title: Decline in pneumococcal disease in young children during the COVID-19 pandemic associated with suppression of seasonal respiratory viruses, despite persistent pneumococcal carriage: A prospective cohort study

abstract:
BackgroundInvasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from non-pharmacological interventions. We used multiple ongoing cohort surveillance projects in children <5 years to test this hypothesis.

MethodsThe first SARS-CoV-2 cases were detected in February-2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), non-alveolar lower respiratory infections necessitating chest X-rays (NA-LRI), nasopharyngeal pneumococcal carriage in non-respiratory visits, nasopharyngeal respiratory virus detection (by PCR), and nationwide invasive pneumococcal disease (IPD). Monthly rates (January-2020 through February-2021 vs. mean monthly rates 2016-2019 [expected rates]) adjusted for age and ethnicity, were compared.

FindingsCAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios, [IRRs] 0{eta}07 and 0{eta}19, respectively); NA-LRI and non-pneumonia IPD were also reduced, with a lesser magnitude (IRRs, 0{eta}46 and 0{eta}42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced and density of colonization and pneumococcal serotype distributions were similar to previous years. The pneumococcus-associated disease decline was temporally associated with a full suppression of RSV, influenza viruses, and hMPV, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels.

InterpretationReductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic were not predominantly related to reduced pneumococcal transmission and carriage but were strongly associated with the complete disappearance of specific respiratory viruses.

FundingPartially funded by Pfizer, Inc.

category: epidemiology


title: BIOCHEMICAL AND HAEMATOLOGICAL CHANGES ASSOCIATED WITH TRANSPLACENTAL CONGENITAL MALARIA IN KOGI STATE, NORTH CENTRAL NIGERIA

abstract: BackgroundTransplacental congenital malaria is a vertical transplacental transmission of malaria parasites from the mother to the baby in utero or perinatally during labor. Cord blood that conveyed oxygen and nutrients from mother to fetus and return with carbon dioxide and other waste materials can transmit malaria pathogen. This study is aim to establish early diagnosis of transplacental congenital malaria using cord blood biochemical and haematological indices. Cord blood from 164 babies delivered at three hospitals in Kogi State between January and December, 2020 were microscopically investigated for malaria parasite. Biochemical and Haematological analyses were done using SYSMEX XP-300, Roche 9180 and VIS Spectrophotometer model 721. The data obtained were expressed as mean {+/-}standard deviation using SPSS 23. The indicator level of statistical significance was set at p<0.05. The results showed significant (p<0.05) decreased in values of WBC, platelet, sodium, potassium, urea, creatinine, RBC, PCV, haemoglobin and MCHC in malaria infected cord blood in comparison to malaria negative control group. Significant (P<0.05) increased activities of liver enzymes (AST, ALT, ALP), total protein, bicarbonate and chloride in malaria infected cord blood when compared with malaria negative group. However, no statistically significant difference in lymphocyte, MCV, MCH, neutrophil and mixed of both malaria infected and malaria negative cord blood. This study suggests that cord blood biochemical and haematological indices can be used to diagnose and manage transplacental congenital malaria in fetus and neonates.

category: pathology


title: Cognitive reserve in a sample of Cuban older adults with Mild Cognitive Impairment

abstract:
IntroductionAging is a natural process that occurs in all individuals. Due to the increase in aging figures worldwide, the diagnosis of mild cognitive impairment and other dementia syndromes has increased. An element of essential relevance in protecting against the risk of suffering from dementia is the cognitive reserve.

ObjectiveTo indicate the levels of cognitive reserve in a sample of Cuban older adults with Mild Cognitive Impairment.

MethodsAn exploratory study was carried out using questionnaires, with a cross-sectional, quantitative design. The sampling was non-probabilistic and intentional, obtaining a sample of 51 older adults with mild cognitive impairment. The information collection was carried out from the Cognitive Reserve Scale (CRS). Quantitative data was analyzed through frequency analysis.

ResultsMost of the participants showed higher levels of cognitive reserve for carrying out activities of daily life and for relating to other people. The dimensions most affected were Formation / Information and Hobbies.

ConclusionsThe research allowed a preliminary approach to the cognitive reserve of older adults. It would be interesting to conduct investigations of this nature in larger samples, including groups of healthy controls, which would allow comparison of results. In addition, it would be relevant to investigate the impact of institutionalization.

category: psychiatry and clinical psychology


title: The Effect of Image Resolution on Automated Classification of Chest X-rays

abstract: Deep learning models have received much attention lately for their ability to achieve expert-level performance on the accurate automated analysis of chest X-rays. Although publicly available chest X-ray datasets include high resolution images, most models are trained on reduced size images due to limitations on GPU memory and training time. As compute capability continues to advance, it will become feasible to train large convolutional neural networks on high-resolution images. To verify that this will lead to increased performance, we perform a systematic evaluation to measure the effect of input chest X-ray image resolution on accuracy. This study is based on the publicly available MIMIC-CXR-JPG dataset, comprising 377,110 high resolution chest X-ray images, and provided with 14 labels to the corresponding free-text radiology reports. Our original hypothesis that increased resolution would lead to higher accuracy held true for some but not all of the tasks. We find, interestingly, that tasks that require a large receptive field are better suited to downscaled input images, and we verify this qualitatively by inspecting effective receptive fields and class activation maps of trained models. Finally, we show that stacking an ensemble across resolutions outperforms each individual learner at all input resolutions while providing interpretable scale weights, suggesting that multi-scale features are crucially important to information extraction from high-resolution chest X-rays.

category: radiology and imaging


title: Failure of the choroid plexus in Alzheimer's disease

abstract: Aging and Alzheimers disease (AD), a major age-related disorder, are both characterized by inflammatory changes in the cerebrospinal fluid (CSF). The origin and the mechanisms underlying these inflammatory changes, however, remain poorly understood. Here, we report that aging elicits inflammatory changes in the CSF that become accentuated uniquely in AD compared to other inflammatory and neurodegenerative disorders. We show that the choroid plexus (ChP), which produces CSF, gains a pro-inflammatory profile, exhibits perturbed metabolism and contributes to the CSF changes observed in AD. We then use MRI imaging to establish a correlation between cognitive decline and increased volume of significantly remodelled ChP in patients with AD, and provide clinical relevance to the identified ChP pathology. These findings collectively suggest that ChP, unable to resolve inflammatory insults efficiently over the lifetime, participates in the inflammation and the pathogenesis of AD.

category: neurology


title: Pathogenesis of Alzheimer's disease: Involvement of the Choroid Plexus


title: The association between statin and COVID-19 adverse outcomes: National COVID-19 cohort in South Korea

abstract:
BackgroundThere currently exists limited and conflicting clinical data on the use of statins amongst COVID-19 patients. Given the both paucity and lack of consensus among data on statins efficacy and safety amongst COVID-19 patients, the current guideline is to continue statin in COVID-19 patients, who have previously been treated with statins. The aim of this paper was to compare hospitalized patients with COVID-19 who did and did not receive statins, in terms of COVID-19 outcomes.

MethodsWe conducted population-based retrospective study using South Koreas nationwide healthcare database as of May 15 2020. We identified 4,349 patients hospitalized with COVID-19 and aged 40 years or older. The cohort entry was defined as the date of hospitalization. Statin users were individuals with inpatient and outpatient prescription records of statins in the 240 days before cohort entry, and non-users were those without such records during this period. Our primary outcome was a composite endpoint of all-cause death, intensive care unit (ICU) admission, mechanical ventilation use and cardiovascular outcomes (myocardial infarction (MI), transient cerebral ischemic attacks (TIA) or stroke). We conducted inverse probability of treatment weighting (IPTW)-adjusted logistic regression analysis to estimate odds ratio (OR) and corresponding 95% confidence intervals (CI), to compare outcomes between statin users and non-users.

Findings1,115 patients were statin users (mean age = 65.9 years; 60% female), and 3,234 were non-users (mean age = 58.3 years; 64% female). Statin use was not associated with increased risk of the primary outcome (IPTW OR 0.82; 95% CI: 0.60-1.11). Subgroup analysis showed a protective role of statins, for individuals with hypertension (IPTW OR 0.40; 95% CI: 0.23-0.69, p for interaction: 0.0087).

InterpretationGiven that statins are not detrimental and that it may be beneficial amongst hypertensive patients and relatively cheap, we would encourage further investigation into statin for the prevention and treatment of COVID-19.

FundingYGCs work was partially supported by 2020R1G1A1A01006229 awarded by the National Research Foundation of Korea.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThere is limited and conflicting data reporting on statin use among COVID-19 patients, and its association with COVID-19 outcomes

Added value of this studyWe report no difference in COVID-19 outcomes between patients who used and did not use statins prior to COVID-19 diagnosis, except in hypertensive patients in which statins was shown to have a protective effect.

Implications of all the available evidenceAs statins are not detrimental and relatively cheap, we encourage further investigation into statin for the prevention and treatment of COVID-19.

category: infectious diseases


title: Binary toxin expression by Clostridioides difficile is associated with worse disease

abstract:
BackgroundThe incidence of Clostridioides difficile infection (CDI) has increased over the past two decades and is considered an urgent threat by the Centers for Disease Control. Hypervirulent strains such as ribotype 027, that possess genes for an additional toxin C. difficile binary toxin (CDT) are contributing to increased morbidity and mortality. In the mouse model, CDT activates Toll-like receptor 2 resulting in suppression of a protective type 2 innate immune response mediated by eosinophils.

MethodsWe retrospectively tested stool from 215 CDI patients for CDT by enzyme-linked immunosorbent assay (ELISA). Stratifying patients by CDT status, we assessed if disease severity and clinical outcomes correlated with CDT positivity. Additionally, we performed 16 S rRNA gene sequencing to examine if CDT positive samples had an altered fecal microbiota.

ResultsWe found that patients with CdtB, the pore forming component of CDT, detected in their stool were more likely to have severe disease and had higher 90-day mortality compared to CDT negative patients. CDT positive patients also had higher C. difficile bacterial burden and white blood cell counts. There was no significant difference in gut microbiome diversity between CDT positive and negative patients.

ConclusionsPatients with fecal samples that were positive for CDT had increased disease severity and worse clinical outcomes. Utilization of PCR and C. difficile Toxins A and B testing may not reveal the entire picture when diagnosing CDI and the detection of CDT-expressing strains may be valuable during patient treatment.

SummaryWe found that CDI patients with CDT detected in stool by immunoassay were more likely to have severe disease and had higher 90-day mortality.


title: Wastewater based surveillance system to detect SARS-CoV-2 genetic material for countries with on-site sanitation facilities: an experience from Bangladesh

abstract:
The presence of SARS-CoV-2 genetic materials in wastewater has become a matter of grave for many countries of the world. Wastewater based epidemiology, in this context, emerged as an important tool in developed countries where proper sewage system is available. Due to the recent shift in the spread of the infection from urban to rural areas, it is now equally important to develop a similar mechanism for rural areas as well. Considering the urgency of the issue a study was conducted in 14 districts of Bangladesh and a total of 238 sewage samples were collected in two different periods from December 2020 to January 2021. We are the first to propose a surveillance system for both urban and rural areas where a proper sewage system is absent. Based on RT-PCR analysis of the water samples, in more than 92% of cases, we found the presence of the SARS-COV-2 gene (ORF1ab, N, and Internal Control-IC). The trend of Ct value varies for different study locations. The spread of genetic material for on-site ({Delta}m = 0.0749) sanitation system was found more prominent than that of off-site sewage system ({Delta}m = 0.0219); which indicated the shift of genetic material from urban to rural areas. Wastewater samples were also measured for physicochemical parameters, including pH (6.30 - 12.50) and temperature (22.10 - 32.60) {o}C. The highest viral titer of 1975 copy/mL in sewage sample was observed in a sample collected from the isolation ward of the SARS-COV-2 hospital. Additionally, a correlation was found between bacterial load and SARS-CoV-2 genetic materials. The results indicated the association of increased Ct values with decreasing number of patients and vice versa. The findings reported in this paper contributed to the field of wastewater-based epidemiology dealing with SARS-COV-2 surveillance for developing countries where proper sewage system is absent and highlighting some of the challenges associated with this approach in such settings.

HighlightsO_LIDevelopment of wastewater-based surveillance system based on on-site sanitation system for developing countries.
C_LIO_LIAssociation of different environmental parameters with the presence of SARS CoV-2 genetic material in wastewater.
C_LIO_LIPrediction of the viral concentration of sewage system using viral load and copy number parameter.
C_LI

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title: External Validation of a Mobile Clinical Decision Support System for Diarrhea Etiology Prediction in Children: A Multicenter Study in Bangladesh and Mali

abstract:
BackgroundDiarrheal illness is a leading cause of antibiotic use for children in low- and middle-income countries. Determination of diarrhea etiology at the point-of-care without reliance on laboratory testing has the potential to reduce inappropriate antibiotic use.

MethodsThis prospective observational study aimed to develop and externally validate the accuracy of a mobile software application ("App") for the prediction of viral-only etiology of acute diarrhea in children 0-59 months in Bangladesh and Mali. The App used previously derived and internally validated models using combinations of "patient-intrinsic" information (age, blood in stool, vomiting, breastfeeding status, and mid-upper arm circumference), pre-test odds using location-specific historical prevalence and recent patients, climate, and viral seasonality. Diarrhea etiology was determined with TaqMan Array Card using episode-specific attributable fraction (AFe) >0.5.

ResultsOf 302 children with acute diarrhea enrolled, 199 had etiologies above the AFe threshold. Viral-only pathogens were detected in 22% of patients in Mali and 63% in Bangladesh. Rotavirus was the most common pathogen detected (16% Mali; 60% Bangladesh). The viral seasonality model had an AUC of 0.754 (0.665-0.843) for the sites combined, with calibration-in-the-large =-0.393 (-0.455 - -0.331) and calibration slope {beta}=1.287 (1.207 - 1.367). By site, the pre-test odds model performed best in Mali with an AUC of 0.783 (0.705 - 0.86); the viral seasonality model performed best in Bangladesh with AUC 0.710 (0.595 - 0.825).

ConclusionThe App accurately identified children with high likelihood of viral-only diarrhea etiology. Further studies to evaluate the Apps potential use in diagnostic and antimicrobial stewardship are underway.

category: public and global health


title: 'I don't feel like I'm learning how to be a doctor': early insights regarding the impact of Covid-19 on UK medical student professional identity

abstract:
PhenomenonProfessional identity development is recognised as a core goal of medical education alongside knowledge and skill acquisition. Identity is a complex entity that can be conceptualised as externally influenced, but individually constructed. Integration from legitimate bystander to  old timer of the medical community of practice provides a backdrop for individual negotiation of professional identity. During Covid-19, the medical community of practice and education experienced significant disruption. We sought to investigate how these disruptions impacted professional identity development by examining conflicts between students identities highlighted by the pressures of the pandemic.

ApproachA mixed-methods survey was distributed to medical students in the UK. The survey was active from 2nd May to 15th June 2020, during the height of the first wave of the Covid-19 pandemic in the UK. Operating within the paradigm of constructivism, we conducted a reflexive thematic analysis of qualitative responses. Analysis was focused around the disruption to medical education, actions taken by medical students during this disruption, and the tension between student actions where they existed in conflict.

FindingsThree themes were constructed to describe the identities that participants felt were in conflict during the first wave of the Covid-19 pandemic: Status and role as a future doctor; status and role as a student; and status and role as a member of the wider community. Students noted that lack of clinical exposure was detrimental to their education, implicitly recognising that many aspects of professional identity formation are forged in the clinical environment. Participants were keen to volunteer clinically but struggled to balance this with academic work. Participants worried about the risk to their families and the wider community, and wanted to ensure that their skills would add value to the clinical environment. Volunteers felt frustrated when they were unable to perform tasks which aligned with their identities as future doctors, with the exception of participants who worked as interim FY1s (FiY1s), which aligned well with the roles of FY1s.

InsightsAs hypothesised, the participants in this study experienced disruptions to their professional identity development during the first wave of the Covid-19 pandemic in 2020. This work provides early evidence, collected at the beginning of the pandemic, that the effects of disruptions to professional identity development were wide-reaching, often negative, and represent an important topic for future exploration. Given that the pandemic has highlighted areas of identity tension, these findings have the potential to provide insight into how medical training can better nurture professional identity development during and beyond international crises.

category: medical education


title: COVID-19 vaccine response in people with multiple sclerosis

abstract:
ObjectiveTo investigate the effect of disease modifying therapies on serological response to SARS-CoV2 vaccines in people with multiple sclerosis

Methods473 people with multiple sclerosis from 5 centres provided one or more dried blood spot samples and questionnaires about COVID-19. Information about disease and drug history was extracted from their medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV2 receptor binding domain. Seropositivity was expressed according to validated cut-off indices. Antibody titers were partitioned into tertiles using data from people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (Univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following SARS-CoV2 vaccine according to disease modifying therapy. We used regression modelling to explore the effect of factors including vaccine timing, treatment duration, age, vaccine type and lymphocyte count on vaccine response.

ResultsCompared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio 0.03; 95% confidence interval 0.01-0.06, p<0.001) and fingolimod (odds ratio 0.41; 95% confidence interval 0.01-0.12) were associated with lower seroconversion following SARS-CoV2 vaccine. All other drug groups did not differ significantly from the untreated cohort. Time since last anti-CD20 treatment and total time on treatment were significantly related with response to vaccination. Vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications.

InterpretationSome disease modifying therapies carry a risk of attenuated response to SARS-CoV2 vaccination in people with MS. We provide recommendations for the practical management of this patient group.


title: Preterm birth increases placental expression of multidrug resistance (MDR) transporters irrespective of prepregnancy body mass index (BMI)

abstract:
ContextPreterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition, however few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected pro-inflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype.

ObjectiveTo determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and pro-inflammatory cytokine levels are altered by PTB and maternal BMI.

Design and OutcomesA cross-sectional study was conducted to assess the effect of PTB (+/- chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin [IL]-6 and 8 expression in 60 preterm and 36 term pregnancies.

ResultsABCB1 expression was increased in preterm compared to term placentae (p=0.04). P-gp (p=0.008) and BCRP (p=0.01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, p=0.007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (p=0.0005), and PTC was associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes.

ConclusionsPTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6. This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.

category: obstetrics and gynecology


title: Specialized interferon ligand action in COVID19

abstract:
The impacts of IFN signaling on COVID19 pathology are multiple, with protective and harmful effects being documented. We report here a multi-omics investigation of IFN signaling in hospitalized COVID19 patients, defining the biosignatures associated with varying levels of 12 different IFN ligands. Previously we showed that seroconversion associates with decreased production of select IFN ligands (Galbraith et al, 2021). We show now that the antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of ligands, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage associate with levels of IFNB and IFNA6. Differential IFN ligand production is linked to distinct constellations of circulating immune cells. Lastly, IFN ligands associate differentially with activation of the kynurenine pathway, dysregulated fatty acid metabolism, and altered central carbon metabolism. Altogether, these results reveal specialized IFN ligand action in COVID19, with potential diagnostic and therapeutic implications.

IMPACT STATEMENTAnalysis of multi-omics signatures associated with 12 different IFN ligands reveals their specialized action in COVID19.

category: allergy and immunology


title: Design and quality control of large-scale two-sample Mendelian randomisation studies

abstract:
BackgroundMendelian randomization studies are susceptible to meta-data errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors.

MethodsWe invited cancer GWAS to share summary association statistics with the FAMRC and subjected the collated data to a comprehensive QC pipeline. We identified meta data errors through comparison of study-specific statistics to external reference datasets (the NHGRI-EBI GWAS catalog and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants:

1) GWAS hits for fatty acids, 2) GWAS hits for cancer and 3) a 1000 genomes reference set.

ResultsWe collated summary data from six fatty acid and 49 cancer GWAS. Meta data errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (13%). After resolving analytical issues and excluding unreliable data, we created a dataset of 219,842 genetic associations with 87 cancer types.

ConclusionIn this large MR collaboration, 13% of included studies were affected by a substantial meta data error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of post-GWAS analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).


title: COVID-19 pandemic in Saint Petersburg, Russia: combining surveillance and population-based serological study data in May, 2020 - April, 2021

abstract:
BackgroundThe COVID-19 pandemic in Russia has already resulted in 500,000 excess deaths, with more than 5.6 million cases registered officially by July 2021. Surveillance based on case reporting has become the core pandemic monitoring method in the country and globally. However, population-based seroprevalence studies may provide an unbiased estimate of the actual disease spread and, in combination with multiple surveillance tools, help to define the pandemic course. This study summarises results from four consecutive serological surveys conducted between May 2020 and April 2021 at St. Petersburg, Russia and combines them with other SARS-CoV-2 surveillance data.

MethodsWe conducted four serological surveys of two random samples (May-June, July-August, October-December 2020, and February-April 2021) from adults residing in St. Petersburg recruited with the random digit dialing (RDD), accompanied by a telephone interview to collect information on both individuals who accepted and declined the invitation for testing and account for non-response. We have used enzyme-linked immunosorbent assay CoronaPass total antibodies test (Genetico, Moscow, Russia) to report seroprevalence. We corrected the estimates for non-response using the bivariate probit model and also accounted the test performance characteristics, obtained from independent assay evaluation. In addition, we have summarised the official registered cases statistics, the number of hospitalised patients, the number of COVID-19 deaths, excess deaths, tests performed, data from the ongoing SARS-CoV-2 variants of concern (VOC) surveillance, the vaccination uptake, and St. Petersburg search and mobility trends. The infection fatality ratios (IFR) have been calculated using the Bayesian evidence synthesis model.

FindingsAfter calling 113,017 random mobile phones we have reached 14,118 individuals who responded to computer-assisted telephone interviewing (CATI) and 2,413 provided blood samples at least once through the seroprevalence study. The adjusted seroprevalence in May-June, 2020 was 9.7% (95%: 7.7-11.7), 13.3% (95% 9.9-16.6) in July-August, 2020, 22.9% (95%: 20.3-25.5) in October-December, 2021 and 43.9% (95%: 39.7-48.0) in February-April, 2021. History of any symptoms, history of COVID-19 tests, and non-smoking status were significant predictors for higher seroprevalence. Most individuals remained seropositive with a maximum 10 months follow-up. 92.7% (95% CI 87.9-95.7) of participants who have reported at least one vaccine dose were seropositive. Hospitalisation and COVID-19 death statistics and search terms trends reflected the pandemic course better than the official case count, especially during the spring 2020. SARS-CoV-2 circulation showed rather low genetic SARS-CoV-2 lineages diversity that increased in the spring 2021. Local VOC (AT.1) was spreading till April 2021, but B.1.617.2 substituted all other lineages by June 2021. The IFR based on the excess deaths was equal to 1.04 (95% CI 0.80-1.31) for the adult population and 0.86% (95% CI 0.66-1.08) for the entire population.

ConclusionApproximately one year after the COVID-19 pandemic about 45% of St. Petersburg, Russia residents contracted the SARS-CoV-2 infection. Combined with vaccination uptake of about 10% it was enough to slow the pandemic until the Delta VOC started to spread. Combination of several surveillance tools provides a comprehensive pandemic picture.

FundingPolymetal International plc.


title: Performance of three molecular tests for SARS-CoV-2 on a university campus estimated jointly with Bayesian latent class modeling

abstract: Accurate tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been critical in efforts to control its spread. The accuracy of molecular tests for SARS-CoV-2 has been assessed numerous times, usually in reference to a gold standard diagnosis. One major disadvantage of that approach is the possibility of error due to inaccuracy of the gold standard, which is especially problematic for evaluating testing in a real-world surveillance context. We used an alternative approach known as Bayesian latent class modeling (BLCM), which circumvents the need to designate a gold standard by simultaneously estimating the accuracy of multiple tests. We applied this technique to a collection of 1,716 tests of three types applied to 853 individuals on a university campus during a one-week period in October 2020. We found that reverse transcriptase polymerase chain reaction (RT-PCR) testing of saliva samples performed at a campus facility had higher sensitivity (median: 0.923; 95% credible interval: 0.732-0.996) than RT-PCR testing of nasal samples performed at a commercial facility (median: 0.859; 95% CrI: 0.547-0.994). The reverse was true for specificity, although the specificity of saliva testing was still very high (median: 0.993; 95% CrI: 0.983-0.999). An antigen test was less sensitive and specific than both of the RT-PCR tests. These results suggest that RT-PCR testing of saliva samples at a campus facility can be an effective basis for surveillance screening to prevent SARS-CoV-2 transmission in a university setting.


title: Immunosequencing of the T-cell receptor repertoire reveals signatures specific for diagnosis and characterization of early Lyme disease

abstract: Lyme disease, the most common tick-borne illness in the United States, is most frequently caused by infection with Borrelia burgdorferi. Although early antibiotic treatment can prevent development of severe illness and late manifestations, diagnosis is challenging in patients who do not present with a typical erythema migrans rash. To support a diagnosis of Lyme disease in such cases, guidelines recommend 2-tiered serologic testing. However, 2-tiered testing has numerous limitations, including ambiguity in interpretation and lower sensitivity in early disease. We developed a diagnostic approach for Lyme disease based on the T-cell response to B. burgdorferi infection by immunosequencing T-cell receptor (TCR) repertoires in blood samples from 3 independent cohorts of patients with laboratory-confirmed or clinically diagnosed early Lyme disease, as well as endemic and non-endemic controls. We identified 251 public, Lyme-associated TCRs that were used to train a classifier for detection of early Lyme disease with 99% specificity. In a validation cohort of individuals with early Lyme disease, TCR testing demonstrated a 1.9-fold increase in sensitivity compared to standard 2-tiered testing (STTT; 56% versus 30%), with a 3.1-fold increase [≤]4 days from the onset of symptoms (44% versus 14%). TCR positivity predicted subsequent seroconversion in 37% of initially STTT-negative patients, suggesting that the T-cell response is detectable before the humoral response. While positivity for both tests declined after treatment, greater declines in posttreatment sensitivity were observed for STTT compared to TCR testing. Higher TCR scores were associated with clinical measures of disease severity, including abnormal liver function test results, disseminated rash, and number of symptoms. A subset of Lyme-associated TCRs mapped to B. burgdorferi antigens, demonstrating high specificity of a TCR immunosequencing approach. These results support the clinical utility of T-cell-based testing as a sensitive and specific diagnostic for early Lyme disease, particularly in the initial days of illness.


title: Genomic analyses of human adenoviruses unravel novel recombinant genotypes associated with severe infections in pediatric patients

abstract: BackgroundHuman Adenoviruses (HAdVs) are highly contagious pathogens of clinical importance, especially among the pediatric population. Studies on comparative viral genomic analysis of cases associated with severe and mild infections due to HAdV are limited. Using whole-genome sequencing (WGS), we investigated whether there were any differences between circulating HAdV strains associated with severe infections (meningitis, sepsis, convulsion, sudden infant death syndrome, death, and hospitalization) and mild clinical presentations in pediatric patients hospitalized between the years 1998 and 2017 in a tertiary care hospital group in Bern, Switzerland covering a population base of approx. 2 million inhabitants. The HAdV species implicated in causing severe infections in this study included HAdV species C genotypes (HAdV1, HAdV2, and HAdV5). Clustering of the HAdV whole-genome sequences of the severe and mild cases did not show any differences except for one sample (isolated from a patient presenting with sepsis, meningitis, and hospitalization) that formed its own cluster with HAdV species C genotypes. This isolate showed intertypic recombination events involving four genotypes, had the highest homology to HAdV89 at complete genome level, but possessed the fiber gene of HAdV1, thereby representing a novel genotype of HAdV species C. The incidence of potential recombination events was higher in severe cases than in mild cases. Our findings confirm that recombination among HAdVs is important for molecular evolution and emergence of new strains. Therefore, further research on HAdVs, particularly among susceptible groups, is needed and continuous surveillance is required for public health preparedness including outbreak investigations.


title: The Effect of Incarceration on Tuberculosis Treatment Outcomes in Brazil: a Retrospective Cohort Study

abstract:
BackgroundTuberculosis notifications in Latin American prisons have more than doubled over the past two decades; however, treatment outcomes and their determinants among incarcerated individuals in this region are not well understood.

MethodsNewly diagnosed drug-susceptible tuberculosis cases reported to Brazils Sistema de Informacao de Agravos de Notificacao (SINAN) between January 2015 and December 2017 were included. Multivariate logistic regression was used to assess socioeconomic and clinical factors associated with treatment success among incarcerated individuals.

ResultsIncarcerated individuals (n=17,776) had greater treatment success than non-incarcerated individuals (n=160,728; 82.2% vs 75.1%, p<0.0001), including after adjusting for demographic and clinical risk factors (adjusted Odds Ratio [aOR]: 1.27; 95% CI: 1.19-1.34). These differences were partially mediated by increased use of directly observed therapy among incarcerated individuals (DOT) (61% vs 47%, p<0.001), which was associated with greater efficacy in the incarcerated population (aOR 2.56 vs aOR 2.17; p<0.001). DOT was associated with improved treatment success among incarcerated subpopulations at elevated risk of poor outcomes.

ConclusionTuberculosis treatment success among incarcerated individuals in Brazil is higher than non-incarcerated individuals, but both fall below WHO targets. Expanding the use of DOT and services for socially and medically vulnerable individuals may improve outcomes in carceral settings.


title: COVID-19 Mortality in Women and Men in Sub-Saharan Africa: A Cross Sectional Study

abstract:
ObjectiveTo investigate differences of COVID-19 related mortality among women and men across sub-Saharan Africa (SSA) from the beginning of the pandemic.

DesignA cross sectional study.

SettingData from 20 member nations of the WHO African region until September 1, 2020.

Participants69,580 cases of COVID-19, stratified by sex (men, n=43071; women, n=26509) and age (0-39 years, n=41682; 40-59 years, n=20757; 60+ years, n=7141).

Main outcome measuresWe computed the SSA- and country-specific case fatality rates (CFRs) and sex-specific CFR differences across various age groups, using a Bayesian approach.

ResultsA total of 1,656 (2.4% of total cases reported; 1656/69580) deaths were reported, with men accounting for 1168/1656 (70.5%) of total deaths. In SSA, women had a lower CFR than men (mean CFRdiff = -0.9%; 95% credible intervals -1.1% to -0.6%). The mean CFR estimates increased with age, with the sex-specific CFR differences being significant among those aged 40 or more (40-59 age-group: mean CFRdiff = -0.7%; 95% credible intervals -1.1% to -0.2%; 60+ age-group: mean CFRdiff = -3.9%; 95% credible intervals -5.3% to -2.4%). At the country level, seven of the twenty SSA countries reported significantly lower CFRs among women than men overall. Moreover, corresponding to the age-specific datasets, significantly lower CFRs in women than men were observed in the 60+ age-group in seven countries and 40-59 age-group in one country.

Conclusions>Sex and age are important predictors of COVID-19 mortality. Countries should prioritize the collection and use of sex-disaggregated data to understand the evolution of the pandemic. This is essential to design public health interventions and ensure that policies promote a gender sensitive public health response.

Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LILittle is known on the impact of COVID-19 among different sexes and age-groups in sub-Saharan Africa (SSA).
C_LIO_LIThe availability of data on COVID-19 cases and deaths, disaggregated by both age and sex from the WHO African region has been scarce.
C_LIO_LIIn most of the non-African countries, sex-specific COVID-19 severity and mortality were substantially worse for men than for women, during the first wave of the novel coronavirus (COVID-19) pandemic.
C_LI

What this study addsO_LITo the best of our knowledge, this is the largest study focussing on the COVID-19 related fatalities among men and women in SSA, and it confirmed that both sex and age are important predictors of COVID-19 mortality in SSA, similar to other regions.
C_LIO_LIIn SSA, overall, men had a higher case fatality rate (CFR) than women. When disaggregated by age, this difference persisted only in individuals aged 40 or more. 7 among the 20 SSA countries included in this study also reported significantly higher CFRs in men than women for the age-aggregated dataset.
C_LIO_LIPublic health prevention activities and responses should take into account gender differences in terms of disease severity and mortality, especially among men aged 40 or more in SSA.
C_LI


title: Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2: a population-based cohort analysis

abstract:
ObjectivesTo calculate the observed rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2, infection with SARS-CoV-2, and to compare them to background (expected) rates in the general population.

DesignCohort study using routinely collected primary care records.

SettingRoutine practice in the United Kingdom.

ParticipantsTwo mutually exclusive vaccinated cohorts included people vaccinated with either ChAdOx1 or BNT162b2 between 8 December 2020 and 6 March 2021. A third cohort consisted of people newly infected with SARS-Cov-2 identified by a first positive RT-PCR test between 1 September 2020 and 28 February 2021. The fourth general population cohort for background rates included those people with a visit between 1 January 2017 and 31 December 2019. In total, we included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population.

InterventionsFirst-dose of either ChAdOx1 or BNT162b2

Main outcome measuresOutcomes included venous thrombosis, arterial thrombosis, thrombocytopenia, and thrombosis with thrombocytopenia. Outcome rates were estimated for recipients of the ChAdOx1 or BNT162b2 vaccines, for people infected with SARS-CoV-2, and background rates in the general population. Indirectly standardized incidence ratios (SIR) were estimated.

ResultsWe included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population for background rates. The SIRs for pulmonary embolism were 1.23 [95% CI, 1.09-1.39] after vaccination with ChAdOx1, 1.21 [1.07-1.36] after vaccination with BNT162b2, and 15.31 [14.08 to 16.65] for infection with SARS-CoV-2. The SIRs for thrombocytopenia after vaccination were 1.25 [1.19 to 1.31] for ChAdOx1 and 0.99 (0.94 to 1.04) for BNT162b2. Rates of deep vein thrombosis and arterial thrombosis were similar among those vaccinated and the general population.

ConclusionsChAdOx1 and BNT162b2 had broadly similar safety profiles. Thrombosis rates after either vaccine were mostly similar to those of the general population. Rates of pulmonary embolism increased 1.2-fold after either vaccine and 15-fold with SARS-CoV-2 infection. Thrombocytopenia was more common among recipients of ChAdOx1 but not of BNT162b2.

Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISpontaneous reports of unusual and severe thrombosis with thrombocytopenia syndrome (TTS) raised concerns regarding the safety of adenovirus-based vaccines against SARS-CoV-2
C_LIO_LIIn a cohort study including over 280,000 people aged 18-65 years vaccinated with ChAdOx1 in Denmark and Norway, Potteg[a]rd et al reported increased rates of venous thromboembolic events as well as thrombocytopenia among vaccine recipients.
C_LI

What this study addsO_LIIn this cohort study, ChAdOx1 and BNT162b2 were seen to have broadly similar safety profiles.
C_LIO_LIRates of thrombosis after either vaccine were generally similar to those of the general population. Rates of pulmonary embolism were though 1.2-fold higher than background rates after either vaccine, which compared to 15-fold higher after SARS-CoV-2 infection.
C_LIO_LIThrombocytopenia was more common among recipients of ChAdOx1 but not of BNT162b2.
C_LI


title: Existing human mobility data sources poorly predicted the spatial spread of SARS-CoV-2 in Madagascar

abstract: For emerging epidemics such as the COVID-19 pandemic, quantifying travel is a key component of developing accurate predictive models of disease spread to inform public health planning. However, in many LMICs, traditional data sets on travel such as commuting surveys as well as non-traditional sources such as mobile phone data are lacking, or, where available, have only rarely been leveraged by the public health community. Evaluating the accuracy of available data to measure transmission-relevant travel may be further hampered by limited reporting of suspected and laboratory confirmed infections. Here, we leverage case data collected as part of a COVID-19 dashboard collated via daily reports from the Malagasy authorities on reported cases of SARS-CoV-2 across the 22 regions of Madagascar. We compare the order of the timing of when cases were reported with predictions from a SARS-CoV-2 metapopulation model of Madagascar informed using various measures of connectivity including a gravity model based on different measures of distance, Internal Migration Flow data, and mobile phone data. Overall, the models based on mobile phone connectivity and the gravity-based on Euclidean distance best predicted the observed spread. The ranks of the regions most remote from the capital were more difficult to predict but interestingly, regions where the mobile phone connectivity model was more accurate differed from those where the gravity model was most accurate. This suggests that there may be additional features of mobility or connectivity that were consistently underestimated using all approaches, but are epidemiologically relevant. This work highlights the importance of data availability and strengthening collaboration among different institutions with access to critical data - models are only as good as the data that they use, so building towards effective data-sharing pipelines is essential.


title: Vibrio cholerae multifaceted adaptive strategies in response to bacteriophage predation in an endemic region of the Democratic Republic of the Congo

abstract: Bacteriophage predation of toxigenic Vibrio cholerae O1 (the causative agent of cholera) has been linked with seasonal patterns of disease and with clinical response to infection in humans 1-4. However, we still lack a clear demonstration of how the interplay between bacteria and bacteriophage can influence shifts in strain populations. We analyzed toxigenic V. cholerae O1 isolated from patients in the Great Lakes, a cholera endemic region of the Democratic Republic of the Congo (DRC), between 2013-2017. Bayesian phylogeography shows that all strains derived from the East Africa T10 introduction event5, consistent with establishment of a regional endemic focus, and identified two major lineages, with the most recent correlating to ST515, a cholera cluster previously found in the Lake Kivu and expanding northward6. We also identified a novel ICP1 bacteriophage, genetically distinct from previous ICP1 isolates detected in Asia 7,8, from stool samples of cholera patients. The presence of phages in specific regions of the DRC resulted in the independent emergence, along both internal and external branches of the cholera phylogeny, of distinct mutational pathways in genes of the O1 biosynthetic gene cluster associated with phage resistance. Our data evidence, for the first time, V. cholerae multi-peaked adaptive landscape during outbreaks, and a complex co-evolutionary dynamic linked to presence of predatory phages.


title: High parental vaccine motivation at a neighborhood-based vaccine and testing site serving a predominantly Latinx community

abstract:
PurposeTo understand vaccine attitudes of Latinx parents highly impacted by COVID-19. Methods. In April 2021, we surveyed parents about their attitudes for COVID-19 vaccination of their children at a community-based outdoor testing/vaccination site serving predominantly low-income, Latinx persons in San Francisco.

ResultsAmong 1,033 parents (75% Latinx), 92% would "definitely" or "probably" vaccinate their children. Vaccine hesitancy was higher for younger children; concerns included side effects and impacts on fertility. Doctors and community organizations were noted as trusted sources of information, including among vaccine-hesitant parents.

ConclusionLatinx parents accessing neighborhood-based COVID-19 testing/vaccination services are highly motivated to vaccinate their children for COVID-19.


title: Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection

abstract: Increasing evidence suggests immune dysregulation in individuals recovering from SARS- CoV-2 infection. We have undertaken an integrated analysis of immune responses at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 individuals recovering from mild, moderate, severe, or critical COVID-19. Anti-Spike and anti-RBD IgG responses were largely stable up to 24wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper and regulatory T cells) in COVID-19 convalescents compared to healthy controls, which were most strongly evident at 12 and 16wpi. RNA sequencing suggested ongoing immune and metabolic dysregulation in convalescents months after infection. Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.

category: genetic and genomic medicine


title: Longitudinal Transitions in Initiation, Cessation, and Relapse of Smoking and E-Cigarette Use Among US Youth and Adults

abstract:
IntroductionLongitudinal surveys provide data to estimate transition probabilities between cigarette smoking, e-cigarette use, and dual use of both, facilitating projections of future use and the impact of policies.

MethodsWe fit a continuous time Markov multi-state model for youth (ages 12-17y) and adults ([≥]18y) in Waves 1-4.5 of the Population Assessment of Tobacco and Health (PATH) longitudinal survey and estimated smoking and e-cigarette transition frequencies, including initiation, cessation, and relapse. We validated transition frequency results in a microsimulation model by projecting smoking and e-cigarette use prevalence over time.

ResultsThere was more volatility in smoking and e-cigarette use among youth than among adults. For youth never smokers, annual smoking initiation among never/current/former e-cigarette users occurred in 0.4% (95% CI 0.2-0.6%)/8.8% (7.0-10.7%)/3.1% (2.1-4.2%), and current e-cigarette users were more likely to quit e-cigarettes than to initiate smoking (absolute difference in annual probability 46.5%, 38.7-54.2%). For adult current smokers, annual smoking cessation among never/current/former e-cigarette users occurred in 22.6% (20.9-24.3%)/14.5% (11.5-17.4%)/15.1% (12.1-18.2%). For adult current dual users, 14.5% quit smoking and 49.5% quit e-cigarettes annually. For adult former smokers, annual smoking relapse among never/current/former e-cigarette users occurred in 17.7% (15.8-19.6%)/29.3% (23.8-34.7%)/32.8% (27.1-38.6%). Using these transition probabilities in a microsimulation model accurately projected smoking and e-cigarette use prevalence at 12 and 24 months compared to PATH empirical data (root-mean-square error <0.7%).

DiscussionPATH Waves 1-4.5 contain sufficient data to generate smoking and e-cigarette use transition frequency estimates for youth and adults in a microsimulation model. E-cigarette use among youth is especially volatile.

IMPLICATIONSThis study estimates longitudinal transitions between nine cigarette smoking and e-cigarette use states among both youth and adults. Youth smoking and e-cigarette use was more volatile than that of adults. Smoking initiation, cessation, and relapse differed by e-cigarette use status, but it is not clear that e-cigarette use itself caused these differences. A tobacco and nicotine policy model parametrized with our estimates accurately predicted smoking and e-cigarette use prevalence over two years, enabling future work to project the outcomes and cost-effectiveness of policies targeting smoking and e-cigarette use.


title: Activity Space Maps: a novel human mobility data set for quantifying time spent at risk

abstract: Activity Space Maps are a novel global-scale movement and mobility data set which describes how people distribute their time through geographic space. The maps are intended for use by researchers for the purposes of epidemiological modeling. Activity Space Maps are designed to complement existing digitally-collected mobility data sets by quantifying the amount of time that people spend in different locations. This information is important for estimating the duration of contact with the environment and the potential risk of exposure to disease. More concretely, the type of information contained in Activity Space Maps will make it easier to model the spatial transmission patterns of vector-borne diseases like malaria and Dengue fever. We will discuss the motivation for designing Activity Space Maps, how the maps are generated from mobile phone user app location history data, and discuss an example use case demonstrating how such data may be used together with spatial epidemiological data to advance our understanding of spatial disease patterns and the relationship between travel behaviors and infection risk.


title: Aspergillosis and Mucormycosis in COVID-19 Patients; a Systematic Review and Meta-analysis.

abstract: Fungal infections have increased in number since the onset of this lethal pandemic. The aim of this study is to assess risk factors and case fatality in COVID-19 cases with aspergillosis or mucormycosis. Systematic review and meta-analysis was done according to PRISMA guidelines. Data bases used were Google scholar, Pakmedinet, PUBMED and MEDLINE. 21 case reports and case series of mucormycosis in COVID-19 patients were identified and mean age was 56.3 years (36 males and 12 females). The most common comorbidity was diabetes and site was Rhino orbital mucormycosis. Case fatality of 48 combined cases was calculated to be 52%. 19 articles of aspergillosis were included. Diabetes was the most common comorbidity in cases. The number of male cases were more than females. Incidence of aspergillosis in critically sick COVID-19 patients was calculated to be 9.3%. Case fatality was calculated to be 51.2%. Screening can be a beneficial tool for decreasing the morbidity and mortality.


title: Airway recommendations for perioperative patients during the COVID-19 pandemic: a scoping review

abstract:
PurposeNumerous guideline recommendations for airway and perioperative management during the COVID-19 pandemic have been published. We identified, synthesized, and compared guidelines intended for anesthesiologists.

SourceMember society websites of the World Federation of Societies of Anesthesiologists and the European Society of Anesthesiologists were searched. Recommendations focused on perioperative airway management of patients with proven or potential COVID-19 disease were included. Accelerated screening was used; data extraction was performed by one reviewer and verified by a second. Data was organized into themes based on perioperative phase of care.

Principal FindingsThirty unique sets of recommendations were identified. None reported methods for systematically searching or selecting evidence to be included. Four were updated following initial publication. For induction and airway management, most recommended minimizing personnel and having the most experienced anesthesiologist perform tracheal intubation. Significant congruence was observed amongst recommendations that discussed personal protective equipment. Of those that discussed tracheal intubation methods, most (96%) recommended video laryngoscopy, while discordance existed regarding use of flexible bronchoscopy. Intraoperatively, 23% suggested specific anesthesia techniques and most (63%) recommended a specific operating room for patients with COVID-19. Postoperatively, a minority discussed extubation procedures (33%), or care in the recovery room (40%). Non-technical considerations were discussed in 27% and psychological support for healthcare providers in 10%.

ConclusionRecommendations for perioperative airway management of patients with COVID-19 overlap to a large extent. However, we also identified significant differences. This may reflect the absence of a coordinated response towards studying and establishing best-practices in perioperative patients with COVID-19.

RegistrationOpen Science Framework (https://osf.io/a2k4u/)

category: anesthesia


title: Severity, criticality, and fatality of the SARS-CoV-2 Beta variant

abstract: Severity (acute-care hospitalization), criticality (ICU hospitalization), and fatality of SARS-CoV-2 Beta (B.1.351) variant was investigated through case-control studies applied to complete national cohorts of infection, disease, and death cases in Qatar. Compared to Alpha (B.1.1.7) variant, odds of progressing to severe disease were 1.24-fold (95% CI: 1.11-1.39) higher for Beta. Odds of progressing to critical disease were 1.49-fold (95% CI: 1.13-1.97) higher. Odds of COVID-19 death were 1.57-fold (95% CI: 1.03-2.43) higher. Findings highlight risks to healthcare systems, particularly to intensive care facilities and resources, with increased circulation of Beta.


title: Association of chronic kidney disease, ethnicity and socioeconomic status with COVID-19 hospitalisation and mortality: a UK Biobank study

abstract:
O_LIIn individuals with chronic kidney disease (CKD), Black and South Asian ethnic groups are twice as likely to have severe COVID-19 compared to White participants, whilst the most socially deprived groups are at a 50-60% increased risk of severe COVID-19.
C_LIO_LIThis study is the first to highlight the association between ethnicity and socioeconomic deprivation and the risk of severe COVID-19 among those with CKD in the UK.
C_LIO_LIInterventions to reduce morbidity and mortality amongst these groups and policy and practice improvements are needed to address the broad disparity among CKD patients.
C_LI

category: nephrology


title: Immunogenomic intertumor heterogeneity across primary and metastatic sites in a patient with lung adenocarcinoma

abstract:
BackgroundLung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy.

MethodsIn order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a young female never-smoker with late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T-cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors.

ResultsWe observed heterogeneous mutation, methylation, and T cell patterns across distinct metastases including a set of prevalent T cell clonotypes which were completely excluded from left-side thoracic tumors. Though a limited number of predicted neoantigens were shared, these were associated with homology of the T cell repertoire across metastases. Lastly, ratio of methylated neoantigen coding mutations was negatively associated with T-cell density, richness and clonality, suggesting neoantigen methylation may partially drive immunosuppression.

ConclusionsOur study demonstrates heterogeneous genomic and T cell profiles across synchronous metastases and how restriction of unique T cell clonotypes within an individual may differentially shape the genomic and epigenomic landscapes of synchronous lung metastases.

category: oncology


title: A mucosal antibody response is induced by intra-muscular SARS-CoV-2 mRNA vaccination

abstract:
Although SARS-CoV-2 infects the upper respiratory tract, we know little about the amount, type, and kinetics of antibodies (Ab) generated at this site in response to intramuscular COVID-19 vaccination, and whether these Ab protect against subsequent "breakthrough" infections. We collected longitudinal serum and saliva samples from participants receiving two doses of mRNA COVID-19 vaccines over a 6-month period and measured the relative level of anti-Spike and anti-Receptor Binding Domain (RBD) Ab. We detected anti-Spike/RBD IgG and IgA and associated secretory component in the saliva of most participants receiving 1 dose of mRNA vaccine. Administration of a second dose of mRNA boosted the IgG but not the IgA response, with only 30% of participants remaining positive for IgA at this timepoint. At 6 months post-dose 2, these participants exhibited greatly diminished anti-Spike/RBD IgG and IgA levels concomitant with a reduction in neutralizing activity in the saliva, although the level of secretory component associated anti-Spike was less susceptible to decay. Examining two prospective cohorts of subjects that were monitored for infections post-vaccination, we found that participants who were subsequently infected with SARS-CoV-2 had lower levels of vaccine-induced serum anti-Spike/RBD IgA at 2-4 weeks post-dose 2 compared to participants who did not experience an infection, whereas IgG levels were comparable between groups. These data emphasize the importance of developing COVID-19 vaccines that elicit a durable IgA response.

One-Sentence SummaryOur study delves into whether intra-muscular mRNA vaccination regimes confer a local IgA response in the oral cavity and whether the IgA response is associated with protection against breakthrough infection.


title: mRNA vaccine-induced IgA protect against SARS-CoV-2 breakthrough infection


title: Systemic and mucosal IgA responses are variably induced in response to SARS-CoV-2 mRNA vaccination and are associated with protection against subsequent infection


title: Epigenome-wide Association Study of Alcohol Use Disorder in Five Brain Regions

abstract: Alcohol Use Disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n=53) and controls (n=58) using a brain region-specific approach, in which sample sizes ranged between 46 and 94. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted Correlation Network Analysis (WGCNA), gene-set and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q <.05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < .05) were found in the CN (n=6), VS (n=18) and ACC (n=1). In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD.

category: addiction medicine


title: Combined Metabolic Activators Improve Cognitive Functions without Altering Motor Scores in Parkinson's Disease

abstract: The neuropathologic hallmarks of Parkinsons disease (PD) are associated with mitochondrial dysfunction and metabolic abnormalities. We have reported that the Combined Metabolic Activators (CMA), consisting of L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate can be used in treating metabolic abnormalities. These metabolic activators are the precursors of nicotinamide adenine dinucleotide (NAD+) and glutathione (GSH) and used in activation of mitochondrial and global metabolism. We have performed a placebo-controlled, phase-2 study in Alzheimers disease (AD) patients and reported that the cognitive functions in AD patients is significantly improved 29% in the CMA group whereas it is improved only 14% in the placebo group after 84 days of CMA administration. Here, we designed a randomized, double-blinded, placebo-controlled, phase-2 study in PD patients with CMA administration. We found that the cognitive functions in PD patients is significantly improved 21% in the CMA group, whereas it is improved only 11% in the placebo group after 84 days of CMA administration. We also found that the administration of CMA did not affect motor functions in PD patients. We performed a comprehensive multi-omics analysis of plasma proteins and metabolites, and revealed the molecular mechanism associated with the treatment of the patients. In conclusion, our results show that treating PD patients with CMAs leads to enhanced cognitive function, as recently reported in AD patients.


title: Adverse events following COVID-19 virus vaccination in Japanese young population: The first cross-sectional study conducted by a questionnaire survey after the first-time-injection

abstract:
A cross-sectional study was conducted to clarify the adverse events of COVID-19 vaccines in Japanese young population.

The proportion of participants with adverse events at the vaccination site (immediately or within 30 minutes after vaccination) was 0.5%, and anaphylaxis occurred in one female student (0.03%).

We analyzed 1,877 data obtained from a questionnaire survey of 1,993 vaccinated individuals. Eighty-two percent of participants complained of local adverse events. Injection site pain was the most common local adverse event (71%). Systemic adverse events occurred in 48% of participants. The most common adverse event was myalgia (34%).

A multivariable logistic regression model was used to determine risk factors.

Local adverse events were associated with sex (female) and allergy history, with odds ratios (ORs) (95% confidence interval [CI]) of 2.15 (1.69-2.73) and 1.73 (1.10-2.74), respectively. Systemic adverse events were associated with sex (female), age (<20 years old), allergy history, and history of adverse events with previous medications, with ORs (95% CI) of 2.49 (2.03-3.06), 1.80 (1.44-2.24), 1.39 (1.03-1.89), and 1.53 (1.02-2.29).

The results of this study clarified for the first time that age less than 20 years is a risk factor for systemic adverse events from the COVID-19 Vaccine Moderna Intramuscular Injection. This information will give impacts on considering adverse events and its mechanisms in mRNA vaccination.


title: SARS-CoV-2-specific Humoral and Cell-mediated Immune Responses after Immunization with Inactivated COVID-19 Vaccine in Kidney Transplant Recipients (CVIM 1 Study)

abstract: Immunogenicity following inactivated SARS-CoV-2 vaccination among solid organ transplant recipients has not been assessed. Seventy-five patients (37 kidney transplant [KT] recipients and 38 non-transplant controls) received two doses, at 4-week intervals, of an inactivated whole-virus SARS-CoV-2 vaccine. SARS-CoV-2-specific humoral (HMI) and cell-mediated immunity (CMI) were measured before, 4 weeks post-first dose, and 2 weeks post-second dose. The median age of KT recipients was 50 years (IQR, 42-54) and 89% were receiving calcineurin inhibitors/mycophenolate/corticosteroid regimens. The median time since transplant was 4.5 years (IQR, 2-9.5). Among 35 KT patients, anti-RBD IgG titer after vaccination was not significantly different to baseline, but was significantly lower than in controls (7.8 [95%CI 0.2-15.5] vs 2,691 [95%CI 1,581-3,802], p<0.001) as well as the percentage of surrogate virus neutralizing antibody inhibition (2 [95% CI -1-6] vs 71 [95%CI 61-81], p<0.001). However, the mean of SARS-CoV-2 mixed peptides-specific T-cell responses measured by enzyme-linked immunospot assays was significantly increased compared with baseline (66 [95%CI 36-99] vs. 34 [95%CI 19-50] T-cells/106 PBMCs, p=0.02) and comparable to that in controls. Our findings revealed weak HMI and marginal CMI responses in fully vaccinated KT recipients receiving inactivated SARS-CoV-2 vaccine. (Thai Clinical Trials Registry, TCTR20210226002).


title: Tear antibodies to SARS-CoV-2: implications for transmission

abstract:
ObjectivesSARS-CoV-2 can be transmitted by aerosols and the ocular surface may be an important route of transmission. Little is known about protective antibody responses to SARS-CoV-2 in tears after infection or vaccination. We analysed SARS-CoV-2 specific IgG and IgA responses in human tears after either COVID-19 infection or vaccination.

MethodsWe recruited 16 subjects with COVID-19 infection an average of 7 months previously and 15 subjects before and 2 weeks after Comirnaty (Pfizer-BioNtech) vaccination. Plasma, saliva and basal tears were collected. Pre-pandemic plasma, saliva and basal tears from 11 individuals were included as healthy controls. Antibody responses to 5 SARS-CoV-2 antigens were measured via multiplex.

ResultsIgG antibodies to Spike and Nucleoprotein were detected in tears, saliva and plasma from subjects with prior SARS-CoV-2 infection in comparison to uninfected controls. While RBD-specific antibodies were detected in plasma, minimal RBD-specific antibodies were detected in tears and saliva. In contrast, high levels of IgG antibodies to Spike and RBD, but not Nucleoprotein, were induced in tears, saliva and plasma of subjects receiving 2 doses of the Comirnaty vaccine. Increased levels of IgA1 and IgA2 antibodies to SARS-CoV-2 antigens were detected in plasma following infection or vaccination, but were unchanged in tears and saliva.

ConclusionBoth infection and vaccination induce SARS-CoV-2-specific IgG antibodies in tears. RBD-specific IgG antibodies in tears were induced by vaccination but were not present 7 months post-infection. This suggests neutralising antibodies may be low in the tears late following infection.


title: Hydroxychloroquine Prophylaxis against Coronavirus Disease-19: Practice Outcomes among Health-Care Workers

abstract:
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus responsible for the ongoing Covid-19 pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine(HCQ) could prevent SARS CoV-2 in healthcare workers(HCW) at high-risk of exposure.

MethodThis voluntary observational study for the prevention and treatment of COVID-19 was conducted at a tertiary care center, from 12th June to 12th October 2020(total 16 weeks). All consented asymptomatic HCWs of CIMS hospital were administered 400 mg HCQ twice a day on day one followed by 400 mg once weekly to be taken with meals up to 16 weeks. Data collected included OPD registration, risk assessment, medical and family history (related to COVID), physical examination and vitals, pulse oximetry, ECG (pre and post HCQ), drug adherence, side effects, adverse drug reactions.

ResultThe study enrolled 927 full-time, hospital-based HCWs ((including doctors, nurses, paramedical, lab technicians, sanitary workers and others), of whom 731(78.85%) initially started HCQ while 196 (21.14%) did not volunteer. The median age and weight of the study population was 27.5 years and 69.5 kg respectively. No major associated co-morbidities were present in these HCWs. There was an increased trend towards non adherence to HCQ with each proceeding week more so after week 11. Of the 731 HCWs taking HCQ a total of 167(22.8%) tested COVID positive at different intervals of time as against 30 HCW (15.3%) out of 196 not taking HCQ. The rate of COVID-19 positive was statistically significantly higher in the HCWs taking HCQ (p=0.0220; 95% CI: 1.14% to 12.94%), as compared to those not on HCQ. Thus HCQ was not prophylactically effective against COVID 19 infection. No participants in this study experienced grade 3 or 4 adverse events. No significant difference in the median of ECG changes in QTc between pre and post HCQ administration of 46 HCWs was observed.

ConclusionsThis clinical study did not detect a reduction in SARS CoV-2 transmission with prophylactic administration of 400 mg/HCQ in HCWs. All participants who did contract SARSCoV-2 were either asymptomatic or had mild disease courses with full recoveries. All adverse events were self-limiting and no serious cardiovascular events were reported with use of HCQ. In the absence of robust data, it seems premature to recommend HCQ as a prophylactic panacea for COVID-19.


title: Estimating infection-related human mobility networks based on time series data of COVID-19 infection in Japan

abstract: Comprehensive and evidence-based countermeasures against emerging infectious diseases have become increas-ingly important in recent years. COVID-19 and many other infectious diseases are spread by human movement and contact, but complex transportation networks in 21 century make it difficult to predict disease spread in rapidly changing situations. It is especially challenging to estimate the network of infection transmission in the countries that the traffic and human movement data infrastructure is not yet developed. In this study, we devised a method to estimate the network of transmission of COVID-19 from the time series data of its infection and applied it to determine its spread across areas in Japan. We incorporated the effects of soft lockdowns, such as the declaration of a state of emergency, and changes in the infection network due to government-sponsored travel promotion, and predicted the spread of infection using the Tokyo Olympics as a model. The models used in this study are available online, and our data-driven infection network models are scalable, whether it be at the level of a city, town, country, or continent, and applicable anywhere in the world, as long as the time-series data of infections per region is available. These estimations of effective distance and the depiction of infectious disease networks based on actual infection data are expected to be useful in devising data-driven countermeasures against emerging infectious diseases worldwide.


title: COVID19 vaccine type and humoral immune response in patients receiving dialysis

abstract:
BackgroundPatients on dialysis vaccinated with the attenuated adenovirus SARS-CoV-2 vaccine might mount an impaired response to vaccination.

MethodsWe evaluated the humoral vaccination response among 2,099 fully vaccinated patients receiving dialysis. We used commercially available assays (Siemens) to assess prevalence of no response or diminished response to COVID-19 vaccination by vaccine type. We defined "no seroconversion" as lack of change from negative to positive in total RBD Ig antibody, no detectable response on semiquantitative RBD IgG antibody (index value <1) as "no RBD IgG response", and a semiquantitative RBD IgG index value <10 as "diminished RBD IgG response"

ResultsOf the 2,099 fully vaccinated patients on dialysis, the proportion receiving the mRNA1273, BNT162b2, and Ad26.COV2.S were 62% (n=1316), 20% (n=416) and 18% (n=367), respectively. A third (33.3%) of patients receiving the attenuated adenovirus Ad26.COV2.S vaccine failed to seroconvert and an additional 36% had no detectable or diminished IgG response even 28-60 days post vaccination.

ConclusionOne in three fully vaccinated patients receiving dialysis had evidence of an impaired immune response to the attenuated adenovirus Ad26.COV2.S vaccine.


title: Exploring polygenic-environment and residual-environment interactions for depressive symptoms within the UK Biobank

abstract: Substantial advances have been made in identifying genetic contributions to depression, but little is known about how the effect of genes can be modulated by the environment, creating a gene-environment interaction. Using multivariate reaction norm models (MRNMs) within the UK Biobank (N=61294-91644), we investigate whether the polygenic and residual variation of depressive symptoms are modulated by 25 a-priori selected covariate traits: 12 environmental variables, 5 biomarkers and polygenic risk scores for 8 mental health disorders. MRNMs provide unbiased polygenic-covariate interaction estimates for a quantitative trait by controlling for outcome-covariate correlations and residual-covariate interactions. Of the 25 selected covariates, 11 significantly modulate depressive symptoms, but no single interaction explains a large proportion of phenotypic variation. Results are dominated by residual-covariate interactions, suggesting that covariate traits (including neuroticism, childhood trauma and BMI) typically interact with unmodelled variables, rather than a genome-wide polygenic score, to influence depressive symptoms. Only average sleep duration has a polygenic-covariate interaction explaining a demonstrably non-zero proportion of the variability in depressive symptoms. This effect is small, accounting for only 1.22% (95% CI [0.54,1.89]) of variation. The presence of an interaction highlights a specific focus for intervention, but the negative results here indicate a limited contribution from polygenic-environment interactions.


title: Comparative analysis of post-vaccination anti-spike IgG antibodies in old Nursing Home Residents and in middle-aged Healthcare workers

abstract:
The current consensus is that 2 doses of mRNA vaccines against SARS-CoV-2 are needed for people without COVID-19 history, while for those who had suffered COVID-19, a single dose may be enough to achieve high levels of immunization. This consensus has been based on results obtained in middle-aged populations, whereas only few data exist for the oldest and most frail adults such as nursing home residents (NH-Res) that is, the population most vulnerable to develop severe forms of COVID-19.

In this study, we studied the anti-SARS-CoV-2 IgG(S) level of NH-Res and healthcare workers (HCWs) with or without a history of COVID-19 infection taking into account the time since immunization (COVID-19 and/or vaccination). 654 subjects were analyzed: 397 NH-Res (median age 88, IQR 82-93 years, 75% women) and 257 Health Care Workers (HCWs, median 46, IQR 38-54 years, 81% women). NH-Res and HCWs were classified in one of the following 3 groups: No-COVID history and 2 vaccine shots (COV-NO/2VACC); Yes-COVID history and 1 (COV-YES/1VACC) or 2 (COV-YES/2VACC) vaccine injections.

The time-related decrease in IgG (S) in subjects without COVID-19 history, SARS-COV-2 serology would be negative in HCWs approximately 220 days and in residents 180 days after vaccination. This time-related decrease was much slower in those with history of COVID. NH-Res belonging into the COV-NO/2VACC and the COV-YES/1VACC groups showed lower IgG (S) levels than the same groups of HCWs (for both groups, p<0.0001), whereas in the group COV-YES/2VACC, IgG (S) levels were similar in NH-Res and HCWs (p=0.88). These results remained unchanged after adjustment for age and duration since immunization. Thus, in NH-Res, 2 vaccine shots were associated with a more pronounced immune response, whereas in HCWs, 1 or 2 vaccine shots in patients with COVID-19 history did make any difference. These results indicate significant differences in mRNA vaccination between NH-Res and middle-aged controls, and could contribute to the specification of vaccine policy in this very old, frail population.


title: Lymphocyte count is a universal predictor to the health status and outcomes of patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-regression analysis

abstract:
BackgroundThis study aimed to evaluate the prediction capabilities of clinical laboratory biomarkers to the prognosis of COVID-19 patients.

MethodsObservational studies reporting at least 30 cases of COVID-19 describing disease severity or mortality were included. Meta-data of demographics, clinical symptoms, vital signs, comorbidities, and 14 clinical laboratory biomarkers on initial hospital presentation were extracted. Taking the outcome group as the analysis unit, meta-regression analysis with the generalized estimating equations (GEE) method for clustered data was performed sequentially. The unadjusted effect of each potential predictor of the three binary outcome variables (i.e., severe vs. non-severe, critically severe vs. non-critically severe, and dead vs. alive) was examined one by one by fitting three series of simple GEE logistic regression models due to missing data. The worst one was dropped one at a time. Then, a final multiple GEE logistic regression model for each of the three outcome variables was obtained.

FindingsMeta-data was extracted from 76 articles, reporting a total of 26,627 cases of COVID-19. Patients were recruited across 16 countries. The number of studies (patients) included in the final models of the analysis for severity, critical severity, and mortality was 38 studies (9,764 patients), 21 studies (4,792 patients), and 24 studies (14,825 patients), respectively. After adjusting for the effect of age, lymphocyte count mean or median [≤] 1.03 (estimated hazard ratio [HR] = 46.2594, p < 0.0001), smaller lymphocyte count mean or median (HR < 0.0001, p = 0.0028), and lymphocyte count mean or median [≤] 0.8714 (HR = 17.3756, p = 0.0079) were the strongest predictor of severity, critical severity, and mortality, respectively.

InterpretationLymphocyte count should be closely watched for COVID-19 patients in clinical practice.


title: The cost of illness for childhood clinical pneumonia and invasive pneumococcal disease in Nigeria

abstract:
BackgroundPneumococcal disease contributes significantly to childhood morbidity and mortality and treatment is costly. Nigeria recently introduced the Pneumococcal Conjugate Vaccine (PCV) to prevent pneumococcal disease. The aim of this study is to estimate health provider and household costs for the treatment of pneumococcal disease in children aged <5 years (U5s), and to assess the impact of these costs on household income.

MethodsWe recruited U5s with clinical pneumonia, pneumococcal meningitis or pneumococcal septicaemia from a tertiary and a secondary level hospital in Kano, Nigeria. We obtained resource utilisation data from medical records to estimate costs of treatment to provider, and household expenses and income loss data from caregiver interviews to estimate costs of treatment to households. We defined catastrophic health expenditure (CHE) as household costs exceeding 25% of monthly household income and estimated the proportion of households that experienced it. We compared CHE across tertiles of household income (from the poorest to least poor).

ResultsOf 480 participants recruited, 244 had outpatient pneumonia, and 236 were hospitalised with pneumonia (117), septicaemia (66) and meningitis (53). Median (IQR) provider costs were US$17 (US$14-22) for outpatients and US$272 (US$271-360) for inpatients. Median household cost was US$51 (US$40-69). Overall, 33% of households experienced CHE, while 53% and 4% of the poorest and least poor households, experienced CHE respectively. The odds of CHE increased with admission at the secondary hospital, a diagnosis of meningitis or septicaemia, higher provider costs, and caregiver having a non-salaried job.

ConclusionProvider costs are substantial, and households incur treatment expenses that considerably impact on their income and this is particularly so for the poorest households. Sustaining the PCV programme and ensuring high and equitable coverage to lower disease burden will reduce the economic burden of pneumococcal disease to the healthcare provider and households.

O_TEXTBOXWhat is already known?O_LIChildren <5 years have the highest incidence of pneumonia and invasive pneumococcal disease (IPD) and Nigeria bears the largest burden in sub-Saharan Africa.
C_LIO_LIPneumococcal conjugate vaccine (PCV) was introduced in Nigeria in 2016 to reduce the burden of pneumococcal disease
C_LIO_LIPCV is currently subsidised through Gavi financial support and Nigeria will transition to full self-financing in a few of years
C_LIO_LIThere is no contextual evidence in Nigeria on economic burden of IPD to the health system and society that can support longer term investments in PCV when Gavi co-financing terminates
C_LI

What are the new findings?O_LITreatment of one hospitalised episode of pneumococcal disease cost on average, US$300 to the provider, and US$83 to the household with significant variation by clinical syndrome and level of care
C_LIO_LIOverall, a third of the households encountered costs that were catastrophic (i.e., >25% of household income)
C_LIO_LIBurden of CHE varied by household income tertile ranging from 4% in the least poor households (highest income tertile) to 53% in the poorest households (lowest income tertile)
C_LIO_LIDespite the short illness duration, pneumococcal disease syndromes result in huge economic costs to providers and households
C_LI

What do the new findings imply?O_LISustaining the PCV programme and achieving high PCV coverage has the potential of saving resources at both provider and household level
C_LIO_LIHouseholds are at risk of further impoverishment from catastrophic expenses associated with treatment of pneumococcal disease. This risk can also be significantly reduced by PCV.
C_LI

C_TEXTBOX


title: SARS-CoV-2 viral load monitoring by extraction-free testing of saliva

abstract: Real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) remains the foundation of SARS-CoV-2 testing due to its accessibility, scalability, and superior assay performance. Variability in specimens and methods prevent standardization of RT-qPCR assays and reliable quantitative reporting to assess viral load. We developed an extraction-free RT-qPCR assay for detection of SARS-CoV-2 in saliva and monitored viral load until convalescence in COVID-19 patients. Comparison of 231 matched anterior nares swab and saliva specimens demonstrated that extraction-free testing of saliva has equivalent analytical and clinical assay performance compared to testing of RNA extracts from either anterior nares or saliva specimens. Analysis of specimen pairs revealed higher viral loads in the nasal cavity compared to the oral cavity, although this difference did not impact clinical sensitivity for COVID-19. Extraction-free testing of a combination specimen consisting of both nasal swab and saliva is also demonstrated. Assessment of viral load by RT-qPCR and parallel digital droplet PCR (ddPCR) revealed that cycle threshold (Ct) values less than approximately 30 correlated well with viral load, whereas Ct values greater than 30 correspond to low viral loads <10 copies/{micro}L. Therefore, extraction-free saliva testing maximizes testing efficiency without compromising assay performance and approximates viral loads >10 copies/{micro}L. This technology can facilitate high-throughput laboratory testing for SARS-CoV-2, monitor viral load in individual patients, and assess efficacy of therapies for COVID-19.


title: SARS-CoV-2 antibody binding and neutralization in dried blood spot eluates and paired plasma

abstract: Widescale assessment of SARS-CoV-2-specific antibodies is critical to understanding population seroprevalence, correlates of protection, and the longevity of vaccine-elicited responses. Most SARS-CoV-2 studies characterize antibody responses in plasma/sera. While reliable and broadly used, these samples pose several logistical restrictions such as requiring venipuncture for collection and cold chain for transportation and storage. Dried blood spots (DBS) overcome these barriers as they can be self-collected by fingerstick and mailed and stored at ambient temperature. Here, we evaluate the suitability of DBS for SARS-CoV-2 antibody assays by comparing several antibody responses between paired plasma and DBS from SARS-CoV-2 convalescent and vaccinated individuals. We found that DBS not only reflected plasma antibody binding by ELISA and epitope profiles using phage-display, but also yielded SARS-CoV-2 neutralization titers that highly correlated with paired plasma. Neutralization measurement was further streamlined by adapting assays to a high-throughput 384-well format. This study supports the adoption of DBS for numerous SARS-CoV-2 binding and neutralization assays.


title: Estimating the contribution of transmission in primary healthcare clinics to community-wide TB disease incidence, and the impact of infection prevention and control interventions, in KwaZulu-Natal, South Africa

abstract:
BackgroundThere is a high risk of Mycobacterium tuberculosis (Mtb) transmission in healthcare facilities in high burden settings. Recent World Health Organization guidelines on tuberculosis infection prevention and control (IPC) recommend a range of measures to reduce transmission in healthcare and institutional settings. These were evaluated primarily based on evidence for their effects on transmission to healthcare workers in hospitals. To estimate the overall impact of IPC interventions, it is necessary to also consider their impact on community-wide tuberculosis incidence and mortality.

MethodsWe developed an individual-based model of Mtb transmission between household members, in primary healthcare clinics (PHCs), and in other congregate settings; drug sensitive and multidrug resistant tuberculosis disease development and resolution; and HIV and antiretroviral therapy (ART) and their effects on tuberculosis. The model was parameterised using data from a high HIV prevalence, rural/peri-urban community in KwaZulu-Natal, South Africa, including data on social contact in clinics and other settings by sex, age group, and HIV/ART status; and data on the prevalence of tuberculosis in clinic attendees and the general population. We estimated the proportion of disease in adults that resulted from transmission in PHC clinics in 2019, and the impact of a range of IPC interventions in clinics on community-wide TB incidence and mortality.

ResultsWe estimate that 7.6% (plausible range 3.9-13.9%) of drug sensitive and multidrug resistant tuberculosis in adults resulted from transmission in PHC clinics in the study community in 2019. The proportion is higher in HIV-positive people, at 9.3% (4.8%-16.8%), compared to 5.3% (2.7%-10.1%) in HIV-negative people. We estimate that IPC interventions could reduce the number of incident TB cases in the community in 2021-2030 by 3.4-8.0%, and the number of deaths by 3.0-7.2%.

ConclusionsA non-trivial proportion of tuberculosis results from transmission in PHC clinics in the study communities, particularly in HIV-positive people. Implementing IPC interventions could lead to moderate reductions in disease burden. We therefore recommend that IPC measures in clinics should be implemented both for their benefits to staff and patients, but also for their likely effects on TB incidence and mortality in the surrounding community.


title: Domestic and international mobility trends in the United Kingdom during the COVID-19 pandemic: An analysis of Facebook data

abstract: Since early March 2020, the COVID-19 epidemic across the United Kingdom has led to a range of social distancing policies, which resulted in changes to mobility across different regions. An understanding of how these policies impacted travel patterns over time and at different spatial scales is important for designing effective strategies, future pandemic planning and in providing broader insights on the population geography of the country. Crowd level data on mobile phone usage can be used as a proxy for population mobility patterns and provide a way of quantifying in near-real time the impact of social distancing measures on changes in mobility. Here we explore patterns of change in densities, domestic and international flows and co-location of Facebook users in the UK from March 2020 to March 2021. We find substantial heterogeneities across time and region, with large changes observed compared to pre-pandemic patterns. The impacts of periods of lockdown on distances travelled and flow volumes are evident, with each showing variations, but some significant reductions in co-location rates. Clear differences in multiple metrics of mobility are seen in central London compared to the rest of the UK, with each of Scotland, Wales and Northern Ireland showing significant deviations from England at times. Moreover, the impacts of rapid changes in rules on international travel to and from the UK are seen in substantial fluctuations in traveller volumes by destination. While questions remain about the representativeness of the Facebook data, previous studies have shown strong correspondence with census-based data and alternative mobility measures, suggesting that findings here are valuable for guiding strategies.


title: Phenotyping Antidepressant Treatment Response with Deep Learning in Electronic Health Records

abstract: Efficient, accurate phenotyping for antidepressant treatment response in electronic health records (EHRs) could facilitate precision psychiatry applications but remains a challenge. Increasingly, artificial intelligence methods using "deep learning" applied to clinical data have shown promise in complex classification problems. Here, we systematically evaluate the performance of eight deep-learning-based natural language processing models in classifying response to antidepressants in a large real-world healthcare setting. We obtained data spanning 1990-2018 for adults with depression and a co-occurring antidepressant prescription from the EHR data warehouse of the Mass General Brigham healthcare system (n=111,572). Clinical notes were collected for the following time windows after antidepressant initiation: (1) 2 days to 4 weeks, (2) 4-12 weeks, and (3) 12-26 weeks. A stratified random sample of these note sets (total 4,299 across time periods) were manually reviewed to classify response status as "improved" or "no evidence of improvement" in depression symptoms. All models performed well, with areas under the receiver operator curve (AUROC) of at least 0.80. Positive predictive values (PPVs) ranged from 0.72 - 0.91. In general, models incorporating more information-dense and longer text sequences performed better than others. The best performing model (Longformer-large with sliding window) had an AUROC = 0.88 and PPV = 0.84 at a specificity of 0.88. Our results indicate that deep learning methods applied to EHR data can accurately classify antidepressant response in a real-world healthcare setting. Automated treatment response classification may facilitate a range of research and clinical decision support applications.