Methylome-wide association study of early life stressors and adult mental health.

The environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data were assayed at 713 522 CpG sites from 9537 participants of the Generation Scotland: Scottish Family Health Study, a family-based cohort with extensive genetic, medical, family history and lifestyle information. Methylome-wide association studies of eight early life environment phenotypes and two adult mental health phenotypes (major depressive disorder and brief resilience scale) were conducted using DNA methylation data collected from adult whole blood samples. Two genes involved with different developmental pathways (PRICKLE2, Prickle Planar Cell Polarity Protein 2 and ABI1, Abl-Interactor-1) were annotated to CpG sites associated with preterm birth (P < 1.27 × 10-9). A further two genes important to the development of sensory pathways (SOBP, Sine Oculis Binding Protein Homolog and RPGRIP1, Retinitis Pigmentosa GTPase Regulator Interacting Protein) were annotated to sites associated with low birth weight (P < 4.35 × 10-8). The examination of methylation profile scores and genes and gene-sets annotated from associated CpGs sites found no evidence of overlap between the early life environment and mental health conditions. Birth date was associated with a significant difference in estimated lymphocyte and neutrophil counts. Previous studies have shown that early life environments influence the risk of developing mental health disorders later in life; however, this study found no evidence that this is mediated by stable changes to the methylome detectable in peripheral blood.

Medicare-mandated shared decision making for left atrial appendage closure in clinical practice.

INTRODUCTION: The Centers for Medicare & Medicaid Services (CMS) required a shared decision-making (SDM) interaction, with an "independent" physician, before left atrial appendage closure (LAAC). The purpose of this study is to better understand how this requirement is implemented in clinical practice. METHODS: We surveyed LAAC-performing centers. The characteristics of respondent and nonrespondent hospitals were compared using the CMS Provider of Services File for 2017. RESULTS: We received 86 responses out of 269 surveys mailed (32%). Respondent and nonrespondent hospital affiliations were similar: mean hospital size 525 beds, 15% for-profit, and 34% teaching hospitals. Thirty-four respondents (39.5%) stated that the implanting physician conducts some or all of the SDM interactions. The percentage of patients who decide not to undergo LAAC after the SDM interaction was estimated at 8.1%. Out of 72 responses to an open-ended question about the benefit of the SDM interaction, 44 (61%) described the requirement in negative terms, of which most felt the requirement was burdensome for patients and providers. Only 28 respondents (39%) described the requirement in positive or mixed terms. CONCLUSION: In violation of the letter of the CMS policy for LAAC, implanting physicians perform the SDM interaction at nearly 40% of responding hospitals. Most respondents felt the SDM requirement was burdensome for patients. More detailed guidance from CMS on how to comply with the policy may result in better alignment between the intent of the policy and how it is implemented.

Prospectively accelerated dynamic speech magnetic resonance imaging at 3 T using a self-navigated spiral-based manifold regularized scheme.

This work develops and evaluates a self-navigated variable density spiral (VDS)-based manifold regularization scheme to prospectively improve dynamic speech magnetic resonance imaging (MRI) at 3 T. Short readout duration spirals (1.3-ms long) were used to minimize sensitivity to off-resonance. A custom 16-channel speech coil was used for improved parallel imaging of vocal tract structures. The manifold model leveraged similarities between frames sharing similar vocal tract postures without explicit motion binning. The self-navigating capability of VDS was leveraged to learn the Laplacian structure of the manifold. Reconstruction was posed as a sensitivity-encoding-based nonlocal soft-weighted temporal regularization scheme. Our approach was compared with view-sharing, low-rank, temporal finite difference, extra dimension-based sparsity reconstruction constraints. Undersampling experiments were conducted on five volunteers performing repetitive and arbitrary speaking tasks at different speaking rates. Quantitative evaluation in terms of mean square error over moving edges was performed in a retrospective undersampling experiment on one volunteer. For prospective undersampling, blinded image quality evaluation in the categories of alias artifacts, spatial blurring, and temporal blurring was performed by three experts in voice research. Region of interest analysis at articulator boundaries was performed in both experiments to assess articulatory motion. Improved performance with manifold reconstruction constraints was observed over existing constraints. With prospective undersampling, a spatial resolution of 2.4 × 2.4 mm2/pixel and a temporal resolution of 17.4 ms/frame for single-slice imaging, and 52.2 ms/frame for concurrent three-slice imaging, were achieved. We demonstrated implicit motion binning by analyzing the mechanics of the Laplacian matrix. Manifold regularization demonstrated superior image quality scores in reducing spatial and temporal blurring compared with all other reconstruction constraints. While it exhibited faint (nonsignificant) alias artifacts that were similar to temporal finite difference, it provided statistically significant improvements compared with the other constraints. In conclusion, the self-navigated manifold regularized scheme enabled robust high spatiotemporal resolution dynamic speech MRI at 3 T.

A sex-specific genome-wide association study of depression phenotypes in UK Biobank.

There are marked sex differences in the prevalence, phenotypic presentation and treatment response for major depression. While genome-wide association studies (GWAS) adjust for sex differences, to date, no studies seek to identify sex-specific markers and pathways. In this study, we performed a sex-stratified genome-wide association analysis for broad depression with the UK Biobank total participants (N = 274,141), including only non-related participants, as well as with males (N = 127,867) and females (N = 146,274) separately. Bioinformatics analyses were performed to characterize common and sex-specific markers and associated processes/pathways. We identified 11 loci passing genome-level significance (P < 5 × 10-8) in females and one in males. In both males and females, genetic correlations were significant between the broad depression GWA and other psychopathologies; however, correlations with educational attainment and metabolic features including body fat, waist circumference, waist-to-hip ratio and triglycerides were significant only in females. Gene-based analysis showed 147 genes significantly associated with broad depression in the total sample, 64 in the females and 53 in the males. Gene-based analysis revealed "Regulation of Gene Expression" as a common biological process, but suggested sex-specific molecular mechanisms. Finally, sex-specific polygenic risk scores (PRSs) for broad depression outperformed total and the opposite sex PRSs in the prediction of broad major depressive disorder. These findings provide evidence for sex-dependent genetic pathways for clinical depression as well as for health conditions comorbid with depression.

Adipocyte derived exosomes promote cell invasion and challenge paclitaxel efficacy in ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. METHODS: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. RESULTS: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells. CONCLUSIONS: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.

Clarifying the causes of consistent and inconsistent findings in genetics.

As research in genetics has advanced, some findings have been unexpected or shown to be inconsistent between studies or datasets. The reasons these inconsistencies arise are complex. Results from genetic studies can be affected by various factors including statistical power, linkage disequilibrium, quality control, confounding and selection bias, as well as real differences from interactions and effect modifiers, which may be informative about the mechanisms of traits and disease. Statistical artefacts can manifest as differences between results but they can also conceal underlying differences, which implies that their critical examination is important for understanding the underpinnings of traits. In this review, we examine these factors and outline how they can be identified and conceptualised with structural causal models. We explain the consequences they have on genetic estimates, such as genetic associations, polygenic scores, family- and genome-wide heritability, and describe methods to address them to aid in the estimation of true effects of genetic variation. Clarifying these factors can help researchers anticipate when results are likely to diverge and aid researchers' understanding of causal relationships between genes and complex traits.

Exploring polygenic-environment and residual-environment interactions for depressive symptoms within the UK Biobank.

Substantial advances have been made in identifying genetic contributions to depression, but little is known about how the effect of genes can be modulated by the environment, creating a gene-environment interaction. Using multivariate reaction norm models (MRNMs) within the UK Biobank (N = 61294-91644), we investigate whether the polygenic and residual variance components of depressive symptoms are modulated by 17 a priori selected covariate traits-12 environmental variables and 5 biomarkers. MRNMs, a mixed-effects modelling approach, provide unbiased polygenic-covariate interaction estimates for a quantitative trait by controlling for outcome-covariate correlations and residual-covariate interactions. A continuous depressive symptom variable was the outcome in 17 MRNMs-one for each covariate trait. Each MRNM had a fixed-effects model (fixed effects included the covariate trait, demographic variables, and principal components) and a random effects model (where polygenic-covariate and residual-covariate interactions are modelled). Of the 17 selected covariates, 11 significantly modulate deviations in depressive symptoms through the modelled interactions, but no single interaction explains a large proportion of phenotypic variation. Results are dominated by residual-covariate interactions, suggesting that covariate traits (including neuroticism, childhood trauma, and BMI) typically interact with unmodelled variables, rather than a genome-wide polygenic component, to influence depressive symptoms. Only average sleep duration has a polygenic-covariate interaction explaining a demonstrably nonzero proportion of the variability in depressive symptoms. This effect is small, accounting for only 1.22% (95% confidence interval: [0.54, 1.89]) of variation. The presence of an interaction highlights a specific focus for intervention, but the negative results here indicate a limited contribution from polygenic-environment interactions.

The cost burden of metastatic prostate cancer in the US populations covered by employer-sponsored health insurance.

BACKGROUND: Recent advancements in the clinical management of metastatic prostate cancer include several costly therapies and diagnostic tests. The objective of this study was to provide updated information on the cost to payers attributable to metastatic prostate cancer among men aged 18 to 64 years with employer-sponsored health plans and men aged 18 years or older covered by employer-sponsored Medicare supplement insurance. METHODS: By using Merative MarketScan commercial and Medicare supplemental data for 2009-2019, the authors calculated differences in spending between men with metastatic prostate cancer and their matched, prostate cancer-free controls, adjusting for age, enrollment length, comorbidities, and inflation to 2019 US dollars. RESULTS: The authors compared 9011 patients who had metastatic prostate cancer and were covered by commercial insurance plans with a group of 44,934 matched controls and also compared 17,899 patients who had metastatic prostate cancer and were covered by employer-sponsored Medicare supplement plans with a group of 87,884 matched controls. The mean age of patients with metastatic prostate cancer was 58.5 years in the commercial samples and 77.8 years in the Medicare supplement samples. Annual spending attributable to metastatic prostate cancer was $55,949 per person-year (95% confidence interval [CI], $54,074-$57,825 per person-year) in the commercial population and $43,682 per person-year (95% CI, $42,022-$45,342 per person-year) in the population covered by Medicare supplement plans, both in 2019 US dollars. CONCLUSIONS: The cost burden attributable to metastatic prostate cancer exceeds $55,000 per person-year among men with employer-sponsored health insurance and $43,000 among those covered by employer-sponsored Medicare supplement plans. These estimates can improve the precision of value assessments of clinical and policy approaches to the prevention, screening, and treatment of prostate cancer in the United States.

Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system.

Antidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of DNA methylation may therefore reveal the biological processes underpinning the efficacy and side effects of antidepressants. We performed a methylome-wide association study (MWAS) of self-reported antidepressant use accounting for lifestyle factors and MDD in Generation Scotland (GS:SFHS, N = 6428, EPIC array) and the Netherlands Twin Register (NTR, N = 2449, 450 K array) and ran a meta-analysis of antidepressant use across these two cohorts. We found ten CpG sites significantly associated with self-reported antidepressant use in GS:SFHS, with the top CpG located within a gene previously associated with mental health disorders, ATP6V1B2 (ß = -0.055, pcorrected = 0.005). Other top loci were annotated to genes including CASP10, TMBIM1, MAPKAPK3, and HEBP2, which have previously been implicated in the innate immune response. Next, using penalised regression, we trained a methylation-based score of self-reported antidepressant use in a subset of 3799 GS:SFHS individuals that predicted antidepressant use in a second subset of GS:SFHS (N = 3360, ß = 0.377, p = 3.12 × 10-11, R2 = 2.12%). In an MWAS analysis of prescribed selective serotonin reuptake inhibitors, we showed convergent findings with those based on self-report. In NTR, we did not find any CpGs significantly associated with antidepressant use. The meta-analysis identified the two CpGs of the ten above that were common to the two arrays used as being significantly associated with antidepressant use, although the effect was in the opposite direction for one of them. Antidepressants were associated with epigenetic alterations in loci previously associated with mental health disorders and the innate immune system. These changes predicted self-reported antidepressant use in a subset of GS:SFHS and identified processes that may be relevant to our mechanistic understanding of clinically relevant antidepressant drug actions and side effects.

Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine/glutamate transporter SLC7A11 as a top target.

Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value < 6.8 × 10-8) with the five leading probes located in SLC7A11 (p = 7.75 × 10-108), JDP2 (p = 1.44 × 10-56), GAS5 (p = 2.71 × 10-47), TRA2B (p = 3.54 × 10-42), and SLC43A1 (p = 1.18 × 10-40). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer's disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p = 5.37 × 10-09). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p = 6.32 × 10-38 and p = 5.41 × 10-14). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N = 615) and showed strong hypomethylation in AUD (p < 10-17). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p < 10-4), increased liver function enzymes (GGT (p = 1.03 × 10-21), ALT (p = 1.29 × 10-6), and AST (p = 1.97 × 10-8)) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11 expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention.

Adjustable prosthetic sockets: a systematic review of industrial and research design characteristics and their justifications.

BACKGROUND: The prosthetic socket is a key component that influences prosthesis satisfaction, with a poorly fitting prosthetic socket linked to prosthesis abandonment and reduced community participation. This paper reviews adjustable socket designs, as they have the potential to improve prosthetic fit and comfort through accommodating residual limb volume fluctuations and alleviating undue socket pressure. METHODS: Systematic literature and patent searches were conducted across multiple databases to identify articles and patents that discussed adjustable prosthetic sockets. The patents were used to find companies, organisations, and institutions who currently sell adjustable sockets or who are developing devices. RESULTS: 50 literature articles and 63 patents were identified for inclusion, representing 35 different designs used in literature and 16 commercially available products. Adjustable sockets are becoming more prevalent with 73% of publications (literature, patents, and news) occurring within the last ten years. Two key design characteristics were identified: principle of adjustability (inflatable bladders, moveable panels, circumferential adjustment, variable length), and surface form (conformable, rigid multi-DOF, and rigid single DOF). Inflatable bladders contributed to 40% of literature used designs with only one identified commercially available design (n = 16) using this approach. Whereas circumferential adjustment designs covered 75% of identified industry designs compared to only 36% of literature devices. Clinical studies were generally small in size and only 17.6% of them assessed a commercially available socket. DISCUSSION: There are clear differences in the design focus taken by industry and researchers, with justification for choice of design and range of adjustment often being unclear. Whilst comfort is often reported as improved with an adjustable socket, the rationale behind this is not often discussed, and small study sizes reduce the outcome viability. Many adjustable sockets lack appropriate safety features to limit over or under tightening, which may present a risk of tissue damage or provide inadequate coupling, affecting function and satisfaction. Furthermore, the relationship between design and comfort or function are rarely investigated and remain a significant gap in the literature. Finally, this review highlights the need for improved collaboration between academia and industry, with a strong disconnect observed between commercial devices and published research studies.

Neural Correlates of Naturally Occurring Speech Errors during Picture Naming in Healthy Participants.

Most of our knowledge about the neuroanatomy of speech errors comes from lesion-symptom mapping studies in people with aphasia and laboratory paradigms designed to elicit primarily phonological errors in healthy adults, with comparatively little evidence from naturally occurring speech errors. In this study, we analyzed perfusion fMRI data from 24 healthy participants during a picture naming task, classifying their responses into correct and different speech error types (e.g., semantic, phonological, omission errors). Total speech errors engaged a wide set of left-lateralized frontal, parietal, and temporal regions that were almost identical to those involved during the production of correct responses. We observed significant perfusion signal decreases in the left posterior middle temporal gyrus and inferior parietal lobule (angular gyrus) for semantic errors compared to correct trials matched on various psycholinguistic variables. In addition, the left dorsal caudate nucleus showed a significant perfusion signal decrease for omission (i.e., anomic) errors compared with matched correct trials. Surprisingly, we did not observe any significant perfusion signal changes in brain regions proposed to be associated with monitoring mechanisms during speech production (e.g., ACC, superior temporal gyrus). Overall, our findings provide evidence for distinct neural correlates of semantic and omission error types, with anomic speech errors likely resulting from failures to initiate articulatory-motor processes rather than semantic knowledge impairments as often reported for people with aphasia.

Using major depression polygenic risk scores to explore the depressive symptom continuum.

BACKGROUND: Major depression (MD) is often characterised as a categorical disorder; however, observational studies comparing sub-threshold and clinical depression suggest MD is continuous. Many of these studies do not explore the full continuum and are yet to consider genetics as a risk factor. This study sought to understand if polygenic risk for MD could provide insight into the continuous nature of depression. METHODS: Factor analysis on symptom-level data from the UK Biobank (N = 148 957) was used to derive continuous depression phenotypes which were tested for association with polygenic risk scores (PRS) for a categorical definition of MD (N = 119 692). RESULTS: Confirmatory factor analysis showed a five-factor hierarchical model, incorporating 15 of the original 18 items taken from the PHQ-9, GAD-7 and subjective well-being questionnaires, produced good fit to the observed covariance matrix (CFI = 0.992, TLI = 0.99, RMSEA = 0.038, SRMR = 0.031). MD PRS associated with each factor score (standardised ß range: 0.057-0.064) and the association remained when the sample was stratified into case- and control-only subsets. The case-only subset had an increased association compared to controls for all factors, shown via a significant interaction between lifetime MD diagnosis and MD PRS (p value range: 2.23 × 10-3-3.94 × 10-7). CONCLUSIONS: An association between MD PRS and a continuous phenotype of depressive symptoms in case- and control-only subsets provides support against a purely categorical phenotype; indicating further insights into MD can be obtained when this within-group variation is considered. The stronger association within cases suggests this variation may be of particular importance.

Genetic and shared couple environmental contributions to smoking and alcohol use in the UK population.

Alcohol use and smoking are leading causes of death and disability worldwide. Both genetic and environmental factors have been shown to influence individual differences in the use of these substances. In the present study we tested whether genetic factors, modelled alongside common family environment, explained phenotypic variance in alcohol use and smoking behaviour in the Generation Scotland (GS) family sample of up to 19,377 individuals. SNP and pedigree-associated effects combined explained between 18 and 41% of the variance in substance use. Shared couple effects explained a significant amount of variance across all substance use traits, particularly alcohol intake, for which 38% of the phenotypic variance was explained. We tested whether the within-couple substance use associations were due to assortative mating by testing the association between partner polygenic risk scores in 34,987 couple pairs from the UK Biobank (UKB). No significant association between partner polygenic risk scores were observed. Associations between an individual's alcohol PRS (b = 0.05, S.E. = 0.006, p < 2 × 10-16) and smoking status PRS (b = 0.05, S.E. = 0.005, p < 2 × 10-16) were found with their partner's phenotype. In support of this, G carriers of a functional ADH1B polymorphism (rs1229984), known to be associated with greater alcohol intake, were found to consume less alcohol if they had a partner who carried an A allele at this SNP. Together these results show that the shared couple environment contributes significantly to patterns of substance use. It is unclear whether this is due to shared environmental factors, assortative mating, or indirect genetic effects. Future studies would benefit from longitudinal data and larger sample sizes to assess this further.

Epigenetic prediction of major depressive disorder.

Variation in DNA methylation (DNAm) is associated with lifestyle factors such as smoking and body mass index (BMI) but there has been little research exploring its ability to identify individuals with major depressive disorder (MDD). Using penalised regression on genome-wide CpG methylation, we tested whether DNAm risk scores (MRS), trained on 1223 MDD cases and 1824 controls, could discriminate between cases (n = 363) and controls (n = 1417) in an independent sample, comparing their predictive accuracy to polygenic risk scores (PRS). The MRS explained 1.75% of the variance in MDD (ß = 0.338, p = 1.17 × 10-7) and remained associated after adjustment for lifestyle factors (ß = 0.219, p = 0.001, R2 = 0.68%). When modelled alongside PRS (ß = 0.384, p = 4.69 × 10-9) the MRS remained associated with MDD (ß = 0.327, p = 5.66 × 10-7). The MRS was also associated with incident cases of MDD who were well at recruitment but went on to develop MDD at a later assessment (ß = 0.193, p = 0.016, R2 = 0.52%). Heritability analyses found additive genetic effects explained 22% of variance in the MRS, with a further 19% explained by pedigree-associated genetic effects and 16% by the shared couple environment. Smoking status was also strongly associated with MRS (ß = 0.440, p ≤ 2 × 10-16). After removing smokers from the training set, the MRS strongly associated with BMI (ß = 0.053, p = 0.021). We tested the association of MRS with 61 behavioural phenotypes and found that whilst PRS were associated with psychosocial and mental health phenotypes, MRS were more strongly associated with lifestyle and sociodemographic factors. DNAm-based risk scores of MDD significantly discriminated MDD cases from controls in an independent dataset and may represent an archive of exposures to lifestyle factors that are relevant to the prediction of MDD.

Drivers of US health care spending for persons with seizures and/or epilepsies, 2010-2018.

OBJECTIVE: This study was undertaken to characterize spending for persons classified with seizure or epilepsy and to determine whether spending has increased over time. METHODS: In this cross-sectional study, we pooled data from the Medical Expenditure Panel Survey (MEPS) household component files for 2010-2018. We matched cases to controls on age and sex of a population-based sample of MEPS respondents (community-dwelling persons of all ages) with records associated with a medical event (e.g., outpatient visit, hospital inpatient) for seizure, epilepsy, or both. Outcomes were weighted to be representative of the civilian, noninstitutionalized population. We estimated the treated prevalence of epilepsy and seizure, health care spending overall and by site of care, and trends in spending growth. RESULTS: We identified 1078 epilepsy cases and 2344 seizure cases. Treated prevalence was .38% (95% confidence interval [CI] = .34-.41) for epilepsy, .76% (95% CI = .71-.81) for seizure, and 1.14% (95% CI = 1.08-1.20) for epilepsy or seizure. The difference in annual spending for cases compared to controls was $4580 (95% CI = $3362-$5798) for epilepsy, $7935 (95% CI, $6237-$9634) for seizure, and $6853 (95% CI = $5623-$8084) for epilepsy or seizure, translating into aggregate costs of $5.4 billion, $19.0 billion, and $24.5 billion. From 2010 to 2018, the annual growth rate in total spending incurred for seizures and/or epilepsies was 7.6% compared to 3.6% among controls. SIGNIFICANCE: US economic burden of seizures and/or epilepsies is substantial and warrants interventions focused on their unique and overlapping causes.

Gynecologic surgical skill acquisition through simulation with outcomes at the time of surgery: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of simulation training vs traditional hands-on surgical instruction on learner operative skills and patient outcomes in gynecologic surgeries. DATA SOURCES: PubMed, Embase, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials from inception to January 12, 2021. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials, prospective comparative studies, and prospective single-group studies with pre- and posttraining assessments that reported surgical simulation-based training before gynecologic surgery were included. METHODS: Reviewers independently identified the studies, obtained data, and assessed the study quality. The results were analyzed according to the type of gynecologic surgery, simulation, comparator, and outcome data, including clinical and patient-related outcomes. The maximum likelihood random effects model meta-analyses of the odds ratios and standardized mean differences were calculated with estimated 95% confidence intervals. RESULTS: Twenty studies, including 13 randomized controlled trials, 1 randomized crossover trial, 5 nonrandomized comparative studies, and 1 prepost study were identified. Most of the included studies (14/21, 67%) were on laparoscopic simulators and had a moderate quality of evidence. Meta-analysis showed that compared with traditional surgical teaching, high- and low-fidelity simulators improved surgical technical skills in the operating room as measured by global rating scales, and high-fidelity simulators decreased the operative time. Moderate quality evidence was found favoring warm-up exercises before laparoscopic surgery. There was insufficient evidence to conduct a meta-analysis for other gynecologic procedures. CONCLUSION: Current evidence supports incorporating simulation-based training for a variety of gynecologic surgeries to increase technical skills in the operating room, but data on patient-related outcomes are lacking.

Polygenic scores for schizophrenia and major depression are associated with psychosocial risk factors in children: evidence of gene-environment correlation.

BACKGROUND: Whilst genetic and environmental risk factors for schizophrenia (SCZ) and major depressive disorder (MDD) have been established, it is unclear whether exposure to environmental risk factors is genetically confounded by passive, evocative or active gene-environment correlation (rGE). STUDY OBJECTIVE: This study aims to investigate: (a) whether the genetic risk for SCZ/MDD in children is correlated with established environmental and psychosocial risk factors in two British community samples, the 1958 National Child Development Study (NCDS) and the Millennium Cohort Study (MCS), (b) whether these associations vary between both psychopathologies, and (c) whether findings differ across the two cohorts which were born 42 years apart. METHODS: Polygenic risk scores (PRS) from existing large genome-wide associations studies (GWAS) were applied to test the correlation between the child genetic risk for SCZ/MDD and known environmental risk factors. In addition, parental and child genetic data from MCS were used to distinguish between passive and evocative rGE. RESULTS: The child polygenic risk for SCZ and MDD was correlated with single parenthood in MCS. Moreover, the lack of father's involvement in child care was associated with the genetic risk for SCZ in NCDS. However, we also found associations between several indicators of low socioeconomic status and heightened genetic risk for MDD in children in both cohorts. Further, the genetic risk for MDD was associated with parental lack of interest in the child's education in NCDS as well as more maternal smoking and less maternal alcohol consumption during childhood in MCS. According to sensitivity analyses in MCS (controlling for parental genotype), more than half of our significant correlations reflected passive rGE. CONCLUSIONS: Findings suggest that several established environmental and psychosocial risk factors for SCZ and MDD are at least partially associated with children's genetic risk for these psychiatric disorders.

The impact of government-mandated shared decision-making for implantable defibrillators: A natural experiment.

BACKGROUND: In 2018, the Centers for Medicare and Medicaid Services (CMS) mandated that patients considering implantation of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death undergo shared decision-making (SDM) using a decision-aid. OBJECTIVE: To observe the impact of the CMS's mandate on core measures of SDM using a natural experiment. RESEARCH DESIGN, SUBJECTS, AND MEASURES: Patients who underwent implantation of a primary prevention ICD within the Emory Healthcare system between 2017-2019 (pre and post SDM mandate) were surveyed. Survey domains included knowledge about the ICD, decisional conflict, values-choice concordance, and engagement in decision-making. Patients who had an ICD implant after the mandate were also asked about their views of the decision aid (DA). Responses of patients who had ICD implanted prior to the mandate were compared to those after the mandate using either Student t test or Chi-Squared tests. RESULTS: Of 101 patients who completed the survey, 45 had an ICD placed before the mandate and 56 had an ICD placed after. There were no major differences between knowledge, decisional conflict, values choice concordance, or patient engagement. Compared to patients with ICDs placed before the mandate, patients with ICDs after the mandate were more likely to subjectively feel more informed about the benefits of the procedure but were less likely to be able to correctly identify the frequency of complications. CONCLUSIONS: Policy effects to promote SDM that solely focus on a decision-aid may not substantively impact patient centered care.

A meta-analysis of genome-wide association studies of epigenetic age acceleration.

'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father's age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.