title: Genetic and environmental determinants of diastolic heart function

abstract: Diastole is the sequence of physiological events that occur in the heart during ventricular filling and principally depends on myocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processes and is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine learning cardiac motion analysis to measure diastolic functional traits in 39,559 participants of UK Biobank and perform a genome-wide association study. We identified 9 significant, independent loci near genes that are associated with maintaining sarcomeric function under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes were independent predictors of diastolic function and we found a causal relationship between ventricular stiffness and heart failure. Our results provide novel insights into the genetic and environmental factors influencing diastolic function that are relevant for identifying causal relationships and tractable targets in heart failure.


title: The importance of time post-vaccination in determining the decrease in vaccine efficacy against SARS-CoV-2 variants of concern

abstract: With the development of high-efficacy vaccines against SARS-CoV-2, an urgent open question is whether currently available vaccines protect with similar efficacy against infection with SARS-CoV-2 variants of concern (VOC). Recent reports quantifying the extent by which VOC can evade vaccine immunity resulted in a range of estimates for the same VOC, which makes them difficult to interpret. One possible explanation for the discrepancies between different studies is an inconsistency in terms of the time post-vaccination of the sampled population. Here we present a model based on the observed correlation between antibody neutralization levels and vaccine efficacy, which demonstrates the impact of time post-vaccination on the comparison of the vaccine efficacy for VOC versus non-VOC infections. Our model predicts and exemplifies several possible consequences for vaccine efficacy in VOC infections: 1) a delay in the onset of vaccine efficacy against VOC; 2) a transient increase in susceptibility to breakthrough infection with VOC compared to non-VOC as a function of time after vaccination. We review preliminary data indicating that such phenomena are observed in studies of the B.1.1.7 and B.1.351 variants. We find that ignoring the strong dependence on the time post-vaccination can lead to contradictory reports of relative efficacy against VOC versus non-VOC, with implications on mitigation strategies against VOC and the design of vaccine efficacy studies.

category: epidemiology


title: Operationalizing a routine wastewater monitoring laboratory for SARS-CoV-2

abstract: Wastewater-based testing for SARS-CoV-2 is a novel tool for public health monitoring, but additional laboratory capacity is needed to provide routine monitoring at all locations where it has the potential to be useful. Few standardization practices for SARS-CoV-2 wastewater analysis currently exist, and quality assurance/quality control procedures may vary across laboratories. Alongside counterparts at many academic institutions, we built out a laboratory for routine monitoring of wastewater at the University of California, Berkeley. Here, we detail our groups establishment of a wastewater testing laboratory including standard operating procedures, laboratory buildout and workflow, and a quality assurance plan. We present a complete data analysis pipeline and quality scoring framework and discuss the data reporting process. We hope that this information will aid others at research institutions, public health departments, and wastewater agencies in developing programs to support wastewater monitoring for public health decision-making.


title: Percolation across households in mechanistic models of non-pharmaceutical interventions in SARS-CoV-2 disease dynamics

abstract: Since the emergence of the novel coronavirus disease, mathematical modelling has become an important tool for planning strategies to combat the pandemic by supporting decision-making and public policies, as well as allowing an assessment of the effect of different intervention scenarios. A proliferation of compartmental models was observed in the mathematical modelling community, aiming to understand and make predictions regarding the spread of COVID-19. Such approach has its own advantages and challenges: while compartmental models are suitable to simulate large populations, the underlying well-mixed population assumption might be problematic when considering non-pharmaceutical interventions (NPIs) which strongly affect the connectivity between individuals in the population. Here we propose a correction to an extended age-structured SEIR framework with dynamic transmission modelled using contact matrices for different settings in Brazil. By assuming that the mitigation strategies for COVID-19 affect the connections between different households, network percolation theory predicts that the connectivity across all households decreases drastically above a certain threshold of removed connections. We incorporated this emergent effect at population level by modulating the home contact matrices through a percolation correction function, with the few remaining parameters fitted to to hospitalisation and mortality data from the city of Sao Paulo. We found significant support for the model with implemented percolation effect using the Akaike Information Criteria (AIC). Besides better agreement to data, this improvement also allows for a more reliable assessment of the impact of NPIs on the epidemiological dynamics.


title: BNT162b2 mRNA vaccinations in Israel: understanding the impact and improving the vaccination policies by redefining the immunized population

abstract:
By the end of February 2021, when 48% of the Israeli population was immune, the number of new positive COVID-19 cases significantly dropped across all ages. Understanding which parameters influenced this drop and how to minimize the number of hospitalizations and overall positive cases is urgently needed.

In this study we conducted an observational analysis which included COVID-19 data with over 12,000,000 PCR tests from 250 cities in Israel. In addition, we performed a simulation of different vaccination campaigns to find the optimal policy.

Our analysis revealed that cities with younger populations reached a decrease in new cases when a lower percentage of their residents were immunized, showing that median age is a crucial parameter effecting overall immunity, while other parameters appeared to be insignificant. This variance between cities is explained by recalculating the immunized population and multiplying each individual by a factor symbolizing the impact of their age on the spread on the virus. This factor is easily calculated from historical data of positive cases per age.

The simulation proves that prioritizing different age groups or changing the rate of vaccinations drastically effects the overall hospitalizations and positive cases.

One-Sentence Summaryunderstanding what influences reaching covid-19 overall immunity and how to maximize the effect of the vaccination campaign.

category: health policy


title: The impact of COVID-19 pandemic on influenza transmission: molecular and epidemiological evidence

abstract:
To quantify the impact of COVID-19-related control measures on the spread of human influenza virus, we analyzed case numbers, viral molecular sequences, personal behavior data, and policy stringency data from various countries, and found consistent evidence of decrease in influenza incidence after the emergence of COVID-19.

Article SummaryWe quantify a noticeable decrease in H1N1 and H3N2 cases and genetic diversity in selected countries since the onset of the COVID-19 pandemic.

category: infectious diseases


title: The potential of SARS-CoV-2 antigen-detection tests in the screening of asymptomatic persons

abstract:
ObjectivesTo assess the performance of antigen-based rapid diagnostic tests (Ag-RDTs) for SARS CoV-2 when implemented for large-scale universal screening of asymptomatic individuals.

MethodsThis study presents data from a pragmatic implementation study for universal Ag-RDT-based screening at a tertiary care hospital in Germany where all incoming patients without symptoms suggestive of SARS-CoV-2 were screened with an Ag-RDT prior to admission since October 2020.

ResultIn total, 49,542 RDTs were performed in 27,199 asymptomatic individuals over a duration of five months. Out of 222 positive results, 196 underwent in-house confirmatory testing with PCR, out of which 170 were confirmed positive, indicating a positive predictive value (PPV) of 86.7%. Negative Ag-RDTs were not routinely tested with PCR, but a total of 94 cases of false negative Ag-RDTs were detected due to PCR tests being performed within the following five days with a median CT-value of 33.

ConclusionsThis study provides evidence that Ag-RDTs can have a high diagnostic yield for transmission relevant infections with limited false-positives when utilized at the point of care on asymptomatic patients and thus can be a suitable public-health test for universal screening.


title: Wastewater-based epidemiology for tracking COVID-19 trend and variants of concern in Ohio, United States

abstract: The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 129 million confirm cases. Many health authorities around the world have implemented wastewater-based epidemiology as a rapid and complementary tool for the COVID-19 surveillance system and more recently for variants of concern emergence tracking. In this study, three SARS-CoV-2 target genes (N1, N2, and E) were quantified from wastewater influent samples (n = 250) obtained from the capital city and 7 other cities in various size in central Ohio from July 2020 to January 2021. To determine human-specific fecal strength in wastewater samples more accurately, two human fecal viruses (PMMoV and crAssphage) were quantified to normalize the SARS-CoV-2 gene concentrations in wastewater. To estimate the trend of new case numbers from SARS-CoV-2 gene levels, different statistical models were built and evaluated. From the longitudinal data, SARS-CoV-2 gene concentrations in wastewater strongly correlated with daily new confirmed COVID-19 cases (average Spearmans r = 0.70, p < 0.05), with the N2 gene being the best predictor of the trend of confirmed cases. Moreover, average daily case numbers can help reduce the noise and variation from the clinical data. Among the models tested, the quadratic polynomial model performed best in correlating and predicting COVID-19 cases from the wastewater surveillance data, which can be used to track the effectiveness of vaccination in the later stage of the pandemic. Interestingly, neither of the normalization methods using PMMoV or crAssphage significantly enhanced the correlation with new case numbers, nor improved the estimation models. Whole-genome sequencing result showed that those detected SARS-CoV-2 variants of concern from the wastewater matched with the clinical isolates from the communities. The findings from this study suggest that wastewater surveillance is effective in COVID-19 trend tracking and variant emergence and transmission within a community.

category: public and global health


title: SARS-CoV-2 infection in pregnancy in Denmark - characteristics and outcomes after confirmed infection in pregnancy: a nationwide, prospective, population-based cohort study

abstract:
IntroductionAssessing the risk factors for and consequences of infection with SARS-CoV-2 during pregnancy is essential to guide clinical guidelines and care. Previous studies on the influence of SARS-CoV-2 infection in pregnancy have been among hospitalised patients, which may have exaggerated risk estimates of severe outcomes because all cases of SARS-CoV-2 infection in the pregnant population were not included. The objectives of this study were to identify risk factors for and outcomes after SARS-CoV-2 infection in pregnancy independent of severity of infection in a universally tested population, and to identify risk factors for and outcomes after severe infection requiring hospital admission.

Material and MethodsThis was a prospective population-based cohort study in Denmark using data from the Danish National Patient Register and Danish Microbiology Database and prospectively registered data from medical records. We included all pregnancies between March 1 and October 31, 2020 and compared women with a positive SARS-CoV-2 test during pregnancy to non-infected pregnant women. Cases of SARS-CoV-2 infection in pregnancy were both identified prospectively and through register linkage to secure that all cases were identified and that cases were pregnant during infection. Main outcome measures were pregnancy, delivery, maternal, and neonatal outcomes. Severe infection was defined as hospital admission due to COVID-19.

