title: Use of real-world evidence data to evaluate the comparative effectiveness of second-line type 2 diabetes medications on chronic kidney disease

abstract: Chronic kidney disease (CKD) is a common complication of type 2 diabetes mellitus (T2DM). Approximately one-third of patients with T2DM also have CKD. In clinical trial studies, several anti-diabetic medications (ADM) show evidence of preventing the progression of CKD. Biguanides (e.g., metformin) are widely accepted as the first line medication. However, the comparativeness effectiveness of second line ADMs on CKD outcomes in T2DM is unclear. In addition, results from clinical trials may not generalize into routine clinical practice. In this study, we aimed to investigate the association of second line ADMs with incident CKD and CKD hospitalization in T2DM patients using real-world data from electronic health records. Our study found that treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors was significantly associated with a lower risk of CKD incidence in both primary analysis (hazard ratio, 0.43; 95% CI, [0.22;0.87]; p-value,0.02) (SU) as a second-line ADM. Treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor was significantly associated with lower CKD incidence (hazard ratio, 0.7; 95% CI, [0.53;0.96]; p-value, 0.03) and lower CKD hospitalization events (hazard ratio, 0.6; 95% CI, [0.37; 0.96]; p-value, 0.04) in the primary analysis. However, both associations were not significant in the sensitivity analysis. We did not observe significant association between use of GLP-1, TZD, insulin and CKD incidence or hospitalization compared to use of SU as the second-line ADM.

category: endocrinology


title: Mass mask-wearing notably reduces COVID-19 transmission

abstract:
Mask-wearing has been a controversial measure to control the COVID-19 pandemic. While masks are known to substantially reduce disease transmission in healthcare settings [1-3], studies in community settings report inconsistent results [4-6].

Investigating the inconsistency within epidemiological studies, we find that a commonly used proxy, government mask mandates, does not correlate with large increases in mask-wearing in our window of analysis. We thus analyse the effect of mask-wearing on transmission instead, drawing on several datasets covering 92 regions on 6 continents, including the largest survey of individual-level wearing behaviour (n=20 million) [7]. Using a hierarchical Bayesian model, we estimate the effect of both mask-wearing and mask-mandates on transmission by linking wearing levels (or mandates) to reported cases in each region, adjusting for mobility and non-pharmaceutical interventions.

We assess the robustness of our results in 123 experiments spanning 22 sensitivity analyses. Across these analyses, we find that an entire population wearing masks in public leads to a median reduction in the reproduction number R of 25.8%, with 95% of the medians between 22.2% and 30.9%. In our window of analysis, the median reduction in R associated with the wearing level observed in each region was 20.4% [2.0%, 23.3%]1. We do not find evidence that mandating mask-wearing reduces transmission. Our results suggest that mask-wearing is strongly affected by factors other than mandates.

We establish the effectiveness of mass mask-wearing, and highlight that wearing data, not mandate data, are necessary to infer this effect.

category: epidemiology


title: Massive social protests amid the pandemic in selected  Colombian  cities:  Did  they increase COVID-19 cases?

abstract:
BackgroundSince April 28, 2021, in Colombia there are social protests with numerous demonstrations in various cities. The aim of this study was to assess the effect of social protests on the number and trend of the confirmed COVID-19 cases in some selected Colombian cities where social protests had more intensity.

MethodsWe performed and interrupted time-series analysis (ITSA) and Autoregressive Integrated Moving Average (ARIMA) models, based on the confirmed COVID-19 cases in Colombia, between March 1 and May 15, 2021, for Bogota, Cali, Barranquilla, Medellin, and Bucaramanga. The ITSA models estimated the effect of social demonstrations on the number and trend of cases for each city by using Newey-West standard errors. ARIMA models assessed the overall pattern of the series and effect of the intervention. We considered May 2, 2021, as the intervention date for the analysis, five days after social demonstrations started in the country.

FindingsDuring the study period the number of cases by city was 1,014,815 for Bogota, 192,320 for Cali, 175,269 for Barranquilla, 311,904 for Medellin, and 62,512 for Bucaramanga. Heterogeneous results were found among cities. Only for the cities of Cali and Barranquilla statistically significant changes in trend of the number of cases were obtained after the intervention: positive in the first city, negative in the second one. None ARIMA models show evidence of abrupt changes in the trend of the series for any city and intervention effect was only significant for Bucaramanga.

InterpretationSocial protests had a heterogeneous effect on the number and trend of COVID-19 cases. Different effects might be related to the epidemiologic moment of the pandemic and the characteristics of the social protests. Assessing the effect of social protests within a pandemic is complex and there are several methodological limitations. Further analyses are required with longer time-series data.


title: Benefits of Surveillance Testing and Quarantine in a SARS-CoV-2 Vaccinated Population of Students on a University Campus

abstract: Surveillance testing and quarantine have been effective measures for limiting SARS-CoV-2 transmission on university campuses. However, the importance of these measures needs to be re-evaluated in the context of a complex and rapidly changing environment that includes vaccines, variants, and waning immunity. Also, recent guidelines from the CDC suggest that vaccinated students do not need to participate in surveillance testing. We used an agent-based SEIR model to evaluate the utility of surveillance testing and quarantine in a fully vaccinated student population where vaccine effectiveness may be impacted by the type of vaccination, the presence of variants, and the loss of vaccine-induced or natural immunity over time. We found that weekly surveillance testing at 90% vaccine effectiveness only marginally reduces viral transmission as compared to no testing. However, at 50%-75% effectiveness, surveillance testing can provide over 10-fold reduction in the number of infections on campus over the course of the semester. We also show that a 10-day quarantine protocol for exposures has limited effect on infections until vaccine effectiveness drops to 50%, and that increased surveillance testing for exposures is at least as effective as quarantine at limiting infections. Together these findings provide a foundation for universities to design appropriate mitigation protocols for the 2021-2022 academic year.


title: Remdesivir to treat COVID-19: can dosing be optimized?

abstract:
The antiviral remdesivir has been approved by regulatory bodies such as EMA and FDA for the treatment of COVID-19. However, its efficacy is debated and toxicity concerns might limit the therapeutic range of this drug. Computational models that aid in balancing efficacy and toxicity would be of great help. Parametrizing models is difficult because the prodrug remdesivir is metabolized to its active form (RDV-TP) upon cell entry, which complicates dose-activity relationships.

Here, we employ a computational model that allows predicting drug efficacy based on the binding affinity of RDV-TP for its target polymerase in SARS-CoV-2. We identify an optimal infusion rate to maximize remdesivir efficacy. We also assess drug efficacy in suppressing both wild-type and resistant strains, and thereby selection of resistance.

Our results differ from predictions using prodrug dose-response curves (pseudo-EC50s). We expect that reaching 90% inhibition (EC90) is insufficient to suppress SARS-CoV-2 in lungs. While standard dosing mildly inhibits viral polymerase and therefore likely reduces morbidity, we also expect selection for resistant mutants for most realistic parameter ranges. To increase efficacy and safeguard against resistance, we recommend continuing remdesivir use with companion antivirals and/or with dosing regimens that substantially increase the levels of RDV-TP.

category: pharmacology and therapeutics


title: Classification and Visualisation of Normal and Abnormal Radiographs; a comparison between Eleven Convolutional Neural Network Architectures

abstract: This paper investigates the classification of radiographic images with eleven convolutional neural network (CNN) architectures (GoogleNet, VGG-19, AlexNet, SqueezeNet, ResNet-18, Inception-v3, ResNet-50, VGG-16, ResNet-101, DenseNet-201 and Inception-ResNet-v2). The CNNs were used to classify a series of wrist radiographs from the Stanford Musculoskeletal Radiographs (MURA) dataset into two classes - normal and abnormal. The architectures were compared for different hyper-parameters against accuracy and Cohens kappa coefficient. The best two results were then explored with data augmentation. Without the use of augmentation, the best results were provided by Inception-Resnet-v2 (Mean accuracy = 0.723, Mean kappa = 0.506). These were significantly improved with augmentation to Inception-Resnet-v2 (Mean accuracy = 0.857, Mean kappa = 0.703). Finally, Class Activation Mapping was applied to interpret activation of the network against the location of an anomaly in the radiographs.

category: radiology and imaging


title: Prevalence evolution of SARS-CoV-2 infection in the Municipality of Sao Paulo, 2020 - 2021

abstract:
ObjectivesTo estimate the evolution of the prevalence of SARS-CoV-2 virus infection among residents aged 18 years or over in the municipality of Sao Paulo.

MethodsThis is a population-based household survey conducted every 15 days, between June and September 2020 and January and February 2021. In total, 11 phases were performed. The presence of antibodies against SARS-CoV-2 was identified in venous blood using a lateral flow test, Wondfo Biotech. In the last phase, it was combined with an immunoenzymatic test, Euroimmun. Participants also answered a semi-structured questionnaire on sociodemographic and economic factors and social distancing measures. Prevalence estimates and 95% confidence intervals were estimated according to the region, Human Development Index, sex, age group, ethnicity, education, income and variables associated with risk or prevention of the infection. To compare the frequencies among the categories of each variable, the chi-square test with Rao Scott correction was used, considering a 5% significance level.

ResultsIn total, 23,397 individuals were interviewed and had their samples collected. The estimated prevalence of antibodies against SARS-CoV-2 ranged from 9.7% (95%CI: 7.9-11.8%) to 25.0% (95%CI: 21.7-28.7). The prevalence of individuals with antibodies against SARS-CoV-2 was higher among black and pardo people, people with lower schooling, people with lower income and among residents of regions with lower Human Development Index. The lowest prevalences were associated with recommended measures of disease protection. The proportion of asymptomatic infection was 45.1%.

