title: Coping under stress: Prefrontal control predicts stress burden during the COVID-19 crisis

abstract:
BackgroundThe coronavirus (COVID-19) pandemic has confronted millions of people around the world with an unprecedented stressor, affecting physical and mental health. Accumulating evidence suggests that emotional and cognitive self-regulation is particularly needed to effectively cope with stress. Therefore, we investigated the predictive value of affective and inhibitory prefrontal control for stress burden during the COVID-19 crisis.

MethodPhysical and mental health burden were assessed using an online survey, which was administered to 104 participants of an ongoing German at-risk birth cohort during the first wave in April 2020. Two follow-ups were carried out during the pandemic, one capturing the relaxation during summer and the other the beginning of the second wave of the crisis. Prefrontal activity during emotion regulation and inhibitory control were assessed prior to the COVID-19 crisis.

ResultsIncreased inferior frontal gyrus activity during emotion regulation predicted lower stress burden at the beginning of the first and the second wave of the crisis. In contrast, inferior and medial frontal gyrus activity during inhibitory control predicted effective coping only during the summer, when infection rates decreased but stress burden remained unchanged. These findings remained significant when controlling for sociodemographic and clinical confounders such as stressful life events prior to the crisis or current psychopathology.

ConclusionsWe demonstrate that differential stress-buffering effects are predicted by the neural underpinnings of emotion regulation and cognitive regulation at different stages during the pandemic. These findings may inform future prevention strategies to foster stress coping in unforeseen situations.

HighlightsO_LIHealth threatening stressors, such as the COVID-19 pandemic, significantly worsen well-being.
C_LIO_LIResults reveal high levels of stress during the course of the pandemic with an increase of stress burden towards the second wave.
C_LIO_LISelf-regulation is an important coping strategy to restore allostasis.
C_LIO_LIHigher prefrontal activity during emotion regulation predicted less stress during the peaks of infection rates in the first and second wave
C_LIO_LIHigher prefrontal inhibitory control predicted less stress burden between both waves when infection rates were low.
C_LIO_LIOur findings highlight the importance of prefrontal regulation as effective coping mechanisms in the face of unprecedented stressors.
C_LI


title: SARS-CoV-2 antibody prevalence in Sierra Leone, March 2021: a cross-sectional, nationally representative, age-stratified serosurvey

abstract:
BackgroundAs of 26 March 2021, the Africa CDC had reported 4,159,055 cases of COVID-19 and 111,357 deaths among the 55 African Union Member States; however, no country has published a nationally representative serosurvey as of May 2021. Such data are vital for understanding the pandemics progression on the continent, evaluating containment measures, and policy planning.

MethodsWe conducted a cross-sectional, nationally representative, age-stratified serosurvey in Sierra Leone in March 2021 by randomly selecting 120 Enumeration Areas throughout the country and 10 randomly selected households in each of these. One to two persons per selected household were interviewed to collect information on socio-demographics, symptoms suggestive of COVID-19, exposure history to laboratory-confirmed COVID-19 cases, and history of COVID-19 illness. Capillary blood was collected by fingerstick, and blood samples were tested using the Hangzhou Biotest Biotech RightSign COVID-19 IgG/IgM Rapid Test Cassette. Total seroprevalence was was estimated after applying sampling weights.

FindingsThe overall weighted seroprevalence was 2.6% (95% CI 1.9-3.4). This is 43 times higher than the reported number of cases. Rural seropositivity was 1.8% (95% CI 1.0-2.5), and urban seropositivity was 4.2% (95% CI 2.6-5.7).

InterpretationAlthough overall seroprevalence was low compared to countries in Europe and the Americas (suggesting relatively successful containment in Sierra Leone), our findings indicate enormous underreporting of active cases. This has ramifications for the countrys third wave (which started in June 2021), where the average number of daily reported cases was 87 by the end of the month--this could potentially be on the order of 3,700 actual infections, calling for stronger containment measures in a country with only 0.2% of people fully vaccinated. It may also reflect significant underreporting of incidence and mortality across the continent.

FundingThis study was supported by NIAID K08 AI139361, the Sierra Leone Ministry of Health and Sanitation, and the Africa CDC.

category: public and global health


title: COVID-19 vaccines and evidence-based medicine

abstract:
OBJECTIVETo clarify efficacy, effectiveness, and harm of available vaccines for COVID-19, using measures in evidence-based medicine (EBM) that, in addition to relative risk reduction, consider absolute risk reduction and variations in baseline risks.

DESIGNSystematic review of studies that have considered impacts of vaccines in relation to baseline risks. Calculation of risk reduction and harms from published data in two random controlled trials and one population-based implementation study. Analysis of risk reductions in geographical areas with varying baseline risks. Comparison of results concerning COVID-19 vaccine and selected prior vaccines.

SETTINGRandom controlled trials of Pfizer and Moderna vaccines in multiple countries; population-based study using Pfizer vaccine in Israel. Counties with varying baseline risks in the United States; states with varying baseline risks in India.

PARTICIPANTS43,448 and 30,420 subjects in the random controlled trials; 1,198,236 subjects in the population-based study.

INTERVENTIONSMulti-site random controlled trials of vaccine efficacy; population-based administration of vaccine with determination of effectiveness by comparison of vaccinated and unvaccinated subjects.

MAIN OUTCOME MEASURESRelative risk reduction (RRR), absolute risk reduction (ARR), number needed to be vaccinated to prevent one symptomatic infection (NNV), absolute risk of the intervention (ARI), and number needed to harm (NNH).

RESULTSA systematic review of literature in medicine and public health showed very few reports regarding ARR, NNV, ARI, and NNH; use of these indicators to compare benefits versus harms; or analysis of these EBM indicators in the context of varying baseline risks. From data in the two random controlled trials and one population-based study, calculated ARR was approximately 1 percent (as compared to RRR of 50 to 95 percent), and NNV was in the range of 100 to 500. In comparisons of ARR and NNV versus ARI and NNH, benefits and harms were not markedly different. From a sensitivity analysis of ARR and NNV in population groups with varying baseline risks, the effectiveness of vaccines as measured by ARR and NNV was substantially higher in regions with high as compared to low baseline risks. The ARR for COVID-19 vaccines was somewhat smaller and the NNV somewhat larger than achieved by some vaccines to prevent influenza and smallpox.

CONCLUSIONThe efficacy and effectiveness of major COVID-19 vaccines, as measured by RRR, are impressive. As measured by ARR and NNV, which take into account variation in baseline risks, the effectiveness of the vaccines is substantially higher in areas with higher baseline risks. This finding can contribute to educational efforts, informed consent procedures, and policy making about priorities for vaccine distribution, especially under conditions of access barriers linked to poverty and inequality.

WHAT IS ALREADY KNOWN ON THIS TOPICMajor COVID-19 vaccines so far have shown impressive efficacy in random controlled trials and effectiveness in population-based studies. To determine efficacy and effectiveness, these studies have used relative risk reduction (RRR), which shows the difference in event rate between those receiving and not receiving a vaccine. Reports of efficacy and effectiveness have not yet clarified other key indicators from evidence-based medicine (EBM) that consider variations baseline risks. Such indicators include measures of benefits such as absolute risk reduction (ARR) and number needed to be vaccinated (NNV), as well as measures of harm such as absolute risk of the intervention (ARI) and number needed to harm (NNH).

WHAT THIS STUDY ADDSFor COVID-19 vaccines, calculated ARR is somewhat lower and NNV somewhat higher than for certain prior vaccines such as those for influenza and smallpox. Indicators of harm for COVID-19 vaccines, as measured by ARI and NNH, appear to be in the same order of magnitude as indicators of benefit such as ARR and NNV. The effectiveness of COVID-19 vaccines, as measured by ARR and NNV, is substantially higher in geographical areas with high baseline risk, compared to areas with low baseline risk.

These findings can assist in informed consent procedures, educational efforts, and priority setting in policies about distribution of vaccines, especially in the context of access barriers related to poverty and inequality.


title: The health impacts of a 4-month long community-wide COVID-19 lockdown: Findings from a prospective longitudinal study in the state of Victoria, Australia.

abstract:
ObjectivesTo determine health impacts during, and following, an extended community lockdown and COVID-19 outbreak in the Australian state of Victoria, compared with the rest of Australia.

MethodsA national cohort of 898 working-age Australians enrolled in a longitudinal cohort study, completing surveys before, during, and after a 112-day community lockdown in Victoria (8 July - 27 October 2020). Outcomes included psychological distress, mental and physical health, work, social interactions and finances. Regression models examined health changes during and following lockdown.

ResultsThe Victorian lockdown led to increased psychological distress. Health impacts coincided with greater social isolation and work loss. Following the extended lockdown, mental health, work and social interactions recovered to an extent whereby no significant long-lasting effects were identified in Victoria compared to the rest of Australia.

ConclusionThe Victorian community lockdown had adverse health consequences, which reversed upon release from lockdown. Governments should weigh all potential health impacts of lockdown. Services and programs to reduce the negative impacts of lockdown may include increases in mental health care, encouraging safe social interactions and supports to maintain employment relationships.


title: Nowcasting food insecurity on a global scale

abstract: Lack of regular physical or economic access to safe, nutritious and sufficient food is a critical issue affecting millions of people world-wide. Estimating how many and where these people are is of fundamental importance for governments and humanitarian organizations to take informed and timely decisions on relevant policies and programmes. In this study, we propose a machine learning approach to predict the prevalence of people with insufficient food consumption and of people using crisis or above crisis food-based coping when primary data is not available. Making use of a unique global data set, we show that the proposed models can explain up to 78% of the variation in insufficient food consumption and crisis or above food-based coping levels. We also show that the proposed models can be used to nowcast the food security situation in near-real time and propose a method to identify which variables are driving the changes observed in predicted trends, which is key to make predictions serviceable to decision makers.

category: nutrition


title: The Role of CRP, Interleukin-6 and Their Derived Immune-Inflammatory Indices in Early Prediction of Severity and Mortality of COVID-19 Patients

abstract:
BackgroundIn coronavirus disease 2019 (COVID-19), finding sensitive biomarkers is critical for detecting severe cases early and intervening effectively.

ObjectivesTo compare and evaluate the predictive value of C-reactive protein (CRP), interleukin-6 (IL-6), and their derived immune-inflammatory indices (CRP/albumin (CRP/alb), lymphocyte/CRP (L/CRP), and lymphocyte/IL-6 (L/IL-6)) in COVID-19 patients.

