Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

A wide variety of pathologies can produce focal lesions within the spleen. These are being more frequently encountered as imaging technology improves. It is vital that radiologists are aware of these pathologies to enable accurate diagnosis. The role of ultrasound contrast in splenic disease will be discussed and illustrated with cases likely to be encountered by general and abdominal radiologists.

OBJECTIVES: The INCAPS COVID Oceania study aimed to assess the impact caused by the COVID-19 pandemic on cardiac procedure volume provided in the Oceania region. METHODS: A retrospective survey was performed comparing procedure volumes within March 2019 (pre-COVID-19) with April 2020 (during first wave of COVID-19 pandemic). Sixty-three (63) health care facilities within Oceania that perform cardiac diagnostic procedures were surveyed, including a mixture of metropolitan and regional, hospital and outpatient, public and private sites, and 846 facilities outside of Oceania. The percentage change in procedure volume was measured between March 2019 and April 2020, compared by test type and by facility. RESULTS: In Oceania, the total cardiac diagnostic procedure volume was reduced by 52.2% from March 2019 to April 2020, compared to a reduction of 75.9% seen in the rest of the world (p<0.001). Within Oceania sites, this reduction varied significantly between procedure types, but not between types of health care facility. All procedure types (other than stress cardiac magnetic resonance [CMR] and positron emission tomography [PET]) saw significant reductions in volume over this time period (p<0.001). In Oceania, transthoracic echocardiography (TTE) decreased by 51.6%, transoesophageal echocardiography (TOE) by 74.0%, and stress tests by 65% overall, which was more pronounced for stress electrocardiograph (ECG) (81.8%) and stress echocardiography (76.7%) compared to stress single-photon emission computerised tomography (SPECT) (44.3%). Invasive coronary angiography decreased by 36.7% in Oceania. CONCLUSION: A significant reduction in cardiac diagnostic procedure volume was seen across all facility types in Oceania and was likely a function of recommendations from cardiac societies and directives from government to minimise spread of COVID-19 amongst patients and staff. Longer term evaluation is important to assess for negative patient outcomes which may relate to deferral of usual models of care within cardiology.

[Figure: see text].

The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.

OBJECTIVE: The aim of this study is to find the most suitable heat wave definition among 15 different ones and to evaluate its impact on total, age-, and gender-specific mortality for Bandafassi, Senegal. METHODS: Daily weather station data were obtained from Kedougou situated at 17 km from Bandafassi from 1973 to 2012. Poisson generalized additive model (GAM) and distributed lag non-linear model (DLNM) are used to investigate the effect of heat wave on mortality and to evaluate the nonlinear association of heat wave definitions at different lag days, respectively. RESULTS: Heat wave definitions, based on three or more consecutive days with both daily minimum and maximum temperatures greater than the 90th percentile, provided the best model fit. A statistically significant increase in the relative risk (RRs 1.4 (95% Confidence Interval (CI): 1.2-1.6), 1.7 (95% CI: 1.5-1.9), 1.21 (95% CI: 1.08-1.3), 1.2 (95% CI: 1.04-1.5), 1.5 (95% CI: 1.3-1.8), 1.4 (95% CI: 1.2-1.5), 1.5 (95% CI: 1.07-1.6), and 1.5 (95% CI: 1.3-1.8)) of total mortality was observed for eight definitions. By using the definition based on the 90th percentile of minimum and maximum temperature with a 3-day duration, we also found that females and people aged ≥ 55 years old were at higher risks than males and other different age groups to heat wave related mortality. CONCLUSION: The impact of heat waves was associated with total-, age-, gender-mortality. These results are expected to be useful for decision makers who conceive of public health policies in Senegal and elsewhere. Climate parameters, including temperatures and humidity, could be used to forecast heat wave risks as an early warning system in the area where we conduct this research. More broadly, our findings should be highly beneficial to climate services, researchers, clinicians, end-users and decision-makers.

BACKGROUND: Ocrelizumab safety outcomes have been well evaluated in clinical trials and open-label extension (OLE) studies. However, risk factors for infection in patients with multiple sclerosis (MS) receiving ocrelizumab have not been extensively studied in the real-world setting. OBJECTIVE: The aim of this study was to examine factors determining risk of self-reported infections and antimicrobial use in patients receiving ocrelizumab for MS. METHODS: A retrospective, observational cohort study was conducted in patients receiving ocrelizumab at the Royal Melbourne Hospital. Infection type and number were reported by patients, and the associations of potential clinical and laboratory risk factors with self-reported infection and antimicrobial use were estimated using univariate and multivariable logistic regression models. RESULTS: A total of 185 patients were included in the study; a total of 176 infections were reported in 89 patients (46.1%), and antimicrobial use was identified in 47 patients (25.3%). In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25-0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88-0.99), higher serum IgA (OR 0.37, 95% CI 0.17-0.80) and higher serum IgG (OR 0.81, 95% CI 0.67-0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75-0.96) and higher serum IgA (OR 0.23, 95% CI 0.07-0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06-1.41) and higher Expanded Disability Status Scale (EDSS) score (OR 1.99, 95% CI 1.02-3.86) were associated with increased odds of antimicrobial use. CONCLUSIONS: Higher serum IgA and IgG and older age were associated with reduced odds of infection. Our findings highlight that infection risk is not uniform in patients with MS receiving ocrelizumab and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy.

