title: SARS-CoV-2 antigenemia/viremia masks seroconversion in a COVID-19 patient

abstract: Immune responses against SARS-CoV-2 have been vigorously analyzed. It has been proposed that a subset of mild or asymptomatic cases with undetectable antibodies may clear the virus in a T-cell cytotoxic-dependent manner, albeit recent data revealed the importance of B-cells in that regard. We hypothesized that underdiagnosed antigenemia/viremia may conceal humoral response possibly through immunocomplex formation. We report the first case of late-onset seroconversion detected following decline in antigenemia/viremia levels. Consequently, classification of at least a subset of COVID-19 cases as non-responders might not represent a true immunobiological phenomenon, rather reflect antibody masking due to prolonged antigenemia/viremia.


title: The successful use of volunteers to enhance NHS Test and Trace contact tracing of in-patients with Covid-19: a Pilot Study

abstract:
Contact tracing in the UK for Covid-19 is performed by NHS Test and Trace (NHSTT) via telephone or email. This study estimates how many patients who have been admitted to hospital are not reached by NHSTT and the number of their contacts who were not advised to self-isolate.

Medical Student volunteers conducted face to face interviews with patients diagnosed with Covid-19 on an infectious diseases ward. Data on their close contacts were sent to NHSTT.

20 cases were enrolled. 13(65%) did not engage with NHSTT, 4(20%) because they had no positive PCR, 9(45%) because of severity of illness, language or intellectual difficulties. 49 close contacts were identified of whom 33(67%) were from cases who had not engaged with NHSTT. "Backwards" contacts tracing information was collected from 11(55%) cases and 8(40%) gave detailed information.

These data suggest that NHSTT fails to engage nearly two thirds of Covid-19 in-patients and fails to advise two thirds of their close contacts to self isolate.Volunteers used face to face interviews to overcome false negative tests, illness and communication problems to identify both close contacts and data on sources of infection.

category: infectious diseases


title: New-Onset IgG Autoantibodies in Hospitalized Patients with COVID-19

abstract: Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. We developed three different protein arrays to measure hallmark IgG autoantibodies associated with Connective Tissue Diseases (CTDs), Anti-Cytokine Antibodies (ACA), and anti-viral antibody responses in 147 hospitalized COVID-19 patients in three different centers. Autoantibodies were identified in approximately 50% of patients, but in <15% of healthy controls. When present, autoantibodies largely targeted autoantigens associated with rare disorders such as myositis, systemic sclerosis and CTD overlap syndromes. Anti-nuclear antibodies (ANA) were observed in [~]25% of patients. Patients with autoantibodies tended to demonstrate one or a few specificities whereas ACA were even more prevalent, and patients often had antibodies to multiple cytokines. Rare patients were identified with IgG antibodies against angiotensin converting enzyme-2 (ACE-2). A subset of autoantibodies and ACA developed de novo following SARS-CoV-2 infection while others were transient. Autoantibodies tracked with longitudinal development of IgG antibodies that recognized SARS-CoV-2 structural proteins such as S1, S2, M, N and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. COVID-19 patients with one or more autoantibodies tended to have higher levels of antibodies against SARS-CoV-2 Nonstructural Protein 1 (NSP1) and Methyltransferase (ME). We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.

category: allergy and immunology


title: Association of COVID-19 incidence with objectively and subjectively measured mental health proxies in the Austrian Football League: an epidemiological study

abstract:
ObjectiveWe aimed to explore the association of COVID-19 incidence with mental health in 225 team and staff members of five professional Austrian Football clubs captured by objective (location variance) or subjective (self-reported sleep quality, level of recovery, perceived risk of infection) mental health proxies.

MethodsData collected during the implementation of a novel monitoring concept to enable safe continuation of professional Football during the COVID-19 pandemic were matched with Austrian COVID-19 incidence data and smartphone collected location data (time-period June 17th to July 31st, 2020). Multivariable linear regression models explored the association of COVID-19 incidence, defined as daily novel or active cases of COVID-19, with the objective and subjective health proxies while adjusting for the occurrence of one COVID-19 case in a staff member in one of the clubs, team status (i.e. player vs staff) and game days.

ResultsData from 115 participants were analysed. An increasing number of novel COVID-19 cases was significantly associated with deteriorating sleep quality (B 0.48, 95% CI 0.05; 1.00) but with none of the other mental health proxies. An increasing number of active COVID-19 cases was significantly associated with an increase in perceived infection risk (B 0.04, 95% CI 0.00; 0.07) and location variance (B 0.28, 95% CI 0.06; 0.49).

ConclusionThe adverse association of an increasing COVID-19 incidence with mental health in professional Footballers and staff members became obvious particularly in subjectively measured mental health. During the ongoing pandemic, targeted mental care should be included in the daily routines of this population.

O_TEXTBOXSUMMARY BOX

O_LIAn increasing COVID-19 incidence is associated with deterioration of mental health in players and staff members of professional Football teams.
C_LIO_LIThe perceived COVID-19 infection risk is more pronounced in staff members than in players of professional Football clubs.
C_LIO_LISurprisingly, a rise in the number of active COVID-19 cases results in an increasing location variance.
C_LI

C_TEXTBOX

category: epidemiology


title: UK osteopathic practice in 2019: a retrospective analysis of practice data.

abstract:
BackgroundThis study describes osteopathic activity, scope of practice and the osteopathic patient profile in order to understand the role osteopathy plays within the UK health system a decade after our previous survey.

MethodWe used a retrospective questionnaire survey design to ask about osteopathic practice and audit patient case notes. All UK registered osteopaths were invited to participate in the survey.

The survey was conducted using a web-based system. Each participating osteopath was asked about themselves, their practice and asked to randomly select and extract data from up to 8 random new patient health records during 2018. All patient related data were anonymised.

ResultsThe survey response rate was 500 osteopaths (9.4% of the profession) who provided information about 395 patients and 2,215 consultations.

Most osteopaths were self-employed (81.1%; 344/424 responses) working alone either exclusively or often (63.9%; 237/371) and were able to offer 48.6% of patients an appointment within 3 days (184/379).

Patient ages ranged from 1 month to 96 years (mean 44.7 years, Std Dev. 21.5), of these 58.4% (227/389) were female. Infants <1 years old represented 4.8% (18/379) of patients.

The majority of patients presented with musculoskeletal complaints (81.0%; 306/378). Persistent complaints (present for more than 12 weeks before appointment) were the most common (67.9%; 256/377) and 41.7% (156/374) of patients had co-existing medical conditions. The most common treatment approaches used at the first appointment were soft-tissue techniques (73.9%; 292/395), articulatory techniques (69.4%; 274/395) and high velocity low amplitude thrust (34.4%; 136/395). The mean number of treatments per patient was 7 (mode 4).

ConclusionTo better understand the role of osteopathy in UK health service delivery, the profession needs to do more research with patients in order to understand their needs and their expected outcomes of care, and for this to inform osteopathic practice and education.

category: rehabilitation medicine and physical therapy


title: Timing and Dose of Pharmacological Thromboprophylaxis in Adult Trauma Patients: Perceptions, Barriers, and Experience of Saudi Arabia Practicing Physicians

abstract:
BackgroundPharmacological venous thromboembolism prophylaxis (PVTE-Px) in trauma care is challenging and frequently delayed until post injury bleeding risk is perceived to be sufficiently low; yet data for optimal initiation time is lacking. This study assessed practice pattern of PVTE-Px initiation time and dose in traumatic brain injury (TBI), spinal cord injury (SCI), and non-operative (NOR) solid organ injuries.

MethodsMulticenter, cross sectional, observational, survey-based study involving intensivists, trauma surgeons, general surgeons, spine orthopedics, and neurosurgeons practicing in trauma centers. The data of demographics, PVTE-Px timing and dose, and five clinical case scenarios were obtained. Analyses were stratified by early initiators vs. late initiators and logistic regression models were used to identify factors associated with early initiation of PVTE-Px.

ResultsOf 102 physicians (29 % response rate), most respondents were intensivists (63.7%) and surgeons (who are general and trauma surgeons) (22.5%); majority were consultants (58%), practicing at level 1 trauma centers (40.6%) or academic teaching hospitals (45.1%). A third of respondents (34.2%) indicated that decision to initiate PVTE-Px in TBI and SCI was made by a consensus between surgical, critical care, and neurosurgical services. For patients with NOR solid organ injuries, 34.2% of respondents indicated trauma surgeons initiated the decision on PVTE-Px timing. About 53.7% of the respondents considered their PVTE-Px practice as appropriate, half used combined mechanical and PVTE-Px (57.1%), 52% preferred enoxaparin (40 mg once daily), and only 6.5% used anti-Xa level to guide enoxaparin prophylactic dose. Responses to clinical cases varied. For TBI and TBI with intracranial pressure monitor, 40.3% and 45.6% of the respondents were early initiators with stable repeated head computed tomography [CT], respectively. For SCI, most respondents were early initiators without repeated CT spine (36.8%). With regards to NOR solid organ injuries [gunshot wound to the liver and grade IV splenic injuries], 49.1% and 36.4% of respondents were early initiators without a repeat CT abdomen.

ConclusionsVariations were observed in PVTE-Px initiation time influenced by trauma type. Our findings suggested enoxaparin is preferred in a standard prophylactic dose. More robust data from randomized trials are needed and the use of clinicians judgment is recommended.

Key MessagesO_LIIdeal time to initiate therapy, agent selection, dosing, and monitoring of pharmacological venous thromboembolism prophylaxis (PVTE-Px) for trauma patients is challenging.
C_LIO_LIVariations were observed in PVTE-Px initiation time influenced by trauma type.
C_LIO_LIOur study results are relatively in line with the recent evidence-based clinical literature
C_LIO_LIOur findings suggested limited awareness of augmented renal clearance (ARC) and utilization of serum anti-factor-Xa (anti-Xa) level.
C_LI

category: surgery


title: Efficacy and Safety of FLOT regimen vs DCF, FOLFOX, and ECF regimens as Perioperative Chemotherapy Treatments for Resectable Gastric Cancer PatientsShort title: Comparative Study of Chemotherapy Regimens for Gastric Cancer

abstract:
PurposeThis study aimed to compare the efficacy and toxicity of perioperative chemotherapy regimens including ECF, DCF, FOLFOX, and FLOT to identify the most effective chemotherapy regimen with less toxicity.

