Prolonged airway explant culture enables study of health, disease, and viral pathogenesis (preprint)

In vitro models play a major role in studying airway physiology and disease. However, the native lungs complex tissue architecture and non-epithelial cell lineages are not preserved in these models. Ex vivo tissue models could overcome in vitro limitations, but methods for long-term maintenance of ex vivo tissue has not been established. We describe methods to culture human large airway explants, small airway explants, and precision-cut lung slices for at least 14 days. Human airway explants recapitulate genotype-specific electrophysiology, characteristic epithelial, endothelial, stromal and immune cell populations, and model viral infection after 14 days in culture. These methods also maintain mouse, rabbit, and pig tracheal explants. Notably, intact airway tissue can be cryopreserved, thawed, and used to generate explants with recovery of function 14 days post-thaw. These studies highlight the broad applications of airway tissue explants and their use as translational intermediates between in vitro and in vivo studies.

Hidden evolutionary constraints dictate the retention of coronavirus accessory genes (preprint)

Genetic innovation is fundamental to the ability of viruses to adapt in the face of host immunity. Coronaviruses exhibit many mechanisms of innovation given flexibility in genomic composition relative to most RNA virus families (1-5). Examples include the acquisition of unique accessory genes that can originate by capture of cellular genes or through duplication and divergence of existing viral genes (6-8). Accessory genes may be influential in dictating viral host range and cellular tropism, but little is known about how selection acts on these variable regions of virus genomes. We used experimental evolution of mouse hepatitis virus (MHV) with an inactive native phosphodiesterase, NS2, that encodes a complementing cellular AKAP7 gene (9), to simulate the capture of a host gene and found hidden patterns of constraint that determine the fate of coronavirus accessory genes. After courses of serial infection, AKAP7 was retained under strong selection but rapidly lost under relaxed selection. In contrast, the gene encoding inactive NS2, ORF2, remained intact, suggesting it is under cryptic evolutionary constraint. Guided by the retention of ORF2 and hints of similar patterns in related betacoronaviruses, we analyzed the evolution of SARS-CoV-2 ORF8, which arose via gene duplication (6) and contains premature stop codons in several globally successful lineages. As with MHV ORF2, the coding-defective SARS-CoV-2 ORF8 gene remains largely intact, mirroring patterns observed during MHV experimental evolution and extending these findings to viruses currently adapting to humans. Retention of inactive genes challenges assumptions on the dynamics of gene loss in virus genomes and can help guide evolutionary analysis of emerging and pandemic coronaviruses.

Genetic tracing of market wildlife and viruses at the epicenter of the COVID-19 pandemic (preprint)

Zoonotic spillovers of viruses have occurred through the animal trade worldwide. The start of the COVID-19 pandemic was traced epidemiologically to the Huanan Wholesale Seafood Market, the site with the most reported wildlife vendors in the city of Wuhan, China. Here, we analyze publicly available qPCR and sequencing data from environmental samples collected in the Huanan market in early 2020. We demonstrate that the SARS-CoV-2 genetic diversity linked to this market is consistent with market emergence, and find increased SARS-CoV-2 positivity near and within a particular wildlife stall. We identify wildlife DNA in all SARS-CoV-2 positive samples from this stall. This includes species such as civets, bamboo rats, porcupines, hedgehogs, and one species, raccoon dogs, known to be capable of SARS-CoV-2 transmission. We also detect other animal viruses that infect raccoon dogs, civets, and bamboo rats. Combining metagenomic and phylogenetic approaches, we recover genotypes of market animals and compare them to those from other markets. This analysis provides the genetic basis for a short list of potential intermediate hosts of SARS-CoV-2 to prioritize for retrospective serological testing and viral sampling.

Gender differences in COVID-19 knowledge, risk perception, and public stigma among the general community: Findings from a nationwide cross-sectional study in India.

Introduction: Individual and community characteristics predictive of knowledge, perception, and attitude on COVID-19, specifically on gender, have not been adequately explored. Objective: To examine the gender differences in COVID-19 knowledge, self-risk perception and public stigma among the general community and to understand other socio-demographic factors which were predictive of them. Method: A nationally representative cross-sectional multi-centric survey was conducted among adult individuals(≥18 yrs) from the community member (N = 1978) from six states and one union territory of India between August 2020 to February 2021. The participants were selected using systematic random sampling. The data were collected telephonically using pilot-tested structured questionnaires and were analyzed using STATA. Gender-segregated multivariable analysis was conducted to identify statistically significant predictors (p < 0.05) of COVID-19-related knowledge, risk perception, and public stigma in the community. Results: Study identified significant differences between males and females in their self-risk perception (22.0% & 18.2% respectively) and stigmatizing attitude (55.3% & 47.1% respectively). Highly educated males and females had higher odds of having COVID-19 knowledge (aOR: 16.83: p < 0.05) than illiterates. Highly educated women had higher odds of having self-risk perception (aOR: 2.6; p < 0.05) but lower public stigma [aOR: 0.57; p < 0.05]. Male rural residents had lower odds of having self-risk perception and knowledge [aOR: 0.55; p < 0.05 & aOR: 0.72; p < 0.05] and female rural residents had higher odds of having public stigma [aOR: 1.36; p < 0.05]. Conclusion: Our study findings suggest the importance of considering thegender differentials and their background, education status and residential status in designing effective interventions to improve knowledge and reduce risk perception and stigma in the community about COVID-19.

Contingency management with stepped care for unhealthy alcohol use among individuals with HIV: Protocol for a randomized controlled trial.

BACKGROUND: Although unhealthy alcohol use is associated with increased morbidity and mortality among people with HIV (PWH), many are ambivalent about engaging in treatment and experience variable responses to treatment. We describe the rationale, aims, and study design for the Financial Incentives, Randomization, with Stepped Treatment (FIRST) Trial, a multi-site randomized controlled efficacy trial. METHODS: PWH in care recruited from clinics across the United States who reported unhealthy alcohol use, had a phosphatidylethanol (PEth) >20 ng/mL, and were not engaged in formal alcohol treatment were randomized to integrated contingency management with stepped care versus treatment as usual. The intervention involved two steps; Step 1: Contingency management (n = 5 sessions) with potential rewards based on 1) short-term abstinence; 2) longer-term abstinence; and 3) completion of healthy activities to promote progress in addressing alcohol consumption or conditions potentially impacted by alcohol; Step 2: Addiction physician management (n = 6 sessions) plus motivational enhancement therapy (n = 4 sessions). Participants' treatment was stepped up at week 12 if they lacked evidence of longer-term abstinence. Primary outcome was abstinence at week 24. Secondary outcomes included alcohol consumption (assessed by TLFB and PEth) and the Veterans Aging Cohort Study (VACS) Index 2.0 scores; exploratory outcomes included progress in addressing medical conditions potentially impacted by alcohol. Protocol adaptations due to the COVID-19 pandemic are described. CONCLUSIONS: The FIRST Trial is anticipated to yield insights on the feasibility and preliminary efficacy of integrated contingency management with stepped care to address unhealthy alcohol use among PWH. CLINICALTRIALS: gov identifier: NCT03089320.

Impact of COVID-19 on hand surgery transfers at a level-1 trauma center

Background: The COVID-19 pandemic significantly impacted elective surgical volume across the country;however, its effect on urgent transfers is unclear. This study sought to understand the impact of COVID-19 on transfers for hand surgery evaluation at a single quaternary referral center during the initial 3 mo of state mandated restrictions. Methods: A retrospective analysis was performed comparing the rate and character of transfers for hand surgery evaluation from March to June of 2020 to a temporally matched cohort averaged across 2018 and 2019. The primary outcome of this study was transfer frequency, with secondary outcomes of treatment rendered and type of disposition. Results: The rate of transfer between emergency departments for hand surgery evaluation was not statistically different from before to during COVID (ED-to-ED transfer rate: 4.3% and 5.1% respectively, P =0.68). Patient demographics were similar, with no difference in age (pre-COVID-19 mean 48.6 yr vs. intra-COVID-19 mean 53.2 yr, P =0.31) or type of insurance (P =0.99). Regarding reason for transfer, both cohorts were similar in the number of transfers for trauma versus infection (pre-COVID-19 infection: 11 trauma: 20.5 vs. intra-COVID-19 infection: 4 trauma: 17 P =0.99). We observed similar rates of transfers requiring procedural intervention (pre-COVID-19 69.8% vs. intra-COVID-19 57.1% P =0.19). Lastly, there was no difference in admission patterns, with pre-COVID-19 rates (71.4%) similar to those during COVID-19 (52%) P =0.15. Conclusions: Despite the many changes to healthcare in the US during the COVID-19 pandemic, the practice of transferring for evaluation to a Level 1 hand surgery center was similar to pre-pandemic years. Level VI Evidence: Presenting a single descriptive study.

Celebrating 60 years of general practice training programs in Australia

Over the years, training for general practice has undergone several iterations, with profession-led training starting this year.2 Yet, the mission is essentially unchanged and follows the lead of the RACGP through acknowledging that the patient is at the centre of care, supported in the first instance by their regular GP to provide patient-centred, comprehensive, high-quality, continuous, coordinated, and accessible care.3 This year also heralds the arrival of a new triennium of continuing professional development (CPD) standards for Australian GPs. With that in mind, AJGP will now publish the answers to the clinical challenge in the following issue, to ensure that all current and aspiring GPs, regardless of location and circumstances, may benefit from this program. GPs continue to be the most common health professional seen by the Australian public, with 84% having at least one consultation each year, rising to 95% for those with a chronic disease,5 leading us full circle to the RACGP mission, which places patients at the forefront.

Outcomes of meningococcal serogroup B disease in children after implementation of routine infant 4CMenB vaccination in England: an active, prospective, national surveillance study.

BACKGROUND: In 2015, the UK included 4CMenB, a multi-component, recombinant protein-based vaccine against meningococcal serogroup B (MenB) disease, in the national infant immunisation programme. We aimed to assess the effect of 4CMenB vaccination on the severity of MenB disease presentation and outcomes. METHODS: In this active, prospective, national surveillance study, we used data from the UK Health Security Agency national surveillance of meningococcal disease. We included data from follow-up of children younger than 5 years with laboratory-confirmed MenB disease who were eligible for 4CMenB vaccination with general practice 3-6 months after disease onset. All invasive MenB isolates were tested using the Meningococcal Antigen Typing System to determine whether the isolate was potentially preventable by 4CMenB. Admission to intensive care, death, and, when possible, reported sequelae in survivors were reviewed alongside vaccine status. For the epidemiological analysis, we compared laboratory-confirmed MenB disease cases before 4CMenB implementation (Sept 1, 2010, to March 31, 2015) with those after implementation (Sept 1, 2015, to March 31, 2020). For clinical follow-up and outcomes, we included all children younger than 5 years with laboratory-confirmed MenB disease between Sept 1, 2015, and March 31, 2021. FINDINGS: Between Sept 1, 2015, and March 31, 2021, there were 371 cases of MenB disease in children younger than 5 years, including 256 (69%) in those younger than 1 year and 128 (35%) in those younger than 3 months. After the introduction of 4CMenB, the peak age of patients with MenB disease shifted from 5-6 months to 1-3 months. Overall, 108 (29%) of 371 children were too young for vaccination, unvaccinated, or developed MenB disease within 14 days of the first dose. Of 110 meningococcal strains characterised, 11 (92%) of 12 were potentially preventable by 4CMenB in unvaccinated children compared with 53 (66%) of 80 in partly vaccinated and 11 (69%) of 16 in fully vaccinated children. 78 (21%) of 371 children required intensive care, and the case fatality ratio was 5% (17 of 371), with 11 of 17 deaths occurring before 1 year of age, including seven in infants who were too young (<8 weeks) for vaccination. Of 354 survivors, 57 (16%) had 74 sequelae reported; 45 (61%) of 74 were neurological, 17 (23%) were physical, two (3%) were behavioural or psychological, and ten (14%) were other complications. Prevalence of sequelae was similar in unvaccinated (15 [15%] of 98) and vaccinated (42 [16%] 256) children, as were composite outcomes of death or sequelae, and intensive care or death or sequelae. INTERPRETATION: Cases of MenB disease in vaccine-eligible children declined after 4CMenB implementation, but morbidity in vaccinated and unvaccinated children remained unchanged, highlighting the importance of vaccination to prevent MenB disease. The lower peak age of infants with MenB disease after 4CMenB implementation, with a higher case fatality ratio in young infants, highlights the importance of timely vaccination. FUNDING: UK Health Security Agency.

Fatal drug use in the COVID-19 pandemic response: Changing trends in drug-involved deaths before and after stay-at-home orders in Louisiana.

The effect of disaster events on increasing drug-involved deaths has been clearly shown in previous literature. As the COVID-19 pandemic led to stay-at-home orders throughout the United States, there was a simultaneous spike in drug-involved deaths around the country. The landscape of a preexisting epidemic of drug-involved deaths in the United States is one which is not geographically homogenous. Given this unequal distribution of mortality, state-specific analysis of changing trends in drug use and drug-involved deaths is vital to inform both care for people who use drugs and local policy. An analysis of public health surveillance data from the state of Louisiana, both before and after the initial stay-at-home order of the COVID-19 pandemic, was used to determine the effect the pandemic may have had on the drug-involved deaths within this state. Using the linear regression analysis of total drug-involved deaths, as well as drug-specific subgroups, trends were measured based on quarterly (Qly) deaths. With the initial stay-at-home order as the change point, trends measured through quarter 1 (Q1) of 2020 were compared to trends measured from quarter 2 (Q2) of 2020 through quarter 3 (Q3) of 2021. The significantly increased rate of change in Qly drug-involved deaths, synthetic opioid-involved deaths, stimulant-involved deaths, and psychostimulant-involved deaths indicates a long-term change following the initial response to the COVID-19 pandemic. Changes in the delivery of mental health services, harm reduction services, medication for opioid use disorder (MOUD), treatment services, withdrawal management services, addiction counseling, shelters, housing, and food supplies further limited drug-involved prevention support, all of which were exacerbated by the new stress of living in a pandemic and economic uncertainty.

The Contribution of Environmental Science to Mental Health Research: A Scoping Review.

Mental health is influenced by multiple complex and interacting genetic, psychological, social, and environmental factors. As such, developing state-of-the-art mental health knowledge requires collaboration across academic disciplines, including environmental science. To assess the current contribution of environmental science to this field, a scoping review of the literature on environmental influences on mental health (including conditions of cognitive development and decline) was conducted. The review protocol was developed in consultation with experts working across mental health and environmental science. The scoping review included 202 English-language papers, published between 2010 and 2020 (prior to the COVID-19 pandemic), on environmental themes that had not already been the subject of recent systematic reviews; 26 reviews on climate change, flooding, air pollution, and urban green space were additionally considered. Studies largely focused on populations in the USA, China, or Europe and involved limited environmental science input. Environmental science research methods are primarily focused on quantitative approaches utilising secondary datasets or field data. Mental health measurement was dominated by the use of self-report psychometric scales. Measures of environmental states or exposures were often lacking in specificity (e.g., limited to the presence or absence of an environmental state). Based on the scoping review findings and our synthesis of the recent reviews, a research agenda for environmental science's future contribution to mental health scholarship is set out. This includes recommendations to expand the geographical scope and broaden the representation of different environmental science areas, improve measurement of environmental exposure, prioritise experimental and longitudinal research designs, and giving greater consideration to variation between and within communities and the mediating pathways by which environment influences mental health. There is also considerable opportunity to increase interdisciplinarity within the field via the integration of conceptual models, the inclusion of mixed methods and qualitative approaches, as well as further consideration of the socio-political context and the environmental states that can help support good mental health. The findings were used to propose a conceptual model to parse contributions and connections between environmental science and mental health to inform future studies.

Ultrasound-guided glenohumeral joint injections for shoulder pain in ALS: A case series.

Introduction: Shoulder pain is a common secondary impairment for people living with ALS (PALS). Decreased range of motion (ROM) from weakness can lead to shoulder pathology, which can result in debilitating pain. Shoulder pain may limit PALS from participating in activities of daily living and may have a negative impact on their quality of life. This case series explores the efficacy of glenohumeral joint injections for the management of shoulder pain due to adhesive capsulitis in PALS. Methods: People living with ALS and shoulder pain were referred to sports medicine-certified physiatrists for diagnostic evaluation and management. They completed the Revised ALS Functional Rating Scale and a questionnaire asking about their pain levels and how it impacts sleep, function, and quality of life at baseline pre-injection, 1-week post-injection, 1 month post-injection, and 3 months post-injection. Results: We present five cases of PALS who were diagnosed with adhesive capsulitis and underwent glenohumeral joint injections. Though only one PALS reported complete symptom resolution, all had at least partial symptomatic improvement during the observation period. No complications were observed. Conclusions: People living with ALS require a comprehensive plan to manage shoulder pain. Glenohumeral joint injections are safe and effective for adhesive capsulitis in PALS, but alone may not completely resolve shoulder pain. Additional therapies to improve ROM and reduce pain should be considered.

Comparing antibody assays as correlates of protection against COVID-19 in the COVE mRNA-1273 vaccine efficacy trial.

The best assay or marker to define mRNA-1273 vaccine-induced antibodies as a correlate of protection (CoP) is unclear. In the COVE trial, participants received two doses of the mRNA-1273 COVID-19 vaccine or placebo. We previously assessed IgG binding antibodies to the spike protein (spike IgG) or receptor binding domain (RBD IgG) and pseudovirus neutralizing antibody 50 or 80% inhibitory dilution titer measured on day 29 or day 57, as correlates of risk (CoRs) and CoPs against symptomatic COVID-19 over 4 months after dose. Here, we assessed a new marker, live virus 50% microneutralization titer (LV-MN50), and compared and combined markers in multivariable analyses. LV-MN50 was an inverse CoR, with a hazard ratio of 0.39 (95% confidence interval, 0.19 to 0.83) at day 29 and 0.51 (95% confidence interval, 0.25 to 1.04) at day 57 per 10-fold increase. In multivariable analyses, pseudovirus neutralization titers and anti-spike binding antibodies performed best as CoRs; combining antibody markers did not improve correlates. Pseudovirus neutralization titer was the strongest independent correlate in a multivariable model. Overall, these results supported pseudovirus neutralizing and binding antibody assays as CoRs and CoPs, with the live virus assay as a weaker correlate in this sample set. Day 29 markers performed as well as day 57 markers as CoPs, which could accelerate immunogenicity and immunobridging studies.

Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH.

BACKGROUND & AIMS: The LIVIFY trial investigated the safety, tolerability, and efficacy, of Vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH). METHODS: This double-blind phase 2a study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, Vonafexor 100 mg twice daily (VONA-100BID), Vonafexor 200 mg once daily (VONA-200QD), or 400 mg Vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, Vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. Efficacy endpoints were reduction in liver fat content (LFC) from baseline to Week 12 by magnetic resonance imaging proton density fat fraction (MRI-PDFF, primary), imaging biomarker of fibrotic steatohepatitis (corrected T1 signal), and liver enzymes. RESULTS: One hundred and twenty patients were randomised (Part A, n=24; Part B, n=96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD, (-6.3% [0.9]), VONA-200QD (-5.4% [0.9]), versus placebo (-2.3% [0.9], p=0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with Vonafexor. Creatinine based glomerular filtration rate (eGFR) improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of subjects in the placebo, VONA-100QD, and VONA-200QD arms, respectively. CONCLUSIONS: In patients with suspected fibrotic NASH, Vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit. CLINICAL TRIAL NUMBER (EUDRACT): 2018-003119-22. GOV IDENTIFIER: NCT03812029. IMPACT AND IMPLICATIONS: NASH has become a leading cause for chronic liver disease and patients are also at higher risk for the development of chronic kidney disease. There are no approved therapies and only few options to treat this population. LIVIFY Phase 2a trial results show that single daily administration of oral Vonafexor, a FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-Cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials to ultimately provide therapies for the unmet medical need in NASH.

Lessons learned from the Last Gift study: ethical and practical challenges faced while conducting HIV cure-related research at the end of life.

The Last Gift is an observational HIV cure-related research study conducted with people with HIV at the end of life (EOL) at the University of California San Diego. Participants agree to voluntarily donate blood and other biospecimens while living and their bodies for a rapid research autopsy postmortem to better understand HIV reservoir dynamics throughout the entire body. The Last Gift study was initiated in 2017. Since then, 30 volunteers were enrolled who are either (1) terminally ill with a concomitant condition and have a prognosis of 6 months or less or (2) chronically ill with multiple comorbidities and nearing the EOL.Multiple ethical and logistical challenges have been revealed during this time; here, we share our lessons learnt and ethical analysis. Issues relevant to healthcare research include surrogate informed consent, personal and professional boundaries, challenges posed conducting research in a pandemic, and clinician burnout and emotional support. Issues more specific to EOL and postmortem research include dual roles of clinical care and research teams, communication between research personnel and clinical teams, legally required versus rapid research autopsy, identification of next of kin/loved ones and issues of inclusion. Issues specific to the Last Gift include logistics of body donation and rapid research autopsy, and disposition of the body as a study benefit.We recommend EOL research teams to have clear provisions around surrogate informed consent, rotate personnel to maintain boundaries, limit direct contact with staff associated with clinical care and have a clear plan for legally required versus research autopsies, among other recommendations.

Risk factors for SARS-CoV-2 related mortality and hospitalization before vaccination: A meta-analysis

The literature remains scarce regarding the varying point estimates of risk factors for COVID-19 associated mortality and hospitalization. This meta-analysis investigates risk factors for mortality and hospitalization, estimates individual risk factor contribution, and determines drivers of published estimate variances. We conducted a systematic review and meta-analysis of COVID-19 related mortality and hospitalization risk factors using PRISMA guidelines. Random effects models estimated pooled risks and meta-regression analyses estimated the impact of geographic region and study type. Studies conducted in North America and Europe were more likely to have lower effect sizes of mortality attributed to chronic kidney disease (OR: 0.21, 95% CI: 0.09–0.52 and OR: 0.25, 95% CI: 0.10–0.63, respectively). Retrospective studies were more likely to have decreased effect sizes of mortality attributed to chronic heart failure compared to prospective studies (OR: 0.65, 95% CI: 0.44–0.95). Studies from Europe and Asia (OR: 0.42, 95% CI: 0.30–0.57 and OR: 0.49, 95% CI: 0.28–0.84, respectively) and retrospective studies (OR: 0.58, 95% CI: 0.47–0.73) reported lower hospitalization risk attributed to male sex. Significant geographic population-based variation was observed in published comorbidity related mortality risks while male sex had less of an impact on hospitalization among European and Asian populations or in retrospective studies.

Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals.

