title: Image- vs. histogram-based considerations in semantic segmentation of pulmonary hyperpolarized gas images

abstract: Magnetic resonance imaging (MRI) using hyperpolarized gases has made possible the novel visualization of airspaces in the human lung, which has advanced research into the growth, development, and pathologies of the pulmonary system. In conjunction with the innovations associated with image acquisition, multiple image analysis strategies have been proposed and refined for the quantification of such lung imaging with much research effort devoted to semantic segmentation, or voxelwise classification, into clinically oriented categories based on ventilation levels. Given the functional nature of these images and the consequent sophistication of the segmentation task, many of these algorithmic approaches reduce the complex spatial image information to intensity-only considerations, which can be contextualized in terms of the intensity histogram. Although facilitating computational processing, this simplifying transformation results in the loss of important spatial cues for identifying salient image features, such as ventilation defects (a well-studied correlate of lung pathophysiology), as spatial objects. In this work, we discuss the interrelatedness of the most common approaches for histogram-based optimization of hyperpolarized gas lung imaging segmentation and demonstrate how certain assumptions lead to suboptimal performance, particularly in terms of measurement precision. In contrast, we illustrate how a convolutional neural network is optimized (i.e., trained) directly within the image domain to leverage spatial information. This image-based optimization mitigates the problematic issues associated with histogram-based approaches and suggests a preferred future research direction. Importantly, we provide the entire processing and evaluation framework, including the newly reported deep learning functionality, as open-source through the well-known Advanced Normalization Tools ecosystem.

category: radiology and imaging


title: The Impact of the Variation of CT Scanner on the Prediction of Human Papillomavirus (HPV) Association of Oropharyngeal Cancer (OPC) using Radiomic Models

abstract: Studies have shown that radiomic features are sensitive to the variability of imaging parameters (e.g., scanner model) and one of the major challenges in these studies lies in improving the robustness of quantitative features against the variations in imaging datasets from multi-center studies. Here, we assess the impact of scanner choice on the computed tomography (CT)-derived radiomic features to predict association of oropharyngeal squamous cell carcinoma with human papillomavirus (HPV). This experiment was performed on CT image datasets acquired with two different scanner manufacturers. We demonstrate strong scanner dependency by developing a machine learning model to classify HPV status from radiological images. These experiments revealed the effect of scanner manufacturers on the robustness of the radiomic features, and the extent of this dependency is reflected on the performance of HPV prediction models. The results of this study highlight the importance of implementing an appropriate approach to reduce the impact of imaging parameters on radiomic features and consequently on the machine learning models.


title: How pain neuroscience education is performed in patients with chronic musculoskeletal pain: a scoping review protocol

abstract:
BackgroundPain Neuroscience Education (PNE) is an effective widely used strategy in the field of chronic pain management. The objective of this scoping review is to summarize the literature to identify how PNE is performed in patients with chronic musculoskeletal pain.

MethodsThis scoping review will be performed in accordance with the Joanna Briggs Institute methodology. Studies will be included if they meet the following population, concept, and context criteria: any patient with chronic musculoskeletal pain aged over 18 years old, any PNE delivery method, any context. No study design, publication type, and data restrictions will be applied. MEDLINE, Cochrane Central, Scopus, PsycInfo and PEDro databases will be searched up to March 2021. Additional records will be identified through searching in grey literature and reference lists of all relevant and included studies. Two reviewers will independently screen all title, abstracts and full-text studies for inclusion. A data collection form will be developed by the research team to extract the characteristics of the studies included. A tabular and accompanying narrative summary of the information will be provided.

ConclusionsThis will be the first scoping review to provide a comprehensive overview of the topic. The results will add meaningful information for future research and clinical practice. Furthermore, any knowledge gaps on the topic will be identified. The results of this research will be published in a peer-reviewed journal and will be presented at relevant (inter)national scientific events.

category: rehabilitation medicine and physical therapy


title: Microbiota of Chronic Prostatitis/Chronic Pelvic Pain Syndrome are Distinct from Interstitial Cystitis/Bladder Pain Syndrome

abstract: Urologic chronic pelvic pain syndrome patients include men chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and patients, mainly women, with interstitial cystitis/bladder pain syndrome (IC/BPS or IC). CP/CPPS is marked by severe chronic pelvic pain of unknown etiology that is differentially associated with prostatic inflammation. Microbes are known to modulate sensory responses, and microbiota are increasingly understood to drive normal biological processes and pathogenesis, including inflammation. Recent studies have linked fecal dysbiosis with chronic pelvic pain in IC/BPS, suggesting a role for microbiota in modulating UCPPS pain. Similarly, dysbiosis has been reported in CP/CPPS patients, but the relationship between with the dysbiosis of IC/BPS patients is unclear. Here, we characterized the fecal microbiota of men with CP/CPPS and women and men with IC/BPS. Similar to recent reports, we identified fecal dysbiosis in men with CP/CPPS relative to healthy controls among specific phyla and overall differences in diversity and richness. Interestingly, we also observed differences between CP/CPPS microbiota and IC/BPS microbiota that were not likely due to sex differences. These findings suggest that CP/CPPS is marked by changes in the gut microbiome, but these changes differ from IC/BPS. Taken together, UCPPS appears associated with distinct dybioses among CP/CPPS and IC/BPS, raising the possibility of distinct contributions to underlying pelvic pain mechanisms and/or etiologies.

category: urology


title: Detection of dementia on raw voice recordings using deep learning: A Framingham Heart Study

abstract:
BackgroundIdentification of reliable, affordable, and easy-to-use strategies for detection of dementia are sorely needed. Digital technologies, such as individual voice recordings, offer an attractive modality to assess cognition but methods that could automatically analyze such data are not readily available.

Methods and findingsWe used 1264 digital voice recordings of neuropsychological examinations administered to participants from the Framingham Heart Study (FHS), a community-based longitudinal observational study. The recordings were 73 minutes in duration, on average, and contained at least two speakers (participant and clinician). Of the total voice recordings, 483 were of participants with normal cognition (NC), 451 recordings were of participants with mild cognitive impairment (MCI), and 330 were of participants with dementia (DE). We developed two deep learning models (a two-level long short-term memory (LSTM) network and a convolutional neural network (CNN)), which used the raw audio recordings to classify if the recording included a participant with only NC or only DE and to differentiate between recordings corresponding to those that were non-demented (NDE (NC+MCI)) and DE. Based on 5-fold cross-validation, the LSTM model achieved a mean ({+/-}std) area under the receiver operating characteristic curve (AUC) of 0.740{+/-}0.017, mean balanced accuracy of 0.647{+/-}0.027, and mean weighted F1-score of 0.596{+/-}0.047 in predicting cases with DE from those with NC. The CNN model achieved a mean AUC of 0.805{+/-}0.027, mean balanced accuracy of 0.743{+/-}0.015, and mean weighted F1-score of 0.742{+/-}0.033 in predicting cases with DE from those with NC. For the task related to classification of participants with DE from NDE, the LSTM model achieved a mean AUC of 0.734{+/-}0.014, mean balanced accuracy of 0.675{+/-}0.013, and mean weighted F1-score of 0.671{+/-}0.015. The CNN model achieved a mean AUC of 0.746{+/-}0.021, mean balanced accuracy of 0.652{+/-}0.020, and mean weighted F1-score of 0.635{+/-}0.031 in predicting cases with DE from those who were NDE.

ConclusionThis proof-of-concept study demonstrates the potential that raw audio recordings of neuropsychological testing performed on individuals recruited within a community cohort setting can facilitate dementia screening.

category: neurology


title: Sex differences in Cerebral Small Vessel Disease: a systematic review and meta-analysis.

abstract:
BackgroundCerebral small vessel disease (SVD) is an important cause of acute ischemic stroke and vascular dementia. Several studies recruiting more males than females have reported sex differences regarding SVD incidence and severity, but it is unclear whether this reflects underlying sex-specific mechanisms or recruitment bias. This work aimed to systematically review and meta-analyze potential sex differences in SVD by assessing the male-to-female ratio (M:F) of recruited participants and incidence of SVD, risk factor presence, distribution and severity of SVD features.

MethodsFull text of 228 studies from four databases of recent systematic reviews on SVD and an independent search of MEDLINE were evaluated against inclusion and exclusion criteria (registered protocol: CRD42020193995). Data from participants with clinical or non-clinical presentations of SVD with radiological evidence of SVD were extracted. Sex ratios of total participants or SVD groups were calculated and differences in sex ratios across time, countries, SVD severity and risk factors for SVD were explored.

ResultsAmongst 123 relevant studies (n = 36,910 participants) including 53 community-based, 67 hospital-based and 3 mixed studies, more males were recruited in hospital-based than in community-based studies (M:F = 1.16 (0.70) vs M:F = 0.79 (0.35), respectively; p <0.001). More males had moderate to severe SVD (M:F = 1.08 (0.81) vs M:F = 0.82 (0.47) in healthy to mild SVD; p <0.001), especially in stroke presentations where M:F was 1.67 (0.53). M:F of recent research (2015-2020) did not differ from that published pre-2015 and no geographical trends were apparent. There were insufficient sex-stratified data to explore M:F and risk factors for SVD.

ConclusionsOur results highlight differences in male-to-female ratios in SVD that may reflect sex-specific variability in risk factor exposures, study participation, clinical recognition, genuine SVD severity, or clinical presentation and have important clinical and translational implications.


title: Language disorder in progressive supranuclear palsy and corticobasal syndrome: neural correlates and detection by the MLSE screening tool

abstract:
BackgroundProgressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) affect speech and language as well as motor functions. Clinical and neuropathological data indicate a close relationship between these two disorders and the non-fluent variant of primary progressive aphasia (nfvPPA). We use the recently developed Mini Linguistic State Examination tool (MLSE) to study speech and language disorders in patients with PSP, CBS, and nfvPPA, in combination with structural magnetic resonance imaging (MRI).

