title: Social predictors of food insecurity during the stay-at-home order due to the COVID-19 pandemic in Peru. Results from a cross-sectional web-based survey

abstract:
BackgroundStay-at-home orders and social distancing have been implemented as the primary tools to reduce the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, this approach has indirectly lead to the unemployment of 2{middle dot}3 million Peruvians, in Lima, Peru alone. As a result, the risk of food insecurity may have increased, especially in low-income families who rely on a daily wage. This study estimates the prevalence of moderate or severe food insecurity (MSFI) and identifies the associated factors that explain this outcome during the stay-at-home order.

MethodsA cross-sectional web-based survey, with non-probabilistic sampling, was conducted between May 18 and June 30, 2020, during the stay-at-home order in Peru. We used social media advertisements on Facebook to reach 18-59-year-olds living in Peru. MSFI was assessed using the Food Insecurity Experience Scale (FIES). Rasch model methodology requirements were considered, and factors associated with MSFI were selected using stepwise forward selection. A Poisson generalized linear model (Poisson GLM), with log link function, was employed to estimate adjusted prevalence ratios (aPR).

FindingsThis analysis is based on 1846 replies. The prevalence of MSFI was 23{middle dot}2%, and FIES proved to be an acceptable instrument with reliability 0{middle dot}72 and infit 0{middle dot}8-1{middle dot}3. People more likely to experience MSFI were those with low income (less than 255 US$/month) in the pre-pandemic period (aPR 3{middle dot}77; 95%CI, 1{middle dot}98-7{middle dot}16), those whose income was significantly reduced during the pandemic period (aPR 2{middle dot}27; 95%CI, 1{middle dot}55-3{middle dot}31), and those whose savings ran out in less than 21 days (aPR 1{middle dot}86; 95%CI, 1{middle dot}43-2{middle dot}42). Likewise, heads of households (aPR 1{middle dot}20; 95%CI, 1{middle dot}00-1{middle dot}44) and those with probable SARS-CoV2 cases as relatives (aPR 1{middle dot}29; 95%CI, 1{middle dot}05-1{middle dot}58) were at an increased risk of MSFI. Additionally, those who perceived losing weight during the pandemic (aPR 1{middle dot}21; 95%CI, 1{middle dot}01-1{middle dot}45), and increases in processed foods prices (aPR 1{middle dot}31; 95%CI, 1{middle dot}08-1{middle dot}59), and eating less minimally processed food (aPR 1{middle dot}82; 95%CI, 1{middle dot}48-2{middle dot}24) were more likely to experience MSFI.

InterpretationPeople most at risk of MSFI were those in a critical economic situation before and during the pandemic. Social protection policies should be reinforced to prevent or mitigate these adverse effects.

FundingNone.

category: public and global health


title: Initial real world evidence for lower viral load of individuals who have been vaccinated by BNT162b2

abstract: One of the key questions regarding COVID19 vaccines is whether they can reduce viral shedding. To date, Israel vaccinated substantial parts of the adult population, which enables extracting real world signals. The vaccination rollout started on Dec 20th 2020, utilized mainly the BNT162b2 vaccine, and focused on individuals who are 60 years or older. By now, more than 75% of the individuals of this age group have been at least 14 days after the first dose, compared to 25% of the individuals between ages 40-60 years old. Here, we traced the Ct value distribution of 16,297 positive qPCR tests in our lab between Dec 1st to Jan 31st that came from these two age groups. As we do not have access to the vaccine status of each test, our hypothesis was that if vaccines reduce viral load, we should see a difference in the Ct values between these two age groups in late January but not before. Consistent with this hypothesis, until Jan 15th, we did not find any statistically significant differences in the average Ct value between the groups. In stark contrast, our results in the last two weeks of January show a significant weakening in the average Ct value of 60+ individuals to the 40-60 group. To further corroborate these results, we also used a series nested linear models to explain the Ct values of the positive tests. This analysis favored a model that included an interaction between age and the late January time period, consistent with the effect of vaccination. We then used demographic data and the daily vaccination rates to estimate the effect of vaccination on viral load reduction. Our estimate suggests that vaccination reduces the viral load by 1.6x to 20x in individuals who are positive for SARS-CoV-2. This estimate might improve after more individuals receive the second dose. Taken together, our findings indicate vaccination is not only important for individuals protection but can reduce transmission.

category: epidemiology


title: Sero-surveillance for IgG to SARS-CoV-2 at antenatal care clinics in two Kenyan referral hospitals

abstract: The high proportion of SARS-CoV-2 infections that remain undetected presents a challenge to tracking the progress of the pandemic and implementing control measures in Kenya. We determined the prevalence of IgG to SARS-CoV-2 in residual blood samples from mothers attending antenatal care services at 2 referral hospitals in Kenya. We used a validated IgG ELISA for SARS-Cov-2 spike protein and adjusted the results for assay sensitivity and specificity. In Kenyatta National Hospital, Nairobi, seroprevalence in August 2020 was 49.9% (95% CI 42.7-58.0). In Kilifi County Hospital seroprevalence increased from 1.3% (95% CI 0.04-4.7) in September to 11.0% (95% CI 6.2-16.7) in November 2020. There has been substantial, unobserved transmission of SARS-CoV-2 in parts of Nairobi and Kilifi Counties.


title: Explaining ethnicity disparities in COVID-19 mortality: population-based, prospective cohort study

abstract: Ethnic disparities in COVID-19 hospitalizations and mortality have been reported but there is scant understanding of how these inequalities are embodied. The UK Biobank prospective cohort study comprises around half a million people who were aged 40-69 years at study induction between 2006 and 2010 when information on ethnic background and potential explanatory factors was captured. Study members were linked to a national mortality registry. In an analytical sample of 448,664 individuals (248,820 women), 354 deaths were ascribed to COVID-19 between 5th March and the end of follow-up on 17th September 2020. In age- and sex-adjusted analyses, relative to White participants, Black study members experienced around seven times the risk of COVID-19 mortality (odds ratio; 95% confidence interval: 7.25; 4.65, 11.33), while there was a doubling in the Asian group (1.98; 1.02, 3.84). Controlling for baseline comorbidities, socioeconomic circumstances, and lifestyle factors explained 53% of the differential in risk for Asian people (1.37; 0.68, 2.77) and 27% in Black study members (4.28; 2.67, 6.86). The residual risk in ethnic minority groups for COVID-19 deaths may be ascribed to unknown genetic factors or unmeasured phenotypes, most obviously racial discrimination.


title: Explaining ethnic disparities in COVID-19 mortality: population-based, prospective cohort study


title: Circular functional analysis of OCT data for precise identification of structural phenotypes in the eye.

abstract:
Progressive optic neuropathies such as glaucoma are major causes of blindness globally. Multiple sources of subjectivity and analytical challenges are often encountered by the clinicians in the process of early diagnosis and clinical management of these diseases. In glaucoma, the structural damage is often characterized by neuroretinal rim (NRR) thinning of the optic nerve head, and other clinical parameters. Optical coherence tomography (OCT) is a popular and quantitative eye imaging platform for precise and reproducible measurement of such parameters in the clinic.

Baseline structural heterogeneity in the eyes can play a key role in the progression of optic neuropathies, and thus present challenges to clinical decision-making. To address this, large and diverse normative OCT databases with mathematically precise description of phenotypes can help with early detection and characterization of the different phenotypes that are encountered in the clinic. In this study, we generated a new large dataset of OCT generated high-resolution circular data on NRR phenotypes, along with other clinical covariates, of nearly 4,000 healthy eyes as part of a well-established clinical cohort (LVPEI-GLEAMS) of Asian Indian participants.

In this study, we (1) generated high-resolution circular OCT measurements of NRR thickness in a given eye, (2) introduced CIFU, a new computational pipeline for CIrcular FUnctional data modeling and analysis that is demonstrated using the OCT dataset, and (3) addressed the disparity of representation of the Asian Indian population in normative OCT databases. We demonstrated CIFU by unsupervised circular functional clustering of the OCT NRR data, meta-clustering to characterize the clustering output using clinical covariates, and presenting a circular visualization of the results. Upon stratification by age, we identified a healthy NRR phenotype cluster in the age group 40-49 years with predictive potential for glaucoma.

category: health informatics


title: Poor antigen-specific responses to the second BNT162b2 mRNA vaccine dose in SARS-CoV-2-experienced individuals

abstract:
The use of COVID-19 vaccines will play the major role in helping to end the pandemic that has killed millions worldwide. COVID-19 vaccines have resulted in robust humoral responses and protective efficacy in human trials, but efficacy trials excluded individuals with a prior diagnosis of COVID-19. As a result, little is known about how immune responses induced by mRNA vaccines differ in individuals who recovered from COVID-19. Here, we evaluated longitudinal immune responses to two-dose BNT162b2 mRNA vaccination in 15 adults who recovered from COVID-19, compared to 21 adults who did not have prior COVID-19 diagnosis. Consistent with prior studies of mRNA vaccines, we observed robust cytotoxic CD8+ T cell responses in both cohorts following the second dose. Furthermore, SARS-CoV-2-naive individuals had progressive increases in humoral and antigen-specific antibody-secreting cell (ASC) responses following each dose of vaccine, whereas SARS-CoV-2-experienced individuals demonstrated strong humoral and antigen-specific ASC responses to the first dose but muted responses to the second dose of the vaccine at the time points studied. Together, these data highlight the relevance of immunological history for understanding vaccine immune responses and may have significant implications for personalizing mRNA vaccination regimens used to prevent COVID-19, including booster shots.

