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Showing papers by "Uppsala University published in 2021"


Journal ArticleDOI
TL;DR: The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only and no commercial use is authorized.
Abstract: Supplementary Table 9, column 'Edoxaban', row 'eGFR category', '95 mL/min' (page 15). The cell should be coloured green instead of yellow. It should also read "60 mg"instead of "60 mg (use with caution in 'supranormal' renal function)."In the above-indicated cell, a footnote has also been added to state: "Edoxaban should be used in patients with high creatinine clearance only after a careful evaluation of the individual thromboembolic and bleeding risk."Supplementary Table 9, column 'Edoxaban', row 'Dose reduction in selected patients' (page 16). The cell should read "Edoxaban 60 mg reduced to 30 mg once daily if any of the following: creatinine clearance 15-50 mL/min, body weight <60 kg, concomitant use of dronedarone, erythromycin, ciclosporine or ketokonazole"instead of "Edoxaban 60 mg reduced to 30 mg once daily, and edoxaban 30 mg reduced to 15mg once daily, if any of the following: creatinine clearance of 30-50 mL/min, body weight <60 kg, concomitant us of verapamil or quinidine or dronedarone."

4,285 citations


Journal ArticleDOI
05 Apr 2021-Nature
TL;DR: In this paper, the pseudo-halide anion formate (HCOO−) was used to suppress anion-vacancy defects that are present at grain boundaries and at the surface of the perovskite films.
Abstract: Metal halide perovskites of the general formula ABX3—where A is a monovalent cation such as caesium, methylammonium or formamidinium; B is divalent lead, tin or germanium; and X is a halide anion—have shown great potential as light harvesters for thin-film photovoltaics1–5. Among a large number of compositions investigated, the cubic α-phase of formamidinium lead triiodide (FAPbI3) has emerged as the most promising semiconductor for highly efficient and stable perovskite solar cells6–9, and maximizing the performance of this material in such devices is of vital importance for the perovskite research community. Here we introduce an anion engineering concept that uses the pseudo-halide anion formate (HCOO−) to suppress anion-vacancy defects that are present at grain boundaries and at the surface of the perovskite films and to augment the crystallinity of the films. The resulting solar cell devices attain a power conversion efficiency of 25.6 per cent (certified 25.2 per cent), have long-term operational stability (450 hours) and show intense electroluminescence with external quantum efficiencies of more than 10 per cent. Our findings provide a direct route to eliminate the most abundant and deleterious lattice defects present in metal halide perovskites, providing a facile access to solution-processable films with improved optoelectronic performance. Incorporation of the pseudo-halide anion formate during the fabrication of α-FAPbI3 perovskite films eliminates deleterious iodide vacancies, yielding solar cell devices with a certified power conversion efficiency of 25.21 per cent and long-term operational stability.

1,616 citations


Journal ArticleDOI
TL;DR: In this paper, the authors analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app.
Abstract: Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called 'long COVID', are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app1. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76-4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.

