Severe PTSD is marked by reduced oxytocin and elevated vasopressin.

Neuroendocrine analyses of posttraumatic stress disorder (PTSD) have generally focused on hypothalamic-pituitary-adrenal (HPA) axis alterations. In the present analyses, we examine two additional neuroendocrine factors that have been previously implicated in biological stress responses: oxytocin (OT) and arginine vasopressin (AVP). Here we examined basal neuropeptide status in military veterans clinically diagnosed with PTSD (n = 29) and in two non-traumatized comparison groups with previous stress exposure (n = 11 SWAT trainees and n = 21 ultramarathon runners). PTSD patients showed low levels of plasma OT and high levels of AVP. The ratio of AVP/OT robustly related to PTSD status, and emerged as a statistically plausible mediator of relationships between the number of personal traumatic experiences and subsequent PTSD symptom burden. Over the course of behavioral therapy for PTSD, measures of OT showed a significant but modest normalization. Plasma cortisol levels were not statistically different among the three groups. This study suggests that AVP/OT ratios may represent a neuroendocrine predictor of severe PTSD, as well as a potential treatment response biomarker.

Efficacy, acceptability and side-effects of oral versus long-acting- injectables antipsychotics: Systematic review and network meta-analysis.

Long-acting injectable antipsychotics (LAIs) are primarily used for relapse prevention, but in some settings and situations, they may also be useful for acute treatment of schizophrenia. We conducted a systematic review and frequentist network meta-analysis of randomized-controlled trials (RCTs), focusing on adult patients in the acute phase of schizophrenia. Interventions were risperidone, paliperidone, aripiprazole, olanzapine, and placebo, administered either orally or as LAI. We synthesized data on overall symptoms, complemented by 17 other efficacy and tolerability outcomes. Confidence in the evidence was assessed with the Confidence-in-Network-Meta-Analysis-framework (CINeMA). We included 115 RCTs with 25,550 participants. All drugs were significantly more efficacious than placebo with the following standardized mean differences and their 95 % confidence intervals: olanzapine LAI -0.66 [-1.00; -0.33], risperidone LAI -0.59[-0.73;-0.46], olanzapine oral -0.55[-0.62;-0.48], aripiprazole LAI -0.54[-0.71; -0.37], risperidone oral -0.48[-0.55;-0.41], paliperidone oral -0.47[-0.58;-0.37], paliperidone LAI -0.45[-0.57;-0.33], aripiprazole oral -0.40[-0.50; -0.31]. There were no significant efficacy differences between LAIs and oral formulations. Sensitivity analyses of the primary outcome overall symptoms largely confirmed these findings. Moreover, some side effects were less frequent under LAIs than under their oral counterparts. Confidence in the evidence was moderate for most comparisons. LAIs are efficacious for acute schizophrenia and may have some benefits compared to oral formulations in terms of side effects. These findings assist clinicians with insights to weigh the risks and benefits between oral and injectable agents when treating patients in the acute phase.

Comorbidity clusters in patients with rheumatoid arthritis identify a patient phenotype with a favourable prognosis.

OBJECTIVES: We aimed to cluster patients with rheumatoid arthritis (RA) based on comorbidities and then examine the association between these clusters and RA disease activity and mortality. METHODS: In this population-based study, residents of an eight-county region with prevalent RA on 1 January 2015 were identified. Patients were followed for vital status until death, last contact or 31 December 2021. Diagnostic codes for 5 years before the prevalence date were used to define 55 comorbidities. Latent class analysis was used to cluster patients based on comorbidity patterns. Standardised mortality ratios were used to assess mortality. RESULTS: A total of 1643 patients with prevalent RA (72% female; 94% white; median age 64 years, median RA duration 7 years) were studied. Four clusters were identified. Cluster 1 (n=686) included patients with few comorbidities, and cluster 4 (n=134) included older patients with 10 or more comorbidities. Cluster 2 (n=200) included patients with five or more comorbidities and high prevalences of depression and obesity, while cluster 3 (n=623) included the remainder. RA disease activity and survival differed across the clusters, with cluster 1 demonstrating more remission and mortality comparable to the general population. CONCLUSIONS: More than 40% of patients with prevalent RA did not experience worse mortality than their peers without RA. The cluster with the worst prognosis (<10% of patients with prevalent RA) was older, had more comorbidities and had less disease-modifying antirheumatic drug and biological use compared with the other clusters. Comorbidity patterns may hold the key to moving beyond a one-size-fits-all perspective of RA prognosis.

