings of writing as having ‘therapeutic’ applications which has stifled experimentation by qualitative researchers. Similarly, the assumption that writing exercises have a therapeutic component (by design, intention or as a predictable but unintended side effect) may make ethics committees cautious in their policing of buy generic zithromax online such methods. Though again, the ‘research interview’ is often structured by, and experienced as, a confessional (Crowe 1998) and therapeutic opportunity (Birch and Miller 2000).Of course, the open-endedness of writing presents challenges as well as opportunities (Phillips and Kara 2021).

As Phillips and Kara (2021, 76) recognise, we write ‘within the means available to us’, with dominant discourses often infiating work that hopes to be creative, searching and illuminating, becoming more conventional or hegemonic. Writing obviously has the potential to be an exclusionary activity, with the possibilities for participation influenced by numerous factors such as class, buy generic zithromax online gender, health and cultural differences, alongside past educational experiences, language fluency, habit, practice and even time available. Participation can be challenging and uncomfortable, and may be prefigured by pre-existing attitudes and aptitudes to the written form—and the sharing thereof. As Phillips et al.

(2021, 54) poignantly note, ‘creative writing is not for everyone, all of the buy generic zithromax online time’. Rather than acting as a participatory method, instituting writing as the method by which people take part in research can deter participation (Phillips and Kara 2021). However, McMillan buy generic zithromax online and McNicol (2021, 86) suggest rather than an imposition of what writing should be, there are ways of working that can allow ‘a community’s existing ways of writing and knowing to come through’. Such can involve cultivating a sense of inclusion, safety and trust among participants (Phillips et al.

2021)—many of the core values of qualitative research at large, around building rapport and relationships are particularly applicable to using writing as a method of participatory inquiry.It is important to bear in mind that writing is directly affected by the nature of the intended audience, and particularly the levels to which any audience may be imagined to have been conferred with evaluative powers (Elizabeth 2008). Similarly, and as with any form of qualitative research, accounts produced through writing are shaped by the possibilities and buy generic zithromax online desires for levels of anonymity for the authors involved. Further, we must recognise that writing fixes words—and as Elizabeth (2008) notes, hence also fixing constructions of selves and narratives. Though given that most interview research involves a subsequent transcription to an often equally fixed written form, this is perhaps not too dissimilar.

Indeed, the opportunity for a level of editorial oversight of one’s own words and buy generic zithromax online stories is one of the benefits brought about through participatory-writing. However, while writing as a mode of inquiry can be less intrusive and less pressurised, especially when taking place in the writer’s own time and space, this also means there are also fewer opportunities for researchers to provide emotional support, reassurance or to steer questioning away from distressing topics (Burtt 2020). There are thus complex ethical considerations prior to asking participants to write, to sit and mediate on a topic, in ways that—though possibly enjoyable, comforting and buy generic zithromax online self-revelatory, can also be frustrating and saddening (Elizabeth 2008. Phillips and Kara 2021).As well as affecting those doing the writing, writing also has the potential to affect readers in ways that formal academic writing cannot (Phillips and Kara 2021).

Participants’ writings can be well suited to disseminating research, particularly as the expressive nature of a participant’s writing can be seen to be ‘evoking’ emotion rather than just ‘explaining’ emotion. Showing rather than telling (Andrews buy generic zithromax online 2018). Participant-produced stories have an ‘enlivening’ quality, and can have a valuable role to play as communicative resources, building—and bridging—empathy (Parr 2021). Parr's work in particular demonstrates how stories can lead to changes in behaviours and styles of engagement within professional communities (Parr 2021).1Participatory-writing with people affected by rare genetic conditionsThis research is part of a larger participatory study working creatively and collaboratively with families touched by genetic conditions to explore the experiences of patients and participants in genomic medicine and research.

Our aim is to identify the buy generic zithromax online overlaps and gaps between practitioner and patient accounts of ethically relevant issues as they occur in clinical genomics and find ways of supporting people to feel more comfortable when having challenging conversations. Our principal research question is whether accounts of patient experience might contribute to the preparedness of clinicians to deal with the ethical challenges of genomics practice.It was this ambitious research question that piqued our interest in participatory writing, with the hope that such narratives might express and evoke aspects of lived experience in productive and affective ways, beyond what was possible through more conventional social-scientific registers and/or participatory practices of ‘patient engagement’. As Frank (2012) buy generic zithromax online notes, equipping healthcare professionals with a sense of ‘what to listen for’ can enhance ‘professional listening’.Co-production is at the heart of the research project. Our research is directly informed and guided by people with lived experience.

We have a participatory steering group who attend project meetings, share their ideas and experiences, and contribute and comment on the design of research activities. This has allowed us to develop relationships with participants, build trust and confidence, and buy generic zithromax online demonstrate our commitment to confidentiality, giving people a voice, and effecting change. Thus, we see ‘patient and public involvement’ as a constant and continual process, rather than an initial involvement at the outset of the project. Our research involves continued dialogue and input from people with lived experience of genomics and the active enrolment of their expertise, feedback and insights into the design of this project—in all its extents, including research buy generic zithromax online questions, methodology, recruitment and dissemination.

Our participants have acted as peer-researchers and had oversight of the writing of this article.Conversations with members of this steering group indicated an interest in, and encouragement to, explore ways of researching using arts-based methods. Working with an author and life-writing tutor, we designed a participatory-writing programme that would encompass an hour-long online facilitated workshop on a weekly basis for 6 weeks. We were conscious of accommodating the availability of people with often buy generic zithromax online complex caring responsibilities (particularly during buy antibiotics). Finding a mutually acceptable time to run the writing group was one of the largest challenges, although the extent to which individual participants committed to attending despite, and alongside, their commitments of caring and work (exacerbated by buy antibiotics lockdowns) gave some insight into how much potential value people saw in this work.

Aware of the online and disembodied nature of the groups, we sent participants a small ‘care package’ of stationery ahead of the meetings to show our appreciation and to help build a sense of occasion. We were aware that through writing (and reading others’ stories), people would be brushing up against personal and emotional topics, which could cause, or even reveal, a level of upset and anxiety buy generic zithromax online. Our aim was that the writing groups might exist as a ‘safe space’ to explore these narratives. However, while we had hoped participants would find being involved in our research empowering and cathartic, we were keen to stress that our research activities did not constitute a buy generic zithromax online form of ‘art therapy’.

In preparing for the possibility of distress, we appointed a colleague (external to the project) with extensive pastoral experience who could be called on to support participants (and researchers) should the experience become challenging.Initially, we recruited participants through our existing networks and relationships. A ‘purposive sampling’ technique (Sarantakos 2012) with our aim being ‘not to choose a representative sample, rather to select an illustrative one’ (Valentine 1997, 112). These were people who served as ‘patient representatives’ on ethical and governance panels relating buy generic zithromax online to genomics or who were active in patient led organisations. These were people whose voices and expertise had already been sought out in different fora.

Through a level of ‘snowballing’, these initial participants made suggestions for others within their advocacy networks and patient communities who they felt could contribute to—and enjoy taking part in—our research. The participant buy generic zithromax online group was mixed in gender, though with a larger number of women, and ages ranging from mid-30s to early 50s. All of our participants had direct experience of genetic disease within their families, with many having a significant level of caring responsibility as a result. Our participants had experience of participating in large genomic medicine projects, such as the buy generic zithromax online 100 000 Genomes Project and/or the Deciphering Developmental Disorders Study.

Many of the participants we were working with had an active blogging practice, and were keen to take part in research in a way that made use of their skills, interests and communicative strengths—but also to get something out of the research themselves, in learning new ways to hone their writing practice. Others took a little more convincing, and were particularly hesitant about how doing some writing could be scientifically productive or of value.Week by week, each session involved our professional writing tutor introducing different creative writing exercises, designed to enable both novice and experienced writers to begin to express ideas and thoughts with greater fluency. This included being introduced to, and trying out, techniques such as free-writing, narrative-distancing and writing in response to a given prompt (such as telling the story of a cherished buy generic zithromax online object). At the end of each session, participants were given a creative exercise to tackle in their own time.

During the introduction and after each in-session activity participants were invited to reflect directly on their experience and the content of their writing. Participants were invited, but never pressured, to share their writing with the group by reading a short excerpt buy generic zithromax online. Discussion was guided by the facilitator to focus on the experience of the process of writing, and to prompt the group to notice any thematic similarities or differences in written accounts. The emphasis throughout was on building confidence in expressing lived experience.Our first writing group—who affectionately became known as the ‘Thursday Writers’—consisted of five participants, alongside the life-writing tutor, and the first author (RG), who took a participatory role in the group, rather than solely an observational one.2 Our intent was that participants would read extracts buy generic zithromax online from their writing, and hopefully share it with the research team.