MethodsOn admission, 85 confirmed COVID-19 patients, their measured and collected laboratory data were obtained and compared.

ResultsLevels of CRP, IL-6, and CRP/alb were significantly higher (P=0.001) in severe patients and non-survivors, but L/CRP and L/IL-6 were significantly lower (P=0.001). We observed the best predictive performance for COVID-19 severity at 1.65 for CRP/alb and 260.86 for L/CRP with 84.7% diagnostic accuracy for both. The best diagnostic accuracy for COVID-19 in-hospital mortality was 87.1% by IL-6 at 120 pg/ml and 85.9% by L/IL-6 at 5.40. The multi-marker prediction surpassed the performance of a single biomarker prediction. IL-6 was an independent risk factor associated with severe disease development (odds ratio (OR): 1.033; 95% confidence interval (CI): 1.002-1.066).

ConclusionsPretreatment values of CRP, IL-6, and their derived indices could be included in the diagnostic work-up of COVID-19 to determine the severity and predict the outcome.

category: infectious diseases


title: SARS-CoV-2 Seroprevalence among First Responders in Northeastern Ohio

abstract:
ObjectivesFirst responders including firefighters, emergency medical technicians (EMT), paramedics, and police officers are working on the front lines to fight the COVID-19 pandemic and facing a higher risk of infection. This study assessed the seroprevalence among first responders in northeastern Ohio during May-September 2020.

MethodsA survey and IgG antibody test against SARS-CoV-2 were offered to University Hospitals Health System affiliated first responder departments.

ResultsA total of 3080 first responders with diverse job assignments from more than 400 fire and police departments participated in the study. Among them, 73 (2.4%) were seropositive while only 0.8% had previously positive RT-PCR results. Asymptomatic infection accounts for 46.6% of seropositivity. By occupation, seropositive rates were highest among administration/support staff (3.8%), followed by paramedics (3.0%), EMTs (2.6%), firefighters (2.2%), and police officers (0.8%). Seroprevalence was not associated with self-reported exposure as work exposure rates were: paramedics 48.2%, firefighters 37.1%, EMTs 32.3%, police officers 7.7%, and administration/support staff 4.4%. Self-reported community exposure was strongly correlated with self-reported work exposure rate rather than seroprevalence suggesting a potential impact of risk awareness. Additionally, no significant difference was found among gender or age groups; however, black Americans have a higher positivity rate than other races although they reported lower exposure.

ConclusionsDespite the high work-associated exposure rate to SARS-CoV-2 infection, first responders with different roles demonstrated seroprevalence no higher than their administrative/supportive colleagues, which suggests infection control measures are effective in preventing work-related infection.


title: Trajectories of hospitalisation for patients infected with SARS-CoV-2 variant B.1.1.7 in Norway, December 2020 - April 2021

abstract:
BackgroundThe SARS-CoV-2 variant of concern (VOC) B.1.1.7 has spread worldwide and has been associated with increased risk of severe disease. Studies on patient trajectories and outcomes among hospitalised patients infected with B.1.1.7 are essential for hospital capacity planning.

MethodsUsing linked individual-level data from national registries, we conducted a cohort study on cases of SARS-CoV-2 in Norway hospitalised between 21 December 2020 and 25 April 2021. We calculated adjusted hazard ratios using survival analysis to examine the association between B.1.1.7 and time from symptom onset to hospitalisation, and length of stay (LoS) in hospital and an intensive care unit compared to non-VOC. We calculated adjusted odds ratios using logistic regression to examine the association between B.1.1.7 and mortality (up to 30 days post discharge) compared to non-VOC.

ResultsWe included 946 B.1.1.7 patients and 157 non-VOC. The crude median time from symptom onset to hospitalisation was 8 days (IQR: 5-10) for B.1.1.7 and 8 days (IQR: 4-11) for non-VOC. The crude median LoS in hospital was 5.0 days (IQR: 2.6-10.0) for B.1.1.7 patients and 5.1 days (IQR: 2.5-9.9) for non-VOC. Fifty-four (6%) B.1.1.7 patients died, compared to 14 (9%) non-VOC. There was no difference in the unadjusted or adjusted estimates of our outcome measures for B.1.1.7 and non-VOC patients.

ConclusionsB.1.1.7 does not appear to influence hospitalised patient trajectories, compared to non-VOC. These findings, along with the success of ongoing vaccination programmes, are encouraging for ongoing capacity planning in the hospital sector.


title: Heterogeneity of hypoxemia severity according to oxygenation index in COVID-19 pneumonia

abstract:
ObjectiveTo compare hypoxemia severity of patients with COVID-19 pneumonia that arrive at an emergency department as classified by three oxygenation indexes.

DesignRetrospective analysis of pulse oximeter saturation and arterial blood gas analysis obtained at arrival.

SettingTertiary referral hospital in Mexico City converted early in the pandemic to a COVID-19 center.

Patients and measurementsA total of 2,960 patients with suspected COVID-19 pneumonia were admitted to the emergency department from April 2020 until March 2021. Pulse oximeter saturation and arterial blood gas analysis was obtained in all of them. Pulse oximeter saturation (SpO2) to inspired oxygen fraction ratio (FiO2), oxygen saturation in arterial blood (SatO2) to FiO2 ratio, and oxygen pressure in arterial blood to FiO2 ratio were calculated for every patient.

InterventionsNone.

Main ResultsA strong correlation was seen between PaO2/FiO2 & SpO2/FiO2 (rho = 0.6, p < 0.001), and SatO2/FiO2 & SpO2/FiO2 (rho = 0.65, p < 0.001), while a very strong correlation was seen between PaO2/FiO2 & SatO2/FiO2 (rho = 0.88, p < 0.001). When classifying severity by quantiles, considerable cross-over was observed when comparing oxygenation indexes, as only 785 (26.5%) patients were in the same quintile across the three indexes.

ConclusionsHypoxemia severity is heterogeneous according to the oxygenation index utilized. This limits their usefulness as sole markers of severity, as inter-observer variability, especially on FiO2 estimation, and different practices limit consistent follow up and treatment decisions.

category: intensive care and critical care medicine


title: Joint estimation of relaxation and diffusion tissue parameters for prostate cancer grading with relaxation-VERDICT MRI

abstract:
PurposeThe Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumours (VERDICT) technique has shown promise discriminating normal from prostate cancer (PCa) tissue and Gleason grade 3+3 from 3+4. However, VERDICT currently doesnt account for the inherent relaxation properties of the tissue that could add complementary information and potentially enhance its diagnostic power. The aim of this work is to introduce relaxation-VERDICT (rVERDICT) for prostate, a model for the joint estimation of diffusion and relaxation parameters.

Methods72 men with suspected PCa underwent multiparametric MRI (mp-MRI) and VERDICT MRI. Among these, 44 underwent targeted biopsy and were analysed with rVERDICT using deep neural networks for fast fitting ([~]60 times faster than non-linear least squares minimisation approach). A convolutional neural network classifier assessed the rVERDICT parameters in differentiating Gleason grades measured with accuracy, F1-score and Cohens kappa. To assess repeatability, five men were imaged twice.

ResultsThere were 37 cancer lesions: 6 Gleason 3+3, 18 Gleason 3+4, and 13 Gleason [≥]4+3. The rVERDICT intracellular volume fraction fic discriminated between Gleason 3+3 and 3+4 (p=0.003); Gleason 3+4 and [≥]4+3 (p=0.040); and between 5-class Gleason grades with (accuracy, F1-score,kappa)=(8,7,3) percentage points higher than classic VERDICT, and (12,13,24) percentage points higher than the ADC from mp-MRI. Repeatability of rVERDICT parameters was high (R2=0.79-0.98,CV=1%-7%,ICC=92%-98%). T2 values estimated with rVERDICT were not significantly different from those estimated with an independent multi-TE acquisition (p>0.05).

ConclusionrVERDICT allows for accurate, fast and repeatable estimation of diffusion and relaxation properties of PCa and enables discriminating Gleason grade groups.

category: oncology


title: Change in disease dynamics and health care utilization in children during COVID19 in a tertiary care hospital of Eastern India.

abstract: This retrospective, observational study was conducted by collecting data from medical records during COVID 19 pandemic from March 2020 till August 2020. This was compared with the data of 2019 during similar months. The impact of COVID 19 on use of preventive and curative paediatric health care service units like outpatient department, casualty, intensive care and immunization clinic were assessed. Data from 2019 to 2020 were compared using standard parametric and nonparametric tests. There was a significant decline in routine OPD (68%) attendance during the COVID 19 period as compared to pre-COVID period. Paediatric ward admissions and PICU admissions were decreased by 55% and 42% respectively. We also observed a significant 43% decline in the number of children attending immunization clinic in the year 2020. The fear of COVID 19 pandemic and the measures taken to control the pandemic has affected the health seeking behaviour of patients. This evaluation of trends in healthcare use may help in planning the delivery of healthcare service delivery in future.

category: health systems and quality improvement


title: Genomic epidemiology of SARS-CoV-2 in Pakistan

abstract: Pakistan has been severely affected by the COVID-19 pandemic. To investigate the initial introductions and transmissions of the SARS-CoV-2 in the country, we performed the largest genomic epidemiology study of COVID-19 in Pakistan and generated 150 complete SARS-CoV-2 genome sequences from samples collected before June 1, 2020. We identified a total of 347 variants, 29 of which were over-represented in Pakistan. Meanwhile, we found over one thousand intra-host single-nucleotide variants. Several of them occurred concurrently, indicating possible interactions among them. Some of the hypermutable positions were not observed in the polymorphism data, suggesting strong purifying selections. The genomic epidemiology revealed five distinctive spreading clusters. The largest cluster consisted of 74 viruses which were derived from different geographic locations and formed a deep hierarchical structure, indicating an extensive and persistent nation-wide transmission of the virus that was probably contributed by a signature mutation of this cluster. Twenty-eight putative international introductions were identified, several of which were consistent with the epidemiological investigations. No progenies of any of these 150 viruses have been found outside of Pakistan, most likely due to the nonphmarcological intervention to control the virus. This study has inferred the introductions and transmissions of SARS-CoV-2 in Pakistan, which could provide a guidance for an effective strategy for disease control.


title: Low frequency of community-acquired bacterial co-infection in patients hospitalized for COVID-19 based on clinical, radiological and microbiological criteria; a retrospective cohort study.

abstract:
BackgroundTo define the frequency of respiratory community-acquired bacterial co-infection in patients with coronavirus disease 2019 (COVID-19) based on a complete clinical assessment, including prior antibiotic use, clinical characteristics, inflammatory markers, chest computed tomography (CT) results and microbiological test results.

