title: Factors Associated with Timely Test Seeking, Test Turnaround, and Public Reporting of COVID-19: a retrospective analysis in Ontario, Canada

abstract:
BackgroundMinimizing delays in disease identification and reporting improves the timeliness of surveillance data, and can reduce transmission of COVID-19. Our study investigates factors associated with timely testing and reporting of COVID-19 during the first pandemic wave in one province of Canada.

MethodsWe identified all persons with confirmed SARS-CoV-2 infection residing in private households across the largest province of Canada, Ontario from the date of the first confirmed case in Ontario (January 25) to July 19, 2020. Our primary outcomes consisted of: (1) specimen collection within 1 day of symptom onset (test seeking), (2) test result reported to local public health within 1 day of specimen collection (test turnaround), and (3) entry of case data into the provincial database within 1 day of reporting test results (reporting). We examined 14 covariates including eight case characteristics, and six neighborhood characteristics. In addition to descriptive measures, logistic regression models were fitted. Unadjusted models included the covariate alone, while adjusted models included age, gender, month, and region.

FindingsAmong 27,198 COVID-19 cases from January 25 2020 to July 19 2020, 28{middle dot}7% had timely test seeking, 40{middle dot}2% had timely test turnaround, and 75{middle dot}5% had timely reporting. Male gender had lower odds of timely test seeking (adjusted odds ratio [aOR] 0{middle dot}79 [95% CI: 0{middle dot}74-0{middle dot}85]) compared to females. Healthcare worker status (aOR 2{middle dot}77 [95% CI: 2{middle dot}52-3{middle dot}05] compared to non-healthcare workers), and age [≥]80 years (aOR 1{middle dot}59 [95% CI: 1{middle dot}33-1{middle dot}91] compared to 40-59 year olds) were associated with timely test seeking. Specimen collection on Fridays and Saturdays (aOR 0{middle dot}88 [95% CI: 0{middle dot}79-0{middle dot}98], aOR 0{middle dot}83 [95% CI: 0{middle dot}74-0{middle dot}92] respectively, compared to Wednesdays) had lower odds of timely test turnaround. Urban areas (aOR 1{middle dot}55 [95% CI: 1{middle dot}41-1{middle dot}70] compared to rural areas) were associated with timely test turnaround. Urban areas (aOR 0{middle dot}79 [95% CI: 0{middle dot}70-0{middle dot}89] compared to rural areas) were less likely to have timely reporting.

InterpretationIndividual, neighborhood, and administrative factors are associated with timely testing and reporting of SARS-CoV-2 infections. These findings present considerations for developing targeted strategies to minimize delays and improve timely testing and reporting of SARS-CoV-2 infections.

FundingThis study was funded by Public Health Ontario.

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and medRxiv up to November 30 2020 to identify studies examining the impact of delays in the disease reporting process on the public health response to COVID-19. We used the search terms ("2019-nCoV" OR "COVID-19" OR "SARS-CoV-2") AND ("delays" OR "timely" OR "reporting" OR "test" OR "turnaround"), and reviewed reference lists of any relevant articles in the original search. Numerous modeling studies have highlighted the importance of timely testing and reporting to effectively control the spread of COVID-19. Additional studies have also identified delays of only 1 day in testing were associated with increased risk of secondary transmission within households. However no study has described the multiple delays in the disease reporting process of COVID-19 and examined factors associated with timely disease reporting using a large population cohort.

Added value of this studyOur study described timely test seeking, test turnaround, and reporting for laboratory-confirmed COVID-19 cases in Ontario, Canada and identified associated individual, neighbourhood, and administrative factors. To the best of our knowledge, this study is the first to describe detailed delays in the disease reporting process of COVID-19 and identified associated factors using a large population cohort.

Implications of all the available evidenceNumerous individual, neighborhood, and administrative characteristics are associated with timely testing and reporting of COVID-19. These identified factors may be used to develop strategies such as broadened test access, prioritization of vulnerable populations, and increased testing capacity to reduce delays in testing and reporting and improve the effectiveness of public health response to COVID-19.


title: Ketamine and attentional bias to threat: dynamic causal modeling of magnetoencephalographic connectivity in treatment-resistant depression

abstract: The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (MDD) and bipolar disorder. While its underlying mechanism of antidepressant action is not fully understood, modulating glutamatergically-mediated connectivity appears to be a critical component moderating antidepressant response. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with MDD and 15 healthy volunteers who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and six to nine hours after both drug and placebo infusions. During scanning, participants completed an attentional dot probe task that included emotional faces. Antidepressant response was measured across timepoints using the Montgomery-Asberg Depression Rating Scale (MADRS). Dynamic causal modeling (DCM) was used to measure changes in parameter estimates of connectivity via a biophysical model that included realistic local neuronal architecture and receptor channel signaling, modeling connectivity between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus. Clinically, ketamine administration significantly reduced depressive symptoms in MDD participants. Within the model, ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in MDD participants post-ketamine were associated with faster -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamines antidepressant effects.

category: psychiatry and clinical psychology


title: A rapid review of equity considerations in large-scale testing campaigns during infectious disease epidemics

abstract:
ContextLarge-scale testing is an intervention that is instrumental for infectious disease control and a central tool for the COVID-19 pandemic. Our rapid review aimed to identify if and how equity has been considered in large-scale testing initiatives.

MethodsWe searched Web of Science and PubMed in November 2020 and followed PRISMA recommendations for scoping reviews. Articles were analyzed using descriptive and thematic analysis.

ResultsOur search resulted in 291 studies of which 41 were included for data extraction after full article screening. Most of the included articles (83%) reported on HIV-related screening programs, while the remaining programs focused on other sexually transmitted infections (n=3) or COVID-19 (n=4). None of the studies presented a formal definition of (in)equity in testing, however, 23 articles did indirectly include elements of equity in the program or intervention design, largely through the justification of their target population.

ConclusionThe studies included in our rapid review did not explicitly consider equity in their design or evaluation. It is imperative that equity is incorporated into the design of infectious disease testing programs and serves as an important reminder of how equity considerations are needed for SARS-CoV-2 testing and vaccination programs.

category: public and global health


title: Anti-cardiolipin and other anti-phospholipid antibodies in critically ill COVID-19 positive and negative patients

abstract:
BackgroundReports of severe COVID-19 being associated with thrombosis, anti-phospholipid antibodies (APLA), anti-phospholipid syndrome (APS) have yielded disparate conclusions. Studies comparing COVID-19 patients with contemporaneous controls of similar severity are lacking.

Methods22 COVID+ and 20 COVID- patients with respiratory failure admitted to intensive care were studied longitudinally. Demographic and clinical data were obtained from the day of admission. APLA testing included anti-cardiolipin (aCL), anti-{beta}2glycoprotien 1 ({beta}2GP1), anti-domain 1 beta2 glycoprotein 1 ({beta}2GP1) and anti-phosphatidyl serine/prothrombin complex (PS/PT). Anti-nuclear antibodies (ANA) were detected by immunofluorescence and antibodies to cytokines by a commercially available multiplexed array. ANOVA was used for continuous variables and Fishers exact test was used for categorical variables with =0.05 and the false discovery rate at q=0.05.

ResultsAPLA were predominantly IgG aCL (48%) followed by IgM (21%) in all patients, with a tendency toward higher frequency among the COVID+. aCL was not associated with surrogate markers of thrombosis but IgG aCL was strongly associated with worse disease severity and higher ANA titers regardless of COVID-19 status. An association between aCL and anti-cytokine autoantibodies tended to be higher among the COVID+.

ConclusionsPositive APLA serology was associated with more severe disease regardless of COVID-19 status.

KEY MESSAGESO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LICOVID-19 is associated with coagulopathy and high morbidity and mortality.
C_LIO_LICOVID-19 shares some of these clinical features with anti-phospholipid syndrome.
C_LIO_LIReports of an association of anti-phospholipid antibodies with high risk COVID-19 have yielded disparate conclusions, but they lacked longitudinal follow up and control groups of similar severity.
C_LI

What does this study add?O_LIAnti-phospholipid syndrome serology assessed longitudinally was predominantly anticardiolipin IgG autoantibodies, in 48% of patients.
C_LIO_LIAnticardiolipin serology was associated with worse disease severity in both COVID-19 positive and negative patients.
C_LI

How might this impact on clinical practice or future developments?O_LIThe use of anti-phospholipid antibodies tests in the COVID-19 clinical setting needs to be taken in context; whereas they are associated with more serve disease, they do not discriminate between COVID-19 positive and negative patients.
C_LI

category: rheumatology


title: Excess Serum Interleukin-18 Distinguishes Patients with Pathogenic Mutations in PSTPIP1

abstract:
ObjectiveDominantly-inherited mutations in PSTPIP1 cause a family of monogenic autoinflammatory diseases epitomized by Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome. The connections between PSTPIP1 and PAPA are poorly understood, although in vitro evidence suggests increased activation of the pyrin-inflammasome. We sought to identify biomarkers of potential mechanistic, diagnostic, and therapeutic utility specific to autoinflammatory diseases.

MethodsClinical and genetic data and sera were obtained from patients referred with concern for PAPA syndrome, as well as relevant disease controls. Serum Interleukin-18 (IL-18) and related biomarkers were assessed by bead-based assay.

ResultsSymptoms in PSTPIP1 mutation-positive PAPA patients overlapped with those of mutation-negative PAPA-like patients, but the former were younger at onset and had more arthritis. We found uniform elevation of total IL-18 in PAPA patients at a level approaching NLRC4-associated Macrophage Activation Syndrome (MAS) and well beyond Familial Mediterranean Fever. IL-18 elevation in PAPA patients sera persisted despite fluctuations in disease activity. IL-18 Binding Protein (IL-18BP) was modestly elevated, and as such PAPA patients had detectable free IL-18. PAPA patients did not develop MAS, and CXCL9 (an indicator of Interferon-gamma activity) was rarely elevated in their sera.