ConclusionThe estimated prevalence of SARS-CoV-2 infection was lower than the cumulative incidence variation, except for the last phase of the study. The differences in prevalence estimates observed among subpopulations showed the social inequality as a risk of infection. The lower prevalence observed among those who could follow prevention measures reinforce the need to maintain the social distancing measures as ways to prevent SARS-CoV-2 infection.

category: public and global health


title: De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies including Myoclonic Atonic Epilepsy

abstract: FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment by regulating cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental epileptic encephalopathies (DEE) and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Two variants led to the same amino acid change. All individuals had a DEE with childhood onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the DEE subtype Myoclonic Atonic Epilepsy (MAE). We provide gene burden testing using two independent statistical tests to support FZR1 association with DEE. Further, we provide functional evidence that the missense variants are loss-of-function (LOF) alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homolog fzr and overexpression studies, we show that patient variants do not support proper neurodevelopment. With the recent report of a patient with neonatal-onset DEE with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and DEE, and expands the associated phenotype. We conclude that heterozygous LOF of FZR1 leads to DEE associated with a spectrum of neonatal to childhood onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed MAE/DEE cases.

category: neurology


title: Awareness and Agreement with Neurofibromatosis Care Guidelines among Neurofibromatosis Specialists

abstract:
IntroductionGiven the wide range of neurofibromatoses (NF) symptoms and medical specialties involved in NF care, we sought to evaluate the level of awareness of, and agreement with, published NF clinical guidelines among United States NF specialists.

MethodsAn anonymous, cross-sectional online survey was distributed to attendees of a large NF research conference. Respondents self-reported demographics, practice characteristics, awareness of seven NF guideline publications, and level of agreement with up to 40 individual guidelines using a 5-point Likert scale. We calculated the proportion of guidelines that each clinician rated "strongly agree", and assessed for differences in guideline awareness and agreement by respondent characteristics.

ResultsSixty-three clinicians (49% female; 80% academic practice) across >8 medical specialties completed the survey. Awareness of each guideline publication ranged from 53%-79% of respondents; specialists had higher awareness of publications endorsed by their medical professional organization (p<0.05). The proportion of respondents who "strongly agree" with individual guidelines ranged from 17%-83%; for 16 guidelines, less than 50% of respondents "strongly agree". There were no significant differences in overall agreement with guidelines based on clinicians gender, race, specialty, years in practice, practice type (academic/private practice/other), practice location (urban/suburban/rural), or involvement in NF research (p>0.05 for all).

ConclusionsWe identified wide variability in both awareness of, and agreement with, published NF care guidelines among NF experts. Future efforts should focus on evidence-based, consensus-driven methods to update and disseminate guidelines across this multi-specialty group. Patients and caregivers should also be consulted to anticipate barriers to accessing and implementing guideline-driven care.


title: FAMILY RESILIENCE IN CAREGIVING ELDERLY WITH DEMENTIA: A SYSTEMATIC REVIEW

abstract:
ObjectiveDementia patients have complex needs that may become a burden to those who caregive them. They are treated at home by family members due to financial limitations and lack of support from health services. Therefore, the measurement of self-resilience in caregivers needs special attention from professionals.

MethodThis study used a systematic review method from 4 databases consisting of the CINAHL, ProQuest, PubMed, and Google Scholar between 2015 till 2020; 17 articles were considered to meet the inclusion criteria.

ResultsCaregiver of elderly with dementia has a tendency to experience burdens that affect the quality of the care performed. The level of resilience that caregivers have can help reduce the level of burden they experience and improve their quality of life.

ConclusionsSocial support and formal support by health workers for caregivers have a significantly positive effect in increasing the level of resilience of caregivers.

category: nursing


title: Analysis of common PI3K-AKT-MTOR mutations in pediatric surgical epilepsy by droplet digital PCR reveals novel clinical and molecular insights

abstract:
Focal malformations of cortical development (FMCD) including focal cortical dysplasia (FCD), hemimegalencephaly (HMEG) and megalencephaly (MEG), constitute a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism, and intellectual disability. Importantly, FCD is the most common cause of intractable pediatric focal epilepsy. Gain and loss of function mutations in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we aimed to assess droplet digital Polymerase Chain Reaction (ddPCR) as a first-tier molecular diagnostic method, as well as define genotype-phenotype relationships among the most common PI3K-AKT-MTOR pathway mutations in FMCD.

A total of 144 specimens, including 113 brain samples, were collected from 58 individuals with intractable focal epilepsy phenotypes including FCD, MEG, HMEG and other types of developmental cortical lesions. We designed an ultra-deep and highly sensitive molecular diagnostic panel using ddPCR for six of the most common mutations in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key phenotype, neuroimaging and neuropathological data.

Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of %. Variant allele fractions (VAF) ranged from 0.1% to 22.67% across all positive samples. Our data shows that MTOR mutations are mostly associated with FCD, whereas PIK3CA mutations are more frequent in the HMEG-DMEG spectrum. The presence of one of these common PI3K-AKT-MTOR-mutations correlated with earlier onset of seizures. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or neuropathological examination. Interestingly, we could not identify the six most common pathogenic variants in other types of cortical lesions (e.g., polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the FCD-HMEG-MEG spectrum. Finally, our data suggest that ultra-deep targeted molecular analysis for the most common PI3K-AKT-MTOR mutations via ddPCR is an effective molecular diagnostic approach for FMCD phenotypes with a good diagnostic yield when paired with neuroimaging and neuropathology evaluations. The high sensitivity and low DNA input requirements suggests that ddPCR is an effective molecular diagnostic tool for disorders caused by somatic mutations with a narrow mutational spectrum, including specific subtypes of pediatric epilepsy surgical phenotypes such as FCD and HMEG.

category: genetic and genomic medicine


title: Red Blood Cell Stiffness Driving Patient Symptoms: A Study of Red Blood Cell Population Rigidity in Sickle Cell Patient Genotype SC Relation to Overlooked Clinical Symptoms

abstract: Sickle cell disease (SCD) is a systemic hematological disease. Various genotypes of the disease exist; however, the two most common include hemoglobin SS (Hgb SS) and hemoglobin SC (Hgb SC) disease. Hgb SC is typically considered a less severe genotype; however, some patients with SC disease still have significant complications. Ektacytometry is utilized to measure red blood cell deformability in sickle cell patients and may help identify patients at risk for severe disease. We described a patient with genotype hemoglobin SC with a more severe phenotype, who we show to have very rigid red blood cells via ektacytometry.

category: hematology


title: Evaluation of the Access Bio CareStartTM rapid SARS-CoV-2 antigen test in asymptomatic individuals tested at a community mass-testing program in Western Massachusetts

abstract:
BackgroundPoint-of-care antigen-detecting rapid diagnostic tests (RDTs) for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) represent a scalable tool for SARS-CoV-2 infections surveillance. Data on their performance in real-world community settings is paramount for their implementation.

MethodWe evaluated the accuracy of CareStart COVID-19 Antigen test (CareStart) in a testing site in Holyoke, Massachusetts. We compared CareStart to a SARS-CoV-2 reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) reference, using anterior nasal swab samples. We calculated the sensitivity, specificity, and expected positive and negative predictive values at different SARS-CoV-2 prevalence estimates.

ResultsWe performed 666 tests on 591 unique individuals. 573 (86%) were asymptomatic. There were 52 positive tests by RT-qPCR. The sensitivity of CareStart was 49.0% (95% Confidence Interval (CI): 34.8 - 63.4) and specificity was 99.5% (95% CI: 98.5 - 99.9). Among positive RT-qPCR tests, the median cycle threshold (Ct) was significantly lower in samples that tested positive on CareStart. Using a Ct [≤] 30 as a benchmark for positivity increased the sensitivity to 64.9% (95% CI: 47.5 - 79.8).

ConclusionsCareStart has a high specificity and moderate sensitivity. The utility of RDTs, such as CareStart, in mass implementation should prioritize use cases in which a higher specificity is more important.

category: infectious diseases


title: Determination of IgG1 and IgG3 SARS-CoV-2 spike protein and nucleocapsid binding. Who is binding who and why?

abstract:
The involvement of IgG3 in the humoral immune response to SARS-CoV2 infection has been implicated in the pathogenesis of ARDS in COVID-19. The exact molecular mechanism is unknown but may be due to the differential ability of IgG3 Fc region to fix complement and stimulate cytokine release. We examined convalescent patients antibodies binding to immobilised nucleocapsid and spike protein by MALDI-ToF mass spectrometry. IgG3 was a major immunoglobulin found in all samples. Differential analysis of the spectral signatures found for nucleocapsid versus spike protein demonstrated that the predominant humoral immune response to nucleocapsid was IgG3, whilst against spike it was IgG1. However, the spike protein displayed a strong affinity for IgG3 itself which it would bind from control plasma samples as well as from those previously infected with SARS-CoV2, much in the way Protein-G binds IgG1. Furthermore, detailed spectral analysis indicated a mass shift consistent with hyper-glycosylation or glycation was a characteristic of the IgG3 captured by the spike protein.

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title: National Trends and Disparities in Hospitalization for Hypertensive Emergencies Among Medicare Beneficiaries, 1999-2019

abstract:
ImportanceIn the last two decades, hypertension control in the U.S. population has not improved, and there are widening disparities. Less is known, however, about progress in reducing hospitalizations related to hypertensive emergencies.

ObjectivesTo describe trends in national hospitalization rates for hypertensive emergencies, overall and by demographic and geographical subgroups.

Design, Setting and, ParticipantsSerial cross-sectional analysis of Medicare fee-for-service beneficiaries aged 65 years or older between 1999 and 2019 using Medicare denominator and inpatient files.

Main Outcome and MeasuresTrends in hospitalization for hypertensive emergencies, overall and by specific subgroups.

ResultsThe sample consisted of 397,238 individual Medicare fee-for-service beneficiaries. From 1999 through 2019, the annual hospitalization rates for hypertensive emergencies increased significantly from 51.5 to 125.9 per 100,000 beneficiary-years; this increase was most pronounced among the following subgroups: adults [≥]85 years (66.8 to 274.1), females (64.9 to 160.1), Blacks (144.4 to 369.5), and Medicare-Medicaid insured (dual eligible, 93.1 to 270.0). Across all subgroups, Black adults had the highest hospitalization rate in 2019, and there was a significant increase in the differences in hospitalizations between Blacks and Whites from 1999 to 2019. Marked geographic variation was also present, with the highest hospitalization rates in the South (so-called "Stroke Belt"). Among 3,143 counties and county-equivalents included in the study, less than 1% of counties either had no change (n=7) or decreased (n=20) hospitalization rates since 1999. Among patients hospitalized for a hypertensive emergency, the observed 30-day all-cause mortality rate decreased from 2.6% to 1.7% and 30-day all-cause readmission rate decreased from 15.7% to 11.8%.

