Surrogate method for partial association between mixed data with application to well-being survey analysis (preprint)

This paper is motivated by the analysis of a survey study of college student wellbeing before and after the outbreak of the COVID-19 pandemic. A statistical challenge in well-being survey studies lies in that outcome variables are often recorded in different scales, be it continuous, binary, or ordinal. The presence of mixed data complicates the assessment of the associations between them while adjusting for covariates. In our study, of particular interest are the associations between college students' wellbeing and other mental health measures and how other risk factors moderate these associations during the pandemic. To this end, we propose a unifying framework for studying partial association between mixed data. This is achieved by defining a unified residual using the surrogate method. The idea is to map the residual randomness to the same continuous scale, regardless of the original scales of outcome variables. It applies to virtually all commonly used models for covariate adjustments. We demonstrate the validity of using such defined residuals to assess partial association. In particular, we develop a measure that generalizes classical Kendall's tau in the sense that it can size both partial and marginal associations. More importantly, our development advances the theory of the surrogate method developed in recent years by showing that it can be used without requiring outcome variables having a latent variable structure. The use of our method in the well-being survey analysis reveals (i) significant moderation effects (i.e., the difference between partial and marginal associations) of some key risk factors; and (ii) an elevated moderation effect of physical health, loneliness, and accommodation after the onset of COVID-19.

Risk factors for SARS-CoV-2 seropositivity in a health care worker population during the early pandemic.

BACKGROUND: While others have reported severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2) seroprevalence studies in health care workers (HCWs), we leverage the use of a highly sensitive coronavirus antigen microarray to identify a group of seropositive health care workers who were missed by daily symptom screening that was instituted prior to any epidemiologically significant local outbreak. Given that most health care facilities rely on daily symptom screening as the primary method to identify SARS-CoV-2 among health care workers, here, we aim to determine how demographic, occupational, and clinical variables influence SARS-CoV-2 seropositivity among health care workers. METHODS: We designed a cross-sectional survey of HCWs for SARS-CoV-2 seropositivity conducted from May 15th to June 30th 2020 at a 418-bed academic hospital in Orange County, California. From an eligible population of 5,349 HCWs, study participants were recruited in two ways: an open cohort, and a targeted cohort. The open cohort was open to anyone, whereas the targeted cohort that recruited HCWs previously screened for COVID-19 or work in high-risk units. A total of 1,557 HCWs completed the survey and provided specimens, including 1,044 in the open cohort and 513 in the targeted cohort. Demographic, occupational, and clinical variables were surveyed electronically. SARS-CoV-2 seropositivity was assessed using a coronavirus antigen microarray (CoVAM), which measures antibodies against eleven viral antigens to identify prior infection with 98% specificity and 93% sensitivity. RESULTS: Among tested HCWs (n = 1,557), SARS-CoV-2 seropositivity was 10.8%, and risk factors included male gender (OR 1.48, 95% CI 1.05-2.06), exposure to COVID-19 outside of work (2.29, 1.14-4.29), working in food or environmental services (4.85, 1.51-14.85), and working in COVID-19 units (ICU: 2.28, 1.29-3.96; ward: 1.59, 1.01-2.48). Amongst 1,103 HCWs not previously screened, seropositivity was 8.0%, and additional risk factors included younger age (1.57, 1.00-2.45) and working in administration (2.69, 1.10-7.10). CONCLUSION: SARS-CoV-2 seropositivity is significantly higher than reported case counts even among HCWs who are meticulously screened. Seropositive HCWs missed by screening were more likely to be younger, work outside direct patient care, or have exposure outside of work.

Dichotomy of neutralizing antibody, B cell and T cell responses to SARS-CoV-2 vaccination and protection in healthy adults (preprint)

Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group - broad responders - neutralize a range of SARS-CoV-2 variants, whereas the other - narrow responders - neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+ B cells and CCR6+ CD4+ T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.

