title: Informing patients that they are at high risk for serious complications of viral infection increases vaccination rates

abstract: For many vaccine-preventable diseases like influenza, vaccination rates are lower than optimal to achieve community protection. Those at high risk for infection and serious complications are especially advised to be vaccinated to protect themselves. Using influenza as a model, we studied one method of increasing vaccine uptake: informing high-risk patients, identified by a machine learning model, about their risk status. Patients (N=39,717) were evenly randomized to (1) a control condition (exposure only to standard direct mail or patient portal vaccine promotion efforts) or to be told via direct mail, patient portal, and/or SMS that they were (2) at high risk for influenza and its complications if not vaccinated; (3) at high risk according to a review of their medical records; or (4) at high risk according to a computer algorithm analysis of their medical records. Patients in the three treatment conditions were 5.7% more likely to get vaccinated during the 112 days post-intervention (p < .001), and did so 1.4 days earlier (p < .001), on average, than those in the control group. There were no significant differences among risk messages, suggesting that patients are neither especially averse to nor uniquely appreciative of learning their records had been reviewed or that computer algorithms were involved. Similar approaches should be considered for COVID-19 vaccination campaigns.


title: Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

abstract: Neutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap/NET-derived histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the FDA-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.

category: hematology


title: Community Led Testing among People Who Inject Drugs: A community centered model to find new cases of HIV and Hepatitis C in Nepal

abstract:
BackgroundPeople Who Inject Drugs (PWIDs) have sub-optimal HIV and HCV testing as the available testing services are inadequate in low and middle-income countries. We examined a model of Community-Led Testing (CLT) in Nepal, exploring the feasibility of HIV and HCV testing by trained lay service providers who had similar backgrounds to those of PWIDs. We also assessed the prevalence of HIV and HCV within this study population and the associated risk factors among PWIDs.

MethodsA mix-method cross-sectional study was conducted among 1029 PWIDs in five major districts of Nepal from July 2019 to February 2020. Trained PWID peers performed the screening for HIV and HCV using Rapid Diagnostic Test (RDT) kits. Acceptability and feasibility of the testing was assessed. The participants sociodemographic characteristics and injecting and non-injecting risk characteristics were determined. The association of risk and prevention characteristics with testing results were assessed using multiple logistic regression.

ResultsPWIDs shared that the test providers were friendly and competent in counseling and testing. Of total PWIDs (n=1,029), 20.6% were HCV-positive and 0.2% were HIV-positive. HCV positivity was associated with needle sharing (AOR: 1.83, 95% CI: 1.27,2.64; p=0.001) and reuse of syringe/needle (AOR: 2.26; 95% CI: 1.34, 3.79; p=0.002). In addition, PWIDs were more likely to be HCV-positive who started opioid substitution therapy (OST) (AOR: 1.88, 95% CI: 1.26, 2.80, p=0.002) and attended the rehabilitation center (AOR: 1.66, 95% CI: 1.10, 2.53, p=0.017).

ConclusionsThis CLT model was found to be a novel approach of testing of HIV and HCV which was acceptable to PWIDs in Nepal and showed the high prevalence of HCV and its association with injecting-related risk behaviors and being users of OST and rehabilitation. The findings highlight the need of community-led testing in hotspots, OST settings, and rehabilitation centers to screen new HIV and HCV infections.

category: hiv aids


title: Seven-month kinetics of SARS-CoV-2 antibodies and protective role of pre-existing antibodies to seasonal human coronaviruses on COVID-19

abstract: Unraveling the long-term kinetics of antibodies to SARS-CoV-2 and its determinants, including the impact of pre-existing antibodies to human coronaviruses causing common cold (HCoVs), is essential to understand protective immunity to COVID-19 and devise effective surveillance strategies. IgM, IgA and IgG levels against six SARS-CoV-2 and four HCoV antigens were quantified by Luminex, and antibody neutralization capacity was assessed by flow cytometry, in a cohort of health care workers followed-up for 6 months. Seroprevalence increased over time from 13.5% (month 0) and 15.6% (month 1) to 16.4% (month 6). Levels of antibodies, including those with neutralizing capacity, were stable over time, except IgG to nucleocapsid antigen and IgM levels that waned. After the peak response, anti-spike antibody levels increased from [~]150 days post-symptom onset in all individuals (73% for IgG), in the absence of any evidence of re-exposure. Pre-existing antibodies to alpha-HCoV were lower in individuals who subsequently seroconverted for SARS-CoV-2. IgG and IgA to HCoV were significantly higher in asymptomatic than symptomatic seropositive individuals. Thus, pre-existing cross-reactive HCoVs antibodies could have a protective effect against SARS-CoV-2 infection and COVID-19 disease.

category: infectious diseases


title: Risk of plague transmission from human cadavers: a systematic review

abstract:
Plague can be fatal. Ebola has raised concern of the risk of infection from bodies of people that have died from other dangerous infectious diseases. We sought to estimate the risk of human remains from someone who was infected with plague transmitting Yersinia pestis. With no clear direct evidence, we developed a causal chain and carefully searched and assessed the literature at each step: we assessed the infectiousness of body fluids of people ill with plague; we sought for reported infection acquired from human and animal cadavers; and examined evidence of body fluid infectiousness of cadavers, seeking any information about the length of infectiousness. We concluded that pneumonic plague can occur after intense manipulation of the cadaver, presumably from inhalation of respiratory droplets; and that bubonic plague can occur after contact with infected blood in people with skin cuts or abrasions. Establishing a quantitative measure of risk was not possible from the evidence available.

Author summaryPlague is an infectious disease that is of particular concern due to its high risk for human outbreaks. Understanding the level and duration of infectiousness of the body of someone who was infected with plague is essential to establish adequate preventive measures while handling corpses. We found limited evidence that human cadavers who have died from plague remain infectious, both from inhalation of particles generated by handling and by direct skin contact.


title: COVID-19 Spreading dynamics in an age-structured population with selective relaxation of restrictions for vaccinated individuals : a mathematical modeling study

abstract:
BackgroundCOVID-19 vaccination of healthcare and other essential workers is underway in many countries while immunization of the general public is expected to begin in the next several weeks. We consider the question of whether people who have received the vaccine can be selectively and immediately permitted to return to normal activities.

MethodsWe use a delay differential equation model to calculate the effects of vaccinee "immunity passports" on the epidemic spreading trajectories. The model incorporates age-structuring to account for children who are ineligible for vaccination, and senior citizens who are especially vulnerable to the disease. We consider consensus strains of virus as well as high-transmissibility variants such as B1.1.7 and B1.351 in our analysis.

ResultsWe find that with high vaccine efficacy of 80 percent or greater, unrestricted vaccinee--vaccinee interactions do not derail the epidemic from a path towards elimination. Vaccinee--non-vaccinee interactions should however be treated with far more caution. At current vaccine administration rates, it may be the better part of a year before COVID-19 transmission is significantly reduced or ceased. With lower vaccine efficacy of approximately 60 percent, restrictions for vaccinees may need to remain in place until the elimination of the disease is achieved. In all cases, the death tolls can be reduced by vaccinating the vulnerable population first.

ConclusionsDesigning high-efficacy vaccines with easily scalable manufacturing and distribution capacity should remain on the priority list in academic as well as industrial circles. Performance of all vaccines should continue to be monitored in real time during vaccination drives with a view to analysing socio-demographic determinants of efficacy, if any, and optimizing distribution accordingly. A speedy and efficacious vaccination drive augmented with selective relaxations for vaccinees will provide the smoothest path out of the pandemic with the least additional caseloads, death tolls and socio-economic cost.


title: Antibiotics and hospital-associated Clostridioides difficile infection: systematic review and meta-analysis 2020 update.

abstract:
BackgroundClostridioides difficile infection (CDI) is the most common cause of healthcare facility-associated (HCFA) infectious diarrhoea in high-income countries. Antibiotic use is the most important modifiable risk factor for CDI. The most recent systematic review covered studies published until 31st December 2012.

ObjectivesTo update the evidence for epidemiological associations between specific antibiotic classes and HCFA-CDI for the period 1st January 2013 to 31st December 2020.

Data sourcesPubMed, Scopus, Web of Science Core Collection, WorldCat, and Proquest Dissertations and Theses.

Study eligibility criteria, participants and exposuresEligible studies were those conducted among adult hospital inpatients, measured exposure to individual antibiotics or antibiotic classes, included a comparison group, and measured the occurrence of HCFA-CDI as an outcome.

Study appraisal and synthesis methodsThe Newcastle-Ottawa Scale for the Assessment of Quality was used to appraise study quality. To assess the association between each antibiotic class and HA-CDI, a pooled random effects meta-analysis was undertaken. Metaregression and sub-group analysis was used to investigate study characteristics identified a priori as potential sources of heterogeneity.

ResultsCarbapenems, and 3rd and 4th generation cephalosporin antibiotics remain most strongly associated with HCFA-CDI, with cases more than twice as likely to have recent exposure to these antibiotics prior to developing CDI. Modest associations were observed for fluoroquinolones clindamycin, and beta-lactamase inhibitor combination penicillin antibiotics.

LimitationsIndividual study effect sizes were variable and heterogeneity was observed for most antibiotic classes. Availability of a single reviewer to select, extract and critically appraise the studies.

ConclusionsThis review provides the most up to date synthesis of evidence in relation to the risk of HCFA-CDI associated with exposure to specific antibiotic classes. Studies were predominantly conducted in North America or Europe and more studies outside of these settings are needed.