MethodsThis study was conducted within a cohort of prospectively included patients admitted for COVID-19 in our tertiary medical centres between 1-3-2020 and 1-6-2020. A multidisciplinary study team developed a diagnostic protocol to retrospectively categorize patients as unlikely, possible or probable bacterial co-infection based on clinical, radiological and microbiological parameters in the first 72 hours of admission. Within the three categories, we summarized patient characteristics and antibiotic consumption.

ResultsAmong 281 included COVID-19 patients, bacterial co-infection was classified as unlikely in 233 patients (82.9%), possible in 35 patients (12.4%) and probable in 3 patients (1.1%). Ten patients (3.6%) could not be classified due to inconclusive data. Within 72 hours of hospital admission, 81% of the total study population and 78% of patients classified as unlikely bacterial co-infection received antibiotics.

ConclusionsCOVID-19 patients are unlikely to have a respiratory community-acquired bacterial co-infection. Prospective studies should define the safety of restrictive antibiotic use in COVID-19 patients.


title: Transcranial direct current stimulation combined with alcohol cue inhibitory control training reduces the risk of early alcohol relapse: a randomized placebo-controlled clinical trial

abstract:
BackgroundApproximately half the people with alcohol use disorder (AUD) relapse into alcohol reuse in the few weeks following withdrawal treatment. Brain stimulation and cognitive training represent recent forms of complementary interventions in the context of AUD.

ObjectiveTo evaluate the clinical efficacy of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) combined with alcohol cue inhibitory control training (ICT) as part of rehabilitation.

MethodsA randomized clinical trial was conducted on patients (n=125) withsevere AUD at a withdrawal treatment unit. Each patient was randomly assigned to one of four conditions, in a 2 [verum vs. sham tDCS] x 2 [alcohol cue vs. neutral ICT] factorial design. The primary outcome of the treatment was the measured abstinence rate after two weeks or more (up to one year).

ResultsVerum tDCS improved the abstinence rate at the 2-week follow-up compared to the sham condition, independently of the training condition (79.7% [95% CI = 69.8-89.6] vs. 60.7% [95% CI = 48.3-73.1]; p = 0.02). A priori contrasts analyses revealed higher abstinence rates for the verum tDCS associated with alcohol cue ICT (86.1% [31/36; 95% CI= 74.6-97.6]) than for the other three conditions (64% [57/89; 95% CI = 54-74]). These positive clinical effects on abstinence did not persist beyond two weeks after the intervention.

ConclusionsAUD patients who received tDCS applied to DLPFC showed a significantly higher abstinence rate during the weeks following rehabilitation. When combined with alcohol-specific ICT, brain stimulation may provide better clinical outcomes.

Trial RegistrationClinicalTrials.gov number NCT03447054

category: addiction medicine


title: Thyroid function and risk of anemia: a multivariable-adjusted and Mendelian Randomization analysis in the UK Biobank

abstract:
ContextThyroid dysfunction is associated with higher anemia prevalence, though causality remains unclear.

ObjectiveTo investigate a potential causal relationship between thyroid function and anemia.

DesignCross-sectional and Mendelian Randomization study

SettingEuropeans from UK Biobank

Participants445,482 participants, mean age 56.77 years (SD 8.0) and 54.2% were women. Self-reported clinical diagnosis of hypothyroidism was stated by 21,860 (4.9%); self-reported clinical diagnosis of hyperthyroidism by 3,431 (0.8%).

Main Outcome MeasureAnemia, defined as hemoglobin level of <13 g/dL in men and <12 g/dL in women, was present in 18,717 (4.2%) participants.

ResultsIn cross-sectional logistic regression analyses, self-reported clinical diagnoses of hypo- and hyperthyroidism were associated with higher odds of anemia (OR 1.12, 95%CI 1.05-1.19 and OR 1.09, 95%CI 0.91-1.30), though with wide confidence intervals for hyperthyroidism. Although we considered a possible non-linear relationship, we did not observe an association of higher or lower genetically-influenced thyrotropin (TSH) with anemia (versus middle tertile: OR lowest tertile 0.98, 95% CI 0.95-1.02; highest tertile 1.02, 95% CI 0.98-1.06), nor of genetically-influenced free thyroxine (fT4) with anemia. Individuals with genetic variants in the DIO3OS gene implicated in intracellular regulation of thyroid hormones had a higher anemia risk (OR 1.05, 95% CI 1.02-1.10); no association was observed with variants in DIO1 or DIO2 genes.

ConclusionsWhile self-reported clinical diagnosis of hypothyroidism was associated with a higher prevalence of anemia, we did not found evidence supporting this association was causal. However, intracellular regulation of thyroid hormones might play a role in developing anemia.

category: endocrinology


title: Use of the Elimination Strategy in Response to the COVID-19 Pandemic: Health and Economic Impacts for New Zealand Relative to Other OECD Countries

abstract:
BackgroundIn response to the COVID-19 pandemic, some countries in the Asia-Pacific Region used very intensive control measures, and one of these, New Zealand (NZ), adopted a clear "elimination strategy". We therefore aimed to compare key health and economic outcomes of NZ relative to OECD countries as of mid-June 2021.

MethodsThis analysis compared health outcomes (cumulative death rates from COVID-19 and "excess death" rates) and economic measures (quarterly GDP and unemployment levels) across OECD countries.

ResultsNZ had the lowest cumulative COVID-19 death rate in the OECD at 242 times lower than the 38-OECD-country average: 5{middle dot}2 vs 1256 per million population. When considering "excess deaths", NZ had the largest negative value in the OECD, equivalent to around 2000 fewer deaths than expected. When considering the average GDP change over the five quarters of 2020 to 2021-Q1, NZ was the sixth best performer (at 0{middle dot}5% vs -0{middle dot}3% for the OECD average). The increase in unemployment in NZ was also less than the OECD average (1{middle dot}1 percentage points to a peak of 5{middle dot}2%, vs 3{middle dot}3 points to 8{middle dot}6%, respectively).

ConclusionsNew Zealands elimination strategy response to COVID-19 produced the best mortality protection outcomes in the OECD. In economic terms it also performed better than the OECD average in terms of adverse impacts on GDP and employment. Nevertheless, a fuller accounting of the benefits and costs needs to be done once the population is vaccinated and longer-term health and economic outcomes are considered.

category: epidemiology


title: COVID-19 in Children with Down Syndrome: Data from the Trisomy 21 Research Society Survey

abstract:
ImportanceAdults with Down syndrome (DS) are at higher risk for severe outcomes of coronavirus disease 2019 (COVID-19), but further evidence is required to determine the exact risks for children with DS. The clinical features and epidemiological characteristics of COVID-19 in children with DS, and risk factors for severe outcomes, must be established to inform COVID-19 shielding advice and vaccination priority.

ObjectiveTo determine risk factors for a severe course of COVID-19 in pediatric DS patients and to compare the prevalence of severe COVID-19 between pediatric patients with and without DS.

DesignThis retrospective cohort study included pediatric cases (aged <18 years) with DS from the Trisomy 21 Research Society international survey and pediatric cases from the general population published by the US Centers for Disease Control and Prevention (COVID-NET) collected during the first wave of the COVID-19 pandemic (controls).

SettingCohorts included 328 children with DS (127 hospitalized, 39%) and 224 children without DS (all hospitalized) with COVID-19. Of the pediatric DS patients, 64.1% were from low-to-middle-income countries (LMICs), and 35.9% from high-income countries (HICs).

ParticipantsClinicians, family members, or caregivers completed the survey on behalf of children with DS affected by COVID-19.

ResultsAmong the 328 COVID-19 patients with DS; older age, obesity, and epilepsy were significant risk factors for hospitalization; and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. The 127 hospitalized COVID-19 patients with DS had a higher incidence of cough, fever, nasal signs and shortness of breath than controls. Compared with controls, hospitalized children with DS (especially those from LMICs) had a higher prevalence of COVID-19-related medical complications (pneumonia, ARDS, acute renal failure).

Conclusions and relevanceChildren with DS are at higher risk for severe COVID-19 than the general pediatric population. Efforts should be made to monitor the health of children and young people with DS during the ongoing pandemic and to report any COVID-19 signs and symptoms in a timely manner, especially for those who have comorbidities which are risk factors for severe COVID-19. When vaccination rollout for pediatric populations begins, children with DS should be prioritised.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the epidemiological and clinical characteristics of coronavirus disease 2019 (COVID-19) in paediatric patients with Down syndrome (DS)?

FindingsHospitalised COVID-19 patients <18 years of age with DS from a range of countries had a higher incidence of respiratory symptoms, fever, and several medical complications from COVID-19 than patients without DS <18 years from the United States (US). Older age, obesity, and epilepsy were significant risk factors for hospitalisation among paediatric COVID-19 patients with DS; and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. Mortality rates were low in all paediatric COVID-19 patients (with and without DS), in contrast to previous findings in adults with DS (who exhibit higher mortality than those without DS).

SignificanceChildren with DS are at increased risk for more severe presentations of COVID-19. Efforts should be made to ensure comprehensive and early detection of COVID-19 in this population, and to identify children with DS who present comorbidities that pose a risk for a severe course of COVID-19. Children with DS should be prioritised for COVID-19 vaccination as part of childrens vaccination programmes.


title: COVID-19 Flow-Maps: An open geographic information system on COVID-19 and human mobility for Spain

abstract: COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, which has spread all over the world leading to a global pandemic. The fast progression of COVID-19 has been mainly related to the high contagion rate of the virus and the worldwide mobility of humans. In the absence of pharmacological therapies, governments from different countries have introduced several non-pharmaceutical interventions to reduce human mobility and social contact. Several studies based on Anonymised Mobile Phone Data have been published analysing the relationship between human mobility and the spread of coronavirus. However, to our knowledge, none of these data-sets integrates cross-referenced geo-localised data on human mobility and COVID-19 cases into one all-inclusive open resource. Herein we present COVID-19 Flow-Maps, a cross-referenced Geographic Information System that integrates regularly updated time-series accounting for population mobility and daily reports of COVID-19 cases in Spain at different scales of time spatial resolution. This integrated and up-to-date data-set can be used to analyse the human dynamics to guide and support the design of more effective non-pharmaceutical interventions.


title: Gut microbiome diversity measures for metabolic conditions: a systematic scoping review

abstract:
ObjectiveEvidence on the association between the gut microbiome and metabolic conditions has been increasing during the past decades. Unlike the straightforward identification of beneficial non-pathogenic bacteria as a potential probiotic for clinical use, the analysis of gut microbiome diversity is more complex and required a better understanding of various measures. We aim to summarize an elaborated list of gut microbiome diversity measures.

