title: The effectiveness of Vaxzevria and CoronaVac vaccines: A nationwide longitudinal retrospective study of 61 million Brazilians (VigiVac-COVID19).

abstract:
BackgroundHigh rates of virus transmission and the presence of variants of concern can affect vaccine effectiveness (VE). Both conditions occur in low-income countries, which primarily use viral vector or inactivated virus vaccine technologies. Such countries conducted few VE analyses, and most lack the power to evaluate effectiveness in subgroups.

MethodsThe present retrospective cohort study evaluated the effectiveness of Vaxzevria and CoronaVac vaccines for COVID-19-related infection in 75,919,840 Brazilian vaccinees from January 18 to July 24, 2021.

Study outcomes included documented infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19-related hospitalization, ICU admission, and death. We estimated VE using Cox regression adjusted for individual demographic characteristics.

ResultsVaccination with Vaxzevria or CoronaVac was effective against SARS-CoV-2 infection and highly effective against hospitalization, ICU admission, and death in individuals up to 79 years. From 80-89 years of age, Vaxzevria led to 89.9%(95CI:87.7-91.7) VE against death versus 67.2%(95CI:63.6-70.5) for CoronaVac. Above 90 years, 65.4%(95CI:46.1-77.8) protection was conferred to Vaxzevria-vaccinated individuals versus 33.6%(95CI:21.9-43.5) in CoronaVac-vaccinated individuals. Furthermore, the post-vaccination daily incidence rate shows a stepwise increase from younger to elder decades of life.

ConclusionsVaxzevria demonstrated overall effectiveness against severe COVID-19 up to 89 years and CoronaVac up to 79 years of age. There is a stepwise effectiveness reduction for both vaccines for each decade of life. Our results suggest that individuals aged 80 years or older may benefit from an expedited booster dose. Ongoing evaluations, including any additional vaccines authorized, are crucial to monitoring long-term vaccine effectiveness.


title: Influence of age on the effectiveness and duration of protection in Vaxzevria and CoronaVac vaccines

category: epidemiology


title: The impact of the COVID-19 pandemic on adult mental health in the UK: A rapid systematic review

abstract:
BackgroundThere is evidence that the COVID-19 pandemic has affected the mental health of the UK population, but this needs synthesising to guide effective policy recommendations and ensure support is targeted to populations most at risk. We conducted a rapid systematic review of the evidence of the impact of COVID-19 and associated restrictions on the mental health of UK adults, including risk and protective factors.

MethodA range of databases were searched to identify eligible studies. Studies were eligible if they reported primary quantitative or qualitative research on the mental health of UK adults between March 2020 and March 2021. Journal publications and pre-prints were included. Reviews, position papers, protocol papers and studies published in languages other than English were excluded. The study authors screened papers for eligibility and included 102 papers in the analysis.

ResultsThe evidence from this review indicates that the mental health of UK adults has declined since the start of the pandemic, with different populations being unequally affected. Populations particularly affected are women, young adults, ethnic minorities, people from lower socio-economic backgrounds, people with pre-existing conditions and people who have had COVID-19. Other risk factors include having to isolate and time spent watching pandemic related news. Protective factors include social contact and maintaining healthy behaviours, such as physical activity.

ConclusionsPolicy should aim to discourage risky behaviours while ensuring support is available for people to engage in protective behaviours. Interventions should be directed towards populations that have been most adversely affected. Addressing the decline in mental health across the UK population since the COVID-19 pandemic will require increasing mental health provision and ensuring equitable access to support.

category: public and global health


title: Associations between gestational weight gain adequacy and neonatal outcomes in Tanzania

abstract:
IntroductionGestational weight gain (GWG) is associated with fetal and newborn health; however, data from sub-Saharan Africa are limited.

MethodsWe used data from a prenatal micronutrient supplementation trial among a cohort of HIV-negative pregnant women in Dar es Salaam, Tanzania to estimate the relationships between GWG and newborn outcomes. GWG adequacy was defined as the ratio of the total observed weight gain over the recommended weight gain based on the Institute of Medicine body mass index (BMI)-specific guidelines. Newborn outcomes assessed were: stillbirth, perinatal death, preterm birth, low birthweight, macrosomia, small-for-gestational age (SGA), large-for-gestational age (LGA), stunting at birth, and microcephaly. Modified Poisson regressions with robust standard error were used to estimate the relative risk of newborn outcomes as a function of GWG adequacy.

ResultsOf 7561 women included in this study, 51% had severely inadequate (<70%) or inadequate GWG (70-90%), 31% had adequate GWG (90-125%), and 18% had excessive GWG ([≥]125%). Compared to adequate GWG, severely inadequate GWG was associated with a higher risk of low birthweight, SGA, stunting at birth, and microcephaly; whereas excessive GWG was associated with a higher risk of LGA and macrosomia.

ConclusionInterventions to support optimal gestational weight gain are needed and are likely to improve newborn outcomes.


title: An evaluation of community-based comprehensive vision care for the ageing population

abstract:
ObjectiveThis study was conducted to evaluate the real-world effectiveness and potential cost-effectiveness of a community-based vision care programme for the ageing population aged 60 years or above.

MethodsData from a total of 8899 subjects participating in a community based comprehensive vision care programme from 2015 to 2019 were extracted and analyzed to evaluate the effectiveness of the programme in terms of the prevalence of visual impairment (VI), the change in the prevalence of VI after refractive error correction, and the types of ocular disorders detected. VI was defined by a) visual acuity (VA) worse than 6/18 in any eye (worse eye) and b) VA worse than 6/18 in the better eye. The cost-effectiveness from the funders perspective was also estimated in terms of cost per VI avoided from such a programme.

ResultsThe study found that referenced to VA of the worse eye, the prevalence of VI was 39.1% (3482/8899, 95% CI: 38.1%-40.1%) based on presenting VA and reduced to 13.8% (1227/8899, 95% CI: 13.1%-14.5%) based on best-corrected VA. Referenced to the VA in the better eye, the prevalence of VI was 17.3% (1539/8899, 95% CI: 16.5%-18.1%) based on presenting VA and decreased to 4.2% (373/8899, 95% CI: 3.8%-4.6%) after best-corrected VA. Uncorrected refractive error was the major cause of presenting VI. From the funders perspective, the cost per VI case prevented was HK$1921 based on VA in the worse eye and HK$3715 based on the better eye.

ConclusionA community-based programme was effective to detect the VI and reduced a relative 65% to 76% VI after refractive error correction for the community-dwelling ageing population. The ageing population can benefit from regular comprehensive vision care.


title: Irradiation of the Subventricular Zone and Subgranular Zone: an Atlas-based analysis on Overall Survival in High- and Low-grade Glioma Patients

abstract:
BackgroundNeural stem cells in the subventricular- (SVZ) and subgranular zone (SGZ) are hypothesized to support growth of glioma. Therefore, irradiation of the SVZ and SGZ might reduce tumor growth and might improve overall survival (OS). However, it may also inhibit the repair capacity of brain tissue. The aim of this retrospective cohort study is to assess the impact of SVZ and SGZ radiotherapy doses on OS of patients with high-grade (HGG) or low-grade (LGG) glioma.

MethodsWe included 273 glioma patients who received radiotherapy. We created an SVZ atlas, shared openly with this work, while SGZ labels were taken from the CoBRA atlas. Next, SVZ and SGZ regions were automatically delineated on T1 MR-images. Dose and OS correlations were investigated with Cox regression and Kaplan-Meier analysis.

ResultsCox regression analyses showed significant hazard ratios for SVZ dose (univariate: 1.029/Gy, p<0.001; multivariate: 1.103/Gy, p = 0.002) and SGZ dose (univariate: 1.023/Gy, p<0.001; multivariate: 1.055/Gy, p<0.001) in HGG patients. Kaplan-Meier analysis showed significant correlations between OS and high/low dose groups for HGG patients (SVZ: respectively 10.7 months (>30.33 Gy) vs 14.0 months (<30.33 Gy) median OS, p = 0.011; SGZ: respectively 10.7 months (>29.11 Gy) vs 15.5 months (<29.11 Gy) median OS, p<0.001). No correlations between dose and OS were not found for LGG patients.

ConclusionIrradiation doses on neurogenic areas correlate negatively with OS in patients with HGG. Whether sparing of the SVZ and SGZ during radiotherapy improves OS, should be subject of prospective studies.

Key PointsO_LINeural stem cells in the SVZ and SGZ are hypothesized to support growth of glioma.
C_LIO_LIHigher radiation doses on the SVZ and SGZ correlate with lower OS in HGG patients.
C_LIO_LIAvoidance of neurogenic niches should be considered to improve OS of HGG patients.
C_LI

Importance of StudySurvival rates and quality of life of patients with glioma are still suboptimal, therefore improvement of radiation treatment planning and delivery is required. The SVZ and SGZ of the adult human brain are a source of brain tissue repair but may also be the source of glioma growth enhancement. By investigating the effects of radiotherapy on SVZ and SGZ, we gain insight into associations between tumor progression and survival. We included 273 adult patients with high- and low- grade glioma who received radiation treatment. We found that irradiation doses on neurogenic areas correlate with lower OS in patients with HGG. Avoidance of SVZ and SGZ should be considered to improve OS. These study results will contribute to optimization of brain tumor radiotherapy, focused on increasing OS. In order to facilitate future research into the role of the SVZ, we also provide stereotaxic standard space atlas labels for SVZ and SGZ.

category: radiology and imaging


title: Retrospective Exploratory Analysis of Task-Specific Effects on Brain Activity after Stroke

abstract:
BackgroundEvidence supports cortical reorganization in sensorimotor areas induced by constraint-induced movement therapy (CIMT). However, only a few studies examined the neural plastic changes as a function of task specificity. This retrospective exploratory analysis aims to evaluate the functional brain activation changes during a precision and a power grasp task in chronic stroke survivors who received two-weeks of CIMT compared to a no-treatment control group.

MethodsFourteen chronic stroke survivors, randomized to CIMT (n=8) or non-CIMT (n=6), underwent functional MRI (fMRI) before and after a two-week period. Two behavioral measures, the 6-item Wolf Motor Function Test (WMFT-6) and the Motor Activity Log (MAL), and fMRI brain scans were collected before and after a two-week period. During scan runs, participants performed two different grasp tasks (precision, power). Pre to post changes in laterality index (LI) were compared by group and task for two predetermined motor regions of interest: dorsal premotor cortex (PMd) and primary motor cortex (MI).

