title: A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

abstract: The genetic etiology of autism spectrum disorder (ASD) is multifactorial with contributions from rare variants, polygenic risk, and sex. How combinations of factors determine risk for ASD is unclear. In 11,313 ASD families (N = 37,375 subjects), we investigated the effects rare and polygenic risk individually and in combination. We show that genetic liability for ASD differs by sex, with females having a greater polygenic load, and males having a lower liability threshold as evident by a negative correlation of rare and polygenic risk. Multiple genetic factors were associated with differing sets of behavioral traits with effects that differed by sex. Furthermore, the correlation of parental age with genetic risk for ASD was attributable to de novo mutations and sex-biased effects of inherited risk in parents. Our results demonstrate that a phenotypic spectrum of ASD is attributable to the relative loadings and gene-by-sex effects of rare and common variation.


title: Thyroid dysfunction diagnosis from routine laboratory tests based on machine learning

abstract: Approximately 2.4 million patients in Japan need treatment for thyroid disease, including Graves disease and Hashimotos disease. However, only 450,000 of them are receiving treatment, and many patients with thyroid dysfunction remain largely overlooked. In this retrospective study, we aimed to screen patients with hyperthyroidism and hypothyroidism who would greatly benefit from prompt medical treatment. We examined routine laboratory finding data and machine learning algorithms to investigate whether such accurate and robust screening is possible to prevent overlooking and misdiagnosing thyroid dysfunction. We succeeded in developing a machine learning method to construct a classification model for detecting hyperthyroidism and hypothyroidism in patients using 11 routine laboratory tests. We collected electronic health records and medical checkup data from four hospitals in Japan. As a result of cross-validation and external evaluation, we achieved a high classification accuracy for the hyperthyroidism and hypothyroidism models.

category: health informatics


title: A novel variant of interest of SARS-CoV-2 with multiple spike mutations is identified from travel surveillance in Africa

abstract: At the end of 2020, the Network for Genomic Surveillance in South Africa (NGS-SA) detected a SARS-CoV-2 variant of concern (VOC) in South Africa (501Y.V2 or PANGO lineage B.1.351)1. 501Y.V2 is associated with increased transmissibility and resistance to neutralizing antibodies elicited by natural infection and vaccination2,3. 501Y.V2 has since spread to over 50 countries around the world and has contributed to a significant resurgence of the epidemic in southern Africa. In order to rapidly characterize the spread of this and other emerging VOCs and variants of interest (VOIs), NGS-SA partnered with the Africa Centres for Disease Control and Prevention and the African Society of Laboratory Medicine through the Africa Pathogen Genomics Initiative to strengthen SARS-CoV-2 genomic surveillance across the region.

category: infectious diseases


title: Differences in risk for SARS-CoV-2 infection among healthcare workers

abstract: Healthcare workers (HCWs) are a risk group for SARS-CoV-2 infection, but which healthcare work that conveys risk and to what extent such risk can be prevented is not clear. Starting on April 24th, 2020, all employees at work (n=15,300) at the Karolinska University Hospital, Stockholm, Sweden were invited and 92% consented to participate in a SARS-CoV-2 cohort study. Complete SARS-CoV-2 serology was available for n=12,928 employees and seroprevalences were analyzed by age, sex, profession, patient contact, and hospital department. Relative risks were estimated to examine the association between type of hospital department as a proxy for different working environment exposure and risk for seropositivity, adjusting for age, sex, sampling week, and profession. Wards that were primarily responsible for COVID-19 patients were at increased risk (adjusted OR 1.95 (95% CI 1.65-2.32) with the notable exception of the infectious diseases and intensive care units (adjusted OR 0.86 (95% CI 0.66-1.13)), that were not at increased risk despite being highly exposed. Several units with similar types of work varied greatly in seroprevalences. Among the professions examined, nurse assistants had the highest risk (adjusted OR 1.62 (95% CI 1.38-1.90)). Although healthcare workers, in particular nurse assistants, who attend to COVID-19 patients are a risk group for SARS-CoV-2 infection, several units caring for COVID-19 patients had no excess risk. Large variations in seroprevalences among similar units suggest that healthcare work-related risk of SARS-CoV-2 infection may be preventable.


title: Characterizing the countrywide epidemic spread of influenza A(H1N1)pdm09 virus in Kenya between 2009 and 2018

abstract:
BackgroundThe spatiotemporal patterns of spread of influenza A(H1N1)pdm09 viruses on a countrywide scale are unclear in many tropical/subtropical regions mainly because spatiotemporally representative sequence data is lacking.

MethodsWe isolated, sequenced, and analyzed 383 influenza A(H1N1)pdm09 viral genomes isolated from hospitalized patients between 2009 and 2018 from seven locations across Kenya. Using these genomes and contemporaneously sampled global sequences, we characterized the spread of the virus in Kenya over several seasons using phylodynamic methods.

ResultsThe transmission dynamics of influenza A(H1N1)pdm09 virus in Kenya was characterized by: (i) multiple virus introductions into Kenya over the study period, although these were remarkably few, with only a few of those introductions instigating seasonal epidemics that then established local transmission clusters; (ii) persistence of transmission clusters over several epidemic seasons across the country; (iii) seasonal fluctuations in effective reproduction number (Re) associated with lower number of infections and seasonal fluctuations in relative genetic diversity after an initial rapid increase during the early pandemic phase, which broadly corresponded to epidemic peaks in the northern and southern hemispheres; (iv) high virus genetic diversity with greater frequency of seasonal fluctuations in 2009-11 and 2018 and low virus genetic diversity with relatively weaker seasonal fluctuations in 2012-17; and (v) virus migration from multiple geographical regions to multiple geographical destinations in Kenya.

ConclusionConsiderable influenza virus diversity circulates within Africa, as demonstrated in this report, including virus lineages that are unique to the region, which may be capable of dissemination to other continents through a globally migrating virus population. Further knowledge of the viral lineages that circulate within understudied low-to-middle income tropical and subtropical regions is required to understand the full diversity and global ecology of influenza viruses in humans and to inform vaccination strategies within these regions.


title: Genomic monitoring unveil the early detection of the SARS-CoV-2 B.1.351 lineage (20H/501Y.V2) in Brazil

abstract: Sao Paulo State, the most populous area in Brazil, currently experiences a second wave of the COVID-19 pandemic which overwhelmed the healthcare system. Recently, due to the paucity of SARS-CoV-2 complete genome sequences, we established a Network for Pandemic Alert of Emerging SARS-CoV-2 Variants to rapidly understand the spread of SARS-CoV-2 and monitor in nearly real-time the circulating SARS-CoV-2 variants into the state. Through full genome analysis of 217 SARS-CoV-2 complete genome sequences obtained from the largest regional health departments we were able to identify the co-circulation of multiple SARS-CoV-2 lineages such as i) B.1.1 (0.92%), ii) B.1.1.1 (0.46%), iii) B.1.1.28 (25.34%), iv) B.1.1.7 (5.99%), v) B.1.566 (1.84%), vi) P.1 (64.05%), and P.2 (0.92%). Further our analysis allowed the detection, for the first time in Brazil of the South African variant of concern (VOC), the B.1.351 (501Y.V2) (0.46%). The identified lineage was characterized by the presence of the following mutations: ORF1ab: T265I, R724K, S1612L, K1655N, K3353R, SGF 3675_F3677del, P4715L, E5585D; Spike: D80A, D215G, L242_L244del, A262D, K417N, E484K, N501Y, D614G, A701V, C1247F; ORF3a: Q57H, S171L, E: P71L; ORF7b: Y10F, N: T205I; ORF14: L52F. Origin of the most recent common ancestor of this genomic variant was inferred to be between middle October to late December 2020. Analysis of generated sequences demonstrated the predominance of the P.1 lineage and allowed the early detection of the South African strain for the first time in Brazil. Our findings highlight the importance to increase active monitoring to ensure the rapid detection of new SARS-CoV-2 variants with a potential impact in pandemic control and vaccination strategies.


title: Clinical Evidence for Improved Outcomes with Histamine Antagonists and Aspirin in 22,560 COVID-19 Patients

abstract: COVID-19 has spurred much interest in the therapeutic potential of repurposed drugs. A family of acid-reducing drugs, known as histamine H2 receptor antagonists (H2RA), competitively bind the H2R and block its stimulation by histamine; examples of such drugs are famotidine (e.g., Pepcid) and ranitidine (e.g., Zantac). A dense web of functionalities between histamine and H2RAs, on the one hand, and downstream cellular pathways, on the other hand, links disparate physiological pathways in gastrointestinal contexts (e.g., acid reduction) to the dysregulated inflammatory cas-cades (cytokine storm) underlying the pathophysiology of COVID-19. Is famotidine beneficial in treating COVID-19? This question remains unresolved, though not for lack of effort: over 10 studies have examined the potential therapeutic value of famotidine in COVID-19, but have found conflicting results (pro-famotidine, anti-famotidine, and neutral). Given the contradictory reports, we have undertaken the new analysis reported herein. Notably, studies published thus far rest upon substantially smaller datasets than drawn upon in the present work. We analyzed a cohort of 22,560 COVID-19 patients taking H1/H2 receptor antagonists, focusing on 1,379 severe cases requiring respiratory support. We analyzed outcomes for treatment with the H1RAs loratadine (e.g., Claritin) and cetirizine (e.g., Zyrtec), the H2RA famotidine, aspirin, and a famotidine & aspirin combination. For cases that reached the point of respiratory support, we found a significantly reduced fatality risk for famotidine treatment. We did not detect a benefit from dual-histamine receptor blockade (concurrently targeting H1 and H2 receptors). Notably, famotidine combined with aspirin did exhibit a significant synergistic survival benefit (odds ratio of 0.55). The relative risk for death decreased by 32.5%--an immense benefit, given the more than 2.6 million COVID-19-related deaths thus far. We found lower levels of serum markers for severe disease (e.g., C-reactive protein) in famotidine users, consistent with prior findings by others and with a role for famotidine in attenuating cytokine release. The large, international, multi-center retrospective study reported here, sampling over 250,000 COVID-19 cases, hopefully helps clarify the possible value of clinically-approved histamine antagonists such as famotidine. Given these findings, alongside the cost-effectiveness and mild side-effects of popular drugs like famotidine and aspirin, we suggest that further prospective clinical trials, perhaps utilizing the aspirin combination reported here, are advisable.


title: SARS-CoV-2 infectivity by viral load, S gene variants and demographic factors and the utility of lateral flow devices to prevent transmission

abstract:
BackgroundHow SARS-CoV-2 infectivity varies with viral load is incompletely understood. Whether rapid point-of-care antigen lateral flow devices (LFDs) detect most potential transmission sources despite imperfect sensitivity is unknown.