DesignSystematic search was conducted in three databases: PubMed, Embase, and Cochrane Central Register of Clinical Trials for randomized controlled trials, quasi-experimental and observational studies for the relationship between gut microbiota and metabolic diseases published in 2019 with the English language.

ResultsThe measurement methods of alpha diversity and beta diversity were explored. Of 5929 potential studies, 47 were included in the systematic review (14632 patients). Of 13 alpha diversity measures, the Shannon index was the most commonly used in 37 studies (78.7%), followed by Chao1 index (19 studies), Operational Taxonomic Unit (OTU) richness (15 studies), Simpson index (13 studies), and Abundance-based Coverage Estimators (ACE) index (10 studies). Of 2 beta diversity measures, the UniFrac was the most commonly used in 24 studies (unweighted 17 studies and weighted 16 studies), followed by Bray-Curtis dissimilarity (16 studies).

ConclusionVarious measurement of gut microbiome diversity have been used in the literature. All measurements have unique characteristics, advantages, and disadvantages which lead to different usage frequency. The measures were chosen considering cost, simplicity, and types of research.

Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABS{blacktriangleright} Alpha diversity, including Shannon index diversity, chao1 diversity, etc., is the average species diversity within a habitat type at a local scale while beta-diversity, such as Bray-Curtis dissimilarity and UniFrac, indicates the differentiation between microbial communities from different environments.
{blacktriangleright}Alpha- and beta-diversity are the two most diverse measures of gut microbiota diversity with no consensus on which measurement methods should be used in metabolic condition study.

What are the new findings?{blacktriangleright} Distinct characteristics, advantages, and disadvantages of each microbiome diversity measurement method lead to a variety of usage frequencies in metabolic condition studies. Shannon diversity is the most widely used alpha diversity while there is no predilection for beta diversity.

How might it impact on clinical practice in the foreseeable future?{blacktriangleright} Further researchers on metabolic condition with microbiome diversity measurement will have impartial evidence on which measurement methods are most rationally appropriate for their studies regarding simplicity, cost, and efficacy.

category: gastroenterology


title: Safeguarding Adolescent Mental Health in India (SAMA): study protocol for co-design and feasibility study of a school systems intervention targeting adolescent anxiety and depression in India.

abstract:
IntroductionSymptoms of anxiety and depression in Indian adolescents are common. Schools can be opportune sites for delivery of mental health interventions. India, however, is without a whole-school mental health approach. This article describes the study design for the Safeguarding Adolescent Mental Health in India (SAMA) project. The aim of SAMA is to co-design and feasibility test a suite of multi-component interventions across the intersecting systems of adolescents, schools, families and their local communities in India.

Methods and analysisOur project will co-design and feasibility test four interventions to run in parallel in eight schools (three assigned to waitlist) in Bengaluru and Kolar in Karnataka, India. The primary aim is to reduce the prevalence of adolescent anxiety and depression. Co-design of interventions will build on existing evidence and resources. Interventions for adolescents at school will be universal, incorporating curriculum and social components. Interventions for parents and teachers will target mental health literacy, and also for teachers, training in positive behaviour practices. Intervention in the school community will target school climate to improve student mental health literacy and care. Intervention for the wider community will be via adolescent-led films and social media. We will generate intervention cost estimates, test outcome measures and identify pathways to increase policy action on the evidence.

Ethics and disseminationEthical approval has been granted by the National Institute of Mental Health Neurosciences Research Ethics Committee (NIMHANS/26th IEC (Behv Sc Div / 2020/2021)) and the University of Leeds School of Psychology Research Ethics Committee (PSYC-221). Certain data will be available on a data sharing site. Findings will be disseminated via peer-reviewed journals and conferences.

Article SummaryO_ST_ABSStrengths and LimitationsC_ST_ABSO_LIA key strength of this study is its focus on depression and anxiety prevention, both of which are the common adolescent mental health problems in India.
C_LIO_LIThe study utilises a public mental health systems approach, which adopts a  person-in-context perspective and recognises multiple determinants of mental health.
C_LIO_LIExtensive co-design of interventions will promote cultural relevance and acceptability by key stakeholders, including adolescents, teachers, parents and school communities.
C_LIO_LIThe Covid-19 pandemic makes this research more pertinent but may affect recruitment of the schools / adolescents or may lead to participation bias if the study processes are conducted online by excluding those with limited access or who lack technical skills.
C_LIO_LIThe opt-in approach to consent may lead to participation bias.
C_LI


title: Communicating about COVID-19 vaccine development and safety

abstract:
PurposeBeliefs that the risks from the vaccine outweigh the risks from getting COVID-19 and concerns that the vaccine development process was rushed and lacking rigor have been identified as important drivers of hesitancy and refusal to get a COVID-19 vaccine. We tested whether messages designed to address these beliefs and concerns might promote intentions to get a COVID-19 vaccine.

MethodAn online survey fielded between March 8-March 23, 2021 with US Veteran (n=688) and non-Veteran (n=387) respondents. In a between-subjects experiment, respondents were randomly assigned to a control group (with no message) or to read one of two intervention messages: 1. a fact-box styled message comparing the risks of getting COVID-19 compared to the vaccine, and 2. a timeline styled message describing the development process of the COVID-19 mRNA vaccines.

ResultsMost respondents (60%) wanted a COVID-19 vaccine. However, 17% expressed hesitancy and 23% did not want to get a COVID-19 vaccine. The fact-box styled message and the timeline message did not significantly improve vaccination intentions, F(2,358)=0.86, p=.425, [Formula], or reduce the time respondents wanted to wait before getting vaccinated, F(2,306)=0.79, p=.453, [Formula], compared to no messages.

DiscussionWe did not find an impact on vaccine intention based on providing information about vaccine risks and development. Further research is needed to identify how to effectively address concerns about the risks associated with COVID-19 vaccines and the development process and to understand additional factors that influence vaccine intentions.


title: Moderate-Intensity Exercise Versus High-Intensity Interval Training to Recover Walking Post-Stroke: Protocol for a Randomized Controlled Trial

abstract:
BackgroundStroke results in neurologic impairments and aerobic deconditioning that contribute to limited walking capacity which is a major barrier post-stroke. Current exercise recommendations and stroke rehabilitation guidelines recommend moderate-intensity aerobic training post-stroke. Locomotor high-intensity interval training is a promising new strategy that has shown significantly greater improvements in aerobic fitness and motor performance than moderate-intensity aerobic training in other populations. However, the relative benefits and risks of high-intensity interval training and moderate-intensity aerobic training remain poorly understood following stroke. In this study, we hypothesize that locomotor high-intensity interval training will result in greater improvements in walking capacity than moderate-intensity aerobic training.

MethodsUsing a single-blind, 3-site randomized controlled trial, 50 chronic (>6 months) stroke survivors are randomly assigned to complete 36 locomotor training sessions of either high-intensity interval training or moderate-intensity aerobic training. Main eligibility criteria are: age 40-80 years, single stroke for which the participant received treatment (experienced 6 months to 5 years prior to consent), walking speed [≤]1.0 m/s, able to walk at least 3 minutes on the treadmill at [≥] 0.13 m/s (0.3 mph), stable cardiovascular condition (American Heart Association class B), and the ability to walk 10 meters overground without continuous physical assistance. The primary outcome (walking capacity) and secondary outcomes (self-selected and fast gait speed, aerobic fitness and fatigue) are assessed prior to initiating training and after 4 weeks, 8 weeks, and 12 weeks of training.

DiscussionThis study will provide fundamental new knowledge to inform the selection of intensity and duration dosing parameters for gait recovery and optimization of aerobic training interventions in chronic stroke. Data needed to justify and design a subsequent definitive trial will also be obtained. Thus, the results of this study will inform future stroke rehabilitation guidelines on how to optimally improve walking capacity following stroke.

Trial RegistrationClinicalTrials.gov Identifier: NCT03760016. First posted: November 30, 2018. https://clinicaltrials.gov/ct2/show/NCT03760016

category: rehabilitation medicine and physical therapy


title: A Retrospective analysis of DIC score and SIC score in prediction of COVID-19 severity

abstract:
BackgroundThe novel Disseminated Intravascular Coagulation (DIC) score [platelet count, prolonged prothrombin time, D-dimer, and fibrinogen] and Sepsis Induced Coagulopathy (SIC) score [platelet count, International normalized ratio, and Sequential organ failure assessment score] are markers of coagulopathy, which, for the first time, are explored in line with the COVID-19 disease outcomes. The correlation of D-dimer with these findings is also studied.

Patients and methodsA retrospective analysis of hospital-based records of 168 COVID-19 patients. Data including D-dimer, routine investigations, DIC and SIC scorings (all within three days of admission) were collected and correlated with the outcomes. The study was conducted in a tertiary care center catering to population of North India.

ResultsHigher DIC score (1{middle dot}59 {+/-} 1{middle dot}18 v/s 0{middle dot}96 {+/-} 1{middle dot}18), SIC score (1{middle dot}60 {+/-} 0{middle dot}89 v/s 0{middle dot}63 {+/-} 0{middle dot}99), and D-dimer titers (1321{middle dot}33 {+/-} 1627{middle dot}89 v/s 583{middle dot}66 {+/-} 777{middle dot}71 ng/ml) were significantly associated with severe COVID-19 disease (P<0{middle dot}05). DIC score and SIC score [≥] 1, and D-dimer [≥] 1315 ng/ml for severe disease; DIC score [≥] 1, SIC score [≥] 2, and D-dimer [≥] 600 ng/ml for Pulmonary Embolism (PE); and DIC score and SIC score [≥] 1, and D-dimer level [≥] 990 ng/ml for mortality were the respective cut-off values we found from our study.

ConclusionHigher DIC scores, SIC scores, and D-dimer values are associated with severe COVID-19 disease, in-hospital mortality, and PE risk. They can serve as easily accessible early markers of severe disease and prioritize hospital admissions in the presently overburdened scenario, and may be used to develop prognostic prediction models.

