title: The impact of vaccination on incidence and outcomes of SARS-CoV-2 infection in patients with kidney failure in Scotland

abstract:
BackgroundPatients with kidney failure requiring kidney replacement therapy (KRT) are at high risk of complications and death following SARS-CoV-2 infection with variable antibody responses to vaccination reported. We investigated the effects of COVID-19 vaccination on incidence of infection, hospitalization and death of COVID-19 infection.

MethodsStudy design was an observational data linkage cohort study. Multiple healthcare datasets were linked to ascertain all SARS-CoV-2 testing, vaccination, hospitalization, and mortality data for all patients treated with KRT in Scotland, from the start of the pandemic over a period of 20 months. Descriptive statistics, survival analyses and vaccine effectiveness were calculated.

ResultsAs of 19th September 2021, 93% (n=5281) of the established KRT population in Scotland had received two doses of an approved SARS-CoV-2 vaccine. Over the study period, there were 814 cases of SARS-CoV-2 infection (15.1% of the KRT population). Vaccine effectiveness against infection and hospitalization was 33% (95% CI 0-52) and 38% (95% CI 0-57) respectively. 9.2% of fully vaccinated individuals died within 28 days of a SARS-CoV-2 positive PCR test (7% dialysis patients and 10% kidney transplant recipients). This compares to <0.1% of the vaccinated Scottish population being admitted to hospital or dying death due to COVID19 during that period.

ConclusionsThese data demonstrate a primary vaccine course of two doses has limited impact on COVID-19 infection and its complications in patients treated with KRT. Adjunctive strategies to reduce risk of both COVID-19 infection and its complications in this population are urgently required.

category: nephrology


title: High Sensitivity and NPV for BinaxNOW Rapid Antigen Test in Children at a Mass Testing Site During Prevalent Delta Variant

abstract:
SARS-CoV-2 continues to develop new, increasingly infectious variants including delta and omicron. We evaluated the efficacy of the Abbott BinaxNOW Rapid Antigen Test against Reverse Transcription Polymerase Chain Reaction ("RT-PCR") in 1054 pediatric participants presenting to a high-volume Coronavirus Disease 2019 (COVID-19) testing site while the delta variant was predominant. Participants were grouped by COVID-19 exposure and symptom status. RT-PCR demonstrated an overall prevalence of 5.2%. For all participants, sensitivity of the BinaxNOW was 92.7% (95% CI 82.4%-98.0%) and specificity was 98.0% (95% CI 97.0%-98.8%). For symptomatic participants, positive predictive value (PPV) was 72.7% (95% CI 54.5%-86.7%) and negative predictive value (NPV) was 99.2% (95% CI 98.2%-100%). Among asymptomatic participants, PPV was 71.4% (95% CI 53.7%-85.4%) and NPV was 99.7% (95% CI 99.0%-100%). Our reported sensitivity and NPV are higher than other pediatric studies, potentially because of higher viral load from the delta variant, but specificity and PPV are lower.

ImportanceThe BinaxNOW rapid antigen COVID-19 test had a sensitivity of nearly 92% in both symptomatic and asymptomatic children when performed at a high-throughput setting during the more transmissible delta variant dominant period. The test may play an invaluable role in asymptomatic screening and keeping children safe in school.

category: infectious diseases


title: An integrated lab-on-a-chip device for RNA extraction, amplification and CRISPR-Cas12a-assisted detection for COVID-19 screening in resource-limited settings

abstract: In response to the ongoing COVID-19 pandemic and disparities of vaccination coverage in low- and middle-income countries, it is vital to adopt a widespread testing and screening programme, combined with contact tracing, to monitor and effectively control the infection dispersion in areas where medical resources are limited. This work presents a lab-on-a-chip platform, namely "IFAST-CRISPR", as an affordable, rapid and high-precision molecular diagnostic means for SARS-CoV-2 detection. The herein proposed "sample-to-answer" platform integrates RNA extraction, amplification and CRISPR-Cas-based detection with lateral flow readout in one device. The microscale dimensions of the device containing immiscible liquids, coupled with the use of silica paramagnetic beads and GuHCl, streamline sample preparation, including RNA concentration, extraction and purification, in 15 min with minimal hands-on steps. By combining RT-LAMP with CRISPR-Cas12 assays targeting the nucleoprotein (N) gene, visual identification of [≥] 470 copies mL-1 genomic SARS-CoV-2 samples was achieved in 45 min, with no cross-reactivity towards HCoV-OC43 nor H1N1. On-chip assays showed the ability to isolate and detect SARS-CoV-2 from 1,000 genome copies mL-1 of replication-deficient viral particles in 1 h. This simple, affordable and integrated platform demonstrated a visual, faster, and yet specificity and sensitivity-comparable alternative to the costly gold-standard RT-PCR assay, requiring only a simple heating source. Further investigations on multiplexing and direct interfacing of the accessible Swan-brand cigarette filter for saliva sample collection could provide a complete work flow for COVID-19 diagnostics from saliva samples suitable for low-resource settings.


title: Genome-wide analyses of 200,453 individuals yields new insights into the causes and consequences of clonal hematopoiesis

abstract: Clonal hematopoiesis (CH) is one of the most extensively studied somatic mutational phenomena, yet its causes and consequences remain poorly understood. We identify 10,924 individuals with CH amongst 200,453 whole-exome sequenced UK Biobank participants and use their linked genome-wide DNA genotypes to map the landscape of inherited predisposition to CH. We increase the number of European-ancestry genome-wide significant (P<5x10-8) germline associations with CH from four to 14 and identify one new transcriptome-wide significant (P<3.2x10-6) association. Genes at new loci implicate DNA damage repair (PARP1, ATM, and CHEK2), hematopoietic stem cell migration/homing (CD164), and myeloid oncogenesis (SETBP1) in CH development. Several associations were CH-subtype specific and, strikingly, variants at TCL1A and CD164 had opposite associations with DNMT3A-versus TET2-mutant CH, mirroring recently reported differences in lifelong behavior of these two most common CH subtypes and proposing important roles for these loci in CH pathogenesis. Using Mendelian randomization, we show, amongst other findings, that smoking and longer leukocyte telomere length are causal risk factors for CH and demonstrate that genetic predisposition to CH increases risks of myeloproliferative neoplasia, several non-hematological malignancies, atrial fibrillation, and blood epigenetic age acceleration.

category: hematology


title: Effect of Vaccination on Household Transmission of SARS-CoV-2 Delta VOC

abstract: 1The SARS-CoV-2 Delta variant of concern (VOC), which has shown increased transmission compared with previous variants, emerged rapidly globally during the first half of 2021, and became one of the most widespread SARS-CoV-2 variants worldwide. We utilized total population data from 24,693 Danish households with 53,584 potential secondary cases to estimate household transmission of the Delta VOC in relation to vaccination status. We found that the vaccine effectiveness against susceptibility (VES) was 61% (95%-CI: 59-63) and that the vaccine effectiveness against transmissibility (VET) was 42% (95%-CI: 39-45). We also found that unvaccinated individuals with an infection exhibited a higher viral load (one third of a standard deviation) compared to fully vaccinated individuals with a breakthrough infection. Our results imply that vaccinations reduce susceptibility as well as transmissibility. The results are important for policy makers to select strategies for reducing transmission of SARS-CoV-2.


title: Older Adults Mount Less Durable Humoral Responses to a Two-dose COVID-19 mRNA Vaccine Regimen, but Strong Initial Responses to a Third Dose

abstract:
BackgroundThird COVID-19 vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults.

MethodsWe measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement, and virus neutralization against ancestral and Omicron (BA.1) strains from pre-vaccine up to one month following the third dose, in 151 adults aged 24-98 years who received COVID-19 mRNA vaccines.

ResultsFollowing two vaccine doses, humoral immunity was weaker, less functional and less durable in older adults, where a higher number of chronic health conditions was a key correlate of weaker responses and poorer durability. Third doses boosted antibody binding and function to higher levels than second-doses, and induced responses in older adults that were comparable in magnitude to those in younger adults. Humoral responses against Omicron were universally weaker than against the ancestral strain after both second and third doses; nevertheless, after three doses, anti-Omicron responses in older adults reached equivalence to those in younger adults. After three vaccine doses, the number of chronic health conditions, but not age per se, was the strongest consistent correlate of weaker humoral responses.

ConclusionResults underscore the immune benefits of third COVID-19 vaccine doses, particularly in older adults.


title: Evaluating Real-World COVID-19 Vaccine Effectiveness Using a Test-Negative Case-Control Design

abstract:
It is important to assess the extent to which the real-world effectiveness of marketed vaccines is consistent with that observed in the clinical trials, and to characterize how well vaccines prevent COVID-19 symptoms. We conducted a modified test-negative design (TND) to evaluate the RW effectiveness of three COVID-19 vaccines by leveraging data from an on-going, US community-based registry. Vaccine effectiveness was examined in two ways: considering cases who (1) tested positive for COVID-19 (695 cases, 1,786 controls) and who (2) tested positive with at least one moderate/severe COVID-19 symptom (165 cases, 2,316 controls). Any vaccination (full or partial) was associated with a 95% reduction in the odds of having a positive COVID-19 test [adjusted odds ratio (aOR) = 0.05 (95% confidence interval (CI): 0.04, 0.06)]. Full vaccination was associated with an aOR of 0.03 (95% CI: 0.03, 0.05) while partial vaccination had an aOR of 0.08 (95% CI: 0.06, 0.12). Any vaccination was associated with a 71% reduction in the odds of testing positive and having at least one moderate/severe symptom (aOR=0.29 (95% CI: 0.20, 0.40)). High effectiveness was observed across all three vaccine manufacturers both for prevention of positive COVID-19 test results and prevention of moderate/severe COVID-19 symptoms.