Registration numberProspero CRD42020181817


title: Group IIA Secreted Phospholipase A2 Plays a Central Role in the Pathobiology of COVID-19

abstract: There is an urgent need to identify cellular and molecular mechanisms responsible for severe COVID-19 disease accompanied by multiple organ failure and high mortality rates. Here, we performed untargeted/targeted lipidomics and focused biochemistry on 127 patient plasma samples, and showed high levels of circulating, enzymatically active secreted phospholipase A2 Group IIA (sPLA2-IIA) in severe and fatal COVID-19 disease compared with uninfected patients or mild illness. Machine learning demonstrated that sPLA2-IIA effectively stratifies severe from fatal COVID-19 disease. We further introduce a PLA-BUN index that combines sPLA2-IIA and blood urea nitrogen (BUN) threshold levels as a critical risk factor for mitochondrial dysfunction, sustained inflammatory injury and lethal COVID-19. With the availability of clinically tested inhibitors of sPLA2-IIA, our study opens the door to a precision intervention using indices discovered here to reduce COVID-19 mortality.


title: Evolutionary trajectories and transmission dynamics of multidrug-resistant Mycobacterium tuberculosis in Tibet, China

abstract:
ObjectiveTibet has the highest prevalence of both tuberculosis disease and multidrug-resistant tuberculosis (MDR-TB) in China. The circulated Mycobacterium tuberculosis strains from Tibet were sequenced to investigate the underlying drivers for the high burden of MDR-TB.

MethodsUsing whole-genome sequencing data of 576 M. tuberculosis strains isolated from consecutive patients in Tibet, we mapped resistance-conferring mutations onto phylogenetic trees to determine their evolution and spread. The impact of drug resistance on bacterial population growth was assessed with a Bayesian (Skyline Plot) analysis. Multivariable logistic regression was used to identify risk factors for the development of rifampicin resistance.

ResultsOf the 576 isolates, 284 (49.3%), 280 (48.6%), and 236 (41.0%) were, respectively, genetically resistant to isoniazid, rifampicin, or both (MDR-TB). Among the isoniazid- and rifampicin-resistant strains, the proportions in phylogenetically-inferred clusters were 77.8% (221/284) and 62.1% (174/280), respectively. Nearly half (47.2%, 134/284) of the isoniazid-resistant strains were in six major clades, which contained between 8 and 58 strains with katG S315T, katG S315N, or fabG1 promoter -15 C>T resistance mutations. These major clades exponentially expanded after emerging with isoniazid resistance and stabilized before evolving into MDR-TB twenty years later. Isoniazid-resistant isolates showed an increased risk of accumulating rifampicin resistance compared to isoniazid-susceptible strains, with an adjusted odds ratio of 3.81 (95% confidence interval 2.47-5.95).

ConclusionHistorical expansion of isoniazid-resistant strains and their increased likelihood of acquiring rifampicin resistance both contributed to the high burden of MDR-TB in Tibet, highlighting the need to detect INH-resistant strains promptly and to control their transmission.


title: The spatio-temporal distribution of COVID-19 infection in England between January and June 2020.

abstract:
The spatio-temporal dynamics of an outbreak provide important insights to help direct public health resources intended to control transmission. They also provide a focus for detailed epidemiological studies and allow the timing and impact of interventions to be assessed.

A common approach is to aggregate case data to administrative regions. Whilst providing a good visual impression of change over space, this method masks spatial variation and assumes that disease risk is constant across space. Risk factors for COVID-19 (e.g. population density, deprivation and ethnicity) vary from place to place across England so it follows that risk will also vary spatially. Kernel density estimation compares the spatial distribution of cases relative to the underlying population, unfettered by arbitrary geographical boundaries, to produce a continuous estimate of spatially varying risk.

Using test results from healthcare settings in England (Pillar 1 of the UK Government testing strategy) and freely available methods and software, we estimated the spatial and spatio-temporal risk of COVID-19 infection across England for the first six months of 2020. Widespread transmission was underway when partial lockdown measures were introduced on the 23rd March 2020 and the greatest risk erred towards large urban areas. The rapid growth phase of the outbreak coincided with multiple introductions to England from the European mainland. The spatio-temporal risk was highly labile throughout.

In terms of controlling transmission, the most important practical application is the accurate identification of areas within regions that may require tailored intervention strategies. We recommend that this approach is absorbed into routine surveillance outputs in England. Further risk characterisation using widespread community testing (Pillar 2) data is needed as is the increased use of predictive spatial models at fine spatial scales.


title: Nosocomial outbreak of SARS-CoV-2 in a 'non-COVID-19' hospital ward: virus genome sequencing as a key tool to understand cryptic transmission

abstract:
BackgroundDissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in healthcare institutions affects both patients and health-care workers (HCW), as well as the institutional capacity to provide essential health services.

MethodsWe conducted an investigation of a cluster of SARS-CoV-2 positive cases detected in a "non-COVID-19" hospital ward during Summer 2020. The magnitude of the nosocomial outbreak was disclosed by massive testing, challenging the retrospective reconstruction of the introduction and transmission events. An in-depth contact tracing investigation was carried out to identify the contacts network during the 15-day period before the screening. In parallel, positive SARS-CoV-2 RNA samples were subjected to virus genome sequencing.

ResultsOf the 245 tested individuals, 48 (21 patients and 27 HCWs) tested positive for SARS-CoV-2. HCWs were mostly asymptomatic, but the mortality among the vulnerable patient group reached 57.1% (12/21). Phylogenetic reconstruction revealed that all cases were part of the same transmission chain, thus confirming a single origin behind this nosocomial outbreak. By combining vast epidemiological and genomic data, including analysis of emerging minor variants, we unveiled a scenario of silent SARS-CoV-2 dissemination within the hospital ward, mostly driven by the close contact within the HCWs group and between HCWs and patients. This investigation triggered enhanced prevention and control measures, leading to a more timely detection and containment of novel nosocomial outbreaks.

ConclusionsThe present study shows the benefit of combining genomic and epidemiological data for the investigation of complex nosocomial outbreaks, and provides valuable data to minimize the risk of transmission of COVID-19 in healthcare facilities.

Short summarySARS-CoV-2 nosocomial outbreaks are of utmost public health concern. Here, we performed an in-depth investigation of a high-fatality rate nosocomial outbreak by combining vast genomic and epidemiological data, providing valuable information to understand cryptic transmission of SARS-CoV-2 within healthcare institutions.


title: A Second Wave? What Do People Mean By COVID Waves?- A Working Definition of Epidemic Waves

abstract:
Policymakers and researchers describe the COVID-19 epidemics by waves without a common vocabulary on what constitutes an epidemic wave, either in terms of a working definition or operationalization, causing inconsistencies and confusions. A working definition and operationalization can be helpful to characterize and communicate about epidemics. We propose a working definition of epidemic waves in the ongoing COVID-19 pandemic and an operationalization based on the public data of the effective reproduction number R. Our operationalization characterizes the numbers and durations of waves (upward and downward) in 178 countries and reveals patterns that can enable healthcare organizations and policymakers to make better description and assessment of the COVID crisis to make more informed resource planning, mobilization, and allocation temporally in the continued COVID-19 pandemic.

One Sentence SummaryA working definition and operationalization of waves to enable common ground to understand and communicate COVID-19 crisis.


title: A Second Wave? What Do People Mean By COVID Waves? - A Working Definition of Epidemic Waves

category: public and global health


title: Beliefs associated with Intentions of Non-Physician Healthcare Workers to Receive the COVID-19 Vaccine in Ontario, Canada

abstract: Achieving herd immunity of SARS-CoV-2 through vaccines will require a concerted effort to understand and address barriers to vaccine uptake. We conducted a web-based survey of non-physician HCWs, informed by the Theoretical Domains Framework, measuring intention to vaccinate, beliefs and sources of influence relating to the COVID-19 vaccines, and sociodemographic characteristics. Vaccination non-intent was associated with beliefs that vaccination was not required because of good health, lower confidence that the COVID-19 vaccine would protect their family and patients, and that getting vaccinated was a professional responsibility. Vaccination non-intent was strongly associated with mistrust about how fast the vaccines were developed and vaccine safety concerns. Communication directed at non-physician HCWs should be tailored by ethnic subgroups and settings to increase salience. Messaging should leverage emotions (e.g., pride, hope, fear) to capture interest, while addressing safety concerns and confirming the low risk of side effects in contrast to the substantial morbidity and mortality of COVID-19. Emergent data about reduced transmission post-vaccination will be helpful.


title: Evolving Infection Paradox of SARS-CoV-2: Fitness Costs Virulence?

abstract: SARS-CoV-2 is evolved into eight fundamental clades where four (G, GH, GR, and GV) are globally prevalent in 2020. How the featured co-occurring mutations of these clades are linked with viral fitness is the main question here and we thus proposed a hypothetical model using in silico approach to explain the plausible epistatic effects of those mutations on viral replication and transmission. Molecular docking and dynamics analyses showed the higher infectiousness of a spike mutant through more favorable binding of G614 with the elastase-2. RdRp mutation p.P323L significantly increased genome-wide mutations (p<0.0001) since more flexible RdRp (mutated)-NSP8 interaction may accelerate replication. Superior RNA stability and structural variation at NSP3:C241T might impact protein and/or RNA interactions. Another silent 5UTR:C241T mutation might affect translational efficiency and viral packaging. These four G-clade-featured co-occurring mutations might increase viral replication. Sentinel GH-clade ORF3a:p.Q57H constricted ion-channel through inter-transmembrane-domain interaction of cysteine(C81)-histidine(H57) and GR-clade N:p.RG203-204KR would stabilize RNA interaction by a more flexible and hypo-phosphorylated SR-rich region. GV-clade viruses seemingly gained the evolutionary advantage of the confounding factors; nevertheless, N:p.A220V might modulate RNA binding with no phenotypic effect. Our hypothetical model needs further retrospective and prospective studies to understand detailed molecular events featuring the fitness of SARS-CoV-2.


title: Dominant Clade-featured SARS-CoV-2 Co-occurring Mutations Reveals Plausible Epistasis: An in silico based Hypothetical Model


title: CIITA G-286A promoter polymorphism impairs monocytes HLA-DR expression in septic shock and is rescued by interferon-γ

abstract:
Monocyte HLA-DR is an increasingly recognized markers of sepsis-induced immunodepression, but its regulatory mechanisms remain poorly understood in sepsis. Several evidence for positive selection on the 5 promoter region of HLA class II transactivator (CIITA) gene, the master regulator of MHC class II, have been gathered in the European population, and its role in sepsis has never been demonstrated, whilst suggested in autoimmune disease. We aim to describe the effect of rs3087456 polymorphism, localized on CIITA promoter III (pIII), on mortality of patients with septic shock, and investigate the mechanisms regulating HLA-DR expression. Genotyping of 203 patients with septic shock showed that, in A dominant model, GG genotype was associated with 28-day mortality (OR 2.29; 95%CI: 1.01 to 5.22; P = 0.043). Monocyte HLA-DR remained low in patients with GG genotype whereas it increases as early as at the end of the first week in intensive care in patients with AA or AG genotype. Using site-directed mutagenesis, in vitro reporter gene promoter activity of the pIII was decreased in GG genotype in monocyte cell line. Interferon-{gamma} (IFN-{gamma}) restored pIII activity in GG genotype as well as restore, in ex vivo experiment in healthy volunteers, CIITA pIII expression of GG genotype. Hereby, we demonstrated that rs3087456, a positively selected polymorphism of CIITA proximal promoter, significantly impact monocyte HLA-DR expression in patients with septic shock through CIITA promoter activity, that can be rescued using IFN-{gamma}, offering a new perspective in genetic susceptibility to sepsis and targeted immunomodulatory therapy.