One Sentence SummaryPrior history of COVID-19 affects adaptive immune responses to mRNA vaccination.

category: infectious diseases


title: Robust immune responses after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2 experienced individuals


title: The effect of respiratory activity, ventilatory therapy and facemasks on total aerosol emissions

abstract: Background Exhaled respirable aerosols (<5 m diameter) present a high risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) transmission. Many guidelines recommend using aerosol precautions during "aerosol generating procedures" (AGPs) and droplet (>5 m) precautions at other times. However, there is emerging evidence that respiratory activities such as cough and not AGPs are the important source of aerosols. Methods We used a novel chamber with an optical particle counter sampling at 100 L/min to count and size-fractionate all exhaled particles (0.5-25 m). We compared emissions from ten healthy subjects during respiratory "activities" (quiet breathing, talking, shouting, forced expiratory maneuvers, exercise and coughing) with respiratory "therapies" designated as AGPs: high flow nasal oxygen (HFNO) and single or dual circuit non-invasive positive pressure ventilation, NIPPV-S and NIPPV-D, respectively. Activities were repeated wearing facemasks. Results Compared to quiet breathing, respiratory activities increased particle counts between 34.6-fold (95% confidence interval [CI], 15.2 to 79.1) during talking, to 370.8-fold (95% CI, 162.3 to 847.1) during coughing (p<0.001). During quiet breathing, HFNO at 60 L/min increased counts 2.3-fold (95% CI, 1.2 to 4.4) (p=0.03) and NIPPV-S and NIPPV-D at 25/10 cm H2O increased counts by 2.6-fold (95% CI, 1.7 to 4.1) and 7.8-fold (95% CI, 4.4 to 13.6) respectively (p<0.001). During activities, respiratory therapies and facemasks reduced emissions compared to activities alone. Conclusion Talking, exertional breathing and coughing generate substantially more aerosols than the respiratory therapies HFNO and NIPPV which can reduce total emissions. The risk of aerosol exposure is underappreciated and warrants widespread targeted interventions.


title: Identification of endothelial-derived proteins in plasma associated with cardiovascular risk factors

abstract: Endothelial cell (EC) dysfunction is a well-established response to cardiovascular disease (CVD) risk factors, such as smoking and obesity. Risk factor exposure can modify EC signalling and behaviour, leading to arterial and venous disease development. Biomarker panels to assess EC dysfunction are lacking, but could be useful for risk stratification and to monitor treatment response. Here, we used affinity proteomics to identify EC-derived proteins circulating in plasma that were associated with CVD risk factor exposure. 216 proteins, known to be expressed in ECs across vascular beds, were measured in plasma samples (n=1005) from the population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot. We identified 38 EC-derived proteins that were associated with body mass index, total cholesterol, low density lipoprotein, smoking, hypertension or diabetes. Sex-specific analysis revealed female- and male-only associations were most frequently observed with BMI, or total cholesterol, respectively. We showed a relationship between individual CVD risk, calculated with the Framingham risk score, and the corresponding biomarker profiles; presenting the concept of measuring EC-derived proteins in plasma to infer vascular status.

category: cardiovascular medicine


title: How to decide which COVID-19 patient with myocardial infarction to send to the Cath Lab? - A case series of COVID-19 patients with myocardial infarction

abstract:
INTRODUCTIONThe Coronavirus pandemic has hit the world with its vast contagiousness, high morbidity, and mortality. Apart from the direct damage to the lung tissue, the corona virus infection is able to predispose patients to thrombotic disease, thus causing cerebral or coronary incidents.

AIMSThe aim of this study was to find a clinical or laboratory parameter, that would help in distinguishing between COVID-19 patients with myocardial infarction (MI), who have an infarct-related artery (IRA) and therefore, require immediate revascularization, and those, who have no IRA.

METHODSThis was a single-center, observational study of 10 consecutive patients with COVID-19, who were admitted with confirmed MI.

RESULTSIn our study group the mean age was 67.5 {+/-} 8.3 years, half of the patients were female; all of them had arterial hypertension; 8 patients (80%) had dyslipidemy; 4 (40%) had diabetes. 30% of the patients with MI did not have an IRA, and did not require pPCI. Patients with MI and IRA had significantly higher hsTrI values (48.9 {+/-} 43.2 vs 0.6 {+/-} 0.7, p=0.007) and exclusively typical chest pain 100% vs 0%, p=0.007), compared to patients with MI without an IRA. The ECG changes had only marginal statistical significance. Our results suggest that using a higher cut-off value for hsTrI (>7.5 times upper reference range) increases the specificity and positive predictive value for diagnosing a MI with the presence of IRA and need for pPCI, to 100%

CONCLUSIONIn our analysis we confirm that a higher cut-off value for hsTrI helps distinguish between COVID patients with MI, who have IRA and therefore, require immediate revascularization, compared to those, who have no IRA.


title: Multivariate spatio-temporal analysis of the global COVID-19 pandemic

abstract: The Covid-19 pandemic has caused significant mortality and disruption on a global scale not seen in living memory. Understanding the spatial and temporal vectors of transmission as well as similarities in the trajectories of recorded cases and deaths across countries can aid in understanding the benefit or otherwise of varying interventions and control strategies on virus transmission. It can also highlight emerging globa trends as they occur. Data on number of cases and deaths across the globe have been made available through a variety of databases and provide a wide range of opportunities for the application of multivariate statistical methods to extract information on similarity or difference from them. Here we conduct spatial and temporal multivariate statistical analyses of global Covid-19 cases and deaths for the period spanning January to August 2020, using a variety of distance based multivariate methods to cluster countries according to similar temporal trends in cases and deaths resulting from COVID-19. We also use novel air passenger data as a proxy for movement between countries. The air passenger movement can act as an important vector of transmission and thus scaling covariance matrices before conducting dimension reduction techniques can account for known structures in the data and help highlight important residual spatial and/or temporal trends that may then be attributable to the success of interventions or other cultural differences. Global temporal structure is found to be of significantly more importance than local spatial structure in terms of global dynamics. Our results highlight a significant global change in case and mortality daynamics from early-August, consistent in timing with the emergence of new strains with highger levels of transmission. We propose the methodology offers great potential in real-time analysis of complex, noisy spatio-temporal data and the extraction of emerging changes in pandemic dynamics that can support policy and decision makers.


title: Rapid Impact Analysis of B 1.1.7 Variant on the Spread of SARS-CoV-2 in North Carolina

abstract:
BackgroundSeveral cases of the B1.1.7 variant of the SARS-CoV-2 virus were identified in North Carolina first on January 23, 2021 in Mecklenburg County and later in Guilford County on January 28, 2021.[1,2] This variant has been associated with higher levels of transmissibility.[3-6] This study examines the potential impact of increased transmissibility as the B1.1.7 variant becomes more predominant given current vaccine distribution plans and existing non-pharmaceutical interventions (NPIs).

MethodWe explored the anticipated impact on the effective reproduction number for North Carolina and Guilford County given the date of import of B1.1.7. The approximate growth rate in proportion of B1.1.7 observed in the United Kingdom was fit and used to establish the estimate share of B1.1.7 circulating in North Carolina. Using the nowcasted reproduction numbers, a stochastic discrete compartmental model was fit with the current vaccination rates and B1.1.7 transmissibility to estimate the impact on the effective reproduction number.

ResultsWe found that the effective reproduction number for North Carolina and Guilford County may exceed one, indicating a return to accelerating spread of infection in April as the proportion of B1.1.7 increases. The effective reproduction number will likely decrease into March, then increase as the proportion of B1.1.7 increases in circulation in the population.

ConclusionsExisting non-pharmaceutical interventions will need to remain in effect through the spring. Given the current vaccination rate and these interventions, it is likely that there will be an increase in SARS-CoV-2 infections. The impact of the variant will likely be heterogeneous across North Carolina given the reproduction number and volume of susceptible persons in each county at the time of introduction of the variant. Age-based vaccinations will likely reduce the overall impact on hospitalizations. This analysis underlines the need for population level genetic surveillance to confirm the proportion of variants circulating.


title: L18F substrain of SARS-CoV-2 VOC-202012/01 is rapidly spreading in England

abstract: The Variant of Concern (VOC)-202012/01 (also known as B.1.1.7) is a rapidly growing lineage of SARS-CoV-2. In January 2021, VOC-202012/01 constituted about 80% of SARS-CoV-2 genomes sequenced in England and was present in 27 out of 29 countries that reported at least 50 viral genomes. As this strain will likely spread globally towards fixation, it is important to monitor its molecular evolution. Based on GISAID data we systematically estimated growth rates of mutations acquired by the VOC lineage to find that L18F substitution in viral spike protein has initiated a substrain characterized by replicative advantage of 1.70 [95% CI: 1.56-1.96] in relation to the remaining VOC-202012/01 substrains. The L18F mutation is of significance because when recently analyzed in the context of the South African strain 501Y.V2 it has been found to compromise binding of neutralizing antibodies. We additionally indicate three mutations that were acquired by VOC-202012/01 in the receptor binding motif of spike, specifically E484K, F490S, and S494P, that may also give rise to escape mutants. Such mutants may hinder efficiency of existing vaccines and expand in response to the increasing after-infection or vaccine-induced seroprevalence.


title: Influence of sex on disease severity in children with COVID-19 and Multisystem Inflammatory Syndrome in Latin America

abstract: Data from adult studies how that COVID-19 is more severe in men than women. However, no data are available for the pediatric population. For this reason, we performed this study aiming to understand if sex influenced disease severity and outcomes in a large cohort of latin-american children with COVID-19 and Multisystem Inflammatory Syndrome (MIS-C). We found that a higher percentage of male children developed MIS-C (8.9% vs 5% in females) and died (1.2% and 0.4% in females), although on multivariate adjusted analyses the only statistically significant difference was found in need of hospitalization, with females less frequently admitted compared with boys (25.6% vs 35.4%). This data are preliminary and need further independent studies to better assess the role of sex.

category: pediatrics


title: Impact on Mental Health of students due to restriction caused by COVID-19 pandemic: Cross-sectional study

abstract:
BackgroundThe aim of the study was to investigate fear, depression and anxiety symptoms among students of India due to COVID-19 pandemic and its restriction.

MethodThe cross-sectional web-based research was conducted between mid-November and mid-December 2020 with the objective of understanding the psychological and behavioral consequences of the COVID-19 pandemic effect on students due to the constraint of forced control. The questionnaire included a) socio-demographic questions and b) psychometric scales evaluating the psychological and behavioral impact caused by COVID-19 pandemic and restrictions.

ResultsTotal number of 324 students participated in this study in which 44.4% were male and 55.6% were female. Fear of COVID-19 scale showed 68.8% of students had high fear, 24.4% had moderate to severe depression and 51.5% had moderate to severe anxiety. The correlation of fear of COVID-19 scale (FCV-19s) with Generalized Anxiety scale (GAD-7) and brief patient health questionnaire scale (PHQ-9) was found to be 0.492 and 0.474 respectively.

ConclusionThis research concludes that there is a very strong fear of COVID-19 among students, along with anxiety and depression symptoms. This study also concludes that the fear of the COVID-19 scale has strong positive correlation with the anxiety (GAD-7) and depression (PHQ-9) scales.


title: An integrated rural health system baseline assessment of COVID-19 preparedness in Siaya Kenya

abstract:
ObjectiveOur aim was to assess Siaya county COVID-19 preparedness at community and health facility levels and measure baseline household prevalences of fever and cough.