However, participants were quickly very vocal about wanting to share their outputs in full among the other members of the group too, and we created a secure online space where people could upload what they had written in the sessions or as part of the ‘homework’. Some participants chose to use word processors, others uploaded photos of their handwritten pages. Reflecting on the impact of reading other people’s writing and noting points of connection became a regular feature of discussions (a point we will return to later on).Our ‘Thursday Writers’ were hugely supportive of the participatory-writing programme, and several participants supported us to recruit for a second 6-week programme buy generic zithromax online with an additional seven participants (which also ended up running on a Thursday). All of the writing group sessions were recorded, with participants’ consent, which has allowed us to revisit and reflect on the types of narratives that were created and shared, alongside those which were uploaded to a ‘sharing folder’ (one for each group—it was key that the ‘safe space’ created for sharing writing was limited to the people who were in the online sessions together).

Participants also consented to their written pieces being used in publications, a question which was revisited in the drafting of this article.After each 6-week programme, buy generic zithromax online we arranged reflective interviews with participants, giving everyone an opportunity to share their thoughts and experiences regarding participating in the writing groups. The written pieces that participants had produced throughout the course also served as an elicitory device during these conversations (Bagnoli 2009), allowing us to delve further into the context, meaning and emotions surrounding the participant’s writing, as well as asking them to reflect on what the piece represented or evoked that may be outside of view to others.We have specifically chosen not to attribute interview quotes nor written pieces to individuals. This is to aid confidentiality, which was an important theme for participants (see later discussion). While we could have chosen to use pseudonyms or participant codes, buy generic zithromax online these can be reductive.

Through not attributing quotes or pieces of writing to individuals, we are able to demonstrate commonalities across different and diverse rare genetic conditions.Engaging with the written pieces produced through participatory-writing involved paying close attention to the stories (and, processes of storying) that were written, aiming to better understand their impact and significance (Phillips et al. 2021). For us, this buy generic zithromax online involved drawing on aspects of dialogical narrative analysis (DNA) (Frank 2010, 2012). Such an analytical approach involves questioning:What is the storyteller’s art, through which she or he represents life in the form of a story?.

And what form of life is reflected in such a representation, including the resources to tell particular kinds of buy generic zithromax online stories, affinities with those who will listen to and understand such stories, vulnerabilities including not being able to tell an adequate story, and contests, including which version of a story trumps which other versions?. (Frank 2012, 33).DNA involves understanding stories as artful representations of lives. It involves considering why someone might choose to tell such a story and exploring how identities are being formed and sustained by the storying process. DNA’s concern is how to speak with a research participant rather than about them, and show what is at stake in a story buy generic zithromax online as a form of response.

A central premise of DNA is that it does not seek to interpret stories or ‘discover truths’ that have ‘escaped the attention of the storytellers’ (Frank 2012), rather the intent is to witness stories, and enable voices to be both heard and evocative—often through positioning them into dialogue with other, but similar, diffuse voices. Thus, the purpose of a dialogical narrative analysis is not to ‘display mastery over the story, but rather to expand the listener’s openness to how much the story is saying’ (Frank 2010, 88).Writing everyday storiesSimilarly to Phillips et al. (2021), our approach was not to extract stories from our participants, but enable them to recount the stories that were of buy generic zithromax online importance to them. Although we were interested in the dawn of genomic medicine and the sociotechnical imaginaries involved (Mwale and Farsides 2021), we were also interested in what everyday life is like for the people who live with, and care for, those with genetic conditions, and how genomics acts to reconfigure (or, perhaps, does not) aspects of people’s lives outside of the clinic.

As Prainsack, buy generic zithromax online Schicktanz, and Werner-Felmayer (2014, 11) argue, genetics takes place ‘outside of the clinic as well as within. It takes place in families, patient groups, state organisations, on the Internet, and on the international market’.The phrase ‘everyday life’ is often associated with the ‘ordinary, routine and repetitive aspects of social life that are pervasive and yet frequently overlooked and taken-for-granted’ (Pinder 2011, 223). Finding significance in the everyday and respect for the ‘mundane’ draws from a feminist commitment to understand the material conditions of people’s lived experience and practices (Hanson 1992). Attending to ‘everyday life’ allows buy generic zithromax online a focus on those practices and aspects of life that are hidden by dominant narratives (Highmore 2002).

An everyday perspective challenges privileging certain spaces, such as ‘the clinic’, as being the locus of how and where people experience genomic medicine, to instead explore that which exceeds these formalised encounters and overflows into other domains of life. For Lefebvre (1991, 97), everyday buy generic zithromax online life is ‘what is left over’. Our participants’ writing provided us with a viewpoint of those things which are ‘left over’ from accounts of genomics. It draws our attention to the way that geneticisation (Lippman 1991) and genohype (Kakuk 2006) infiate everyday life, but also how, frequently, at an everyday level, these new sociotechnical regimes may have little impact.

With genomics being presented as a cornucopia and salve for all manner of health and social buy generic zithromax online challenges, understanding ‘what is left over’ is an important effort in making visible the inconspicuous aspects of living with rare genetic conditions. As Nicholas and Gillett (1997) argue, to begin to appreciate the bioethical issues at stake, we need to fill in the gaps that exist within our understanding, something which cannot be done without narrative insights. Similarly, reflecting on genetics practice at large, Featherstone et al. (2006, xii) buy generic zithromax online argue that ‘a sound appreciation of everyday social reality is of profound importance for professional practice’.

Thus, as Frank (2012, 36) notes, ‘to describe the world may be the most effective way to change it’.Many of the pieces of writing that emerged from the groups touched on these sorts of everyday realities, and hidden complexities, of caring for people affected by rare genetic conditions.With ‘My Day Begins’, I just sat down, and I was typing rather than writing freehand because I’m faster. And yeah, there buy generic zithromax online it was, and I hardly had to change anything, after the first draft. I was really pleased with it, and you know I started off just trying to make it as factual as possible, as matter of fact as possible. And it wasn’t until I shared it with other people that then they went ‘Whoa’.

And I buy generic zithromax online went ‘Whoa?. Really?. This is life.’ And I thought that was very interesting.As one of our participants commented, writing these sorts of creative pieces allowed them to draw attention to the complexities involved in care—practical, emotional and identity-based complexities, not just medicalised complexities. As the author of ‘My Day Begins’ (figure 1) notes,'My Day Begins'—a piece of buy generic zithromax online writing from one of our writing groups.

WAV, wheelchair accessible vehicle." data-icon-position data-hide-link-title="0">Figure 1 'My Day Begins'—a piece of writing from one of our writing groups. WAV, wheelchair accessible vehicle.There’s stuff in there about the complexity of caring for somebody, the practical complexities, and there’s buy generic zithromax online stuff about the emotional complexity of being part of a wider family unit and still having to cope. And there’s this stuff in there about having to put aside your sense of self and be a parent or a carer. And I think a lot of people who don't have caring responsibilities would never think twice about that.Bury (1982, 169) noted how illness can result in ‘biographical disruptions’, where ‘the structures of everyday life and the forms of knowledge which underpin them are disrupted’.

Such was certainly buy generic zithromax online present in the written pieces that our participants produced. Though, rather than a singular disruption, years with no diagnosis, potential misdiagnoses and potentially having to adapt to receiving a diagnosis for a condition different to what had been expected (Dheensa, Lucassen, and Fenwick 2019), means that genomics follows multiple disruptions to both forms of knowledge and everyday life. Figure 2 exemplifies this.'Freewriting, Session #3'—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 2 'Freewriting, Session #3'—a piece of writing from one of our writing groups.Yet even in writing these representations, participants were keen to hold attention to these acts as being specifically everyday. They were buy generic zithromax online aware and quite critical of the possibility for acts of interpretation to render their writing as something very different.

One participant described the challenge of eliciting empathetic responses, rather than just solely sympathetic responses.Sometimes I feel in this juxtaposition about not wanting to be personified as a superhero, because we’re not, we are just doing what the majority of parents would do if they had to do it, that is how it is.As a route to enabling the possibility of empathetic response, many of those who took part in the participatory-writing sessions commented how their pieces perhaps captured aspects of their lives that they felt were outside the view and understanding of medical professionals. The lack of alignment between families and healthcare professionals as to what ethical practice around genomics might mean and require (Dheensa, Fenwick, and Lucassen 2016) can be produced in part by this lack of visibility and knowledge about what is important and what is experienced on an everyday level.‘They [healthcare professionals] tend to have a close in view of it rather than a bird’s eye view of it, in a way all of that stuff and stress is invisible.’‘I think clinic doctors perhaps don't see anything like this side of things.’‘I’ve written quite a lot and I think other people have as well about how it feels to be a family with or without a diagnosis, rather than what the medics or what the team seems to think is important.’Noting things as being exterior to buy generic zithromax online more commonplace comprehensions was not always presented as disenfranchisement or critique of healthcare professionals, but rather a way of drawing attention to the multiple forms of lived expertise that parents were called on to develop and mobilise. One piece, ‘Word Salad Counsellor’ (figure 3), in particular showcased how engagements with genomic medicine required patients and parents to develop new skills and knowledges, specifically in navigating the complex scientific languages through which clinicians enact and practice care.'Word Salad Counsellor'—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 3 'Word Salad Counsellor'—a piece of writing from one of our writing groups.There is much to take away from figure 3. The use of humour to mask painful experiences.