KeypointsO_LICIITA G-286A polymorphism reduces promotor activity and significantly impact monocyte HLA-DR expression and mortality in septic shock
C_LIO_LIDownregulatory effects of CIITA G-286A polymorphism on monocyte HLA-DR expression can be reverse by IFN-{gamma} in patients with septic shock
C_LI

category: intensive care and critical care medicine


title: Widespread Cortical Thickness Reductions Following Non-medical Use of Ketamine: a Structural MRI Study of Individuals with Ketamine Dependence

abstract:
BackgroundA version of ketamine, called Esketamine has been approved for treatment-resistant depression (TRD). Ketamine ("K powder"), a "dissociative" anesthetic agent, however, has been used non-medically alone or with other illicit substances. Our previous studies showed a link between non-medical ketamine use and brain structural and functional alterations. We found dorsal prefrontal gray matter reduction in chronic ketamine users. It is unknown, however, whether these observations might parallel findings of cortical thickness alterations. This study aimed at exploring cortical thickness abnormalities following non-medical, long-term use of ketamine.

MethodsStructural brain images were acquired for 95 patients with ketamine dependence, and 169 drug-free healthy controls. FreeSurfer software was used to measure cortical thickness for 68 brain regions. Cortical thickness was compared between the two groups using analysis of covariance (ANCOVA) with covariates of age, gender, educational level, smoking, drinking, and whole brain mean cortical thickness. Results were considered significant if the Bonferroni corrected P-value < 0.01.

ResultsCompared to healthy controls, patients with ketamine dependence have widespread decreased cortical thickness, with the most extensive reductions in the frontal (including the dorsolateral prefrontal cortex, DLPFC) and parietal (including the precuneus) lobes. Increased cortical thickness was not observed in ketamine users relative to comparison subjects. Estimated total lifetime ketamine consumption is correlated with the right inferior parietal and the right rostral middle frontal cortical thickness reductions.

ConclusionsThis study provides first evidence that, compared with healthy controls, chronic ketamine users had cortical thickness reductions.

category: addiction medicine


title: Effect of antihypertensive drug treatment on long-term blood pressure reduction: An individual patient-level data meta-analysis of 352,744 Participants from 51 large-scale randomised clinical trials

abstract:
ObjectivesEvidence from randomised trials on long-term blood pressure (BP) reduction from pharmacologic treatment is limited. To investigate the effects of antihypertensive drugs on long-term BP change and examine its variation over time and among people with different clinical characteristics

DesignIndividual participant-level data meta-analysis

Setting and data sourceThe Blood Pressure Lowering Treatment Trialists Collaboration involving 51 large-scale long-term randomised clinical trials

Participants352,744 people (42% women) with mean age of 65 years and mean baseline systolic/diastolic BP of 152/87 mmHg, of whom 18% were current smokers, 50% had cardiovascular disease, 29% had diabetes, and 72% were taking antihypertensive treatment at baseline

InterventionPharmacological BP-lowering treatment

OutcomeDifference in longitudinal changes in systolic and diastolic BP between randomised treatment arms over an average follow-up of four years

ResultDrugs were effective in lowering BP, with the maximum effect becoming apparent after 12-month follow-up and with gradual attenuation towards later years. Based on measures taken [≥]12 months post-randomisation, more intense BP-lowering treatment reduced systolic/diastolic BP (95% confidence interval) by -11.2 (-11.4 to -11.0)/-5.6 (-5.8 to -5.5) mmHg than less intense treatment; active treatment by -5.1 (-5.3 to -5.0)/-2.3 (-2.4 to -2.2) mmHg lower than placebo, and active arm by -1.4 (-1.5 to -1.3)/-0.6 (-0.7 to -0.6) mmHg lower than the control arm for drug class comparison trials. BP reductions were consistently observed across a wide range of baseline BP values and ages, and by sex, history of cardiovascular disease and diabetes, and prior antihypertensive treatment use.

ConclusionPharmacological agents were effective in lowering long-term BP among individuals with a wide range of characteristics, but the net between-group reductions were modest, which is partly attributable to the intended trial goals.

category: cardiovascular medicine


title: Prediction of type 1 diabetes at birth: cord blood metabolites versus genetic risk score in the MoBa cohort.

abstract:
Background and aimGenetic markers are established as predictive of type 1 diabetes, but unknown early life environment is believed to be involved. Umbilical cord blood may reflect perinatal metabolism and exposures. We studied whether selected polar metabolites in cord blood contribute to prediction of type 1 diabetes.

MethodsUsing a targeted UHPLC-QQQ-MS platform, we quantified 27 low molecular weight metabolites (including amino acids, small organic acids and bile acids) in 166 children, who later developed type 1 diabetes, and 177 random control children in the Norwegian Mother, Father and Child (MoBa) cohort. We analysed the data using logistic regression (estimating odds ratios per standard deviation [aOR]), area under the receiver operating characteristic curve (AUC) and k-means clustering. Metabolites were compared to a genetic risk score based on 51 established non-HLA SNPs, and a four-category HLA risk group.

ResultsThe strongest associations for metabolites were aminoadipic acid (aOR=1.23,95%CI:0.97-1.55), indoxyl sulfate (aOR=1.15,95%CI:0.87-1.51), and tryptophan (aOR=0.84,95%CI:0.65-1.10), with other aORs close to 1.0, and none significantly associated with type 1 diabetes. K-means clustering identified six clusters, none of which were associated with type 1 diabetes. Cross-validated AUC showed no predictive value of metabolites (AUC 0.49), while the non-HLA genetic risk score AUC was 0.56 and the HLA risk group AUC was 0.78.

ConclusionsIn this large study, we found no support of a predictive role of cord blood concentrations of selected bile acids and other small polar metabolites in the development of type 1 diabetes.

TweetPredicting childhood type 1 diabetes with cord blood biomarkers: genetic risk score works but metabolites do not

@OsloDiabetes #T1D

category: endocrinology


title: Estimating the spreading and dominance of SARS-CoV-2 VOC 202012/01 (lineage B.1.1.7) across Europe

abstract: We develop a two strain, age-structured, compartmental model to assess the spreading potential of the B.1.1.7 variant across several European metropolitan areas and countries. The model accounts for B.1.1.7 introductions from the UK and different locations, as well as local mitigation policies in the time period 2020/09 - 2021/02. In the case of an increase of transmissibility of 50%, the B.1.1.7 variant has the potential to become dominant in all investigated areas by the end of March 2021.

category: epidemiology


title: Heterogeneity in COVID-19 severity patterns among age-gender groups: an analysis of 778 692 Mexican patients through a meta-clustering technique

abstract:
We apply a meta-clustering technique to discover age-gender unbiased COVID-19 patient subphenotypes based on phenotypical before admission, including pre-existing comorbidities, habits and demographic features, to study the potential early severity stratification capabilities of the discovered subgroups through characterizing their severity patterns including prognostic, ICU and morbimortality outcomes. We used the Mexican Government COVID-19 open data including 778,692 SARS-CoV-2 population-based patient-level data as of September 2020. The meta-clustering technique consists of a two-stage clustering approach combining dimensionality reduction and hierarchical clustering: 56 clusters from independent age-gender clustering analyses supported 11 clinically distinguishable meta-clusters (MCs). MCs 1-3 showed high recovery rates (90.27-95.22%), including healthy patients of all ages; children with comorbidities alongside priority in medical resources; and young obese smokers. MCs 4-5 showed moderate recovery rates (81.3-82.81%): patients with hypertension or diabetes of all ages; and obese patients with pneumonia, hypertension and diabetes. MCs 6-11 showed low recovery rates (53.96-66.94%): immunosuppressed patients with high comorbidity rate; CKD patients with poor survival length and recovery; elderly smokers with COPD; severe diabetic elderly with hypertension; and oldest obese smokers with COPD and mild cardiovascular disease. Group outcomes conformed to the recent literature on dedicated age-gender groups. These results can potentially help in the clinical patient understanding and their stratification towards automated early triage, prior to further tests and laboratory results are available, or help decide priority in vaccination or resource allocation among vulnerable subgroups or locations where additional tests are not available.

Code available at: https://github.com/bdslab-upv/covid19-metaclustering


title: Subphenotyping of COVID-19 patients at pre-admission towards anticipated severity stratification: an analysis of 778 692 Mexican patients through an age-gender unbiased meta-clustering technique


title: Smelling Household-Odorants Effectively Screens for COVID-19

abstract: Key to curtailing the COVID-19 pandemic are wide-scale testing strategies1,2. An ideal test is one that would not rely on transporting, distributing, and collecting physical specimens. Given the olfactory impairment associated with COVID-193-7, we developed a novel measure of olfactory perception that relies on smelling household odorants and rating them online. We tested the performance of this real-time tool in 12,020 participants from 134 countries who provided 171,500 perceptual ratings of 60 different household odorants. We observed that olfactory ratings were indicative of COVID-19 status in a country, significantly correlating with national infection rates over time. More importantly, we observed remarkable indicative power at the individual level (90% sensitivity and 80% specificity). Critically, olfactory testing remained highly effective in participants with COVID-19 but without symptoms, and in participants with symptoms but without COVID-19. In this, the current odorant-based olfactory test stands apart from symptom-checkers (including olfactory symptom-checkers)3, and even from antigen tests8, to potentially provide a first line of screening that can help halt disease progression at the population level.


title: A Novel Olfactory Self-Test Effectively Screens for COVID-19


title: Assessing the impact of SIGN 136 on opioid prescribing rates in Scotland: An interrupted time series analysis

abstract:
BackgroundOpioids can be effective analgesics, but long-term use may be associated with harms. In 2013, the first national, comprehensive, evidence-based pain management guideline was published, from the Scottish Intercollegiate Guideline Network (SIGN 136: Management of Chronic Pain) with key recommendations on analgesic prescribing. This study aimed to examine the potential impact on national opioid prescribing rates in Scotland.