DesignThere was retrospective and prospective data collection using standard tools. We determined the prevalence of fever and cough in households. We evaluated household knowledge about COVID-19 prevention and adherence to preventive measures. We evaluated the presence of a workforce, essential infrastructure and equipment needed for COVID-19 case management, and the availability of essential maternal and child health services in health facilities.

SettingSiaya in rural Western Kenya

Participantshouseholds and health facilities in Siaya

ResultsWe visited 19474 households and assessed 152 facilities. The prevalences of fever and cough ranged from 1.4% to 4.3% and 0.2 to 0.8% respectively; 97% and 98% of households had not received a guest from nor travelled outside Siaya respectively; 97% knew about frequent handwashing, 66% knew about keeping distance, and 80% knew about wearing a mask; 63% washed their hands countless times; 53% remained home; and 74% used a mask when out in public. The health facility assessment showed: 93.6% were dispensaries and health centers; 90.4% had nurses; 40.5% had oxygen capacity; 13.5% had pulse oximeters; and 2 ventilators were available; 94.2% of facilities did not have COVID-19 testing kits; 94% and 91% of facilities continued to provide antenatal care and immunization services respectively. Health care worker training in COVID-19 had been planned.

ConclusionsHousehold prevalence of fever and cough was low suggesting Siaya had not entered the active community transmission phase in June 2020. Our assessment revealed a need for training in COVID-19 case management, and a need for basic equipment and supplies including pulse oximeters and oxygen. Future interventions should address these gaps.

Strengths and limitationsO_LIThis study provides an example of how to successfully carry out an integrated rural health system baseline assessment of COVID-19 preparedness; an approach that would be useful for any country experiencing COVID-19 with a significant rural population.
C_LIO_LISome of our data were retrospective in nature and therefore vulnerable to multiple sources of bias including: recall bias and misclassification.
C_LI

Clinical Trial registrationClinicaltrials.gov NCT04501458 5/8/2020

ProtocolThe full protocol has been accepted for publication: Kaseje N, Kaseje D, Oruenjo K, Milambo J and Kaseje M: Engaging community health workers, technology, and youth in the COVID-19 response with concurrent critical care capacity building: A protocol for an integrated community and health system intervention to reduce mortality related to COVID-19 infection in Western Kenya. Wellcome Open Research.

Ethical review approvalsreceived from the University of Nairobi Ethics Review Committee and Jaramogi Oginga Odinga Teaching and Referral Hospital Ethics Review Committee (approval number IERC/JOOTR/219/20)


title: Development of a Community Orientation Program (COP) as a Community-Based Medical Education method for undergraduate medical students: An experience from India

abstract:
BackgroundIntraregional cultural and linguistic differences are common in the Low- and Middle-income countries. They must focus on innovative teaching for the undergraduate (UG) medical students to make them sensitive to the social and contextual determinants of health to achieve the health for all goal. The early introduction of community-based medical education could be a game changing strategy.

ObjectivesTo describe the methods, evaluation, implication, and challenges of a Community Orientation Programme (COP) adopted for the Indian Medical Graduates (IMG). Methods: The COP was arranged for the first-year UG students, including the community and the local administration. The program was divided into phases like-initial preparation, theoretical sessions, field visits, group activities, data analysis, and dissemination of the findings. In this learner-centric, supervised educational program, the key aim was to focus on developing students communication skills, observation power and enhancing their motivation for learning new things through collaborative learning. A mixture of adult learning theories like behaviorism, cognitivism, constructivism, sociocultural theory, critical theory, and humanism included keeping the students needs, cultural differences, and varying motivational levels. A structured feedback mechanism from the students was developed to identify the gaps.

ConclusionThe COP has provided a holistic learning framework for the students based on several complementary learning theories in the Indian context. It has touched upon most of the national- and institutional-level objectives envisioned by the regulatory body for the IMGs. All stakeholders should promote such programs and solve the challenges collectively.

category: medical education


title: epiLiver a novel tumor specific, high throughput and cost-effective blood test for specific detection of liver cancer (HCC)

abstract: Robust cost effective and high-throughput tests for early detection of cancer in otherwise healthy people could potentially revolutionize public-health and the heavy personal and public burden of the morbidity and mortality from cancer. Several studies have delineated tumor specific DNA methylation profiles that could serve as biomarkers for early detection of Hepatocellular Carcinoma (HCC) as well as other cancers in liquid biopsies. Several published DNA methylation markers fail to distinguish HCC DNA from DNA from other tissues and other cancers that are potentially present in plasma. We describe a set of DNA methylation signatures in HCC that are "categorically" distinct from normal tissues and blood DNA methylation profiles. We develop a classifier combined of 4 CG sites that is sufficient to detect HCC in TCGA HCC data set at high accuracy. A single CG site at the F12 gene is sufficient to differentiate HCC samples from thousands of other blood samples, normal tissues and 31 tumors in the TCGA and Gene Expression Omnibus (GEO) data repository (n=11,704). A "next generation sequencing"-targeted-multiplexed high-throughput assay was developed, which was used to examine in a clinical study plasma samples from HCC, chronic hepatitis B (CHB) patients and healthy controls (n=398). The sensitivity for HCC detection was 84.5% at a specificity of 95% and AUC of 0.94. Applying this assay for routine follow up of people who are at high risk for developing HCC could have a significant impact on reducing the morbidity and mortality from HCC.

category: oncology


title: Cohort Profile: Epigenetics in Pregnancy (EPIPREG)-population-based sample of European and South Asian pregnant women living in Norway with epigenome-wide DNA methylation (850k) in peripheral blood leukocytes

abstract:
PurposePregnancy is a valuable model to study the association between DNA methylation and several cardiometabolic traits, due to its direct potential to influence mothers and childs health. Epigenetics in Pregnancy (EPIPREG) is a population-based sample with the aim to study associations between DNA-methylation in pregnancy and cardiometabolic traits in South Asian and European pregnant women and their offspring.

ParticipantsIn EPIPREG we have quantified epigenome-wide DNA methylation in maternal peripheral blood leukocytes in gestational week 28{+/-}1 in Europeans (n=312) and South Asians (n=168) that participated in the population-based cohort STORK Groruddalen, in Norway. DNA methylation was measured with Infinium MethylationEPIC Kit (850k sites), with technical validation of four CpG sites using bisulphite pyrosequencing in a subset (n=30). The sample is well characterized with few missing data on e.g. genotype, universal screening for gestational diabetes, objectively measured physical activity, bioelectrical impedance, anthropometrics, biochemical measurements, and a biobank with maternal serum and plasma, urine, placenta tissue. In offspring, we have repeated ultrasounds during pregnancy, cord blood, and anthropometrics up to 4 years of age.

Results to dateWe have quantified DNA methylation in peripheral blood leukocytes in nearly all eligible women from the STORK Groruddalen study, to minimize the risk of selection bias. Genetic principal components distinctly separated Europeans and South Asian women, which fully corresponded with the self-reported ethnicity. Technical validation of 4 CpG sites from the methylation bead chip showed high concordance with bisulfite pyrosequencing (R=0.98, p<0.001).

Future plansWe plan to study associations between DNA methylation and cardiometabolic traits and outcomes. We hope to identify cohorts with similar data to replicate our findings, collaborate on joint efforts such as meta-analysis, and serve as a replication cohort for other studies.

Strengths and limitations of this study- Epigenome-wide DNA methylation data in maternal peripheral blood leukocytes in gestational week 28{+/-}1 in 312 Europeans and 168 South Asians living in Norway
- EPIPREGs population-based design and comprehensive phenotyping allows for studies of a wide range of phenotypic traits, exposures and outcomes in relation to DNA methylation
- The inclusion of women with both European and South Asian ethnic background enables interesting studies into the role of DNA methylation in ethnic disparities in health.
- The wide range of collected phenotypes, exposures and outcomes makes the EPIPREG sample well suited to serve as a replication cohort for other cohorts with DNA methylation data
- The EPIPREG sample has limited statistical power for epigenome-wide association studies, and we are interested in collaborative efforts such as meta-analysis of several cohorts

category: genetic and genomic medicine


title: The Construction and Analysis of ceRNA Network and Immune Infiltration in Kidney Renal Clear Cell Carcinoma

abstract:
BackgroundKidney renal clear cell carcinoma (KIRC) has the highest invasion, mortality and metastasis of the renal cell carcinomas and seriously affects patients quality of life. However, the composition of the immune microenvironment and regulatory mechanisms at transcriptomic level such as ceRNA of KIRC are still unclear.

MethodsWe constructed a ceRNA network associated with KIRC by analyzing the long noncoding RNA (lncRNA), miRNA and mRNA expression data of 506 tumor tissue samples and 71 normal adjacent tissue samples downloaded from the Cancer Genome Atlas (TCGA) database. In addition, we estimated the proportion of 22 immune cell types in these samples through "The Cell Type Identification by Estimating Relative Subsets of RNA Transcripts". Based on the ceRNA network and immune cells screened by univariate Cox analysis and Lasso regression, two nomograms were constructed to predict the prognosis of patients with KIRC. Receiver operating characteristic curves (ROC) and calibration curves were employed to assess the discrimination and accuracy of the nomograms. Consequently, co-expression analysis was carried out to explore the relationship between each prognostic gene in a Cox proportional hazards regression model of ceRNA and each survival-related immune cell in a Cox proportional hazards regression model of immune cell types to reveal the potential regulatory mechanism.

ResultsWe established a ceRNA network consisting of 12 lncRNAs, 25 miRNAs and 136 mRNAs. Two nomograms containing seven prognostic genes and two immune cells, respectively, were successfully constructed. Both ROC [Area Under Curves (AUCs) of 1, 3 and 5-year survival in the nomogram based on ceRNA network: 0.779, 0.747 and 0.772; AUCs of 1, 3 and 5-year survivals in nomogram based on immune cells: 0.603, 0.642 and 0.607] and calibration curves indicated good accuracy and clinical application value of both models. Through co-correlation analysis between ceRNA and immune cells, we found both LINC00894 and KIAA1324 were positively correlated with follicular helper T (Tfh) cells and negatively correlated with resting mast cells.