MethodsWe combined SARS-CoV-2 testing and contact tracing data from England between 01-September-2020 and 28-February-2021. We used multivariable logistic regression to investigate relationships between PCR-confirmed infection in contacts of community-diagnosed cases and index case viral load, S gene target failure (proxy for B.1.1.7 infection), demographics, SARS-CoV-2 incidence, social deprivation, and contact event type. We used LFD performance to simulate the proportion of cases with a PCR-positive contact expected to be detected using one of four LFDs.

Results231,498/2,474,066 (9%) contacts of 1,064,004 index cases tested PCR-positive. PCR-positive results in contacts independently increased with higher case viral loads (lower Ct values) e.g., 11.7%(95%CI 11.5-12.0%) at Ct=15 and 4.5%(4.4-4.6%) at Ct=30. B.1.1.7 infection increased PCR-positive results by [~]50%, (e.g. 1.55-fold, 95%CI 1.49-1.61, at Ct=20). PCR-positive results were most common in household contacts (at Ct=20.1, 8.7%[95%CI 8.6-8.9%]), followed by household visitors (7.1%[6.8-7.3%]), contacts at events/activities (5.2%[4.9-5.4%]), work/education (4.6%[4.4-4.8%]), and least common after outdoor contact (2.9%[2.3-3.8%]). Contacts of children were the least likely to test positive, particularly following contact outdoors or at work/education. The most and least sensitive LFDs would detect 89.5%(89.4-89.6%) and 83.0%(82.8-83.1%) of cases with PCR-positive contacts respectively.

ConclusionsSARS-CoV-2 infectivity varies by case viral load, contact event type, and age. Those with high viral loads are the most infectious. B.1.1.7 increased transmission by [~]50%. The best performing LFDs detect most infectious cases.

Key pointsIn 2,474,066 contacts of 1,064,004 SARS-CoV-2 cases, PCR-positive tests in contacts increased with higher index case viral loads, the B.1.1.7 variant and household contact. Children were less infectious. Lateral flow devices can detect 83.0-89.5% of infections leading to onward transmission.


title: Impact of COVID-19 in Individuals with Autism Spectrum Disorders: Analysis of a National Private Claims Insurance Database

abstract: The COVID-19 pandemic continues to have a detrimental impact on individuals with disabilities. Data from FAIR Healths FH(R) NPIC (National Private Insurance Claims) database,1 one of the nations largest databases of private insurance claim records, were analyzed to understand the experiences of individuals with ASD in COVID-19 pandemic. Multivariate logistic regression models revealed that individuals with ASD + ID were nine times more likely to be hospitalized (OR = 9.3; 95% CI: 6.9 - 12.5) and were nearly six times more likely have an elevated length of hospital stay(OR = 5.9; 95% CI: 3.5 - 10.1) compared those without ASD + ID. These findings point to their need for prioritization in access to vaccines for preventing COVID-19 infection and morbidities.

category: epidemiology


title: Is convalescent plasma futile in COVID-19? A Bayesian re-analysis of the RECOVERY randomised controlled trial

abstract:
IntroductionRandomised trials are generally performed from a frequentist perspective reporting point estimates and 95% confidence intervals. This approach can confuse "evidence of no effect" with "no evidence of an effect" and does not allow for contextual knowledge. The RECOVERY trial evaluated convalescent plasma for patients hospitalised with COVID-19, the interaction test for the primary outcome was not statistically significant, and the trial concluded no evidence of an effect. From the clinical immunology perspective, there is strong justification to expect differential responses to convalescent plasma in patients who already have their own antibodies to SARS-CoV2 (seropositive) versus those who do not (seronegative).

MethodsOutcome data was extracted from the RECOVERY trial both overall and for seronegative participants. A Bayesian re-analysis with a wide variety of priors (vague, optimistic, skeptical and pessimistic) was performed calculating the posterior probability for both any benefit or a modest benefit (number needed to treat of 100).

ResultsAcross all patients, when analysed with a vague prior the likelihood of any benefit or a modest benefit was estimated to be 64% and 18% respectively. In contrast, in the seronegative subgroup, the likelihood of any benefit or a modest benefit was estimated to be 90% and 74%. Results were broadly consistent across all prior distributions.

ConclusionPerforming clinical trials during a pandemic is challenging, and RECOVERY has provided high quality evidence for numerous therapies. However, the use of frequentist hypothesis testing in this trial has led to the trialists and governing bodies to conclude a strong evidence of no effect. Based on this trial, and other prior knowledge there remains a strong probability that convalescent plasma provides at least a modest benefit in seronegative patients.


title: Genomic epidemiology of SARS-CoV-2 transmission lineages in Ecuador

abstract: Characterisation of SARS-CoV-2 genetic diversity through space and time can reveal trends in virus importation and domestic circulation, and permit the exploration of questions regarding the early transmission dynamics. Here we present a detailed description of SARS-CoV-2 genomic epidemiology in Ecuador, one of the hardest hit countries during the early stages of the COVID-19 pandemic. We generate and analyse 160 whole genome sequences sampled from all provinces of Ecuador in 2020. Molecular clock and phylgeographic analysis of these sequences in the context of global SARS-CoV-2 diversity enable us to identify and characterise individual transmission lineages within Ecuador, explore their spatiotemporal distributions, and consider their introduction and domestic circulation. Our results reveal a pattern of multiple international importations across the country, with apparent differences between key provinces. Transmission lineages were mostly introduced before the implementation of non-pharmaceutical interventions (NPIs), with differential degrees of persistence and national dissemination.


title: SLAMP: A Rapid Fluorometric RT-LAMP Assay for Sensitive and Specific Detection of SARS-CoV-2 from Human Saliva

abstract: Rapid testing methods can identify outbreaks and trigger preventive strategies for slowing the spread of SARS-CoV-2, the virus that causes COVID-19. The "gold-standard" detection method for SARS-CoV-2 is reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed on samples collected using a nasopharyngeal (NP) swab. While NP RT-qPCR provides high sensitivity, it requires trained personnel to administer and suffers from lengthy time-to-result. Recently, the testing community has turned to rapid saliva-based screening methods including saliva-to-RT-qPCR and/or saliva-to-RT-LAMP (reverse transcription loop-mediated isothermal amplification) to identify infected individuals regardless of symptomatic presentation. Here, we report a simple and rapid RT-LAMP fluorometric assay performed directly on heat-inactivated saliva, without the addition of buffers or proteinase K treatments we call saliva LAMP (SLAMP). Over the course of two days, a total of 243 individuals were tested using NP RT-qPCR, saliva-based qPCR, and saliva-based RT-LAMP. Of the 243 NP RT-qPCR tests, 65 were positive, 178 were negative, and SLAMP demonstrated a 91% sensitivity and 98% specificity. SLAMP sensitivity becomes 95% when samples negative in saliva tests while positive in NP RT-qPCR are excluded from evaluation, potentially indicating significant differences in viral titer between collection sites on the body. SLAMP is performed in triplicates and takes 45 min to run in the laboratory, requiring less technician time and instrument run time than NP RT-qPCR. These results demonstrate that saliva-based RT-LAMP can enable frequent and rapid screening of large numbers of people to identify pre-symptomatic and asymptomatic individuals thereby controlling outbreaks.


title: Increased household secondary attacks rates with Variant of Concern SARS-CoV-2 index cases

abstract:
IMPORTANCEHigher secondary attack rates related to variant of concern (VOC) index cases have been reported, but have not been explored within households, which continue to be an important source of coronavirus disease 2019 (COVID-19) transmission

OBJECTIVETo compare secondary attack rates in households with VOC versus non-VOC index cases.

DESIGNA retrospective cohort study of household index cases reported from February 7 - 27, 2021. A propensity-score matched cohort was derived to calculate adjusted estimates.

SETTINGOntario, Canada.

PARTICIPANTSA population-based cohort of all private households with index cases. We excluded cases in congregate settings, as well as households with one individual or with >1 case with the same earliest symptom onset date.

EXPOSUREVOC status, defined as either individuals confirmed as B.1.1.7 using whole genome sequencing or those that screened positive for the N501Y mutation using real-time PCR.

MAIN OUTCOME AND MEASUREHousehold secondary attack rate, defined as the number of household secondary cases that occurred 1-14 days after the index case divided by the total number of household secondary contacts.