MethodThis retrospective cohort study(2014-2021) was based on 152 eligible resectable gastric cancer patients who had received one of the perioperative chemotherapy regimens including ECF, DCF, FOLFOX, or FLOT, and followed for at least two years. The primary endpoint of this study was Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR), and R0 resection. We also considered toxicity according to CTCAE (v.4.0) criteria as a secondary endpoint.

ResultsOf included patients, 32(21%), 51(33.7%), 37(24.3%), and 32(21%) had received ECF, DCF, FOLFOX and FLOT, respectively. After the median 30 months follow-up, overall survival was higher with the FLOT regimen in comparison with other regimens (hazard ratio [HR] = 0. 276). The median OS of the FLOT regimen was 39 months. Besides, the median OS was 28, 25, and 21 months for DCF, FOLOFX, and ECF regimens, respectively. Moreover, a median PFS of 24, 18, 17, and 14 months was observed for FLOT, DCF, FOLFOX, and ECF regimens, respectively (Log-rank <0.001). FLOT regimen showed 84. 4% ORR, was notably higher than other groups (p-value<0. 01).

ConclusionsFor resectable gastric cancer patients, the perioperative FLOT regimen led to a significant improvement in patients OS and PFS in comparison with ECF, DCF, and FOLFOX regimens. As such, the FLOT regimen could be considered the optimal option for managing resectable gastric cancer patients.

category: oncology


title: Efficacy and Safety of FLOT regimen vs DCF, FOLFOX, and ECF regimens as Perioperative Chemotherapy Treatments for Resectable Gastric Cancer Patients


title: Trans-ethnic eQTL meta-analysis of human brain reveals regulatory architecture and candidate causal variants for brain-related traits

abstract: While large-scale genome-wide association studies (GWAS) have identified hundreds of loci associated with neuropsychiatric and neurodegenerative traits, identifying the variants, genes and molecular mechanisms underlying these traits remains challenging. Integrating GWAS results with expression quantitative trait loci (eQTLs) and identifying shared genetic architecture has been widely adopted to nominate genes and candidate causal variants. However, this integrative approach is often limited by the sample size, the statistical power of the eQTL dataset, and the strong linkage disequilibrium between variants. Here we developed the multivariate multiple QTL (mmQTL) approach and applied it to perform a large-scale trans-ethnic eQTL meta-analysis to increase power and fine-mapping resolution. Importantly, this method also increases power to identify conditional eQTLs that are enriched for cell type specific regulatory effects. Analysis of 3,188 RNA-seq samples from 2,029 donors, including 444 non-European individuals, yields an effective sample size of 2,974, which is substantially larger than previous brain eQTL efforts. Joint statistical fine-mapping of eQTL and GWAS identified 301 variant-trait pairs for 23 brain-related traits driven by 189 unique candidate causal variants for 179 unique genes. This integrative analysis identifies novel disease genes and elucidates potential regulatory mechanisms for genes underlying schizophrenia, bipolar disorder and Alzheimers disease.

category: genetic and genomic medicine


title: Ranking videolaryngoscopes and direct laryngoscopes by orotracheal intubation performance in children: protocol of a systematic review and network meta-analysis of randomized clinical trials at patient level.

abstract:
BackgroundVideolaryngoscopy was shown to improve glottic visualization in children as compared to direct laryngoscopy, but at the expenses of delayed time for intubation. As little evidence is available regarding the relative performance of different laryngoscopes at present, we designed this systematic review and network meta-analysis to rank the different videolaryngoscopes (VLs) and direct laryngoscopes (DLs) for orotracheal intubation in children.

MethodsWe will conduct a search in PubMed, LILACS, Scielo, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 1) on 27/01/2021. We will include randomized clinical trials fully reported with patients aged [≤] 18 years, making comparisons between different types of laryngoscopes (any of both VLs and DLs) for failed first intubation attempt, intubation time, number of attempts at intubation or number of unsuccessful intubations, failed intubation, glottic view score, or adverse responses to endotracheal intubation. Pooled effects will be estimated by both fixed and random-effects models and presented according to qualitative and quantitative heterogeneity assessment. Sensitivity analyses will be performed as well as a priori subgroup, meta-regression and multiple meta-regression analyses. Additionally, network meta-analyses will be applied to rank the different VLs and DLs. We will also assess the risk of selective publication by funnel plot asymmetry.

DiscussionThis systematic review and network meta-analysis aim to understand which laryngoscopes perform better than others for orotracheal intubation.

Systematic review registrationThe current protocol was submitted to PROSPERO on 25/01/2021.

category: anesthesia


title: Development and external validation of prognostic models for COVID-19 to support risk stratification in secondary care

abstract:
ObjectivesExisting UK prognostic models for patients admitted to hospital with COVID-19 are limited by reliance on comorbidities, which are under-recorded in secondary care, and lack of imaging data among the candidate predictors. Our aims were to develop and externally validate novel prognostic models for adverse outcomes (death, intensive therapy unit (ITU) admission) in UK secondary care; and externally validate the existing 4C score.

DesignCandidate predictors included demographic variables, symptoms, physiological measures, imaging, laboratory tests. Final models used logistic regression with stepwise selection.

SettingModel development was performed in data from University Hospitals Birmingham (UHB). External validation was performed in the CovidCollab dataset.

ParticipantsPatients with COVID-19 admitted to UHB January-August 2020 were included.

Main outcome measuresDeath and ITU admission within 28 days of admission.

Results1040 patients with COVID-19 were included in the derivation cohort; 288 (28%) died and 183 (18%) were admitted to ITU within 28 days of admission. Area under the receiver operating curve (AUROC) for mortality was 0.791 (95%CI 0.761-0.822) in UHB and 0.767 (95%CI 0.754-0.780) in CovidCollab; AUROC for ITU admission was 0.906 (95%CI 0.883-0.929) in UHB and 0.811 (95%CI 0.795-0.828) in CovidCollab. Models showed good calibration. Addition of comorbidities to candidate predictors did not improve model performance. AUROC for the 4C score in the UHB dataset was 0.754 (95%CI 0.721-0.786).

ConclusionsThe novel prognostic models showed good discrimination and calibration in derivation and external validation datasets, and outperformed the existing 4C score. The models can be integrated into electronic medical records systems to calculate each individual patients probability of death or ITU admission at the time of hospital admission. Implementation of the models and clinical utility should be evaluated.

Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIWe developed novel prognostic models predicting mortality and ITU admission within 28 days of admission for patients hospitalised with COVID-19, using a large routinely collected dataset gathered at admission with a wide range of possible predictors (demographic variables, symptoms, physiological measures, imaging, laboratory test results).
C_LIO_LIThese novel models showed good discrimination and calibration in both derivation and external validation cohorts, and outperformed the existing ISARIC model and 4C score in the derivation dataset. We found that addition of comorbidities to the set of candidate predictors included in model derivation did not improve model performance.
C_LIO_LIIf integrated into hospital electronic medical records systems, the model algorithms will provide a predicted probability of mortality or ITU admission for each patient based on their individual data at, or close to, the time of admission, which will support clinicians decision making with regard to appropriate patient care pathways and triage. This information might also assist clinicians in explaining complex prognostic assessments and decisions to patients and their relatives.
C_LIO_LIA limitation of the study was that in the external validation cohort we were unable to examine all of the predictors included in the original full UHB model due to only a reduced set of candidate predictors being available in CovidCollab. Nevertheless, the reduced model performed well and the results suggest it may be applicable in a wide range of datasets where only a reduced set of predictor variables is available.
C_LIO_LIFurthermore, it was not possible to carry out stratified analysis by ethnicity as the UHB dataset contained too few patients in most of the strata, and no ethnicity data was available in the CovidCollab dataset.
C_LI

category: public and global health


title: What does 16S rRNA gene-targeted next generation sequencing contribute to the study of infective endocarditis in valve tissue?

abstract: Infective endocarditis (IE) is a severe and life-threatening disease. Identification of infectious etiology is essential for establishing the appropriate antimicrobial treatment and decreasing mortality. The aim of this study was to explore potential utility of metagenomics for improving microbiological diagnosis of IE. In this work, next-generation sequencing (NGS) of V3-V4 region of the 16S rRNA gene was performed in 27 heart-valve tissues (18 natives, 5 intravascular devices, and 4 prosthetics) of patients diagnosed by IE. Initial microbiological diagnosis, blood culture (BC) and/or PCR, was compared with NGS-based diagnosis. Metagenomics matched with conventional techniques diagnosis in 24/27 cases (88.9%). The same bacterial family was assigned to 24 cases, the same genus to 23 cases, and the same specie for 13 cases. In 22 of them, the etiological agent was represented by percentages >99% of the reads and in two by [~]70%. Staphylococcus aureus was detected in a previously undiagnosed patient, making the microbiological diagnosis possible in one more sample than with previously used techniques. The remaining two patients showed no coincidence between traditional and NGS microbiological diagnoses. Minority records verified mixed infections in four cases and suggested confections in two cases, supported by clinical data. In conclusion: 16S rRNA gene-targeted NGS allowed to diagnose one case of IE without microbiological entity based on traditional techniques. However, the application of metagenomics to the study of IE in resected heart valves provides no benefits in comparison with BC and/or PCR. More studies are needed before implementation of NGS for the diagnosis of IE.


title: Longitudinal analyses reveal age-specific immune correlates of COVID-19 severity

abstract: Severe COVID-19 disproportionately impacts older individuals and those with comorbidities. It is estimated that approximately 80% of COVID-19 deaths are observed among individuals >65 years of age. However, the immunological underpinnings of severe COVID-19 in the aged have yet to be defined. This study captures the longitudinal immune response to SARS-CoV-2 infection in a cohort of young and aged patients with varying disease severity. Phenotypic transcriptional and functional examination of the peripheral mononuclear cells revealed age-, time, and disease severity-specific adaptations. Gene expression signatures within memory B cells suggest qualitative differences in the antibody responses in aged patients with severe disease. Examination of T cells showed profound lymphopenia, that worsened over time and correlated with lower levels of plasma cytokines important for T cell survival in aged patients with severe disease. Single cell RNA sequencing revealed augmented signatures of activation, exhaustion, cytotoxicity, and type-I interferon signaling in memory T cells and NK cells. Although hallmarks of a cytokine storm were evident in both groups, older individuals exhibited elevated levels of chemokines that mobilize inflammatory myeloid cells, notably in those who succumbed to disease. Correspondingly, we observed a re-distribution of DC and monocytes with severe disease that was accompanied by a rewiring towards a more regulatory phenotype. Several of these critical changes, such as the reduction of surface HLA-DR on myeloid cells, were reversed in young but not aged patients over time. In summary, the data presented here provide novel insights into the impact of aging on the host response to SARS-CoV2 infection.


title: Risk-stratified lifestyle intervention to prevent type 2 diabetes

abstract:
BackgroundLifestyle intervention (LI) can successfully prevent type 2 diabetes, but response to LI strongly varies depending on risk subphenotypes. We tested if individuals with prediabetes and a high-risk phenotype benefit from an intensification of LI.

