Showing papers by "Monash University published in 2020"

Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review.

Abstract: Importance The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19. Observations SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. Conclusions and Relevance As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

Mental Health, Substance Use, and Suicidal Ideation During the COVID-19 Pandemic - United States, June 24-30, 2020.

Abstract: The coronavirus disease 2019 (COVID-19) pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders.* Symptoms of anxiety disorder and depressive disorder increased considerably in the United States during April-June of 2020, compared with the same period in 2019 (1,2). To assess mental health, substance use, and suicidal ideation during the pandemic, representative panel surveys were conducted among adults aged ≥18 years across the United States during June 24-30, 2020. Overall, 40.9% of respondents reported at least one adverse mental or behavioral health condition, including symptoms of anxiety disorder or depressive disorder (30.9%), symptoms of a trauma- and stressor-related disorder (TSRD) related to the pandemic† (26.3%), and having started or increased substance use to cope with stress or emotions related to COVID-19 (13.3%). The percentage of respondents who reported having seriously considered suicide in the 30 days before completing the survey (10.7%) was significantly higher among respondents aged 18-24 years (25.5%), minority racial/ethnic groups (Hispanic respondents [18.6%], non-Hispanic black [black] respondents [15.1%]), self-reported unpaid caregivers for adults§ (30.7%), and essential workers¶ (21.7%). Community-level intervention and prevention efforts, including health communication strategies, designed to reach these groups could help address various mental health conditions associated with the COVID-19 pandemic.

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.

Abstract: Importance Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using theI2statistic. The primary analysis was an inverse variance–weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios. Exposures Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as “low” for 6 of the 7 mortality results and as “some concerns” in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82];P Conclusions and Relevance In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

A serological assay to detect SARS-CoV-2 seroconversion in humans.

Abstract: Here, we describe a serological enzyme-linked immunosorbent assay for the screening and identification of human SARS-CoV-2 seroconverters. This assay does not require the handling of infectious virus, can be adjusted to detect different antibody types in serum and plasma and is amenable to scaling. Serological assays are of critical importance to help define previous exposure to SARS-CoV-2 in populations, identify highly reactive human donors for convalescent plasma therapy and investigate correlates of protection.

Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline.

Abstract: In systematic reviews that lack data amenable to meta-analysis, alternative synthesis methods are commonly used, but these methods are rarely reported. This lack of transparency in the methods can cast doubt on the validity of the review findings. The Synthesis Without Meta-analysis (SWiM) guideline has been developed to guide clear reporting in reviews of interventions in which alternative synthesis methods to meta-analysis of effect estimates are used. This article describes the development of the SWiM guideline for the synthesis of quantitative data of intervention effects and presents the nine SWiM reporting items with accompanying explanations and examples.

Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium

Abstract: BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

GW190425: Observation of a Compact Binary Coalescence with Total Mass ∼ 3.4 M O

Abstract: On 2019 April 25, the LIGO Livingston detector observed a compact binary coalescence with signal-to-noise ratio 12.9. The Virgo detector was also taking data that did not contribute to detection due to a low signal-to-noise ratio, but were used for subsequent parameter estimation. The 90% credible intervals for the component masses range from to if we restrict the dimensionless component spin magnitudes to be smaller than 0.05). These mass parameters are consistent with the individual binary components being neutron stars. However, both the source-frame chirp mass and the total mass of this system are significantly larger than those of any other known binary neutron star (BNS) system. The possibility that one or both binary components of the system are black holes cannot be ruled out from gravitational-wave data. We discuss possible origins of the system based on its inconsistency with the known Galactic BNS population. Under the assumption that the signal was produced by a BNS coalescence, the local rate of neutron star mergers is updated to 250-2810.

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia

Abstract: Background Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising effica...

Delay or Avoidance of Medical Care Because of COVID-19-Related Concerns - United States, June 2020.