ResultsThe CIMT group showed significant improvements in both the WMFT-6 and the MAL post-intervention, whereas the non-CIMT group showed improvements in only the MAL. Two weeks of CIMT resulted in a relative increase in activity in a key region of the motor network, PMd of the lesioned hemisphere, under precision grasp task conditions compared to the non-treatment control group. No changes in LI were observed in MI for either task or group. Conclusions: These findings provide evidence for task-specific effects of CIMT in the promotion of recovery-supportive cortical reorganization in chronic stroke survivors.

category: rehabilitation medicine and physical therapy


title: Monocytes and neutrophil levels are potentially linked to progression to IPF for patients with indeterminate UIP CT pattern.

abstract:
RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Identifying patients early may allow intervention which could limit progression. The  indeterminate for UIP (iUIP) CT pattern, defined in the 2018 IPF guidelines, could be a precursor to IPF but there is limited data on how patients with iUIP progress over time.

ObjectiveTo evaluate the radiological progression of iUIP and explore factors linked to progression to IPF.

MethodsWe performed a retrospective analysis of a lung fibrosis clinic cohort (n=230) seen between 2013-2017. Cases with iUIP were identified; first ever CTs for each patient found and categorised as  non-progressor or  progressors (the latter defined as increase in extent of disease or to  definite or  probable UIP CT pattern) during their follow up. Lung function trends, haematological data and patient demographics were examined to explore disease evolution and potential contribution to progression.

Results48 cases with iUIP CT pattern were identified. Of these, 32 had follow up CT scans, of which 23 demonstrated progression. 17 patients in this cohort were diagnosed with IPF over a mean (S.D.) period of 3.9 ({+/-}1.9) years. Monocyte [HR 23, CI 1.6-340, p=0.03] and neutrophil levels [HR 1.8, CI 1.3-2.3, p<0.001] obtained around the time of initial CT, were associated with progression to IPF using Cox proportional hazard modelling.

Conclusion53% of our evaluable iUIP patients progressed to IPF over a mean of four years. Monocyte and neutrophil levels at initial CT were significantly associated with progression in disease. These data provide a single-centre analysis of the evolution of patients with iUIP CT pattern, and first signal for potential factors associated with progression to IPF.

Key messageO_ST_ABSWhat is the key question?C_ST_ABSHow does the  indeterminate for UIP (iUIP) interstitial CT pattern evolve over time and what factors are associated with progression to definite and probable UIP pattern.

What is the bottom line?In this retrospective single centre analysis, 53% of evaluable cases with iUIP on initial CT scan progressed to probable or definite UIP CT pattern over an average of 4 years. Monocyte and neutrophil levels performed around the time of initial CT were significantly associated with progression to definite and probable UIP pattern.

Why read on?We discuss the implications of these findings, its strengths and limitations.

category: respiratory medicine


title: A conformational variant of p53 (U-p53AZ) as blood-based biomarker for the prediction of the onset of symptomatic Alzheimer's disease

abstract:
BackgroundOngoing research seeks to identify blood-based biomarkers able to predict the onset and progression of Alzheimers disease (AD). A potential biomarker is the unfolded conformational variant of p53, previously observed in individuals in the prodromal and clinical AD stages. In this retrospective study, we compare diagnostic and prognostic performances of measures of the amyloid {beta} load with those of a conformational variant of U-p53 in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort.

MethodsImmunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing in plasma samples from the AIBL study identified the clinically relevant AZ 284(R) peptide, representing a measure of the U-p53 conformational variant (U-p53AZ). Based on U-p53AZ quantification via IP/LC electrospray ionisation-coupled MS/MS (AlzoSure(R) Predict test) on 515 samples from 482 individuals from the AIBL cohort, the predictive performance of U-p53AZ was assessed and compared with amyloid load as measured by amyloid {beta}-positron emission tomography (A{beta}-PET). Its predictive performance was determined at 36, 54, 72 and 90 months following baseline assessment.

ResultsU-p53AZ was able to identify individuals with AD dementia with an area under the receiver operating characteristic curve (AUC) of 99%. U-p53AZ outperformed the conventional A{beta}-PET measures in predicting the onset of AD dementia both from preclinical (AUC=98%) and prodromal stages (AUC=89%), even 90 months prior to onset (AUC=99%). Additionally, the estimated predictive performance of U-p53AZ was superior (AUC [≥]98%) to other risk factors (i.e., gender, A{beta}-PET and APOE {varepsilon}4 allele status) in identifying individuals at high risk for progression to AD.

ConclusionThese findings support use of U-p53AZ as blood-based biomarker predicting if individuals, at both asymptomatic and MCI stages, would progress to AD at least six years prior to the onset of clinical AD dementia.

category: neurology


title: Factors associated with self-reported health among New Zealand military Veterans: a cross-sectional study.

abstract:
ObjectiveTo identify factors associated with better or poorer self-reported health status in New Zealand Military Veterans.

DesignAn online cross-sectional survey.

ParticipantsThe total number of eligible Veterans is unknown, but a total of 1,817 Veterans responded, including 1009 serving personnel providing a 26% response rate from that group.

Study variablesHealth status was self-reported using the EQ-5D-5L, which asks about problems across five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), with five levels of severity (e.g. no, slight, moderate, severe or extreme problems). The EQ-5D-5L also contains a visual analogue scale (EQ-VAS), scaled from 0 (worst) to 100 (best) imagined health. Hypothetical relationships with better health were positive social support, sleep and psychological flexibility; with poorer health, exposure to psychological trauma, distress and hazardous drinking.

ResultsThe proportion of Veterans reporting  any problems compared to  no problems with the five EQ-5D dimensions, was similar to those found in the general NZ population, although a higher proportion of Veterans reported problems with mobility, self-care, usual activities and pain/discomfort. Psychological flexibility and better sleep quality were associated with higher EQ-VAS scores; distress was associated with lower EQ-VAS scores.

ConclusionIn this sample of New Zealand Veterans, psychological flexibility and good sleep are associated with better self-rated health, and distress and poor sleep with diminished health. These factors might be used as sentinel health indicators in assessing Veteran health status. As distress, psychological flexibility and sleep are closely related, cognitive behavioural therapy encompassing these domains may be useful in improving the health of New Zealand Veterans.

Strengths and limitations of this studyO_LIMany studies of Veterans have focused on adverse outcomes, but we have been able to focus on a holistic measure of  health.
C_LIO_LIThe study was sufficiently powered to detect important relationships indicating opportunities for intervention.
C_LIO_LIThe exact response rate is unknown, and possible bias may be a limitation.
C_LIO_LIThe cross-sectional design means that we cannot explore cause and effect relationships.
C_LI

category: occupational and environmental health


title: The WORC* database: MRI and CT scans, segmentations, and clinical labels for 930 patients from six radiomics studies

abstract:
The WORC database consists in total of 930 patients composed of six datasets gathered at the Erasmus MC, consisting of patients with: 1) well-differentiated liposarcoma or lipoma (115 patients); 2) desmoid-type fibromatosis or extremity soft-tissue sarcomas (203 patients); 3) primary solid liver tumors, either malignant (hepatocellular carcinoma or intrahepatic cholangiocarcinoma) or benign (hepatocellular adenoma or focal nodular hyperplasia) (186 patients); 4) gastrointestinal stromal tumors (GISTs) and intra-abdominal gastrointestinal tumors radiologically resembling GISTs (246 patients); 5) colorectal liver metastases (77 patients); and 6) lung metastases of metastatic melanoma (103 patients). For each patient, either a magnetic resonance imaging (MRI) or computed tomography (CT) scan, collected from routine clinical care, one or multiple (semi-)automatic lesion segmentations, and ground truth labels from a gold standard (e.g., pathologically proven) are available. All datasets are multicenter imaging datasets, as patients referred to our institute often received imaging at their referring hospital. The dataset can be used to validate or develop radiomics methods, i.e., using machine or deep learning to relate the visual appearance to the ground truth labels, and automatic segmentation methods. See also the research article related to this dataset: Starmans et al., Reproducible radiomics through automated machine learning validated on twelve clinical applications, Submitted.

Specifications Table

O_TBL View this table:
org.highwire.dtl.DTLVardef@b12793org.highwire.dtl.DTLVardef@9d440corg.highwire.dtl.DTLVardef@dea161org.highwire.dtl.DTLVardef@352338org.highwire.dtl.DTLVardef@9b5483_HPS_FORMAT_FIGEXP  M_TBL C_TBL

category: oncology


title: SARS-CoV-2 susceptibility and ACE2 gene variations within diverse ethnic backgrounds

abstract:
BackgroundHost genetics play a major role in COVID-19 susceptibility and severity. Here, we analyse an ethnically diverse cohort of National Health Service (NHS) patients in the United Kingdom (UK) to assess the association between variants in the ACE2 locus and COVID-19 risk.

MethodsWe analysed whole-genome sequencing (WGS) data of 6,274 participants who were tested for SARS-CoV-2 from the UKs 100,000 Genomes Project (100KGP) for the presence of ACE2 coding variants and expression quantitative trait loci (eQTLs).

FindingsWe identified a splice site variant (rs2285666) associated with increased ACE2 expression with an overrepresentation in SARS-CoV-2 positive patients relative to 100KGP controls (p = .015), and in hospitalised European patients relative to outpatients in intra-ethnic comparisons (p = .029). We also compared the prevalence of 288 eQTLs, of which 23 were enriched in SARS-CoV-2 positive patients. The eQTL rs12006793 had the largest effect size (d = 0.91), which decreases ACE2 expression and is more prevalent in controls, thus potentially reducing risk of COVID-19. We identified three novel nonsynonymous variants predicted to alter ACE2 function, and showed that three variants (p.K26R, p.H378R, p.Y515N) alter receptor affinity for the viral Spike (S) protein. Variants p.K26R and p.N720D are more prevalent in the European population (p < .001), but Y497H is less prevalent compared to East Asians (p = .020).

InterpretationOur results demonstrate that the spectrum of genetic variants in ACE2 may inform risk stratification of COVID-19 patients and could partially explain the differences in disease susceptibility and severity among different ethnic groups.