Clinicaltrials.gov NCT04368065


title: USING SYSTEM DYNAMICS MODELING TO ASSESS THE IMPACT OF CONNECTICUT GOOD SAMARITAN LAWS: A PROTOCOL PAPER

abstract:
BackgroundWe applied a participatory system dynamics (SD) modeling approach to evaluate the effectiveness and impact of Connecticuts Good Samaritan Laws (GSLs) that are designed to promote bystander intervention during an opioid overdose event and reduce opioid overdose-related adverse outcomes. Our SD model can be used to predict whether additional revisions of the statutes might make GSLs more effective. SD modeling is a novel approach for assessing the impact of GSLs; and, in this protocol paper, we describe its applicability to our policy question, as well as expected outcomes of this approach.

MethodsThis project began in February 2021 and is expected to conclude by March 2022. During this time, a total of six group model-building (GMB) sessions will have been held with key stakeholders to elicit feedback that will, in turn, contribute to the development of a more robust SD model. Session participants include bystanders who witness an overdose, law enforcement personnel, first responders, pharmacists, physicians, and other health care professionals who work in at least two major metropolitan areas of Connecticut (New Haven and Hartford). Due to the restrictions imposed by the COVID-19 pandemic, the sessions are being held virtually via Zoom. The information obtained during these sessions will be integrated with a draft SD model that has already been developed by the modeling team as part of a previous CDC-funded project. Model calibration and policy simulations will then be performed to assess the impact of the current GSLs and to make recommendations for future public policy changes.

DiscussionAn SD modeling approach enables capture of complex interrelationships among multiple health outcomes to better assess the drivers of the opioid epidemic in Connecticut. The models simulation results are expected not only to align with current real-world data but also to recreate historical trends and infer future trends in a situationally relevant fashion. This will facilitate the work of policy makers who are devising and implementing time-sensitive changes to address opioid overdose-related deaths at the state level. Replicating our approach as described can be applied to make similar improvements in other jurisdictions.

CONTRIBUTIONS TO THE LITERATURE- System dynamics (SD) modeling and group model-building (GMB) approaches enable the group to start with a simple concept model and apply the collective knowledge of the group to finish the session with a much more developed model that can produce impressively accurate simulation results.
- The model will be used to understand the impact of Connecticuts Good Samaritan Laws (GSLs), as well as their limitations, and to deduce factors to further improve public health laws to counter opioid overdose-related deaths.
- The approach can be applied to other jurisdictions, taking into account local conditions and existing Good Samaritan legislation.

category: addiction medicine


title: Penetrance and disease expression of (likely) pathogenic variants associated with inherited cardiomyopathies in the general population

abstract:
Background(Likely) pathogenic variants associated with arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are recommended to be reported as secondary findings in genome sequencing studies. This provides opportunities for early diagnosis, but also fuels uncertainty in variant carriers (G+), since disease penetrance is incomplete. We assessed the prevalence and disease expression of G+ in the general population.

MethodsWe identified (likely) pathogenic variants associated with ACM, DCM and/or HCM in 200,643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analysed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analysed early signs of disease expression.

ResultsWe found a prevalence of 1:578, 1:251 and 1:149 for (likely) pathogenic variants associated with ACM, DCM and HCM respectively. Compared to controls, cardiovascular mortality was higher in DCM G+ (OR 1.67 [95% CI 1.04;2.59], p=0.030), but similar in ACM and HCM G+ (p[≥]0.100). More specifically, cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (OR 3.66 [95% CI 2.24;5.81], p=4.9*10-7) and HCM G+ (OR 3.03 [95% CI 1.98;4.56], p=5.8*10-7), but comparable in ACM G+ (p=0.172). In contrast, ACM G+ had more ventricular arrhythmias (p=3.3*10-4). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ (p=0.009).

ConclusionsIn the general population, (likely) pathogenic variants associated with ACM, DCM or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease expression in these carriers from the general population remains low. Decisions on application of cascade screening and frequency of cardiological examination should be based on multiple factors, such as the variant and disease expression.

Journal Subjects TermsCardiomyopathy, Genetics, Heart failure, Hypertrophy, Magnetic Resonance imaging

category: cardiovascular medicine


title: Association between child sexual abuse and mid-life employment earnings.

abstract:
ImportanceIndividuals who have been sexually abused are at a greater risk for poor health, but associations with economic outcomes in mid-life have been overlooked.

ObjectivesWe investigated associations between child sexual abuse ([≤]18 years) and economic outcomes at 33-37 years, while considering type of report (official/retrospective) and characteristics of abuse (type, severity, and chronicity).

DesignThis cohort study used data collected for the Quebec Longitudinal Study of Kindergarten Children.

SettingThe Quebec Longitudinal Study of Kindergarten Children is a population-based sample.

ParticipantsParticipants were 3,020 boys and girls attending kindergarten in the Canadian Province of Quebec in 1986/88 and followed up until 2017.

Main outcome/MeasuresChild sexual abuse (0-18 years old) was assessed using both retrospective self-report questionnaires and objective reports (notification to Child Protection Services). Information on employment earnings was obtained from government tax return records. Tobit regressions were used to test associations of sexual abuse with earnings adjusting for sex and family socioeconomic background.

ResultsOf the 3,020 participants 1,320 [43.7%] self-reported no sexual abuse, 1,340 [44.3%] had no official report but were missing on the retrospective questionnaire, 340 [11.3%] reported retrospective sexual abuse, and 20 [0.7%] had official report. In the fully adjusted model, individuals who retrospectively reported being sexually abused earned US$4,031 (CI=-7,134 to -931) less per year at age 33-37 years, while those with official reports earned US$16,042 (CI=-27,465 to -4,618) less, compared to participants who were not abused. Among individuals with retrospectively reported abuse, those who experienced intra-familial abuse earned US$4,696 (CI=-9,316 to -75) less than individuals who experienced extra-familial abuse, while participants who experienced penetration earned US$6,188 (CI=-12,248 to -129) less than those who experienced non-contact abuse.

Conclusion and RelevanceChild sexual abuse puts individuals at risk for lasting reductions in employment earnings in adulthood. Early identification and support for sexual abuse victims could help reduce the economic gap and improve long-term outcomes.

Key PointsO_ST_ABSQuestionC_ST_ABSIs child sexual abuse associated with lower mid-life employment earnings?

FindingsIn a large population-based cohort (n=3,020), children exposed to sexual abuse had lower annual employment earnings from age 33-37 years than children nonexposed, after adjustment for childhood socioeconomic circumstances. These differences were more pronounced for individuals with official Child Protection Service reports compared to those with retrospective reports, and for individuals who experienced more severe forms of sexual abuse (i.e., penetration, intra-familial).

MeaningChildren exposed to sexual abuse are at risk of poor socioeconomic outcomes in mid-adulthood; interventions and support to improve long-term economic participation should be considered.

category: epidemiology


title: Updated projections for COVID-19 omicron wave in Florida

abstract: In this report, we use a detailed simulation model to assess and project the COVID-19 epidemic in Florida. The model is a data-driven, stochastic, discrete-time, agent based model with an explicit representation of people and places. Using the model, we find that the omicron variant wave in Florida is likely to cause many more infections than occurred during the delta variant wave. Due to testing limitations and often mild symptoms, however, we anticipate that omicron infections will be underreported compared to delta. We project that reported cases of COVID-19 will continue to grow significantly and peak in early January 2022, and that the number of reported COVID-19 deaths due to omicron may be 1/3 of the total caused by the delta wave.


title: Genome-wide Discovery for Diabetes-Dependent Triglycerides-Associated Loci

abstract: We aimed to discover loci associated with triglyceride (TG) levels in the context of type 2 diabetes (T2D). We conducted a genome-wide association study (GWAS) in 424,120 genotyped participants of the UK Biobank (UKB) with T2D status and TG levels. We stratified the cohort based on T2D status and conducted association analyses of TG levels for genetic variants with minor allele count (MAC) at least 20 in each stratum. Effect differences of genetic variants by T2D status were determined by Cochrans Q-test and we validated the significantly associated variants in the Mass General Brigham Biobank (MGBB). Among 21,176 T2D and 402,944 non-T2D samples from UKB, stratified GWAS identified 19 and 315 genomic risk loci significantly associated with TG levels, respectively. Only chr6p21.32 exhibited genome-wide significant heterogeneity (I2=98.4%; pheterogeneity=2.1x10-15), with log(TG) effect estimates of -0.066 (95%CI: - 0.082, -0.050) and 0.002 (95%CI: -0.002, 0.006) for T2D and non-T2D, respectively. The lead variant rs9274619:A (allele frequency 0.095) is located 2Kb upstream of the HLA-DQB1 gene. We replicated this finding among 25,137 participants (6,951 T2D cases) of MGBB (pheterogeneity=9.5x10-3). Phenome-wide interaction association analyses showed that the lead variant was strongly associated with a concomitant diagnosis of type 1 diabetes (T1D) as well as diabetes-associated complications. In conclusion, we identified an intergenic variant near HLA-DQB1 significantly associates with decreased triglycerides only among those with T2D and highlights an immune overlap with T1D.

category: genetic and genomic medicine


title: Innate immune responses in patients treated with SBRT irradiation enhances prostate cancer remissions

abstract:
Stereotactic body radiation therapy (SBRT) is a curative therapeutic modality employing large fractional doses of highly conformal radiation therapy for cancer treatment. To understand the mechanisms underlying clinical responses to radiation therapy, SBRT offers a unique window for high-throughput analysis of post-radiation molecular events to inform predictive biomarker discovery and strategies for multi-disciplinary therapeutics. We performed longitudinal analysis of plasma proteins and metabolites from patients treated with prostate SBRT, comparing cohorts of patients in clinical remission to cohorts experiencing PSA-determined cancer progression. We observed onset of post-SBRT DNA Damage Response (DDR), cell cycle arrest, and immune response signaling in patients within one hour of treatment and innate immune response signaling that persisted for up to three months following treatment. Furthermore, patients in remission experienced more robust immune responses and metabolite elevations consistent with a pro-inflammatory, M1-mediated innate immune activation in the short-term following SBRT, whereas patients with disease progression had less robust immune responses and M2-mediated metabolite elevations. We interpret these data to support a critical role for innate immune activation in the clinical outcomes of patients receiving radiation therapy for prostate cancer potentially improving future multidisciplinary therapeutic strategies.

