Recruitment location influences bias and uncertainty in SARS-CoV-2 seroprevalence estimates The initial phase of the COVID-19 pandemic in the US was marked by limited diagnostic testing, resulting in the need for seroprevalence studies to estimate cumulative incidence and define epidemic dynamics. In lieu of systematic representational surveillance, venue-based sampling was often used to rapidly estimate a communitys seroprevalence. However, biases and uncertainty due to site selection and use of convenience samples are poorly understood. Using data from a SARS-CoV-2 serosurveillance study we performed in Somerville, Massachusetts, we found that the uncertainty in seroprevalence estimates depends on how well sampling intensity matches the known or expected geographic distribution of seropositive individuals in the study area. We use GPS-estimated foot traffic to measure and account for these sources of bias. Our results demonstrated that study-site selection informed by mobility patterns can markedly improve seroprevalence estimates. Such data should be used in the design and interpretation of venue-based serosurveillance studies.
Unrepresentative Big Surveys Significantly Overestimate US Vaccine Uptake Surveys are a crucial tool for understanding public opinion and behavior, and their accuracy depends on maintaining statistical representativeness of their target populations by minimizing biases from all sources. Increasing data size shrinks confidence intervals but magnifies the impact of survey bias - an instance of the Big Data Paradox 1. Here we demonstrate this paradox in estimates of first-dose COVID-19 vaccine uptake in US adults: Delphi-Facebook 2,3 (about 250,000 responses per week) and Census Household Pulse 4 (about 75,000 per week). By May 2021, Delphi-Facebook overestimated uptake by 17 percentage points and Census Household Pulse by 14, compared to a benchmark from the Centers for Disease Control and Prevention (CDC). Moreover, their large data sizes led to minuscule margins of error on the incorrect estimates. In contrast, an Axios-Ipsos online panel 5 with about 1,000 responses following survey research best practices 6 provided reliable estimates and uncertainty. We decompose observed error using a recent analytic framework 1 to explain the inaccuracy in the three surveys. We then analyze the implications for vaccine hesitancy and willingness. We show how a survey of 250,000 respondents can produce an estimate of the population mean that is no more accurate than an estimate from a simple random sample of size 10. Our central message is that data quality matters far more than data quantity, and compensating the former with the latter is a mathematically provable losing proposition.
Prognostication for prelabor rupture of membranes and the time of delivery in nationwide insured women: development, validation, and deployment ImportancePrognostic predictions of prelabor rupture of membranes lack proper sample sizes and external validation.

ObjectiveTo develop, validate, and deploy statistical and/or machine learning prediction models using medical histories for prelabor rupture of membranes and the time of delivery.

DesignA retrospective cohort design within 2-year period (2015 to 2016) of a single-payer, government-owned health insurance database covering 75.8% individuals in a country

SettingNationwide healthcare providers (n=22,024) at primary, secondary, and tertiary levels

Participants12-to-55-year-old women that visit healthcare providers using the insurance from [~]1% random sample of insurance holders stratified by healthcare provider and category of family: (1) never visit; (2) visit only primary care; and (3) visit all levels of care

PredictorsMedical histories of diagnosis and procedure (International Classification of Disease version 10) before the latest visit of outcome within the database period

Main Outcomes and MeasuresPrelabor rupture of membranes prognostication (area under curve, with sensitivity, specificity, and likelihood ratio), the time of delivery estimation (root mean square error), and inference time (minutes), with 95% confidence interval

ResultsWe selected 219,272 women aged 33 {+/-} 12 years. The best prognostication achieved area under curve 0.73 (0.72 to 0.75), sensitivity 0.494 (0.489 to 0.500), specificity 0.816 (0.814 to 0.818), and likelihood ratio being positive 2.68 (2.63 to 2.75) and negative 0.62 (0.61 to 0.63). This outperformed models from previous studies according to area under curve of an external validation set, including one using a biomarker (area under curve 0.641; sensitivity 0.419; sensitivity 0.863; positive likelihood ratio 3.06; negative likelihood ratio 0.67; n=1177). Meanwhile, the best estimation achieved {+/-} 2.2 and 2.6 weeks respectively for predicted events and non-events. Our web application only took 5.14 minutes (5.11 to 5.18) per prediction.