MethodsFifty-one patients (PSP N = 13, CBS N = 19, nfvPPA N = 19) and 30 age-matched controls completed the MLSE, the short form of the Boston Diagnostic Aphasia Examination (BDAE), and the Addenbrookes Cognitive Examination III. Thirty-eight patients and all controls underwent structural MRI at 3 Tesla, with T1 and T2-weighted images processed by surface-based and subcortical segmentation within FreeSurfer 6.0.0 to extract cortical thickness and subcortical volumes. Morphometric differences were compared between groups and correlated with severity of speech and language impairment.

ResultsCBS and PSP patients showed impaired MLSE performance, compared to controls, with a similar language profile to nfvPPA, albeit less severe. All patient groups showed reduced cortical thickness in bilateral frontal regions and striatal volume. PSP and nfvPPA patients also showed reduced superior temporal cortical thickness, with additional thalamic and amygdalo-hippocampal volume reductions in nfvPPA. Multivariate analysis of brain-wide cortical thickness and subcortical volumes with MLSE domain scores revealed associations between performance on multiple speech and language domains with atrophy of left-lateralised fronto-temporal cortex, amygdala, hippocampus, putamen and caudate.

ConclusionsThe effect of PSP and CBS on speech and language overlaps with nfvPPA. These three disorders cause a common anatomical pattern of atrophy in the left frontotemporal language network and striatum. The MLSE is a short clinical screening tool that can identify the language disorder of PSP and CBS, facilitating clinical management and patient access to future clinical trials.


title: Design of optical cavity for air sanification through ultraviolet germicidal irradiation

abstract: The transmission of airborne pathogens represents a major issue to worldwide public health. Ultraviolet light irradiation can contribute to the sanification of air to reduce the pathogen transmission. This study concerns the design of a compact filter for airborne pathogen inactivation by means of UV-C LED sources, whose effective irradiance is enhanced thanks to high reflective surfaces. Ray-tracing and computational fluid dynamic simulations are both used to model the device and to maximize the performance inside the filter volume. Simulations foresee the inhibition of SARS-Cov 2 also in the case of high air fluxes. This study demonstrates that current available LED technology is effective for air sanification purposes.

category: occupational and environmental health


title: Estimating Causal Treatment Effects of Femoral and Tibial Derotational Osteotomies on Foot Progression in Children with Cerebral Palsy

abstract:
BackgroundFoot progression deviations are a common and important problem for children with CP. Tibial and femoral derotational osteotomies (TDO, FDO) are used to treat foot progression deviations, but outcomes are unpredictable. The available evidence for the causal effects of TDO and FDO is limited and weak, and thus modeling approaches are needed.

MethodsWe queried our clinical database for individuals with a diagnosis of cerebral palsy (CP) who were less than 18 years old and had baseline and follow up gait data collected within a 3-year time span. We then used the Bayesian Causal Forest (BCF) algorithm to estimate the causal treatment effects of TDO and FDO on foot progression deviations (separate models). We examined average treatment effects and heterogeneous treatment effects (HTEs) with respect to clinically relevant covariates.

ResultsThe TDO and FDO models were able to accurately predict follow-up foot progression (r2 [~]0.7, RMSE [~]8{degrees}). The estimated causal effect of TDO was bimodal and exhibited significant heterogeneity with respect to baseline levels of foot progression and tibial torsion as well as changes in tibial torsion at follow-up. The estimated causal effect of FDO was unimodal and largely homogeneous with respect to baseline or change characteristics.

ConclusionsThis study demonstrated the potential for causal machine-learning algorithms to impact treatment in children with CP. The causal model is accurate and appears sensible - though no gold-standard exists for validating the causal estimates. The model results can provide guidance for planning surgical corrections, and partly explain unsatisfactory outcomes observed in prior observational clinical studies.

category: orthopedics


title: Polycystic ovary syndrome susceptibility loci inform disease etiological heterogeneity

abstract:
PurposePolycystic ovary syndrome (PCOS) is a complex disorder with heterogenous phenotypes and unclear etiology. A recent phenotypic clustering study identified metabolic and reproductive subtypes of PCOS. We attempted to deconstruct the PCOS heterogeneity from a genetic perspective.

MethodsWe applied k-means clustering to categorize the genome-wide significant PCOS variants into clusters based on their associations with selected quantitative traits that likely reflect PCOS etiological pathways. We evaluated the association of each cluster with PCOS related traits and disease outcomes. We then applied Mendelian randomization to estimate the causal effect of the traits on PCOS and PCOS on disease outcomes.

ResultsClustering analysis suggested three categories of variants: adiposity, insulin resistant, and reproductive. Significant associations were observed for variants in the adiposity cluster with body mass index (BMI), waist circumference and breast cancer, and variants in insulin resistant cluster with fasting insulin and glucose values, and homeostatic model assessment of insulin resistance (HOMA-IR). Sex hormone binding globulin (SHBG) has strong association with all three clusters. Mendelian randomization supported the causal role of BMI and SHBG on PCOS. No causal associations were observed for PCOS on disease outcomes.

Main ConclusionsOur study provides genetic evidence for the heterogeneity in PCOS etiologies, corresponding to the reported phenotypic subtypes. Such studies will improve the current PCOS diagnosis criteria that do not distinguish the heterogeneity. Classification of women with PCOS to inform appropriate treatment will be more accurate in the future with improvements in clustering analysis for PCOS.

category: genetic and genomic medicine


title: A common TMPRSS2 variant protects against severe COVID-19

abstract:
Infection with SARS-CoV-2 has a wide range of clinical presentations, from asymptomatic to life-threatening. Old age is the strongest factor associated with increased COVID19-related mortality, followed by sex and pre-existing conditions. The importance of genetic and immunological factors on COVID19 outcome is also starting to emerge, as demonstrated by population studies and the discovery of damaging variants in genes controlling type I IFN immunity and of autoantibodies that neutralize type I IFNs. The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus spike protein, facilitating entry into target cells. We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760), which has a minor allele frequency of [~]25% in the population. In a large population of SARS-CoV-2 positive patients, we show that this variant is associated with a reduced likelihood of developing severe COVID19 (OR 0.87, 95%CI:0.79-0.97, p=0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p=1.3x10-3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, impacts the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells.

TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID19. Further studies are needed to assess the expression of the TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID19. Clinical trials are needed to confirm this.


title: Sexual violence in older adults: a Belgian prevalence study

abstract:
BackgroundSexual violence (SV) is an important public health problem which may cause long-lasting health problems. SV in older adults remains neglected in research, policies and practices. Valid SV prevalence estimates and associated risk factors in older adults are currently unavailable.

ObjectiveTo measure lifetime and past 12-months sexual victimisation in older adults living in Belgium, its correlates, assailant characteristics and the way that victims framed their SV experiences.

DesignCross-sectional general population study.

SettingCommunity-dwelling, assisted living and nursing homes.

Participants513 people of 70 years and older living in Belgium.

MethodsSV was measured using behaviourally specific questions based on a broad definition of SV. Participants were selected via a cluster random probability sampling with a random route finding approach. Information on sexual victimisation, correlates, assailant characteristics and framing was collected via structured face-to-face interviews.

ResultsLifetime SV prevalence was 44% (55% F, 29% M). Past 12-months prevalence was 8% (9% F, 8% M). Female sex and a higher number of sexual partners were associated with lifetime SV (p <.05), non-heterosexual sexual orientation with past 12-months SV (p <.05). Correlates generally linked to elder abuse and neglect were not linked with SV.  Someone unknown was identified as most common assailant.

ConclusionsSV appears to be common in older adults in Belgium. Both correlates and assailant characteristics seem to differ from previous studies on elder abuse and neglect. Recognising older adults as a risk group for sexual victimisation in research, policies and practices is of the utmost importance.

category: geriatric medicine


title: Impact of remdesivir on 28 day mortality in hospitalized patients with COVID-19: February 2021 Meta-analysis

abstract:
BackgroundThe COVID-19 pandemic has stimulated worldwide investigation into a myriad of potential therapeutic agents, including antivirals such as remdesivir. The first RCT reporting results on the impact of remdesivir on COVID-19 in a peer reviewed journal was the ACTT-1 trial published in November, 2020. The ACTT-1 trial showed more rapid clinical improvement and a reduced risk of 28-day mortality in patients who received remdesivir.

This study is a meta-analysis of peer reviewed RCTs aims to estimate the association of remdesivir therapy compared to the usual care or placebo on all-cause mortality in hospitalized patients with COVID-19. Software based tools to accelerate the analysis process.

MethodsMeta-analysis of peer reviewed RCTs comparing remdesivir to usual care or placebo. The protocol for this meta-analysis was registered and published in the PROSPERO database (CRD42021229985) on February 5, 2021.

ResultsFour English language RCTs were identified, including data from 7,333 hospitalized patients worldwide using remdesivir in COVID-19 positive patients.

Meta-analysis of all identified RCTs showed no difference in survival in patients who received remdesivir therapy compared to usual care or placebo. The random effects meta-analysis has a summary odd ratio is 0.89 (95% CI 0.65-1.21, p = 0.30). Considerable variability in the severity of illness is noted with the rates of IMV at the time of randomization ranging from 0% to 27%.

ConclusionsThis meta-analysis of randomized controlled trials published in peer-reviewed literature by February 1, 2021 did not show reduced mortality in hospitalized patients with COVID-19 who received remdesivir. Further research is needed to clarify the role of remdesivir therapy in the management of COVID-19.

category: infectious diseases


title: Comparison of COVID-19 vaccine prioritization strategies in the United States

abstract: A key public health question during any disease outbreak when limited vaccine is available is who should be prioritized for early vaccination. Most vaccine prioritization analyses only consider variation in risk of infection and death by a single risk factor, such as age. We provide a more granular approach with stratification by demographics, risk factors, and location. We use this approach to compare the impact of different COVID-19 vaccine prioritization strategies on COVID-19 cases, deaths and disability-adjusted life years (DALYs) over the first 6 months of vaccine rollout, using California as a case example. We estimate the proportion of cases, deaths and DALYs averted relative to no vaccination for strategies prioritizing vaccination by a single risk factor and by multiple risk factors (e.g. age, location). We find that age-based targeting averts the most deaths (62% for 5 million individuals vaccinated) and DALYs (38%) of strategies targeting by a single risk factor and targeting essential workers averts the least deaths (31%) and DALYs (24%) over the first 6 months of rollout. However, targeting by two or more risk factors simultaneously averts up to 40% more DALYs. Our findings highlight the potential value of multiple-risk-factor targeting of vaccination against COVID-19 and other infectious diseases.


title: Comparison of COVID-19 vaccine prioritization strategies


title: Risk factor targeting for vaccine prioritization during the COVID-19 pandemic


title: Factors associated with increased mortality in critically ill COVID-19 patients in a Mexican public hospital: the other faces of health system oversaturation.

abstract:
BACKGROUNDThe lethality rate of COVID-19 in Mexico is one of the highest worldwide, but in-hospital factors associated with this increased rate have yet to be explored. This study aims to evaluate those factors that could be associated with mortality at 28-days in critically ill COVID-19 patients in Mexico.

METHODSThis is a retrospective analysis of the patients included in the clinical trial (NCT04381858) which recruited patients with severe COVID-19 with high oxygen requirement or mechanical ventilation from May to October 2020. The primary outcome, death at 28, was analyzed.

RESULTSBetween May and October 2020, 196 predominantly male patients (n=122, 62.2%) with an average of 58.1 years ({+/-} 15.5), were included in the cohort. Mortality at 28 days was 44.3 % (n= 84). Patients included in the second trimester had a greater mortality rate when compared with those recruited in the first trimester (54.1 vs 32.1, p< 0.01). On multivariate analysis, the detected protective factors were the use of fentanyl HR 0.51 (95%CI 0.31 - 0.85, p=0.01), the use of antibiotics HR 0.22 (95% CI 0.13 - 0.36, p<0.01), and a previously healthy state (no comorbidities other than obesity) HR 0.58 (95%CI 0.35 - 0.94, p =0.03); risk factors were severe kidney injury (AKIN3) HR 1.74 (95%CI 1.04 - 2.9, p=0.035), elevated D-Dimer levels HR 1.02 (95%CI 1.007 - 1.04, p=0.005), shock OR 5.8 (2.4 - 13.8, p<0.01), and recruitment in the second trimester OR 2.3 ((1.1 - 4.8, p=0.02).

CONCLUSIONSIn-hospital mortality in critically ill COVID-19 patients has increased in our center. The appropriate use of antibiotics, the type of sedation, and AKIN3 are modifiable factors directly related to this increased mortality. The increase in mortality observed in the second trimester is explained by hospital overcrowding that began in August 2020.


title: Serological reconstruction of COVID-19 epidemics through analysis of antibody kinetics to SARS-CoV-2 proteins

abstract: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a complex antibody response that varies by orders of magnitude between individuals and over time. Waning antibody levels lead to reduced sensitivity of serological diagnostic tests over time. This undermines the utility of serological surveillance as the SARS-CoV-2 pandemic progresses into its second year. Here we develop a multiplex serological test for measuring antibodies of three isotypes (IgG, IgM, IgA) to five SARS-CoV-2 antigens (Spike (S), receptor binding domain (RBD), Nucleocapsid (N), Spike subunit 2, Membrane-Envelope fusion) and the Spike proteins of four seasonal coronaviruses. We measure antibody responses in several cohorts of French and Irish hospitalized patients and healthcare workers followed for up to eleven months after symptom onset. The data are analysed with a mathematical model of antibody kinetics to quantify the duration of antibody responses accounting for inter-individual variation. One year after symptoms, we estimate that 36% (95% range: 11%, 94%) of anti-S IgG remains, 31% (9%, 89%) anti-RBD IgG remains, and 7% (1%, 31%) anti-N IgG remains. Antibodies of the IgM isotype waned more rapidly, with 9% (2%, 32%) anti-RBD IgM remaining after one year. Antibodies of the IgA isotype also waned rapidly, with 10% (3%, 38%) anti-RBD IgA remaining after one year. Quantitative measurements of antibody responses were used to train machine learning algorithms for classification of previous infection and estimation of time since infection. The resulting diagnostic test classified previous infections with 99% specificity and 98% (95% confidence interval: 94%, 99%) sensitivity, with no evidence for declining sensitivity over the time scale considered. The diagnostic test also provided accurate classification of time since infection into intervals of 0 - 3 months, 3 - 6 months, and 6 - 12 months. Finally, we present a computational method for serological reconstruction of past SARS-CoV-2 transmission using the data from this test when applied to samples from a single cross-sectional sero-prevalence survey.


title: A study of sociodemographic and clinical profiles of HIV-1 infected North Indian patients

abstract: The aim of this study was to analyze the sociodemographic, clinical, immunologic, and risk factors of drug-resistant (>1000 copies/ml) and virologically suppressed (<1000 to <40 copies /ml to target not detected levels) patients at the ART center, Sarojini Naidu Medical College, Agra, North India. A total of 193 patients on first-line antiretroviral therapy were included those were recruited from December 2009 to November 2016. The patients included in this study had a CD4 cell count of [≤] 350 cubic/mm. The details of Demographic, clinical, and social factors were collected in a patient information leaflet and statistically analyzed. After viral load, two groups of patients were observed. The drug-resistant group (N=58) had a viral load [≥]1000 copies/ml and virologically suppressed group (N=135) had a viral load <1000 copies/ml to target not detected level. A comparison statement result was presented in both groups of drug-resistant and virologically suppressed patients. Males were observed in the highest frequency (42, 72.41%). The heterosexual mode of transmission was predominant (40, 68.96%, and 98,72.59%). The highest number of married couples and illiterates in the two groups. Tuberculosis was observed in the highest numbers in the two groups. The analysis of socioeconomic factors of North Indian patients will be a concern issue in the demographic profiles of HIV-1 patients. The clinical features, analysis would help clinicians in further therapy implementation, monitoring CD4 and Viral load counts of North Indian patients.

category: epidemiology


title: Genetic heterogeneity and subtypes of major depression

abstract: Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment and postpartum depression; N[~]3 000-47 000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders or traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (-0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.

category: psychiatry and clinical psychology


title: Comparative analysis of policies and programs to support families and children during COVID-19

abstract:
BackgroundPolicies and programs that promote positive social environments for young children and their families have the potential to improve early childhood development and long-term health. However, due to the community-wide public health measures implemented to reduce transmission of COVID-19, many families are experiencing health and socio-economic challenges and pre-existing supports and services may no longer be available. In this study, we compared the policies and programs countries have implemented to support maternal and child health during the first wave of COVID-19.

MethodsWe compared the policies and programs implemented to support child health and well-being during the first wave of COVID-19 in Australia, Canada, the Netherlands, Singapore, the UK, and the USA. A grey literature review was performed to identify policies, announcements, and guidelines released from governmental and public health organizations within each country related to children, parents, families, early childhood development, adverse childhood experiences, child welfare, pre-school, or daycares. We also performed a manual search of government websites. Both provincial and federal government policies were included for Canada.

ResultsThe main policies identified were focused on prenatal care, well-baby visit and immunization schedules, financial supports, domestic violence and housing, childcare supports, child protective services, and food security. All of the included countries implemented some of these policies, but there was a large variation in the number, size, and barriers to access these supports. None of the countries implemented supports in all of the potential areas identified.

ConclusionPolitical legacy and previous redistributive policies might have influenced the variation in policies and programs introduced by governments. As the COVID-19 pandemic continues, further opportunity for governments to implement supportive programs and policies for children and families exists.

category: public and global health


title: Normal Tissue Complication Probability (NTCP) prediction model for osteoradionecrosis of the mandible in head and neck cancer patients following radiotherapy: Large-scale observational cohort

abstract:
Background and purposeOsteoradionecrosis (ORN) of the mandible represents a severe, debilitating complication of radiation therapy (RT) for head and neck cancer (HNC). At present, no Normal Tissue Complication Probability (NTCP) models for risk of ORN exist. The aim of this study was to develop a multivariable clinical/dose-based NTCP model for the prediction of ORN any grade (ORNI-IV) and Grade IV (ORNIV) following radiotherapy ({+/-} chemotherapy) in HNC patients.

MethodsIncluded HNC patients were treated with (chemo-)radiotherapy between 2005 and 2015. Mandible bone radiation dose-volume parameters, and clinical variables (i.e. age, sex, tumor site, pre-RT dental extractions, chemotherapy history, post-operative RT and smoking status), were considered as potential predictors. The patient cohort was randomly divided into a training (70%) and independent test (30%) cohort. Bootstrapped forward variable selection was performed in the training cohort to select the predictors for the NTCP models. Final NTCP model(s) were validated on the holdback test subset.