1,222 citations


Journal ArticleDOI
Renu R. Bahadoer1, Esmée A Dijkstra2, Boudewijn van Etten2, Corrie A.M. Marijnen1, Corrie A.M. Marijnen3, Hein Putter1, Elma Meershoek-Klein Kranenbarg1, Annet G H Roodvoets1, Iris D. Nagtegaal4, Regina G. H. Beets-Tan3, Lennart Blomqvist5, Tone Fokstuen5, Albert J. ten Tije, Jaume Capdevila6, Mathijs P. Hendriks, Ibrahim Edhemovic7, Andrés Cervantes8, Per Nilsson5, Bengt Glimelius9, Cornelis J.H. van de Velde1, Geke A. P. Hospers2, L. Østergaard, F. Svendsen Jensen, P. Pfeiffer, K.E.J. Jensen, M.P. Hendriks, W.H. Schreurs, H.P. Knol, J.J. van der Vliet, J.B. Tuynman, A.M.E. Bruynzeel, E.D. Kerver, S. Festen, M E van Leerdam, G.L. Beets, L.G.H. Dewit, C.J.A. Punt, Pieter J. Tanis, E.D. Geijsen, P. Nieboer, W.A. Bleeker, A.J. Ten Tije, R.M.P.H. Crolla, A.C.M. van de Luijtgaarden, J.W.T. Dekker, J.M. Immink, F.J.F. Jeurissen, A.W.K.S. Marinelli, H.M. Ceha, T.C. Stam, P. Quarles an Ufford, W.H. Steup, A.L.T. Imholz, R.J.I. Bosker, J.H.M. Bekker, G.J. Creemers, G.A.P. Nieuwenhuijzen, H. van den Berg, W.M. van der Deure, R.F. Schmitz, J.M. van Rooijen, A.F.T. Olieman, A.C.M. van den Bergh, Derk Jan A. de Groot, Klaas Havenga, Jannet C. Beukema, J. de Boer, P.H.J.M. Veldman, E.J.M. Siemerink, J.W.P. Vanstiphout, B. de Valk, Q.A.J. Eijsbouts, M.B. Polée, C. Hoff, A. Slot, H.W. Kapiteijn, K.C.M.J. Peeters, F.P. Peters, P.A. Nijenhuis, S.A. Radema, H. de Wilt, P. Braam, G.J. Veldhuis, D. Hess, T. Rozema, O. Reerink, D. Ten Bokkel Huinink, A. Pronk, Janet R. Vos, M. Tascilar, G.A. Patijn, C. Kersten, O. Mjåland, M. Grønlie Guren, A.N. Nesbakken, J. Benedik, I. Edhemovic7, V. Velenik, J. Capdevila6, E. Espin, R. Salazar, S. Biondo, V. Pachón, J. die Trill, J. Aparicio, E. Garcia Granero, M.J. Safont, J.C. Bernal, A. Cervantes8, A. Espí Macías, L. Malmberg, G. Svaninger, H. Hörberg, G. Dafnis, A. Berglund, L. Österlund, K. Kovacs, J. Hol, S. Ottosson, G. Carlsson, C. Bratthäll, J. Assarsson, B.L. Lödén, P. Hede, I. Verbiené, O. Hallböök, A. Johnsson, M.L. Lydrup, K. Villmann, P. Matthiessen, J.H. Svensson, J. Haux, S. Skullman, T. Fokstuen5, Torbjörn Holm, P. Flygare, M. Walldén, B. Lindh, O. Lundberg, C. Radu, L. Påhlman, A. Piwowar, K. Smedh, U. Palenius, S. Jangmalm, P. Parinkh, H. Kim, M.L. Silviera 
TL;DR: The Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control.
Abstract: Summary Background Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. Methods In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1–14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15–21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3–14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov , NCT01558921 , and is now complete. Findings Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5–5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8–27·6) in the experimental group versus 30·4% (26·1–34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60–0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). Interpretation The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. Funding Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

586 citations


Journal ArticleDOI
TL;DR: In this article, the authors combined single-cell transcriptomics analysis with spatial antibody-based protein profiling to create a high-resolution singlecell type map of human tissues, which was used to explore the expression of human protein-coding genes in 192 individual cell type clusters.
Abstract: Advances in molecular profiling have opened up the possibility to map the expression of genes in cells, tissues, and organs in the human body. Here, we combined single-cell transcriptomics analysis with spatial antibody-based protein profiling to create a high-resolution single–cell type map of human tissues. An open access atlas has been launched to allow researchers to explore the expression of human protein-coding genes in 192 individual cell type clusters. An expression specificity classification was performed to determine the number of genes elevated in each cell type, allowing comparisons with bulk transcriptomics data. The analysis highlights distinct expression clusters corresponding to cell types sharing similar functions, both within the same organs and between organs.

384 citations



Journal ArticleDOI
13 Apr 2021-JAMA
TL;DR: In this article, the effect of continued vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.
Abstract: Importance The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. Objective To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. Design, setting, and participants Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. Interventions A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. Main outcomes and measures The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). Results Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P Conclusions and relevance Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. Trial registration ClinicalTrials.gov Identifier: NCT03548987.

264 citations


Journal ArticleDOI
TL;DR: Prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints, and a phase 3 study (Clarity AD) in early Alzheimer’s disease is underway.
Abstract: Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia. BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer’s disease is underway. Clinical Trials.gov NCT01767311 .

259 citations


Journal ArticleDOI
19 Aug 2021
TL;DR: In this paper, the authors present a strategic blueprint to substantially improve our ability to discover and develop new antibiotics, and propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding.
Abstract: An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

255 citations


Journal ArticleDOI
TL;DR: In this paper, the authors systematically review and update the vast state-of-the-art literature of amyloid-β (Aβ) science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics.
Abstract: Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.

251 citations


Journal ArticleDOI
18 May 2021-JAMA
TL;DR: This cohort study describes COVID-19–related symptoms persisting 8 months after SARS-CoV-2 infection among Swedish health care workers and self-reported effects of the residual symptoms on respondents' home, work, and social function.
Abstract: This cohort study describes COVID-19–related symptoms persisting 8 months after SARS-CoV-2 infection among Swedish health care workers and self-reported effects of the residual symptoms on respondents’ home, work, and social function.

Journal ArticleDOI
TL;DR: The European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis as discussed by the authors have been published for the management of venous thrombotic vessels.

Journal ArticleDOI
TL;DR: In this paper, the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1093/mnras/stab1242
Abstract: © 2021 The Author(s) Published by Oxford University Press on behalf of the Royal Astronomical Society. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1093/mnras/stab1242

Journal ArticleDOI
TL;DR: In this paper, the authors analyzed the landscape of approved and investigational therapies that target kinases and trends within it, including the most popular targets of kinase inhibitors and their expanding range of indications.
Abstract: The FDA approval of imatinib in 2001 was a breakthrough in molecularly targeted cancer therapy and heralded the emergence of kinase inhibitors as a key drug class in the oncology area and beyond. Twenty years on, this article analyses the landscape of approved and investigational therapies that target kinases and trends within it, including the most popular targets of kinase inhibitors and their expanding range of indications. There are currently 71 small-molecule kinase inhibitors (SMKIs) approved by the FDA and an additional 16 SMKIs approved by other regulatory agencies. Although oncology is still the predominant area for their application, there have been important approvals for indications such as rheumatoid arthritis, and one-third of the SMKIs in clinical development address disorders beyond oncology. Information on clinical trials of SMKIs reveals that approximately 110 novel kinases are currently being explored as targets, which together with the approximately 45 targets of approved kinase inhibitors represent only about 30% of the human kinome, indicating that there are still substantial unexplored opportunities for this drug class. We also discuss trends in kinase inhibitor design, including the development of allosteric and covalent inhibitors, bifunctional inhibitors and chemical degraders. The FDA approval of imatinib in 2001 heralded the emergence of kinase inhibitors as a key drug class in the oncology area and beyond. This article analyses the landscape of approved and investigational therapies that target kinases and trends within it, including the most popular targets of kinase inhibitors, their expanding range of indications and strategies for kinase inhibitor design.

Journal ArticleDOI
TL;DR: Recent in vivo findings and other advances in understanding endothelial barrier function are described with the goal of identifying and reconciling controversies over cellular and molecular processes that regulate the vascular barrier in health and disease.

Journal ArticleDOI
David V. Conti1, Burcu F. Darst1, Lilit C. Moss1, Edward J. Saunders2  +251 moreInstitutions (100)
TL;DR: This paper conducted a meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants.
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Journal ArticleDOI
23 Mar 2021-JAMA
TL;DR: In this article, the authors evaluated clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs).
Abstract: Importance: Convalescent plasma is a proposed treatment for COVID-19. Objective: To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs). Data Sources: PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021. Study Selection: The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting. Data Extraction and Synthesis: Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation. Main Outcomes and Measures: All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events. Results: A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences. Conclusions and Relevance: Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

Journal ArticleDOI
Ji Chen1, Ji Chen2, Cassandra N. Spracklen3, Cassandra N. Spracklen4  +475 moreInstitutions (146)
TL;DR: This paper aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available.
Abstract: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

Journal ArticleDOI
TL;DR: Proton-coupled electron transfer (PCET) reactions are fundamental to energy transformation reactions in natural and artificial systems and are increasingly recognized in areas such as catalysis and as discussed by the authors.
Abstract: Proton-coupled electron transfer (PCET) reactions are fundamental to energy transformation reactions in natural and artificial systems and are increasingly recognized in areas such as catalysis and...

Journal ArticleDOI
M. G. Aartsen1, Rasha Abbasi2, Markus Ackermann, Jenni Adams1  +440 moreInstitutions (60)
TL;DR: In this article, the authors present an overview of a next-generation instrument, IceCube-Gen2, which will sharpen our understanding of the processes and environments that govern the Universe at the highest energies.
Abstract: The observation of electromagnetic radiation from radio to γ-ray wavelengths has provided a wealth of information about the Universe. However, at PeV (1015 eV) energies and above, most of the Universe is impenetrable to photons. New messengers, namely cosmic neutrinos, are needed to explore the most extreme environments of the Universe where black holes, neutron stars, and stellar explosions transform gravitational energy into non-thermal cosmic rays. These energetic particles havemillions of times higher energies than those produced in the most powerful particle accelerators on Earth. As neutrinos can escape from regions otherwise opaque to radiation, they allow an unique view deep into exploding stars and the vicinity of the event horizons of black holes. The discovery of cosmic neutrinos with IceCube has opened this new window on the Universe. IceCube has been successful in finding first evidence for cosmic particle acceleration in the jet of an active galactic nucleus. Yet, ultimately, its sensitivity is too limited to detect even the brightest neutrino sources with high significance, or to detect populations of less luminous sources. In thiswhite paper, we present an overview of a next-generation instrument, IceCube-Gen2, which will sharpen our understanding of the processes and environments that govern the Universe at the highest energies. IceCube-Gen2 is designed to: (a) Resolve the high-energy neutrino sky from TeV to EeV energies (b) Investigate cosmic particle acceleration through multi-messenger observations (c) Reveal the sources and propagation of the highest energy particles in the Universe (d) Probe fundamental physics with high-energy neutrinos IceCube-Gen2 will enhance the existing IceCube detector at the South Pole. It will increase the annual rate of observed cosmic neutrinos by a factor of ten compared to IceCube, and will be able to detect sources five times fainter than its predecessor. Furthermore, through the addition of a radio array, IceCube- Gen2 will extend the energy range by several orders of magnitude compared to IceCube. Construction will take 8 years and cost about $350M. The goal is to have IceCube-Gen2 fully operational by 2033. IceCube-Gen2 will play an essential role in shaping the new era of multimessenger astronomy, fundamentally advancing our knowledge of the highenergy Universe. This challenging mission can be fully addressed only through the combination of the information from the neutrino, electromagnetic, and gravitational wave emission of high-energy sources, in concert with the new survey instruments across the electromagnetic spectrum and gravitational wave detectors which will be available in the coming years.

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TL;DR: The International Classification of Retinopathy of Prematurity, Third Edition (ICROP3) as discussed by the authors is a consensus statement that creates a standard nomenclature for classification of ROP.

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03 Jun 2021-Nature
TL;DR: In this paper, the authors analyzed a combined total of 45,148 dissolved oxygen and temperature profiles and calculate trends for 393 temperate lakes that span 1941 to 2017, finding that a decline in dissolved oxygen is widespread in surface and deep water habitats.
Abstract: The concentration of dissolved oxygen in aquatic systems helps to regulate biodiversity1,2, nutrient biogeochemistry3, greenhouse gas emissions4, and the quality of drinking water5. The long-term declines in dissolved oxygen concentrations in coastal and ocean waters have been linked to climate warming and human activity6,7, but little is known about the changes in dissolved oxygen concentrations in lakes. Although the solubility of dissolved oxygen decreases with increasing water temperatures, long-term lake trajectories are difficult to predict. Oxygen losses in warming lakes may be amplified by enhanced decomposition and stronger thermal stratification8,9 or oxygen may increase as a result of enhanced primary production10. Here we analyse a combined total of 45,148 dissolved oxygen and temperature profiles and calculate trends for 393 temperate lakes that span 1941 to 2017. We find that a decline in dissolved oxygen is widespread in surface and deep-water habitats. The decline in surface waters is primarily associated with reduced solubility under warmer water temperatures, although dissolved oxygen in surface waters increased in a subset of highly productive warming lakes, probably owing to increasing production of phytoplankton. By contrast, the decline in deep waters is associated with stronger thermal stratification and loss of water clarity, but not with changes in gas solubility. Our results suggest that climate change and declining water clarity have altered the physical and chemical environment of lakes. Declines in dissolved oxygen in freshwater are 2.75 to 9.3 times greater than observed in the world’s oceans6,7 and could threaten essential lake ecosystem services2,3,5,11. Analysis of temperate lakes finds a widespread decline in dissolved oxygen concentrations in surface and deep waters, which is associated with reduced solubility at warmer surface water temperatures and increased stratification at depth.