One Sentence SummaryFollowing SBRT, proteomic and metabolomic profiles reveal a robust immune activation that correlates with prostate cancer remission

category: urology


title: Applying Machine Learning and AI Explanations to Analyze Vaccine Hesitancy

abstract:
The paper identifies and quantifies the impact of race, poverty, politics and age on COVID-19 vaccination rates in counties across the continental US. Both traditional Ordinary Least Square (OLS) regression analysis and Random Forest machine learning algorithms are applied to quantify contributing factors for county level vaccination hesitancy. With the machine learning model, joint effects of multiple variables (race/ethnicity, partisanship, age etc.) are considered simultaneously to capture the unique combination of what factors affect the vaccination rate. By implementing a state-of-the-art Artificial Intelligence Explanations (AIX) algorithm, it is possible to solve the black box problem with machine learning models and provide answers to the "how much" question for each measured impact factor in every county.

For most counties a higher percentage vote for Republicans, a greater African American population share, and a higher poverty rate lower the vaccination rate. While a higher Asian population share increases the predicted vaccination rate. The impact on the vaccination rate from the Hispanic population proportion is positive in the OLS model, but only positive for counties with very high Hispanic population (65% and more) in the Random Forest model. Both the proportion of seniors and the one for young people in a county have a significant impact in the OLS model -- positive and negative, respectively. In contrast, the impacts are ambiguous in the Random Forest model.

Because results vary between geographies and since the AIX algorithm is able to quantify vaccine impacts individually for each county, this research can be tailored to local communities. This way it is a helpful tool for local health officials and other policy makers to improve vaccination rates.

An interactive online mapping dashboard that identifies impact factors for individual U.S. counties is available at https://www.cpp.edu/_clange/vacmap.html. It is apparent that the influence of impact factors is not universally the same across different geographies.

category: public and global health


title: Integrative transcriptomics analysis for uterine leiomyosarcoma identifies aberrant activation of cell cycle-dependent kinases and their potential therapeutic significance.

abstract:
PurposeUterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates.

Experimental DesignTranscriptome analysis was carried out using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis was then used to identify potential therapeutic target genes for uterine leiomyosarcoma. Moreover, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using the SK-UT-1, SK-LMS-1, and SKN cell lines.

ResultsWe identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The Ingenuity Pathway Analysis showed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI 2536 or prexasertib) were found to exert a superior anti-cancer effect against cell lines at low nanomolar concentrations and induced cell cycle arrest. In SK-UT-1 tumor-bearing mice, BI 2536 monotherapy demonstrated a marked tumor regression. Moreover, the prexasertib and cisplatin combination therapy also reduced tumorigenicity and prolonged survival.

ConclusionWe identified the upregulated expression of PLK1 and CHEK1; their kinase activity was considered to be activated in uterine leiomyosarcoma. BI 2536 and prexasertib demonstrate a significant anti-cancer effect; thus, cell cycle-related kinases may represent a promising therapeutic strategy for treating uterine leiomyosarcoma.

Translational relevanceThe development of next-generation sequencing has had an immense impact on cancer research. However, the biological features of uterine leiomyosarcoma are not fully understood. Hence, no effective treatment strategies have been established based on its molecular background. In this research, we were able to assess the transcriptional profiles of 46 patients with uterine leiomyosarcoma using three independent datasets and through the assistance of our cohort. The integrative transcriptional analysis showed that the upregulation and activation of cell cycle-related genes were the dominant features of uterine leiomyosarcoma. Afterward, we demonstrated that PLK1 or CHEK1 inhibition induced cell cycle arrest and caused DNA damage, which resulted in cell death in leiomyosarcoma-derived cell lines. Moreover, these drugs had a more significant anti-cancer effect in the mice model. These data suggest that cell-cycle-dependent kinases represent novel therapeutic targets and could potentially improve the outcome for patients with uterine leiomyosarcoma.

category: obstetrics and gynecology


title: Capturing additional genetic risk from family history for improved polygenic risk prediction

abstract: Family history of complex traits may reflect transmitted rare pathogenic variants, intrafamilial shared exposures to environmental and lifestyle factors, as well as a common genetic predisposition. We developed a latent factor model to quantify trait heritability in excess of that captured by a common variant-based polygenic risk score, but inferable from family history. We applied our model to predict adult height for 941 children in the Avon Longitudinal Study of Parents and Children cohort as well as 11 complex diseases for [~]400,000 European ancestry participants in the UK Biobank. Parental history brought consistent significant improvements in the predictive power of polygenic risk prediction. For instance, a joint predictor was able to explain [~]55% of the total variance in sex-adjusted adult height z-scores, close to the estimated heritability. Our work showcases an innovative paradigm for risk calculation, and supports incorporation of family history into polygenic risk score-based genetic risk prediction models.


title: Benefits and Cost of a $35 Insulin Cost-Sharing Cap for Medicare Patients

abstract:
BACKGROUNDTo improve insulin affordability, Congress is considering capping insulin cost-sharing to $35 per 30-day supply for Medicare patients. The potential benefits and cost of this cap are unclear. Additionally, it is unknown whether the benefits of this cap would vary between Medicare patients with type 1 versus type 2 diabetes.

METHODSWe conducted a cross-sectional analysis of the IQVIA Longitudinal Prescription Database, which reports prescriptions dispensed from 92% of U.S. pharmacies, and the Optum Clinformatics Data Mart, a national claims database from Medicare Advantage patients. The IQVIA analysis included patients who only had dispensed insulin prescriptions paid by Medicare in 2019. We estimated the proportion of Medicare patients who would benefit from an insulin cost-sharing cap of $35 per 30-day supply. Among these patients, we calculated the mean annual decrease in insulin out-of-pocket spending. We summed this decrease across patients to estimate the caps cost to the federal government. The Optum analysis included Medicare Advantage patients with diabetes and [≥]1 dispensed insulin prescription in 2019. We used linear regression to compare the proportion of patients who would benefit from a $35 cap and annual savings among these patients by diabetes type, adjusting for demographic characteristics and payer type.

RESULTSThe IQVIA analysis included 2,227,229 patients who only had dispensed insulin prescriptions paid by Medicare in 2019. Mean (SD) age was 69.2 (11.4) years. The $35 cap would benefit 887,051 (39.0%) of patients, lowering annual insulin out-of-pocket spending by $338, from $687 to $349. Across all patients in the sample, aggregate savings (i.e., the caps cost to the federal government) would be $299,402,402, or a mean of $134.4 per patient. Among the 60,300 Medicare Advantage patients in the Optum Analysis, mean age was 72.6 (9.3) years; 2,686 (4.5%) had type 1 diabetes and 57,614 (95.6%) had type 2 diabetes. The $35 cap would benefit a higher proportion of patients with type 1 diabetes (64.0%) compared with patients with type 2 diabetes (59.4%). Among patients with type 1 diabetes who would benefit from the cap, annual savings would be greater ($284) compared with their counterparts with type 2 diabetes ($231; p<.001 in adjusted analyses for all comparisons).

CONCLUSIONSA $35 insulin cost-sharing cap would benefit a sizable proportion of Medicare patients using insulin and may particularly lower out-of-pocket spending for patients with type 1 diabetes. The estimated cost of this cap to the federal government would be $134.4 per Medicare patient using insulin.

category: health policy


title: Persistence of endogenous SARS-CoV-2 and pepper mild mottle virus RNA in wastewater settled solids

abstract:
Limited information is available on the decay rate of endogenous SARS-CoV-2 and pepper mild mottle virus (PMMoV) RNA in wastewater and primary settled solids, potentially limiting an understanding of how transit or holding times within wastewater infrastructure might impact RNA measurements and their relationship to community COVID-19 infections. In this study, primary settled solids samples were collected from two wastewater treatment plants in the San Francisco Bay Area. Samples were thoroughly mixed, aliquoted into subsamples, and stored at 4{degrees}C, 22{degrees}C, and 37 {degrees}C for 10 days. The concentration of SARS-CoV-2 (N1 and N2 targets) and PMMoV RNA was measured using an RT-ddPCR. Limited decay (< 1 log10 reduction) was observed in the detection of viral RNA targets at all temperature conditions, suggesting that SARS-CoV-2 and PMMoV RNA can be highly persistent in solids. First-order decay rate constants ranged from 0.011 - 0.098 day-1 for SARS-CoV-2 RNA and 0.010 - 0.091 day-1 for PMMoV RNA, depending on temperature conditions. Slower decay was observed for SARS-CoV-2 RNA in primary settled solids compared to previously reported decay in wastewater influent. Further research is needed to understand if solid content and wastewater characteristics might influence the persistence of viral RNA targets.

SynopsisSARS-CoV-2 and PMMoV genomic RNA is highly stable in wastewater settled solids over 10 days at several environmentally relevant temperatures.

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title: A 2-Gene Host Signature for Improved Accuracy of COVID-19 Diagnosis Agnostic to Viral Variants

abstract: The continued emergence of SARS-CoV-2 variants is one of several factors that may cause false negative viral PCR test results. Such tests are also susceptible to false positive results due to trace contamination from high viral titer samples. Host immune response markers provide an orthogonal indication of infection that can mitigate these concerns when combined with direct viral detection. Here, we leverage nasopharyngeal swab RNA-seq data from patients with COVID-19, other viral acute respiratory illnesses and non-viral conditions (n=318) to develop support vector machine classifiers that rely on a parsimonious 2-gene host signature to predict COVID-19. Optimal classifiers achieve an area under the receiver operating characteristic curve (AUC) greater than 0.9 when evaluated on an independent RNA-seq cohort (n=553). We show that a classifier relying on a single interferon-stimulated gene, such as IFI6 or IFI44, measured in RT-qPCR assays (n=144) achieves AUC values as high as 0.88. Addition of a second gene, such as GBP5, significantly improves the specificity compared to other respiratory viruses. The performance of a clinically practical 2-gene RT-qPCR classifier is robust across common SARS-CoV-2 variants, including Omicron, and is unaffected by cross-contamination, demonstrating its utility for improving accuracy of COVID-19 diagnostics.


title: Adolescents Hospitalized with SARS-CoV-2: Analysis of Clinical Profile and Risk Factors for Severe Disease over a two-year period

abstract:
IntroductionThere is a lack of studies in adolescents with COVID-19 from developing countries. We aimed to describe the clinical profile and risk factors for severe disease in adolescents hospitalized with COVID-19.

MethodsA retrospective analysis of a prospectively admitted cohort of COVID-19 patients was performed at a tertiary hospital in north India. Adolescents aged 12 to 18 years who were hospitalized during the first wave (March 2020 to December 2020) and the second wave (March 2021 to June 2021) of the pandemic were included. Data on the demographic details, clinical presentation, laboratory parameters, disease severity at admission, treatments received, and in-hospital outcomes were retrieved and logistic regression was used to identify the risk factors for occurrence of moderate or severe disease.

ResultsThe study included 197 adolescents with median (IQR) age 15 (13-17) years, of whom 117 (59.4%) were male. Among these, 170 (86.3%) were admitted during the 1st wave. Underlying comorbidities were present in 9 (4.6%) patients. At the time of hospital admission, 60 (30.9%) patients were asymptomatic. In the severity grading, 148 (84.6%) had mild, 16 (9.1%) had moderate, and 11 (6.3%) had severe disease. Fever (14.9%) and cough (14.9%) were the most commonly encountered symptoms. The median (IQR) duration of hospital stay was 10 (8-13) days and 6 (3.1%) patients died in hospital. The odds of moderate to severe disease were 3.8 for second wave, 1.9 for fever and 1.1 for raised C reactive protein (CRP).

ConclusionIn our single-center study from northern India, adolescents admitted with COVID-19 had predominantly asymptomatic or mild disease. Admission during the second wave of COVID-19 pandemic, presence of fever and raised CRP were risk factors for moderate or severe disease.

Lay SummaryFrom 3rd January 2022 onwards, adolescents between 15 to 18 years of age in India will be given Covaxin vaccine, as per the latest Indian government guidelines. In our study, we aimed to describe the clinical profile and risk factors for severe disease in adolescents hospitalized with COVID-19. Our study included 197 adolescents. 170 (86.3%) of them were admitted during the 1st wave and the rest 27 (13.7%) during the 2nd wave. At the time of hospital admission, 60 (30.9%) patients were asymptomatic. In the severity grading, 148 (84.6%) had mild, 16 (9.1%) had moderate, and 11 (6.3%) had severe disease. Fever (14.9%) and cough (14.9%) were the most commonly encountered symptoms. The median (IQR) duration of hospital stay was 10 (8-13) days and 6 (3.1%) patients died in hospital. 2nd wave, fever and high C reactive protein increased the odds of moderate to severe disease.


title: Development, validation, and evaluation of prediction models to identify individuals at high risk of lung cancer for screening in the English primary care population using the QResearch database: research protocol and statistical analysis plan

abstract:
Background and research aimLung cancer is a research priority in the UK. Early diagnosis of lung cancer can improve patients survival outcomes. The DART-QResearch project is part of a larger academic-industrial collaborative initiative, using big data and artificial intelligence to improve patient outcomes with thoracic diseases. There are two general research aims in the DART-QResearch project: (1) to understand the natural history of lung cancer, (2) to develop, validate, and evaluate risk prediction models to select patients at high risk for lung cancer screening.

MethodsThis population-based cohort study uses the QResearch(R) database (version 45) and includes patients aged between 25 and 84 years old and without a diagnosis of lung cancer at cohort entry (study period: 1 January 2005 to 31 December 2020). The team conducted a literature review (with additional clinical input) to inform the inclusion of variables for data extraction from the QResearch database. The following statistical techniques will be used for different research objectives, including descriptive statistics, multi-level modelling, multiple imputation for missing data, fractional polynomials to explore non-linear relationships between continuous variables and the outcome, and Cox regression for the prediction model. We will update our QCancer (lung, 10-year risk) algorithm, and compare it with the other two mainstream models (LLP and PLCOM2012) for lung cancer screening using the same dataset. We will evaluate the discrimination, calibration, and clinical usefulness of the prediction models, and recommend the best one for lung cancer screening for the English primary care population.

DiscussionThe DART-QResearch project focuses on both symptomatic presentation and asymptomatic patients in the lung cancer care pathway. A better understanding of the patterns, trajectories, and phenotypes of symptomatic presentation may help GPs consider lung cancer earlier. Screening asymptomatic patients at high risk is another route to achieve earlier diagnosis of lung cancer. The strengths of this study include using large-scale representative population-based clinical data, robust methodology, and a transparent research process. This project has great potential to contribute to the national cancer strategic plan and yields substantial public and societal benefits through earlier diagnosis of lung cancer.


title: Modeling the USA Winter 2021 Resurgence

abstract:
The current USA 2021 CoVID-19 Winter Resurgence is modeled here with the same function used for analyzing prior USA CoVID-19 waves: O_FD O_INLINEFIG[Formula 1]C_INLINEFIGM_FD(1)C_FD Here, N(t) gives the total number of CoVID-19 cases above the previous baseline, and tR sets the initial tdbl = tR (ln 2) pandemic tdbl doubling time. Larger S values indicate that uninfected people are improving their pandemic mitigation efforts, such as Social Distancing and vaccinations ; while{delta} 0 > 0 accelerates the post-peak [Formula] tail-off, and is empirically associated with mask-wearing. The pandemic wave end is when N(t) no longer increases.

The USA Summer 2021 resurgence results from our prior medrxiv.org preprints* were used as a baseline. By 11/15/2021, an additional [Formula] cases above baseline were found, signaling the USA Winter 2021 resurgence. This CoVID-19 wave is still in its initial stages. Presently, our analysis indicates that this CoVID-19 wave can infect virtually all susceptible persons; just like the initial stage of the USA Summer 2021 resurgence. Data up through 12/30/2021 gives these paremeter values: O_FD O_INLINEFIG[Formula 2]C_INLINEFIGM_FD(2)C_FD These values are identical to the prior 2020 USA Winter Resurgence results. Also, the [Formula] and the [Formula] values are similar. However, while the Winter 2020 Resurgence showed a significant mask-wearing effect [Formula], this initial USA Winter 2021 Resurgence shows practically no mask-wearing effects [Formula]. If mask-wearing were to quickly rise to the Winter 2020 levels, it would give these projected totals: O_FD O_INLINEFIG[Formula 3]C_INLINEFIGM_FD(3)C_FD More robust mask-wearing and enhanced Social Distancing measures could further reduce these values (with 3 Figures).


title: A novel time-based surface EMG measure for quantifying hypertonia in paretic arm muscles during daily activities after hemiparetic stroke

abstract: After stroke, paretic arm muscles are constantly exposed to abnormal neural drive from the injured brain. As such, hypertonia, broadly defined as an increase in muscle tone, is prevalent especially in distal muscles, which impairs daily function or in long-term leads to a flexed resting posture in the wrist and fingers. However, there currently is no quantitative measure that can reliably track how hypertonia is expressed on daily basis. In this study, we propose a novel time-based surface electromyography (sEMG) measure that can overcome the limitations of the coarse clinical scales often measured in functionally irrelevant context and the magnitude-based sEMG measures that suffer from signal non-stationarity. We postulated that the key to robust quantification of hypertonia is to capture the "true" baseline in sEMG for each measurement session, by which we can define the relative duration of activity over a short time segment continuously tracked in a sliding window fashion. We validate that the proposed measure of sEMG active duration is robust across parameter choices (e.g., sampling rate, window length, threshold criteria), robust against typical noise sources present in paretic muscles (e.g., low signal-to-noise ratio, sporadic motor unit action potentials), and reliable across measurements (e.g., sensors, trials, and days), while providing a continuum of scale over the full magnitude range for each session. Furthermore, sEMG active duration could well characterize the clinically observed differences in hypertonia expressed across different muscles and impairment levels. The proposed measure can be used for continuous and quantitative monitoring of hypertonia during activities of daily living while at home, which will allow for the study of the practical effect of pharmacological and/or physical interventions that try to combat its presence.

category: rehabilitation medicine and physical therapy


title: Multiomic characterisation of high grade serous ovarian carcinoma enables high resolution patient stratification

abstract:
BackgroundHigh grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer; most patients experience disease recurrence which accumulates chemoresistance, leading to treatment failure. Previous investigations have characterised HGSOC at the genomic and transcriptomic level, identifying subtypes of patients with differential outcome and treatment response. However, the relationship between molecular events identified at the gene sequence, gene copy number and gene expression levels remains poorly defined.

MethodsWe perform multi-layer molecular characterisation of a large retrospective HGSOC cohort (n=362) with detailed clinical annotation to interrogate the relationship between patient groups defined by gene mutation, copy number events, gene expression patterns and infiltrating immune cell burden. We construct a high resolution picture of the molecular landscape in HGSOC and identify features of tumours associated with distinct clinical behaviour in patients.

ResultsBRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival (multivariable hazard ratio 0.40 and 0.53) and higher chemotherapy response rates at first- and second-line treatment. CCNE1-gained (CCNE1g) cases demonstrated shorter survival (multivariable hazard ratio 1.52, 95% CI 1.10-2.10), under-representation of FIGO stage IV cases (P=0.017) and no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and derived subtypes: the TCGA DIF, IMR, PRO and MES subtypes correlated with the Tothill C4, C2, C5 and C1 subtypes (P<0.001). IMR/C2 cases displayed higher BRCA1/2m frequency (25.5% and 32.5%) and significantly greater infiltration of immune cells (P<0.001), while PRO/C5 cases had the highest CCNE1g rate (23.9% and 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all transcriptomic subtypes (hazard ratio range 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations (P=0.005); RB loss was further associated with favourable survival within cases harbouring HRR aberrations (multivariable hazard ratio 0.50, 95% CI 0.30-0.84).