Conclusions and RelevanceAmong Medicare fee-for-service beneficiaries aged 65 years or older, hospitalization rates for hypertensive emergencies increased substantially and significantly from 1999 to 2019. Black adults had the largest increase in hospitalization rates across age, sex, race, and dual-eligible strata. There was significant national variation, with the highest rates generally in the South.

KEY POINTSO_ST_ABSQuestionC_ST_ABSHow have hospitalization rate for hypertensive emergencies among US adults aged 65 years and older changed between 1999 and 2019 and are there any differences across demographic and geographical subgroups?

FindingsIn this serial cross-sectional study that included 397,238 individual Medicare fee-for-service beneficiaries, there was a marked increase in hospitalization rates for hypertensive emergencies from 1999 to 2019, and this increase was most pronounced among Black adults across age, sex, race, and dual-eligible strata. Significant national variation was observed, with the highest hospitalization rates generally in the South.

MeaningBetween 1999 and 2019, hospitalization rates for hypertensive emergencies increased substantially and differences across demographic and geographic subgroups persisted.

category: cardiovascular medicine


title: Understanding the Potential Impact of Different Drug Properties On SARS-CoV-2 Transmission and Disease Burden: A Modelling Analysis

abstract:
BackgroundThe unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear.

Methods and FindingsWe develop a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care to explore the potential public-health impact of a range of different potential therapeutics, under a range of different scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) drug efficacy in the absence of supportive care. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. We find the impact of drugs like dexamethasone (which are delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics.

ConclusionsThere is a global asymmetry in who is likely to benefit from advances in the treatment of COVID-19 to date, which have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.


title: Prevalence and Risk Factors of Stroke in Bangladesh: A Nationwide Population-Based Survey

abstract:
BackgroundThis community survey was conducted to estimate the prevalence of stroke and its associated common risk factors among the Bangladeshi population.

MethodsThis was a population-based cross-sectional study, carried out in 8 administrative divisions and 64 districts to estimate the prevalence of stroke throughout the country. The study adopted a two-stage cluster random sampling approach. The calculated sample size was 25,287. A semi-structured questionnaire was used to identify suspected stroke patients who were subsequently confirmed by consultant neurologists.

ResultIn the first stage, Interviewers identified 561 respondents as suspected stroke in 64 districts. Of the 25,287 respondents, 54.9% were male. The mean age was 39.9 years. In the second stage of the study; among all the respondents, 288 were confirmed as stroke patients which provided a prevalence of 11.39 per 1000 population. The highest stroke prevalence (14.71 per thousand) was found in the Mymensingh division and the lowest (7.62 per thousand) found in the Rajshahi division. It was 30.10 per thousand in the age group of more than 60 years. The prevalence of stroke among males was twice that of females (13.62 versus 8.68 per thousand). The prevalence was slightly higher in rural areas (11.85 versus 11.07). Out of a total of 288 cases, 79.7% (213) patients had an ischemic stroke, 15.7% (42) had hemorrhagic, and 4.6% (12) were diagnosed as subarachnoid hemorrhage. The majority of the stroke patients had hypertension (79.2%), followed by dyslipidemia (38.9%), tobacco use in any form (37.2%), diabetes (28.8%), ischemic heart disease (20.1%).

ConclusionWe have found a stroke prevalence of 11.39 per 1000 population, the highest being in the Mymensingh division. The prevalence was much higher in the elderly and male population. More than three fourth had an ischemic stroke. Hypertension, dyslipidemia, tobacco use, diabetes, ischemic heart disease are the most common risk factors observed among stroke patients.

Summary BoxAlready Known:

{blacksquare}The prevalence of stroke in Bangladesh was found to be 3 per thousand.
{blacksquare}Hypertension, diabetes, dyslipidemia, smoking, and ischemic heart disease were common risk factors.

New Findings:

{blacksquare}This is the first-ever nationwide survey in Bangladesh that revealed a stroke prevalence of 11.39 per thousand.
{blacksquare}There was a wide regional variation of stroke prevalence.
{blacksquare}The prevalence was twice among males.

Impact of the study result:

{blacksquare}The study result will help the policymakers in deciding what to do for which regions of this country to handle the stroke burden.
{blacksquare}It will also help the clinicians to identify common risk factors among stroke patients.


title: COVID-19 Transmission Dynamics Underlying Epidemic Waves in Kenya

abstract:
Policy decisions on COVID-19 interventions should be informed by a local, regional and national understanding of SARS-CoV-2 transmission. Epidemic waves may result when restrictions are lifted or poorly adhered to, variants with new phenotypic properties successfully invade, or when infection spreads to susceptible sub-populations. Three COVID-19 epidemic waves have been observed in Kenya. Using a mechanistic mathematical model we explain the first two distinct waves by differences in contact rates in high and low social-economic groups, and the third wave by the introduction of a new higher-transmissibility variant. Reopening schools led to a minor increase in transmission between the second and third waves. Our predictions of current population exposure in Kenya ([~]75% June 1st) have implications for a fourth wave and future control strategies.

One Sentence SummaryCOVID-19 spread in Kenya is explained by mixing heterogeneity and a variant less constrained by high population exposure


title: Rapid spread of the SARS-CoV-2 δ variant in the area of Paris (France) in June 2021

abstract: Analysing 9,030 variant-specific tests performed on SARS-CoV-2 positive samples collected in France between 31 May and 21 June 2021 reveals a rapid growth of the {delta} variant in 3 French regions. The next weeks will prove decisive but the magnitude of the estimated transmission advantages could represent a major challenge for public health authorities.


title: Rapid spread of the SARS-CoV-2 δ variant in French regions in June 2021


title: Evidence for a serotonergic subtype of major depressive disorder: A NeuroPharm-1 study.

abstract:
Selective serotonin reuptake inhibitors (SSRIs) are the first line pharmacological treatment of Major Depressive Disorder (MDD), but only about half of patients benefit from it. Cerebral serotonin 4 receptor (5-HT4R) binding measured with positron emission tomography (PET) is inversely related to serotonin levels and can serve as a proxy for brain serotonin levels. We here determine if 5-HT4R differs between healthy and MDD individuals and if it is associated with successful outcomes of serotonergic treatment of MDD. We [11C]-SB207145 PET-scanned 100 (71 F) untreated patients with moderate to severe MDD and 91 (55 F) healthy controls; 40 patients were re-scanned after 8 weeks treatment. All patients started treatment with the SSRI escitalopram and were followed clinically after 1, 2, 4, 8 and 12 weeks. Treatment response was measured as change from baseline.

Before treatment, patients with MDD had 8% lower global 5-HT4R binding than controls (95%CI[-13.1%;-2.5%], p<0.001). Non-responders did not differ from controls, whereas remitters had 9% lower binding than controls ([-16.1%;-2.7%], p=0.004). Independent of treatment outcomes, patients reduced their neostriatal 5-HT4R binding (-9%, [-12.8%;-5.0%], p<0.001) after serotonergic intervention.

Overall, patients with MDD have lower cerebral 5-HT4R binding than controls, suggesting that 5-HT4R is a biomarker for MDD. The observation that SSRI treatment leads to reduced neostriatal 5-HT4R binding supports that the treatment does indeed increase brain 5-HT levels. Patients who remit to SSRIs have lower cerebral 5-HT4R prior to treatment than controls whereas non-responders do not differ. We propose that non-responders to SSRIs constitute a subgroup with non-serotonergic depression.

ClinicalTrials.gov Identifier: NCT02869035

Registry name: Treatment Outcome in Major Depressive Disorder

URL: https://clinicaltrials.gov/ct2/show/NCT02869035?term=NCT02869035&draw=2&rank=1

category: psychiatry and clinical psychology


title: Clinician views on best practice community care for people with complex emotional needs and how it can be achieved: a qualitative study

abstract:
BackgroundService provision for people with complex emotional needs (CEN) is recurrently identified as needing to be transformed: there are serious concerns about quality, accessibility, fragmentation of the service system and the stigma and therapeutic pessimism service users say they encounter. We use the term CEN as a working description to refer to the needs experienced by people who may have been diagnosed with a  personality disorder. Understanding clinician perspectives is vital for service transformation, as their views and experiences shed light on potential barriers to achieving good care, and how these might be overcome. In this study, we aimed to explore these views.

MethodsWe used a qualitative interview design. A total of fifty participants from a range of professions across specialist and generic community mental health services across England who provide care to people with CEN took part in six focus groups and sixteen one-to-one interviews. We analysed the data using a thematic approach.

FindingsMain themes were: 1) Defining Best Practice, 2) Facilitators of Best Care, 3) Barriers to Best Care, 4) Systemic Challenges. Across these themes, staff highlighted in particular the need for care that was person-centred, relational, empathic, and trauma informed. However, major barriers to achieving this are stigmatising attitudes and behaviour towards people with CEN, especially in generic mental health services, lack of development of coherent service systems offering clear long-term pathways and ready access to high quality treatment, and lack of well-developed structures for staff training and support.

DiscussionOverall, the findings point towards clinician views as generally congruent with those of service users, reinforcing the need for priorities towards systemwide change to ensure that we can provide the best practice care for these individuals. Particularly prominent is the need to put in place system-wide training and support for clinicians working with CEN, encompassing generic as well as specialist services, and to challenge the stigma still experienced throughout the system.

ConclusionsStaff working with this service user group report that delivering best practice care services to be flexible, integrated, and sustainably funded, and for staff to be supported through ongoing training and supervision.


title: Knowledge and use of lactational amenorrhea as a family planning method among adolescent mothers in Uganda: a secondary analysis of Demographic and Health Surveys between 2006 and 2016

abstract:
ObjectiveTo assess the level of knowledge and use of lactational amenorrhea method (LAM) among adolescents in Uganda between 2006 and 2016 using nationally representative data from Demographic and Health Surveys (DHS).

