Lay media reporting of rosiglitazone risk: extent, messaging and quality of reporting

<p>Abstract</p> <p>Background</p> <p>A meta-analysis suggested the use of rosiglitazone was associated with an increased risk for cardiovascular (CV) events. Rosiglitazone remained available for use as more definitive safety trials were ongoing. This issue was reported in the lay media.</p> <p>Objective</p> <p>To review lay media articles to determine the extent of media coverage, the nature of the messaging, and to assess the quality of reporting.</p> <p>Methods</p> <p>The Factiva media database was used to identify articles published between May 18 and August 31, 2007. Two reviewers (a lay person and a physician) screened full text articles for eligibility, appraised the articles for their tone (worrisome, neutral, not worrisome), and for the quality of medical data reporting.</p> <p>Results</p> <p>The search identified 156 articles, 95 of which were eligible for our review. Agreement between the lay and medical reviewers in the appraisal of the article tone was 67.4%. Among those with agreement, the articles were often appraised as "worrisome" (75.3%). Among those with disagreement, the lay reviewer was significantly more likely to appraise articles as worrisome compared to the medical reviewer (77.4% vs. 3.2%, X2 = 9.11, P = 0.003). Cardiovascular risk was discussed in 91.6% of the articles, but risk was often reported in qualitative or relative terms.</p> <p>Conclusion</p> <p>There were many lay media articles addressing the safety of rosiglitazone, and the general messaging of these articles was considered "worrisome" by reviewers. Quality of risk reporting in the articles reviewed was poor. The impact of such media coverage on public anxiety and confidence in treatment should be explored.</p

Clinical and medication profiles stratified by household income in patients referred for diabetes care

BACKGROUND: Low income individuals with diabetes are at particularly high risk for poor health outcomes. While specialized diabetes care may help reduce this risk, it is not currently known whether there are significant clinical differences across income groups at the time of referral. The objective of this study is to determine if the clinical profiles and medication use of patients referred for diabetes care differ across income quintiles. METHODS: This cross-sectional study was conducted using a Canadian, urban, Diabetes Education Centre (DEC) database. Clinical information on the 4687 patients referred to the DEC from May 2000 – January 2002 was examined. These data were merged with 2001 Canadian census data on income. Potential differences in continuous clinical parameters across income quintiles were examined using regression models. Differences in medication use were examined using Chi square analyses. RESULTS: Multivariate regression analysis indicated that income was negatively associated with BMI (p < 0.0005) and age (p = 0.023) at time of referral. The highest income quintiles were found to have lower serum triglycerides (p = 0.011) and higher HDL-c (p = 0.008) at time of referral. No significant differences were found in HBA1C, LDL-c or duration of diabetes. The Chi square analysis of medication use revealed that despite no significant differences in HBA1C, the lowest income quintiles used more metformin (p = 0.001) and sulfonylureas (p < 0.0005) than the wealthy. Use of other therapies were similar across income groups, including lipid lowering medications. High income patients were more likely to be treated with diet alone (p < 0.0005). CONCLUSION: Our findings demonstrate that low income patients present to diabetes clinic older, heavier and with a more atherogenic lipid profile than do high income patients. Overall medication use was higher among the lower income group suggesting that differences in clinical profiles are not the result of under-treatment, thus invoking lifestyle factors as potential contributors to these findings