HighlightsDIC scores, SIC scores, and D-dimer values are hereby studied in association with COVID-19 disease severity, in-hospital mortality, and PE risk. They serve as easily accessible early markers of severe disease and prioritize hospital admissions in the presently overburdened scenario, and may be used to develop prognostic prediction models.

category: respiratory medicine


title: Runners with chronic mid-portion Achilles tendinopathy have greater Triceps surae intracortical inhibition than healthy controls

abstract:
ObjectivesThis study aimed to investigate short-interval intracortical inhibition (SICI) and muscle function in the Triceps surae of runners with mid-portion Achilles tendinopathy (AT).

MethodsRunners with (n=11) and without (n=13) AT were recruited. Plantar flexor isometric peak torque and rate of torque development (RTD) were measured using an isokinetic dynamometer. Triceps surae endurance was measured as single leg heel raise (SLHR) to failure test. SICI was assessed using paired-pulse transcranial magnetic stimulation during a sustained contraction at 10% of plantar flexor isometric peak torque.

ResultsTriceps surae SICI was 14.3% (95%CI: -2.1 to 26.4) higher in AT than control group (57.9%, 95%CI: 36.2, to 79.6; and 43.6% 95%CI:16.2 to 71.1; p=0.032) irrespective of the tested muscle. AT performed 16 (95%CI: 7.9 to 23.3, p<0.001) fewer SLHR repetitions on the symptomatic side compared to controls, and 14 (95%CI: 5.8 to 22.0, p=0.004), fewer SLHR repetitions on the non-symptomatic compared to controls. We found no between-groups differences in isometric peak torque (p=0.971) or RTD (p=0.815).

PerspectiveOur data suggest greater intracortical inhibition for the Triceps surae muscles for the AT group accompanied by reduced SLHR endurance, without deficits in isometric peak torque or RTD. The increased SICI observed in the AT group could be negatively influencing Triceps surae endurance; thus, rehabilitation aiming to reduce intracortical inhibition should be considered to improve patient outcomes. Furthermore, SLHR is a useful clinical tool to assess plantar flexor function in AT patients.

category: sports medicine


title: Empirical evaluation of the sensitivity of background incidence rate characterization for adverse events across an international observational data network

abstract:
Background incidence rates are routinely used in safety studies to evaluate the association of an exposure and an outcome. Systematic research on the sensitivity of background rates to the choice of the study parameters is lacking. We used 12 electronic health record and administrative claims data sources to calculate incidence rates of 15 adverse events. We examined the influence of age, race, sex, database, time-at-risk start (anchoring) event and duration, season and year, prior observation and clean window. For binary comparisons, we calculated incidence rate ratios and performed random-effect model meta-analysis. Background rates were highly sensitive to demographic characteristics of the population, especially age, with rates varying up to a factor of 1,000 across age groups. Rates varied by up to a factor of 100 by database. Incidence rates were highly influenced by the choice of anchoring (e.g., health visit, vaccination, or arbitrary date) for the time-at-risk start, especially at short times at risk, and less influenced by secular or seasonal trends. Therefore, comparing background to observed rates requires appropriate adjustment, and results should be interpreted in the context of design choices.

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category: health informatics


title: Self-assessment of COVID-19 vaccination efficacy using a simple POCT for SARS-CoV-2 S1 protein antibody IgG-IgM

abstract:
BackgroundMore than ten novel COVID-19 vaccines have been approved with protections against SARS-CoV-2 infections ranges between 52-95%. It is of great interest to the vaccinees who have received the COVID-19 vaccines, vaccine developers and authorities to identify the non-responders in a timely manner so intervention can take place by either giving additional boosts of the same vaccine or switching to a different vaccine to improve the protection against the SARS-CoV-2 infections. A robust correlation was seen between binding antibody titer and efficacy (p=0.93) in the clinic studies of 7 COVID-19 vaccines, so it is of urgency to develop a simple POCT for vaccinees to self-assess their immune response at home.

MethodsUsing CHO cell-expressed full length SARS-CoV2 S1 protein as coating antigen on colloidal gold particles, a SARS-CoV-2 S1 IgG-IgM antibody lateral flow test kit (POCT) was developed. The test was validated with negative human sera collected prior to the COVID-19 outbreaks, and blood samples from human subjects prior, during, and post-immunization of COVID-19 vaccines.

ResultsThe specificity of the POCT was 99.0%, as examined against 947 normal human sera and 20 whole blood samples collected pre-immunization. The limit of detection was 50 IU/mL of pseudovirus neutralizing titer (PVNT) using human anti-SARS-2 neutralizing standards from convalescent sera. The sensitivity of POCT for SARS-CoV-2 S1 protein antibody IgG-IgM was compared with SARS-CoV-2 RBD antibody ELISA and determined to be 100% using 23 blood samples from vaccinated human subjects and 10 samples from non-vaccinated ones. Whole blood samples were collected from 119 human subjects (ages between 22-61 years) prior to, during, and post-vaccination of five different COVID-19 vaccines. Among them, 115 people tested positive for SARS-CoV-2 S1 antibodies (showing positive at least once) and 4 people tested negative (tested negative at least twice on different days), demonstrating 96.64% of seroconversion after full-vaccination. 92.3% (36/39) of the human subjects who were younger than 45 achieved seroconversion within 2 weeks while only 57.1% (4/7) of subjects older than 45 tested positive for S1 antibodies, suggesting that younger people develop protection much faster than older ones. Even though the S1 antibody level in 88% of human subjects vaccinated with inactivated virus dropped below 50 IU/mL two months later, one boost could quickly raise the S1 antibody titer above 50 IU/mL of PVNT, indicates that the initial vaccination was successful and immunization memory was developed.

ConclusionUsing the lateral flow tests of SARS-CoV2 S1 IgG+IgM, vaccinated human subjects can easily self-assess the efficacy of their vaccination at home. The vaccine developer could quickly identify those non-responders and give them an additional boost to improve the efficacy of their vaccines. Vaccinees who failed in response could switch to different types of COVID-19 vaccines since there are more than 10 COVID-19 vaccines approved using three different platform technologies.

HighlightsO_LIMore than ten novel COVID-19 vaccines have been approved with protections against SARS-CoV-2 infections ranges between 52-95%. It is of great interest to the vaccinees who have received the COVID-19 vaccines, vaccine developers and authorities to identify the non-responders in a timely manner.
C_LIO_LIA highly specific and very simple lateral flow test kit for measurement of SARS-CoV-2 S1IgG+IgM antibodies post-immunization of COVID-19 vaccine using peripheral blood was developed as a home-test assay with a limit of detection (LOD) at 50 IU/mL of pseudovirus neutralizing titer (PVNT).
C_LIO_LIAfter full vaccinations with COVID-19 vaccines, 96.6% of the volunteers successfully achieved the seroconversion of SARS-CoV-2 S1 IgG+IgM antibody.
C_LIO_LI92.3% (36/39) of the human subjects who were younger than 45 achieved seroconversion within 2 weeks while only 57.1% (4/7) of subjects older than 45 tested positive for S1 antibodies, suggesting that younger people develop protection much faster than older ones.
C_LIO_LIEven though the S1 antibody level in 88% of human subjects vaccinated with inactivated virus dropped below the detection 2-6 months later, one boost could quickly raise the S1 antibody titer above 50 IU/mL of PVNT, indicating that the initial vaccination was successful and immunization memory was developed.
C_LI


title: A Cascaded Droplet Microfluidic Platform Enables High-throughput Single Cell Antibiotic Susceptibility Testing at Scale

abstract: Single-cell antibiotic susceptibility testing (AST) offers a promising technology by achieving unprecedented rapid testing time; however, its potential for clinical use is marred by its limited capacity for performing AST with scalable antibiotic numbers and concentrations. To lift the one antibiotic condition per device restriction common in single-cell AST, we develop a cascaded droplet microfluidic platform that uses an assembly line design to enable scalable single-cell AST. Such scalability is achieved by executing bacteria/antibiotic mixing, single-cell encapsulation, incubation, and detection in a streamlined workflow, facilitating susceptibility testing of each new antibiotic condition in 2 min after a 90 min setup time. As a demonstration, we test 3 clinical isolates and 8 positive urine specimens against 15 antibiotic conditions for generating antiprograms in [~]2 h and achieve 100% and 93.8% categorical agreement, respectively, compared to laboratory-based clinical microbiology reports which becomes available only after 48 h.


title: Clinical management and impact of scarlet fever in the modern era: findings from a cross-sectional study of cases in London, 2018-2019.

abstract:
BackgroundScarlet fever incidence has risen steeply in recent years, and is associated with wider outbreaks of severe Group A Streptococcal infections. Yet, few studies of its epidemiology, clinical features, and management have been undertaken in the antibiotic era.

AimTo characterize symptomatology, management, and consequences of scarlet fever and identify associations with delayed diagnosis.

Design/SettingCross-sectional study of children with scarlet fever in London, 2018-2019.

Methodsonline survey of parents/guardians of children with scarlet fever identified by Health Protection Teams, recording demographics, symptoms, care-seeking, and management; logistic regression for factors associated with delayed diagnosis; Coxs regression for consequences of delayed diagnosis.

ResultsResponses represented 412 cases in a period with 6828 notifications for children 0-14 years old, and 410 school/nursery outbreaks. 70% first sought care from general practice, and 31% had multiple consultations. For 28%, scarlet fever was not considered at first consultation: in these cases, symptoms were frequently attributed to viral infection (60%, 64/106). Delay in diagnosis beyond first consultation occurred more frequently among children aged 5+ who presented with sore throat (odds ratio 2.8 vs. 5+ without sore throat; 95%CI 1.3-5.8; P=0.006). On average, cases with delayed diagnosis took one day longer to return to baseline activities, and required one additional day off school versus those diagnosed at first consultation.

ConclusionsIn assessing children with fever, rash, and sore throat, practitioners should be alert to the possibility of scarlet fever: it is frequently missed at first consultation, and prompt recognition speeds clinical recovery and public health management.

How this fits in [4 sentences summarising key messages of background and findings]- In the five years leading up to the pandemic lockdown of 2020, scarlet fever incidence rose markedly in England and Wales, prompting this investigation of cases in London 2018-2019.
- Prompt recognition of the disease by carers and clinicians can direct timely antibiotic therapy, limit transmission in the household and community, and direct the identification and control of outbreaks.
- In this study, delayed diagnosis was more likely to occur among older children presenting with sore throat--perhaps reflecting a lower index of suspicion in this age group.
- Cases with delayed diagnosis took longer to return to normal activities, and required more time off from school than those diagnosed at the first consultation.


title: Adverse effects and antibody titers in response to the BNT162b2 mRNA COVID-19 vaccine in a prospective study of healthcare workers

abstract:
BackgroundmRNA COVID-19 vaccines are playing a key role in controlling the COVID-19 pandemic. The relationship between post-vaccination symptoms and strength of antibody responses is unclear.

