Humoral and cellular immune responses eleven months after the third dose of BNT162b2 an mRNA-based COVID-19 vaccine in people with HIV – a prospective observational cohort study

BACKGROUND: We investigated long-term durability of humoral and cellular immune responses to third dose of BNT162b2 in people with HIV (PWH) and controls. METHODS: In 378 PWH with undetectable viral replication and 224 matched controls vaccinated with three doses of BNT162b2, we measured IgG-antibodies against the receptor binding domain of SARS-CoV-2 spike protein three months before third dose of BNT162b2, and four and eleven months after. In 178 PWH and 135 controls, the cellular response was assessed by interferon-γ (IFN-γ) release in whole blood four months after third dose. Differences in antibody or IFN-γ concentrations were assessed by uni- and multivariable linear regressions. FINDINGS: Before the third dose the concentration of SARS-CoV-2 antibodies was lower in PWH than in controls (unadjusted geometric mean ratio (GMR): 0.68 (95% CI: 0.54-0.86, p = 0.002). We observed no differences in antibody concentrations between PWH and controls after four (0.90 (95% CI: 0.75-1.09), p = 0.285) or eleven months (0.89 (95% CI: 0.69-1.14), p = 0.346) after the third dose. We found no difference in IFN-γ concentrations four months after the third dose between PWH and controls (1.06 (95% CI: 0.71-1.60), p = 0.767). INTERPRETATION: We found no differences in antibody concentrations or cellular response between PWH and controls up to eleven months after third dose of BNT162b2. Our findings indicate that PWH with undetectable viral replication and controls have comparable immune responses to three doses of the BNT162b2 vaccine. FUNDING: This work was funded by the Novo Nordisk Foundation (NFF205A0063505, NNF20SA0064201), the Carlsberg Foundation (CF20-476 0045), the Svend Andersen Research Foundation (SARF2021), and Bio- and Genome Bank Denmark

Can postponement of an adverse outcome be used to present risk reductions to a lay audience? A population survey

BACKGROUND: For shared decision making doctors need to communicate the effectiveness of therapies such that patients can understand it and discriminate between small and large effects. Previous research indicates that patients have difficulties in understanding risk measures. This study aimed to test the hypothesis that lay people may be able to discriminate between therapies when their effectiveness is expressed in terms of postponement of an adverse disease event. METHODS: In 2004 a random sample of 1,367 non-institutionalized Danes aged 40+ was interviewed in person. The participants were asked for demographic information and asked to consider a hypothetical preventive drug treatment. The respondents were randomized to the magnitude of treatment effectiveness (heart attack postponement of 1 month, 6 months, 12 months, 2 years, 4 years and 8 years) and subsequently asked whether they would take such a therapy. They were also asked whether they had hypercholesterolemia or had experienced a heart attack. RESULTS: In total 58% of the respondents consented to the hypothetical treatment. The proportions accepting treatment were 39%, 52%, 56%, 64%, 67% and 73% when postponement was 1 month, 6 months, 12 months, 2 years, 4 years and 8 years respectively. Participants who thought that the effectiveness information was difficult to understand, were less likely to consent to therapy (p = 0.004). CONCLUSION: Lay people can discriminate between levels of treatment effectiveness when they are presented in terms of postponement of an adverse event. The results indicate that such postponement is a comprehensible measure of effectiveness

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenLoss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.US National Institutes of Health (NIH) Training 5-T32-GM007748-33 Doris Duke Charitable Foundation 2006087 Fulbright Diabetes UK Fellowship BDA 11/0004348 Broad Institute from Pfizer, Inc. NIH U01 DK085501 U01 DK085524 U01 DK085545 U01 DK085584 Swedish Research Council Dnr 521-2010-3490 Dnr 349-2006-237 European Research Council (ERC) GENETARGET T2D GA269045 ENGAGE 2007-201413 CEED3 2008-223211 Sigrid Juselius Foundation Folkh lsan Research Foundation ERC AdG 293574 Research Council of Norway 197064/V50 KG Jebsen Foundation University of Bergen Western Norway Health Authority Lundbeck Foundation Novo Nordisk Foundation Wellcome Trust WT098017 WT064890 WT090532 WT090367 WT098381 Uppsala University Swedish Research Council and the Swedish Heart- Lung Foundation Academy of Finland 124243 102318 123885 139635 Finnish Heart Foundation Finnish Diabetes Foundation, Tekes 1510/31/06 Commission of the European Community HEALTH-F2-2007-201681 Ministry of Education and Culture of Finland European Commission Framework Programme 6 Integrated Project LSHM-CT-2004-005272 City of Kuopio and Social Insurance Institution of Finland Finnish Foundation for Cardiovascular Disease NIH/NIDDK U01-DK085545 National Heart, Lung, and Blood Institute (NHLBI) National Institute on Minority Health and Health Disparities N01 HC-95170 N01 HC-95171 N01 HC-95172 European Union Seventh Framework Programme, DIAPREPP Swedish Child Diabetes Foundation (Barndiabetesfonden) 5U01DK085526 DK088389 U54HG003067 R01DK072193 R01DK062370 Z01HG000024info:eu-repo/grantAgreement/EC/FP7/20201

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Localisation of nursery areas based on comparative analyses of the horizontal and vertical distribution patterns of juvenile Baltic cod (Gadus morhua)

Knowledge of the spatial distribution of juvenile cod is essential for obtaining precise recruitment data to conduct sustainable management of the eastern and western Baltic cod stocks. In this study, the horizontal and vertical distribution and density patterns of settled juvenile 0- and 1-group Baltic cod are determined, and their nursery areas are localised according to the environmental factors affecting them. Comparative statistical analyses of biological, hydrographic and hydroacoustic data are carried out based on standard ICES demersal trawl surveys and special integrated trawl and acoustic research surveys. Horizontal distribution maps for the 2001-2010 cohorts of juvenile cod are further generated by applying a statistical log-Gaussian Cox process model to the standard trawl survey data. The analyses indicate size-dependent horizontal and distinct vertical and diurnal distribution patterns related to the seabed topography, water layer depth, and the presence of hydrographic frontal zones (pycnoclines) as well as intraspecific patterns in relation to the presence of adult cod. The extent of the nursery areas also depends on the cod year class strength. Juvenile cod (≥3 cm) are present in all areas of the central Baltic Sea (CBS), showing broad dispersal. However, their highest density in the Baltic Basins is found at localities with a 40-70 m bottom depth in waters with oxygen concentrations above 2 ml O₂.l⁻¹ and temperatures above 5°C. The smallest juveniles are also found in deep sea localities down to a 100 m depth and at oxygen concentrations between 2-4 ml O₂.l⁻¹. The vertical, diurnally stratified and repeated trawling and hydroacoustic target strength-depth distributions obtained from the special surveys show juvenile cod concentrations in frontal zone water layers (pycnocline). However, the analyses indicate that in the CBS, juvenile cod of all sizes do not appear to aggregate in dense schooling patterns, which differs from what has been reported from the North Sea