FundingThe 100KGP is funded by the National Institute for Health Research and NHS England. Funding was also obtained from Stanford University, Palo Alto.

category: genetic and genomic medicine


title: Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease

abstract: We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species that are putatively in the mechanistic pathway to coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 phenotyped individuals from the Busselton Health Study. In our discovery GWAS we identified 667 independent loci associations with these lipid species (479 novel), followed by meta-analysis and validation in two independent cohorts. Lipid endophenotypes (134) identified for CAD were associated with variation at 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in [~]456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P<1x10-3), 43 loci were associated with at least one of the 134 lipid endophenotypes. The findings of this study illustrate the value of integrative biology to investigate the genetics and lipid metabolism in the aetiology of atherosclerosis and CAD, with implications for other complex diseases.


title: Real-time Continuous Measurement of Lactate through a Minimally-invasive Microneedle Biosensor: a Phase I Clinical Study

abstract:
IntroductionDetermination of blood lactate levels supports decision-making in a range of medical conditions. Invasive blood-sampling and laboratory access are often required, and measurements provide a static profile at each instance. We conducted a Phase I clinical study validating performance of a microneedle patch for minimally-invasive, continuous lactate measurement in healthy volunteers.

MethodsFive healthy adult participants wore a solid microneedle biosensor on their forearms and undertook aerobic exercise for 30 minutes. The microneedle biosensor quantifies lactate concentrations in interstitial fluid (ISF) within the dermis continuously and in real-time. Outputs were captured as sensor current and compared with lactate concentrations from venous blood and microdialysis.

ResultsThe biosensor was well-tolerated. Participants generated a median peak venous lactate of 9.25 mmol/L (Interquartile range, 6.73 to 10.71). Microdialysate concentrations of lactate closely correlated with blood. Microneedle biosensor current followed venous lactate concentrations and dynamics, with good agreement seen in all participants. There was an estimated lag-time of 5 minutes (IQR -4 to 11 minutes) between microneedle and blood lactate measurements.

ConclusionThis study provides first-in-human data on use of a minimally-invasive microneedle biosensor for continuous lactate measurement, providing dynamic monitoring. The platform offers distinct advantages to frequent blood sampling in a wide range of clinical settings, especially where access to laboratory services is limited or blood sampling is infeasible.

category: infectious diseases


title: Evaluation of the relationship between quantitative PCR results and cell culturing of SARS2-CoV with respect to symptoms onset and Viral load - a systematic review

abstract:
BackgroundViral culture is currently the most accurate method to demonstrate viability and infectivity of Severe acute respiratory syndrome Coronavirus (SARS-2 CoV). Routine clinical diagnosis, however, is mostly performed by PCR - based assays that do not discriminate between infectious and non-virus. Herein, we aimed to determine the correlation between positive viral cultures and either PCR positivity, the Cycle Threshold (Ct) or the number of viral copies.

MethodsA systematic electronic literature search was performed and studies that reported both viral SARS-CoV-2 culture and PCR-based assays were included. A separate search for samples from blood, urine, stool, breast milk and tears were performed. To convert Ct values reported in the reviewed studies were to viral genomic copies, calibration experiments with four different reaction performed, using quantified RNA molecules.

ResultsA total 540 articles were reviewed, and 38 studies were included in this review. Out of 276 positive-culture of non-severe patients, 272 (98.55%) were negative ten days after symptoms onset, while PCR assays remained positive for up to 67 days. In severely ill or immunocompromised patients positive-culture was obtained up to 32 days and out of 168 cultures, 31 (18.45%) stayed positive after day 10. In non-severe patients, in Ct value greater than 30 only 10.8% were still culture-positive while in Ct >35 it was nearly universally negative. The minimal calculated number of viral genome copies in culture-positive sample was 2.5 x 103 copies / mL. These findings were similar in immunocompromised patients. Recovering positive culture from non-respiratory samples was sporadically obtained in stool or urine samples. Conversion of Ct values to viral genome copies showed variability between different PCR assays and highlighted the need to standardize reports to correctly compare results obtained in different laboratories.

ConclusionDuring the pandemic phase, non-severe COVID-19 patients who are recovering and are not immuno-suppressed, can be regarded as non-infectious, within 10 days from symptom onset, or with Ct value greater than 35 (or a calculated viral load lower than 1.2x103 copies / mL). These findings have important implications for recovering patients and asymptomatic patients, with respect to isolation criteria. The conversion of Cq values to viral genome copies described herein may be useful in future work, enabling a more standardized comparison between results reported in different studies from different laboratories.


title: Predominance of antibody-resistant SARS-CoV-2 variants in vaccine breakthrough cases from the San Francisco Bay Area, California

abstract: Associations between vaccine breakthrough cases and infection by SARS coronavirus 2 (SARS-CoV-2) variants have remained largely unexplored. Here we analyzed SARS-CoV-2 whole-genome sequences and viral loads from 1,373 persons with COVID-19 from the San Francisco Bay Area from February 1 to June 30, 2021, of which 125 (9.1%) were vaccine breakthrough infections. Fully vaccinated were more likely than unvaccinated persons to be infected by variants carrying mutations associated with decreased antibody neutralization (L452R, L452Q, E484K, and/or F490S) (78% versus 48%, p = 1.96e-08), but not by those associated with increased infectivity only (N501Y) (85% versus 77%, p = 0.092). Differences in viral loads were non-significant between unvaccinated and fully vaccinated persons overall (p = 0.99) and according to lineage (p = 0.09 - 0.78). Viral loads were significantly higher in symptomatic as compared to asymptomatic vaccine breakthrough cases (p < 0.0001), and symptomatic vaccine breakthrough infections had similar viral loads to unvaccinated infections (p = 0.64). In 5 cases with available longitudinal samples for serologic analyses, vaccine breakthrough infections were found to be associated with low or undetectable neutralizing antibody levels attributable to immunocompromised state or infection by an antibody-resistant lineage. Taken together, our results suggest that vaccine breakthrough infecions are overrepresnted by circulating antibody-resistant SARS-CoV-2 variants, and that symptomatic breakthrough infections may potentially transmit COVID-19 as efficiently as unvaccinated infections, regardless of the infecting lineage.


title: Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections

abstract:
BackgroundReports of waning vaccine-induced immunity against COVID-19 have begun to surface. With that, the comparable long-term protection conferred by previous infection with SARS-CoV-2 remains unclear.

MethodsWe conducted a retrospective observational study comparing three groups: (1)SARS-CoV-2-naive individuals who received a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine, (2)previously infected individuals who have not been vaccinated, and (3)previously infected and single dose vaccinated individuals. Three multivariate logistic regression models were applied. In all models we evaluated four outcomes: SARS-CoV-2 infection, symptomatic disease, COVID-19-related hospitalization and death. The follow-up period of June 1 to August 14, 2021, when the Delta variant was dominant in Israel.

ResultsSARS-CoV-2-naive vaccinees had a 13.06-fold (95% CI, 8.08 to 21.11) increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021. The increased risk was significant (P<0.001) for symptomatic disease as well. When allowing the infection to occur at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, though SARS-CoV-2 naive vaccinees had a 5.96-fold (95% CI, 4.85 to 7.33) increased risk for breakthrough infection and a 7.13-fold (95% CI, 5.51 to 9.21) increased risk for symptomatic disease. SARS-CoV-2-naive vaccinees were also at a greater risk for COVID-19-related-hospitalizations compared to those that were previously infected.

ConclusionsThis study demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity. Individuals who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant.


title: COVID-19 and Vitamin D (Co-VIVID Study): a systematic review and meta-analysis of randomized controlled trials

abstract:
BackgroundVitamin D levels have been reported to be associated with COVID-19 susceptibility, severity and mortality events.. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the use of vitamin D intervention on COVID-19 outcomes.

MethodsLiterature search was conducted using PubMed, Cochrane library, and ClinicalTrials.gov databases (latest search on August 5, 2021). We included RCTs reporting the use of vitamin D intervention to control/placebo group in COVID-19. Two independent researchers did literature search, abstracted data, and the risk of bias assessment.

ResultsA total of 6 RCTs with 551 COVID-19 patients were included. The overall collective evidence pooling all the outcomes across all RCTs indicated the beneficial use of vitamin D intervention in COVID-19 (relative risk, RR = 0.60, 95% CI 0.40 to 0.92, Z=2.33, p=0.02, I2 = 48%). However, no statistical significance was observed for individual outcomes of ICU care (RR = 0.11, 95% CI 0.15 to 1.30, Z=1.48, p=0.14, I2 = 66%) and mortality (RR = 0.78, 95% CI 0.25 to 2.40, Z=0.66, p=0.02, I2 = 33%), though decreased rates were noted. The rates of RT-CR positivity was significantly decreased in the intervention group as compared to the non-vitamin D groups (RR = 0.46, 95% CI 0.24 to 0.89, Z=2.31, p=0.02, I2 = 0%).

ConclusionCOVID-19 patients supplemented with vitamin D are more likely to demonstrate fewer rates of ICU admission, mortality events and RT-PCR positivity. However, no statistical significance has been achieved for individual outcomes of ICU and deaths. More RCTs and completion of ongoing trials largely needed to precisely establish the association between vitamin D use and COVID-19.


title: A multidimensional Mendelian randomization study on the impact of gut dysbiosis on chronic diseases and human longevity

abstract: Alterations of the gut microbiota, often referred to as gut dysbiosis, have been associated with several chronic diseases and longevity in pre-clinical models as well as in observational studies. Whether these relationships underlie causal associations in humans remains to be established. We aimed to determine whether gut dysbiosis influences the risk of chronic diseases and longevity using a comprehensive 2-Sample Mendelian randomization (2SMR) approach. We included as exposures inflammatory bowel disease (IBD) as a human model of gut dysbiosis, 11 gut-associated metabolites and pathways and 48 microbial taxa. Study outcomes included eight chronic diseases previously linked with gut dysbiosis using observational studies (Alzheimers disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease) as well as parental longevity and life expectancy. Neither IBD, nor gut-associated metabolites were causally associated with chronic disease or lifespan. After multiple testing correction for 582 tests, no microbial taxa-chronic disease associations remained significant. After robustness analyses and multivariate MR to correct for body mass index and alcohol intake on all 42 nominally significant causal relationships, four associations remained. Altogether, results of this multidimensional Mendelian randomization study suggest that gut dysbiosis has little impact on chronic diseases and human longevity and that previous documented associations may not underly causal relationships. Studies with larger sample sizes and more optimal taxonomic discrimination may ultimately be required to determine whether the human gut microbiota plays a causal role in the etiology of chronic diseases and longevity.


title: The potential impact of Anopheles stephensi establishment on the transmission of Plasmodium falciparum in Ethiopia and prospective control measures

abstract:
BackgroundSub-Saharan Africa has seen substantial reductions in cases and deaths due to malaria over the past two decades. While this reduction is primarily due to an increasing expansion of interventions, urbanisation has played its part as urban areas typically experience substantially less malaria transmission than rural areas. However, this may be partially lost with the invasion and establishment of Anopheles stephensi. An. stephensi, the primary urban malaria vector in Asia, was first detected in Africa during 2012 in Djibouti and was subsequently identified in Ethiopia in 2016, and later in Sudan and Somalia. In Djibouti, malaria cases have increased 30-fold from 2012 to 2019 though the impact in the wider region remains unclear.