ObjectiveTo determine whether adverse effects caused by vaccination with the Pfizer/BioNTech BNT162b2 vaccine are associated with the magnitude of vaccine-induced antibody levels.

DesignSingle center, prospective, observational cohort study.

SettingParticipants worked at Walter Reed National Military Medical Center and were seen monthly at the Naval Medical Research Center Clinical Trials Center.

ParticipantsGenerally healthy adults that were not severely immunocompromised, had no history of COVID-19, and were seronegative for SARS-CoV-2 spike protein prior to vaccination.

MeasuresSeverity of vaccine-associated symptoms was obtained through participant completed questionnaires. Testing for IgG antibodies against SARS-CoV-2 spike protein and receptor binding domain was conducted using microsphere-based multiplex immunoassays.

Results206 participants were evaluated (69.4% female, median age 41.5 years old). We found no correlation between vaccine-associated symptom severity scores and vaccine-induced antibody titers one month after vaccination. We also observed that 1) post-vaccination symptoms were inversely correlated with age and weight and more common in women, 2) systemic symptoms were more frequent after the second vaccination, 3) high symptom scores after first vaccination were predictive of high symptom scores after second vaccination, and 4) older age was associated with lower titers.

LimitationsStudy only observes antibody responses and consists of healthy participants.

ConclusionsLack of post-vaccination symptoms following receipt of the BNT162b2 vaccine does not equate to lack of vaccine-induced antibodies one month after vaccination. This study also suggests that it may be possible to design future mRNA vaccines that confer robust antibody responses with lower frequencies of vaccine-associated symptoms.

FundingThis study was executed by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed by the Uniformed Services University of the Health Sciences (USUHS) through a cooperative agreement by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). This project has been funded by the Defense Health Program, U.S. DoD, under award HU00012120067. Project funding for JHP was in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The funding bodies have had no role in the study design or the decision to submit the manuscript for publication.


title: An immune-protein signature combining TRAIL, IP-10 and CRP for accurate prediction of severe COVID-19 outcome

abstract:
BACKGROUNDAccurately identifying COVID-19 patients at-risk to deteriorate remains challenging. Tools integrating host-protein expression have proven useful in determining infection etiology and hold potential for prognosticating disease severity.

METHODSAdults with COVID-19 were recruited at medical centers in Israel, Germany, and the United States. Severe outcome was defined as intensive care unit admission, non-invasive or invasive ventilation, or death. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) and interferon gamma inducible protein-10 (IP-10; also known as CXCL10) and C-reactive protein (CRP) were measured using an analyzer providing values within 15 minutes. A signature indicating the likelihood of severe outcome was derived generating a score (0-100). Patients were assigned to 4 score bins.

RESULTSBetween March and November 2020, 518 COVID-19 patients were enrolled, of whom 394 were eligible, 29% meeting a severe outcome. The signatures area under the receiver operating characteristic curve (AUC) was 0.86 (95% confidence interval: 0.81-0.91). Performance was not confounded by age, sex, or comorbidities and superior to IL-6 (AUC 0.77; p = 0.033) and CRP (AUC 0.78; p < 0.001). Likelihood of severe outcome increased significantly (p < 0.001) with higher scores. The signature differentiated patients who further deteriorated after meeting a severe outcome from those who improved (p = 0.004) and projected 14-day survival probabilities (p < 0.001).

CONCLUSIONThe derived immune-protein signature combined with a rapid measurement platform is an accurate predictive tool for early detection of COVID-19 patients at-risk for severe outcome, facilitating timely care escalation and de-escalation and appropriate resource allocation.

FUNDINGMeMed funded the study

category: emergency medicine


title: Effects of supervised high-intensity hardstyle kettlebell training on grip strength and health-related physical fitness in insufficiently active older adults: The BELL pragmatic controlled trial

abstract: The Ballistic Exercise of the Lower Limb (BELL) trial examined efficacy and safety of a pragmatic hardstyle kettlebell training program in older adults. Insufficiently active men and women aged 59-79 years, were recruited to a 6-month repeated measures study, involving 3-months usual activity and 3-months progressive hardstyle kettlebell training. Health-related physical fitness outcomes included: grip strength [GS], 6-min walk distance [6MWD], resting heart rate [HR], stair-climb [SC], leg extensor strength [LES], hip extensor strength [HES], Sit-To-Stand [STS], vertical jump [CMVJ], five-times floor transfer [5xFT], 1RM deadlift, body composition (DXA), attendance, and adverse events. Sixteen males (68.8 {+/-} 4.6 yrs, 176.2 {+/-} 7.8 cm, 90.7 {+/-} 11.0 kg, 29.2 {+/-} 2.6 kg/m2) and sixteen females (68.6 {+/-} 4.7 yrs, 163.9 {+/-} 5.4 cm, 70.4 {+/-} 12.7 kg, 26.3 {+/-} 4.9 kg/m2) were recruited. Compliance to the supervised exercise program was very high (91.5%). Kettlebell training increased GS (R: MD = 7.1 kg 95% CI [4.9, 9.3], p < 0.001, L: MD = 6.3 kg 95% CI [4.1, 8.4], p < 0.001), 6MWD (41.7 m, 95% CI [17.9, 65.5], p < .001), 1RM (16.2 kg, 95% CI [2.4, 30.0], p = 0.013), 30s STS (3.3 reps, 95% CI [0.9, 5.7], p = 0.003), LES (R: MD = 61.6 N, 95% CI [4.4, 118.8], p = 0.028), HES (L: MD = 21.0 N, 95% CI [4.2, 37.8], p = 0.007), appendicular skeletal lean mass (MD = 0.65 kg, 95% CI [0.08, 1.22], p = 0.016), self-reported health change (17.1%, 95% CI [4.4, 29.8], p = 0.002) and decreased SC time (2.7 sec, 95% CI [0.2, 5.2], p = 0.025), 5xFT time (6.0 sec, 95% CI [2.2, 9.8], p < 0.001) and resting HR (7.4 bpm, 95% CI [0.7, 14.1], p = 0.032). There were four non-serious adverse events. Mean individual training load for group training sessions during the trial was 100,977 {+/-} 9,050 kg. High-intensity hardstyle kettlebell training was well tolerated and improved grip strength and measures of health-related physical fitness in insufficiently active older adults.


title: Exploration of alcohol use disorder-associated brain miRNA-mRNA regulatory networks

abstract: Alcohol use disorder (AUD) is due to gene expression changes in specific brain regions, but the underlying mechanism is not fully understood. We investigated AUD-associated miRNA-mRNA regulatory networks in multiple brain regions by analyzing transcriptomic changes in two sets of postmortem brain tissue samples and ethanol-exposed human embryonic stem cell (hESC)-derived cortical interneurons. miRNA and mRNA transcriptomes were profiled in 192 postmortem tissue samples (Set 1) from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control Caucasians. Nineteen differentially expressed miRNAs (fold-change>2.0 & P<0.05) and 97 differentially expressed mRNAs (fold-change>2.0 & P<0.001) were identified in one or multiple brain regions of AUD subjects. AUD-associated miRNA-mRNA regulatory networks in each brain region were constructed using differentially expressed and negatively correlated miRNA-mRNA pairs. AUD-relevant pathways (including CREB Signaling, IL-8 Signaling, and Axonal Guidance Signaling) were potentially regulated by AUD-associated brain miRNA-mRNA pairs. Moreover, miRNA and mRNA transcriptomes were mapped in additional 96 postmortem tissue samples (Set 2) from six of the above eight brain regions of eight AUD and eight control Caucasians, and some of the AUD-associated miRNA-mRNA regulatory networks were confirmed. Additionally, miRNA and mRNA transcriptomes were analyzed in hESC-derived cortical interneurons with and without ethanol exposure, and ethanol-influenced miRNA-mRNA regulatory networks were constructed. This study provided evidence that alcohol could induce concerted miRNA and mRNA expression changes in reward-related or alcohol-responsive brain regions. We concluded that altered brain miRNA-mRNA regulatory networks might contribute to AUD development.


title: Comparison of Mental Health Symptom Changes from pre-COVID-19 to COVID-19 by Sex or Gender: A Systematic Review and Meta-analysis

abstract:
ImportanceWomen and gender-diverse individuals have faced disproportionate socioeconomic burden during COVID-19. There have been reports that this has translated into greater negative changes in mental health, but this has been based on cross-sectional research that has not accounted for pre-COVID-19 differences.

ObjectiveTo compare mental health symptom changes since pre-COVID-19 by sex or gender.

Data SourcesMEDLINE, PsycINFO, CINAHL, EMBASE, Web of Science, China National Knowledge Infrastructure, Wanfang, medRxiv, and Open Science Framework (December 31, 2019 to August 30, 2021).

Study SelectionEligible studies compared mental health symptom changes from pre-COVID-19 to COVID-19 by sex or gender.

Data Extraction and SynthesisData was extracted by a single reviewer with validation by a second reviewer. Adequacy of study methods and reporting was assessed using an adapted version of the Joanna Briggs Institute Checklist for Prevalence Studies. A restricted maximum-likelihood random-effects meta-analyses was conducted.

Main Outcomes and MeasuresAnxiety symptoms, depression symptoms, general mental health, and stress measured continuously or dichotomously.

Results12 studies (10 unique cohorts) were included. All compared females or women to males or men; none included gender-diverse individuals. Continuous symptom change differences were not statistically significant for depression (standardized mean difference [SMD]= 0.12, 95% CI -0.09 to 0.33; 4 studies, 4,475 participants; I2=69.0%) and stress (SMD= - 0.10, 95% CI -0.21 to 0.01; 4 studies, 1,533 participants; I2=0.0%), but anxiety (SMD= 0.15, 95% CI 0.07 to 0.22; 4 studies, 4,344 participants; I2=3.0%) and general mental health (SMD= 0.15, 95% CI 0.12 to 0.18; 3 studies, 15,692 participants; I2=0.0%) worsened more among females or women than males or men during COVID-19. There were no significant differences in changes in proportion above a cut-off: anxiety (difference= -0.05, 95% CI -0.20 to 0.11; 1 study, 217 participants), depression (difference= 0.12, 95% CI -0.03 to 0.28; 1 study, 217 participants), general mental health (difference= -0.03, 95% CI -0.09 to 0.04; 3 studies, 18,985 participants; I2=94.0%), stress (difference= 0.04, 95% CI -0.10 to 0.17; 1 study, 217 participants).

Conclusion and RelevanceMental health outcomes did not differ or were worse by amounts below thresholds for clinical significance for women compared to men.

RegistrationPROSPERO (CRD42020179703).

KEY MESSAGESO_ST_ABSQuestionC_ST_ABSDid mental health symptoms worsen more for females or women than males or men in COVID-19?

FindingsWe reviewed almost 65,000 citations and identified 12 studies that provided data to directly compare mental health symptom changes from pre-COVID-19 to during COVID-19 for females or women versus males or men. Statistically significant, but small, sex- or gender-based differences were found in 2 of 8 mental health outcomes.

MeaningMental health changes among females or women were not significantly different from males or men for most outcomes, and differences that were identified were small and less than minimally important difference thresholds.

category: psychiatry and clinical psychology


title: Face mask use and associated factors among students in rural Eastern Uganda amidst the COVID-19 pandemic

abstract:
BackgroundThe Corona Virus Disease of 2019 (COVID-19) has gravely affected several aspects of national and global society, including education. Given the risk it poses, the Government of Uganda (GOU) adopted and recommended face mask use as one of the preventive measures to limit its transmission in communities. However, there is limited data on the levels of face mask usage and associated factors among students in schools in Uganda. This study aimed at assessing the face mask usage and associated factors among students in schools in rural Eastern Uganda amidst the COVID-19 pandemic.

MethodsA cross sectional quantitative descriptive study was conducted among 423 students in schools in rural Eastern Uganda. Multi-stage sampling method was employed in the selection of study participants. The data was collected by trained data collectors using structured questionnaires pre-installed on ODK enabled smart phones. The data entered was cleaned using Excel 2016 and exported to Stata14.0 statistical software (Statacorp, College station, Texas, USA) for analysis. Bivariate and multivariable logistic regression analyses were employed using 95% CI (confidence interval). Variables with p-value < 0.20 and those with literature backup evidence were included in the multivariable model. Variables with p-value < 0.05 were considered to be statistically significant. This study revealed that less than three quarters (62.3%) wore face masks correctly.

ResultsAlmost all, 98.9% of the participants mentioned that they wore face masks due to fear of missing classes and 49.0% disagreed that they were vulnerable to COVID-19. Students in boarding schools (AOR = 1.61, 95%CI: 1.05-2.47), those who believed that they were vulnerable to COVID-19 (AOR = 1.70, 95%CI: 1.11-2.10), and those who disagreed that masks are uncomfortable (AOR = 1.62, 95%CI: 1.06-2.46) were more likely to wear facemasks correctly.

ConclusionThis study revealed that more than a third of the students did not wear face masks correctly. Correct wearing of face masks was associated with being in a boarding school, belief that they were susceptible to COVID-19, and disagreeing that masks were uncomfortable. This therefore highlights the need for sensitization programmes in academic institutions in order to improve students perceptions toward COVID-19 and face masks, and consequently increase correct face mask usage in schools.


title: Enhancing epidemiological investigation of nosocomial SARS-CoV-2 infection with whole genome sequencing: A retrospective cohort study across four hospitals in the UK.

abstract:
BackgroundDespite robust efforts, patients and staff acquire SARS-CoV-2 infection in hospitals. In this retrospective cohort study, we investigated whether whole-genome sequencing (WGS) could enhance the epidemiological investigation of healthcare-associated SARS-CoV-2 acquisition.

Methods and findingsFrom 17-November-2020 to 5-January-2021, 803 inpatients and 329 staff were diagnosed with SARS-CoV-2 infection across four teaching hospitals in Oxfordshire, UK. We classified cases according to epidemiological definitions, sought epidemiological evidence of a potential source for each nosocomial infection, and evaluated if epidemiologically-linked cases had genomic evidence supporting transmission. We compared epidemiological and genomic outbreak identification.

Using national epidemiological definitions, 109/803 (14%) inpatient infections were classified as definite/probable nosocomial, 615 (77%) as community-acquired and 79 (10%) as indeterminate. There was strong epidemiological evidence to support definite/probable cases as nosocomial: 107/109 (98%) had a prior-negative PCR in the same hospital stay before testing positive, and 101(93%) shared time and space with known infected patients/staff. Many indeterminate cases were likely infected in hospital: 53/79 (67%) had a prior-negative PCR and 75 (95%) contact with a potential source. 89/615 (11% of all 803 patients) with apparent community-onset had a recent hospital exposure.

WGS highlighted SARS-CoV-2 is mainly imported into hospitals: within 764 samples sequenced 607 genomic clusters were identified (>1 SNP distinct). Only 43/607 (7%) clusters contained evidence of onward transmission (subsequent cases within [≤]1 SNP). 20/21 epidemiologically-identified outbreaks contained multiple genomic introductions. Most (80%) nosocomial acquisition occurred in rapid super-spreading events in settings with a mix of COVID-19 and non-COVID-19 patients. Hospitals not routinely admitting COVID-19 patients had low rates of transmission. Undiagnosed/unsequenced individuals prevent genomic data from excluding nosocomial acquisition.

ConclusionsOur findings suggest current surveillance definitions underestimate nosocomial acquisition and reveal most nosocomial transmission occurs from a relatively limited number of highly infectious individuals.


title: First clinical experience with a novel optical-ultrasound imaging device on various skin pathologies

abstract:
ObjectivesA compact handheld skin ultrasound imaging device has been developed that uses co-registered optical and ultrasound imaging to provide diagnostic information about the full skin depth and lesions encountered therein. The aim of the current work is to present the first clinical results of the device. Using additional photographic, dermoscopic and ultrasonic images as reference, the images from the device are assessed in terms of the detectability of the skin layer boundaries (between the epidermis, dermis, and subcutis), and in terms of image features produced by common skin lesions.

MethodsCombined optical-ultrasonic recordings of various types of common skin lesions (melanoma, basal cell carcinoma, keratosis, dermatofibroma, naevus, dermatitis, psoriasis) were taken with the device (N = 53) and compared with images from a reference portable skin ultrasound imager. The investigator and two additional independent experts evaluated and compared the images in terms of skin structure detectability and skin lesion features.

ResultsSkin structure detectability was unanimously over 90 % for epidermis, dermis and lesion. Morphological and echogenicity information observed for melanoma, basal cell carcinoma, keratoses, dermatofibroma, naevi, atopic dermatitis, psoriasis were found consistent with those of the reference ultrasound device and relevant ultrasound images in the literature.

ConclusionsThe presented device is able to obtain simultaneous in-vivo optical and ultrasound images of common skin lesions. This has the potential to provide relevant information in a number of settings to be investigated in the future, including preoperative planning of skin cancer treatment.

category: dermatology


title: Causes, Predictors, and Costs of Unplanned 30-Day Readmissions in Patients with Right Heart Failure.

abstract:
OBJECTIVESThe aim of this study was to describe the frequency, causes, factors, and costs associated with right heart failure encounters.

BACKGROUNDMultiple studies have looked into heart failure readmissions but there is no study to our knowledge specifically analyzing patients with right heart failure.

METHODSPatients with right heart failure diagnosis were identified using the 2017 Nationwide Readmission Database (NRD) and were evaluated for the rates, predictors, and costs of unplanned 30 days readmission. Weighted analysis was performed to obtain nationally representative data.

RESULTSWe identified 7142 patients with right heart failure of whom 21% had an unplanned readmission within 30 days of the index discharge. Patients with history of Coronary artery bypass grafting (p=0.033; OR 2.359; 95% CI 1.071 - 5.197), Chronic kidney disease (p<0.001; OR 1.607; 95% CI 1.402 - 1.843), atrial fibrillation (p=0.014; OR 1.417; 95% CI 1.072-1.873) had high odds of unplanned 30 day readmissions while obesity (p<0.001; OR 0.686; 95% CI 0.594 - 0.792) had negative odds of such readmissions.

CONCLUSIONSThirty-day unplanned readmissions remain a significant issue affecting over 1 in 5 patients with right heart failure. Early unplanned readmissions are associated with significant mortality and financial burden in these patients.

category: cardiovascular medicine


title: Clonal hematopoiesis of indeterminate potential is associated with worse kidney function and anemia in a cohort of patients with advanced chronic kidney disease

abstract:
BackgroundClonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. CHIP is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in chronic kidney disease (CKD) has not been investigated.

MethodsWe performed targeted sequencing to detect CHIP mutations in a cohort of 87 adults with eGFR < 60 ml/min/1.73m2. Kidney function, hematologic, and mineral bone disease parameters were assessed cross-sectionally at baseline, and a total of 2,091 creatinine measurements and 3,382 hemoglobin measurements were retrospectively collected over the following 12-year period.

ResultsAt baseline, 20 of 87 (23%) cohort participants had CHIP detected. Those with CHIP had lower baseline eGFR (22.3 {+/-} 11.2 vs. 28.2 {+/-} 11.5 ml/min/1.73 m2, P = 0.04) in age- and sex-adjusted regression models. Individuals with CHIP had a 2.5-fold increased risk of incident 50% decline in eGFR or ESKD in a Cox proportional hazard model adjusted for age and sex (95% confidence interval, 1.3-4.7). The annualized rate of eGFR decline adjusted for age and sex was -2.3 {+/-}1.1 ml/min/1.73m2 per year in those with CHIP versus -1.6 {+/-}0.5 ml/min/1.73m2 per year in those without CHIP. Further, those with CHIP had lower hemoglobin at baseline (11.6 {+/-} 0.3 vs. 12.8 {+/-} 0.2 g/dL, P = 0.0003) and throughout the follow-up period despite a greater use of erythropoiesis-stimulating agents.

ConclusionIn those with pre-existing CKD, CHIP was associated with lower eGFR at baseline, faster progression of CKD, and anemia.

category: nephrology


title: A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

abstract: Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Data from large endometriosis and EOC genome-wide association meta-analyses were used to estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and major EOC histotypes, and to identify shared susceptibility loci. We estimated a significant genetic correlation (rg) between endometriosis and clear cell (rg=0.71), endometrioid (rg=0.48) and high-grade serous (rg=0.19) ovarian cancer, all supported by Mendelian randomization analyses. A bivariate meta-analysis identified 28 loci associated with endometriosis and EOC, including two novel risk loci, and 19 with evidence for a single underlying causal variant. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlighted several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

category: obstetrics and gynecology


title: A Propensity-Matched Nested Case-Control Study of Acute Coronary Syndrome Patients Genotyped for CYP2C19

abstract:
IntroductionTicagrelor is widely considered superior to clopidogrel however a pharmacogenetic substudy of PLATO indicated that the majority of this difference is due to genetic nonresponders to clopidogrel. We evaluated patient outcomes following genotyping for CYP2C19 in a propensity matched acute coronary syndrome cohort treated with either clopidogrel, ticagrelor or aspirin monotherapy.