ConclusionPAPA syndrome is a refractory, and often disabling monogenic autoinflammatory disease associated with chronic elevation of serum IL-18, but not risk for MAS. This finding instructs our understanding of the origins of excess IL-18, its potential spectrum of pathogenic effects, and the possible role for IL-18 blockade in refractory PAPA syndrome.


title: Estimating VO2peak in 18-91 year-old adults: Development and validation of the FitMax - Questionnaire

abstract:
ObjectivesCardiorespiratory fitness plays an essential role in health outcomes and quality of life. Objective assessment of cardiorespiratory fitness is costly, labour intensive and not widely available. Although patient-reported outcome measures estimate cardiorespiratory fitness more cost-efficiently, the current questionnaires lack accuracy. The aim of this study is to develop and validate the FitMax(C)-questionnaire, a self-reported questionnaire to estimate cardiorespiratory fitness in healthcare.

MethodsWe developed the FitMax(C)-questionnaire, consisting of three questions assessing walking, stair climbing, and cycling capacity. A comparison on estimating VO2peak was made with the Duke Activity Status Index (DASI), Veterans Specific Activity Questionnaire (VSAQ) and cardiopulmonary exercise testing as the gold standard. A total of 716 patients and athletes (520 men, 196 women) aged 18{square}91 performed a CPET in our hospital. We randomly selected 70% of the subjects to fit a linear regression model to estimate VO2peak based on the FitMax(C) scores. The remaining 30% of participants was used for validation of this model.

ResultsThe VO2peak estimated by the FitMax(C) strongly correlates with the VO2peak measured objectively with CPET; r=0.95 (0.93{square}0.96) SEE=3.94 ml{middle dot}kg-1{middle dot}min-1. Bias between predicted and measured VO2peak was 0.32 ml{middle dot}kg-1{middle dot}min-1 and the 95% limits of agreement were -8.11 {square} 9.40 ml{middle dot}kg-1{middle dot}min-1. In our sample, the FitMax scored superiorly on correlation and SEE compared with those from the DASI and VSAQ, r=0.80 (0.73{square}0.86) SEE=4.22 ml{middle dot}kg-1{middle dot}min-1 and r=0.88 (0.84{square}0.91) SEE=6.61 ml{middle dot}kg-1{middle dot}min-1, respectively.

ConclusionFitMax(C) is a valid and accessible questionnaire to estimate cardiorespiratory fitness expressed as VO2peak and shows substantial improvement compared to currently used questionnaires.

Key pointsO_LIFitMax(C) relies on three simple single-answer questions, which are recognizable for a large population, to accurately estimate cardiorespiratory fitness.
C_LIO_LIThe FitMax(C) is a self-reported instrument in which involvement of physicians, healthcare providers or other instrumentation is not necessary.
C_LIO_LICardiorespiratory fitness estimated by the FitMax(C) may serve as an easily applicable measure in clinical and non-clinical settings.
C_LI

category: sports medicine


title: Thalamic organization in essential tremor patients with neuropathy: implication for functional neurosurgery

abstract:
BackgroundMechanisms underlying the suboptimal effect of ventral intermediate nucleus deep brain stimulation in patients with essential tremor and co-morbid peripheral neuropathy remain unclear.

ObjectivesWe compared disease-related (location and extension of the ventral intermediate nucleus) and surgery-related (targeting, intraoperative testing) factors in essential tremor patients with and without peripheral polyneuropathy treated with deep brain stimulation of the ventral intermediate nucleus, testing whether the overlap between volume of tissue activated and ventral intermediate nucleus (target coverage) was associated with clinical outcomes.

MethodsPreoperative diffusion magnetic resonance imaging was used for thalamic segmentation, based on preferential cortical connectivity. The target coverage was estimated using a finite element model. Tremor severity was scored at rest, posture, action, and handwriting at baseline, 6, and 12 months. Tremor improvement <50% at 12 months was deemed suboptimal. Vertex-wise shape analysis and edge analysis were performed to compare the ventral intermediate nucleus location and extension.

Results9.7% (18/185) of essential tremor patients treated with deep brain stimulation had co-morbid polyneuropathy. These patients showed a more medial (p=0.03) and anterior (p=0.04) location of the ventral intermediate nucleus, lower target coverage (p=0.049), and worse clinical outcomes (p=0.006) compared to those without polyneuropathy. No differences were observed in the volume of tissue activated between the two groups. Optimal clinical outcomes were associated with greater target coverage (optimal coverage >48%).

ConclusionsIn essential tremor, co-morbid polyneuropathy may result in suboptimal deep brain stimulation outcomes and lower target coverage, likely related to a reorganization of the ventral thalamic nuclei.

category: neurology


title: A cross-sectional study of socioeconomic status and treatment interruption among Japanese workers during the COVID-19 pandemic

abstract:
BackgroundThe COVID-19 pandemic has caused interruptions to chronic disease and non-emergency treatment. The purpose of this study is to examine which socioeconomic status groups are most at risk of treatment interruption.

MethodsThis cross-sectional internet monitor study was conducted on December 22-26, 2020, when Japan experienced its third wave of COVID-19 infection. Out of a total of 33,302 participants in the survey, 9510 (5392 males and 4118 females) who responded that they required regular treatment or hospital visits were included in the analysis. A multilevel logistic model nested in the prefecture of residence was used to estimate the odds ratio (OR) for treatment disruption. We examined separate multivariate models for socioeconomic factors, health factors, and lifestyle factors.

ResultsDuring a period of rapid COVID-19 infection, about 11% of Japanese workers who required regular treatment experienced interruptions to their treatment. The OR of treatment interruption associated with not being married compared to being married was 1.44; manual labor work compared to desk work was 1.30; loss of employment when the COVID-19 pandemic started and continued unemployment compared to being employed over the entire pandemic period was 1.62 and 2.57, respectively; and feeling financially unstable was 2.92.

ConclusionTreatment interruption is a new health inequality brought about by COVID-19 with possible medium- and long-term effects, including excess mortality, morbidity, and productivity loss due to increased presenteeism. Efforts are needed to reduce treatment interruptions among workers who require regular treatment.

category: occupational and environmental health


title: WT1 Tumor Antigen is Overexpressed in Kaposi Sarcoma and is Regulated by KSHV vFLIP

abstract:
PurposeWilms tumor 1 (WT1) is overexpressed in several cancers, and WT1 expression levels are associated with poor prognosis. As a host protein that functions as an oncogene, it represents an important immunotherapeutic target. This study evaluated WT1 expression in Kaposi sarcoma (KS) tumors to assess whether immunotherapy targeting WT1 is a potential therapeutic approach for KS. We also investigated the role of the causal agent of KS, Kaposi sarcoma herpesvirus (KSHV/HHV-8) in regulating WT1 expression.

Experimental designImmunohistochemistry for WT1, KSHV, and B and T cells subsets, followed by image analysis, was performed in 363 KS tumor biopsies. Expression of KSHV vFLIP was evaluated by immunofluorescence. Primary endothelial cell cultures and cell lines were infected with KSHV in vitro, or transduced with an inducible vFLIP vector and induced with doxycycline, and then assessed for WT1 expression. Binding of ESK-1, a T cell receptor mimic therapeutic antibody that recognizes WT1 peptides presented on MHC HLA-A0201, was assessed using flow cytometry.

ResultsWe report overexpression of WT1 in KS tumors, which was associated with increased with increasing histopathologic stage and the proportion of KSHV-infected cells. Areas with high WT1 expression showed sparse T cell infiltrates. KSHV infection in vitro resulted in WT1 upregulation, mediated by the viral protein vFLIP, which resulted in stronger binding of ESK1.

ConclusionsKS lesions express high levels of WT1, a process regulated by the KSHV-encoded vFLIP. These findings suggest that immunotherapy directed against WT1 may represent a therapeutic approach for this cancer.

Translational RelevanceKaposi sarcoma (KS) is a vascular neoplasm caused by the Kaposi sarcoma herpesvirus (KSHV/HHV-8). People living with HIV are not only at a significantly higher risk of developing KS, but also often have a more aggressive clinical course. Although antiretroviral therapy may cause regression of HIV-associated KS lesions, advanced cases of KS also require chemotherapy, which is rarely curative. Wilms tumor 1 (WT1) has been reported to be overexpressed in various cancers, functioning as an oncogene and associated with a poor prognosis. WT1 is also an important immunotherapeutic target, with several WT1-directed therapies showing promising results in early clinical trials for leukemias and solid tumors. Here we report high expression of WT1 in KS, especially in higher histological stages. Our findings provide pre-clinical evidence that supports conducting anti-WT1 immunotherapy trials in KS, and evaluating WT1 expression as a potential biomarker to identify individuals most likely to benefit.

category: oncology


title: Critical COVID-19 represents an endothelial disease with high similarity to kidney disease on the molecular level

abstract: In patients with critical or mild COVID19 (WHO stages 6-8 [n=53] and stages 1-3 [n=66]), 593 urinary peptides significantly affected by disease severity were identified, reflecting the molecular pathophysiology associated with the course of the infection. The peptide profiles were similar compared with those observed in kidney disease, a prototype of target organ damage with major microvascular involvement, thereby confirming the observation that endothelial damage is a hallmark of COVID19. The clinical corollary is that COVID19 is an indication for anti-oxidative, anti-inflammatory and immunosuppressive treatment modalities protecting the endothelial lining.

category: infectious diseases


title: High-resolution longitudinal serum proteome trajectories in COVID-19 reveal patients-specific seroconversion

abstract:
Biomarkers for COVID-19 are urgently needed. Here we bring the powerful technology of mass spectrometry (MS)-based proteomics to bear on this challenge. We measured serum proteomes of COVID-19 patients and symptomatic, but PCR-negative controls, in a time-resolved manner. In 262 controls and 458 longitudinal samples (average of 31 days) of 31 patients, hospitalized for COVID-19, a remarkable 26% of proteins changed significantly. Bioinformatics analyses revealed co-regulated groups and shared biological functions. Proteins of the innate immune system such as CRP, SAA1, CD14, LBP and LGALS3BP decreased early in the time course. In contrast, regulators of coagulation (APOH, FN1, HRG, KNG1, PLG) and lipid homeostasis (APOA1, APOC1, APOC2, APOC3, PON1) increased over the course of the disease. A global correlation map provides a systems-wide functional association between proteins, biological processes and clinical chemistry parameters. Importantly, five SARS-CoV-2 immunoassays against antibodies revealed excellent correlations with an extensive range of immunoglobulin regions, which were quantified by MS-based proteomics. The high-resolution profile of all immunoglobulin regions showed individual-specific differences and commonalities of potential pathophysiological relevance.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/21252236v1_ufig1.gif" ALT="Figure 1">
View larger version (86K):
org.highwire.dtl.DTLVardef@4f1770org.highwire.dtl.DTLVardef@8bdc12org.highwire.dtl.DTLVardef@1d4e21org.highwire.dtl.DTLVardef@1f49622_HPS_FORMAT_FIGEXP  M_FIG C_FIG HighlightsO_LIA total of 720 proteomes of 262 symptomatic controls and 458 longitudinal samples (average 31 days) of hospitalized COVID-19 cases were analyzed
C_LIO_LI26% of the 502 quantified proteins significantly changed in COVID-19 patients
C_LIO_LIThe innate immune and the coagulation system were strongly regulated
C_LIO_LIMS-based profiles of immunoglobulin regions allow the detection of seroconversion in a highly detailed fashion on the patient level
C_LIO_LIITIH4 may be a prospective marker of COVID-19 mortality
C_LI


title: Lower respiratory tract sampling via bronchoscopy in COVID-19 ARDS - A focus on microbiology, cellular morphology, cytology and management impact

abstract:
BackgroundLower respiratory tract (LRT) sampling via bronchoscopy has been done sparingly in COVID-19 ARDS due to the high aerosol risk for the health care workers (HCW). Valuable information can be gained by detailed evaluation of bronchoscopic LRT samples.