Conclusions and RelevancePrelabor rupture of membranes and the time of delivery were predicted by medical histories; but, an impact study is required before clinical application.

Key PointsO_ST_ABSQuestionC_ST_ABSCan we use medical histories of diagnosis and procedure in electronic health records to predict prelabor rupture of membranes and the time of delivery before the day in nationwide insured women?

FindingsIn this prognostic study applying retrospective cohort paradigm, a significant predictive performance was achieved and validated. The area under receiver operating characteristics curve was 0.73 with the estimation errors of {+/-} 2.2 and 2.6 weeks for the time of delivery.

MeaningPreliminary prediction can be conducted in a wide population of insured women to predict prelabor rupture of membranes and estimate the time of delivery. Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and erythrocyte morphology Aging, and the pathogenesis of many common diseases, involves iron homeostasis. A key role in iron homeostasis is played by the spleen, which is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this important role, spleen iron content has not been measured previously in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank using magnetic resonance imaging (MRI). We find that epidemiologic and environmental factors such as increased age, higher red meat consumption and lower alcohol intake correlate with higher spleen iron. Through genome-wide association study, we identify genetic associations between spleen iron and common variation at seven loci, including in two hereditary spherocytosis (HS) genes, ANK1 and SPTA1. HS-causing mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while our common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes observed in some HS allele carriers. Further, we identify an association between spleen iron and MS4A7, which colocalizes with a quantitative trait locus for MS4A7 alternative splicing in whole blood, and with monocyte count and fraction. Through quantification of spleen iron in a large human cohort, we extend our understanding of epidemiological and genetic factors associated with iron recycling and erythrocyte morphology. Patient attrition in Molecular Tumour Boards: A Systematic Review Molecular Tumour Boards (MTBs) were created with the purpose of supporting clinical decision making within precision medicine. Though these meetings are in use globally reporting often focuses on the small percentages of patients that receive treatment via this process and are less likely to report on, and assess, patients who do not receive treatment. A literature review was performed to understand patient attrition within MTBs and barriers to patients receiving treatment. A total of 54 papers were reviewed spanning a 6 year period from 11 different countries. 20% of patients received treatment through the MTB process. Of those that did not receive treatment the main reasons were no mutations identified (26%), no actionable mutations (22%) and clinical deterioration (15%). However, the data was often incomplete due to inconsistent reporting of MTBs with only 53% reporting on patients having no mutations, 48% reporting on presence of actionable mutations with no treatment options and 57% reporting on clinical deterioration. As patient attrition in MTBs is an issue which is very rarely alluded to in reporting, more transparent reporting is needed to understand barriers to treatment and integration of new technologies is required to process increasing omic and treatment data. Development of machine learning models for the prediction of complications after colorectal and small intestine surgery in psychiatric and non-psychiatric patient collectives (P-Study) Psychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs associated with mental health conditions have been constantly on the rise in recent years. Moreover, psychiatric conditions are likely to have a negative effect on the treatment of other medical conditions and surgical outcomes, in addition to their direct effects on the overall quality of life. Our study aims to investigate the impact of preoperative Risk factor, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and length of hospital stay via predictive modeling techniques.

MethodPatient data will be collected from several participating national and international surgical centers The machine learning models will be calculated and coded, but also published according to the TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis).

ResultIt is conceivable to arrive at generalizable models predicting the abovementioned endpoints through large amounts of data from several centers. The models will be subsequently deployed as a free-to-use web-based prediction tool using the Shiny environment [47]. The cost for the hosting server and digital infrastructure will be covered by Dr. Anas Taha. The sponsor will store the data for ten years. Complementary frailty and mortality prediction models on older patients as a tool for assessing palliative care needs BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.

ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.

MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.

ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.

ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es. Risk scores for predicting HIV incidence among adult heterosexual populations in sub-Saharan Africa: a systematic review and meta-analysis IntroductionSeveral HIV risk scores have been developed to identify individuals for prioritised HIV prevention in sub-Saharan Africa. We systematically reviewed HIV risk scores to: (i) identify factors that consistently predicted incident HIV infection, (ii) review inclusion of community-level HIV risk in predictive models, and (iii) examine predictive performance.