MethodsHere we have adapted an existing model of mechanistic malaria transmission to estimate the increase in vector density required to explain the trends in malaria cases seen in Djibouti. To account for the observed plasticity in An. stephensi behaviour, and the unknowns of how it will establish in a novel environment, we sample behavioural parameters in order to account for a wide range of uncertainty. This quantification is then applied to Ethiopia, considering temperature-dependent extrinsic incubation periods, pre-existing vector-control interventions and Plasmodium falciparum prevalence in order to assess the potential impact of An. stephensi establishment on P. falciparum transmission. Following this, we estimate the potential impact of scaling up ITN (insecticide treated nets)/IRS (indoor residual spraying) and implementing piperonyl butoxide (PBO) ITNs and larval source management,, as well as their economic costs.

ResultsWe estimate that annual P. falciparum malaria cases could increase by 50% (95% CI 14-90) if no additional interventions are implemented. The implementation of sufficient control measures to reduce malaria transmission to pre-stephensi levels will cost hundreds of millions of USD.

ConclusionsSubstantial heterogeneity across the country is predicted and large increases in vector control interventions could be needed to prevent a major public health emergency.


title: A composite biomarker for esophageal cancer risk from automated analysis of a non-endoscopic device

abstract: Barretts esophagus containing intestinal metaplasia predisposes to cancer, yet the majority of cases are undiagnosed. The length of a Barretts segment is a key indicator of cancer risk, but measuring it has so far relied on endoscopy, which is expensive and invasive. Cytosponge-TFF3 is a minimally-invasive test that identifies intestinal metaplasia for endoscopic confirmation. We report a machine learning technique to quantify the extent of intestinal metaplasia and predict Barretts segment length from whole-slide image tile counts automatically generated from Cytosponge-TFF3 histology slides. Utilizing data from 529 patients, our segment length prediction model achieves an average validation fold accuracy of 0.84. Applying this algorithm to an independent test set of 162 patients from a screening trial shows a precision of 0.90 for identifying short-segment disease. This advance will enable higher-risk patients to be prioritized for endoscopy while saving more than half of Cytosponge-TFF3-positive patients from endoscopy in the screening setting.

category: gastroenterology


title: Prioritizing COVID-19 vaccination efforts and dose allocation within Madagascar

abstract:
BackgroundWhile mass COVID-19 vaccination programs are underway in high-income countries, limited availability of doses has resulted in few vaccines administered in low and middle income countries (LMICs). The COVID-19 Vaccines Global Access (COVAX) is a WHO-led initiative to promote vaccine access equity to LMICs and is providing many of the doses available in these settings. However, initial doses are limited and countries, such as Madagascar, need to develop prioritization schemes to maximize the benefits of vaccination with very limited supplies. There is some consensus that dose deployment should initially target health care workers, and those who are more vulnerable including older individuals. However, questions of geographic deployment remain, in particular associated with limits around vaccine access and delivery capacity in underserved communities, for example in rural areas that may also include substantial proportions of the population.

MethodsTo address these questions, we developed a mathematical model of SARS-CoV-2 transmission dynamics and simulated various vaccination allocation strategies for Madagascar. Simulated strategies were based on a number of possible geographical prioritization schemes, testing sensitivity to initial susceptibility in the population, and evaluating the potential of tests for previous infection.

ResultsUsing cumulative deaths due to COVID-19 as the main outcome of interest, our results indicate that distributing the number of vaccine doses according to the number of elderly living in the region or according to the population size results in a greater reduction of mortality compared to distributing doses based on the reported number of cases and deaths. The benefits of vaccination strategies are diminished if the burden (and thus accumulated immunity) has been greatest in the most populous regions, but the overall strategy ranking remains comparable. If rapid tests for prior immunity may be swiftly and effectively delivered, there is potential for considerable gain in mortality averted, but considering delivery limitations modulates this.

ConclusionAt a subnational scale, our results support the strategy adopted by the COVAX initiative at a global scale.


title: Serum miRNA-based signature indicates radiation exposure and dose in humans: a multicenter diagnostic biomarker study

abstract: Mouse and non-human primate models showed that serum miRNAs may be used to predict the biological impact of radiation doses. We hypothesized that these results can be translated to humans treated with total body irradiation (TBI), and that miRNAs may be used as clinically feasible biodosimeters. To test this hypothesis, serial serum samples were obtained from 25 patients who underwent allogeneic stem-cell transplantation and profiled for miRNA expression using next-generation sequencing. Circulating exosomes were extracted, their miRNA content sequenced and cross-referenced with the total miRNA fraction. Finally, miRNAs with diagnostic potential were quantified with qPCR and an artificial neural network model was created and validated on an independent group of 12 patients with samples drawn under the same protocol. Differential expression results were largely consistent with previous studies and allowed us to build an 8-miRNA-based model that showed AUC of 0.97 (95%CI 0.89-1.00) and validate it using qPCR in an independent validation set where it showed accuracy >91% for detecting exposure and 87.5% for differentiating between lethal and non-lethal doses. MiRNAs used in the model were miR-150-5p, miR-126-5p, miR-375, miR-215-5p, miR-144-5p, miR-122-5p, miR-320d and miR-10b-5p. Additionally, miRNAs with detectable expression in this and two prior animal sets almost perfectly separated the irradiated from non-irradiated samples in mice, macaques and humans, validating the miRNAs as radiation-responsive through evolutionarily conserved transcriptional regulation mechanisms. We conclude that serum miRNAs reflect radiation exposure and dose for humans undergoing TBI and may be used as functional biodosimeters for precise identification of people exposed to clinically significant radiation doses.


title: Effect of short-term heating on bioefficacy of deltamethrin-coated long-lasting insecticidal nets

abstract:
We recently reported that long-lasting insecticidal nets (LLINs) distributed in Papua New Guinea (PNG) between 2013 and 2019, exhibited severely diminished efficacy to knock down and kill susceptible Anopheles mosquitoes. This coincided with a rise in malaria observed in PNG since 2015. Here we show that LLIN bioefficacy is increased by heating LLINs prior to WHO cone bioassays.

Unused LLINs with low bioefficacy, delivered to PNG in 2019, were heated to 120{degrees}C for 5 minutes. Cone bioassays were performed before and at 1 h, 7 days and 30 days after heating. This led to a significant increase in 24 h mortality (17% to 61%) and 60 min knock down (31% to 72%). The effect was sustained over 30 days.

Bioassays are crucial in quality assurance of LLIN products. Our findings indicate that bioassay results can easily be manipulated. This may have implications for quality assurance procedures used to assess LLINs.


title: An approach to quantifying the interaction between behavioural and transmission clusters: the case of Hepatitis C virus infections in HIV positive men who have sex with men

abstract: We hypothesize that patterns of sexual behaviour play a role in the conformation of transmission networks. If that was the case, behavioural grouping might in turn correlate with transmission networks and have the potential to predict proximity in viral phylogenies. To address this hypothesis, we present an intuitive approach for quantifying interactions between clusters of sexual behaviour along a virus phylogeny. Data from the Swiss HIV Cohort Study on condom use and incident Hepatitis C virus (HCV) sequences served as proof-of-concept. A strict inclusion criteria contrasting with relatively low HCV prevalence hindered our ability to identify significant relationships. This manuscript intends to serve as guide for studies aimed at characterizing interactions between behavioural patterns and transmission networks. Large transmission networks such as those of HIV or COVID-19 are prime candidates for applying this methodological approach.

category: sexual and reproductive health


title: Predicting anti-cancer activity in flavonoids - a graph theoretic approach

abstract: In drug design, there are two major causes of drug failure in the clinic. First, the drug has to work, and second, the drug should be safe. Identifying compounds that work for certain ailments require enormous experimental time and, in general, is cost intensive. In this paper, we are concerned with melanoma, a special type of cancer that affects the skin. In particular, we seek to provide a mathematical model that can predict the ability of flavonoids, a vast and natural class of compounds that are found in plants, in reversing or alleviating melanoma. The basis for our model is the conception of a new graph parameter called, for lack of better terminology, graph activity, which captures melanoma cancer healing properties of the flavonoids. With a superior coefficient of determination, R2 = 1, the new model faithfully reproduces anti-cancer activities of some known data-sets. We demonstrate that the model can be used to rank the healing abilities of flavonoids which could be a powerful tool in the screening, and identification, of compounds for drug candidates.


title: Reduction in initiations of HIV treatment in South Africa during the COVID pandemic

abstract:
BackgroundIn response to the global pandemic of COVID-19, countries around the world began imposing stay-at-home orders, restrictions on transport, and closures of businesses in early 2020. South Africa implemented a strict lockdown in March 2020 before its first COVID-19 wave started, gradually lifted restrictions between May and September 2020, and then re-imposed restrictions in December 2020 in response to its second wave. There is concern that COVID-19-related morbidity and mortality, fear of transmission, and government responses may have led to a reduction in antiretroviral treatment (ART) initiations for HIV-infected individuals in countries like South Africa.