The hyper awareness buy generic zithromax online of space and environment. The use of language, metaphors and similes. The lack of attention to buy generic zithromax online important personal information (e.g. Misgendering the child) in lieu of a focus on complex scientific information.

The unfortunate use of the word ‘exciting’ when attached to what is in fact bad news for this family.In particular, this tongue-in-cheek piece highlights how accessing genomic medicine services can require quickly learning scientific vocabulary in order to interpret clinical communications and be confident in understanding, participating and obtaining, optimum care. The challenges of the technical language surrounding genomics (and health information in general) buy generic zithromax online are well established (Stuckey et al. 2015). The onus is frequently on the patient to acquire the expertise to interpret the information being provided—as described in the quote below from an interview with the author.Yeah, I mean it’s amplified but it’s not amplified by very much at all.

I took your world’s worst plausible genetic counsellor and went from there buy generic zithromax online. The surreal-ness of it actually comes from a lot of the stuff that’s real in a way because I went back to it and thought which bits really chimed?. Of course, it’s all the stuff like, ‘Oh, yes, this is a known buy generic zithromax online variant of not a great deal of significance.’ All those kinds of things. To most people it sounds like Douglas Adams but it’s not, it’s just what arrives in the letter.

Okay, should I worry about this?. Do I need to translate it buy generic zithromax online before I worry about it?. What are we doing here?. … I’ve rapidly built on my A level biology knowledge which was already 30 years out of date.

When I learnt my genetics the human genome hadn’t been sequenced so it’s all happened buy generic zithromax online in my lifetime really and it’s been a bit of a helter-skelter. In a way you’ve got to learn it … it’s all delivered in closed codes and so in order to pick any of the useful information out of that you’ve got to learn it quick.Although not the intended purpose of the writer, the original piece of writing and the follow-up discussion provide invaluable insight into the way theory and practice come together (or do not) in the clinic. The encounter highlights the centrality of what can be described as a ‘diffusion buy generic zithromax online model’ (McNeil 2013) of public engagement efforts around genomics. That is, the aspirations and follow on assumptions that groups will acquire scientific knowledge about new technologies via a ‘trickling down’ or ‘osmosis’ of information.

This is slightly different from—though, entangled with—ideas that suggest a ‘deficit model’ of public engagement, that takes as its starting point a deficiency in understanding that can be solved through more or better education (Marks 2016). A diffusion approach buy generic zithromax online instead assumes that those encountering a new technology will actively seek, access, comprehend and use related information. Institutionally, it is a passive (indeed, neoliberal) approach to public engagement that positions individuals as responsible for their own empowerment. In practice, the prevalence of a diffusion model of public engagement is potentially as equally problematic as the well-critiqued deficit model.

Hoping that those engaging with genomics services will have acquired the confidence, knowledge and skills to equitably participate buy generic zithromax online through a wider diffusion of public understanding of genomics and/or a commitment to self-education is, at best, a sticking plaster. More creative dialogical strategies for developing public engagement around genomics are still very much required (Samuel and Farsides 2018).Participants were keen to use the groups, and their writing, as an opportunity to craft narratives and representations that resisted and challenged what they frequently felt was expected (and indeed, imposed on them) by institutions—whether the wider genomics ‘industry’, or even patient support groups. As such, participants were aware of particular types of writing that would be well received and seen to have extrinsic value, but struggled to square that with the way in buy generic zithromax online which they wanted to tell their own stories and reflect those of their children.We’re thinking more about how our children are represented, and their awareness of themselves. It’s that thing that ‘this child is disabled and they’ve had a horrible life and they’re so sick and blah-blah-blah’, and then people give you funding … And I’ve had conversations with [charity] about it before because they’d written something for a funding bid and it said ‘a lot of these children will die’, and I thought, ‘Do you really need to say that?.

€™, and they were like, ‘Yeah, because that’s what gets people…’. But when you’re thinking about your child and how you want the world to view them and how you want them to view themselves, it’s kind of a different thing I guess.Thus, many of the pieces of writing that participants created aimed to tell positive stories, ‘normal’ stories, that resisted medicalisation and politicisation, even casting it to the margins, such as in ‘My Magical buy generic zithromax online Girl’ (figure 4). As one participant noted, ‘one of the things I really liked, one of the reasons that I write is to share the good stuff that happens’. Intertwined with this, we can witness how participants buy generic zithromax online are keen to reclaim and recentre certain aspects of their identities which perhaps they do not get the opportunity to voice in other (particularly, medical) contexts.

As one participant reflected on their writing. €˜I think there is that bit of still being a mum and not being a carer or a medical secretary’. Parents of children with rare buy generic zithromax online genetic conditions are often implicitly expected to become ‘expert caregivers’—something which healthcare systems rely on, though simultaneously struggle to acknowledge (Baumbusch, Mayer, and Sloan-Yip 2018).‘My Magical Girl’—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 4 ‘My Magical Girl’—a piece of writing from one of our writing groups.Similarly, another participant reflecting on the writing groups explained:We did a narrative piece that I’m just looking at now and I think that does what I like to do, which is just show some of the normal stuff around living with someone with a rare condition. Just trying to show that we do have a normal life and just showing that we do have things in common with other people, we do have things we can talk about and if you come and talk to us or read our writing, it doesn’t have to be about genetics!.

We’ve got other things that are in our lives and are important to us.At first glance, some of the written excerpts appeared to describe aspects of life quite mundane and unremarkable. However, when read through the context of rare genetic conditions, these pieces can draw attention to how such multiple buy generic zithromax online aspects of everyday life are reconfigured and challenged. Indeed, one participant reflected that, ‘I don’t think I wrote particularly much about her condition per se, but then I think things leak out in whatever you’re writing about’. While another noted how ‘no matter what we write about, buy generic zithromax online you can always feel that parenting concern in the back of your mind.

The inability to be completely free of that.’. For example, the written piece ‘My Garden’ (figure 5), touches on the home adaptations and extensions often required to allow domestic spaces to become accessible, the exclusions that can be felt from public spaces lacking specialist play equipment and the vulnerabilities that a rare diagnosis can bring in zithromax times.'My Garden'—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 5 'My Garden'—a piece of writing from one of our writing groups.Many of the pieces written as part of our two writing groups explored some of these other things, whether descriptions of gardens, fond memories or day-to-day conversations. Not all of them were buy generic zithromax online approached through the lens of rare conditions. Instead, caring responsibilities or medical paraphernalia featured as an absent-presence.

Yet, many of these pieces of writing, even when not directly or explicitly mentioning rare disease, carried messages and themes that other participants took to be particularly meaningful when interpreted through their own lived experience of rare genetic conditions, such as ‘The Blanket’ (figure 6).'The Blanket'—a piece of writing from one of our writing groups." data-icon-position data-hide-link-title="0">Figure 6 'The Blanket'—a piece of writing from one of our writing groups.The Blanket was amazing because it was that kind of completionist idea, the idea that the caring and dealing with the genetic odyssey is a never-ending saga and so you never get to complete anything because you’ve got to do it again from scratch tomorrow. The blanket more than anything buy generic zithromax online else kind of touched me. It’s the one I really took away with me.Writing in this way gave participants scope and freedom to tell stories that they felt—as one participant described—‘could only happen by metaphor’. It provided a way to represent buy generic zithromax online aspects of their lives and experiences that exceeded what could be conveyed in oral recollections and explanations.

The blank page and freedom to write about anything was an important way of creating a space where people felt comfortable to explore different narratives, centre different identities and challenge assumptions about life with rare conditions. As one participant explained:I was a bit worried that at the beginning, we would be invited to delve into points in our story that we felt were pivotal or particularly strong memories. And I was very glad buy generic zithromax online that [the facilitator] didn't do that. She was very careful to say, this could be any of your experiences, write about any of it.

And then, of course, you can choose how far you tip-toe into that or not. And that was good.With this in mind, we want to briefly turn our attention to reflecting on the value that writing has had here, as a qualitative method, and how it has allowed us as researchers to explore the lifeworlds of families touched by genetic conditions.Reflecting on the buy generic zithromax online value of participatory-writing for social researchParticipatory-writing has enabled us to learn about many of the things that mattered to our participants. It has given us an insight into their everyday lives. The complexities, the challenges, buy generic zithromax online the frustrations.

Writing (and the interlinked processes of sharing and reading) has allowed our participants to voice their narratives and representations in ways that they found to be important and authentic.The written pieces that were created—whether poem or prose—have been immensely evocative. We have included as many as possible, and in full. Particularly as, to quote Frank (2012, 36), ‘each story must be considered as buy generic zithromax online a whole. Methods that fragment stories serve other purposes’.