ResultsAmong 82 682 pregnancies, 418 women had SARS-CoV-2 infection during pregnancy, corresponding to an incidence of 5.1 per 1000 pregnancies, 23 (5.5%) of which required hospital admission due to COVID-19. Risk factors for infection were asthma (OR 2.19 [1.41-3.41]) and being foreign born (OR 2.12 [1.70-2.64]). Risk factors for hospital admission due to COVID-19 included obesity (OR 2.74 [1.00-7.51]), smoking (OR 4.69 [1.58-13.90]), infection after gestational age (GA) 22 weeks (GA 22-27 weeks: OR 3.77 [1.16-12.29]; GA 28-36 weeks: OR 4.76 [1.60-14.12]) and having asthma (OR 4.53 [1.39-14.79]). We found no difference in any obstetric or neonatal outcomes.

ConclusionsOnly 1 in 20 women with SARS-CoV-2 infection during pregnancy require admission to hospital due to COVID-19. And severe outcomes of SARS-CoV-2 infection in pregnancy are rare.

Key MessagePopulation based cohort study about SARS-CoV-2 infection during pregnancy. Asthma and foreign ethnicity were identified as risk factors for infection while obstetric outcomes did not change. Obesity, smoking, infection after GA 22, and asthma increased the risk of hospital admission.

category: obstetrics and gynecology


title: Investigation and analysis of blood-borne occupational exposure of medical staff in a hospital in Hubei Province

abstract:
ObjectivesBy collecting and sorting out the data of 220 blood-borne occupational exposure medical staff in a hospital in Hubei Province, investigated the present situations and problems of the blood-borne occupational exposure, and the causes were analyzed and the improvement measures for personal safety of the medical staff were also made, which may provide guidance and reference significance for the medical staff.

Methodsa retrospective survey was conducted to analyze occupational exposure populations by influence factors (gender, age, occupation, occurrence places, occurrence links, and exposure of pathogens types.

ResultsThere were 220 medical staff of blood-borne occupational exposure in the hospital in Hubei Province from 2015 to 2017 to be investigated, and the blood-borne occupational exposure populations were mainly concentrated on nurses (65%) and doctors (31.82%) (both of populations accounted for 96.82% in total occupational exposure medical staff), and the age of blood-borne occupational exposure populations were mainly 20~29 years old (61.82%), followed by 30~39 years old (26.82%), 40~49 years old (8.64%), and >50 years old (2.73%). The main occurrence places for blood-borne occupational exposure were wards (46.36%) and treatment room/disposal rooms(26.36%); the main occurrence links of blood-borne occupational exposure were mainly injured during needle extraction (29.09%), stab and cut during treatment (23.64%), disposal of waste (17.27%) and accidental injury during operation (16.82%). The main pathogen types of blood-borne occupational exposure were hepatitis B (HBV) and syphilis, accounting for 36.36% and 10.45%, respectively.

ConclusionsThe population of blood-borne occupational exposure in this hospital mainly concentrated in nurses aged 20-29 years old, followed by doctors, mainly happened at wards and treatment rooms/disposal rooms; the high-risk links were mainly injured during needle extraction and stab and cut during treatment, and the main pathogen types were HBV and syphilis. Those evidences showed that to strengthen the awareness of prevention and operation standard training for the related medical staff (mainly nurses and doctors aged 20-29 years old) and to supervise the relevant departments to do a good job of supervision, it can greatly reduce the incidence and risk of blood-borne occupational exposure in this hospital.

category: occupational and environmental health


title: Modelling the effect of an improved trace and isolate system in the wake of a highly transmissible Covid-19 variant with potential vaccine escape

abstract:
ObjectiveHow helpful would a properly functioning find, test, trace, isolate and support (FTTIS) system be now in the UK with new Covid-19 infections at a low level and half the adult population immunised but with a highly transmissible variant becoming predominant?

Designa dynamic causal model of Covid-19 supplied with the latest available empirical data is used to assess the impact of a new highly transmissible variant.

Settingthe United Kingdom.

Participantsa population based study.

Interventionsscenarios are used to explore a Covid-19 transmission rate 50% more and twice the current rate with or without a more effective FTTIS system.

Main outcome measuresincidence, death rate and reproductive ratio

Resultsa small short third wave of infections occurs which does not occur if FTTIS effectiveness is improved from 25% to 30%.

Conclusiona modest improvement in FTTIS would prevent a third wave caused by a highly transmissible virus.


title: Does reactogenicity after a second injection of the BNT162b2 vaccine predict spike IgG antibody levels in healthy Japanese subjects?

abstract: Adverse reactions are more common after the second injection of messenger RNA vaccines such as Pfizer/BioNTechs BNT162b2. We hypothesized that the degree and severity of reactogenicity after the second injection reflects the magnitude of antibody production against the SARS CoV-2 virus spike protein (spike IgG). Blood samples were obtained from 67 healthy Japanese healthcare workers three weeks after the first injection and two weeks after the second injection of the BNT162b2 vaccine to measure spike IgG levels. Using questionnaires, we calculated an adverse event (AE) score (0-11) for each participant. The geometric mean of spike IgG titers increased from 1,047 antibody units (AU/mL) (95% CI: 855-1282 AU/mL) after the first injection to 17,378 AU/mL (14,622-20,663 AU/mL) after the second injection. The median AE score increased from 2 to 5. Spike IgG levels after the second injection were negatively correlated with age and positively correlated with spike IgG after the first injection. AE scores after the second injection were not significantly associated with log-transformed spike IgG after the second injection, when adjusted for age, sex, and log-transformed spike IgG after the first injection. Although the sample size was relatively small, reactogenicity after the second injection may not accurately reflect antibody production.


title: Possible future waves of SARS-CoV-2 infection generated by variants of concern with a range of characteristics

abstract: Viral reproduction of SARS-CoV-2 provides opportunities for the acquisition of advantageous mutations, altering viral transmissibility, disease severity, and/or allowing escape from natural or vaccine-derived immunity. We use three mathematical models: a parsimonious deterministic model with homogeneous mixing; an age-structured model; and a stochastic importation model to investigate the effect of potential variants of concern (VOCs). Calibrating to the situation in England in May 2021, we find epidemiological trajectories for putative VOCs are wide-ranging and dependent on their transmissibility, immune escape capability, and the introduction timing of a postulated VOC-targeted vaccine. We demonstrate that a VOC with a substantial transmission advantage over resident variants, or with immune escape properties, can generate a wave of infections and hospitalisations comparable to the winter 2020-2021 wave. Moreover, a variant that is less transmissible, but shows partial immune-escape could provoke a wave of infection that would not be revealed until control measures are further relaxed.


title: Social inequalities in hostility toward vaccination against Covid-19

abstract:
In recent decades, France has appeared as a country particularly hostile to vaccination in general. When asked in November 2020 about the intention to take the Covid-19 vaccine, the French public showed, once again, reluctance. Therefore, France appeared as an ideal case study to analyze whether the hostility toward the Covid-19 vaccine has its own reasons or whether it is related to the reluctance to the principle of vaccination itself. Our objective was to determine the specificity of the social determinants of the intention to get the Covid-19 vaccine. Thanks to the use of a large random sample of the general population in France (86,000 individuals), the reluctant to Covid-19 vaccine could be clearly distinguished from the hesitant and the convinced, and thereby thoroughly analyzed. Our analysis highlighted a gendered reluctance toward vaccination in general but even more so regarding vaccination against Covid-19. It might refer to women being more concerned about the possible effects of an injection in their body, especially at the age of maternity and a differentiated socialization making them more sensitive than men to long-term risks and more apprehensive toward rapid technological change. We also found that people at the bottom of the social hierarchy, in terms of level of education, financial resources, and immigration status, were more likely to refuse the Covid-19 vaccine. Nevertheless, this reluctance was less prominent than for vaccination in general, reflecting the actual spread of the epidemic in various social milieux. Finally, our analysis showed that trust in the governments actions was significantly associated with reluctance toward the Covid-19 vaccine, even more than toward vaccination in general.

Specific campaigns should be thought beforehand to reach women and people at the bottom of the social hierarchy to avoid furthering social inequalities in terms of morbidity and mortality.


title: Pregnancy, fertility concerns, and fertility preservation procedures in French breast cancer survivors in the FEERIC national study (on behalf of the Seintinelles research network).

abstract:
ObjectiveTo study fertility concerns and oncofertility practices at time of breast cancer (BC) diagnosis.

DesignThe FEERIC study (Fertility, Pregnancy, Contraception after BC in France) is a prospective, multicenter study.

SettingWeb-based collaborative research platform Seintinelles.

Patients517 patients with prior BC diagnosis free from relapse and aged 18 to 43 years at inclusion (from 12th March 2018 to 27th June 2019).

InterventionBaseline online self-administered questionnaires.

Main Outcome MeasureFertility preservation procedures at BC diagnosis.

ResultsMedian age at BC diagnosis was 33.6 years and 424 patients (82.0%) received chemotherapy. Overall, 236 (45.6%) patients were offered specialized oncofertility counseling, 124 (24.0%) underwent one or more FP procedures with material preservation (oocytes n=108, 20.9%; embryos n=31, 6.0%; both oocytes and embryos n=13, 2.5%; ovarian cryopreservation n=6, 1.2%) and 78 patients received gonadotropin-releasing hormone agonists (15.1%). With a median follow-up of 26.7 months after the end of treatments,133 pregnancies (25.7%) had occurred in 85 patients (16.4%), including 20 unplanned pregnancies (15.0%). Most of the pregnancies were spontaneous (n=113, 87.6%), while 16 (12.4%) required medical interventions. Patients who had an unplanned pregnancy were less likely to have received fertility counseling (p=0.02) and contraceptive counseling (p=0.08) at BC diagnosis.

ConclusionMost of the patients were not offered proper specialized oncofertility counseling at the time of BC diagnosis. Spontaneous pregnancies after BC were very much more frequent than pregnancies resulting from the use of cryopreserved gametes. Adequate contraceptive counseling seems as important as information about fertility and might prevent unplanned pregnancies.

category: oncology


title: Immunity to SARS-CoV-2 persists 9 months post-symptoms with an altered T cell phenotype compared to influenza A virus-specific memory

abstract:
SARS-CoV-2 induces T cell, B cell and antibody responses that are detected for several months in recovered individuals. Whether this response resembles a typical respiratory viral infection is a matter of debate. Here we followed T cell and antibody responses in 24 mainly non-hospitalized SARS-CoV-2 recovered subjects at two time points (median of 45- and 145-days post-symptom onset). Antibody responses were detected in 95% of subjects, with a strong correlation between plasma and salivary anti-S and anti-RBD IgG, as well as a correlation between circulating T follicular helper cells and the SARS-CoV-2-specific IgG response. Based on intracellular cytokine production or proliferation, CD4+ T cell responses to SARS-CoV-2 were detected in all subjects, decaying with a half-life of 5-6 months for S-specific IL-2-producing cells. CD4+ responses were largely of the T helper 1 phenotype, but with a lower ratio of IFN-{gamma}: IL-2 producing cells and a lower frequency of CD8+: CD4+ T cells compared to influenza A virus-(IAV)-specific memory responses within the same subjects. Analysis of secreted molecules also revealed a lower ratio of IFN-{gamma}: IL-2 and IFN-{gamma}: IL-6 and an altered cytotoxic profile for S- and N-specific compared to IAV-specific responses. These data suggest that the memory T-cell phenotype after a single infection with SARS-CoV-2 persists over time, with an altered cytokine and cytotoxic profile compared to long term memory to IAV within the same subjects.

One Sentence SummaryImmunity to SARS-CoV-2 in a cohort of patients, mainly with mild COVID-19 disease, persists to 9 months with an altered T cell cytokine and cytotoxicity profile compared to influenza A virus-specific memory T cells from the same subjects.

category: allergy and immunology


abstract:
Characterized by vomiting, fever, abdominal pain and diarrhea, acute gastroenteritis (AGE) is a common illness in pediatric populations. In Canada, pediatric AGE accounts for 200,000 emergency visits, 20,000 hospital admissions, and 30 deaths a year. Yet, there continues to be significant practice variations in the treatment of AGE. Knowledge translation (KT) can help close the research-practice gap. In particular, art and stories are powerful mediums that cut across age, culture, language, literacy, and gender barriers.

The purpose of this study was to work with parents to develop an e-Book and whiteboard animation video for parents on pediatric AGE. Using a multi-method research process, we developed a 2 minute 57 second video and 39-page e-Book for pediatric AGE. Both tools underwent usability testing with parents in three Canadian emergency department waiting rooms in urban, rural, and remote regions. Focus groups were also conducted with parents in each of the three regions.

Overall, parents felt that digital and paper-based KT tools would be beneficial knowledge dissemination mediums. Our study showed that parents positively rated an e-Book and whiteboard animation video for pediatric AGE. These findings demonstrate how working together with key stakeholders can facilitate the development of KT tools for parents that are usable, relevant, and increase parental confidence. Furthermore, the type of KT tool developed is an important decision that may depend on parental preferences as well as when and where parents access the tools.

This report should be cited asScott, S.D., Le, A., Hartling, L. (2021). Developing and testing two arts-based knowledge translation tools for parents about pediatric acute gastroenteritis. Internal Technical Report. ECHO Research, University of Alberta.

Available at: http://www.echokt.ca/research/technical-reports/

category: pediatrics


title: Developing and testing two arts-based knowledge translation tools for parents about pediatric acute gastroenteritis


title: Impact of AI-based Real Time Image Quality Feedback for Chest Radiographs in the Clinical Routine

abstract:
PurposeTo implement a tool for real time image quality feedback for chest radiographs into the clinical routine and to evaluate the effect of the system on the image quality of the acquired radiographs.

Materials and MethodsA real time Artificial Intelligence (AI) image quality feedback tool is developed that analyzes chest PA x-rays right after the completion of the examination at the x-ray system and provides visual feedback to the system operator with respect to adherence to desired standards of collimation, patient rotation and inspiration. In order to track image quality changes over time, results were compared to image quality assessment for images, acquired prior to system implementation.

ResultsCompared to the image quality prior to the installation of the real time image quality feedback solution, it is shown that a relative increase of images with optimal image quality with respect to collimation, patient rotation and inspiration is achieved by 30% (p<0.01). A relative improvement of 28% (p<0.01) is observed for the increase of images with optimal collimation, followed by a relative increase of 4% (p<0.01) of images with optimal inspiration. Finally, a detailed analysis is presented that shows that the average unnecessarily exposed area is reduced by 34% (p<0.01).

DiscussionThis study shows that it is possible to significantly improve image quality using a real time AI-based image quality feedback tool. The developed tool not only provides objective and impartial criticism and helps x-ray operators identify areas for improvement, but also gives positive feedback.

Key FindingsO_LIA substantial amount of images acquired in the clinical routine does not suffice the international guidelines
C_LIO_LIContinuous AI-based image quality feedback to the x-ray system operator in the clinical routine leads to a significant image quality improvement over time
C_LIO_LIUsing the developed tool, the overall fraction of images with optimal patient positioning could be improved by 30%, followed by a 34% decrease of unnecessarily exposed area.
C_LI

category: radiology and imaging


title: Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer's disease implicate TBCA and TREM2 in disease risk

abstract: The levels of many blood proteins are associated with Alzheimers disease or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins causally associated with the disease. Here, genome-wide and epigenome-wide studies (nindividuals[≤]1,064) were performed on plasma levels of 281 Alzheimers disease-associated proteins, identified by a systematic review of the literature. We quantified the contributions of genetic and epigenetic variation towards inter-individual variability in plasma protein levels. Sixty-one independent genetic and 32 epigenetic loci were associated with expression levels of 49 proteins; eight and 24 of these respective findings are previously unreported. Novel findings included an association between plasma TREM2 levels and a polymorphism and CpG site within the MS4A4A locus. Through Mendelian randomisation analyses, causal associations were observed between higher plasma TBCA and TREM2 levels and lower Alzheimers disease risk. Our data inform the regulation of biomarker levels and their relationships with Alzheimers disease.

category: genetic and genomic medicine


title: Inferring global-scale temporal latent topics from news reports to predict public health interventions for COVID-19

abstract: The COVID-19 pandemic has highlighted the importance of non-pharmacological interventions (NPI) for controlling epidemics of emerging infectious diseases. Despite their importance, NPI have been monitored mainly through the manual efforts of volunteers. This approach hinders measurement of the NPI effectiveness and development of evidence to guide their use to control the global pandemic. We present EpiTopics, a machine learning approach to support automation of the NPI prediction and monitoring at both the document-level and country-level by mining the vast amount of unlabelled news reports on COVID-19. EpiTopics uses a 3-stage, transfer-learning algorithm to classify documents according to NPI categories, relying on topic modelling to support result interpretation. We identified 25 interpretable topics under 4 distinct and coherent COVID-related themes. Importantly, the use of these topics resulted in significant improvements over alternative automated methods in predicting the NPIs in labelled documents and in predicting country-level NPIs for 42 countries.

category: health informatics


title: A functionally distinct neutrophil landscape in severe COVID-19 reveals opportunities for adjunctive therapies

abstract: Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome of respiratory failure and diffuse alveolar damage that results from dysregulated local and systemic immune activation, causing pulmonary vascular, parenchymal and alveolar damage. SARS-CoV-2 infection has become the dominant cause of ARDS worldwide, and emerging evidence implicates neutrophils and their cytotoxic arsenal of effector functions as central drivers of immune-mediated lung injury in COVID-19 ARDS. However, a key outstanding question is whether COVID-19 drives a unique program of neutrophil activation or effector functions that contributes to the severe pathogenesis of this pandemic illness, and whether this unique neutrophil response can be targeted to attenuate disease. Using a combination of high-dimensional single cell analysis and ex vivo functional assays of neutrophils from patients with COVID-19 ARDS compared to non-COVID ARDS (caused by bacterial pneumonia), we identified a functionally distinct landscape of neutrophil activation in COVID-19 ARDS that was intrinsically programmed during SARS-CoV-2 infection. Furthermore, neutrophils in COVID-19 ARDS were functionally primed to produce high amounts of neutrophil extracellular traps (NETs). Surprisingly, this unique pathological program of neutrophil priming escaped conventional therapy with dexamethasone, thereby revealing a promising target for adjunctive immunotherapy in severe COVID-19.

category: intensive care and critical care medicine


title: Adolescent autism and autoimmune diagnoses linked to infant gut bacteria whose prevalence is associated with at-risk genetics and/or diet

abstract:
The earliest predictors of future autoimmune diseases are a series of autoantibodies that are rarely evaluated and very within and between diseases. In addition, autoantibodies often appear just prior to disease onset. All of these factors make it difficult to apply interventions that might prevent disease. Earlier predictors of disease are needed. Here, a general population cohort was used to assess whether gut bacterial biomarkers could be identified prior to disease. Gut microbiome analysis on 1741 one-year old Swedish children was performed on samples collected in the late 1990s. These children were then followed for 18 years for the incidence of five autoimmune diseases and autism. Specific bacterial strains in the gut microbiome of one-year-old children have been identified as exclusive to the 96 subjects (cases) who acquired type 1 diabetes, celiac disease, hypothyroidism, Crohns disease, juvenile idiopathic arthritis, or autism over their next 18 years. None of these strains were found in the 1645 children (controls) who did not acquire any of these diseases. Ten other strains were exclusive to those who remained disease-free. In most cases, the presence or absence of these bacteria were strongly associated with: 1) high-risk class II human leukocyte antigen (HLA) alleles; 2) dietary factors; or 3) a combination of HLA genetics and diet. These results have three significant implications: 1) certain class II HLA haplotypes may serve as bacterial gatekeepers early in life, altering microbiome composition thereby creating the potential for dysbiosis and inflammation; 2) the gut microbiome dysbiosis and inflammation during infancy, largely derived from host HLA genetics and diet, may be a common precedent to all five autoimmune diseases and autism; and 3) HLA gatekeeping may prevent gut colonization of beneficial bacteria in those genetically at-risk individuals who could most benefit from probiotic therapy.

FundingJDRF, Swedish Child Diabetes Foundation, Swedish Council for Working Life and Social Research, Medical Research Council of Southeast Sweden, Regions Ostergotland, and Linkoping University.


title: Evaluating the utility of high-resolution proximity metrics in predicting the spread of COVID-19

abstract: AO_SCPLOWBSTRACTC_SCPLOWHigh resolution mobility datasets have become increasingly available in the past few years and have enabled detailed models for infectious disease spread including those for COVID-19. However, there are open questions on how such a mobility data can be used effectively within epidemic models and for which tasks they are best suited. In this paper, we extract a number of graph-based proximity metrics from high resolution cellphone trace data from X-Mode and use it to study COVID-19 epidemic spread in 50 land grant university counties in the US. We present an approach to estimate the effect of mobility on cases by fitting an ODE based model and performing multivariate linear regression to explain the estimated time varying transmissibility. We find that, while mobility plays a significant role, the contribution is heterogeneous across the counties, as exemplified by a subsequent correlation analysis. We subsequently evaluate the metrics utility for case surge prediction defined as a supervised classification problem, and show that the learnt model can predict surges with 95% accuracy and 87% F1-score.


title: Right Anterior Temporal Degeneration, Emotions, and Loss of Nonverbal Semantics: Guidelines for Diagnosis of the Emotional Semantic Variant Frontotemporal Dementia

abstract:
It has been proposed that focal anterior temporal lobe (ATL) degeneration is a specific, unitary FTLD-TDP-related disease that initially preferentially affects the left or right hemisphere. Patients with early left ATL (lATL) atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia (svPPA) and semantic dementia, prompting appropriate neurological care. There is less consensus regarding the symptoms in right ATL (rATL) predominant cases, who most often present with behavioral and emotional changes leading to a misdiagnosis of a psychiatric disorder, and later of behavioral variant frontotemporal dementia (bvFTD). Uncertainties regarding early symptoms and lack of an overarching framework continues to hinder proper diagnosis and care of patients with rATL disease. Here, we present symptom chronology, cognitive and socioemotional profiles of a large, well-characterized, longitudinally followed cohort of patients with rATL-predominant degeneration and propose new criteria and nosology for the syndrome.

We identified individuals with a clinical diagnosis of bvFTD or svPPA and a structural MRI (n=478). Based on neuroimaging criteria, we identified three groups: patients with rATL-predominant atrophy with relative sparing of the frontal lobes (n=46), patients with frontal-predominant atrophy with relative sparing of the rATL (n=79), and patients with lATL-predominant atrophy with relative sparing of the frontal lobes (n=75). Seventy-eight patients had undergone autopsy. We analyzed patients clinical, neuropsychological, genetic, anatomical, and pathological profiles.

In the rATL-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%), and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in emotional theory of mind, identifying famous people from names and face, and facial affect naming (despite preserved face perception) than the lATL- and frontal-predominant groups. The clinical features were highly sensitive (81%) and specific (84%) in differentiating rATL from bvFTD in the first three years of the disease. FTLD-TDP (84%) was the most common pathology.

Our results suggest that rATL-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive loss of semantic memory for concepts of social-emotional relevance. Although this syndrome exists along a clinical, anatomical, and pathological continuum with svPPA, patients present with progressive behavioral changes. To facilitate early identification and care in clinical and research settings, we propose specific diagnostic criteria and the term "emotional semantic variant frontotemporal dementia" to distinguish this syndrome from other forms of frontotemporal dementia.

category: neurology


title: Right Anterior Temporal Degeneration, Emotions, and Loss of Nonverbal Semantics: The Emotional Semantic Variant Frontotemporal Dementia


title: A year of COVID-19 GWAS results from the GRASP portal reveals potential SARS-CoV-2 modifiers

abstract:
Host genetic variants influence the susceptibility and severity of several infectious diseases, and the discovery of novel genetic associations with Covid-19 phenotypes could help developing new therapeutic strategies to reduce its burden.

Between May 2020 and June 2021, we used Covid-19 data released periodically by UK Biobank and performed 65 Genome-Wide Association Studies (GWAS) in up to 18 releases of Covid-19 susceptibility (N=18,481 cases in June 2021), hospitalization (N=3,260), severe outcomes (N=1,244) and death (N=1,104), stratified by sex and ancestry.

In coherence with previous studies, we observed 2 independent signals at the chr3p21.31 locus (rs73062389-A, OR=1.21, P=4.26x10-15 and rs71325088-C, OR=1.62, P=2.25x10-9) modulating susceptibility and severity, respectively, and a signal influencing susceptibility at the ABO locus (rs9411378-A, OR=1.10, P=3.30x10-12), suggesting an increased risk of infection in non-O blood groups carriers. Additional signals at the APOE (associated with severity and death) LRMDA (susceptibility in non-European) and chr2q32.3 (susceptibility in women) loci were also identified but did not replicate in independent datasets. We then devised an original approach to extract variants exhibiting an increase in significance over time. When applied to the susceptibility, hospitalization and severity analyses, this approach revealed the known DPP9, RPL24 and MAPT loci, amongst thousands of other signals. Finally, this significance trajectory analysis was applied to the larger Covid-19hgi meta-analyses, where additional loci of interest, related to the immune system, were identified.

These results, freely available on the GRASP portal, provide new insights on the genetic mechanisms involved in Covid-19 phenotypes.


title: A year of Covid-19 GWAS results from the GRASP portal reveals potential SARS-CoV-2 modifiers


title: The missing link between genetic association and regulatory function

abstract: The genetic basis of most complex traits is highly polygenic and dominated by non-coding alleles. It is widely assumed that such alleles exert small regulatory effects on the expression of cis-linked genes. However, despite the availability of expansive gene expression and epigenomic data sets, few variant-to-gene links have emerged. We identified 134 gene-trait pairs in which protein-coding variants cause severe or familial forms of nine human traits. For most of these genes, we find that adjacent non-coding variation is associated with common complex forms of the same traits. However, we found limited evidence of colocalization--the same variant influencing both the physiological trait and gene expression--for only 7% of genes, and transcriptome-wide association evidence with correct direction of effect for only 6% of genes, despite the presence of eQTLs in most loci. Fine-mapping variants to regulatory elements and assigning these to genes by linear distance similarly failed to implicate most genes in complex traits. These results contradict the hypothesis that most complex trait-associated variants coincide with currently ascertained expression quantitative trait loci. The field must confront this deficit, and pursue this "missing regulation."


title: Vaccination reduces need for emergency care in breakthrough COVID-19 infections: A multicenter cohort study

abstract:
ImportanceWhile recent literature has shown the efficacy of the COVID-19 vaccine in preventing infection, its impact on need for emergency care/hospitalization in breakthrough infections remain unclear, particularly in regions with a high rate of variant viral strains.

ObjectiveWe aimed to determine if vaccination reduces hospital visits and severe disease in breakthrough COVID-19 infections.

DesignMulticenter observational cohort analysis

SettingEight-hospital acute care regional health system in Michigan, USA

ParticipantsConsecutive adult patients with COVID-19 requiring emergency care (EC)/hospitalization were eligible participants. Between December 15, 2020 and April 30, 2021, 11,834 EC encounters with COVID-19 infection were included.

ExposuresCOVID-19 vaccination

Main Outcomes and MeasuresPrimary endpoint was rate of COVID-19 emergency care/hospitalization encounters comparing unvaccinated (UV), partially vaccinated (PV), and fully vaccinated (FV) cases. Secondary outcome was severe disease represented as a composite outcome (ICU admission, mechanical ventilation, or in-hospital death).

Demographic and clinical variables were obtained from the electronic record. Vaccination data was obtained from the Michigan Care Improvement Registry and the Centers for Disease Control vaccine tracker.

Results10,880 (91.9%) UV, 825 (7%) PV, and 129 (1.1%) FV were included. Average age was 53.0 {+/-} 18.2 and 52.8% were female. Accounting for the COVID-19 vaccination population groups in Michigan, the ED encounters/hospitalizations rate relevant to COVID-19 infection was 96% lower in FV versus UV (e{beta}:0.04,95% CI 0.03 to 0.06, p <0.001) in negative binomial regression. COVID-19 EC visits rate peaked at 22.61, 12.88, and 1.29 visits per 100000 for the UV, PV, and FV groups, respectively. In the propensity-score matching weights analysis, FV had a lower risk of composite disease compared to UV but statistically insignificant (HR 0.84 95% CI 0.52 to 1.38).

ConclusionsThe need for emergency care and/or hospitalization due to breakthrough COVID-19 is an exceedingly rare event in fully vaccinated patients. As vaccination has increased within our region, emergency visits amongst fully vaccinated individuals have remained low and occur much less frequently when compared to unvaccinated individuals. In cases of breakthrough COVID-19, if hospital-based treatment is required, elderly patients with significant comorbidities remain at high risk for severe outcomes regardless of vaccination status.


title: Complement activation induces excessive T cell cytotoxicity in severe COVID-19

abstract: Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathogenesis, and it remains unclear if T cells also contribute to disease pathology. Here, we combined single-cell transcriptomics and proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated, CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Age-dependent generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.


title: Reproducibility of global electrical heterogeneity measurements on 12-lead ECG: The Multi-Ethnic Study of Atherosclerosis.

abstract:
ObjectiveVectorcardiographic (VCG) global electrical heterogeneity (GEH) metrics showed clinical usefulness. We aimed to assess the reproducibility of GEH metrics.

MethodsGEH was measured on two 10-second 12-lead ECGs recorded on the same day in 4,316 participants of the Multi-Ethnic Study of Atherosclerosis (age 69.4{+/-}9.4 y; 2317(54%) female, 1728 (40%) white, 1138(26%) African-American, 519(12%) Asian-American, 931(22%) Hispanic-American). GEH was measured on a median beat, comprised of the normal sinus (N), atrial fibrillation/flutter (S), and ventricular-paced (VP) beats. Spatial ventricular gradients (SVGs) scalar was measured as sum absolute QRST integral (SAIQRST) and vector magnitude QT integral (VMQTi).

ResultsTwo N ECGs with heart rate (HR) bias of -0.64 (95% limits of agreement [LOA] - 5.68 to 5.21) showed spatial area QRS-T angle (aQRST) bias of -0.12 (95%LOA -14.8 to 14.5). Two S ECGs with HR bias of 0.20 (95%LOA -15.8 to 16.2) showed aQRST bias of 1.37 (95%LOA -33.2 to 35.9). Two VP ECGs with HR bias of 0.25 (95%LOA -3.0 to 3.5) showed aQRST bias of -1.03 (95%LOA -11.9 to 9.9). After excluding premature arial or ventricular beat and two additional beats (before and after extrasystole), the number of cardiac beats included in a median beat did not affect the GEH reproducibility. Mean-centered log-transformed values of SAIQRST and VMQTi demonstrated perfect agreement (Bias 0; 95%LOA -0.092 to 0.092).

ConclusionGEH measurements on N, S, and VP median beats are reproducible. SVGs scalar can be measured as either SAIQRST or VMQTi.

SignificanceSatisfactory reproducibility of GEH metrics supports their implementation.

HighlightsO_LIVCG metrics are reliably reproducible, which supports their implementation.
C_LIO_LIGEH is reproducible if measured during atrial fibrillation or ventricular pacing.
C_LIO_LIScalar of spatial ventricular gradient can be measured as either SAIQRST or VMQTi.
C_LI

category: cardiovascular medicine


title: Adaptive vaccination may be needed to extirpate COVID-19: Results from a runtime-alterable strain-drift and waning-immunity model

abstract: In this paper, we present methods for building a Java Runtime-Alterable-Model Platform (RAMP) of complex dynamical systems. We illustrate our methods by building a multivariant SEIR (epidemic) RAMP. Underlying our RAMP is an individual-based model that includes adaptive contact rates, pathogen genetic drift, waning and cross immunity. Besides allowing parameter values, process descriptions, and scriptable runtime drivers to be easily modified during simulations, our RAMP is easily integrated into other computational platforms, such as our illustrated example with R-Studio. Processes descriptions that can be runtime altered within our SEIR RAMP include pathogen variant-dependent host shedding, environmental persistence, host transmission, and within-host pathogen mutation and replication. They also include adaptive social distancing and adaptive application of vaccination rates and variant-valency of vaccines. We present simulation results using parameter values and process descriptions relevant to the current COVID-19 pandemic. Our results suggest that if waning immunity outpaces vaccination rates, then vaccination rollouts may fail to contain the most transmissible variants, particularly if vaccine valencies do not adapt to escape mutations. Our SEIR RAMP is designed for easy-use by individuals and groups involved in formulating social-distancing and adaptive vaccination rollout policies. More generally, our RAMP concept facilitates construction of highly flexible complex systems models of all types, which can then be easily shared among researchers and policymakers as stand alone applications programs.


title: Adaptive vaccination may be needed to eliminate COVID-19: Results from a runtime-alterable strain-drift and waning-immunity model


title: A runtime alterable epidemic model with genetic drift, waning immunity, and vaccinations


title: Prenatal Acetaminophen, Adverse Birth Outcomes, and ADHD: Mediation Analysis in a Prospective Cohort

abstract:
Structured AbstractO_ST_ABSBackgroundC_ST_ABSAlthough we previously reported an association of prenatal acetaminophen exposure with more than two-fold increased odds of child ADHD, it is unknown whether prenatal acetaminophen is associated with adverse birth outcomes, and if birth outcomes may mediate the association of prenatal acetaminophen with ADHD.

MethodsThis birth cohort from Sherbrooke, Quebec, Canada, included 773 live births. Mothers with no thyroid disease enrolled at their first prenatal care visit or delivery. Acetaminophen was measured in meconium for 393 children at delivery. Physician diagnosis of ADHD was determined when children were 6-7 years old. We first tested associations of prenatal acetaminophen with birthweight, preterm birth, gestational age, and small and large for gestational age. Then we assessed whether these birth outcomes mediate the association of prenatal acetaminophen with ADHD. We imputed missing data via multiple imputation and used inverse probability weighting to account for confounding and selection bias.

ResultsAcetaminophen was detected in 222 meconium samples (56.5%). Prenatal acetaminophen exposure was associated with decreased birthweight by 136 grams ({beta} = -136; 95%CI [-229, - 43]), 20% increased weekly hazard of delivery (hazard ratio = 1.20; 95%CI [1.00, 1.43]), and over 60% decreased odds of being born large for gestational age (odds ratio = 0.38; 95%CI [0.20, 0.75]). There was no evidence for adverse birth outcomes mediating the association of prenatal acetaminophen with child ADHD.

ConclusionsAlthough unobserved confounding and confounding by indication are possible, these results warrant further investigation into adverse perinatal effects of prenatal acetaminophen exposure.


title: TOWARD DEVELOPMENT OF GUIDELINES FOR VIRTUAL ADMINISTRATION OF STANDARDIZED LANGUAGE AND LITERACY ASSESSMENTS: RECOMMENDATIONS FOR CLINICIANS AND RESEARCHERS

abstract:
ObjectivesPrevious virtual care literature within the field of speech-language pathology has focused primarily on validating the virtual use of intervention programs. There are fewer articles addressing the validity of conducting standardized paediatric oral language and literacy assessments virtually. Additionally, there is a lack of practical recommendations available on how best to conduct these assessment measures virtually. Given the rapid rise in virtual care as a result of the COVID-19 pandemic, clinicians and researchers require guidance on best practices for virtual administration of these tools imminently.

MethodsWe identified six key themes for recommendations based on two sources (1) our lab meeting discussions and (2) the outcomes of a narrative review of the extant literature. We then conducted semi-structured interviews with a group of 12 clinicians, students and researchers who had administered standardized language and literacy assessments with a variety of monolingual and multilingual school-aged children, with and without speech and language difficulties, in clinical and research settings to generate recommendations within these themes. Subsequently, in line with the Guidelines International Network, these recommendations were rated by group members, and reviewed by external stakeholders. A quasi-delphi consensus procedure was used to reach agreement on ratings for recommendations.

ResultsWe have developed recommendations for the use of standardized language and literacy assessments in virtual care, across six key themes: candidacy for virtual assessment, communication and collaboration with caregivers, technology and equipment, virtual administration, ethics, consent and confidentiality, and considerations for bilingual populations.

ConclusionsThis paper is one of the first to share practical recommendations for virtual assessment in the domain of paediatric oral language and literacy assessment. We hope these recommendations will facilitate future clinical research and that as the body of research grows, that this paper will act as a basis for the development of formal Clinical Practice Guidelines.


title: Toward Development of Guidelines for Virtual Administration of Paediatric Standardized Language and Literacy Assessments: Recommendations for Clinicians and Researchers


title: Intensified stimulation targeting lateral and medial prefrontal cortices for the treatment of social anxiety disorder: A randomized, double-blind, parallel-group, dose-comparison study

abstract:
BackgroundSocial Anxiety Disorder (SAD) is the most common anxiety disorder while remains largely untreated. Disturbed amygdala-frontal network functions are central to the pathophysiology of SAD, marked by hypoactivity of the lateral prefrontal cortex (PFC), and hypersensitivity of the medial PFC and amygdala. The objective of this study was to determine whether modulation of dorsolateral and medial PFC activity with a novel intensified stimulation protocol reduces SAD core symptoms, improves treatment-related variables, and reduces attention bias to threatening stimuli.

MethodsIn this randomized, sham-controlled, double-blind trial, we assessed the efficacy of an intensified stimulation protocol (20 min, twice-daily sessions with 20 min intervals, 5 consecutive days) in two intensities (1 vs 2 mA) compared to sham stimulations. 45 patients with SAD were randomized in three tDCS arms. SAD symptoms, treatment-related variables (worries, depressive state, emotion regulation, quality of life), and attention bias to threatening stimuli (dot-probe paradigm) were assessed before and right after the intervention. SAD symptoms were also assessed at 2-month follow-up.

ResultsBoth 1 mA and 2mA protocols significantly reduced fear/avoidance symptoms, worries and improved, emotion regulation and quality of life after the intervention compared to the sham group. Improving effect of the 2 mA protocol on avoidance symptoms, worries and depressive state was significantly larger than the 1 mA group. Only the 2 mA protocol reduced attention bias to threat-related stimuli, the avoidance symptom at follow-up, and depressive states, as compared to the sham group.

ConclusionsModulation of lateral-medial PFC activity with intensified stimulation can improve cognitive control, motivation and emotion networks in SAD and thereby results in therapeutic effects. These effects can be larger with 2 mA vs 1 mA intensities, though a linear relationship between intensity and efficacy should not be concluded.

category: psychiatry and clinical psychology


title: Initiation and completion of treatment for latent tuberculosis infection in migrants globally: A systematic review and meta-analysis

abstract:
BackgroundLatent Tuberculosis (LTBI) is one of the most prevalent infections globally and is key in development of active tuberculosis disease (TB). In many low-burden countries, LTBI is concentrated within migrant populations reflecting higher disease burden in some countries of origin; national programmes may consequently focus on screening and treating LTBI in migrants to prevent future TB cases. However, little is known about the extent to which migrants initiate treatment for LTBI when testing positive, and their treatment outcomes, which is urgently needed if we are to strengthen these programmes, improve migrant health, and meet TB elimination targets.

MethodsWe did a systematic review and meta-analysis, following PRISMA guidelines and PROSPERO registered (CRD42019140338) to pool global data on LTBI initiation and completion amongst migrants (defined as foreign born), and secondary outcomes to explore the range of both personal and provider level factors associated with initiation and completion. We searched Embase, Medline and Global Health, and hand-searched grey literature (from Jan 1 2000 to Apr 21 2020). Inclusion criteria were primary research articles reporting on LTBI treatment initiation and/or completion amongst migrants; we excluded papers where data were not stratified by migrant status, or where the data related to outcomes prior to the year 2000. There were no geographical or language restrictions.

Results39 publications were included from 13 countries, with treatment initiation and completion data for 31,598 LTBI positive migrants. Overall, 69% (95% CI=51-84%; I2=99.62%) of these initiated treatment; 74% (95% CI=66-81%; I2=99.19%) of migrants who initiated treatment, completed it; among studies with data on the complete pathway from screening positive to completing treatment, 52% (95% CI=40-64%; I2=98.90%) successfully completed treatment. Meta-regression showed that LTBI programmes are improving, with more recent reported data (2010-2020) associated with better rates of treatment initiation and completion. European studies also appeared to have more successful outcomes than those in the Americas and Western Pacific WHO regions.

ConclusionsLTBI treatment initiation and completion amongst migrants have room for improvement. Though the data show improvements in the past decade, the delivery of these programmes will need further strengthening if we are to meet targets to eradicate TB in low-incidence countries. Greater focus will need to be placed on engaging migrants more effectively in the clinic and understanding the diverse barriers and facilitators to migrants initiating and completing treatment. Such efforts must be mindful of, and sensitive to the unique experiences individuals arriving in a new country.

FundingThis study was funded by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) through a joint ESCMID Study Group for Infections in Travellers and Migrants (ESGITM) and ESCMID Study Group for Mycobacterial Infections (ESGMYC) Study Group Research grant, the Rosetrees Trust (PhD studentship grant M775), the NIHR (NIHR Advanced Fellowship NIHR300072), and the Academy of Medical Sciences (SBF005\1111).

O_TEXTBOXO_TEXTBOXNOPanel: Research in ContextC_TEXTBOXNO Evidence before this studyLatent tuberculosis infection (LTBI) is one of the most prevalent infections globally, affecting an estimated 25% of the population; re-activation of LTBI is a major driver of tuberculosis (TB) cases worldwide. In low-incidence TB countries, TB and LTBI are often disproportionately concentrated amongst foreign born individuals, with national programmes increasingly focusing on the diagnosis and treatment of LTBI in migrants and other high-risk groups to prevent future TB cases and meet global elimination targets. However, little is known about the success of these programmes in engaging migrants and ensuring treatment completion - a population who often face multiple barriers to accessing health care on arrival to the host country. Prior to this review we scoped the literature and found two relevant reviews on this topic (Sandgren et al., 2016 & Alsdurf et al., 2016) but which did not specifically focus on migrants and/or lacked formal meta-analyses, and one/both used earlier data pre 2000 that may be less relevant now to current policy. Other studies have reported on migrant-specific outcomes in LTBI programmes globally, but the focus is often on screening practices rather than outcomes and all evidence in this area has not yet been effectively consolidated.

Added value of this studyThis is the first systematic review and meta-analysis specifically exploring LTBI treatment initiation and completion among migrant populations. We report LTBI treatment outcome data on 31,598 migrants from the year 2000 onwards within 13 low-incidence countries (<10 cases per 100,000). The research provides robust insights into the proportion of individuals initiating and completing treatment, using meta-regression to explore heterogeneity. The data show that between 2000-2020, 69% of migrants testing positive for LTBI initiated treatment, and of those starting treatment, approximately 74% completed it. Amongst studies capturing data on both initiation and completion, 52% of LTBI positive migrants successfully initiated and completed. The data also indicate higher initiation and completion in more recent years (2010-2020) with renewed focus on this approach to TB control, and a trend toward more positive outcomes amongst migrants in programmes in the WHO European region. The data show that multiple complex factors impact on treatment outcomes in migrants, including patient demographics and health systems. The evidence was ambivalent with some studies demonstrating positive and detrimental outcomes associated with foreign-born status.

Implications of all the available evidenceDelivery of LTBI programmes will need to be strengthened to improve outcomes in migrants and meet targets to eradicate TB in low-incidence countries. Greater focus will need to be placed on engaging migrants more effectively in the clinic, understanding the varied reasons for migrants declining treatment when testing positive, and ensuring treatment adherence using innovative approaches that are mindful of and sensitive to the unique experiences of this group on arrival to the host country.

C_TEXTBOX


title: Participatory research in health intervention studies involving migrants: a systematic review

abstract:
ObjectiveTo analyse the use of participatory approaches in research of health interventions for migrants, and how utilised approaches embody core participatory principles of democracy and power-distribution.

DesignA systematic review of original articles. Electronic searchers were carried out in the databases MEDLINE, Embase, Global Health and PsychINFO (from inception - Nov 2020).

Eligibility criteria for study selectionThe analysis included original peer-reviewed research which reported on attempts to develop and implement a health intervention for migrants using participatory approaches. We defined migrants as foreign-born individuals; studies using definitions demonstrably outside of this were excluded. Only articles reporting the full research cycle (inception, design, implementation, analysis, evaluation, dissemination) were included.

Data extractionInformation related to who was involved in research (migrants or other non-academic stakeholders), the research stage at which they were involved (inception, design, implementation, analysis, evaluation, dissemination), and how this involvement aligned with the core principles of participatory research - categorising studies as exhibiting active, pseudo, or indirect participation of migrants.

Results1793 publication were screened of which 28 were included in our analysis. We found substantial variation in the application of participatory research approaches: across 168 individual research stages analysed across the 28 studies, we recorded 46 instances of active participation of migrants; 30 instances of proxy participation; and 24 instances of indirect participation. Whilst all studies involved at least one non-academic stakeholder group in at least one stage of the research, just two studies exhibited evidence of active participation of migrants across all research stages.

ConclusionsThese data highlight important shortfalls in the inclusion of migrant groups in developing health interventions that affect their lives and suggest a more rigorous and standardised approach to defining and delivering participatory research is urgently needed to improve the quality of participatory research.

RegistrationThis review followed PRISMA guidelines and is registered on the Open Science Framework (osf.io/2bnz5)

Strengths and LimitationsO_LIThis systematic review represents a robust and novel assessment of the applications of participatory approaches and principles to health intervention research with migrants.
C_LIO_LIThis review casts a critical lens over the application and outcomes of participatory approaches, conceptually focusing on the relationship between the methods used and the populations involved, and how this all relates to participatory principles.
C_LIO_LIThis review is limited by the varied and interchangeable use of participatory research terms within this field. The categorisations and terms we introduce may therefore be defined differently by others.
C_LIO_LIThis review is limited by the lack of clear and consistent reporting of participatory methods utilised; guidelines must be prepared and consistently adopted to improve transparency in all participatory research.
C_LIO_LIThis does not analyse or consider associations between participatory methods, and health or research outcomes; future research to understand any such associations is needed.
C_LI


title: Prescribed footwear and orthoses are not prophylactic in preventing lower extremity injuries in military tactical athletes. A systematic review with meta-analysis.

abstract:
IntroductionMilitary members are exposed to high cumulative physical loads that frequently lead to injury. Prescribed footwear and orthoses have been used to prevent injury. The purpose of this systematic review with meta-analysis was to assess if prescribed prophylactic footwear or foot orthoses reduced lower extremity injury risk in military tactical athletes.

MethodsMEDLINE, Embase, Web of Science, CINAHL, SportDiscus, and DTIC databases were searched for randomized controlled trials published at any time that compared foot orthoses or prescribed footwear (to include shock-absorbing insoles and socks) to a placebo intervention or a no-treatment control. Methodological quality was assessed and numbers of injuries, population at risk, and the duration of the study epoch were extracted and relative risk (RR) calculated. An omnibus meta-analysis was performed assessing all prescribed footwear and orthoses intervention studies, with subgroup analyses conducted on studies with similar interventions [i.e., basketball athletic shoes; athletic shoes (prescribed by foot type); foot orthoses; shock-absorbing insoles; socks; tropical combat boots].

ResultsOf 1,673 studies identified, 22 studies were included. Three of eight studies that employed orthoses demonstrated significantly reduced overuse injuries compared to no treatment controls (RR range: 0.34-0.68); one study showed neoprene insoles significantly decreased overuse injuries (RR: 0.75). There were no other significant effects in the individual studies, and no protective effects observed in the omnibus meta-analysis or in the component sub analyses.

ConclusionsPrescribed footwear and orthoses do not appear to have a prophylactic effect on lower quarter MSKI in military members and cannot be recommended at this time.

category: sports medicine


title: Early microbiome and metabolome signatures in pediatric patients undergoing allogeneic hematopoietic cell transplantation

abstract:
BackgroundThe contribution of the gastrointestinal tract microbiome to outcomes after allogeneic hematopoietic cell transplantation (HCT) is increasingly recognized. Investigations of larger pediatric cohorts aimed at defining the microbiome state and associated metabolic patterns pre-transplant are needed.

MethodsWe sought to describe the pre-transplant stool microbiome in pediatric allogenic HCT patients at four centers. We performed shotgun metagenomic sequencing and untargeted metabolic profiling on pre-transplant stool samples. Samples were compared with normal age-matched controls and by clinical characteristics. We then explored associations between stool microbiome measurements and metabolite concentrations.

ResultsWe profiled stool samples from 88 pediatric allogeneic HCT patients, a median of 4 days before transplant. Pre-transplant stool samples differed from healthy controls based on indices of alpha diversity and in the proportional abundance of specific taxa and bacterial genes. Relative to stool from healthy patients, samples from HCT patients had decreased proportion of Bacteroides, Ruminococcaeae and genes involved in butyrate production, but were enriched for gammaproteobacterial species. No systematic differences in stool microbiome or metabolomic profiles by age, transplant indication or hospital were noted. Stool metabolites demonstrated strong correlations with microbiome composition.

DiscussionStool samples from pediatric allogeneic HCT patients demonstrate substantial dysbiosis early in the transplant course. As microbiome disruptions associate with adverse transplant outcomes, pediatric-specific analyses examining longitudinal microbiome and metabolome change are imperative to identify causal associations and to inform rational design of interventions.

category: transplantation


title: Adaptive doctors: preparing tomorrows doctors for practice in the Anthropocene Epoch

abstract:
BackgroundThe future health workforce needs to be equipped with the knowledge, skills, and motivation to deliver sustainable healthcare and promote planetary health. The aim of this study was to design, implement and evaluate a new suite of planetary health learning activities piloted by medical students for a range of medical professionals.

MethodsThe study consisted of three components: curriculum mapping, development of learning activities and evaluation. Curriculum mapping involved searching program learning outcomes using relevant search terms. Two learning activities were co-developed with medical students comprising of an e-learning component and an inquiry-based small group workshop presented to 99 2nd year students. Evaluation consisted of pre- and post-learning knowledge quizzes and a student feedback survey.

ResultsA total of 30 learning outcomes were identified with the majority located in the first two years of the four-year program. The overall evaluation response rate was 49.5%, and 19% completed the feedback survey. The mean pre- and post-lesson scores, respectively, were 7.09 (SD=1.84) and 9.53 (SD=1.69) out of a possible score of 12, increasing by 2.37 points on average (95% confidence interval [CI] 1.66-3.09). Overall, the new activities were rated as excellent/good by 84.2% of respondents. The e-learning module rated more highly as a meaningful learning experience than the workshop (89% v. 63.2%). The most common criticism was the length of time it took to complete the e-learning.

ConclusionStudents already had a good understanding of planetary health  facts and the e-learning lesson served to confirm, review and update their knowledge. Students embraced the opportunity to engage in interactive learning through the problem-solving group work activity. There is very little vertical alignment of environmental and climate issues across all four years of the medical program in our institution and a variety of learning approaches should be considered when revising the curriculum.

category: medical education


title: The impact of co-circulating pathogens on SARS-CoV-2/COVID-19 surveillance. How concurrent epidemics may decrease true SARS-CoV-2 percent positivity.

abstract:
BackgroundCirculation of non-SARS-CoV-2 respiratory viruses during the COVID-19 pandemic may alter quality of COVID-19 surveillance, with possible consequences for real-time analysis and delay in implementation of control measures. Here, we assess the impact of an increased circulation of other respiratory viruses on the monitoring of positivity rates of SARS-CoV-2 and interpretation of surveillance data.

MethodsUsing a multi-pathogen Susceptible-Exposed-Infectious-Recovered (SEIR) transmission model formalizing co-circulation of SARS-CoV-2 and another respiratory we assess how an outbreak of secondary virus may inflate the number of SARS-CoV-2 tests and affect the interpretation of COVID-19 surveillance data. Using simulation, we assess to what extent the use of multiplex PCR tests on a subsample of symptomatic individuals can support correction of the observed SARS-CoV-2 percent positive during other virus outbreaks and improve surveillance quality.

ResultsModel simulations demonstrated that a non-SARS-CoV-2 epidemic creates an artificial decrease in the observed percent positivity of SARS-CoV-2, with stronger effect during the growth phase, until the peak is reached. We estimate that performing one multiplex test for every 1,000 COVID-19 tests on symptomatic individuals could be sufficient to maintain surveillance of other respiratory viruses in the population and correct the observed SARS-CoV-2 percent positive.

ConclusionsThis study highlights that co-circulating respiratory viruses can disrupt SARS-CoV-2 surveillance. Correction of the positivity rate can be achieved by using multiplex PCR, and a low number of samples is sufficient to avoid bias in SARS-CoV-2 surveillance.

SummaryCOVID-19 surveillance indicators may be impacted by increased co-circulation of other respiratory viruses delaying control measure implementation. Continued surveillance through multiplex PCR testing in a subsample of the symptomatic population may play a role in fixing this problem.

category: epidemiology


title: The Effect of Adolescent Pregnancy on Child Mortality in 46 Low- and Middle-Income Countries

abstract:
IntroductionAdolescent pregnancy is a known health risk to mother and child. Statements and reports of health outcomes typically group mothers under 20 years old together. Few studies examined this risk at a finer age resolution, none of them comprehensively, and with differing results.

MethodsWe analyzed Demographic and Health Surveys (DHS) data from 2004-2018 in Sub-Saharan Africa (SSA) and South Asia, on firstborn children of mothers 25 years old or younger. We examined the association between maternal age and stillbirths, and rates of neonatal (NNMR), infant (IMR), and under-5 mortality (U5MR), using mixed-effects logistic regression adjusting for major demographic variables and exploring the impact of maternal health-seeking.

ResultsIn both regions and across all endpoints, mortality rates of children born to mothers aged <16 years, 16-17 years, and 18-19 years at first birth were about 2-4 times, 1.5-2 times, and 1.2-1.5 times higher, respectively, than among firstborn children of mothers aged 23-25. Absolute mortality rates declined over time, but the age gradient remained similar across time periods and regions. Adjusting for rural/urban residence and maternal education, in SSA in 2014-2018 having a <16 year old mother was associated with odds ratio (ORs) of 3.71 [95% CI 2.50-5.51] for stillbirth, 1.92 [1.60-2.30] for NNMR, 2.13 [1.85-2.46] IMR, and 2.39 [2.13-2.68] U5MR, compared with having a mother aged 23-25. In South Asia in 2014-2018 ORs were 5.12 [2.85-9.20] stillbirth, 2.46 [2.03-2.97] NNMR, 2.62 [2.22-3.08] IMR, and 2.59 [2.22-3.03] U5MR. Part of the effect on NNMR and IMR may be mediated by a lower maternal health-seeking rate.

ConclusionsAdolescent pregnancy is associated with dramatically worse child survival and mitigated by health-seeking behavior, likely reflecting a combination of biological and social factors. Refining maternal age reporting will avoid masking the increased risk to children born to very young adolescent mothers. Collection of additional biological and social data may better reveal mediators of this relationship. Targeted intervention strategies to reduce unintended pregnancy at earlier ages may also improve child survival.

What is already known?O_LIMost previous studies treat under-20 mothers as a single group when looking at risk of child health outcomes.
C_LIO_LIFew studies have assessed the risk gradient versus age within this group, focusing only on neonatal and infant mortality rather than broader child survival outcomes.
C_LIO_LIThese studies found a higher risk of neonatal and infant mortality among younger adolescent mothers, even after adjusting for socio-economic, demographic and health service accessibility variables.
C_LIO_LIThe risk gradients for stillbirths and under-5 mortality outcomes of children born to adolescent mothers remain unexplored.
C_LI

What are the new findings?O_LIThis is the most comprehensive, multi-regional study to-date that investigated the potential impacts of adolescent pregnancy, examining multiple child survival endpoints from stillbirths to under-5 mortality, and quantifying the risk gradient as a function of maternal age from adolescence through young adulthood.
C_LIO_LIChildren of mothers younger than 16 faced 2-4 times higher risk of death at all child mortality stages (stillbirths, neonatal, infant, and under-5) in both sub-Saharan Africa and South Asia regions.
C_LIO_LIThe association extends across socio-economic status (SES) groups in both urban and rural settings and stays consistent when controlling for maternal education and health seeking risk factors.
C_LI

What do the new findings imply?O_LIWe recommend revision of maternal-age-group reporting conventions to make the increased child survival risk with adolescent pregnancy more visible.
C_LIO_LITo improve child survival outcomes, improving health-seeking behavior and quality of maternal care, as well as targeted interventions to reduce unintended pregnancy among adolescents and mitigate its harmful consequences are needed.
C_LIO_LICollecting additional data on the social and biological aspects of adolescent pregnancy could help understand the impact size of these mediators on child health outcomes.
C_LI

category: public and global health


title: NEWS-2 score assessment of inpatient referral during the COVID 19 epidemic

abstract:
AimTo manage patients with suspected coronavirus disease (COVID-19) when they arrive at the hospital emergency department (ED), a clinical severity score is required to quickly identify patients requiring immediate hospital admission and close monitoring. The aim of this study was to evaluate, within the context of the pandemic, the performance of National Early Warning Score 2 (NEWS-2) to anticipate the admission of patients with suspected COVID-19 to a specialised emergency care unit.

MethodsThis retrospective study was conducted on patients presenting at the COVID-19 entrance of the ED of the Vert-Galant private hospital (Paris, France) during the first national pandemic peak from March 20 to April 20, 2020. All patients completed a questionnaire and clinical data and vital signs were recorded. Statistical analysis and modelling were used to estimate the ability of different scores (NEWS-2, qSOFA, CRB-65) to predict hospital emergency admission and/or early COVID-19 diagnosis.

ResultsNEWS-2, with a cut off value of 5, predicted hospital admission with 82% sensitivity, 98% specificity and an area under the curve (AUC) of 96%. NEWS-2 was superior to qSOFA and CRB-65 scores for predicting hospital admission of COVID-19 patients. Multilinear or logistic regression analysis of clinical data did not improve this result.

ConclusionNEWS-2 is an excellent score to predict hospital admission of COVID-19 patients.

category: emergency medicine


title: Short-term variability of proton density fat fraction in pancreas and liver assessed by multi-echo chemical-shift encoding-based MRI at 3 T

abstract:
BACKGROUNDQuantification of pancreatic fat (PF) and intrahepatic lipids (IHL) is of increasing interest in cross-sectional epidemiological and interventional studies in subjects at risk for metabolic diseases. Up to now, short- and medium-term variations as well as their dependence on actual nutritional status are almost unknown.

PURPOSE or HYPOTHESISTo assess short-term intraday variations of PF/IHL after a high-fat meal as well as medium-term changes after 5 days of high-caloric diet with a 1500 kcal surplus on individual daily energy requirement.

STUDY TYPE(retrospective/prospective/longitudinal/case control/cohort etc.) Prospective cohort study.

SUBJECTSTwelve healthy subjects (6m/6f) for intraday variations, 15 healthy male subjects for medium-term high-caloric diet and 11 age- and BMI-matched controls.

FIELDSTRENGTH/SEQUENCE3 T whole-body imager (Magnetom Vida, Siemens Healthineers, Erlangen, Germany), assessment of proton density fat fraction by chemical-shift encoded MRI (multi-echo gradient echo sequence, qDixon).

ASSESSMENTManually drawn regions of interest in head, body and tail of pancreas as well as in liver by an experienced medical physicist carefully avoiding inclusion of surrounding visceral fat (pancreas) or blood-vessels (liver).

STATISTICAL TESTS (please list the significance level)Repeated measurements Anova for variabilities of PF and IHL, linear correlation analyses for relation of PF, IHL and BMI. Significance level p < 0.05 for all.

RESULTS (must have numerical data and statistical testing for each phrase)Non-significant changes in PF in both studies (2.5{+/-}0.9 vs. 2.5{+/-}1.0% after high-fat meal, 1.4{+/-}0.8 vs. 1.6{+/-}0.6% after high-caloric diet and 1.6{+/-}0.7 vs. 1.8{+/-}1.0% in the isocaloric control group), unchanged IHL after high-fat meal (2.5{+/-}0.9 vs. 2.4{+/-}1.0 %) and in the control group (1.1{+/-}0.6 vs. 1.2{+/-}1.1%), but significantly increased IHL after 5-day high-caloric diet (1.6{+/-}2.2% vs. 2.6{+/-}3.6%, p < 0.05).

DATA CONCLUSIONDaytime and nutritional status have no significant influence on ectopic fat depots in pancreas and liver and will therefore represent no major confounders in epidemiologic or clinical studies.


title: EFFECTIVENESS OF ACAMPROSATE FOR TINNITUS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF CLINICAL TRIALS

abstract:
IntroductionThe effectiveness of tinnitus treatment represents a huge gap in the medical science. Acamprosate is a glutamatergic antagonist drug and GABA-agonist that could be used to control tinnitus due to its action on peripheral and central neurotransmission.

PurposeTo assess the effectiveness of acamprosate in the treatment of tinnitus.

Material and MethodsThis is a systematic review and we searched for randomized clinical trials linking acamprosate to tinnitus in six databases: Cochrane - Central Register of Controlled Trials - CENTRAL (2021), PUBMED (1966-2021), EMBASE (1974-2021), IBECS (1982-2021), QINSIGHT (2021) and SCOPUS (2021). Two researchers independently extracted the data and assessed the quality of the studies.

ResultsTwo trials involving 121 patients were included. The methodological quality of these studies was low. Both studies evaluated as primary outcome the efficacy of acamprosate in improving tinnitus. The meta-analysis by random model resulted in no significant difference between the groups treated with acamprosate and placebo (RR = 3,69, 95% CI 0,87-15,62; p=0,08), considering tinnitus improvement. Conclusions: There is no evidence that acamprosate is effective for tinnitus treatment. We recommend new trials using rigorous methodology. Randomization and blinding should be of the highest quality, given the subjective nature of tinnitus and the strong likelihood of a placebo response. The CONSORT statement should be used in the design and reporting of future studies.

category: otolaryngology


title: Prevalence of uncoupling protein one genetic polymorphisms and their relationship with cardiovascular and metabolic health

abstract: The contribution of UCP1 single nucleotide polymorphisms (SNPs) to susceptibility for cardiometabolic pathologies (CMP) and their involvement in specific risk factors for these conditions varies across populations. We tested whether UCP1 SNPs A-3826G, A-1766G, Ala64Thr and A-112C are associated with the most common CMP (cardiovascular disease, hypertension, metabolic syndrome, and type-2 diabetes) and CMP risk factors. This case-control study included blood sample collection from 2,283 Caucasians (1,139 healthy; 1,144 CMP) across Armenia, Greece, Poland, Russia and United Kingdom for genotyping of the above-mentioned SNPs. We extended the results via a systematic review and meta-analysis, covering PubMed, Embase, and Cochrane Library databases. In Armenia the GA genotype and A allele of Ala64Thr were associated with [~]2-fold higher risk for CMP compared to the GG genotype or G allele, respectively (p<0.05). In Greece, A allele of Ala64Thr SNP decreased the risk of CMP by 39%. Healthy individuals with A-3826G GG genotype and carriers of mutant allele of A-112C and Ala64Thr had higher body mass index compared to those carrying other genotypes. In healthy Polish, higher waist-to-hip ratio (WHR) was observed in heterozygotes A-3826G compared to AA homozygotes. Heterozygosity of the A-112C and Ala64Thr SNPs was related to lower WHR in CMP individuals compared to wild type homozygotes (p<0.05). Meta-analysis in case-control studies showed no statistically significant odds ratios in different alleles across the four studied SNPs (p>0.05). Thus, we conclude that the studied SNPs could be associated with the most common CMP and their risk factors in some populations.


title: A novel strategy for the detection of SARS-CoV-2 variants based on multiplex PCR-MALDI-TOF MS

abstract:
BackgroundThe second wave of coronavirus disease 2019 (COVID-19) has been incessantly causing catastrophe worldwide, and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants causes further uncertainty regarding epidemic risk. Here, a novel strategy for the detection of SARS-CoV-2 variants using multiplex PCR coupled with MALDI-TOF MS was developed.

MethodsPlasmids carrying gene sequences containing 9 mutation types in 7 mutated sites (HV6970del, N501Y, K417N, P681H, D614G, E484K, L452R, E484Q and P681R) in the receptor-binding domain of the spike protein of SARS-CoV-2 variants were synthesized. Using the nucleic acid sequence of SARS-CoV-2 nonvariant and a synthetic SARS-CoV-2-variant-carrying plasmid, a MALDI-TOF MS method based on the single-base mass probe extension of multiplex PCR amplification products was established to detect the above nine mutation types. The detection limit of this method was determined via the concentration gradient method. Twenty-one respiratory tract pathogens (9 bacteria, 11 respiratory viruses) and pharyngeal swab nucleic acid samples from healthy people were selected for specific validation. Sixteen samples from COVID-19 patients were used to verify the accuracy of this method.

ResultsThe 9 mutation types could be detected simultaneously by triple PCR amplification coupled with MALDI-TOF MS. SARS-CoV-2 and all six variants (B.1.1.7, B.1.351, B.1.429, B.1.526, P.1 and B.1.617) could be identified. The detection limit for all 9 sites was 1.5x103 copies. The specificity of this method was 100%, and the accuracy of real-time PCR CT values less than 30 among positive samples was 100%. This method is open and extensible, and can be used in a high-throughput manner, easily allowing the addition of new mutation sites as needed to identify and track new SARS-CoV-2 variants as they emerge.

ConclusionsMultiplex PCR-MALDI-TOF MS provides a new detection option with practical application value for SARS-CoV-2 and its variant infection.

Key pointAn all-in-one SARS-CoV-2 variant identification method based on a multiplex PCR-MALDI-TOF MS system was developed. All of the SARS-CoV-2 variants can be identified based on 9 types of 7 mutated sites of RBD of spike protein using this method.

category: infectious diseases


title: COVID-19 antibody detection and assay performance using red cell agglutination

abstract: Red cells can be labelled with peptides from the SARS-CoV-2 spike protein and used for serologic screening of SARS-CoV-2 antibodies. We evaluated 140 convalescent COVID-19 patients and 275 healthy controls using this C19-kodecyte assay. The analytical performance of the new assay was compared with a virus neutralizing assay and 2 commercial chemiluminescent antibody tests (Total assay and IgG assay, Ortho). The C19-kodecyte assay detected SARS-CoV-2 antibodies with a sensitivity of 92.8% and specificity of 96.3%, well within the minimum performance range required by FDA for EUA authorization of serologic tests. The Cohens kappa coefficient was 0.90 indicating an almost perfect agreement with the Total assay. The Pearson correlation coefficient was 0.20 with the neutralizing assay (0.49 with IgG, and 0.41 with Total assays). The limited correlation in assay reaction strengths suggested that the assays may detect different antibody specificities. Our easily scalable C19-kodecyte assay may vastly improve test capacity in blood typing laboratories using their routine setups for column agglutination technique.


title: Impact of baseline SARS-CoV-2 antibody status on syndromic surveillance and the risk of subsequent Covid-19 -- a prospective multicentre cohort study

abstract:
ObjectivesIn a prospective healthcare worker (HCW) cohort, we assessed the risk of SARS-CoV-2 infection according to baseline serostatus.

MethodsBaseline serologies were performed among HCW from 23 Swiss healthcare institutions between June and September 2020, before the second COVID-19 wave. Participants answered weekly electronic questionnaires covering information about nasopharyngeal swabs (PCR/rapid antigen tests) and symptoms compatible with Coronavirus Disease 2019 (COVID-19). Screening of symptomatic staff by nasopharyngeal swabs was routinely performed in participating facilities. We compared numbers of positive nasopharyngeal tests and occurrence of COVID-19 symptoms between HCW with and without anti-nucleocapsid antibodies.

ResultsA total of 4818 HCW participated, whereof 144 (3%) were seropositive at baseline. We analysed 107820 questionnaires with a median follow-up of 7.9 months. Median number of answered questionnaires was similar (24 vs. 23 per person, P=0.83) between those with and without positive baseline serology. Among 2713 HCW with [≥]1 SARS-CoV-2 test during follow-up, 3/67 (4.5%) seropositive individuals reported a positive result (one of whom asymptomatic), compared to 547/2646 (20.7%) seronegative participants, 12 of whom asymptomatic (risk ratio [RR] 0.22; 95% confidence interval [CI] 0.07 to 0.66). Seropositive HCWs less frequently reported impaired olfaction/taste (6/144, 4.2% vs. 588/4674, 12.6%, RR 0.33, 95%-CI: 0.15-0.73), chills (19/144, 13.2% vs. 1040/4674, 22.3%, RR 0.59, 95%-CI: 0.39-0.90), and limb/muscle pain (28/144, 19.4% vs. 1335/4674, 28.6%, RR 0.68 95%-CI: 0.49-0.95). Impaired olfaction/taste and limb/muscle pain also discriminated best between positive and negative SARS-CoV-2 results.

ConclusionsHaving SARS-CoV-2 anti-nucleocapsid antibodies provides almost 80% protection against SARS-CoV-2 re-infection for a period of at least eight months.


title: A clinical observational analysis of aerosol emissions from dental procedures.

abstract: Aerosol generating procedures (AGPs) are defined as any procedure releasing airborne particles <5 m in size from the respiratory tract. There remains uncertainty about which dental procedures constitute AGPs. We quantified the aerosol concentration generated during a range of periodontal, oral surgery and orthodontic procedures using an aerodynamic particle sizer, which measures the total concentration and size distribution across the 0.5-20 m diameter size range. Measurements were conducted in an environment with a sufficiently low background to detect a patients cough, enabling confident identification of aerosol. Phantom head control experiments for each procedure were performed under the same conditions as a comparison. Where aerosol was detected during a patient procedure, we assessed whether the size distribution could be explained by the non-salivary contaminated instrument source in the respective phantom head control procedure, using a two-sided unpaired t-test (comparing the mode widths (log({sigma})) and peak positions (DP,C)). The aerosol size distribution provided a robust fingerprint, describing aerosol emission from a source. 41 patients underwent fifteen different dental procedures. For nine of these, no aerosol was detected above background. Where aerosol was detected, the percentage of procedure time that aerosol was observed above background ranged from 12.7% for ultrasonic scaling, to 42.9% for 3-in-1 air + water syringe. For ultrasonic scaling, 3-in-1 syringe use and surgical drilling, the aerosol size distribution matched the non-salivary contaminated instrument source, with no unexplained aerosol. High and slow speed drilling produced aerosol from patient procedures with different size distributions to those measured from the phantom head controls (mode widths log({sigma})) and peaks (DP,C) p< 0.002) and therefore, may pose a greater risk of salivary contamination. This study provides evidence for sources of aerosol generation during common dental procedures, enabling more informed evaluation of risk and appropriate mitigation strategies.

category: dentistry and oral medicine