MethodsWe analyzed national, public sector, facility-level data from South Africas District Health Information System (DHIS) from January 2019 to March 2021 to quantify changes in ART initiation rates stratified by province, setting, facility size and type and compared the timing of these changes to COVID-19 case numbers and government lockdown levels. We excluded facilities with missing data, mobile clinics, and correctional facilities. We estimated the total number of ART initiations per study month for each stratum and compared monthly totals, by year.

ResultsAt the 2471 facilities in the final data set (59% of all ART sites in the DHIS), 28% fewer initiations occurred in 2020 than in 2019. Numbers of ART initiations declined sharply in all provinces in April-June 2020, compared to the same months in 2019, and remained low for the rest of 2020, with some recovery between COVID-19 waves in October 2020 and possible improvement beginning in March 2021. Percentage reductions were largest in district hospitals, larger facilities, and urban areas. After the initial decline in April-June 2020, most provinces experienced a clear inverse relationship between COVID-19 cases and ART initiations but little relationship between ART initiations and lockdown level.

ConclusionsThe COVID-19 pandemic and responses to it resulted in substantial declines in the number of HIV-infected individuals starting treatment in South Africa, with no recovery of numbers during 2020. These delays may lead to worse treatment outcomes for those with HIV and potentially higher HIV transmission. Exceptional effort will be needed to sustain gains in combating HIV.

category: hiv aids


title: Discordant humoral and T cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy

abstract:
BackgroundSphingosine-1-phosphate receptor (S1P) modulators and antiCD20 therapies impair humoral responses to SARS-CoV-2 mRNA vaccines. Whether disease modifying therapies (DMTs) for multiple sclerosis (MS) also impact T cell immune response to vaccination is unknown.

MethodsIn 101 people with MS, we measured humoral responses via an immunoassay to measure IgG against the COVID-19 spike S1 glycoprotein in serum. We also measured T cell responses using FluoroSpot assay for interferon gamma (IFN-{gamma}) (Mabtech,Sweden) using cryopreserved rested PBMCs and then incubated in cRPMI with 1{micro}g/ml of pooled peptides spanning the entire spike glycoprotein (Genscript, 2 pools; 158 peptides each). Plates were read on an AID iSpot Spectrum to determine number of spot forming cells (SFC)/106 PBMCs. We tested for differences in immune responses across DMTs using linear models.

FindingsHumoral responses were detected in 22/39 (56.4%) participants on anti-CD20 and in 59/63 (93.6%) participants on no or other DMTs. In a subset with immune cell phenotyping (n=88; 87%), T cell responses were detected in 76/88 (86%), including 32/33 (96.9%) participants on anti-CD20 therapies. AntiCD20 therapies were associated with an increase in IFN-{gamma} SFC counts relative to those on no DMT or other DMTs (for antiCD20 vs. no DMT: 425.9% higher [95%CI: 109.6%, 1206.6%] higher; p<0.001; for antiCD20 vs. other DMTs: 289.6% [95%CI: 85.9%, 716.6%] higher; p<0.001).

InterpretationWe identified a robust T cell response in individuals on anti-CD20 therapies despite a reduced humoral response to SARS-CoV-2 vaccination. Follow up studies are needed to determine if this translates to protection against COVID-19 infection.


title: Hydroxychloroquine for pre-exposure prophylaxis of COVID-19 in health care workers: a randomized, multicenter, placebo-controlled trial (HERO-HCQ)

abstract:
ObjectiveTo determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCW).

DesignMulticenter, 1:1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial.

Setting34 clinical centers in the United States.

Participants1360 HCW at risk for COVID-19 infection enrolled between April and November 2020.

InterventionsA loading dose of HCQ 600 mg twice on Day 1 followed by 400 mg daily for 29 days or matching placebo taken orally.

Main Outcome MeasureComposite of confirmed or suspected COVID-19 clinical infection by Day 30 defined as new onset fever, cough, or dyspnea and either a positive SARS-CoV-2 PCR test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected).

ResultsEnrollment for the study was closed before full accrual due to difficulties recruiting additional participants. The primary composite endpoint occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No statistically significant difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6% to 0.9%, p=0.20). We identified no significant safety issues.

ConclusionOral HCQ taken as prescribed appeared to be safe in a group of HCW. No significant clinical benefits were observed. The study was underpowered to rule out a small but potentially important reduction in COVID-19 infections.

Trial RegistrationNCT04334148


title: HMOX1 genetic polymorphisms and outcomes in infectious disease: a systematic review

abstract:
IntroductionHeme-oxygenase 1 (HMOX1) is a critical stress response gene that catalyzes the multistep oxidation of heme. A GT(n) repeat of variable length in the promoter in has been associated with a wide range of human diseases, including infections. This paper aims to summarise and systematically review associations between the length of the HMOX1 GT(n) promoter and infectious disease in humans.

MethodsA search using relevant terms was performed in PubMED and EMBASE through to 15/01/21 identifying all research that studied an association between the HMOX1 GT(n) repeat polymorphism and the incidence and/or outcome of any human infectious disease. Citations were screened for additional studies. Potential studies were screened for inclusion by two authors. Data was extracted on allele frequency, genotype, strength of association, mechanism of genotyping, and potential biases. A narrative review was performed across each type of infection.

Results1,533 studies were identified in the search, and one via citation screening. Sixteen studies were ultimately included, seven in malaria, three in HIV, three in sepsis, and one each in pneumonia, hepatitis C, and acute respiratory distress syndrome (ARDS). Sample sizes for nearly all studies were small (biggest study, n = 1,646). Allelic definition was different across all included studies.

In malaria, three studies suggested that longer alleles were associated with reduced risk of severe malaria, particularly malaria-induced renal dysfunction, with four studies identifying a null association. In sepsis, two studies suggested an association with longer alleles and better outcomes.

ConclusionsDespite the importance of HMOX1 in survival from infection, and the association between repeat length and gene expression, the clinical data supporting an association between repeat length and incidence and/or outcome of infection remain inconclusive. The most promising data supports a potential association with protection from severe malaria, although this was not found in all studies.


title: Overcoming the pitfalls of NGS-based molecular diagnosis of Shwachman-Diamond syndrome

abstract:
PurposeShwachman-Diamond syndrome (SDS) is predominately caused by biallelic mutations in the SBDS gene and is characterized by exocrine pancreatic insufficiency, skeletal abnormalities and pancytopenia. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. We established an efficient approach, HapICE, to infer the haplotype of SBDS based on short-read next-generation sequencing (NGS).

MethodsHapICE based on the Expectation-Maximization algorithm was developed to detect variants in exon 2 of SBDS arising from gene conversion. We retrospectively analyzed two common pathogenic variants (c.183_184delinsCT and c.258+2T>C) in suspected SDS patients and compared the results with those from conventional NGS analysis.

ResultsIn 47 SDS high-risk individuals and 64 available parents, HapICE improved the diagnostic rate by 27.7% compared with conventional methods and revealed 100% (95% CI: 92.5%-100%) concordance with Sanger sequencing. In addition to eighteen patients having consistent genetic results by both methods, HapICE further reported 8 patients with more accurate variant detection and 13 cases with the c.183_184delinsCT variant missing by conventional methods. HapICE also showed better performance in screening for carrier and wild-type status.

ConclusionWe have developed a novel SBDS variant detection tool through regular NGS data that demonstrated precise variant detection performance in clinical scenarios.


title: Evaluation of commercial anti-SARS-CoV-2 antibody assays and comparison of standardized titers in vaccinated healthcare workers.

abstract:
With the availability of vaccines, commercial assays detecting anti-SARS-CoV-2 antibodies (Ab) evolved towards quantitative assays directed to the spike glycoprotein or its receptor binding domain (RBD). The main objective of the present study was to compare the Ab titers obtained with quantitative commercial binding Ab assays, after 1 dose (convalescent individuals) or 2 doses (naive individuals) of vaccine, in healthcare workers (HCW).

Antibody titers were measured in 255 sera (from 150 HCW) with 5 quantitative immunoassays (Abbott RBD IgG II quant, bioMerieux RBD IgG, DiaSorin Trimeric spike IgG, Siemens Healthineers RBD IgG, Wantai RBD IgG). One qualitative total antibody anti RBD detection assay (Wantai) was used to detect previous infection before vaccination. The results are presented in binding Ab units (BAU)/mL after application, when possible, of a conversion factor provided by the manufacturers and established from a World Health Organization (WHO) internal standard.

There was a 100% seroconversion with all assays evaluated after two doses of vaccine. With assays allowing BAU/ml correction, Ab titers were correlated (Pearson correlation coefficient, {rho}, range: 0.85-0.94). The titer differences varied by a mean of 10.6% between Siemens and bioMerieux assays to 60.9% between Abbott and DiaSorin assays. These results underline the importance of BAU conversion for the comparison of Ab titer obtained with the different quantitative assays. However, significant differences persist, notably, between kits detecting Ab against the different antigens.

A true standardization of the assays would be to include the International Standard in the calibration of each assays to express the results in IU/mL.

category: allergy and immunology


title: Infection inhibiting effect of RT-PCR testing-isolation in COVID-19 - a case study of Hiroshima and Fukuoka in Japan -

abstract: A simple method of estimating the effect of reverse transcription polymerase chain reaction (RT-PCR) testing-isolation on the restraint of infection of COVID-19 is proposed. The effect is expressed as the ratio{chi} of the reproductive number to that in the case that no isolation measure would be taken. The method was applied in the case of the third infection wave (from December, 2020 to February, 2021) of Hiroshima and Fukuoka in Japan. The ratio{chi} was estimated to be 0.78 to 0.84 and 0.86 to 0.9 in Hiroshima and Fukuoka, respectively. It is also shown that the reduction of{chi} by 0.07 would have reduced at least 50% of total infected patients during the third infection wave in Fukuoka.


title: Misinformation can prevent the suppression of epidemics

abstract: AO_SCPLOWBSTRACTC_SCPLOWThe effectiveness of non-pharmaceutical interventions, such as mask-wearing and social distancing, as control measures for pandemic disease relies upon a conscientious and well-informed public who are aware of and prepared to follow advice. Unfortunately, public health messages can be undermined by competing misinformation and conspiracy theories, spread virally through communities that are already distrustful of expert opinion. In this article, we propose and analyse a simple model of the interaction between disease spread and (mis-) information dynamics in a heterogeneous population composed of both trusting individuals who seek quality information and will take precautionary measures, and distrusting individuals who are susceptible to misinformation. We show that, as the density of the distrusting population increases, the model passes through a phase transition to a state in which major outbreaks cannot be suppressed. Our work highlights the urgent need for effective measures to combat the spread of misinformation.


title: Procalcitonin to Predict Severity of Acute Cholangitis and Need for Urgent Biliary Decompression: Systematic Scoping Review

abstract:
BackgroundSerum Procalcitonin (PCT) has been reported as a potential biomarker to predict the severity of acute cholangitis (AC) or the need for urgent biliary decompression. This study aimed to identify and summarize the existing research about the serum PCT and the severity of AC, and to find gaps where future studies can be targeted towards.

