SARS-CoV-2 vaccine breakthrough infections with the alpha variant are asymptomatic or mildly symptomatic among health care workers. Vaccine breakthrough SARS-CoV-2 infection has been monitored in 3720 healthcare workers receiving 2 doses of BNT162b2. SARS-CoV-2 infection is detected in 33 subjects, with a 100-day cumulative incidence of 0.93%. Vaccine protection against acquisition of SARS-CoV-2 infection is 83% (95%CI: 58-93%) in the overall population and 93% (95%CI: 69-99%) in SARS-CoV-2-experienced subjects, when compared with a non-vaccinated control group from the same Institution, in which SARS-CoV-2 infection occurs in 20/346 subjects (100-day cumulative incidence: 5.78%). The infection is symptomatic in 16 (48%) vaccinated subjects vs 17 (85%) controls (p=0.001). All analyzed patients, in whom the amount of viral RNA was sufficient for genome sequencing, results infected by the alpha variant. Antibody and T-cell responses are not reduced in subjects with breakthrough infection. Evidence of virus transmission, determined by contact tracing, is observed in two (6.1%) cases. This real-world data support the protective effect of BNT162b2 vaccine. A triple antigenic exposure, such as two-dose vaccine schedule in experienced subjects, may confer a higher protection.
Effect of control measures on the pattern of COVID-19 Epidemics in Japan BackgroundCOVID-19 has spread worldwide since its emergence in 2019. In contrast to many other countries with epidemics, Japan differed in that it avoided lockdowns and instead asked people for self-control. A travel campaign was conducted with a sizable budget, but the number of PCR tests was severely limited. These choices may have influenced the course of the epidemic.

MethodsThe increase or decrease in the classes of SARS-CoV-2 variants was estimated by analyzing the published sequences with an objective multivariate analysis. This approach observes the samples in multiple directions, digesting complex differences into simpler forms. The results were compared over time with the number of confirmed cases, PCR tests, and overseas visitors. The kinetics of infection were analyzed using the logarithmic growth rate.

ResultsThe declared states of emergency failed to alter the movement of the growth rate. Three epidemic peaks were caused by domestically mutated variants. In other countries, there are few cases in which multiple variants have peaked. However, due to the relaxation of immigration restrictions, several infective variants have been imported from abroad and are currently competing for expansion, creating the fourth peak. By April 2021, these foreign variants exceeded 80%. The chaotic situation in Japan will continue for some time, in part because no effort has been made to identify asymptomatic carriers, and details of the vaccination program are undecided.
Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. Uncovering the gastrointestinal passage, intestinal epithelial cellular uptake and Ago2 loading of milk miRNAs in neonates using xenobiotic tracers 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