DesignCross-sectional design involving analysis of three DHS (2006, 2011, and 2016) in Uganda.

SettingThe data was collected in Uganda. The DHS are nationally representative surveys on a wide range of indicators including contraception knowledge and use.

ParticipantsA total of 8,250 adolescents (15-19 years) and 7,110 young women (20-24 years) were included.

Primary outcome measureUse of LAM among adolescents and young women with a livebirth within six months before each survey.

ResultsIn 2016, less than 1% of eligible adolescents correctly used LAM and 56% were passively benefitting from LAM. The median duration of postpartum amenorrhea (PPA) among adolescents in 2016 was 6.9 months, declining from 8.3 months in 2006. Compared to adolescents, eligible young women had higher knowledge of LAM and higher medianPPA duration in 2016. The percentage of eligible adolescents who met the LAM criteria irrespective of whether they reported LAM use (protected by LAM) decreased from 76% in 2006 to 57% in 2016. More than 50% of eligible adolescents were aware of LAM in 2016, increasing from 6% in 2006, potentially in part due to change in survey question.

ConclusionDespite increasing awareness of LAM, reported and correct use of LAM was low among adolescents who could benefit from this method in Uganda, and declining over time. Support for adolescents to harness the benefits of correct LAM use should be increased. Additional research is needed to better understand the dynamics of LAM use in adolescents, including the transition to use of other modern contraceptive methods.

Strengths and limitations of this study[tpltrtarr] Lactational amenorrhea method has the potential to promote healthy timing and spacing of pregnancies and to reduce repeat adolescent births, yet, its use among Ugandan adolescents has not been examined.
[tpltrtarr]This study provides useful insights into the behavior of adolescents mothers which can be targeted to improve their reproductive knowledge and wellbeing.
[tpltrtarr]The study used data from three standardised nationally representative surveys, thus findings are generalizable and comparable over time and across age groups.
[tpltrtarr]Assessment of knowledge of LAM was affected by a change in the phrasing of the question in 2016, thus providing limited comparability with previous surveys.
[tpltrtarr]The measurement of LAM use was based on self-report.

category: sexual and reproductive health


title: NATURAL HISTORY OF LAFORA DISEASE A Prognostic Systematic Review and Individual Participant Data Meta-Analysis.

abstract:
ObjectiveTo describe the clinical course of Lafora Disease (LD) and identify predictors of outcome by means of a prognostic systematic review with individual participant data meta-analysis.

MethodsA search was conducted on MEDLINE and Embase with no restrictions on publication date. Only studies reporting genetically confirmed LD cases were included. Kaplan-Meier estimate was used to assess probability of death and of loss of autonomy. Univariable and multivariable Cox regression models with mixed effects (clustered survival data) were performed to evaluate prognostic factors.

ResultsSeventy-three papers describing 298 genetically confirmed LD cases were selected. Mean age at disease onset was 13.4 years (SD 3.7), with 9.1% aged[≥] 18 years. Overall survival rates in 272 cases were 93% [95% CI 89-96] at 5 years, 62% [95% CI 54-69] at 10 years and 57% [95% CI 49-65] at 15 years. Median survival time was 11 years. The probability of loss of autonomy in 110 cases was 45% [95% CI 36-55] at 5 years, 75% [95% CI 66-84] at 10 years, and 83% [95% CI 74-90] at 15 years. Median loss of autonomy time was 6 years. Asian origin and age at onset <18 years emerged as negative prognostic factors, while type of mutated gene and symptoms at onset were not related to survival or disability.

ConclusionsThis study documented that half of patients survived at least 11 years. The notion of actual survival rate and prognostic factors is crucial to design studies on the effectiveness of upcoming new disease-modifying therapies.


title: A Short Plus Long-Amplicon Based Sequencing Approach Improves Genomic Coverage and Variant Detection In the SARS-CoV-2 Genome

abstract: High viral transmission in the COVID-19 pandemic has enabled SARS-CoV-2 to acquire new mutations that impact genome sequencing methods. The ARTIC.v3 primer pool that amplifies short amplicons in a multiplex-PCR reaction is one of the most widely used methods for sequencing the SARS-CoV-2 genome. We observed that some genomic intervals are poorly captured with ARTIC primers. To improve the genomic coverage and variant detection across these intervals, we designed long amplicon primers and evaluated the performance of a short (ARTIC) plus long amplicon (MRL) sequencing approach. Sequencing assays were optimized on VR-1986D-ATCC RNA followed by sequencing of nasopharyngeal swab specimens from five COVID-19 positive patients. ARTIC data covered >90% of the virus genome fraction in the positive control and four of the five patient samples. Variant analysis in the ARTIC data detected 67 mutations, including 66 single nucleotide variants (SNVs) and one deletion in ORF10. Of 66 SNVs, five were present in the spike gene, including nt22093 (M177I), nt23042 (S494P), nt23403 (D614G), nt23604 (P681H), and nt23709 (T716I). The D614G mutation is a common variant that has been shown to alter the fitness of SARS-CoV-2. Two spike protein mutations, P681H and T716I, which are represented in the B.1.1.7 lineage of SARS-CoV-2, were also detected in one patient. Long-amplicon data detected 58 variants, of which 70% were concordant with ARTIC data. Combined analysis of ARTIC +MRL data revealed 22 mutations that were either ambiguous (17) or not called at all (5) in ARTIC data due to poor sequencing coverage. For example, a common mutation in the ORF3a gene at nt25907 (G172V) was missed by the ARTIC assay. Hybrid data analysis improved sequencing coverage overall and identified 59 high confidence mutations for phylogenetic analysis. Thus, we show that while the short amplicon (ARTIC) assay provides good genomic coverage with high throughput, complementation of poorly captured intervals with long amplicon data can significantly improve SARS-CoV-2 genomic coverage and variant detection.


title: Seroprevalence of COVID-19 in HIV Population

abstract:
BackgroundSeroprevalence helps us to estimate the exact prevalence of a disease in a population. Although the world has been battling this pandemic for more than a year now, we still do not know about the burden of this disease in people living with HIV/AIDS (PLHA). Seroprevalence data in this population subset is scarce in most parts of the world, including India. The current study aimed to estimate the seroprevalence of anti-SARS-CoV-2 IgG antibody among PLHA.

AimTo determine the seroprevalence of SARS-CoV-2 antibodies in PLHA.

MethodThis was a cross-sectional study conducted at a tertiary care hospital in North India. We recruited HIV positive patients following at the ART centre of the institute. Anti-SARS-CoV-2 IgG antibody levels targeting recombinant spike receptor-binding domain (RBD) protein of SARS CoV-2 were estimated in serum sample by the chemiluminescent immunoassay method.

ResultsA total of 164 patients were recruited in the study with a mean age ({+/-}SD) of 41.2 ({+/-}15.4) years, of which 55% were male. Positive serology against SARS CoV-2 was detected in 14% patients (95% CI: 9.1-20.3%).

ConclusionThe seroprevalence of COVID-19 infection in PLHA was lower than the general population in the same region, which ranged from 23.48% to 28.3% around the study period.

category: hiv aids


title: WHotLAMP: A simple, inexpensive, and sensitive molecular test for the detection of SARS-CoV-2 in saliva

abstract: Despite the development of effective vaccines against SARS-CoV-2, epidemiological control of the virus is still challenging due to slow vaccine rollouts, incomplete vaccine protection to current and emerging variants, and unwillingness to get vaccinated. Therefore, frequent testing of individuals to identify early SARS-CoV-2 infections, contact-tracing and isolation strategies remain crucial to mitigate viral spread. Here, we describe WHotLAMP, a rapid molecular test to detect SARS-CoV-2 in saliva. WHotLAMP is simple to use, highly sensitive (3.6 viral RNA copies per microliter of saliva) and specific, as well as inexpensive, making it ideal for frequent screening. Moreover, WHotLAMP does not require toxic chemicals or specialized equipment and thus can be performed in point-of-care settings, and may also be adapted for resource-limited environments or home use. While applied here to SARS-CoV-2, WHotLAMP can be modified to detect other pathogens, making it adaptable for other diagnostic assays, including for use in future outbreaks.


title: Molecular epidemiology of paediatric bloodstream infections caused by Gram-negative bacteria in Oxfordshire, UK

abstract:
ObjectivesGram-negative organisms are common causes of bloodstream infection (BSI) during the neonatal period and early childhood. Whilst several large studies have characterised these isolates in adults, equivalent data (particularly incorporating whole genome sequencing) is lacking in the paediatric population.

MethodsWe performed an epidemiological and sequencing based analysis of Gram-negative bloodstream infections in children <18 years old between 2008 and 2018 in Oxfordshire, UK.

Results327 isolates (296 successfully sequenced) from 287 patients were included. The burden of infection was predominantly in neonates (124/327[38%]). Most infections were caused by Escherichia coli (149/327[46%])/Klebsiella spp. (69/327[21%]) and Enterobacter hormaechei (34/327[10%]). There was no evidence of an increasing incidence of E. coli BSIs (IRRy 0.96, 95%CI 0.90-1.30, p=0.30) and for Klebsiella spp. there was some evidence that the incidence decreased slightly (IRRy 0.91, 95%CI 0.83-1.00, p=0.06). Similarly the proportion of antimicrobial resistant (across all antimicrobial classes evaluated) isolates did not change over time, though we did identify some evidence of sub-breakpoint increases in gentamicin resistance IRRy 1.86, 95%CI 1.33-2.58, pheterogeneity=0.002. The population structure of E. coli BSI isolates in neonates and children mirrors that in adults with a predominance of STs 131/95/73/69 and the same proportion of O-antigen serotypes covered by the ExPEC-4V vaccine. In most cases there was no evidence of transmission/point-source acquisition and whole genome sequencing was able to refute a previously suspected Serratia marcescens outbreak.