BACKGROUND: The outbreak of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) that was first detected in the city of Wuhan, China has now spread to every inhabitable continent, but now the attention has shifted from China to other epicentres. This study explored early assessment of the influence of spatial proximities and travel patterns from Italy on the further spread of SARS-CoV-2 worldwide. METHODS: Using data on the number of confirmed cases of COVID-19 and air travel data between countries, we applied a stochastic meta-population model to estimate the global spread of COVID-19. Pearson's correlation, semi-variogram, and Moran's Index were used to examine the association and spatial autocorrelation between the number of COVID-19 cases and travel influx (and arrival time) from the source country. RESULTS: We found significant negative association between disease arrival time and number of cases imported from Italy (r = -0.43, p = 0.004) and significant positive association between the number of COVID-19 cases and daily travel influx from Italy (r = 0.39, p = 0.011). Using bivariate Moran's Index analysis, we found evidence of spatial interaction between COVID-19 cases and travel influx (Moran's I = 0.340). Asia-Pacific region is at higher/extreme risk of disease importation from the Chinese epicentre, whereas the rest of Europe, South-America and Africa are more at risk from the Italian epicentre. CONCLUSION: We showed that as the epicentre changes, the dynamics of SARS-CoV-2 spread change to reflect spatial proximities.

SARS-CoV-2 has spread rapidly worldwide, but the full impact of the COVID-19 pandemic on the field of hematopoietic cell transplantation (HCT) remains unknown. To understand this better, an 18-item online survey was disseminated by the Worldwide Network for Blood & Marrow Transplantation with questions exploring SARS-CoV-2 testing algorithms, mobilization, and cryopreservation strategies and COVID-19 infections in allogeneic related and autologous hematopoietic progenitor cell (HPC) donors. The aim of this survey was to assess the impact of the outbreak on policies relating to HPC mobilization, collection, and processing with respect to changes in daily routine. A total of 91 individual responses from distinct centers in 6 continents were available for analysis. In these centers, the majority (72%) of allogeneic related and autologous donors are routinely tested for SARS-CoV-2 before HPC collection, and 80% of centers implement cryopreservation of allogeneic HPC grafts before commencing conditioning regimens in patients. Five related and 14 autologous donors who tested positive for COVID-19 did not experience any unexpected adverse events or reactions during growth factor administration (eg, hyperinflammatory syndrome). These data are limited by the small number of survey respondents but nonetheless suggest that centers are following the recommendations of appropriate scientific organizations and provide some preliminary data to suggest areas of further study.

BACKGROUND: Bruton tyrosine kinase (BTK) inhibition targets B-cell and other non-T-cell immune cells implicated in the pathophysiology of pemphigus, an autoimmune disease driven by anti-desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus. OBJECTIVES: To evaluate the efficacy and safety of oral rilzabrutinib in patients with pemphigus vulgaris in a multicentre, proof-of-concept, phase II trial. METHODS: Patients with Pemphigus Disease Area Index severity scores 8-45 received 12 weeks of oral rilzabrutinib 400-600 mg twice daily and 12 weeks of follow-up. Patients initially received between 0 and ≤ 0·5 mg kg-1 prednisone-equivalent corticosteroid (CS; i.e. 'low dose'), tapered after control of disease activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within 4 weeks on zero-to-low-dose CS and safety. RESULTS: In total, 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 had moderate disease (41%) and 16 moderate to severe (59%). The primary endpoint, CDA, was achieved in 14 patients (52%, 95% confidence interval 32-71): 11 using low-dose CS and three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg per day for newly diagnosed patients and from 10·3 to 7·8 mg per day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment-related adverse events were mostly mild (grade 1 or 2); one patient experienced grade 3 cellulitis. CONCLUSIONS: Rilzabrutinib alone, or with much lower CS doses than usual, was safe, with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and support further investigation of rilzabrutinib for the treatment of pemphigus.

Following the importation of Covid-19 into Nigeria on the 27 February 2020 and then the outbreak, the question is: how do we anticipate the progression of the ongoing epidemics following all the intervention measures put in place? This kind of question is appropriate for public health responses and it will depend on the early estimates of the key epidemiological parameters of the virus in a defined population. In this study, we combined a likelihood-based method using a Bayesian framework and compartmental model of the epidemic of Covid-19 in Nigeria to estimate the effective reproduction number (R(t)) and basic reproduction number (R_0). This also enables us to estimate the daily transmission rate (β) that determines the effect of social distancing. We further estimate the reported fraction of symptomatic cases. The models are applied to the NCDC data on Covid-19 symptomatic and death cases from 27 February 2020 and 7 May 2020. In this period, the effective reproduction number is estimated with a minimum value of 0.18 and a maximum value of 1.78. Most importantly, the R(t) is strictly greater than one from April 13 till 7 May 2020. The R_0 is estimated to be 2.42 with credible interval: (2.37, 2.47). Comparing this with the R(t) shows that control measures are working but not effective enough to keep R(t) below one. Also, the estimated fractional reported symptomatic cases are between 10 to 50%. Our analysis has shown evidence that the existing control measures are not enough to end the epidemic and more stringent measures are needed.