ConclusionsThese data paint a high resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.

category: oncology


title: Mendelian gene identification through mouse embryo viability screening

abstract:
The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful.

A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal.

We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease.

Based on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.


title: Outcomes of COVID-19 infection in patients with chronic kidney disease on maintenance hemodialysis at a COVID hospital in India

abstract:
BackgroundPatients with chronic kidney disease (CKD) on hemodialysis are highly vulnerable to COVID-19 infection with a mortality rate higher than the rest of the population. There are several clinical and laboratory parameters that can predict the course and the outcomes in this group of population.

MethodsWe retrospectively collected the baseline demographic, clinical, in-hospital, and laboratory data of the patients with CKD on maintenance hemodialysis who were admitted to our COVID-19 hospital during the first and the second wave.

ResultsWe obtained data for 35 patients from the first and 5 patients from the second wave. The analysis of the data for 35 patients from the first wave revealed shortness of breath (62.9%), and fever (54.3%) being the most common presenting symptoms, and the majority of the patients (57.2 %) presented with moderate to severe disease at admission with 57 % had bilateral lung infiltrates, and required oxygen support (65.7%) at admission. The comparison of clinical and laboratory markers between survivors (27 patients, 77.1%) and non-survivors (8 patients, 22.9%) revealed an older age, severe disease at presentation, invasive mechanical ventilation, baseline severe lymphocytopenia, high serum glutamic oxaloacetic transaminase, blood urea, and inflammatory markers like Interleukin-6 and procalcitonin, fibrinogen and low albumin in non survivors.

ConclusionsThe older age, severe disease at presentation, the requirement of invasive mechanical ventilation, raised baseline Interleukin-6, procalcitonin, serum glutamic oxaloacetic transaminase, blood urea and a low albumin level could be valuable predictors of poor outcomes.


title: Inpatient COVID-19 Mortality Rates: What are the predictors?

abstract:
ObjectiveThis study aims to investigate the relationship between registered nurses and hospital-based medical specialties staffing levels with inpatient COVID-19 mortality rates.

MethodsWe rely on data from AHA Annual Survey Database, Area Health Resource File, and UnitedHealth Group Clinical Discovery Database. We use linear regression to analyze the association between hospital staffing levels and bed capacity with inpatient COVID-19 mortality rates from March 1, 2020, through December 31, 2020.

ResultsHigher staffing levels of registered nurses, hospitalists, and emergency medicine physicians were associated with lower COVID-19 mortality rates. Moreover, a higher number of ICU and skilled nursing beds were associated with better patient outcomes. Hospitals located in urban counties with high infection rates had the worst patient mortality rates.

ConclusionHigher staffing levels are associated with lower inpatient mortality rates for COVID-19 patients. A future assessment is needed to establish benchmarks on the minimum staffing levels for nursing and hospital-based medical specialties during pandemics.


title: Epidemiological waves - types, drivers and modulators in the COVID-19 pandemic

abstract:
IntroductionA discussion of  waves of the COVID-19 epidemic in different countries is a part of the national conversation for many, but there is no hard and fast means of delineating these waves in the available data and their connection to waves in the sense of mathematical epidemiology is only tenuous.

MethodsWe present an algorithm which processes a general time series to identify substantial, significant and sustained periods of increase in the value of the time series, which could reasonably be described as  observed waves. This provides an objective means of describing observed waves in time series.

ResultsThe output of the algorithm as applied to epidemiological time series related to COVID-19 corresponds to visual intuition and expert opinion. Inspecting the results of individual countries shows how consecutive observed waves can differ greatly with respect to the case fatality ratio. Furthermore, in large countries, a more detailed analysis shows that consecutive observed waves have different geographical ranges. We also show how waves can be modulated by government interventions and find that early implementation of non-pharmaceutical interventions correlates with a reduced number of observed waves and reduced mortality burden in those waves.

ConclusionIt is possible to identify observed waves of disease by algorithmic methods and the results can be fruitfully used to analyse the progression of the epidemic.


title: Infectious disease dynamics and restrictions on social gathering size

abstract: Social gatherings can be an important locus of transmission for many pathogens including SARS-CoV-2. During an outbreak, restricting the size of these gatherings is one of several non-pharmaceutical interventions available to policy-makers to reduce transmission. Often these restrictions take the form of prohibitions on gatherings above a certain size. While it is generally agreed that such restrictions reduce contacts, the specific size threshold separating "allowed" from "prohibited" gatherings often does not have a clear scientific basis, which leads to dramatic differences in guidance across location and time. Building on the observation that gathering size distributions are often heavy-tailed, we develop a theoretical model of transmission during gatherings and their contribution to general disease dynamics. We find that a key, but often overlooked, determinant of the optimal threshold is the distribution of gathering sizes. Using data on pre-pandemic contact patterns from several sources as well as empirical estimates of transmission parameters for SARS-CoV-2, we apply our model to better understand relationship between restriction threshold and reduction in cases. We find that, under reasonable transmission parameter ranges, restrictions may have to be set quite low to have any demonstrable effect on cases due to relative frequency of smaller gatherings. We compare our conceptual model with observed changes in reported contacts during lockdown in March of 2020.


title: Mobile Phone Virtual Reality Game for Pediatric Home Burn Dressing Pain Management, a Randomized Clinical Trial

abstract:
ImportanceVirtual Reality (VR) gaming is considered a safe and effective alternative to standard pain alleviation in the hospital, we advocate for its use during repeated redressing at home.

ObjectiveThis study will address the effectiveness and feasibility of the Virtual Reality Pain Alleviation Tool (VR-PAT) that was developed by the research team at the Nationwide Childrens Hospital for repeated at-home burn dressing changes.

Design, Setting and ParticipantsRandomized clinical trial among patients recruited at the Nationwide Childrens Hospital (NCH) outpatient burn clinic between September 2019 and June 2021. We included English-speaking burn patients 5-17 years old requiring daily dressing changes for at least one week after first outpatient dressing change.

InterventionsOne group played an interactive VR-PAT game during dressing changes, while the other utilized standard distraction techniques available in the home for a week. Both child and caretaker were later asked to assess perceived pain. Those in the intervention group were asked to evaluate convenience and enjoyment of the VR-PAT game.

OutcomesPatients were asked to rate perceived pain on a scale of 1-10, and caregivers were asked to rate observed pain on a scale of 1-10. For the VR-PAT group, patients were also asked to rate various aspects of the VR game on a scale of 1-10 and caregivers were asked questions assessing ease of use.

ConclusionsSubjects found the VR-PAT to be a useful distraction during home dressing changes and reported it be easy to implement. In the VR-PAT group, child and caregiver reported pain decreased as the week of dressing changes progressed and was lower than those in the control group after the fourth dressing change. Children playing the VR-PAT reported consistent happiness and fun as the week went on and increased realism and engagement, which means our results werent just due to the novel experience of VR-PAT.

Trial RegistrationClinicalTrials.gov Identifier: NCT04548635

category: pediatrics


title: COVID-19 impact on routine immunisations for vaccine-preventable diseases: Projecting the effect of different routes to recovery

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSIntroductionC_ST_ABSOver the past two decades, vaccination programmes for vaccine-preventable diseases (VPDs) have expanded across low- and middle-income countries (LMICs). However, the rise of COVID-19 resulted in global disruption to routine immunisation (RI) activities. Such disruptions could have a detrimental effect on public health, leading to more deaths from VPDs, particularly without mitigation efforts. Hence, as RIs resume, it is important to estimate the effectiveness of different approaches for recovery.

MethodsWe apply an impact extrapolation method developed by the Vaccine Impact Modelling Consortium to estimate the impact of COVID-19-related disruptions with different recovery scenarios for ten VPDs across 112 LMICs. We focus on deaths averted due to RIs occurring in the years 2020-2030 and investigate two recovery scenarios relative to a no-COVID-19 scenario. In the recovery scenarios, we assume a 10% COVID-19-related drop in RI coverage in the year 2020. We then linearly interpolate coverage to the year 2030 to investigate two routes to recovery, whereby the immunization agenda (IA2030) targets are reached by 2030 or fall short by 10%.

ResultsWe estimate that falling short of the IA2030 targets by 10% leads to 11.26% fewer fully vaccinated persons (FVPs) and 11.34% more deaths over the years 2020-2030 relative to the no-COVID-19 scenario, whereas, reaching the IA2030 targets reduces these proportions to 5% fewer FVPs and 5.22% more deaths. The impact of the disruption varies across the VPDs with diseases where coverage expands drastically in future years facing a smaller detrimental effect.

ConclusionOverall, our results show that drops in RI coverage could result in more deaths due to VPDs. As the impact of COVID-19-related disruptions is dependent on the vaccination coverage that is achieved over the coming years, the continued efforts of building up coverage and addressing gaps in immunity are vital in the road to recovery.

SUMMARYO_ST_ABSWhat is already known?C_ST_ABSO_LIThe impact of vaccination programmes without COVID-19-related disruption has been assessed by the Vaccine Impact Modelling Consortium.
C_LIO_LIThe COVID-19 pandemic has disrupted vaccination programmes resulting in a decline in coverage in the year 2020, the ramifications of this is unclear.
C_LI

What are the new findings?O_LIWe estimate the impact of disruptions to routine immunisation coverage and different routes to recovery. We compare to a scenario without COVID-19-related disruptions (assuming no drops in immunisation coverage).
C_LIO_LIWe estimate that reaching the Immunization Agenda (IA2030) targets leads to 5% fewer FVPs and 5.22% more deaths over the years 2020 to 2030 relative to the scenario with no COVID-19-related disruptions, whereas falling short of the IA2030 targets by 10% leads to 11.26% fewer fully vaccinated persons (FVPs) and 11.34% more deaths.
C_LIO_LIThe impact of the disruption varies across the vaccine-preventable diseases with those forecasted to have vast expansions in coverage post-2020 able to recover more.
C_LI

What do the new findings imply?O_LIA drop in vaccination coverage results in fewer vaccinated individuals and thus more deaths due to vaccine-preventable diseases. To mitigate this, building up coverage of routine immunisations and addressing immunity gaps with activities such as catch-up campaigns are vital in the road to recovery.
C_LI


title: Estimation of excess all-cause mortality due to COVID-19 in Thailand

abstract: Thailand has experienced the most prominent COVID-19 outbreak, resulting in a new record for COVID-19 cases and deaths in 2021. To assess the influence of the COVID-19 outbreak on mortality, we estimated excess all-cause and pneumonia mortality in Thailand during the COVID-19 outbreak from April to October 2021. We used the previous five years mortality to estimate the baseline number of deaths using generalized linear mixed models (GLMMs). The models were adjusted for seasonality and demographics. We found that the estimated cumulative excess death was 14.3% (95% CI: 8.6%-18.8%) higher than the baseline. The results also showed that the excess deaths in males were higher than in females by approximately 26.3%. The excess deaths directly caused by the COVID-19 infections accounted for approximately 75.0% of the all-cause excess deaths. Furthermore, excess pneumonia deaths were also found to be 26.2% (95% CI: 4.8%-46.0%) above baseline. There was a significant rise in excess fatalities, especially in the older age groups. Therefore, the age and sex structure of the population are essential to assessing the mortality impact of COVID-19. Our modeling results could potentially provide insights into the COVID-19 outbreaks and provide a guide for outbreak control and intervention.


title: The combined impact of persistent infections and human genetic variation on C-reactive protein levels

abstract: Multiple human pathogens establish chronic, sometimes life-long infections. Even if they are often latent, these infections can trigger some degree of local or systemic immune response, resulting in chronic low-grade inflammation. There remains an incomplete understanding of the potential contribution of both persistent infections and human genetic variation on chronic low-grade inflammation. We searched for potential associations between seropositivity for 13 persistent pathogens and the plasma levels of the inflammatory biomarker C-reactive protein (CRP), using data collected in the context of the UK Biobank and the CoLaus|PsyCoLaus Study, two large population-based cohorts. We performed backward stepwise regression starting with the following potential predictors: serostatus for each pathogen, polygenic risk score for CRP, as well as demographic and clinical factors known to be associated with CRP. We found evidence for an association between Chlamydia trachomatis (P-value = 5.04e-3) and Helicobacter pylori (P-value = 8.63e-4) seropositivity and higher plasma levels of CRP. We also found an association between pathogen burden and CRP levels (P-value = 4.12e-4). These results improve our understanding of the relationship between persistent infections and chronic inflammation, an important determinant of long-term morbidity in humans.


title: COVID-19 vaccine effectiveness among healthcare workers in Portugal: results from a hospital-based cohort study, December 2020 to November 2021

abstract:
IntroductionHealthcare workers (HCW) were amongst the first prioritized for COVID-19 vaccination but data on COVID-19 vaccine effectiveness among HCW is still limited. This study aims to estimate the COVID-19 vaccine effectiveness (VE) against SARS-CoV-2 symptomatic infection among HCW from Portuguese hospitals.

MethodsIn this prospective cohort study, we analysed data from HCW (all professional categories) from two central hospitals in the Lisbon and Tagus Valley and Centre regions of mainland Portugal between December 2020 and November 2021. VE against symptomatic SARS-CoV-2 infection was estimated as one minus the confounder adjusted hazard ratios by Cox models considering age group, sex, presence of chronic disease and occupational exposure to patients diagnosed with COVID-19 as adjustment variables.

ResultsDuring the 11 months of follow up, the 2213 HCW contributed a total of 1950 person-years at risk and 171 SARS-CoV-2 events occurred. The COVID-19 incidence rate for unvaccinated HCW was 348.7 per 1000 person-years while for fully vaccinated HCW was 43.0 per 1000 person-years. We observed a VE against symptomatic SARS-CoV-2 infection of 73.9% (95% CI: 26.2-90.8%) for complete vaccination status.

ConclusionThis cohort study found a high COVID-19 VE against symptomatic SARS-CoV-2 infection in Portuguese HCW, which is in concordance with previous studies from other countries. Monitoring of VE in this HCW cohort continues during the winter 2021/2022 to evaluate potential VE decay and booster vaccine effect.


title: Exploring the health impacts and inequalities of the new way of working: findings from a cross-sectional study.

abstract:
AimTo explore the working Welsh adult populations ability to work from home, their preferences for the future, and the self-reported health impacts of home-working.

Subject and MethodsA nationally-representative household survey was undertaken across Wales (Public Health Wales COVID-19, Employment and Health in Wales study), with cross-sectional data on home-working being collected between November 2020 and January 2021 from 615 employed working-aged adults in Wales (63.7% female, 32.7% aged 50-59). Respondents were asked about their ability to work from home, their perceptions of its impact on their health and their preferences for time spent home-working in future.

ResultsOver 50% were able to work from home, and showed a preference towards home-working to some capacity, with over a third wishing to work from home at least half the time. However, those living in the most deprived areas, in atypical employment, with high wage precarity or with limiting pre-existing conditions were less likely to report being able to work from home. Of those that could work from home, over 40% reported that it worsened their mental well-being and loneliness, and for people in poorer health, home-working negatively impacted their diet, physical activity, smoking and alcohol use. People aged 30 to 39 and those who lived alone were more likely to report wanting to spend some time working in an office/base instead of at home.

ConclusionThe inequity in the ability to work from home reflects underlying inequalities in Wales, with those facing the greatest insecurity (e.g. those living in most deprived areas, those with more precarious work or financial circumstances) being less able to participate in home-working. Working from home offers greater flexibility, reduces the financial and time costs associated with commuting, and protects individuals from exposure to communicable diseases. However, working from home presents an enormous challenge to preserving the mental-wellbeing of the workforce, particularly for younger individuals and those with low mental well-being. Younger respondents and those in poorer health who could work from home were also more likely to engage in health-harming behaviours, and reduce their engagement in health-protective behaviours such as eating well and moving more. Reflecting on the future, providing pathways for accessing work from home arrangements, integrating hybrid models and preparing targeted health support for at risk groups may be best suited to the working populations preferences and needs.


title: Sleep and circadian indices for planning post-pandemic university timetables

abstract: The aims of the present study were to obtain sleep quality and sleep timing information in a group of university students, and to evaluate the effects of a circadian hygiene education initiative. All students of the University of Padova (approximately 64,000) were contacted by e-mail (major campaigns in October 2019 and October 2020) and directed to an ad hoc website for collection of demographics and sleep quality/timing information. Participants (n=5740) received one of two sets of circadian hygiene advice ("A regular life" or "Bright days and dark nights"). Every month, they were then asked how easy it had been to comply, and provided with the advice again. At any even month from joining, they completed the sleep quality/timing questionnaires again. Information on academic performance was obtained post hoc, together with representative samples of lecture (n=5972) and exam (n=1800) timings, plus lecture attendances (n=25,302). 52% of students had poor sleep quality and 82% showed signs of sleep deprivation. Those who joined in October 2020, after several months of lockdown and distance learning, had better sleep quality, less sleep deprivation and later sleep habits. The "Bright days and dark nights" advice resulted in earlier get-up time/midsleep compared to the "A regular life" advice. Significant changes in most sleep quality and sleep timing variables were observed in both advice groups over time, also in relation to pandemic-related events characterising 2020. Early-chronotype students had better academic performances compared to their later chronotype counterparts. In a multivariate model, sleep quality, chronotype and study subject were independent predictors of academic performance. Taken together, these results underlie the importance of designing circadian-friendly university timetables.

category: neurology


title: Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

abstract: For optimal design of anti-amyloid-{beta} (A{beta}) and anti-tau clinical trials, it is important to understand how A{beta} and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimers disease (AD) continuum. In early stages of AD, increased concentration of soluble CSF p-tau was the main driver of accumulation of insoluble tau aggregates across the brain, and mediated the effect of A{beta} on tau aggregation. Further, higher soluble p-tau concentrations were mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations were associated with cognitive decline, which was mediated by faster increase of tau aggregates. In AD dementia, when A{beta} fibrils and soluble p-tau levels have plateaued, cognitive decline was driven by the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.


title: Consensus on COVID-19 vaccination in pediatric oncohematological patients, on behalf of infectious working group of Italian Association of Pediatric Hematology Oncology

abstract:
Vaccines represent the best tool to prevent the severity course and fatal consequences of pandemic by new Coronavirus 2019 infection (SARS-CoV-2). Considering the limited data on vaccination of pediatric oncohematological patients, we develop a Consensus document to support the Italian pediatric hematological oncological (AIEOP) centers in a scientifically correct communication with families and patients and to promote vaccination. The topics of the Consensus were: SARS-CoV-2 infection and disease (COVID-19) in the pediatric subjects; COVID-19 vaccines (type, schedule); which and when to vaccinate; contraindications and risk of serious adverse events; rare adverse events; third dose and vaccination after COVID-19; and other general prevention measures. Using the Delphi methodology for Consensus, 21 statements and their corresponding rationale were elaborated and discussed with the representatives of 31 centers, followed by voting. AIEOP Centers showed an overall agreement on all the statements that were therefore approved.

This consensus document highlights that children and adolescents affected by hematological and oncological diseases are a fragile category. Vaccination plays an important role to prevent COVID-19, to permit the regular administration of chemotherapy or other treatments, to perform control visits and hospital admissions, and to prevent treatment delays.


title: Genome-wide Association Study of Pulmonary Function in Europeans and Africans from the UK Biobank Identifies Distinct Variants

abstract: Pulmonary function is an indicator of well-being, and pulmonary pathologies are the third major cause of death worldwide. FEV1, FVC, and PEF are quantitively used to assess pulmonary function. We conducted a genome-wide association analysis of pulmonary function in 383,471 individuals of European and 5,978 African descent represented in the UK Biobank. Here, we report 817 variants in Europeans and 3 in Africans associated (p-values < 5 x 10-8) with three pulmonary function parameters; FEV1, FVC and PEF. In addition to 377 variants in Europeans previously reported to be associated with phenotypes related to pulmonary function, we identified 330 novel loci, including an ISX intergenic variant rs369476290 on chromosome 22 in Africans and a KDM2A intron variant rs12790261 on chromosome 11 in Europeans. Remarkably, we find no shared variants among Africans and Europeans. Enrichment analyses of variants separately for each ancestry background revealed significant enrichment for terms related to pulmonary phenotypes in Europeans but not Africans. Further analysis of studies of pulmonary phenotypes revealed individuals of European background are disproportionally overrepresented in datasets compared to Africans, with the gap widening over the past five years. Our findings offer a better understanding of the different variants that modify pulmonary function in Africans and Europeans, a significant finding for future GWAS studies and medicine.


title: Innate and adaptive immune defects associated with lower SARS-CoV-2 BNT162b2 mRNA vaccine response in elderly people

abstract: The immune factors associated with impaired SARS-CoV-2 vaccine response in the elderly are mostly unknown. We studied old and young people vaccinated with SARS-CoV-2 BNT162b2 mRNA before and after the first and second dose. Aging was associated with a lower anti-RBD IgG levels and a decreased magnitude and polyfunctionality of SARS-CoV-2 specific T cell response. The dramatic decrease in thymic function in the elderly, which fueled alteration in T cell homeostasis, and lower CD161+ T cell levels were associated with decreased T cell response two months after vaccination. Additionally, a deficient dendritic cell (DC) homing, activation and Toll like receptor (TLR)-mediated function, along with a proinflammatory functional profile in monocytes, were observed in the elderly, which was also related to lower specific T cell response after vaccination. These findings might be relevant for the improvement of the current vaccination strategies and for the development of new vaccine prototypes.


title: The emergence, spread and vanishing of a French SARS-CoV-2 variant exemplifies the fate of RNA virus epidemics and obeys the Black Queen rule

abstract: The nature and dynamics of mutations associated with the emergence, spread and vanishing of SARS-CoV-2 variants causing successive waves are complex1-5. We determined the kinetics of the most common French variant ("Marseille-4") for 10 months since its onset in July 20205. Here, we analysed and classified into subvariants and lineages 7,453 genomes obtained by next-generation sequencing. We identified two subvariants, Marseille-4A, which contains 22 different lineages of at least 50 genomes, and Marseille-4B. Their average lifetime was 4.1{+/-}1.4 months, during which 4.1{+/-}2.6 mutations accumulated. Growth rate was 0.079{+/-}0.045, varying from 0.010 to 0.173. All the lineages exhibited a "gamma" distribution. Several beneficial mutations at unpredicted sites initiated a new outbreak, while the accumulation of other mutations resulted in more viral heterogenicity, increased diversity and vanishing of the lineages. Marseille-4B emerged when the other Marseille-4 lineages vanished. Its ORF8 gene was knocked out by a stop codon, as reported in several mink lineages and in the alpha variant. This subvariant was associated with increased hospitalization and death rates, suggesting that ORF8 is a nonvirulence gene. We speculate that the observed heterogenicity of a lineage may predict the end of the outbreak.


title: BNT162b2 post-exposure-prophylaxis against COVID-19

abstract:
BackgroundDuring the COVID-19 pandemic, post-exposure-prophylaxis is not a practice. Following exposure, only patient isolation is imposed. Moreover, no therapeutic prevention approach is applied. We asked whether evidence exists for reduced mortality rate following post-exposure-prophylaxis.

MethodsTo estimate the effectiveness of post-exposure-prophylaxis, we obtained data from the Israeli Ministry of Health (MoH) registry. The study population consisted of Israeli residents aged 12 years and older, identified for the first time as PCR-positive for SARS-CoV-2, between December 20th, 2020 (the beginning of the vaccination campaign) and October 7th, 2021. We compared "recently injected" patients - that proved PCR-positive on the same day or on one of the five consecutive days after first vaccination (representing an unintended post-exposure-prophylaxis), to unvaccinated control group.

ResultsAmong Israeli residents identified PCR-positive for SARS-CoV-2, 11,690 were found positive on the day they received their first vaccine injection (BNT162b2) or on one of the 5 days thereafter. In patients over 65 years, 143 deaths occurred among 1413 recently injected (10.12%) compared to 280 deaths among the 1413 unvaccinated (19.82%), odd ratio (OR) 0.46 (95% confidence interval (CI), 0.36 to 0.57; P<0.001). The most significant reduction in the death toll was observed among the 55 to 64 age group, with 8 deaths occurring among the 1322 recently injected (0.61%) compared to 43 deaths among the 1322 unvaccinated control (3.25%), OR 0.18 (95% CI, 0.07 to 0.39; P<0.001).

ConclusionPost-exposure-prophylaxis is effective against death in COVID-19 infection.

Israeli MoH Registry NumberHMO-0372-20


title: Persistence of immunity and impact of a third (booster) dose of an inactivated SARS-CoV-2 vaccine, BBV152; a phase 2, double-blind, randomised controlled trial

abstract:
BackgroundNeutralising antibody responses to SARS-CoV-2 vaccines have been reported to decline within 6 months of vaccination, particularly against Variants of Concern (VOC). We assessed the immunogenicity and safety of a booster dose of BBV152 administered 6 months after the second of a two-dose primary vaccination series.

MethodsIn an ongoing phase 2 trial (ClinicalTrials.gov: NCT04471519) the protocol was amended after six months to re-consent and randomise 184 previously vaccinated participants to receive a third dose of vaccine or placebo on Day 215. The primary outcome was to measure neutralising antibody titres by plaque-reduction neutralisation test (PRNT50) four weeks after the booster; safety as serious adverse events (SAE) was the key secondary outcome.

FindingsFour weeks after a second BBV152 vaccination geometric mean titres (GMTs) of neutralising antibodies were 197{middle dot}0 PRNT50 (95% CI: 155{middle dot}6-249{middle dot}4); this level declined to 23{middle dot}9 PRNT50 (14{middle dot}0-40{middle dot}6) six months later, with a seroconversion rate of 75{middle dot}4% (95% CI: 68{middle dot}4-81{middle dot}6). Four weeks after booster vaccination the GMT increased on Day 243 to 746{middle dot}6 PRNT50 (514{middle dot}9-1081) compared with 100{middle dot}7 PRNT50 (43{middle dot}6-232{middle dot}6) in the placebo group. Corresponding seroconversion rates were 98{middle dot}7% (92{middle dot}8-99{middle dot}9) and 79{middle dot}8% (69{middle dot}6-87{middle dot}8). Increased titres in the placebo group were attributed to natural infection as the study was conducted during the second wave of COVID-19 in India. PRNT50 titres against the SARS-CoV-2 variants increased--Alpha (32{middle dot}6-fold), Beta (161{middle dot}0-fold), Delta (264{middle dot}7-fold), and Delta plus (174{middle dot}2-fold)--after the booster vaccination. We found that vaccine induces both memory B and T cells with a distinct AIM+ specific CD4+T central and effector memory phenotype, including CD8+ TEMRA phenotype. Reactogenicity after vaccine and placebo was minimal and comparable, and no SAEs were reported.

InterpretationSix months after a two-dose BBV152 vaccination series cell mediated immunity and neutralising antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralising antibodies against homologous and heterologous SARS-CoV-2 variants increased 19- to 97-fold after a third vaccination. Booster BBV152 vaccination is safe and may be necessary to ensure persistent immunity to prevent breakthrough infections.

FundingThis work was supported and funded by Bharat Biotech International Limited.


title: Effectiveness of mRNA-1273 against SARS-CoV-2 omicron and delta variants

abstract: SARS-CoV-2 omicron (B.1.1.529) variant is highly transmissible with potential immune escape. We conducted a test-negative case-control study to evaluate mRNA-1273 vaccine effectiveness (VE) against infection and hospitalization with omicron or delta. The large, diverse study population included 26,683 SARS-CoV-2 test-positive cases with variant determined by spike gene status (16% delta, 84% omicron). The 2-dose VE against omicron infection at 14-90 days was 44.0% (95% CI, 35.1-51.6%) but declined quickly. The 3-dose VE was 93.7% (92.2-94.9%) and 86.0% (78.1-91.1%) against delta infection and 71.6% (69.7-73.4%) and 47.4% (40.5-53.5%) against omicron infection at 14-60 days and >60 days, respectively. The 3-dose VE was 29.4% (0.3-50.0%) against omicron infection in immunocompromised individuals. The 3-dose VE against hospitalization with delta or omicron was >99%. Our findings demonstrate high, durable 3-dose VE against delta infection but lower effectiveness against omicron infection, particularly among immunocompromised people. However, 3-dose VE was high against hospitalization with delta or omicron.


title: Differential Peripheral Blood Glycoprotein Profiles in Symptomatic and Asymptomatic COVID-19

abstract: Glycosylation is the most common form of post-translational modification of proteins, critically affecting their structure and function. Using liquid chromatography and mass spectrometry for high-resolution site-specific quantification of glycopeptides coupled with high-throughput artificial intelligence-powered data processing, we analyzed differential protein glyco-isoform distributions of 597 abundant serum glycopeptides and non-glycosylated peptides in 50 individuals who had been seriously ill with COVID-19 and in 22 individuals who had recovered after an asymptomatic course of COVID-19. As additional comparison reference phenotypes, we included 12 individuals with a history of infection with a common cold coronavirus, 16 patients with bacterial sepsis, and 15 healthy subjects without history of coronavirus exposure. We found statistically significant differences, at FDR<0.05, for normalized abundances of 374 of the 597 peptides and glycopeptides interrogated, between symptomatic and asymptomatic COVID-19 patients. Similar statistically significant differences were seen when comparing symptomatic COVID-19 patients to healthy controls (350 differentially abundant peptides and glycopeptides) and common cold coronavirus seropositive subjects (353 differentially abundant peptides and glycopeptides). Among healthy controls and sepsis patients, 326 peptides and glycopeptides were found to be differentially abundant, of which 277 overlapped with biomarkers that showed differential expression between symptomatic COVID-19 cases and healthy controls. Among symptomatic COVID-19 cases and sepsis patients, 101 glycopeptide and peptide biomarkers were found to be statistically significantly abundant. Using both supervised and unsupervised machine learning techniques, we found specific glycoprotein profiles to be strongly predictive of symptomatic COVID-19 infection. LASSO-regularized multivariable logistic regression and K-means clustering yielded accuracies of 100% in an independent test set and of 96% overall, respectively. Our findings are consistent with the interpretation that a majority of glycoprotein modifications observed which are shared among symptomatic COVID-19 and sepsis patients likely represent a generic consequence of a severe systemic immune and inflammatory state. However, there are glyco-isoform changes that are specific and particular to severe COVID-19 infection. These may be representative of either COVID-19-specific consequences or of susceptibility to or predisposition for a severe course of the disease. Our findings support the potential value of glycoproteomic biomarkers in the biomedical understanding, and, potentially, the clinical management of serious acute infectious conditions.


title: Effect of Ozone on Allergic Airway Inflammation

abstract:
BackgroundExposure to O3 has been associated with increased risk of exacerbations of asthma, but the underlying mechanisms are not well studied. We hypothesized that O3 exposure would enhance airway inflammatory responses to allergen and the GSTM1 null genotype would modulate this enhancement.

ProceduresIn a cross-over design, 10 asthmatic subjects (50% with GSTM1 null genotype) who had specific sensitization to Dermatophagoides pteronyssinus (DP) were exposed to 160 ppb O3 or filtered air (FA) control for 4 h with intermittent exercise on two separate days at least three weeks apart. 20 h post-exposure, endobronchial challenge with DP allergen, and sham normal saline (NS) instillation, were performed in two separate lung lobes. Six h later, a second bronchoscopy was performed to collect bronchoalveolar lavage (BAL) fluid from the DP- and NS-challenged lobes for analyses of cellular and biochemical markers of inflammation. Multiple variable regression was used to compare cell and cytokine responses across the four exposure groups (FA-NS, O3-NS, FA-DP, O3-DP). Effect modification by GSTM1 genotype was assessed in stratified regressions.

Main FindingsBAL eosinophil and lymphocyte counts were increased in segments challenged with DP compared to segments that received sham challenges (p<0.01). DP challenge compared to sham challenge also caused a significant increase in BAL concentrations of the Th2 cytokines IL-4, IL-5, IL-10, and IL-13 (p<0.03 for all comparisons). O3 exposure did not significantly affect BAL cells or cytokine levels although BAL neutrophil count with DP challenge was non-significantly higher after O3 compared to after FA exposure (p<0.11). Compared to GSTM1-present subjects, GSTM1-null subjects had significantly reduced inflammatory responses including lower eosinophil (p<0.041) and IL-4 (p<0.014) responses to DP challenge after O3 exposure.

ConclusionsO3 appears to have mixed effects on allergen-induced airway inflammation. While O3 did not cause a clear differential effect on airway cellular or cytokine responses to allergen challenge, those responses did appear to be modulated by the antioxidant enzyme, GSTM1, as evident by the attenuation of airway inflammatory responses to allergen after O3 exposure in the absence of the gene.

HIGHLIGHTSO_LIOzone may increase risk of asthma exacerbation but the exact mechanisms are not clear.
C_LIO_LISusceptibility to ozone-induced airway inflammation may be associated with GSTM1 genotype.
C_LIO_LIOzone may enhance allergen-induced airway recruitment of neutrophils.
C_LIO_LIThe GSTM1 null mutation may decrease both eosinophil and cytokine allergic airway responses after O3 exposure.
C_LI

category: respiratory medicine


title: Genomic and transcriptomic data analyses highlight KPNB1 and MYL4 as novel risk genes for congenital heart disease

abstract: Congenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. CHDs exhibit a complex inheritance pattern. While genetic factors are known to play an important role in the development of CHD, relatively few variants have been discovered so far and very few genome-wide association studies (GWAS) have been conducted. We performed a GWAS of general CHD and five CHD subgroups in FinnGen followed by functional fine-mapping through eQTL analysis in the GTEx database, and target validation in human induced pluripotent stem cell - derived cardiomyocytes (hiPS-CM) from CHD patients. We discovered that the MYL4-KPNB1 locus (rs11570508, beta = 0.24, P = 1.2x10-11) was associated with the general CHD group. An additional four variants were significantly associated with the different CHD subgroups. Two of these, rs1342740627 associated with left ventricular outflow tract obstruction defects and rs1293973611 associated with septal defects, were Finnish population enriched. The variant rs11570508 associated with the expression of MYL4 (normalized expression score (NES) = 0.1, P = 0.0017, in the atrial appendage of the heart) and KPNB1 (NES = -0.037, P = 0.039, in the left ventricle of the heart). Furthermore, lower expression levels of both genes were observed in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) from CHD patients compared to healthy controls. Together, the results demonstrate KPNB1 and MYL4 as in a potential genetic risk loci associated with the development of CHD.


title: Temporary hold of mycophenolate boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients

abstract: Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from autoimmune patients suggest that temporary MPA hold might significantly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine during temporary (5 weeks) MPA hold to 29 kidney transplant recipients, who had not mounted a humoral immune-response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus neutralizing capacity. Interestingly, 21/25 (84%) CNI-treated patients responded, but only 1/4 Belatacept-treated patients. In line with humoral responses, counts and relative frequencies of spike receptor binding domain (RBD) specific B cells were significantly increased on day 7 after vaccination, with an increase in RBD specific CD27++CD38+ plasmablasts. Whereas overall proportions of spike-reactive CD4+ T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67+ and in vivo activated PD1+ T cells significantly increased after re-vaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, MPA hold was safe and augmented all arms of immunity during booster vaccination, suggesting its implementation in vaccination protocols for clinically stable transplant recipients.


title: Does the morphology of the posterior malleolar fragment influence clinical outcomes of trimalleolar fractures after surgical fixation? A systematic review and Meta-analysis

abstract:
BackgroundPosterior malleolus (PM) fractures have historically been classified according to the size of the fragment, to study the need for surgical fixation and to assess clinical outcomes. Recent research has suggested that the morphology of the PM fragment is of more relevance than its size.

ObjectivesThis systematic review aims to determine if the size of the PM fragment influences clinical outcomes of trimalleolar fractures after surgical fixation, and if so, to find out which fracture type has the best outcomes.

MethodsThis systematic review will be conducted according to the PRISMA guidelines. A literature search will be conducted on the electronic databases of PubMed, Embase, Scopus and Ovid with a pre-determined search strategy. A manual bibliography search of included studies will also be done. Original articles in English that have relevant data on the outcomes of PM fractures and its morphology will be included. Data will be extracted from included studies and analysis carried out with the help of appropriate software.

category: orthopedics


title: VarLOCK - sequencing independent, rapid detection of SARS-CoV-2 variants of concern for point-of-care testing, qPCR pipelines and national wastewater surveillance

abstract:
The COVID-19 pandemic continues to pose a threat to the general population. The ongoing vaccination programs provide protection to individuals and facilitate the opening of society and a return to normality. However, emergent and existing SARS-CoV-2 variants capable of evading the immune system endanger the efficacy of the vaccination strategy. To preserve the efficacy of SARS-CoV-2 vaccination globally, aggressive and effective surveillance for known and emerging SARS-CoV-2 Variants of Concern (VOC) is required. Rapid and specific molecular diagnostics can provide speed and coverage advantages compared to genomic sequencing alone, benefitting the public health response and facilitating VOC containment. In this work, we expand the recently developed SARS-CoV-2 CRISPR-Cas detection technology (SHERLOCK) to allow rapid and sensitive discrimination of VOCs, that can be used at point of care and/or implemented in the pipelines of small or large testing facilities, and even determine proportion of VOCs in pooled population-level wastewater samples. This technology aims to complement the ongoing sequencing efforts to allow facile and, crucially, rapid identification of individuals infected with VOCs to help break infection chains. Here, we show the optimisation of our VarLOCK assays (Variant-specific SHERLOCK) for multiple specific mutations in the S gene of SARS-CoV-2 and validation with samples from the Cardiff University Testing Service. We also show the applicability of VarLOCK to national wastewater surveillance of SARS-CoV-2 variants. In addition, we show the rapid adaptability of the technique for new and emerging VOCs such as Omicron.

Short abstractThe COVID-19 pandemic continues to pose a threat as emergent and existing SARS-CoV-2 variants endanger the efficacy of the vaccination strategy. Rapid surveillance for known and emerging SARS-CoV-2 Variants of Concern (VOC) would be assisted by effective molecular diagnostics procedures. Here we develop the recent SARS-CoV-2 CRISPR-Cas detection technology (SHERLOCK) for rapid and sensitive discrimination of VOCs to complement sequencing and allow rapid identification of individuals infected with VOC. We show our assays can be implemented with test samples in the pipelines of large testing facilities, as well as determine the proportion of VOCs in pooled population level wastewater samples and has potential applicability at point of care. We demonstrate the optimisation of new VarLOCK assays (Variant-specific SHERLOCK) for multiple specific mutations in the S gene of SARS-CoV-2 and validate these with samples from the Cardiff University Testing Service, as well as the applicability of VarLOCK to national-level wastewater surveillance of SARS-CoV-2 variants. We also demonstrate the rapid adaptability of the technique for new and emerging VOCs such as Omicron.