ConclusionOur findings support continued use of current empirical treatment guidelines and suggest that O-antigen targeted vaccines may have a role in reducing the incidence of neonatal sepsis.


title: Rifampicin mono-resistant tuberculosis is not the same as multidrug-resistant tuberculosis: a descriptive study from Khayelitsha, South Africa

abstract: Rifampicin mono-resistant TB (RMR-TB) constitutes 38% of all rifampicin-resistant TB (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) within a high TB, RR-TB and HIV burden setting. Patient-level clinical data and stored RR-TB isolates from 2008-2017 with available whole genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare rifampicin-resistance (RR) conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semi-quantitative rifampicin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV-positive individuals (adjusted Odds Ratio 1.4, 95% CI 1.1-1.9) and diagnosis between 2013-2017 versus 2008-2012 (aOR 1.3, 1.1-1.7) were associated with RMR-TB. Among 1,119 (54.8%) patients with available WGS data showing RR-TB, significant differences in the distribution of rpoB RR-conferring mutations between RMR-TB and MDR-TB isolates were observed. Mutations associated with high-level RR were more commonly found among MDR-TB isolates (811/889, 90.2% versus 162/230, 70.4% among RMR-TB, p<0.01). In particular, the rpoB L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR-TB versus 10/889 (1.1%) in MDR-TB (p<0.01). Among 10 isolates with an rpoB L430P mutation, 7 were phenotypically susceptible using the critical concentration of 0.5 {micro}g/ml (range 0.125-1 {micro}g/ml). The majority (215/230, 93.5%) of RMR-TB isolates showed susceptibility to all other TB drugs, highlighting the potential benefits of WGS for simplified treatment. These data suggest that the evolution of RMR-TB differs from MDR-TB with a potential contribution from HIV infection.


title: Sources of variability in methods for processing, storing, and concentrating SARS-CoV-2 in influent from urban wastewater treatment plants

abstract: The rapid emergence of wastewater based surveillance has led to a wide array of SARS-CoV-2 RNA quantification methodologies being employed. Here we compare methods to store samples, inactivate viruses, capture/concentrate viruses, and extract/measure viral RNA from primary influent into wastewater facilities. We found that heat inactivation of the viruses led to a 1-3 log10 decrease compared to chemical inactivation. Freezing influent prior to concentration caused a 1-4 log10 decrease compared to processing fresh samples, but viral capture by membrane adsorption prior to freezing was robust to freeze-thaw variability. Concentration vs. direct extraction, and PCR platform also affected outcome, but by a smaller amount. The choice of nucleocapsid gene target had nearly no effect. Pepper mild-mottle virus was much less sensitive to these methodological differences than was SARS-CoV-2, which challenges its use as a population-level control among studies using different methods. Better characterizing the variability associated with different methodologies, in particular the impact of methods on sensitivity, will aid decision makers in following the effects of vaccination campaigns, early detection of future outbreaks, and potentially monitoring the appearance of SARS-CoV-2 variants in the population.


title: Mild cognitive impairment is not a valid concept and should be replaced by a more restrictive, biologically validated class, named Mild Cognitive Dysfunctions (MCD): a nomothetic network approach.

abstract:
BackgroundNo studies have examined whether interactions between the apolipoprotein E4 (ApoE4) allele and peripheral biomarkers, hypertension, and type 2 diabetes mellitus (T2DM) may impact the neurocognitive, behavioral and social dysfunctions in amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD).

AimsTo clinically define and biologically validate a subgroup of aMCI subjects that take up an intermediate position between controls and AD patients.

MethodsIn 61 healthy controls, 60 subjects with aMCI, and 60 AD patients we measured the features of aMCI/AD using the Consortium to Establish a Registry for Alzheimers Disease (CERAD). A composite BIORISK score was computed using the ApoE4 allele, serum folate, albumin, white blood cells, fasting blood glucose (FBG), atherogenic index of plasma (AIP), T2DM and hypertension.

ResultsClustering and nearest neighbour analyses were unable to validate the aMCI subgroup. We constructed two z unit-based composite scores, the first indicating overall burden of cognitive, social, and behavioural deterioration (OBD), and a second reflecting the interactions between ApoE4, all other biomarkers, hypertension and T2DM (BIORISK). We found that 40.2% of the variance in the OBD score was explained by BIORISK, ApoE4, age and education. The OBD index was used to construct three subgroups (normal, medium, and high OBD) with the medium group (n=45) showing mild cognitive dysfunctions (MCD) in memory, language, orientation, and ADL. People with MCD show OBD and BIORISK scores that are significantly different from controls and AD.

ConclusionsPetersens aMCI criteria cannot be validated and should be replaced by the more restrictive, biologically validated MCD class.


title: INOVASIA Study: A Randomized Open Controlled Trial to Evaluate Prophylactic Pravastatin in the Prevention of Preeclampsia and its Effects on sFlt1/PLGF Levels in Pregnant Women at High Risk of Developing Preeclampsia

abstract:
ObjectivesThe study aim is to evaluate the effect of pravastatin to prevent preeclampsia (PE) in pregnant women at a high risk of developing preeclampsia and the maternal and perinatal outcomes and the sFlt1/PLGF ratio in the Surabaya cohort of the INOVASIA trial.

SettingThis study involved 2 academic hospital (a tertiary and secondary center) in Surabaya, Indonesia.

ParticipantsPregnant women at a high risk of developing PE were recruited and randomized into an intervention group (40) and a control group (40). The inclusion criteria consisted of pregnant women with positive clinical risk factor and abnormal uterine artery doppler examination at 10-20 weeks gestational age.

InteventionsThe control group received low dose aspirin (80 mg/day) and calcium (1 g/day), while the intervention group received additional pravastatin (20 mg twice daily) starting from 14-20 weeks gestation until delivery. Research blood samples were collected before the first dose of pravastatin, and just before delivery.

Primary and Secondary OutcomesThe primary outcome was the rate of maternal preeclampsia, secondary outcomes included maternal-perinatal outcomes and sFlt-1, PLGF, sFlt-1/PlGF ratio and sEng levels.

ResultsThe rate of preeclampsia was (non-significantly) lower in the pravastatin group compared with the control group (17.5% vs 35%). The pravastatin group also had a (non-significant) lower rate of severe preeclampsia, HELLP syndrome, acute kidney injury and severe hypertension. The rate of (iatrogenic) preterm delivery was significantly lower (p 0.048) in the pravastatin group (n=4) compared with the controls (n=12). Neonates in the pravastatin group had significantly higher birthweights, higher Apgar scores, and lower composite neonatal morbidity and NICU admission rates. All biomarkers show a significant deterioration in the control group compared with non-significant changes in the pravastatin group.

ConclusionsPravastatin holds promise in the secondary prevention of preeclampsia and placenta-mediated adverse perinatal outcomes by improving the anti-angiogenic/pro-angiogenic imbalance.

Trial RegistrationClinical Trial Gov (ID: NCT03648970)

Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThe largest randomized clinical trial reporting the effects of pravastatin in the prevention of preeclampsia in pregnant women at a high risk of developing preeclampsia with maternal preeclampsia as primary endpoint
C_LIO_LISecondary outpoints included perinatal outcomes, and sFlt-1, PlGF, sFlt-1/PlGF ratio, and sEng levels
C_LIO_LIInsufficient funding for placebo tables in the setting of Indonesia, a developing country, resulted in the trial design being an open randomized controlled trial
C_LIO_LIIn order to reduce risk of bias, 2 independent MFM consultants evaluated and verified all abnormal outcomes while being blinded for group allocation of the trial participants
C_LI

category: obstetrics and gynecology


title: Widespread Contamination of SARS-CoV-2 on Highly Touched Surfaces in Brazil During the Second Wave of the COVID-19 Pandemic

abstract:
Although SARS-CoV-2 surface contamination has been investigated in temperate climates, few studies have been conducted in the tropics. Here, we investigated the presence of SARS-CoV-2 on high-touch surfaces in a large city in Brazil. A total of 400 surface samples were collected in February 2021 in the City of Recife, Northeastern Brazil. A total of 97 samples (24.2%) tested positive for SARS-CoV-2 by RT-qPCR using the CDC-USA protocol. All the collection sites, except one (18/19, 94.7%) had at least one environmental surface sample contaminated. SARS-CoV-2 positivity was higher in public transport terminals (47/97, 48.4%), followed by health care units (26/97, 26.8%), public parks (14/97, 14.4%), public markets (4/97, 4.1%), and beach areas (4/97, 4.1%). Toilets, ATMs, handrails, playground, and outdoor gym were identified as fomites with the highest rates of viral contamination. Regarding the type of material, SARS-CoV-2 RNA was found more commonly on metal (45/97, 46.3%), followed by plastic (18/97, 18.5%), wood (12/97, 12.3%), rock (10/97, 10.3%), concrete (8/97, 8.2%), and glass (2/97, 2.0%). Taken together, our data indicated extensive SARS-CoV-2 contamination in public surfaces and identified critical control points that need to be targeted to break SARS-CoV-2 transmission chains.

SynopsisWe investigated the presence of SARS-CoV-2 on high-touch surfaces in a large city in Brazil and identified critical points to establish effective control measures aimed at breaking transmission.

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title: Rural prioritization may increase the impact of COVID-19 vaccines in Sub-Saharan Africa due to ongoing internal migration: A modeling study

abstract: How COVID-19 vaccine is distributed within low- and middle-income countries has received little attention outside of equity or logistical concerns but may ultimately affect campaign impact in terms of infections, severe cases, or deaths averted. In this study we examined whether subnational (urban-rural) prioritization may affect the cumulative two-year impact on disease transmission and burden of a vaccination campaign using an agent-based model of COVID-19 in a representative Sub-Saharan Africa country setting. We simulated a range of vaccination strategies that differed by urban-rural prioritization, age group prioritization, timing of introduction, and final coverage level. Urban prioritization averted more infections in only a narrow set of scenarios, when internal migration rates were low and vaccination was started by day 30 of an outbreak. Rural prioritization was the optimal strategy for all other scenarios, e.g., with higher internal migration rates or later start dates, due to the presence of a large immunological naive rural population. Among other factors, timing of the vaccination campaign was important to determining maximum impact, and delays as short as 30 days prevented larger campaigns from having the same impact as smaller campaigns that began earlier. The optimal age group for prioritization depended on choice of metric, as prioritizing older adults consistently averted more deaths across all of the scenarios. While guidelines exist for these latter factors, urban-rural allocation is an orthogonal factor that we predict to affect impact and warrants consideration as countries plan the scale-up of their vaccination campaigns.


title: Early School Years follow up of the Asking Questions in Alcohol Longitudinal Study in Melbourne, Australia (AQUA at 6): Cohort profile

abstract:
PurposeThe Asking Questions about Alcohol in Pregnancy (AQUA) study, established in 2011, is a pre-birth cohort of 1570 mother and child pairs designed to assess the effects of low to moderate prenatal alcohol exposure and sporadic binge drinking on long-term child development. The current follow-up of the children, now aged 6 to 8 years, aims to strengthen our understanding of the relationship between these levels of prenatal alcohol exposure and neuropsychological functioning, facial dysmorphology, and brain structure & function.

Findings to dateOver half (59%) of mothers consumed some alcohol during pregnancy, with one in five reporting at least one binge drinking episode prior to pregnancy recognition. Childrens craniofacial shape was examined at 12 months of age, and low to moderate prenatal alcohol exposure was associated with subtle midface changes. At two years of age, formal developmental assessments showed no evidence that cognitive, language or motor outcome was associated with any of the prenatal alcohol exposures investigated.

ParticipantsBetween June 2018 and April 2021, 802 of the 1342 eligible AQUA study families completed a parent-report questionnaire (60%). Restrictions associated with COVID-19 pandemic disrupted recruitment, but early school-age neuropsychological assessments were undertaken with 696 children (52%), and 482 (36%) craniofacial images were collected. A pre-planned, exposure-representative subset of 146 random children completed a brain MRI. The existing AQUA study biobank was extended through collection of 427 (32%) child buccal swabs.

Future plansWe will investigate the relationship between prenatal alcohol exposure and specific aspects of neurodevelopment at 6-8 years, including brain structure & function. We will also determine whether craniofacial changes identified at 12 months of age are predictive of later developmental impairments. The contribution of genetics and epigenetics to individual variations in outcomes will be examined in conjunction with established and future national and international collaborations.

STRENGTHS AND LIMITATIONSO_LIThe Asking Questions about Alcohol in Pregnancy (AQUA) cohort study was specifically designed to prospectively collect high-quality data on low to moderate prenatal alcohol exposure and relevant confounders to investigate the risk to offspring neurodevelopment.
C_LIO_LIThe children are being followed up for the third time at 6-8 years, using sensitive measures of neuropsychological function, 3D craniofacial photography, and brain MRI.
C_LIO_LIA biobank of birth samples and maternal and child buccal DNA enables investigation of the contribution of genetic and epigenetic factors to neurodevelopmental outcomes.
C_LIO_LIDespite carefully designed questions, reporting bias will need to be considered in the interpretation of findings, especially around alcohol use.
C_LIO_LIThe generalisability of some findings will be limited to a general antenatal population of Caucasian women, from middle-income backgrounds and with a low-risk pregnancy.
C_LI

category: pediatrics


title: Observed and self-reported COVID-19 health protection behaviours on a university campus and the impact of a single simple intervention.

abstract:
ObjectivesHygiene behaviours had been an essential component of attempts to slow the spread of SARS-CoV-2. Most data on adherence to these behaviours is collected via self-reporting, which can differ from observed behaviours. We quantified this discrepancy among a university sample and tested the impact of simple intervention on observed behaviour.

Study designCross-sectional questionnaire of behaviour on campus compared to direct observation on one day without, and one day with, additional signage.

MethodsWe circulated an email inviting all staff and students at our university to complete a questionnaire asking how often they wear a mark or practice hand hygiene when entering campus buildings, and how often they practiced social distancing within campus buildings. We observed all entrants to the main building on one campus on a baseline day and on a day after installing a large sign reminding people that these behaviours were mandatory.

ResultsIn our survey, 172 out of 252 respondents (68%) reported always cleaning their hands, 225 out of 251 (90%) reported always wearing a face covering, and 124 out of 252 (49%) reported always maintaining social distancing. On the baseline day of observation, 50 out of 311 people (16.1%) cleaned their hands and 256 (82.3%) wore a face covering correctly. Out of 119 people whom we could assess, 9 (7%) maintained social distance from others. The signage was associated with significant improvements for cleaning hands (104 / 375 people: 27.7%), wearing a face covering (374 / 375; 99.8%) and maintaining social distance (79 / 144; 54.8%).

ConclusionsGreater use of observational methods will provide a more accurate measure of behaviour than the current reliance on self-report and allow interventions to be robustly tested.


title: State of Emergency and Human Mobility during the COVID-19 Pandemic

abstract:
BackgroundTo help control the spread of the coronavirus disease 2019 (COVID-19), the Japanese government declared a state of emergency (SoE) four times. However, these were less stringent than other nations. It has not been assessed whether soft containment policies were sufficiently effective in promoting social distancing or reducing human contact.

MethodsUtilising the Google mobility index to assess social distancing behaviour in all Japanese prefectures between 15 February 2020 and 21 September 2021, mobility changes were assessed by an interrupted time-series analysis after adjusting for seasonality and various prefecture-specific fixed-effects and distinguishing potential heterogeneity across multiple SoEs and time passed after the declaration.

ResultsThe mobility index for retail and recreation showed an immediate decline after the declaration of the SoE by 7.94 percent-points (95%CI: -8.77 to -7.12) and a further decline after the initial period (beta: -1.27 95%CI: -1.43 to -1.11), but gradually increased by 0.03 percent-points (95%CI: 0.02 - 0.03). This trend was similar for mobilities in other places. Among the four SoEs, the overall declines in human mobility outside the home in the third and fourth SoE were the least significant, suggesting that people were less compliant with social distancing measures during these periods.

ConclusionAlthough less stringent government responses to the pandemic may help promote social distancing by controlling human mobilities outside the home, their effectiveness may decrease if these interventions are repeated and enforced for extended periods, distorting ones health belief by heuristics biases. By combining these with other measures (i.e. risk-communication strategies), even mild containment and closure policies can be effective in curbing the spread of the virus.

What is already known?O_LIHuman mobility, in terms of tracing social distancing and human contact in places such as shops, restaurants, and workplaces, was reported to be a useful indicator for predicting COVID-19 outbreaks.
C_LIO_LIContainment and closure policies, such as country lockdowns and a State of Emergency (SoE) declarations, effectively reduce human mobility.
C_LI

What are the new findings?O_LIThis study first evaluated if longer and repeated SoEs were effective to reduce human mobility.
C_LIO_LIThe findings from this study suggests that although less stringent government responses to the pandemic may help promote social distancing by controlling human mobilities outside the home, their effectiveness decreases if these interventions are repeated and enforced for extended periods.
C_LI

What do the new findings imply?O_LIWhile less stringent government responses to the pandemic are effective in promoting social distancing by controlling human mobilities outside the home, their effectiveness may decrease if similar interventions are repeated for extended periods of time.
C_LIO_LIHowever, by combining these with other measures such as risk-communication strategies, even less costly interventions such as mild containment and closure policies can be effective in curbing the spread of the COVID-19 virus.
C_LI

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIt has been shown that human mobility, in terms of tracing social distancing and human contact in places such as shops, restaurants, and workplaces, was reported to be a useful indicator for predicting COVID-19 outbreaks. Also, previous studies have shown that containment and closure policies, such as country lockdowns and a State of Emergency (SoE) declarations, effectively reduce human mobility. However, it is not explicitly known whether longer and repeated  alerts requesting citizens to avoid nonessential activities with risk communication strategies are equally effective.

Added-value of this studyThis study first evaluated if longer and repeated SoEs were effective to reduce human mobility, suggesting three main findings. First, individuals engage in social distancing behaviours during the initial periods of the SoE but become less compliant as time passes. Second, when mobility changes during each SoE were distinguished, overall declines in mobilities outside the home and increases in stay-at-home time were less obvious during the succeeding SoEs. Third, under the stringent government responses to the pandemic and decline in mobilities, the consumption level--especially for activities outside the home-- sharply declined, suggesting that strong public interventions may worsen the economy.

Implications of all the available evidenceWhile less stringent government responses to the pandemic are effective in promoting social distancing by controlling human mobilities outside the home, their effectiveness may decrease if similar interventions are repeated for extended periods of time. However, by combining these with other measures such as risk-communication strategies, even less costly interventions such as mild containment and closure policies can be effective in curbing the spread of the COVID-19 virus.


title: State of Emergency and Human Mobility during the COVID-19 Pandemic in Japan


title: EXAMINING THE DOUBLE BURDEN OF MALNUTRITION FOR PRESCHOOL CHILDREN AND WOMEN OF REPRODUCTIVE AGE IN LOW- AND MIDDLE-INCOME COUNTRIES: A SCOPING REVIEW PROTOCOL

abstract:
IntroductionThe majority of the populations in Low-and Middle-Income Countries (LMICs) are encountering the double burden of malnutrition (DBM): the coexistence of both undernutrition and overnutrition sequalae. With DBM being a new phenomenon in research, little is known about its etiology, operational definitions and risk factors influencing its manifestation. The proposed scoping review is aimed at mapping literature with regards to the DBM phenomenon among preschool children and women of reproductive age in LMICs who are among the most high-risk groups to encounter DBM.

MethodsA comprehensive literature search will be conducted in the following electronic databases: MEDLINE, EMBASE, Scopus, CINAHL, LILACS and ProQuest Dissertations & Thesis Global. Additionally, searches in other government and institutional sources (World Health Organization website and university repositories) and forward and backward citation tracking of seminal articles will also be done. Two reviewers will independently conduct title and abstract screening and full text screening. Similarly, data extraction and coding will independently be done by two reviewers. Information extracted from included literature will be analysed qualitatively using thematic analysis approach and reported as per the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines.