ResultsOf 1259 included HNC patients, 13.7% (n=173 patients) developed any grade ORN (ORNII-IV primary endpoint) and 5% (n=65) ORNIV (secondary endpoint). All dose and volume parameters of the mandible bone were significantly associated with the development of ORN in univariable models. Multivariable analyses identified D30% and pre-RT dental extraction as independent predictors for both ORNI-IV and ORNIV best-performing NTCP models with an AUC of 0.78 (AUCvalidation=0.75) and 0.81 (AUCvalidation=0.82), respectively.

ConclusionThis study presented NTCP models - based on mandible bone D30% and pre-RT dental extraction - that predict ORNI-IV and ORNIV (i.e. needing invasive surgical intervention) following HNC radiotherapy. Our results suggest that less than 30% of the mandible should receive a dose of 35Gy or more for an ORNI-IV risk lower than 5%. These NTCP models can improve ORN prevention and management by identifying patients at risk of ORN.

category: oncology


title: North Carolina macular dystrophy: phenotypic variability and computational analysis of disease-implicated non-coding variants

abstract:
PurposeNorth Carolina macular dystrophy (NCMD) is an autosomal dominant, congenital disorder affecting the central retina. Here, we report clinical and genetic findings in three families segregating NCMD and use epigenomic datasets from human tissues to gain insights into the effect of NCMD-implicated variants.

MethodsClinical assessment and genetic testing were performed. Publicly-available transcriptomic and epigenomic datasets were analyzed and the  Activity-by-Contact (ABC) method for scoring enhancer elements and linking them to target genes was used.

ResultsA previously-described, heterozygous, non-coding variant upstream of the PRDM13 gene was detected in all six affected study participants (chr6:100,040,987G>C [GRCh37/hg19]). Inter- and intra-familial variability were observed; the visual acuity ranged from 0.0 to 1.6 LogMAR and fundoscopic findings ranged from visually insignificant, confluent, drusen-like macular deposits to coloboma-like macular lesions. Variable degrees of peripheral retinal spots (which were easily detected on widefield retinal imaging) were observed in all study subjects. Notably, a 6-year-old patient developed choroidal neovascularization and required treatment with intravitreal bevacizumab injections. Computational analysis of the five single nucleotide variants that have been implicated in NCMD revealed that these non-coding changes lie within two putative enhancer elements; these elements are predicted to interact with PRDM13 in the developing human retina. PRDM13 was found to be expressed in the fetal retina, with highest expression in the amacrine precursor cell population.

ConclusionsWe provide further evidence supporting the role of PRDM13 dysregulation in the pathogenesis of NCMD and highlight the utility of widefield retinal imaging in individuals suspected to have this condition.

category: ophthalmology


title: Diagnostic accuracy and predictive value of clinical symptoms for the diagnosis of mild COVID 19

abstract:
ObjectiveTo assess the diagnostic accuracy of clinical symptoms and their predictive values in patients with suspected mild COVID-19 and to identify target groups for self-isolation and outpatient treatment without additional testing in the primary health care system.

MethodsWe conducted an open-label prospective study in both male and female patients aged 18 to 72 years with suspected mild COVID-19 who were sequentially enrolled in the study. The clinical diagnosis was performed in accordance with the WHO recommendations based on the acute onset of such symptoms as olfactory dysfunction, hyperthermia, myalgia, nasal congestion, nasal discharge, cough, rhinolalia, sore throat, without pneumonia or hypoxia in persons in contact with a confirmed case of COVID-19. The physician assessed clinical symptoms using a 4-point scale. The patient self-assessed clinical symptoms using a ten-point visual analogue scale (VAS). All enrolled patients underwent laboratory testing to confirm the diagnosis of COVID-19.

ResultsOf the 120 patients underwent testing, the diagnosis of mild COVID-19 was confirmed in 96 patients and ruled out in 24 patients. When assessing symptoms by a physician according to the correlation analysis, hyperthermia, myalgia, nasal congestion and rhinolalia have a positive predictive value with a significance level of more than 0.6. When self-assessing symptoms by a patient, fever, myalgia and nasal congestion have a diagnostic accuracy with a significance level of more than 0.5. Nasal discharge, cough and sore throat have negative predictive values.

DiscussionThe presence of these symptoms in patients with an acute onset of the disease can help to make a clinical diagnosis of coronavirus disease and identify target groups for self-isolation and outpatient treatment without additional testing. Highly suspect asymptomatic patients are not considered as those who have possible mild COVID-19 infection.

RegistrationEthics Committee of Ivano-Frankivsk National Medical University, Protocol No. 114/20 as of 21 May 2020.

category: otolaryngology


title: Endotracheal application of ultraviolet A light in critically ill severe acute respiratory syndrome coronavirus-2 patients: A first-in-human study

abstract:
BackgroundPromising preclinical experiments show that, under specific and monitored conditions, ultraviolet-A (UVA) exposure reduces certain bacteria, fungi, and viruses including coronavirus-229E without harming mammalian columnar epithelial cells. We aimed to evaluate the safety and effects of UVA therapy administered by a novel device via endotracheal tube in critically ill subjects with SARS-CoV-2 infection.

MethodsFive newly intubated mechanically ventilated adults with SARS-CoV-2 infection, with an endotracheal tube size 7.5mm or greater, were treated with UVA for 20 minutes daily for 5 days, and followed for 30 days.

ResultsFive subjects were enrolled (mean age 56.6yrs, 3 male). At baseline, all subjects scored 9/10 on the WHO clinical severity scale (10=death) with predicted mortality ranging from 21 to 95%. Average log changes in endotracheal viral load from baseline to day 5 and day 6 were -2.41 (range -1.16 to -4.54; Friedman P=0.002) and -3.20 (range -1.20 to -6.77; Friedman P<0.001), respectively. There were no treatment-emergent adverse events. One subject died 17 days after enrollment due to intracranial hemorrhagic complications of anticoagulation while receiving extracorporeal membrane oxygenation. The remaining subjects clinically improved and scored 2, 4, 5, and 7 on the WHO scale at day 30. In these subjects, the slope of viral load reduction during UVA treatment correlated with the slope of improvement in clinical WHO severity score over time (Spearman rho=1, P<0.001).

ConclusionIn this first-in-human study, endotracheal UVA therapy under specific and monitored settings, was safe with a significant reduction in respiratory SARS-CoV-2 viral burden over the treatment period.

Trial RegistrationClinicalTrials.gov #NCT04572399.

Key MessagesO_LIWhat is the key question?
Can endotracheal narrow-band UVA therapy be a safe and effective treatment for severe SARS-CoV-2 infection?
C_LIO_LIWhat is the bottom line?
Under specific and monitored settings, endotracheal UVA light therapy may be an effective treatment for SARS-CoV-2 infection. Endotracheal UVA light therapy appears to be well tolerated in critically ill patients with SARS-CoV-2 infection.
C_LIO_LIWhy read on?
This is the fist-in-human trial of internal UVA therapy using a alternative novel approach to combat COVID-19.
C_LI


title: SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: Implications for microclot formation in COVID-19

abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to {beta} and {gamma} fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.


title: A single-center retrospective cohort study of Covid-19 medications: Remdesivir, Favipiravir, Methylprednisolone, Dexamethasone, and Interferon β1a and their combinations

abstract: Many drugs have been suggested to be used for Covid-19. A suitable and efficient choice of drug would make the course of Covid-19 easier. we have investigated the efficacy of different treatment regimen in reducing hospitalization period (HP) and mortality of 324 confirmed Covid-19 patients. Received drugs included single therapy or combinations of Methylprednisolone, Remdesivir, Favipiravir, Interferon {beta}1a, and Dexamethasone. HP and mortality were compared between different treatment groups to evaluate efficacy of each drug. HP and mortality were also calculated for patients in each treatment group based on their underlying diseases and age. we suggest that using IFN-{beta}1a, RDV and corticosteroids might not have a significant effect on the HP or mortality of the Covid-19 patients as it was thought before.


title: Covid-19 in the California State Prison System: An Observational Study of Decarceration, Ongoing Risks, and Risk Factors

abstract:
BackgroundCorrectional institutions nationwide are seeking to mitigate Covid-19-related risks.

ObjectiveTo quantify changes to Californias prison population since the pandemic began and identify risk factors for Covid-19 infection.

DesignWe described residents demographic characteristics, health status, Covid-19 risk scores, room occupancy, and labor participation. We used Cox proportional hazard models to estimate the association between rates of Covid-19 infection and room occupancy and out-of-room labor, respectively.

SettingCalifornia state prisons (March 1-October 10, 2020).

ParticipantsResidents of California state prisons.

MeasurementsChanges in the incarcerated populations size, composition, housing, and activities. For the risk factor analysis, the exposure variables were room type (cells vs dormitories) and labor participation (any room occupant participating in the prior 2 weeks) and the outcome variable was incident Covid-19 case rates.

ResultsThe incarcerated population decreased 19.1% (119,401 to 96,623) during the study period.On October 10, 2020, 11.5% of residents were aged [≥]60, 18.3% had high Covid-19 risk scores, 31.0% participated in out-of-room labor, and 14.8% lived in rooms with [≥]10 occupants. Nearly 40% of residents with high Covid-19 risk scores lived in dormitories. In 9 prisons with major outbreaks (6,928 rooms; 21,750 residents), dormitory residents had higher infection rates than cell residents (adjusted hazard ratio [AHR], 2.51 95%CI, 2.25-2.80) and residents of rooms with labor participation had higher rates than residents of other rooms (AHR, 1.56; 95%CI, 1.39-1.74).

LimitationsInability to measure density of residents living conditions or contact networks among residents and staff.