MethodsWe searched nine databases from inception until February 15, 2021 for studies developing and/or validating HIV risk scores among the heterosexual adult population in sub-Saharan Africa. Studies not prospectively observing seroconversion or recruiting only key populations were excluded. Record screening, data extraction, and critical appraisal were conducted in duplicate. We used random-effects meta-analysis to summarise hazard ratios and the area under the receiver-operating characteristic curve (AUC-ROC).

ResultsFrom 1563 initial search records, we identified 14 risk scores in 13 studies. Seven studies were among sexually active women using contraceptives enrolled in randomised-controlled trials, three among adolescent girls and young women (AGYW), and three among cohorts enrolling both men and women. Consistently identified HIV prognostic factors among women were younger age (pooled adjusted hazard ratio: 1.62 [95% Confidence Interval: 1.17, 2.23], compared to above-25), single/not cohabiting with primary partners (2.33 [1.73, 3.13]) and having sexually transmitted infections (STIs) at baseline (HSV-2: 1.67 [1.34, 2.09]; curable STIs: 1.45 [1.17; 1.79]). Among AGYW only STIs were consistently associated with higher incidence, but studies were limited (n=3). Community-level HIV prevalence or unsuppressed viral load strongly predicted incidence but were only considered in three of 11 multi-site studies. The AUC-ROC ranged from 0.56 to 0.79 on the model development sets. Only the VOICE score was externally validated by multiple studies, with pooled AUC-ROC 0.626 [0.588, 0.663] (I2: 64.02%).

ConclusionsYounger age, non-cohabiting, and recent STIs were consistently identified as predicting future HIV infection. Both community HIV burden and individual factors should be considered to quantify HIV risk. However, HIV risk scores had only low-to-moderate discriminatory ability and uncertain generalisability, limiting their programmatic utility.

Further evidence on the relative value of specific risk factors, studies populations not restricted to  at-risk individuals, and data outside South Africa will improve the evidence base for risk differentiation in HIV prevention programmes.

PROSPERO NumberCRD42021236367 S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: a randomized, double-blind, placebo-controlled clinical trial BACKGROUNDSpinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown.

METHODSWe randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml-1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery.

RESULTSOf the 100 patients analyzed, patients receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml-1 (74.7 mg) or 0.25 mg ml-1 (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: -20.6 mg; 95% confidence interval [CI]: -41 to -0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013-0.32, P = 0.033). The occurrence of adverse events was similar among the groups.

CONCLUSIONSOxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects. Best practices for multi-ancestry, meta-analytic transcriptome-wide association studies: lessons from the Global Biobank Meta-analysis Initiative SUMMARYThe Global Biobank Meta-analysis Initiative (GBMI), through its genetic and demographic diversity, provides a valuable opportunity to study population-wide and ancestry-specific genetic associations. However, with multiple ascertainment strategies and multi-ethnic study populations across biobanks, the GBMI provides a distinct set of challenges in implementing statistical genetics methods. Transcriptome-wide association studies (TWAS) are a popular tool to boost detection power for and provide biological context to genetic associations by integrating single nucleotide polymorphism to trait (SNP-trait) associations from genome-wide association studies (GWAS) with SNP-based predictive models of gene expression. TWAS presents unique challenges beyond GWAS, especially in a multi-biobank and meta-analytic setting like the GBMI. In this work, we present the GBMI TWAS pipeline, outlining practical considerations for ancestry and tissue specificity and meta-analytic strategies, as well as open challenges at every step of the framework. Our work provides a strong foundation for adding tissue-specific gene expression context to biobank-linked genetic association studies, allowing for ancestry-aware discovery to accelerate genomic medicine. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. The effects of modifiable maternal pregnancy exposures on offspring molar-incisor hypomineralisation: A negative control study ObjectivesO_LITo explore the associations between modifiable maternal pregnancy exposures: pre-pregnancy body mass index (BMI), pregnancy smoking and alcohol consumption with offspring molar-incisor hypomineralisation (MIH).
C_LIO_LITo explore for the presence of residual confounding using negative control analyses.
C_LI

MethodsThis study used data from Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective birth cohort. We defined offspring MIH using prospectively collected questionnaire data. We used logistic regression to explore confounder adjusted associations between maternal pre-pregnancy BMI and smoking and alcohol consumption during pregnancy with MIH. We included negative control exposure (paternal BMI, smoking and alcohol around the time of pregnancy) and outcome (offspring dental trauma) analyses to explore for the presence of residual confounding.