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/21262525v4_ufig1.gif" ALT="Figure 1">
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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. The role of classroom volume, occupancy, voice reduction and ffp2 masks in transmission risk of SARS-CoV2 in schools Issues linked to aerosol physics within school buildings and related infection risk still lack a proper recognition in school safety regulations. In this theoretical work we try to shed more light on the critical role of air ventilation, classroom volume, occupancy, and face mask types (surgical vs ffp2) in controlling airborne transmission risk in educational settings. Limited spaces available in many schools require to precisely assess the occupancy/volume ratio in each classroom and to investigate the specific risk levels from aerosolization of viral loads from infective sources. Moreover, most schools are not provided with mechanical HVAC systems. Fundamental questions are therefore: how the specific classroom volume affects the long-range contagion risk in a given classroom? is linear social distancing the right way to assess a volumetric risk problem? How effective are other countermeasures like reduced speaking volume or equipping teachers with microphones? We present here the results of a numerical analysis based on the Gammaitoni-Nucci infection risk model and the consolidated Wells-Riley like approach, with SARS-CoV2 input data and geometric data from a typical high-school classroom in Italy. We investigated separately the case of infective asymptomatic student and infective asymptomatic teacher as source of viral quanta, taking into account thermal gradient effects on the air ventilation rates. First recommendations based on the volumetric nature of aerosol risk are suggested to extend the linear social distancing approach applied so far. Finally we discuss the concept of "cumulative infection risk" over multiple lesson+break cycles in Wells-Riley-like infection models. We believe that any attempt to proper model infection risk in closed environments with cycled changes of the source and the susceptible individuals, should carefully consider this point, particularly when modelling air ventilation breaks in classrooms. Predictors of bovine Schistosoma japonicum infection in rural China In China, bovines are believed to be the most common animal source of human schistosomiasis infections, though little is known about what factors promote bovine infections. The current body of literature features inconsistent, and sometimes contradictory results, and to date, few studies have looked beyond physical characteristics to identify the broader environmental conditions that predict bovine schistosomiasis. Because schistosomiasis is a sanitation-related, water-borne disease transmitted by many animals, we hypothesized that several environmental factors - such as the lack of improved sanitation systems, or participation in agricultural production that is water-intensive - could promote schistosomiasis infection in bovines. Using data collected as a part of a repeat cross-sectional study conducted in rural villages in Sichuan, China from 2007 to 2016, we used a Random Forests, machine learning approach to identify the best physical and environmental predictors of bovine S. japonicum infection. Candidate predictors included: 1) physical/biological characteristics of bovines, 2) human sources of environmental schistosomes, 3) socio-economic indicators, 4) animal reservoirs, and 5) agricultural practices. The density of bovines in a village and agricultural practices such as the area of rice and dry summer crops planted and the use of night soil as an agricultural fertilizer, were among the top predictors of bovine S. japonicum infection in all collection years. Additionally, human infection prevalence, pig ownership and bovine age were found to be strong predictors of bovine infection in at least one year. Our findings highlight that presumptively treating bovines in villages with high bovine density or human infection prevalence may help to interrupt transmission. Furthermore, village-level predictors were stronger predictors of bovine infection than household-level predictors, suggesting future investigations may need to apply a broad ecological lens to identify potential underlying sources of persistent transmission. Population Pharmacokinetic Analysis of Dexmedetomidine in Children using Real World Data from Electronic Health Records and Remnant Specimens AimOur objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and data from electronic health records (EHRs) and explore the impact of patients characteristics and pharmacogenetics on dexmedetomidine clearance.

MethodsDexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modeling. The first stage developed a model without genotype variables; the second stage added pharmacogenetic effects.

ResultsOur final study population included 354 post-cardiac surgery patients age 0 to 22 years (median 16 months). The final two-compartment model included allometric weight scaling and age maturation. Population parameter estimates and 95% confidence intervals were 27.3 L/hr (24.0 - 31.1 L/hr) for total clearance (CL), 161 L (139 - 187 L) for central compartment volume of distribution (V1), 26.0 L/hr (22.5 - 30.0 L/hr) for intercompartmental clearance (Q), and 7903 L (5617 - 11119 L) for peripheral compartment volume of distribution (V2). The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5 - 42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99 - 7.08). Genotype was not statistically or clinically significant.

ConclusionOur study demonstrates the use of real-world EHR data and remnant specimens to perform a population PK analysis and investigate covariate effects in a large pediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.

What is already known about this subject{circ} Previous dexmedetomidine pharmacokinetic (PK) studies in pediatric populations have limited sample size.
{circ}Smaller studies present a challenge for identifying covariates that may impact individual PK profiles.