Methods and findingsWe conducted a risk stratified multicenter randomized controlled intervention study over 12 months with additional 2 year follow up. In eight University Hospitals in Germany, 1105 individuals (female 59%, age 58{+/-}11 years, BMI 31.1{+/-}6.0 kg/m2 (mean{+/-}SD)) with impaired fasting glucose and/or impaired glucose tolerance were included between May 2012 and May 2016 in the study. Participants were stratified into 2 groups; a high- and low-risk phenotype, based on insulin secretion, insulin sensitivity and liver fat content. Low-risk individuals were randomly assigned to conventional LI or control (1:1), high-risk individuals to conventional or intensified LI (1:1), each over one year. Intensified LI included doubling of physical exercise and time of counselling. The primary endpoint was change in post-challenge glucose levels, assessed by frequently sampled oral glucose tolerance tests. Secondary endpoints included changes in liver fat content, assessed by magnetic resonance spectroscopy. A total of 908 (82%) participants completed the study after 12 months of LI. In high-risk individuals, the mean difference estimate between conventional and intensified LI in change in post-challenge glucose levels from baseline was -0.290 mmol/l [CI: -0.544;-0.036], p=0.025. Liver fat content was more reduced by intensified LI than by conventional LI (mean difference estimate: -1.34 percentage points [CI: -2.17;-0.50], p=0.002), and cardiovascular risk decreased stronger with intensified LI than with conventional LI (mean difference estimate -1.82 [CI: -3.13-0.50], p=0.007). In low-risk individuals, conventional LI was not superior to control in reducing postprandial glucose, liver fat or cardiovascular risk. During the total observation period of 3 years, high-risk participants with intensified LI had a higher probability to normalize glucose tolerance compared to conventional LI (p=0.003). The limitations of this study include a relative short duration of LI, a non-completer rate of 18% and an underrepresentation of low risk individuals.

ConclusionsIn high-risk individuals with prediabetes it is possible to improve glycemic and cardiometabolic outcomes by intensification of the commonly recommended conventional LI. Our results show that individualized, risk-phenotype-based LI can be implemented for the prevention of diabetes.

RegistrationNCT01947595

Author summaryO_ST_ABSWhy Was This Study Done?C_ST_ABSO_LIClinical trials in individuals with prediabetes have shown that the onset of type 2 diabetes can be delayed or prevented with lifestyle intervention.
C_LIO_LIAmong individuals with prediabetes, there is a large variability in the response to lifestyle intervention.
C_LIO_LIIt is unknown whether an intensification of intervention is able to improve the beneficial response.
C_LI

What Did the Researchers Do and Find?O_LIThe present multicenter, risk stratified randomized and controlled intervention trial in 1105 German individuals with prediabetes prospectively confirms the existence of a high-risk prediabetes phenotype
C_LIO_LIThe intensification of lifestyle intervention in high-risk individuals improves the glycemic outcome after 1 year of lifestyle intervention, and additionally results in a higher frequency of regression to normal glucose tolerance after 3 years of follow up.
C_LIO_LI.Intensification of lifestyle intervention results in a larger reduction of liver fat content and stronger improves cardiometabolic outcomes in high-risk individuals.
C_LI

What Do These Findings Mean?O_LIStrategies for the prevention of type 2 diabetes should include risk stratification and individualised interventions.
C_LIO_LIOur results highlight a dose-effect relationship for lifestyle intervention and suggest that "one size fits NOT all" in the field of diabetes prevention.
C_LIO_LIIt remains to be clarified whether low risk individuals benefit from lifestyle intervention, as there was a low number of individuals in this risk group in the current study.
C_LI

category: endocrinology


title: Timing of elective tracheotomy and duration of mechanical ventilation amongst patients admitted to intensive care with severe COVID-19: a multicentre prospective cohort study

abstract:
BackgroundThe COVID-19 pandemic has strained intensive care unit (ICU) resources. Tracheotomy is the most frequent surgery performed on ICU patients and can affect the duration of ICU care. We studied the association between when tracheotomy occurs and weaning from mechanical ventilation, mortality, and intraoperative and postoperative complications.

MethodsMulticentre prospective cohort including all COVID-19 patients admitted to ICUs in 36 hospitals in Spain who received invasive mechanical ventilation and tracheotomy between 11 March and 20 July 2020. We used a target emulation trial framework to study the causal effects of early (7 to 10 days post-intubation) versus late (>10 days) tracheotomy on time from tracheotomy to weaning, postoperative mortality, and tracheotomy complications. Cause-specific Cox models were used for the first two outcomes and Poisson regression for the third, all adjusted for potential confounders.

FindingsWe included 696 patients, of whom 142 (20{middle dot}4%) received early tracheotomy. Using late tracheotomy as the reference group, multivariable cause-specific analysis showed that early tracheotomy was associated with faster post-tracheotomy weaning (fully adjusted hazard ratio (HR) [95% confidence interval (CI)]: 1{middle dot}31 [1{middle dot}02 to 1{middle dot}81]) without differences in mortality (fully adjusted HR [95% CI]: 0{middle dot}91 [0{middle dot}56 to 1{middle dot}47]) or intraoperative or postoperative complications (adjusted rate ratio [95% CI]: 0{middle dot}21 [0{middle dot}03 to 1{middle dot}57] and 1{middle dot}49 [0{middle dot}99 to 2{middle dot}24], respectively).

InterpretationEarly tracheotomy reduced post-tracheotomy weaning time, resulting in fewer mechanical ventilation days and shorter ICU stays, without changing complication or mortality rates. These results support early tracheotomy for COVID-19 patients when clinically indicated.

FundingSupported by the NIHR, FAME, and MRC.

Research in contextO_TEXTBOXEvidence before this studyThe optimal timing of tracheotomy for critically ill COVID-19 patients remains controversial. Existing guidelines and recommendations are based on limited experiences with SARS-CoV-1 and expert opinions derived from situations that differ from a pandemic outbreak. Most of the available guidance recommends late tracheotomy (>14 days), mainly due to the potential risk of infection for the surgical team and the high patient mortality rate observed early in the first wave of the COVID-19 pandemic.

Recent publications have shown that surgical teams can safely perform tracheotomies for COVID-19 patients if they use adequate personal protective equipment. Early tracheotomy seems to reduce the length of invasive mechanical ventilation without increasing complications, which may release crucial intensive care unit (ICU) beds sooner.

The current recommendations do not suggest an optimal time for tracheotomy for COVID-19 patients, and no study has provided conclusions based on objective clinical parameters.

Added value of this studyThis is the first study aiming to establish the optimal timing for tracheotomy for critically ill COVID-19 patients requiring invasive mechanical ventilation (IMV). The study prospectively recruited a large multicentre cohort of 696 patients under IMV due to COVID-19 and collected data about the severity of respiratory failure, clinical and ventilatory parameters, and whether patients need to be laid flat during their ICU stay (proned). The analysis focused on the duration of IMV, mortality, and complication rates. We used a prospective cohort study design to compare the  exposures of early (performed at day 7 to 10 after starting IMV) versus late (performed after day 10) tracheotomy and set the treatment decision time on the 7th day after orotracheal intubation.

Implications of all the available evidenceThe evidence suggests that tracheotomy within 10 days of starting COVID-19 patients on mechanical ventilation allows these patients to be removed from ventilation and discharged from ICU quicker than later tracheotomy, without added complications or increased mortality. This evidence may help to release ventilators and ICU beds more quickly during the pandemic.

C_TEXTBOX

category: respiratory medicine


title: Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss

abstract:
PurposeThe ClinGen Variant Curation Expert Panels (VCEPS) provide disease-specific rules for accurate variant interpretation. Using hearing loss-specific American College of Medical Genetics/Association for Molecular Pathology (HL-specific ACMG/AMP) guidelines, the ClinGen Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in resolving conflicting variant interpretations.

MethodsA total of 157 variants across nine hearing loss genes were curated and submitted to ClinVar by the HL VCEP. The curation process consisted of collecting published and unpublished data for each variant by biocurators, followed by bi-monthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific ACMG/AMP guidelines to reach a final classification.

ResultsBefore expert curation, 75% (117/157) of variants had single or multiple VUS submissions (17/157) or had conflicting interpretations in ClinVar (100/157). After applying the HL-specific ACMG/AMP guidelines, 24% (4/17) of VUS variants and 69% (69/100) of discordant variants were resolved into Benign (B), Likely Benign (LB), Likely Pathogenic (LP), or Pathogenic (P). Overall, 70% (109/157) variants had unambiguous classifications (B, LB, LP, P). We quantify the contribution of the HL-specified ACMG/AMP codes to variant interpretation.

ConclusionExpert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study supports the utility of ClinGen VCEPs in helping the community move towards more consistent variant interpretations, which will improve the care of patients with genetic disorders.


title: Structural basis of fitness of emerging SARS-COV-2 variants and considerations for screening, testing and surveillance strategy to contain their threat.

abstract: While emergence of new SAS-COV-2 variants is posing grave challenge to efforts to deal with the COVID-19 pandemic, the structural and molecular basis of their fitness remain poorly understood. We performed in silico analysis of structures of two most frequent SARS-COV-2 mutations, namely, N501Y and E484K, to identify plausible basis of their fitness over the original strain. The analysis suggested that the N501Y mutation is associated with strengthening of intra- as well as intermolecular H-bond in the hACE2 receptor-spike protein complex, which could result in increased affinity and, therefore, higher infectivity. While E484K mutation did not seem to directly affect the binding with hACE2 receptor, it disrupted H-bonding and salt-bridge interaction associated with binding with neutralizing antibody, which could affect chance of re-infection, disease outcome. Survey of several other mutations showing reduction in antibody-mediated neutralization also revealed that similar disruption of H-bonding or salt-bridge or Van der Waals interaction might explain their phenotype. Analysis of GESS database indicated that N501Y, EK484 as well as these other mutations existed since March-April, 2020, might have evolved independently across the world and may keep accumulating, which could affect efficacy of vaccination and antibody-based therapies. Our analysis also indicated that these may spread in spite of current travel restrictions focused on few countries and evolve indigenously warranting intensification of surveillance for emerging mutations among all travellers as well as people in their dwelling zones. Meta-analysis of existing literature showed that repeat testing of travellers, contacts and others under scrutiny 7-11 days after the initial RT-PCR test may significantly help to contain the spread of emerging variants by catching false negative results. In addition, existing evidence calls for development of strain-specific tests, escalated sequencing and broadening the scope of surveillance including in hospitals and animal farms to contain the threat of emerging variants.


title: Assessing antimicrobial resistance, utilization and stewardship in Yemen: An exploratory mixed-methods study

abstract: Antimicrobial resistance (AMR), largely driven by irrational use of antimicrobials, is a global, multi-faceted problem calling for a complete understanding of all contributory factors for effective containment. In conflict settings, war-wounds and malnutrition can combine with existing social determinants to increase demand for antibiotics, compounding irrational use. In this study, we focus on Yemen, a low-income country with active conflict for the last five years, and analyze the current status of awareness and stewardship efforts regarding AMR. We performed a survey of prescribers/physicians and pharmacists to describe perceptions of AMR prevalence, antibiotic use practices and stewardship in Yemen, supported by a non-systematic scoping literature review and a key informant interview. Participants (96%, n=57) reported a perceived high AMR prevalence rate. Prescribers (74%, 20/27) reported pressure to prescribe broad-spectrum antibiotics. In the majority of cases (81%, 22/27), Antimicrobial Sensitivity Tests (AST) were not performed to inform antibiotic choice. The main barrier to AST was cost. Most pharmacists (67%, 18/27) sold antibiotics without prescriptions. Amoxicillin (including amoxicillin-clavulanate) was the most-commonly prescribed (63%, 17/27) or dispensed (82%, 22/27) antibiotic. AST was rated the least important solution to AMR in Yemen. While there was awareness of a high AMR rate, stewardship is poor in Yemen. We note that barriers to the use of AST could be addressed through the deployment of low-cost AST kits. Compulsory continuing education emphasizing the use of AST to guide prescribing and patients awareness programs could help avoid irrational use.


title: How well do face masks protect the wearer compared to public perceptions?

abstract:
IntroductionThere is a growing body of evidence to support the wearing of face masks to reduce spread of infectious respiratory pathogens, including SARS-CoV-2. However, the literature exploring the effectiveness of homemade fabric face masks is still in its infancy. Developing an evidence base is an important step to ensure that public policy is evidence based and truly effective.

MethodsTwo methodologies were used in this study: quantitative fit testing of various face masks to indicate their effectiveness and a survey of 710 US residents about their perceptions of face mask effectiveness. N95, surgical and two fabric face masks were tested on an individual twenty five times each using a TSI 8038+ machine. Our survey was distributed by Qualtrics XM, asking participants to estimate the effectiveness of N95, surgical and fabric face masks.

Results and DiscussionOur results indicate that fabric face masks blocked between 62.6% and 87.1% of fine particles, whereas surgical masks protected against an average of 78.2% of fine particles. N95 masks blocked 99.6% of fine particles. Survey respondents tended to underestimate the effectiveness of masks, especially fabric masks. Together these results suggest that fabric masks may be a useful tool in the battle against the COVID-19 pandemic and that increasing public awareness of the effectiveness of fabric masks may help in this endeavour.


title: The Impact of Distractions on Intracortical Brain-Computer Interface Control of a Robotic Arm

abstract: This was an investigational device observational trial with the objective to evaluate the impact of distractions on intracortical brain-computer interface (BCI) performance. Two individuals with tetraplegia had microelectrode arrays implanted into their motor cortex for trials of intracortical BCI safety and performance. The primary task was moving a robotic arm between two targets as quickly as possible, performed alone and with various secondary distraction conditions. Primary outcomes included targets acquired, path efficiency, and subjective difficulty. There was no difference in the number of targets acquired for either subject with or without distractions. Median path efficiency was similar across all conditions (range: 0.766-0.846) except the motor distraction for Subject P2, where the median path efficiency dropped to 0.675 (p = 0.033, Mann-Whitney U test). Both subjects rated the overall difficulty of the task with and without distractions as low. Overall, intracortical BCI performance was robust to various distractions.


title: High-dimensional profiling reveals phenotypic heterogeneity and disease-specific alterations of granulocytes in COVID-19

abstract:
Since the outset of the COVID-19 pandemic, increasing evidence suggests that the innate immune responses play an important role in the disease development. A dysregulated inflammatory state has been proposed as key driver of clinical complications in COVID-19, with a potential detrimental role of granulocytes. However, a comprehensive phenotypic description of circulating granulocytes in SARS-CoV-2-infected patients is lacking. In this study, we used high-dimensional flow cytometry for granulocyte immunophenotyping in peripheral blood collected from COVID-19 patients during acute and convalescent phases. Severe COVID-19 was associated with increased levels of both mature and immature neutrophils, and decreased counts of eosinophils and basophils. Distinct immunotypes were evident in COVID-19 patients, with altered expression of several receptors involved in activation, adhesion and migration of granulocytes (e.g. CD62L, CD11a/b, CD69, CD63, CXCR4). Paired sampling revealed recovery and phenotypic restoration of the granulocytic signature in the convalescent phase. The identified granulocyte immunotypes correlated with distinct sets of soluble inflammatory markers supporting pathophysiologic relevance. Furthermore, clinical features, including multi-organ dysfunction and respiratory function, could be predicted using combined laboratory measurements and immunophenotyping. This study provides a comprehensive granulocyte characterization in COVID-19 and reveals specific immunotypes with potential predictive value for key clinical features associated with COVID-19.

SignificanceAccumulating evidence shows that granulocytes are key modulators of the immune response to SARS-CoV-2 infection and their dysregulation could significantly impact COVID-19 severity and patient recovery after virus clearance. In the present study, we identify selected immune traits in neutrophil, eosinophil and basophil subsets associated to severity of COVID-19 and to peripheral protein profiles. Moreover, computational modeling indicates that the combined use of phenotypic data and laboratory measurements can effectively predict key clinical outcomes in COVID-19 patients. Finally, patient-matched longitudinal analysis shows phenotypic normalization of granulocyte subsets 4 months after hospitalization. Overall, in this work we extend the current understanding of the distinct contribution of granulocyte subsets to COVID-19 pathogenesis.


title: Preoperative mu-opioid receptor availability predicts weight loss following bariatric surgery

abstract:
BackgroundBariatric surgery is the most effective method for weight loss in morbid obesity. There is significant individual variability in the weight loss outcomes, yet factors leading to postoperative weight loss or weight regain remain elusive. Alterations in the {micro}-opioid receptor (MOR) and dopamine D2 receptor (D2R) systems are associated with obesity, appetite control, and reward processing. The magnitude of initial brain receptor system perturbation is a plausible predictor of long-term surgical weight loss outcomes. The aim was to test this hypothesis by measuring obese subjects MOR and D2R availability with positron emission tomography (PET) preoperatively before bariatric surgery and then assessing their weight development association with regional MOR and D2R availabilities at 2-year follow-up.

MethodsWe studied 19 morbidly obese women (mean BMI 40, mean age 43) scheduled to undergo bariatric surgery, i.e. Roux-en-Y gastric bypass or sleeve gastrectomy, according to their standard clinical treatment. Preoperative MOR and D2R availabilities were measured using PET with [11C]carfentanil and [11C]raclopride, respectively. Subject weight was recorded at 3, 6, 12, and 24 months after surgery. Radiotracer binding potentials (BPND) were extracted and correlated with patient weight at different time points. ROIs were delineated in the striatum and in limbic and paralimbic components of the emotion and reward networks.

ResultsMOR availabilities were not correlated with preoperative weight. MOR availabilities in the amygdala (r = -0.54), insula (r = -0.46), ventral striatum (r = -0.48) and putamen (r = -0.49) were associated with subject weight at 3 months. Significant association was found in the amygdala at 6 months (r = -0.53), 12 (r = -0.49), and 24 months (r = -0.50). D2R availabilities were associated with neither preoperative weight nor weight loss at any follow-up time point.

ConclusionsTo our knowledge, this is the first study to demonstrate that neuroreceptor markers prior to bariatric surgery in patients with morbid obesity are associated with the postoperative weight loss. Preoperative MOR availability in the amygdala was associated with long-term postoperative weight development after surgery suggesting that postoperative weight regain may derive from dysfunction in the opioid system. Postoperative weight loss outcomes after bariatric surgery may be partially predicted based on preoperative receptor availability opening up new potential for treatment possibilities.

Clinical Trials RegistrationSleevePET2, NCT01373892, http://www.clinicaltrials.gov


title: Modeling the asymptomatic prevalence of SARS-CoV-2 epidemic in Italy and the ISTAT survey

abstract:
objectivesAugust 3rd, 2020, the Italian National Institute of Statistics (ISTAT) presented preliminary results of seroprevalence survey on the percentage of individuals affected by Covid-19. The survey aims to define (within the entire population of Italy) the portion of individuals that developed an antibody response against SARS-CoV-2. For the first time one has an estimate of the asymptomatic infected population and the possibility to acknowledge its potential role in the infection spread in Italy, one of the most affected areas in Europe. The information obtained allow a particularly sensitive validation of epidemiological models which include the asymptomatic class.

methodsThe present study is devoted to the construction of a model able to simulate, in a systematic way, the asymptomatic group whose relevance in the, SARS-CoV-2 epidemic, has been recently investigated and discussed. The investigation involves the description of the first epidemic outbreak in Italy as well as the predictive analysis of the ongoing second wave. In particular the possible correction to the data of the serological tests because of their sensitivity and specificity.

resultsThe model: taken as an example of the models presently used, satisfactory reproduces the data of the ISTAT survey showing a relevant predictive power and relegating in a secondary position models which do not include, in the simulation, the presence of asymptomatic groups. The corrections due to the serological test sensitivity (in particular those ones depending on the symptoms onset) make the comparison between data and models less accurate.

conclusionsThe predictions of the model confirm a relevant presence of asymptomatic individuals also during the second pandemic wave in Italy. The ratio of reported to unreported cases is predicted to be roughly 1:4. A more detailed knowledge of the results of the survey could allow to correct, in a relevant way, the data by means of the experimental evidences on the antibodies sensibility. The model analyses of the vaccination strategies, confirms the relevance of a massive administration with the beginning of the year to arrive at the end of the infection within August 2021.


title: Neighbourhood-level risk factors of COVID-19 incidence and mortality

abstract:
BackgroundRacialized and low income communities face disproportionally high rates of coronavirus 2019 (COVID-19) infection and death. However, data on inequities in COVID-19 across granular categories of socio-demographic characteristics is more sparse.

MethodsNeighbourhood-level counts of COVID-19 cases and deaths in Ontario, Canada recorded as of July 28th, 2020 were extracted from provincial and local reportable infectious disease surveillance systems. Associations between COVID-19 incidence and mortality and 18 neighbourhood-level measures of immigration, race, housing and socio-economic characteristics were estimated with Poisson generalized linear mixed models. Housing characteristic variables were subsequently added to models to explore if housing may have a confounding influence on the relationships between immigration, race, and socio-economic status and COVID-19 incidence.

ResultsThere were large inequities in COVID-19 incidence and mortality across the socio-demographic variables examined. Neighbourhoods having a higher proportion immigrants, racialized populations, large households and low socio-economic status were associated with COVID-19 risk. Adjusting for housing characteristics, especially unsuitably crowded housing, attenuated COVID-19 risks. However persistent risk remained for neighbourhoods having high proportions of immigrants, racialized populations, and proportion of Black, Latin American, and South Asian residents.

ConclusionsSocio-demographic factors account for some of the neighbourhood-level differences in COVID-19 across Ontario. Housing characteristics account for a portion, but not all, of the excess burden of COVID-19 experienced by immigrant, racialized, low income and low education populations.


title: Forecasting virus outbreaks with social media data via neural ordinary differential equations

abstract: In the midst of the covid-19 pandemic, social media data collected in real time has the potential of being an early indicator of a new epidemic wave. This possibility is explored here by using a neural ordinary differential equation (neural ODE) that is trained to predict virus outbreaks for a geographic region. It learns from multivariate time series of signals obtained from a novel set of massive online surveys about COVID-19 symptoms. Once trained, the neural ODE is able to capture the dynamics of the interlinked local signals and accurately predict the number of new infections up to two months in advance. Moreover, it can estimate the future effects of changes in the number of infected at a given time, which can be associated with the flow of people entering or leaving a given region or, for instance, with a local vaccination campaign. This work gives compelling preliminary evidence for the predictive power of widely distributed social media surveys for public health application


title: Mitigation policies and vaccination in the COVID-19 pandemic: a modelling study

abstract: The perspective of vaccination to protect human population from infection of SARS-CoV-2 virus has great potential to control the pandemic. Nevertheless, vaccine planning requires phased introduction with age groups, health workers, and vulnerable people. We developed a mathematical model capable of capturing the dynamics of the SARS-CoV-2 dissemination aligned with social distancing, isolation measures, and vaccination. The city of Rio de Janeiro provides a case study to analyze possible scenarios including non-pharmaceutical interventions and vaccination in the epidemic scenario. Our results shows that a combination of different policies such as case isolation and social distancing are more effective for mitigating the epidemics. Furthermore, these policies will still be necessary in a phased vaccination program. Therefore, health surveillance activities should be maintained along with vaccination planning in scheduled groups until a large vaccinated coverage is reached.


title: Impact of age, gender, ethnicity and prior disease status on immunogenicity following administration of a single dose of the BNT162b2 mRNA Covid-19 Vaccine: real-world evidence from Israeli healthcare workers, December-January 2020

abstract: The Pfizer Covid-19 vaccine showed high efficacy in clinical trials but observational data from populations not included in trials are needed. We described immunogenicity 21 days post-dose 1 among 514 Israeli healthcare workers by age, gender, ethnicity and prior COVID19 infection. Immunogenicity was similar by gender and ethnicity but decreased with age. Those with prior infection had antibody titres one magnitude order higher than naive individuals regardless of the presence of detectable IgG antibodies pre-vaccination.


title: REACT-1 round 8 final report: high average prevalence with regional heterogeneity of trends in SARS-CoV-2 infection in the community in England during January 2021

abstract: In early January 2021, England entered its third national lockdown of the COVID-19 pandemic to reduce numbers of deaths and pressure on healthcare services, while rapidly rolling out vaccination to healthcare workers and those most at risk of severe disease and death. REACT-1 is a survey of SARS-CoV-2 prevalence in the community in England, based on repeated cross-sectional samples of the population. Between 6th and 22nd January 2021, out of 167,642 results, 2,282 were positive giving a weighted national prevalence of infection of 1.57% (95% CI, 1.49%, 1.66%). The R number nationally over this period was estimated at 0.98 (0.92, 1.04). Prevalence remained high throughout, but with suggestion of a decline at the end of the study period. The average national trend masked regional heterogeneity, with robustly decreasing prevalence in one region (South West) and increasing prevalence in another (East Midlands). Overall prevalence at regional level was highest in London at 2.83% (2.53%, 3.16%). Although prevalence nationally was highest in the low-risk 18 to 24 year old group at 2.44% (1.96%, 3.03%), it was also high in those over 65 years who are most at risk, at 0.93% (0.82%, 1.05%). Large household size, living in a deprived neighbourhood, and Black and Asian ethnicity were all associated with higher levels of infections compared to smaller households, less deprived neighbourhoods and other ethnicities. Healthcare and care home workers, and other key workers, were more likely to test positive compared to other workers. If sustained lower prevalence is not achieved rapidly in England, pressure on healthcare services and numbers of COVID-19 deaths will remain unacceptably high.


title: Mapping a Pandemic: SARS-CoV-2 Seropositivity in the United States

abstract: Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates. To address this, we analyzed seropositivity in US adults who have not previously been diagnosed with COVID-19. Individuals with characteristics that reflect the US population (n = 11,382) and who had not previously been diagnosed with COVID-19 were selected by quota sampling from 241,424 volunteers (ClinicalTrials.gov NCT04334954). Enrolled participants provided medical, geographic, demographic, and socioeconomic information and 9,028 blood samples. The majority (88.7%) of samples were collected between May 10th and July 31st, 2020. Samples were analyzed via ELISA for anti-Spike and anti-RBD antibodies. Estimation of seroprevalence was performed by using a weighted analysis to reflect the US population. We detected an undiagnosed seropositivity rate of 4.6% (95% CI: 2.6 - 6.5%). There was distinct regional variability, with heightened seropositivity in locations of early outbreaks. Subgroup analysis demonstrated that the highest estimated undiagnosed seropositivity within groups was detected in younger participants (ages 18-45, 5.9%), females (5.5%), Black/African American (14.2%), Hispanic (6.1%), and Urban residents (5.3%), and lower undiagnosed seropositivity in those with chronic diseases. During the first wave of infection over the spring/summer of 2020 an estimate of 4.6% of adults had a prior undiagnosed SARS-CoV-2 infection. These data indicate that there were 4.8 (95% CI: 2.8-6.8) undiagnosed cases for every diagnosed case of COVID-19 during this same time period in the United States, and an estimated 16.8 million undiagnosed cases by mid-July 2020.


title: Trends and opportunities in tick-borne disease geography

abstract: Tick-borne diseases are a growing problem in many parts of the world, and their surveillance and control touches on challenging issues in medical entomology, agricultural health, veterinary medicine, and biosecurity. Spatial approaches can be used to synthesize the data generated by integrative One Health surveillance systems, and help stakeholders, managers, and medical geographers understand the current and future distribution of risk. Here, we performed a systematic review of over 8,000 studies, and identified a total of 303 scientific publications that map tick-borne diseases using data on vectors, pathogens, and hosts (including wildlife, livestock, and human cases). We find that the field is growing rapidly, with the major Ixodes-borne diseases (Lyme disease and tick-borne encephalitis in particular) giving way to monitoring efforts that encompass a broader range of threats. We find a tremendous diversity of methods used to map tick-borne disease, but also find major gaps: data on the enzootic cycle of tick-borne pathogens is severely underutilized, and mapping efforts are mostly limited to Europe and North America. We suggest that future work can readily apply available methods to track the distributions of tick-borne diseases in Africa and Asia, following a One Health approach that combines medical and veterinary surveillance for maximum impact.


title: Point-of-Care CRISPR-Cas-Assisted SARS-CoV-2 Detection in an Automated and Mobile Droplet Magnetofluidic Device

abstract: In the fight against COVID-19, there remains unmet needs in developing point-of-care (POC) diagnostic testing tools that can rapidly and sensitively detect the causative SARS-CoV-2 virus to control disease transmission and improve patient management. Although recent CRISPR-Cas-assisted SARS-CoV-2 detection assays (such as DETECTR and SHERLOCK) are viewed as transformative solutions for POC diagnostic testing, their lack of simple sample processing and full integration within an automated and portable device hamper their potential for POC use. We report herein POC-CRISPR - a new single-step CRISPR-Cas-assisted assay that is coupled to droplet magnetofluidics (DM) - that leverages simple magnetic concentration and transport of nucleic acid-binding magnetic beads to accomplish sample preparation and assay automation. By further adapting the assay into a fully integrated thermoplastic cartridge within a palm-sized mobile device, POC-CRISPR was able to detect 1 genome equivalent (GE)/{micro}L SARS-CoV-2 RNA from a sample volume of 100 {micro}L in 30 min. Moreover, when evaluated with unprocessed clinical nasopharyngeal (NP) swab eluates, POC-CRISPR identified SARS-CoV-2 positive samples in as short as 20 min and achieved full concordance with standard RT-qPCR.


title: Nationwide Seroprevalence of SARS-CoV-2 in Saudi Arabia

abstract:
BackgroundEstimated seroprevalence of Coronavirus Infectious Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is a critical evidence for a better evaluation of the virus spread and monitoring the progress of the COVID-19 pandemic in a population. In the Kingdom of Saudi Arabia (KSA), SARS-CoV-2 seroprevalence has been reported in specific regions, but an extensive nationwide study has not been reported. Here, we report a nationwide study to determine the prevalence of SARS-CoV-2 in the population of KSA during the pandemic, using serum samples from healthy blood donors, non-COVID patients and healthcare workers (HCWs) in six different regions of the kingdom, with addition samples from COVID-19 patients.

MethodsA total of 11703 serum samples were collected from different regions of the KSA including; 5395 samples from residual healthy blood donors (D); 5877 samples from non-COVID patients collected through residual sera at clinical biochemistry labs from non-COVID patients (P); and 400 samples from consented HCWs. To determine the seroprevalence of SARS-CoV-2, all serum samples, in addition to positive control sera from RT-PCR confirmed COVID-19 patients, were subjected to in-house ELISA with a sample pooling strategy, which was further validated by testing individual samples that make up some of the pools, with a statistical estimation method to report seroprevalence estimates

ResultsOverall (combining D and P groups) seroprevalence estimate was around 11% in Saudi Arabia; and was 5.1% (Riyadh), 1.5% (Jazan), 18.4% (Qassim), 20.8% (Hail), 14.7% (ER; Alahsa), and 18.8% in Makkah. Makkah samples were only D group and had a rate of 24.4% and 12.8% in the cities of Makkah and Jeddah, respectively. The seroprevalence in Saudi Arabia across the sampled areas would be 12 times the COVID-19 infection rate. Among HCWs, 7.5% (4.95-10.16 CI 95%) had reactive antibodies to SARS-CoV-2 without reporting any previously confirmed infection. This was higher in HCWs with hypertension. The study also presents the demographics and prevalence of co-morbidities in HCWs and subset of non-COVID-19 population.

ConclusionOur study estimates the overall national serological prevalence of COVID-19 in Saudi Arabia to be 11%, with an apparent disparity between regions.


title: Evidence for SARS-CoV-2 Spike Protein in the Urine of COVID-19 patients

abstract: SARS-CoV-2 infection has so far affected over 42 million people worldwide, causing over 1.1 million deaths. With the large majority of SARS-CoV-2 infected individuals being asymptomatic, major concerns have been raised about possible long-term consequences of the infection. We developed an antigen capture assay to detect SARS-CoV-2 spike protein in urine samples from COVID-19 patients whose diagnosis was confirmed by PCR from nasopharyngeal swabs (NP-PCR+). The study used a collection of 233 urine samples from 132 participants from Yale New Haven Hospital and the Childrens Hospital of Philadelphia obtained during the pandemic (106 NP-PCR+ and 26 NP-PCR-) as well as a collection of 20 urine samples from 20 individuals collected before the pandemic. Our analysis identified 23 out of 91 (25%) NP-PCR+ adult participants with SARS-CoV-2 spike S1 protein in urine (Ur-S+). Interestingly, although all NP-PCR+ children were Ur-S-, 1 NP-PCR-child was found to be positive for spike protein in urine. Of the 23 Ur-S+ adults, only 1 individual showed detectable viral RNA in urine. Our analysis further showed that 24% and 21% of NP-PCR+ adults have high levels of albumin and cystatin C in urine, respectively. Among individuals with albuminuria (>0.3 mg/mg of creatinine) statistical correlation could be found between albumin and spike protein in urine. Together, our data showe that 1 of 4 of SARS-CoV-2 infected individuals develop renal abnormalities such as albuminuria. Awareness about the long-term impact of these findings is warranted.


title: Serosurveillance of SARS CoV 2 among the healthcare workers of a tertiary care teaching institution in Central Kerala during the post lockdown phase

abstract:
BackgroundKerala was the first state to have the confirmed case of COVID-19 in the country and it was first confirmed in Thrissur district on 30 January2020.Our institute being in the heart of the city had to take adequate measures to mitigate the spread and treat the required patients by keeping its staff safe & Healthy. The hallmark of COVID 19 infection is high infectivity, pre-symptomatic transmission and asymptomatic prevalence which could result in high cumulative numbers of infections, hospitalizations, and deaths. Kerala was the first state to confirm community transmission in July 2020.Health care workers being in the forefront in the war against COVID19 are very prone in acquiring the infection and are possible to be asymptomatic sources for cluster formation. Knowing the development of immunity as shown by the presence of anti COV2 antibodies in the population contributes to the epidemiological understanding of the disease. The intent of the study is to do an antibody testing in our hospital to find the serosurveillance of SARS CoV 2 among the healthcare workers in our hospital.

AimTo estimate the seropositivity of SARS CoV 2 among the healthcare workers at Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, six months after revoking the lockdown

MethodologyA cross sectional study among the health care workers of the medical college. Multistage Sampling was done with the hospital block as the first stage and departments as the second stage. In the final stage of sampling the test individuals were selected on a first come first served basis after the antibody test availability was declared open and free for all staff. A consent form and a Google form were given to all staff who volunteered for participating in the study. Each consented participant recruited into the investigation completed a questionnaire which covers details regarding demographics, exposure history, Residence & travel. Blood sample was collected and Anti-SARS COV2 IgG antibody testing which targets the Spike Protein 1(SP1) was done using the VITROS chemiluminescence platform (Orthoclinical diagnostics, USA). Sampling & testing ranged over a time frame from September 5th to December 15th, 2020

ResultsJubilee Mission Medical College has 2785 working staff at the time of study. A total of 420 staff consented and their samples were tested. 37 staff members tested positive for COVID-19 antibody, yielding an overall prevalence of 8.75% (95% CI, 6.23-11.86). 86.5 % (32/37) of them were having a history of COVID-19 Antigen / RT PCR Positivity. We identified a statistically significant linear trend (p value =0.00001), between seropositivity and the degree of severity of COVID 19. Among the various factors which increase the risk of seroconversion, history of undergoing quarantine (p value < 0.001), contact with a confirmed case (p value = 0.002), contact with a caregiver for COVID 19 (p value =0.001) and history of Upper respiratory symptoms (p value =0.001), were found to be significantly associated with positive serology.

ConclusionsThe overall seropositivity in the current study was found to be 8.75% which is comparable to seroprevalence studies conducted in the United States and Wuhan in China. The pattern of seropositivity across the different category of health workers observed in the present study showed a higher prevalence among nurses. This result is also in agreement with a recent published report from united states. Various measures advised by the national and state health authorities were adequately adhered to. Keeping track of the pattern of development of immunity in the community is part of understanding the illness and forecasting the spread. For the tested HCW, it will boost up morale by ending uncertainty. For the hospital administration it will help in decision making about relative focusing of interventions on patients in general and HCWs. By knowing the immunity status of HCWs, the Institution will be able to contribute authentically to the development of intervention strategies and guidelines from time to time, besides following the available guidelines. Being an educational institution, it is obligatory to train all the elements of care delivery to the future generation of health care workers. Getting experienced from a small but relevant sample was expected to facilitate larger community study envisaged in peripheral areas Jubilee served


title: SARS-CoV-2 antigen rapid diagnostic test enhanced with silver amplification technology

abstract: Rapid diagnosis of COVID-19 is essential for instituting measures to prevent viral spread. SARS-CoV-2 antigen rapid diagnostic test (Ag-RDT) based on lateral flow immunochromatography assay (LFIA) principle can visually indicate the presence of SARS-CoV-2 antigens as a band. Ag-RDT is clinically promising as a point-of-care testing because it can give results in a short time without the need for special equipment. Although various antigen capture LFIAs are now available for rapid diagnosis for SARS-CoV-2 infection, they face the problems of low sensitivity. We have previously developed highly specific monoclonal antibodies (mAb) against SARS-CoV-2 nucleocapsid protein (NP) and in this study, we have employed these mAbs to develop a new LFIA that can detect SARS-CoV-2 NP in nasopharyngeal swab samples with higher sensitivity by combining them with silver amplification technology. We also compared the performance of our Ag-RDT against the commercially available Ag-RDTs using clinical samples to find that our newly developed LFIA performed best among tested, highlighting the superiority of silver amplification technology.


title: Automated detection and staging of malaria parasites from cytological smears using convolutional neural networks

abstract:
Microscopic examination of blood smears remains the gold standard for diagnosis and laboratory studies with malaria. Inspection of smears is, however, a tedious manual process dependent on trained microscopists with results varying in accuracy between individuals, given the heterogeneity of parasite cell form and disagreement on nomenclature. To address this, we sought to develop an automated image analysis method that improves accuracy and standardisation of cytological smear inspection but retains the capacity for expert confirmation and archiving of images. Here we present a machine-learning method that achieves red blood cell (RBC) detection, differentiation between infected and uninfected RBCs and parasite life stage categorisation from raw, unprocessed heterogeneous images of thin blood films. The method uses a pre-trained Faster Region-Based Convolutional Neural Networks (R-CNN) model for RBC detection that performs accurately, with an average precision of 0.99 at an intersection-over-union threshold of 0.5. A residual neural network (ResNet)-50 model applied to detect infection in segmented RBCs also performs accurately, with an area under the receiver operating characteristic curve of 0.98. Lastly, using a regression model our method successfully recapitulates intra-erythrocytic developmental cycle (IDC) stages with accurate categorisation (ring, trophozoite, schizont), as well as differentiating asexual stages from gametocytes. To accelerate our methods utility, we have developed a mobile-friendly web-based interface, PlasmoCount, which is capable of automated detection and staging of malaria parasites from uploaded heterogeneous input images of Giemsa-stained thin blood smears. Results gained using either laboratory or phone-based images permit rapid navigation through and review of results for quality assurance. By standardising the assessment of parasite development from microscopic blood smears, PlasmoCount markedly improves user consistency and reproducibility and thereby presents a realistic route to automating the gold standard of field-based malaria diagnosis.

Significance StatementMicroscopy inspection of Giemsa-stained thin blood smears on glass slides has been used in the diagnosis of malaria and monitoring of malaria cultures in laboratory settings for >100 years. Manual evaluation is, however, time-consuming, error-prone and subjective with no currently available tool that permits reliable automated counting and archiving of Giemsa-stained images. Here, we present a machine learning method for automated detection and staging of parasite infected red cells from heterogeneous smears. Our method calculates parasitaemia and frequency data on the malaria parasite intraerythrocytic development cycle directly from raw images, standardizing smear assessment and providing reproducible and archivable results. Developed into a web tool, PlasmoCount, this method provides improved standardisation of smear inspection for malaria research and potentially field diagnosis.


title: Predicting and simulating effects of PEEP changes with machine learning

abstract:
Background/ObjectivesChoosing ventilator settings, especially positive end-expiratory pressure (PEEP), is a very common and non-trivial task in intensive care units (ICUs). Established solutions to this problem are either poorly individualised or come with high costs in terms of used material or time. We propose a novel method relying on machine learning utilising only already routinely measured data.

MethodsUsing the MIMIC-III (with over 60000 ICU stays) and eICU databases (with over 200000 ICU stays) we built a deep learning model that predicts relevant success parameters of ventilation (oxygenation, carbon dioxide elimination and respiratory mechanics). We compare a random forest, individual neural networks and a multi-tasking neural network. Our final model also allows to simulate the expected effects of PEEP changes.

ResultsThe model predicts arterial partial pressures of oxygen and carbon dioxide and respiratory system compliance 30 minutes into the future with mean absolute percentage errors of about 22 %, 10 % and 11 %, respectively.

ConclusionsThe deep learning approach to ventilation optimisation is promising and comes with low cost compared to other approaches.

category: intensive care and critical care medicine


title: Awake prone positioning and oxygen therapy in patients with COVID-19: The APRONOX study

abstract:
PurposeThe awake prone position (PP) strategy for patients with acute respiratory distress syndrome (ARDS) is a safe, simple, and cost-effective technique used to improve hypoxemia. We aimed to evaluate the relationship between awake PP (AP) and endotracheal intubation in patients with coronavirus disease (COVID-19).

MethodsIn this retrospective, multicentre observational study conducted between 1 May and 12 June 2020 in 27 hospitals in Mexico and Ecuador, non-intubated patients with COVID-19 managed with AP or awake supine positioning (AS) were included to evaluate intubation and mortality risk in AP patients through logistic regression models; multivariable adjustment, propensity score analyses, and E-values were calculated to limit confounding. A CART model with cross-validation was also built. This study was registered at https://clinicaltrials.gov/ct2/show/NCT04407468

Results827 non-intubated patients with COVID-19 in the AP (n=505) and AS (n=322) groups were included for analysis. Less patients in the AP group required endotracheal intubation (23.6% vs 40.4%) or died (20% vs 37.9%). AP was a protective factor for intubation even after multivariable adjustment (OR=0.39, 95%CI:0.28-0.56, p<0.0001, E-value=2.01), which prevailed after propensity score analysis (OR=0.32, 95%CI:0.21-0.49, p<0.0001, E-value=2.21), and mortality (adjusted OR=0.38, 95%CI:0.25-0.57, p<0.0001, E-value=1.98). The main variables associated with PP failure in AP patients were age, lower SpO2/FiO2, and management with a non-rebreather mask. In the CART model, only two variables were used: SpO2/FiO2 (F 97.7, p<0.001) and PP (X2 50.5, p<0.001), with an overall percentage of 75.2%.

ConclusionPP in awake hospitalised patients with COVID-19 is associated with a lower risk of intubation and mortality.


title: SARS-CoV-2 Seroepidemiology in Children and Adolescents

abstract:
ObjectivesPediatric SARS-CoV-2 data remain limited and seropositivity rates in children were reported as <1% early in the pandemic. Seroepidemiologic evaluation of SARS-CoV-2 in children in a major metropolitan region of the United States was performed.

MethodsChildren and adolescents [≤]19 years were enrolled in a cross-sectional, observational study of SARS-CoV-2 seroprevalence from July-October 2020 in Northern Virginia, United States. Demographic, health, and COVID-19 exposure information was collected, and blood was analyzed for SARS-CoV-2 spike protein total antibody. Risk factors associated with SARS-CoV-2 seropositivity were analyzed. Orthogonal antibody testing was performed, and samples were evaluated for responses to different antigens.

ResultsIn 1038 children, the anti-SARS-CoV-2 total antibody positivity rate was 8.5%. After multivariate logistic regression, significant risk factors included Hispanic ethnicity, public or absent insurance, a history of COVID-19 symptoms, exposure to person with COVID-19, a household member positive for SARS-CoV-2 and multi-family or apartment dwelling without a private entrance. 66% of seropositive children had no symptoms of COVID-19. Orthogonal antibody testing with a receptor binding domain specific antigen revealed a high concordance of 80.5%. Children also demonstrated a robust immune response to the nucleocapsid antigen.

ConclusionsA much higher burden of SARS-CoV-2 infection, as determined by seropositivity, was found in children than previously reported; this was also higher compared to adults in the same region at a similar time. Contrary to prior reports, we determined children shoulder a significant burden of COVID-19 infection. The role of childrens disease transmission must be considered in COVID-19 mitigation strategies including vaccination.

Article Summary8.5% of children had SARS-CoV-2 antibodies in Fall 2020, double the adult rate. The role of pediatric infection is important to consider in mitigation strategies.

Whats Known on This SubjectSARS-CoV-2 pediatric seroepidemiologic data is limited. Reported viral rates underestimate the burden of infection in children due to mild or asymptomatic disease. Limited cohorts of children suggest low seropositivity rates compared to adults.

What This Study AddsUS children in the largest SARS-CoV-2 seroepidemiology study to date had double the rate of antibodies compared to adults. Most children were asymptomatic. Risk factors include age, ethnicity and living conditions. Most children made antibodies to different antigens of SARS-CoV-2.

category: pediatrics


title: Title: Health and Healthcare Variables Associated with Italy's Excess Mortality during the First Wave of the COVID-19 pandemic: An Ecological Study.

abstract:
BackgroundHealthcare factors have strongly influenced the propagation of COVID-19. The present study aims to examine whether excess mortality during the first phase of the COVID-19 outbreak in Italy was associated with health, healthcare, demographic, and socioeconomic indicators measured at a provincial level.

MethodsThe present ecological study concerns the raw number of deaths from Jan. 1 to Apr. 30, 2020 and the mean number of deaths in the same months of 2015 to 2019, per province. Information on socioeconomic factors and healthcare settings were extracted from the most recently updated databases on the ISTAT website. Two multilevel, multivariate models were constructed to test whether excess mortality was associated with the indicators across 107 provinces in Italy.

ResultsOn linear multilevel, multivariate analysis, AIDS mortality rate (p-value <0.05) correlates positively with excess mortality, while a higher density of General Practitioners (number of GPs per 1,000 population) is associated with lower excess mortality (p-value <0.05). After controlling for the diffusion of COVID-19 in each province, the significance of GP density increases (p-value <0.001) and the rate of hospitalization in long-term care wards is positively associated (p-value <0.05) with excess mortality.

ConclusionSome health and healthcare variables are strongly associated with excess mortality caused by COVID-19 in Italy and should be considered to implement mitigation policies and increase healthcare resilience.


title: Frequency of hospitalization of infants with bronchiolitis during 2017 in Puerto Madryn, Argentina

abstract:
IntroductionBronchiolitis is considered the most frequent disease in infants and still represents an important cause of morbidity and mortality worldwide. Despite its viral etiology, socioeconomic variables could influence the disease outcome. We aimed to determine the frequency of hospital discharge for bronchiolitis in a local Hospital in the city of Puerto Madryn, in the province of Chubut, Patagonia Argentina.

Population and methodsWe performed a cross-sectional study that analyzed all hospitalized patients discharged for bronchiolitis in Hospital "Dr. Andres R. Isola" during the year 2017 and based on data provided by the hospital administrative staff. The study variables were the length of stay, readmission rate and place of origin of hospitalized patients.

ResultsA total of 120 patients were included. The median age was 4.45 months (3.9-5). The mean length-of-stay (LOS) was 7.30 days (5.52-9.08). Of the total number of patients, 24 (20%) had a LOS [≤]3 days and 96 (80%) a >3 days. One hundred patients (88.33%) had no hospital readmissions and 10 patients (8.33%) had hospital readmissions. The median age of patients with readmissions was 4.2 months (2.69-5.71). The mean LOS during readmission was 17.3 days (5.25-29.35). Of the 120 hospitalized children, 100 infants (83.33%) live in areas identified as having "unsatisfied basic needs" in Puerto Madryn.

ConclusionsThe overcrowding as a result of the demographic transformation on the frequency of hospitalization of infants with bronchiolitis was homogeneous within the Puerto Madryn population with "unsatisfied basic needs".


title: Site-specific biases in phase-III clinical trials underestimate the effect of radical cure against Plasmodium vivax hypnozoites

abstract:
Plasmodium vivax relapses caused by reactivating hypnozoites are a major barrier for elimination and control of this form of malaria. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65% to 94%, with substantial variation across trial sites. We performed an analysis of simulated trial data using a transmission model to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. Our analysis revealed that differences in transmission intensity, heterogeneous exposure, and relapse rate can yield efficacy estimates ranging as wide as 12-78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison of the protection of different radical cure treatment regimens against relapse more challenging. We show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect protection against relapse. We predict that site-specific biases are likely to contribute to variation in efficacy estimates both within and across phase-III clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where reinfections from mosquito biting are less common, by preventing reinfections using vector control measures, or by identifying and excluding likely reinfections that occur during follow-up using parasite genotyping methods.

AUTHOR SUMMARYRadical cure holds promise as a strategy for Plasmodium vivax malaria control by clearing the parasites known as hypnozoites that latently infect the liver and cause relapsing infections. The efficacy of radical cure treatment regimens is evaluated in phase-III clinical trials. Recent trial results have noted substantial variation in efficacy estimates across trial sites, complicating the interpretation of the benefit of radical cure. However, P. vivax infections identified during the course of the clinical trial could include reinfections from mosquito biting that do not directly reflect the effect of the therapeutic being trialed, potentially biasing efficacy estimates. In this study, we simulated clinical trials to identify the causes and solutions of these site-specific biases. We found that features of both the trial location, such as the transmission intensity, and the trial design, such as the duration of follow-up, lead to an underestimate of the effect of radical cure against hypnozoites. We then demonstrated that vector control and parasite genotyping are two possible strategies to reduce these biases. These insights can be leveraged to aid in the interpretation of past trial results and to help design future clinical trials that minimize site-specific biases.


title: How radical is radical cure? Site-specific biases in phase-III clinical trials underestimate the effect of radical cure against Plasmodium vivax hypnozoites


title: Investigating the DNA methylation profile of e-cigarette use

abstract:
Rationale and objectivesLittle evidence exists on the health effects of e-cigarette use. DNA methylation may serve as a biomarker for exposure and could be predictive of future health risk. We aimed to investigate the DNA methylation profile of e-cigarette use.

MethodsAmong 117 smokers, 117 non-smokers and 116 non-smoking vapers, we evaluated associations between e-cigarette use and epigenome-wide methylation from saliva. We tested associations between e-cigarette use and methylation scores known to predict smoking and smoking-related disease. We assessed the ability of a methylation score for predicting e-cigarette use and for discriminating lung cancer.

Measurements and Main Results7 CpGs were identified in relation to e-cigarette use at p<1x10-5 and none at p<5.91x10-8. 13 CpGs were associated with smoking at p<1x10-5 and one at p<5.91x10-8. CpGs associated with e-cigarette use were largely distinct from those associated with smoking. There was strong enrichment of known smoking-related CpGs in the smokers but not the vapers. A methylation score for e-cigarette use showed poor prediction internally (AUC 0.55, 0.41-0.69) and externally (AUC 0.57, 0.36-0.74) compared with a smoking score (AUCs 0.80) and was less able to discriminate lung squamous cell carcinoma from adjacent normal tissue (AUC 0.64, 0.52-0.76 versus AUC 0.73, 0.61-0.85).

ConclusionsThe DNA methylation profile for e-cigarette use is largely distinct from that of cigarette smoking, did not replicate in independent samples, and was unable to discriminate lung cancer from normal tissue. The extent to which methylation related to long-term e-cigarette use translates into chronic effects requires further investigation.

Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSIs there a DNA methylation signature of e-cigarette use and is it distinct from that of smoking?

What is the bottom line?Smoke exposure is known to lead to widespread changes in DNA methylation which have been identified in different populations and samples, persist for many years after smoking cessation, and may act as a biomarker for smoking-related disease risk and mortality. Whether a similar methylation profile exists in relation to e-cigarette use has not been widely investigated.

Why read on?We obtained saliva samples from 116 e-cigarette users and compared their DNA methylation profile with 117 smokers and 117 non-smokers. The e-cigarette users in this study had a minimal smoking history, and so we were able to distinguish the effects of e-cigarette use from those of smoke exposure. Overall, we found that the methylation profile associated with e-cigarette use is less pronounced and distinct from that associated with cigarette smoking.


title: A control framework to optimize public health policies in the course of the COVID-19 pandemic

abstract:
The SARS-CoV-2 pandemic triggered substantial economic and social disruptions. Mitigation policies varied across countries based on resources, political conditions, and human behavior. In the absence of widespread vaccination able to induce herd immunity, strategies to coexist with the virus while minimizing risks of surges are paramount, which should work in parallel with reopening societies. To support these strategies, we present a predictive control system coupled with a nonlinear model able to optimize the level of policies to stop epidemic growth. We applied this system to study the unfolding of COVID-19 in Bahia, Brazil, also assessing the effects of varying population compliance. We show the importance of finely tuning the levels of enforced measures to achieve SARS-CoV-2 containment, with periodic interventions emerging as an optimal control strategy in the long-term.

One-sentence summaryWe present an adaptive predictive control algorithm to provide optimal public health measures to slow the COVID-19 transmission rate.


title: Racial and Ethnic Disparities in Years of Potential Life Lost Attributable to COVID-19 in the United States: An Analysis of 45 States and the District of Columbia

abstract: The coronavirus disease 2019 (COVID-19) epidemic in the United States has disproportionately impacted communities of color across the country. Focusing on COVID-19-attributable mortality, we expand upon a national comparative analysis of years of potential life lost (YPLL) attributable to COVID-19 by race/ethnicity (Bassett et al., 2020), estimating percentages of total YPLL for non-Hispanic Whites, non-Hispanic Blacks, Hispanics, non-Hispanic Asians, and non-Hispanic American Indian or Alaska Natives, contrasting them with their respective percent population shares, as well as age-adjusted YPLL rate ratios - anchoring comparisons to non-Hispanic Whites - in each of 45 states and the District of Columbia using data from the National Center for Health Statistics as of December 30, 2020. Using a novel Monte Carlo simulation procedure to quantify estimation uncertainty, our results reveal substantial racial/ethnic disparities in COVID-19-attributable YPLL across states, with a prevailing pattern of non-Hispanic Blacks and Hispanics experiencing disproportionately high and non-Hispanic Whites experiencing disproportionately low COVID-19-attributable YPLL. Furthermore, observed disparities are generally more pronounced when measuring mortality in terms of YPLL compared to death counts, reflecting the greater intensity of the disparities at younger ages. We also find substantial state-to-state variability in the magnitudes of the estimated racial/ethnic disparities, suggesting that they are driven in large part by social determinants of health whose degree of association with race/ethnicity varies by state.


title: R1441G but not G201S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils

abstract:
Gain-of kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause Parkinsons disease (PD), albeit with incomplete and age-dependent penetrance, offering the prospect of disease-modifying treatment strategies via LRRK2 kinase inhibition. LRRK2 phosphorylates a subgroup of RabGTPases including Rab10 and pathogenic mutations enhance LRRK2-mediated phosphorylation of Rab10 at Thr73.

In this study we analyse LRRK2 dependent Rab10Thr73 phosphorylation in human peripheral blood neutrophils isolated from 101 individuals using quantitative immunoblotting and mass spectrometry. Our cohort includes 42 LRRK2 mutation carriers (21 with the G2019S mutation that resides in the kinase domain and 21 with the R1441G mutation that lies within the ROC-COR domain), 27 patients with idiopathic PD, and 32 controls.

We show that LRRK2 dependent Rab10 Thr73 phosphorylation is significantly elevated in all R1441G LRRKR2 mutation carriers irrespective of disease status. PD manifesting and non-manifesting G2019S mutation carriers as well as idiopathic PD samples did not display elevated Rab10 Thr73 phosphorylation. Furthermore, we analysed brain samples of 10 G2019S and 1 R1441H mutation carriers as well as 10 individuals with idiopathic PD and 10 controls. We find high variability for pRab10Thr73 phosphorylation amongst donors irrespective of genetic and disease state.

We conclude that in vivo LRRK2 dependent pRab10Thr73 analysis in human peripheral blood neutrophils is a specific and robust biomarker for LRRK2 kinase activation for individuals with mutations such as R1441G that enhance pRab10Thr73 phosphorylation over 2-fold. We provide the first evidence that the LRRK2 R1441G mutation enhances LRRK2 kinase activity in a primary human cell.

category: neurology


title: Pharmacometabolomics Identifies Candidate Predictor Metabolites of an L-carnitine Treatment Mortality Benefit in Septic Shock

abstract:
BackgroundSepsis-induced metabolic dysfunction contributes to organ failure and death. L-carnitine has shown promise for septic shock, but a recent study demonstrated a non-significant reduction in mortality.

MethodsA pharmacometabolomics study of patients (n=250) in a Phase II trial of L-carnitine to identify metabolic profiles predictive of a 90-day mortality benefit from L-carnitine. The independent predictive value of each pre-treatment metabolite concentration, adjusted for L-carnitine dose, on 90-day mortality was determined by logistic regression. A grid-search analysis maximizing the Z-statistic from a binomial proportion test identified specific metabolite threshold levels that discriminated L-carnitine responsive patients. Threshold concentrations were further assessed by hazard-ratio and Kaplan-Meier estimate.

FindingsAccounting for L-carnitine treatment and dose, 11 1H-NMR metabolites and 12 acylcarnitines were independent predictors of 90-day mortality. Based on the grid-search analysis numerous acylcarnitines and valine were identified as candidate metabolites of drug response. Acetylcarnitine emerged as highly viable for the prediction of an L-carnitine mortality benefit due to its abundance and biological relevance. Using its most statistically significant threshold concentration, patients with acetylcarnitine [≥]35{micro}M were less likely to die at 90 days if treated with L-carnitine (18 g) versus placebo (p=0.01 by log rank test).

InterpretationMetabolomics identified independent predictors of 90-day sepsis mortality. Our proof-of-concept approach shows how pharmacometabolomics may be useful for tackling the heterogeneity of sepsis and informing clinical trial design. Also, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, since sepsis induces alterations in numerous metabolite concentrations.

category: pharmacology and therapeutics


title: Surveillance-to-Diagnostic Testing Program for Asymptomatic SARS-CoV-2 Infections on a Large, Urban Campus - Georgia Institute of Technology, Fall 2020

abstract: A SARS-CoV-2 testing program combining pooled saliva sample surveillance leading to diagnosis and intervention surveyed over 112,000 samples from 18,029 students, staff and faculty, as part of integrative efforts to mitigate transmission at the Georgia Institute of Technology in Fall 2020. Cumulatively, 1,508 individuals were confirmed diagnostically. The surveillance strategy, including focused intensification of testing given case clusters, was effective in disrupting transmission following rapid case increases upon entry in August 2020, and again in November 2020. Owing to broad adoption by the campus community, the program protected higher risk staff while allowing some normalization of research activities.