Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

8th European Conference on Rare Diseases & Orphan Products (ECRD 2016)

MEETING ABSTRACTS: Open Access 8th European Conference on Rare Diseases & Orphan Products (ECRD 2016), Edinburgh, UK. 26-28 May 201

Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During Childhood and Adolescence With Complications During Teenage Years and Young Adulthood

The burden and determinants of complications and comorbidities in contemporary youth-onset diabetes are unknown

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A Histopathological-Biochemical Health Assessment of Blue Mussel Mytilus edulis

Aquaculture of the blue mussel Mytilus edulis in the Gulf of Maine is a growing industry at a time when wild mussel populations are threatened by a rapidly changing ocean. Intertidal mussel beds have largely disappeared in the region raising concerns over the long-term viability of mussel farming. Histology and lipid fatty acid analysis were used to assess gametogenesis, energy investment, and pathology of farmed mussels collected twice monthly for three years in Casco Bay, ME. Energy investment in reproduction and storage differed significantly between years, suggesting interannual variability. Wet weight of fatty acids such as DHA and EPA corresponded to pre-spawning periods, when gonad tissue was most abundant. Overall, pathology assessment showed low levels of common pathogens, parasites, and cellular abnormalities. The survey did, however, reveal high levels of oocyte atresia, a probable indicator of physiological or environmental stress from unfavorable spawning conditions. In addition, the presence of the potentially damaging digenetic trematode Proctoeces maculatus was documented using histology, marking the northernmost detection in the Northwest Atlantic and a likely climate-driven range expansion. These trends may signal a challenging future for blue mussels in the Gulf of Maine. Forward-looking farm mitigation practices informed by these results should be developed to ensure future sustainability of this industry

Recommendations on the Use of Mobile Applications for the Collection and Communication of Pharmaceutical Product Safety Information: Lessons from IMI WEB-RADR

Over a period of 3 years, the European Union's Innovative Medicines Initiative WEB-RADR (Recognising Adverse Drug Reactions; https://web-radr.eu/) project explored the value of two digital tools for pharmacovigilance (PV): mobile applications (apps) for reporting the adverse effects of drugs and social media data for its contribution to safety signalling. The ultimate intent of WEB-RADR was to provide policy, technical and ethical recommendations on how to develop and implement such digital tools to enhance patient safety. Recommendations relating to the use of mobile apps for PV are summarised in this paper. There is a presumption amongst at least some patients and healthcare professionals that information ought to be accessed and reported from any setting, including mobile apps. WEB-RADR has focused on the use of such technology for reporting suspected adverse drug reactions and for broadcasting safety information to its users, i.e. two-way risk communication. Three apps were developed and publicly launched within Europe as part of the WEB-RADR project and subsequently assessed by a range of stakeholders to determine their value as effective tools for improving patient safety; a fourth generic app was later piloted in two African countries. The recommendations from the development and evaluation of the European apps are presented here with supporting considerations, rationales and caveats as well as suggested areas for further research

Recommendations for the Use of Social Media in Pharmacovigilance: Lessons from IMI WEB-RADR

A central problem in e-commerce is determining overlapping communities among individuals or objects in the absence of external identification or tagging. We address this problem by introducing a framework that captures the notion of communities or clusters determined by the relative affinities among their members. To this end we define what we call an affinity system, which is a set of elements, each with a vector characterizing its preference for all other elements in the set. We define a natural notion of (potentially overlapping) communities in an affinity system, in which the members of a given community collectively prefer each other to anyone else outside the community. Thus these communities are endogenously formed in the affinity system and are "self-determined" or "self-certified" by its members. We provide a tight polynomial bound on the number of self-determined communities as a function of the robustness of the community. We present a polynomial-time algorithm for enumerating these communities. Moreover, we obtain a local algorithm with a strong stochastic performance guarantee that can find a community in time nearly linear in the of size the community. Social networks fit particularly naturally within the affinity system framework -- if we can appropriately extract the affinities from the relatively sparse yet rich information from social networks, our analysis then yields a set of efficient algorithms for enumerating self-determined communities in social networks. In the context of social networks we also connect our analysis with results about $(\alpha,\beta)$-clusters introduced by Mishra, Schreiber, Stanton, and Tarjan \cite{msst}. In contrast with the polynomial bound we prove on the number of communities in the affinity system model, we show that there exists a family of networks with superpolynomial number of $(\alpha,\beta)$-clusters.Comment: 22 page