What this study adds{circ} We performed a dexmedetomidine population PK study with a large pediatric cohort using data obtained from electronic health records and remnant plasma specimens to enable increased sample size.
{circ}xsDifferences in PK due to UGT1A4 or UGT2B10 variants or CYP2A6 risk score are not clinically impactful for this population. In Vivo Cortical Microstructure: A Proxy for Tauopathy and Cognitive impairment in the Elderly with and without MCI/Dementia Aggregation of hyperphosphorylated tau protein is currently one of the most reliable indicators of Alzheimers pathology and cognitive impairment in older adults. However, it would be useful to have a non-invasive, accessible proxy measure that does not rely on Positron Emission Tomography (PET). We used data from multi-shell diffusion-weighted imaging (DWI) to assess indices from the Neurite Orientation Dispersion and Density Imaging (NODDI) model to determine possible proxies for tau and relationship with cognitive impairment. After controlling for age, sex, and the time difference between the scan acquisitions (DWI vs. PET), we used multiple factor analysis (MFA) to assess the fit between NODDI indices (orientation dispersion [ODI], neurite density [NDI], and free-water [fISO]), cortical thickness, and tau binding (via PET). We used data from 80 participants from the ADNI-3 sample who had a multi-shell DWI and an [18F]AV-1451 (tau) PET scan. Of these 80, 49 individuals were considered cognitively normal older adults (age ~74 years), 26 individuals had a diagnosis of mild cognitive impairment (age ~75 years), and five individuals had Alzheimers dementia (age ~78 years). fISO and tau shared a large amount of spatial overlap, and both strongly correlated with the first MFA dimension. Macrostructural features (such as cortical thickness and subcortical volume) introduced in a follow-up analysis were less related to this first MFA dimension than fISO and eight percent less than tau. Subsequent mediation analyses demonstrated that fISO mediated the relationship between cortical thickness and tau, explaining all of the variance. Microstructural features derived from advanced DWI acquisitions such as fISO may be useful proxies for tau. Cortical fISO, rather than cortical thickness, may represent the impact of tau on the brain (and, by extension, cognition). How has the prevalence of smoking cigarettes among HIV-infected patients changed over the last decade? Single-center analysis. IntroductionThe WHO report from 2016 estimates the prevalence of smoking as 22% worldwide and 28% in Poland. The prevalence of smoking in HIV-infected persons is 2-3 times higher than in the general population. The study conducted in 2009 in our department among n=116 HIV-infected patients showed 87.1% smoking cigarettes at least 2.5 pack-years (85.0% of males and 93.5% of females). The aim of the present study was to evaluate the change in the prevalence of cigarette smoking among HIV-infected patients over the last decade.

MethodsWe analyzed data from the survey conducted in n=204 HIV-infected patients hospitalized from November 2018 to November 2019 in our department. The survey included: age; sex, number of cigarettes smoked daily presently and in the past, the number of years as a smoker; the influence of HIV diagnosis on the number of cigarettes smoked.

ResultsAmong all n=204 patients current smokers n=78/204 (38.2%) with n=65/176 (36.9%) males and n=13/28 (46.4%) females. Among all n=115 current smokers and ex-smokers n=29 (25.2%) diagnosing the HIV infection had an impact on their smoking habits: n=26 (89.7%) increased and n=3 - all males (10.3%) decreased the number of smoked cigarettes.

ConclusionThe prevalence of smoking cigarettes among HIV-infected individuals in our department has decreased since 2009 but is still much higher than in the general population. The outcome indicates the need to improve smoking education provided by HIV care professionals. Smoking cessation guidance or treatment should become an integral part of HIV care for patients to fully benefit from antiretroviral therapy. 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. The CT Scan Lung Severity Score and Vaccination Status in COVID-19 patients in India: Perspective of an Independent Radiology Practice BackgroundThe COVID-19 patients often undergo a high-resolution CT scan to determine extent of their lung involvement. The aim of this study was to determine lung involvement in confirmed/suspected COVID-19 patients (encountered at an independent radiology practice) and its correlation to vaccination status amidst the second COVID-19 wave in India.

MethodsWe retrospectively queried our data since April 2021 to identify adult patients (>17 years) who had confirmed (positive RT-PCR or antigen test) or suspected COVID-19 (classic symptoms but negative RT-PCR) and received a high-resolution CT scan to determine the extent of their lung involvement using the CT severity (CT-SS) score. Patients were classified in 3 groups based on their vaccination status to determine its correlation with the CT-SS score: fully vaccinated, partially vaccinated, and unvaccinated. Basic descriptive statistics, univariate tests and multivariate linear regression analysis were used.

ResultsWe identified 229 patients (median age 45 years, 60% male) of which 205 (89%) had confirmed COVID-19 (positive RT-PCR) and 24 had suspected disease (negative RT-PCT but classic symptoms). Of the 229 patients 29 (13%) had complete vaccination, 38 (17%) had partial vaccination and 162 (70%) had no vaccination. The CT score of the completely vaccinated patients was significantly lower compared to partially or unvaccinated patients (median 0 v. 3.5 v. 10, respectively p<.01). A multivariate linear regression model showed that partial or fully vaccinated patients had lower CT severity score compared to unvaccinated patients (adjusted R squared = 0.47).

