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Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Inpatient surgical site infections (SSIs) cause morbidity in children. The SSI rate among pediatric ambulatory surgery patients is less clear. To fill this gap, we conducted a multiple-institution, retrospective epidemiologic study to identify incidence, risk factors, and outcomes.
We identified patients aged <22 years with ambulatory visits between October 2010 and September 2015 via electronic queries at 3 medical centers. We performed sample chart reviews to confirm ambulatory surgery and adjudicate SSIs. Weighted Poisson incidence rates were calculated. Separately, we used case–control methodology using multivariate backward logistical regression to assess risk-factor association with SSI.
In total, 65,056 patients were identified by queries, and we performed complete chart reviews for 13,795 patients; we identified 45 SSIs following ambulatory surgery. The weighted SSI incidence following pediatric ambulatory surgery was 2.00 SSI per 1,000 ambulatory surgeries (95% confidence interval [CI], 1.37–3.00). Integumentary surgeries had the highest weighted SSI incidence, 3.24 per 1,000 ambulatory surgeries (95% CI, 0.32–12). The following variables carried significantly increased odds of infection: clean contaminated or contaminated wound class compared to clean (odds ratio [OR], 9.8; 95% CI, 2.0–48), other insurance type compared to private (OR, 4.0; 95% CI, 1.6–9.8), and surgery on weekend day compared to weekday (OR, 30; 95% CI, 2.9–315). Of the 45 instances of SSI following pediatric ambulatory surgery, 40% of patients were admitted to the hospital and 36% required a new operative procedure or bedside incision and drainage.
Our findings suggest that morbidity is associated with SSI following ambulatory surgery in children, and we also identified possible targets for intervention.
A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE).
The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8–40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses.
When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10).
We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.
Several early editions of Thomas More's “Utopia,” first published in 1516, include the Utopian alphabet, as well as a quatrain of poetry in Utopian and its Latin transliteration. This essay traces the material conditions for the Utopian alphabet, exploring the intellectual contexts and epistemological questions that underlie its presence in these early editions and its absence in others. Reproduced by four early modern European printers via woodcut, metal type, or engraved plate, the alphabet in its materiality becomes a key component of “Utopia,” underscoring the intersection between print technology and an expansive humanism extending to ever wider intellectual and geographic horizons.
Brain metastases (BM) are the most common intracranial neoplasm and represent a major clinical challenge across many medical disciplines. The incidence of BM is increasing, largely due to improvements in primary disease therapeutics conferring greater systemic control, and advancements in neuroimaging techniques and availability leading to earlier diagnosis. In recent years, the landscape of BM treatment has changed significantly with the advent of personalized targeted chemotherapies and immunotherapy, the adoption of focal radiotherapy (RT) for higher intracranial disease burden, and the implementation of new surgical strategies. The increasing permutations of options available for the treatment of patients diagnosed with BM necessitate coordinated care by a multidisciplinary team. This review discusses the current treatment regimens for BM as well as examines the salient features of a modern multidisciplinary approach.
Ambulatory healthcare-associated infections (HAIs) occur frequently in children and are associated with morbidity. Less is known about ambulatory HAI costs. This study estimated additional costs associated with pediatric ambulatory central-line–associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTI), and surgical site infections (SSIs) following ambulatory surgery.
Retrospective case-control study.
Four academic medical centers.
Children aged 0–22 years seen between 2010 and 2015 and at risk for HAI as identified by electronic queries.
Chart review adjudicated HAIs. Charges were obtained for patients with HAIs and matched controls 30 days before HAI, on the day of, and 30 days after HAI. Charges were converted to costs and 2015 USD. Mixed-effects linear regression was used to estimate the difference-in-differences of HAI case versus control costs in 2 models: unrecorded charge values considered missing and a sensitivity analysis with unrecorded charge considered $0.