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Cathrine Axfors1, Cathrine Axfors2, Andreas M. Schmitt3, Andreas M. Schmitt4, Perrine Janiaud4, Janneke van’t Hooft1, Janneke van’t Hooft5, Sherief Abd-Elsalam6, Ehab F. Abdo7, Benjamin S. Abella8, Javed Akram9, Ravi K. Amaravadi8, Derek C. Angus10, Yaseen M. Arabi11, Shehnoor Azhar9, Lindsey R. Baden12, Arthur W. Baker13, Leila Belkhir14, Thomas Benfield15, Marvin A.H. Berrevoets, Cheng-Pin Chen16, Tsung-Chia Chen16, Shu-Hsing Cheng16, Chien-Yu Cheng16, Wei-Sheng Chung16, Yehuda Z. Cohen, Lisa N. Cowan, Olav Dalgard17, Olav Dalgard18, Fernando Val, Marcus V. G. Lacerda19, Gisely Cardoso de Melo, Lennie P. G. Derde20, Vincent Dubée, Anissa Elfakir, Anthony C. Gordon21, Carmen M. Hernández-Cárdenas, Thomas Hills22, Thomas Hills23, Andy I. M. Hoepelman20, Yi-Wen Huang16, Bruno Igau, Ronghua Jin24, Felipe Jurado-Camacho, Khalid S. Khan25, Peter G. Kremsner26, Benno Kreuels27, Benno Kreuels28, Cheng-Yu Kuo16, Thuy Le13, Yi-Chun Lin16, Wu-Pu Lin16, Tse-Hung Lin16, Magnus Nakrem Lyngbakken18, Magnus Nakrem Lyngbakken17, Colin McArthur29, Colin McArthur22, Colin McArthur23, Bryan J. McVerry10, Patricia Meza-Meneses, Wuelton Marcelo Monteiro, Susan C. Morpeth30, Ahmad Mourad13, Mark J. Mulligan, Srinivas Murthy31, Susanna Naggie13, Shanti Narayanasamy13, Alistair Nichol, Lewis A. Novack12, Sean M. O'Brien13, Nwora Lance Okeke13, Léna Perez, Rogelio Perez-Padilla, Laurent Perrin, Arantxa Remigio-Luna, Norma E. Rivera-Martinez, Frank W. Rockhold13, Sebastian Rodriguez-Llamazares, Robert Rolfe13, Rossana Rosa32, Helge Røsjø18, Helge Røsjø17, Vanderson de Souza Sampaio, Todd B. Seto33, Todd B. Seto34, Muhammad Shahzad9, Shaimaa Soliman35, Jason E. Stout13, Ireri Thirion-Romero, Andrea B. Troxel, Ting-Yu Tseng16, Nicholas A Turner13, Robert J. Ulrich, Stephen R. Walsh12, Steve Webb36, Steve Webb29, Jesper M. Weehuizen20, Maria Velinova, Hon-Lai Wong16, Rebekah Wrenn13, Fernando G. Zampieri, Wu Zhong, David Moher37, Steven N. Goodman1, John P. A. Ioannidis, Lars G. Hemkens4, Lars G. Hemkens1 
TL;DR: In this article, a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients was presented.
Abstract: Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities. Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.