MethodsLRT samples were obtained by bedside bronchoscopy performed in suspected or confirmed severe COVID-19 ARDS patients on mechanical ventilation. Only positive cases were included in the study. Microbiological, cellular and cytological studies including LRT COVID-19 RT-PCR were performed and analysed.

Results100 samples were collected from 63 patients, 53 were males (84%). 43 patients (68%) had at least 1 comorbidity. 55% cases had secondary bacterial infection as demonstrated by positive culture. Most of these infections were due to multi-drug resistant organisms (94.5%). The most common organisms were Klebsiella pneumoniae and Acinetobacter baumanii in 56.3% and 14.5% cases respectively. Fungal superinfection was observed in 9 patients (14.3%). Bronchoscopy helped confirm COVID-19 diagnosis in 1 patient and helped rule out COVID-19 in 3 patients who were eventually excluded from the study. The median BAL fluid (BALF) WBC count was 953 (IQR; 400-2717), with mean neutrophil count 85.2% ({+/-}13.9), and mean lymphocyte count 14.8% ({+/-}13.9). Repeat sampling done in some patients showed a progressive increase in the total WBC count in BALF, an increase in neutrophil percentage, and a higher chance of isolating an organism on the culture (81% repeat procedures were culture positive). The rate of super-infection increased with longer duration of illness. Patients with superinfection also had an increased WBC count (1001 vs 400), and lower lymphocyte percentage (19% vs 12% - OR - 6.8 [95%CI -14.3 - 0.7]). Bronchoscopic LRT sampling contributed significantly to modifying antibiotic coverage and discontinuing steroids in 37% cases.

ConclusionThis study describes a detailed analysis of bronchoscopic LRT sampling in critically ill COVID-19 patients. This provided important basic and applied information augmenting disease understanding and contributing to clinical management when there was scant information available in the pandemic.


title: Single-Particle Counting Based on Digital Plasmonic Nanobubble Detection for Rapid and Ultrasensitive Diagnostics

abstract:
Rapid and sensitive diagnostics of infectious diseases is an urgent and unmet need as evidenced by the COVID-19 pandemic. Here we report a novel strategy, based on DIgitAl plasMONic nanobubble Detection (DIAMOND), to address these gaps. Plasmonic nanobubbles are transient vapor bubbles generated by laser heating of plasmonic nanoparticles and allow single-particle detection. Using gold nanoparticles labels and an optofluidic setup, we demonstrate that DIAMOND achieves a compartment-free digital counting and works on homogeneous assays without separation and amplification steps. When applied to the respiratory syncytial virus diagnostics, DIAMOND is 150 times more sensitive than commercial lateral flow assays and completes measurements within 2 minutes. Our method opens new possibilities to develop single-particle digital detection methods and facilitate rapid and ultrasensitive diagnostics.

One Sentence SummarySingle-particle digital plasmonic nanobubble detection allows rapid and ultrasensitive detection of viruses in a one-step homogeneous assay.


title: Neutralizing antibody responses 10 months after mild and moderately-severe SARS-CoV-2 infection

abstract:
Improved understanding of immunity offered by the antibodies developed against SARS-CoV-2 is critical. Our study aimed at longitudinal analysis of presence and persistence of neutralizing antibodies over ten months in mild and moderately-severe COVID-19 recovered patients using two immunoassays.

Article Summary LineNeutralizing IgG antibody persistency was demonstrated in 63.3% of the subjects (19 out of 30) at ten months post-infection with zero re-infections.


title: SARS-Cov-2 testing in the United Arab Emirates: Population Attitudes and Beliefs.

abstract:
ObjectivesThe United Arab Emirates responded to the SARS-COV-2 pandemic and widely implemented test-and-trace strategy. In this cross-sectional questionnaire-based study 531 subjects presenting for SARS-COV-2 testing were recruited to study populations beliefs and choices regarding testing and were compared to 156 who never been tested.

ResultsThe community uptake in Abu Dhabi Emirate reached 90% (average of 68% overall). In the great majority it was self-motivated as 6% only had doctor referral. Those who had not taken a test were younger in age (p < 0.001), more likely performing activities such as shopping and eating out (p = 0.001), have a medical illness (p < 0.0001), and working from home (p = 0.005). The tested group reported significantly more agreement with the statement, if someone had negative result no need to stay home or wear mask. In conclusion, SARS-COV-2 testing had extensive coverage and high acceptability in the UAE. Acting on concluded beliefs and attitude are key to ensure the testing coverage efficiency and public empowerment.

category: epidemiology


title: Machine learning-based single cell and integrative analysis reveals that baseline mDC predisposition predicts protective Hepatitis B vaccine response

abstract: Vaccination to prevent infectious disease is one of the most successful public health interventions ever developed. And yet, variability in individual vaccine effectiveness suggests a better mechanistic understanding of vaccine-induced immune responses could improve vaccine design and efficacy. We have previously shown that protective antibody levels could be elicited in a subset of recipients with only a single dose of the hepatitis B virus (HBV) vaccine. Why some, but not all, recipients responded in this way was not clear. Using single cell RNA sequencing of sorted innate immune cell subsets, we identified two distinct myeloid dendritic cell subsets (NDRG1-expressing mDC2 and CDKN1C-expressing mDC4), the ratio of which at baseline (pre-vaccination) predicted immune response to a single dose of HBV vaccine. Our results suggest that the participants in our vaccine study were in one of two different dendritic cell dispositional states at baseline - an NDRG2-mDC2 state in which the vaccine elicited an antibody response after a single immunization or a CDKN1C-mDC4 state in which the vaccine required two or three doses for induction of antibody responses. Genes expressed in these mDC subsets were used as an approach for feature selection prior to the construction of a predictive model using supervised canonical correlation machine learning. The resulting model showed an improved ability to predict serum antibody titers in response to vaccination. Taken together, these results suggest that the propensity of circulating dendritic cells toward either activation or suppression, their "dispositional endotype", could dictate response to vaccination. The fact that these mDCs could be modulated via TLR stimulation could guide progress towards design of effective single dose vaccination strategies.

category: allergy and immunology


title: Deep neural network estimated electrocardiographic-age as a mortality predictor

abstract: The electrocardiogram (ECG) is the most commonly used exam for the screening and evaluation of cardiovascular diseases. Here we propose that the age predicted by artificial intelligence (AI) from the raw ECG tracing (ECG-age) can be a measure of cardiovascular health and provide prognostic information. A deep convolutional neural network was trained to predict a patients age from the 12-lead ECG using data from patients that underwent an ECG from 2010 to 2017 - the CODE study cohort (n=1,558,415 patients). On the 15% hold-out CODE test split, patients with ECG-age more than 8 years greater than chronological age had a higher mortality rate (hazard ratio (HR) 1.79, p<0.001) in a mean follow-up of 3.67 years, whereas those with ECG-age more than 8 years less than chronological age had a lower mortality rate (HR 0.78, p<0.001). Similar results were obtained in the external cohorts ELSA-Brasil (n=14,236) and SaMi-Trop (n=1,631). The ability to predict mortality from the ECG predicted age remains even when we adjust the model for cardiovascular risk factors. Moreover, even for apparent normal ECGs, having a predicted ECG-age 8 or more years greater than chronological age remained a statistically significant predictor of risk (HR 1.53, p<0.001 in CODE 15% test split). These results show that AI-enabled analysis of the ECG can add prognostic information to the interpretation of the 12-lead ECGs.

category: cardiovascular medicine


title: Rapid SARS-CoV-2 variants spread detected in France using specific RT-PCR testing

abstract: SARS-CoV-2 variants raise major concerns regarding the control of COVID-19 epidemics. We analyse 40,000 specific RT-PCR tests performed on SARS-CoV-2-positive samples collected between Jan 26 and Feb 16, 2021. We find a high transmission advantage of variants and show that their spread in the country is more advanced than anticipated.


title: Contact patterns and HPV-genotype interactions yield heterogeneous HPV-vaccine impacts depending on sexual behaviours: an individual-based model

abstract: Human papillomaviruses are common sexually transmitted infections, caused by a large diversity of genotypes. In the context of vaccination against a subgroup of genotypes, better understanding the role of genotype interactions and human sexual behavior on genotype ecology is essential. Herein, we present an individual-based model that integrates realistic heterosexual partnership behaviors and simulates interactions between vaccine and non-vaccine genotypes. Genotype interactions were considered, assuming a previous vaccine-genotype infection shortened (competition) or extended (synergy) the duration of a secondary non-vaccine-genotype infection. Sexual behavior determined papillomavirus acquisition and transmission: only 19.5% of active individuals with 0-1 partner during the year, but >80% of those with [≥]2 partners, were infected before vaccine introduction. Genotype interactions, despite being silent during the pre-vaccination era, markedly impacted genotype ecology after vaccination started, with a significant increase/decrease of non-vaccine prevalence for competitive/synergistic interactions. These changes were more pronounced in individuals with [≤]3 partners (up to 30% of prevalence modification assuming 65% vaccine coverage) but barely visible for individuals with >3 partners (at most 0.30%). Results suggest that considering genotype interactions, in conjunction with heterogeneous sexual behaviors, is essential to anticipate the impact of existing and future anti-papillomavirus vaccines targeting a subgroup of genotypes.


title: Do epigenetic clocks provide explanations for sex differences in lifespan? A cross-sectional twin study

abstract:
BackgroundThe sex gap in life expectancy has been narrowing in Finland over the past four to five decades; however, on average, women still live longer than men. Epigenetic clocks are markers for biological aging that predict lifespan. In this study, we examined the mediating role of lifestyle factors on the association between sex and biological aging in younger and older adults.