ConclusionsBased on the ceRNA network and tumor-infiltrating immune cells, we constructed two nomograms to predict the survival of KIRC patients and demonstrated their value in improving the personalized management of KIRC.


title: Dysautonomia in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders is associated with exercise intolerance and cardiac atrophy

abstract: Dysautonomia is a recognized manifestation in patients with joint hypermobility (JH) disorders. Symptoms can be highly debilitating and commonly include physical deconditioning and poor aerobic fitness. In this study, the prevalence of dysautonomia, range of associated symptoms, patient-reported physical activity levels and echocardiographic features were assessed retrospectively in a cohort of 144 patients (94% female) with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD). Echocardiographic parameters of LV size and function were compared between patients with and without dysautonomia, as well as to reported values from healthy controls. Dysautonomia was identified in 71% of female and 56% of male subjects and was associated with a high burden of symptomatology, most commonly exercise intolerance (78%). Exercise capacity was limited by dysautonomia, often postural symptoms, in half of all patients. We observed a reduction in physical activity following the onset or significant flare of hEDS/HSD, most strikingly noting the proportion of dysautonomic patients with sedentary lifestyle, which increased from 39% to >80%. JH-related dysautonomia was associated with smaller cardiac chamber sizes, consistent with previous reports in positional orthostatic tachycardia syndrome. Dysautonomia is highly prevalent in patients with hEDS/HSD, exercise intolerance is a key feature and leads to drastic decline in physical activity. Unfavorable cardiac geometry may underlie dysautonomia symptoms and may be due to cardiac atrophy in the setting of aerobic deconditioning.


title: Galectin-3 as a potential prognostic biomarker of severe COVID-19 in SARS-CoV-2 infected patients

abstract:
BACKGROUNDPrognostic biomarkers are needed to identify patients at high-risk for severe COVID-19. Galectin-3 is known to drive neutrophil infiltration and release of pro-inflammatory cytokines contributing to airway inflammation.

METHODSIn this prospective cohort, we assessed galectin-3 levels in 156 hospitalized patients with confirmed COVID-19. COVID-19 patients were diagnosed as either critical (>50% lung damage) or moderate (<50% of lung damage) based on computerized tomography. Patients who required invasive mechanical ventilation (IMV) and/or died during hospitalization were categorized as having a severe outcome, and a non-severe outcome if they were discharged and none of the former occurred.

RESULTSElevated serum galectin-3 was significantly higher in critical patients compared to moderate ones (35.91 {+/-} 19.37 ng/mL vs. 25 {+/-} 14.85 ng/mL, p<0.0001). Patients who progressed to a severe outcome including IMV and/or in-hospital death, presented higher galectin-3 levels (41.17 ng/mL [IQR 29.71 - 52.25] vs. 23.76 ng/mL [IQR 15.78 - 33.97] compared to those of a non-severe outcome, p<0.0001). Galectin-3 discriminated well between those with severe and non-severe outcome, with an AUC of 0.75 (95% CI 0.67 - 0.84, p<0.0001) and was found to be an independent predictor of severe outcome regardless of the percentage of lung involvement. Additionally, the combination of galectin-3, CRP and albumin, significantly improved its individual predicting ability with an AUC 0.84 (95% CI 0.77 - 0.91, p<0.0001).

CONCLUSIONCirculating galectin-3 levels can be used to predict severe outcomes in COVID-19 patients, including the requirement of mechanical ventilation and/or death, regardless of the initial severity of the disease.


title: The protective association between statins use and adverse outcomes among COVID-19 patients: a systematic review and meta-analysis

abstract:
IntroductionStatins may reduce a cytokine storm, which has been hypothesized as a possible mechanism of severe COVID-19 pneumonia. The aim of this study was to conduct a systematic review and meta-analysis to report on adverse outcomes among COVID-19 patients by statin usage.

MethodsLiteratures were searched from January 2019 to December 2020 to identify studies that reported the association between statin usage and adverse outcomes, including mortality, ICU admissions, and mechanical ventilation. Studies were meta-analyzed for mortality by the subgroups of ICU status and statin usage before and after COVID-19 hospitalization. Studies reporting an odds ratio (OR) and hazard ratio (HR) were analyzed separately.

ResultsThirteen cohorts, reporting on 110,078 patients, were included in this meta-analysis. Individuals who used statins before their COVID-19 hospitalization showed a similar risk of mortality, compared to those who did not use statins (HR 0.80, 95% CI: 0.50, 1.28; OR 0.62, 95% CI: 0.38, 1.03). Patients who were administered statins after their COVID-19 diagnosis were at a lower risk of mortality (HR 0.53, 95% CI: 0.46, 0.61; OR 0.57, 95% CI: 0.43, 0.75). The use of statins did not reduce the mortality of COVID-19 patients admitted to the ICU (OR 0.65; 95% CI: 0.26, 1.64). Among non-ICU patients, statin users were at a lower risk of mortality relative to non-statin users (HR 0.53, 95% CI: 0.46, 0.62; OR 0.64, 95% CI: 0.46, 0.88).

ConclusionPatients administered statins after COVID-19 diagnosis or non-ICU admitted patients were at lower risk of mortality relative to non-statin users.


title: Current quantitative polymerase chain reaction to detect severe acute respiratory syndrome coronavirus 2 may give positive results for other described coronavirus

abstract: Some weeks after the first CoVID-19 outbreak, the WHO published some qPCR protocol assays developed by different institutions worldwide. These qPCR designs are being used to detect the presence of SARS-CoV-2 in the population, which allow us to monitore the prevalence of the virus during the pandemic. Moreover, the use of these designs is wide spreading and nowadays they are used to detect SARS-CoV-2 in environmental samples to act as epidemiological surveillance tool. However, at the time of designing the published RT-qPCR assays, a lack of SARS-CoV-2 genomes available may explain a low exclusivity in some cases. In this study, we are reporting experimental data which demonstrate that some of the current qPCR used to detect SARS-CoV-2 may give positive results for other described coronavirus different from SARS-CoV-2.


title: Development and Validation of a Simplified Risk Score for the Prediction of Critical COVID-19 Illness in Newly Diagnosed Patients

abstract:
Scores for identifying patients at high risk of progression of the coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are discussed as key instruments for clinical decision-making and patient management during the current pandemic.

Here we used the patient data from the multicenter Lean European Open Survey on SARS-CoV-2 - Infected Patients (LEOSS) and applied a technique of variable selection in order to develop a simplified score to identify patients at increased risk of critical illness or death.

A total of 1,946 patients, who were tested positive for SARS-CoV-2 were included in the initial analysis. They were split into a derivation and a validation cohort (n=1,297 and 649, respectively). A stability selection among a total of 105 baseline predictors for the combined endpoint of progression to critical phase or COVID-19-related death allowed us to develop a simplified score consisting of five predictors: CRP, Age, clinical disease phase (uncomplicated vs. complicated), serum urea and D-dimer (abbreviated as CAPS-D score). This score showed an AUC of 0.81 (CI95%: 0.77-0.85) in the validation cohort for predicting the combined endpoint within 7 days of diagnosis and 0.81 (CI95%: 0.77-0.85) during the full follow-up. Finally, we used an additional prospective cohort of 682 patients, who were diagnosed largely after the "first wave" of the pandemic to validate predictive accuracy of the score, observing similar results (AUC for an event within 7 days: 0.83, CI95%, 0.78-0.87; for full follow-up: 0.82, CI95%, 0.78-0.86).

We thus successfully establish and validate an easily applicable score to calculate the risk of disease progression of COVID-19 to critical illness or death.


title: COVID-19 infection and outcomes in a population-based cohort of 17,173 adults with intellectual disabilities compared with the general population

abstract:
ObjectivesTo compare COVID-19 infection, severe infection, mortality, case-fatality, and excess deaths, among adults with intellectual disabilities and those without.

DesignRecord-linkage of all adults recorded with intellectual disabilities in Scotlands Census, 2011, and a 5% sample of other adults, to COVID-19 test results (Electronic Communication of Surveillance in Scotland), hospitalisations (Scottish Morbidity Record 01), and deaths (National Records of Scotland).

SettingGeneral population; 24th January 2020 - 15th August 2020

ParticipantsSuccessful linkage of 94.8% provided data on 17,173 adults with, and 195,859 without, intellectual disabilities.

OutcomesCrude rates of COVID-19 infection, severe infection (hospitalisation/death), mortality, and case fatality; age-, sex- and deprivation-standardised severe infection and mortality ratios; annual all-cause mortality for 2020 and 2015-2019.

ResultsAdults with intellectual disabilities had higher rates of COVID-19 infection (957/100,000 versus 513/100,000); severe infection (549/100,000 versus 237/100,000); mortality (259/100,000 versus 114/100,000); and case-fatality (30% versus 24%). Poorer COVID-19 outcomes remained after standardising for age, sex and deprivation: standardised severe infection ratio 2.59 (95% CI 1.80, 3.39) and mortality ratio 3.20 (95% CI 2.16, 4.25). These were higher among 55-64 year olds: 7.12 (95% CI 3.73, 10.50) and 16.16 (95% CI7.69, 24.63) respectively. Among adults with intellectual disabilities, all-cause mortality was only slightly higher in 2020 than the previous five years: standardised mortality ratios 2.49 (95% CI 2.17, 2.81) and 2.38 (95% CI 2.26, 2.49) respectively.

ConclusionsAdults with intellectual disabilities were more likely to be infected with COVID-19, and had worse outcomes once infected, particularly those under 65 years. Non-pharmaceutical interventions directed at formal and informal carers are essential to reduce transmission and all adults with intellectual disabilities should be immediately prioritised for vaccination regardless of age.

Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LICOVID-19 mortality is higher within multi-occupancy residences.
C_LIO_LIAdults with intellectual disabilities may be at higher risk of COVID-19 mortality than other adults, but there are gaps in the evidence.
C_LIO_LICOVID-19 case-fatality may be no different, or as much as 2.75 times higher in adults with intellectual disabilities compared with other adults.
C_LI

What this study addsO_LICompared with general population adults, adults with intellectual disabilities were almost twice as likely to become infected with COVID-19, 2.3 times as likely to have severe infection, 2.3 times as likely to have COVID-19 mortality, and had 25% higher COVID-19 case-fatality.
C_LIO_LIAfter standardising for age, sex and deprivation, people with intellectual disabilities were 3.2 times more at risk of covid-19 mortality and 2.6 times more at risk of severe infection relative to those with no intellectual disabilities
C_LIO_LICompared with general population adults, adults with intellectual disabilities had poorer outcomes among non-elderly age-groups particularly those aged 55-65 years, men, and those living in less-deprived neighbourhoods.
C_LIO_LINon-pharmaceutical initiatives are important for carers and care-provider organisations, and adults with intellectual disabilities should be prioritised in the national rollouts of COVID-19 vaccination programmes, regardless of age, sex, or neighbourhood deprivation.
C_LI


title: Modelling the impact of reopening schools in early 2021 in the presence of the new SARS-CoV-2 variant and with roll-out of vaccination against COVID-19

abstract:
BackgroundFollowing the resurgence of the COVID-19 epidemic in the UK in late 2020 and the emergence of the alpha (also known as B117) variant of the SARS-CoV-2 virus, a third national lockdown was imposed from January 4, 2021. Following the decline of COVID-19 cases over the remainder of January 2021, the question of when and how to reopen schools became an increasingly pressing one in early 2021. This study models the impact of a partial national lockdown with social distancing measures enacted in communities and workplaces under different strategies of reopening schools from March 8, 2021 and compares it to the impact of continual full national lockdown remaining until April 19, 2021.

MethodsWe used our previously published agent-based model, Covasim, to model the emergence of the alpha variant over September 1, 2020 to January 31, 2021 in presence of Test, Trace and Isolate (TTI) strategies. We extended the model to incorporate the impacts of the roll-out of a two-dose vaccine against COVID-19, with 200,000 daily vaccine doses prioritised by age starting with people 75 years or older, assuming vaccination offers a 95% reduction in disease acquisition risk and a 30% reduction in transmission risk. We used the model, calibrated until January 25, 2021, to simulate the impact of a full national lockdown (FNL) with schools closed until April 19, 2021 versus four different partial national lockdown (PNL) scenarios with different elements of schooling open: 1) staggered PNL with primary schools and exam-entry years (years 11 and 13) returning on March 8, 2021 and the rest of the schools years on March 15, 2020; 2) full-return PNL with both primary and secondary schools returning on March 8, 2021; 3) primary-only PNL with primary schools and exam critical years (years 11 and 13) going back only on March 8, 2021 with the rest of the secondary schools back on April 19, 2021 and 4) part-rota PNL with both primary and secondary schools returning on March 8, 2021 with primary schools remaining open continuously but secondary schools on a two-weekly rota-system with years alternating between a fortnight of face-to-face and remote learning until April 19, 2021. Across all scenarios, we projected the number of new daily cases, cumulative deaths and effective reproduction number R until April 30, 2021.

ResultsOur calibration across different scenarios is consistent with alpha variant being around 60% more transmissible than the wild type. We find that strict social distancing measures, i.e. national lockdowns, were essential in containing the spread of the virus and controlling hospitalisations and deaths during January and February 2021. We estimated that a national lockdown over January and February 2021 would reduce the number of cases by early March to levels similar to those seen in October 2020, with R also falling and remaining below 1 over this period. We estimated that infections would start to increase when schools reopened, but found that if other parts of society remain closed, this resurgence would not be sufficient to bring R above 1. Reopening primary schools and exam critical years only or having primary schools open continuously with secondary schools on rotas was estimated to lead to lower increases in cases and R than if all schools opened. Without an increase in vaccination above the levels seen in January and February, we estimate that R could have increased above 1 following the reopening of society, simulated here from April 19, 2021.

FindingsOur findings suggest that stringent measures were integral in mitigating the increase in cases and bringing R below 1 over January and February 2021. We found that it was plausible that a PNL with schools partially open from March 8, 2021 and the rest of the society remaining closed until April 19, 2021 would keep R below 1, with some increase evident in infections compared to continual FNL until April 19, 2021. Reopening society in mid-April, without an increase in vaccination levels, could push R above 1 and induce a surge in infections, but the effect of vaccination may be able to control this in future depending on the transmission blocking properties of the vaccines.


title: Modelling the impact of reopening schools in the UK in early 2021 in the presence of the alpha variant and with roll-out of vaccination against SARS-CoV-2


title: High School Sports During the CoVID-19 Pandemic: The Impact of Sport Participation on the Health of Adolescents

abstract:
ContextDuring the fall of 2020, some high schools across the US allowed their students to participate in interscholastic sports while others cancelled or postponed their sport programs due to concerns regarding CoVID19 transmission. It is unknown what effect this has had on the physical and mental health of student athletes.

ObjectiveIdentify the impact of playing a sport during the CoVID19 pandemic on the health of student athletes.

DesignCross-sectional study.

SettingSample recruited via email.

Patients or Other Participants559 Wisconsin high school athletes (age=15.7+1.2 yrs., female=44%) from 44 high schools completed an online survey in October 2020. A total of 171 (31%) athletes played (PLY) a fall sport, while 388 (69%) did not play (DNP).

Main Outcome Measure(s)Demographics included: sex, grade and sports played. Assessments included the General Anxiety Disorder-7 Item (GAD-7) for anxiety, Patient Health Questionnaire-9 Item (PHQ-9) for depression, the Pediatric Functional Activity Brief Scale (PFABS) for physical activity, and the Pediatric Quality of Life Inventory 4.0 (PedsQL) for quality of life. Univariable comparisons between the two groups were made via t-tests or chi-square tests. Means for each continuous outcome measure were compared between the groups by ANOVA models that controlled for Age, Sex, Teaching method (Virtual, Hybrid, or In-person), and the % of students eligible for free lunch.

RESULTSPLY group participants were less likely to report moderate to severe symptoms of anxiety (PLY=6.6%, DNP=44.1%, p<0.001) and depression (PLY=18.2%, DNP=40.4%, p<0.001). PLY athletes reported higher (better) PFABS scores (mean: [95%CI]), (PLY=23.2[22.0,24.5], DNP=16.4[15.0,17.8], p <0.001) and higher (better) PedsQL total scores (PLY=88.4[85.9,90.9], DNP=79.6[76.8,82.4], p <0.001).

CONCLUSIONSAdolescent athletes who played a sport during the CoVID19 pandemic reported fewer symptoms of anxiety and depression, as well as higher physical activity and quality of life scores compared to adolescent athletes who did not play a sport.

Key pointsO_LIHigh school students who played a sport during the CoVID-19 pandemic in the fall of 2020 were less likely to report anxiety and depression symptoms than athletes who did not play a sport.
C_LIO_LIHigh school students who played a sport during the CoVID-19 pandemic in the fall of 2020 reported higher physical activity and quality of life scores compared to high school athletes who did not play a sport.
C_LIO_LIParticipation in high school sports may have significant physical and mental health benefits for US adolescent athletes during the CoVID-19 pandemic.
C_LI


title: An optimized MRI and PET based clinical protocol for improving the differential diagnosis of Geriatric Depression and Alzheimer's Disease

abstract:
OBJECTIVEMRI derived hippocampal volume (HV) and amyloid PET may be useful clinical biomarkers for differentiating between geriatric depression and Alzheimers Disease (AD). Here we investigated the incremental value of HV and 18F-flutemetmol PET in tandem and sequentially to improve discrimination in unclassified participants.

METHODTwo approaches were compared in 41 participants with geriatric depression and 27 participants with probable AD: (1) amyloid and HV combined in one model and (2) HV first and then amyloid.

RESULTSBoth HV({chi}2(1) = 6.46: p= 0.011) and amyloid ({chi}2(1) =11.03: p=0.0009) were significant diagnostic predictors of depression (sensitivity: 95%, specificity: 89%). (2) 51% of participants were correctly classified according to clinical diagnosis based on HV alone, increasing to 87% when adding amyloid data (sensitivity: 94%, specificity: 78%).

CONCLUSIONHippocampal volume may be a useful gatekeeper for identifying depressed individuals at risk for AD who would benefit from additional amyloid biomarkers when available.

category: psychiatry and clinical psychology


title: Synchronizability predicts effective responsive neurostimulation for epilepsy prior to treatment

abstract: Despite the success of responsive neurostimulation (RNS) for epilepsy, clinical outcomes vary significantly and are hard to predict. The ability to forecast clinical response to RNS therapy before device implantation would improve patient selection for RNS surgery and could prevent a costly and ineffective intervention. Determining and validating biomarkers predictive of RNS response is difficult, however, due to the heterogeneity of the RNS patient population and clinical procedures; large, multi-center datasets are needed to quantify patient variability and to account for stereotypy in the treatment paradigm of any one center. Here we use a distributed, cloud-based pipeline to analyze a federated dataset of intracranial EEG recordings, collected prior to RNS surgery, from a retrospective cohort of 30 patients across three major epilepsy centers. Based on recent work modelling the controllability of distributed brain networks, we hypothesize that broader brain network connectivity, beyond the seizure onset zone, can predict RNS response. We demonstrate how intracranial EEG recordings can be leveraged through network analysis to uncover biomarkers that predict response to RNS therapy. Our findings suggest that peri-ictal changes in synchronizability, a global network metric shown to accurately predict outcome from resective epilepsy surgery, can distinguish between good and poor RNS responders under the current RNS therapy guidelines (area under the receiver operating characteristic curve of 0.75). Furthermore, this study also provides a proof-of-concept roadmap for multicenter collaboration where practical considerations impede sharing datasets fully across centers.

category: neurology


title: Spinal fluid antibodies against multiple sclerosis candidate bacteria in demyelinating disease

abstract: A panel of 10 IgG enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of anti-microbial immune responses in the cerebrospinal fluid (CSF) of patients with demyelinating diseases (DD). Selection of the anti-microbial ELISA assays was guided by previous RNA sequencing studies that established a multiple sclerosis (MS) microbial candidate list. Microbial antigens included on the ELISA panel were derived from Akkermansia muciniphila, Atopobium vaginae, Bacteroides fragilis, Lactobacillus paracasei, Odoribacter splanchnicus, Pseudomonas aeruginosa, Cutibacterium (Propionibacterium) acnes, Fusobacterium necrophorum, Porphyromonas gingivalis, and Streptococcus mutans. Spinal fluid responses from patients with demyelinating diseases (DD, N=14) were compared to those with other neurological diseases (OND, N=8), and non-MS (Control, N=13) control patients. Commercial positive and negative control CSF specimens were run with each assay. ELISA Index values were derived for each specimen against each of the 10 bacterial antigen preparations. Intrathecal production of anti-microbial antibodies was assessed by comparing CSF and comparably diluted serum. CSF reactivity was significantly higher in the DD group compared to the controls against Akkermansia, Atopobium, Bacteroides, Lactobacillus, Odoribacter, and Fusobacterium. Four of the 11 tested DD group subjects had elevated antibody indexes against at least one of the 10 bacterial antigens, suggesting intrathecal production of anti-bacterial antibodies. This CSF serological study supports the hypothesis that several of the previously identified MS candidate microbes may contribute to demyelination in some patients.


title: Identification of Somatic Structural Variants in Solid Tumors By Optical Genome Mapping

abstract: Genomic structural variants comprise a significant fraction of somatic mutations driving cancer onset and progression. However, such variants are not readily revealed by standard next generation sequencing. Optical genome mapping (OGM) surpasses short read sequencing in detecting large (>500bp) and complex structural variants (SVs) but requires isolation of ultra-high molecular weight DNA from the tissue of interest. We have successfully applied a protocol involving a paramagnetic nanobind disc to a wide range of solid tumors. Using as little as 6.5mg of input tumor tissue, we show successful extraction of high molecular weight genomic DNA that provides a high genomic map rate and effective coverage by optical mapping. We demonstrate the systems utility at identifying somatic SVs affecting functional and cancer-related genes for each sample. Duplicate/triplicate analysis of select samples shows intra-sample reliability but also intra-sample heterogeneity. We also demonstrate that simply filtering SVs based on a GRCh38 human control database provides high positive and negative predictive values for true somatic variants. Our results indicate that the solid tissue DNA extraction protocol, OGM and SV analysis can be applied to a wide variety of solid tumors to capture SVs across the entire genome with functional importance in cancer prognosis and treatment.


title: Do Assisted Living Facilities That Offer a Dementia Care Program Differ from Those That Do Not? A Population-Level Cross-Sectional Study in Ontario, Canada

abstract:
ObjectiveTo identify the characteristics of licensed assisted living facilities that provide a dementia care program compared to assisted living facilities that do not provide such a program.