Journal ArticleDOI
01 Apr 2021
TL;DR: A review of the state-of-the-art in Miocene climate, ocean circulation, biogeochemical cycling, ice sheet dynamics, and biotic adaptation research can be found in this article.
Abstract: The Miocene epoch (23.03–5.33 Ma) was a time interval of global warmth, relative to today. Continental configurations and mountain topography transitioned towards modern conditions, and many flora and fauna evolved into the same taxa that exist today. Miocene climate was dynamic: long periods of early and late glaciation bracketed a ∼2 Myr greenhouse interval – the Miocene Climatic Optimum (MCO). Floras, faunas, ice sheets, precipitation, pCO2, and ocean and atmospheric circulation mostly (but not ubiquitously) covaried with these large changes in climate. With higher temperatures and moderately higher pCO2 (∼400–600 ppm), the MCO has been suggested as a particularly appropriate analogue for future climate scenarios, and for assessing the predictive accuracy of numerical climate models – the same models that are used to simulate future climate. Yet, Miocene conditions have proved difficult to reconcile with models. This implies either missing positive feedbacks in the models, a lack of knowledge of past climate forcings, or the need for re‐interpretation of proxies, which might mitigate the model‐data discrepancy. Our understanding of Miocene climatic, biogeochemical, and oceanic changes on broad spatial and temporal scales is still developing. New records documenting the physical, chemical, and biotic aspects of the Earth system are emerging, and together provide a more comprehensive understanding of this important time interval. Here we review the state‐of‐the‐art in Miocene climate, ocean circulation, biogeochemical cycling, ice sheet dynamics, and biotic adaptation research as inferred through proxy observations and modelling studies.

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TL;DR: An insufficient reporting of model performance and parameterization, heavy reliance on model selection with AICc and low utilization of spatial cross‐validation are found; it is explained how ENMeval 2.0 can help address these issues.

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TL;DR: In this paper, a cross-sectional survey with a global sample of gay men and other men who have sex with men (MSM) from April 16, 2020 to May 4, 2020, through a social networking app was conducted.
Abstract: There is an urgent need to measure the impacts of COVID-19 among gay men and other men who have sex with men (MSM). We conducted a cross-sectional survey with a global sample of gay men and other MSM (n = 2732) from April 16, 2020 to May 4, 2020, through a social networking app. We characterized the economic, mental health, HIV prevention and HIV treatment impacts of COVID-19 and the COVID-19 response, and examined whether sub-groups of our study population are disproportionately impacted by COVID-19. Many gay men and other MSM not only reported economic and mental health consequences, but also interruptions to HIV prevention and testing, and HIV care and treatment services. These consequences were significantly greater among people living with HIV, racial/ethnic minorities, immigrants, sex workers, and socio-economically disadvantaged groups. These findings highlight the urgent need to mitigate the negative impacts of COVID-19 among gay men and other MSM.

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TL;DR: In this article, a two-sample Mendelian randomization (MR) study was conducted to identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding.
Abstract: To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10−8), hospitalization (OR = 0.61, P = 8 × 10−8) and susceptibility (OR = 0.78, P = 8 × 10−6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.

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TL;DR: This paper reviews the recent progress in DSSC research towards this goal through the development of new device structures, alternative redox shuttles, solid-state hole conductors, TiO2 photoelectrodes, catalyst materials, and sealing techniques, and proposes a scalable cell fabrication process.
Abstract: Dye-sensitized solar cells (DSSCs) are an efficient photovoltaic technology for powering electronic applications such as wireless sensors with indoor light. Their low cost and abundant materials, as well as their capability to be manufactured as thin and light-weight flexible solar modules highlight their potential for economic indoor photovoltaics. However, their fabrication methods must be scaled to industrial manufacturing with high photovoltaic efficiency and performance stability under typical indoor conditions. This paper reviews the recent progress in DSSC research towards this goal through the development of new device structures, alternative redox shuttles, solid-state hole conductors, TiO2 photoelectrodes, catalyst materials, and sealing techniques. We discuss how each functional component of a DSSC has been improved with these new materials and fabrication techniques. In addition, we propose a scalable cell fabrication process that integrates these developments to a new monolithic cell design based on several features including inkjet and screen printing of the dye, a solid state hole conductor, PEDOT contact, compact TiO2, mesoporous TiO2, carbon nanotubes counter electrode, epoxy encapsulation layers and silver conductors. Finally, we discuss the need to design new stability testing protocols to assess the probable deployment of DSSCs in portable electronics and internet-of-things devices.