MethodsOur sample included same-sex younger and older twins (21-42-y, n = 1110; 50-76-y, n = 763) and younger opposite-sex twins (21-30-y, n = 302). Blood-based DNA methylation (DNAm) was used to compute epigenetic age acceleration by four epigenetic clocks as a measure of biological aging. Path modelling was used to study whether the association between sex and biological aging is mediated through lifestyle-related factors, i.e. education, body mass index, smoking, alcohol use, and physical activity.

FindingsIn comparison to women, men were biologically older and, in general, they had unhealthier life habits. The effect of sex on biological aging was partly mediated by smoking, but only in older twins. Sex was directly associated with biological aging and the association was stronger in older twins.

InterpretationPreviously reported sex differences in lifespan are also evident in biological aging. Declining smoking prevalence among men is a plausible explanation for the narrowing of the difference in life expectancy between the sexes. Data generated by the epigenetic clocks may help in estimating the effects of lifestyle and environmental factors on aging and in predicting aging in future generations.


title: Inequalities in the decline and recovery of pathological cancer diagnoses during the first six months of the COVID-19 pandemic: a population-based study

abstract:
BackgroundThe restructuring of healthcare systems to cope with the demands of the COVID-19 pandemic has led to a reduction in clinical services such as cancer screening and diagnostics.

MethodsData from the four Northern Ireland pathology labs was used to assess trends in pathological cancer diagnoses from 1st March to 12th September 2020 overall and by cancer site, gender and age. These trends were compared to the same timeframe from 2017-2019.

ResultsBetween 1st March and 12th September 2020 there was a 23% reduction in cancer diagnoses compared to the same time period in the preceding three years. Although some recovery occurred in August and September 2020, this revealed inequalities across certain patient groups. Pathological diagnoses of lung, prostate and gynaecological malignancies remained well below pre-pandemic levels. Males and younger/middle-aged adults, particularly the 50-59 year old patient group, also lagged behind other population demographic groups in terms of returning to expected numbers of pathological cancer diagnoses.

ConclusionsThere is a critical need to protect cancer diagnostic services in the ongoing pandemic to facilitate timely investigation of potential cancer cases. Targeted public health campaigns may be needed to reduce emerging inequalities in cancer diagnoses as the COVID-19 pandemic continues.


title: SARS-CoV-2 genomic surveillance identifies naturally occurring truncations of ORF7a that limit immune suppression

abstract:
Over 200,000 whole genome sequences of SARS-CoV-2 have been determined for viruses isolated from around the world. These sequences have been critical for understanding the spread and evolution of SARS-CoV-2. Using global phylogenomics, we show that mutations frequently occur in the C-terminal end of ORF7a. We have isolated one of these mutant viruses from a patient sample and used viral chal-lenge experiments to demonstrate that {Delta}115 mutation results in a growth defect. ORF7a has been implicated in immune modulation, and we show that the C-terminal truncation results in distinct changes in interferon stimulated gene expression. Collectively, this work indicates that ORF7a mutations occur frequently and that these changes affect viral mechanisms responsible for suppressing the immune response.

HighlightsO_LIORF7a mutations are found in SARS-CoV-2 genomes isolated from around the globe.
C_LIO_LIORF7a mutation results in a replication defect.
C_LIO_LIAn ORF7a mutation limits viral suppression of the interferon response.
C_LI


title: Impact of the Tier system on SARS-CoV-2 transmission in the UK between the first and second national lockdowns

abstract:
ObjectiveMeasure the effects of the Tier system on the COVID-19 pandemic in the UK between the first and second national lockdowns, before the emergence of the B.1.1.7 variant of concern.

DesignModelling study combining estimates of the real-time reproduction number Rt (derived from UK case, death and serological survey data) with publicly available data on regional non-pharmaceutical interventions. We fit a Bayesian hierarchical model with latent factors using these quantities, to account for broader national trends in addition to subnational effects from Tiers.

SettingThe UK at Lower Tier Local Authority (LTLA) level.

Primary and secondary outcome measuresReduction in real-time reproduction number Rt.

ResultsNationally, transmission increased between July and late September, regional differences notwithstanding. Immediately prior to the introduction of the tier system, Rt averaged 1.3 (0.9 - 1.6) across LTLAs, but declined to an average of 1.1 (0.86 - 1.42) two weeks later. Decline in transmission was not solely attributable to Tiers. Tier 1 had negligible effects. Tiers 2 and 3 respectively reduced transmission by 6% (5%-7%) and 23% (21%-25%). 93% of LTLAs would have begun to suppress their epidemics if every LTLA had gone into Tier 3 by the second national lockdown, whereas only 29% did so in reality.

ConclusionsThe relatively small effect sizes found in this analysis demonstrate that interventions at least as stringent as Tier 3 are required to suppress transmission, especially considering more transmissible variants, at least until effective vaccination is widespread or much greater population immunity has amassed.

Strengths and limitations of this studyO_LIFirst study to measure effects of UK Tier system for SARS-CoV-2 control at national and regional level.
C_LIO_LIModel makes minimal assumptions and is primarily data driven.
C_LIO_LIInsufficient statistical power to estimate effects of individual interventions that comprise Tiers, or their interaction.
C_LIO_LIEstimates show that Tiers 1 and 2 are insufficient to suppress transmission, at least until widespread population immunity has amassed. Emergence of more transmissible variants of concern unfortunately supports this conclusion.
C_LI


title: Adverse childhood experiences and multiple mental health outcomes through adulthood: a prospective birth cohort study

abstract:
This study examined the association between adverse childhood experiences (ACEs) and mental health-related outcomes spanning ages 16-55 years, using a prospective birth cohort representative of those born around 1958 in Great Britain.

We found a dose-response association between prospectively and retrospectively reported ACEs and all studied mental health-related outcomes, after accounting for multiple covariates. Among those with 2+ (vs 0) prospective ACEs, the risk of clinically significant psychological distress was up to 2.14 times higher, and of seeing a mental health specialist up to 2.85 times higher. Our findings reiterate the need for early-life interventions to reduce inequalities in mental health.


title: An integrated framework for building trustworthy data-driven epidemiological models: Application to the COVID-19 outbreak in New York City

abstract: Epidemiological models can provide the dynamic evolution of a pandemic but they are based on many assumptions and parameters that have to be adjusted over the time when the pandemic lasts. However, often the available data are not sufficient to identify the model parameters and hence infer the unobserved dynamics. Here, we develop a general framework for building a trustworthy data-driven epidemiological model, consisting of a workflow that integrates data acquisition and event timeline, model development, identifiability analysis, sensitivity analysis, model calibration, model robustness analysis, and forecasting with uncertainties in different scenarios. In particular, we apply this framework to propose a modified susceptible-exposed-infectious-recovered (SEIR) model, including new compartments and model vaccination in order to forecast the transmission dynamics of COVID-19 in New York City (NYC). We find that we can uniquely estimate the model parameters and accurately predict the daily new infection cases, hospitalizations, and deaths, in agreement with the available data from NYCs governments website. In addition, we employ the calibrated data-driven model to study the effects of vaccination and timing of reopening indoor dining in NYC.


title: Depression and anxiety before and during the COVID-19 lockdown: a longitudinal cohort study with university students

abstract:
BackgroundFor young people, just as in the general population, COVID-19 caused many changes in their lives, including an increased risk for mental illness symptoms. We aimed to study the impact of the COVID-19 pandemic in anxiety and depression symptoms in a cohort of university students.

MethodsThis study is part of broader longitudinal research on university students mental health with data of the Portuguese version of The Patient Health Questionnaire (PHQ-9) and the Portuguese version of the Generalised Anxiety Disorder (GAD-7) with evaluations on January, May and October 2019 and June 2020, as well as socio-demographic information.

Results341 university students (257 females and 84 males) were included, with a mean age of 19.91 (SD=1.58). In June 2020, the mean for perceived wellbeing loss was 60.47% (SD=26.56) and 59.54% (SD=28.95) for mental health loss. The proportion of students with scores equal to or above 15 in the PHQ-9 ranged between 22.6% and 25.5% in 2019 and 37.0% in June 2020. The proportion of GAD-7 scores above cut-off ten ranged between 46.0% and 47.8% in 2019 and 64.5% in 2020. Compared with preceding trends, PHQ-9 scores were 3.11 (CI=2.40-3.83) higher than expected, and GAD-7 scores were 3.56 (CI=2.75-5.37) higher.

DiscussionCOVID-19 impacted negatively depressive and anxiety symptoms, confirming previous studies and young peoples vulnerability in such uncertain times.


title: The acoustic quality and health in urban environments (SALVE) project: Study design, rationale and methodology

abstract:
Sound pressure levels expressed in variations of decibel (dB) formulations are a common approach to describe the urban acoustic environment (AE). In recent years, different approaches gained traction to describe the urban AE, like the soundscape ecology approach, which focuses on the natural environment. To determine the feasibility of applying this approach to cities, a comprehensive dataset of high-quality sound recordings with high spatial and temporal resolution is essential.

The acoustic quality and health in urban environments (SALVE) project aims to establish a spatially and temporally high-resolution dataset of the urban AE using land use categories. Since 2019, we assess the AE at selected places in the densely populated city of Bochum, Germany. For a high temporal resolution, we used automatic devices at 52 locations that recorded every 26 minutes for three minutes. For a high spatial resolution, we used manual devices to perform a five-minute recording four times a year at 730 selected locations. Altogether, we ended up with 1,500,493 minutes of sound recordings.