MethodsTrends in national and regional community opioid prescribing data for Scotland were analysed from quarter one (Q1) 2005 to Q2 2020. Interrupted time series regression examined the association of SIGN 136 publication with prescribing rates for opioid-containing drugs. Gabapentinoid prescribing was used as an outcome control.

ResultsAfter a positive prescribing trend pre-publication, the timing of SIGN 136 publication was associated with a negative change in trend of opioid prescribing rates (-2.82 items per 1,000 population per quarter [PTPPQ]; P<0.01). By Q2 2020, the relative reduction in opioid prescribing rate was -20.67% (95% CI: -23.67, -17.77). This persisted after controlling for gabapentinoid prescribing and was mainly driven by reduction in weak opioids, whereas strong opioid prescribing rates continued to rise. Gabapentinoid prescribing showed a significant rise in level (8.00 items per 1,000 population; P=0.01) and trend (0.27 items PTPPQ; P=0.01) following SIGN 136 publication.

ConclusionsPublication of SIGN 136 was associated with a reduction in opioid prescribing rates. This suggests that changes in clinical policy through evidence-based national clinical guidelines may affect community opioid prescribing, though this may be partially replaced by gabapentinoids, and other factors may also contribute.


title: Assessing the impact of a national clinical guideline for the management of chronic pain on opioid prescribing rates: A controlled interrupted time series analysis


title: Does advance contact with research participants increase response to questionnaires: A Systematic Review and meta-Analysis

abstract:
BackgroundQuestionnaires remain one of the most common forms of data collection in epidemiology, psychology and other human-sciences. However, results can be badly affected by non-response. One way to potentially reduce non-response is by sending potential study participants advance communication. The last systematic review to examine the effect of questionnaire pre-notification on response is ten years old, and lacked a risk of bias assessment.

ObjectivesUpdate Edwards et al. (2009) to include 1) recently published studies, 2) an assessment of risk of bias.

MethodsData sources: Edwards et al. (2009); 13 data-bases; the references in, and citations of included studies. Eligibility criteria: Randomised control trials examining the impact of pre-notification on response. Data extraction: data extraction was done twice by a single unblinded reviewer. Risk of bias was assessed using the Cochrane Risk of Bias tool and funnel plots.

Results103 trials were included. Over-all pre-notification increased response, OR = 1.38 (95%CI: 1.25-1.53). However, when studies at high or unclear risk of bias were excluded the effect was greatly reduced (OR = 1.11, 95% CI: 1.01-1.21).

ConclusionsThe evidence implies that while pre-notification does increase response rates, this may not be of clinical utility.


title: REACT-1 round 9 interim report: downward trend of SARS-CoV-2 in England inFebruary 2021 but still at high prevalence

abstract:
Background and MethodsEngland entered its third national lockdown of the COVID-19 pandemic on 6th January 2021 with the aim of reducing the daily number of deaths and pressure on healthcare services. The real-time assessment of community transmission study (REACT-1) obtains throat and nose swabs from randomly selected people in England in order to describe patterns of SARS-CoV-2 prevalence. Here, we report data from round 9a of REACT-1 for swabs collected between 4th and 13th February 2021.

ResultsOut of 85,473 tested-swabs, 378 were positive. Overall weighted prevalence of infection in the community in England was 0.51%, a fall of more than two thirds since our last report (round 8) in January 2021 when 1.57% of people tested positive. We estimate a halving time of 14.6 days and a reproduction number R of 0.72, based on the difference in prevalence between the end of round 8 and the beginning of round 9. Although prevalence fell in all nine regions of England over the same period, there was greater uncertainty in the trend for North West, North East, and Yorkshire and The Humber. Prevalence fell substantially across all age groups with highest prevalence among 18- to 24-year olds at 0.89% (0.47%, 1.67%) and those aged 5 to12 years at 0.86% (0.60%, 1.24%). Large household size, living in a deprived neighbourhood, and Asian ethnicity were all associated with increased prevalence. Healthcare and care home workers were more likely to test positive compared to other workers.

ConclusionsThere is a strong decline in prevalence of SARS-CoV-2 in England among the general population five to six weeks into lockdown, but prevalence remains high: at levels similar to those observed in late September 2020. Also, the number of COVID-19 cases in hospitals is higher than at the peak of the first wave in April 2020. The effects of easing of social distancing when we transition out of lockdown need to be closely monitored to avoid a resurgence in infections and renewed pressure on health services.


title: Modeling the evolution of SARS-CoV-2 under non-pharmaceutical interventions

abstract:
Social and behavioral non-pharmaceutical interventions (NPIs), such as mask-wearing, social distancing, and travel restrictions, as well as diagnostic tests, have been broadly implemented in response to the COVID-19 pandemic. Epidemiological models and data analysis affirm that wide adoption of NPIs helps to control the pandemic. However, SARS-CoV-2 has extensively demonstrated its ability to evolve. Therefore, it is crucial to examine how NPIs may affect the evolution of the virus. Such evolution could have important effects on the spread and impact of the pandemic.

We used evo-epidemiological models to examine the effect of non-pharmaceutical interventions and testing on two evolutionary trajectories for SARS-CoV-2: attenuation and test evasion. Our results show that when stronger measures are taken, selection may act to reduce virulence. Additionally, the timely application of NPIs could significantly affect the competition between viral strains, favoring reduced virulence. Furthermore, a higher testing rate can select for a test-evasive viral strain, even if that strain is less infectious than the detectable competing strain. Importantly, if a less detectable strain evolves, epidemiological metrics such as confirmed daily cases may distort our assessment of the pandemic. Our results highlight the important implications NPIs can have on the evolution of SARS-CoV-2.


title: Analysis of opioid distribution before and after recreational marijuana legalization in California

abstract: The opioid epidemic has risen to an all-time high. Harm reduction and prevention policies have not alleviated this crisis. Recent investigations have highlighted the efficacy and safety of marijuana-based products for pain management. Providing alternative pain treatment options may help mitigate the opioid epidemic. The distribution of codeine, fentanyl, hydrocodone, morphine, and oxycodone per 100K people and by 3-digit zip codes and overdose rates from 2014 to 2018 in California, which legalized recreational marijuana in 2016, were compared to Texas, where marijuana is functionally prohibited. Drug weights were obtained from the Automation of Reports and Consolidated Orders System and converted to oral morphine milligram equivalents. Overdose data was retrieved from the Centers for Disease Controls WONDER database. California (-43.7%) and Texas (-27.3%) showed significant reductions in cumulative opioid distribution from 2014 to 2018. Opioid distribution per 100K people decreased -38.9% in California relative to -26.4% in Texas. Opioid and heroin overdoses increased between 1999 and 2019 by +11.6% in California but +272.7% in Texas. This evidence supports marijuana legalization as a mitigating factor to the opioid epidemic. Continued studies on safer pain management alternatives and policies will help identify measures that help combat the opioid epidemic.


title: Opioid distribution trends in California post recreational marijuana legalization


title: Artificial Intelligence for Advance Requesting of Immunohistochemistry in Diagnostically Uncertain Prostate Biopsies

abstract:
The use of immunohistochemistry in the reporting of prostate biopsies is an important adjunct when the diagnosis is not definite on haematoxylin and eosin (H&E) morphology alone. The process is however inherently inefficient with delays while waiting for pathologist review to make the request and duplicated effort reviewing a case more than once. In this study, we aimed to capture the workflow implications of immunohistochemistry requests and demonstrate a novel artificial intelligence tool to identify cases in which immunohistochemistry (IHC) is required and generate an automated request.

We conducted audits of the workflow for prostate biopsies in order to understand the potential implications of automated immunohistochemistry requesting and collected prospective cases to train a deep neural network algorithm to detect tissue regions that presented ambiguous morphology on whole slide images. These ambiguous foci were selected on the basis of the pathologist requesting immunohistochemistry to aid diagnosis. A gradient boosted trees classifier was then used to make a slide level prediction based on the outputs of the neural network prediction. The algorithm was trained on annotations of 219 immunohistochemistry-requested and 80 control images, and tested by 3-fold cross-validation. Validation was conducted on a separate validation dataset of 212 images.

Non IHC-requested cases were diagnosed in 17.9 minutes on average, while IHC-requested cases took 33.4 minutes over multiple reporting sessions. We estimated 11 minutes could be saved on average per case by automated IHC requesting, by removing duplication of effort. The tool attained 99% accuracy and 0.99 Area Under the Curve (AUC) on the test data. In the validation, the average agreement with pathologists was 0.81, with a mean AUC of 0.80.

We demonstrate the proof-of-principle that an AI tool making automated immunohistochemistry requests could create a significantly leaner workflow and result in pathologist time savings.

category: pathology


title: Change in burden of disease in UK children and young people (0-24 years) over the past 20 years and estimation of potential burden in 2040: analysis using Global Burden of Disease (GBD) data.

abstract:
BackgroundThe epidemiological transition and medical innovations have led to changes in causes of ill-health and disability by children and young people (CYP) in many wealthy countries over the past two decades. However this has not been systematically examined at a national level in the UK. Here we examined changes in disability-adjusted life-years (DALYs) by cause for 0-24 year olds by age-group.

MethodsWe used data on DALYS by cause, sex and age-group for the UK from 1998 to 2017 from the 2017 Global Burden of Disease (GBD) study. We modified the GBD cause-hierarchy to be more relevant to paediatrics. We assessed current causes of burden in 2017 and change at cause-level for 1998-2007 and 2008-2017 by age. We then used Holt-Winters doubly exponentiated time-series models to forecast change in DALYs by age to 2040.

