Mechanisms underlying exercise intolerance in Long COVID: an accumulation of multi-system dysfunction (preprint)

The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS-CoV-2 virus ('Long COVID') is not fully understood. Cases were recruited from a Long COVID clinic (N=32; 44{+/-} 12y; 10(31%)men), and age/sex-matched healthy controls (HC) (N=19; 40{+/-} 13y; 6(32%)men) from University College London staff and students. We assessed exercise performance, lung and cardiac function, vascular health, skeletal muscle oxidative capacity and autonomic nervous system (ANS) function. Key outcome measures for each physiological system were compared between groups using potential outcome means(95% confidence intervals) adjusted for potential confounders. Long COVID participant outcomes were compared to normative values. When compared to HC, cases exhibited reduced Oxygen Uptake Efficiency Slope (1847(1679,2016) vs (2176(1978,2373) ml/min, p=0.002) and Anaerobic Threshold (13.2(12.2,14.3) vs 15.6(14.4,17.2) ml/Kg/min, p<0.001), and lower oxidative capacity on near infrared spectroscopy ({tau}: 38.7(31.9,45.6) vs 24.6(19.1,30.1) seconds, p=0.001). In cases, ANS measures fell below normal limits in 39%. Long COVID is associated with reduced measures of exercise performance and skeletal muscle oxidative capacity in the absence of evidence of microvascular dysfunction, suggesting mitochondrial pathology. There was evidence of attendant ANS dysregulation in a significant proportion. These multi-system factors might contribute to impaired exercise tolerance in Long COVID sufferers.

Establishing SARS-CoV-2 Membrane protein-specific antibodies as a valuable serological target via high-content microscopy

The prevalence and strength of serological responses mounted towards SARS-CoV-2 proteins other than nucleocapsid (N) and spike (S), which may be of use as additional serological markers, remains underexplored. Using high content microscopy to assess antibody responses against full length StrepTagged SARS-CoV-2 proteins, we found that 85% (166/196) of unvaccinated individuals with RT-PCR confirmed SARS-CoV-2 infections and 74% (31/42) of individuals infected after being vaccinated developed detectable IgG against the structural protein M, which is higher than previous estimates. Compared with N antibodies, M IgG displayed a shallower time-dependent decay and greater specificity. Sensitivity for SARS-CoV-2 seroprevalence was enhanced when N and M IgG detection was combined. These findings indicate that screening for M seroconversion may be a good approach for detecting additional vaccine breakthrough infections and highlight the potential to use HCM as a rapidly deployable method to identify the most immunogenic targets of newly emergent pathogens. Graphical

Lipid nanoparticle library towards development next generation genomic medicines

Ionizable amino lipids are a major constituent of the lipid nanoparticles for delivering nucleic acid therapeutics (e.g., DLin-MC3-DMA in ONPATTRO , ALC-0315 in Comirnaty , SM-102 in Spikevax ). Scarcity of lipids that are suitable for cell therapy, vaccination, and gene therapies continue to be a problem in advancing many potential diagnostic/therapeutic/vaccine candidates to the clinic. Herein, we describe the development of novel ionizable lipids to be used as functional excipients for designing vehicles for nucleic acid therapeutics/vaccines in vivo or ex vivo use in cell therapy applications. We first studied the transfection efficiency (TE) of LNP-based mRNA formulations of these ionizable lipid candidates in primary human T cells and established a workflow for engineering of primary immune T cells. We then adapted this workflow towards bioengineering of CAR constructs to T cells towards non-viral CAR T therapy. Lipids were also tested in rodents for vaccine applications using self-amplifying RNA (saRNA) encoding various antigens. We have then evaluated various ionizable lipid candidates and their biodistribution along with the mRNA/DNA translation exploration using various LNP compositions. Further, using ionizable lipids from the library, we have shown gene editing of various targets in rodents. We believe that these studies will pave the path to the advancement in nucleic acid based therapeutics and vaccines, or cell gene therapy agents for early diagnosis and detection of cancer, and for targeted genomic medicines towards cancer treatment and diagnosis.

Using the "omnicell" automatic drug dispensing cabinet to monitor sedative drugs in a critical care unit

Introduction: Automatic drug dispensers are now widely used in critical care.1-2 They can provide information about dispensed drugs. Good practice in sedation restricts the use of sedatives and titrates doses to defined responses.3-4 Objectives: To extract drug dispenser issuing records for sedatives and link these to patient records to evaluate sedative use. Method(s): in October 2019, we introduced two Omnicell XT automated dispensing cabinets (Omnicell inc. CA, USA) into a 42 bedded general/neurological unit. ICNARC (Intensive care national audit and research centre) and CCMDS (Critical care minimum data set) data was collected using the Ward Watcher program. Dispenser issuing records for alfentanil, propofol and midazolam were obtained as Excel files for 13 months from January 2020. Output time stamps were converted to dates and times. Outputs were linked to outputs of the ICNARC and CCMDS records for the patients that the drugs were issued to. All the outputs had patients identified by their unique hospital numbers. These were used in Excel "power queries" to produce a spread sheet with a single row per patient. Multiple admissions used the first diagnosis, the final outcome and the total length of stay. The total dose of sedatives was calculated from ampoule dose and number. The duration of treatment was calculated from the first and last issues of the drug. ICNARC codes were used to identify the primary system in the admission diagnostic code and those patients admitted for COVID-19. Variables were compared using Chi Squared, Mann-Whitney U and Kruskal Wallis Tests. The significance of associations was established using Spearman's Rho. Linear regression was used to define relationships more clearly. Result(s): Table one summarises the patient characteristics with respect to all admissions during the study period and for patients who had had the studied drugs issued to them. Midazolam was used in fewer patients, they were more likely to be male, heavier (p>0001) and to die than patients receiving Propofol or Alfentanil (p>0.001). With respect to diagnostic groups, all the sedatives, particularly Midazolam (p<0.001), were more likely to be used in patients with COVID-19. The relationship between the dose of sedative drugs and patient age and weight was explored using the dose per advanced respiratory day. All three drugs had a significant but weak negative relationship with age, lower doses being given to older people (Propofol r2 = 0.02, p=0.01. Alfentanil r2 = 0.04, p=0.00. Midazolam r2 = 0.07, p=0.00.). There was also a weak but significant relationship between increasing dose of Propofol with patient weight (r2 = 0.02, p=0.01), but there was no relation between weight and doses of the other drugs. Conclusion(s): Information from automatic drug dispensers can be interpreted and combined with other datasets to produce clinically relevant information. The limited weak relationships between drug dose and age and weight suggests that sedative drugs could have been better titrated to response.

Moral Judgments Impact Perceived Risks From COVID-19 Exposure

The COVID-19 pandemic created enormously difficult decisions for individuals trying to navigate both the risks of the pandemic and the demands of everyday life. Good decision making in such scenarios can have life and death consequences. For this reason, it is important to understand what drives risk assessments during a pandemic, and to investigate the ways that these assessments might deviate from ideal risk assessments. In a preregistered online study of U.S. residents (N = 841) using two blocks of vignettes about potential COVID exposure scenarios, we investigated the effects of moral judgment, importance, and intentionality on COVID infection risk assessments. Results demonstrate that risk judgments are sensitive to factors unrelated to the objective risks of infection. Specifically, activities that are morally justified are perceived as safer while those that might subject people to blame or culpability, are seen as riskier, even when holding objective risk fixed. Similarly, unintentional COVID exposures are judged as safer than intentional COVID exposures. While the effect sizes are small, these findings may have implications for public health and risk communications, particularly if public health officials are themselves subject to these biases.

Identification of Evolutionary Trajectories Shared across Human Betacoronaviruses.

Comparing the evolution of distantly related viruses can provide insights into common adaptive processes related to shared ecological niches. Phylogenetic approaches, coupled with other molecular evolution tools, can help identify mutations informative on adaptation, although the structural contextualization of these to functional sites of proteins may help gain insight into their biological properties. Two zoonotic betacoronaviruses capable of sustained human-to-human transmission have caused pandemics in recent times (SARS-CoV-1 and SARS-CoV-2), although a third virus (MERS-CoV) is responsible for sporadic outbreaks linked to animal infections. Moreover, two other betacoronaviruses have circulated endemically in humans for decades (HKU1 and OC43). To search for evidence of adaptive convergence between established and emerging betacoronaviruses capable of sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1, and SARS-CoV-2), we developed a methodological pipeline to classify shared nonsynonymous mutations as putatively denoting homoplasy (repeated mutations that do not share direct common ancestry) or stepwise evolution (sequential mutations leading towards a novel genotype). In parallel, we look for evidence of positive selection and draw upon protein structure data to identify potential biological implications. We find 30 candidate mutations, from which 4 (codon sites 18121 [nsp14/residue 28], 21623 [spike/21], 21635 [spike/25], and 23948 [spike/796]; SARS-CoV-2 genome numbering) further display evolution under positive selection and proximity to functional protein regions. Our findings shed light on potential mechanisms underlying betacoronavirus adaptation to the human host and pinpoint common mutational pathways that may occur during establishment of human endemicity.

Regenerative medicine: postnatal approaches.

Paper 2 of the paediatric regenerative medicine Series focuses on recent advances in postnatal approaches. New gene, cell, and niche-based technologies and their combinations allow structural and functional reconstitution and simulation of complex postnatal cell, tissue, and organ hierarchies. Organoid and tissue engineering advances provide human disease models and novel treatments for both rare paediatric diseases and common diseases affecting all ages, such as COVID-19. Preclinical studies for gastrointestinal disorders are directed towards oesophageal replacement, short bowel syndrome, enteric neuropathy, biliary atresia, and chronic end-stage liver failure. For respiratory diseases, beside the first human tracheal replacement, more complex tissue engineering represents a promising solution to generate transplantable lungs. Genitourinary tissue replacement and expansion usually involve application of biocompatible scaffolds seeded with patient-derived cells. Gene and cell therapy approaches seem appropriate for rare paediatric diseases of the musculoskeletal system such as spinal muscular dystrophy, whereas congenital diseases of complex organs, such as the heart, continue to challenge new frontiers of regenerative medicine.

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial.

BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.

Public trust is earned: Historical discrimination, carceral violence, and the COVID-19 pandemic.

OBJECTIVE: To assess whether knowledge of Tuskegee, the U.S. Immigration and Customs Enforcement (ICE) agency's detainment of children, and satisfaction with the George Floyd death investigation were associated with trust in actors involved in the development and distribution of coronavirus vaccines. DATA SOURCES AND STUDY SETTING: National survey with a convenience sample of Black (n = 1019) and Hispanic (n = 994) adults between July 1 and 26, 2021. STUDY DESIGN: Observational study using stratified adjusted logistic regression models to measure the association between ratings of the trustworthiness of actors involved in the development and distribution of coronavirus vaccines. PRINCIPAL FINDINGS: Among Black respondents, lower satisfaction with the George Floyd death investigation was associated with lower trustworthiness ratings of pharmaceutical companies (ME: -0.09; CI: -0.15, 0.02), the FDA (ME: -0.07; CI: -0.14, -0.00), the Trump Administration (ME: -0.09; CI: -0.16, -0.02), the Biden Administration (ME: -0.07, CI: -0.10, 0.04), and elected officials (ME: -0.10, CI: -0.18, -0.03). Among Hispanic respondents, lower satisfaction was associated with lower trustworthiness ratings of the Trump Administration (ME: -0.14, CI: -0.22, -0.06) and elected officials (ME: -0.11; CI: -0.19, -0.02). Greater knowledge of ICE's detainment of children and families among Hispanic respondents was associated with lower trustworthiness ratings of state elected officials (ME: -0.09, CI: -0.16, 0.01). Greater knowledge of the US Public Health Service Study of Syphilis in Tuskegee was associated with higher trustworthiness ratings of their usual source of care (ME: 0.09; CI: 0.28, 0.15) among Black respondents (ME: 0.09; CI: 0.01, 0.16). CONCLUSIONS: Among Black respondents, lower satisfaction with the George Floyd death investigation was associated with lowered levels of trust in pharmaceutical companies, some government officials, and administrators; it was not associated with the erosion of trust in direct sources of health care delivery, information, or regulation. Among Hispanic respondents, greater knowledge of the ICE detainments was associated with lower trustworthiness ratings of elected state officials. Paradoxically, higher knowledge of the Study of Syphilis in Tuskegee was associated with higher trustworthiness ratings in usual sources of care.

Building a green future: Examining the job creation potential of electricity, heating, and storage in low-carbon buildings

Job creation is paramount when considering global transitions to low-carbon, clean-energy solutions. The building sector, critical to reducing greenhouse gas emissions on a global scale, has technologies available that rely on electricity rather than fossil fuels for energy and indoor heating and cooling. Solar photovoltaic, energy storage in the form of prosumer batteries, and heat pumps represent three readily deployable solutions to reduce carbon emissions in both new and retrofitted buildings. This study investigates the creation of jobs for each solution and then for all three combined across key countries in North America, Europe, and Asia. While other studies have explored aggregated job creation within nations, regions or globally, this first-of-a-kind study employs a micro-level approach examining six individual building archetypes: residential, hospital, hotel, office, retail, and education. Using the best available data as of 2022, the first-order assessment finds that more than 2 million new jobs and more than 141 million job years can be generated in Europe and the United States alone during the transition to net zero living.

Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial (preprint)

Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.4 Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway.5 In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2.6,7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months.8,9 Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.10,11 Our results demonstrate, consistent with model predictions, that a safe, widely available,12 well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.

Remote graphic elicitation: A critical reflection on the emotional affordance and disruption management in caregiver research

Graphic elicitation, an arts‐based method that focuses on participant‐led drawing activities, is often conducted with the researcher in situ and discussed in an interview setting, either during or after drawing. However, the COVID‐19 pandemic and the subsequent lockdowns have meant that using graphic elicitation in its current form required a re‐evaluation. Reflecting on a research project that undertook graphic elicitation remotely, this paper considers the emotional affordance and disruption management of the method in caregiver research. While informal caregiving may be an emotionally fraught topic for the participants, we demonstrate how graphic elicitation explores emotions and experiences with sensitivity and care. Furthermore, we show that graphic elicitation enabled us to acknowledge the pandemic but maintain focus on caregiving itself. The caregivers were responsive to the method and found it rewarding and insightful, albeit with some initial hesitancy and ingrained perceptions of arts‐based outputs. Through our discussions, we show the potential for remote graphic elicitation in geography as a method to explore potentially sensitive, emotionally charged topics like caregiving. [ FROM AUTHOR] Copyright of Area is the property of Wiley-Blackwell 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.)

Dual-Scale Cnn Architecture for Covid-19 Detection from Lung Ct Images

Coronavirus Disease 2019 (COVID-19) is a terrible illness affecting the respiratory systems of animals and humans. By 2020, this sickness had become a pandemic, affecting millions worldwide. Prevention of the spread of the virus by conducting fast tests for many suspects has become difficult. Recently, many deep learning-based methods have been developed to automatically detect COVID-19 infection from lung Computed Tomography (CT) images of the chest. This paper proposes a novel dual-scale Convolutional Neural Network (CNN) architecture to detect COVID-19 from CT images. The network consists of two different convolutional blocks. Each path is similarly constructed with multi-scale feature extraction layers. The primary path consists of six convolutional layers. The extracted features from multipath networks are flattened with the help of dropout, and these relevant features are concatenated. The sigmoid function is used as the classifier to identify whether the input image is diseased. The proposed network obtained an accuracy of 99.19%, with an Area Under the Curve (AUC) value of 0.99. The proposed network has a lower computational cost than the existing methods regarding learnable parameters, the number of FLOPS, and memory requirements. The proposed CNN model inherits the benefits of densely linked paths and residuals by utilizing effective feature reuse methods. According to our experiments, the proposed approach outperforms previous algorithms and achieves state-of-the-art results.

Coronavirus Surrogate Persistence and Cross-Contamination on Food Service Operation Fomites

This study investigated the persistence and transfer rate of phi 6 bacteriophage (SARS-CoV-2 surrogate) on food contact surfaces and fomites that are commonly present in food service operations. Coupons (e.g., stainless steel, cutting board) were inoculated with phi 6 and phi 6 survival was quantifi ed over 30 days. The results showed that phi 6 persisted for up to 13 days on sponges, stainless steel, tabletops, countertops, cutting boards, and light switches. Additionally, phi 6 was found for 10 days on microfi ber towels and wooden fl oors. We examined the transfer rate of phi 6 from food contact surfaces to wiping tools, hands, and produce. Fomites and hands were inoculated with 107 or 103 PFU/cm2 phi 6 to simulate high and low contamination levels, and surfaces were allowed to dry for 1 hr. The inoculated surfaces were swabbed with sponges or towels or touched with hands or produce, and then these samples were analyzed. The results indicated that food contact surfaces, fomites, and hands can serve as sources of viral transmission within food service operations. Enveloped phi 6 could persist for days on inanimate surfaces and pose a high risk of cross-contamination in food service operations. The results of this study could be used by the food service industry to address sanitation practices and by public health agencies to provide science-based recommendations to stakeholders.

Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection.

T cell responses precede antibody and may provide early control of infection. We analyzed the clonal basis of this rapid response following SARS-COV-2 infection. We applied T cell receptor (TCR) sequencing to define the trajectories of individual T cell clones immediately. In SARS-COV-2 PCR+ individuals, a wave of TCRs strongly but transiently expand, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains but not with circulating human coronaviruses. Many expanding CDR3s were present at high frequency in pre-pandemic repertoires. Early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the preinfection naive repertoire. High-frequency naive precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection.

Fever, Rash, and Cough in a 7-Year-Old Boy.

A 7-year-old boy presented to the emergency department with fever, cough, congestion, abdominal pain, myalgias, and morbilliform rash. Several aspects of the patient's history, including recent travel, living on a farm, exposure to sick contacts, and new medications, resulted in a wide differential diagnosis. Initial laboratory testing revealed leukocytosis with neutrophilia and elevated atypical lymphocytes, but did not reveal any infectious causes of illness. He was discharged from the hospital, but then represented to the emergency department a day later with worsening rash, continued fever, abdominal pain, and poor intake. He was then admitted. A more comprehensive laboratory evaluation was initiated. During this hospital course, the patient's physical examination changed when he developed head and neck edema, and certain laboratory trends became clearer. With the assistance of several specialists, the team was able to reach a more definitive diagnosis and initiate treatment to appropriately manage his condition.

Consensus Clinical Guidance for Diagnosis and Management of Adult COVID-19 Encephalopathy Patients.

Encephalopathy, a common condition among patients hospitalized with COVID-19, can be a challenge to manage and negatively affect prognosis. While encephalopathy may present clinically as delirium, subsyndromal delirium, or coma and may be a result of systemic causes such as hypoxia, COVID-19 has also been associated with more prolonged encephalopathy due to less common but nevertheless severe complications, such as inflammation of the brain parenchyma (with or without cerebrovascular involvement), demyelination, or seizures, which may be disproportionate to COVID-19 severity and require specific management. Given the large number of patients hospitalized with severe acute respiratory syndrome coronavirus-2 infection, even these relatively unlikely complications are increasingly recognized and are particularly important because they require specific management. Therefore, the aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through consensus agreement of the Global COVID-19 Neuro Research Coalition. A systematic literature search of MEDLINE, medRxiv, and bioRxiv was conducted between January 1, 2020, and June 21, 2021, with additional review of references cited within the identified bibliographies. A modified Delphi approach was then undertaken to develop recommendations, along with a parallel approach to score the strength of both the recommendations and the supporting evidence. This review presents analysis of contemporaneous evidence for the definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and both acute and long-term management.

Immediate and Contributory Causes of Death in Patients Hospitalized with Covid-19

Background: Accurate determination of the immediate and contributory causes of death in patients with COVID-19 is important for optimal care and instituting mitigation strategies. Method(s): All deaths in Qatar between March 1, 2020 and August 31, 2022 flagged for likely relationship to COVID-19 by were evaluated by two independent reviewers trained to determine and assign the most likely immediate underlying cause of death. Each decedent's electronic medical records was comprehensively reviewed, and the cause of death was assigned based on the most plausible underlying event that triggered the event(s) that led to death based on clinical documentation and a review of laboratory, microbiology, pathology, and radiology data. After cause assignment, each case was categorized into major diagnostic groups by organ system, syndrome, or disease classification. Result(s): Among 749 deaths flagged for likely association with COVID-19, the most common admitting diagnoses were respiratory tract infection (91%) and major adverse cardiac event (MACE, 2.3%). The most common immediate cause of death was COVID pneumonia (66.2%), followed by MACE (7.1%), hospital associated pneumonia (HAP, 6.8%), bacteremia (6.3%), disseminated fungal infection (DFI, 5.2%), and thromboembolism (4.5%). The median length of hospital stay was 23 days (IQR 14,38). COVID pneumonia remained the predominant cause irrespective of the time from admission, though the proportion dropped with increasing length of stay in the hospital. Other than COVID pneumonia, MACE was the predominant cause of death in first two weeks but declined thereafter. No death occurred due to bacteremia, HAP, or DFI in the first week after hospitalization, but became increasing common with increased length of stay in the hospital accounting for 9%, 12%, and 10% of all deaths after 4 weeks in the hospital respectively. The majority of deaths (86%) occurred in the intensive care unit setting. COVID pneumonia accounted for approximately two-thirds of deaths in each setting. MACE and HAP were approximately equally represented in both settings while bacteremia and disseminated fungal infection were more common in the intensive care unit setting. Conclusion(s): Nearly one-third of patients with COVID infection die of non- COVID causes, some of which are preventable. Mitigation strategies should be instituted to reduce the risk of such deaths. (Figure Presented).

Quaternary Ammonium Compounds: A Chemical Class of Emerging Concern.

Quaternary ammonium compounds (QACs), a large class of chemicals that includes high production volume substances, have been used for decades as antimicrobials, preservatives, and antistatic agents and for other functions in cleaning, disinfecting, personal care products, and durable consumer goods. QAC use has accelerated in response to the COVID-19 pandemic and the banning of 19 antimicrobials from several personal care products by the US Food and Drug Administration in 2016. Studies conducted before and after the onset of the pandemic indicate increased human exposure to QACs. Environmental releases of these chemicals have also increased. Emerging information on adverse environmental and human health impacts of QACs is motivating a reconsideration of the risks and benefits across the life cycle of their production, use, and disposal. This work presents a critical review of the literature and scientific perspective developed by a multidisciplinary, multi-institutional team of authors from academia, governmental, and nonprofit organizations. The review evaluates currently available information on the ecological and human health profile of QACs and identifies multiple areas of potential concern. Adverse ecological effects include acute and chronic toxicity to susceptible aquatic organisms, with concentrations of some QACs approaching levels of concern. Suspected or known adverse health outcomes include dermal and respiratory effects, developmental and reproductive toxicity, disruption of metabolic function such as lipid homeostasis, and impairment of mitochondrial function. QACs' role in antimicrobial resistance has also been demonstrated. In the US regulatory system, how a QAC is managed depends on how it is used, for example in pesticides or personal care products. This can result in the same QACs receiving different degrees of scrutiny depending on the use and the agency regulating it. Further, the US Environmental Protection Agency's current method of grouping QACs based on structure, first proposed in 1988, is insufficient to address the wide range of QAC chemistries, potential toxicities, and exposure scenarios. Consequently, exposures to common mixtures of QACs and from multiple sources remain largely unassessed. Some restrictions on the use of QACs have been implemented in the US and elsewhere, primarily focused on personal care products. Assessing the risks posed by QACs is hampered by their vast structural diversity and a lack of quantitative data on exposure and toxicity for the majority of these compounds. This review identifies important data gaps and provides research and policy recommendations for preserving the utility of QAC chemistries while also seeking to limit adverse environmental and human health effects.