MethodsICD10 coding identified 6,985 acute coronary syndrome patients at Waitemat[a] District Health Board over a five year period (2012-2016). Ticagrelor was subsidised by The Pharmaceutical Management Agency of New Zealand in July 2013. Patients were genotyped for CYP2C19 *2, *3 and *17 alleles using the Nanosphere Verigene analyser and treatment was tailored accordingly. Logistic regression and nearest neighbour propensity matching was employed in a 1:3 fashion with each treatment group to balance patient characteristics.

ResultsA total of 146 patients were genotyped and compared with 438 matched patients taking either clopidogrel, ticagrelor or aspirin monotherapy. Post July 2013 clopidogrel was prescribed more often in responders than in those without genotype information (68 vs 39%, {chi}2 9, 95% CI 4 to 34, p=0.003). Conversely, ticagrelor was used more frequently in clopidogrel nonresponders. Mortality with personalised treatment was equivalent to ticagrelor (HR 0.8, 95% CI 0.3 to 1.8) but higher in those treated with clopidogrel (HR 2.3, 95 % CI 1 to 5.3). Readmissions with ACS were higher in nonresponders treated with clopidogrel versus those treated with genotype appropriate dual antiplatelet therapy (HR 3.9, 95% CI 0.8 to 18, p =0.03).

ConclusionPersonalised antiplatelet management was equivalent to ticagrelor with respect to all-cause mortality and ACS readmissions. It also led to more appropriate use of both clopidogrel and ticagrelor and potential cost savings.

category: genetic and genomic medicine


title: CFTR-mediated monocyte-macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons

abstract: Cystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR). Converging lines of evidence suggest that CF carriers with only one defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. Here, we performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control PBMCs or THP-1 cells incubated with the plasma of these subjects. Transcriptomic analyses revealed suppression of cytokine-enriched immune-related genes (IL-1{beta}, CXCL8, CREM) implicating lipopolysaccharide tolerance in innate immune cells (monocytes) of CF probands and their parents and in the control innate immune cells incubated with proband or parent plasma. These data suggest that not only a homozygous but also a heterozygous CFTR mutation can modulate the immune/inflammatory system. This conclusion is further supported by the findings of lower numbers of circulating monocytes in CF probands and their parents compared to healthy controls, the abundance of mononuclear phagocyte subsets (macrophages, monocytes, and activated dendritic cells) which correlated with Pseudomonas aeruginosa infection, lung disease severity, and CF progression in the probands. This study provides insight into demonstrated CFTR-related innate immune dysfunction in individuals with CF and carriers of a CFTR mutation that may serve as a target for personalized therapy.


title: The acceptance of covid-19 vaccines in Sub-Saharan Africa: Evidence from 6 national phone surveys

abstract:
IntroductionRecent debates surrounding the lagging covid-19 vaccination campaigns in low-income countries center around vaccine supply and financing. Yet, relatively little is known about attitudes towards covid-19 vaccines in these countries and in Africa in particular. In this paper, we provide cross-country comparable estimates of the willingness to accept a covid-19 vaccine in six Sub-Saharan African countries.

MethodsWe use data from six national high-frequency phone surveys from countries representing 38% of the Sub-Saharan African population (Burkina Faso, Ethiopia, Malawi, Mali, Nigeria, and Uganda). Samples are drawn from large, nationally representative sampling frames providing a rich set of demographic and socio-economic characteristics by which we disaggregate our analysis. Using a set of re-calibrated survey weights, our analysis adjusts for the selection biases common in remote surveys.

ResultsAcceptance rates in the six Sub-Saharan African countries studied are generally high, with at least four in five people willing to be vaccinated in all but one country. Vaccine acceptance ranges from nearly universal in Ethiopia (97.9%, 97.2% to 98.6%) to below what would likely be required for herd immunity in Mali (64.5%, 61.3% to 67.8%). We find little evidence for systematic differences in vaccine hesitancy by sex or age but some clusters of hesitancy in urban areas, among the better educated, and in richer households. Safety concerns about the vaccine in general and its side effects emerge as the primary reservations toward a covid-19 vaccine across countries.

ConclusionsOur findings suggest that limited supply, not inadequate demand, likely presents the key bottleneck to reaching high covid-19 vaccine coverage in Sub-Saharan Africa. To turn intent into effective demand, targeted communication campaigns bolstering confidence in the safety of approved vaccines and reducing concerns about side effects will be crucial to safeguard the swift progression of vaccine rollout in one of the worlds poorest regions.

O_TEXTBOXWhat is already known?O_LIEstimates of vaccine acceptance in high- and middle-income countries have found rates to cluster around 70% with considerable cross-country variation.
C_LIO_LIAs vaccine rollout is severely lagging, low-income countries and particularly Sub-Saharan Africa (SSA) with almost two thirds of the global poor population remain exposed to covid-19 and its impacts on lives and livelihoods.
C_LIO_LIMuch of the current debate on vaccination campaigns in SSA focuses on supply-chain and financial factors, yet there is a dearth of robust, comparable evidence on covid-19 vaccine hesitancy in these countries.
C_LI

What are the key findings?O_LICovid-19 vaccine acceptance is high in six Sub-Saharan African countries with an estimated four in five people or more in all but one study country willing to take an approved, free vaccine.
C_LIO_LIClusters of hesitancy vary by country but generally comprise urban areas, richer households, and those with more education.
C_LI

What do the new findings imply?O_LILimited supply, rather than inadequate demand, likely presents the key bottleneck to achieving high covid-19 vaccine coverage in Sub-Saharan Africa.
C_LIO_LITo reach mass coverage, information campaigns should bolster confidence in vaccine safety and alleviate concerns about side effects.
C_LI

C_TEXTBOX

category: health policy


title: Transmissibility of COVID-19 among Vaccinated Individuals: A Rapid Literature Review

abstract:
ObjectivesThis is an update of a previous report that examined literature published up to March 11th, 2021. Sixteen additional studies have been included in this update. The objective of this report is to identify comparative observational studies and randomized controlled trials (RCTs) evaluating the efficacy and effectiveness of COVID-19 vaccination in reducing forward transmission from vaccinated people, and studies examining the biological plausibility of vaccination-induced transmission reduction.

MethodA search of databases, MEDLINE, Embase, L-OVE and the Cochrane Central Register of Controlled Trials was conducted to identify RCTs or comparative observational studies evaluating the efficacy and effectiveness of COVID-19 vaccination in the prevention of transmission, asymptomatic infections and transmissibility of COVID-19 among vaccinated persons. An additional search of grey literature was conducted. This search is current to May 4th, 2021.

ResultsIn this update, 16 additional studies, including 9 human and 7 animal studies, were included. Therefore, this review examines a total of 33 included studies: 21 human studies and 12 preclinical animal studies. Evidence from two large household surveillance studies from the UK suggests that a single or full dose of AstraZeneca (AZ) and Pfizer-BioNtech (PfBnT) vaccines may prevent household transmission of COVID-19 after 14 days of vaccination by up to 54%. The AZ vaccine trials in the general population suggest that an initial low dose followed by a standard dose may provide up to 59% protection against asymptomatic or unknown infection, although efficacy against these outcomes was not demonstrated following two standard doses. PfBnT vaccine observational studies in the general population suggest up to 90% effectiveness against asymptomatic infection after seven or more days of full dose vaccination. Up to 75% effectiveness against asymptomatic infection was reported after full- dose in healthcare workers. Across RCTs examining asymptomatic infection in the general population, one dose of Moderna was shown to provide an efficacy of 61.4% against asymptomatic infection 21 days after the first dose; in another trial, the J&J vaccine had an efficacy of 74% 28 days after the first dose. Lastly, seven of eight studies found significantly increased cycle threshold, suggestive of lower viral load, in PfBnT or AZ vaccinated individuals compared with those who were unvaccinated.

ConclusionThe AZ and PfBnT vaccines may prevent household transmission of COVID-19 after 14 days of vaccination. More studies have found the vaccines to significantly reduce the risk of asymptomatic infection and significantly increase cycle threshold, suggestive of lower viral load. Further research is needed to evaluate post-vaccination infectivity and transmission of both the wild type COVID-19 virus and the variants of concern from other jurisdictions.

category: infectious diseases


title: Evolution of Anti-SARS-CoV-2 IgG Antibody and IgG Avidity Post Pfizer and Moderna mRNA Vaccinations

abstract: Messenger RNA (mRNA) based vaccines (Pfizer/BioNTech and Moderna) are highly effective at providing immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is uncertainty about the duration of immunity, evolution of IgG antibody levels and IgG avidity (an index of antibody-antigen binding strength), and differences in the immune responses between vaccines. Here we performed a prospective pilot study of 71 previously COVID-19 free subjects upon receiving both doses of either the Pfizer (n = 54) or Moderna (n = 17) mRNA vaccine. Anti-spike protein receptor binding domain (RBD) IgG antibodies were measured longitudinally using a qualitative finger stick MidaSpot rapid test at the point-of-care for initial screening and a quantitative dry blood spot-based pGOLD laboratory test over [~] four months post-vaccination. The average anti-RBD IgG antibody levels peaked at [~] two weeks after the second dose of the vaccine and declined thereafter, while antibody avidity increased, suggesting antibody maturation. Moderna vaccine recipients compared to Pfizer vaccine recipients exhibited higher side effect severity, higher peak anti-RBD IgG antibody levels, and higher avidity up to the 90 days period. Differences in antibody levels diminished at [~] 120 days post-vaccination, in line with the similar efficacy observed in the two vaccines. The MidaSpot rapid test detected 100% anti-SARS-CoV-2 RBD positivity for fully vaccinated subjects in both Pfizer and Moderna cohorts post full vaccination but turned negative greater than 90 days post-vaccination for 5.4% of subjects in the Pfizer cohort, whose quantitative anti-IgG were near the minimum levels of the group. Immune responses were found to vary greatly among vaccinees. Personalized longitudinal monitoring of antibodies could be necessary to assess the immunity duration of vaccinated individuals.