ResultsIn 2017, neonatal and congenital disorders were the main causes of DALYS across 0-24 year olds, with other the other large causes being anxiety and depression, endocrine and immune disorders, and lower respiratory tract infections. Total DALYS were highest amongst neonates and lowest amongst 1-9 year olds, rising with age amongst 10-24 year olds. Between 1998-2017, total DALYs fell in each age-group, with the largest falls in infants. The greatest changes in DALYS from 2008 to 2017 were falls in neonatal and congenital causes amongst infants, falls in infectious diseases and injuries in older age-groups, and rises in neonatal causes, mental health, acne and somatic symptoms in all age-groups other than infants. These patterns were forecast to continue to 2040.

ConclusionsWe forecast falls in causes that have historically dominated disease in CYP, particularly congenital disorders, infectious diseases, cancers and injuries, representing falls in the prevalence of many infectious diseases and improvements in road safety and also improvements in survival from cancer and many congenital conditions. Forecast increases in DALYS from mental health problems, other adolescent health issues and the consequences of neonatal survival, such as neuro-disability and epilepsy, have potential implications for the training of paediatricians and workforce needs over the next two decades. The impact of the COVID-19 pandemic, climate change and changes in child poverty require further research.

category: pediatrics


title: Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression

abstract:
Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset.

We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N=4,178, 65.5% female; mean age=41.5 years; N=1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age=45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets.

In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD.

These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.

category: psychiatry and clinical psychology


title: Telomere shortening as a stress biomarker in children and adolescents affected by natural disasters.

abstract: Natural disasters have a substantial psychosocial impact. A known biological marker of stress is telomere shortening. In this study, we tested the change in behavior symptoms and telomere length and its shortening in two-time points for about fifteen months, in populations that suffered extreme climate events, comprising flood or drought events. As expected, we observed telomere shortening in children and adolescents after a stressful situation which was directly associated with the worsening of externalizing symptoms and post-traumatic symptoms using a reliable change index. Beyond the psychosocial impact, natural events seem to affect the biology of individuals in development. These findings can help to understand vulnerabilities related to stress impact and to point target populations whose mitigation actions should be addressed in case of a disaster.


title: Self-testing for the detection of SARS-CoV-2 infection with rapid antigen tests.

abstract:
IntroductionSelf-testing for COVID-19 infection with lateral flow assay SARS-CoV-2 rapid antigen detection tests (RDT), provides rapid results and could enable frequent and extensive testing in the community, thereby improving the control of SARS-CoV-2. The objective of this study is to evaluate the performance of self-testing using RDT without assistance.

MethodsParticipants visiting a municipal SARS-CoV-2 testing centre, received self-testing kits containing either the BD Veritor System (BD RDT) or Roche SARS-CoV-2 antigen detection test (Roche RDT). Oro-nasopharyngeal swabs were collected from the participants for qRT-PCR testing. As a proxy for contagiousness, viral culture was performed on a selection of qRT-PCR positive samples to determine the Ct-value at which the chance of a positive culture was dropping below 0.5 (Ct-value cut-off). Sensitivity and specificity of self-testing were compared to qRT-PCR with a Ct-value below the Ct value cut-off. Determinants independently associated with a false-negative self-test result were determined.

ResultsA total of 3,215 participants were included (BD RDT n=1604; Roche RDT n=1611). Sensitivity and specificity of self-testing compared to the qRT-PCR results with Ct-value below the Ct-value cut-off was 78.0% (95% CI:72.5-82.8) and 99.4% (95%CI: 99.0-99.6) respectively. Determinants independently associated with a false-negative self-testing results were: higher age, low viral load and finding self-testing difficult.

DiscussionSelf-testing using currently available RDTs has a high specificity and relatively high sensitivity to identify individuals with a high probability of contagiousness. The performance of two tests were comparable. This application has the potential for frequent and extensive testing which may be an aid to lift restrictions to society while controlling the spread of SARS-CoV-2.


title: Associations between health literacy and sociodemographic factors: A cross-sectional study in Malaysia utilising the HLS-M-Q18

abstract: Health literacy is progressively seen as an indicator to describe a nations health status. To improve health literacy, countries need to address health inequalities by examining different social demographic factors across the population. This assessment is crucial to identify and evaluate strengths and limitations of a country in addressing health issues. By addressing these health inequalities, a country would be better informed to take necessary steps to improve the nations health literacy. This study examines health literacy levels in Malaysia and analyses socio-demographic factors that are associated with health literacy. A cross-sectional survey was carried out using the HLS-M-Q18 instrument which was validated for the Malaysian population. Multi-stage random sampling strategy was used in this study utilising several sampling techniques including quota sampling, cluster sampling and simple random sampling to allow random data collection. A total of 855 respondents were sampled. Results found significant associations between health literacy and age, health status and health problems. Findings also suggest that lower health literacy levels were found to be associated with the younger generation. The findings of this study have provided baseline data of the health literacy of Malaysians and provide evidence toward potential areas of intervention.


title: An allele-specific primer extension assay to quantify the proportion of B.1.1.7-specific SARS-CoV-2 RNA in wastewater

abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed millions of lives to date. Antigenic drift has resulted in viral variants with putatively greater transmissibility, virulence, or both. Early and near real-time detection of these variants of concern (VOC) and the ability to accurately follow their incidence and prevalence in communities is wanting. Wastewater-based epidemiology (WBE), which uses nucleic acid amplification tests to detect viral fragments, is a faithful proxy of COVID-19 incidence and prevalence, and thus offers the potential to monitor VOC viral load in a given population. Here, we describe and validate a primer extension PCR strategy targeting a signature mutation in the N gene of SARS-CoV-2. This allows quantification of the proportional expression of B.1.1.7 versus non-B.1.1.7 alleles in wastewater without the need to employ quantitative RT-PCR standard curves. We show that the wastewater B.1.1.7 profile correlates with its clinical counterpart and benefits from a near real-time and facile data collection and reporting pipeline. This assay can be quickly implemented within a current SARS-CoV-2 WBE framework with minimal cost; allowing early and contemporaneous estimates of B.1.1.7 community transmission prior to, or in lieu of, clinical screening and identification. Our study demonstrates that this strategy can provide public health units with an additional and much needed tool to rapidly triangulate VOC incidence/prevalence with high sensitivity and lineage specificity.


title: Near real-time determination of B.1.1.7 in proportion to total SARS-CoV-2 viral load in wastewater using an allele-specific primer extension PCR strategy


title: The early dynamics of the SARS-CoV-2 epidemic in Portugal

abstract:
BackgroundGenomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National Institute of Health in the early stages of the COVID-19 epidemic, in collaboration with more than 50 laboratories distributed nationwide. This unprecedented collaborative effort culminated in the generation of 1275 SARS-CoV-2 genome sequences, which represent 15.5% of all confirmed cases in March 2020, making Portugal one of the countries generating the highest volumes of SARS-CoV-2 genomic data during early COVID-19 pandemic.

MethodsWe reconstructed and characterized the spatio-temporal dynamics of SARS-CoV-2 introductions and early dissemination in Portugal using recent phylodynamic models that allow integration of individual-based travel history, in order to obtain a more realistic reconstruction of the viral dynamics.

ResultsWe detected at least 277 independent SARS-CoV-2 introductions, mostly from European countries (namely the United Kingdom, Spain, France, Italy and Switzerland), which was broadly consistent with the available travel history data, as well as with the countries with most frequent connectivity and/or with the highest number of Portuguese immigrants. Although most introductions were estimated to have occurred during the last week of February and the first week of March 2020, it is likely that SARS-CoV-2 was silently circulating in Portugal several weeks before the first confirmed local cases on March 2, 2020.

Discussion and ConclusionWhile the implemented preventive and early control measures seem to have been successful in mitigating community transmission from most independent introductions, our results suggest that their earlier implementation could have largely minimized the number of introductions and subsequent virus expansion. Here we lay the foundation for genomic epidemiology of SARS-CoV-2 in Portugal, and highlight the need for systematic, continuous and geographically-representative genomic surveillance to guide national and international public health authorities toward the characterization and control of SARS-CoV-2 circulating diversity.


title: A Complex Model of Clinical Narrative Information for the Diagnostic Act

abstract:
BackgroundThe act of diagnosis is one which precipitates semiotic closure, the complex integration of signs and symptoms through cognitive perspectives to ultimately activate causal reasoning and calibrate the assignment of a disease entity to the patient. In writing about this act, physicians encode both structured and unstructured information into the medical record. Unstructured information contains a latent structure which entwines both the cognitive components of the diagnostic act and the linguistic patterns associated with clinical documentation. Existing models of clinical language primarily use a physical or dialogic model of information as their basis, and do not adequately account for the complexity inherent in the diagnostic act.

MethodsFraming the diagnostic information collected in clinical care as a narrative, we developed a model representative of said information, accounting for its content and structure, as well as the inherent complexity therein. Using an exemplar text, we present the use of known predication and semantic relations from ontological (the Unified Medical Language System) and linguistic theory (Rhetorical Structure Theory) to facilitate the operationalization of the model, and analyze the result.

ResultsThe resulting model is demonstrated to be complex, representative of the clinical narrative text, and is fundamentally aligned with the clinical acts of both documentation and diagnosis. We find the models representation of the cognitive aspects of narrative consistent with models of reading, as well as an adequate model of information as presented by clinical medicine and the clinical sub-language.

ConclusionsWe present a model to represent diagnostic information in the physicians note which accounts for the clinical and textual narrative precipitated by the cognition involved in encoding said information into the unstructured medical record. This model prepends the development of (computational) linguistic models of the clinical sublanguage within the physicians note as it relates to diagnosis, beyond the information level of the lexical unit. Such analysis would facilitate better reflection on the structure and meaning of the clinical note, offering improvements to medical education and care.

category: medical education


title: Neurophobia: A study of Australian medical students and junior doctors

abstract:
BackgroundNeurological disorders are the leading cause disability in Australia and the world. Combating the perceived difficulty of neurology or "neurophobia" and improving physician education is a key component in addressing this problem. We aim to conduct the first study to identify whether neurophobia exists in medical students and junior doctors in an Australian population and try to identify factors that may contribute to this in this population.

MethodsA 24 question online validated survey was distributed via email broadcast to all medical students and junior doctors at a metropolitan tertiary care centre in Australia. Responses were collected over 6 weeks with weekly reminder emails for 4 weeks after the initial invitation email.

Results114 medical students and junior doctors participated in the study. Participants perceived neurology as the most difficult medical speciality compared to 10 other medical specialties (p=0.001). The top three factors contributing to this perceived difficulty were: a lack of understanding of neuroanatomy, lack of diagnostic certainty and lack of clinical exposure. 65% of the participants stated that they had too little planned teaching in neurology with only 36% of the participants having performed a neurology rotation during medical school.

ConclusionThe prevalence of neurophobia in this Australian cohort of medical students and junior doctors is consistent with previous findings from around the world. This concerning finding requires further examination into the contributing factors in order to created trials of targeted interventions in order to resolve this.


title: High false-positive rate of fluorodeoxyglucose positron emission tomography to detect lymph node metastasis in microinvasive cervical cancer after conization

abstract: We aimed to estimate the positive predictive value of fluorodeoxyglucose positron emission tomography (FDG PET) to detect lymph node metastasis in patients with microinvasive cervical cancer who recently underwent conization. We retrospectively collected data of patients fulfilling the following criteria: 1) cervical cancer stage 1A1 (by FIGO staging revised in 1994) without invasion of the lymphovascular space diagnosed by conization from September 2008 to July 2018, 2) FDG PET within 3 months after diagnosis, 3) lymph node metastasis suspected by FDG PET, and 4) histologic confirmation or follow-up imaging study for suspected lymph node metastasis. Lymph node metastasis was suspected in 31 regions in 18 patients; however, no true metastasis was found. In conclusion, lymph node metastasis suspected by FDG PET in microinvasive cervical cancer after conization might be false positive. Lymph node dissection should not be performed for such patients.

category: obstetrics and gynecology


title: Prognostic value and peripheral immunologic correlates of early FDG PET response imaging in a phase II trial of risk-adaptive chemoradiation for unresectable non-small cell lung cancer

abstract:
IntroductionWe hypothesized that FDG PET imaging during chemoradiation for unresectable non-small cell lung cancer (NSCLC) is prognostic for survival, and that tumor PET response is correlated with peripheral T-cell function.

Methods45 patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on the phase II FLARE-RT trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). FDG PET imaging was performed prior to treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactorial radiologic interpretation. PET responders received 60 Gy in 30 fractions, while non-responders received concomitant boosts to 74 Gy in 30 fractions. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor (TCR) sequencing, and plasma cytokines analysis were performed.

ResultsMedian follow-up was 18.8 months, 1-year overall survival (OS) 82%, 1-year progression-free survival (PFS) 53%, and 1-year locoregional control (LRC) 88%. Higher mid-treatment PET total lesion glycolysis was detrimental to OS (1-yr 87% vs. 63%, p<0.001), PFS (1-yr 60% vs. 26%, p=0.044) and LRC (1-yr 94% vs. 65%, p=0.012), even after adjustment for clinical/treatment factors. Higher PD-L1 tumor proportion score (TPS) was correlated with PET response (p=0.017): 6/6 patients with high PD-L1 (TPS>50%) were classified as PET responders, while 4/5 patients classified as PET non-responders had negative PD-L1 (TPS<1%). Higher TCR richness and clone distribution slope was associated with improved OS (p=0.018-0.035); clone distribution slope was correlated with PET response (p=0.031). Germline DNA alterations in immunologic pathways had an outsized effect on OS and PET response; of the top 30 SNPs ranked by association with PET response status (p<0.016), a plurality (13/30) came from immunologic pathways.

ConclusionsMid-chemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral T-cell biomarkers.

category: oncology


title: Linking electronic health records for research on a nationwide cohort including over 54 million people in England

abstract:
ObjectivesDescribe a new England-wide electronic health record (EHR) resource enabling whole population research on Covid-19 and cardiovascular disease whilst ensuring data security and privacy and maintaining public trust.

DesignCohort comprising linked person-level records from national healthcare settings for the English population accessible within NHS Digitals new Trusted Research Environment.

SettingEHRs from primary care, hospital episodes, death registry, Covid-19 laboratory test results and community dispensing data, with further enrichment planned from specialist intensive care, cardiovascular and Covid-19 vaccination data.

Participants54.4 million people alive on 1st January 2020 and registered with an NHS general practitioner in England.

Main measures of interestConfirmed and suspected Covid-19 diagnoses, exemplar cardiovascular conditions (incident stroke or transient ischaemic attack (TIA) and incident myocardial infarction (MI)) and all-cause mortality between 1st January and 31st October 2020.

ResultsThe linked cohort includes over 96% of the English population. By combining person-level data across national healthcare settings, data on age, sex and ethnicity are complete for over 95% of the population. Among 53.2M people with no prior diagnosis of stroke/TIA, 98,721 had an incident stroke/TIA, of which 30% were recorded only in primary care and 4% only in death registry records. Among 53.1M people with no prior history of MI, 62,966 had an incident MI, of which 8% were recorded only in primary care and 12% only in death records. A total of 959,067 people had a confirmed or suspected Covid-19 diagnosis (714,162 in primary care data, 126,349 in hospital admission records, 776,503 in Covid-19 laboratory test data and 48,433 participants in death registry records). While 58% of these were recorded in both primary care and Covid-19 laboratory test data, 15% and 18% respectively were recorded in only one.

ConclusionsThis population-wide resource demonstrates the importance of linking person-level data across health settings to maximize completeness of key characteristics and to ascertain cardiovascular events and Covid-19 diagnoses. Although established initially to support research on Covid-19 and cardiovascular disease to benefit clinical care and public health and to inform health care policy, it can broaden further to enable a very wide range of research.

category: health informatics


title: Temporal and geographical variation of COVID-19 in-hospital fatality rate in Brazil

abstract:
BackgroundPrevious studies have shown that COVID-19 In-Hospital Fatality Rate (IHFR) varies between regions and has been diminishing over time. It is believed that the continuous improvement in the treatment of patients, age group of hospitalized, and the availability of hospital resources might be affecting the temporal and regional variation of IHFR. In this study, we explored how the IHFR varied over time and among age groups and federative states in Brazil. In addition, we also assessed the relationship between hospital structure availability and peaks of IHFR.

MethodsA retrospective analysis of all COVID-19 hospitalizations with confirmed outcomes in 22 states between March 01 and September 22, 2020 (n=345,281) was done. We fit GLM binomial models with additive and interaction effects between age groups, epidemiological weeks, and states. We also evaluated the association between the modeled peak of IHFR in each state and the variables of hospital structure using the Spearman rank correlation test.

ResultsWe found that the temporal variation of the IHFR was heterogeneous among the states, and in general it followed the temporal trends in hospitalizations. In addition, the peak of IHFR was higher in states with a smaller number of doctors and intensivists, and in states in which a higher percentage of people relied on the Public Health System (SUS) for medical care.

ConclusionsOur results suggest that the pressure over the healthcare system is affecting the temporal trends of IHFR in Brazil.

Key MessagesO_LITemporal variation of age adjusted In-Hospital Fatality Rate (IHFR) was markedly heterogeneous among Brazilian states from March to September of 2020.
C_LIO_LIIn several states, the IHFR increased in association with the increase in the number of hospitalizations, which suggests that the overload of the healthcare system might be affecting the temporal trends of IHFR in Brazil.
C_LIO_LIThe IHFR remained low in the states with higher rates of hospital resources, even with the high demand for hospitalization.
C_LIO_LIThe number of doctors and intensivist physicians per habitant was more strongly correlated with the peak of IHFR in the Brazilian states than the number of ICU beds.
C_LI

category: health policy


title: Real-time analysis of a mass vaccination effort via an Artificial Intelligence platform confirms the safety of FDA-authorized COVID-19 vaccines

abstract: As the COVID-19 vaccination campaign unfolds as one of the most rapid and widespread in history, it is important to continuously assess the real world safety of the FDA-authorized vaccines. Curation from large-scale electronic health records (EHRs) allows for near real-time safety evaluations that were not previously possible. Here, we advance context- and sentiment-aware deep neural networks over the multi-state Mayo Clinic enterprise (Minnesota, Arizona, Florida, Wisconsin) for automatically curating the adverse effects mentioned by physicians in over 108,000 EHR clinical notes between December 1st 2020 to February 8th 2021. We retrospectively compared the clinical notes of 31,069 individuals who received at least one dose of the Pfizer/BioNTech or Moderna vaccine to those of 31,069 unvaccinated individuals who were propensity matched by demographics, residential location, and history of prior SARS-CoV-2 testing. We find that vaccinated and unvaccinated individuals were seen in the the clinic at similar rates within 21 days of the first or second actual or assigned vaccination dose (first dose Odds Ratio = 1.13, 95% CI: 1.09-1.16; second dose Odds Ratio = 0.89, 95% CI: 0.84-0.93). Further, the incidence rates of all surveyed adverse effects were similar or lower in vaccinated individuals compared to unvaccinated individuals after either vaccine dose. Finally, the most frequently documented adverse effects within 7 days of each vaccine dose were arthralgia (Dose 1: 0.59%; Dose 2: 0.39%), diarrhea (Dose 1: 0.58%; Dose 2: 0.33%), erythema (Dose 1: 0.51%; Dose 2: 0.31%), myalgia (Dose 1: 0.40%; Dose 2: 0.34%), and fever (Dose 1: 0.27%; Dose 2: 0.31%). These remarkably low frequencies of adverse effects recorded in EHRs versus those derived from active solicitation during clinical trials (arthralgia: 24-46%; erythema: 9.5-14.7%; myalgia: 38-62%; fever: 14.2-15.5%) emphasize the rarity of vaccine-associated adverse effects requiring clinical attention. This rapid and timely analysis of vaccine-related adverse effects from contextually rich EHR notes of 62,138 individuals, which was enabled through a large scale Artificial Intelligence (AI)-powered platform, reaffirms the safety and tolerability of the FDA-authorized COVID-19 vaccines in practice.