MethodsFollowing the PRISMA Extension for Scoping Reviews, MEDLINE, EMBASE, and Google Scholar were searched for all peer-reviewed articles with relevant keywords including "cholangitis" and "procalcitonin" from their inception to July 13, 2021.

ResultsWe identified six studies. All the studies employed case-control design and aimed to evaluate the usefulness of serum PCT to predict the severity of AC with key identified outcomes. While potential cut-off values of serum PCT for severe AC ranged from 1.8-3.1 ng/mL, studies used different severity criteria and the definition of urgent biliary decompression. No studies proposed cut-off PCT values for the need for urgent biliary decompression.

ConclusionThis scoping review identified that the current level of evidence regarding the usefulness of serum PCT in assessing the severity of AC. Further clinical research is warranted with a focus on standardized outcome measures employing prospective or experimental designs.


title: Uptake of xenobiotic milk induces microRNA profile changes in the neonate intestine

abstract:
BackgroundExclusive breastfeeding is the best source of nutrition for most infants, but it is not always possible. Enteral nutrition influences intestinal gene regulation and the susceptibility for inflammatory bowel disorders, such as necrotizing enterocolitis (NEC). In modern neonatology it is observed that lactase activity increases during intestinal maturation, but formula-fed infants exhibit lower activity levels than milk-fed infants.

ObjectiveWe interrogate the transmissibility of milk miRNAs, since human breast milk has a high miRNA content in comparison to other body fluids. Our data contribute to the controversial discussion whether milk miRNAs could influence gene regulation in term and preterm neonates and thus might vertically transmit developmental relevant signals.

DesignFollowing their cross-species profiling via miRNA deep-sequencing we utilized dietary xenobiotic taxon-specific milk miRNA as tracers in human and porcine neonates, followed by functional studies in primary human fetal intestinal epithelial cells (HIEC-6) using Ad5-mediated miRNA-gene transfer.

ResultsWe show that mammals have in common many milk miRNAs yet exhibit taxon-specific miRNA fingerprints. We traced intact bovine-specific miRNAs from formula-nutrition in human preterm stool and 9 days after the onset of enteral feeding in intestinal cells of preterm piglets. Few hours after introducing enteral feeding in preterm piglets with supplemented reporter miRNAs (cel-miR-39-5p/-3p), we observed enrichment of the xenobiotic cel-miR in blood serum and in Ago2-immunocomplexes from intestinal biopsies. In contrast, we did not observe xenobiotic miRNAs in neonatal porcine cerebrospinal fluid.

ConclusionsTaken together, our data point to a transmissibility of milk miRNA signals, which could be relevant at least for intestinal maturation. Ad5-based miRNA-gene transfer into HIEC-6 revealed putative milk miRNA targets on the protein and transcriptome levels. Results suggest that milk miRNAs could influence gene expression in intestinal epithelia of neonates under special conditions.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/21262525v4_ufig1.gif" ALT="Figure 1">
View larger version (80K):
org.highwire.dtl.DTLVardef@8e0435org.highwire.dtl.DTLVardef@1b6747corg.highwire.dtl.DTLVardef@1998821org.highwire.dtl.DTLVardef@b84a04_HPS_FORMAT_FIGEXP  M_FIG C_FIG It is already known that exclusive breastfeeding is the best source of nutrition for neonates.Human breast milk has a high miRNA content in comparison to other body fluids. It is controversially discussed whether they could influence gene regulation in term and preterm neonates and thus might vertically transmit developmental relevant signals. Here, we contribute important new findings: Mammals have in common a significant number of milk miRNAs yet exhibit taxon-specific fingerprints. These differences allowed us to exploit xenobiotic miRNAs as tracers in human preterm neonates, who routinely received formula-supplemented nutrition in addition to breast milk. Tracer miRNAs survived the gastrointestinal (GI) transit in human preterm neonates. In a preterm piglet model the reporter miRNA did not only survive GI transit, but accumulated in the bloodstream few hours post-feeding. Moreover, we show that, cel-mir-39-5p and cel-miR-39-3p became loaded to Ago2 in intestinal tissue samples, which is prerequisite for milk microRNAs biological relevance. Adenovirus type 5-based miRNA-gene transfer into HIEC-6 allowed us to examine predicted bovine milk miRNA targets on the protein and transcriptome levels.

category: pediatrics


title: Xenobiotic tracers uncover the gastrointestinal passage, cellular uptake and Ago2 loading of milk microRNAs in neonates


title: Xenobiotic tracers uncover the gastrointestinal passage, intestinal epithelial cellular uptake and Ago2 loading of milk miRNAs in neonates


title: Uncovering the gastrointestinal passage, intestinal epithelial cellular uptake and Ago2 loading of milk miRNAs in neonates using xenobiotic tracers


title: Low risk of SARS-CoV-2 transmission via fomite, even in cold-chain

abstract:
BackgroundCountries continue to debate the need for decontamination of cold-chain food packaging to reduce possible SARS-CoV-2 fomite transmission among workers. While laboratory-based studies demonstrate persistence of SARS-CoV-2 on surfaces, the likelihood of fomite-mediated transmission under real-life conditions is uncertain.

MethodsUsing a quantitative risk assessment model, we simulated in a frozen food packaging facility 1) SARS-CoV-2 fomite-mediated infection risks following worker exposure to contaminated plastic packaging; and 2) reductions in these risks attributed to masking, handwashing, and vaccination.

FindingsIn a representative facility with no specific interventions, SARS-CoV-2 infection risk to a susceptible worker from contact with contaminated packaging was 2{middle dot}8 x 10-3 per 1h-period (95%CI: 6{middle dot}9 x 10-6, 2{middle dot}4 x 10-2). Implementation of standard infection control measures, handwashing and masks (9{middle dot}4 x 10-6 risk per 1h-period, 95%CI: 2{middle dot}3 x 10-8, 8{middle dot}1 x 10-5), substantially reduced risk (99{middle dot}7%). Vaccination of the susceptible worker (two doses Pfizer/Moderna, vaccine effectiveness: 86-99%) combined with handwashing and masking reduced risk to less than 1{middle dot}0 x 10-6. Simulating increased infectiousness/transmissibility of new variants (2-, 10-fold viral shedding) among a fully vaccinated workforce, handwashing and masks continued to mitigate risk (2{middle dot}0 x 10-6 -1{middle dot}1 x 10-5 risk per 1h-period). Decontamination of packaging in addition to these interventions reduced infection risks to below the 1{middle dot}0 x 10-6 risk threshold.

InterpretationFomite-mediated SARS-CoV-2 infection risks were very low under cold-chain conditions. Handwashing and masking provide significant protection to workers, especially when paired with vaccination.

FundingU.S. Department of Agriculture


title: Comparative analyses of all FDA EUA-approved rapid antigen tests and RT-PCR for COVID-19 quarantine and surveillance-based isolation

abstract:
BackgroundRapid antigen (RA) tests are being increasingly employed to detect SARS-CoV-2 infections in quarantine and surveillance. Prior research has focused on RT-PCR testing, a single RA test, or generic diagnostic characteristics of RA tests in assessing testing strategies.

MethodsFor 18 RA tests with emergency use authorization from the United States of America FDA and an RT-PCR test, we conducted a comparative analysis of the post-quarantine transmission, the effective reproduction number during serial testing, and the false-positive rates. To quantify the extent of transmission, we developed an analytical mathematical framework informed by COVID-19 infectiousness, test specificity, and temporal diagnostic sensitivity data.

ResultsWe demonstrate that the relative effectiveness of RA and RT-PCR tests in reducing post-quarantine transmission depends on the quarantine duration and the turnaround time of testing results. For quarantines of two days or shorter, conducting a RA test on exit from quarantine reduces onward transmission more than a single RT-PCR test (with a 24-h delay) conducted upon exit. Applied to a complementary approach of performing serial testing at a specified frequency paired with isolation of positives, we have shown that RA tests outperform RT-PCR with a 24-h delay. The results from our modeling framework are consistent with quarantine and serial testing data collected from a remote industry setting.

ConclusionsThese RA test-specific results are an important component of the tool set for policy decision-making, and demonstrate that judicious selection of an appropriate RA test can supply a viable alternative to RT-PCR in efforts to control the spread of disease.

Plain language summaryPrevious research has determined optimal timing for testing in quarantine and the utility of different frequencies of testing for disease surveillance using RT-PCR and generalized rapid antigen tests.

However, these strategies can depend on the specific rapid antigen test used. By examining 18 rapid antigen tests, we demonstrate that a single rapid antigen test performs better than RT-PCR when quarantines are two days or less in duration. In the context of disease surveillance, the ability of a rapid antigen test to provide results quickly counteracts its lower sensitivity with potentially more false positives. These analytical results based on highly controlled test validation were consistent with real-world data obtained from quarantine and serial testing in an industrial setting.


title: Comparative analyses of FDA EUA-approved rapid antigen tests and RT-PCR for COVID-19 quarantine and surveillance-based isolation


title: Country-level Association of Socioeconomic, Environmental and Healthcare-Related Factors with the Disease-Burden and Mortality Rate of COVID-19

abstract:
BackgroundCOVID-19 pandemic is rapidly expanding throughout the world right now. Caused by a novel strain of the coronavirus, the manifestation of this pandemic shows a unique level of disease burden and mortality rate in different countries.

ObjectiveIn this paper, we investigated the effects of several socioeconomic, environmental, and healthcare-related factors on the disease burden and mortality rate of COIVID-19 across countries. Our main objective is to provide a macro-level understanding of the most influential socioeconomic, environmental, and healthcare-related factors associated with the disease burden and mortality rate metrics without human bias.