Association between sinusitis and incident rheumatic diseases: a population-based study.

OBJECTIVES: To determine whether antecedent sinusitis is associated with incident rheumatic disease. METHODS: This population-based case-control study included all individuals meeting classification criteria for rheumatic diseases between 1995 and 2014. We matched three controls to each case on age, sex and length of prior electronic health record history. The primary exposure was presence of sinusitis, ascertained by diagnosis codes (positive predictive value 96%). We fit logistic regression models to estimate ORs for incident rheumatic diseases and disease groups, adjusted for confounders. RESULTS: We identified 1729 incident rheumatic disease cases and 5187 matched controls (mean age 63, 67% women, median 14 years electronic health record history). After adjustment, preceding sinusitis was associated with increased risk of several rheumatic diseases, including antiphospholipid syndrome (OR 7.0, 95% CI 1.8 to 27), Sjögren's disease (OR 2.4, 95% CI 1.1 to 5.3), vasculitis (OR 1.4, 95% CI 1.1 to 1.9) and polymyalgia rheumatica (OR 1.4, 95% CI 1.0 to 2.0). Acute sinusitis was also associated with increased risk of seronegative rheumatoid arthritis (OR 1.8, 95% CI 1.1 to 3.1). Sinusitis was most associated with any rheumatic disease in the 5-10 years before disease onset (OR 1.7, 95% CI 1.3 to 2.3). Individuals with seven or more codes for sinusitis had the highest risk for rheumatic disease (OR 1.7, 95% CI 1.3 to 2.4). In addition, the association between sinusitis and incident rheumatic diseases showed the highest point estimates for never smokers (OR 1.7, 95% CI 1.3 to 2.2). CONCLUSIONS: Preceding sinusitis is associated with increased incidence of rheumatic diseases, suggesting a possible role for sinus inflammation in their pathogenesis.

Are the results of open randomised controlled trials comparing antipsychotic drugs in schizophrenia biased? Exploratory meta- and subgroup analysis.

A recent meta-epidemiological study did not reveal major differences between the results of blinded and open randomised-controlled trials (RCTs). Fewer patients may consent to double-blind RCTs than to open RCTs, compromising generalisability, making this question very important. However, the issue has not been addressed in schizophrenia. We used a database of randomised, acute-phase antipsychotic drug trials. Whenever at least one open and one blinded RCT was available for a comparison of two drugs, we contrasted the results by random-effects meta-analysis with subgroup tests. The primary outcome was overall symptoms as measured by the Positive and Negative Syndrome Scale, supplemented by seven secondary efficacy and side-effect outcomes. We also examined whether open RCTs were biased in favour of more recently introduced antipsychotics, less efficacious or more prone to side-effects antipsychotics, and pharmaceutical sponsors. 183 RCTs (155 blinded and 28 open) with 34715 participants comparing two active drugs were available. The results did not suggest general differences between open and blinded RCTs, which examined two active drugs. Only 12 out of 122 subgroup tests had a p-value below 0.1, four below 0.05, and if a Bonferroni correction for multiple tests had been applied, only one would have been significant. There were some exceptions which, however, did not always confirm the originally hypothesized direction of bias. Due to the relatively small number of open RCTs, our analysis is exploratory, but this fundamental question should be given more scientific attention. Currently, open RCTs should be excluded from meta-analyses, at least in sensitivity analyses.

Multiple morbidities are associated with serious infections in patients with rheumatoid arthritis.