ConclusionWe present here the real-world findings from an independent radiology practice (a unique and common practice model), in India amid the second COVID-19 wave showing significantly lower CT severity score in fully or partially vaccinated patients compared to unvaccinated patients. Complete vaccination in patients could be critical in preventing severe lung disease. Pathogenesis of Alzheimer's disease: Involvement of the Choroid Plexus Aging and Alzheimers disease (AD), a major age-related disorder, are both characterized by inflammatory changes in the cerebrospinal fluid (CSF). The origin and the mechanisms underlying these inflammatory changes, however, remain poorly understood. Here, we report that aging elicits inflammatory changes in the CSF that become accentuated uniquely in AD compared to other inflammatory and neurodegenerative disorders. We show that the choroid plexus (ChP), which produces CSF, gains a pro-inflammatory profile, exhibits perturbed metabolism and contributes to the CSF changes observed in AD. We then use MRI imaging to establish a correlation between cognitive decline and increased volume of significantly remodelled ChP in patients with AD, and provide clinical relevance to the identified ChP pathology. These findings collectively suggest that ChP, unable to resolve inflammatory insults efficiently over the lifetime, participates in the inflammation and the pathogenesis of AD. The incidence of delirium in an acute geriatric community hospital: an observational cohort feasibility study. ObjectivesDelirium in hospitalised older adults is associated with negative health outcomes. Admission to an alternative care setting may lower the incidence of delirium. The Acute Geriatric Community Hospital (AGCH) was recently opened in the Netherlands and uses a multi-component non-pharmacological intervention strategy to prevent delirium. The objective of this study was to describe the incidence of delirium at the AGCH and compare this incidence to existing rates from literature. If a possible effect on delirium is seen in this comparison this would support conducting a larger prospectively controlled study on delirium in this new care setting.

DesignProspective cohort feasibility study; exploratory meta-analysis of proportions.

Setting and ParticipantsThe AGCH is an acute geriatric unit in a skilled nursing facility for patients aged >65 years with acute medical conditions.

MethodsDelirium assessment using the Confusion Assessment Method (CAM) upon admission and on day one, two and three or until delirium had resolved. Patients charts were reviewed if CAM was missing. In an linear mixed-effects model, the delirium incidence rate in AGCH was compared to pooled delirium incidence rates from six studies found in a high-quality review.

Results214 patients from the AGCH (mean age 81.9 years, 47% male, 12% with a history of dementia) were included in the analysis. Delirium developed in 8% (18/214) (95% confidence interval [CI] 5-13%) of patients during AGCH admission compared to 16% (95% CI 12-21%) in hospitals. Admission to the AGCH was associated with a decreased delirium incidence rate compared to the hospital control group (OR[odds ratio]= 0.49, 95% CI 0.24-0.98, p-value=0.044).

Conclusions and implicationsThe delirium incidence in the AGCH was low compared to those incidences found in general hospitals in literature. Based on these findings a controlled observational or randomized study measuring delirium in this care setting is recommended. 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. Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. 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. Significant Sparse Polygenic Risk Scores across 813 traits in UK Biobank We present a systematic assessment of polygenic risk score (PRS) prediction across more than 1,500 traits using genetic and phenotype data in the UK Biobank. We report 813 sparse PRS models with significant (p < 2.5 x 10-5) incremental predictive performance when compared against the covariate-only model that considers age, sex, types of genotyping arrays, and the principal component loadings of genotypes. We report a significant correlation between the number of genetic variants selected in the sparse PRS model and the incremental predictive performance (Spearmans {rho} = 0.61, p = 2.2 x 10-59 for quantitative traits, {rho} = 0.21, p = 9.6 x 10-4 for binary traits). The sparse PRS model trained on European individuals showed limited transferability when evaluated on non-European individuals in the UK Biobank. We provide the PRS model weights on the Global Biobank Engine (https://biobankengine.stanford.edu/prs).