Herein lies one of the challenges of participatory-writing, in that what is produced does not lend itself well to buy generic zithromax online the demands and constraints of academic publishing!. Though we hope to also demonstrate what is achievable even when time is short. One of the largest challenges of the method that we and our participants reflected on were discussions around privacy and confidentiality.There’s a lot of stuff now that I have to be so careful, because of protecting the kids’ privacy. There’s stuff I’d like to talk about because it affects me, some of the conversations that we’ve had to have, I can’t put those anywhere and it’s not that I want to necessarily share that as such, it’s a difficult one in that sometimes it is just cathartic to get it buy generic zithromax online out and write it out but then I’m always mindful, who is reading this?.

How can this come back in the future?. How would that get back?. How would I feel if my kids, how would they feel if this was out buy generic zithromax online there?. Writing brings with it a greater sense of permeance and mobility.

It produces a record buy generic zithromax online in ways different to that of conversation. In our research, we always ensured that people felt comfortable to not share what they had written—and indeed, some people did not. Throughout the process we stressed the optional nature and modular approach to sharing, allowing people to choose what was shared with us as researchers, what was shared within the group, and what—if anything—could be shared more widely, for example, the pieces of writing featured in this publication. Participants assessed this issue on a piece-by-piece basis and knew that we as researchers wanted them to retain buy generic zithromax online full control over everything they had written.It was encouraging that participants reflected on how writing had, as a method, both encouraged and enabled them to detail aspects of their experience that might not have come to the fore had we relied solely on oral interviews.

Writing, as one of our participants described, ‘really threw a light on those things that it’s really hard to explain under other circumstances’. Another participant described noticing that the written medium had encouraged them to ‘dig a little bit more’ into their feelings:[You] can twiddle with it, so like we might come out of this meeting now and I might think, ‘oh god, I wish I’d said that’. Whereas if you’ve got a week or so buy generic zithromax online to actually play with it and add or take away from it or whatever, because sometimes you write something and it’s done, but then you start typing it up and you’ll just rephrase it in a different way. So, there’s that time to actually consider it.The opportunity to creatively use metaphors, write-between-the-lines, and crucially, take the time to craft and edit narratives gave our participants the opportunity to consider how they responded, and to convey what they felt was an added level of detail.

For some, it was particularly the opportunities that buy generic zithromax online writing offered to make these narratives ‘more lively and interesting’ that was appealing. This liveliness is particularly important if we take seriously Vannini’s claims that social research ought to consider the ‘unique and novel ways it can reverberate with people, what social change or intellectual fascination it can inspire, what impressions it can animate, what surprises it can generate, what expectations it can violate, what new stories it can generate’(Vannini 2015, 12). This involves recognising the performative quality of words themselves and the intersubjective means by which knowledge is co-created by writer and reader (Anderson 2014), a shift from aiming to explain how something might ‘feel’ to instead attempting to expressively evoke how something might ‘feel’.Writing in this way has thus been a valuable method for us. But it buy generic zithromax online was also an approach which our participants valued and embraced.

Participants described the cathartic release of writing something and then ‘letting go of it’, something that also enabled them to have a level of distance from what was produced and represented.I’m usually writing something because I know that I’m going to put it somewhere somebody can read it. But this, I was just writing it. I suppose in some ways that was different […] in terms of the idea of a revelation and buy generic zithromax online feeling things.Writing provided a way for participants to navigate and negotiate vulnerability on their own terms. It produced a level of solidarity and sociality among the groups too, one that acted as a counter to what one participant described as ‘the isolation and loneliness that lots of carers feel’.

We’d—perhaps naively—initiated this research in the hopes of producing material that would be engaging and informative to healthcare professionals, however, it quickly became apparent that reading other people’s writing was powerful and rewarding for other families affected by rare conditions too.I think being able to connect to buy generic zithromax online what other people were saying. I know there was a piece in particular that [participant] wrote, and I felt like that could have been something that I actually could have written myself. The language that she used, the situation that it was about, it was definitely something that I thought, ‘Wow that’s my life, I could have written that.’ That was quite strange actually, it was nice though.This overlapped with what participants felt to be another strand of value in writing about their experiences. Being heard.There’s just something about knowing that people are listening and actually giving you a really buy generic zithromax online nice way to talk about things.