Practical anatomy online learning among COVID-19 pandemic era: perceptions of 1 st -year MBBS students

Introduction: With the rise of the COVID-19 pandemic, digital learning has been implemented in medical colleges across India to continue the ongoing medical education. Anatomy is the basis of medical science and is best learned through offline classes that allow students to experience the texture of structures and handling of specimens. During this pandemic period, cadaveric dissection was not used to study anatomy. The aim of this study was to learn about students' attitudes regarding virtual teaching and learning in anatomy, as well as the problems they may confront. Material(s) and Method(s): A descriptive cross-sectional study was conducted in the department of anatomy among the 50 1 st -year MBBS students of All India Institute of Medical Sciences, Rajkot in April 2021. Google Forms were used to obtain informed consent from students. Prevalidated questionnaires were given online to the students and responses were noted and descriptive statistical data was derived from the analysis. Result(s): About 37 (74%) respondents found traditional classes are better than online teaching. Majority preferred to attend anatomy practicals offline with safety precautions. About 17 (34%) showed interest in prerecorded videos. About 35 (60%) students faced social isolation as an impact of online learning. Technical issues and distractions were the key problems faced while learning anatomy online. Conclusion(s): Prerecorded videos of the practicals are helpful in teaching anatomy practicals, and can be used in future to ensure an unbroken, continuous, and effective delivery of medical education.Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Emergency room presentations of people with anorexia nervosa.

People with anorexia nervosa (AN) tend to shy away from engaging in typical primary care provider relationships in order to avoid detection. Therefore, they may seek care for their medical concerns through a local emergency department (ED). Inherently, AN is associated with a litany of medical complications, which become more prevalent as the severity of their eating disorder increases. Notwithstanding the typical young age at the onset of AN, no body system is immune to these medical complications. Thus, ED providers may need to pursue a medical diagnosis in order to explain presenting symptoms in people with AN. In addition to the medical issues, AN is also a serious mental illness with high mortality rates, including deaths by suicide. Therefore, ED providers also need to be familiar with relevant mental health issues for these people.

People with anorexia nervosa frequent emergency departments to obtain their medical care. It is thus important for emergency department personnel to be familiar with this increasingly common and serious disorder. As opposed to most other mental illnesses, anorexia nervosa is associated with many dangerous medical complications, which become more problematic as the malnutrition and weight loss become more severe. All body systems are adversely affected. The mortality rate of anorexia nervosa is the second highest of all mental disorders, with medical complications and suicide being the top two causes of death. Mandated medical care may occasionally be required to obtain ongoing treatment for people with anorexia nervosa when they present to the emergency department with severe malnutrition and other emergent complications.

Immunity to Seasonal Coronavirus Spike Proteins Does Not Protect from SARS-CoV-2 Challenge in a Mouse Model but Has No Detrimental Effect on Protection Mediated by COVID-19 mRNA Vaccination.

Seasonal coronaviruses have been circulating widely in the human population for many years. With increasing age, humans are more likely to have been exposed to these viruses and to have developed immunity against them. It has been hypothesized that this immunity to seasonal coronaviruses may provide partial protection against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it has also been shown that coronavirus disease 2019 (COVID-19) vaccination induces a back-boosting effects against the spike proteins of seasonal betacoronaviruses. In this study, we tested if immunity to the seasonal coronavirus spikes from OC43, HKU1, 229E, or NL63 would confer protection against SARS-CoV-2 challenge in a mouse model, and whether pre-existing immunity against these spikes would weaken the protection afforded by mRNA COVID-19 vaccination. We found that mice vaccinated with the seasonal coronavirus spike proteins had no increased protection compared to the negative controls. While a negligible back-boosting effect against betacoronavirus spike proteins was observed after SARS-CoV-2 infection, there was no negative original antigenic sin-like effect on the immune response and protection induced by SARS-CoV-2 mRNA vaccination in animals with pre-existing immunity to seasonal coronavirus spike proteins. IMPORTANCE The impact that immunity against seasonal coronaviruses has on both susceptibility to SARS-CoV-2 infection as well as on COVID-19 vaccination is unclear. This study provides insights into both questions in a mouse model of SARS-CoV-2.

Post-COVID-19 elective surgery and transformation: exploring the role of ambulatory spinals in the high-risk patient population

At Whipps Cross Hospital, multi-morbid (high-risk) patients undergoing urological surgery are routinely listed on the surgical inpatient pathway. The 'Getting it right first time' [1] review of anaesthesia recommended day-case surgery as the default for suitable procedures, to help with waiting lists as well as to provide patients with a safe environment. To improve patient choice and postoperative outcomes, an ambulatory spinal pathway was piloted. Methods An earlier scoping exercise identified a pool of urology high-risk patients who could potentially benefit from an ambulatory spinal pathway. Based on this, prilocaine use for ambulatory spinal anaesthetic was provisionally approved by the drugs and therapeutic committee. A pilot ambulatory pathway was put in place, which helped identify suitable patients. The pilot pathway was limited to a select group of anaesthetists to minimise variations. Postoperatively, patients were followed up at 3 and 24 h and assessed for postoperative nausea, vomiting, pain, mobilisation, neurological symptoms and cognitive impairment. Results The total number of patients was 19. Mean ASA was 2.9. Average age was 74 years. The mean dose of hyperbaric prilocaine 2% used was 2.9 ml, 21% of cases utilised additional intrathecal additives. Regarding intra-operative analgesia, only paracetamol was used in 15% of cases. There were no conversions to general anaesthetic. The most common procedure was a cystoscopy with or without biopsy (42%). With comorbidities, diabetes mellitus was the most common (58%), followed by cardiac disease (53%) and respiratory disease (42%). At 3 h, 100% of patients were eating and all sensation had returned, 0% had cognitive impairment, 47% were sitting out and 42% mobilising. Sixteen per cent had hypotension and 5% had pain at rest. At 24 h, 0% had cognitive impairment, 50% had required analgesia and 84% were mobilising. All patients reported they would have a spinal anaesthetic again in the future. Discussion With an ageing population, who have multiple comorbidities, there is huge benefit regarding providing the choice of a spinal anaesthetic rather than general anaesthetic, which allows patients to go home the same day. This will not only provide financial savings to the service provider but also help clear the backlog of surgeries due to the COVID-19 pandemic and enhance patient recovery.

Deep Learning and Medical Imaging for COVID-19 Diagnosis: A Comprehensive Survey (preprint)

COVID-19 (Coronavirus disease 2019) has been quickly spreading since its outbreak, impacting financial markets and healthcare systems globally. Countries all around the world have adopted a number of extraordinary steps to restrict the spreading virus, where early COVID-19 diagnosis is essential. Medical images such as X-ray images and Computed Tomography scans are becoming one of the main diagnostic tools to combat COVID-19 with the aid of deep learning-based systems. In this survey, we investigate the main contributions of deep learning applications using medical images in fighting against COVID-19 from the aspects of image classification, lesion localization, and severity quantification, and review different deep learning architectures and some image preprocessing techniques for achieving a preciser diagnosis. We also provide a summary of the X-ray and CT image datasets used in various studies for COVID-19 detection. The key difficulties and potential applications of deep learning in fighting against COVID-19 are finally discussed. This work summarizes the latest methods of deep learning using medical images to diagnose COVID-19, highlighting the challenges and inspiring more studies to keep utilizing the advantages of deep learning to combat COVID-19.

Omicron, Long-COVID, and the Safety of Elective Surgery for Adults and Children: Joint Guidance from the Therapeutics and Guidelines Committee of the Surgical Infection Society and the Surgery Strategic Clinical Network, Alberta Health Services.

Background: Active and recent coronavirus disease 2019 (COVID-19) infections are associated with morbidity and mortality after surgery in adults. Current recommendations suggest delaying elective surgery in survivors for four to 12 weeks, depending on initial illness severity. Recently, the predominant causes of COVID-19 are the highly transmissible/less virulent Omicron variant/subvariants. Moreover, increased survivability of primary infections has engendered the long-COVID syndrome, with protean manifestations that may persist for months. Considering the more than 600,000,000 COVID-19 survivors, surgeons will likely be consulted by recovered patients seeking elective operations. Knowledge gaps of the aftermath of Omicron infections raise questions whether extant guidance for timing of surgery still applies to adults or should apply to the pediatric population. Methods: Scoping review of relevant English-language literature. Results: Most supporting data derive from early in the pandemic when the Alpha variant of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) predominated. The Omicron variant/subvariants generally cause milder infections with less organ dysfunction; many infections are asymptomatic, especially in children. Data are scant with respect to adult surgical outcomes after Omicron infection, and especially so for pediatric surgical outcomes at any stage of the pandemic. Conclusions: Numerous knowledge gaps persist with respect to the disease, the recovered pre-operative patient, the nature of the proposed procedure, and supporting data. For example, should the waiting period for all but urgent elective surgery be extended beyond 12 weeks, e.g., after serious/critical illness, or for patients with long-COVID and organ dysfunction? Conversely, can the waiting periods for asymptomatic patients or vaccinated patients be shortened? How shall children be risk-stratified, considering the distinctiveness of pediatric COVID-19 and the paucity of data? Forthcoming guidelines will hopefully answer these questions but may require ongoing modifications based on additional new data and the epidemiology of emerging strains.

Natural cubic splines for the analysis of Alzheimer's clinical trials.

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.

ICT-enabled teaching and learning modalities followed in pharmacy education during COVID-19 in India

The transformation from conventional to online teaching and learning created an unprecedented learning environment and many challenges for the trainers and learners during COVID-19 in India. In this context, many synchronous and asynchronous online teaching tools were used to continue the pharmacy educational process and to develop and update the instructional strategies with suitable online tools & interactive methodologies. Indian Ministry of Education (MoE) initiated massive online open courses platforms which were utilized to understand the fundamentals of pharmacyrelated subjects. Introductory and advanced pharmacy practice experiences learning was provided to students through online simulation activities, video reflection, case, and problem-based online discussions, and objective structured clinical and practical examination. Virtual conferencing applications and digital education platforms of MoE were majorly used to conduct the pharmacy education during the crisis and investments in digitization become mandatory in pharmacy education and COVID-19 fast-forwarded its process. Information and communication technology enabled continuity of pharmacy education during the pandemic and improved the student-teacher contact hours, self-paced, collaborative, and contextual learning environment in India. © 2022 Sadagoban Gopal Krishnamoorthy et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

Immunity to seasonal coronavirus spike proteins does not protect from SARS-CoV-2 challenge in a mouse model but has no detrimental effect on protection mediated by COVID-19 mRNA vaccination (preprint)

Seasonal coronaviruses have been circulating widely in the human population for many years. With increasing age, humans are more likely to have been exposed to these viruses and to have developed immunity against them. It has been hypothesized that this immunity to seasonal coronaviruses may provide partial protection against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it has also been shown that coronavirus disease 2019 (COVID-19) vaccination induces a back-boosting effects against the spike proteins of seasonal betacoronaviruses. In this study, we tested if immunity to the seasonal coronavirus spikes from OC43, HKU1, 229E or NL63 would confer protection against SARS-CoV-2 challenge in a mouse model, and whether pre-existing immunity against these spikes would weaken the protection afforded by mRNA COVID-19 vaccination. We found that mice vaccinated with the seasonal coronavirus spike proteins had no increased protection as compared to the negative controls. While a negligible back-boosting effect against betacoronavirus spike proteins was observed after SARS-CoV-2 infection, there was no negative original antigenic sin-like effect on the immune response and protection induced by SARS-CoV-2 mRNA vaccination in animals with pre-existing immunity to seasonal coronavirus spike proteins.

ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 diabetes in children and adolescents.

Since the 2018 ISPAD guidelines on this topic, follow-up of large cohorts from around the globe have continued informing the current incidence and prevalence of co-morbidities and complications in young adults with youth-onset type 2 diabetes (T2D). This chapter focuses on the risk factors, diagnosis and presentation of youth-onset T2D, the initial and subsequent management of youth-onset T2D, and management of co-morbidities and complications. We include key updates from the observational phase of the multi-center Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial, the SEARCH for Diabetes in Youth (SEARCH) study and new data from the Restoring Insulin Secretion (RISE) study, a head-to-head comparison of youth onset vs adult-onset T2D. We also include an expanded section on risk factors associated with T2D, algorithms and tables for treatment, management, and assessment of co-morbidities and complications, and sections on recently approved pharmacologic therapies for the treatment of youth-onset T2D, social determinants of health, and settings of care given COVID-19 pandemic.

Quarantine of Travellers during the Initial Phase of the COVID-19 Pandemic- Experience from a Rural Setting in Kerala, India

Introduction: Quarantine of travellers was one of the major public health strategies enforced by the state to curb the transmission of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the initial phases. Proper quarantine requires commitment from the person, support, and monitoring from the public health system. Aim: To understand the process, practices, perceptions, and difficulties of quarantined persons during the initial phase of the Coronavirus Disease-2019 (COVID-19) in a panchayat in Alappuzha, Kerala, India. Materials and Methods: A cross-sectional study was conducted from May to September 2020 using a semi-structured questionnaire through telephonic interview among quarantined individuals in a panchayat in Alappuzha, Kerala. Quarantine practices, the process of quarantine, perceptions, and difficulties faced were explored to understand their viewpoint. The perceptions of the healthcare providers were also enquired qualitatively. The data collected was entered in Microsoft Excel and statistical analysis was done using the Statistical Package for the Social Sciences (SPSS) version 27 (SPSS Inc, Chicago, USA). Results: Out of the 182 quarantined individuals, 152 were in home quarantine of which 89 (58.6%) observed strict room quarantine and 132 (72.5%) had a quarantine period of more than 14 days which was the guideline then. Majority were contacted by the health staff during the period;however, 28% were not satisfied with the information that was conveyed to them. Majority adhered to infection control guidelines during quarantine. Almost half (46.7%) of them reported emotional problems during quarantine of which the major issues were loneliness and lack of social contact. Almost one-third of them had experienced stigma and rejection from people in the neighbourhood. Conclusion: Quarantine to be used effectively as a public health measure requires that the concerns and problems should also be taken care of. Adequate information regarding the need and process of quarantine should be provided and there should be a system to cater to the emotional concerns of the persons. Awareness regarding the purpose and role of quarantine among the general public will enable quarantine to be used as a powerful tool for disease control in the future.

Thrombotic Events and Anticoagulation-Related Bleeding Complications in Critically Ill Patients with Coronavirus Disease 2019.

Background: Thrombosis (T) is common in coronavirus disease 2019 (COVID-19) patients, and d-dimer concentrations correlate with outcomes. Controversy exists with regards to anticoagulation (AC) for patients. We implemented a full-heparinization AC protocol from the onset of the pandemic and hypothesized that a safety signal would be undetectable. Patients and Methods: Prospective evaluation of 111 patients with COVID-19 critical illness hospitalized from March to June 2020. All patients received therapeutic heparinoid-based AC from admission. Incidences of T, bleeding (B), or both (BT) were noted. The primary outcome was mortality. Kruskal-Wallis test and logistic regression were performed. Results are expressed as n (%), median (interquartile range) and odds ratios with 95% confidence intervals. Alpha was set at 0.05. Results: Thirty-two patients (28%) had T, 23 (20%) had B, and 14 (12%) had BT; 42 (40%) patients were unaffected. Two logistic regression models (outcome = mortality) evaluated BT as T, or BT as B. For BT as T, neither T, B, nor male gender predicted mortality; similarly, for BT as B, neither T, B, nor male gender predicted mortality. Factors associated with higher odds of death included higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00-1.13; p = 0.0045), higher d-dimer concentration (OR, 1.00; 95% CI, 1.00-1.01; p = 0.043), and higher activated partial thromboplastin time (aPTT; OR, 1.09; 95% CI, 1.02-1.16; p = 0.010). Conclusions: Neither T nor B predicted mortality in this prospective cohort of anticoagulated patients with COVID-19 critical illness. These data support continued full-dose heparinoid prophylaxis.

Paradoxical Positioning: Does "Head Up" Always Improve Mechanics and Lung Protection?

OBJECTIVES: Head-elevated body positioning, a default clinical practice, predictably increases end-expiratory transpulmonary pressure and aerated lung volume. In acute respiratory distress syndrome (ARDS), however, the net effect of such vertical inclination on tidal mechanics depends upon whether lung recruitment or overdistension predominates. We hypothesized that in moderate to severe ARDS, bed inclination toward vertical unloads the chest wall but adversely affects overall respiratory system compliance (C rs ). DESIGN: Prospective physiologic study. SETTING: Two medical ICUs in the United States. PATIENTS: Seventeen patients with ARDS, predominantly moderate to severe. INTERVENTION: Patients were ventilated passively by volume control. We measured airway pressures at baseline (noninclined) and following bed inclination toward vertical by an additional 15°. At baseline and following inclination, we manually loaded the chest wall to determine if C rs increased or paradoxically declined, suggestive of end-tidal overdistension. MEASUREMENTS AND MAIN RESULTS: Inclination resulted in a higher plateau pressure (supineΔ: 2.8 ± 3.3 cm H 2 O [ p = 0.01]; proneΔ: 3.3 ± 2.5 cm H 2 O [ p = 0.004]), higher driving pressure (supineΔ: 2.9 ± 3.3 cm H 2 O [ p = 0.01]; proneΔ: 3.3 ± 2.8 cm H 2 O [ p = 0.007]), and lower C rs (supine Δ: 3.4 ± 3.7 mL/cm H 2 O [ p = 0.01]; proneΔ: 3.1 ± 3.2 mL/cm H 2 O [ p = 0.02]). Following inclination, manual loading of the chest wall restored C rs and driving pressure to baseline (preinclination) values. CONCLUSIONS: In advanced ARDS, bed inclination toward vertical adversely affects C rs and therefore affects the numerical values for plateau and driving tidal pressures commonly targeted in lung protective strategies. These changes are fully reversed with manual loading of the chest wall, suggestive of end-tidal overdistension in the upright position. Body inclination should be considered a modifiable determinant of transpulmonary pressure and lung protection, directionally similar to tidal volume and positive end-expiratory pressure.

Learning about COVID-19: sources of information, public trust, and contact tracing during the pandemic.

OBJECTIVE: To assess the association between public attitudes, beliefs, and information seeking about the COVID-19 pandemic and willingness to participate in contact tracing in Michigan. METHODS: Using data from the quarterly Michigan State of the State survey conducted in May 2020 (n = 1000), we conducted multiple regression analyses to identify factors associated with willingness to participate in COVID-19 contact tracing efforts. RESULTS: Perceived threat of the pandemic to personal health (B = 0.59, p = <.00, Ref = No threat) and general trust in the health system (B = 0.17, p < 0.001), were the strongest positive predictors of willingness to participate in contact tracing. Concern about misinformation was also positively associated with willingness to participate in contact tracing (B = 0.30, p < 0.001; Ref = No concern). Trust in information from public health institutions was positively associated with willingness to participate in contact tracing, although these institutions were not necessarily the main sources of information about COVID-19. CONCLUSION: Policy makers can enhance willingness to participate in public health efforts such as contact tracing during infectious disease outbreaks by helping the public appreciate the seriousness of the public health threat and communicating trustworthy information through accessible channels.

Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity.

The determinants of severe COVID-19 in healthy adults are poorly understood, which limits the opportunity for early intervention. We present a multiomic analysis using machine learning to characterize the genomic basis of COVID-19 severity. We use single-cell multiome profiling of human lungs to link genetic signals to cell-type-specific functions. We discover >1,000 risk genes across 19 cell types, which account for 77% of the SNP-based heritability for severe disease. Genetic risk is particularly focused within natural killer (NK) cells and T cells, placing the dysfunction of these cells upstream of severe disease. Mendelian randomization and single-cell profiling of human NK cells support the role of NK cells and further localize genetic risk to CD56bright NK cells, which are key cytokine producers during the innate immune response. Rare variant analysis confirms the enrichment of severe-disease-associated genetic variation within NK-cell risk genes. Our study provides insights into the pathogenesis of severe COVID-19 with potential therapeutic targets.

Global, regional, and national minimum estimates of children affected by COVID-19-associated orphanhood and caregiver death, by age and family circumstance up to Oct 31, 2021: an updated modelling study.

BACKGROUND: In the 6 months following our estimates from March 1, 2020, to April 30, 2021, the proliferation of new coronavirus variants, updated mortality data, and disparities in vaccine access increased the amount of children experiencing COVID-19-associated orphanhood. To inform responses, we aimed to model the increases in numbers of children affected by COVID-19-associated orphanhood and caregiver death, as well as the cumulative orphanhood age-group distribution and circumstance (maternal or paternal orphanhood). METHODS: We used updated excess mortality and fertility data to model increases in minimum estimates of COVID-19-associated orphanhood and caregiver deaths from our original study period of March 1, 2020-April 30, 2021, to include the new period of May 1-Oct 31, 2021, for 21 countries. Orphanhood was defined as the death of one or both parents; primary caregiver loss included parental death or the death of one or both custodial grandparents; and secondary caregiver loss included co-residing grandparents or kin. We used logistic regression and further incorporated a fixed effect for western European countries into our previous model to avoid over-predicting caregiver loss in that region. For the entire 20-month period, we grouped children by age (0-4 years, 5-9 years, and 10-17 years) and maternal or paternal orphanhood, using fertility contributions, and we modelled global and regional extrapolations of numbers of orphans. 95% credible intervals (CrIs) are given for all estimates. FINDINGS: The number of children affected by COVID-19-associated orphanhood and caregiver death is estimated to have increased by 90·0% (95% CrI 89·7-90·4) from April 30 to Oct 31, 2021, from 2 737 300 (95% CrI 1 976 100-2 987 000) to 5 200 300 (3 619 400-5 731 400). Between March 1, 2020, and Oct 31, 2021, 491 300 (95% CrI 485 100-497 900) children aged 0-4 years, 736 800 (726 900-746 500) children aged 5-9 years, and 2 146 700 (2 120 900-2 174 200) children aged 10-17 years are estimated to have experienced COVID-19-associated orphanhood. Globally, 76·5% (95% CrI 76·3-76·7) of children were paternal orphans, whereas 23·5% (23·3-23·7) were maternal orphans. In each age group and region, the prevalence of paternal orphanhood exceeded that of maternal orphanhood. INTERPRETATION: Our findings show that numbers of children affected by COVID-19-associated orphanhood and caregiver death almost doubled in 6 months compared with the amount after the first 14 months of the pandemic. Over the entire 20-month period, 5·0 million COVID-19 deaths meant that 5·2 million children lost a parent or caregiver. Our data on children's ages and circumstances should support pandemic response planning for children globally. FUNDING: UK Research and Innovation (Global Challenges Research Fund, Engineering and Physical Sciences Research Council, and Medical Research Council), Oak Foundation, UK National Institute for Health Research, US National Institutes of Health, and Imperial College London.