Aim here is to outline our sampling design, methods used, and applied quality procedures in order to achieve a well-defined and high quality dataset presented for further scientific analysis. To the best of our knowledge, this represents one of the most extensive datasets currently available, which will provide a comprehensive database for future in-depth analyses of the associations between the urban AE, urban fabric and human health.

HighlightsO_LIA conceptual sampling framework for measuring the urban acoustic environment is given
C_LIO_LIOne of the most extensive datasets of the urban acoustic environment is introduced
C_LIO_LIExperiences and results of the field work of the SALVE-Project are presented
C_LI


title: Changes in lipids and inflammation in adults with super-refractory status epilepticus on a ketogenic diet

abstract:
ObjectiveTo test the hypothesis that increased ketone body production with a ketogenic diet (KD) will correlate with reductions in pro-inflammatory cytokines, lipid subspecies, and improved clinical outcomes in adults treated with an adjunctive ketogenic diet for super-refractory status epilepticus (SRSE).

MethodsAdults (18 years or older) were treated with a 4:1 (fat:carbohydrate and protein) ratio enteral KD as adjunctive therapy to pharmacologic seizure suppression for SRSE. Blood and urine samples and clinical measurements were collected at baseline (n=10), after 1 week (n=8), and after 2 weeks of KD (n=5). Urine acetoacetate, serum {beta}-hydroxybutyrate, lipidomics, pro-inflammatory cytokines (IL-1{beta}, IL-6), chemokines (CCL3, CCL4, CXCL13), and clinical measurements were obtained at these 3 time points. Univariate and multivariate data analyses were performed to determine the correlation between ketone body production and circulating lipids, inflammatory biomarkers, and clinical outcome.

ResultsChanges in lipids included an increase in ceramides, mono-hexosyl ceramide, sphingomyelin, phosphocholine, and phosphoserines, and there was a significant reduction in pro-inflammatory mediators IL-6 and CXCL13 seen at 1 and 2 weeks of KD. Higher blood {beta}-hydroxybutyrate levels at baseline correlated with better clinical outcome however, ketone body production did not correlate with other variables during treatment. Higher chemokine CCL3 levels following treatment correlated with greater length of intensive care unit stay, higher modified Rankin Scale score (worse neurologic disability) at discharge and 6-month follow up.

ConclusionsAdults receiving an adjunctive enteral ketogenic diet for super-refractory status epilepticus have alterations in select pro-inflammatory cytokines and lipid species that may predict response to treatment.


title: A longitudinal study of healthcare workers' surveillance during the ongoing COVID-19 Epidemics in Italy: is SARS-CoV-2 still a threat for the Health-care System?

abstract:
ObjectivesIn spring 2020, Northern Italy was the first area outside China to be involved in the SARS-CoV-2 pandemic. This observational study depicts SARS-CoV-2 prevalence and serological curves among first-line healthcare workers (HCWs) at Padua University Hospital (PdUH), North-East Italy.

Method344 HCWs, working at the PdUH Emergency Department and Infectious Disease Unit, underwent a SARS-CoV-2 RNA nasopharyngeal swab with paired IgM and IgG antibody detection for 4 consecutive weeks. At every session, a questionnaire recorded symptoms, signs and recent contacts with SARS-CoV-2 patients. Positive cases were followed up for 5 months.

ResultsTwenty-seven HCWs (7.84%) had positive serology (Abs) with 12 positive swabs during the study period. Two additional HCWs were positive by swab but without Abs. Fourteen cases (4%) had SARS-CoV-2 infection before the beginning of the study. An HCW with autoimmune disease showed false Ab results. 46% of individuals with Abs reported no symptoms, in accordance with previous population studies. Fever, nasal congestion, diarrhoea and contacts with SARS-CoV-2 individuals correlated to SARS-CoV-2 infection. 96% of Abs+ cases showed persistent positive antibodies 5 months later and none was re-infected.

DiscussionCorrect use of PPEs and separate paths for positive/negative patients in the hospital can result in a low percentage of SARS-CoV-2 infections among HCWs, even in high risk settings. Frequent testing for SARS-CoV-2 with nasopharyngeal swabs is worthwhile, irrespective of HCWs symptoms, due to the lack of specificity together with the high percentage of asymptomatic cases. Further studies are needed to elucidate the neutralizing effect of SARS-CoV-2 antibodies.


title: Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome

abstract: Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal (Mycoplasma salivarium), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.


title: Acceptance of COVID-19 Vaccine in Pakistan Among Health Care Workers

abstract:
ObjectiveAcceptance of the COVID-19 vaccine will impart a pivotal role in eradicating the virus. In Pakistan, health care workers (HCWs) are the first group to receive vaccination. This survey aimed at the level of acceptance to the COVID-19 vaccine and predictors of non-acceptance in HCWs.

MethodThis was a cross-sectional study design and data were collected through 3rd December 2020 and February 14th, 2021. An English questionnaire was distributed through social media platforms and administration of affiliate hospitals along with snowball sampling for private hospitals.

ResultsOut of 5,237 responses, 3,679 (70.2%) accepted COVID-19 vaccination and 1,284 (24.5%) wanted to delay until more data was available. Only 5.2% of HCWs rejected being vaccinated. Vaccine acceptance was more in young (76%) and female gender (63.3%) who worked in a tertiary care hospital (51.2%) and were direct patient care providers (61.3%). The reason for rejection in females was doubtful vaccine effectiveness (31.48%) while males rejected due to prior COVID-19 exposure (42.19%) and side effect profile of the vaccine (33.17%). Logistic regression analysis demonstrated age between 51-60 years, female gender, Pashtuns, those working in the specialty of medicine and allied, taking direct care of COVID-19 patients, higher education, and prior OCVID-19 infection as the predictors for acceptance or rejection of COVID-19 vaccine.

ConclusionA high overall acceptance rate was observed among HCWs, favoring a successful nationwide vaccination program in Pakistan.


title: Evidence of long-lasting humoral and cellular immunity against SARS-CoV-2 even in elderly COVID-19 convalescents showing a mild to moderate disease progression

abstract:
After the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in China in late 2019, a pandemic evolved that has claimed millions of lives so far. While about 80 % of infections cause mild or moderate COVID-19 disease, some individuals show a severe progression or even die. Most countries are far from achieving herd-immunity, however, the first approved vaccines offer hope for containment of the virus. Although much is known about the virus, there is a lack of information on the immunity of convalescent individuals.

We here evaluate the humoral and cellular immune response against SARS-CoV-2 in 41 COVID-19 convalescents. As previous studies mostly included younger individuals, one advantage of our study is the comparatively high mean age of the convalescents included in the cohort considered (54 {+/-} 8.4 years). While anti-SARS-CoV-2 antibodies were still detectable in 95 % of convalescents up to 8 months post infection, an antibody-decay over time was generally observed in most donors. Using a multiplex assay, our data additionally reveal that most convalescents exhibit a broad humoral immunity against different viral epitopes. We demonstrate by flow cytometry that convalescent donors show a significantly elevated number of natural killer cells when compared to healthy controls, while no differences were found concerning other leucocyte subpopulations. We detected a specific long-lasting cellular immune response in convalescents by stimulating immune cells with SARS-CoV-2-specific peptides, covering domains of the viral spike, membrane and nucleocapsid protein, and measuring interferon-{gamma} (IFN-{gamma}) release thereafter. We modified a commercially available ELISA assay for IFN-{gamma} determination in whole-blood specimens of COVID-19 convalescents. One advantage of this assay is that it does not require special equipment and can, thus, be performed in any standard laboratory. In conclusion, our study adds knowledge regarding the persistence of immunity of convalescents suffering from mild to moderate COVID-19. Moreover, our study provides a set of simple methods to characterize and confirm experienced COVID-19.


title: Disease burden of bloodstream infections caused by antimicrobial-resistant bacteria: a population-level study-Japan, 2015-2018

abstract:
BackgroundAntimicrobial resistance (AMR) is a global health problem. However, quantitative evaluation of its disease burden is challenging. This study aimed to estimate the disease burden of bloodstream infections (BSIs) caused by major antimicrobial-resistant bacteria in Japan between 2015 and 2018 in terms of disability-adjusted life-years (DALYs).

MethodsWe estimated the DALYs of BSIs caused by the six major antimicrobial-resistant bacteria in Japan by utilising comprehensive national surveillance data of all routine bacteriological test results from more than 1,400 hospitals between 2015 and 2018. We modified the methodology of a previous study by Cassini and colleagues to enable comparison of our results with those in other countries.

ResultsWe estimated that 135.8 (95% uncertainty interval [UI] 128.6-142.9) DALYs per 100,000 population was attributable to BSIs caused by the six antimicrobial-resistant bacteria in 2018. Staphylococcus aureus (MRSA), fluoroquinolone-resistant Escherichia coli (FQREC), and third-generation cephalosporin-resistant E. coli (3GREC) accounted for 88.6% of the total. The burden did not decrease during the study period and was highest in people aged 65 years or older.

ConclusionOur results revealed for the first time the disease burden of BSIs caused by six major antimicrobial-resistant bacteria in Japan. The estimated disease burden associated with AMR in Japan is substantial and has not begun to decrease. Notably, the burden from FQREC and 3GREC has increased steadily and that from MRSA is larger than EU/EEA area, whereas that from other bacteria was comparatively small. Our results are expected to provide useful information for healthcare policymakers for prioritising interventions for AMR.

FundingMinistry of Health, Labour and Welfare research grant (20HA2003); Japan Agency for Medical Research and Development Research Program on Emerging and Re-emerging Infectious Diseases (JP19fk0108061)


title: SARS CoV-2 escape variants exhibit differential infectivity and neutralization sensitivity to convalescent or post-vaccination sera

abstract: Towards eradicating COVID19, developing vaccines that induce high levels of neutralizing antibodies is a main goal. As counter measurements, viral escape mutants rapidly emerge and potentially compromise vaccine efficiency. Herein we monitored ability of convalescent or Pfizer-BTN162b2 post-vaccination sera to neutralize wide-type SARS-CoV2 or its UK-B.1.1.7 and SA-B.1.351 variants. Relative to convalescent sera, post-vaccination sera exhibited higher levels of neutralizing antibodies against wild-type or mutated viruses. However, while SARS-CoV2 wild-type and UK-N501Y were similarly neutralized by tested sera, the SA-N501Y/K417N/E484K variant moderately escaped neutralization. Significant contribution to infectivity and sensitivity to neutralization was attributed to each of the variants and their single or combined mutations, highlighting alternative mechanisms by which prevalent variants with either N501Y or E484K/K417N mutations spread. Our study validates the clinical significance of currently administered vaccines, but emphasizes that their efficacy may be compromised by circulated variants, urging the development of new ones with broader neutralization functions.


title: An evaluation of toxigenic Clostridioides difficile positivity as a patient outcome metric of antimicrobial stewardship in Saudi Arabia

abstract:
BackgroundAntimicrobial stewardship has been associated with a reduction in the incidence of health care associated Clostridium difficile infection (HA-CDI). However, CDI remains under-recognized in many low and middle-income countries where clinical and surveillance resources required to identify HA-CDI are often lacking. The rate of toxigenic C. difficile stool positivity in the stool of hospitalized patients may offer an alternative metric for these settings, but its utlity remains largely untested.

Aim/ObjectiveTo examine the impact of an antimicrobial stewardship on the rate of toxigenic C. difficile positivity among hospitalized patients presenting with diarrhoea

MethodsA 12-year retrospective review of laboratory data was conducted to compare the rates of toxigenic C. difficile in diarrhoea stool of patients in a hospital in Saudi Arabia, before and after implementation of an antimicrobial stewardship program

ResultThere was a significant decline in the rate of toxigenic C difficile positivity from 9.8 to 7.4% following the implementation of the antimicrobial stewardship program, and a reversal of a rising trend.

DiscussionThe rate of toxigenic C. difficile positivity may be a useful patient outcome metric for evaluating the long term impact of antimicrobial stewardship on CDI, especially in settings with limited surveillance resources. The accuracy of this metric is however dependent on the avoidance of arbitrary repeated testing of a patient for cure, and testing only unformed or diarrhoea stool specimens. Further studies are required within and beyond Saudi Arabia to examine the utility of this metric.


title: PRESENT SITUATION OF SUICIDE IN BANGLADESH: A REVIEW

abstract: The most important global cause of mortality is suicide. It is often neglected by researchers, health professionals, health policymakers, and the medical profession. This review was aimed to provide a narrative understanding of the present situation of suicide in Bangladesh based on the existing literature. We conducted a review combining articles and abstracts with full HTML and PDF format. We searched PubMed, PubMed Central, Google Scholar, ScienceDirect and BanglaJOL, google using multiple terms related to suicide without any date boundary and without any basis of types of studies, that is, all types of studies were scrutinized. Finally, 16 articles were selected for review. Report suggested that every day almost 32 people commit suicide in 2019 which was 29 and 30 in 2015 and 2017 respectively. The mortality rate of suicide found 39.6 per 100,000 in Bangladesh. The most common method is hanging followed by poisoning and jumping under the train. The most prevalent age group is age under 40 years. The rate of suicide in children is also increasing. In contrast to most Asian countries, more Bangladeshi women commit suicide than men. The mean age of male and female were 28.86 {+/-} 11.27 years and 25.31 {+/-} 7.70 years respectively. The most common associated factors of suicide are younger age, lower education, students, nuclear family, family history of suicide, use substance, problem in workplace, financial constraints, affair, domestic violence, divorce, and physical illness. Most of the suicidal event occurred at night, followed by morning (6 am-12 am), and evening. Its a criminal offence in Bangladesh. The source of information is mainly police, forensic reports, media and courts. Till now there is no nationwide survey of suicide is conducted. Besides, suicide surveillance strategy is yet to be established. Suicide is a neglected and under attended public health problem in Bangladesh with few research and paucity of literature. Now nationwide survey conduction and establishment of national suicide surveillance are a time demanded step.


title: Associations Between Google Search Trends for Symptoms and COVID-19 Confirmed and Death Cases in the United States

abstract: We utilize functional data analysis techniques to investigate patterns of COVID-19 positivity and mortality in the US and their associations with Google search trends for COVID-19 related symptoms. Specifically, we represent state-level time series data for COVID-19 and Google search trends for symptoms as smoothed functional curves. Given these functional data, we explore the modes of variation in the data using functional principal component analysis (FPCA). We also apply functional clustering analysis to identify patterns of COVID-19 confirmed case and death trajectories across the US. Moreover, we quantify the associations between Google COVID-19 search trends for symptoms and COVID-19 confirmed case and death trajectories using dynamic correlation. Finally, we examine the dynamics of correlations for the top nine Google search trends of symptoms commonly associated with COVID-19 confirmed case and death trajectories. Our results reveal and characterize distinct patterns for COVID-19 spread and mortality across the US. The dynamics of these correlations suggest the feasibility of using Google queries to forecast COVID-19 cases and mortality for up to three weeks in advance. Our results and analysis framework set the stage for the development of predictive models for forecasting COVID-19 confirmed cases and deaths using historical data and Google search trends for nine symptoms associated with both outcomes.


title: Prior COVID-19 Infection and Antibody Response to Single Versus Double Dose mRNA SARS-CoV-2 Vaccination

abstract: The double dose regimen for mRNA vaccines against SARS-CoV-2 presents both a hope and a challenge for global efforts to curb the COVID-19 pandemic. With supply chain logistics impacting the rollout of population-scale vaccination programs, increasing attention has turned to the potential efficacy of single versus double dose vaccine administration for select individuals. To this end, we examined response to Pfizer-BioNTech mRNA vaccine in a large cohort of healthcare workers including those with versus without prior COVID-19 infection. For all participants, we quantified circulating levels of SARS-CoV-2 anti-spike (S) protein IgG at baseline prior to vaccine, after vaccine dose 1, and after vaccine dose 2. We observed that the anti-S IgG antibody response following a single vaccine dose in persons who had recovered from confirmed prior COVID-19 infection was similar to the antibody response following two doses of vaccine in persons without prior infection (P[≥]0.58). Patterns were similar for the post-vaccine symptoms experienced by infection recovered persons following their first dose compared to the symptoms experienced by infection naive persons following their second dose (P=0.66). These results support the premise that a single dose of mRNA vaccine could provoke in COVID-19 recovered individuals a level of immunity that is comparable to that seen in infection naive persons following a double dose regimen. Additional studies are needed to validate our findings, which could allow for public health programs to expand the reach of population wide vaccination efforts.


title: COVID-19 in New York state: Effects of demographics and air quality on infection and fatality

abstract: The coronavirus disease 2019 (COVID-19) has had a global impact that has been unevenly distributed amongst and, even within countries. Multiple demographic and environmental factors have been associated with the risk of COVID-19 spread and fatality, including age, gender, ethnicity, poverty, and air quality among others. However, specific contributions of these factors are yet to be understood. Here, we attempted to explain the variability in infection, death, and fatality rates by understanding the contributions of a few selected factors. We compared the incidence of COVID-19 in New York State (NYS) counties during the first wave of infection and analyzed how different demographic and environmental variables associate with the variation observed across the counties. We observed that the two important COVID-19 metrics of infection rates and death rates to be well correlated, and both metrics being highest in counties located near New York City, considered one of the epicenters of the infection in the US. In contrast, disease fatality was found to be highest in a different set of counties despite registering a low infection rate. To investigate this apparent discrepancy, we divided the counties into three clusters based on COVID-19 infection, death rate, or fatality, and compared the differences in the demographic and environmental variables such as ethnicity, age, population density, poverty, temperature, and air quality in each of these clusters. Furthermore, a regression model built on this data reveals PM2.5 and distance from the epicenter are significant risk factors for high infection rate, while disease fatality has a strong association with age and PM2.5. Our results demonstrate, for the NYS, distinct contributions of old age, PM2.5, ethnicity these factors to the overall COVID-19 burden and highlight the detrimental impact of poor air quality. These results could help design and direct location-specific control and mitigation strategies.


title: Diagnostic value in colorectal tumorous lesions of SDC2/TFPI2 methylation based on bowel subsite difference

abstract:
BackgroundSDC2 methylation is a potential biomarker for colorectal cancer detection with specificity over 90%, but its sensitivity is usually less than 90%. The study aims to improve the sensitivity and specificity by adding TFPI2 methylation as a complement.

MethodsTFPI2 was identified using colorectal cancer samples from TCGA database with SDC2 methylation level lower than 0.2. SDC2/TFPI2 methylation specific PCR was performed using tissue samples (184 cancer and 54 healthy control) and stool samples (289 cancer, 190 adenoma and 217 healthy control). Detection sensitivity was calculated among tumors from different biopsy locations.

Results88% of 50 TCGA specimens of colorectal cancer with SDC2 methylation level lower than 0.2 showed TFPI2 methylation level higher than 0.2. SDC2/TFPI2 combined detection in stool specimens showed AUC value of 0.98 with the specificity of 96.40% and sensitivity of 96.60% for cancer vs control, AUC value of 0.87 with the specificity of 95.70% and sensitivity of 80.00% for adenoma vs control. The sensitivities were much higher than those of SDC2, and the improvement was most significant in lesions from left colon and rectum.

ConclusionsThis research indicated that the addition of TFPI2 can reduce the miss detection rate of colorectal cancer and adenomas while maintaining high specificity, probably by finding neoplasms in left colon.The method is non-invasive and has good compliance, also avoiding the pain of bowel preparation and risk of cross infection during endoscopy, so it will provide an easy and precise tool for colorectal cancer and its precancerous lesions screening.

category: gastroenterology


title: Mandatory public health measures for COVID-19 are associated with improved mortality, equity and economic outcomes

abstract: We review approaches to the COVID-19 pandemic in a systematic way by comparing countries/states representative of the mandatory vs. voluntary approach to non-pharmaceutical interventions in Europe and the US. We use a comparative tabular format to examine differences in mortality, economic impact and equity between regions with mandatory versus voluntary policies. Mandatory shelter-in-place policies were associated with 3 to 4 fold lower population adjusted mortality in the US model and 11 fold lower in the European one. We conclude that voluntary policies are less effective, based on historical precedent and the current analysis. Moreover, effects on health equity mirrored the increased mortality outcomes of voluntary policies and there was no apparent economic benefit associated with voluntary measures.


title: SARS-CoV-2 detection and genomic sequencing from hospital surface samples collected at UC Davis

abstract:
RationaleThere is little doubt that aerosols play a major role in the transmission of SARS-CoV-2. The significance of the presence and infectivity of this virus on environmental surfaces, especially in a hospital setting, remains less clear.