The emergence of SARS-CoV-2 variants with evidence of antibody escape highlight the importance of addressing whether the total CD4+ and CD8+ T cell recognition is also affected. Here, we compare SARS-CoV-2-specific CD4+ and CD8+ T cells against the B.1.1.7, B.1.351, P.1, and CAL.20C lineages in COVID-19 convalescents and in recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. The total reactivity against SARS-CoV-2 variants is similar in terms of magnitude and frequency of response, with decreases in the 10%-22% range observed in some assay/VOC combinations. A total of 7% and 3% of previously identified CD4+ and CD8+ T cell epitopes, respectively, are affected by mutations in the various VOCs. Thus, the SARS-CoV-2 variants analyzed here do not significantly disrupt the total SARS-CoV-2 T cell reactivity; however, the decreases observed highlight the importance for active monitoring of T cell reactivity in the context of SARS-CoV-2 evolution.

Adapting a Physical Earthquake-Aftershock Model to Simulate the Spread of COVID-19.

There exists a need for a simple, deterministic, scalable, and accurate model that captures the dominant physics of pandemic propagation. We propose such a model by adapting a physical earthquake/aftershock model to COVID-19. The aftershock model revealed the physical basis for the statistical Epidemic Type Aftershock Sequence (ETAS) model as a highly non-linear diffusion process, thus permitting a grafting of the underlying physical equations into a formulation for calculating infection pressure propagation in a pandemic-type model. Our model shows that the COVID-19 pandemic propagates through an analogous porous media with hydraulic properties approximating beach sand and water. Model results show good correlations with reported cumulative infections for all cases studied. In alphabetical order, these include Austria, Belgium, Brazil, France, Germany, Italy, New Zealand, Melbourne (AU), Spain, Sweden, Switzerland, the UK, and the USA. Importantly, the model is predominantly controlled by one parameter (α), which modulates the societal recovery from the spread of the virus. The obtained recovery times for the different pandemic waves vary considerably from country to country and are reflected in the temporal evolution of registered infections. These results provide an intuition-based approach to designing and implementing mitigation measures, with predictive capabilities for various mitigation scenarios.

Lessons From the Field: Rapid Antigen Testing Is Efficient and Practical for Mitigation of Coronavirus Disease 2019 Outbreaks in Long-Term Care Facilities.

Background: Mitigation of coronavirus disease 2019 (COVID-19) outbreaks in long-term care facilities (LTCFs) is facilitated by rapid identification and isolation of infectious individuals to interrupt viral transmission. Immunochromatographic (IC) tests, or rapid antigen tests, have high sensitivity and specificity during the contagious period for COVID-19. Mathematical modeling predicts frequent IC surveillance will be more efficient than polymerase chain reaction (PCR)-based strategies, especially during community surges when reporting of PCR results can be delayed. However, there are few published field studies evaluating IC testing strategies in this long-term care setting. Methods: In fall and winter of 2020, the Marin Health and Human Services Department implemented thrice-weekly IC mass testing by nonlaboratory workers in outbreaks that occurred in 2 LTCFs, in addition to then-standard semiweekly PCR testing. The IC test performance was characterized using same-day PCR specimens as reference standard. Cumulative incidence and duration of transmission for the 2 IC intervention facility outbreaks were compared with 6 reference LTCFs that used weekly to semiweekly PCR alone during an outbreak response. Results: Of 123 same-day test pairs, IC test sensitivity and specificity were 75% (95% confidence interval [CI], 48%-93%) and 100% (95% CI, 97%-100%), respectively. The median duration of outbreak transmission was 19.5 days in the 2 intervention sites and 28 days in the reference facilities (P = .40). Cumulative incidence for the outbreaks among LTCF residents was 41% in the intervention facilities versus 52% in the reference facilities (P = .04, Fisher 2-sided exact). Conclusions: Thrice-weekly mass IC testing as used by nonlaboratory personnel can be highly practical and effective for COVID-19 outbreak mitigation in the LTCF setting.

Molecular Pathology, Diagnostics and Therapeutics: A Story of Success in 2022.

Molecular pathology, diagnostics and therapeutics are three closely related topics of critical importance in medical research and clinical practice [...].