ConclusionDespite reductions in room occupancy and mixing, California prisons still house many medically vulnerable residents in risky settings. Reducing risks further requires a combination of strategies, including rehousing, decarceration, and vaccination.

Funding SourcesHorowitz Family Foundation; National Institute on Drug Abuse; National Science Foundation Graduate Research Fellowship; Open Society Foundations.


title: SARS-CoV-2-specific T Cell Memory is Sustained in COVID-19 Convalescents for 8 Months with Successful Development of Stem Cell-like Memory T Cells

abstract: Memory T cells contribute to rapid viral clearance during re-infection, but the longevity and differentiation of SARS-CoV-2-specific memory T cells remain unclear. We conducted direct ex vivo assays to evaluate SARS-CoV-2-specific CD4+ and CD8+ T cell responses in COVID-19 convalescents up to 254 days post-symptom onset (DPSO). Here, we report that memory T cell responses were maintained during the study period. In particular, we observed sustained polyfunctionality and proliferation capacity of SARS-CoV-2-specific T cells. Among SARS-CoV-2-specific CD4+ and CD8+ T cells detected by activation-induced markers, the proportion of stem cell-like memory T (TSCM) cells increased, peaking at approximately 120 DPSO. Development of TSCM cells was confirmed by SARS-CoV-2-specific MHC-I multimer staining. Considering the self-renewal capacity and multipotency of TSCM cells, our data suggest that SARS-CoV-2-specific T cells are long-lasting after recovery from COVID-19. The current study provides insight for establishing an effective vaccination program and epidemiological measurement.


title: Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England

abstract: The B.1.1.7 variant of concern (VOC) is increasing in prevalence across Europe. Accurate estimation of disease severity associated with this VOC is critical for pandemic planning. We found increased risk of death for VOC compared with non-VOC cases in England (HR: 1.67 (95% CI: 1.34 - 2.09; P<.0001). Absolute risk of death by 28-days increased with age and comorbidities. VOC has potential to spread faster with higher mortality than the pandemic to date.


title: The COVIDome Explorer Researcher Portal

abstract: COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. In order to expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients including matched analysis of the whole blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate here the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide.

category: allergy and immunology


title: Deep learning-based end-to-end automated stenosis classification and localization on catheter coronary angiography

abstract:
BackgroundAutomatic coronary angiography (CAG) assessment may help in faster screening and diagnosis of patients. Current CNN-based vessel-segmentation suffers from sampling imbalance, candidate frame selection, and overfitting; few have shown adequate performance for CAG stenosis classification. We aimed to provide an end-to-end workflow that may solve these problems.

MethodsA deep learning-based end-to-end workflow was employed as follows: 1) Candidate frame selection from CAG videograms with CNN+LSTM network, 2) Stenosis classification with Inception-v3 using 2 or 3 categories (<25%, >25%, and/or total occlusion) with and without redundancy training, and 3) Stenosis localization with two methods of class activation map (CAM) and anchor-based feature pyramid network (FPN). Overall 13744 frames from 230 studies were used for the stenosis classification training and 4-fold cross-validation for image-, artery-, and per-patient-level. For the stenosis localization training and 4-fold cross-validation, 690 images with >25% stenosis were used.

ResultsOur model achieved an accuracy of 0.85, sensitivity of 0.96, and AUC of 0.86 in per-patient level stenosis classification. Redundancy training was effective to improve classification performance. Stenosis position localization was adequate with better quantitative results in anchor-based FPN model, achieving global-sensitivity for LCA and RCA of 0.68 and 0.70 with mean square error (MSE) values of 39.3 and 37.6 pixels respectively, in the 520 x 520 pixel image.

ConclusionA fully-automatic end-to-end deep learning-based workflow that eliminates the vessel extraction and segmentation step was feasible in coronary artery stenosis classification and localization on CAG images.

Key PointsO_LIThe fully-automatic, end-to-end workflow which eliminated the vessel extraction and segmentation step for supervised-learning was feasible in the stenosis classification on CAG images, achieving an accuracy of 0.85, sensitivity of 0.96, and AUC of 0.86 in per-patient level.
C_LIO_LIThe redundancy training improved the AUC values, accuracy, F1-score, and kappa score of the stenosis classification.
C_LIO_LIStenosis position localization was assessed in two methods of CAM-based and anchor-based models, which performance was acceptable with better quantitative results in anchor-based models.
C_LI

Summary StatementA fully-automatic end-to-end deep learning-based workflow which eliminated the vessel extraction and segmentation step was feasible in the stenosis classification and localization on CAG images. The redundancy training improved the stenosis classification performance.

category: cardiovascular medicine


title: High seroprevalence of anti-SARS-CoV-2 antibodies after the first wave of the COVID-19 pandemic in a vulnerable population in Perpignan, France

abstract:
BackgroundIn March 2020, many cases of COVID-19 were reported in three socially deprived neighbourhoods of the city of Perpignan, in the south of France, where large sedentary gypsy communities live. A study to measure seroprevalence was conducted in July 2020 to assess the level of contamination in these neighbourhoods after the first wave of the pandemic, and to identify factors associated with seropositivity.

MethodsSCoPe is a cross-sectional survey conducted in selected persons aged six years old and over living in three neighbourhoods in Perpignan. Households were selected by systematic sampling and participants by random sampling. Collected blood samples were tested for SARS-CoV-2 IgG and IgM antibodies using the EIecsys(R) immunoassay to target the coronaviruss spike protein. Antibody seroprevalence was estimated from weighted data and associated factors were investigated using multivariate logistic regression.

ResultsThe seroprevalence of anti-SARS-CoV-2 antibodies was 35.4% (95% CI: 30.2-41.0). Over a fifth of seropositive individuals (21.7% ([14.1-31.8]) did not report any COVID-19 symptom. People aged 15-64 years old were at greater risk of seropositivity than those aged 65 years or over. Obesity prevalence was 40.7% (35.8-45.8) and obese people were more likely to be seropositive (aOR=2.0 [1.1-3.8]). The risk of being seropositive was higher in households with clinical COVID-19 cases (One case: aOR=2.5 [1.3-5.0]). In the neighbourhood with the highest measured seroprevalence, people living in a dwelling with 1-2 rooms had a higher risk of being seropositive than those living in a 4-room house (aOR=2.8 [1.2-6.3]). Working during the lockdown was associated with a lower risk of seropositivity (aOR=0.2 [0.03-1.0]).

ConclusionTransmission prevalence of the SARS-COV-2 virus in this vulnerable population was very high during the COVID-19 pandemics first wave. Our results highlight the need to strengthen and adapt preventive measures by taking into account all social determinants of health, especially housing conditions.


title: Serological surveys to estimate cumulative incidence of SARS-CoV-2 infection in adults (Sero-MAss study), Massachusetts, July-August 2020

abstract:
BackgroundThe SARS-CoV-2 pandemic is an unprecedented global health crisis. The state of Massachusetts was especially impacted during the initial stages; however, the extent of asymptomatic transmission remains poorly understood due to limited asymptomatic testing in the "first wave." To address this gap, a geographically representative and contact-free seroprevalence survey was conducted in July-August 2020, to estimate prior undetected SARS-CoV-2 infections.

MethodsStudents, faculty, librarians and staff members at the University of Massachusetts, Amherst without a previous COVID-19 diagnosis were invited to participate in this study along with one member of their household in June 2020. Two separate sampling frames were generated from administrative lists: all undergraduates and their household members (primary sampling group) were randomly selected with probability proportional to population size. All staff, faculty, graduate students and librarians (secondary sampling group) were selected as a simple random sample. After informed consent and a socio-behavioral survey, participants were mailed test kits and asked to return self-collected dried blood spot (DBS) samples. Samples were analyzed via ELISA for anti-SARS-CoV-2 IgG antibodies, and then IgM antibodies if IgG-positive. Seroprevalence estimates were adjusted for survey non-response. Binomial models were used to assess factors associated with seropositivity in both sample groups separately.

ResultsApproximately 27,000 persons were invited via email to assess eligibility. Of the 1,001 individuals invited to participate in the study, 762 (76%) returned blood samples for analysis. In the primary sampling group 548 returned samples, of which 230 enrolled a household member. Within the secondary sampling group of 214 individuals, 79 enrolled a household member. In the primary sample group, 36 (4.6%) had IgG antibodies detected for an estimated weighed prevalence for this population of 5.3% (95% CI: 3.5 to 8.0). In the secondary sampling group, 10 (3.4%) of 292 individuals had IgG antibodies detected for an estimated adjusted prevalence of 4.0% (95% CI: 2.2 to 7.4). No samples were IgM positive. No association was found in either sample group between seropositivity and self-reported work duties or customer-facing hours. In the primary sampling group, self-reported febrile illness since Feb 2020, male sex, and minority race (Black or American Indian/Alaskan Native) were associated with seropositivity. No factors except geographic regions within the state were associated with evidence of prior SARS-CoV-2 infection in the secondary sampling group.

InterpretationThis study provides insight into the seroprevalence of university-related populations and their household members across the state of Massachusetts during the summer of 2020 of the pandemic and helps to fill a critical gap in estimating the levels of sub-clinical and asymptomatic infection. Estimates like these can be used to calibrate models that estimate levels of population immunity over time to inform public health interventions and policy.

FundingUMass Faculty Fund (A Lover); UMass Faculty Discretionary Funds (N Reich); UMass Institute for Applied Life Science "Midigrant" (#169076; A. Lover); and D. Alfandari was supported by grants from the USPHS (R24OD021485).


title: Serological surveys to estimate cumulative incidence of SARS-CoV-2 infection in adults (Sero-MAss study), Massachusetts, July-August 2020- a mail-based cross-sectional study


title: Development and application of an evidence-based directed acyclic graph to evaluate the associations between metal mixtures and cardiometabolic outcomes

abstract:
BackgroundExposure to individual metals (and metalloids; hereafter  metals) is associated with adverse cardiometabolic outcomes. Specifying analytic models to assess relationships among metal mixtures and cardiometabolic outcomes requires evidence-based models of the (assumed) causal structures; however, such models have not been previously published.

MethodsWe conducted a systematic literature review to develop an evidence-based directed acyclic graph (DAG) identifying relationships among metals, cardiometabolic health indicators, and potential confounders. To evaluate the consistency of the DAG with data from 1797 participants in the San Luis Valley Diabetes Study (SLVDS; mean age=54 years, 53% women, 48% Hispanic), we tested conditional independence statements suggested by the DAG and by 100 DAGs with the same structure but randomly permuted nodes using linear (continuous outcomes), logistic (dichotomous outcomes), or Bayesian kernel machine regression (BKMR; statements with metal coexposures) models. Based on minimally sufficient adjustment sets identified by the DAG, we specified BKMR models assessing associations between urinary metal mixtures and cardiometabolic outcomes in the SLVDS population.

ResultsTwenty-nine articles met the inclusion criteria for the systematic review. From these articles, we developed an evidence-based DAG with 382 testable conditional independence statements (71% supported by SLVDS data). Only 3% of the DAGs with randomly permuted nodes indicated more agreement with the data than our evidence-based DAG. Applying the evidence-based DAG in a pilot analysis, we did not observe evidence for an association among metal mixtures and cardiometabolic outcomes.

ConclusionsWe developed, tested, and applied an evidence-based approach to analyze associations between metal mixtures and cardiometabolic health.

What this study addsWe conducted a systematic literature review to develop an evidence-based directed acyclic graph (DAG) of the presumed causal relationship between exposure to metal mixtures and cardiometabolic outcomes. Using real data, we evaluated the testable conditional independence statements. The evidence-based DAG outperformed 97% of DAGs with randomly permuted nodes. We applied the evidence-based DAG to select covariates for a pilot analysis. Environmental Epidemiology readers can (1) plan future research based on our systematic literature review, (2) use our process to evaluate other evidence-based DAGs, and (3) apply the evidence-based covariates sets to further explore relationships between metal mixtures and cardiometabolic health.


title: Higher COVID-19 vaccination rates are linked to decreased county-level COVID-19 incidence across USA

abstract: Real world evidence studies of mass vaccination across health systems have reaffirmed the safety1 and efficacy2,3 of the FDA-authorized mRNA vaccines for COVID-19. However, the impact of vaccination on community transmission remains to be characterized. Here, we compare the cumulative county-level vaccination rates with the corresponding COVID-19 incidence rates among 87 million individuals from 580 counties in the United States, including 12 million individuals who have received at least one vaccine dose. We find that cumulative county-level vaccination rate through March 1, 2021 is significantly associated with a concomitant decline in COVID-19 incidence (Spearman correlation {rho} = -0.22, p-value = 8.3e-8), with stronger negative correlations in the Midwestern counties ({rho} = -0.37, p-value = 1.3e-7) and Southern counties ({rho} = -0.33, p-value = 4.5e-5) studied. Additionally, all examined US regions demonstrate significant negative correlations between cumulative COVID-19 incidence rate prior to the vaccine rollout and the decline in the COVID-19 incidence rate between December 1, 2020 and March 1, 2021, with the US western region being particularly striking ({rho} = -0.66, p-value = 5.3e-37). However, the cumulative vaccination rate and cumulative incidence rate are noted to be statistically independent variables, emphasizing the need to continue the ongoing vaccination roll out at scale. Given confounders such as different coronavirus restrictions and mask mandates, varying population densities, and distinct levels of diagnostic testing and vaccine availabilities across US counties, we are advancing a public health resource to amplify transparency in vaccine efficacy monitoring (https://public.nferx.com/covid-monitor-lab/vaccinationcheck). Application of this resource highlights outliers like Dimmit county (Texas), where infection rates have increased significantly despite higher vaccination rates, ostensibly owing to amplified travel as a "vaccination hub"; as well as Henry county (Ohio) which encountered shipping delays leading to postponement of the vaccine clinics. This study underscores the importance of tying the ongoing vaccine rollout to a real-time monitor of spatio-temporal vaccine efficacy to help turn the tide of the COVID-19 pandemic.


title: Decisive Conditions for Strategic Vaccination against SARS-CoV-2

abstract: While vaccines against SARS-CoV-2 are being administered, in most countries it may still take months until their supply can meet demand. The majority of available vaccines elicits strong immune responses when administered as prime-boost regimens. Since the immunological response to the first ("prime") injection may provide already a substantial reduction in infectiousness and protection against severe disease, it may be more effective--under certain immunological and epidemiological conditions--to vaccinate as many people as possible with only one shot, instead of administering a person a second ("boost") shot. Such a vaccination campaign may help to more effectively slow down the spread of SARS-CoV-2, reduce hospitalizations, and reduce fatalities, which is our objective. Yet, the conditions which make single-dose vaccination favorable over prime-boost administrations are not well understood. By combining epidemiological modeling, random sampling techniques, and decision tree learning, we find that single-dose vaccination is robustly favored over prime-boost vaccination campaigns, even for low single-dose efficacies. For realistic scenarios and assumptions for SARS-CoV-2, recent data on new variants included, we show that the difference between prime-boost and single-shot waning rates is the only discriminative threshold, falling in the narrow range of 0.01-0.02 day-1 below which single-dose vaccination should be considered.


title: Adjusting COVID-19 seroprevalence survey results to account for test sensitivity and specificity

abstract: Population-based seroprevalence surveys can provide useful estimates of the number of individuals previously infected with SARS-CoV-2 and still susceptible as well as contribute to better estimates of the case fatality rate and other measures of COVID-19 severity. No serological test is 100% accurate, however, and the standard correction that epidemiologists use to adjust estimates relies on estimates of the test sensitivity and specificity often based on small validation studies. This paper develops a fully Bayesian approach to adjust observed prevalence estimates for sensitivity and specificity. Application to a seroprevalence survey conducted in New York State in 2020 demonstrates that this approach results in more realistic - and narrower - credible interval than the standard sensitivity analysis using confidence interval endpoints. In addition, the model permits incorporating data on the geographical distribution of reported case counts to create informative priors on the cumulative incidence to produce estimates and credible intervals for smaller geographic areas than often can be precisely estimated with seroprevalence surveys.


title: High-frequency screening combined with diagnostic testing for control of SARS-CoV-2 in high-density settings: an economic evaluation of resources allocation for public health benefit

abstract: SARS-CoV-2 spreads quickly in dense populations, with serious implications for universities, workplaces, and other settings where exposure reduction practices are difficult to implement. Rapid screening has been proposed as a tool to slow the spread of the virus; however, many commonly used diagnostic tests (e.g., RT-qPCR) are expensive, difficult to deploy (e.g., require a nasopharyngeal specimen), and have extended turn-around times. We evaluated testing regimes that combined diagnostic testing using qPCR with high-frequency screening using a novel reverse-transcription loop-mediated isothermal amplification (RT-LAMP, herein LAMP) assay. We used a compartmental susceptible-exposed-infectious-recovered (SEIR) model to simulate screening of a university population. We also developed a Shiny application to allow administrators and public health professionals to develop optimal testing strategies given site-specific assumptions about testing investment, target population, and cost. The frequency of screening, especially when pooling samples, was more important for minimizing epidemic size than test sensitivity, behavioral compliance, contact tracing capacity, and time between testing and results. Our results suggest that when testing budgets are limited, it is safer and more cost-effective to allocate the majority of funds to screening. Rapid, cost-effective, and scalable screening tests, like LAMP, should be viewed as critical components of SARS-CoV-2 testing in high-density populations.


title: Altered gene expression and PTSD symptom dimensions in World Trade Center responders

abstract:
Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD.

We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N=1,016), using case/control status as the predictor and correcting for these variables.

We identified 66 genes significantly associated with highest lifetime CAPS score (FDR-corrected p<0.05), and 31 genes associated with past-month CAPS. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our overall analysis. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were down-regulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls.

The distinction in significant genes between lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.


title: Comparing a new device to measure lung volumes with three traditional methods in individuals with different lung conditions

abstract:
BackgroundLung volumes can be measured by body plethysmography (BP), by inert gas dilution during a single-breath or multiple breaths and by radiographic methods based on chest roentgenogram or CT scanning. Our objective was to analyze the concordance between several methods including a new instrument in a variety of pulmonary conditions.

MethodsWe recruited four groups of adult volunteers at the COPD and Tobacco Clinic of a respiratory referral hospital: patients with lung bullae, with obstructive lung diseases, with restrictive lung diseases and healthy controls; all subjects underwent lung volume measurements according to ATS/ERS standards in random order with each method and then CT scanning. Differences among groups were estimated by Kruskal-Wallis tests. Concordance correlation coefficients (CCC) and Bland-Altman plots were performed.

ResultsSixty-two patients were studied including 15 with lung bullae, 14 with obstructive lung diseases, 12 with restrictive lung disease and 21 healthy subjects. Highest concordance was obtained between BP and CT scanning (CCC 0.95, mean difference -0.35 L) and the lowest, with TLC-DLCOsb (CCC 0.65, difference - 1.05 L). TLC measured by BP had a moderate concordance with Minibox (CCC=0.91, mean difference -0.19 L). Minibox, on the other hand had the lowest intratest repeatibility (2.7%) of all tested methods.

ConclusionsLung volumes measured by BP and CT had a substantial concordance in the scenario of varied pulmonary conditions including lung bullae, restrictive and obstructive diseases. The new minibox device, had low intratest variability, and was easy to perform, with a reasonable concordance with BP.

category: respiratory medicine


title: Torque teno virus load predicts allograft rejection but not viral infection after kidney transplantation

abstract:
The main challenge of immunosuppressive therapy after solid organ transplantation is to create a new immunological balance that prevents organ rejection and does not promote opportunistic infection. Torque teno virus (TTV) a ubiquitous and non-pathogenic single-stranded DNA virus has been proposed as a marker of functional immunity in immunocompromised patients. Here investigate whether TTV loads predict the risk of common viral infection and allograft rejection in kidney transplantation recipients.

In a retrospective cohort of 389 kidney transplantation recipients, individual TTV loads in were measured by qPCR in consecutive plasma samples during one year follow-up. The endpoints were allograft rejection, BK polyomavirus (BKPyV) viremia and cytomegalovirus (CMV) viremia. Repeated TTV measurements and rejection and infection survival data were analysed in a joint model.

During follow-up, TTV DNA detection in the transplant recipients increased from 85 to 100%. The median viral load increased to 107 genome copies/ml within three months after transplantation. Rejection, BKPyV viremia and CMV viremia occurred in 23%, 27% and 17% of the patients, respectively. With every 10-fold TTV load-increase, the risk of rejection decreased considerably (HR: 0.74, CI 95%: 0.71-0.76), while the risk of BKPyV and CMV viremia remained the same (HR: 1.03, CI 95%: 1.03-1.04 and HR: 1.01, CI 95%: 1.01-1.01).

In conclusion, TTV load kinetics predict allograft rejection in kidney transplantation recipients, but not the BKPyV and CMV infection. The potential use of TTV load levels as a guide for optimal immunosuppressive drug dosage to prevent allograft rejection deserves further validation.

category: transplantation


title: Using Project-based Learning to Enhance Curricular Integration and Relevance of Basic Medical Sciences in Pre-clerkship Years

abstract:
IntroductionIntegration levels vary in the basic medical pre-clerkship years. We aimed to discover the deficiencies and increase the level of integration for the multidisciplinary curriculum of the 1st 2 academic years at The Faculty of Medicine, Helwan University. We used Project-based learning (PtBL) via designing "Clinically-applied team-based integrated research project" tasks. The purpose was to make students fully appreciate the relationship between basic disciplines and their relevance to practice hence boosts their learning.

MethodsWe designed interdisciplinary integrated research project tasks (cases/symptoms/signs) that followed each modules objectives. Students worked in teams to write and deliver project reports. They analyzed the assigned tasks and used reasoning to create diagnoses, relate the condition to the disrupted normal structure/functions, suggest/contraindicate specific treatment plans, and create preventive plans based on their understanding of the basic medical sciences. A survey was introduced to assess students perceptions of the learning approach used. Students responses were analyzed.

ResultsDeficient-, unrelated-, & should be related in an interdisciplinary way-topics in the curriculum were discovered and reported during the projects design. Students (n=694) completed the survey (52% response rate). Most (84.6%) were satisfied by the integrated interdisciplinary project, and 57.9% preferred substituting the traditional lectures completely by integrated PtBL. Students significantly (P=0.000) understood the relation between objectives of disciplines after project completion (mean 3.66, SD {+/-}0.92) than before it (mean 3.46, SD {+/-}0.91). A significant relation was detected between the rank given to the perceived degree of the integration between basic to clinical sciences in the projects and both the rank perceived for students developed clinical reasoning (P=0.000) and the students choice of implementing future learning via the integrated project tasks (P=0.002).

ConclusionsThe PtBL can be used as a complementary learning method to elevate the level of integration within a multidisciplinary approach to boost students learning.

category: medical education


title: Early and long-term risk of new-onset atrial fibrillation after transient ischemic attack

abstract:
BackgroundTransient ischemic attack (TIA) provides a unique opportunity to optimize secondary preventive treatments to avoid subsequent ischemic stroke (IS). Although atrial fibrillation (AF) is the leading cause of cardioembolism in IS and anticoagulation prevents stroke recurrence (SR), limited data exists about the risk of new-onset AF after TIA.

MethodsWe carried out a prospective cohort study of consecutive patients with TIA from January 2006 to June 2010. The risk of new diagnosis of AF and SR was defined after a median follow-up time of 6.5 (5.0-9.6) years. In a subgroup of consecutive patients, a panel of biomarkers was assessed during the first 24 h of the onset of symptoms.

Results723 TIA patients were included. New-onset AF was diagnosed in 116 (16.0%) patients, 42 (36.2%) of them during admission. 204 (28.2%) patients were included in the biomarker substudy. New-onset AF was associated with sex (female) (hazard ratio [HR] 1.61 [95% CI, 1.07-2.41]), age (HR 1.05 [95% CI, 1.03-1.07]), previous ischemic heart disease (HR 1.84 [95% CI 1.15-2.97]) and cortical DWI pattern (HR 2.81 [95% CI 1.87-4.21]). In the Kaplan-Meier analysis, NT-proBNP [≥]218.2 pg/ml (log-rank test P<0.001) was associated with significant risk of new-onset AF during the first five years of follow-up. Patients with a new diagnosis of AF after admission and before five years of follow-up had the highest risk of SR (P=0.002).

ConclusionThe risk of new diagnosis of AF after TIA is clinically relevant. We identified clinical, neuroimaging and biomarker predictors of new-onset AF.

category: neurology


title: Non-uniform UV-C dose across N95 facepieces can cause 2.9-log variation in SARS-CoV-2 inactivation

abstract: During public health crises like the COVID-19 pandemic, ultraviolet-C (UV-C) decontamination of N95 respirators for emergency reuse has been implemented to mitigate shortages. However, decontamination efficacy across N95s is poorly understood, due to the dependence on received UV-C dose, which varies across the complex three-dimensional N95 shape. Robust quantification of UV-C dose across N95 facepieces presents challenges, as few UV-C measurement tools have sufficient 1) small, flexible form factor, and 2) angular response. To address this gap, we combine optical modeling and quantitative photochromic indicator (PCI) dosimetry with viral inactivation assays to generate high-resolution maps of "on-N95" UV-C dose and concomitant SARS-CoV-2 viral inactivation across N95 facepieces within a commercial decontamination chamber. Using modeling to rapidly identify on-N95 locations of interest, in-situ measurements report a 17.4 {+/-} 5.0-fold dose difference across N95 facepieces in the chamber, yielding 2.9 {+/-} 0.2-log variation in SARS-CoV-2 inactivation. UV-C dose at several on-N95 locations was lower than the lowest-dose locations on the chamber floor, highlighting the importance of on-N95 dose validation. Overall, we couple optical simulation with in-situ PCI dosimetry to relate UV-C dose and viral inactivation at specific on-N95 locations, informing the design of safe and effective decontamination protocols.

category: occupational and environmental health


title: Robust methylation-based classification of brain tumors using nanopore sequencing

abstract: DNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumors. In fact, DNA methylation profiling of human brain tumors already profoundly impacts clinical neuro-oncology. However, current implementations using hybridization microarrays are time-consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification using random forests complemented by a medium-resolution copy number profile derived from the same raw data. Here, we demonstrate that this approach allows to discriminate a wide spectrum of primary brain tumors using public reference data of 82 distinct tumor entities. We developed a pseudo-probability score as a confidence score for interpretation in a clinical context. Using bootstrap sampling in a discovery cohort of N = 56 cases, we find that a minimum set of 1,000 random CpG features is sufficient for high-confidence classification by ad hoc random forests for most cases and demonstrate robustness across laboratories with matching results in 13/13 cases. When applying the confidence score threshold to an independent validation series (N = 111), the method demonstrated 100% specificity for the remaining 93 cases. In a prospective benchmarking (N = 15), median time to results was 21.1 hours. In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumors. The integrated confidence score facilitates possible clinical implementation, while requiring further prospective evaluation.


title: A distinct cognitive profile in individuals with 3q29 deletion syndrome

abstract:
Background3q29 deletion syndrome is associated with mild to moderate intellectual disability. However, a detailed understanding of the deletions impact on cognitive ability is lacking. The goal of this study was to address this knowledge gap. A second goal was to ask whether the cognitive impact of the deletion predicted psychopathology in other domains.

MethodsWe systematically evaluated cognitive ability, adaptive behavior, and psychopathology in 32 individuals with the canonical 3q29 deletion using gold-standard instruments and a standardized phenotyping protocol.

ResultsMean FSIQ was 73 (range 40-99). Verbal subtest score (mean 80, range 31-106) was slightly higher and had a greater range than nonverbal subtest score (mean 75, range 53-98). Spatial ability was evaluated in a subset (n = 24) and was lower than verbal and nonverbal ability (mean 71, range 34-108). There was an average 14-point difference between verbal and nonverbal subset scores; 60% of the time the verbal subset score was higher than the nonverbal subset score. Study subjects with a verbal ability subtest score lower than the nonverbal subtest score were 4 times more likely to have a diagnosis of intellectual disability (suggestive, p-value 0.07). The age at which a child first spoke two-word phrases was strongly associated with measures of verbal ability (p-value 2.56e-07). Cognitive ability was correlated with adaptive behavior measures (correlation 0.42, p-value 0.02). However, though group means found equivalent score, there was, on average, a 10-point gap between these skills (range -33 to 33), in either direction, in about 50% of the sample suggesting that suggesting that cognitive measures only partially inform adaptive ability. Cognitive ability scores did not have any significant relationship to cumulative burden of psychopathology nor to individual neurodevelopmental or psychiatric diagnoses.

ConclusionsIndividuals with 3q29 deletion syndrome have a complex pattern of cognitive disability. Two-thirds of individuals with the deletion will exhibit significant strength in verbal ability; this may mask deficits in non-verbal reasoning, leading to an over-estimation of overall ability. Deficits in verbal ability may be the driver of intellectual disability diagnosis. Cognitive ability is not a strong indicator of other neurodevelopmental or psychiatric impairment; thus individuals with 3q29 deletion syndrome who exhibit IQ scores within the normal range should receive all recommended behavioral evaluations.


title: A Rapid Method to Evaluate Pre-Travel Testing Programs for COVID-19: A Study in Hawaii

abstract:
BackgroundPre-travel testing programs are being implemented around the world to curb COVID-19 and its variants from incoming travelers. A common approach is a single pre-travel test, 72 hours before departure, such as in Hawaii; however this raises concerns for those who are incubating or those infected after pre-travel testing or during transit. We need a rapid method to assess the effectiveness of pre-travel testing programs, and we use Hawaii as our case study.

MethodsWe invited travelers departing from Kahului main airport at the end of their visit to Maui (major tourist destination among the Hawaiian islands) and performed COVID-19 PCR testing. Eligible participants needed a negative pre-travel test and a Hawaiian stay [≤] 14 days. We designed for anonymous testing at the end of travel so that travel plans would be unaffected, and we aimed for [≥] 70% study participation.

ResultsAmong consecutive eligible travelers, 282 consented and 111 declined to participate, leading to a 72% (67-76%, 95% confidence interval) participation rate. Among 281 tested participants, two were positive with COVID-19, with an estimated positivity rate of 7 cases per 1,000 travelers. The top states of residence are California (58%) and Washington (21%). The mean length of stay was 7.7 {+/-} 0.2 days. Regarding pre-travel testing, 87% had non-nasopharyngeal tests and 66% had self-administered tests.

ConclusionsThis positivity rate leads to an estimated 17-30 infected travelers arriving daily to Maui in November-December 2020, and an estimated 52-70 infected travelers arriving daily to Hawaii during the same period. These counts surpass the Maui District Health Offices projected ability to accommodate 10 infected visitors daily in Maui; therefore, an additional mitigation layer for travelers is recommended. This rapid field study can be replicated widely in airports to assess effectiveness of pre-travel programs and can be expanded to evaluate COVID-19 importation and its variants.


title: Meta-Analysis of the Dynamics of the Emergence of Mutations and Variants of SARS-CoV-2

abstract:
The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged in late December 2019 in Wuhan, China, and is the causative agent for the worldwide COVID-19 pandemic. SARS-CoV-2 is a 29,811 nucleotides positive-sense single-stranded RNA virus belonging to the betacoronavirus genus. Due to inefficient proofreading ability of the viral RNA-dependent polymerase complex, coronaviruses are known to acquire new mutations following replication, which constitutes one of the main factors driving the evolution of its genome and the emergence of new genetic variants. In the last few months, the identification of new B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil) variants of concern (VOC) highlighted the importance of tracking the emergence of mutations in the SARS-CoV-2 genome and their impact on transmissibility, infectivity, and neutralizing antibody escape capabilities. These VOC demonstrate increased transmissibility and antibody escape, and reduce current vaccine efficacy. Here we analyzed the appearance and prevalence trajectory of mutations that appeared in all SARS-CoV-2 genes from December 2019 to January 2021. Our goals were to identify which modifications are the most frequent, study the dynamics of their spread, their incorporation into the consensus sequence, and their impact on virus biology. We also analyzed the structural properties of the spike glycoprotein of the B.1.1.7, B.1.351 and P.1 variants. This study offers an integrative view of the emergence, disappearance, and consensus sequence integration of successful mutations that constitute new SARS-CoV-2 variants and their impact on neutralizing antibody therapeutics and vaccines.

IMPORTANCESARS-CoV-2 is the etiological agent of COVID-19, which has caused > 2 million deaths worldwide as of January, 2021. Mutations occur in the genome of SARS-CoV-2 during viral replication and affect viral infectivity, transmissibility and virulence. In early March 2020, the D614G mutation in the spike protein emerged, which increased the viral transmissibility and is now found in >90% of all SARS-CoV-2 genomic sequences in GISAID database. Between October and December 2020, B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil) variants of concern (VOCs) emerged, which have increased neutralizing antibody escape capabilities because of mutations in the receptor binding domain of the spike protein. Characterizing mutations in these variants is crucial because of their effect on adaptive immune response, neutralizing antibody therapy, and their impact on vaccine efficacy. Here we tracked and analyzed mutations in SARS-CoV-2 genes over a twelve-month period and investigated functional alterations in the spike of VOCs.


title: Meta-Analysis and Structural Dynamics of the Emergence of Genetic Variants of SARS-CoV-2


title: Secondary attack rates of COVID-19 in Norwegian families: A nation-wide register-based study

abstract:
BackgroundReported transmission rates of SARS-CoV-2 within families vary widely, and there are few reports on transmission from children to other family members. More knowledge is needed to guide infection control measures.

ObjectiveTo characterize the family index case for detected SARS-CoV-2 and describe testing and secondary attack rates in the family.

DesignRegister-based cohort study.

SettingIndividual-level administrative data of all families and all PCR tests for SARS-CoV-2 in Norway in 2020.

ParticipantsAll families with at least one parent and one child below the age of 20, who lived at the same address (N=662 582), where at least one member tested positive for SARS-CoV-2 in 2020.

Main outcome measuresSecondary attack rates (SAR7) were defined as the share of non-index family members with a positive PCR test within seven days of the index case. SARs were calculated separately for parent- and child-index cases, and for parent- and child-secondary cases.

ResultsWe identified 7548 index cases, comprising 26 991 individuals, of which 12184 were parents and 14808 children. The index was a parent in 66% of the cases. Among the children, 42% of the index cases were in the age group 17-20 and only 8% 0-6 years. When the index was a parent, SAR7 was 24% (95%CI 24 to 25), whilst SAR7 was 14% (95%CI 13 to 15) when the index was a child. However, SAR7 was 24% (95%CI 20 to 28) when the index was a child aged 0-6 years and declined steeply with increasing age of the index child. SAR7 from index parent to other parents was 35% (95%CI 33 to 36), and from index child to other children 12% (95%CI 11 to 13). SAR7 from index child aged 0-6 to parents was 27% (95%CI 22 to 33). The percent of non-index family members tested within 7 days after the index case, increased from about 20% in April to 80% in December, however, SAR7 stabilized at about 20% from May.

ConclusionParents and older children are most often index cases for SARS-CoV-2 in families in Norway, while parents and young children more often transmit the virus within the families. This study suggests that whilst the absolute infection numbers are low for young children because of their low introduction rate, when infected, young children and parents transmit the virus to the same extent within the family.

O_TBL View this table:
org.highwire.dtl.DTLVardef@92d4f4org.highwire.dtl.DTLVardef@1daf608org.highwire.dtl.DTLVardef@4eb655org.highwire.dtl.DTLVardef@1a488a8org.highwire.dtl.DTLVardef@107f464_HPS_FORMAT_FIGEXP  M_TBL C_TBL


title: Dissecting Disease Tolerance in Plasmodium vivax Malaria Using the Systemic Degree of Inflammatory Perturbation

abstract:
Homeostatic perturbation caused by infection fosters two major defense stratagems, resistance and tolerance, which promote the hosts survival. Resistance relates to the ability of the host to restrict the pathogen load. Tolerance minimizes collateral tissue damage without directly affecting pathogen fitness. These concepts have been explored mechanistically in murine models of malaria but only superficially in human disease. Indeed, individuals infected with Plasmodium vivax may present with asymptomatic malaria, only mild symptoms, or be severely ill. We and others have reported a diverse repertoire of immunopathological events that potentially underly susceptibility to disease severity in vivax malaria. Nevertheless, the combined epidemiologic, clinical, parasitological, and immunologic features associated with defining the disease outcomes are still not fully understood. In the present study, we perform an extensive outlining of cytokines and inflammatory proteins in plasma samples from a cohort of individuals from the Brazilian Amazon infected with P. vivax and presenting with asymptomatic (n=108) or symptomatic (n=134) disease (106 with mild presentation and 28 with severe malaria), as well as from uninfected endemic controls (n=128) to elucidate these gaps further. We employ highly multidimensional Systems Immunology analyses using the molecular degree of perturbation to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity as well as with other clinical and epidemiologic characteristics. The findings mapped the relationships between the systemic degree of inflammatory perturbation and parasitemia values to define the disease tolerance in vivax malaria.

Author SummaryPlasmodium vivax infection can result in a broad spectrum of disease manifestations, ranging from asymptomatic malaria to severe life-threatening disease. Despite significant advances in the current understanding of the critical factors associated with the disease outcomes in vivax malaria, the immunopathological events responsible for the diversity of severe manifestations in the disease remain deeply unknown. Here, a large panel of cytokines/chemokines were assessed in plasma samples from a Brazilian cohort of P. vivax patients presenting with asymptomatic infection or symptomatic malaria at the time of diagnosis, as well as from uninfected endemic controls, to define the relationships between systemic inflammation, disease presentation, parasitemia, and epidemiologic characteristics. In-depth analyses using the molecular degree of perturbation were employed to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity. Moreover, the discoveries diagrammed the occurrence of disease tolerance by narrowing down the interactions between the systemic degree of inflammatory perturbation and parasitemia values in vivax malaria patients.