It’s as far away from medicalised as you can get, isn’t it, just doing creative writing.The creativity of the medium, and its differentiation from the language and communication styles associated with more clinical discourse became something that in itself had a generative potential. Participants felt enabled to claim an ownership buy generic zithromax online and validity to their representations of experiences. The written form had an authority and level of definition that empowered people to write about the more-than-medical realities that constitute life with rare genetic conditions. It provided an important outlet for people to voice their narratives—often stories that they felt had no place or might even undermine their expertise.

As one participant commented, buy generic zithromax online ‘nobody asks me this stuff’. Another described how,I think people see you swan-like gliding along, having these silly ideas about how easy you’re making it look. They don’t see any of all of the bits that are going on behind it and writing about nappies and children being resuscitated and all of that kind of thing. I suppose I feel it allows me to tell people what it’s really like.Again, it emphasises the value of taking an everyday approach, buy generic zithromax online and considering what is ‘left over’ (Lefebvre 1991), what exceeds or escapes more formalised representations of life with rare conditions, and what is absent from the genomic imaginaries and promissory discourses that are created and mobilised at a political level.ConclusionIn the spirit of dialogical narrative analysis, our aim has never been to ‘summarise our findings’, but ‘rather to open continuing possibilities of listening and of responding to what is heard’ (Frank 2012, 36).

Stories are integral to medical care, as Nicholas and Gillett (1997, 296) argue, ‘in its representation of subjective experience, narrative gives us access to the perceptions and valuation of other human beings, and thus narrative bioethics is a means of thinking about the meaning of illness in the life of a patient and about the role of the physician in the patient-physician interaction’. The stories produced through our writing groups provide a window into the worlds of genomic medicine, the worlds outside of the clinic buy generic zithromax online. They are powerful, and exist as a reminder of the wider context in which families affected by rare disease are operating—the structural, social, administrative and bureaucratic challenges which must be navigated. Challenges that are compounded by one another.

But also, the joys, the normality, the forgettability, the not-quite-all-consuming nature of rare conditions, and the opportunities that families find to resist a wholescale medicalisation or pathologisation of buy generic zithromax online life. These stories do not provide answers or solutions. Instead, their value lies in helping to unfold the implications of experiences and illuminating what is often submerged or eclipsed by wider sociotechnical frames (Morris 2001). As Featherstone buy generic zithromax online et al.

(2006, 149) argue ‘it is vital for researchers and practitioners alike to ground their work in an understanding of everyday family practices that is sensitive to their complexities’.We know that stories have lives, that stories travel, that stories remain memorable (Parr 2021). We hope that the excerpts we have showcased here, along with those that will be published buy generic zithromax online elsewhere, might prompt greater understanding of the lived experiences of families whose lives have become entwined with the genomics agenda. Narratives can serve as a reminder of how medical practices are experienced by patients, but also how medical encounters are situated within, against and alongside everything else that happens in people’s lives (Nicholas and Gillett 1997). As Morris (2001, 55) has described, this is not a practice of thinking about stories, but rather a process of thinking with stories, ‘allowing narrative to work on us’.Data availability statementNo data are available.

Due to the highly personal, sensitive and emotional nature of the qualitative data generated, and in order to respect participant’s buy generic zithromax online preferences and consent, at this stage data is not being made publicly available beyond what has been published in this article. Interested parties are welcome to contact the corresponding author for further details.Ethics statementsPatient consent for publicationNot applicable.Ethics approvalThis study involves human participants. This project and other elements of the authors' research were granted ethical and research governance approval by The Brighton and Sussex Medical School Research Governance and Ethics Committee (ER/BSMS9KQM/2). Participants gave informed consent to participate in the study before taking part.AcknowledgmentsThe buy generic zithromax online authors thank the peer reviewers and editors, who provided deep engagement with their work and for the generosity, kindness and openness towards this manuscript.Notes1.

There is a long tradition of using stories, narratives and writing as a way to prompt healthcare professionals to reflect on medical ethics (Jones 1999. Nelson 1997) buy generic zithromax online. This often takes literary sources as a starting point, though there is a growing interest in gathering stories from much more diverse places. For example, Gualtieri and Akhtar (2013) describe how blogs written by patients can offer insights and rich narratives, and provide a means to reflect on the psychosocial and emotional consequences of chronic disease.

Using ‘found’ material in this way however can create complexities around consent (Hookway 2008) and thus there are buy generic zithromax online opportunities to think about more equitable and participatory ways of researching and writing with participants.2. RG has lived experience of a rare genetic condition themselves. The decision for RG to be present was discussed with potential participants who suggested they would be keen for them to be there..