Illuminating the dynamic rare biosphere of the Greenland Ice Sheet's Dark Zone

Greenland's Dark Zone is the largest contiguous region of bare terrestrial ice in the Northern Hemisphere and microbial processes play an important role in driving its darkening and thereby amplifying melt and runoff from the ice sheet. However, the dynamics of these microbiota have not been fully identified. Here we present joint 16S rRNA gene and 16S rRNA (cDNA) comparison of input (snow), storage (cryoconite), and output (supraglacial stream water) habitats across the Dark Zone over the melt season. We reveal that all three Dark Zone communities have a preponderance of rare taxa exhibiting high protein synthesis potential (PSP). Furthermore, taxa with high PSP represent highly connected ‘bottlenecks’ within community structure, consistent with their roles as metabolic hubs. Finally, low abundance-high PSP taxa affiliated with Methylobacterium within snow and stream water suggest a novel role for Methylobacterium in the carbon cycle of Greenlandic snowpacks, and importantly, the export of potentially active methylotrophs to the bed of the Greenland Ice Sheet. By comparing the dynamics of bulk and potentially active microbiota in the Dark Zone of the Greenland Ice Sheet we provide novel insights into the mechanisms and impacts of the microbial colonization of this critical region of our melting planet

Protocol for a feasibility study incorporating a randomised pilot trial with an embedded process evaluation and feasibility economic analysis of ThinkCancer!: a primary care intervention to expedite cancer diagnosis in Wales

Abstract Background Compared to the rest of Europe, the UK has relatively poor cancer outcomes, with late diagnosis and a slow referral process being major contributors. General practitioners (GPs) are often faced with patients presenting with a multitude of non-specific symptoms that could be cancer. Safety netting can be used to manage diagnostic uncertainty by ensuring patients with vague symptoms are appropriately monitored, which is now even more crucial due to the ongoing COVID-19 pandemic and its major impact on cancer referrals. The ThinkCancer! workshop is an educational behaviour change intervention aimed at the whole general practice team, designed to improve primary care approaches to ensure timely diagnosis of cancer. The workshop will consist of teaching and awareness sessions, the appointment of a Safety Netting Champion and the development of a bespoke Safety Netting Plan and has been adapted so it can be delivered remotely. This study aims to assess the feasibility of the ThinkCancer! intervention for a future definitive randomised controlled trial. Methods The ThinkCancer! study is a randomised, multisite feasibility trial, with an embedded process evaluation and feasibility economic analysis. Twenty-three to 30 general practices will be recruited across Wales, randomised in a ratio of 2:1 of intervention versus control who will follow usual care. The workshop will be delivered by a GP educator and will be adapted iteratively throughout the trial period. Baseline practice characteristics will be collected via questionnaire. We will also collect primary care intervals (PCI), 2-week wait (2WW) referral rates, conversion rates and detection rates at baseline and 6 months post-randomisation. Participant feedback, researcher reflections and economic costings will be collected following each workshop. A process evaluation will assess implementation using an adapted Normalisation Measure Development (NoMAD) questionnaire and qualitative interviews. An economic feasibility analysis will inform a future economic evaluation. Discussion This study will allow us to test and further develop a novel evidenced-based complex intervention aimed at general practice teams to expedite the diagnosis of cancer in primary care. The results from this study will inform the future design of a full-scale definitive phase III trial. Trial registration ClinicalTrials.gov NCT04823559. </jats:sec

Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema

Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks

The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis

SummaryWe identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3Sci), which accelerates circadian locomotor rhythms in mice. ZFHX3 regulates transcription via direct interaction with predicted AT motifs in target genes. The mutant protein has a decreased ability to activate consensus AT motifs in vitro. Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3Sci/+ SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed. Moreover, mutant ZFHX3 had a decreased ability to activate AT motifs in the promoters of these neuropeptide genes. Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3Sci/+ SCN slices. In conclusion, by cloning Zfhx3Sci, we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms

The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an at Motif-Driven Axis

We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3Sci), which accelerates circadian locomotor rhythms in mice. ZFHX3 regulates transcription via direct interaction with predicted AT motifs in target genes. The mutant protein has a decreased ability to activate consensus AT motifs in vitro. Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3Sci/+ SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed. Moreover, mutant ZFHX3 had a decreased ability to activate AT motifs in the promoters of these neuropeptide genes. Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3Sci/+ SCN slices. In conclusion, by cloning Zfhx3Sci, we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms