Perceived Anxiety in Family Caregivers of Individuals with Autism Spectrum Disorder, Down Syndrome and Williams Syndrome during the Lockdown of the First COVID-19 Wave in Spain.

The lockdown during the first wave of COV- ID-19 in Spain has been related to higher levels of anxiety in the general population. However, the emotional impact on Spanish caregivers of individuals with neurodevelopmental disorders (NDD) has not been studied so far.

Anxiety, concerns and emotion regulation in individuals with Williams syndrome and Down syndrome during the COVID-19 outbreak: a global study.

Individuals with neurodevelopmental conditions (NDCs) have been reported to experience increased levels of anxiety during the COVID-19 pandemic. In our study, we document how individuals with Down Syndrome (DS; N = 557; Mage = 16.52; 233 female) and Williams syndrome (WS, N = 247; Mage = 18.43; 113 female) experienced the first wave (April 2020-May 2020) of the COVID-19 pandemic across the world. Using multilevel linear mixed regressions, we studied (a) parental reported anxiety of individuals with DS and WS, (b) these individuals' specific concerns, and (c) their use and efficacy of emotion regulation (ER) strategies during the first wave of COVID-19. Predictors of anxiety, such as the age of the individual with NDC, type of condition, and time, were investigated. Individuals with WS experienced higher levels of anxiety compared to those with DS and the older the individuals with NDC were the more anxiety they experienced. In terms of concerns, group effects indicated that individuals with WS scored higher for most of the concerns. There were no gender differences in concerns, yet most of the concerns increased with age except for concerns about loss of routine, boredom, loss of institutional support and family conflict. Finally, significant group effects were found and indicated a more frequent use of a variety of adaptive and maladaptive ER strategies in individuals with WS. We did not identify group differences in the efficacy of ER strategies. Our results indicate that individuals with WS are likely to exhibit higher levels of anxiety, but also higher levels of concerns depending on their age. Similarly, individuals with WS use a variety of ER strategies more frequently but these strategies are not necessarily more efficient for them. We discuss the impact of these findings in relation to anxiety identification and support across individuals with NDCs.

Retention and Critical Outcomes Among New Methadone Maintenance Patients Following Extended Take-Home Reforms (preprint)

Background: Approximately 1,800 opioid treatment programs (OTPs) in the US dispense methadone to upwards of 400,000 patients with opioid use disorder (OUD) annually, operating under longstanding highly restrictive guidelines. OTPs were granted novel flexibilities beginning March 15, 2020 allowing for reduced visit frequency and extended take-home doses to minimize COVID exposure with great variation across states and sites. We sought to use electronic health records to compare retention in treatment, opioid use, and adverse events among patients newly entering methadone maintenance in the post-reform period in comparison with year-ago, unexposed, controls.Methods: Retrospective observational cohort study across 9 OTPs, geographically dispersed nationally, in the National Institute of Drug Abuse Clinical Trials Network. Newly enrolled OTP methadone maintenance patients for a new care episode between April 15-October 14, 2020 (post-COVID, reform period) v. March 15-September 14, 2019 (pre-COVID, unexposed controls) were assessed. The primary outcome was 6-month retention. Secondary outcomes were opioid use and critical outcomes including emergency department (ED) visits, hospitalizations, and overdose.Findings: 821 individuals were newly admitted in the post-COVID and year-ago control periods, average age 38·3 (SD 11·1), 58·9% male. The only difference across pre- and post-reform groups was the prevalence of psychostimulant use disorder (25·7%v·32·9%,p=0·02)· Six-month retention rates were equivalent between groups (60·0% vs 60·1%) and hazards of discontinuation (HR=1·02,95%CI=0·81-1·27) and adverse events in the aggregate (X2 (1)=0·55,p=0·46) were non-inferior in the post-COVID period. However rates of opioid use throughout care was higher among post-COVID intakes compared to pre-COVID controls (64·8% v 51·1%,p<0·001). Moderator analyses accounting for stimulant use and site-level variation in take-home schedules did not change findings·Interpretation: Meaningful increases in take-home schedules were not associated with worse retention or adverse events despite slightly elevated rates of measured opioid use. Relaxed guidelines were not associated with increased harms and findings could inform permanent system redesign.Funding: SDHHS NIDA CTN UG1 DA013035-15.Declaration of Interest: Dr. Williams receives equity, consulting fees, and travel expenses from Ophelia Health Inc. a telehealth company for the treatment of opioid use disorder. Other authors have no financial conflicts to disclose.Ethical Approval: In accordance with applicable federal regulations (45 CFR 46·116(d)), the study was approved for a waiver of informed consent by the New York University Institutional Review Board.

Anxiety and Emotion Regulation in Young People with Williams Syndrome and Down Syndrome During the COVID-19 Outbreak: A Global Study (preprint)

Young people with neurodevelopmental conditions (NDCs) have been reported to experience increased levels of anxiety during the COVID-19 pandemic. In our study, we document how young people with Down Syndrome (DS; N=557) and Williams syndrome (WS, N=247) experienced the first wave of the COVID-19 pandemic across the world. Using multilevel linear mixed regressions, we studied (a) parental reported anxiety of young people with DS and WS, (b) these young people’s specific concerns, and (c) their use and efficacy of emotion regulation (ER) strategies. Predictors of anxiety, such as the age of the individual with NDC, type of condition, and time, were investigated. Young people with WS experienced higher levels of anxiety compared to those with DS and the older the people with NDC were, the more anxiety they experienced. In terms of concerns, group effects indicated that young people with WS scored higher for most of the concerns. Higher financial concerns were found in males compared to females, whereas most of the concerns increased with age except for concerns about loss of institutional support and family conflict. Finally, significant group effects were found and indicated a more frequent use of a variety of adaptive and maladaptive ER strategies in young people with WS. We only identified group differences in ER efficacy for two strategies: isolation/withdrawal was more efficient for young people with DS, while repetitive behaviours were more efficient for young people with WS. Our results indicate that young people with WS are likely to exhibit higher levels of anxiety, but also of concerns depending on their age and gender. Similarly, young people with WS use a variety of ER strategies more frequently but these strategies are not necessarily more efficient for them. We discuss the impact of these findings in relation to anxiety identification and support across young people with NDCs.

Serum Biomarkers Predict Symptom Duration in Long Term COVID-19 Across a Diverse Population (preprint)

Background: Prolonged symptoms after SARS-CoV-2 infection are well-documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with serologic biomarkers remain elusive. Methods: Adult inpatient and outpatient SARS-CoV-2 RT-PCR positive patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1-3 months for up to one year after diagnosis; they completed symptom surveys and underwent sampling procedures (blood draw and nasal swab) at each visit. Findings: Our cohort (n=617) ranged from asymptomatic to critical COVID-19 infections. 40% of participants reported at least one symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days, median time from diagnosis to sustained symptom resolution with no recurring symptoms for one month or longer was 214 days. Serum anti-nucleocapsid IgG level in the first week of infection was predictive of time to symptom resolution. A prior diagnosis of lung disease was associated with longer time to symptom resolution. COVID-19 disease severity, ethnicity, sex, cytomegalovirus (CMV) seropositivity, and remdesivir use did not affect time to sustained symptom resolution. More than 90% of participants had SARS-CoV-2-specific antibody>1000 AU/mL nine months after diagnosis. Interpretation: Our findings showed that all disease severities had a similar risk of developing post-COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration. Trial Registration: National clinical trial database NCT04664309.Funding: NIH CTSA grant, U54 NIH Grant, R21 NIEHS, Sean N Parker Center for Allergy and Asthma Research at Stanford University, the Sunshine Foundation, the Crown Foundation, and the Parker Foundation.Declaration of Interest: Dr. Boyd received support for the current manuscript from Meso Scale Discovery and NIH; 418 received consulting fees by Regeneron for expert testimony, has stocks or stock options in 419 AbCellera Biologics; Dr. Chinthrajah reports grants from NIAID, CoFAR, Aimmune, DBV 420 Technologies, Astellas, Regeneron, Stanford Maternal and Child Health Research Institute 421 (MCHRI), and FARE. She is an Advisory Board Member at Alladapt Therapeutics, Novartis, 422 Genentech, Sanofi, Allergenis, and Nutricia; Dr. Manisha Desai received support from Chan 423 Zuckerberg Foundation; Dr. Maecker received grants or contracts from NIH, Bill & Melinda 424 Gates Foundation, Ionis Corporation, Amgen Corporation; Consulting fees from Magarray Corp; 425 payment or honoraria from UCLA, UC Davis; leadership or fiduciary role at Cytek SAB; stocks 426 or stock options at BD Biosciences; Dr. Nadeau reports grants from National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS), and Food Allergy Research & Education (FARE); Director of World Allergy Organization (WAO) , Advisor at Cour Pharma, Consultant for Excellergy, Red tree ventures, and Phylaxis, Co-founder of Before Brands, Alladapt, Latitude, and IgGenix; and National Scientific Committee member at Immune Tolerance Network (ITN), and National Institutes of Health (NIH) clinical research centers, outside the submitted work; patents include, “Mixed allergen composition and methods for using the same”, “Granulocyte-based methods for detecting and monitoring immune system disorders”, “Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders,” and “Methods of isolating allergen-specific antibodies from humans and uses thereof”; Dr. Benjamin Pinsky received grants or contracts for the present manuscript from MesoScale Diagnostics; Dr. Angele Rogers was a Clinical Trials Advisory Board Member for Merck; Dr. Sindher reports support for the present manuscript from the NIH, Regeneron, DBV Technologies, Aimmune, Novartis, CoFAR, FARE, participated on a DSMB for Astra Zeneca, DBV, and received payment or honorarium from FARE; Neera Ahuja, Maja Artandi, Linda Barman, Catherine Blish, Andra Blomkalns, William Collins, MacKenzie Cox, Linda Geng, Xiaolin Jia, Megan Mahoney, Monali Manohar, Ruth O’hara, Rajan Puri, Katharina Roltgen, Laura Vaughan, Samuel Yang, Shu Cao, Iris Chang, Hena Din, Evan Do, Andrea Fernandez, Alexandra Lee, Natasha Purington, Yael Rosenberg-Hasson, Theo Snow, Daniel Solis, Michelle Verghese, and Yingjie Weng have no conflict of interest.Ethical Approval: This study was reviewed and approved by the Stanford Administrative Panel on Human Subjects in Medical Research.

Seven Days Treatment With the Angiotensin II Type 2 Receptor Agonist C21 in Hospitalized COVID-19 Patients: A Placebo-Controlled Randomized Phase 2 Trial (preprint)

Background: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Methods: Double-blind, placebo-controlled, multi-centre, randomized phase 2 trial to evaluate efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. Findings: 106 patients were randomised (51 C21, 55 placebo). There was no significant group difference in CRP (primary endpoint). In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (p=0.057). A post hoc analysis showed that at day 14, the proportion of patients still requiring supplemental oxygen was reduced by 90% in the C21 group compared to placebo (p=0.003). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Interpretation: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, there was a marked reduction of requirement for oxygen at day 14. Funding: Vicore Pharma AB and LifeArc.Clinical Trial Registration Details: The study protocol is available online at ClinicalTrials.gov, NCT04452435.Funding Information: Vicore Pharma AB and LifeArc.Declaration of Interests: Dr. Tornling reports personal fees from Vicore Pharma and Vicore Pharma shares. Dr. Batta reports a grant from LifeArc Medical Research Charity; personal fees from Vicore Pharma; Vicore Pharma stock options; in addition, Dr. Batta has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending. Dr. Porter has nothing to disclose. Dr. Williams has nothing to disclose. Dr. Bengtsson reports consultancy fees from Vicore Pharma. Dr. Parmar reports grants from Vicore Pharma, during the conduct of the study. Dr. Kashiva reports grants from Vicore Pharma, during the conduct of the study. Dr. Hallberg reports personal fees from Vicore Pharma. Anne Katrine Cohrt reports personal fees from Vicore Pharma and Vicore Pharma stock options. Kate Westergaard reports personal fees from Vicore Pharma. Dr. Dalsgaard reports a grant from LifeArc Medical Research Charity, during the conduct of the study; personal fees from Vicore Pharma; Vicore Pharma stocks and stock options; in addition, Dr. Dalsgaard has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending. Dr. Raud reports a grant from LifeArc Medical Research Charity; personal fees from Vicore Pharma; Vicore Pharma stocks and stock options; in addition, Dr. Raud has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending.Ethics Approval Statement: The protocol, patient information, patient consent form and other documents, as required, were approved by properly constituted IECs and by the national regulatory authorities.

Safety and Efficacy of Upadacitinib in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic Dermatitis: Results From a Pivotal Phase 3, Randomised, Double-Blind, Placebo-Controlled Study (AD Up) (preprint)

Background: Systemic therapies are typically combined with topical corticosteroids (TCS) in the management of moderate-to-severe atopic dermatitis (AD). Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 being developed for AD. AD Up was designed to assess the efficacy and safety of UPA+TCS versus placebo (PBO)+TCS in adolescents and adults with moderate-to-severe AD.Methods: AD Up (ClinicalTrials.gov, NCT03568318) is an ongoing pivotal, phase 3, randomised, double-blinded, placebo-controlled, multicentre study that enrolled patients from 171 clinical centres across the Asia-Pacific region, Europe, Middle East, North America, and Oceania. Adolescents (aged 12–17 years) and adults (aged 18–75 years) with chronic AD (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] ≥16, validated Investigator’s Global Assessment for AD [vIGA-AD™] ≥3, and Worst Pruritus Numerical Rating Scale [NRS] score ≥4) were eligible to participate. Patients were randomised (1:1:1) to receive UPA 15 mg, UPA 30 mg, or PBO once daily, all in combination with TCS (medium-potency TCS [or lowpotency TCS or topical calcineurin inhibitor for sensitive skin areas] until skin was clear or almost clear or for up to 3 consecutive weeks, followed by low-potency TCS for 7 days; if lesions returned or persisted, step-down approach was repeated), stratified by baseline disease severity, geographic region, and age using interactive response technology. Study investigators, study site personnel, and patients remained blinded throughout the study. Efficacy was analysed in the intention-to-treat population, defined as all patients who were randomised in the main study. The coprimary endpoints were proportion of patients achieving ≥75% reduction from baseline in EASI (EASI 75) at week 16 and proportion of patients achieving vIGA-AD of clear or almost clear with ≥2 grades of improvement (vIGA-AD 0/1) at week 16. Selected key secondary endpoints included proportions of patients achieving EASI 90 at weeks 4 and 16, EASI 75 at weeks 2 and 4, and percent Worst Pruritus NRS improvement ≥4 at weeks 1, 4, and 16. Safety was assessed via adverse event (AE) monitoring. Missing responses were handled based on nonresponder imputation incorporating multiple imputation to handle missing data due to coronavirus disease 2019 (COVID-19; NRI-C). Safety was analysed in all patients in the main study who received ≥1 dose of study drug.Findings: Between Aug 30, 2018, and Dec 20, 2019, 901 patients were randomised. At week 16, significantly greater proportions of patients treated with UPA 15 mg+TCS or UPA 30 mg+TCS than PBO+TCS achieved the coprimary endpoints—EASI 75 (64·6% [194 of 300 patients] and 77·1% [229 of 297] vs 26·4% [80 of 304]; adjusted difference vs PBO+TCS: 38·1% [95% CI 30·8–45·4] and 50·6% [43·8–57·4]; p<0·001 for both doses) and vIGA-AD 0/1 (39·6% [119 of 300] and 58·6% [174 of 297] vs 10·9% [33 of 304]; adjusted difference vs PBO+TCS: 28·5% [22·1–34·9]; 47·6% [41·1–54·0]; p<0·001 for both doses). The superiority of both UPA doses vs PBO was also demonstrated for all key secondary endpoints (p<0·001). During the double-blind period, UPA 15 and 30 mg were well tolerated in combination with TCS, and no new important safety signals beyond the events in the current label. Higher rates of acne were reported in this AD study. Incidences of AEs leading to discontinuation of study drug and serious AEs were similar among treatment groups. No deaths or opportunistic infections (excluding herpes zoster), active tuberculosis, lymphoma, adjudicated gastrointestinal perforations, adjudicated major adverse cardiovascular events, or adjudicated venous thromboembolic events were reported. Efficacy and safety results for adolescents were consistent with those for the overall population.Interpretation: In this phase 3 study, UPA+TCS was well tolerated and superior to PBO+TCS across coprimary and all key secondary endpoints. UPA as combination therapy demonstrated a positive benefit-risk profile in adults and adolescents with moderate-to-severe AD.Trial Registration: ClinicalTrials.gov number: NCT03568318Funding: AbbVie Inc. Declaration of Interest: KR has served as advisor and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Affibody, Almirall, Amgen, Avillion, Biogen, Bausch Health (Valeant), Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Covagen, Dermira, Forward Pharma, Fresenius, Galapagos, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO Pharma, Lilly, Medac, Merck, Novartis, Miltenyi Biotec, Ocean Pharma, Pfizer, Regeneron, Samsung Bioepis, Sanofi, Sun Pharma, Takeda, UCB, and XenoPort. HDT, JZ, XHuang, XHu, BH, BL, ADC are full-time employees of AbbVie Inc., and may hold AbbVie stock or stock options. MdB-W has been a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Galderma, Janssen, LEO Pharma, Lilly, Pfizer, Regeneron, Sanofi Genzyme, and UCB. TB is an advisor, speaker, and researcher for AbbVie, Allmiral, AnaptysBio, Arena, Asana Biosciences, Astellas, Bayer, BioVersys, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Dermavant/Roivant, Dermtreat, Domain Therapeutics, DS Biopharma, RAPT Therapeutics (FLX Bio), Galapagos/MorphoSys, Galderma, Glenmark, GlaxoSmithKline, Incyte, Kymab, LEO Pharma, Lilly, L´Oréal, Menlo Therapeutics, Novartis, Pfizer, Pierre Fabre, Sanofi/Regeneron, and UCB. WS is a consultant for AbbVie, Pfizer, Regeneron, and Sanofi. He is a speaker for Regeneron and Sanofi, and has received research grants from AbbVie, AB Biosciences, Genentech, Glenmark, LEO Pharma, Regeneron, Sanofi, and Vanda. KK has received consulting fees, honoraria, or grant support or lecturing fees from AbbVie, Japan Tobacco, LEO Pharma, 24 Maruho, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Procter & Gamble, Sanofi, Taiho Pharmaceutical, and Torii Pharmaceutical. TW has received lecture or consultancy fees from AbbVie, Almirall, Astellas, Galderma, Janssen/Johnson & Johnson, LEO Pharma, Lilly, Novartis, Pfizer, and Regeneron/Sanofi. JIS is an advisor, speaker, or consultant for AbbVie, Asana Biosciences, Dermavant, Galderma, GlaxoSmithKline, Glenmark, Kiniksa, LEO Pharma, Lilly, Menlo Therapeutics, Novartis, Pfizer, Realm Pharma, and Regeneron-Sanofi. He is also a researcher for GlaxoSmithKline.Ethical Approval: Independent ethics committees or institutional review boards at each study site approved the study protocol, informed consent form(s), and recruitment materials prior to patient enrolment. The study was conducted in accord with the International Conference for Harmonisation guidelines, applicable regulations, and the Declaration of Helsinki. Adult patients and parents/legal guardians of adolescent patients provided written informed consent prior to any screening or study-related procedures. An adolescent substudy was added after the protocol was initiated to allow enrolment of additional adolescents to fulfil a regulatory commitment.

Acute aortic dissection in a patient with Williams syndrome infected by COVID-19.

Cardiovascular involvement in COVID-19 has different features. Here we report the ominous fate of a neglected adolescent with Williams syndrome that was infected by SARS-CoV-2 and ended by acute aortic dissection.

The Protective Effect of SARS-CoV-2 Antibodies in Scottish Healthcare Workers (preprint)

Background: Healthcare workers (HCW) are believed to be at increased risk of SARS-CoV-2 infection. The extent of that increased risk compared to the general population and the groups most at risk have not been extensively studied. It is also not known to what extent the natural production of antibodies to SARS-CoV-2 is protective against re-infection.Methods: A prospective observational study of health and social care workers in NHS Tayside (Scotland, UK) from May to September 2020. The Siemens SARS-CoV-2 total antibody assay was used to establish seroprevalence in this cohort. Controls, matched for age and sex to the general Tayside population, were studied for comparison. New infections post antibody testing were recorded to determine if the presence of SARS-CoV-2 antibodies protect against re-infection.Results: A total of 2063 health and social care workers were recruited for this study. 300 HCW had a positive antibody test (14.5%). 11/231 control sera tested positive (4.8%). HCW therefore had an increased likelihood of a positive test (Odds ratio 3.4 95% CI 1.85-6.16, p<0.0001). Dentists, healthcare assistants and porters were the job roles most likely to test positive. Those working in front-line roles with COVID-19 patients were more likely to test positive (17.4% vs. 13.4%, p=0.02). 97.3% of patients who had previously tested positive for SARS-CoV-2 by RT-PCR had positive antibodies. 18.7% of HCW had an asymptomatic infection. There were 38 new infections with SARS-CoV-2 in HCW who were previously antibody negative and 1 symptomatic RT-PCR positive re-infection in a HCW who had detectable antibodies 76 days prior to re-infection. The presence of antibodies was therefore associated with an 85% reduced risk of re-infection with SARS-CoV-2 (HR 0.15, 95% CI 0.06 to 0.35, p=0.026).Conclusion: In this study, HCW were three times more likely to test positive for SARS-CoV-2 than the general population. Almost all of the infected individuals developed an antibody response and this was 85% effective in protecting against re-infection with SARS-CoV-2.Funding Statement: NHS Tayside COVID-19 Research Fund, JDC is supported by the British Lung Foundation Chair of Respiratory Research.Declaration of Interests: JDC reports grants and personal fees from GlaxoSmithKline, Boehringer-Ingelheim, Astrazeneca, Pfizer, Bayer Healthcare, Grifols, Napp, Insmed and Zambon outside the submitted work; All other authors report no conflicts of interest.Ethics Approval Statement: West of Scotland Research Ethics committee, approval number 20/WS/0078.

Effectiveness, Safety, and Acceptability of Medical Abortion at Home vs. In the Clinic: A Systematic Review and Meta-Analysis in Response to COVID-19 (preprint)

Background: Increased access to home-based medical abortion may offer women a convenient, safe, and effective abortion method, reduce burdens on healthcare systems, and support social distancing during the COVID-19 pandemic. We compared the evidence on the effectiveness, safety, and acceptability of home-based to clinic-based medical abortion among women seeking abortion in any setting.Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) and non-randomized studies (NRSs) was conducted. We searched Cochrane Central Register of Controlled Trials, POPLINE, and WHO ICTRP from inception to 10 July 2019. We searched MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, Google Scholar, and PubMed from inception to 14 June 2020. Successful abortion was the main outcome of interest. Eligible studies were RCTs and NRSs studies with a concurrent comparison group comparing home vs. clinic-based medical abortion. Risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated. Estimates were pooled using a random-effects model. We used the GRADE approach to assess risk of bias by outcome and to evaluate the overall quality of the evidence. We registered the study with PROSPERO, number CRD42020183171.Findings: We identified 6277 potentially eligible records. Nineteen studies (three RCTs and 16 NRSs) were included with 11,576 women seeking abortion up to nine weeks gestation. Neither the RCTs nor the NRS found any difference between home-based and clinic-based administration of medical abortion in having a successful abortion (RR 0.99, 95% CI: 0.98-1.01, I2 =0%; RR 0.99, 95% CI: 0.97-1.01, I2 =52%, respectively). The certainty of the evidence for the 16 NRS was downgraded from low to very low due to high risk of bias and publication bias. The certainty of the evidence for the three RCTs was downgraded from high to moderate by one level for high risk of bias.Interpretation: Home-based medical abortion is effective, safe, and acceptable to women. This evidence should be used to expand women’s abortion options and ensure access to abortion for women during COVID-19 and beyond.Funding: This review is supported by the William & Flora Hewlett Foundation.Declaration of Interests: The authors declare no competing interests.

Rough-Fuzzy CPD: A Gradual Change Point Detection Algorithm (preprint)

Changepoint detection is the problem of finding abrupt or gradual changes in time series data when the distribution of the time series changes significantly. There are many sophisticated statistical algorithms for solving changepoint detection problem, although there is not much work devoted towards gradual changepoints as compared to abrupt ones. Here we present a new approach to solve changepoint detection problem using fuzzy rough set theory which is able to detect such gradual changepoints. An expression for the rough-fuzzy estimate of changepoints is derived along with its mathematical properties concerning fast computation. In a statistical hypothesis testing framework, asymptotic distribution of the proposed statistic on both single and multiple changepoints is derived under null hypothesis enabling multiple changepoint detection. Extensive simulation studies have been performed to investigate how simple crude statistical measures of disparity can be subjected to improve their efficiency in estimation of gradual changepoints. Also, the said rough-fuzzy estimate is robust to signal-to-noise ratio, high degree of fuzziness in true changepoints and also to hyper parameter values. Simulation studies reveal that the proposed method beats other fuzzy methods and also popular crisp methods like WBS, PELT and BOCD in detecting gradual changepoints. The applicability of the estimate is demonstrated using multiple real-life datasets including Covid-19. We have developed the python package "roufcp" for broader dissemination of the methods.

Significance between Air pollutants, Meteorological Factors and COVID-19 Infections: Probable Evidences in India (preprint)

SARS-CoV-2 (Coronavirus) disease represents the causative agent with a potentially fatal risk which is having great global human health concern. Earlier studies suggested that air pollutants and meteorological factors were considered as the risk factors for acute respiratory infection, which carries harmful pathogens and affects the immunity. The study intended to explore the correlation between air pollutants, meteorological factors and the daily reported infection cases caused by novel coronavirus in India. The daily positive infected cases, air pollution and meteorological factors in 288 districts were collected from January 30, 2020 to April 23, 2020 in India. Speraman’s correlation and generalised additive model were applied to investigate the correlations of four air pollutants (PM2.5, PM10, NO2 and SO2) and eight meteorological factors (Temp, DTR, RH, AH, AP, RF, WS and WD) with COVID-19 infected cases. The study indicated that a 10 µg/m3 increase during (Lag0-14) in PM2.5, PM10 and NO2 was resulted in 2.21% (95%CI: 1.13 to 3.29), 2.67% (95% CI: 0.33 to 5.01) and 4.56 (95% CI: 2.22 to 6.90) increase in daily counts of COVID 19 infected cases respectively. However, only 1 unit increase in meteorological factor levels in case of daily mean temperature and DTR during (Lag0-14) associated with 3.78% (95%CI: 1.81 to 5.75) and 1.82% (95% CI: -1.74 to 5.38) rise of COVID-19 infected cases respectively. In addition, SO2 and relative humidity were negatively associated with COVID-19 infected cases at Lag0-14 with decrease of 7.23% (95% CI: -10.99 to -3.47) and 1.11% (95% CI: -3.45 to 1.23) for SO2 and for relative humidity respectively. The study recommended that there is significant relationship between air pollutants and meteorological factors with COVID-19 infected cases, which substantially explain the effect of national lockdown and suggested positive implications for control and prevention of the spread of SARS-CoV-2 disease. 

CovidDeep: SARS-CoV-2/COVID-19 Test Based on Wearable Medical Sensors and Efficient Neural Networks (preprint)

The novel coronavirus (SARS-CoV-2) has led to a pandemic. The current testing regime based on Reverse Transcription-Polymerase Chain Reaction for SARS-CoV-2 has been unable to keep up with testing demands, and also suffers from a relatively low positive detection rate in the early stages of the resultant COVID-19 disease. Hence, there is a need for an alternative approach for repeated large-scale testing of SARS-CoV-2/COVID-19. We propose a framework called CovidDeep that combines efficient DNNs with commercially available WMSs for pervasive testing of the virus. We collected data from 87 individuals, spanning three cohorts including healthy, asymptomatic, and symptomatic patients. We trained DNNs on various subsets of the features automatically extracted from six WMS and questionnaire categories to perform ablation studies to determine which subsets are most efficacious in terms of test accuracy for a three-way classification. The highest test accuracy obtained was 98.1%. We also augmented the real training dataset with a synthetic training dataset drawn from the same probability distribution to impose a prior on DNN weights and leveraged a grow-and-prune synthesis paradigm to learn both DNN architecture and weights. This boosted the accuracy of the various DNNs further and simultaneously reduced their size and floating-point operations.

Single-Cell Transcriptomic Analysis of SARS-CoV-2 Reactive CD4 + T Cells (preprint)

The contribution of CD4+ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present large-scale single-cell transcriptomic analysis of viral antigen-reactive CD4+ T cells from 32 COVID-19 patients. In patients with severe disease compared to mild disease, we found increased proportions of cytotoxic follicular helper (TFH) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2, and reduced proportion of SARS-CoV-2 reactive regulatory T cells. Importantly, the CD4-CTLs were highly enriched for the expression of transcripts encoding chemokines that are involved in the recruitment of myeloid cells and dendritic cells to the sites of viral infection. Polyfunctional T helper (TH)1 cells and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, our analyses provide so far unprecedented insights into the gene expression patterns of SARS-CoV-2 reactive CD4+ T cells in distinct disease severities.Funding: This work was funded by NIH grants U19AI142742 (P.V., A.S., C.H.O), U19AI118626 (P.V., A.S., G.S.), R01HL114093 (P.V., F.A., G.S.,), R35-GM128938 (F.A), S10RR027366 (BD FACSAria-II), S10OD025052 (Illumina Novaseq6000), the William K. Bowes Jr Foundation (P.V.), and Whittaker foundation (P.V., C.H.O.). Supported by the Wessex Clinical Research Network and National Institute of Health Research UK. Conflict of Interest: The authors declare no competing financial interests.Ethical Approval: Ethical approval for this study from the Berkshire Research Ethics Committee 20/SC/0155 and the Ethics Committee of La Jolla Institute for Immunology (LJI) was in place. Written consent was obtained from all subjects.

Structural Motifs, Disorder, and the Efficacy of Viral Vaccines (preprint)

We demonstrate that it is possible to draw direct numerical correlations between virus particles and effective virus-like particle (VLP) derived vaccines through extraction of a Bragg-Williams order parameter from electron microscopy. The method has its roots in studies of disorder in metal alloys, and is adapted to describe the type and occurrence of structural motifs within the arrangement of viral coat proteins, captured by the value of the order parameter as a measure of disorder. A conventional approach to viral vaccine design consists of replicating select proteins to create a VLP designed to trigger an immune response while remaining non-infectious. Understanding variations between viruses and vaccine strains therefore tends to focus on differences between proteins, which can be characterized through genetic analysis. While such an approach provides vital information about the functioning and interactions of the proteins, it does not yet yield an early-stage pathway towards predicting the efficacy of a vaccine, and so large-scale clinical trials are required to obtain critical information. With the urgency associated with pandemics, including Coronavirus Disease-2019 (COVID-19) originating from the SARS-CoV-2 virus, there is a need for earlier indications of whether a vaccine has the necessary characteristics. Application of the methodology to Dengue and influenza virus particles indicates that temperature and pH during incubation could potentially be exploited to fine-tune the order parameter of VLP-based vaccines to match the corresponding virus. Additionally, utilization of an Ising model plot reveals a clear relationship between case fatality rate and order parameter for distinct virus families.