title: Real-time analysis of a mass vaccination effort confirms the safety of FDA-authorized mRNA vaccines for COVID-19 from Moderna and Pfizer/BioNtech


title: Quantitative fluorescence in situ hybridization (FISH) of magnetically confined bacteria enables rapid determination of early-stage human bacteremia

abstract: The current diagnosis of bacteremia mainly uses blood culture, which is insufficient to offer rapid and quantitative determination of pathogens in blood. Here, we report a quantitative and sequential multiplexed fluorescence in situ hybridization in a microfluidic device ({micro}FISH) that enables early and rapid (2-hour) diagnosis of bacteremia without prior blood culture. Mannose-binding lectin-coated magnetic nanoparticles enrich a broad range of pathogens, and {micro}FISH enables identification and quantification of the magnetically confined bacteria. We detect Escherichia coli (E. coli) and measure their relative proportions to universal bacteria levels in the bacteremic blood of a porcine model and human whole blood collected from E. coli-infected patients, which was elusive with the conventional bacteremia diagnosis methods. Thus, {micro}FISH can be used as a versatile tool to rapidly identify pathogens and further assess the number of both culturable and non-culturable bacteria in biological and environmental samples.


title: Wastewater Monitoring of SARS-CoV-2 from Acute Care Hospitals Identifies Nosocomial Transmission and Outbreaks

abstract:
BackgroundSARS-CoV-2 has been detected in wastewater and its abundance correlated with community COVID-19 cases, hospitalizations and deaths. We sought to use wastewater-based detection of SARS-CoV-2 to assess the epidemiology of SARS-CoV-2 in hospitals.

MethodsBetween August and December 2020, twice-weekly wastewater samples from three tertiary-care hospitals (totaling >2100 dedicated inpatient beds) were collected. Wastewater samples were concentrated and cleaned using the 4S-silica column method and assessed for SARS-CoV-2 gene-targets (N1, N2 and E) and controls using RT-qPCR. Wastewater SARS-CoV-2 as measured by quantification cycle (Cq), genome copies and genomes normalized to the fecal biomarker PMMoV were compared to the total daily number of patients hospitalized with active COVID-19, confirmed cases of hospital-acquired infection, and the occurrence of unit-specific outbreaks.

ResultsOf 165 wastewater samples collected, 159 (96%) were assayable. The N1-gene from SARS-CoV-2 was detected in 64.1% of samples, N2 in 49.7% and E in 10%. N1 and N2 in wastewater increased over time both in terms of amount of detectable virus and the proportion of samples that were positive, consistent with increasing hospitalizations (Pearsons r=0.679, P<0.0001, Pearsons r=0.728, P<0.0001, respectively). Despite increasing hospitalizations through the study period, wastewater analysis was able to identify incident nosocomial-acquired cases of COVID-19 (Pearsons r =0.389, P<0.001) and unit-specific outbreaks by increases in detectable SARS-CoV-2 N1-RNA (median 112 copies/ml) versus outbreak-free periods (0 copies/ml; P<0.0001).

ConclusionsWastewater-based monitoring of SARS-CoV-2 represents a promising tool for SARS-CoV-2 passive surveillance and case identification, containment, and mitigation in acute-care medical facilities.

Supplemental Material includedO_ST_ABSKey-points summaryC_ST_ABSSAS-CoV-2 RNA is detectable in hospital wastewater. Wastewater SARS-CoV-2 RNA increases in conjunction with COVID-19-related hospitalizations. Spikes in SARS-CoV-2 wastewater signal correspond to incident hospital-acquired cases and outbreaks, suggesting passive surveillance via wastewater has great promise for COVID-19 monitoring.


title: Multicenter cohort study of children hospitalized with SARS-CoV-2 infection

abstract:
BackgroundA cohort study was conducted to describe and compare the characteristics of SARS-CoV-2 infection in hospitalized children in three countries.

MethodsThis was a retrospective cohort of consecutive children admitted to 15 hospitals (13 in Canada and one each in Iran and Costa Rica) up to November 16, 2020. Cases were included if they had SARS-CoV-2 infection or multi-system inflammatory syndrome in children (MIS-C) with molecular detection of SARS-CoV-2 or positive SARS-CoV-2 serology.

ResultsOf 211 included cases (Canada N=95; Costa Rica N=84; Iran N=32), 103 (49%) had a presumptive diagnosis of COVID-19 or MIS-C at admission while 108 (51%) were admitted with other diagnoses. Twenty-one (10%) of 211 met criteria for MIS-C. Eighty-seven (41%) had comorbidities. Children admitted in Canada were older than those admitted to non-Canadian sites (median 4.1 versus 2.2 years; p<0.001) and less likely to require mechanical ventilation (3/95 [3%] versus 15/116 [13%]; p<0.05). Sixty-four of 211 (30%) required supplemental oxygen or intensive care unit (ICU) admission and 4 (1.9%) died. Age < 30 days, admission outside Canada, presence of at least one comorbidity and chest imaging compatible with COVID-19 predicted severe or critical COVID-19 (defined as death or need for supplemental oxygen or ICU admission).

ConclusionsApproximately half of hospitalized children with confirmed SARS-CoV-2 infection or MIS-C were admitted with other suspected diagnoses. Disease severity was higher at non-Canadian sites. Neonates, children with comorbidities and those with chest radiographs compatible with COVID-19 were at increased risk for severe or critical COVID-19.

Main pointsApproximately half of hospitalized children with laboratory confirmed MIS-C or SARS-CoV-2 infection were admitted with another primary diagnoses. The severity of disease was higher in the middle income countries (Costa Rica and Iran) than in Canada.


title: COVID-19 Vaccine Hesitancy in Underserved Communities of North Carolina

abstract:
BackgroundIn the United States, underserved communities including Blacks and Latinx are disproportionately affected by COVID-19, and widespread vaccination is critical for curbing this pandemic. This study sought to estimate the prevalence of COVID-19 vaccine hesitancy, describe attitudes related to vaccination, and identify correlates among racial minority and marginalized populations across 9 counties in North Carolina.

MethodsWe conducted a cross-sectional survey with a self-administered questionnaire distributed at free COVID-19 testing events in underserved rural and urban communities from August 27 - December 15, 2020. Vaccine hesitancy was defined as the response of "no" or "dont know/not sure" to whether the participant would get the COVID-19 vaccine as soon as it became available.

ResultsThe sample comprised 948 participants including 27.7% Whites, 59.6% Blacks, 12.7% Latinx, and 63% female. Thirty-two percent earned <$20K annually, 60% owned a computer and [~]80% had internet access at home. The prevalence of vaccine hesitancy was 68.9% including 62.7%, 74%, and 59.5% among Whites, Blacks, and Latinx, respectively. Between September and December, the largest decline in vaccine hesitancy occurred among Whites (27.5 percentage points), followed by Latinx (17.6) and the smallest decline was among Black respondents (12.0). 51.2% of the respondents reported vaccine safety concerns, 23.7% wanted others to get of the respondents reported they would trust health care providers with information about the COVID-19 vaccine. Factors associated with hesitancy in multivariable logistic regression included being female (OR=1.90 95%CI[1.36, 2.64]), being Black (OR=1.68 [1.106 2.45]), calendar month (OR=0.76 [0.63, 0.92]), safety concerns (OR=4.28 [3.06, 5.97]), and government distrust (OR=3.57 [2.26, 5.63]).

ConclusionsThis study reached underserved minority populations in a number of different locations to investigate COVID-19 vaccine hesitancy. We built on existing relationships and further engaged the community, stake holders and health department to provide free COVID-19 testing. This direct approach permitted assessment of vaccine hesitancy (which was much higher than national estimates), distrust, and safety concerns.

HighlightsO_LIThis study surveyed 948 adults at COVID-19 testing sites in 9 counties of North Carolina between August 27 and December 15, 2020 where vaccine hesitancy was widespread including 74% in Blacks, 62.7% in Whites and 59.5% in Latinx.
C_LIO_LIVaccine hesitancy declined over time but remained high for Blacks.
C_LIO_LIOn-site surveys conducted in underserved areas that were paper-based and self-administered permitted reaching adults with no internet (17%), no cell phone (20%), no computer (40%) and yearly incomes less than 20K (31%).
C_LIO_LIWidespread vaccine hesitancy in predominately minority communities of NC must be addressed to successfully implement mass COVID-19 vaccination programs.
C_LI


title: A Prospective Clinical Evaluation of a Patient Isolation Hood During the COVID-19 Pandemic

abstract:
BackgroundHealthcare workers have frequently become infected with SARS-CoV-2 whilst treating patients with COVID-19. A variety of novel devices have been proposed to reduce COVID-19 cross contamination.

ObjectiveTo test whether a novel patient isolation hood was safe and comfortable, and could potentially reduce HCW COVID-19 infections.

MethodsProspective cohort study of 20 patients, entailing staff/patient questionnaires, and safety aspects of prototype isolation hoods.Prospective collection of HCW COVID-19 data.Assessment of the hoods safety and practicality, and adverse event reporting.

Outcome MeasuresQuestionnaires responses, adverse events reporting, rates of HCW infections during study period (20/6/2020 -21/7/2020).HCW COVID-19 infections reported until last recorded HCW COVID-19 diagnosis (20/6/2020 -27/9/2020).

ResultsOf the 60 (of 64) eligible individual staff surveys, 60 favoured isolation hood use.Staff were unanimous in: perceiving the hood as safe (60/60), preferring its use (56/56), and understanding its potential COVID-19 cross-contamination minimisation (60/60). All eight patients who completed the questionnaire thought the isolation hood helped prevent COVID-19 cross-infection, was safe, and comfortable. There were no reported patient safety adverse events. The overall attack COVID-19 attack rate from 20/6/2020-27/9/2020 among registered nurses was 3.4% (102/2994): ICUs 2.2% (3/138), Geriatric wards 13.2% (26/197), and COVID-19 Wards 18.3% (32/175). The COVID-19 attack rate among medical staff was: all junior medical staff 2.1% (24/932), senior medical staff 0.7% (4/607), aged care/rehabilitation 6.7% (2/30), and ICU all medical staff 8.6% (3/35).

ConclusionsThe isolation hood was strongly endorsed by staff and patients, and post-study became part of standard ICU therapy. ICU nurse COVID-19 infection rates were low. ICU HCWs feel safer when treating patients with COVID-19 using an isolation hood.


title: Plasma Hydrogen Sulfide Production Capacity is Positively Associated with Post-Operative Survival in Patients Undergoing Surgical Revascularization

abstract:
ObjectiveHydrogen sulfide (H2S) is a gaseous signaling molecule and redox factor important for cardiovascular function. Deficiencies in its production or bioavailability are implicated in atherosclerotic disease. However, it is unknown if circulating H2S levels differ between vasculopaths and healthy individuals, and if so, whether H2S measurements can be used to predict surgical outcomes. Here, we examine: 1) Plasma H2S levels in patients undergoing vascular surgery and compare these to healthy controls, and 2) Associations between H2S levels and mortality in surgical revascularization patients.

Approach & ResultsPatients undergoing carotid endarterectomy, open lower extremity revascularization or leg amputation were enrolled. Peripheral blood was also collected from a matched cohort of 20 patients without peripheral or coronary artery disease. Plasma H2S production capacity and sulfide concentration were measured using the lead acetate and monobromobimane methods, respectively. Plasma H2S production capacity and plasma sulfide concentrations were reduced in patients with PAD (p<0.001, p=0.013 respectively). Patients that underwent surgical revascularization were divided into high versus low H2S production capacity groups by median split. Patients in the low H2S production group had increased probability of mortality (p=0.003). This association was robust to correction for potentially confounding variables using Cox proportional hazard models.

ConclusionsCirculating H2S levels were lower in patients with atherosclerotic disease. Patients undergoing surgical revascularization with lower H2S production capacity, but not sulfide concentrations, had increased probability of mortality within 36 months post-surgery. This work provides insight on the role H2S plays as a diagnostic and potential therapeutic for cardiovascular disease.

HIGHLIGHTSO_LIVascular disease patients have higher plasma hydrogen sulfide levels than controls without vascular disease as measured by two distinct methods, the lead acetate hydrogen sulfide release method and the HPLC-based monobromobimane method.
C_LIO_LIOnly the lead acetate hydrogen sulfide release method robustly predicts survival after vascular surgery intervention over 35 months of follow up.
C_LIO_LIThe lead acetate release method measures non-enzymatic hydrogen sulfide release from plasma which requires iron and is catalyzed by vitamin B6.
C_LI


title: Simple Scoring Tool to Estimate Risk of Hospitalization and Mortality in Ambulatory and Emergency Department Patients with COVID-19

abstract:
BackgroundAccurate methods of identifying patients with COVID-19 who are at high risk of poor outcomes has become especially important with the advent of limited-availability therapies such as monoclonal antibodies. Here we describe development and validation of a simple but accurate scoring tool to classify risk of hospitalization and mortality.

MethodsAll consecutive patients testing positive for SARS-CoV-2 from March 25-October 1, 2020 within the Intermountain Healthcare system were included. The cohort was randomly divided into 70% derivation and 30% validation cohorts. A multivariable logistic regression model was fitted for 14-day hospitalization. The optimal model was then adapted to a simple, probabilistic score and applied to the validation cohort and evaluated for prediction of hospitalization and 28-day mortality.

Results22,816 patients were included; mean age was 40 years, 50.1% were female and 44% identified as non-white race or Hispanic/Latinx ethnicity. 6.2% required hospitalization and 0.4% died. Criteria in the simple model included: age (0.5 points per decade); high-risk comorbidities (2 points each): diabetes mellitus, severe immunocompromised status and obesity (body mass index[≥]30); non-white race/Hispanic or Latinx ethnicity (2 points), and 1 point each for: male sex, dyspnea, hypertension, coronary artery disease, cardiac arrythmia, congestive heart failure, chronic kidney disease, chronic pulmonary disease, chronic liver disease, cerebrovascular disease, and chronic neurologic disease. In the derivation cohort (n=16,030) area under the receiver-operator characteristic curve (AUROC) was 0.82 (95% CI 0.81-0.84) for hospitalization and 0.91 (0.83-0.94) for 28-day mortality; in the validation cohort (n=6,786) AUROC for hospitalization was 0.8 (CI 0.78-0.82) and for mortality 0.8 (CI 0.69-0.9).

ConclusionA prediction score based on widely available patient attributes accurately risk stratifies patients with COVID-19 at the time of testing. Applications include patient selection for therapies targeted at preventing disease progression in non-hospitalized patients, including monoclonal antibodies. External validation in independent healthcare environments is needed.

category: emergency medicine


title: Modelling the Impact of Delaying Vaccination Against SARS-CoV-2 Assuming Unlimited Vaccines Supply

abstract:
BackgroundAt the moment we have more than 109 million cases and 2.4 million deaths around the world and vaccination represents the only hope to control the pandemic. Imperfections in planning vaccine acquisition and difficulties in implementing distribution among the population, however, have hampered the control of the virus so far.

MethodsWe propose a new mathematical model to estimate the impact of vaccination delay against COVID-19 on the number of cases and deaths by the disease in Brazil. We apply the model to Brazil as a whole and to the State of Sao Paulo, the most affected by COVID-19 in Brazil. We simulated the model for the populations of the State of Sao Paulo and Brazil as a whole, varying the scenarios related to vaccine efficacy and compliance from the populations.

ResultsThe model projects that, in the absence of vaccination, almost 170 thousand deaths and more than 350 thousand deaths until the end of 2021 for Sao Paulo and Brazil, respectively. If in contrast, Sao Paulo and Brazil had enough vaccine supply and so started a vaccination campaign in January with the maximum vaccination rate, compliance and efficacy, they could have averted more than 112 thousand deaths and 127 thousand deaths, respectively. In addition, that for each month of delay the number of deaths increases monotonically in a logarithm fashion, for both the State of Sao Paulo and Brazil as a whole.

ConclusionsOur model shows that the current delay in the vaccination schedules that is observed in many countries has serious consequences in terms of mortality by the disease and should serve as an alert to health authorities to speed the process up such that the highest number of people to be immunized is reached in the shortest period of time.


title: An efficient benchmark for COVID-19 pandemic testing effectiveness

abstract: The positivity rate of testing is currently used both as a benchmark of testing adequacy and for assessing the evolution of the COVID-19 pandemic. However, since the former is a prerequisite for the latter, its interpretation is often conflicting. We propose as a benchmark for COVID-19 testing effectiveness a new metric, termed  Severity Detection Rate (SDR), that represents the daily needs for new Intensive Care Unit (ICU) admissions, per 100 cases detected (t-i) days ago, per 10,000 tests performed (t-i) days ago. Based on the announced COVID-19 monitoring data in Greece from May 2020 until August 2021, we show that beyond a certain threshold of daily tests, SDR reaches a plateau of very low variability that begins to reflect testing adequacy. Due to the stabilization of SDR, it was possible to predict with great accuracy the daily needs for new ICU admissions, 12 days ahead of each testing data point, over a period of 10 months, with Pearson r = 0.98 (p = 10-197), RMSE = 7,16. We strongly believe that this metric will help guide the timely decisions of both scientists and government officials to tackle pandemic spread and prevent ICU overload by setting effective testing requirements for accurate pandemic monitoring. We propose further study of this novel metric with data from more countries to confirm the validity of the current findings.


title: A novel benchmark for COVID-19 pandemic testing effectiveness enables the accurate prediction of new Intensive Care Unit admissions


title: Impact of environmental temperature on Covid-19 spread: Model and analysis of measurements recorded during the second pandemic in Cyprus

abstract: The paper investigates the effect of the environmental temperature on the spread of COVID-19. We study the daily numbers of the cases infected and deaths caused by Covid-19 during the second wave of the pandemic within 2020, and how they were affected by the daily average-high temperature for the districts of the Republic of Cyprus. Among the findings of the paper, we show that (i) the average ratio of the PCR to rapid positive tests is [~]2.57{+/-}0.25, as expected from the tests responses, indicating that PCR overestimates positivity by [~]2.5 times; (ii) the average age of deaths caused by Covid-19 increases with rate about a year of age per week; (iii) the probability of a person infected by Covid-19 to develop severe symptoms leading to death is strongly depended on the persons age, while the probability of having a death on the age of [~]67 or younger is less than 1/1000; (iv) the number of infected cases and deaths declined dramatically when the environmental temperature reaches and/or climbs above the critical temperature of TC=30.1{+/-}2.4 C0; (v) the observed negative correlation between the exponential growth rate of the infected cases and the environmental temperature can be described within the framework of chemical kinetics, with at least two competing reactions, the connection of the coronavirus towards the receptor and the dissolution of the coronavirus; the estimated activation energy difference corresponding to the competing chemical reactions, 0.212{+/-}0.25 eV, matches the known experimental value; and (vi) the infected cases will decline to zero, when the environmental temperature climbs above the critical temperature within the summery days of 2021, which is expected for the Republic of Cyprus by the 16th of May, 2021.


title: Vaccination efforts in Brazil: scenarios and perspectives under a mathematical modeling approach

abstract: An agent-based model is proposed to access the impact of vaccination strategies to halt the COVID-19 spread. The model is parameterized using data from Sao Paulo State, Brazil. It was considered the two vaccines that are already approved for emergency use in Brazil, the CoronaVac vaccine developed by the Chinese bio-pharmaceutical company Sinovac and the Oxford-AstraZeneca vaccine (ChadOx1) developed by Oxford University and the British laboratory AstraZeneca. Both of them are two-dose schemes, but the efficacy and the interval between doses are different. We found that even in the worst scenario, in which the vaccine does not prevent infection either severe symptoms, the number of deaths decreases from 122 to 99 for CoronaVac application and to 80 for ChadOx1 administration. The same patterns have been seen in hospitalizations. Nevertheless, we show that when a low risk perception occurs, the reduction values decrease between 2% to 4%. Moreover, the increase of disease prevalence also jeopardizes immunization, showing the importance of the mitigation measures maintenance. On the other hand, doubling the vaccination rate would be able to significantly decrease the disease outcomes, reducing deaths by up to 74.4%. In conclusion, vaccination, along with non-pharmaceutical measures, is key to the control of COVID-19 in Brazil.