Ethics and DisseminationEthical approval is not required for this study because the review is based on literature from publicly available sources. The dissemination of our findings will be done through presentations in relevant conferences and publication in a peer-reviewed journal.

Strengths and limitationsO_LITo the best of our knowledge, this is the first scoping review that focuses on exploring the etiology of the double burden of malnutrition among preschool children and women of reproductive age in Low-and Middle-Income Countries.
C_LIO_LIThis review will encompass comprehensive literature search and will utilize a renowned thematic analysis framework to synthesis the findings of the study.
C_LIO_LIThe findings of this review will be important in not only mapping the current literature with regards to the double burden of malnutrition phenomenon for risk populations but also guiding secondary data analysis for our subsequent studies.
C_LIO_LIThe anticipated dearth of causation literature and longitudinal studies in this area of research may limit our findings, specifically in understanding the etiology of double burden of malnutrition.
C_LI

category: nutrition


title: Seroprevalence of anti-SARS-CoV-2 antibodies in women attending antenatal care in eastern Ethiopia

abstract:
Information on the cumulative incidence of SARS-CoV-2 in East Africa is scarce. We conducted serosurveillance of anti-SARS-CoV-2 antibodies among pregnant women attending their first antenatal care visit in three health facilities in eastern Ethiopia.

We collected data using questionnaire and a blood sample from 3,312 pregnant women between April 1, 2020 and March 31, 2021 at health facilities in Haramaya, Aweday and Harar. We selected 1,447 blood samples at random and assayed these for anti-SARS-CoV-2 antibodies at Hararghe Health Research laboratory using WANTAI(R) SARS-CoV-2 Rapid Test for total immunoglobulin. Temporal trends in seroprevalence were analysed with a {chi}2 test for trend and multivariable binomial regression.

Among 1,447 sera tested, 83 were positive for anti-SARS-CoV-2 antibodies giving a crude seroprevalence of 5.7% (95% CI 4.6%, 7.0%). Of 160 samples tested in April-May, 2020, none was seropositive; the first seropositive sample was identified in June and seroprevalence rose steadily thereafter ({chi}2 test for trend, p=0.003) reaching a peak of 11.8% in February, 2021. In the multivariable model, seroprevalence was approximately 3% higher in first-trimester mothers compared to later presentations, and rose by 0.75% (95% CI 0.31%, 1.20%) per month of calendar time.

This clinical convenience sample illustrates the dynamic of the SARS-CoV-2 epidemic in young adults in eastern Ethiopia; infection was rare before June 2020 but it spread in a linear fashion thereafter, rather than following intermittent waves, and reached 10% by the beginning of 2021. After one year of surveillance, most pregnant mothers remained susceptible.


title: Paternal body mass index before conception associated with offspring's birth weight in Chinese population: a prospective study

abstract:
Whether paternal epigenetic information of nutrition might be inherited by their offspring remained unknown. evaluate the relationship between preconception paternal body weight and their offsprings birth weight in 1,810 Chinese mother-father-baby trios. Information on paternal and maternal preconception body weight and height was collected via a self-reported questionnaire. Birth weight was collected from medical records. Paternal preconception body weight was associated with offsprings birth weight (p trend=0.02) after multivariable adjustment. Each standard deviation increment of paternal body mass index was associated with an additional 29.6 g increase of birth weight (95% confident interval: 5.7g, 53.5g). The association was more pronounced in male neonates, and neonates with overweight mothers, and with mothers who gained excessive gestational weight, compared to their counterparts (all p interaction<0.05). Sensitivity analyses showed similar pattern to that of the main analysis. Paternal preconception body weight was associated with birth weight of their offspring.

Impact statementO_ST_ABSWhat is already known on this subject?C_ST_ABSMore efforts have previously been put on the maternal contribution to birth weight, however, it is uncertain whether paternal pre-conceptional body weight, an indicator for epigenetic information, might be inherited by their offspring.

What do the results of this study add?In the current study that included 1,810 Chinese mother-father-baby trios, a small but significant association was observed between paternal preconception body weight and offsprings birth weight (p trend=0.02).

What are the implications of these findings for clinical practice and/or further research?Paternal epigenetic information of nutrition could be inherited by their offspring.


title: Using aggregate patient data at the bedside via an on-demand consultation service

abstract: Using evidence derived from previously collected medical records to guide patient care has been a long standing vision of clinicians and informaticians, and one with the potential to transform medical practice. As a result of advances in technical infrastructure, statistical analysis methods, and the availability of patient data at scale, an implementation of this vision is now possible. Motivated by these advances, and the information needs of clinicians in our academic medical center, we offered an on-demand consultation service to derive evidence from patient data to answer clinician questions and support their bedside decision making. We describe the design and implementation of the service as well as a summary of our experience in responding to the first 100 requests. Consultation results informed individual patient care, resulted in changes to institutional practices, and motivated further clinical research. We make the tools and methods developed to implement the service publicly available to facilitate the broad adoption of such services by health systems and academic medical centers.

category: health informatics


title: Predicting arterial age using carotid ultrasound images, pulse wave analysis records, cardiovascular biomarkers and deep learning

abstract: Cardiovascular disease --an age-related disease-- is the leading cause of death worldwide. We built an arterial age predictor by training deep learning models to predict age from 233,388 pulse wave analysis records, 8,279 carotid ultrasound images and arterial health biomarkers (e.g blood pressure) collected from 502,000 UKB participants. We predicted age with a R-Squared of 67.1+/-0.6% and a root mean squared error of 4.29+/-0.04 years. Attention maps for carotid ultrasound images suggest that the predictions are driven by vascular features, for the largest part. Accelerated arterial aging is 32.6+/-7.3% GWAS-heritable, and we identified 192 single nucleotide polymorphisms in 109 genes (e.g NPR3, involved in blood volume and pressure) significantly associated with this phenotype. Similarly, we identified biomarkers (e.g electrocardiogram features), clinical phenotypes (e.g chest pain), diseases (e.g hypertension), environmental (e.g smoking) and socioeconomic (e.g income and education) variables associated with accelerated arterial aging. Finally, carotid ultrasound images, pulse wave analysis records and blood pressure biomarkers capture different facets of arterial aging. For example, carotid ultrasound-measured and pulse wave analysis-measured accelerated arterial aging phenotypes are only .164+/-.009 correlated. In conclusion, our predictor suggests potential lifestyle and therapeutic interventions to slow arterial aging, and could be used to assess the efficiency of emerging rejuvenating therapies on the arterial system.


title: Completion of electronic nursing documentation of inpatient admission assessment: insights from Australian metropolitan hospitals

abstract:
IntroductionElectronic nursing documentation is an essential aspect of inpatient care and multidisciplinary communication. Analysing data in electronic medical record (eMR) systems can assist in understanding clinical workflows, improving care quality, and promoting efficiency in the healthcare system. This study aims to assess timeliness of completion of an electronic nursing admission assessment form and identify patient and facility factors associated with form completion in three metropolitan hospitals.

Materials and MethodsRecords of 37,512 adult inpatient admissions (November 2018-November 2019) were extracted from the hospitals eMR system. A dichotomous variable descriptive of completion of the nursing assessment form (Yes/No) was created. Timeliness of form completion was calculated as the interval between date and time of admission and form completion. Univariate and multivariate multilevel logistic regression were used to identify factors associated with form completion.

ResultsAn admission assessment form was completed for 78.4% (n=29,421) of inpatient admissions. Of those, 78% (n=22,953) were completed within the first 24 hours of admission, 13.3% (n=3,910) between 24-72 hours from admission, and 8.7% (n=2558) beyond 72 hours from admission. Patient length of hospital stay, admission time, and admitting units nursing hours per patient day were associated with form completion. Patient gender, age, and admitting unit type were not associated with form completion.

DiscussionForm completion rate was high, though more emphasis needs to be placed on the importance of timely completion to allow for adequate patient care planning. Staff education, qualitative understanding of delayed form completion, and streamlined guidelines on nursing admission and eMR use are recommended.

Statement on conflicts of interestDeclarations of interest: none

Summary TableWhat was already known on the topic

O_LIElectronic clinical documentation is an essential aspect of inpatient care and multidisciplinary communication
C_LIO_LITimely completion of documentation enables prompt team communication and facilitates quality patient care planning
C_LIO_LIAustralian hospitals are moving towards fully adopting eMR-based technologies to manage patient care processes and multidisciplinary communication
C_LI

What this study added to our knowledge

O_LIThe timeliness of electronic nursing documentation can be improved
C_LIO_LIThere are patient- and facility-related factors which influence the completion of electronic nursing forms
C_LIO_LIThe application of advanced modelling techniques to existing eMR data assists in understanding clinician practices, processes and workflows
C_LI


title: Clinical Pharmacy Services Provided in Public Sector Hospitals in Nigeria: A National Survey

abstract:
BackgroundStudies show that clinical pharmacy services are effective in optimizing medicines use and patients outcomes. This study aimed to determine the clinical pharmacy services provided in public sector hospitals in Nigeria.

MethodsThis was an online survey of 296 primary, secondary and tertiary care hospitals sampled purposively across the 36 States and Federal Capital Territory in Nigeria. Data analysis was conducted descriptively, and via Chi-square test and multivariate analysis of variance (MANOVA).

Key findingsResponses were obtained from 272 hospitals in the country with a survey completion rate of 88%. This included 55 tertiary, 72 secondary, and 145 primary healthcare centres (PHCs). Pharmacists provided pharmaceutical care services in all the tertiary care hospitals, 94% of the secondary, and in only 6% of the PHCs surveyed. The composition of the pharmacy department per level of care was similar across the six geopolitical regions (V = 0.383, F = 1.453, P = 0.06) with more pharmacy staff employed in the tertiary care hospitals compared to the secondary care facilities. The majority ([≥]75%) of the tertiary and secondary care hospitals provided medicines information, patient education and counselling, alongside in- and outpatient dispensing services. However, fewer than 30% reported routine pharmacists involvement in multidisciplinary ward rounds, medication chart review, therapeutic guidelines development, antibiotic stewardship programmes, and drug therapy monitoring. Pharmacists routinely provided medication error reporting services in only about half of the hospitals in the sample, and this was not associated with the level of care (p > 0.05).

ConclusionsThe findings of this study demonstrate disparity in clinical pharmacy service availability across the various levels of care in Nigeria. It also highlights the need to scale up and prioritize their integration within the primary care sector.

category: health systems and quality improvement


title: Antibody neutralization to SARS-CoV-2 and variants after one year in Wuhan

abstract: Most COVID-19 patients can build effective humoral immunity against SARS-CoV-2 after recovery(1, 2). However, it remains unknown how long the protection can maintain and how efficiently it can protect people from the reinfection of the emerging SARS-CoV-2 variants. Here we evaluated the sera from 248 COVID-19 convalescents around one year post-infection in Wuhan, the earliest epicenter of SARS-CoV-2. We demonstrated that the SARS-CoV-2 immunoglobulin G (IgG) maintains at a high level and potently neutralizes the infection of the original strain (WT) and the B.1.1.7 variant in most patients. However, they showed varying degrees of efficacy reduction against the other variants of concern (P.1, B.1.525, and especially B.1.351) in a patient-specific manner. Mutations in RBD including K417N, E484K, and E484Q/L452R (B.1.617) remarkably impair the neutralizing activity of the convalescents sera. Encouragingly, we found that a small fraction of patients sera showed broad neutralization potency to multiple variants and mutants, suggesting the existence of broadly neutralizing antibodies recognizing the epitopes beyond the mutation sites. Our results suggest that the SARS-CoV-2 vaccination effectiveness relies more on the timely re-administration of the epitope-updated vaccine than the durability of the neutralizing antibodies.


title: Evaluation of the effectiveness of remdesivir in treating severe COVID-19 using data from the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, national cohort study.

abstract:
BackgroundRemdesivir has been evaluated in clinical trial populations, but there is a sparsity of evidence evaluating effectiveness in general populations.

MethodsAdults eligible to be treated with remdesivir, requiring oxygen but not ventilated, were identified from UK patients hospitalised with COVID-19. Patients treated with remdesivir within 24h of hospitalisation were compared with propensity-score matched controls; estimates of effectiveness were calculated for short-term outcomes (14-day mortality, 28-day mortality, time-to-recovery among others) using multivariable modelling.

Results9,278 out of 39,330 patients satisfied eligibility criteria. 1,549 patients were identified as  treated and matched with 4,964 controls. Patients were 62% male, mean (SD) age 63.1 (15.6) years, 80%  White ethnicity, and symptomatic for a median of 6 days prior to baseline. There was no statistically significant benefit of remdesivir at 14 days in terms of mortality or clinical status; there were signals of effectiveness in time-to-recovery after day 9, and a reduction in 28-day mortality.

ConclusionIn a real-world setting, initiation of remdesivir within 24h of hospitalisation in conjunction with standard of care was not associated with a benefit at 14 days but supports clinical trial evidence of a potential reduction in 28-day mortality.


title: Evaluation of the effectiveness of remdesivir in severe COVID-19 using observational data from a prospective national cohort study


title: Tocilizumab in COVID-19 - A Bayesian reanalysis of RECOVERY

abstract:
BackgroundRandomised Evaluation of COVID-19 Therapy (RECOVERY) demonstrated that tocilizumab reduces mortality in hospitalized COVID-19 patients. However, substantial uncertainty remains whether tocilizumabs effect is similar across clinically relevant subgroups. Whether this uncertainty can be resolved with Bayesian methods is unknown.

Design, Setting, Participants, and InterventionsRECOVERY was a controlled, open-label, platform UK trial that randomized (1:1) 4116 adults with oxygen saturation <92% on room air or receiving oxygen therapy with C-reactive protein [≥]75 mg/L to either usual care or tocilizumab plus usual care.

Main outcome measuresMortality and hospital discharge within 28 days.

MethodsUsing Bayesian methods, we combined RECOVERY with evidence-based priors in-corporating previous COVID-19 tocilizumab RCTs. The probability of tocilizumabs benefit for respiratory support and corticosteroid subgroups and sensitivity analyses were performed with different prior distributions and baseline risks.

ResultsFor all-cause mortality, the posterior probabilities of decreased deaths with tocilizumab were >99% and 19% in patients using and not using corticosteroids, respectively. In patients on simple oxygen only, non-invasive ventilation and invasive mechanical ventilation, the probabilities of decreased mortality were 96%, >99% and 77%, respectively. The probabilities for a clinically significant mortality reduction, as assessed by an absolute risk difference > 3% (number needed to treat [≤] 33), were 77%, 96%, 56%, respectively. Sensitivity analyses highlighted the uncertainty and lack of conclusive evidence for tocilizumabs effect in patients on invasive mechanical ventilation and those without concurrent corticosteroids. Posterior probabilities of benefit for hospital discharge outcome were high and consistent across most subgroups.

ConclusionsIn this Bayesian reanalysis, COVID-19 hospitalized patients exposed to corticosteroids or on non-invasive ventilation have a high probability of a clinically meaningful mortality benefit from tocilizumab. Tocilizumab also likely improves discharge from hospital in most subgroups. Future research should further address if patients on invasive mechanical ventilation can also benefit from tocilizumab.


title: Self-collection and pooling of samples as resources-saving strategies for RT-PCR-based SARS-CoV-2 surveillance, the example of travelers in French Polynesia

abstract: In French Polynesia, the first case of SARS-CoV-2 infection was detected on March 10th, 2020, in a resident returning from France. Between March 28th and July 14th, international air traffic was interrupted and local transmission of SARS-CoV-2 was brought under control, with only 62 cases recorded. The main challenge for reopening the air border without requiring travelers to quarantine on arrival was to limit the risk of re-introducing SARS-CoV-2. Specific measures were implemented, including the obligation for all travelers to have a negative RT-PCR test for SARS-CoV-2 carried out within 3 days before departure, and to perform another RT-PCR testing 4 days after arrival. Because of limitation in available medical staff, travelers were provided a kit allowing self-collection of oral and nasal swabs. In addition to increase our testing capacity, self-collected samples from up to 10 travelers were pooled before RNA extraction and RT-PCR testing. When a pool tested positive, RNA extraction and RT-PCR were performed on each individual sample. We report here the results of COVID-19 surveillance (COV-CHECK PORINETIA) conducted between July 15th, 2020, and February 15th, 2021, in travelers using self-collection and pooling approaches. We tested 5,982 pools comprising 59,490 individual samples, and detected 273 (0.46%) travelers positive for SARS-CoV-2. A mean difference of 1.17 Ct (CI 95% 0.93 - 1.41) was found between positive individual samples and pools (N=50), probably related to the volume of samples used for RNA extraction (200 {micro}L versus 50 {micro}L, respectively). Retrospective testing of positive samples self-collected from October 20th, 2020, using variants-specific amplification kit and spike gene sequencing, found at least 6 residents infected by the B1.1.7 UK variant. Self-collection and pooling approaches allowed large-scale screening for SARS-CoV-2 using less human, material and financial resources. Moreover, this strategy allowed detecting the introduction of SARS-CoV-2 variants in French Polynesia.


title: Endonuclease-based genotyping of the RBM, a first-line method for the surveillance of emergence or evolution of SARS-CoV-2 Variants.

abstract: Since the beginning of the Covid-19 pandemics, variants have emerged. Whereas most of them have no to limited selective advantage, some display increased transmissibility and/or resistance to immune response. To date, most of the mutations involved in the functional adaptation are found in the Receptor Binding Module (RBM), close to the interface with the human receptor ACE2. In this study, we thus developed and validated a fast and simple molecular assay allowing the detection and partial identification of the mutations in the RBM coding sequence. After the amplification of the region of interest, the amplicon is heat-denatured and hybridized with an amplicon of reference. The presence of a mutation in the heteroduplex can be cleaved by a mismatch-specific endonuclease and the cleavage pattern is analysed by capillary electrophoresis. The approach was first validated on viral RNA purified different SARS-CoV-2 variants produced in the lab before being implemented for clinical samples. The results highlighted the performance of the assay for the detection of mutations in the RBM from clinical samples. The procedure can be easily set up for high throughput identification of the presence of mutations and serve as a first-line screening to select the samples for full genome sequencing.


title: Neutrophil Lymphocyte Ratio as a Predictor of Glucocorticoid Effectiveness in Covid-19 Treatment

abstract: Glucocorticoids have been shown to improve outcomes of patients with severe cases of Covid-19. However, criteria for prescribing glucocorticoids are currently limited. To identify potential for targeting, we perform an observational analysis of mortality of hospitalized patients. Our results agree with current clinical understanding that glucocorticoids benefit patients with severe cases of Covid-19, and that elevated Neutrophil/Lymphocyte Ratio (NLR) is associated with mortality. Furthermore, our results suggest that glucocorticoids could be targeted to patients with elevated NLR (especially in the range 6-25) at time of admission. Finally, we note there are also high-risk patients with low NLR, suggesting varying presentations of severe Covid-19.


title: The relative strength and timing of innate immune and CD8 T-cell responses underlie the heterogeneous outcomes of SARS-CoV-2 infection

abstract:
SARS-CoV-2 infection results in highly heterogeneous outcomes, from cure without symptoms to acute respiratory distress and death. While immunological correlates of disease severity have been identified, how they act together to determine the outcomes is unknown. Here, using a new mathematical model of within-host SARS-CoV-2 infection, we analyze diverse clinical datasets and predict that a subtle interplay between innate and CD8 T-cell responses underlies disease heterogeneity. Our model considers essential features of these immune arms and immunopathology from cytokines and effector cells. Model predictions provided excellent fits to patient data and, by varying the strength and timing of the immune arms, quantitatively recapitulated viral load changes in mild, moderate, and severe disease, and death. Additionally, they explained several confounding observations, including viral recrudescence after symptom loss, prolonged viral positivity before cure, and mortality despite declining viral loads. Together, a robust conceptual understanding of COVID-19 outcomes emerges, bearing implications for interventions.

TeaserModeling explains how a subtle interplay between innate immune and CD8 T-cell responses determines the severity of COVID-19.