Cellular and Humoral Immunity and Infection Responses to SARS-CoV-2:Immune Biomolecular Mechanisms by Case Study within SARS-CoV-2 Pathogenesis and Other Infections (preprint)

The coronavirus 2019 (COVID-19) pandemic was caused by a positive sense single-stranded RNA (ssRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, other human coronaviruses (hCoVs) exist, of which Middle East Respiratory Syndrome (MERS) and SARS-CoV (SARS) showed higher mortality rates without causing a pandemic. As of December 2022, SARS-CoV-2 has resulted in over 6.6 million deaths worldwide through an array of acute to chronic pathologies. Historical pandemics include smallpox and influenza with efficacious therapeutics utilized to reduce overall disease burden. Therefore, immune system process analysis is required to compare innate and adaptive immune system interactions. Lymphatic system organs include bone marrow and thymus using a network of nodes throughout which white blood cells traverse glycolipid membranes utilizing cytokines and chemokine gradients that affect cell development, differentiation, proliferation, and migration processes as well as genetic factors affecting cell receptor expression. Innate processes involve antigen-presenting cells and B lymphocyte cellular responses to pathogens relevant to other viral and bacterial infections but also in oncogenic diseases. Such processes utilize cluster of differentiation (CD) marker expression, major histocompatibility complexes (MHC), pleiotropic interleukins (IL) and chemokines. The adaptive immune system consists of Natural Killer (NK) and T cells. Other viruses are also contributory to cancer including human papillomavirus (cervical carcinoma ), Epstein-Barr virus (EBV) ( lymphoma), hepatitis B and C (hepatocellular carcinoma) and human T cell leukemia virus-1 (adult T-cell leukemia). Bacterial infections also increase the risk of developing cancer( e.g. H. pylori). Therefore, as the above factors can cause both morbidity and mortality along-side being transmitted within clinical and community settings, it is appropriate to now examine advances in single cell sequencing, FACS analysis and many other laboratory techniques that allow insights into discoveries of newer cell types. These developments offer improved clarity and understanding that over-lap with known autoimmune conditions that could be affected by innate B cell or T cell responses to SARS-CoV-2 infection. Thus, this review quantifies and outlines the nature of specific receptors and proteins relevant to clinical laboratories and medical research by documenting both innate and adaptive immune system cells within current coronavirus immunology case study data and other pathologies to date.

Mental health outcomes following COVID-19 infection: Evidence from 11 UK longitudinal population studies (preprint)

Background Evidence on associations between COVID-19 illness and mental health is mixed. We examined longitudinal associations between COVID-19 and mental health while considering: 1) pre-pandemic mental health, 2) time since infection; 3) subgroup differences; and 4) confirmation of infection via self-reported test, and serology data. Methods Using data from 11 UK longitudinal studies, involving 54,442 participants, with 2 to 8 repeated measures of mental health and COVID-19 between April 2020 and April 2021, we standardised continuous mental health scales within each study across time. We investigated associations between COVID-19 (self-report, test-confirmed, serology-confirmed) and mental health using multilevel generalised estimating equations. We examined whether associations varied by age, sex, ethnicity, education and pre-pandemic mental health. Effect-sizes were pooled in random-effects meta-analyses. Outcomes Pooled estimates of the standardized difference in outcome between those with and without self-reported COVID-19 suggested associations with subsequent psychological distress (0.10 [95%CI: 0.06; 0.13], I 2 =42.8%), depression (0.08 [0.05; 0.10], I 2 =20.8%), anxiety (0.08 [0.05; 0.10], I 2 =0%), and lower life satisfaction (−0.06 [-0.08; -0.04], I 2 =29.2%). Associations did not vary by time since infection until 3+ months and were present in all age groups, with some evidence of stronger effects in those aged 50+. Self-reported COVID-19, whether suspected or test-confirmed and irrespective of serology status, was associated with poorer mental health. Interpretation Self-reporting COVID-19 was longitudinally associated with deterioration in mental health and life satisfaction. Our findings have important implications for mental health service provision, given the substantial prevalence of COVID-19 in the UK and worldwide. Funding MRC and NIHR