OBJECTIVE: To assess the association between a comprehensive list of morbidities and serious infection (SI) in patients with rheumatoid arthritis (RA). METHODS: This study evaluated SI risk associated with 55 comorbidities using a population-based inception cohort including all adult patients with incident RA from 1999 through 2014 with follow up through 2021. Morbidities and SI were ascertained using previously validated international classification of disease (ICD)-9 and ICD-10 codes. Conditional frailty models were utilized to analyze the association between each morbidity and SI: Model 1 adjusted for age, sex, and calendar year; Model 2 adjusted for factors in Model 1 and the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) Risk Score of Infections; and Model 3 adjusted for factors in Model 1 and the Mayo SI Risk Score. RESULTS: 911 patients (70 % female, mean age 56 years, 66 % seropositive) were included. There were 293 SI among 155 patients (17 %), corresponding to an incidence of 3.9 SI per 100 person-years. Eighteen SI were fatal. Risk of SI was significantly increased in 27 of 55 morbidities in Model 1, 11 morbidities in Model 2, and 23 morbidities in Model 3. Additionally, several morbidities included in the RABBIT and Mayo risk scores continued to have large effect sizes despite adjustment. Serious infection risk increased by 11-16 % per morbidity in the three models. CONCLUSIONS: Several morbidities are associated with an increased risk for SI. Future risk scores may include morbidities identified in this study for improved SI risk assessment.

Multimorbidity in Psoriasis as a Risk Factor for Psoriatic Arthritis: A Population-Based Study.

OBJECTIVES: To examine multimorbidity in psoriasis and its association with the development of PsA. METHODS: A retrospective cohort study was performed using the Rochester Epidemiology Project. Population-based incidence (2000-2009) and prevalence (Jan 1, 2010) cohorts of psoriasis were identified by manual chart review. A cohort of individuals without psoriasis (comparators) were identified (1:1 matched on age, sex, and county). Morbidities were defined using ≥2 Clinical Classification Software codes ≥30 days apart within prior five years. PsA was defined using ClASsification of Psoriatic ARthritis (CASPAR) criteria. χ2 and rank-sum tests were used to compare morbidities, and age-, sex-, and race-adjusted Cox models to examine the association of baseline morbidities in psoriasis with development of PsA. RESULTS: Among 817 incident psoriasis patients, the mean age was 45.2 years with 52.0% females, and 82.0% moderate/severe psoriasis. No multimorbidity differences were found between incident psoriasis patients and comparators. However, in the 1,088 prevalent psoriasis patients, multimorbidity was significantly more common compared with 1,086 comparators (OR : 1.35 and OR : 1.48 for ≥2 and ≥5 morbidities, respectively). Over a median 13.3-year follow-up, 23 patients (cumulative incidence: 2.9% by 15 years) developed PsA. Multimorbidity (≥2 morbidities) was associated with a 3-fold higher risk of developing PsA. CONCLUSION: Multimorbidity was more common in the prevalent but not incident cohort of psoriasis compared with the general population, suggesting patients with psoriasis may experience accelerated development of multimorbidity. Moreover, multimorbidity at psoriasis onset significantly increased the risk of developing PsA, highlighting the importance of monitoring multimorbid psoriasis patients for the development of PsA.

Multimorbidity phenotypes in ankylosing spondylitis and their association with disease activity and functional impairment: Data from the prospective study of outcomes in ankylosing spondylitis cohort.

OBJECTIVES: To examine the association of multimorbidity phenotypes at baseline with disease activity and functional status over time in ankylosing spondylitis (AS). METHODS: Patient-reported AS morbidities (comorbidities, N = 28 and extra-musculoskeletal manifestations, EMMs, N = 3) within 3 years of enrollment with a prevalence ≥1 %, were included from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) cohort. We defined multimorbidity as ≥2 morbidities (MM2+) and substantial multimorbidity as ≥5 morbidities (MM5+). Multimorbidity clusters or phenotypes were identified using K-median clustering. Disease activity (ASDAS-CRP) and functional status (BASFI) measures were collected every 6 months. Generalized estimating equation method was used to examine the associations of multimorbidity counts and multimorbidity clusters with measures of disease activity and functional status over time. RESULTS: Among 1,270 AS patients (9,885 visits) with a median follow-up of 2.9 years (IQ range: 1.0-6.8 years), the prevalence of MM2+ and MM5+ was 49 % and 9 % respectively. We identified five multimorbidity clusters: depression (n = 321, 25 %), hypertension (n = 284, 22 %), uveitis (n = 274, 22 %), no morbidities (n = 238, 19 %), and miscellaneous (n = 153, 12 %). Patients in the depression cluster were more likely to be female and had significantly more morbidities and worse disease activity and functional status compared to those with no morbidities. CONCLUSION: Approximately 49 % of AS patients in the PSOAS cohort had multimorbidity and five distinct multimorbidity phenotypes were identified. In addition to the number of morbidities, the type of morbidity appears to be important to longitudinal outcomes in AS. The depression cluster was associated with worse disease activity and function.

Long-Acting Injectable Second-Generation Antipsychotics vs Placebo and Their Oral Formulations in Acute Schizophrenia: A Systematic Review and Meta-Analysis of Randomized-Controlled-Trials.

BACKGROUND AND HYPOTHESIS: Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia. STUDY DESIGN: We conducted a systematic review and meta-analysis of randomized-controlled-trials (RCTs) comparing the second-generation long-acting injectable antipsychotics (SGA-LAIs) olanzapine, risperidone, paliperidone, and aripiprazole with placebo or their oral counterparts in acutely ill patients with schizophrenia. We analyzed 23 efficacy and tolerability outcomes, with the primary outcome being overall symptoms of schizophrenia. The results were obtained through random effects, pairwise meta-analyses, and subgroup tests. The study quality was assessed using the Cochrane-Risk-of-Bias-Tool version-1. STUDY RESULTS: Sixty-six studies with 16 457 participants were included in the analysis. Eleven studies compared second-generation long-acting injectable antipsychotics (SGA-LAIs) with a placebo, 54 compared second-generation oral antipsychotics (SGA-orals) with a placebo, and one compared an SGA-LAI (aripiprazole) with its oral formulation. All 4 SGA-LAIs reduced overall symptoms more than placebo, with mean standardized differences of -0.66 (95% CI: -0.90; -0.43) for olanzapine, -0.64 (-0.80; -0.48) for aripiprazole, -0.62 (-0.76; -0.48) for risperidone and -0.42 (-0.53; -0.31) for paliperidone. The side-effect profiles of the LAIs corresponded to the patterns known from the oral formulations. In subgroup tests compared to placebo, some side effects were less pronounced under LAIs than under their oral formulations. CONCLUSIONS: SGA-LAIs effectively treat acute schizophrenia. Some side effects may be less frequent than under oral drugs, but due to the indirect nature of the comparisons, this finding must be confirmed by RCTs comparing LAIs and orals head-to-head.

Decline in Incidence of Extra-Articular Manifestations of Rheumatoid Arthritis: A Population-Based Cohort Study.

OBJECTIVE: The focus of this study was to assess changes in the cumulative incidence of extra-articular manifestations of rheumatoid arthritis (ExRAs) and associated mortality risk. METHODS: This study evaluated trends in occurrence of ExRAs using a population-based inception cohort that included all adult patients with incident rheumatoid arthritis (RA) from 1985 through 2014 meeting the 1987 American College of Rheumatology criteria. Patients were divided into two cohorts based on the incidence date of RA, 1985 to 1999 and 2000 to 2014. The occurrence of ExRAs was determined by manual chart review, and the 10-year cumulative incidence was estimated for each ExRA in both cohorts. Cox proportional hazard models were used to determine associations between specific demographic and RA disease characteristics and ExRAs and between ExRAs and mortality. RESULTS: There were 907 patients included, 296 in the 1985 to 1999 cohort and 611 in the 2000 to 2014 cohort. The 10-year cumulative incidence of any ExRA decreased significantly between the earlier and later cohorts (45.1% vs 31.6%, P < 0.001). This was largely driven by significant declines in subcutaneous rheumatoid nodules (30.9% vs 15.8%, P < 0.001) and nonsevere ExRAs (41.4% vs 28.8%, P = 0.001). Identified risk factors for the development of any ExRAs include rheumatoid factor positivity (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.43-2.86) and current smoking (HR 1.61, 95% CI 1.10-2.34). Mortality was increased in patients with either nonsevere (HR 1.83, 95% CI 1.18-2.85) or severe ExRAs (HR 3.05, 95% CI 1.44-6.49). CONCLUSIONS: The incidence of ExRAs has decreased over time. Mortality remains increased in patients with ExRAs.

Relapse in clinically stable adult patients with schizophrenia or schizoaffective disorder: evidence-based criteria derived by equipercentile linking and diagnostic test accuracy meta-analysis.

BACKGROUND: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder. METHODS: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation. FINDINGS: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented. INTERPRETATION: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores. FUNDING: German Research Foundation (grant number: 428509362).

Utilisation of cardiovascular preventive services in a rheumatoid arthritis population-based cohort.

OBJECTIVES: The objective is to examine utilisation of cardiovascular preventive services in patients with rheumatoid arthritis (RA), compared with a non-RA population, and to examine cardiovascular disease (CVD) screening rates among RA patients without diabetes mellitus (DM), hypertension or hyperlipidaemia to non-RA patients with one of these diagnoses. METHODS: All ≥18-year-old patients with an RA diagnosis living in one of eight Minnesota counties on 1 January 2015 were included and matched (1:1) by sex, age and county to non-RA comparators. Rates of screening for CVD risk factors, including DM (ie, glucose), hypertension (ie, blood pressure) and hyperlipidaemia (ie, lipids), were compared between groups using Cox models. RESULTS: The study included 1614 patients with RA and 1599 non-RA comparators. DM screening was more common among patients with RA (HR: 1.10, 95% CI: 1.01 to 1.19), as was hypertension screening (HR: 1.37, 95% CI: 1.24 to 1.52). Hyperlipidaemia screening in RA was similar to comparators (HR: 0.99, 95% CI: 0.89 to 1.10). Conversely, patients with RA and no CVD risk factors had a lower probability of undergoing diabetes (HR: 0.67, 95% CI: 0.57 to 0.78) and hyperlipidaemia screening (HR: 0.65, 95% CI: 0.54 to 0.79) than non-RA patients with only one CVD risk factor diagnosis. Hypertension screening was similar between both groups. CONCLUSIONS: RA patients undergo CVD preventive screening at rates at least comparable to the general population. However, patients with RA as their sole CVD risk factor were less likely to undergo screenings, despite an equivalent-to-higher risk as the traditional CVD risk factors. These findings demonstrate opportunities for improvement of RA patient care.

Gut Microbiome Wellness Index 2 for Enhanced Health Status Prediction from Gut Microbiome Taxonomic Profiles.

Recent advancements in human gut microbiome research have revealed its crucial role in shaping innovative predictive healthcare applications. We introduce Gut Microbiome Wellness Index 2 (GMWI2), an advanced iteration of our original GMWI prototype, designed as a robust, disease-agnostic health status indicator based on gut microbiome taxonomic profiles. Our analysis involved pooling existing 8069 stool shotgun metagenome data across a global demographic landscape to effectively capture biological signals linking gut taxonomies to health. GMWI2 achieves a cross-validation balanced accuracy of 80% in distinguishing healthy (no disease) from non-healthy (diseased) individuals and surpasses 90% accuracy for samples with higher confidence (i.e., outside the "reject option"). The enhanced classification accuracy of GMWI2 outperforms both the original GMWI model and traditional species-level α-diversity indices, suggesting a more reliable tool for differentiating between healthy and non-healthy phenotypes using gut microbiome data. Furthermore, by reevaluating and reinterpreting previously published data, GMWI2 provides fresh insights into the established understanding of how diet, antibiotic exposure, and fecal microbiota transplantation influence gut health. Looking ahead, GMWI2 represents a timely pivotal tool for evaluating health based on an individual's unique gut microbial composition, paving the way for the early screening of adverse gut health shifts. GMWI2 is offered as an open-source command-line tool, ensuring it is both accessible to and adaptable for researchers interested in the translational applications of human gut microbiome science.

Eggerthella lenta augments preclinical autoantibody production and metabolic shift mimicking senescence in arthritis.