Design, Setting, and ParticipantsPopulation-level cross-sectional study in Ontario, Canada on all licensed assisted living facilities in 2018 (n = 738).

MethodsData on facility-level characteristics (e.g., resident and suite capacities, etc.) and the provision of other provincially regulated care services (e.g., pharmacist and medical services, skin and wound care, etc.) attributed to licensed assisted living facilities were examined. Multivariable Poisson regression with robust standard errors was used to model the characteristics of assisted living facilities associated with the provision of a dementia care program.

ResultsThere were 123 (16.7%) assisted living facilities that provided a dementia care program. Nearly half of these facilities had a resident capacity exceeding 140 older adults (44.7%) and more than 115 suites (46.3%). All assisted living facilities that provided a dementia care program also provided nursing services, meals, assistance with bathing and hygiene, and administered medications. After adjusting for facility characteristics and other provincially regulated care services, the prevalence of a dementia care program was nearly three times greater in assisted living facilities that offered assistance with feeding than those that did not (Prevalence Ratio [PR] = 2.91, 95% Confidence Interval [CI] 1.98 to 4.29), and almost twice as great among assisted living facilities that provided medical services than those that did not (PR = 1.78, 95% CI 1.00 to 3.17).

ConclusionsA dementia care program was more prevalent in assisted living facilities that housed many older adults, had many suites, and provided at least five of the other 12 regulated care services. These findings deepen the understanding of specialized care for dementia in assisted living facilities.

BRIEF SUMMARYO_ST_ABSQuestionC_ST_ABSDo licensed assisted living facilities that provide a dementia care program differ from those that do not in Ontario, Canada?

FindingsAssisted living facilities that provide a dementia care program house many older adults, have many suites, and offer at least five of the other 12 regulated care services.

MeaningAssisted living facilities that provide a dementia care program are larger and provide an array of care services.

DisclosuresWe have no perceived or actual conflicts, financial or otherwise, to disclose.

Author ContributionsDRM and APC conceptualized the study. AR created the dataset, and DRM conducted the statistical analyses. DRM wrote the manuscript, and all authors critically read and contributed to it.

Data AvailabilityThe dataset from this study is held securely in coded form at ICES. While data sharing agreements prohibit ICES from making the data set publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS. The full data set creation plan and underlying analytic code are available from the corresponding author upon request, understanding that the programs may rely upon coding templates or macros that are unique to ICES.

category: geriatric medicine


title: COVID-19 in pregnancy: characteristics and outcomes of pregnant women admitted to hospital because of SARS-CoV-2 infection in the Nordic countries.

abstract:
IntroductionPopulation-based studies about the consequences of SARS-CoV-2 infection (COVID-19) in pregnancy are few and have limited generalizability to the Nordic population and health care systems.

Material and methodThis study examines pregnant women with COVID-19 in the five Nordic countries. Pregnant women were included if they were admitted to hospital between March 1 and June 30, 2020 and had a positive SARS-CoV-2 PCR test 14 days or fewer prior to the admission. Cause of admission was classified as obstetric or COVID-19 related.

ResultsIn the study areas, 214 pregnant women with a positive test were admitted to hospital, of which 56 women needed hospital care due to COVID-19. The rate of admission due to COVID-19 was 0.4 per 1000 deliveries in Denmark, Finland, and Norway and 3.8 per 1000 deliveries in the Swedish regions. Women hospitalized because of COVID-19 were more frequently obese (P < 0.001) and had migrant background (P < 0.001) compared to the total population of women who delivered in 2018. Twelve women (21.4%) needed intensive care. Preterm delivery (n=12, 25%, P < 0.001) and cesarean delivery (n=21, 43,8%, P < 0.001) were more frequent in women with COVID-19 compared to the women who delivered in 2018. No maternal deaths, stillbirths or neonatal deaths were reported.

ConclusionsThe risk of admission due to severe COVID-19 disease in pregnancy was low in the Nordic countries. A fifth of the women required intensive care and we observed higher rates of preterm and cesarean deliveries. National public health policies appear to have had an impact on the rates of admission due to severe COVID-19 disease in pregnancy. Nordic collaboration is important in collecting robust data and assessing rare outcomes.

Key MessageRisk of hospital admission due to COVID-19 infection among pregnant women was low in the Nordic countries, but varied between the countries, which is most likely related to different national public health strategies.


title: The humoral response to BK polyomavirus in kidney transplant recipients is dominated by IgM antibodies that use a distinct repertoire compared to IgG against the same antigen

abstract: 1.The BK polyomavirus (BKPyV) persists asymptomatically in the kidney and active replication is only seen in immunosuppressed individuals, such as kidney transplant (KTx) recipients, in whom BKPyV reactivation can cause significant morbidity. KTx recipients with BKPyV reactivation mount a robust humoral response, but this often fails to clear the virus. In order to characterize the BKPyV-specific B-cell receptor (BCR) repertoire in KTx recipients, we used fluorescence-labeled BKPyV virus-like particles (VLPs) to sort with BKPyV-specific B-cells, then single-cell RNAseq to obtain paired heavy and light chain antibody sequences, and gene transcriptome data. The BCR repertoire was highly diverse in terms of both V-gene usage and clonotype diversity, with approximately 3% repertoire overlap between patients. The BKPyV-specific response was characterized by the presence of both memory IgG and memory IgM B-cells with extensive somatic hypermutation, which expressed distinct BCR repertoires within the same patient. The gene expression profile of IgG and IgM memory B-cells was highly similar, with only 19 genes, including CD83, CD79A and PARP1 showing significant differential expression. These results confirm that the IgM memory B-cells are a significant component of the BKPyV-specific humoral response, and show for the first time that IgG and IgM repertoires directed against the same antigen can have significant differences.

category: allergy and immunology


title: Dose-Response Effect of Acupuncture for Melasma: A Prospective Cohort Study in a Tertiary Hospital in Thailand

abstract:
BackgroundMelasma is a common skin pigmentation disorder. Acupuncture shows benefits for patients with melasma, although no standardized method or optimal number of sessions have been determined.

ObjectiveTo comparatively assess clinical outcomes of melasma between five vs ten standard acupuncture sessions.

MethodsWe performed a prospective observational cohort study in all melasma patients at the Acupuncture Clinic, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. All patients were treated with standard acupuncture procedure twice a week and were evaluated after the fifth and the tenth sessions of acupuncture, with a follow-up one week after the last session. Participants were divided into two treatment groups: Groups A and B received five and ten acupuncture sessions respectively. Melasma outcomes were assessed by using the Melanin Index (MI), Melasma Area and Severity Index (MASI), patient-reported improvement scores and acupuncture-related adverse events.

ResultsOf 113 participants, 67 received five sessions of acupuncture treatment while 39 received ten sessions. 7 participants did not finish treatment. After five sessions of acupuncture in Group A, the mean MI decreased by 28.7 (95%CI -38.5 to -18.8), whereas the median MASI decreased by 3.4 (-6.9, -1.2) points. After ten sessions of acupuncture in Group B, the mean MI decreased by 31.3 (95%CI -45.0 to -17.6), whereas the median MASI decreased by 5.4 (-9.9, - 3.0) points. The first five sessions of acupuncture had a higher effect on the change in magnitude than the last five sessions, although there was no statistically significant difference. However, ten-session of acupuncture, had not reached the peak benefit on melasma yet. Further studies should be done with a higher number of sessions to determine the optimal rounds of treatment. Twenty-nine participants reported minor side effects, mostly consisting of persistent pain and small hematoma. Group B had RR of having adverse events 1.8 times (95% CI 1.0-3.4) compared to group A.

ConclusionAcupuncture has a potential dose-response effect on clinical and patient-reported melasma outcomes with minor side effects.

category: dermatology


title: Short Practical Regimen of Acupuncture for Melasma: A Prospective Cohort Study in a Tertiary Hospital in Thailand


title: Patterns of COVID-19 pandemic dynamics following deployment of a broad national immunization program

abstract: Studies on the real-life impact of the BNT162b2 vaccine, recently authorized for the prevention of coronavirus disease 2019 (COVID-19), are urgently needed. Here, we analysed the temporal dynamics of the number of new COVID-19 cases and hospitalization in Israel following a rapid vaccination campaign initiated on December 20th, 2020. We conducted a retrospective descriptive analysis of data originating from the Israeli Ministry of Health (MOH) from March 2020 to February 2021. In order to distill the possible effect of the vaccinations from other factors, including a third lockdown imposed in Israel on January 2021, we compared the time-dependent changes in number of COVID-19 cases and hospitalizations between (1) individuals aged 60 years and older, eligible to receive the vaccine earlier, and younger age groups; (2) the latest lockdown (which was imposed in parallel to the vaccine rollout) versus the previous lockdown, imposed on September 2020; (3) early-vaccinated cities compared to late-vaccinated cities; and (4) early-vaccinated geographical statistical areas (GSAs) compared to late-vaccinated GSAs. In mid-January, the number of COVID-19 cases and hospitalization started to decline, with a larger and earlier decrease among older individuals, followed by younger age groups, by the order in which they were prioritized for vaccination. This fast and early decline in older individuals was more evident in early-vaccinated compared to late-vaccinated cities. Such a pattern was not observed in the previous lockdown. Our analysis demonstrates evidence for the real-life impact of a national vaccination campaign in Israel on the pandemic dynamics. We believe that our findings have major public health implications in the struggle against the COVID-19 pandemic, including the public s perception of the need for and benefit of nationwide vaccination campaigns. More studies aimed at assessing the effectiveness and impact of vaccination both on the individual and on the population level, with longer followup, are needed.


title: PROTOCOL: A cohort study examining the association between mirtazapine and mortality risk in adults with a diagnosis of depression

abstract: This protocol describes a cohort study comparing the risks of mortality and serious self-harm (suicide or near-fatal deliberate self-harm) between adults with depression prescribed mirtazapine, a selective serotonin reuptake inhibitor (SSRI), amitriptyline, or venlafaxine. The study is set within English primary care electronic health records from the Clinical Practice Research Datalink (CPRD) and covers the period 01 January 2005 - 30 November 2018. The study described uses an active comparator new user design: patients are included if they are first prescribed an SSRI before being prescribed mirtazapine, a different SSRI, amitriptyline, or venlafaxine as their second antidepressant. Patients are followed from the initial prescription for the second antidepressant until an outcome (mortality, serious self-harm), end of CPRD follow-up, or study end. Inverse probability of treatment weighting is used to account for confounding variables. The protocol was submitted to the CPRD Independent Scientific Advisory Committee for review and was approved in November 2019 (protocol number 19_241).


title: Novel SARS-CoV-2 spike variant identified through viral genome sequencing of the pediatric Washington D.C. COVID-19 outbreak

abstract:
The SARS-CoV-2 virus has emerged as a global pandemic, severely impacting everyday life. Significant resources have been dedicated towards profiling the viral genome in the adult population. We present an analysis of viral genomes acquired from pediatric patients presenting to Childrens National Hospital in Washington D.C, including 24 with primary SARS CoV2 infection and 3 with Multisystem Inflammatory Syndrome in Children (MIS-C) undergoing treatment at our facility. Viral genome analysis using next generation sequencing indicated that approximately 81% of the analyzed strains were of the GH clade, 7% of the cases belonged to the GR clade, and 12% of the cases belonged to S, V, or G clades. One sample, acquired from a neonatal patient, presented with the highest viral RNA load of all patients evaluated at our center. Viral sequencing of this sample identified a SARS-CoV-2 spike variant, S:N679S. Analysis of data deposited in the GISAID global database of viral sequences shows the S:N679S variant is present in eight other sequenced samples within the US mid-Atlantic region. The similarity of the regional sequences suggests transmission and persistence of the SARS-CoV-2 variant within the Capitol region, raising the importance of increasing the frequency of SARS-CoV-2 genomic surveillance.

IMPORTANCEA variant in the SARS-CoV-2 spike protein was identified in a febrile neonate who was hospitalized with COVID-19. This patient exhibited the highest viral RNA load of any COVID-19 patient tested at our center. Viral sequencing identified a spike protein variant, S:N679S, which is proximal to the cleavage site at residue 681. The SARS-CoV-2 surface spike is a protein trimer (three subunits) which serves as the key target for antibody therapies and vaccine development. Study of viral sequences from the GISAID database revealed eight related sequences from the US mid-Atlantic region. The identification of this variant in a very young patient, its critical location in the spike polyprotein, and the evidence that it has been detected in other patients in our region underscores the need for increased viral sequencing to monitor variant prevalence and emergence, which may have a direct impact on recommended public health measures and vaccination strategies.


title: Genome-wide association study reveals genetic risk factors for trigeminal neuralgia

abstract:
BackgroundWhile many clinical risk factors of trigeminal neuralgia (TN) have been identified, the genetic basis of TN is largely unknown. Here, we perform the first genome-wide association study (GWAS) for TN using three independent DNA biobanks - BioVU, the UK Biobank, and Finngen.

ObjectiveTo elucidate the genetic basis of TN.

MethodsUsing GWAS summary statistics generated from BioVU, the UK Biobank, and Finngen, we performed fixed-effect meta-analysis across 490,912 individuals (1,188 TN cases and 489,724 controls) to identify genetic risk factors for TN. Genome-wide significance was defined as p < 5.0x10-8.

ResultsWe identify an intergenic locus on chromosome 1p22.2 flanked by ZNF326 and SNORD3G containing 5 SNPs (rs77449572, rs543311093, rs35117749, rs71666259, and rs116010656) reaching genome-wide significance (p < 5.0 x 10-8), where rs77449572 is the sentinel variant (p = 1.72 x 10-9). The SNP rs77449572 overlaps an enhancer element in cortex-derived neurospheres. In addition, rs71666259 and rs116010656 are located in enhancer elements in embryonic stem cells (HUES48), suggesting potential functional consequences of this locus. We also identify a second locus on chromosome 5q35.1 containing sentinel variant rs62376947 reaching genome-wide significance (p = 2.49 x 10-8).

ConclusionsTo our knowledge, we perform the first GWAS of TN. Future studies should be aimed at understanding the extent to which genetic variation stratifies response to neuropathic pain medication and whether genetic information may be used to identify patients who are likely to benefit (or not) from surgical intervention.


title: Machine learning approach to dynamic risk modeling of mortality in COVID-19: a UK Biobank cohort study

abstract: The COVID-19 pandemic has created an urgent need for robust, scalable monitoring tools supporting stratification of high-risk patients. This research aims to develop and validate prediction models, using the UK Biobank, to estimate COVID-19 mortality risk in confirmed cases. From the 11,245 participants testing positive for COVID-19, we develop a data-driven random forest classification model with excellent performance (AUC: 0.91), using baseline characteristics, pre-existing conditions, symptoms, and vital signs, such that the score could dynamically assess mortality risk with disease deterioration. We also identify several significant novel predictors of COVID-19 mortality with equivalent or greater predictive value than established high-risk comorbidities, such as detailed anthropometrics and prior acute kidney failure, urinary tract infection, and pneumonias. The model design and feature selection enables utility in outpatient settings. Possible applications include supporting individual-level risk profiling and monitoring disease progression across patients with COVID-19 at-scale, especially in hospital-at-home settings.


title: Expression of ACE2 receptor, soluble ACE2, Angiotensin I, Angiotensin II and Angiotensin (1-7), is modulated in COVID-19 patients.

abstract: Although SARS-CoV-2 is primarily a pulmonary-tropic virus, it is nonetheless responsible for multi-organ failure in patients with severe forms of COVID-19, particularly those with hypertension or cardiovascular disease. Infection requires virus binding to the angiotensin I converting enzyme 2 (ACE2) monocarboxypeptidase, a regulator of blood pressure homeostasis through its ability to catalyze the proteolysis of Angiotensin II (AngII) into Ang(1-7). Although assumed, it had not been proven so far whether the SARS-CoV-2 replication in COVID-19 patients could modulate the expression of the ACE2 receptor and/or the AngII plasma levels. We demonstrate here, that in COVID-19 patients the ACE2 mRNA expression is markedly reduced in circulating blood cells. This ACE2 gene dysregulation mainly affects the monocytes which also show a lower expression of membrane ACE2 protein. Moreover, a significant decrease in soluble ACE2 plasma levels is observed in COVID-19 patients, whereas the concentration of sACE2 returns to normal levels in patients recovered from COVID-19. In the plasma of COVID-19 patients, we also found an increase in AngI and AngII. On the other hand, the plasma levels of Ang(1-7) remains almost stable in COVID-19 patients. Despite the Ang(1-7) presence in the plasma of COVID-19 patients it seems insufficient to prevent the effects of massive AngII accumulation. These are the first direct evidence that the SARS-CoV-2 may affect the expression of blood pressure regulators with possible harmful consequences on COVID-19 outcome.

category: hematology


title: Genomic surveillance of SARS-CoV-2 in the Bronx enables clinical and epidemiological inference

abstract:
The Bronx was an early epicenter of the COVID-19 pandemic in the USA. We conducted temporal genomic surveillance of SARS-CoV-2 genomes across the Bronx from March-October 2020. Although the local structure of SARS-CoV-2 lineages mirrored those of New York City and New York State, temporal sampling revealed a dynamic and changing landscape of SARS-CoV-2 genomic diversity. Mapping the trajectories of variants, we found that while some became  endemic to the Bronx, other, novel variants rose in prevalence in the late summer/early fall. Geographically resolved genomes enabled us to distinguish between cases of reinfection and persistent infection in two pediatric patients. We propose that limited, targeted, temporal genomic surveillance has clinical and epidemiological utility in managing the ongoing COVID pandemic.

One sentence summaryTemporally and geographically resolved sequencing of SARS-CoV-2 genotypes enabled surveillance of novel genotypes, identification of endemic viral variants, and clinical inferences, in the first wave of the COVID-19 pandemic in the Bronx.


title: Genomic surveillance of SARS-CoV-2 during the first year of the pandemic in the Bronx enabled clinical and epidemiological inference


title: A mathematical model to identify optimal combinations of drug targets for dupilumab poor responders in atopic dermatitis

abstract:
BackgroundSeveral biologics for atopic dermatitis (AD) have demonstrated good efficacy in clinical trials, but with a substantial proportion of patients being identified as poor responders. This study aims to understand the pathophysiological backgrounds of patient variability in drug response, especially for dupilumab, and to identify promising drug targets in dupilumab poor responders.

MethodsWe conducted model-based meta-analysis of recent clinical trials of AD biologics and developed a mathematical model that reproduces reported clinical efficacies for nine biological drugs (dupilumab, lebrikizumab, tralokinumab, secukinumab, fezakinumab, nemolizumab, tezepelumab, GBR 830, and recombinant interferon-gamma) by describing systems-level AD pathogenesis. Using this model, we simulated the clinical efficacy of hypothetical therapies on virtual patients.

ResultsOur model reproduced reported time courses of %improved EASI and EASI-75 of the nine drugs. The global sensitivity analysis and model simulation indicated the baseline level of IL-13 could stratify dupilumab good responders. Model simulation on the efficacies of hypothetical therapies revealed that simultaneous inhibition of IL-13 and IL-22 was effective, whereas application of the nine biologic drugs was ineffective, for dupilumab poor responders (EASI-75 at 24 weeks: 21.6% vs. max. 1.9%).

ConclusionOur model identified IL-13 as a potential predictive biomarker to stratify dupilumab good responders, and simultaneous inhibition of IL-13 and IL-22 as a promising drug therapy for dupilumab poor responders. This model will serve as a computational platform for model-informed drug development for precision medicine, as it allows evaluation of the effects of new potential drug targets and the mechanisms behind patient variability in drug response.


title: Contractile cell apoptosis regulates airway smooth muscle remodeling in asthma

abstract:
RationaleInvestigations on the mechanisms of airway smooth muscle remodeling, a prominent asthma feature contributing to its clinical manifestations and severity, have largely focused on its hyperplastic growth. Conversely, limited data and virtually no translational research have been produced on a plausible role of apoptosis in the homeostasis and remodeling of airway smooth muscle.