Our search identified 177 patients with ambulatory CLABSIs, 53 with ambulatory CAUTIs, and 26 with SSIs following ambulatory surgery who were matched with 382, 110, and 75 controls, respectively. Additional cost associated with an ambulatory CLABSI was $5,684 (95% confidence interval [CI], $1,005–$10,362) and $6,502 (95% CI, $2,261–$10,744) in the 2 models; cost associated with a CAUTI was $6,660 (95% CI, $1,055, $12,145) and $2,661 (95% CI, −$431 to $5,753); cost associated with an SSI following ambulatory surgery at 1 institution only was $6,370 (95% CI, $4,022–$8,719).
Ambulatory HAI in pediatric patients are associated with significant additional costs. Further work is needed to reduce ambulatory HAIs.
Catheter-associated urinary tract infections (CAUTIs) occur frequently in pediatric inpatients, and they are associated with increased morbidity and cost. Few studies have investigated ambulatory CAUTIs, despite at-risk children utilizing home urinary catheterization. This retrospective cohort and case-control study determined incidence, risk factors, and outcomes of pediatric patients with ambulatory CAUTI.
Broad electronic queries identified potential patients with ambulatory urinary catheters, and direct chart review confirmed catheters and adjudicated whether ambulatory CAUTI occurred. CAUTI definitions included clean intermittent catheterization (CIC). Our matched case-control analysis assessed risk factors.
Five urban, academic medical centers, part of the New York City Clinical Data Research Network.
Potential patients were age <22 years who were seen between October 2010 and September 2015.
In total, 3,598 eligible patients were identified; 359 of these used ambulatory catheterization (representing186,616 ambulatory catheter days). Of these, 63 patients (18%) experienced 95 ambulatory CAUTIs. The overall ambulatory CAUTI incidence was 0.51 infections per 1,000 catheter days (1.35 for indwelling catheters and 0.47 for CIC; incidence rate ratio, 2.88). Patients with nonprivate medical insurance (odds ratio, 2.5; 95% confidence interval, 1.1–6.3) were significantly more likely to have ambulatory CAUTIs in bivariate models but not multivariable models. Also, 45% of ambulatory CAUTI resulted in hospitalization (median duration, 3 days); 5% resulted in intensive care admission; 47% underwent imaging; and 88% were treated with antibiotics.
Pediatric ambulatory CAUTIs occur in 18% of patients with catheters; they are associated with morbidity and healthcare utilization. Ambulatory indwelling catheter CAUTI incidence exceeded national inpatient incidence. Future quality improvement research to reduce these harmful infections is warranted.
Traits of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are strongly associated in children and adolescents, largely due to genetic factors. Less is known about the phenotypic and aetiological overlap between ADHD and ASD traits in adults.
We studied 6866 individuals aged 20–28 years from the Swedish Study of Young Adult Twins. Inattention (IA) and hyperactivity/impulsivity (HI) were assessed using the WHO Adult ADHD Self-Report Scale-V1.1. Repetitive and restricted behaviours (RRB) and social interaction and communication (SIC) were assessed using the Autism-Tics, ADHD, and other Comorbidities inventory. We used structural equation modelling to decompose covariance between these ADHD and ASD trait dimensions into genetic and shared/non-shared environmental components.
At the phenotypic level, IA was similarly correlated with RRB (r = 0.33; 95% Confidence Interval (CI) 0.31–0.36) and with SIC (r = 0.32; 95% CI 0.29–0.34), whereas HI was more strongly associated with RRB (r = 0.38; 95% CI 0.35–0.40) than with SIC (r = 0.24; 95% CI 0.21–0.26). Genetic and non-shared environmental effects accounted for similar proportions of the phenotypic correlations, whereas shared environmental effects were of minimal importance. The highest genetic correlation was between HI and RRB (r = 0.56; 95% 0.46–0.65), and the lowest was between HI and SIC (r = 0.33; 95% CI 0.23–0.43).
We found evidence for dimension-specific phenotypic and aetiological overlap between ADHD and ASD traits in adults. Future studies investigating mechanisms underlying comorbidity between ADHD and ASD may benefit from exploring several symptom-dimensions, rather than considering only broad diagnostic categories.
Recent literature suggests that Ca supplements have adverse effects on cardiovascular health. The effects of a Ca-rich supplement administered alone or in combination with short-chain fructo-oligosaccharides (scFOS) on serum lipids in postmenopausal women were examined using secondary data from a 24-month double-blind randomised controlled study. A total of 300 postmenopausal women were randomly assigned to daily supplements of 800 mg of Ca (2·4 g Aquamin) (Ca), 800 mg of Ca with 3 g of scFOS (CaFOS) or control (maltodextrin) (MD). A full lipid profile, body composition, blood pressure and a range of cytokines were measured at baseline and after 24 months. Intention-to-treat ANCOVA assessed treatment effects between the groups. A significant time-by-treatment effect was observed for LDL and total cholesterol for the Ca and CaFOS groups, with both groups having lower LDL and total cholesterol concentrations compared with MD after 24 months. The control group had mean (5·2 mmol/l) total cholesterol concentrations above the normal range (≤5 mmol/l) at 24 months, whereas values remained within the normal range in the treatment groups. There was no significant treatment effect on HDL-cholesterol, TAG, body composition, blood pressure or cytokine concentrations at 24 months, with the exception of IL-4, where there was a significant increase in the CaFOS group compared with the placebo. This study demonstrates a lipid-lowering effect of both the Ca-rich supplement alone and the supplement with scFOS. At the 4-year follow-up, there was no significant difference between the groups for reported diagnosed cardiovascular conditions.
Postprandial inflammation is an important factor for human health since chronic low-grade inflammation is associated with chronic diseases. Dairy products have a weak but significant anti-inflammatory effect on postprandial inflammation. The objective of the present study was to compare the effect of a high-fat dairy meal (HFD meal), a high-fat non-dairy meal supplemented with milk (HFM meal) and a high-fat non-dairy control meal (HFC meal) on postprandial inflammatory and metabolic responses in healthy men. A cross-over study was conducted in nineteen male subjects. Blood samples were collected before and 1, 2, 4 and 6 h after consumption of the test meals. Plasma concentrations of insulin, glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, TAG and C-reactive protein (CRP) were measured at each time point. IL-6, TNF-α and endotoxin concentrations were assessed at baseline and endpoint (6 h). Time-dependent curves of these metabolic parameters were plotted, and the net incremental AUC were found to be significantly higher for TAG and lower for CRP after consumption of the HFM meal compared with the HFD meal; however, the HFM and HFD meals were not different from the HFC meal. Alterations in IL-6, TNF-α and endotoxin concentrations were not significantly different between the test meals. The results suggest that full-fat milk and dairy products (cheese and butter) have no significant impact on the inflammatory response to a high-fat meal.
This white paper identifies knowledge gaps and new challenges in healthcare epidemiology research, assesses the progress made toward addressing research priorities, provides the Society for Healthcare Epidemiology of America (SHEA) Research Committee's recommendations for high-priority research topics, and proposes a road map for making progress toward these goals. It updates the 2010 SHEA Research Committee document, “Charting the Course for the Future of Science in Healthcare Epidemiology: Results of a Survey of the Membership of SHEA,” which called for a national approach to healthcare-associated infections (HAIs) and a prioritized research agenda. This paper highlights recent studies that have advanced our understanding of HAIs, the establishment of the SHEA Research Network as a collaborative infrastructure to address research questions, prevention initiatives at state and national levels, changes in reporting and payment requirements, and new patterns in antimicrobial resistance.
Impulsivity and compulsivity represent useful conceptualizations that involve dissociable cognitive functions, which are mediated by neuroanatomically and neurochemically distinct components of cortico-subcortical circuitry. The constructs were historically viewed as diametrically opposed, with impulsivity being associated with risk-seeking and compulsivity with harm-avoidance. However, they are increasingly recognized to be linked by shared neuropsychological mechanisms involving dysfunctional inhibition of thoughts and behaviors. In this article, we selectively review new developments in the investigation of the neurocognition of impulsivity and compulsivity in humans, in order to advance our understanding of the pathophysiology of impulsive, compulsive, and addictive disorders and indicate new directions for research.