Author summaryPolygenic risk scores (PRSs), an approach to estimate genetic predisposition on disease liability by aggregating the effects across multiple genetic variants, has attracted increasing research interest. While there have been improvements in the predictive performance of PRS for some traits, the applicability of PRS models across a wide range of human traits has not been clear. Here, applying penalized regression using Batch Screening Iterative Lasso (BASIL) algorithm to more than 269,000 individuals of white British ancestry in UK Biobank, we systematically characterize PRS models across more than 1,500 traits. We report 813 traits with PRS models of statistically significant predictive performance. While the statistical significance does not necessarily directly translate into clinical relevance, we investigate the properties of the 813 significant PRS models and report a significant correlation between predictive performance and estimated SNP-based heritability. We find that the number of genetic variants selected in our sparse PRS model is significantly correlated with the incremental predictive performance in both quantitative and binary traits. Our transferability assessment of PRS models in UK Biobank revealed that the sparse PRS models trained on individuals of European ancestry had a lower predictive performance for individuals of African and Asian ancestry groups. Quantifying the role of naturally- and vaccine-derived neutralizing antibodies as a correlate of protection against COVID-19 variants The functional relationship between neutralizing antibodies (NAbs) and protection against SARS-CoV-2 infection and disease remains unclear. We jointly estimated protection against infection and disease progression following natural infection and vaccination from meta-study data. We find that NAbs are strongly correlated with prevention of infection and that any history of NAbs will stimulate immune memory to moderate disease progression. We also find that natural infection provides stronger protection than vaccination for the same level of NAbs, noting that infection itself, unlike vaccination, carries risk of morbidity and mortality, and that our most potent vaccines induce much higher NAb levels than natural infection. These results suggest that while sterilizing immunity may decay, we expect protection against severe disease to be robust over time and in the face of immune-evading variants. Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Stability of the stroke code during the COVID-19 pandemic in the region of Madrid: a retrospective cohort study Acute Stroke (AS) is the most common time-dependent disease attended in the Emergency Medicine Service (EMS) of Madrid (SUMMA 112). Community of Madrid has been one of the most affected regions in Spain by the coronavirus disease 2019 (COVID19) pandemic. A significant reduction in AS hospital admissions has been reported during the COVID-19 pandemic compared to the same period one year before. As international clinical practice guidelines support those patients with suspected acute stroke should be accessed via EMS, it is important to know whether the pandemic has jeopardized urgent pre-hospital stroke care, the first medical contact for most patients. We aimed to examine the impact of the COVID-19 in stroke codes (SC) in our EMS among three periods of time: the COVID-19 period, the same period the year before, and the 2019-2020 seasonal influenza period. Methods: We compared the SC frequency among the periods with high cumulative infection rate (above the median of the series) of the first wave of COVID-19, seasonal influenza, and also with the same period of the year before. Results: 1,130 SC were attended during the three periods. No significant reduction in SC was found during the COVID-19 pandemic. The reduction of hospital admissions might be attributable to patients attending the hospital by their means. The maximum SC workload seen during seasonal influenza has not been reached during the pandemic. We detected a non-significant deviation from the SC protocol, with a slight increase in hospitals transfers to hospitals without stroke units. Investigating trends in those who experience menstrual bleeding changes after SARS-CoV-2 vaccination Early in 2021, many people began sharing that they experienced unexpected menstrual bleeding after SARS-CoV-2 inoculation. We investigated this emerging phenomenon of changed menstrual bleeding patterns among a convenience sample of currently and formerly menstruating people using a web-based survey. In this sample, 42% of people with regular menstrual cycles bled more heavily than usual while 44% reported no change after being vaccinated. Among respondents who typically do not menstruate, 71% of people on long-acting reversible contraceptives, 39% of people on gender-affirming hormones, and 66% of post-menopausal people reported breakthrough bleeding. We found increased/breakthrough bleeding was significantly associated with age, systemic vaccine side effects (fever, fatigue), history of pregnancy or birth, and ethnicity. Generally, changes to menstrual bleeding are not uncommon nor dangerous, yet attention to these experiences is necessary to build trust in medicine.

TeaserIncreased bleeding can occur post SARS-CoV-2 vaccines; this study investigates patterns in who experiences these changes. Adjunctive Ketamine for Sedation in Critically Ill Mechanically Ventilated Patients: An Active-Controlled, Pilot, Feasibility Clinical Trial ObjectiveKetamine has been shown to decrease sedative requirements in intensive care unit (ICU). Randomized trials are limited on patient-centered outcomes. We designed this pilot clinical trial to evaluate the feasibility of using ketamine as an adjunct analgosedative compared with standard of care (SOC) alone and determine preliminary effect size on 28-day mechanical ventilation (MV) duration and ventilator-free days (VFDs).