RESULTSWe included 1,259 index VOC and non-VOC cases in the propensity score-matched analysis. The secondary attack rate for VOC index cases in this matched cohort was 1.31 times higher than non-VOC index cases (RR=1.31, 95%CI 1.14-1.49), similar to the unadjusted estimate. In stratified analyses, the higher secondary attack rate for VOC compared to non-VOC index cases was accentuated for asymptomatic index cases (RR=1.91, 95% CI 0.96-3.80) and presymptomatic cases (RR=3.41, 95%CI 1.13-10.26)

CONCLUSIONS AND RELEVANCEThis study provides strong evidence of increased transmissibility in households due to VOCs and suggests that asymptomatic and pre-symptomatic transmission may be of particular importance for VOCs. Our study suggests that more aggressive public health measures will be needed to control VOCs and that ongoing research is needed to understand mechanisms of VOC transmissibility to curb their associated morbidity and mortality.


title: Autoantibodies stabilize neutrophil extracellular traps in COVID-19

abstract: The release of neutrophil extracellular traps (NETs) by hyperactive neutrophils is recognized to play an important role in the thromboinflammatory milieu inherent to severe presentations of COVID-19. At the same time, a variety of functional autoantibodies have been observed in individuals with severe COVID-19 where they likely contribute to immunopathology. Here, we aimed to determine the extent to which autoantibodies might target NETs in COVID-19 and, if detected, to elucidate their potential functions and clinical associations. We measured anti-NET antibodies in 328 individuals hospitalized with COVID-19 alongside 48 healthy controls. We found high anti-NET activity in the IgG and IgM fractions of 27% and 60% of patients, respectively. There was a strong correlation between anti-NET IgG and anti-NET IgM (r=0.4, p<0.0001). Both anti-NET IgG and IgM tracked with high levels of circulating NETs, impaired oxygenation efficiency, and high circulating D-dimer. Furthermore, patients who required mechanical ventilation had a greater burden of anti-NET antibodies than did those not requiring oxygen supplementation. Levels of anti-NET IgG (and to a lesser extent anti-NET IgM) demonstrated an inverse correlation with the efficiency of NET degradation by COVID sera. Furthermore, purified IgG from COVID sera with high levels of anti-NET antibodies impaired the ability of healthy control serum to degrade NETs. In summary, many individuals hospitalized with COVID-19 have anti-NET antibodies, which likely impair NET clearance and may potentiate SARS-CoV-2-mediated thromboinflammation.


title: Antibodies against type-I Interferon: detection and association with severe clinical outcome in COVID-19 patients

abstract:
ObjectivesImpairment of type I interferon (IFN-I) immunity has been reported in critically-ill COVID-19 patients. This defect can be explained in a subset of patients by the presence of circulating autoantibodies (auto-Abs) against IFN-I. We set out to improve the detection and the quantification of IFN-I auto-Abs in a cohort of critically-ill COVID-19 patients, in order to better evaluate the prevalence of these Abs as the pandemic progresses, and how they correlate with the clinical course of the disease.

MethodsThe concentration of anti-IFN-2 Abs was determined in the serum of 84 critically-ill COVID-19 patients who were admitted to ICU in Hospices Civils de Lyon, France using a commercially available kit (Thermo-Fisher, Catalog #BMS217).

ResultsA total of 21/84 (25%) critically-ill COVID-19 patients had circulating anti-IFN-2 Abs above cut-off (>34 ng.mL-1). Among them, 15/21 had Abs with neutralizing activity against IFN-2, i.e. 15/84 (18%) of critically-ill patients. In addition, we noticed an impairment of the IFN-I response in the majority of patients with neutralizing anti-IFN-2 Abs. There was no significant difference in the clinical characteristics or outcome of with or without neutralizing anti-IFN-2 auto-Abs. We detected anti-IFN-2 auto-Abs in COVID-19 patients sera throughout their ICU stay. Finally, we also found auto-Abs against multiple subtypes of IFN-I including IFN-{omega}.

ConclusionsWe reported that 18% of critically-ill COVID-19 patients were positive for IFN-I auto-Abs, confirming that the presence of these antibodies is associated with higher risk of developing a criticall COVID-19 form.

category: allergy and immunology


title: Cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination

abstract: While evidence for pre-existing SARS-CoV-2-cross-reactive CD4+ T cells in unexposed individuals is increasing, their functional significance remains unclear. Here, we comprehensively determined SARS-CoV-2-cross-reactivity and human coronavirus-reactivity in unexposed individuals. SARS-CoV-2-cross-reactive CD4+ T cells were ubiquitous, but their presence decreased with age. Within the spike glycoprotein fusion domain, we identified a universal immunodominant coronavirus-specific peptide epitope (iCope). Pre-existing spike- and iCope-reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher IgG titers. Importantly, the cells were also reactivated after primary BNT162b2 COVID-19 mRNA vaccination in which their kinetics resembled that of secondary immune responses. Our results highlight the functional importance of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Abundant spike-specific cross-immunity may be responsible for the unexpectedly high efficacy of current vaccines even with single doses and the high rate of asymptomatic/mild infection courses.


title: COVID-associated pediatric hospitalization and ICU admission trends across a multi-state health system and the broader US population

abstract: Public health concerns are emerging based on reports of new SARS-CoV-2 variant strains purportedly triggering a rise in COVID-associated hospitalizations and ICU admissions, particularly in younger patients and the pediatric population. However, analyzing health records of COVID patients from the electronic health records (EHRs) of a multi-state US healthcare system, we find that there is actually a significant drop in COVID-associated hospitalization rates and ICU admission rates in March 2021 compared to February 2021. We further triangulate these EHR-derived insights with the official US government epidemiological data sets to show that during this same time period, there is no apparent nation-wide spike in pediatric hospitalizations. Our study motivates the need to develop a real-time system that integrates various COVID hospitalization and ICU monitoring efforts from the EHR databases of various health systems together with national epidemiological data sets. By infusing SARS-CoV-2 genomic sequencing data to flag potentially new or emergent viral strains, as well as county-level COVID vaccine rollout rates and shifts in SARS-CoV-2 PCR positivity rates into such a real-time monitoring system, public health policies and media reporting can be more effectively informed through the rigor of holistic biomedical data sciences.


title: Visuomotor brain network activation and functional connectivity among individuals with autism spectrum disorder

abstract:
Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and predictive of functional outcomes, though their neural underpinnings remain poorly understood. Using functional magnetic resonance imaging (fMRI), we examined both brain activation and functional connectivity during visuomotor behavior in 27 individuals with ASD and 30 typically developing (TD) controls (ages 9-35 years). Participants maintained a constant grip force while receiving visual feedback at three different visual gain levels. Relative to controls, ASD participants showed increased force variability, especially at high gain, and reduced entropy. Brain activation was greater in individuals with ASD than controls in supplementary motor area, bilateral superior parietal lobules, and left middle frontal gyrus at high gain. During motor action, functional connectivity was reduced between parietal-premotor and parietal-putamen in individuals with ASD compared to controls. Individuals with ASD also showed greater age-associated increases in functional connectivity between cerebellum and visual, motor, and prefrontal cortical areas relative to controls. These results indicate that visuomotor deficits in ASD are associated with atypical activation and functional connectivity of posterior parietal, premotor, and striatal circuits involved in translating sensory feedback information into precision motor behaviors, and that functional connectivity of cerebellar-cortical sensorimotor and non-sensorimotor networks show delayed maturation.

HIGHLIGHTSO_LIIndividuals with ASD show impaired precision manual force control, especially when visual feedback is magnified
C_LIO_LIVisuomotor deficits in ASD are associated with increased activity in frontal and parietal cortex and reduced parietal-frontal and parietal-putamen functional connectivity
C_LIO_LIVisuomotor-dependent functional connectivity of cerebellum with visual, motor, and prefrontal cortices shows atypical age-associated trajectories in ASD
C_LI

category: psychiatry and clinical psychology


title: Which traits predict elevated distress during the Covid-19 pandemic? Results from a large, longitudinal cohort study with psychiatric patients and healthy controls

abstract:
BackgroundThe Covid-19 pandemic resulted in repeated, prolonged restrictions in daily life. Social distancing policies as well as health anxiety are thought to lead to mental health impairment. However, there is lack of longitudinal data identifying at-risk populations particularly vulnerable for elevated Covid-19-related distress.

MethodsWe collected data of N=1268 participants (n=622 healthy controls (HC), and n=646 patients with major depression, bipolar disorder, schizophrenia or schizoaffective disorder) at baseline (2014-2018) and during the first lockdown in Germany (April-May 2020). We obtained information on Covid-19 restrictions (number and subjective impact of Covid-19 events), and Covid-19-related distress (i.e., subjective fear and isolation). Using multiple linear regression models including trait variables and individual Covid-19 impact, we sought to predict Covid-19-related distress.

ResultsHC and patients reported similar numbers of Covid-19-related events, and similar subjective impact rating. They did not differ in Covid-19-related subjective fear. Patients reported significantly higher subjective isolation. 30.5% of patients reported worsened self-rated symptoms since the pandemic. Subjective fear in all participants was predicted by four variables: trait anxiety (STAI-T), conscientiousness (NEO-FFI), Covid-19 impact, and sex. Subjective isolation in HC was predicted by social support (FSozu), Covid-19 impact, age, and sex; in patients, it was predicted by social support and Covid-19 impact.

ConclusionOur data shed light on differential effects of the pandemic in psychiatric patients and HC. They identify relevant, easy-to-obtain variables for risk profiles related to interindividual differences in Covid-19-related distress for direct translation into clinical practice.


title: Use of multiple Polygenic Risk Scores for distinguishing Schizophrenia-spectrum disorder and Affective psychosis categories; the EUGEI study

abstract: Schizophrenia (SZ), Bipolar Disorder (BD) and Depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUGEI case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). Participants (573 cases, 1005 controls) of european ancestry from 17 sites as part of the EUGEI study were successfully genotyped following standard quality control procedures. Using standardised PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparison, both PRS-SZ (OR=0.7, 95 %CI 0.53-0.92) and PRS-D (OR=1.29, 95%CI 1.05-1.6) differentiated global AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR=2.38, 95%CI 1.32-4.29). Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards potential usefulness of PRSs for diagnostic prediction in specific populations such as high-risk or early psychosis phases.


title: Growth Functions as a tool to model SARS-CoV-2 pandemic trajectory and related-deaths worldwide

abstract: The international scientific community from different areas of knowledge has made efforts to provide information and methods that contribute to the adoption of the most appropriate measures to curb the spread of the COVID-19 disease. In particular, the data analysis community has been very active in publishing a large number of papers. A good part of them is related to the prediction of epidemic variables (number of cases and deaths) in different time horizons. To solve the problem of the prediction of COVID-19, an important place is occupied by the sigmoidal growth functions, as they have often been used successfully in previous epidemic outbreaks. The objective of this work was to investigate, on a statistical basis, the ability of classical growth functions to model the data from the COVID-19 pandemic. But for that, it was necessary to establish a clear classification of the 5 types of problems that can be faced with data analysis techniques in this specific context and to define a methodology based on quantitative metrics to measure the performance in solving these different types of problems. The basic concept used was that of an epidemic wave consisting of an initial-increasing and a final-decreasing phase. A classification of the COVID-19 waves in 4 types was done based on mining data from all available countries. Thus, it was possible to determine the resolvability of each type of problem depending on the stage of the epidemic wave. The biggest conclusion was the impossibility of solving the long-term forecasting problems (problem 5 - to estimate the total value of an epidemic wave) with data from the first phase only. Using this theoretical-methodological framework, we evaluated, using metrics specifically designed for these types of problems, the performance of 3 classic growth functions: Logistics, Gompertz and Richards (a generalization of the previous two) in 2 types of problems: (1) Description of the trajectory of the epidemic and (2) Prediction of the total numbers of cases and deaths. We used data from 10 countries, 7 of them with more than 100 daily deaths on the peak day. The results show a generalized underperformance of the logistic function in all aspects and place the Gompertz function as the best cost-benefit alternative, as it has performance comparable to the Richards function, but it has one less parameter to be adjusted, in the process of regression of the model to the observed data.

category: public and global health


title: Overview of The Current Progress of Facultative Anaerobic Bacteria in Cancer Biotherapy with TNF-α as Main Mechanism of Action

abstract:
This review article focuses on the use of infectious bacteria as delivery tool for tumour necrosis factor  (TNF-), a well-studied cytokine, in the context of immunotherapy for cancer treatment. The tumour targeting properties of certain bacteria strains has been known for decades as well as the tumour catabolizing effect of TNF-. The combination of these two have been studied in murine models for various types of cancer with promising results. Research in this fascinating field is unfortunately uncommon, thus the number of high-quality articles is limited. Search was done via Google Scholar in combination with PubMed, to increase the coverage and find peer-reviewed, original, and primary research articles.

Key findings show that attenuated or genetically modified species of bacteria have fewer side effects and can be effective in delivering cytokines to tumour sites. TNF- is produced by macrophages/monocytes during acute inflammation or infection, thus can be triggered by infectious bacteria which in turn induce apoptosis. The cytotoxic effect of the bacteria can be enhanced with localized irradiation. Promising results have been shown in bladder, breast, colon, glial, lung, ovarian, pancreatic, prostate, and renal cancer cells.

The need for better, safer, and more effective cancer treatment is apparent as traditional chemotherapy and radiation can cause a lot of harm for the patient, and not necessarily prolong the lifespan. The success-rate for these treatments vary greatly depending on the type of cancer, but for tumours that cannot be surgically removed the outcome is generally quite poor. A drawback of chemotherapy is that tumours can grow resistant to the treatment while healthy cells continue to be exposed, increasing the risk of severe side effects. Different types of biological therapies are a modern and possibly safer approach, even though immunotherapy comes with substantial risks. Using the innate immune system to fight tumour cells is not always safe, because uncontrolled and excessive release of pro-inflammatory signalling molecules can result in multisystem organ failure and death. This phenomenon is called cytokine release syndrome (cytokine storm) and is one of the major risks of immunotherapy. However, tailored biological therapies have proven their effectiveness for a wide range of cancer types, and the next step in this evolution is to genetically engineer both delivery systems and mechanisms of action. This approach can be combined with the traditional radiation and chemotherapy for increased effectiveness, even if biological therapies as a stand-alone treatment, can be a goal for the future.

category: oncology


title: Overview of The Current Progress of Facultative Anaerobic Bacteria in Cancer Biotherapy with TNF-alpha as Main Mechanism of Action


title: HBA Copy Number and Kidney Disease Risk among Black Americans: a Longitudinal Cohort Study

abstract:
BackgroundAlpha globin gene (HBA) copy number is variable among people of African descent. HBA limits endothelial nitric oxide signaling and variation in gene copy number could modify kidney disease risk in this population.

ObjectiveTo examine the association of HBA copy number with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). We hypothesized that higher HBA copy number would be associated with greater CKD prevalence and ESKD incidence.

DesignProspective, longitudinal cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study which enrolled participants from 2003 through 2007 and conducted follow-up through June 2014. Data were analyzed from January 2018 through January 2021.

SettingCommunity-dwelling participants enrolled throughout the contiguous United States

ParticipantsBlack Americans age 45 years and older

MeasurementsHBA copy number was measured using droplet-digital PCR on genomic DNA; copy number ranged from 2 to [≥] 5 copies. The prevalence ratio (PR) of CKD and relative risk (RR) of incident reduced estimated glomerular filtration rate (eGFR) were calculated using modified Poisson multivariable regression employing a log-linear effect of HBA allele count. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression.

ResultsAmong 9,918 participants, HBA gene copy number frequencies were 4%, 28%, 67%, and 1% for 2, 3, 4, and [≥]5 copies, respectively. After adjusting for demographic, clinical, and genetic risk factors, each additional copy of HBA was associated with 14% greater prevalence of CKD (PR = 1.14, 95% CI 1.07 to 1.21; P < 0.0001). While there was no significant association with incident reduced eGFR (RR = 1.06, 95% CI 0.94 to 1.18; p = 0.36), the hazard of incident ESKD was 28% higher for each additional copy of HBA (HR = 1.28, 95% CI 1.01 to 1.61; P = 0.04).

LimitationsThis study did not identify the mechanism by which HBA copy number modifies kidney disease risk. This study focused on Black Americans, a population with a high frequency of the 3.7 kb gene deletion; it is unknown whether HBA modifies kidney disease risk in other populations with the 3.7 kb deletion.

ConclusionsIncreasing HBA copy number was associated with greater prevalent CKD and incident ESKD in a national longitudinal study of Black Americans.

Funding SourceNational Institutes of Health

category: genetic and genomic medicine


title: Clinical implementation of RNA sequencing for Mendelian disease diagnostics

abstract:
BackgroundLack of functional evidence hampers variant interpretation, leaving a large proportion of cases with a suspected Mendelian disorder without genetic diagnosis after genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies, and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA-sequencing (RNA-seq) in routine diagnostics.

MethodsWe implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease which previously underwent WES.

ResultsWe detected on average 12,500 genes per sample including around 60% disease genes - a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than one week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions.

ConclusionTogether, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics.

One sentence summaryImplementation of RNA-seq as a complementary tool in standard diagnostics achieves a 16% in diagnosis rate over whole exome sequencing.


title: Machine Learning Prediction of Biomarkers from SNPs and of Disease Risk from Biomarkers in the UK Biobank

abstract: We use UK Biobank data to train predictors for 48 blood and urine markers such as HDL, LDL, lipoprotein A, glycated haemoglobin, ... from SNP genotype. For example, our predictor correlates [~] 0.76 with lipoprotein A level, which is highly heritable and an independent risk factor for heart disease. This may be the most accurate genomic prediction of a quantitative trait that has yet been produced (specifically, for European ancestry groups). We also train predictors of common disease risk using blood and urine biomarkers alone (no DNA information). Individuals who are at high risk (e.g., odds ratio of > 5x population average) can be identified for conditions such as coronary artery disease (AUC [~] 0.75), diabetes (AUC [~] 0.95), hypertension, liver and kidney problems, and cancer using biomarkers alone. Our atherosclerotic cardiovascular disease (ASCVD) predictor uses [~] 10 biomarkers and performs in UKB evaluation as well as or better than the American College of Cardiology ASCVD Risk Estimator, which uses quite different inputs (age, diagnostic history, BMI, smoking status, statin usage, etc.). We compare polygenic risk scores (risk conditional on genotype: (risk score | SNPs)) for common diseases to the risk predictors which result from the concatenation of learned functions (risk score | biomarkers) and (biomarker | SNPs).


title: T-cell responses as a correlate of COVID-19 vaccination. A pilot study in Health Care Workers.

abstract:
BackgroundIt is crucial to assess the levels of protection generated by natural infection or SARS-CoV-2 vaccines, mainly in individuals professionally exposed and in vulnerable groups. Measuring T-cell responses may complement antibody tests currently in use as correlates of protection. Our aim was to assess the feasibility of a validated assay of T-cell responses.

MethodsTwenty health-care-workers (HCW) were included. Antibody test to SARS-CoV-2 N and S-proteins in parallel with a commercially available whole-blood-interferon-gamma-release-assay (IGRA) to S-peptides and two detection methods, CLIA and ELISA were determined.

ResultsIGRA test detected T-cell responses in naturally exposed and vaccinated HCW already after first vaccination dose. The correlation by the two detection methods was very high (R>0.8) and sensitivity and specificity ranged between 100 and 86% and 100-73% respectively. Even though there was a very high concordance between specific antibody levels and the IGRA assay in the ability to detect immune response to SARS-CoV-2, there was a relatively low quantitative correlation. In the small group primed by natural infection, one vaccine dose was sufficient to reach immune response plateau. IGRA was positive in one, with Ig(S) antibody negative vaccinated immunosuppressed HCW illustrating another advantage of the IGRA-test.

ConclusionWhole-blood-IGRA-tests amenable to automation and constitutes a promising additional tool for measuring the state of the immune response to SARS-CoV-2; they are applicable to large number of samples and may become a valuable correlate of protection to COVID-19, particularly for vulnerable groups at risk of being re-exposed to infection, as are health-care-workers.


title: Commercialized kit to assess T-cell responses against SARS-CoV-2 S peptides. A pilot study in Health Care Workers.


title: Equity Impacts of Dollar Store Vaccine Distribution

abstract: We use geospatial data to examine the unprecedented national program currently underway in the United States to distribute and administer vaccines against COVID-19. We quantify the impact of the proposed federal partnership with the company Dollar General to serve as vaccination sites and compare vaccine access with Dollar General to the current Federal Retail Pharmacy Partnership Program. Although dollar stores have been viewed with skepticism and controversy in the policy sector, we show that, relative to the locations of the current federal program, Dollar General stores are disproportionately likely to be located in Census tracts with high social vulnerability; using these stores as vaccination sites would greatly decrease the distance to vaccines for both low-income and minority households. We consider a hypothetical alternative partnership with Dollar Tree and show that adding these stores to the vaccination program would be similarly valuable, but impact different geographic areas than the Dollar General partnership. Adding Dollar General to the current pharmacy partners greatly surpasses the goal set by the Biden administration of having 90% of the population within 5 miles of a vaccine site. We discuss the potential benefits of leveraging these partnerships for other vaccinations, including against influenza.

category: health economics


title: Signatures of COVID-19 severity and immune response in the respiratory tract microbiome

abstract:
RationaleViral infection of the respiratory tract can be associated with propagating effects on the airway microbiome, and microbiome dysbiosis may influence viral disease.

ObjectiveTo define the respiratory tract microbiome in COVID-19 and relationship disease severity, systemic immunologic features, and outcomes.

Methods and MeasurementsWe examined 507 oropharyngeal, nasopharyngeal and endotracheal samples from 83 hospitalized COVID-19 patients, along with non-COVID patients and healthy controls. Bacterial communities were interrogated using 16S rRNA gene sequencing, commensal DNA viruses Anelloviridae and Redondoviridae were quantified by qPCR, and immune features were characterized by lymphocyte/neutrophil (L/N) ratios and deep immune profiling of peripheral blood mononuclear cells (PBMC).

Main ResultsCOVID-19 patients had upper respiratory microbiome dysbiosis, and greater change over time than critically ill patients without COVID-19. Diversity at the first time point correlated inversely with disease severity during hospitalization, and microbiome composition was associated with L/N ratios and PBMC profiles in blood. Intubated patients showed patient-specific and dynamic lung microbiome communities, with prominence of Staphylococcus. Anelloviridae and Redondoviridae showed more frequent colonization and higher titers in severe disease. Machine learning analysis demonstrated that integrated features of the microbiome at early sampling points had high power to discriminate ultimate level of COVID-19 severity.

ConclusionsThe respiratory tract microbiome and commensal virome are disturbed in COVID-19, correlate with systemic immune parameters, and early microbiome features discriminate disease severity. Future studies should address clinical consequences of airway dysbiosis in COVID-19, possible use as biomarkers, and role of bacterial and viral taxa identified here in COVID-19 pathogenesis.


title: A Rapid SARS-CoV-2 Variant Detection by Molecular-Clamping Based RT-qPCR

abstract: We applied XNA-based Molecular Clamping Technology to develop a multiplex qPCR assay for rapid and accurate detection of SARS-CoV-2 mutations. A total of 278 previously tested SARS-COV-2 positive samples originating primarily from San Francisco Bay Area were tested, including 139 Samples collected in middle January and 139 samples collected at the end of February 2021, respectively. The SARS-CoV-2 Spike-gene D614G mutation was detected from 58 samples (41.7%) collected in January 2021 and, 78 samples (56.1%) collected in February. Notably, while there were no N501Y mutation detected in samples from January, seven of the February samples were tested positive for the N501Y and D614G mutations. The results suggest a relatively recent and speedy spreading of the UK variant (B.1.1.7) in Northern California. This new Molecular Clamping technology-based multiplex RT-qPCR assay is highly sensitive and specific and can help speed up large scale testing for SARS-CoV-2 variants.


title: Rapid, Affordable and Scalable SARS-CoV-2 Detection from Saliva

abstract: Here we present an inexpensive, rapid, and robust RT-LAMP based SARS-CoV-2 detection method that is easily scalable, enabling point of care facilities and clinical labs to determine results from patients saliva directly in 30 minutes for less than $2 a sample. The method utilizes a novel combination of widely available reagents that can be prepared in bulk, plated and frozen and remain stable until samples are received. This innovation dramatically reduces preparation time, enabling high-throughput automation and testing with time to results (including setup) in less than one hour for 96 patient samples simultaneously when using a 384 well format. By utilizing a dual-reporter (phenol red pH indicator for end-point detection and SYTO-9 fluorescent dye for real-time), the assay also provides internal validation of results and redundancy in the event of an instrument malfunction.


title: Diagnostic Utility of Antigen Detection Rapid Diagnostic Tests for Covid- 19: A Systematic Review and Meta-Analysis

abstract:
BackgroundEarly detection of coronavirus disease (COVID-19) infection to improve disease management, becomes the greatest challenge. Despite high sensitivity of RT-PCR, not only it was reported that 20-67% of infected patients have false negative results. Rapid diagnostic tests (RDTs) are widely used as a point-of-care test for SARS-CoV-2 detection in both pharyngeal and blood specimens. To be less time-consuming, not seem so costly, and requiring no special training make it more favorable, but the low sensitivity is the main limitation. Several reports indicated rapid test of blood and pharyngeal samples has the same sensitivity as the RT-PCR, but some reports have lower sensitivity especial in asymptomatic patients.

MethodsIn the present survey, we investigate the eligible studies for sensitivity and specificity of rapid tests and explore the factors that influence the result to help better diagnose COVID-19 infection. 20 studies met the inclusion criteria, which impose 33 different tests.

ResultsOur findings showed, type of sample, type of assay, time of sampling, and load of virus influence on sensitivity of RDTs.

ConclusionThis research extends our knowledge of how to improve the sensitivity of RDTs to better diagnose of infected patients to address the controlling COVID-19 pandemic.


title: Local genetic covariance between serum urate and kidney function obtained from local Bayesian regressions.

abstract:
Hyperuricemia is associated with several cardiometabolic and renal diseases, such as gout and chronic kidney disease. Previous studies have examined the shared genetic basis of chronic kidney disease and hyperuricemia either using single-variant tests or estimating whole-genome genetic correlations between the traits. Individual variants typically explain a small fraction of the genetic correlation between traits, thus reducing the power to map pleiotropic loci. Alternatively, genome-wide estimates of genetic correlation, while useful, do not shed light on what regions may be implicated in the shared genetic basis of traits. Therefore, to fill the gap between these two approaches, we used local Bayesian regressions to estimate the genetic covariance between markers for chronic kidney disease and hyperuricemia in specific genomic regions. We identified 267 linkage disequilibrium segments with statistically significant covariance estimates, 17 of which had a positive directionality and 250 negative, the latter being consistent with the directionality of the overall genetic covariance. These 267 significant segments implicated 188 genetically distinct shared loci. Many of these loci validate previously identified shared loci with consistent directionality, including 22 loci previously identified as shared. Numerous novel shared loci were also identified, such as THBS3/MTX1/GBAP1, LINC01101, SLC7A9/CEP89, CYP24A1, KCNS3, CHD9, ARL15, PAX8, and IGF1R. Finally, to examine potential biological mechanisms for these shared loci, we have implicated a subset of the genomic segments that are associated with gene expression using colocalization analyses. In particular, five genes (FGF5, ARL6IP5, TRIM6, BCL2L1, and NTRK1) expressed in the kidney are causal candidates potentially contributing to pleiotropic pathways between chronic kidney disease and hyperuricemia. The regions identified by our local Bayesian regression approach may help untangle and explain the association between chronic kidney disease and hyperuricemia.

Author SummaryChronic kidney disease is of increased prevalence among people with hyperuricemia, suggesting a shared genetic etiology. Since markers for chronic kidney disease and hyperuricemia have an overall non-zero genetic correlation, there appears to be genetic basis to the shared etiology. However, genome-wide genetic correlation estimates do not elucidate the specific genomic regions contributing to both traits, particularly regions that contribute to the traits with opposite directionality to the overall directionality. We have implemented local Bayesian regressions to identify small genomic segments contributing to the overall genetic correlation. Our method is applicable to any pair of traits that have a shared genetic relationship. We have found numerous novel shared loci, validated previously reported loci, and identified new shared pathways simultaneously contributing to the markers between chronic kidney disease and hyperuricemia. These loci all merit detailed investigation as they may involve underlying biological mechanisms with the potential to explain the common pathogenesis of hyperuricemia and chronic kidney disease.


title: Single site performance of AI software for stroke detection and triage

abstract:
BackgroundRecently developed software utilizing artificial intelligence for fast detection and triage of stroke cases has the potential to accelerate stroke care and improve patient outcomes. We performed this analysis to evaluate the performance and time-to-notification of one such software - RAPID LVO.

MethodsWe created a database of 151 consecutive acute stroke patients for whom CT scans were processed by the RAPID LVO software over a period of eight months. The LVO notification and time to notification of the software were collected, alongside patient information and the CTA findings.

ResultsRAPID LVO achieved a sensitivity of 63.6% and specificity of 85.8% for large vessel occlusion, with an average time to notification of 32.53 minutes.

ConclusionsRAPID LVO has low sensitivity, moderate specificity and high time-to-notification performance. Our study data demonstrated in particular low overall sensitivity (63%) for distal occlusions (M2-3). The disparity between the observed performance and the performance reported in RAPID LVOs FDA clearance demonstrates the importance of independent, multi-center evaluation. The gap between the performance in this study compared to published records of RAPID AI may be due to differences in imaging hardware, software implementation, connectivity or clinical definitions.

category: radiology and imaging


title: Unsupervised Learning for Large Scale Data: The ATHLOS Project

abstract: 1Recent technological advancements in various domains, such as the biomedical and health, offer a plethora of big data for analysis. Part of this data pool is the experimental studies that record various and several features for each instance. It creates datasets having very high dimensionality with mixed data types, with both numerical and categorical variables. On the other hand, unsupervised learning has shown to be able to assist in high-dimensional data, allowing the discovery of unknown patterns through clustering, visualization, dimensionality reduction, and in some cases, their combination. This work highlights unsupervised learning methodologies for large-scale, high-dimensional data, providing the potential of a unified framework that combines the knowledge retrieved from clustering and visualization. The main purpose is to uncover hidden patterns in a high-dimensional mixed dataset, which we achieve through our application in a complex, real-world dataset. The experimental analysis indicates the existence of notable information exposing the usefulness of the utilized methodological framework for similar high-dimensional and mixed, real-world applications.


title: Using 2D Video-based Pose Estimation for Automated Prediction of Autism Spectrum Disorders in Preschoolers

abstract: Clinical research in autism has recently witnessed promising digital phenotyping results, mainly focused on single feature extraction, such as gaze, head turn on name-calling or visual tracking of the moving object. The main drawback of these studies is the focus on relatively isolated behaviors elicited by largely controlled prompts. We recognize that while the diagnosis process understands the indexing of the specific behaviors, ASD also comes with broad impairments that often transcend single behavioral acts. For instance, the atypical nonverbal behaviors manifest through global patterns of atypical postures and movements, fewer gestures used and often decoupled from visual contact, facial affect, speech. Here, we tested the hypothesis that a deep neural network trained on the non-verbal aspects of social interaction can effectively differentiate between children with ASD and their typically developing peers. Our model achieves an accuracy of 80.9% (F1 score: 0.818; precision: 0.784; recall: 0.854) with the prediction probability positively correlated to the overall level of symptoms of autism in social affect and repetitive and restricted behaviors domain. Provided the non-invasive and affordable nature of computer vision, our approach carries reasonable promises that a reliable machine-learning-based ASD screening may become a reality not too far in the future.


title: Detection of SARS-CoV-2 antibodies formed in response to the BNT162b2 and mRNA-1237 mRNA vaccine by commercial antibody tests

abstract:
PURPOSEWith rapid approval of SARS-CoV-2 vaccines, the ability of clinical laboratories to detect vaccine-induced antibodies with available high-throughput commercial assays is unknown. We aimed to determine if commercial serology assays can detect vaccine-induced antibodies (VIAs) and understand the vaccination response.

METHODSThis cohort study recruited healthcare workers and residents of long-term care facilities (receiving the BNT162b2 and mRNA-1273 products, respectively) who underwent serum collection pre-vaccination (BNT162b2 group), 2-weeks post vaccination (both groups), and pre-2nd dose (both groups). Sera were tested for the presence of SARS-CoV-2 IgG using four commercial assays (Abbott Architect SARS-CoV-2 IgG, Abbott Architect SARS-CoV-2 IgG II Quant, DiaSorin Liaison Trimeric S IgG, and GenScript cPASS) to detect VIAs. Secondary outcomes included description of post-vaccination antibody response and correlation with neutralising titers.

RESULTS225 participants (177 receiving BNT162b2 and 48 receiving mRNA-1273) were included (median age 41 years,; 66-78% female). Nucleocapsid IgG was found in 4.1% and 21.9% of the BNT162b2 (baseline) and mRNA-1273 (2-weeks post first dose). All anti-spike assays detected antibodies post-vaccination, with an average increase of 87.2% (range 73.8-94.3%; BNT162b2), and 25.2% (range 23.8-26.7%; mRNA-1273) between the first and last sampling time points (all p<0.05). Neutralising antibodies were detected at all post-vaccine timepoints for both vaccine arms, with increasing titers over time (all p<0.05).

CONCLUSIONAnti-spike vaccine-induced SARS-CoV-2 IgG are detectable by commercially available high-throughput assays and increases over time. Prior to second dose of vaccination, neutralising antibodies are detectable in 73-89% of individuals, suggesting the majority of individuals would have some degree of protection from subsequent infection.


title: Increasing concentration of COVID-19 by socioeconomic determinants and geography in Toronto, Canada: an observational study

abstract:
BackgroundInequities in the burden of COVID-19 observed across Canada suggest heterogeneity within community transmission.

ObjectivesTo quantify the magnitude of heterogeneity in the wider community (outside of long-term care homes) in Toronto, Canada and assess how the magnitude in concentration evolved over time (January 21 to November 21, 2020).

DesignRetrospective, population-based observational study using surveillance data from Ontarios Case and Contact Management system.

SettingToronto, Canada.

ParticipantsLaboratory-confirmed cases of COVID-19 (N=33,992).

MeasurementsWe generated epidemic curves by SDOH and crude Lorenz curves by neighbourhoods to visualize inequities in the distribution of COVID-19 cases by social determinants of health (SDOH) and estimated the crude Gini coefficient. We examined the correlation between SDOH using Pearson correlation coefficients.

ResultsThe Gini coefficient of cumulative cases by population size was 0.41 (95% CI: 0.36-0.47) and were estimated for: household income (0.20, 95%CI: 0.14-0.28); visible minority (0.21, 95%CI: 0.16-0.28); recent immigration (0.12, 95%CI: 0.09-0.16); suitable housing (0.21, 95%CI: 0.14-0.30); multi-generational households (0.19, 95%CI: 0.15-0.23); and essential workers (0.28, 95% CI: 0.23-0.34). Most SDOH were highly correlated.

Locally acquired cases were concentrated in higher income neighbourhoods in the early phase of the epidemic, and then concentrated in lower income neighbourhoods. Mirroring the trajectory of epidemic curves by income, the Lorenz curve shifted over time from below to above the line of equality with a similar pattern across SDOH.

LimitationsStudy relied on area-based measures of the SDOH and individual case counts of COVID-19. We cannot infer concentration of cases by specific occupational exposures given limitation to broad occupational categories.

ConclusionCOVID-19 is increasingly concentrated by SDOH given socioeconomic inequities and structural racism.

Primary Funding SourceCanadian Institutes of Health Research.


title: Therapeutic application of alpha-1-antitrypsin in COVID-19

abstract:
RationaleThe treatment options for COVID-19 patients are sparse and do not show sufficient efficacy. Alpha-1-antitrypsin (AAT) is a multi-functional host-defense protein with anti-proteolytic and anti-inflammatory activities.

ObjectivesThe aim of the present study was to evaluate whether AAT is a suitable candidate for treatment of COVID-19.

MethodsAAT and inflammatory markers were measured in the serum of COVID-19 patients. Human cell cultures were employed to determine the cell-based anti-protease activity of AAT and to test whether AAT inhibits the host cell entry of vesicular stomatitis virus (VSV) particles bearing the spike (S) protein of SARS-CoV-2 and the replication of authentic SARS-CoV-2. Inhaled and / or intravenous AAT was applied to nine patients with mild-to-moderate COVID-19.

Measurements and Main ResultsThe serum AAT concentration in COVID-19 patients was increased as compared to control patients. The relative AAT concentrations were decreased in severe COVID-19 or in non-survivors in ratio to inflammatory blood biomarkers. AAT inhibited serine protease activity in human cell cultures, the uptake of VSV-S into airway cell lines and the replication of SARS-CoV-2 in human lung organoids. All patients, who received AAT, survived and showed decreasing respiratory distress, inflammatory markers, and viral load.

ConclusionAAT has anti-SARS-CoV-2 activity in human cell models, is well tolerated in patients with COVID-19 and together with its anti-inflammatory properties might be a good candidate for treatment of COVID-19.

FundingThis work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, the BMBF, the State of Lower Saxony, and The State of Saarland.

Scientific Knowledge on the SubjectCOVID-19 is caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2) and is a serious global health threat. Efficacious treatments are not available and there are no drugs that can prevent progression towards respiratory and extra-pulmonary organ failure. AAT has been studied in vitro and has activity against SARS-CoV-2. We searched PubMed and Google Scholar using the search terms "COVID-19", "SARS-CoV-2", "therapy", and "-1-antitrypsin" (AAT) for research published in 2020 and 2021.

What This Study Adds to the FieldThis study shows the results of a translational program with a focus on the biology of AAT in COVID-19. The data show that there is a relative deficiency of AAT in relation to systemic inflammation. AAT inhibits serine protease activity in human airway cells and the replication of SARS-CoV-2 in human lung organoids. Inhaled and / or intravenous application of AAT in nine patients was associated with clinical stabilization. The findings of this exploratory study suggest that AAT has a mechanistic role in the pathophysiology of COVID-19 based on its anti-inflammatory and anti-viral activities. This offers the possibility to test and develop AAT application for treatment of different phenotypes or stages of COVID-19, including severe, inflammatory courses or early stages. Inhaled treatment could be an option to administer AAT non-invasively in early stages.


title: Statins Are Associated with Improved 28-day Mortality in Patients Hospitalized with SARS-CoV-2 Infection

abstract:
BackgroundStatins may be protective in viral infection and have been proposed as treatment in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

ObjectiveWe evaluated the effect of statins on mortality in four groups hospitalized with (SARS-CoV-2) infection (continued statin, newly initiated statin, discontinued statin, never on statin).

DesignIn a single center cohort study of 1179 patients hospitalized with SARS-CoV-2 infection, the outcome of death, Intensive Care Unit (ICU) admission or hospital discharge was evaluated. Patients statin use, laboratory data, and co-morbidities were determined via chart review and electronic health records. Using marginal structural models to account for timing of statin initiation and competing risks, we compared the likelihood of severe outcomes in the four statin exposure groups.

SettingAcademic medical center in the United States

ParticipantsPatients hospitalized with SARS-CoV-2 infection

Measurements28-day mortality, ICU admission, or discharge

ResultsAmong 1179 patients, 360 were never on a statin, 311 were newly initiated on a statin, 466 were continued on a statin, and 42 had a statin discontinued. In this cohort, 154 (13.1%) patients died by 28-days. With marginal structural model analysis, statin use reduced the hazard of 28-day mortality (HR 0.566 [CI 0.372, 0.862], p = 0.008). Both new initiation of statins (HR 0.493 [CI 0.253, 0.963], p=0.038) and continuing statin therapy reduced the hazard of 28-day mortality (HR 0.270 [CI 0.114, 0.637], p=0.003). Sensitivity analysis found that statin use was associated with improved mortality for patients > 65 years, but not for patients 65 years or younger.

LimitationObservational design

ConclusionStatin therapy during hospitalization for SARS-CoV-2 infection, including new initiation and continuation of therapy, was associated with reduced short-term mortality.


title: Characterization of heart rate changes associated with autonomic dysreflexia during penile vibrostimulation and urodynamics

abstract:
PurposeAutonomic dysreflexia, often accompanied by heart rate changes, increases the risk of cardio-cerebrovascular complications in individuals with spinal cord injury. Thus, our aim was to characterize these changes during penile vibrostimulation and urodynamics.

Materials and MethodsWe analyzed the cardiovascular (i.e. blood pressure and heart rate) data from two prospective studies, i.e. 21 individuals with chronic spinal cord injuries and history of autonomic dysreflexia, who underwent penile vibrostimulation (n=11, study 1) or urodynamics (n=10, study 2).

ResultsThe cohorts median age was 41 years (range 22 -53). Overall 47 episodes of autonomic dysreflexia were recorded (i.e. penile vibrostimulation n=37, urodynamics n=10), while at least one episode was recorded in each participant. At the threshold of autonomic dysreflexia, bradycardia was observed during penile vibrostimulation and urodynamics in 43% and 30% of all episodes, respectively. At the peak of autonomic dysreflexia during penile vibrostimulation and urodynamics, bradycardia was observed in 65% and 50%, respectively. In contrast, tachycardia was detected only once during urodynamics.

ConclusionOur findings reveal that heart rate changes associated with autonomic dysreflexia during penile vibrostimulation and urodynamics appear to be related to the magnitude of systolic blood pressure increases. Thus, highly elevated systolic blood pressure associated with bradycardia suggest the presence of severe autonomic dysreflexia, which can lead to devastating cerebro-cardiovascular consequences. Therefore, we recommend cardiovascular monitoring during penile vibrostimulation and urodynamics to detect autonomic dysreflexia and stop assessments before systolic blood pressure is dangerously increasing, thereby reducing the risk of potentially life-threatening complications in this cohort.

category: cardiovascular medicine


title: Raised cardiovascular disease mortality after central nervous system tumour diagnosis: analysis of 171 926 patients from UK and USA

abstract:
BackgroundPatients with central nervous system (CNS) tumours have significant morbidity and mortality. Some studies showed CNS tumours patients may be at risk for cardiovascular disease (CVD) mortality. The magnitude of CVD risk among CNS tumours patients has not been comprehensively assessed. If CVD mortality is elevated in this population, there may be a potential for risk reduction to improve outcomes. We examined CVD mortality risk in patients with malignant and non-malignant CNS tumours.

MethodsWe conducted analyses using UK (Wales)-based Secure Anonymised Information Linkage (SAIL) for 8,743 CNS tumour patients diagnosed in 2000-2015 (54.9% of whom died), and US-based National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) for 163,183 patients in 2005-2015 (39.6% of whom died). We calculated age-, sex-, and calendar-year-adjusted standardised mortality ratios (SMRs) for CVD death in CNS tumour patients compared to Welsh and US residents. We used multivariable cause-specific Cox regression models to examine factors associated with CVD mortality among CNS tumour patients. We stratified all analyses by malignancy and main histological types.

ResultsCVD was the second commonest cause of death for CNS tumour patients in SAIL (UK) and SEER (US) (9.5% & 11.7%, respectively). Patients with CNS tumours had higher CVD mortality than the general population (SAIL SMR=2.64, 95% CI=2.39-2.90, SEER SMR=1.38, 95% CI=1.35-1.42). Malignant CNS tumour patients had over 2-fold higher CVD mortality risk in both US and UK cohorts. SMRs for non-malignant tumours were almost 2-fold higher in SAIL than in SEER (SAIL SMR=2.73, 95% CI=2.46-3.02, SEER 1.30, 95% CI=1.26-1.33). The greatest magnitude of excess CVD mortality risk, particularly from cerebrovascular disease, was substantially greater in patients diagnosed at age younger than 50 years and within the first year after their cancer diagnosis (SAIL SMR=2.98, 95% CI=2.39-3.66; SEER SMR=2.14 95% CI=2.03-2.25). Age, sex, race/ethnicity in USA, deprivation in UK and no surgery were associated with CVD mortality.

DiscussionCVD mortality is high among patients diagnosed with both malignant and non-malignant CNS tumours compared to the general population. Targeted interventions and risk stratification tools might improve survival.


title: Timing is everything: the relationship between COVID outcomes and the date at which mask mandates are relaxed

abstract:
ImportanceSeveral states including Texas and Mississippi have lifted their mask mandates, sparking concerns that this policy change could lead to a surge in cases and hospitalizations.

ObjectiveTo estimate the increase in incidence, hospitalizations, and deaths in Texas and Mississippi following the removal of mask mandates, and to evaluate the relative reduction of these outcomes if policy change is delayed by 90 days.

Design, Setting, and ParticipantsThis study uses an age-stratified compartmental model parameterized to incidence data in Texas and Mississippi to simulate increased transmission following policy change in March or June 2021, and to estimate the resulting number of incidence, hospitalizations, and deaths.

Main Outcomes and MeasuresThe increase in incidence, hospitalizations, and deaths if mask mandates are lifted on March 14 compared to lifting on June 12.

ResultsIf transmission is increased by 67% when mask mandates are lifted, we projected 11.39 (CrI: 11.22 - 11.55) million infections, 170,909 (CrI: 167,454 - 174,379) hospitalizations, and 5647 (5511 - 5804) deaths (Figure 1) in Texas from March 14 through the end of 2021. Delaying NPI lift until June reduces the average number of infections, hospitalizations, and deaths by 36%, 65%, and 62%, respectively. Proportionate differences were similar for the state of Mississippi. Peak hospitalization rates would be reduced by 79% and 63% in Texas and Mississippi, respectively.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/21254646v1_fig1.gif" ALT="Figure 1">
View larger version (32K):
org.highwire.dtl.DTLVardef@49cbbforg.highwire.dtl.DTLVardef@df7928org.highwire.dtl.DTLVardef@18b5885org.highwire.dtl.DTLVardef@160b6d1_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure 1:C_FLOATNO Cumulative number of infections, hospitalizations, and deaths for (A) Texas and (B) Mississippi through 2021 if NPI were lifted on March 14 (red) or June 12 (blue).

C_FIG Conclusions and RelevanceRemoval of mask mandates in March 2021 is premature. Delaying this policy change until June 2021, when a larger fraction of the population has been vaccinated, will avert more than half of the expected COVID-19 hospitalizations and deaths, and avoid an otherwise likely strain on healthcare capacity.


title: South to North Migration Patterns of Tuberculosis Patients Diagnosed in the Mexican Border with Texas

abstract:
BackgroundImmigration is a determinant of tuberculosis (TB) epidemiology. The US-Mexican border state of Tamaulipas serves as a migration waypoint for further immigration to the US, and has the second highest incidence of TB in Mexico. Here, we determined the contribution and characteristics of immigrants to the TB burden in Tamaulipas.

MethodsTB surveillance data from Tamaulipas (2006-2013) was used to conduct a cross-sectional characterization of TB immigrants (born outside Tamaulipas) and identify their association with TB treatment outcomes.

ResultsImmigrants comprised 30.8% of the TB patients, with >99% originating from internal Mexican migration. Most migration was from South to North, with cities adjacent to the US border as destinations. Immigrants had higher odds of risk factors for TB [older age ([≥] 65 yr old, OR 2.4, 95% CI 2.1, 2.8), low education (OR 1.3, 95% CI 1.2, 1.4), diabetes (OR 1.2, 95% CI 1.1, 1.4)], or abandoning TB treatment (adjusted OR 1.2, 95% CI 1.0, 1.5).

ConclusionsThe US port of entry of Tamaulipas has a predominant south to north migration, positively impacting TB prevalence in this region. There is a need to identify strategies to prevent and manage TB more effectively in this Mexican migration waypoint.


title: Genomic epidemiology of SARS-CoV-2 in Russia reveals recurring cross-border transmission throughout 2020

abstract: SARS-CoV-2 has spread rapidly across the globe, with most nations failing to prevent or substantially delay its introduction. While many countries have imposed some limitations on trans-border passenger traffic, the effect of these measures on the spread of COVID-19 strains remains unclear. Here, we report an analysis of whole-genome sequencing of 3206 SARS-CoV-2 samples from 78 regions of Russia covering the period between March and November 2020. We describe recurring imports of multiple COVID-19 strains throughout this period, giving rise to 457 uniquely Russian transmission lineages, as well as repeated cross-border transmissions of local circulating variants out of Russia.


title: High SARS-CoV-2 attack rates following exposure during singing events in the Netherlands, September-October 2020

abstract:
BackgroundPrevious reports suggest SARS-CoV-2 transmission risk increases during singing events. From September-October 2020, several clusters of COVID-19 cases among singing events were reported across the Netherlands. Our aim was to investigate whether singing increased SARS-CoV-2 transmission risk during these events.

MethodsData from 5 events were retrospectively collected from spokespersons and singing group members via questionnaires. Information was consolidated with the National Notifiable Diseases Surveillance System. Specimens were requested for sequencing for point source and cluster assessment. We described outbreaks in terms of person, place and time and depicted potential SARS-CoV-2 transmission routes. A previously published model (AirCoV2) was used to estimate mean illness risk of 1 person through airborne transmission under various scenarios.

ResultsEvents included 9-21 persons (mean: 16), aged 20-89 years (median: 62). Response rates ranged 58-100%. Attack rates were 53-74%. Limited sequencing data was obtained from 2 events. Events lasted 60-150 minutes (singing: 20-120). Rooms ranged 320-3000m3. SARS-CoV-2 transmission likely occurred during all events; with a possible index case identified in 4 events. AirCoV2 showed 86% (54-100%) mean illness risk for 120 minutes of singing, smaller room (300m3), 1 air exchange/hour (ACH), and supershedder presence.

ConclusionsDroplet transmission and indirect contact probably caused some cases, but unlikely explain the high attack rates. AirCoV2 indicated that airborne transmission due to singing is possible in case of supershedder presence. Airflow expelling respiratory droplets >1.5m possibly influenced transmission. It is possible that singing itself increased SARS-CoV-2 transmission risk through airborne transmission.

SummaryThis outbreak investigation among five singing events with high SARS-CoV-2 attack rates (53-74%) suggested that airflow expelling respiratory droplets >1.5m possibly influenced transmission and it is possible that singing itself increased SARS-CoV-2 transmission risk through airborne transmission.


title: High SARS-CoV-2 attack rates following exposure during five singing events in the Netherlands, September-October 2020


title: The ventral striatum harbours patient specific intracranial neural signatures of obsessions and compulsions

abstract: Deep brain stimulation is a treatment option for patients with refractory obsessive-compulsive disorder. A new generation of stimulators hold promise for closed loop stimulation, with adaptive stimulation in response to biological signals Here we aimed to discover a suitable biomarker in the ventral striatum in patients with obsessive compulsive disorder using local field potentials. We induced obsessions and compulsions and trained a deep learning model on the recorded time series. Average classification sensitivities were 47% for obsessions and 66% for compulsions for patient specific models at 25% chance level. Sensitivity for obsessions reached over 90% in one patient, whereas performance was near chance level when the model was trained across patients. Optimal sensitivity for obsessions and compulsions was obtained at different recording sites. This study shows that closed loop stimulation is a viable option for OCD, but that intracranial biomarkers for obsessive-compulsive disorder are patient and not disorder specific.


title: Development of Childhood Asthma Prediction Models using Machine Learning Approaches

abstract:
BackgroundWheeze is common in early life and often transient. It is difficult to identify which children will experience persistent symptoms and subsequently develop asthma. Machine learning approaches have the potential for better predictive performance and generalisability over existing childhood asthma prediction models.