ObjectivesWe aimed at demonstrating an involvement of apoptosis, an essential regulator of organ structure and cell turnover, in the pathophysiology of airway smooth muscle remodeling in asthma.

MethodsMurine experimental asthma was modeled to analyze airway hyperresponsiveness, contractile tissue remodeling and apoptosis detection outcomes at early and late cutoffs, and under pharmacological inhibition of apoptosis by employing a caspase blocker. Clinical investigation followed through analyses on human bronchial biopsies.

ResultsAirway hyperresponsiveness and contractile tissue remodeling were already established in early experimental asthma, and a subsequent upregulation of apoptosis limited the airway contractile tissue growth. Caspase inhibition elicited chaotic pulmonary mechanics and an unusual growth of airway smooth muscle that was structurally disorganized. In bronchial biopsies, airway smooth muscle increased from controls through subjects with intermittent and persistent moderate and severe asthma. Cleaved poly-ADP ribose polymerase (c-PARP, a byproduct of caspase activity) was increased in severe asthma.

ConclusionsApoptosis is involved in airway contractile cell turnover and in shaping the size, structure and proper function of the airway smooth muscle layer. Apoptosis inhibitors may complicate concomitant asthma, whereas agents favouring airway contractile cell apoptosis may provide a novel pipeline of therapeutic development.

Key messagesO_LIHow normal airway smooth muscle structure is preserved, and whether counteracting responses to remodeling are elicited in asthma, are outstanding questions not probed in vivo nor in the clinical setting.
C_LIO_LIIn this work, combined investigations on murine experimental asthma and human bronchial biopsies show that airway contractile cell apoptosis is involved in the homeostasis of airway smooth muscle, and apoptotic activity is upregulated as part of the remodeling process of this tissue in asthma.
C_LIO_LIApoptosis arises as a key regulator of the size and structure of the airway smooth muscle layer. This concept draws implications for clinical practice and drug development.
C_LI


title: Susceptibility and risk of suffering SARS-COV-2 infection by demographic characteristics and pre-existing medical conditions among middle-aged and older adults in Tarragona, Spain: results from the COVID19 TARRACO Cohort Study, March-June 2020

abstract: Objective: To analyse susceptibility/risk of suffering COVID19 among adults with distinct underlying medical conditions. Methods: Cohort study (population-based) including 79,083 people >=50 years-old in Tarragona (Southern Catalonia, Spain). At study start (01/03/2020) baseline cohort characteristics (demographic, previous comorbidities, chronic medications and vaccinations history) were recorded. Primary outcome was laboratory-confirmed COVID19 incurred in cohort members throughout 01/03/2020-30/06/2020. Risk of suffering COVID19 was evaluated by Cox regression, estimating multivariable hazard ratios (HRs) adjusted for age/sex and previous comorbidities. Results: Across study period, 536 laboratory-confirmed COVID19 cases were observed (mean incidence: 39.5 cases per 100,000 persons-week). In multivariable-analysis, age/years (HR: 1.01; 95% CI: 1.00-1.02; p=0.050), nursing-home (HR: 20.19; 95% CI: 15.98-25.51; p<0.001), neurological disease (HR: 1.35; 95% CI: 1.03-1.77; p=0.029), taking diuretics (HR: 1.39; 95% CI: 1.10-1.75; p=0.006), antiplatelet (HR: 1.36; 95% CI: 1.05-1.76; p=0.021) and benzodiazepines (HR: 1.24; 95% CI: 1.00-1.53; p=0.047) significantly increased risk; while smoking (HR: 0.57; 95%CI: 0.41-0.80; p=0.001), angiotensin converting enzyme inhibitors (HR: 0.78; 95% CI: 0.61-1.00; p=0.048), angiotensin II receptor blockers (HR: 0.70; 95%CI: 0.51-0.96; p=0.027) and statins (HR: 0.75; 95% CI: 0.58-0.96; p=0.025) were associated with reduced risk. Among non-institutionalised persons, cancer, renal and cardiac disease appeared also related to increased risk, whereas influenza vaccination was associated with reduced risk. Conclusion: In a setting with relatively low incidence of COVID19 across the first wave of pandemic period, age, nursing-home residence and multiple comorbidities appear predisposing for COVID19 among middle-aged/older adults. Conversely, statins, angiotensin-receptor blockers/inhibitors and influenza vaccination were related with decreased risk. KEYWORDS: Coronavirus; SARS-COV-2; COVID19; Incidence; Risk.


title: Associations of DMT therapies with COVID-19 severity in multiple sclerosis

abstract: Background: People with multiple sclerosis (MS) are a vulnerable group for severe COVID-19, particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. Methods: Data from 12 data-sources in 28 countries were aggregated. Demographic and clinical covariates were queried, alongside COVID-19 clinical severity outcomes, hospitalisation, admission to ICU, requiring artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression. Results: 657 (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analysed. Older age, progressive MS-phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalisation (aOR=1.56,95%CI=1.01-2.41; aOR=2.43,95%CI=1.48-4.02) and ICU admission (aOR=2.30,95%CI=0.98-5.39; aOR=3.93,95%CI=1.56-9.89), though only rituximab was associated with higher risk of artificial ventilation (aOR=4.00,95%CI=1.54-10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalisation (aOR=1.75,95%CI=1.29-2.38; aOR=2.76,95%CI=1.87-4.07) and ICU admission (aOR=2.55,95%CI=1.49-4.36; aOR=4.32,95%CI=2.27-8.23) but only rituximab with artificial ventilation (aOR=6.15,95%CI=3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalisation (aOR=1.86,95%CI=1.13-3.07; aOR=2.88,95%CI=1.68-4.92) and ICU admission (aOR=2.13,95%CI=0.85-5.35; aOR=3.23,95%CI=1.17-8.91), but only rituximab with ventilation (aOR=5.52,95%CI=1.71-17.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Conclusions: Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalisation, ICU admission, and requiring artificial ventilation, and ocrelizumab with hospitalisation and ICU admission, suggesting their use may be a risk factor for more severe COVID-19.


title: SARS-CoV-2 transmission, vaccination rate and the fate of resistant strains

abstract: Vaccines are thought to be the best available solution for controlling the ongoing SARS-CoV-2 pandemic [1,2]. However, the emergence of vaccine-resistant strains [3-6] may come too rapidly for current vaccine developments to alleviate the health, economic and social consequences of the pandemic [7,8]. To quantify and characterize the risk of such a scenario, we created a SIR-derived model [9,10] with initial stochastic dynamics of the vaccine-resistant strain to study the probability of its emergence and establishment. Using parameters realistically resembling SARS-CoV-2 transmission, we model a wave-like pattern of the pandemic and consider the impact of the rate of vaccination and the strength of non-pharmaceutical intervention measures on the probability of emergence of a resistant strain. We found a counterintuitive result that the highest probability for the establishment of the resistant strain comes at a time of reduced non-pharmaceutical intervention measures when most individuals of the population have been vaccinated. Consequently, we show that a period of transmission reduction close to the end of the vaccination campaign can substantially reduce the probability of resistant strain establishment. Our results suggest that policymakers and individuals should consider maintaining non-pharmaceutical interventions [7,11,12] throughout the entire vaccination period.


title: Confirmed forecasts for the expansion of the COVID-19 epidemic in the S. Paulo city, Brazil

abstract:
ObjectiveA SEIR compartmental model was previously selected to estimate future outcomes to the dynamics of the Covid-19 epidemic breakout in Brazil.

MethodCompartments for individuals vaccinated, and prevalent SARS-Cov-2 variants were not included. A time-dependent incidence weight on the reproductive basic number accounted for Non Pharmaceutical Interventions (NPI). A first series of published data from March 1st to May 8, 2020 was used to adjust all model parameters aiming to forecast one year of evolutionary outbreak. The cohort study was set as a city population-based analysis.

AnalysisThe population-based sample, 25,366 during the study period, was the number of confirmed cases on exposed individuals. The analysis was applied to predict the consequences of holding for posterior NPI releases, and indicates the appearance of a second wave starting last quarter of 2020.

FindingsBy March 1st2021, the number of confirmed cases was predicted to reach 0.47Million (0.24-0.78), and fatalities would account for 21 thousand (12-33), 5 to 95% CRI. A second series of data published from May 9, 2020 to March 1st, 2021 confirms the forecasts previously reported for the evolution of infected people and fatalities.

NoveltyBy March 1st 2021, the number of confirmed cases reached 527,710 (12% bellow predicted average of accumulated cases), and fatalities accounted for 18,769 (10% above the accumulated average of estimated fatalities). After March 1st, new peaks on reported numbers of daily new infected and new fatalities appeared as a combined result to the appearance of the prevalent SARS-CoV-2 P1 variant, and the increased number of vaccinated individuals.


title: Confirmed forecasts for the expansion of the COVID-19 epidemic in the largest Brazilian City


title: Lower regional gray matter volume in the absence of higher cortical amyloid burden in late-life depression

abstract: Late-life depression (LLD) is associated with a risk of developing Alzheimers disease (AD). However, the role of AD-pathophysiology in LLD, and its association with clinical symptoms and cognitive function are elusive. In this study, one hundred subjects underwent amyloid positron emission tomography (PET) imaging with [18F]-flutemetamol and structural MRI: 48 severely depressed elderly subjects (age 74.1{+/-}7.5 years, 33 female) and 52 age-/gender-matched healthy controls (72.4{+/-}6.4 years, 37 female). The Geriatric Depression Scale (GDS) and Rey Auditory Verbal Learning Test (RAVLT) were used to assess the severity of depressive symptoms and episodic memory function respectively. Amyloid deposition was quantified using the standardized uptake value ratio. Whole-brain voxel-wise comparisons of amyloid deposition and gray matter volume (GMV) between LLD and controls were performed. Multivariate analysis of covariance was conducted to investigate the association of regional differences in amyloid deposition and GMV with clinical factors, including GDS and RAVLT. As a result, there were no significant group differences in amyloid deposition. In contrast, LLD showed significant lower GMV in the left temporal and parietal region. GMV reduction in the left temporal region was associated with episodic memory dysfunction, but not with depression severity. Regional GMV reduction was not associated with amyloid deposition. LLD is associated with lower GMV in regions that overlap with AD-pathophysiology, and which are associated with episodic memory function. The lack of corresponding associations with amyloid suggests that lower GM driven by non-amyloid pathology may play a central role in the neurobiology of LLD presenting as a psychiatric disorder.