Results5536 mother/offspring pairs were included (297 MIH cases [5.4%]). We found a positive association between maternal mean BMI and offspring MIH (OR per 1-kg/m2 difference in maternal BMI: 1.04, 95% CI: 1.00, 1.08). In subsequent analyses, we found evidence that this effect was non-linear and being driven by women in the highest BMI quintiles. In negative control analyses, we found no evidence of association between paternal BMI and offspring MIH (OR: 0.94, 95% CI: 0.89, 1.00) and maternal BMI and offspring dental trauma (OR: 0.99, 95% CI: 0.96, 1.02). There was no clear evidence of an association for maternal pregnancy smoking (OR: 0.76, 95%CI: 0.46, 1.22) and alcohol consumption (OR: 0.79, 95% CI: 0.56, 1.21) with offspring MIH with results imprecisely estimated.

ConclusionIn summary we found evidence of a possible intrauterine effect of high maternal pre-pregnancy BMI on offspring MIH. We did not find robust evidence for an intrauterine effect of maternal pregnancy smoking or alcohol consumption on offspring MIH. Our findings provide further support for women of reproductive age to maintain a healthy weight. Future studies are warranted to explore possible mechanisms on how the pregnancy environment may relate to offspring MIH. Transdiagnostic Profiles of Behaviour and Communication Relate to Academic and Socioemotional Functioning and Neural White Matter Organisation BackgroundBehavioural and language difficulties co-occur in multiple neurodevelopmental conditions. Our understanding of these problems has arguably been slowed by an overreliance on study designs that compare deficit/diagnostic groups and fail to capture the overlap across different neurodevelopmental disorders and the heterogeneity within them.

MethodsWe recruited a large transdiagnostic cohort of children with complex needs (N = 805) to identify distinct subgroups of children with common profiles of behavioural and language strengths and difficulties. We then investigated whether and how these data-driven groupings could be distinguished from a comparison sample (N = 158) on measures of academic and socioemotional functioning and patterns of global and local white matter connectome organisation. Academic skills were assessed via standardised measures of reading and maths. Socioemotional functioning was captured by the parent-rated version of the Strengths and Difficulties Questionnaire.

ResultsWe identified three distinct subgroups of children, each with different levels of difficulties in structural language, pragmatic communication, and hot and cool executive functions. All three subgroups struggled with academic and socioemotional skills relative to the comparison sample, potentially representing three alternative but related developmental pathways to difficulties in these areas. The children with the weakest language skills had the most widespread difficulties with learning, whereas those with more pronounced difficulties with hot executive skills experienced the most severe difficulties in the socioemotional domain. Each data-driven subgroup could be distinguished from the comparison sample based on both shared and subgroup-unique patterns of neural white matter organisation. Children with the most pronounced deficits in language, cool executive, or hot executive function were differentiated from the comparison sample by altered connectivity in predominately thalamocortical, temporal-parietal-occipital, and frontostriatal circuits, respectively.

ConclusionThese findings advance our understanding of commonly co-morbid behavioural and language problems and their relationship to behavioural outcomes and neurobiological substrates. Transdiagnostic Profiles of Behaviour and Communication Relate to Academic and Socioemotional Functioning and Neural White Matter Organisation Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19) In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications. Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases ObjectiveTo study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).

MethodsNeutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication.

ResultsMTX patients showed a significantly lower median antibody response compared to AIRD patients without immunosuppressive therapy (p< 0.001). Young age (<60 years) and MTX-hold after vaccination were found to be the main factors influencing antibody response after vaccination, while BMI or MTX dose demonstrated no effect. For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001) and all patients with antibody levels (14 %) below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher median neutralising antibody levels after second vaccination, compared to patients who continued MTX therapy during both vaccinations (68.82 %, 92.73 %, p=<0.001). This effect was particularly pronounced in patients older than 60 years (p=0.0016). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.

ConclusionMTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age. Commercialized kit to assess T-cell responses against SARS-CoV-2 S peptides. A pilot study in Health Care Workers. BackgroundIt is crucial to assess the levels of protection generated by natural infection or SARS-CoV-2 vaccines, mainly in individuals professionally exposed and in vulnerable groups. Measuring T-cell responses may complement antibody tests currently in use as correlates of protection. Our aim was to assess the feasibility of a validated assay of T-cell responses.

MethodsTwenty health-care-workers (HCW) were included. Antibody test to SARS-CoV-2 N and S-proteins in parallel with a commercially available whole-blood-interferon-gamma-release-assay (IGRA) to S-peptides and two detection methods, CLIA and ELISA were determined.

ResultsIGRA test detected T-cell responses in naturally exposed and vaccinated HCW already after first vaccination dose. The correlation by the two detection methods was very high (R>0.8) and sensitivity and specificity ranged between 100 and 86% and 100-73% respectively. Even though there was a very high concordance between specific antibody levels and the IGRA assay in the ability to detect immune response to SARS-CoV-2, there was a relatively low quantitative correlation. In the small group primed by natural infection, one vaccine dose was sufficient to reach immune response plateau. IGRA was positive in one, with Ig(S) antibody negative vaccinated immunosuppressed HCW illustrating another advantage of the IGRA-test.

ConclusionWhole-blood-IGRA-tests amenable to automation and constitutes a promising additional tool for measuring the state of the immune response to SARS-CoV-2; they are applicable to large number of samples and may become a valuable correlate of protection to COVID-19, particularly for vulnerable groups at risk of being re-exposed to infection, as are health-care-workers. The effect of D-cycloserine on brain processing of breathlessness over pulmonary rehabilitation - an experimental medicine study BackgroundPulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial NMDA-receptor agonist, D-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.

Methods72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg D-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between D-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions.

ResultsNo difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference.

ConclusionsThis is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D-cycloserine would not be worthwhile.

Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSDoes the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity?

What is the bottom line?Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation.

Why read on?This study highlights both the value of functional magnetic resonance imaging in "de-risking" expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness. The Ophthalmic Surgical Backlog caused by the COVID-19 Pandemic: A population-based and microsimulation modelling study BackgroundJurisdictions worldwide ramped down ophthalmic surgeries to mitigate the effects of coronavirus disease 2019 (COVID-19), creating a global surgical backlog. We sought to predict the long-term impact of COVID-19 on ophthalmology surgical care delivery.

MethodsThis is a population-based and a microsimulation modelling study. Provincial administrative data from January 2019 to May 2021 was used to estimate the backlog size and wait-times following the COVID-19 pandemic. For the post-pandemic recovery phase, we estimated the resources required to clear the backlog of patients accumulated on the waitlist during the pandemic.

ResultsA total of 56,923 patients were on the waitlist in the province of Ontario awaiting non-emergency ophthalmic surgery as of March 15, 2020. The number of non-emergency surgeries performed in the province decreased by 45-98% from March to May 2020, and 48-80% from April to May 2021 compared to the same months in 2019. By 2 years and 3 years, the overall estimated number of patients awaiting surgery grew by 129% and 150%, respectively. The estimated mean wait-time for patients for all subspecialty surgeries increased to 282 (SD 91) in March 2023 compared to 94 days (SD 97) in 2019. The provincial monthly additional resources required to clear the backlog by March 2023 was estimated to be a 34% escalation from the pre-pandemic volumes (4,626 additional surgeries).