ObjectiveTo apply machine learning approaches for predicting school-age asthma (age 10) in early life (Childhood Asthma Prediction in Early life, CAPE model) and at preschool age (Childhood Asthma Prediction at Preschool age, CAPP model).

MethodsData on clinical symptoms and environmental exposures were collected from children enrolled in the Isle of Wight Birth Cohort (N=1368, [~]15% asthma prevalence). Recursive Feature Elimination (RFE) identified the optimal subset of features predictive of school-age asthma for each model. Seven state-of-the-art machine learning classification algorithms were used to develop the models and the results were compared. To optimize the models, training was performed by applying 5-fold cross-validation, imputation and resampling. Predictive performances were evaluated on the test set and externally validated in the Manchester Asthma and Allergy Study (MAAS) cohort.

ResultsRFE identified eight and 12 predictors for the CAPE and CAPP models, respectively. The best predictive performance was demonstrated by a Support Vector Machine (SVM) algorithm for both the CAPE model (area under the receiver operating curve, AUC=0.71) and CAPP model (AUC=0.82). Both models demonstrated good generalisability in MAAS (CAPE 8YR=0.71, 11YR=0.71, CAPP 8YR=0.83, 11YR=0.79).

ConclusionUsing machine learning approaches improved upon the predictive performance of existing regression-based models, with good generalisability and ability to rule in asthma.

category: respiratory medicine


title: Humoral response to Pfizer mRNA vaccine against SARS CoV2, in patients with autoimmune inflammatory rheumatic diseases and the impact on the rheumatic disease activity

abstract:
BackgroundThe registration trials of mRNA vaccines against SARS CoV2 did not address patients with autoimmune inflammatory rheumatoid diseases (AIRD).

AimsTo assess the humoral response to mRNA vaccine against SARS CoV2, in AIRD patients treated with immunomodulating drugs and the impact on AIRD activity.

MethodsConsecutive patients treated at the rheumatology institute who received their first SARS-CoV-2 (Pfizer) vaccine were recruited to the study, at their routine visit. The patients were invited for serology test 4-6 weeks after receiving the second dose of vaccine. IgG Antibodies (Ab) against SARS COV2 virus were detected using the SARS-Cov-2 IgG II Quant (Abbott) assay

ResultsOne hundred fifty-six consecutive patients (76% females) treated at a single rheumatology center (mean age (range) 59.1 (21-83) years), mean (range) disease duration 10.8 (1-55) years), were recruited to the study. Thirty-five percents of patients received conventional synthetic (cs)DMARDs only, 64% biological/targeted synthetic (b/ts) DMARDs, 34% received combined treatment with csDMARDs and b/tsDMARDs and 32% corticosteroids (mean dose(range) 5.8mg(2.5-20mg) prednisone). One hundred thirty-seven patients (88%) were seropositive for IgG Ab against SARS CoV2 virus (median 2832.5 AU/ml, range 58-29499). Nineteen (12%) patients had negative tests, 11/19 were treated with B cell depleting agents. The reported side effects of the vaccine were minor (muscle sore, headache, low grade fever). The rheumatic disease remained stable in all patients.

ConclusionsThe vast majority of AIRD patients developed a significant humoral response following the administration of the second dose of the Pfeizer mRNA vaccine against SARS CoV2 virus. Only minor side effects were reported and no apparent impact on AIRD activity was noted.

category: rheumatology


title: Pharmacogenomics of hypertension in chronic kidney disease: the CKD-PGX study

abstract:
BackgroundPatients with chronic kidney disease (CKD) often have uncontrolled hypertension despite polypharmacy. Pharmacogenomic drug-gene interactions (DGIs) may impact the metabolism or efficacy of antihypertensive agents. We hypothesized that providing a panel of 11 pharmacogenomic predictors of antihypertensive response would improve hypertension control.

MethodsA prospective cohort with CKD and hypertension was followed to assess the effect of pharmacogenomic testing on blood pressure control. The analysis population included 382 hypertensive subjects genotyped for cross-sectional assessment of drug-gene interactions and 335 subjects followed for 1 year to assess systolic (SBP) and diastolic blood pressure (DBP).

ResultsMost participants (58.2%) with uncontrolled hypertension had a DGI reducing the efficacy of one or more antihypertensive agents. Subjects with a DGI had 1.88-fold (95% CI 1.2-2.8) higher odds of uncontrolled hypertension as compared to those without a DGI, adjusted for race and CKD grade. CYP2C9 reduced metabolism genotypes were associated with losartan response and uncontrolled hypertension (Odds Ratio 5.2, CI 1.9 -14.7). CYP2D6 intermediate or poor metabolizers had less frequent uncontrolled hypertension compared to normal metabolizers taking metoprolol or carvedilol (OR 0.55, CI 0.3-0.95). In 335 subjects completing 1 year follow-up, SBP (-4.0 mmHg, CI 1.6-6.5) and DBP (-3.3 mmHg, CI 2.0-4.6) were improved. The magnitude of reductions in SBP (-14.8 mmHg, CI 10.3-19.3) and DBP (-8.4 mmHg, CI 5.9-10.9) were greatest in the 90 individuals with uncontrolled hypertension and an actionable genotype.

ConclusionsThere is a potential role for the addition of pharmacogenomic testing to optimize antihypertensive regimens in patients with CKD.

category: nephrology


title: Spatiotemporal Correlations of Mesoscale Neocortical Activities in Patients with Focal Epilepsy

abstract:
Brain function is reflected in both the action potentials of individual neurons and interactions through e.g. synaptic currents reflected in widespread, slow fluctuations of the local field potential (LFP). We analyzed microelectrode array data to determine state-dependent correlations between action potential and LFP during seizure events as well as interictally in patients with focal epilepsy. We also examined activity in two different cortical network territories: the seizure core and surrounding penumbra (Schevon et al., 2012).

The cross-correlation of spiking activity in the core showed an association of the ictal action potentials with the global oscillatory aspect of the seizure activity and indicated local failure of inhibitory restraint surrounding the ictal spike. These patterns were not observed in the penumbra.

Our analyses from clinical recordings and a model of a single ictal spike in the core revealed that both the temporal and spatial components of the networks cross-correlation can be approximated by a sine cardinal (sinc) function. The biological interpretation of these findings is that important functional differences across the neocortical network exist, with a critical role of the millimeter-range excitatory connections within the grey matter. Therefore, localized intervention that prevents escape of hyperactivity from the seizure core may be considered as a therapeutic strategy.

Significance StatementAnalysis and modeling of spatiotemporal cross-correlation between multi-unit spike activity and the local field potential of human seizure activity demonstrates a difference of network functionality between the seizure core and its surrounding penumbral network. In this study, we show that millimeter-range excitatory connections, known to exist within the gray matter of neocortex, play a critical role in propagating the effects of ictal hyperexcitation. These findings contribute to our understanding of ictal mechanisms and hold promise for further development of strategies to detect the ictal core territory and prevent seizure propagation.

category: neurology


title: Efficient Maternal to Neonatal transfer of SARS-CoV-2 and BNT162b2 antibodies

abstract:
BackgroundThe significant risks posed to mothers and fetuses by COVID-19 in pregnancy have sparked a worldwide debate surrounding the pros and cons of antenatal SARS-CoV-2 inoculation, as we lack sufficient evidence regarding vaccine effectiveness in pregnant women and their offspring. We aimed to provide substantial evidence for the effect of BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection.

MethodsA multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to three study groups: vaccinated (n=86); PCR confirmed SARS-CoV-2 infected during pregnancy (n=65), and unvaccinated non-infected controls (n=62). Maternal and fetal blood samples were collected from parturients prior to delivery and from the umbilical cord following delivery, respectively. Sera IgG and IgM titers were measured using Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD and N).

ResultsBNT162b2 mRNA vaccine elicits strong maternal humoral IgG response (Anti-S and RBD) that crosses the placenta barrier and approaches maternal titers in the fetus within 15 days following the first dose. Maternal to neonatal anti-COVID-19 antibodies ratio did not differ when comparing sensitization (vaccine vs. infection). IgG transfer rate was significantly lower for third-trimester as compared to second trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group.

ConclusionsAntenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.

category: obstetrics and gynecology


title: Quantifying Face Mask Comfort

abstract: Face mask usage is one of the most effective ways to limit SARS-CoV-2 transmission, but a mask is only useful if user compliance is high. Through anonymous surveys, we show that mask discomfort is the primary source of noncompliance in mask wearing. Further, through these surveys, we identify three critical parameters that dictate mask comfort: air resistance, water vapor permeability, and face temperature change. To validate these parameters in a physiological context, we performed experiments to measure the respiratory rate and change in face temperature while wearing different types of commonly used masks. Finally, using values of these parameters from experiments and the literature, and surveys asking users to rate the comfort of various masks, three machine learning algorithms were trained and tested to generate overall comfort scores for those masks. Although all three models tested performed with an accuracy of approximately 70%, the multiple linear regression model also provides a simple analytical expression to predict the comfort scores for any face mask provided the input parameters. As face mask usage is crucial during the COVID-19 pandemic, the ability of this quantitative framework to predict mask comfort is likely to improve user experience and prevent discomfort-induced noncompliance.

category: occupational and environmental health


title: Replication of LZTFL1 gene region as a susceptibility locus for COVID-19 in Latvian population.

abstract: The severity of COVID-19 disease is partly determined by host genetic factors that have been reported by GWAS. We evaluated nine previously reported genome-wide significant associations regardless of the disease severity in a representative sample from the population of Latvia. Our cohort consisted of 475 SARS-CoV-2 positive cases, from which 146 were hospitalized individuals and 2217 controls. We found three variants from Neanderthal introgression event at the 3p21.31 region to be significantly associated with increased risk of SARS-CoV-2 infection and hospitalization status. The strongest association was displayed by rs71325088 with Bonferroni adjusted P=0.007, OR=1.46 [95% CI 1.17-1.81]. We performed fine-mapping by exploring 1 Mb region at 3p21.31 locus and identified 9 SNPs with even lower p-values with the strongest association estimated for rs2191031 P=5e-05, OR = 1.40[CI 95% 1.19-1.64] located in the LZTFL1. We show clear replication of 3p.21.31 locus in an independent cohort which favors further functional investigation of leading variants.