PNEUMOMEDIASTINUM IN PATIENTS WITH COVID-19: AN OBSERVATIONAL COHORT STUDY

Co-morbidities include obesity, diabetes, hypertension (HTN), and chronic lung disease. B Introduction: b Pneumomediastinum (PMS), a rare occurrence, has been increasingly reported among patients diagnosed with COVID-19. B Conclusions: b Mechanical ventilation, obesity, older age and female sex are associated with higher mortality in COVID-19 patients with PMS. [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

COVID-19 – An Opportunity to Improve Access to Primary Care Through Organizational Innovations? (preprint)

Background: COVID-19 catalyzed a rapid and substantial reorganization of primary care, accelerating the spread of existing strategies and fostering a proliferation of innovations. Access to primary care is an essential component of a health care system, particularly during a pandemic. We describe organizational innovations aiming to improve access to primary care and related contextual changes, during the first year of the COVID-19 pandemic in two Canadian provinces, Quebec and Nova Scotia. Methods: We conducted a multiple case studies, based on 63 semi-structured interviews (n=33 in Quebec, n=30 in Nova Scotia) conducted between October 2020 and May 2021 and a review of related internal documents from both jurisdictions. We recruited a diverse range of provincial and regional stakeholders (e.g., policymakers, decision-makers, family physicians, nurses) involved in reorganizing primary care during COVID-19 using purposeful sampling (e.g., based on role, region). Interviews were transcribed verbatim and thematic analysis was conducted in NVivo12. Emerging results were discussed by team members to identify salient themes and organized into logic models. Results: We identified and analyzed six organizational innovations. Four of these - centralized public online booking systems, centralized access centers for unattached patients, and interim primary care clinics for unattached patients and community connector to health and social services for older adults – pre-dated COVID-19 but were accelerated by the pandemic context. The remaining two innovations were created to specifically address pandemic-related needs: COVID-19 hotlines and COVID dedicated primary healthcare clinics. Innovation spread and proliferation was influenced by several factors such as a strengthened sense of community amongst providers, decreased patient demand at the beginning of the first wave, renewed policy and provider interest in population-wide access (versus attachment of patients only), suspended performance targets (e.g., continuity ≥80%) in Quebec, in modality of care delivery, modified fee codes, and greater regional flexibility to implement tailored innovations. Conclusion: COVID-19 accelerated the uptake and creation of organizational innovations to potentially improve access to primary healthcare, removing, at least temporarily, certain longstanding barriers. Many stakeholders believed this reorganization would have positive impacts on access to primary care after COVID-19. Further studies should analyze the effectiveness and sustainability of innovations adapted, developed, and implemented during the COVID-19 pandemic.

Did the COVID-19 pandemic result in more family physicians stopping practice? Results from Ontario, Canada (preprint)

Purpose To understand changes in family physician practice patterns and whether more family physicians stopped working during the COVID-19 pandemic compared to previous years. Methods We analyzed administrative data from Ontario, Canada two ways: cross-sectional and longitudinal. First, we identified the percentage and characteristics of all family physicians who had a minimum of 50 billing days in 2019 but no billings during the first six months of the pandemic. Second, for each year from 2010 to 2020, we calculated the percentage of physicians who billed for services in the first quarter of the calendar year but submitted no bills between April and September of the given year. Results We found 3.1% of physicians working in 2019 (N=385/12,247) reported no billings in the first six months of the pandemic. Compared with other family physicians, a higher portion were age 75 or older (13.0% vs. 3.4%, p<0.001), had fee-for-service reimbursement (38% vs 25%, p<0.001), and had a panel size under 500 patients (40% vs 25%, p<0.001). Between 2010 and 2019, an average of 1.6% of physicians who practiced in the first quarter had no billings in each of the second and third quarters of the calendar year compared to 3.0% in 2020 (p<0.001). Conclusions Approximately twice as many family physicians stopped work in Ontario, Canada during COVID-19 compared to previous years, but the absolute number was small and those who did had smaller patient panels. More research is needed to understand the impact on primary care attachment and access to care.

Disruption Caused by the COVID-19 Pandemic on HbA1c Testing and Its Implications for Diabetes (DM) Management/Diagnosis

We explored the impact of the COVID-19 pandemic on DM management/diagnosis. We extracted routine HbA1c data from laboratory systems at 5 UK hospitals from October2017-September2020 (representing 3.3million people;~4.8% of the UK population). From these data(3million tests), we calculated monthly missed monitoring/diagnostic tests from 23 March-30September 2020. We found that HbA1c tests dropped by 82-88% in April and had not reached expected volumes by September(Figure 1). During the 6-month period, in people with DM/at risk of DM, 206,422 monitoring tests were missed. Of these, 23,466 (11.4%) had previous HbA1c values ≥59mmol/mol. The testing delay in this group would, on average, result in a mean increase in HbA1c of 5.7 mmol/mol above that expected if monitoring was according to NICE guidance. There were also an estimated 81,245 missed diagnostic tests. Of these, ~6,105(7.5%) would be expected to be in the pre-DM range(42-47 mmol/mol) and ~3,633(4.5%) within DM range (≥48 mmol/mol), with ~1,333 of these having HbA1c values of ≥76 mmol/mol. Extrapolating to the UK population, this equates to missed monitoring tests in 489,000 people with sub-optimally-controlled DM, ~127,000 missed pre-DM and 76,000 missed DM diagnoses. Our findings illustrate the widespread collateral impact of implementing measures to mitigate COVID-19 impact in people with, or being investigated for DM.

The PUPPY Study – Protocol for a Longitudinal Mixed Methods Study Exploring Problems Coordinating and Accessing Primary Care for Attached and Unattached Patients Exacerbated During the COVID-19 Pandemic Year (preprint)

Background The COVID-19 pandemic significantly disrupted primary care in Canada, with many walk-in clinics and family practices initially closing or being perceived as inaccessible, pharmacies remaining open with restrictions on patient interactions, rapid uptake of virtual care, and reduced referrals for lab tests, diagnostics, and specialist care. The PUPPY Study (Problems Coordinating and Accessing Primary Care for Attached and Unattached Patients Exacerbated During the COVID-19 Pandemic Year) seeks to understand the impact of COVID-19 across the quadruple aim of primary care, with particular focus on the impacts on patients without attachment to a regular provider and those with chronic health conditions. Objective The PUPPY Study objective is to understand the impact of COVID-19 across the quadruple aim of primary care. Methods The PUPPY study builds on an existing research program exploring patients’ access and attachment to primary care, pivoted to adapt to the emerging COVID-19 context. We will undertake a longitudinal mixed methods study to understand critical gaps in primary care access and coordination, comparing data pre- and post-pandemic in three Canadian provinces (Quebec, Ontario, and Nova Scotia). Multiple data sources will be used including: a policy review; qualitative interviews with primary care policymakers, providers (i.e., family physicians, nurse practitioners, and pharmacists), and patients (N=120); and medication prescribing and healthcare billings. The findings will inform the strengthening of primary care during and beyond the COVID-19 pandemic. Results Funding was provided by the Canadian Institutes of Health Research COVID-19 Rapid Funding Opportunity Grant. Ethical approval to conduct this study was granted in Ontario (Queens Health Sciences & Affiliated Teaching Hospitals Research Ethics Board, file number 6028052; Western University Health Sciences Research Ethics Board, project 116591; University of Toronto Health Sciences Research Ethics Board, protocol number 40335), Québec (Centre intégré universitaire de santé et de services sociaux de l’Estrie, project number 2020-3446) and Nova Scotia (Nova Scotia Health Research Ethics Board, file number 1024979). Conclusions This is the first study of its kind exploring the impacts of COVID-19 on primary care systems, with particular focus on the issues of patient’s attachment and access to primary care. Through a multi-stakeholder, cross-jurisdictional approach, the PUPPY Study will generate findings and implications for future policy and practice.

Pre-pandemic mental health and disruptions to healthcare, economic, and housing outcomes during COVID –19: evidence from 12 UK longitudinal studies (preprint)

Background The COVID-19 pandemic and associated virus suppression measures have disrupted lives and livelihoods and people already experiencing mental ill-health may have been especially vulnerable. Aim To quantify mental health inequalities in disruptions to healthcare, economic activity and housing. Method 59,482 participants in 12 UK longitudinal adult population studies with data collected prior to and during the COVID-19 pandemic. Within each study we estimated the association between psychological distress assessed pre-pandemic and disruptions since the start of the pandemic to three domains: healthcare (medication access, procedures, or appointments); economic activity (employment, income, or working hours); and housing (change of address or household composition). Meta-analyses were used to pool estimates across studies. Results Across the analysed datasets, one to two-thirds of participants experienced at least one disruption, with 2.3-33.2% experiencing disruptions in two or more domains. One standard deviation higher pre-pandemic psychological distress was associated with: (i) increased odds of any healthcare disruptions (OR=1.30; [95% CI:1.20–1.40]) with fully adjusted ORs ranging from 1.24 [1.09–1.41] for disruption to procedures and 1.33 [1.20– 1.49] for disruptions to prescriptions or medication access; (ii) loss of employment (OR=1.13 [1.06–1.21]) and income (OR=1.12 [1.06 –1.19]) and reductions in working hours/furlough (OR=1.05 [1.00–1.09]); (iii) no associations with housing disruptions (OR=1.00 [0.97–1.03]); and (iv) increased likelihood of experiencing a disruption in at least two domains (OR=1.25 [1.18–1.32]) or in one domain (OR=1.11 [1.07–1.16]) relative to no disruption. Conclusion People experiencing psychological distress pre-pandemic have been more likely to experience healthcare and economic disruptions, and clusters of disruptions across multiple domains during the pandemic. Failing to address these disruptions risks further widening the existing inequalities in mental health.

Clinical and functional effects of the COVID-19 pandemic and social distancing on Veterans with psychotic disorders and recently-housed Veterans (preprint)

Background: The COVID pandemic has upended the daily lives of everyone in the United States, negatively impacting social interactions, work, and living situations. The pandemic could lead to or exacerbate mental health issues, especially in people who are already vulnerable to such effects. Within the Department of Veterans Affairs (VA) healthcare system two populations vulnerable to social and functional disruptions include those who have recently experienced homelessness (recently housed Veterans, RHV) and those who have a psychotic disorder (PSY). Methods and Findings: We conducted phone interviews with PSY (n = 81), RHV (n = 76) and control Veterans (CTL, n = 74) between mid-May – mid-August, 2020 (“current”) and a retrospective assessment relative to January, 2020 (“pre-COVID”). We assessed clinical factors (e.g., depression, anxiety, loneliness) and community integration (e.g., family and social functioning, work) at both time periods, and risk and protective factors (e.g., resilience, uncertainty) for the current period. The two vulnerable groups had higher levels of clinical symptoms and poorer community integration relative to CTL, as expected. Regarding the effect of the pandemic, results showed that all three groups experienced worse clinical outcomes (i.e., increased depression, anxiety, loneliness) currently vs. pre-COVID; there were no significant interactions between group and time period indicating all three groups were equally impacted by the pandemic. For community integration, there was a small but significant decrease in social networks in all three groups currently vs. pre-COVID. RHV showed a small but significant increase in independent living relative to pre-COVID ratings. Finally, RHV had greater levels of intolerance of uncertainty compared to PSY and CTL. Conclusions: Our results indicate that vulnerable and non-vulnerable Veterans were equally negatively impacted by the COVID-19 pandemic. The lack of a disproportionate effect of the pandemic on the vulnerable groups may be due to the availability and utilization of comprehensive VA services available to vulnerable Veterans (e.g., housing and financial support, medical and mental health services), which may have helped to mitigate the impact of the pandemic.

Pre-school childcare and inequalities in child development (preprint)

Centre-based childcare may benefit pre-school children and alleviate inequalities in early childhood development, but evidence on socio-emotional and physical health outcomes is limited. Data were from the UK Millennium Cohort Study (n=14,376). Inverse-probability weighting was used to estimate confounder-adjusted population-average effects of centre and non-centre-based childcare (compared to parental care only) between ages 26-31 months on (age 3): internalising and externalising symptoms, pro-social behaviour, independence, emotional dysregulation, vocabulary, school readiness, and body mass index. To assess impacts on inequalities, controlled direct effects of low parental education and lone parenthood on all outcomes were estimated under two hypothetical scenarios: 1) universal take-up of centre-based childcare; and 2) parental care only. On average, non-centre based childcare improved vocabulary and centre-based care improved school readiness, with little evidence of other benefits. However, socio-economic inequalities were observed for all outcomes and were attenuated in scenario 1 (universal take-up). For example, inequalities in externalising symptoms (according to low parental education) were reduced from a confounder-adjusted standard deviation difference of 7.8 (95% confidence intervals: 6.7, 8.8), to 1.7 (0.6, 2.7). Inequalities by parental education in scenario 2 (parental care only) were wider than in scenario 1 for externalising symptoms (at 3.4 (2.4, 4.4)), and for emotional dysregulation and school readiness. Inequalities by lone parenthood, which were smaller, fell in scenario 1, and fell further in scenario 2. Universal access to centre-based pre-school care may alleviate inequalities, while restricted access (e.g. during lockdown for a pandemic such as Covid-19) may widen some inequalities in socioemotional and cognitive development.

Mental health and health behaviours before and during the COVID-19 lockdown: Longitudinal analyses of the UK Household Longitudinal Study (preprint)

BackgroundThere are concerns that COVID-19 mitigation measures, including the "lockdown", may have unintended health consequences. We examined trends in mental health and health behaviours in the UK before and during the initial phase of the COVID-19 lockdown and differences across population subgroups. MethodsRepeated cross-sectional and longitudinal analysis of the UK Household Longitudinal Study, including representative samples of adults (aged 18+) interviewed in four survey waves between 2015 and 2020 (n=48,426). 9,748 adults had complete data for longitudinal analyses. Outcomes included psychological distress (General Health Questionnaire-12 (GHQ)), loneliness, current cigarette smoking, use of e-cigarettes and alcohol consumption. Cross-sectional prevalence estimates were calculated and multilevel Poisson regression assessed associations between time period and the outcomes of interest, as well as differential associations by age, gender, education level and ethnicity. ResultsPsychological distress increased one month into lockdown with the prevalence rising from 19.4% (95% CI 18.7%-20.0%) in 2017-19 to 30.3% (95% CI 29.1%-31.6%) in April 2020 (RR=1.3, 95% CI: 1.1,1.4). Groups most adversely affected included women, young adults, people from an Asian background and those who were degree educated. Loneliness remained stable overall (RR=0.9, 95% CI: 0.6,1.5). Smoking declined (RR=0.9, 95% CI=0.8,1.0) and the proportion of people drinking four or more times per week increased (RR=1.4, 95% CI: 1.3,1.5), as did binge drinking (RR=1.5, 95% CI: 1.3,1.7). ConclusionsPsychological distress increased one month into lockdown, particularly among women and young adults. Smoking declined, but adverse alcohol use generally increased. Effective measures are required to mitigate adverse impacts on health. O_LSTWhat is already known on this topicC_LSTO_LICountries around the world have implemented radical COVID-19 lockdown measures, with concerns that these may have unintended consequences for a broad range of health outcomes. C_LIO_LIEvidence on the impact of lockdown measures on mental health and health-related behaviours remains limited. C_LI O_LSTWhat this study addsC_LSTO_LIIn the UK, psychological distress markedly increased during lockdown, with women particularly adversely affected. C_LIO_LICigarette smoking fell, but adverse drinking behaviour generally increased. C_LI