DesignPilot, single-center, active-controlled, open-label, randomized clinical trial.

SettingMedical, surgical, and transplant ICUs at King Faisal Specialist Hospital and Research Center, Saudi Arabia.

Patients and MethodsAdult patients who were intubated within 24 hours, expected to require MV for the next calendar day, and had institutional pain and sedation protocol initiated.

InterventionAdjunct ketamine infusion 1-2 g/kg/min for 48 hours versus SOC.

Measurements and Main ResultsTotal of 83 patients (43 in SOC and 40 in ketamine) were included. Demographics were balanced between groups. Median MV duration was 7 (interquartile range [IQR] 3-9.25 days) in ketamine and 5 (IQR 2-8 days) in SOC, p= 0.15. Median VFDs was 19 (IQR 0-24.75 days) in ketamine and 19 (IQR 0-24 days) in the SOC (p=0.70). More patients attained goal RASS score at 24 and 48 hours in ketamine (67.5% and 73.5%, respectively) compared with SOC (52.4% and 66.7%, respectively). Sedatives and vasopressors cumulative doses, and hemodynamic changes were similar. ICU length-of-stay was 12.5 (IQR 6-21.2 days) in ketamine, compared with 12 (IQR 5.5-23 days) in SOC, p=0.89. Consent and protocol adherence rate were adequate. No serious adverse events were observed in either group.

ConclusionsUse of ketamine as an adjunct analgosedative agent appeared to be feasible and safe with no negative impact on outcomes, including hemodynamics. The protocol of this pilot trial could be improved by modifying ketamine dosing regimen. These findings provide a basis for future, adequately powered, multicenter trial to investigate its association with patient-centered outcomes further. Meta-analytic findings on reading in children with cochlear implants This meta-analysis study aims to quantify the group differences in reading skills between children with cochlear implants and their hearing peers and between children with cochlear implants and children with hearing aids (aged between 3 to 18 years old). Of the 5,642 articles screened, 47 articles met predetermined inclusion criteria (published between 2002 and 2019). The robust variance estimation based meta-analysis models were used to synthesize all the effect sizes. Children with cochlear implants scored significantly lower than their hearing peers in phonological awareness (g = - 1.62, p < .001), vocabulary (g = -1.50, p < .001), decoding (g = -1.24, p < .001), and reading comprehension (g = -1.39, p < .001), but not for fluency (g = -.67, p = .054). Compared to children with hearing aids, children with cochlear implants scored significantly lower in phonological awareness (g = -.30, p = .028). The percentage of unilateral cochlear implant negatively impacts the group difference between children with cochlear implants and their hearing peers. Findings from this study confirm a positive shift in reading outcomes for profoundly deaf children due to cochlear implantation. Some children with cochlear implants may need additional supports in educational settings. A novel echo-parameter supersedes the Society of Thoracic Surgeons risk score in predicting post transcatheter aortic valve replacement mortality ObjectiveTo accurately predict post-TAVR mortality, we proposed a family of new echo-parameters (augmented blood pressure) derived from blood pressure and aortic valve gradient measurements and examined them in this study.

Patients and MethodsPatients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between January 1, 2012, and June 30, 2017, were identified to retrieve baseline demographics, echocardiographic and mortality data. Augmented blood pressure parameters and valvulo-arterial impedance were evaluated by univariate and multivariate Cox regression. Receiver operating characteristic curve analysis was used to assess the model performance against the Society of Thoracic Surgeons (STS) risk score.

ResultsThe final cohort contained 974 patients with a mean age of 81.4{+/-}8.3 years old, and 56.6% were male. The mean STS risk score was 8.2{+/-}5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Both univariate and multivariate Cox regression showed that augmented systolic blood pressure and augmented mean arterial pressure (AugMAP) parameters were independent predictors for 1-year post-TAVR mortality (all p<0.0001). A univariate model of AugMAP1 supersedes the STS score model in predicting 1-year post-TAVR mortality (area under curve: 0.700 vs. 0.587, p=0.0051).

ConclusionAugmented mean arterial pressure provides a simple but effective approach for clinicians to quickly estimate the clinical outcome of TAVR patients. It can be incorporated in the assessment of TAVR candidacy. Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders.