title: Use of repeated mammograms to evaluate risk of breast cancer: a systematic review of methods used in the literature

abstract:
ObjectiveThis systematic review aimed to assess methods used to relate repeated mammographic images to breast cancer risk, including the time from mammogram to diagnosis of breast cancer, and methods for analysis of data from either one or both breasts (averaged or assessed individually).

DesignA systematic review was performed.

SettingThe databases including Medline (Ovid) 1946-, Embase.com 1947-, CINAHL Plus 1937-, Scopus 1823-, Cochrane Library (including CENTRAL), and Clinicaltrials.gov were searched through October 2021 to extract published articles in English describing the relationship of change in mammographic features with risk of breast cancer.

ParticipantsWomen with mammogram images.

Main outcome measureBreast cancer incidence.

ResultsTwenty articles were included in the final review. We found that BIRADs and Cumulus were most commonly used for classifying mammographic density and automated assessment was used on more recent digital mammograms. Time between mammograms varied from 1 to median of 4.1 years, and only 9 of the studies used more than 2 mammograms to quantify features. One study used a prediction horizon of 5 and 10 years, one used 5 years only and another 10 years only, while in the others the prediction horizon was not clearly defined with investigators using the next screening mammogram.

ConclusionThis review provided an updated overview of the state of the art and revealed research gaps; based on these, we provide recommendations for future studies using repeated measure methods for mammogram images to make the use of accumulating image data. By following these recommendations, we expect to improve risk classification and risk prediction for women to tailor screening and prevention strategies to level of risk.

Article summaryO_ST_ABSStrengths and limitations of the studyC_ST_ABSO_LITo the best of our knowledge, this is the most recent systematic review on the topic of using multiple mammogram images to define risk of breast cancer.
C_LIO_LIThis review was performed strictly following systematic review guidelines including a medical librarian with expertise in searching, multiple independent reviewers involved in study selection and data extraction, and reporting following PRISMA 2020 guidelines.
C_LIO_LIDue to heterogeneity of methods for assessment and classification (categorical and continuous) of mammographic features including breast density and time to breast cancer, we did not perform risk of bias or conduct a meta-analysis.
C_LIO_LIFew studies looked at repeated measures of non-density features.
C_LI


title: Swiss public health measures associated with reduced SARS-CoV-2 transmission using genome data

abstract: Genome sequences allow quantification of changes in case introductions from abroad and local transmission dynamics. We sequenced 11,357 SARS-CoV-2 genomes from Switzerland in 2020 - the 6th largest effort globally. Using these data, we estimated introductions and their persistence throughout 2020. By contrasting estimates with null models, we estimate at least 83% of introductions were adverted during Switzerlands border closures. Further, transmission chain persistence roughly doubled after the partial lockdown was lifted. Then, using a novel phylodynamic method, we suggest transmission in newly introduced outbreaks slowed 36 - 64% upon outbreak detection in summer 2020, but not in fall. This could indicate successful contact tracing over summer before overburdening in fall. The study highlights the added value of genome sequencing data for understanding transmission dynamics.

category: epidemiology


title: Persistent frustration-induced reconfigurations of brain networks predict individual differences in irritability

abstract:
BackgroundFrustration, the response to blocked goal attainment, is a universal affective experience, but how the brain embodies frustration is not known. Understanding brain network dynamics during frustration may provide insight into pediatric irritability, one of the most frequent reasons for psychiatric consultation in youth and a risk factor for affective disorders and suicidality.

MethodsUsing fMRI, we investigated changes in neural network architecture from a baseline resting-state, through a task that included frustrative nonreward (FNR) and anticipation of new feedback following FNR (FNR+1), to a post-task resting-state in a transdiagnostic sample of 66 youth (33 female, mean age 14 years). Using a train/test/held-out procedure, we aimed to predict past-week irritability from the global efficiency (i.e., Eglob, capacity for parallel information processing) of brain networks before, during, and after frustration.

ResultsCompared to pre-task resting state, FNR+1 and the post-state resting state were uniquely associated with a more segregated brain network organization. Nodes that were originally affiliated with the default-mode-temporal-limbic and fronto-parietal networks contributed most to this reconfiguration. Solely Eglob of brain networks that emerged after the frustrating task predicted self- and observer-rated irritability in previously unseen data. Self-reported irritability was predicted by Eglob of a fronto-temporal-limbic module, while observer-rated irritability was predicted by Eglob of motor-parietal and ventral-prefrontal-subcortical modules.

DiscussionWe characterize frustration as an evolving brain network process and demonstrate the importance of the post-frustration recovery period for the pathophysiology of irritability; an insight that, if replicated, suggests specific intervention targets for irritability.

category: psychiatry and clinical psychology


title: Quantifying changes in vaccine coverage in mainstream media as a result of COVID-19 outbreak

abstract:
BackgroundAchieving vaccine-derived herd immunity depends on public acceptance of vaccination, which in turn relies on peoples understanding of its risks and benefits. The fundamental objective of public health messaging on vaccines is therefore the clear and concise communication of often complex information, and increasingly the countering of misinformation. The primary outlet shaping societal understanding is the mainstream online news media. There was widespread media coverage of the multiple vaccines that were rapidly developed in response to COVID-19. We studied vaccine coverage on the front pages of mainstream online news, using text-mining analysis to quantify the amount of information and sentiment polarization of vaccine coverage delivered to readers.

MethodsWe analyzed 28 million articles from 172 major news sources, across 11 countries between July 2015 and April 2021. We employed keyword-based frequency analysis to estimate the proportion of coverage given to vaccines in our dataset. We performed topic detection using BERTopic and Named Entity Recognition to identify the leading subjects and actors mentioned in the context of vaccines. We used the Vader Python module to perform sentiment polarization quantification of all our English-language articles.

ResultsWe find that the proportion of headlines mentioning vaccines on the front pages of international major news sites increased from 0.1% to 3.8% with the outbreak of COVID-19. The absolute number of negatively polarized articles increased from a total of 6,698 before the COVID-19 outbreak 2015-2019 compared to 28,552 in 2020-2021. Overall, however, before the COVID-19 pandemic, vaccine coverage was slightly negatively polarized (57% negative) whereas with the outbreak, the coverage was primarily positively polarized (38% negative).

ConclusionsBecause of COVID-19, vaccines have risen from a marginal topic to a widely discussed topic on the front pages of major news outlets. Despite a perceived rise in hesitancy, the mainstream online media, i.e. the primary information source to most individuals, has been strongly positive compared to pre-pandemic vaccine news, which was mainly negative. However, the pandemic was accompanied with an order of magnitude increase in vaccine news volume that due to pre-pandemic low frequency sampling bias may contribute to a perceived negative sentiment. These results highlight the important interactions between the volume of news and overall polarisation. To the best of our knowledge, our work is the first systematic text mining study of vaccines in the context of COVID-19.

category: public and global health


title: Effectiveness of non-pharmaceutical measures (NPIs) on COVID-19 in Europe: A systematic literature review

abstract:
BackgroundThe study objective was to conduct a systematic review to assess the effectiveness of non-pharmaceutical interventions (NPIs) to reduce the transmission of SARS-CoV-2 in Europe during the first wave of the pandemic.

MethodsWe searched OVID Medline, EMBASE, and the Cochrane and Campbell Databases for Systematic Reviews published up to April 15th 2021. Focusing on community (meso-level) and society (macro-level) level NPIs, we included all study designs, while a geographic restriction was limited to the EU, UK and European Economic Area (EEA) countries. Using the PICO framework, two reviewers independently extracted data and assessed quality using appropriate quality appraisal tools. A qualitative synthesis was performed, with NPIs grouped initially by a) Physical Distancing measures, b) Case detection and management measures, and c) hygiene measures and subsequently by country.

ResultsOf 17,692 studies initially assessed, 45 met all inclusion criteria. Most studies (n=30) had a modelling study design, while 13 were observational, one quasi-experimental and one experimental. Evidence from across the European continent, presented by country, indicates that the implementations of physical distancing measures (i.e., lockdowns/quarantines), preferably earlier in the pandemic, reduce the number of cases and hospitalisation across settings and for which the timing and duration are essential parameters. Case detection and management measures were also identified as effective measures at certain levels of testing and incidence, while hygiene and safety measures complemented the implementation of physical distancing measures.

ConclusionsThis literature review represents a comprehensive assessment of the effectiveness of NPIs in Europe up to April 2021. Despite heterogeneity across studies, NPIs, as assessed within the context of this systematic review at the macro and meso level, are effective in reducing SARS-CoV-2 transmission rates and COVID-19 hospitalisation rates and deaths in the European Region and may be applied as response strategies to reduce the burden of COVID-19 in forthcoming waves.


title: Understanding national trends in COVID-19 vaccine hesitancy in Canada - April 2020 to March 2021

abstract:
ObjectiveKey to reducing COVID-19 morbidity and mortality and reducing the need for further lockdown measures in Canada and worldwide is widespread acceptance of COVID-19 vaccines. Vaccine hesitancy has emerged as a key barrier to achieving optimal vaccination rates, for which there is little data among Canadians. This study examined rates of vaccine hesitancy and their correlates among Canadian adults.

MethodsThis study analyzed data from five age, sex and province-weighted population-based samples to describe rates of hesitancy between April 2020 and March 2021 among Canadians who completed online surveys as part of the iCARE Study, and various sociodemographic, clinical and psychological correlates. Vaccine hesitancy was assessed by asking: "If a vaccine for COVID-19 were available today, what is the likelihood that you would get vaccinated?" Responses were dichotomized into  very likely,  unlikely,  somewhat unlikely (reflecting some degree of vaccine hesitancy) vs  extremely likely to get the vaccine, which was the comparator.

ResultsOverall, 15,019 respondents participated in the study. A total of 42.2% of respondents reported vaccine hesitancy over the course of the study, which was lowest during surveys 1 (April 2020) and 5 (March 2021) and highest during survey 3 (November 2020). Fully adjusted multivariate logistic regression analyses revealed that women, those aged 50 and younger, non-Whites, those with high school education or less, and those with annual household incomes below the poverty line in Canada (i.e., $60,000) were significantly more likely to report being vaccine hesitant over the study period, as were essential and healthcare workers, parents of children under the age of 18, and those who do not get regular flu vaccines. Believing engaging in infection prevention behaviours (like vaccination) is important for reducing virus transmission and high COVID-19 health concerns (being infected and infecting others) were associated with 77% and 54% reduction in vaccine hesitancy, respectively, and having high personal financial concerns (worried about job or income loss) was associated with 1.33 times increased odds of vaccine hesitancy.

ConclusionResults point to the importance of targeting vaccine efforts to women, younger people and socioeconomically disadvantaged groups, and that vaccine messaging should emphasize the benefits of getting vaccinated, and how the benefits (particularly to health) far outweigh the risks. Future research is needed to monitor ongoing changes in vaccine intentions and behaviour, as well as to better understand motivators and facilitators of vaccine acceptance, particularly among vulnerable groups.


title: Computations of State Ventilation and Respiratory Parameters

abstract:
BackgroundIn mechanical ventilation, there are still some challenges to turn a modern ventilator into a fully reactive device, such as lack of a comprehensive target variable and the unbridged gap between input parameters and output results. This paper aims to present a state ventilation which can provide a measure of two primary, but heterogenous, ventilation support goals. The paper also tries to develop a method to compute, rather than estimate, respiratory parameters to obtain the underlying causal information.

MethodsThis paper presents a state ventilation, which is calculated based on minute ventilation and blood gas partial pressures, to evaluate the efficacy of ventilation support and indicate disease progression. Through mathematical analysis, formulae are derived to compute dead space volume/ventilation, alveolar ventilation, and CO2 production.

ResultsMeasurements from a reported clinical study are used to verify the analysis and demonstrate the application of derived formulae. The state ventilation gives the expected trend to show patient status, and the calculated mean values of dead space volume, alveolar ventilation, and CO2 production are 158mL, 8.8L/m, and 0.45L/m respectively for a group of patients.

Discussions and ConclusionsState ventilation can be used as a target variable since it reflects patient respiratory effort and gas exchange. The derived formulas provide a means to accurately and continuously compute respiratory parameters using routinely available measurements to characterize the impact of different contributing factors.

category: respiratory medicine


title: NEMoE: A nutrition aware regularized mixture of experts model addressing diet-cohort heterogeneity of gut microbiota in Parkinson's disease

abstract: The microbiome plays a fundamental role in human health and diet is one of the strongest modulators of the gut microbiome. However, interactions between microbiota and host health are complex and diverse. Understanding the interplay between diet, the microbiome and health state could enable the design of personalized intervention strategies and improve the health and wellbeing of affected individuals. A common approach to this is to divide the study population into smaller cohorts based on dietary preferences in the hope of identifying specific microbial signatures. However, classification of patients based solely on diet is unlikely to reflect the microbiome-host health relationship or the taxonomic microbiome makeup. To this end, we present a novel approach, the Nutrition-Ecotype Mixture of Experts (NEMoE) model, for establishing associations between gut microbiota and health state that accounts for diet-specific cohort variability using a regularized mixture of experts model framework with an integrated parameter sharing strategy to ensure data driven diet-cohort identification consistency across taxonomic levels. The success of our approach was demonstrated through a series of simulation studies, in which NEMoE showed robustness with regard to parameter selection and varying degrees of data heterogeneity. Further application to real-world microbiome data from a Parkinsons disease cohort revealed that NEMoE is capable of not only improving predictive performance for Parkinsons Disease but also for identifying diet-specific microbiome markers of disease. Our results indicate that NEMoE can be used to uncover diet-specific relationships between nutritional-ecotype and patient health and to contextualize precision nutrition for different diseases.

category: nutrition


title: Neutralization breadth of SARS CoV-2 viral variants following primary series and booster SARS CoV-2 vaccines in patients with cancer

abstract: Patients with cancer are more likely to have impaired immune responses to SARS CoV-2 vaccines. We studied the breadth of responses against SARS CoV-2 variants followingly primary vaccination in 178 patients with a variety of tumor types, and after booster doses in a subset. Neutralization of alpha, beta, gamma and delta SARS-CoV-2 variants was impaired relative to wildtype (Wuhan), regardless of vaccine type. Regardless of viral variant, mRNA1273 was the most immunogenic, followed by BNT162b2 and then Ad26.COV2.S. Neutralization of more variants (breadth) was associated with higher magnitude of wildtype neutralization, and increase with time since vaccination; increased age associated with lower breadth. Anti-spike binding antibody concentrations were a good surrogate for breadth (PPV=90% at >1000U/ml). Booster SARS-CoV-2 vaccines conferred enhanced breadth. These data suggest that achieving a high antibody titer is desirable to achieve broad neutralization; a single booster dose with current vaccines increases breadth of responses against variants.

category: oncology


title: The impact of chemosensory dysfunctions on weight loss

abstract:
BackgroundThe role of chemosensory senses (olfaction, taste, and trigeminal) is crucial, and their dysfunctions profoundly affect the quality of life, potentially impacting eating behaviors. However, it is unclear which chemosensory symptoms could lead to undernutrition. This study aims to investigate which findings in patients smell and taste workup are predictors of weight loss.

MethodsThis is a retrospective study based on a validated questionnaire consecutively given to adult patients presented in smell and taste consultations during a 10-year period. Psychophysical tests were used to measure chemosensory function (Sniffin Sticks, taste powder, and Taste Strips tests).

ResultsWe included 554 patients (307 females) with a median age of 51 years (IQR 23). Among them, 76 (13.7%) reported involuntary weight loss due to chemosensory disorders occurred over periods ranging from 3 to 36 months. We found that the odds of losing weight were 2.1 times higher when patients reported changes in aroma perception (p-value=0.012; 95% CI 1.15 - 3.83). Parosmia, but not phantosmia nor smell loss, was a significant predictor of weight loss (OR 2.22; p-value=0.015; 95% CI 1.17 - 4.2). Furthermore, the duration of symptoms for more than two years was protective for weight loss (OR 0.44; p-value=0.014; 95% CI 0.23 - 0.85). Regarding putative etiologies, post-traumatic chemosensory dysfunction was also a significant predictor (OR 2.08; p-value=0.039; 95% CI 1.04 - 4.16). Concerning psychophysical tests, we found that the probability of a patient to present weight loss increased by 8% for every 1-unit reduction in Taste Strips score (p-value=0.006; 95% CI 0.87 - 0.98).

ConclusionWe recommend investigating weight loss in smell and taste consultations, especially when patients report changes in aroma perception, parosmia, duration of symptoms for less than two years, head injury, and when low Taste Strips score is measured.

category: otolaryngology


title: DiagnosisQA: A semi-automated pipeline for developing clinician validated diagnosis specific QA datasets.

abstract: Question answering (QA) is one of the oldest research areas of AI and Computational Linguistics. QA has seen significant progress with the development of state-of-the-art models and benchmark datasets over the last few years. However, pre-trained QA models perform poorly for clinical QA tasks, presumably due to the complexity of electronic healthcare data. With the digitization of healthcare data and the increasing volume of unstructured data, it is extremely important for healthcare providers to have a mechanism to query the data to find appropriate answers. Since diagnosis is central to any decision-making for the clinicians and patients, we have created a pipeline to develop diagnosis-specific QA datasets and curated a QA database for the Cerebrovascular Accident (CVA). CVA, also commonly known as Stroke, is an important and commonly occurring diagnosis amongst critically ill patients. Our method when compared to clinician validation achieved an accuracy of 0.90(with 90% CI [0.82,0.99]). Using our method, we hope to overcome the key challenges of building and validating a highly accurate QA dataset in a semiautomated manner which can help improve performance of QA models.

category: health informatics


title: An ST131 clade and a Phylogroup A clade bearing a novel Escherichia coli O-antigen cluster predominate among bloodstream E. coli isolates from southwest Nigeria hospitals

abstract:
Escherichia coli bloodstream infections are typically attributed to a limited number of lineages that carry virulence factors associated with invasion and, in recent years, invasive E. coli are increasingly multiply antimicrobial resistant. In Nigeria, E. coli is a common cause of bloodstream infections but the identity of circulating clones is largely unknown and surveillance of their antimicrobial resistance has been limited. We verified and whole genome-sequenced 68 bloodstream E. coli isolates recovered between 2016 and 2018 at three sentinel sites in southwestern Nigeria and susceptibility tested 67 of them. Resistance to antimicrobials commonly used in Nigeria was high, with 67(100%), 62 (92.5%), 53 (79%) and 37(55%) showing resistance to trimethoprim, ampicillin, ciprofloxacin and aminoglycosides, respectively. All the isolates were susceptible to carbapenems and colistin. The strain set included isolates from globally disseminated high risk clones including those belonging to ST12 (n=2), ST131 (n=12) and ST648 (n = 4). Twenty-three (33.82%) of the isolates clustered within two clades. The first of these consisted of ST131 strains, comprised of O16:H5 and O25:H4 sub-lineages. The second was an ST10-ST167 complex clade comprised of strains carrying capsular genes that may have originated in Klebsiella. We additionally determined that four temporally-associated ST90 strains from one sentinel were closely related enough to suggest that at least some of them represented a retrospectively detected outbreak cluster. Our data demonstrate that a broad repertoire of invasive E. coli isolates cause bloodstream infections in southwest Nigeria. In addition to pandemic lineages, particularly ST131, these include a previously undescribed lineage carrying an O-antigen cluster previously only reported from Klebsiella. Genomic surveillance is valuable for tracking these and other clones and for outbreak identification.

Data SummaryPhylogenetic tree, clinical data, and epidemiological data were visualized using Microreact (https://microreact.org/project/hmj3KwxS1dmmFPCKFx6qeA-invasive-escherichia-coli-sw-nigeria-2016-2018). All the sequence data have been deposited in the ENA under the project ID PRJEB29739 (https://www.ebi.ac.uk/ena/browser/view/PRJEB29739). Accessions can be found in Table S6.

category: infectious diseases


title: Exploring the Role of Microbiome in Susceptibility, Treatment Response and Outcome among Tuberculosis Patients from Pakistan; Study Protocol for a Prospective Cohort Study (Micro-STOP)

abstract:
IntroductionTuberculosis (TB) caused by Mycobacterium tuberculosis is a common infectious disease associated with significant morbidity and mortality, especially in low and middle-income countries. Successful treatment of the disease requires prolonged intake (6 - 8 months) of multiple antibiotics with potentially detrimental consequences on the composition and functional potential of the human microbiome. The protocol described in the current study aims to identify microbiome (oral and gut) signatures associated with TB pathogenesis, treatment response and, outcome in humans.

Methods and analysisFour hundred and fifty, newly diagnosed TB patients from three district levels (Peshawar, Mardan, Swat) TB diagnosis and treatment centers will be recruited in this non-interventional, prospective cohort study and will be followed and monitored until treatment completion. Demographic and dietary intake data, anthropometric measurement and blood, stool and salivary rinse samples will be collected at baseline, day 15, month-2 and end of the treatment. Additionally, we will recruit age ({+/-} 3 years) and sex-matched healthy controls (n=30). Blood sampling will allow monitoring of the immune response during the treatment, while salivary rinse and fecal samples will allow monitoring of dynamic changes in oral and gut microbiome diversity. Within this prospective cohort study, a nested case-control study design will be conducted to assess perturbations in oral and gut microbiome diversity (microbial dysbiosis) and immune response and compare between the patients groups (treatment success vs failure).

Ethics and disseminationThe study has received ethics approval from the Ethic Board of Khyber Medical University Peshawar, and administrative approval from Provincial TB Control Program of Khyber Pakhtunkhwa, Pakistan. The study results will be presented in national and international conferences and published in peer-reviewed journals.

Trial registration numberNCT04985994; pre-results

Strengths and limitations of the studyO_LIProspective study design.
C_LIO_LILarge sample size, several sampling time points, and samples taken before, during and after anti-tuberculosis treatment will ensure capture of an accurate picture of any emerging microbial dysbiosis and immune modulation; this will provide new understanding of how these two factors are mutually influenced and how they are impacted by treatment and outcome in TB patients.
C_LIO_LIIn addition to microbial signatures, collection of socio-demographic, anthropometric, nutrition and co-morbidities data will permit further subgroup analysis and meaningful results that will be shared with the scientific community.
C_LIO_LIA potential weakness is that not all patients may be able to provide samples for all of the specified time points.
C_LIO_LIAnother weakness is the raised likelihood that some participants will withdraw since the study is carried out in resource poor communities
C_LI


title: Three year experience of Upper Gastrointestinal Endoscopic procedures at a tertiary care hospital of South Punjab

abstract:
IntroductionEndoscopy has become a necessity in diagnosing gastrointestinal (GI) disorders. The objective of our study was to evaluate the different indications and findings of upper GI endoscopy.

MethodsThis retrospective analysis was undertaken at department of Gastroenterology, Nishtar Hospital Multan. Records of all upper GI endoscopic procedures from 1st January 2018 till 31st December 2020 were evaluated.

ResultsA total 3299 upper GI endoscopic procedures were perfumed during the three-year time period. Mean age was 47 years. Majority of patients were males. Almost 48% of patients belonged to the middle-aged group. The most common indication was upper GI bleeding (57%), followed by dyspepsia (15%). The most common finding was esophageal varices (43%), followed by portal gastropathy (26%) and gastritis (16%).

ConclusionThis study concludes that the majority of endoscopies are being undertaken as a result of complications of cirrhosis and portal hypertension.

category: gastroenterology


title: Differences in COVID-19 vaccination coverage by occupation in England: a national linked data study

abstract:
BackgroundMonitoring differences in COVID-19 vaccination uptake in different groups is crucial to help inform the policy response to the pandemic. A key gap is the absence of data on uptake by occupation.

MethodsUsing nationwide population-level data, we calculated the proportion of people who had received two doses of a COVID-19 vaccine (assessed on 31 August 2021) by detailed occupational categories in adults aged 40-64 and estimated adjusted odds ratios to examine whether these differences were driven by occupation or other factors, such as education. We also examined whether vaccination rates differed by ability to work from home.

ResultsOur study population included 14,298,147 adults 40-64. Vaccination rates differed markedly by occupation, being higher in administrative and secretarial occupations (90.8%); professional occupations (90.7%); and managers, directors and senior officials (90.6%); and lowest (83.1%) in people working in elementary occupations. We found substantial differences in vaccination rates looking at finer occupational groups even after adjusting for confounding factors, such as education. Vaccination rates were higher in occupations which can be done from home and lower in those which cannot. Many occupations with low vaccination rates also involved contact with the public or with vulnerable people

ConclusionsIncreasing vaccination coverage in occupations with low vaccination rates is crucial to help protecting the public and control infection, especially in occupations that cannot be done from home and involve contacts with the public. Policies such as  work from home if you can may only have limited future impact on hospitalisations and deaths

What is already known on this subject?Whilst several studies highlight differences in vaccination coverage by ethnicity, religion, socio-demographic factors and certain underlying health conditions, there is very little evidence on how vaccination coverage varies by occupation, in the UK and elsewhere. The few study looking at occupational differences in vaccine hesitancy focus on healthcare workers or only examined broad occupational groups. There is currently no large-scale study on occupational differences in COVID-19 vaccination coverage in the UK.

What this study adds?Using population-level linked data combining the 2011 Census, primary care records, mortality and vaccination data, we found that the vaccination rates of adults aged 40 to 64 years in England differed markedly by occupation. Vaccination rates were high in administrative and secretarial occupations, professional occupations and managers, directors and senior officials and low in people working in elementary occupations. Adjusting for other factors likely to be linked to occupation and vaccination, such as education, did not substantially alter the results. Vaccination rates were also associated with the ability to work from home, with the vaccination rate being higher in occupations which can be done performed from home. Policies aiming to increase vaccination rates in occupations that cannot be done from home and involve contacts with the public should be priorities


title: SHP2 promotes NETosis through ERK5 pathway and mediates the development of psoriasis

abstract: Psoriasis is a chronic inflammatory disease which infiltrated a large number of neutrophils among skin lesions. Here, we investigated the contribution of tyrosine phosphatase SHP2 in neutrophils, as well as its pathogenesis in psoriasis. We combined single-cell RNA sequencing with experimental verification to declare that SHP2 in neutrophils could promote the NETs formation through the ERK5 pathway, and resulted in the infiltration of inflammatory immune cells, which leads to psoriasis. Our study provides evidence for the role of SHP2 in NETosis in the progression of psoriasis, and SHP2 may be a potential therapeutic target for the treatment of psoriasis.

category: allergy and immunology


title: Using mobile phone data to estimate dynamic population changes and improve the understanding of a pandemic: A case study in Andorra

abstract:
Compartmental models are often used to understand and predict the progression of an infectious disease such as COVID-19. The most basic of these models consider the total population of a region to be closed. Many incorporate human mobility into their transmission dynamics, usually based on static and aggregated data. However, mobility can change dramatically during a global pandemic as seen with COVID-19, making static data unsuitable. Recently, large mobility datasets derived from mobile devices have been used, along with COVID-19 infections data, to better understand the relationship between mobility and COVID-19. However, studies to date have relied on data that represent only a fraction of their target populations, and the data from mobile devices have been used for measuring mobility within the study region, without considering changes to the population as people enter and leave the region.

This work presents a unique case study in Andorra, with comprehensive datasets that include telecoms data covering 100% of mobile subscribers in the country, and results from a serology testing program that more than 90% of the population voluntarily participated in. We use the telecoms data to both measure mobility within the country and to provide a real-time census of people entering, leaving and remaining in the country. We develop multiple SEIR (compartmental) models parameterized on these metrics and show how dynamic population metrics can improve the models. We find that total daily trips did not have predictive value in the SEIR models while country entrances did. As a secondary contribution of this work, we show how Andorras serology testing program was likely impacted by people leaving the country. Overall, this case study suggests how using mobile phone data to measure dynamic population changes could improve studies that rely on more commonly used mobility metrics and the overall understanding of a pandemic.


title: cfTrack: Exome-wide mutation analysis of cell-free DNA to simultaneously monitor the full spectrum of cancer treatment outcomes: MRD, recurrence, and evolution

abstract:
PurposeCell-free DNA (cfDNA) offers a non-invasive approach to monitor cancer. Here we develop a method using whole-exome sequencing (WES) of cfDNA for simultaneously monitoring the full spectrum of cancer treatment outcomes, including MRD, recurrence, evolution, and second primary cancer.

Experimental DesignThree simulation datasets were generated from 26 cancer patients to benchmark the detection performance of MRD/recurrence and second primary cancers. For further validation, cfDNA samples (n=76) from cancer patients (n=35) with six different cancer types were used for validating the performance of cancer monitoring during various treatments.

ResultsWe present a cfDNA-based cancer monitoring method, named cfTrack. Taking advantage of the broad genome coverage of WES data, cfTrack can sensitively detect MRD and cancer recurrence by integrating signals across the known clonal tumor mutations of a patient. In addition, cfTrack detects tumor evolution and second primary cancers by de novo identifying emerging tumor mutations. A series of machine learning and statistical denoising techniques are applied to enhance the detection power. On the simulation data, cfTrack achieved an average AUC of 99% on the validation dataset and 100% on the independent dataset in detecting recurrence in samples with tumor fraction [≥]0.05%. In addition, cfTrack yielded an average AUC of 88% in detecting second primary cancers in samples with tumor fraction [≥]0.2%. On real data, cfTrack accurately monitors tumor evolution during treatment, which cannot be accomplished by previous methods.

ConclusionOur results demonstrated that cfTrack can sensitively and specifically monitor the full spectrum of cancer treatment outcomes using exome-wide mutation analysis of cfDNA.

Translational RelevanceContinuous cancer monitoring is clinically necessary for cancer patients to detect minimal residual disease (MRD), recurrence, and progression, allowing for early intervention and therapy adjustment. Cell-free DNA (cfDNA) in blood has become an appealing option due to its non-invasiveness. Until now, cfDNA-based cancer monitoring methods have been focused on deep sequencing at a few known mutations, which are however insufficient when tumors evolve or new tumors emerge. We present the method, cfTrack, which for the first time uses whole-exome sequencing (WES) of cfDNA to track the full range of cancer treatment outcomes, including MRD, recurrence, evolution, and second primary cancer. We demonstrate that, even with very low tumor fractions, cfTrack achieves sensitive and specific monitoring of tumor MRD/recurrence/evolution based on both simulation data and a cohort of cancer patients. These findings demonstrate the clinical utility of cfTrack.

category: pathology


title: Early neurodevelopmental problems and risk for avoidant/restrictive food intake disorder (ARFID) in the general child population: a Japanese birth cohort study

abstract:
BackgroundAn overrepresentation of neurodevelopmental disorders (NDDs) has been observed in individuals with avoidant/restrictive food intake disorder (ARFID). Previous studies on the association between ARFID and NDDs are limited to cross-sectional data from clinical samples of small size. This study aimed to extend previous research by using prospectively collected data in children from a general population sample. We examined the occurrence and predictive power of early neurodevelopmental problems in 4-7-year-old children with suspected ARFID.

MethodsData were collected via parent-report in 3,728 children born between 2011 and 2014 in Kochi prefecture, a sub-sample of the Japan Environment and Childrens Study (JECS). Neurodevelopmental problems were assessed with several instruments at different time points between 0.5 and 3 years of age as part of the JECS. In an add-on study, ARFID was identified cross-sectionally (between 4 and 7 years of age) using a newly developed screening tool.

ResultsCirca 3% of children at high risk for NDDs in preschool age screened positive for ARFID between age 4 and 7 years, reflecting a three times increased risk of suspected ARFID. A fifth (20.8%) of children with suspected ARFID had likely NDDs, compared to 8.6% of children without suspected ARFID. Developmental delay trajectories of children with and without suspected ARFID started to divert after the age of 6 months. Only 2.2% of children with early feeding problems later screened positive for ARFID. The inclusion of neurodevelopmental problems improved the prediction of later ARFID.

ConclusionsThe results mirror the previously observed overrepresentation of NDDs in ARFID populations, although to a weaker extent. In non-clinical populations, early feeding problems are common and rarely develop into ARFID, however, our findings imply that they should be monitored closely in children with high neurodevelopmental risk in order to prevent ARFID.


title: NREM sleep signatures of memory disruption and psychiatric symptoms in young people with 22q11.2 deletion syndrome

abstract:
BackgroundYoung people with 22q11.2 Deletion Syndrome (22q11.2DS) are at increased risk of schizophrenia, intellectual disability, Attention-Deficit Hyperactivity Disorder (ADHD) and autism spectrum disorder. In common with these conditions, 22q11.2DS is also associated with sleep problems. We investigated whether abnormal sleep or sleep-dependent network activity in 22q11.2DS may reflect convergent, early signatures of neural circuit disruption also evident in associated neurodevelopmental conditions.

MethodsWe recorded high-density sleep EEG in young people (6-20 years) with 22q11.2DS (n=28) and their unaffected siblings (n=17), quantifying the associations between sleep architecture, EEG oscillations (spindles and slow-waves) and psychiatric symptoms. We also measured performance on a memory task before and after sleep.

Results22q11.2DS was associated with significant alterations in sleep architecture, including a greater proportion of N3 sleep and lower proportions of N1 and REM sleep than in siblings. During NREM sleep, deletion carriers showed increased power in slow delta and sigma oscillations, increased slow-wave and spindle amplitudes, and altered coupling between spindles and slow-waves. Spindle and slow-wave amplitudes correlated positively with overnight memory in controls, but negatively in 22q11.2DS. Mediation analyses indicated that increased slow-wave amplitude in 22q11.2DS was statistically mediated via ADHD symptoms.

ConclusionsThis first study of sleep EEG in 22q11.2DS highlights several alterations in EEG signatures of NREM sleep, some of which were associated with ADHD symptoms. ADHD symptoms have previously been associated with incident psychotic symptoms in 22q11.2DS; our findings may therefore reflect delayed or compromised neurodevelopmental processes which precede, and may be biomarkers for, psychotic disorders.


title: A study of the benefits of vaccine mandates and vaccine passports for SARS-CoV-2

abstract:
ObjectiveTo evaluate the benefits of vaccine mandates and vaccine passports (VMVP) for SARS-CoV-2 by estimating the benefits of vaccination and exclusion of unvaccinated people from different settings.

MethodsQuantified the benefits of vaccination using meta-analyses of randomized controlled trials (RCTs), cohort studies, and transmission studies to estimate the relative risk reduction (RRR), absolute risk reduction (ARR), and number needed to vaccinate (NNV) for transmission, infection, and severe illness/hospitalization. Estimated the baseline infection risk and the baseline transmission risks for different settings. Quantified the benefits of exclusion using these data to estimate the number of unvaccinated people needed to exclude (NNE) to prevent one transmission in different settings. Modelled how the benefits of vaccination and exclusion change as a function of baseline infection risk. Studies were identified from recent systematic reviews and a search of MEDLINE, MEDLINE In-Process, Embase, Global Health, and Google Scholar.

ResultsData on infection and severe illness/hospitalization were obtained from 10 RCTs and 19 cohort studies of SARS-CoV-2 vaccines, totalling 5,575,049 vaccinated and 4,341,745 unvaccinated participants. Data from 7 transmission studies were obtained, totalling 557,020 index cases, 49,328 contacts of vaccinated index cases, and 1,294,372 contacts of unvaccinated index cases. The estimated baseline infection risk in the general population is 3.04%. The estimated breakthrough infection risk in the vaccinated population is 0.57%. Vaccines are very effective at reducing the risk of infection (RRR=88%, ARR=2.59%, NNV=39) and severe illness/hospitalization (RRR=89%, ARR=0.15%, NNV=676) in the general population. While the latter effect is small, vaccines nearly eliminate the baseline risk of severe illness/hospitalization (0.16%). Among an infected persons closest contacts (primarily household members), vaccines reduce transmission risk (RRR=41%, ARR=11.04%, NNV=9). In the general population, the effect of vaccines on transmission risk is likely very small for most settings and baseline infection risks (NNVs [≥] 1,000). Infected vaccinated people have a nontrivial transmission risk for their closest contacts (14.35%), but it is less than unvaccinated people (23.91%). The transmission risk reduction gained by excluding unvaccinated people is very small for most settings: healthcare (NNE=4,699), work/study places (NNE=2,193), meals/gatherings (NNE=531), public places (NNE=1,731), daily conversation (NNE=587), and transportation (NNE=4,699). Exclusion starts showing benefits on transmission risk for some settings when the baseline infection risk is between 10% to 20%.

ConclusionsThe benefits of VMVP are clear: the coercive element to these policies will likely lead to increased vaccination levels. Our study shows that higher vaccination levels will drive infections lower and almost eliminate severe illness/hospitalization from the general population. This will substantially lower the burden on healthcare systems. The benefits of exclusion are less clear. The NNEs suggest that hundreds, and even thousands, of unvaccinated people may need to be excluded from various settings to prevent one SARS-CoV-2 transmission from unvaccinated people. Therefore, consideration of the costs of exclusion is warranted, including staffing shortages from losing unvaccinated healthcare workers, unemployment/unemployability, financial hardship for unvaccinated people, and the creation of a class of citizens who are not allowed to fully participate in many areas of society.

RegistrationThis study is not registered.

FundingThis study received no grant from any funding agency, commercial, or not-for-profit sectors. It has also received no support of any kind from any individual or organization.


title: Many Oil Wells, One Evil: Potentially toxic metals concentration, seasonal variation and Human Health Risk Assessment in Drinking Water Quality in Ebocha-Obrikom Oil and Gas Area of Rivers State, Nigeria.

abstract:
BackgroundOil and natural gas extraction have produced environmental pollution at levels that affect reproductive health of indigenous populations. Accordingly, polluted drinking water from physical, chemical and heavy metals can result in serious health problems, like anemia, kidney failure, immunosuppression, neurological impairments, gastrointestinal as well as respiratory irritation, skeletal system abnormalities, liver inflammation, liver cancer, cardiovascular diseases after chronic exposure and other cancer diseases with negative health effects. These diseases types remain associated to high amounts of heavy metal elements such as lead, chromium, zinc, copper, cadmium, manganese as well as nickel etc.

ObjectivesCompare differences in water quality parameters in the study area (determine the level of pollutions in the different sites).

MethodologyThe investigation made use of standard analytical procedures. All sampling, conservation, transportation and analysis followed standard procedures described in APHA (2012). To prevent degradation of the organic substances, all obtained samples were transferred to the laboratory, while keeping in an icebox.

ResultsResult shows that during wet season, the mean values obtained for water quality parameters were significantly lower in site 9 compared with that obtained in other sites (p<0.05) with the exemptions of temperature, DO, BOD, COD, acidity, TH, TDS, K, Mg, Zn, Mn, Cd, Pb, Cu, Cr, NH3, NO2, NO3, Ni though slightly lower in most cases in site 9 were not significantly different (p>0.05) and both alkalinity and SO4 which were significantly higher in site 9 than site 1 (p<0.05). Result obtained during dry season reveals that there is no remarkable difference in pH, acidity, Pb and Ni between the nine sites (p>0.05) while other water quality parameters were significantly lower in site 9 than other sites excluding Cl and Mg which were both significantly higher in site 9 than site 8 (p<0.05).

ConclusionTo guarantee quality groundwater supply for various purposes in Nigerias core Niger Delta region, extra efforts must be taken to fully understand hydrogeochemical features and its suitability. Thus, this study will aid in the development of a quantitative understanding of the effects of diverse causes on groundwater level fluctuations in any aquifer around the world. Also, this analysis reinforces a valuable resource for researchers, activists and public officials seeking to help enhance community awareness, planning and performance. The verdicts would remain a valuable guideline for policymakers, the Ministry of Water Resources and development practitioners, as this highlights the requirement for suitable approaches toward mitigating toxic element of water resources contamination in the core Niger Delta toward safeguarding health of the public from carcinogenic as well as non-carcinogenic risks.

HIGHLIGHTSO_LIMany tropical countries are suffering from severe groundwater pollution. Governments at all levels are doing little or very little to provide clean and accessible water to citizens, especially in Nigerias Niger Delta region.
C_LIO_LIThis study aims to determine the level of pollutions in the different sites.
C_LIO_LIResult depicts that during wet and dry season, the mean values obtained for water quality parameters were significantly lower in site 9 compared with that obtained in other sites.
C_LIO_LIResult reveals that groundwater at location 3, 4 and 7 were heavily polluted during wet and dry season. Hence, an alliance is needed to address the rising global health emergency threat caused by groundwater pollution in Nigerias core Niger Delta region, which is threatening millions of people. The situation will only get worse and faster unless there is a coordinated response to the problem through a worldwide alliance of organizations capable of bringing meaningful change.
C_LIO_LIThe disease risk as well as illness to millions of individuals living in close proximity to gas flaring remain a cause for worry in its own right, the gases as well as toxins impact released into the atmosphere through continuously flaring gases has worldwide implications.
C_LIO_LIRegarding the environmental and social conditions of the area, gas flaring significantly increases the health hazards, first through releasing dangerous pollutants directly into the atmosphere as well as through pollutants transfer to the food chain.
C_LIO_LIGroundwater pollution has a financial cost that runs into billions of Naira, in addition to the human and environmental effect. Thus, there is need for tougher environmental regulations.
C_LIO_LIAt present, no coordinated action being taken, real change will only occur if governments as well as key stakeholder organizations form a global alliance toward addressing the issue. Starting with a strategy to finance well closure as well as relocation of sites that are most dangerous (location 3, 4 & 7) as soon as possible, as well as providing support through capital and experience is required. Even though the cost will remain substantial, it will provide an opportunity toward investing in the Niger Delta infrastructure as well as economy. Furthermore, the expense of closing the most dangerous groundwater open wells will be a drop in the bucket compared to the cost of the health consequences.
C_LI

category: toxicology


title: A Prospective Cohort Study Towards Improving Enhanced Recovery After Cesarean (ERAC) Pathways.

abstract:
ObjectiveTo evaluate whether Enhanced Recovery After Cesarean (ERAC) pathways reduces inpatient and outpatient opioid use, pain scores and improves the indicators of postoperative recovery.

Study designThis is a prospective cohort study of all patients older than 18 undergoing an uncomplicated cesarean delivery (CD) at an academic medical center. We excluded complicated CD, patients with chronic pain disorders, chronic opioid use, acute postpartum depression, or mothers whose neonate demised before their discharge. Lastly, we excluded non-English and non-Spanish speaking patients. Our study compared the outcomes in patients before (pre-ERAC) and after (post-ERAC) implementation of an ERAC pathways. Primary outcomes were inpatient morphine milligram equivalent (MME) use and the patients delta pain scores. Secondary outcomes were outpatient MME prescriptions as well as indicators of postoperative recovery.

ResultsOf 308 patients undergoing CD from October 2019 to September 2020, 196 were enrolled in the pre-ERAC cohort and 112 in the post-ERAC cohort. Patients in the post-ERAC cohort were less likely to require opioids in the postoperative period compared to the pre-ERAC cohort (35.7% vs. 18.4%, p<0.001). In addition, there was a significant reduction in the MME per stay in this cohort [16.8 MME (11.2-33.9) vs. 30 MME (20-49), p<0.001]. In the post-ERAC cohort, there was also a reduction in the number of patients who required prescribed opioids at the time of discharge (86.6 vs. 98%, p<0.001) as well as in the amount of MMEs prescribed [150 MME (112-150) vs. 150 MME (150-225), p<0.001; different shape of distribution]. Patients in the post-ERAC cohort had lower delta pain scores [2.2 (1.3-3.7) vs. 3.3 (2.3-4.7), p<0.001].

ConclusionOur study has illustrated that our ERAC pathways reduced inpatient and outpatient opioid use as well as patient-reported pain scores while improving indicators of postoperative recovery.

category: obstetrics and gynecology


title: Survey of residential indoor Particulate Matter measurements 1990-2019

abstract:
We surveyed literature on measurements of indoor particulate matter in all size fractions, in residential environments free of solid fuel combustion. Data from worldwide studies from 1990-2019 were assembled into the most comprehensive collection to date. Out of 2,752 publications retrieved, 538 articles from 433 research projects met inclusion criteria and reported unique data, from which more than 2,000 unique sets of indoor PM measurements were collected. Distributions of mean concentrations were compiled, weighted by study size. Long-term trends, the impact of non-smoking, air cleaners, and the influence of outdoor PM were also evaluated. Similar patterns of indoor PM distributions for North America and Europe could reflect similarities in the indoor environments of these regions. Greater observed variability for all regions of Asia may reflect greater heterogeneity in indoor conditions, but also low numbers of studies for some regions. Indoor PM concentrations of all size fractions were mostly stable over the survey period, with the exception of observed declines in PM2.5 in European and North American studies, and in PM10 in North America. While outdoor concentrations were correlated with indoor concentrations across studies, indoor concentrations had higher variability, illustrating a limitation of using outdoor measurements to approximate indoor PM exposures.

Practical implicationsO_LIResidential indoor PM concentration ranges for several size fractions measured in different worldwide regions are provided and may inform future public health research and practice, including PM exposure and risk assessment, and evaluation of IAQ-related interventions and consumer products, such as portable air cleaners.
C_LIO_LIThis long-term indoor PM concentration record provides insights regarding the degree of change in observed indoor PM concentrations by world region and some of the factors contributing to increasing or decreasing temporal trends.
C_LIO_LIOutdoor air pollution remains a major influence on indoor concentrations of PM of all sizes.
C_LIO_LIGreater variability of indoor concentrations of PM relative to outdoor concentrations demonstrate the potential for exposure misclassification when using outdoor concentrations to estimate indoor exposures and risk.
C_LIO_LIIAQ interventions, including removing environmental tobacco smoke or using filtration-based portable air cleaners, can produce major improvements in IAQ through reduced indoor particle concentrations.
C_LI

category: occupational and environmental health


title: Mapping the human genetic architecture of COVID-19: an update

abstract: The Coronavirus Disease 2019 (COVID-19) pandemic continues to pose a major public health threat especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity we formed the COVID19 Host Genetics Initiative. Here we present GWAS meta-analysis of up to 125,584 cases and over 2.5 million controls across 60 studies from 25 countries, adding 11 new genome-wide significant loci compared to those previously identified. Genes in novel loci include SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.

category: genetic and genomic medicine


title: The β-NGF/TrkA signalling pathway is associated with the production of anti- nucleoprotein IgG in convalescent COVID-19

abstract:
BackgroundThe presentation of SARS-CoV-2 infection varies from asymptomatic to severe COVID. Similarly, high variability in the presence, titre and duration of specific antibodies has been reported. While some host factors determining these differences, such as age and ethnicity have been identified, the underlying molecular mechanisms underpinning these differences remain poorly defined.

MethodsWe analysed serum and PBMC from 17 subjects with a previous PCR confirmed SARS-CoV-2 infection and 10 unexposed volunteers following the first wave of the pandemic, in the UK. Anti-NP IgG and neutralising antibodies were measured, as well as a panel of infection and inflammation related cytokines. The virus-specific T cell response was determined by IFN-{gamma} ELISPOT and flow cytometry after over-night incubation of PBMCs with pools of selected SARS-CoV-2 specific peptides.

ResultsSeven of 17 convalescent subjects had undetectable levels of anti-NP IgG, and a positive correlation was shown between anti-NP IgG levels and the titre of neutralising antibodies (IC50). In contrast, a discrepancy was noted between antibody levels and T cell IFN-{gamma} production by ELISpot following stimulation with specific peptides. Among the analysed cytokines, {beta}-NGF and IL-1 levels were significantly different between anti-NP positive and negative subjects, and only {beta}-NGF significantly correlated with anti-NP positivity. Interestingly, CD4+ T cells of anti-NP negative subjects expressed lower amounts of the {beta}-NGF-specific receptor TrkA.

ConclusionsOur results suggest that the {beta}-NGF/TrkA signalling pathway is associated with the production of anti-NP specific antibody in mild SARS-CoV-2 infection and the mechanistic regulation of this pathway in COVID-19 requires further investigation.


title: COVID-19 convalescents exhibit deficient humoral and T cell responses to variant of concern Spike antigens at 12 month post-infection

abstract:
BackgroundThe duration and magnitude of SARS-CoV-2 immunity after infection, especially with regard to the emergence of new variants of concern (VoC), remains unclear. Here, immune memory to primary infection and immunity to VoC was assessed in mild-COVID-19 convalescents one year after infection and in the absence of viral re-exposure or COVID-19 vaccination.

MethodsSerum and PBMC were collected from mild-COVID-19 convalescents at [~]6 and 12 months after a COVID-19 positive PCR (n=43) and from healthy SARS-CoV-2-seronegative controls (n=15-40). Serum titers of RBD and Spike-specific Ig were quantified by ELISA. Virus neutralisation was assessed against homologous, pseudotyped virus and homologous and VoC live viruses. Frequencies of Spike and RBD-specific memory B cells were quantified by flow cytometry. Magnitude of memory T cell responses was quantified and phenotyped by activation-induced marker assay, while T cell functionality was assessed by intracellular cytokine staining using peptides specific to homologous Spike virus antigen and four VoC Spike antigens.

FindingsAt 12 months after mild-COVID-19, >90% of convalescents remained seropositive for RBD-IgG and 88.9% had circulating RBD-specific memory B cells. Despite this, only 51.2% convalescents had serum neutralising activity against homologous live-SARS-CoV-2 virus, which decreased to 44.2% when tested against live B.1.1.7, 4.6% against B.1.351, 11.6% against P.1 and 16.2%, against B.1.617.2 VoC. Spike and non-Spike-specific T cells were detected in >50% of convalescents with frequency values higher for Spike antigen (95% CI, 0.29-0.68% in CD4+ and 0.11-0.35% in CD8+ T cells), compared to non-Spike antigens. Despite the high prevalence and maintenance of Spike-specific T cells in Spike  high-responder convalescents at 12 months, T cell functionality, measured by cytokine expression after stimulation with Spike epitopes corresponding to VoC was severely affected.

InterpretationsSARS-CoV-2 immunity is retained in a significant proportion of mild COVID-19 convalescents 12 months post-infection in the absence of re-exposure to the virus. Despite this, changes in the amino acid sequence of the Spike antigen that are present in current VoC result in virus evasion of neutralising antibodies, as well as evasion of functional T cell responses.

FundingThis work was funded by project grants from The Hospital Research Foundation and Womens and Childrens Hospital Foundation, Adelaide, Australia. MGM is THRF Early Career Fellow. BGB is THRF Mid-Career Fellow. This project has been supported partly with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.S. and Contract No. 75N9301900065 to A.S, D.W.

Evidence before this studyWe regularly searched on PubMed and Google Scholar in June-October 2021 using individual or combinations of the terms "long-term immunity", "SARS-CoV-2", "antigenic breadth", "variant of concern" and "COVID-19". We found studies that had assessed immune correlates at multipe time points after COVID-19 disease onset in convalescents, but not the antigenic breadth of T cells and antibodies and not in relation to VoC. Other immune studies in virus naive vaccinees, or vaccinated convalescents evaluated VoC-specific immunity, but not in convalescents that have not been vaccinated. In summary, we could not find long-term studies providing and in-depth evaluation of functionality of humoral and cell-mediated immunity, combined with addressing the adaptability of these immune players to VoC.

Added value of this studyThe window of opportunity to conduct studies in COVID-19 convalescents (i.e. natural immunity to SARS-CoV-2) is closing due to mass vaccination programs. Here, in a cohort of unvaccinated mild-COVID-19 convalescents, we conducted a comprehensive, longitudinal, long-term immune study, which included functional assays to assess immune fitness against antigenically different VoC. Importantly, the cohort resided in a SARS-CoV-2-free community for the duration of the study with no subsequent re-exposure or infection. Our findings reveal a deeply weakened humoral response and functional vulnerability of T cell responses to VoC Spike antigens.

Implications of all the available evidenceThis study provides a valuable snapshot of the quality of SARS-CoV-2 natural immunity and its durability in the context of a pandemic in which new variants continuously emerge and challenge pre-existing immune responses in convalescents and vacinees. Our results serve as a warning that delays in vaccination programs could lead to an increase in re-infection rates of COVID-19 convalescents, caused by virus variants that escape humoral and cell-mediated immune responses. Furthermore, they reinforce the potential benefit of booster vaccination that is tuned to the active variants.


title: Genome wide association study of human bacteremia Escherichia coli isolates identifies genetic determinants for the portal of entry but not fatal outcome

abstract: Escherichia coli is an important cause of bloodstream infections (BSI), which is of concern given its high mortality and increasing worldwide prevalence. Finding bacterial genetic variants that might contribute to patient death is of interest to better understand its mechanism and implement diagnostic methods that specifically look for those factors. E. coli samples isolated from patients with BSI are an ideal dataset to systematically search for those variants, as long as the influence of host factors such as comorbidities are taken into account. Here we performed a genome-wide association study (GWAS) using data from 910 patients with E. coli BSI from hospitals in Paris, France; we looked for associations between bacterial genetic variants and three patient outcomes (death at 28 days, septic shock and admission to intensive care unit), as well as two portals of entry (urinary and digestive tract), using various clinical variables from each patient to account for host factors. We did not find any associations between genetic variants and patient outcomes, potentially confirming the strong influence of host factors in influencing the course of BSI; we however found a strong association between the papGII/papGIII operon and entrance of E. coli through the urinary tract, which demonstrates the power of bacterial GWAS even when applied to actual clinical data. Despite the lack of associations between E. coli genetic variants and patient outcomes, we estimate that increasing the sample size by one order of magnitude could lead to the discovery of some putative causal variants. The adoption of bacterial genome sequencing of clinical isolates might eventually lead to the elucidation of the mechanisms behind BSI progression and the development of sequence-based diagnostics.


title: A prototype vaccination model for endemic Covid-19 under waning immunity and imperfect vaccine take-up

abstract: In this paper, for an infectious disease such as Covid-19, we present a SIR model which examines the impact of waning immunity, vaccination rates, vaccine efficacy, and the proportion of the susceptible population who aspire to be vaccinated. Under an assumed constant control reproduction number, we provide simple conditions for the disease to be eliminated, and conversely for it to exhibit the more likely endemic behaviour. With regard to Covid-19, it is shown that if the control reproduction number is set to the basic reproduction number (say 6) of the dominant delta (B1.617.2) variant, vaccination alone, even under the most optimistic of assumptions about vaccine efficacy and high vaccine coverage, is very unlikely to lead to elimination of the disease. The model is not intended to be predictive but more an aid to understanding the relative importance of various biological and control parameters. For example, from a long-term perspective, it may be found that in the UK, through changes in societal behaviour (such as mask use, ventilation, and level of homeworking), without formal government interventions such as on-off lockdowns, the control reproduction number can still be maintained at a level significantly below the basic reproduction number. Even so, our simulations show that endemic behaviour ensues. The model obtains equilibrium values of the state variables such as the infection prevalence and mortality rate under various scenarios.


title: High-resolution ultrasonography of gingival biomarkers for periodontal diagnosis in healthy and diseased subjects

abstract: Periodontal disease affects nearly 50% of Americans but diagnostic methods have remained the same for decades. Periodontal examination via physical probing provides critical metrics such as pocket depth, clinical attachment level, and gingival recession; however, this practice is time consuming, variable, and often painful. In this study, we investigated high-frequency ultrasound (40 MHz) for the image-based measurement of periodontal metrics. Imaging was performed at midbuccal sites for a set of periodontally healthy (n = 10) and diseased (n = 6) subjects and image-based measurements were compared to gold-standard physical probing measurements. Human operators identified relevant markers (e.g., cementoenamel junction, gingival margin, alveolar bone crest) in B-mode ultrasound images from 66 teeth to calculate gingival height and alveolar bone level. These metrics were correlated to clinical measurements of probing pocket depth and clinical attachment level for disease staging (1.57-mm bias and 0.25-mm bias, respectively). Interoperator bias was negligible (<0.1 mm) for gingival height measurements and 0.45 mm for alveolar bone level measurements. The ultrasonographic measurements of gingival height and alveolar bone level served as effective diagnostic surrogates for clinical probing measurements while offering more detailed anatomical information and painless operation.

category: dentistry and oral medicine


title: The role of antiviral treatment in curbing the COVID-19 pandemic: a modeling study.

abstract: Despite the development of safe and effective vaccines, effective treatments for COVID-19 disease are still urgently needed. Several antiviral drugs have shown to be effective in reducing progression of COVID-19 disease. In the present work, we use an agent-based mathematical model to assess the potential population impact of the use of antiviral treatments in four countries with different demographic structure and current levels of vaccination coverage: Kenya, Mexico, United States (US) and Belgium. We analyzed antiviral effects on reducing hospitalization and death, and potential antiviral effects on reducing transmission. For each country, we varied daily treatment initiation rate (DTIR) and antiviral effect in reducing transmission (AVT). Irrespective of location and AVT, widespread antiviral treatment of symptomatic adult infections ([≥]20% DTIR) prevented the majority of COVID-19 deaths, and recruiting 6% of all adult symptomatic infections daily reduced mortality by a third in all countries. Furthermore, our model projected that targeting antiviral treatment to the oldest age group (65 years old and older, DTIR of 20%) can prevent over 47% of deaths. Our results suggest that early antiviral treatment (as soon as possible after inception of infection) is needed to mitigate transmission, preventing 50% more infections compared to late treatment (started 3 to 5 days after symptoms onset). Our results highlight the synergistic effect of vaccination and antiviral treatment: as the vaccination rate increases, antivirals have a larger relative impact on population transmission. These results suggest that antiviral treatments can become a strategic tool that, in combination with vaccination, can significantly reduce COVID-19 hospitalizations and deaths and can help control SARS-CoV-2 transmission.

category: epidemiology


title: Could widespread use of antiviral treatment curb the COVID-19 pandemic? A modeling study.


title: Impact of the COVID-19 pandemic on routine surveillance for adults with chronic hepatitis B virus (HBV) infection in the UK.

abstract:
Background and aimsTo determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (ALT and HBV viral load).

MethodsWe used anonymised electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK NHS Trusts.

ResultsWe report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID years, both in terms of the proportion of patients who had [≥]1 measurement annually, and the mean number of measurements per patient.

ConclusionsFurther investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.


title: Disparities in COVID-19 Fatalities among Working Californians

abstract:
BackgroundInformation on the occupational distribution of COVID-19 mortality is limited.

ObjectiveTo characterize COVID-19 fatalities among working Californians.

DesignRetrospective study of laboratory-confirmed COVID-19 fatalities with dates of death from January 1 to December 31, 2020.

SettingCalifornia.

ParticipantsCOVID-19 accounted for 8,050 (9.9%) of 81,468 fatalities among Californians 18-64 years old. Of these decedents, 2,486 (30.9%) were matched to state employment records and classified as "confirmed working." The remainder were classified as "likely working" (n=4,121 [51.2%]) or "not working" (n=1,443 [17.9%]) using death certificate and case registry data.

MeasurementsWe calculated age-adjusted overall and occupation-specific COVID-19 mortality rates using 2019 American Community Survey denominators.

ResultsConfirmed and likely working COVID-19 decedents were predominantly male (76.3%), Latino (68.7%), and foreign-born (59.6%), with high school or less education (67.9%); 7.8% were Black. The overall age-adjusted COVID-19 mortality rate was 30.0 per 100,000 workers (95% confidence interval [CI], 29.3-30.8). Workers in nine occupational groups had mortality rates higher than this overall rate, including those in farming (78.0; 95% CI, 68.7-88.2); material moving (77.8; 95% CI, 70.2-85.9); construction (62.4; 95% CI, 57.7-67.4); production (60.2; 95% CI, 55.7-65.0); and transportation (57.2; 95% CI, 52.2-62.5) occupations. While occupational differences in mortality were evident across demographic groups, mortality rates were three-fold higher for male compared with female workers and three- to seven-fold higher for Latino and Black workers compared with Asian and White workers.

LimitationsThe requirement that fatalities be laboratory-confirmed and the use of 2019 denominator data may underestimate the occupational burden of COVID-19 mortality.

ConclusionCalifornians in manual labor and in-person service occupations experienced disproportionate COVID-19 mortality, with the highest rates observed among male, Latino, and Black workers.


title: Gut microbiome composition is predictive of incident type 2 diabetes

abstract:
OBJECTIVETo examine the previously unknown long-term association between gut microbiome composition and incident type 2 diabetes in a representative population cohort.

RESEARCH DESIGN AND METHODSWe collected fecal samples of 5 572 Finns (mean age 48.7 years, 54.1% women) in 2002 who were followed up for incident type 2 diabetes until Dec 31st, 2017. The samples were sequenced using shotgun metagenomics. We examined associations between gut microbiome compositions and incident diabetes using multivariable-adjusted Cox regression models. We first used the Eastern Finland sub-population to obtain initial findings and validated these in the Western Finland sub-population.

RESULTSAltogether 432 cases of incident diabetes occurred over the median follow-up of 15.8 years. We detected 4 species and 2 clusters consistently associated with incident diabetes in the validation models. These 4 species were Clostridium citroniae (HR, 1.21; 95% CI, 1.04-1.42), C. bolteae (HR, 1.20; 95% CI, 1.04-1.39), Tyzzerella nexilis (HR, 1.17; 95% CI, 1.01-1.36), and Ruminococcus gnavus (HR = 1.17; 95% CI, 1.01-1.36). The positively associated clusters, cluster 1 (HR, 1.18; 95% CI, 1.02-1.38) and cluster 5 (HR, 1.18; 95% CI, 1.02-1.36), mostly consisted of these same species.

CONCLUSIONSWe observed robust species-level taxonomic features predictive of incident type 2 diabetes over a long-term follow-up. These findings build on and extend previous mainly cross-sectional evidence and further support links between dietary habits, metabolic diseases, and type 2 diabetes that are modulated by the gut microbiome. The gut microbiome could potentially be used to improve risk prediction and to uncover novel therapeutic targets for diabetes.


title: Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in infliximab- and vedolizumab-treated patients

abstract: We report SARS-CoV-2 vaccine-induced immunity and risk of breakthrough infections in patients with inflammatory bowel disease treated with infliximab, a commonly used anti-TNF drug and those treated with vedolizumab, a gut-specific antibody targeting integrin a4b7 that does not impact systemic immunity. In infliximab-treated patients, the magnitude of anti-SARS-CoV2 antibodies was reduced 4-6-fold. One fifth of both infliximab- and vedolizumab-treated patients did not mount a T cell response. Antibody half-life was shorter in infliximab-treated patients. Breakthrough SARS-CoV-2 infections occurred more frequently in infliximab-treated patients and the risk was predicted by the level of antibody response after second vaccine dose. Overall, recipients of two doses of the BNT162b2 vaccine had higher anti-SARS-CoV-2 antibody concentrations, higher seroconversion rates, shorter antibody half-life and less breakthrough infections compared to ChAdOx1 nCoV-19 vaccine recipients. Irrespective of biologic treatment, higher, more sustained antibody levels were observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Patients treated with anti-TNF therapy should be offered third vaccine doses.


title: Frontline Healthcare workers suffering from psychosomatic disorders during COVID-19 (a pandemic): A Systematic review

abstract:
PurposeThe emergence of SARS CoV-2, has imposed high pressure on the healthcare system worldwide. As a consequence, frontline healthcare workers were impacted widely. The aim of this systematic review is to examine the impact of COVID-19 on mental status of FHW during pandemic.

MethodsDatabases such as PubMed, Scopus, google scholar were searched extensively from the date of inception till April 2021. All cross-sectional studies published in English assessing the mental condition and well-being of frontline caregivers during COVID-19 were included in the study. The quality assessment was done by Newcastle Ottawa scale.

ResultsTen thousand eight hundred sixty-nine articles were found. After conscientious literature search, total 78 articles were included satisfying the objective of the review. The highest and lowest values for the rates of depression, anxiety and insomnia was found to be 99.51% & 6.07%, 85.7% & 73.6%, and 5.3% & 11.4%, respectively.

ConclusionIt has been found that FHW were psychologically impacted by the pandemic. This could be due to lack of resources such as PPE, organizational support, inefficient relevant knowledge regarding the novel virus, its extremely indelible transmission rates, fear of contamination, stigmatization, and/or due to prevalence of ignorance by government and health policy makers.

Prospero registration no- CRD42021244612

category: psychiatry and clinical psychology


title: Common Mechanisms of Virus-Mediated Oncogenesis in Bladder Cancers Arising In Solid Organ Transplant Recipients

abstract: A small percentage of bladder cancers in the general population have been found to harbor polyomaviruses and papillomaviruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer, have been reported to harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from any potential oncovirus, we performed whole genome sequencing and transcriptomic sequencing on bladder cancer specimens from 43 transplant patients. Roughly a third of the tumors from this patient population contained viral sequences, among which the most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). BKPyV presence was validated by Large T antigen staining and revealed heterogeneous staining patterns between cases ranging from less than one percent to 100% of tumor tissue staining positive. In most cases of BKPyV-positive tumors, the viral genome was integrated into the host chromosome consistent with microhomology-mediated end joining and, in some cases, resulting in focal amplifications of the tumor genome. In BKPyV-positive tumors, significant changes in the expression of E2F- and DREAM-regulated genes amongst others were also observed consistent with the depletion of RB-family members by BKPyV Large T antigen in the tumors. We identified four mutation signatures in our cases with APOBEC3 and SBS5 mutations being the most abundant. We also identified a widespread mutation signature most similar to that caused by the antiviral, ganciclovir, and several cases harbored a high mutation burden associated with aristolochic acid, a nephrotoxic compound found in some herbal medicines. The results indicate that viruses may play a causal role in the development of bladder cancer among immunosuppressed individuals.


title: Evaluation of Pre-operational Factors Contributing to a Dorsal Column Stimulator Explantation

abstract:
ObjectivesImplantation of a dorsal column stimulator (DCS) for axial spine and radicular pain is a commonly performed procedure. Despite the benefits of this device to reduce pain and improve quality of life, some patients elect to have the device explanted. The purpose of this study is to describe pre-operational factors among patients who elected to have their DCS explanted and how these factors are associated with reason for explantation.

Materials and MethodsWe conducted a retrospective descriptive study using the database of a private outpatient orthopedic clinic. We included all patients who had a DCS explanted between January 1, 2007 and June 19, 2014. Data was collected on patient demographics, past medical and back surgery history, as well as details of implantation, permanent device implantation, and subsequent explantation. Reasons for explantation were categorized as: inadequate pain control using three categories (with no device-related pain/discomfort, with device-related pain/discomfort, or inadequate pain control and patient wants MRI), or pain resolved.

ResultsA consecutive sample of 100 subjects who underwent explantation of a DCS was identified for review. Of these 100 subjects, 14 were excluded. Based on our data, we hypothesize that sex (57% female, 43% male) degenerative disc disease (72%), previous back surgery (70%), BMI classified as overweight (subject average = 28.3), history of tobacco usage (57%), and history of narcotic use (80%) may be potential risk factors for explantation.

ConclusionsWith respect to clinical evaluation of patients as candidates for spinal cord stimulator implantation, we cannot recommend that any of the evaluated variables be considered a contraindication to proceeding with a trial procedure. Future studies are planned to compare these data to a control group of subjects to establish risk factors predisposing individuals to explantation of a DCS.

category: pain medicine


title: SARS-CoV-2 Delta vaccine breakthrough transmissibility in Alachua, Florida

abstract:
BackgroundSARS-CoV-2 Delta variant has caused a dramatic resurgence in infections in the United Sates, raising questions regarding potential transmissibility among vaccinated individuals.

MethodsBetween October 2020 and July 2021, we sequenced 4,439 SARS-CoV-2 full genomes, 23% of all known infections in Alachua County, Florida, including 109 vaccine breakthrough cases. Univariate and multivariate regression analyses were conducted to evaluate associations between viral load (VL) level and patient characteristics. Contact tracing and phylogenetic analysis were used to investigate direct transmissions involving vaccinated individuals.

ResultsThe majority of breakthrough sequences with lineage assignment were classified as Delta variants (74.6%) and occurred, on average, about three months (104 {+/-} 57.5 days) after full vaccination, at the same time (June-July 2021) of Delta variant exponential spread within the county. Six Delta variant transmission pairs between fully vaccinated individuals were identified through contact tracing, three of which were confirmed by phylogenetic analysis. Delta breakthroughs exhibited broad VL values during acute infection (IQR 1.2 - 8.64 Log copies/ml), on average 38% lower than matched unvaccinated patients (3.29 - 10.81 Log copies/ml, p<0.00001). Nevertheless, 49-50% of all breakthroughs, and 56-60% of Delta-infected breakthroughs exhibited VL above the transmissibility threshold (4 Log copies/ml) irrespective of time post vaccination.

ConclusionsDelta infection transmissibility and general VL patterns in vaccinated individuals suggest limited levels of sterilizing immunity that need to be considered by public health policies. In particular, ongoing evaluation of vaccine boosters should address whether extra vaccine doses might curb breakthrough contribution to epidemic spread.


title: Tenofovir Disoproxil Fumarate and severity of COVID-19 in people with HIV infection

abstract:
BackgroundEffective, safe, and affordable antivirals are needed for COVID-19. Tenofovir has not been studied in randomized trials despite evidence consistent with its effectiveness against COVID-19.

MethodsWe studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4-cell count, HIV-RNA viral load, comorbidities and the following outcomes: laboratory-confirmed SARS-CoV-2 infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/ FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting.

ResultsOf 51,558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2,402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% CI) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88-6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals [≥]50 years and 1.15 (0.59, 1.93) in younger individuals.

ConclusionOur findings suggest that, compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.

category: hiv aids


title: ANALYSIS OF IMMUNE ESCAPE VARIANTS FROM ANTIBODY-BASED THERAPEUTICS AGAINST COVID-19.

abstract: Accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID19 convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), the few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of Spike protein (e.g, {Delta}HV69-70, {Delta}LGVY141-144 and {Delta}AL243-244). Continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and fitness of emerging variants.


title: International impact of large multi-centre surgical trials of arthroscopic subacromial decompression

abstract:
ObjectivesTo examine temporal trends in incidence of arthroscopic subacromial decompression (ASAD) surgery internationally during conduct and after publication of placebo controlled trials finding no evidence of meaningful benefit of ASAD for shoulder impingement.

DesignObservational study of incidence rates.

SettingLarge routinely collected datasets were used: outpatient data from Belgium and UK, and insurance claims and outpatient data from US. UK data were from Clinical Practice Research Datalink and Belgium and US data were from IQVIA. US and UK data spanned 2005 - 2019 and Belgium data 2011 - 2019.

ParticipantsPatients were eligible for inclusion in the study if they had at least one visit recorded in the database in a given year and cases were defined as patients undergoing ASAD for the first time in their records in a given year.

Outcome measuresWe calculated incidence of ASAD over time, overall and stratified by age and sex. Characteristics of patients undergoing ASAD were also assessed over time.

ResultsUK incidence has fallen since a peak of 4.7 per 10,000 person years in 2011 (when the CSAW trial began) to 1.8 in 2019. US incidence shows no clear pattern and remains consistently higher than the UK, at 11.5 per 100,000 person years in 2019. Changes in incidence patterns were similar across different age groups and sexes. The number of cases in Belgium was too small for meaningful conclusions.

ConclusionsWe found ASAD rates have fallen in the UK during conduct and after publication of two large surgical RCTs from the UK and Finland that questioned the effectiveness of ASAD for shoulder impingement. A similar impact on clinical practice has not been seen in US. Further work to understand the barriers or concerns preventing international uptake of high quality evidence into clinical practice is needed.

Strengths and limitations of this studyO_LIThis is the most comprehensive study of ASAD incidence we are aware of. Routinely collected datasets were used to assess proportions of the patients undergoing this procedure in several countries
C_LIO_LIStandardised case definitions were used across databases to increase comparability of findings
C_LIO_LITemporal changes in database coverage and quality of reporting can influence findings. The observed variation in ASAD incidence may not be entirely attributable to changes in ASAD surgery rates.
C_LI

category: orthopedics


title: Genome-wide association study of autopsy-confirmed Multiple System Atrophy identifies common variants near ZIC1 and ZIC4

abstract:
Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied common genetic variation in only autopsy-confirmed cases (N = 731) and controls (N = 2,898).

The most strongly disease-associated markers were rs16859966 on chromosome 3 (P = 8.6 x 10-7, odds ratio (OR) = 1.58, [95% confidence interval (CI) = 1.32-1.89]), rs7013955 on chromosome 8 (P = 3.7 x 10-6, OR = 1.8 [1.40-2.31]), and rs116607983 on chromosome 4 (P = 4.0 x 10-6, OR = 2.93 [1.86-4.63]), all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms with P-values below 5 x 10-5. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4).

Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4 positive neurons were significantly reduced in patients with olivopontocerebellar atrophy.

These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.


title: The primacy of meeting the essential needs of public university students during the COVID-19 pandemic: a new higher education priority

abstract:
ObjectivesWe investigated the holistic experiences of university students during the pandemic.

Participants38 students in a public university system in New York City (NYC) purposively selected from neighborhoods highly affected by the pandemic based on level of self-reported impact

MethodsWe conducted virtual in-depth interviews from May to August 2021 and analyzed data using thematic coding and constant comparison techniques informed by grounded theory.

ResultsFinancial and social support systems, such as governmental and school resources, were critical to addressing essential needs and allowing students to persist. For those whose essential needs were met, faculty members flexibility and students experience with online learning were central to their academic success.

ConclusionsInstitutions of higher education should strengthen financial and social support systems to meet students essential needs. Academic policies to bolster online pedagogy and facultys flexibility can facilitate student retention and completion.

category: health economics


title: Machine Learning Based Prediction of COVID-19 Mortality Suggests Repositioning of Anticancer Drug for Treating Severe Cases

abstract: Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center  Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimers Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.


title: Creation of a ustekinumab external control arm for Crohn's disease using electronic health records data: a pilot study

abstract:
ObjectivesThe use of external control arms to study treatment effects is growing in interest among drug sponsors and regulators. However, experience with performing these kinds of studies for complex, immune-mediated diseases is limited. We sought to analyze a retrospective cohort of Crohns patients to predict the outcome of a prospective cohort.

MethodsWe queried electronic health records databases and screened records at the University of California, San Francisco to identify patients meeting the eligibility criteria of TRIDENT, a concurrent trial involving ustekinumab as a reference arm. Timepoints were defined to balance the tradeoff between missing disease activity and bias. We compared two imputation models by their impacts on cohort membership and outcomes. We compared the results of ascertaining disease activity using structured data algorithms against manual review. We used these data to estimate ustekinumabs real-world effectiveness.

ResultsScreening identified 183 patients. 30% of the cohort had missing baseline data. Two imputation models were tested and had similar effects on cohort definition and outcomes. Algorithms for ascertaining non-symptom-based elements of disease activity were similar in accuracy to manual review. The final cohort consisted of 56 patients. 34% of the cohort was in steroid-free clinical remission by week 24.

ConclusionsWe predict that a third of the ustekinumab-treated cohort in TRIDENT will be in steroid-free remission by week 24. However, our prediction is limited by substantial missing data. Efforts to improve real-world data capture and align trial design with clinical practice may enable more robust future studies and improve trial efficiency.

STUDY HIGHLIGHTSO_ST_ABSWHAT IS KNOWNC_ST_ABSO_LIExternal control arm studies are receiving growing interest from drug sponsors and regulators as a potential source of real-world evidence
C_LIO_LIHowever, the feasibility and robustness of this approach is currently limited
C_LIO_LIUstekinumab is an FDA-approved treatment of moderately to severely active Crohns disease
C_LI

WHAT IS NEW HEREO_LIWe derived a retrospective cohort of patients designed to resemble the participants of TRIDENT, a concurrent phase 2b trial using ustekinumab as a reference arm
C_LIO_LIWe predict that about 34% of the ustekinumab-assigned participants in TRIDENT will be in steroid-free clinical remission by week 24.
C_LIO_LIEHR structured data algorithms may be an accurate and less laborious alternative to manual abstraction of non-symptom-based components of the Crohns Disease Activity Index
C_LIO_LIReal-world practice differs from controlled studies in important ways, including the treatment goals and the timing of encounters
C_LIO_LIThese differences can pose challenges to the feasibility of external control arm studies, and must be addressed to enable this novel study design
C_LIO_LIThe methods, data, and code used in this pilot study are shared here for reproducibility and enhancement by others
C_LI