Abstract: Temporary disruptions in routine and nonemergency medical care access and delivery have been observed during periods of considerable community transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1). However, medical care delay or avoidance might increase morbidity and mortality risk associated with treatable and preventable health conditions and might contribute to reported excess deaths directly or indirectly related to COVID-19 (2). To assess delay or avoidance of urgent or emergency and routine medical care because of concerns about COVID-19, a web-based survey was administered by Qualtrics, LLC, during June 24-30, 2020, to a nationwide representative sample of U.S. adults aged ≥18 years. Overall, an estimated 40.9% of U.S. adults have avoided medical care during the pandemic because of concerns about COVID-19, including 12.0% who avoided urgent or emergency care and 31.5% who avoided routine care. The estimated prevalence of urgent or emergency care avoidance was significantly higher among the following groups: unpaid caregivers for adults* versus noncaregivers (adjusted prevalence ratio [aPR] = 2.9); persons with two or more selected underlying medical conditions† versus those without those conditions (aPR = 1.9); persons with health insurance versus those without health insurance (aPR = 1.8); non-Hispanic Black (Black) adults (aPR = 1.6) and Hispanic or Latino (Hispanic) adults (aPR = 1.5) versus non-Hispanic White (White) adults; young adults aged 18-24 years versus adults aged 25-44 years (aPR = 1.5); and persons with disabilities§ versus those without disabilities (aPR = 1.3). Given this widespread reporting of medical care avoidance because of COVID-19 concerns, especially among persons at increased risk for severe COVID-19, urgent efforts are warranted to ensure delivery of services that, if deferred, could result in patient harm. Even during the COVID-19 pandemic, persons experiencing a medical emergency should seek and be provided care without delay (3).

Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19.

Abstract: To the Editor — We report the kinetics of immune responses in relation to clinical and virological features of a patient with mild-to-moderate coronavirus disease 2019 (COVID-19) that required hospitalization. Increased antibody-secreting cells (ASCs), follicular helper T cells (TFH cells), activated CD4+ T cells and CD8+ T cells and immunoglobulin M (IgM) and IgG antibodies that bound the COVID-19causing coronavirus SARS-CoV-2 were detected in blood before symptomatic recovery. These immunological changes persisted for at least 7 d following full resolution of symptoms. A 47-year-old woman from Wuhan, Hubei province, China, presented to an emergency department in Melbourne, Australia. Her symptoms commenced 4 d earlier with lethargy, sore throat, dry cough, pleuritic chest pain, mild dyspnea and subjective fevers (Fig. 1a). She traveled from Wuhan to Australia 11 d before presentation. She had no contact with the Huanan seafood market or with known COVID-19 cases. She was otherwise healthy and was a non-smoker taking no medications. Clinical examination revealed a temperature of 38.5 °C, a pulse rate of 120 beats per minute, a blood pressure of 140/80 mm Hg, a respiratory rate of 22 breaths per minute, and oxygen saturation 98% while breathing ambient air. Lung auscultation revealed bi-basal rhonchi. At presentation on day 4, SARS-CoV-2 was detected in a nasopharyngeal swab specimen by real-time reverse-transcriptase PCR. SARS-CoV-2 was again detected at days 5–6 in nasopharyngeal, sputum and fecal samples, but was undetectable from day 7 (Fig. 1a). Blood C-reactive protein was elevated at 83.2, with normal counts of lymphocytes (4.3 × 109 cells per liter (range, 4.0 × 109 to 12.0 × 109 cells per liter)) and neutrophils (6.3 × 109 cells per liter (range, 2.0 × 109 to 8.0 × 109 × 109 cells per liter)). No other respiratory pathogens were detected. Her management was intravenous fluid rehydration without supplemental oxygenation. No antibiotics, steroids or antiviral agents were administered. Chest radiography demonstrated bi-basal infiltrates at day 5 that cleared on day 10 (Fig. 1b). She was discharged to home isolation on day 11. Her symptoms resolved completely by day 13, and she remained well at day 20, with progressive increases in plasma SARS-CoV-2-binding IgM and IgG antibodies from day 7 until day 20 (Fig. 1c and Extended Data Fig. 1). The patient was enrolled through the Sentinel Travelers Research Preparedness Platform for Emerging Infectious Diseases novel coronavirus substudy (SETREP-ID-coV) and provided written informed consent before the study. Patient care and research were conducted in compliance with the Case Report guidelines and the Declaration of Helsinki. Experiments were performed with ethics approvals HREC/17/MH/53, HREC/15/MonH/64/2016.196 and UoM#1442952.1/#1443389.4. We analyzed the kinetics and breadth of immune responses associated with clinical resolution of COVID-19. As ASCs are key for the rapid production of antibodies following infection with Ebola virus1,2 and infection with and vaccination against influenza virus2,3, and activated circulating TFH cells (cTFH cells) are concomitantly induced following vaccination against influenza virus3, we defined the frequency of CD3–CD19+CD27hiCD38hi ASC and CD4+CXCR5+ICOS+PD-1+ cTFH cell responses before symptomatic recovery. ASCs appeared in the blood at the time of viral clearance (day 7; 1.48%) and peaked on day 8 (6.91%). The emergence of cTFH cells occurred concurrently in blood at day 7 (1.98%), increasing on day 8 (3.25%) and day 9 (4.46%) (Fig. 1d). The peak of both ASCs and cTFH cells was markedly higher in the patient with COVID-19 than in healthy control participants (0.61% ± 0.40% and 1.83% ± 0.77%, respectively (average ± s.d.); n = 5). Both ASCs and cTFH cells were prominently present during convalescence (day 20) (4.54% and 7.14%, respectively; Fig. 1d). Thus, our study provides evidence on the recruitment of both ASCs and cTFH cells in this patient’s blood while she was still unwell and 3 d before the resolution of symptoms. Since co-expression of CD38 and HLA-DR is the key phenotype of the activation of CD8+ T cells in response to viral infections, we analyzed co-expression of CD38 and HLA-DR. As per reports for Ebola and influenza1,4, co-expression of CD38 and HLA-DR on CD8+ T cells (assessed as the frequency of CD38+HLA-DR+ CD8+ T cells) rapidly increased in this patient from day 7 (3.57%) to day 8 (5.32%) and day 9 (11.8%), then decreased at day 20 (7.05%) (Fig. 1e). Furthermore, the frequency of CD38+HLA-DR+ CD8+ T cells was much higher in this patient than in healthy individuals (1.47% ± 0.50%; n = 5). CD38+HLA-DR+ T cells were also recently documented in a patient with COVID-19 at one time point5. Similarly, co-expression of CD38 and HLA-DR on CD4+ T cells (assessed as the frequency of CD38+HLA-DR+ CD4+ T cells) increased between day 7 (0.55%) and day 9 (3.33%) in this patient, relative to that of healthy donors (0.63% ± 0.28%; n = 5), although at lower levels than that of CD8+ T cells. CD38+HLA-DR+ T cells, especially CD8+ T cells, produced larger amounts of granzymes A and B and perforin (~34–54% higher) than did their parent cells (CD8+ or CD4+ populations; Fig. 1e). Thus, the emergence and rapid increase in activated CD38+HLA-DR+ T cells, especially CD8+ T cells, at days 7–9 preceded the resolution of symptoms. Details on data reproducibility are in the Life Sciences Reporting Summary. Analysis of CD16+CD14+ monocytes, which are related to immunopathology, showed lower frequencies of CD16+CD14+ monocytes in the blood of this patient at days 7, 8 and 9 (1.29%, 0.43% and 1.47%, respectively) than in that of healthy control donors (9.03% ± 4.39%; n = 5) (Fig. 1f), possibly indicative of the efflux of CD16+CD14+ monocytes from the blood to the site of infection. No differences in activated HLA-DR+CD3–CD56+ natural killer cells were found. As pro-inflammatory cytokines and chemokines are predictive of severe clinical outcomes for influenza6, we quantified 17 pro-inflammatory cytokines and chemokines in plasma. We found low levels of the chemokine MCP-1 (CCL2) in the patient’s plasma (Extended Data Fig. 2a), although this was comparable to results obtained for healthy donors (22.15 ± 13.81; n = 5), patients infected with influenza A virus or influenza B, assessed at days 7–9

A minimal common outcome measure set for COVID-19 clinical research

Abstract: Summary Clinical research is necessary for an effective response to an emerging infectious disease outbreak. However, research efforts are often hastily organised and done using various research tools, with the result that pooling data across studies is challenging. In response to the needs of the rapidly evolving COVID-19 outbreak, the Clinical Characterisation and Management Working Group of the WHO Research and Development Blueprint programme, the International Forum for Acute Care Trialists, and the International Severe Acute Respiratory and Emerging Infections Consortium have developed a minimum set of common outcome measures for studies of COVID-19. This set includes three elements: a measure of viral burden (quantitative PCR or cycle threshold), a measure of patient survival (mortality at hospital discharge or at 60 days), and a measure of patient progression through the health-care system by use of the WHO Clinical Progression Scale, which reflects patient trajectory and resource use over the course of clinical illness. We urge investigators to include these key data elements in ongoing and future studies to expedite the pooling of data during this immediate threat, and to hone a tool for future needs.

The FLUXNET2015 dataset and the ONEFlux processing pipeline for eddy covariance data

Abstract: The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.

Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel

Abstract: Abstract

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Abstract: Importance Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (–1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support–free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration ClinicalTrials.gov Identifier:NCT02735707

Trial of Anifrolumab in Active Systemic Lupus Erythematosus

Abstract: Background Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant...

The future of social media in marketing.

Abstract: Social media allows people to freely interact with others and offers multiple ways for marketers to reach and engage with consumers. Considering the numerous ways social media affects individuals and businesses alike, in this article, the authors focus on where they believe the future of social media lies when considering marketing-related topics and issues. Drawing on academic research, discussions with industry leaders, and popular discourse, the authors identify nine themes, organized by predicted imminence (i.e., the immediate, near, and far futures), that they believe will meaningfully shape the future of social media through three lenses: consumer, industry, and public policy. Within each theme, the authors describe the digital landscape, present and discuss their predictions, and identify relevant future research directions for academics and practitioners.

APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline

Abstract: Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the e3/e4 or e4/e4 alleles) are distinguished from those without APOE4 (e3/e3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

Drug treatments for covid-19: living systematic review and network meta-analysis.

Abstract: Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. Results 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low. Conclusion Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. Systematic review registration This review was not registered. The protocol is publicly available in the supplementary material. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.

New-Onset Diabetes in Covid-19.

Abstract: Diabetes and Covid-19 Diabetes is associated with an increased risk of severe Covid-19. New-onset diabetes and metabolic complications of preexisting diabetes, including diabetic ketoacidosis and h...

Connecting the Dots: Multivariate Time Series Forecasting with Graph Neural Networks

Abstract: Modeling multivariate time series has long been a subject that has attracted researchers from a diverse range of fields including economics, finance, and traffic. A basic assumption behind multivariate time series forecasting is that its variables depend on one another but, upon looking closely, it is fair to say that existing methods fail to fully exploit latent spatial dependencies between pairs of variables. In recent years, meanwhile, graph neural networks (GNNs) have shown high capability in handling relational dependencies. GNNs require well-defined graph structures for information propagation which means they cannot be applied directly for multivariate time series where the dependencies are not known in advance. In this paper, we propose a general graph neural network framework designed specifically for multivariate time series data. Our approach automatically extracts the uni-directed relations among variables through a graph learning module, into which external knowledge like variable attributes can be easily integrated. A novel mix-hop propagation layer and a dilated inception layer are further proposed to capture the spatial and temporal dependencies within the time series. The graph learning, graph convolution, and temporal convolution modules are jointly learned in an end-to-end framework. Experimental results show that our proposed model outperforms the state-of-the-art baseline methods on 3 of 4 benchmark datasets and achieves on-par performance with other approaches on two traffic datasets which provide extra structural information.

Global low back pain prevalence and years lived with disability from 1990 to 2017: estimates from the Global Burden of Disease Study 2017.

Abstract: Background Low back pain (LBP) is a common musculoskeletal problem globally. Updating the prevalence and burden of LBP is important for researchers and policy makers. This paper presents, compares and contextualizes the global prevalence and years lived with disability (YLDs) of LBP by age, sex and region, from 1990 to 2017. Methods Data were extracted from the GBD (the Global Burden of Disease, Injuries, and Risk Factors Study) 2017 Study. Age, sex and region-specific analyses were conducted to estimate the global prevalence and YLDs of LBP, with the uncertainty intervals (UIs). Results The age-standardized point prevalence of LBP was 8.20% (95% UI: 7.31-9.10%) in 1990 and decreased slightly to 7.50% (95% UI: 6.75-8.27%) in 2017. The prevalent numbers of people with LBP at any one point in time in 1990 was 377.5 million, and this increased to 577.0 million in 2017. Age-standardized prevalence of LBP was higher in females than males. LBP prevalence increased with age, and peaked around the ages of 80 to 89 years, and then decreased slightly. Global YLDs were 42.5 million (95% UI: 30.2 million-57.2 million) in 1990 and increased by 52.7% to 64.9 million (95% UI: 46.5 million-87.4 million) in 2017. YLDs were also higher in females than males and increased initially with age; they peaked at 35-39 years of age in 1990, before decreasing, whereas in 2017, they peaked at 45-49 years of age, before decreasing. Western Europe had the highest number of LBP YLDs. Conclusions Globally, LBP is the leading global cause of YLDs. Greater attention is urgently needed to mitigate this increasing burden and the impact it is having on health and social systems.

GW190412: Observation of a binary-black-hole coalescence with asymmetric masses

Abstract: We report the observation of gravitational waves from a binary-black-hole coalescence during the first two weeks of LIGO’s and Virgo’s third observing run. The signal was recorded on April 12, 2019 at 05∶30∶44 UTC with a network signal-to-noise ratio of 19. The binary is different from observations during the first two observing runs most notably due to its asymmetric masses: a ∼30 M⊙ black hole merged with a ∼8 M⊙ black hole companion. The more massive black hole rotated with a dimensionless spin magnitude between 0.22 and 0.60 (90% probability). Asymmetric systems are predicted to emit gravitational waves with stronger contributions from higher multipoles, and indeed we find strong evidence for gravitational radiation beyond the leading quadrupolar order in the observed signal. A suite of tests performed on GW190412 indicates consistency with Einstein’s general theory of relativity. While the mass ratio of this system differs from all previous detections, we show that it is consistent with the population model of stellar binary black holes inferred from the first two observing runs.

Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies.

Abstract: Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.

A serological assay to detect SARS-CoV-2 seroconversion in humans

Abstract: SARS-Cov-2 (severe acute respiratory disease coronavirus 2), which causes Coronavirus Disease 2019 (COVID19) was first detected in China in late 2019 and has since then caused a global pandemic. While molecular assays to directly detect the viral genetic material are available for the diagnosis of acute infection, we currently lack serological assays suitable to specifically detect SARS-CoV-2 antibodies. Here we describe serological enzyme-linked immunosorbent assays (ELISA) that we developed using recombinant antigens derived from the spike protein of SARS-CoV-2. Using negative control samples representing pre-COVID 19 background immunity in the general adult population as well as samples from COVID19 patients, we demonstrate that these assays are sensitive and specific, allowing for screening and identification of COVID19 seroconverters using human plasma/serum as early as two days post COVID19 symptoms onset. Importantly, these assays do not require handling of infectious virus, can be adjusted to detect different antibody types and are amendable to scaling. Such serological assays are of critical importance to determine seroprevalence in a given population, define previous exposure and identify highly reactive human donors for the generation of convalescent serum as therapeutic. Sensitive and specific identification of coronavirus SARS-Cov-2 antibody titers may, in the future, also support screening of health care workers to identify those who are already immune and can be deployed to care for infected patients minimizing the risk of viral spread to colleagues and other patients.