Although the etiology of rheumatoid arthritis (RA) is unknown, a strong genetic predisposition and the presence of preclinical antibodies before the onset of symptoms is documented. An expansion of Eggerthella lenta is associated with severe disease in RA. Here, using a humanized mouse model of collagen-induced arthritis, we determined the impact of E. lenta abundance on RA severity. Naïve mice gavaged with E. lenta produce preclinical rheumatoid factor and, when induced for arthritis, develop severe disease. The augmented antibody response was much higher in female mice, and among patients with RA, women had higher average load of E. lenta. Expansion of E. lenta increased CXCL5 and CD4 T cells, and both interleukin-17- and interferon-γ-producing B cells. Further, E. lenta gavage caused gut dysbiosis and decline in amino acids and nicotinamide adenine dinucleotide with an increase in microbe-dependent bile acids and succinyl carnitine causing systemic senescent-like inflammation.

Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis.

Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D2 receptor (D2R) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The D2R occupancy curves showed that the risk increased substantially when D2R occupancy exceeded 75-85%, except for D2R partial agonists that had smaller ORs albeit high D2R occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current D2R therapeutic window for EPS.

Gene-respiratory disease interactions for rheumatoid arthritis risk.

OBJECTIVE: We aimed to identify gene by respiratory tract disease interactions that increase RA risk. METHODS: In this case-control study using the Mass General Brigham Biobank, we matched incident RA cases, confirmed by ACR/EULAR criteria, to four controls on age, sex, and electronic health record history. Genetic exposures included a validated overall genetic risk score (GRS) for RA, a Human Leukocyte Antigen (HLA) GRS for RA, and the MUC5B promoter variant, an established risk factor for RA-associated interstitial lung disease (ILD). Preceding respiratory tract diseases came from diagnosis codes (positive predictive value 86%). We estimated attributable proportions (AP) and multiplicative odds ratios (OR) with 95% confidence intervals (CI) for RA for each genetic and respiratory exposure using conditional logistic regression models, adjusting for potential confounders. RESULTS: We identified 653 incident RA cases and 2,607 matched controls (mean 54 years, 76% female). The highest tertile of the overall GRS and the HLA GRS were both associated with increased RA risk (OR 2.28, 95% CI 1.89,2.74; OR 2.02, 95% CI 1.67-2.45). ILD and the HLA GRS exhibited a synergistic relationship for RA risk (OR for both exposures 4.30, 95% CI 1.28,14.38; AP 0.51, 95% CI-0.16,1.18). Asthma and the MUC5B promoter variant also exhibited a synergistic interaction for seropositive RA (OR for both exposures 2.58, 95% CI 1.10,6.07; AP 0.62, 95% CI 0.24,1.00). CONCLUSION: ILD-HLA GRS and asthma-MUC5B promoter variant showed synergistic interactions for RA risk. Such interactions may prove useful for RA prevention and screening.

The Incidence and Outcomes of Breast Implants Among 1696 Women over more than 50 Years.

OBJECTIVE: To investigate the incidence of women with breast implants in 1964-2017 MATERIALS AND METHODS: All women with breast implants in Olmsted County, MN between January 1, 1992 and December 31, 2017 were identified, and a comprehensive review of individual medical records was performed, adding to a previously identified cohort of women with breast implants in 1964-1991. Incidence rates were calculated and were age- and sex-adjusted to the US white female 2010 population. RESULTS: In 1992-2017, 948 women with breast implants were identified, totaling 1696 Olmsted County, MN women with breast implants in 1964-2017. Overall incidence was 63.3 (95% CI 60.2-66.4) per 100,000 women, but incidence varied significantly over time. Women in 1964-1991 were more likely to have implants for cosmetic reasons and more likely to have silicone implants compared to the 1992-2017 cohort. The overall standardized mortality ratio was 1.17 (95% CI 0.99-1.38) in 1964-1991 and 0.94 (95% CI 0.66-1.29) in 1992-2017. In 1992-2017, breast reconstruction patients had a significantly elevated risk of implant rupture and implant removal versus breast augmentation patients. CONCLUSION: The incidence of breast implants among women in Olmsted County, MN has varied drastically over the past five decades, with significant changes in the trends for implant type and reason. The findings of this study may provide further insight regarding how risks associated with implants may vary over time. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .