Stem cells are required for tissue maintenance and homeostasis during an organism's lifetime. Neural stem cells (NSCs) can be in an actively dividing state or in a quiescent state. The balance between stem cell quiescence and cycling activity determines the rate of neurogenesis. With age, more NSCs enter the quiescent state, while the total number of NSCs decreases. Here we reconsider an existing mathematical model of how neural stem cells switch between active and quiescent states from the point of view of control theory by considering the activation rate, self-renewal probability, and division rate as control parameters rather than as pre-defined functions. Our goal is to test whether those modifications to the basic model could explain the observed decline of neural stem cells with age better than Gomerzian time-dependent parameters, and compare the output from different model variants to experimental data from mice using AIC. We find that time-dependent activation rate provides the best fit to the activated cell fraction (ACF) of NSCs over time, but that other model variants with constant parameter values can better fit the total number of NSCs over time. We also consider an alternate model for NSCs with nonlinear feedback from progenitor cells that affect NSC parameters, and compare all models to experimental stem cell and progenitor data. However, all of the feedback models considered provide a worse fit to the experimental data. This suggests that when switching between active and quiescent stem cells is considered, a time-dependent linear model outperforms the integral feedback mechanism considered by other models of stem cell lineages. Fitting progenitor data for both the time varying models and feedback models indicates that four or five intermediate transit amplifying progenitor states are necessary. Our modeling suggests that in order to determine whether an increase in age-related neural stem cell quiescence is determined by by a decreasing stem cell activation rate or an increased stem cell depletion rate, additional experiments should be designed to explore whether or not depletion of the stem cell pool is occurring, and that a higher resolution time series for activated cell fraction (ACF) would be best to resolve this issue.

BACKGROUND: Serological tests for anti-SARS-CoV-2 antibodies are becoming of great interest to determine seroprevalence in a given population, define previous exposure and identify highly reactive human donors for the generation of convalescent serum as therapeutic. OBJECTIVES: We evaluated the diagnostic performance of the Abbott ARCHITECT SARS-CoV-2 IgG test, a fully automated indirect immunoassay that detects antibodies directed to a recombinant SARS-CoV-2 Nucleocapsid antigen. STUDY DESIGN: Abbott ARCHITECT SARS-CoV-2 IgG immunoassay was compared to an indirect immunofluorescence assay (IFA) on sera from patients with COVID-19 collected at different days after symptoms onset or infected by other human coronaviruses. Comparison with neutralization test was also performed. RESULTS: After 7, 14 and >14 days after onset ARCHITECT was positive on 8.3 %; 61.9 % and 100 % of the tested samples compared to 58.3 %; 85.7 % and 100 % by IFA. The sensitivity was 72 % vs. IFA and 66.7 % vs. a real-time PCR, the specificity was 100 %. On 18 samples with neutralizing activity, 17 were positive by Abbott ARCHITECT SARS-CoV-2 IgG. CONCLUSIONS: In our study, Abbott ARCHITECT SARS-CoV-2 IgG assay showed a satisfactory performance, with a very high specificity. IgG reactivity against SARSCoV-2 N antigen was detectable in all patients by two weeks after symptoms onset. In addition, concordance between this serological response and viral neutralization suggests that a strong humoral response may be predictive of a neutralization activity, regardless of the target antigens. This finding supports the use of this automated serological assay in diagnostic algorithm and public health intervention, especially for high loads of testing.

PURPOSE OF REVIEW: Community-acquired bacterial meningitis is a continually changing disease. This review summarises both dynamic epidemiology and emerging data on pathogenesis. Updated clinical guidelines are discussed, new agents undergoing clinical trials intended to reduce secondary brain damage are presented. RECENT FINDINGS: Conjugate vaccines are effective against serotype/serogroup-specific meningitis but vaccine escape variants are rising in prevalence. Meningitis occurs when bacteria evade mucosal and circulating immune responses and invade the brain: directly, or across the bloodCbrain barrier. Tissue damage is caused when host genetic susceptibility is exploited by bacterial virulence. The classical clinical triad of fever, neck stiffness and headache has poor diagnostic sensitivity, all guidelines reflect the necessity for a low index of suspicion and early Lumbar puncture. Unnecessary cranial imaging causes diagnostic delays. cerebrospinal fluid (CSF) culture and PCR are diagnostic, direct next-generation sequencing of CSF may revolutionise diagnostics. Administration of early antibiotics is essential to improve survival. Dexamethasone partially mitigates central nervous system inflammation in high-income settings. New agents in clinical trials include C5 inhibitors and daptomycin, data are expected in 2025. SUMMARY: Clinicians must remain vigilant for bacterial meningitis. Constantly changing epidemiology and emerging pathogenesis data are increasing the understanding of meningitis. Prospects for better treatments are forthcoming.

BACKGROUND Emerging studies noted that liver injury in coronavirus disease 2019 (COVID-19) patients may be induced by virus-mediated inflammation, which was confirmed by liver pathology. The aim of this study was to observe clinical characteristics and explore risk factors in COVID-19 patients with liver injury. MATERIAL AND METHODS In this retrospective study, 40 confirmed COVID-19 patients with normal alanine transaminase (ALT) on admission were divided into a group of normal ALT patients whose ALT was always less than 40 U/l during hospitalization and a group of elevated ALT patients whose ALT was at least once more than 40 U/l after admission. Clinical data, especially virus-induced inflammatory parameters, were analyzed for risk factors and predictive value. The Mann-Whitney U test and t test for comparing means and logistic regression were performed for analysis of risk factors. Area under the ROC curve was used for predictive values. RESULTS Sixteen of 40 (40.0%) patients developed elevated ALT, many of them with more severe COVID-19. The highest ALT level was 101 U/l. The risk factors for liver injury were C-reactive protein (CRP), interleukin 6 (IL6), erythrocyte sedimentation rate (ESR), CD8+T cell count, and severity of disease, and CRP (OR 1.13, 95% CI 1.045-1.222, p=0.002) was the independent risk factor. CONCLUSIONS Liver injury in COVID-19 patients was mild and associated with inflammatory markers, especially CRP, which suggests that liver injury may be induced by virus-mediated inflammation in COVID-19 patients.

Total excess mortality peaked during a COVID19 outbreak in Stockholm, but 25% of these deaths were not recognized as Covid-19-related nor occurred in hospitals. Estimate of total excess mortality may give a more comprehensive picture of the total disease burden during a COVID19 outbreak, and may facilitate managing future outbreaks.

Background: COVID-19 outbreaks in aged care facilities (ACFs) often have devastating consequences. However, epidemiologically these outbreaks are not well defined. We aimed to define such outbreaks in ACFs by systematically reviewing literature published during the current COVID-19 pandemic. Methods: We searched 11 bibliographic databases for literature published on COVID-19 in ACFs between December 2019 and September 2020. Original studies reporting extractable epidemiological data as part of outbreak investigations or non-outbreak surveillance of ACFs were included in this systematic review and meta-analysis. PROSPERO registration: CRD42020211424. Findings: We identified 5,148 publications and selected 49 studies from four continents reporting data on 214,380 residents in 8,502 ACFs with 25,567 confirmed cases of COVID-19. Aged care residents form a distinct vulnerable population with single-facility attack rates of 45% [95% CI 32-58%] and case fatality rates of 23% [95% CI 18-28%]. Of the cases, 31% [95% CI 28-34%] were asymptomatic. The rate of hospitalization amongst residents was 37% [95% CI 35-39%]. Data from 21 outbreaks identified a resident as the index case in 58% of outbreaks and a staff member in 42%. Findings from the included studies were heterogeneous and of low to moderate quality in risk of bias assessment. Interpretation: The clinical presentation of COVID-19 varies widely in ACFs residents, from asymptomatic to highly serious cases. Preventing the introduction of COVID-19 into ACFs is key, and both residents and staff are a priority group for COVID-19 vaccination. Rapid diagnosis, identification of primary and secondary cases and close contacts plus their isolation and quarantine are of paramount importance. Funding: Queensland Advancing Clinical Research Fellowship awarded to Prof. Gulam Khandaker by Queensland Health's Health Innovation, Investment and Research Office (HIRO), Office of the Director-General.

Background: Evaluation of large-scale stunting interventions in Indonesia has never been carried out, because it found limited sensitive and specific interventions that were carried out massively at the village level. The provincial government of South Sulawesi Indonesia in 2020 has implemented a stunting intervention model called Gammarana. The purpose of this evaluation is to analyze the impact of Gammarana on changes in stunting at the project site. Location project as many as 30 villages with an estimated 60,000 units population. Design and methods: Evaluation in this study using a retrospective method and internal and external audit to document potential, then validated after the field visit Gammarana first phase in 2020. Basic Logic Model evaluation model with 22 indicators (input, process, secondary output and primary output). Proving the effect of Gammarana on changes in stunting by comparing the phenomena in the comparison village. Results: The comparison villages were set as equal and comparable in 13 indicators that could disturb the study conclusions. The result of the initial condition is that the conditions of the two villages of Gammarana and Villages Comparison are seen as the same in various characteristics, so that whatever the results of this evaluation study are believed to be the impact of Gammarana Project. Conclusions: this protocol eligible to evaluation of Gammarana Project Intervention in Enrekang District, South Sulawesi Indonesia.

Special attention and efforts to protect from or reduce health-related outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus triggering coronavirus disease 2019 (COVID-19), should be applied in susceptible populations, including frail older people. In particular, the early death cases occurred primarily in older people with a frailty status, possibly due to a weaker immune system fostering faster progression of the viral infection. Frailty is an age-related multidimensional clinical condition defined as a non-specific state of vulnerability, identifying older people at increased risk of falls, institutionalization, hospitalization, disability, dementia, and death. Among frailty phenotypes, social frailty has been least studied. It considers the role of socioeconomic context as a vulnerability status later in life. COVID-19 does not affect all populations equally, and social inequalities contribute to drive the spread of infections. It was known that the perception of social isolation, e.g., loneliness, affects mental and physical health, but the implicated molecular mechanisms, also related to the immune system, and its associated cognitive and health-related sequelae, are poorly understood. The increasing psychological distress derived by prolonged exposure to stress due to the lockdown scenario, and the reduced sources of support, contributed to making heavy demands on personal resources, i.e., self-efficacy and interpersonal variables. So, perceived loneliness may be a factor associated with psychological distress and an outcome in itself. In the COVID-19 pandemic era, a correct assessment of social frailty may be essential in terms of the prevention of late-life neuropsychiatric disorders.

INTRODUCTION: Alcohol withdrawal syndrome (AWS) is a serious consequence of alcohol use disorder (AUD). Due to the current COVID-19 pandemic there was a closure of Pennsylvania (PA) liquor stores on March 17, 2020. METHODS: This is a retrospective, observational study of AWS patients presenting to a tertiary care hospital. We used descriptive statistics for continuous and categorical variables and compared AWS consults placed to the medical toxicology service for six months preceding liquor store closure to those placed between March 17, 2020 and August 31, 2020. We compared this to consults placed to the medical toxicology service placed from October 1, 2019 through March 16, 2020. Charts were identified based on consults placed to the medical toxicology service, and alcohol withdrawal was determined via chart review by a medical toxicologist. This study did not require IRB approval. We evaluated Emergency Department (ED) length of stay (LOS), weekly and monthly consultation rate, rate of admission and ED recidivism, both pre- and post-liquor store closure. RESULTS: A total of 324 AWS consults were placed during the ten month period. 142 (43.8%) and 182 (56.2%) consults were pre- and post-liquor store closure. The number of consults was not statistically significant comparing these two time frames. There was no significant difference by patient age, gender, or race or by weekly or monthly consultation rate when comparing pre- and post-liquor store periods. The median ED LOS was 7 h (95% Confidence Interval (CI) Larson et al. (2012), Pollard et al. (2020) [5, 11]) and did not significantly differ between pre- and post-liquor store periods (p = 0.78). 92.9% of AWS patients required admission without significant difference between the pre- and post-liquor store closure periods (94.4% vs. 91.8%, p = 0.36). There was a significant increase in the number of AWS patients requiring a return ED visit (Odds Ratio 2.49; 95% CI [1.38, 4.49]) post closure. CONCLUSION: There were nearly 2.5 times greater odds of ED recidivism among post-liquor store closure AWS patients compared with pre-closure AWS patients.

BACKGROUND: Acute lower respiratory infection (ALRI) is a major cause of morbidity and mortality worldwide in young children and is predominately caused by viral respiratory pathogens. This study aims to identify the viral etiologies of ALRI in hospitalized children in Jordan University Hospital and compare the clinical characteristics of influenza virus infection with other respiratory viruses. METHODS: A retrospective viral surveillance study that included 152 children below 15 years of age admitted with ALRI from December 2018 through April 2019 was conducted. We recorded results of real-time reverse transcriptasepolymerase chain reaction (RT-PCR) for common respiratory viruses. Clinical and demographic information of the study population was collected from patients' electronic medical records. RESULTS: 152 patients were identified with a median age of 1 year (mean was 2.1 years). Ninety-five patients (62.5%) were males. One or more viral respiratory pathogens were detected in 145 (95.3%) children. Respiratory syncytial virus was the most detected virus in 68 patients (44.8%). Influenza virus was detected in 25 patients (16.4%). Children with influenza infection had more fever and lower leukocyte count compared to children infected with other viruses. The severity of the ALRI correlated significantly with several factors, including age less than six months and the presence of neuromuscular disease (p<0.05). CONCLUSION: Viral detection was common among children admitted with ALRI. Viruses, including influenza, are recognized as significant contributors to the morbidity associated with ALRI. More attention is needed on strategies for the prevention and detection of viral ALRI in developing countries.

BACKGROUND: Hyperpolarised gas magnetic resonance imaging (MRI) can be used to assess ventilation patterns. Previous studies have shown the image-derived metric of ventilation defect per cent (VDP) to correlate with forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) and FEV(1) in asthma. OBJECTIVES: The aim of this study was to explore the utility of hyperpolarised xenon-129 ((129)Xe) ventilation MRI in clinical care and examine its relationship with spirometry and other clinical metrics in people seen in a severe asthma service. METHODS: 26 people referred from a severe asthma clinic for MRI scanning were assessed by contemporaneous (129)Xe MRI and spirometry. A subgroup of 18 patients also underwent reversibility testing with spirometry and MRI. Quantitative MRI measures of ventilation were calculated, VDP and the ventilation heterogeneity index (VH(I)), and compared to spirometry, Asthma Control Questionnaire 7 (ACQ7) and blood eosinophil count. Images were reviewed by a multidisciplinary team. RESULTS: VDP and VH(I) correlated with FEV(1), FEV(1)/FVC and forced expiratory flow between 25% and 75% of FVC but not with ACQ7 or blood eosinophil count. Discordance of MRI imaging and symptoms and/or pulmonary function tests also occurred, prompting diagnostic re-evaluation in some cases. CONCLUSION: Hyperpolarised gas MRI provides a complementary method of assessment in people with difficult to manage asthma in a clinical setting. When used as a tool supporting clinical care in a severe asthma service, occurrences of discordance between symptoms, spirometry and MRI scanning indicate how MRI scanning may add to a management pathway.

Purpose: This article examines the preliminary impact of the Sars-CoV-2 pandemic on India's economic and budgetary landscape C the most affected developing country from the first wave of the pandemic It also includes a discussion of the monetary and fiscal responses adopted and the challenges faced in formulating the response to the pandemic Design/methodology/approach: Using high-frequency economic and fiscal indicators, this article evaluates the economic impact of the pandemic on the Indian economy Further, it uses data from government sources and news to highlight the measures adopted at the national and subnational level in response to the pandemic Findings: The difficult economic conditions prior to the pandemic limited the fiscal space available to the government As a result, the national and subnational governments have been cautious of accumulating excessive debt and have primarily responded with liquidity-enhancing measures, in addition to some fiscal measures for the most vulnerable Overdependence on consumption taxes has led to unprecedented revenue shortfalls prompting the exploration of new avenues for revenue generation and implementation of austerity measures C some of which may be counterproductive in the long run Originality/value: The paper highlights the policy response of the largest democracy that has been hit hard by the pandemic It also highlights various institutional and resource constraints that influenced the policies adopted India's experience in responding to the virus could provide lessons for other developing countries ? 2020, Emerald Publishing Limited

Background: Patients on maintenance hemodialysis (MHD) are at high risk of infection with SARS-Cov-2 and death due to COVID-19. This vulnerable population has been prioritized for vaccination, but the level of protection achieved in these immunocompromised patients is unclear. Objectives: To evaluate the protection of MHD patients against COVID-19 after 2 doses (2D) of BNT162b2, and the safety and impact on immune responses of a 3rd dose (3D). Design: Prospective observational. Setting, Patients, intervention and measurements: REIN national registry was used to compare the severity of 1474 cases of COVID-19 diagnosed in MHD patients after 0, 1 or 2 doses of mRNA vaccine. Anti-spike receptor binding domain (RBD) IgG and interferon gamma-producing CD4+ and CD8+ specific-T cells were measured after 2D and 3D of BNT162b2 in a monocentric cohort of 75 MHD patients. Results: Vaccination reduced disease severity but 11% of MHD patients infected after 2D still died. Tolerance to 3D of BNT162b2 was excellent. MHD patients with humoral response similar to healthy volunteers after 2D did not generate more immune effectors after 3D and had more side effects. In contrast, 2/3 of MHD patients with suboptimal response after 2D reached optimal titer of anti-RBD IgG and/or developed spike-specific CD8+ T cells after 3D. Presence of spike-specific CD4+ T cells after 2D was associated with response to 3D in multivariate analysis (OR=4.80 [1.23-21.54]; p=0.029). Limitations: Limited number of patients injected with 3D. Conclusion: Standard scheme of vaccination provides insufficient protection to some MHD patients. Anti-RBD IgG and specific CD4+ T cells should be measured after 2D. Among patients with suboptimal humoral response, those with specific CD4+ T cells could benefit of a 3rd dose of vaccine.

IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.

Silaturahmi merupakan kegiatan yang sudah menjadi budaya bagi masyarakat Indonesia karena sudah diwariskan secara turun-temurun. Kegiatan ini dilakukan untuk menjalin tali persaudaraan. Umumnya, silaturahmi dilakukan dengan cara berkunjung ke rumah-rumah kerabat, sanak keluarga, ataupun individu lainnya yang memiliki hubungan erat. Namun, dengan eksisnya pandemi COVID-19, silaturahmi tidak bisa dilakukan seperti biasanya. Hal ini merupakan imbas dari pemberlakuan social distancing dalam bentuk Pembatasan Sosial Berskala Besar (PSBB) yang tentu menjadi penghambat berlangsungnya kegiatan ini. Oleh karena itu, kami membuat penelitian ini dengan tujuan untuk mengetahui seberapa besar dampak pandemi terhadap budaya silaturahmi di Indonesia. Dalam hal ini, yang akan diteliti ialah tren frekuensi silaturahmi yang menurun serta dampaknya dari segi sosial dan budaya sebagai dampak adanya pergeseran cara dan media, yaitu luring menjadi daring. Untuk mencapai tujuan tersebut kami menggunakan metode kuesioner dan studi pustaka dalam memperoleh data. Setelah dilakukan analisis, pandemi COVID-19 sangat mempengaruhi budaya silaturahmi di Indonesia, terutama perubahan dalam cara bersilaturahmi. Adapun manfaat dari jurnal ini ditujukan bagi masyarakat agar dapat memutuskan kebijakan yang tepat berdasar pola dinamika silaturahmi yang terjadi saat pandemic. Kata-kata kunci: silaturahmi, COVID-19, social distancing, perubahan tren Silaturahmi is one of Indonesian cultures that has become a heritage from generation to generation. This activity was carried out to forge the relationship. Silaturahmi usually was done by visiting the relatives house (family, friends, or closest one). However it cant be done like it used to be since the existence of the COVID-19 brought up to the world. This is the impact of the social distancing implementation in the form of the Pembatasan Sosial Berskala Besar (PSBB) announced by the Indonesian government which has been one of the deterrents to do Silaturahmi. Therefore, we arrange this journal with the aim of finding how big is the impact of this COVID-19 pandemic to Indonesian silaturahmi culture. In this case, what will be examined is the trend of decreasing silaturahmi frequency and its impact from a social and cultural perspective as a result of shifting methods and media, namely offline to online. To achieve this goal we used a questionnaire method and literature study to obtain data. After the data analysis was fulfilled, the COVID-19 pandemic greatly affected the Indonesian silaturahmi culture, especially changes in the way of how to do the traditional silaturahmi. The benefits of this journal are intended for the public to be able to decide the right policies based on the dynamic patterns of friendship that occur during a pandemic. Keywords: COVID-19, shifting trends, silaturahmi, social distancing

COVID-19 caused significant disruption to cancer services around the world. The health system in Aotearoa New Zealand has fared better than many other regions, with the country being successful, so far, in avoiding sustained community transmission. However, there was a significant initial disruption to services across the cancer continuum, resulting in a decrease in the number of new diagnoses of cancer in March and April 2020. Te Aho o Te Kahu, Aotearoa New Zealand's national Cancer Control Agency, coordinated a nationwide response to minimise the impact of COVID-19 on people with cancer. The response, outlined in this paper, included rapid clinical governance, a strong equity focus, development of national clinical guidance, utilising new ways of delivering care, identifying and addressing systems issues and close monitoring and reporting of the impact on cancer services. Diagnostic procedures and new cancer registrations increased in the months following the national lockdown, and the cumulative number of cancer registrations in 2020 surpassed the number of registrations in 2019 by the end of September. Cancer treatment services C surgery, medical oncology, radiation oncology and haematology C continued during the national COVID-19 lockdown in March and April 2020 and continued to be delivered at pre-COVID-19 volumes in the months since. We are cautiously optimistic that, in general, the COVID-19 pandemic does not appear to have increased inequities in cancer diagnosis and treatment for Mori in Aotearoa New Zealand.

INTRODUCTION: Domiciliary care workers (DCWs) continued providing social care to adults in their own homes throughout the COVID-19 pandemic. Evidence of the impact of COVID-19 on health outcomes of DCWs is currently mixed, probably reflecting methodological limitations of existing studies. The risk of COVID-19 to workers providing care in peoples homes remains unknown. OBJECTIVES: To quantify the impact of COVID-19 upon health outcomes of DCWs in Wales, to explore causes of variation, and to extrapolate to the rest of the UK DCW population. METHODS: Mixed methods design comprising cohort study of DCWs and exploratory qualitative interviews. Data for all registered DCWs in Wales is available via the SAIL Databank using a secured, privacy-protecting encrypted anonymisation process. Occupational registration data for DCWs working during the pandemic will be combined with EHR outcome data within the SAIL Databank including clinical codes that identify suspected and confirmed COVID-19 cases. We will report rates of suspected and confirmed COVID-19 infections and key health outcomes including mortality and explore variation (by factors such as age, sex, ethnicity, deprivation quintile, rurality, employer, comorbidities) using regression modelling, adjusting for clustering of outcome within Health Board, region and employer. A maximum variation sample of Welsh DCWs will be approached for qualitative interview using a strategy to include participants that vary across factors such as sex, age, ethnicity and employer. The interviews will inform the quantitative analysis modelling. We will generalise the quantitative findings to other UK nations. DISCUSSION: Using anonymised linked occupational and EHR data and qualitative interviews, the OSCAR study will quantify the risk of COVID-19 on DCWs health and explore sources of variation. This will provide a secure base for informing public health policy and occupational guidance.

A major goal of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efforts is to elicit antibody responses that confer protection. Mapping the epitope targets of the SARS-CoV-2 antibody response is critical for vaccine design, diagnostics, and development of therapeutics. Here, we develop a pan-coronavirus phage display library to map antibody binding sites at high resolution within the complete viral proteomes of all known human-infecting coronaviruses in patients with mild or moderate/severe coronavirus disease 2019 (COVID-19). We find that the majority of immune responses to SARS-CoV-2 are targeted to the spike protein, nucleocapsid, and ORF1ab and include sites of mutation in current variants of concern. Some epitopes are identified in the majority of samples, while others are rare, and we find variation in the number of epitopes targeted between individuals. We find low levels of SARS-CoV-2 cross-reactivity in individuals with no exposure to the virus and significant cross-reactivity with endemic human coronaviruses (CoVs) in convalescent sera from patients with COVID-19.

Objective: This study aimed to assess the role of Tocilizumab therapy (TCZ) in terms of ICU admission and mortality rate of critically ill patients with severe COVID-19 pneumonia. Design: Patients with COVID-19 pneumonia were prospectively enrolled in SMAtteo COvid19 REgistry (SMACORE). A retrospective analysis of patients treated with TCZ matched using propensity score to patients treated with Standard Of Care (SOC) was conducted. Setting: The study was conducted at IRCCS Policlinico San Matteo Hospital, Pavia, Italy, from March 14, 2020 to March 27, 2020. Participants: Patients with a confirmed diagnosis of COVID-19 hospitalized in our institution at the time of TCZ availability. Interventions: TCZ was administered to 21 patients. The first administration was 8 mg/kg (up to a maximum 800 mg per dose) of Tocilizumab intravenously, repeated after 12 h if no side effects were reported after the first dose. Main Outcomes and Measures: ICU admission and 7-day mortality rate. Secondary outcomes included clinical and laboratory data. Results: There were 112 patients evaluated (82 were male and 30 were female, with a median age of 63.55 years). Using propensity scores, the 21 patients who received TCZ were matched to 21 patients who received SOC (a combination of hydroxychloroquine, azithromycin and prophylactic dose of low weight heparin). No adverse event was detected following TCZ administration. This study found that treatment with TCZ did not significantly affect ICU admission (OR 0.11; 95% CI between 0.00 and 3.38; p = 0.22) or 7-day mortality rate (OR 0.78; 95% CI between 0.06 and 9.34; p = 0.84) when compared with SOC. Analysis of laboratory measures showed significant interactions between time and treatment regarding C-Reactive Protein (CRP), alanine aminotransferase (ALT), platelets and international normalized ratio (INR) levels. Variation in lymphocytes count was observed over time, irrespective of treatment. Conclusions: TCZ administration did not reduce ICU admission or mortality rate in a cohort of 21 patients. Additional data are needed to understand the effect(s) of TCZ in treating patients diagnosed with COVID-19.

IMPORTANCE: The National COVID Cohort Collaborative (N3C) is a centralized, harmonized, high-granularity electronic health record repository that is the largest, most representative COVID-19 cohort to date. This multicenter data set can support robust evidence-based development of predictive and diagnostic tools and inform clinical care and policy. OBJECTIVES: To evaluate COVID-19 severity and risk factors over time and assess the use of machine learning to predict clinical severity. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective cohort study of 1 926 526 US adults with SARS-CoV-2 infection (polymerase chain reaction >99% or antigen <1%) and adult patients without SARS-CoV-2 infection who served as controls from 34 medical centers nationwide between January 1, 2020, and December 7, 2020, patients were stratified using a World Health Organization COVID-19 severity scale and demographic characteristics. Differences between groups over time were evaluated using multivariable logistic regression. Random forest and XGBoost models were used to predict severe clinical course (death, discharge to hospice, invasive ventilatory support, or extracorporeal membrane oxygenation). MAIN OUTCOMES AND MEASURES: Patient demographic characteristics and COVID-19 severity using the World Health Organization COVID-19 severity scale and differences between groups over time using multivariable logistic regression. RESULTS: The cohort included 174 568 adults who tested positive for SARS-CoV-2 (mean [SD] age, 44.4 [18.6] years; 53.2% female) and 1 133 848 adult controls who tested negative for SARS-CoV-2 (mean [SD] age, 49.5 [19.2] years; 57.1% female). Of the 174 568 adults with SARS-CoV-2, 32 472 (18.6%) were hospitalized, and 6565 (20.2%) of those had a severe clinical course (invasive ventilatory support, extracorporeal membrane oxygenation, death, or discharge to hospice). Of the hospitalized patients, mortality was 11.6% overall and decreased from 16.4% in March to April 2020 to 8.6% in September to October 2020 (P = .002 for monthly trend). Using 64 inputs available on the first hospital day, this study predicted a severe clinical course using random forest and XGBoost models (area under the receiver operating curve = 0.87 for both) that were stable over time. The factor most strongly associated with clinical severity was pH; this result was consistent across machine learning methods. In a separate multivariable logistic regression model built for inference, age (odds ratio [OR], 1.03 per year; 95% CI, 1.03-1.04), male sex (OR, 1.60; 95% CI, 1.51-1.69), liver disease (OR, 1.20; 95% CI, 1.08-1.34), dementia (OR, 1.26; 95% CI, 1.13-1.41), African American (OR, 1.12; 95% CI, 1.05-1.20) and Asian (OR, 1.33; 95% CI, 1.12-1.57) race, and obesity (OR, 1.36; 95% CI, 1.27-1.46) were independently associated with higher clinical severity. CONCLUSIONS AND RELEVANCE: This cohort study found that COVID-19 mortality decreased over time during 2020 and that patient demographic characteristics and comorbidities were associated with higher clinical severity. The machine learning models accurately predicted ultimate clinical severity using commonly collected clinical data from the first 24 hours of a hospital admission.