ObjectivesWe aimed to analyze surface swabs for SARS-CoV-2 RNA and infectivity, and to determine their suitability for sequence analysis.

MethodsSamples were collected during two waves of COVID-19 at the University of California, Davis Medical Center, in COVID-19 patient serving and staff congregation areas. qRT-PCR positive samples were investigated in Vero cell cultures for cytopathic effects and phylogenetically assessed by whole genome sequencing.

Measurements and Main ResultsImproved cleaning and patient management practices between April and August 2020 were associated with a substantial reduction of SARS-CoV-2 qRT-PCR positivity (from 11% to 2%) in hospital surface samples. Even though we recovered near-complete genome sequences in some, none of the positive samples (11 of 224 total) caused cytopathic effects in cultured cells suggesting this nucleic acid was either not associated with intact virions, or they were present in insufficient numbers for infectivity. Phylogenetic analysis suggested that the SARS-CoV-2 genomes of the positive samples were derived from hospitalized patients. Genomic sequences isolated from qRT-PCR negative samples indicate a superior sensitivity of viral detection by sequencing.

ConclusionsThis study confirms the low likelihood that SARS-CoV-2 contamination on hospital surfaces contains infectious virus, disputing the importance of fomites in COVID-19 transmission. Ours is the first report on recovering near-complete SARS-CoV-2 genome sequences directly from environmental surface swabs.


title: A Comprehensive County Level Framework to Identify Factors Affecting Hospital Capacity and Predict Future Hospital Demand

abstract:
BackgroundAs of February 19, 2021, our review yielded a small number of studies that investigated high resolution hospitalization demand data from a public health planning perspective. The earlier studies compiled were conducted early in the pandemic and do not include any analysis of the hospitalization trends in the last 3 months when the US experienced a substantial surge in hospitalization and ICU demand. The earlier studies also focused on COVID 19 transmission influence on COVID 19 hospitalization rates. While this emphasis is understandable, there is evidence to suggest that non COVID hospitalization demand is being displaced due to the hospitalization and ICU surge. Further, with the discovery of multiple mutated variants of COVID 19, it is important to remain vigilant in an effort to control the pandemic. Given these circumstances, the development of a high resolution framework that examines overall hospitalizations and ICU usage rate for COVID and non COVID patients would allow us to build a prediction system that can identify potential vulnerable locations for hospitalization capacity in the nation so that appropriate remedial measures can be planned.

MethodThe current study recognizes that COVID 19 has affected overall hospitalizations - not only COVID 19 hospitalizations. Drawing from the recently released Department of Health and Human services (DHH) weekly hospitalization data (or the time period August 28th, 2020 to January 22nd, 2021.), we study the overall hospitalization and ICU usage as two components: COVID 19 hospitalization and ICU per capita rates; and non COVID hospitalization and ICU per capita rates. A mixed linear mixed model is adopted to study the response variables in our study. The estimated models are subsequently employed to generate predictions for county level hospitalization and ICU usage rates in the future under a host of COVID 19 transmission scenarios considering the new variants of COVID 19 and vaccination impacts.

FindingsWe find a significant association of the virus transmissibility with COVID (positive) and non COVID (negative) hospitalization and ICU usage rates. Several county level factors including demographics, mobility and health indicators are also found to be strongly associated with the overall hospitalization and ICU demand. Among the various scenarios considered, the results indicate a small possibility of a new wave of infections that can substantially overload hospitalization and ICU usage. In the scenario where vaccinations proceed as expected reducing transmission, our results indicate that hospitalizations and ICU usage rates are likely to reduce significantly.

InterpretationThe research exercise presents a framework to predict evolving hospitalization and ICU usage trends in response to COVID 19 transmission rates while controlling for other factors. Our work highlights how future hospitalization demand varies by location and time in response to a range of pessimistic and optimistic scenarios. Further, the exercise allows us to identify vulnerable counties and regions under stress with high hospitalization and ICU rates that can be assisted with remedial measures. The model will also allow hospitals to understand evolving displaced non COVID hospital demand.


title: Causal effects from non-alcoholic fatty liver disease on kidney function: A Mendelian randomization study

abstract:
Background & aimsAn observational association between nonalcoholic fatty liver disease (NAFLD) and kidney function impairment has been reported. A genetic variant linked to an increased risk of NAFLD, the G allele of rs738409, has been reported to be associated with a reduction in estimated glomerular filtration rate (eGFR).

Approach & ResultsIn this Mendelian randomization (MR) study, we first performed single-variant MR with rs738409 as a genetic instrument to predict NAFLD. Another genetic instrument was developed from a previous genome-wide association study for the NAFLD phenotype in the Million Veteran Program cohort among individuals of European ancestry (68,725 cases and 95,472 controls). The eGFR outcome was assessed in individuals of white British ancestry included in the UK Biobank (N = 321,405). Further, the associations were reassessed in two negative control subgroups (body mass index < 25 kg/m2 and serum alanine aminotransferase level < 20 IU/mL) with a low probability of developing NAFLD. As a replication analysis, a summary-level MR was performed with the European ancestry CKDGen dataset (N = 567,460). In the UK Biobank dataset, a genetic predisposition for NAFLD, either by rs738409 or a group of variants, was significantly associated with a reduced eGFR even with adjustment for major metabolic disorders. Although the associations were not significant in the negative control subgroups with a low probability of developing NAFLD, they were significant in the subgroups with a remaining risk of NAFLD, suggesting the absence of a horizontal pleiotropic pathway. The summary-level MR from the CKDGen dataset supported the causal effects of NAFLD on reduced eGFR.

ConclusionsThis MR analysis supports the causal reduction in kidney function by NAFLD.


title: Detecting microstructural deviations in individuals with deep diffusion MRI tractometry

abstract: Most diffusion MRI (dMRI) studies of disease rely on statistical comparisons between large groups of patients and healthy controls to infer altered tissue state. Such studies often require data from a significant number of patients before robust inferences can be made, and clinical heterogeneity can greatly challenge their discriminative power. Moreover, for clinicians and researchers studying small datasets, rare cases, or individual patients, this approach is clearly inappropriate. There is a clear and unmet need to shift away from the current standard approach of group-wise comparisons to methods with the sensitivity for detection of altered tissue states at the individual level. This would ultimately enable the early detection and interpretation of microstructural abnormalities in individual patients, an important step towards personalised-medicine in translational imaging. To this end, Detect was developed to advance dMRI-based Tractometry towards single-subject analysis. By: 1) operating on the manifold of white matter pathways; and 2) learning normative microstructural features to better discriminate patients from controls, our framework captures idiosyncrasies in patterns along brain white matter pathways in the individual. This novel approach paves the way from traditional group-based comparisons to true personalised radiology, taking microstructural imaging from the bench to the bedside.

category: radiology and imaging


title: A comparison of denoising methods in dynamic MRS using pseudo-synthetic data

abstract:
PurposeMR spectroscopy of dynamic systems is limited by low signal to noise. Denoising along a series of acquired spectra exploits their temporal correlation to improve the quality of individual spectra, and reduce errors in fitting metabolite peaks. In this study we compare the performance of several denoising methods.

MethodsSix different denoising methods were considered: SIFT (Spectral Improvement by Fourier Thresholding), HSVD (Hankel Singular Value Decomposition), spline, wavelet, sliding window and sliding Gaussian. Pseudo-synthetic data was constructed to mimic 31Phosphorus spectra from exercising muscle. For each method the optimal tuning parameters were determined for SNRs of 2, 5, 10 and 20 using a Monte Carlo approach. Denoised data from each method was then fitted using the AMARES algorithm and the results compared to the pseudo-synthetic ground truth.

ResultsAll six methods produced improvements in both fitting accuracy and agreement with the ground truth, compared to unprocessed noisy data. The least effective methods, SIFT and HSVD, achieved around 10-20% reduction in RMS error, while the most effective, Spline, reduced RMS error by 70%. The improvement from denoising was typically greater for lower SNR data.

ConclusionsIndirect time domain denoising of dynamic MR spectroscopy data can substantially improve subsequent metabolite fitting. Spline-based denoising was found to be the most flexible and effective technique.


title: Practical strategies for SARS-CoV-2 RT-PCR testing in resource-constrained settings

abstract: Alternatives to nasopharyngeal sampling are needed to increase capacity for SARS-CoV-2 testing. Among 275 participants, we piloted the collection of nasal mid-turbinate swabs amenable to self-testing, including polyester flocked swabs as well as 3D printed plastic lattice swabs, placed into viral transport media or an RNA stabilization agent. Flocked nasal swabs identified 104/121 individuals who were PCR-positive for SARS-CoV-2 by nasopharyngeal sampling (sensitivity 87%, 95% CI 79-92%), mostly missing those with low viral load (<103 viral copies/uL). 3D-printed nasal swabs showed similar sensitivity. When nasal swabs were placed directly into RNA preservative, the mean 1.4 log decrease in viral copies/uL compared to nasopharyngeal samples was reduced to <1 log, even when samples were left at room temperature for up to 7 days. We also evaluated pooling strategies that involved pooling specimens in the lab versus pooling swabs at the point of collection, finding both successfully detected samples >102 viral copies/uL.


title: The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH): Protocol for a prospective longitudinal cohort study of healthcare and ancillary workers in UK healthcare settings

abstract:
IntroductionThe COVID-19 pandemic has resulted in significant morbidity and mortality, and has devastated economies in many countries. Amongst the groups identified as being at increased risk from COVID-19 are healthcare workers (HCWs) and ethnic minority groups. Emerging evidence suggests HCWs from ethnic minority groups are at increased risk of adverse COVID-19-related physical and mental health outcomes. To date there has been no large-scale analysis of these risks in UK healthcare workers or ancillary workers in healthcare settings, stratified by ethnicity or occupation type, and adjusted for potential confounders. This paper reports the protocol for a prospective longitudinal questionnaire study of UK HCWs, as part of the UK-REACH programme (The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers).

Methods and analysisA baseline questionnaire with follow-up questionnaires at 4 and 8 months will be administered to a national cohort of UK healthcare workers and ancillary workers in healthcare settings, and those registered with UK healthcare regulators. With consent, data will be linked to health records, and participants followed up for 25 years.

Univariate associations between ethnicity and primary outcome measures (clinical COVID-19 outcomes, and physical and mental health) and key confounders/explanatory variables will be tested, followed by multivariable analyses to test for associations between ethnicity and key outcomes adjusted for the confounder/explanatory variables, with interactions included as appropriate. Using follow-up data, multilevel models will be used to model changes over time by ethnic group, facilitating understanding of absolute and relative risks in different ethnic groups, and generalisability of findings.

Ethics and disseminationThe study is approved by Health Research Authority (reference 20/HRA/4718), and carries minimal risk to participants. We aim to manage the small risk of participant distress due to being asked questions on sensitive topics by clearly indicating on the participant information sheet that the questionnaire covers sensitive topics and that participants are under no obligation to answer these, or indeed any other, questions, and by providing links to support organisations. Results will be disseminated with reports to Government and papers uploaded to pre-print servers and submitted to peer reviewed journals.

Registration detailsTrial ID: ISRCTN11811602

STRENGTHS AND LIMITATIONS OF THIS STUDYO_LINational, UK-wide, study, aiming to capture variety of healthcare worker job roles including ancillary workers in healthcare settings.
C_LIO_LILongitudinal study including three waves of questionnaire data collection, and linkage to administrative data over 25 years, with consent.
C_LIO_LIUnique support from all major UK healthcare worker regulators, relevant healthcare worker organisations, and a Professional Expert Panel to increase participant uptake and the validity of findings.
C_LIO_LIPotential for self-selection bias and low response rates, and the use of electronic invitations and online data collection makes it harder to reach ancillary workers without regular access to work email addresses.
C_LI


title: Outcomes of Percutaneous Tracheostomy for Patients with SARS-CoV-2 Respiratory Failure

abstract:
BackgroundSARS-CoV-2 can cause severe respiratory failure leading to prolonged mechanical ventilation. Data are just emerging about the practice and outcomes of tracheostomy in these patients. We reviewed our experience with tracheostomies for SARS-CoV-2 at our tertiary-care, urban teaching hospital.

MethodsWe reviewed the demographics, comorbidities, timing of mechanical ventilation, tracheostomy, and ICU and hospital lengths-of-stay (LOS) in SARS-CoV-2 patients who received tracheostomies. Early tracheostomy was considered <14 days of ventilation. Medians with interquartile ranges (IQR) were calculated and compared with Wilcoxon rank sum, Spearman correlation, Kruskal-Wallis, and regression modeling.

ResultsFrom March 2020 to January 2021, our center had 370 patients intubated for SARS-CoV-2, and 59 (16%) had percutaneous bedside tracheostomy. Median time from intubation to tracheostomy was 19 (IQR 17 - 24) days. Demographics and comorbidities were similar between early and late tracheostomy, but early tracheostomy was associated with shorter ICU LOS and a trend towards shorter ventilation. To date, 34 (58%) of patients have been decannulated, 17 (29%) before hospital discharge; median time to decannulation was 24 (IQR 19-38) days. Decannulated patients were younger (56 vs 69 years), and in regression analysis, pneumothorax was associated was associated with lower decannulation rates (OR 0.05, 95CI 0.01 - 0.37). No providers developed symptoms or tested positive for SARS-CoV-2.

ConclusionsTracheostomy is a safe and reasonable procedure for patients with prolonged SARS-CoV-2 respiratory failure. We feel that tracheostomy enhances care for SARS-CoV-2 since early tracheostomy appears associated with shorter duration of critical care, and decannulation rates appear high for survivors.

category: intensive care and critical care medicine


title: Comparison of the clinical characteristics and mortality in ARDS due to COVID-19 versus ARDS due to Influenza A-H1N1pdm09

abstract:
ImportanceInfection with the SARS-Cov-2 and Influenza A-H1N1 viruses is responsible for the first pandemics of the 21st century. Both of these viruses can cause severe pneumonia and acute respiratory distress syndrome (ARDS). The clinical differences and mortality associated with these two pandemic pneumonias in patients with ARDS are not well established

ObjectiveTo compare case-fatality between ARDS-Covid-19 and ARDS-Influenza A (H1N1), adjusting for known prognostic risk factors.

Design, Setting and ParticipantsOne hundred forty-seven patients with COVID-19 were compared with 94 with Influenza A-H1N1, all of these were admitted to the intensive care unit of the Referral Center for Respiratory Diseases and COVID-19 in Mexico City and fulfilled the criteria of ARDS.

ResultsPatients arrived at the hospital after 9 days of symptoms. Influenza patients had more obesity, more use of Norepinephrine, and higher levels of lactic dehydrogenase and glucose, and fewer platelets and lower PaO2/FIO2. Crude mortality was higher in COVID than in influenza (39% vs. 22%; p = 0.005). In a Cox proportional hazard model, patients with a diagnosis of COVID-19 had a hazard ratio (HR) = 3.7; 95% Confidence Interval [CI] = 1.9-7.4, adjusted for age, gender, sequential organ failure assessment (SOFA) score, ventilatory ratio, and prone ventilation. In the fully adjusted model, the ventilatory ratio and the absence of prone-position ventilation were also predictors of mortality.

CONCLUSIONCOVID-19 patients treated in an intensive care unit (ICU) had a 3.7 times higher risk of death than similar patients with Influenza A-H1N1, after adjusting for SOFA score and other relevant risk factors for mortality.

QuestionIs the mortality of ARDS associated with Covid-19 greater than that of ARDS associated to influenza H1N1?

FindingsIn a Cox proportional hazard model, patients with a diagnosis of COVID-19 had a hazard ratio (HR) = 3.7; 95% Confidence Interval [CI] = 1.9-7.4, adjusted for age, gender, sequential organ failure assessment (SOFA) score.

MeaningCOVID-19 patients treated in an intensive care unit (ICU) had a 3.7 times higher risk of death than similar patients with Influenza A-H1N1


title: Household secondary attack rate of COVID-19 by household size and index case characteristics

abstract: In this population-wide study in Ontario, Canada, we investigated the household secondary attack rate (SAR) to understand its relationship to household size and index case characteristics. We identified all patients with confirmed COVID-19 between July 1 and November 30, 2020. Cases within households were matched based on reported residential address; households were grouped based on the number of household contacts. The majority of households (68.2%) had a SAR of 0%, while 3,442 (11.7%) households had a SAR [≥]75%. Overall household SAR was 19.5% and was similar across household sizes, but varied across index case characteristics. Households where index cases had longer delays between symptom onset and test seeking, households with older index cases, households with symptomatic index cases, and larger households located in diverse neighborhoods, were associated with greater household SAR. Our findings present characteristics associated with greater household SARs and proposes immediate testing as a method to reduce household transmission and incidence of COVID-19.


title: A Novel SARS-CoV-2 Variant of Concern, B.1.526, Identified in New York

abstract: Recent months have seen surges of SARS-CoV-2 infection across the globe with considerable viral evolution1-3. Extensive mutations in the spike protein may threaten efficacy of vaccines and therapeutic monoclonal antibodies4. Two signature mutations of concern are E484K, which plays a crucial role in the loss of neutralizing activity of antibodies, and N501Y, a driver of rapid worldwide transmission of the B.1.1.7 lineage. Here, we report the emergence of variant lineage B.1.526 that contains E484K and its alarming rise to dominance in New York City in early 2021. This variant is partially or completely resistant to two therapeutic monoclonal antibodies in clinical use and less susceptible to neutralization by convalescent plasma or vaccinee sera, posing a modest antigenic challenge. The B.1.526 lineage has now been reported from all 50 states in the US and numerous other countries. B.1.526 rapidly replaced earlier lineages in New York upon its emergence, with an estimated transmission advantage of 35%. Such transmission dynamics, together with the relative antibody resistance of its E484K sub-lineage, likely contributed to the sharp rise and rapid spread of B.1.526. Although SARS-CoV-2 B.1.526 initially outpaced B.1.1.7 in the region, its growth subsequently slowed concurrent with the rise of B.1.1.7 and ensuing variants.


title: A Novel and Expanding SARS-CoV-2 Variant, B.1.526, Identified in New York


title: Emergence and Expansion of the SARS-CoV-2 Variant B.1.526 Identified in New York


title: The differential impact of the COVID-19 epidemic on Medicaid expansion and non-expansion states

abstract: Medicaid expansion is a federally-funded program to expand health care access and coverage to economically challenged populations by increasing eligibility to Medicaid enrollment and investing in public health preventive services in the individual states. Yet, when the COVID-19 epidemic plagued the country, fourteen states were practicing their chosen decision not to enact the Medicaid expansion policy. We examined the consequences of this nationwide split in Medicaid design on the spread of the COVID-19 epidemic between the expansion and non-expansion states. Our study shows that, on average, the expansion states had 217.56 fewer confirmed COVID-19 cases per 100,000 residents than the non-expansion states [-210.41; 95%CI (-411.131) - (-2.05); P<0.05]. Also, the doubling time of COVID-19 cases in Medicaid expansion states was longer than that of non-expansion states by an average of 1.68 days [1.6826; 95%CI 0.4035-2.9617; P<0.05]. These findings suggest that proactive investment in public health preparedness was an effective protective policy measure in this crisis, unsurpassed by the benefits of COVID-19 emergency plans and funds. The study findings could be relevant to policymakers and healthcare strategists in non-expansion states considering their states preparations for such public health crises.


title: Clinical evaluation of the molecular-based BD SARS-CoV-2/Flu for the BD MAX™ System

abstract: Efficient and accurate assays for the differential diagnosis of COVID-19 and/or influenza (flu) could facilitate optimal treatment for both diseases. Diagnostic performance related to SARS-CoV-2 and Flu A/B detection was characterized for the BD SARS-CoV-2/Flu for BD MAX System ("MAX SARS-CoV-2/Flu") multiplex assay in comparison with BD BioGx SARS-CoV-2 Reagents for BD MAX System ("BioGx SARS-CoV-2") and the Cepheid Xpert(R) Xpress Flu/RSV ("Xpert Flu"). Two hundred and thirty-five nasopharyngeal specimens were obtained from external vendors. MAX SARS-CoV-2/Flu had positive percent agreement (PPA) and negative percent agreement (NPA) values for SARS-CoV-2 and Flu A/B that met FDA-EUA acceptance criteria of >95%.