MethodsWe developed a multiple linear regression model using backward elimination to find the best fitting between reported death and cases across countries for country-level aggregated independent factors keeping COVID-19 test statistic in consideration. Notably, the method requires minimum human intervention and handles confounding effects intrinsically.

ResultsOur results show that while the COVID-19 pandemic is seemingly spreading more rapidly in economically affluent countries, it Is more deadly in countries with inadequate healthcare infrastructure, lower capacity of handling epidemics, and lower allocation of the healthcare budget. We also did not find evidence of any association between environmental factors and COVID-19.

ConclusionWe took the number of tests performed into account and normalized the case and mortality counts based on the cumulative distribution of cases across days. Our analysis of the standardized factors provides both the direction and relative importance of different factors leading to several compelling insights into the most influential socioeconomic and healthcare infrastructure-related factors from a country-level view.


title: Retrospective mortality and prevalence of SARS-CoV-2 antibodies in greater Omdurman, Sudan: a population-based cross-sectional survey

abstract:
BackgroundEven after adjusting for the expected lower severity due to the younger age of the population, relatively low SARS-CoV-2 incidence and mortality rates have been reported throughout Africa. For investigating whether this is truly the case, we conducted a survey to estimate the COVID-19 related mortality and cumulative incidence of SARS-CoV-2 infections in Omdurman the most populated city of the tripartite metropolis Khartoum in Sudan.

MethodsA retrospective, cross-sectional, mortality and seroprevalence survey was conducted in Omdurman, Sudan, from March 1, until April 10 2021. A two-stage cluster sampling method was used to investigate the death rate for the pre-pandemic (January 1, 2019-February 29, 2020) and pandemic (March 1, 2020 - day of the survey) period using questionnaires. The seroprevalence survey was performed in a subset of households and all consenting members were tested with a rapid serological test (SD-Biosensor) and a subgroup additionally with ELISA (EUROIMMUN). Fishers exact test was used to assess differences between the pre-and pandemic periods and a random effect and Bayesian latent class model to adjust for test performance.

FindingsData from 27315 people (3716 households) for the entire recall period showed a 67% (95% CI 32-110) increase in death rate between the pre-pandemic (0.12 deaths/10000 people/day [95% CI 0.10-0.14]) and pandemic (0.20 [0.16-0.23]) periods. Notably, a 74% (30-133) increase in death was observed among people aged [≥]50 years. The adjusted seroprevalence of SARS-CoV-2 was 54.6% (95% CI 51.4-57.8). The seroprevalence was significantly associated with age, increasing up to 80.7% (71.7-89.7) for the oldest age group ([≥]50 years).

InterpretationOur results showed a significant elevated mortality for the pandemic period with a considerable excess mortality in Omdurman, Sudan. The overall high seroprevalence indicated a different age pattern compared to other countries, with a significant increase by age.

FundingMedecins Sans Frontieres


title: Correlation between Proinflammatory cytokines and severity of COVID-19 within Palestinian Population

abstract: COVID-19 was characterized by cytokine storm and endothelial dysfunction in severely ill patients. As the severity of the infection was corelated with ethnicity, this study aimed to assess the correlation of proinflammatory cytokine serum level and COVID-19 symptoms within the Palestinian population. In cross-sectional study, serum samples of 27 non-hospitalized patients and 63 hospitalized patients SARS-CoV-2 infected patients, were tested for total antibodies, IL-6, TNF-, IFN-{gamma} and IL-1{beta} using the ELISA test. Results showed that most common symptoms within patients were Joint pain, cough, and fever (73.3%, 69.7% and 50% respectively). Serum total antibodies (IGs) levels in non-hospitalized patients were higher than hospitalized patients ((44.7 COI and 9.2 COI). TNF- and IL-6 were lower in non-hospitalized patients compared to hospitalized patients (48{+/-}17.9 pg/ml, 193.3{+/-}350.5 pg/ml respectively). On the other hand, IFN-{gamma}, in non-hospitalized patients (1{+/-}2 IU/ml) was significantly higher than hospitalized patients (0.4{+/-}0.26 IU/ml). IL-1{beta} was slightly lower in hospitalized patients (8.8{+/-}13.6 pg/ml) compared to non-hospitalized patients (12.5{+/-}24.5 pg/ml). Common mild symptoms of COVID-10 were negatively associated with proinflammatory cytokines serum level. In conclusion as it with other populations worldwide, IL-6 and TNF- are playing a major role in the complications of SARS-CoV-2 infection. Monitoring the two cytokines is crucial for management and treatment of complicated consequence of COVID-19.


title: Data sharing in the age of predictive psychiatry: An adolescent perspective

abstract:
BackgroundAdvances in genetics and digital phenotyping in psychiatry have given rise to testing services targeting young people, which claim to predict psychiatric outcomes before difficulties emerge. These services raise several ethical challenges surrounding data sharing and information privacy.

ObjectivesThis study aimed to investigate young peoples interest in predictive testing for mental health challenges, and their attitudes towards sharing biological, psychosocial and digital data for such purpose.

MethodsEighty UK adolescents aged 16-18 participated in the study. Participants took part in a digital role-play where they played the role of clients of a fictional predictive psychiatry company and chose what sources of personal data they wished to provide for a risk assessment. After the role-play, participants reflected upon their choices during a peer-led interview.

FindingsParticipants saw multiple benefits in predictive testing services, but were highly selective with regards to type the data they were willing to share. Largely due to privacy concerns, digital data sources such as social media or Google search history were less likely to be shared than psychosocial and biological data, including school grades and ones DNA. Participants were particularly reluctant to share digital data with schools (but less so with health systems).

ConclusionsEmerging predictive psychiatric services are valued by young people; however, these services must consider privacy vs. utility trade-offs from the perspective of different stakeholders, including adolescents.

Clinical implicationsRespecting adolescents need for transparency, privacy and choice in the age of digital phenotyping is critical to the responsible implementation of predictive psychiatric services.

category: psychiatry and clinical psychology


title: Identification and Mitigation of High-Risk Pregnancy with the Community Maternal Danger Score Mobile Application in Gboko, Nigeria

abstract:
IntroductionNigeria constitutes 1% of the worlds population yet accounts for 10% of global maternal mortality. Risk analyses within rural regions of Nigeria are not routinely conducted, yet could help inform access to skilled birth care. The objectives of this study were to assess the proportion of women at risk for mortality or morbidity in Benue State, Nigeria by analysing data collected during routine antenatal visits and through the Community Maternal Danger Score (CMDS), a validated risk-analysis tool.

MethodsTwo cohorts, comprised of pregnant women presenting to primary healthcare centres within Gboko, Benue State between 2015-2017 and 2020-2021, were included in this study. The 2015-2017 cohort had their risk assessed retrospectively through analysis of routinely collected data. Identification of risk was based on their age, parity, and disease status (HIV and diabetes). The 2020-2021 cohort had their risk assessed prospectively using the CMDS.

ResultsRoutinely collected data from 2015-2017 demonstrated that up to 14.9% of women in Gboko were at risk for mortality or morbidity. The CMDS reported that up to 21.5% of women were at a similar level of risk; a significant difference of 6.6% (p=0.006). The CMDS was more efficient in obtaining and assessing this data, and the identification was available in real-time for midwives and pregnant women.

ConclusionRoutine data collected in Gboko identifies a high proportion of pregnant women at risk for mortality or morbidity. The CMDS is an evidence-based risk analysis tool that expands on this assessment by also estimating individual and community-level risk, which allows for more efficient mitigation and prevention strategies of maternal mortality.


title: Social contacts and other risk factors for respiratory infections among internally displaced people in Somaliland

abstract:
BackgroundPopulations affected by humanitarian crises experience high burdens of acute respiratory infections (ARI), potentially driven by risk factors for severe disease such as poor nutrition and underlying conditions, and risk factors that may increase transmission such as overcrowding and the possibility of high social mixing. However, little is known about social mixing patterns in these populations.

MethodsWe conducted a cross-sectional social contact survey among internally displaced people (IDP) living in Digaale, a permanent IDP camp in Somaliland. We included questions on household demographics, shelter quality, crowding, travel frequency, health status, and recent diagnosis of pneumonia, and assessed anthropometric status in children. We calculated age-standardised social contact matrices to assess population mixing, and conducted regression analysis on risk factors for recent self-reported pneumonia.

ResultsWe found crowded households with high proportions of recent self-reported pneumonia (46% in children). 20% of children younger than five are stunted, and crude death rates are high in all age groups. ARI risk factors are common, but we did not find any significant associations with self-reported pneumonia. Participants reported around 10 direct contacts per day. Social contact patterns are assortative by age, and physical contact rates are very high (78%).

ConclusionsARI risk factors are very common in this population, while the large degree of contacts that involve physical touch could further increase transmission. Such IDP settings potentially present a perfect storm of risk factors for ARIs and their transmission, and innovative approaches to address such risks are urgently needed.


title: GWAS meta-analysis reveals dual neuronal and immunological etiology for pain susceptibility

abstract: Chronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system and is coincident with a growing opioid crisis. While numerous genetic risk factors have been identified, its genetic basis remains poorly understood. Here, we conducted a meta-analysis of genome-wide association study (GWAS) summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, of which 62 have not been previously associated with a pain-related trait. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Two-sample Mendelian randomization indicated that depression, neuroticism, and immunological traits mediate many of these effects. These analyses double the number of known risk loci for pain susceptibility and support dual causation from neuronal and immunological genes, providing leads toward targets for novel pain medications.


title: Durability of antibody responses elicited by a single dose of Ad26.COV2.S and substantial increase following late boosting

abstract:
BackgroundWe evaluated the durability of SARS-CoV-2 antibody levels elicited by the single dose Janssen COVID-19 vaccine, Ad26.COV2.S, and the impact on antibody responses of boosting with Ad26.COV2.S after 6 months in clinical trial participants.

MethodsSpike-binding antibody and SARS-CoV-2 neutralizing antibody levels elicited by a single-dose Ad26.COV2.S (5x1010 viral particles [vp]) primary regimen and booster doses (5x1010 vp and 1.25x1010 vp) were assessed by ELISA and wild-type VNA in sera from participants in a Phase 1/2a clinical trial (Cohort 1a, 18-55 years old, N=25; Cohort 2a, 18-55 years old boosted at 6 months, N=17; Cohort 3, [≥]65 years old, N=22) and a Phase 2 clinical trial (18-55 and [≥]65-year old participants boosted at 6 months, total N=73). Neutralizing antibody levels were determined approximately 8 months after the primary vaccination in participants aged 18-55 years and approximately 9 months in participants aged [≥]65 years. Binding antibody levels were evaluated 6 months after primary vaccination and 7- and 28-days after booster doses in both age groups.

ResultsA single dose of Ad26.COV2.S elicited neutralizing antibodies that remained largely stable for approximately 8-9 months and binding antibodies that remained stable for at least 6 months irrespective of age group. A 5x1010 vp booster dose at 6 months post prime vaccination in 18-55-year-old adults elicited a steep and robust 9-fold increase at Day 7 post boost compared to Day 29 levels following the initial immunization. A lower booster dose of 1.25x1010 vp at 6 months in adults 18-55 and [≥]65 years of age also elicited a rapid and high increase of 6-7.7 fold at Day 28 post boost compared to Day 29 levels following the initial immunization, with similar magnitude of post-boost responses in both age groups.

ConclusionsA single dose of Ad26.COV2.S, which demonstrated protection in a Phase 3 efficacy trial, elicited durable neutralizing and binding antibodies for at least 8 and 6 months, respectively, in adults >18 years of age at levels similar to Day 29 responses. A 5x1010 vp or 1.25x1010 vp booster dose at 6 months elicited rapid and robust increases in spike binding antibody levels. The anamnestic responses after booster immunization imply robust immune memory elicited by single-dose Ad26.COV2.S.


title: Sex differences in incidence and mortality of bloodstream infections. Results from the population-based HUNT study in Norway

abstract:
ObjectiveTo examine the effect of sex on risk of bloodstream infections (BSI) and BSI mortality and to assess to what extent known risk factors for BSI mediate this association in the general population.

ParticipantsThe prospective, population-based HUNT2 Survey (1995-97) in Norway invited 93,898 inhabitants [≥]20 years in the Nord-Trondelag region, whereof 65,237 (69.5%) participated. 46.8% of the participants were men.

ExposuresSex and potential mediators between sex and BSI; health behaviours (smoking, alcohol consumption), education attainment, cardiovascular risk factors (systolic blood pressure, non-HDL cholesterol, body mass index) and previous or current comorbidities.

Main outcome measuresSex differences in risk of first-time BSI, BSI mortality (death within first 30 days after a BSI), BSI caused by the most frequent bacteria, and the impact of known BSI risk factors as mediators.

ResultsWe documented a first-time BSI for 1,840 (2.9%) participants (51.3% men) during a median follow-up of 14.8 years. Of these, 396 (0.6%) died (56.6% men). Men had 41% higher risk of any first-time BSI (95% confidence interval (CI), 28 to 54%) than women. An estimated 34% of the excess risk of BSI in men was mediated by known BSI risk factors. The hazard ratio (HR) with 95% CI for BSI due to S. aureus was 2.09 (1.28 to 2.54), S. pneumoniae 1.36 (1.05 to 1.76), and E. coli 0.97 (0.84 to 1.13) in men vs women. BSI related mortality was higher in men compared to women with HR 1.87 (1.53 to 2.28).

ConclusionsThis large population-based study show that men have higher risk of BSI than women. One-third of this effect was mediated by known risk factors for BSI. This raises important questions regarding sex specific approaches to reduce the burden of BSI.


title: Epidemiology of the use of inferior vena cava filters in Brazil between 2008 and 2019

abstract:
Purposeto study the totality of inferior vena cava filters placed in the Brazilian Public Health System, which insures more than 160 million Brazilians, trends by geographic region and in-hospital deaths after filter placements and also due to pulmonary embolism between 2008 and 2019.

Patients and methodspublic and open data regarding in-hospital mortality due to pulmonary embolism and all inferior vena cava filters placed in Brazilian public hospitals between January 2008 and December 2019 were extracted from the Brazilian Public Health Systems databases.

Results9108 inferior vena cava filters were placed, 98.18% of which was therapeutic. There was an overall increasing use of these devices, statistically significant for all Brazilian regions, except the North. In-hospital mortality rate in patients who received inferior vena cava filters was 6.21%, stable over time. We observed an upward trend in in-hospital mortality rate due to pulmonary embolism, statistically significant for all Brazilian regions, except the North.

ConclusionWe observed a low standardized rate of inferior vena cava filter placements in Brazil between 2008 and 2019, but with a trend towards an increasing trend use. Almost all indications for filter placement were therapeutic. In hospital mortality in patients receiving inferior vena cava filters was high, 6.21%, and stable over time, whereas the trend of in-hospital mortality rate due to pulmonary embolism is increasing. Our findings were heterogeneous across Brazilian regions and contrasted to those observed in the USA, which is likely due to cultural and socioeconomic factors.

category: cardiovascular medicine


title: Nomogram-Based Prognostic Model to predict the High blood pressure in Children and Adolescents: Findings from 342,736 individuals in China

abstract:
BackgroundPredicting the potential risk factors of High blood pressure(HBP) among children and adolescents is still a knowledge gap. Our study aimed to establish and validate a nomogram-based model for identifying children and adolescents at risk of developing HBP based on a population-based prospective study.

MethodsHypertension was defined as systolic blood pressure or diastolic blood pressure above 95th percentile, using age, gender and height-specific cut-points. Penalized regression with Lasso was used to identify the strongest predictors of hypertension. Internal validation was conducted by 5-fold cross-validation and bootstrapping approach. The predictive variables were identified along with the advanced nomogram plot by conducting univariate and multivariate logistic regression analyses. A nomogram was constructed by training group comprised of 239,546(69.89%)participants and subsequently validated by externally group with 103,190(30.11%)participants.

ResultsOf 342,736 children and adolescents, a total of 55,480(16.19%) youths were identified with HBP with mean age 11.51{+/-}1.45 year and 183,487 were boys(53.5%). Nine significant relevant predictors were identified including: age, gender, weight status, birthweight, breastfeeding, gestational hypertension, family history of obesity, family history of hypertension and physical activity. An acceptable discrimination[Area under the receiver operating characteristic curve(AUC):0.742(Development group), 0.740(Validation group)] and good calibration(Hosmer and Lemeshow statistics, P > 0.05) were observed in our models. An available web-based nomogram was built online.

ConclusionsThis model composed of age, gender, early life factors, family history of disease, and lifestyle factors may predict the risk of HBP among children and adolescents, which has developed a promising nomogram that may aid in more accurately for identifying the HBP among youths in primary care.

Funding SourcesThe work was supported by the National Natural Science Foundation of China (No. 81673193).


title: The efficacy and safety of bamlanivimab treatment against COVID-19: A meta-analysis

abstract:
BackgroundBamlanivimab is routinely used in the treatment of coronavirus disease 2019 (COVID-19) in worldwide. We performed a meta-analysis to investigate the efficacy and safety of bamlanivimab treatment in patients with COVID-19.

MethodsWe searched articles from Web of Science, PubMed, Embase, the Cochrane Library and MedRxiv between 30 January 2020 and August 5, 2021. We selected randomized clinical trials (RCTs) and observational studies with a control group to assess the efficiency of bamlanivimab in treating patients with COVID-19.

ResultsOur meta-analysis retrieved 3 RCTs and 7 cohort studies including 14461 patients. Bmlanivimab may help outpatients to prevent hospitalization or emergency department visit (RR 0.41 95%CI 0.29 to 0.58), reduce ICU admission (RR 0.47 95%CI 0.23 to 0.92) and mortality (RR 0.32 95%CI 0.13 to 0.77) from the disease. The combination of bamlanivimab and etesevimab may had a greater potential for positive treatment outcome.

ConclusionBamlanivimab has demonstrated clinical efficacy on mild or moderate ill patients with COVID-19 to prevent hospitalization, reduce severity and mortality from the disease. Combinations of two or more monoclonal antibody increase the effect. Well-designed clinical trials to identify the clinical and biochemical characteristics in COVID-19 patients population that could benefit from bamlanivimab are warranted in the future.

Key pointsO_ST_ABSQuestionC_ST_ABSCan bamlanivimab treat COVID-19 patients? What are the factors that have great impact on the treatment outcome?

FindingsIn this meta-analysis that retrieved 3 RCTs and 7 cohort studies and included 14461 adults, Bmlanivimab may help outpatients to prevent hospitalization or emergency department visit (RR 0.41 95%CI 0.29 to 0.58), reduce ICU admission (RR 0.47 95%CI 0.23 to 0.92) and mortality (RR 0.32 95%CI 0.13 to 0.77) from the disease.

MeaningIn COVID-19 pandemic, the use of bamlanivimab may be warranted. Combinations of two or more monoclonal antibody increase the effect.

category: pharmacology and therapeutics


title: Threat imminence reveals links among unfolding of anticipatory physiological response, cortical-subcortical intrinsic functional connectivity, and anxiety

abstract:
Excessive expression of threat-anticipatory defensive responses is central in anxiety. Animal research indicates that anticipatory responses are dynamically organized by threat imminence and rely on conserved circuitry. Insight from translational work on threat imminence could guide mechanistic research mapping abnormal function in this circuitry to aberrant defensive responses in anxiety. Here, we initiate such research.

Fifty pediatric anxiety patients and healthy-comparisons (33 females) completed a threat-anticipation task whereby cues signaled delivery of highly-painful (threat) or non-painful (safety) heat. Temporal changes in skin-conductance indexed defensive responding as function of threat imminence. Resting-state functional connectivity data were used to identify intrinsic-function correlates of anticipatory response within a specific functional network derived from translational research.

Results indicate that anxiety was associated with greater increase in anticipatory response as threats became more imminent. Magnitude of increase in threat-anticipatory responses corresponded to intrinsic connectivity within a cortical-subcortical circuit; importantly, more severe anxiety was associated with greater connectivity between ventromedial prefrontal cortex and hippocampus and basolateral amygdala, a circuit implicated in animal models of anxiety. These findings link basic-translational and clinical research, highlighting aberrant intrinsic function in conserved defensive circuitry as potential pathophysiological mechanism in anxiety.