title: Application of Digital Twin and Heuristic Computer Reasoning to Workflow Management: Gastroenterology Outpatient Centers Study

abstract: The workflow in a large medical procedural suite is characterized by high variability of input and suboptimum throughput. Today, Electronic Health Record systems do not address the problem of workflow efficiency: there is still high frustration from medical staff who lack real-time awareness and need to act in response of events based on their personal experiences rather than anticipating. In a medical procedural suite, there are many nonlinear coupling mechanisms between individual tasks that could wrong and therefore is difficult for any individual to control the workflow in real-time or optimize it in the long run. We propose a system approach by creating a digital twin of the procedural suite that assimilates Electronic Health Record data and supports the process of making rational, data-driven, decisions to optimize the workflow on a continuous basis. In this paper, we focus on long term improvements of gastroenterology outpatient centers as a prototype example and use six months of data acquisition in two different clinical sites to validate the artificial intelligence algorithms.

category: health systems and quality improvement


title: Vitamin D Supplements for Prevention of Covid-19 or other Acute Respiratory Infections: a Phase 3 Randomized Controlled Trial (CORONAVIT)

abstract:
BACKGROUNDVitamin D metabolites support innate immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory pathogens. Randomized controlled trials of vitamin D to prevent coronavirus disease 2019 (Covid-19) have not yet reported.

METHODSWe randomly assigned 6200 U.K. adults to receive an offer of a postal finger-prick 25-hydroxyvitamin D (25[OH]D) test with provision of a 6-month supply of higher-dose vitamin D (3200 IU/d, n=1550) or lower-dose vitamin D (800 IU/d, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, vs. no offer of testing or supplementation (n=3100). The primary outcome was the proportion of participants experiencing at least one swab test- or doctor-confirmed acute respiratory infection (ARI) of any cause at six months. Secondary outcomes included incidence of swab test-confirmed Covid-19.

RESULTSOf 3100 participants offered testing, 2958 (95.4%) accepted, and 2690 (86.8%) had 25(OH)D <75 nmol/L and were sent vitamin D supplements (1356 higher-dose, 1334 lower-dose). 76 (5.0%) vs. 87 (5.7%) vs. 136 (4.6%) participants in higher-dose vs. lower-dose vs. no-offer groups experienced at least one ARI of any cause (odds ratio [OR] for higher-dose vs. no-offer 1.09, 95% CI 0.82-1.46; lower-dose vs. no-offer 1.26, 0.96-1.66). 45 (3.0%) vs. 55 (3.6%) vs. 78 (2.6%) participants in higher-dose vs. lower-dose vs. no-offer groups developed Covid-19 (OR for higher-dose vs. no-offer 1.13, 0.78-1.63; lower-dose vs. no-offer 1.39, 0.98-1.97).

CONCLUSIONSAmong adults with a high baseline prevalence of vitamin D insufficiency, implementation of a test-and-treat approach to vitamin D replacement did not reduce risk of all-cause ARI or Covid-19.

TRIAL REGISTRATIONClinicalTrials.gov no. NCT04579640

category: infectious diseases


title: Accuracy of Rapid Antigen Testing across SARS-CoV-2 Variants

abstract: Variants of SARS-CoV-2 have mutations in the viral genome that may alter the accuracy of rapid diagnostic tests. We conducted analytical and clinical accuracy studies of two FDA-approved rapid antigen tests--SCoV-2 Ag Detect Rapid Test (InBios International, Seattle) and BinaxNOW COVID-19 Ag CARD; (Abbott Laboratories, Chicago)--using three using replication-competent variants or strains, including Omicron (B.1.1.529/BA.1), Delta (B.1.617.2), and a wild-type of SARS-CoV-2 (USA-WA1/2020). Overall, we found non-significant differences in the analytical limit of detection or clinical diagnostic accuracy of rapid antigen testing across SARS-CoV-2 variants. This study provides analytical and clinical performance data to demonstrate the preserved accuracy of rapid antigen testing across SARS-CoV-2 variants among symptomatic adults.


title: Pre-exposure prophylaxis with Evusheld™ elicits limited neutralizing activity against the omicron variant in kidney transplant patients

abstract:
The combination of cilgavimab-tixagevimab (Evusheld, Astra Zeneca) became the mainstay for protecting transplant recipients with poor response to vaccination against the omicron variant. Serum neutralizing capacity against SARS-CoV-2 is positively associated with protection against severe forms of Covid-19.

Both anti-RBD IgG titers and neutralizing antibody titers against the omicron BA.1 variant were measured in serum samples collected from 63 adult kidney transplant recipients who received prophylactic injections of Evusheld. Patients who received prophylactic Ronapreve (casirivimab-imdevimab, n = 39) and those who were infected with SARS-CoV-2 during the fifth wave of the pandemic (n = 14) served as negative and positive controls, respectively.

After a median interval from injection of 29 days (interquartile range 29-33 days), only 9.5% of patients who received Evusheld were able to neutralize the omicron variant compared to 71% of patients who were infected with SARS-CoV-2 and 2.6% of those who received Ronapreve. Interestingly, convalescent patients displayed higher levels of neutralizing antibodies than those who received EvusheldTM (median: 2.3 log IC50, IQR: 1.5-2.7 versus 0.00 log IC50, IQR: 0&[ndash] 0.05; p<0.001). A high interindividual variability in anti-RBD IgG titers was observed after Evusheld (range: 262-7032 BAU/mL). This variability was largely explained by the patientsbody mass index, which showed an inverse correlation with anti-RBD IgG titers.

These findings suggest that Evusheld given at a dose of 300 mg is not sufficient to elicit an anti-RDB titer that confers in vivo neutralizing activity and support recent FDA recommendations, derived from in vitro models, regarding the need to increase the dose of Evusheld


title: Environmental chemical-wide associations with immune biomarkers in the US: A cross-sectional analysis

abstract: Exposure to environmental chemicals influence immune system functions, and humans are exposed to a wide range of chemicals, termed the chemical exposome. Thus, a comprehensive analysis of the effects across multiple chemical families with immune biomarkers is needed. In this study, we tested the associations between environmental chemicals and immune biomarkers. We analyzed the United States cross-sectional National Health and Nutrition Examination Survey (NHANES 1999-2018). Chemicals were measured in blood or urine (198 chemicals, 17 families). Immune biomarkers included percentages of lymphocytes, neutrophils, monocytes, basophils, and eosinophils, and counts of red blood cells, white blood cells, and mean corpuscular volume. We conducted survey-weighted, multivariable linear regressions of log2-transformed chemicals on immune measures, adjusted for age, sex, race/ethnicity, poverty-income ratio, waist circumference, cotinine concentration, creatinine for urinary chemicals, and survey cycle. We accounted for multiple comparisons using a false discovery rate (FDR). Among 45,528 adult participants, using survey weights, the mean age was 45.7 years, 51.4% were female, and 69.3% were Non-Hispanic White. There were 65 chemicals associated with white blood cell count. For example, a doubling in the concentration of blood lead was associated with a decrease of 61 white blood cells per {micro}L (95% CI: 23-99; FDR=0.005). 122 (61.6%) chemicals were associated with at least one of the eight immune biomarkers. Chemicals in the Metals family were associated with all eight immune measures. Concentrations of a wide variety of biomarkers of exposure to chemicals such as metals and smoking-related compounds, were highly associated with immune system biomarkers, with implications for immune function and toxicology. This environmental chemical-wide association study identified chemicals from multiple families for further toxicological and epidemiological investigation.

category: epidemiology


title: The relationship between wild-type transthyretin amyloid load and ligamentum flavum thickness in lumbar stenosis patients

abstract:
BackgroundOne key contributor to lumbar stenosis is thickening of the ligamentum flavum (LF), a process still poorly understood. Wild-type transthyretin amyloid (ATTRwt) has been found in the LF of patients undergoing decompression surgery, suggesting that amyloid may play a role. However, it is unclear whether within patients harboring ATTRwt, the amount of amyloid is associated with LF thickness.

MethodsFrom an initial cohort of 324 consecutive lumbar stenosis patients whose LF specimens from decompression surgery were sent for analysis (2018-2019), 33 patients met the following criteria: (1) Congo red-positive amyloid in the LF; (2) ATTRwt by mass spectrometry-based proteomics; and (3) an available preoperative MRI. Histological specimens were digitized, and amyloid load quantified through Trainable Weka Segmentation (TWS) machine learning. LF thicknesses were manually measured on axial T2-weighted preoperative MRI scans at each lumbar level, L1-S1. The sum of thicknesses at every lumbar LF level (L1-S1) equals "lumbar LF burden."

ResultsPatients had a mean age of 72.7 years (range 59-87), were mostly male (61%) and white (82%); and predominantly had surgery at L4-L5 levels (73%). Amyloid load was positively correlated with LF thickness (R=0.345, p=0.0492) at the levels of surgical decompression. Furthermore, amyloid load was positively correlated with lumbar LF burden (R=0.383, p=0.0279).

ConclusionsAmyloid load is positively correlated with LF thickness and lumbar LF burden across all lumbar levels, in a dose-dependent manner. Further studies are needed to validate these findings, uncover the underlying pathophysiology, and pave the way towards using therapies that slow LF thickening.

category: pathology


title: Brain iron and mental health symptoms in youth with and without prenatal alcohol exposure

abstract: Prenatal alcohol exposure (PAE) negatively affects brain development and increases the risk of poor mental health. We investigated if brain susceptibility, measuring iron, or volume were associated with internalizing or externalizing symptoms in youth with and without PAE. T1-weighted and quantitative susceptibility mapping (QSM) MRI scans were collected for 19 PAE and 40 unexposed participants aged 7.5-15 years. Magnetic susceptibility and volume of basal ganglia and limbic structures were extracted using FreeSurfer. Internalizing and externalizing problems were assessed using the Behavioural Assessment System for Children (BASC-2-PRS). Susceptibility in the nucleus accumbens was negatively associated with internalizing problems, while amygdala susceptibility was positively associated with internalizing problems across groups. In the PAE group, thalamus susceptibility was negatively associated with internalizing problems, and putamen susceptibility was positively associated with externalizing problems. Brain volume was not related to internalizing or externalizing symptoms. These findings highlight that brain iron is related to internalizing and externalizing symptoms differently in some brain regions for youth with and without PAE. Atypical iron levels (high or low) may indicate mental health problems across individuals, and iron in the thalamus and putamen may be particularly important for behaviour in individuals with PAE.

category: radiology and imaging


title: Longitudinal changes of white matter hyperintensities in sporadic small vessel disease: a systematic review and meta-analysis

abstract:
Background and objectivesWhite matter hyperintensities (WMH) are frequent imaging features of small vessel disease (SVD) and related to poor clinical outcomes. WMH progression over time is well described, but regression was also noted recently, although the frequency and associated factors are unknown. This systematic review and meta-analysis aims to assess longitudinal intra-individual WMH volume changes in sporadic SVD.

MethodsFollowing PRISMA guidelines we searched EMBASE and MEDLINE for papers up to 28 January 2022 on WMH volume changes using MRI on [≥]2 time-points in adults with sporadic SVD. We classified populations (healthy/community-dwelling, stroke, cognitive, other vascular risk factors, depression) based on study characteristics. We performed random-effects meta-analyses with Knapp-Hartung adjustment to determine mean WMH volume change (change in mL, % of intracranial volume [%ICV], or mL/year), 95%CI and prediction intervals (PI, limits of increase and decrease) using unadjusted data. Risk of Bias Assessment tool for Non-randomised Studies (RoBANS) was used to assess risk of bias.

ResultsForty papers, 10,932 participants, met the inclusion criteria. Mean WMH volume increased over time by: 1.74 mL (95% CI 1.23, 2.26; PI -1.24, 4.73 mL; 27 papers, N=7411, mean time interval 2.7 years, SD=1.65); 0.25%ICV (95% CI 0.14, 0.36; PI -0.06, 0.56; 6 papers, N=1071, mean time interval 3.5 years, SD =1.54); or 0.61 mL/year (95% CI 0.37, 0.85; PI -0.25, 1.46; 7 papers, N=2450). Additionally, 13 papers specifically mentioned and/or provided data on WMH regression, which occurred in asymptomatic, stroke, and cognitive presentations of SVD.

DiscussionNet mean WMH volume increases over time mask wide-ranging change (e.g. mean increase of 1[3/4]mL ranging from 1[1/4]mL decrease to 4[3/4]ml increase), with regression documented explicitly in up to 1/3 of participants. More knowledge on underlying mechanisms, associated factors and clinical correlates is needed, as WMH regression could be an important intervention target.

category: neurology


title: Frequency of preclinical Alzheimer's disease in Japanese clinical study settings: a meta-analysis

abstract:
BackgroundMany of earlier studies reporting the frequency of preclinical Alzheimers disease (AD) among cognitive normal (CN) individuals have based on the clinical study cohort from Western countries, and it has not been validated whether the frequency of preclinical AD in Asian country cohort may differ from that in Western countries.

MethodsWe conducted meta-analysis of earlier literature and original data of 4 Japanese cohort study (i.e., AMED-Preclinical, Brain/Minds Aging Imaging Study, J-ADNI, and A4 study screening conducted in Japan), among which we incorporated cognitive normal (CDR = 0) clinical study participants who were examined their amyloid status by amyloid-PET or CSF.

ResultsIn total, among the reviewed 658 Japanese CN participants from 10 different groups, 103 turned out to be amyloid positive, and the estimated overall frequency of preclinical AD (of any stage) was 17.2% (95% CI: 12.0 - 23.0%) with a high statistical heterogeneity of I2 = 64%. In meta-regression, being the Japanese cohort was barely significantly associated with the lower frequency of preclinical AD (p = 0.048).

ConclusionsOur study suggested that currently there is no robust evidence to support the lower frequency of preclinical AD in clinical study settings of Japan than that of Western countries.


title: Increased Circulating miR-155 identifies a subtype of preeclamptic patients

abstract: Preeclampsia is a heterogeneous disorder which affect maternal and fetal outcomes. The current classifications of preeclampsia such as "early-" and "late-" types, and "mild" and "severe" forms, are too imprecise to delineate the pathophysiology of preeclampsia. Here we reported that roughly one third of preeclampsia patients had high expression of maternal serum miR-155 in the case-control study and longitudinal study. The maternal serum miR-155 increased as early as 11-13+6 weeks of gestation. The patients with high serum miR-155 had severer clinical symptoms such as higher blood pressure and urine protein, and more adverse maternal and fetal outcomes. Moreover, these patients could be clustered as one group according to clinical manifestation by t-distributed stochastic neighbor embedding analysis. Therefore, these data suggest that preeclamptic patients with high maternal serum miR-155 could be viewed as a subtype of preeclampsia.

category: obstetrics and gynecology


title: Identification of deleterious neutrophil states and altered granulopoiesis in sepsis

abstract: Sepsis is a condition of high mortality arising from dysregulation of the host immune response. Gene expression studies have identified multiple immune endotypes but gaps remain in our understanding of the underlying biology and heterogeneity. We used single-cell multi-omics to profile 272,993 cells across 48 whole blood samples from 26 sepsis patients (9 with paired convalescent samples), 6 healthy controls and 7 post-surgery patients. We identified immature neutrophil populations specific to sepsis and demonstrated the immunosuppressive nature of sepsis neutrophils in vitro. An IL1R2+ neutrophil state was expanded in a transcriptomic sepsis endotype associated with increased early mortality (sepsis response signature 1, SRS1), together with enrichment of the response to IL-1 pathway in mature neutrophils, marking IL-1 out as a potential target for immunotherapy in SRS1 sepsis patients. We confirmed the expansion of immature neutrophils, specifically IL1R2+ neutrophils, in SRS1 in additional cohorts of patients (n = 906 RNA-sequencing samples, n = 41 CyTOF samples). Neutrophil changes persisted in convalescence, implicating disrupted granulopoiesis. Our findings establish a cellular immunological basis for transcriptomically defined sepsis endotypes and emphasise the relevance of granulopoietic dysfunction in sepsis, identifying opportunities for precision medicine approaches to the condition.

category: genetic and genomic medicine


title: Predicting Adverse Drug Effects: A Heterogeneous Graph Convolution Network with a Multi-layer Perceptron Approach

abstract:
We exploit a heterogeneous graph convolution network (GCN) combined with a multi-layer perceptron (MLP), which is denoted by GCNMLP, to explore potential side effects of drugs. By inferring the relationship among similar drugs, our approach in silico methods shortens the time consumption in uncovering the side effects unobserved in routine drug prescriptions. In addition, it highlights the relevance in exploring the mechanism of well-documented drugs. Our results predict drug side effects with area under precision-recall (AUPR) curve AUPR = 0.941, substantially outperforming the non-negative matrix factorization (NMF) method with AUPR=0.600. Moreover, new side effects are obtained using the GCNMLP.

Author summaryWe propose the GCNMLP to study drug side effects. By making better drug side effect prediction our approach improves personalized medicine.

category: health informatics


title: The contribution of malaria and sickle cell disease to anaemia among children aged 6 to 59 months in Nigeria: A secondary analysis using data from the 2018 Demographic and Health Survey

abstract:
IntroductionAnaemia is a major cause of morbidity and mortality among children in sub-Saharan Africa. Anaemia has many aetiologies best addressed by different treatments, so regional studies of the aetiology of anaemia may be required.

MethodsWe analysed data from Nigerias 2018 Demographic and Health Survey (DHS) to study predictors of anaemia among children ages 6-59m. We computed the fraction of anaemia at different degrees of severity attributable to malaria and sickle cell disease (SCD) using a regression model adjusting for demographic and socioeconomic risk factors. We also estimated the contribution of the risk factors to haemoglobin concentration.

ResultsWe found that 63.7% (95% CI: 58.3-69.4) of semi-severe anaemia (<80 g/L) was attributable to malaria compared to 12.4% (95% CI: 11.1-13.7) of mild-to-severe (adjusted haemoglobin concentration <110 g/L) and 29.6% (95% CI: 29.6-31.8) of moderate-to-severe (<100 g/L) anaemia and that SCD contributed 0.6% (95%CI: 0.4-0.9), 1.3% (95% CI: 1.0-1.7), and 7.3% (95%CI: 5.3-9.4) mild-to-severe, moderate-to-severe, and semi-severe anaemia, respectively. Sickle trait was protective against anaemia and was associated with higher haemoglobin concentration compared to children with normal haemoglobin (HbAA) among malaria-positive but not malaria-negative children.

ConclusionThis approach used offers a new tool to estimate the contribution of malaria to anaemia in many settings using widely available DHS data. The fraction of anaemia among young children in Nigeria attributable to malaria and SCD is higher at more severe levels of anaemia. Prevention of malaria and SCD and timely treatment of affected individuals would reduce cases of severe anaemia.

category: hematology


title: People with HIV receiving suppressive antiretroviral therapy show typical antibody durability after dual COVID-19 vaccination, and strong third dose responses

abstract:
BackgroundLonger-term humoral responses to two-dose COVID-19 vaccines remain incompletely characterized in people living with HIV (PLWH), as do initial responses to a third dose.

MethodsWe measured antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement and viral neutralization against wild-type and Omicron strains up to six months following two-dose vaccination, and one month following the third dose, in 99 PLWH receiving suppressive antiretroviral therapy, and 152 controls.

ResultsThough humoral responses naturally decline following two-dose vaccination, we found no evidence of lower antibody concentrations nor faster rates of antibody decline in PLWH compared to controls after accounting for sociodemographic, health and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after two doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantially exceeded post-second-dose levels, though anti-Omicron responses were consistently weaker than against wild-type.

Nevertheless, post-third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post-third-dose responses.

ConclusionPLWH receiving suppressive antiretroviral therapy mount strong antibody responses after two- and three-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron.


title: Risk of SARS-CoV-2 transmission by fomites: a clinical observational study in highly infectious COVID-19 patients

abstract:
BackgroundThe contribution of droplet-contaminated surfaces for virus transmission has been discussed controversially in the context of the current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic. Importantly, the risk of fomite-based transmission has not been systematically addressed.

MethodsWe initiated this single-center observational study to evaluate whether hospitalized COVID-19 patients can contaminate stainless steel carriers by coughing or intensive moistening with saliva and to assess the risk of SARS-CoV-2 transmission upon detection of viral loads and infectious virus in cell culture. Fifteen hospitalized patients with a high baseline viral load (CT value [≤] 25) shortly after admission were included. We documented clinical and laboratory parameters and used patient samples to perform virus culture, quantitative PCR and virus sequencing.

ResultsNasopharyngeal and oropharyngeal swabs of all patients were positive for viral RNA on the day of the study. Infectious SARS-CoV-2 could be isolated from 6 patient swabs (46.2 %). While after coughing, no infectious virus could be recovered, intensive moistening with saliva resulted in successful viral recovery from steel carriers of 5 patients (38.5 %).

ConclusionsTransmission of infectious SARS-CoV-2 via fomites is possible upon extensive moistening, but unlikely to occur in real-life scenarios and from droplet-contaminated fomites.


title: Mathematical modelling of COVID-19 transmission dynamics with vaccination: A case study in Ethiopia

abstract: In this paper, we consider a mathematical model of COVID-19 transmission with vaccination where the total population was subdivided into nine disjoint compartments, namely, Susceptible(S), Vaccinated with the first dose(V1), Vaccinated with the second dose(V2), Exposed (E), Asymptomatic infectious (I), Symptomatic infectious (I), Quarantine (Q), Hospitalized (H) and Recovered (R). We computed a reproduction parameter, Rv, using the next generation matrix. Analytical and numerical approach is used to investigate the results. In the analytical study of the model: we showed the local and global stability of disease-free equilibrium, the existence of the endemic equilibrium and its local stability, positivity of the solution, invariant region of the solution, transcritical bifurcation of equilibrium and conducted sensitivity analysis of the model. From these analysis, we found that the disease-free equilibrium is globally asymptotically stable for Rv < 1 and unstable for Rv > 1. A locally stable endemic equilibrium exists for Rv > 1, which shows persistence of the disease if the reproduction parameter is greater than unity. The model is fitted to cumulative daily infected cases and vaccinated individuals data of Ethiopia from May 01, 2021 to January 31, 2022. The unknown parameters are estimated using the least square method with built-in MATLAB function  lsqcurvefit. Finally, we performed different simulations using MATLAB and predicted the vaccine dose that will be administered at the end of two years. From the simulation results, we found that it is important to reduce the transmission rate, infectivity factor of asymptomatic cases and increase the vaccination rate, quarantine rate to control the disease transmission. Predictions show that the vaccination rate has to be increased from the current rate to achieve a reasonable vaccination coverage in the next two years.


title: Performance of Gazelle COVID-19 point-of-care test for detection of nucleocapsid antigen from SARS-CoV-2

abstract: SARS-CoV-2 antigen assays offer simplicity and rapidity in diagnosing COVID-19. We assessed the clinical performance of Gazelle COVID-19 test, a fluorescent lateral flow immunoassay with an accompanying Reader utilizing image-recognition software for detection of nucleocapsid antigen from SARS-CoV-2. We performed a prospective, operator-blinded, observational study at 2 point-of-care (POC) sites. Nasal swab specimens from symptomatic patients were tested with Gazelle COVID-19 test and real-time polymerase chain reaction (RT-P CR) assay. Overall, data from 1524 subjects was analyzed, and 133 were positive by RT-PCR. Mean (range) age of participants was 34.7 (2-94) years and 570 (37.4%) were female. The sensitivity and the specificity of the Gazelle COVID-19 test were 96.3% and 99.7%. The PPV of Gazelle COVID-19 test was 97.0%, NPV 99.6%, and accuracy 99.4%. In POC settings, Gazelle COVID-19 test had high diagnostic accuracy for detection of SARS-CoV-2 in nasal swab samples of symptomatic subjects suspected of COVID-19.


title: Explainable machine learning for real-time hypoglycaemia and hyperglycaemia prediction and personalised control recommendations

abstract:
BackgroundThe occurrences of acute complications arising from hypoglycaemia and hyperglycaemia peak as young adults with type 1 diabetes (T1D) take control of their own care. Continuous glucose monitoring (CGM) devices provide real-time blood glucose readings enabling users to manage their control pro-actively. Machine learning algorithms can use CGM data to make ahead-of-time risk predictions and provide insight into an individuals longer-term control.

MethodsWe introduce explainable machine learning to make predictions of hypoglycaemia (<70mg/dL) and hyperglycaemia (>270mg/dL) 60 minutes ahead-of-time. We train our models using CGM data from 153 people living with T1D in the CITY survey totalling over 28000 days of usage, which we summarise into (short-term, medium-term, and long-term) blood glucose features along with demographic information. We use machine learning explanations (SHAP) to identify which features have been most important in predicting risk per user.

ResultsMachine learning models (XGBoost) show excellent performance at predicting hypoglycaemia (AUROC: 0.998) and hyperglycaemia (AUROC: 0.989) in comparison to a baseline heuristic and logistic regression model.

ConclusionsMaximising model performance for blood glucose risk prediction and management is crucial to reduce the burden of alarm-fatigue on CGM users. Machine learning enables more precise and timely predictions in comparison to baseline models. SHAP helps identify what about a CGM users blood glucose control has led to predictions of risk which can be used to reduce their long-term risk of complications.

category: endocrinology


title: Risk of death following SARS-CoV-2 infection or COVID-19 vaccination in young people in England: a self-controlled case series study

abstract:
ObjectivesTo assess whether there is a change in the incidence of cardiac and all-cause death in young people following COVID-19 vaccination or SARS-CoV-2 infection in unvaccinated individuals.

DesignSelf-controlled case series.

SettingNational, linked electronic health record data in England.

Study populationIndividuals aged 12-29 who had received at least one dose of COVID-19 vaccination and died between 8 December 2020 and 2 February 2022 and registered by 16 February 2022 within 12 weeks of COVID-19 vaccination; Individuals aged 12-29 who died within 12 weeks of testing positive for SARS-CoV-2.

Main outcome measuresCardiac and all-cause deaths occurring within 12 weeks of vaccination or SARS-CoV-2 infection.

ResultsCompared to the baseline period, there was no evidence of a change in the incidence of cardiac death in the six weeks after vaccination, whether for each of weeks 1 to 6 or the whole six-week period. There was a decrease in the risk of all-cause death in the first week after vaccination and no change in each of weeks 2 to 6 after vaccination or whole six-week period after vaccination. Subgroup analyses by sex, age, vaccine type, and last dose also showed no change in the risk of death in the first six weeks after vaccination. There was a large increase in the incidence of cardiac and all-cause death in the overall risk period after SARS-CoV-2 infection among the unvaccinated.

ConclusionThere is no evidence of an association between COVID-19 vaccination and an increased risk of death in young people. By contrast, SARS-CoV-2 infection was associated with substantially higher risk of cardiac related death and all-cause death.

What is already known on this topicSeveral studies have highlighted the association between COVID-19 vaccination and the risk of myocarditis, myopericarditis, and other cardiac problems, especially in young people, but associated risk of mortality is unclear. Since younger people have lower risk of COVID-19 hospitalisation and mortality, the mortality risk associated with vaccination is potentially more important to them in balancing the risk and benefit of vaccination.

What this study addsAlthough there is a risk of myocarditis or myopericarditis with COVID-19, there is no evidence of increased risk of cardiac or all-cause mortality following COVID-19 vaccination in young people aged 12 to 29. Given the increased risk of mortality following SARS-CoV-2 infection in this group, the risk-benefit analysis favours COVID-19 vaccination for this age group.


title: Calcium Channel Blockers: clinical outcome associations with reported pharmacogenetics variants in 32,000 patients

abstract:
BackgroundDihydropiridine calcium channel blockers (dCCB) (e.g. amlodipine) are widely used for treating hypertension. Pharmacogenetic variants impact treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited. We aimed to estimate associations between reported pharmacogenetic variants and incident adverse events in a community-based cohort prescribed dCCB, including in high-risk subgroups.

MethodsWe analysed up to 32,360 UK Biobank European-ancestry participants prescribed dCCB in primary care electronic health records (from UK General Practices, 1990 to 2017). We investigated 23 genetic variants in 16 genes reported in PharmGKB, including CYP3A5 and RYR3. Outcomes were incident diagnosis of coronary heart disease (CHD), heart failure (HF), chronic kidney disease (CKD), edema, and switching antihypertensive medication. Secondary analysis in patients with history of heart disease was also performed.

ResultsParticipants were aged 40 to 79 years at first dihydropyridine prescription (treatment duration 1 month to 40 years, mean 5.9 years). Carriers of rs877087 T allele in the ryanodine receptor 3 (RYR3) had increased risk of HF (Hazard Ratio 1.13: 95% Confidence Intervals 1.02 to 1.25, p=0.02). We estimated that if rs877087 T allele carriers were prescribed an alternative treatment the incidence of HF in patients prescribed dCCB would reduce by 9.2% (95%CI 3.1 to 15.4). In patients with a history of heart disease when first prescribed dCCB (N=2,296), RYR3 rs877087 homozygotes had increased risk of new CHD or HF compared to CC variant (HR 1.25, 95%CI 1.09 to 1.44, p=0.002). Two variants increased likelihood of switching to an alternate antihypertensive medication (rs10898815 in gene NUMA1 HR 1.16: 95%CI 1.07 to 1,27, p=0.0009; rs776746 in CYP3A5 HR 1.59: 95%CI 1.09 to 2.32, p=0.02). rs776746 in CYP3A5 also increased CKD risk (HR 2.12, p=0.002). The remaining previously reported variants were not strongly or consistently associated with the studied clinical outcomes.

ConclusionsIn this large primary care cohort, patients with common genetic variants in NUMA1, CYP3A5 and RYR3 had increased adverse clinical outcomes. Work is needed to establish whether outcomes of dCCB prescribing could be improved by prior knowledge of such pharmacogenetics variants supported by clinical evidence of association with adverse events.


title: Existential suffering as a motive for assisted suicide: difficulties, acceptability, management and roles from the perspectives of Swiss professionals

abstract:
BackgroundExistential suffering is often a part of the requests for assisted suicide (AS). Its definitions have gained in clarity recently and refer to a distress arising from an inner realization that life has lost its meaning. There is however a lack of consensus on how to manage existential suffering, especially in a country where AS is legal and little is known about the difficulties faced by professionals confronted with these situations.

ObjectivesTo explore the perspectives of Swiss professionals involved in end-of-life care and assisted suicide on the management of existential suffering when it is part of AS requests, taking into account the question of roles, as well as on the difficulties they encounter along the way and their views on the acceptability of existential suffering as a motive for AS.

MethodsA qualitative study based on face-to-face interviews was performed among twenty-six participants from the fields of palliative and primary care as well as from EXIT right-to-die organization. A semi-structured interview guide exploring four themes was used. Elements from the grounded theory approach were applied.

ResultsAlmost all participants reported experiencing difficulties when facing existential suffering. Two-thirds considered existential suffering as a justifiable reason for requesting AS. Concerning the management of existential suffering, participants referred to the notion of being present, respect, explore the suffering, give meaning, working together, psychological support, spiritual support, relieve physical symptoms and palliative sedation.

ConclusionThis study offers a unique opportunity to reflect on what are desirable responses to existential suffering when it is part of AS requests. Existential suffering is plural and certainly implies a multiplicity of responses as well. These situations remain however difficult and controversial according to Swiss professionals. Clinicians education should better address these issues and give them the tool to take care of patients with existential suffering.

category: palliative medicine


title: Patients Experiences of Using Smartphone Apps to Manage their Gestational Diabetes Diagnosis: A Systematic Review - protocol (version 1)

abstract:
BackgroundGestational diabetes is a strong predictor of type 2 diabetes onset. However, women who make healthy dietary and lifestyle choices can significantly reduce their risk. There is a need to understand the factors facilitating or preventing women from using smartphone apps that may encourage these behaviours.

MethodsWe plan to conduct a systematic review of patient experiences when using mobile health applications to manage gestational diabetes. We will include primary studies of qualitative data around patient experiences of using these applications, as well as the barriers and facilitators to using technologies. We will search the following electronic databases: Medline, Embase, PsycINFO, Global Health, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), AMED and CINAHL and manually search the reference lists of included studies. We will include primary studies involving direct user interviews and where the results have been analysed using qualitative methods. To assess the quality of included studies, we will use the CASP qualitative research checklist.

Expected resultsWe intend to use summary tables to report the characteristics of the study population, the overarching themes that emerged, and recommendations for research and practice.

category: primary care research


title: Statistical and functional convergence of common and rare variant risk for autism spectrum disorders at chromosome 16p

abstract: The dominant human genetics paradigm for converting association to mechanism ("variant-to-function") involves iteratively mapping individual associations to specific SNPs and to the proximal genes through which they act. In contrast, here we demonstrate the feasibility of extracting biological insight from a very large (>10Mb) region of the genome, and leverage this approach to derive insight into autism spectrum disorder (ASD). Using a novel statistical framework applied in an unbiased scan of the genome, we identified the 33Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of common polygenic risk for ASD. This region includes the recurrent 16p11.2 copy number variant (CNV) - one of the largest single genetic risk factors for ASD, and whose pathogenic mechanisms are undefined. Analysis of bulk and single-cell RNA-sequencing data from post-mortem human brain samples revealed that common polygenic risk for ASD within 16p associated with decreased average expression of genes throughout this 33-Mb region. Similarly, analysis of isogenic neuronal cell lines with CRISPR/Cas9-mediated deletion of 16p11.2 revealed that the deletion also associated with depressed average gene expression across 16p. The effects of the rare deletion and diffuse common variation were correlated at the level of individual genes. Finally, analysis of chromatin contact patterns by Hi-C revealed patterns which may explain this transcriptional convergence, including elevated contact throughout 16p, and between 16p11.2 and a distal region on 16p (Mb 0-5.2) which showed the greatest gene expression changes in both the common and rare variant analyses. These results demonstrate that elevated 3D chromatin contact may coordinate genetic and transcriptional disease liability across large genomic regions, exemplifying a novel approach for extracting biological insight from genetic association data. As applied to ASD, our analyses highlight the 33Mb p-arm of chromosome 16 as a novel locus for ASD liability and provide insight into disease liability originating from the 16p11.2 CNV.

category: psychiatry and clinical psychology


title: A hypothesis-free data science approach to identifying novel patterns of clinical interest in clinicians' treatment preferences: clusters of high Pericyazine and Promazine use in England

abstract:
BackgroundData analysis can be used to identify signals suggestive of variation in treatment choice or clinical outcome. Analyses to date have generally focused on an hypothesis-driven approach.

MethodsHere we report an innovative hypothesis-blind approach (calculating chemical-class proportions for every chemical substance prescribed in each Clinical Commissioning Group and ranking chemicals by (a) their kurtosis and (b) a ratio between inter-centile differences) applied to Englands national prescribing data, and demonstrate how this identified unusual prescribing of two antipsychotics.

OutcomesWe identified that, while promazine and pericyazine are barely used by most clinicians, they make up a substantial proportion of all antipsychotic prescribing in two small geographic regions in England.

InterpretationData-driven approaches can be effective at identifying unusual clinical choices. More widespread adoption of such approaches, combined with clinician and decision-maker engagement could lead to better optimised patient care.

FundingNIHR Biomedical Research Centre, Oxford; Health Foundation; National Institute for Health Research (NIHR) School of Primary Care Research and Research for Patient Benefit

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIdentifying variation in clinical activity typically employs a traditional approach whereby measures are prospectively defined, and adherence then assessed in data. We are aware of no prior work using data science techniques hypothesis-blind to systematically identify outliers for any given treatment choice or clinical outcome (numerators) as a proportion of automatically generated denominators.

Added value of this studyHere we report an innovative hypothesis-blind approach applied to Englands national prescribing data, to identify chemical substances with substantial prescribing patterns between organisations. As illustrative examples we show that promazine and pericyazine, while rarely used by most clinicians, made up a substantial proportion of all antipsychotic prescribing in two small geographic regions in England.

Implications of all the available evidenceThe choice of antipsychotics between English regions could be further investigated using qualitative methods to explore the implications for patient care. More broadly, data-driven approaches can be effective at identifying unusual clinical choices. More widespread adoption of such approaches, combined with clinician and decision-maker engagement could lead to better optimised patient care.


title: The World Health Organization's Disease Outbreak News: a retrospective database

abstract: The World Health Organization (WHO) notifies the global community about disease outbreaks through the Disease Outbreak News (DON). These online reports tell important stories about both outbreaks themselves and the high-level decision making that governs information sharing during public health emergencies. However, they have been used only minimally in global health scholarship to date. Here, we collate all 2,789 of these reports from their first use through the start of the Covid-19 pandemic (January 1996 to December 2019), and develop an annotated database of the subjective and often inconsistent information they contain. We find that these reports are dominated by a mix of persistent worldwide threats (particularly influenza and cholera) and persistent epidemics (like Ebola virus disease in Africa or MERS-CoV in the Middle East), but also document important periods in history like the anthrax bioterrorist attacks at the turn of the century, the spread of chikungunya and Zika virus to the Americas, or even recent lapses in progress towards polio elimination. We present three simple vignettes that show how researchers can use these data to answer both qualitative and quantitative questions about global outbreak dynamics and public health response. However, we also find that the retrospective value of these reports is visibly limited by inconsistent reporting (e.g., of disease names, case totals, mortality, and actions taken to curtail spread). We conclude that sharing a transparent rubric for which outbreaks are considered reportable, and adopting more standardized formats for sharing epidemiological metadata, might help make the DON more useful to researchers and policymakers.

category: public and global health


title: Research on the Emotions of Uninfected People during the COVID-19 Epidemic in China

abstract:
BackgroundThe negative emotions induced by the ongoing coronavirus disease 2019 (COVID-19) epidemic are affecting peoples health. In order to identify emotional problems and promote early intervention to reduce the risk of disease, we studied the emotional states of Chinese people during the epidemic.

MethodWe adopted the Automated Neuropsychological Assessment Metrics mood scale and prepared an online questionnaire. Then, we conducted an exploratory factor analysis of the effective responses of 567 participants from 31 provinces and cities in China. Finally, we analyzed the characteristics of the distribution of different types of emotions and compared them via several statistical methods.

ResultsThe original scale was modified to have six dimensions that yielded reliable internal consistency values ranging from 0.898 to 0.965 and explained 74.96% of the total variance. We found that a total of 33.9% of respondents felt negative emotions more strongly, were less happy and had less energy than other respondents (p<0.001). People with these traits had relatively serious emotional problems and were typically over 60 years old, doctoral degree holders, enterprise personnel and residents in an outbreak area.

ConclusionThirty-three percent of people without COVID-19 had emotional problems. Psychotherapy should be provided as early as possible for people with emotional problems caused by the epidemic, and the modified scale could be used to survey the publics mood during public health events to detect problems and facilitate early intervention.


title: A comparison of paediatric hypertension clinical practice guidelines and their ability to predict adult hypertension in an African birth cohort

abstract: It remains unclear which paediatric hypertension clinical practice guideline (CPG) should be applied in an African population. We therefore aimed to compare three commonly used CPG (2017 AAP, 2016 ESH and 2004 Fourth Report) developed in high-income countries for use in South African children at four paediatric ages (children: 5yrs and 8yrs; adolescents: 13yrs and 17yrs) to determine which best predicts elevated blood pressure (EBP) in young adulthood (22yrs and 28yrs). Moreover, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each specific paediatric CPG was calculated. The 2017 AAP definition identified more children and adolescents with hypertension when compared to the 2004 Fourth Report and 2016 ESH guidelines. In computed hazards ratios, from ages 8yrs to 17yrs, all three paediatric CPG significantly predicted the risk of EBP in young adulthood (p[≤]0.008). However, sensitivity to predict EBP at age 22yrs for all CPG was generally low (17.0% - 33.0%) with higher specificity (87.4% - 93.1%). Sensitivity increased at age 28yrs (51.4.0% - 70.1%), while specificity decreased (52.8% - 65.1%). Both PPV and NPV at both adult age points varied widely (17.9% - 79.9% and 29.3% - 92.5% respectively). The performance of these paediatric CPG in terms of AUC were not optimal at both adult age points, however, the AAP definition at 17yrs met an acceptable level of performance (AUC= 0.71). Our results highlight the need for more research to examine if an African-specific CPG would better identify high-risk children to minimise their trajectory towards adult hypertension.


title: Weighting of risk factors for low birth weight: A linked routine data cohort study in Wales, UK.

abstract:
BackgroundGlobally 20 million children are born with a birth weight below 2,500 grams every year which is considered as a low birthweight (LBW) baby. This study investigates the contribution of modifiable risk factors to inform activities that reduce the rates of LBW in Wales.

MethodThe cohort (N = 693,377) was comprised of children born between 1st January 1998 and 31st December 2018 in Wales. A multivariable logistic regression model and a predictive model using decision tree were used to investigate the associations between the risk factors and LBW.

ResultsThe study found that non-singleton children had the highest risk of LBW (adjusted odds ratio 21.74, 95% confidence interval (CI) 21.09 - 22.40), followed by pregnancy interval less than one year (2.92, 95% CI 2.70 - 3.15), maternal diabetes (2.03, 95% CI 1.81 - 2.28), maternal hospital admission for anaemia (1.26, 95% CI 1.16 - 1.36), depression (1.58, 95% CI 1.43 - 1.75), serious mental illness (1.46, 95% CI 1.04 - 2.05), anxiety (1.22, 95% CI 1.08 - 1.38) and use of anti-depressant medication during pregnancy (1.92, 95% CI 1.20 - 3.07). Additional maternal risk factors include smoking (1.80, 95% CI 1.76 - 1.84), alcohol-related hospital admission (1.60, 95% CI 1.30 - 1.97), substance misuse (1.35, 95% CI 1.29 - 1.41), living in areas of high deprivation, and evidence of domestic abuse.

ConclusionThis work suggests that to address LBW, measures need to focus on improving maternal health, addressing pre-term births, promoting awareness of sufficient pregnancy interval, ensuring adequate support and resources for mothers mental health and wellbeing.

What is already known on this topicO_LIEach year 6.9% of live births are identified as low birth weight (LBW) in the UK.
C_LIO_LILBW children are at risk of poor cognitive development, which is associated with developmental disabilities and poor academic achievement in later life.
C_LIO_LIThe progress to reduce the LBW prevalence in high income regions (including Europe) is not satisfactory to meet World Health Organisation (WHO) LBW target by 2025.
C_LI

What this study addsO_LIThis work has built an e-cohort using data-linkage across multiple routinely collected administrative datasets to investigate the risk factors of LBW for the population of Wales.
C_LIO_LINon-singleton children had 22 times higher risk of LBW than singleton children.
C_LIO_LIFindings suggested that the most important factors to address to reduce the risk of LBW are multiple births, underlying maternal physical (diabetes, anaemia) and mental health, maternal smoking, and substance use (alcohol/drugs), adequate pregnancy interval, higher deprivation, and domestic abuse during pregnancy.
C_LI

How this study might affect research, practice, or policyO_LIThis finding suggests that to address the LBW, adequate support is needed to the mother and their family when they are planning for and during pregnancy.
C_LIO_LIMultiagency (doctors, midwives, security department) can liaise between them and can take necessary mitigative action to reduce the prevalence of LBW.
C_LI


title: Hypertension perspectives and health behaviors of African youth: The effect of health education and employment

abstract: In South Africa between 1998 and 2016, hypertension rates in young adults (15-34 years) more than doubled calling for preventive interventions. However, with many youth unemployed, young adults struggle to prioritize health or implement healthy behaviors. We conducted six focus group discussions comparing hypertension-related beliefs and behaviors between NEET youth (n=20; not in employment, education or training) and previously NEET youth on a health-focused learnership (n=20). While all youth viewed hypertension as life threatening leading to cardiovascular disease or death, especially if left untreated, only youth undertaking health education felt empowered to implement healthy behaviors for disease prevention. In contrast, NEET youth felt hypertension was inevitable and described negative experiences at clinics and fear of lifelong medication use if diagnosed as reasons not to be screened. Our results suggest that engaging NEET youth in culturally appropriate health education programs can motivate preventive health behavior for chronic diseases such as hypertension.


title: Evaluation of different diffusion-weighted image techniques for head and neck radiation treatment: phantom and volunteer studies

abstract:
PurposeTo quantitatively compare and assess the geometric distortion and apparent diffusion coefficient (ADC) accuracy of conventional single-shot EPI (SSEPI)-DWI, readout segmentation of long variable echo-trains (RESOLVE)-DWI, and BLADE-DWI techniques in both phantom and volunteer imaging studies.

MethodsPhantom measurements were obtained using the QIBA DWI phantom at 0{degrees} and at ambient temperature (~17{degrees}). DW images were acquired using SSEPI-DWI, RESOLVE-DWI, and BLADE-DWI. Image geometric distortion factors (compression and dilation, shear distortion), and image shift factors were measured and compared with computed tomography images. ADC and signal-to-noise ratio (SNR) values were measured for the various DWI techniques. Images were also obtained from three healthy volunteers and three oropharynx cancer patients. Geometric distortion parameters and ADC values were analyzed in the following head and neck regions of interest (ROI): salivary glands, tonsils, and primary tumors (patient only). The metric evaluation included Dice similarity coefficient and Hausdorff distance mean. T2-weighted images were used as a reference to evaluate geometric distortion.

ResultsIn the phantom experiment, the vials were prominently distorted on the SSEPI-DWI and RESOLVE-DWI images but were less distorted on the BLADE-DWI image, as determined by the overall effects of Image geometric distortion factors. The paired t-test showed no significant difference (0.15 < p < 0.88) in ADC values among the three DWI techniques; however, BLADE-DWI led to a lower SNR in vials. In the volunteer and patient studies, an ROI-based overlap metrics analysis of the salivary glands and gross tumor volumes were less distorted for BLADE-DWI than for EPI-based DWI, as determined by Wilcoxon paired signed-rank test.

ConclusionBLADE-DWI demonstrated excellent geometric accuracy, with similar quantitative ADC values to those of EPI-based DW-MRI, thus potentially making this technique suitable for target volume delineation and functional assessment for head and neck radiation treatment in the future.


title: The gut microbiome is a significant risk factor for future chronic lung disease

abstract:
BackgroundThe gut-lung axis is generally recognized, but there are few large studies of the gut microbiome and incident respiratory disease in adults.

Objectives3To investigate the associations between gut microbiome and respiratory disease and to construct predictive models from baseline gut microbiome profiles for incident asthma or chronic obstructive pulmonary disease (COPD).

MethodsShallow metagenomic sequencing was performed for stool samples from a prospective, population-based cohort (FINRISK02; N=7,115 adults) with linked national administrative health register derived classifications for incident asthma and COPD up to 15 years after baseline. Generalised linear models and Cox regressions were utilised to assess associations of microbial taxa and diversity with disease occurrence. Predictive models were constructed using machine learning with extreme gradient boosting. Models considered taxa abundances individually and in combination with other risk factors, including sex, age, body mass index and smoking status.

ResultsA total of 695 and 392 significant microbial associations at different taxonomic levels were found with incident asthma and COPD, respectively. Gradient boosting decision trees of baseline gut microbiome predicted incident asthma and COPD with mean area under the curves of 0.608 and 0.780, respectively. For both incident asthma and COPD, the baseline gut microbiome had C-indices of 0.623 for asthma and 0.817 for COPD, which were more predictive than other conventional risk factors. The integration of gut microbiome and conventional risk factors further improved prediction capacities. Subgroup analyses indicated gut microbiome was significantly associated with incident COPD in both current smokers and non-smokers, as well as in individuals who reported never smoking.

ConclusionsThe gut microbiome is a significant risk factor for incident asthma and incident COPD and is largely independent of conventional risk factors.

category: respiratory medicine


title: Dampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and associates with malignancy risk in long-term renal transplant recipients

abstract:
BackgroundMalignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients.

MethodsA cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks.

ResultsMonocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density.

ConclusionsDampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.

category: transplantation


title: Computer-assisted analysis of polysomnographic recordings improves inter-scorer associated agreement and scoring times

abstract:
Study ObjectivesTo investigate inter-scorer agreement and scoring time differences associated with visual and computer-assisted analysis of polysomnographic (PSG) recordings.

MethodsA group of 12 expert scorers reviewed 5 PSGs that were independently selected in the context of each of the following tasks: (i) sleep stating, (ii) detection of EEG arousals, (iii) analysis of the respiratory activity, and (iv) identification of leg movements. All scorers independently reviewed the same recordings, hence resulting in 20 scoring exercises from an equal amount of different subjects. The procedure was repeated, separately, using the classical visual manual approach and a computer-assisted (semi-automatic) procedure. Resulting inter-scorer agreement and scoring times were examined and compared among the two methods.

ResultsComputer-assisted sleep scoring showed a consistent and statistically relevant effect toward less time required for the completion of each of the PSG scoring tasks. Gain factors ranged from 1.26 (EEG arousals) to 2.41 (limb movements). Inter-scorer kappa agreement was also consistently increased with the use of supervised semi-automatic scoring. Specifically, agreement increased from K=0.76 to K=0.80 (sleep stages), K=0.72 to K=0.91 (limb movements), K=0.55 to K=0.66 (respiratory activity), and K=0.58 to K=0.65 (EEG arousals). Inter-scorer agreement on the examined set of diagnostic indices did also show a trend toward higher Interclass Correlation Coefficient scores when using the semi-automatic scoring approach.

ConclusionsComputer-assisted analysis can improve inter-scorer agreement and scoring times associated with the review of PSG studies resulting in higher efficiency and overall quality in the diagnosis sleep disorders.


title: Fat tails, fat earnings, fat mistakes: On the need to disclose distribution parameters of qEEG databases

abstract: Neurometry (a.k.a. quantitative EEG or qEEG) is a popular method to assess clinically relevant abnormalities in the electroencephalogram. Neurometry is based on norm values for the distribution of specific EEG parameters and believed to show good psychometric properties such as test-retest reliability. Many psychometric properties only hold under the Gaussian distribution and become problematic when distributions are fat-tailed. EEG signals are typically fat-tailed and do not show fast convergence to a Gaussian distribution. To circumvent this property of EEG, log-transformations have frequently, but not always been employed. In Monte Carlo simulations, we investigated the impact of fat-tails (i.e. deviations from Gaussian) on the cut-off criteria and changeability of what in neurometry is termed "abnormal EEG". Even slight deviations from the Gaussian distribution as measured by skewness and kurtosis lead to large inflation in the number of false positive qEEG findings. The more stringent the cutoff value adopted, the larger the inflation. For these reasons, we argue that distribution properties of qEEG databases should be disclosed in much more detail to avoid questionable research practices and promote diagnostic transparency. Moreover, "abnormal EEG" seems to recover spontaneously at rates not compatible with the alleged test-retest reliability of qEEG. Alternative methods should be employed to determine cut-off values for diagnostics purposes, since a large number of false positive results emerge even when slight deviations from the Gaussian distribution are present. We provide recommendations for the improvement of psychometric properties of existing qEEG databases.


title: Age-stratified normative cognitive scores in urban and rural Maharashtra -- a community-based study

abstract:
Background and objectivesIndian ethnic and educational diversities necessitate obtaining normative cognitive data in different populations. We aimed to evaluate cognitive scores using a Marathi translation of the Kolkata Cognitive Battery (KCB), and to study the association of KCB components with depression and socio-demographic variables.

MethodologyWe studied 2651 individuals aged [≥]40 years, without pre-existing neuropsychiatric conditions, from urban (Mumbai) and rural districts of Maharashtra. For each component of KCB, the lowest 10th percentile score was used to define cognitive impairment.

ResultsWe studied 1435 (54%) rural and 1216 (46%) urban residents equally divided by gender (1316 women, 1335 men), average age 54 years. KCB scores were significantly lower with female sex, older age, illiteracy and depression. The largest effect sizes attributable to these factors were in the domains of calculation (gender), visuo-constructional ability (VCA; rurality) and verbal fluency (VF; depression). Scores remained significantly lower in rural residents after controlling for age, sex and education, particularly for VCA, immediate recall and calculation.

ConclusionThis Marathi KCB having been validated on large urban as well as rural samples, may be used to study cognition in Marathi speaking populations with appropriate cut-offs tailored to the degree of urbanization of the population.


title: Normative cognitive scores in western India, stratified by age, rurality, cognitive domains, and psychiatric comorbidity.


title: Systematic Review and Meta-analysis of Mental Health Impact on BAME Populations with Preterm Birth

abstract:
BackgroundPreterm birth (PTB) is one of the main causes of neonatal deaths globally, with approximately 15 million infants are born preterm. Therefore, the mental health (MH) impact experienced by mothers experiencing a PTB is important, especially within the Black, Asian and Minority Ethnic (BAME) populations.

AimThe aims of the study were to determine the prevalence of MH conditions among BAME women with PTB as well as the MH assessments used to characterise the MH outcomes.

MethodsA systematic methodology was developed and published as a protocol in PROSPERO (CRD42020210863). Multiple databases were used to extract relevant data. I2 and Eggers tests were used to detect the heterogeneity and publication bias. A Trim and fill method was used to demonstrate the influence of publication bias and the credibility of conclusions.

ResultsThirty-nine studies met the eligibility criteria from a possible 3526. The prevalence rates of depression among PTB-BAME mothers were significantly higher than full-term mothers with a standard median deviation (SMD) of 1.5 and a 95% confidence interval (CI) 29-74%. The subgroup analysis indicated, depressive symptoms to be time sensitive. Women within the very PTB category demonstrated a significantly higher prevalence of depression than those categorised as non-very PTB. The prevalence rates of anxiety and stress among PTB-BAME mothers were significantly higher than full-term mothers (OR of 88% and 60% with a CI of 42%-149% and 24-106%, respectively).

ConclusionBAME women with PTB suffers with MH conditions. Many studies did not report on BAME population specific MH outcomes. Therefore, the impact of PTB is not accurately represented in this population, and thus could negatively influence the quality of maternity services.

Core TipThis study demonstrates the mental health impact due to preterm birth among the Black, Asian and Ethnic minority women. There is minimal research available at present around this subject matter, and potential disease sequalae.


title: Patient-Level Clinical Expertise Enhances Prostate Cancer Recurrence Predictions with Machine Learning

abstract: With rising access to electronic health record data, application of artificial intelligence to create clinical risk prediction models has grown. A key component in designing these models is feature generation. Methods used to generate features differ in the degree of clinical expertise they deploy (from minimal to population-level to patient-level), and subsequently the extent to which they can extract reliable signals and be automated. In this work, we develop a new process that defines how to systematically implement patient-level clinician feature generation (CFG), which leverages clinical expertise to define concepts relevant to the outcome variable, identify each concepts associated features, and finally extract most features on a per-patient level by manual chart review. We subsequently apply this method to identifying and extracting patient-level features predictive of cancer recurrence from progress notes for a cohort of prostate cancer patients. We evaluate the performance of the CFG process against an automated feature generation (AFG) process via natural language processing techniques. The machine learning outcome prediction model leveraging the CFG process has a mean AUC-ROC of 0.80, in comparison to the AFG model that has a mean AUC-ROC of 0.74. This relationship remains qualitatively unchanged throughout extensive sensitivity analyses. Our analyses illustrate the value of in-depth specialist reasoning in generating features from progress notes and provide a proof of concept that there is a need for new research on efficient integration of in-depth clinical expertise into feature generation for clinical risk prediction.

category: oncology


title: SCENTinel 1.1 rapidly screens for COVID-19 related olfactory disorders

abstract: The COVID-19 pandemic has increased the prevalence of people suffering from olfactory disorders. In the absence of quick, population-wide olfactory tests, we developed SCENTinel, a rapid, inexpensive smell test to assess odor detection, intensity, and identification ability, which can discriminate anosmia (e.g., total smell loss) from normosmia (e.g., normal sense of smell) using a single odor. A new version, SCENTinel 1.1, extends the original test with one of four possible odors and a hedonic subtest ("how pleasant is the odor"). The purpose of this study was to determine if SCENTinel 1.1 can discriminate other types of olfactory disorders common to COVID-19, such as hyposmia (e.g., reduced sense of smell), parosmia (e.g., distorted odor perception), and phantosmia (e.g., odor sensation without an odor source). Participants (N=381) were divided into three groups based on their self-reported olfactory function: quantitative smell disorder (anosmia or hyposmia, N=135), qualitative smell disorder (parosmia and/or phantosmia; n=86), and normosmia (N=66). SCENTinel 1.1 classifies anosmia and normosmia groups with high sensitivity (AUC=0.94), similar to SCENTinel 1.0 (AUC=0.95). SCENTinel 1.1 also accurately discriminates quantitative from qualitative (AUC=0.76), and normosmia (AUC=0.84), and normosmia from qualitative (AUC=0.73) groups. We also considered a subset of participants who only reported one type of olfactory disorder. SCENTinel 1.1 discriminates hyposmia from parosmia (AUC=0.89), and anosmia (AUC=0.78); as well as parosmia from anosmia (AUC=0.82). Participants with parosmia had a significantly lower hedonic score than those without parosmia, indicating odor distortions are unpleasant. SCENTinel 1.1 is a rapid smell test that can discriminate quantitative (anosmia, hyposmia) and qualitative (parosmia, phantosmia) olfactory disorders, and it is among the only direct tests to rapidly screen for parosmia.

category: otolaryngology


title: Persistence of rare Salmonella Typhi genotypes susceptible to first-line antibiotics in the remote islands of Samoa

abstract:
For decades, the remote island nation of Samoa (pop. ~200,000) has faced endemic typhoid fever despite improvements in water quality, sanitation, and economic development. We recently described the epidemiology of typhoid fever in Samoa from 2008-2019 by person, place, and time; however, the local Salmonella enterica serovar Typhi (S. Typhi) population structure, evolutionary origins, and genomic features remained unknown. Herein, we report whole genome sequence analyses of 306 S. Typhi isolates from Samoa collected between 1983 and 2020. Phylogenetics revealed a dominant population of rare genotypes 3.5.4 and 3.5.3, together comprising 292/306 (95.4%) of Samoan versus 2/4934 (0.04%) global S. Typhi isolates. Three distinct 3.5.4 genomic sub-lineages were identified and their defining polymorphisms were determined. These dominant Samoan genotypes, which likely emerged in the 1970s, share ancestry with other clade 3.5 isolates from South America, Southeast Asia, and Oceania. Additionally, a 106-kb pHCM2 phenotypically-cryptic plasmid, detected earliest in a 1992 Samoan S. Typhi isolate, was identified in 106/306 (34.6%) of Samoan isolates; this is more than double the observed proportion of pHCM2-containing isolates in the global collection. In stark contrast with global S. Typhi trends, resistance-conferring polymorphisms were detected in only 15/306 (4.9%) of Samoan S. Typhi, indicating overwhelming susceptibility to antibiotics that are no longer effective in most of South and Southeast Asia. This country-level genomic framework can help local health authorities in their ongoing typhoid surveillance and control efforts, as well as to fill a critical knowledge gap in S. Typhi genomic data from Oceania.

IMPORTANCEIn this study we used whole genome sequencing and comparative genomics analyses to characterize the population structure, evolutionary origins, and genomic features of S. Typhi associated with decades of endemic typhoid fever in Samoa. Our analyses of Samoan isolates from 1983 to 2020 identified a rare S. Typhi population in Samoa that likely emerged around the early 1970s and evolved into sub-lineages that presently dominate. The dominance and persistence of these endemic genotypes in Samoa are not readily explained by any apparent genomic competitive advantage or widespread acquisition of antimicrobial resistance. These data establish the necessary framework for future genomic surveillance of S. Typhi in Samoa for public health benefit.


title: CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online

abstract:
PurposeLarge copy number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts.

MethodsWe developed a web-application combining >250,000 patient and population CNVs together with a large set of biomedical annotations and provide tools for CNV classification based on ACMG/ClinGen guidelines and gene-set enrichment analyses.

ResultsHere, we introduce the CNV-ClinViewer (https://cnv-ClinViewer.broadinstitute.org), an open-source web-application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface.

ConclusionOverall, this resource facilitates semi-automated clinical CNV interpretation and genomic loci exploration and, in combination with clinical judgment, enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators patient care and for basic scientists translational genomic research.


title: Genetically predicted on-statin LDL response is associated with higher intracerebral hemorrhage risk

abstract: Statins lower low-density lipoprotein (LDL) cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced LDL reduction increases risk of intracerebral hemorrhage (ICH) has been debated for almost two decades. Here, we explored whether genetically predicted on-statin LDL response is associated with ICH risk using Mendelian Randomization. Utilizing genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms (SNP) of on-statin LDL response and tested it in the population-based UK-Biobank (UKB). We extracted statin drug and dose information from primary care data on a subset of 225,195 UKB participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal LDL measurements with generalized mixed models and explored associations with incident ICH using Cox regression analysis. Statins were prescribed at least once to 75,973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean LDL decreased by 3.45 mg/dl per year (95% CI: [-3.47, -3.42]) over follow-up. A higher genetic score of statin response (one SD increment) was associated with significant additional reductions in LDL levels (-0.05 mg/dl per year, [-0.07, -0.02]), showed concordant lipidomic effects on other lipid traits as statin use, and was associated with a lower risk for incident myocardial infarction (HR per SD increment 0.98 95% CI [0.96, 0.99]) and peripheral artery disease (HR per SD increment 0.92 95% CI [0.86, 0.98]). Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher ICH risk in a model adjusting for statin dose (HR per SD increment 1.15, 95% CI [1.04, 1.27]). On the contrary, there was no association with ICH risk among statin non-users (p=0.89). These results provide further support for the hypothesis that statin-induced LDL reduction may be causally associated with ICH risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacologic LDL-lowering in the pathogenesis of ICH.


title: SynTL: A synthetic-data-based transfer learning approach for multi-center risk prediction

abstract:
ObjectivesWe propose a synthetic-data-based transfer learning approach (SynTL) to incorporate multi-center healthcare data for improving the risk prediction of a target population, accounting for challenges including heterogeneity, data sharing, and privacy constraints.

MethodsSynTL combines locally trained risk prediction models from each source population with the target population to adjust for the data heterogeneity through a flexible distance-based transfer learning approach. Heterogeneity-adjusted synthetic data are then generated for source populations where individual-level data are not shareable. The synthetic data are then combined with the target and source data for joint training of the target model. We evaluate SynTL via extensive simulation studies and an application to multi-center data from the electronic Medical Records and Genomics (eMERGE) Network to predict extreme obesity.

ResultsSimulation studies show that SynTL outperforms methods without adjusting for the data heterogeneity and methods that are trained in a single population over a wide spectrum of settings. SynTL has low communication costs where each participating site only needs to share parameter estimates to the target, requiring only one round of communication. SynTL protects against negative transfer when some source populations are highly different from the target. Using eMERGE data, SynTL achieves an area under the receiver operating characteristic curve (AUC) around 0.79, which outperforms other benchmark methods (0.50 - 0.67).

ConclusionSynTL improves the risk prediction performance of the target population, and is robust to the level of heterogeneity between the target and source populations. It protects patient-level information and is highly communication efficient.


title: Medication Against Conflict

abstract:
The consequences of successful public health interventions for social violence and conflict are largely unknown. This paper closes this gap by evaluating the effect of a major health intervention - the successful expansion of anti-retroviral therapy (ART) to combat the HIV/AIDS pandemic - in Africa. To identify the effect, we combine exogenous variation in the scope for treatment and global variation in drug prices. We find that the ART expansion significantly reduced the number of violent events in African countries and sub-national regions. The effect pertains to social violence and unrest, not civil war. The evidence also shows that the effect is not explained by general improvements in economic prosperity, but related to health improvements, greater approval of government policy, and increased trust in political institutions. Results of a counterfactual simulation reveal the largest potential gains in countries with intermediate HIV prevalence where disease control has been given relatively low priority.

JEL-classification: C36, D47, I15, O10

category: hiv aids


title: The efficacy, safety and immunogenicity Nanocovax: results of a randomized, double-blind, placebo-controlled Phase 3 trial.

abstract:
BackgroundNanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. In a Phase 1 and 2 studies, (NCT04683484) the vaccine was found to be safe and induce a robust immune response in healthy adult participants.

MethodsWe conducted a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, immunogenicity, and protective efficacy of the Nanocovax vaccine against Covid-19 in approximately 13,007 volunteers aged 18 years and over. The immunogenicity was assessed based on Anti-S IgG antibody response, surrogate virus neutralization, wild-type SARS-CoV-2 neutralization and the types of helper T-cell response by intracellular staining (ICS) for interferon gamma (IFNg) and interleukin-4 (IL-4). The vaccine efficacy (VE) was calculated basing on serologically confirmed cases of Covid-19.

FindingsUp to day 180, incidences of solicited and unsolicited adverse events (AE) were similar between vaccine and placebo groups. 100 serious adverse events (SAE) were observed in both vaccine and placebo groups (out of total 13007 participants). 96 out of these 100 SAEs were determined to be unrelated to the investigational products. 4 SAEs were possibly related, as determined by the Data and Safety Monitoring Board (DSMB) and investigators. Reactogenicity was absent or mild in the majority of participants and of short duration. These findings highlight the excellent safety profile of Nanocovax.

Regarding immunogenicity, Nanocovax induced robust IgG and neutralizing antibody responses. Importantly, Anti S-IgG levels and neutralizing antibody titers on day 42 were higher than those of natural infected cases. Nanocovax was found to induce Th2 polarization rather than Th1.

Post-hoc analysis showed that the VE against symptomatic disease was 51.5% (95% confidence interval [CI] was [34.4%-64.1%]. VE against severe illness and death were 93.3% [62.2-98.1]. Notably, the dominant strain during the period of this study was Delta variant.

InterpretationNanocovax 25 microgram (mcg) was found to be safe with the efficacy against symptomatic infection of Delta variant of 51.5%.

FundingResearch was funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04922788.

category: infectious diseases


title: Association of COVID-19 with risks of hospitalization and mortality from other disorders post-infection: A study of the UK Biobank

abstract:
BackgroundMore than 0.4 billion cases of COVID-19 have been reported worldwide. The sequalae of COVID-19 remains unclear, especially whether it may be associated with increased hospitalization and mortality from other diseases.

MethodsWe leveraged a large prospective cohort of the UK biobank (UKBB) (N=412,096; current age 50-87) to identify associations of COVID-19 with hospitalization and mortality due to different diseases post-infection. We conducted a comprehensive survey on disorders from all systems (up to 135 disease categories). Multivariable Cox and Poisson regression was conducted controlling for main confounders. For sensitivity analysis, we also conducted separate analysis for new-onset and recurrent cases, and other sensitivity analysis such as the prior event rate adjustment (PERR) approach to minimize effects of unmeasured confounders.

ResultsCompared to individuals with no known history of COVID-19, those with severe COVID-19 (requiring hospitalization) exhibited higher hazards of hospitalization and/or mortality due to multiple disorders (median follow-up=608 days), including disorders of respiratory, cardiovascular, neurological, gastrointestinal, genitourinary and musculoskeletal systems. Increased hazards of hospitalizations and/or mortality were also observed for injuries due to fractures, various infections and other non-specific symptoms. These results remained largely consistent after sensitivity analyses. Severe COVID-19 was also associated with increased all-cause mortality (HR=14.700, 95% CI: 13.835-15.619).

Mild (non-hospitalized) COVID-19 was associated with modestly increased risk of all-cause mortality (HR=1.237, 95% CI 1.037-1.476) and mortality from neurocognitive disorders (HR=9.100, 95% CI: 5.590-14.816), as well as hospital admission from a few disorders such as aspiration pneumonitis, musculoskeletal pain and other general signs/symptoms.

ConclusionsIn conclusion, this study revealed increased risk of hospitalization and mortality from a wide variety of pulmonary and extra-pulmonary diseases after COVID-19, especially for severe infections. Mild disease was also associated with increased all-cause mortality. Further studies are required to replicate our findings.


title: Waning effectiveness of BNT162b2 and ChAdOx1 COVID-19 vaccines over six months since second dose: a cohort study using linked electronic health records

abstract:
BackgroundThe rate at which COVID-19 vaccine effectiveness wanes over time is crucial for vaccination policies, but is incompletely understood with conflicting results from different studies.

MethodsThis cohort study, using the OpenSAFELY-TPP database and approved by NHS England, included individuals without prior SARS-CoV-2 infection assigned to vaccines priority groups 2-12 defined by the UK Joint Committee on Vaccination and Immunisation. We compared individuals who had received two doses of BNT162b2 or ChAdOx1 with unvaccinated individuals during six 4-week comparison periods, separately for subgroups aged 65+ years; 16-64 years and clinically vulnerable; 40-64 years and 18-39 years. We used Cox regression, stratified by first dose eligibility and geographical region and controlled for calendar time, to estimate adjusted hazard ratios (aHRs) comparing vaccinated with unvaccinated individuals, and quantified waning vaccine effectiveness as ratios of aHRs per-4-week period. The outcomes were COVID-19 hospitalisation, COVID-19 death, positive SARS-CoV-2 test, and non-COVID-19 death.

FindingsThe BNT162b2, ChAdOx1 and unvaccinated groups comprised 1,773,970, 2,961,011 and 2,433,988 individuals, respectively. Waning of vaccine effectiveness was similar across outcomes and vaccine brands: e.g. in the 65+ years subgroup ratios of aHRs versus unvaccinated for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test ranged from 1.23 (95% CI 1.15-1.32) to 1.27 (1.20-1.34) for BNT162b2 and 1.16 (0.98-1.37) to 1.20 (1.14-1.27) for ChAdOx1. Despite waning, rates of COVID-19 hospitalisation and COVID-19 death were substantially lower among vaccinated individuals compared to unvaccinated individuals up to 26 weeks after second dose, with estimated aHRs <0.20 (>80% vaccine effectiveness) for BNT162b2, and <0.26 (>74%) for ChAdOx1. By weeks 23-26, rates of SARS-CoV-2 infection in fully vaccinated individuals were similar to or higher than those in unvaccinated individuals: aHRs ranged from 0.85 (0.78-0.92) to 1.53 (1.07-2.18) for BNT162b2, and 1.21 (1.13-1.30) to 1.99 (1.94-2.05) for ChAdOx1.

InterpretationThe rate at which estimated vaccine effectiveness waned was strikingly consistent for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test, and similar across subgroups defined by age and clinical vulnerability. If sustained to outcomes of infection with the Omicron variant and to booster vaccination, these findings will facilitate scheduling of booster vaccination doses.


title: Ventricular and Atrial Pressure-Volume Loops: Analysis of the Effects Induced by Right Centrifugal Pump Assistance

abstract:
Background and ObjectiveThe main indications for right ventricular assist device (RVAD) support are right heart failure after implantation of a left ventricular assist device (LVAD) or early graft failure following heart transplantation. About 30-40% of patients will need RVAD support after LVAD implantation. Pulmonary hypertension is also an indication for right heart assistance. Several types of RVAD generating pulsatile or continuous flow are available on the market. These assist devices can be connected to the cardiovascular system in different ways. We sought to analyse the effects induced by different RVAD connections when right ventricular elastance is modified using a numerical simulator. The analysis was based on the behaviour of both left and right ventricular and atrial loops in the pressure-volume plane.

MethodsNew modules of the cardiovascular network and a right ventricular centrifugal pump were implemented in CARDIOSIM(C) software simulator platform. The numerical pump model generated continuous flow when connected in series or parallel to the right ventricle. When the RVAD was connected in series (parallel), the pump removed blood from the right ventricle (atrium) and ejected it into the pulmonary artery. In our study, we analysed the effects induced by RVAD support on left/right ventricular/atrial loops when right ventricular elastance slope (EesRIGHT) changed from 0.3 to 0.8 mmHg/ml with the pump connected either in series or parallel. The effect of low and high rotational pump speed was also addressed.

ResultsPercentage changes up to 60% were observed for left ventricular pressure-volume area and external work during in-parallel RVAD support at 4000 rpm with EesRIGHT = 0.3mmHg/ml. The same pump setting and connection type led to percentage variation up to 20% for left ventricular ESV and up to 25% for left ventricular EDV with EesRIGHT = 0.3mmHg/ml. Again the same pump setting and connection generated up to 50% change in left atrial pressure-volume loop area (PVLAL-A) and only 3% change in right atrial pressure-volume loop area (PVLAR-A) when EesRIGHT = 0.3mmHg/ml. Percentage variation was lower when EesRIGHT was increased up to 0.8 mmHg/ml.

ConclusionEarly recognition of right ventricular failure followed by aggressive treatment is desirable to achieve a more favourable outcome. RVAD support remains an option for advanced right ventricular failure although onset of major adverse events may preclude its use.

category: cardiovascular medicine


title: The effect of access to safe Water, Sanitation, and Hygiene (WASH) facilities on Child Growth Failure among children 6/59 months in Ecuador applying a random intercept multilevel model using cross-sectional ENSANUT 2018 data.

abstract:
1.BackgroundChild Growth Failure - measured as stunting, wasting and underweight - is still an important public health issue affecting 23.1% of children. Typically, literature focused on unproper dietary habits, but living in an unhealthy environment unable to prevent pathogens is another fundamental cause.

ObjectiveTo estimate the association between access to safe water, sanitation, and hygiene (WASH) facilities and risk for Child Growth Failure in under-5 children in Ecuador Design: Cross-sectional multilevel study using the Ecuadorian National Survey on Health and Nutrition (ENSANUT) 2018.

Participants17,688 children 6/59 months residing in 15,382 households.

Main outcome measuresAssociation between the access to safely managed WASH factors and the probability of suffering from: a) stunting, b) underweight and c) wasting; controlling for childs sex, childs age, antenatal care visits, pre-term delivery, assumption of micronutrient during the pregnancy, mothers age, mothers education, mothers height, mothers ethnic group, area and region of residence, the number of people living at home and the family per capita income. The final model is a two-levels random intercept logistic regression focused on the risk of suffering from stunting and underweight. Multilevel logistic models were applied for both the unadjusted and the adjusted estimates. The average marginal effects with the 95% confidence interval and p-value are estimated.

ResultsA safely managed sanitation system showed the strongest protective effect on underweight (-38.1%, 95% CI -16.9% and -59.4%) and stunting (-14.9%, 95% CI -4.7% and -25.1%). Important protective effects against stunting are observed also thanks to safely managed drinking water (-10.9%, 95% CI -0.1% and -21.6%) and applying proper hygiene habits (-9.5%, 95% CI -0.1% and -19.0%). A potential protective effect on underweight was observed also for proper hygiene habits although a wide confidence interval. No effect was observed between safely managed drinking water and the risk of being underweight. Women are characterized by an important lower risk for both stunting and underweight. Stunting is lower after the 24th month of life while no change is observed for underweight. Pre-term deliveries showed a strong growth of the risk for both stunting and underweight, while antenatal care visits significantly reduced the risk of both stunting and underweight as a high mothers education. Genetical (mothers height) and cultural (mothers ethnic group) aspects play an important role with the highest risk for stunting among Indigenous (+32.5%, 95% CI 19.6%-45.4%) and the lowest among Afro-Ecuadorian children (-20.7%, 95% CI 2.0% and -43.4%). Each additional centimetre of the mothers height from the average value (154.2 cm) reduces the risk for the child of suffering from both stunting (-6.1%, 95% CI -5.3% and -6.7%) and underweight (-5.1%, 95% CI -3.7% and -6.5%).

ConclusionsWASH factors play a fundamental role to prevent undernutrition, especially chronic undernutrition (stunting). The study found potential biases due to the use of self-reported cross-sectional data. No data on dietary habits were available for this study which is a potential lack to be considered for the future.

category: epidemiology


title: Vaccine Equity in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis

abstract:
BackgroundEvidence to date has shown that inequality in health, and vaccine coverage in particular, can have ramifications to wider society. However, whilst individual studies have sought to characterise these heterogeneities in immunisation coverage at national level, few have taken a broad and quantitative view of the contributing factors to heterogeneity in vaccine coverage and impact. This systematic review aims to highlight these geographic, demographic, and sociodemographic characteristics through a qualitative and quantitative approach, vital to prioritise and optimise vaccination policies.

MethodsA systematic review of two databases (PubMed and Web of Science) was undertaken using Medical Subject Headings (MeSH) and keywords to identify studies examining factors on vaccine inequality and heterogeneity in vaccine coverage. Inclusion criteria were applied independently by two researchers. Studies including data on key characteristics of interest were further analysed through a meta-analysis to produce a pooled estimate of the risk ratio using a random effects model for that characteristic.

ResultsOne hundred and eight studies were included in this review. We found that inequalities in wealth, education, and geographic access can affect vaccine impact and vaccine dropout. We estimated those living in rural areas were not significantly different in terms of full vaccination status compared to urban areas but noted considerable heterogeneity between countries. We found that females were 3% (95%CI[1%, 5%]) less likely to be fully vaccinated than males. Additionally, we estimated that children whose mothers had no formal education were 28% (95%CI[18%,47%]) less likely to be fully vaccinated than those whose mother had primary level, or above, education. Finally, we found that individuals in the poorest wealth quintile were 27% (95%CI [16%,37%]) less likely to be fully vaccinated than those in the richest.

ConclusionsWe found a nuanced picture of inequality in vaccine coverage and access with wealth disparity dominating, and likely driving, other disparities. This review highlights the complex landscape of inequity and further need to design vaccination strategies targeting missed subgroups to improve and recover vaccination coverage following the COVID-19 pandemic.

RegistrationProspero CRD42021261927


title: Elevated T-cell exhaustion and urinary tumor DNA levels are associated with BCG failure in patients with non-muscle invasive bladder cancer

abstract:
BackgroundThe functional status of immune cells within the tumor microenvironment and tumor characteristics may explain Bacillus Calmette-Guerin (BCG)-failure in high-risk non-muscle invasive bladder cancer (NMIBC).

ObjectiveTo characterize molecular correlates of BCG-failure using a multiomics approach.

Design, Setting, and ParticipantsBCG-treated NMIBC patients (n=156) were included. Metachronous tumors were analyzed using RNA-sequencing (n=170) and whole exome sequencing (n=198). Urine samples were analyzed for immune-oncology related proteins (n=190), and tumor-derived DNA (tdDNA; n=192).

Outcome Measurement and Statistical AnalysisPrimary endpoint was BCG-failure. Cox regression, Wilcoxon Rank Sum test, t-test or Fishers exact test were used.

Results and LimitationsBCG caused activation of the immune system regardless of clinical response; however, immune-inhibitory proteins were observed in the urine of BCG-unresponsive patients post-treatment (CD70, PD1, CD5). BCG-failure was associated with post-BCG T-cell exhaustion (p=0.0021). Pre-BCG tumors from patients with post-BCG T-cell exhaustion were characterized by high expression of cell division and immune-related genes. A high post-BCG exhaustion prediction score in pre-BCG tumors was associated with worse post-BCG high-grade recurrence free survival (HGRFS), reflecting BCG-failure (p=0.0084). Pre-BCG tumors of class 2a and 2b were likewise associated with worse post-BCG HGRFS(p=0.0023). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p=0.023) and mutations in MUC4 (p=0.0007). Finally, absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p=0.028). The retrospective design, lack of maintenance BCG, and partial overlap in analyses are limitations to the study.

ConclusionsBCG failure may be caused by T-cell exhaustion. Tumor subtype and Pre-BCG tumor characteristics may identify patients at high risk of BCG-failure prior to treatment. Urinary measurements have the potential to be used as a real-time assessment of treatment response.

Patient SummaryA dysfunctional immune response to BCG therapy may explain lack of response to the treatment.

category: urology