InterpretationThe magnitude of the ophthalmic surgical backlog from COVID-19 has important implications for the recovery phase. The estimates from this microsimulation modelling can be adapted to other jurisdictions to assist with recovery planning for vision saving surgeries. Precision MRI Phenotyping Enables Detection of Small Changes in Body Composition for Longitudinal Cohorts Longitudinal studies provide unique insights into the impact of environmental factors and lifespan issues on health and disease. Here we investigate changes in body composition in 3,088 free-living participants, part of the UK Biobank in-depth imaging study. All participants underwent neck-to-knee MRI scans at the first imaging visit and after approximately two years (second imaging visit). Image-derived phenotypes for each participant were extracted using a fully-automated image processing pipeline, including volumes of several tissues and organs: liver, pancreas, spleen, kidneys, total skeletal muscle, iliopsoas muscle, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), as well as fat and iron content in liver, pancreas and spleen. Overall, no significant changes were observed in BMI, body weight, or waist circumference over the scanning interval, despite some large individual changes. A significant decrease in grip strength was observed, coupled to small, but statistically significant, decrease in all skeletal muscle measurements. Significant increases in VAT and intermuscular fat in the thighs were also detected in the absence of changes in BMI, waist circumference and ectopic-fat deposition. Adjusting for disease status at the first imaging visit did not have an additional impact on the changes observed. In summary, we show that even after a relatively short period of time significant changes in body composition can take place, probably reflecting the obesogenic environment currently inhabited by most of the general population in the United Kingdom. Economic evaluation of disease elimination: an extension to the net-benefit framework and application to human African trypanosomiasis The global health community has earmarked a number of diseases for elimination or eradication, and these goals have often been praised on the premise of long-run cost-savings. However, decision-makers must contend with a multitude of demands on health budgets in the short- or medium-term, and costs-per-case often rise as the burden of a disease falls, rendering such efforts beyond the cost-effective use of scarce resources. In addition, these decisions must be made in the presence of substantial uncertainty regarding the feasibility and costs of elimination or eradication efforts. Therefore, analytical frameworks are necessary to consider the additional effort for reaching global goals, like elimination or eradication, that are beyond the cost-effective use of country resources. We propose a modification to the net-benefit framework to consider the implications of switching from an optimal strategy, in terms of cost-per-burden-averted, to a strategy with a higher likelihood of meeting the global target of elimination of transmission by a specified date. We illustrate the properties of our framework by considering the economic case of efforts to eliminate transmission of gambiense human African trypanosomiasis (gHAT), a vector-borne parasitic disease in West and Central Africa, by 2030.

Significance StatementVarious diseases are earmarked for elimination by the global health community. While the health economic implications of elimination have been discussed before, the combination of uncertainty, cost-effectiveness in terms of cases averted, and elimination in the face of rising per-case costs has not been tackled before. We propose an approach that considers the tension between the dual objectives of cost-effectiveness and elimination while incorporating uncertainty in these objectives. We apply our method to strategies against human African trypanosomiasis in three settings, but this method could be directly applied to simulation-based studies of the cost-effectiveness of other disease elimination efforts. The method yields common metrics of efficiency when stakeholders have different objectives. Xenobiotic tracers uncover the gastrointestinal passage, cellular uptake and Ago2 loading of milk microRNAs in neonates BackgroundExclusive breastfeeding is the best source of nutrition for most infants, but it is not always possible. Enteral nutrition influences intestinal gene regulation and the susceptibility for inflammatory bowel disorders, such as necrotizing enterocolitis (NEC). In modern neonatology it is observed that lactase activity increases during intestinal maturation, but formula-fed infants exhibit lower activity levels than milk-fed infants.

ObjectiveWe interrogate the transmissibility of milk miRNAs, since human breast milk has a high miRNA content in comparison to other body fluids. Our data contribute to the controversial discussion whether milk miRNAs could influence gene regulation in term and preterm neonates and thus might vertically transmit developmental relevant signals.

DesignFollowing their cross-species profiling via miRNA deep-sequencing we utilized dietary xenobiotic taxon-specific milk miRNA as tracers in human and porcine neonates, followed by functional studies in primary human fetal intestinal epithelial cells (HIEC-6) using Ad5-mediated miRNA-gene transfer.

ResultsWe show that mammals have in common many milk miRNAs yet exhibit taxon-specific miRNA fingerprints. We traced intact bovine-specific miRNAs from formula-nutrition in human preterm stool and 9 days after the onset of enteral feeding in intestinal cells of preterm piglets. Few hours after introducing enteral feeding in preterm piglets with supplemented reporter miRNAs (cel-miR-39-5p/-3p), we observed enrichment of the xenobiotic cel-miR in blood serum and in Ago2-immunocomplexes from intestinal biopsies. In contrast, we did not observe xenobiotic miRNAs in neonatal porcine cerebrospinal fluid.

ConclusionsTaken together, our data point to a transmissibility of milk miRNA signals, which could be relevant at least for intestinal maturation. Ad5-based miRNA-gene transfer into HIEC-6 revealed putative milk miRNA targets on the protein and transcriptome levels. Results suggest that milk miRNAs could influence gene expression in intestinal epithelia of neonates under special conditions.

Graphical abstract

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org.highwire.dtl.DTLVardef@8e0435org.highwire.dtl.DTLVardef@1b6747corg.highwire.dtl.DTLVardef@1998821org.highwire.dtl.DTLVardef@b84a04_HPS_FORMAT_FIGEXP  M_FIG C_FIG It is already known that exclusive breastfeeding is the best source of nutrition for neonates.Human breast milk has a high miRNA content in comparison to other body fluids. It is controversially discussed whether they could influence gene regulation in term and preterm neonates and thus might vertically transmit developmental relevant signals. Here, we contribute important new findings: Mammals have in common a significant number of milk miRNAs yet exhibit taxon-specific fingerprints. These differences allowed us to exploit xenobiotic miRNAs as tracers in human preterm neonates, who routinely received formula-supplemented nutrition in addition to breast milk. Tracer miRNAs survived the gastrointestinal (GI) transit in human preterm neonates. In a preterm piglet model the reporter miRNA did not only survive GI transit, but accumulated in the bloodstream few hours post-feeding. Moreover, we show that, cel-mir-39-5p and cel-miR-39-3p became loaded to Ago2 in intestinal tissue samples, which is prerequisite for milk microRNAs biological relevance. Adenovirus type 5-based miRNA-gene transfer into HIEC-6 allowed us to examine predicted bovine milk miRNA targets on the protein and transcriptome levels. High gamma activity distinguishes frontal cognitive control regions from adjacent cortical networks Though the lateral frontal cortex is broadly implicated in cognitive control, functional MRI (fMRI) studies suggest fine-grained distinctions within this region. To examine this question electrophysiologically, we placed electrodes on the lateral frontal cortex in patients undergoing awake craniotomy for tumor resection. Patients performed verbal tasks with a manipulation of attentional switching, a canonical control demand. Power in the high gamma range (70-250 Hz) distinguished electrodes based on their location within a high-resolution fMRI network parcellation of the frontal lobe. Electrodes within the canonical fronto-parietal control network showed increased power in the switching condition, a result absent in electrodes within default mode, language, cingulo-opercular and somato-motor networks. High gamma results contrasted with spatially distributed power decreases in the beta range (12-30 Hz). These results confirm the importance of fine-scale functional distinctions within the human frontal lobe, and pave the way for increased precision of functional mapping in tumor surgeries. Signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with COVID-19 caused by the Omicron variant of SARS-CoV-2 in Houston, Texas Genetic variants of SARS-CoV-2 continue to dramatically alter the landscape of the COVID-19 pandemic. The recently described variant of concern designated Omicron (B.1.1.529) has rapidly spread worldwide and is now responsible for the majority of COVID-19 cases in many countries. Because Omicron was recognized very recently, many knowledge gaps exist about its epidemiology and clinical severity and disease course. A comprehensive genome sequencing study of SARS-CoV-2 in the Houston Methodist healthcare system identified 862 symptomatic patients with infections caused by Omicron from late November 2021 through December 18, 2021. Omicron very rapidly increased in only three weeks to cause 90% of all new COVID-19 cases. Compared to patients infected with either Alpha or Delta variants in our healthcare system, Omicron patients were significantly younger, had significantly increased vaccine breakthrough rates, and were significantly less likely to be hospitalized. Omicron patients required less intense respiratory support and had a shorter length of hospital stay, consistent with decreased disease severity. Although the number of Omicron patients we studied is relatively small, in the aggregate the data document the unusually rapid spread and increased occurrence of COVID-19 caused by the Omicron variant in metropolitan Houston, and provide information about disease character.