Pre-Pulse Inhibition (PPI) is a neural process where suppression of a startle response is elicited by preceding the startling stimulus (Pulse) with a weak, non-startling one (Pre-Pulse). Defective PPI is widely employed as a behavioural endophenotype in humans and mammalian disorder-relevant models for neuropsychiatric disorders. We have developed a user-friendly, semi-automated, high-throughput-compatible Drosophila light-off jump response PPI paradigm, with which we demonstrate that PPI, with similar parameters measured in mammals, exists in adults of this model organism. We report that Drosophila PPI is affected by reduced expression of Dysbindin and both reduced and increased expression of Nmdar1 (N-methyl-D-aspartate receptor 1), perturbations associated with schizophrenia. Studying the biology of PPI in an organism that offers an abundance of genetic tools and a complex and well characterized connectome will greatly facilitate our efforts to gain deeper insight into the aetiology of human mental disorders, while reducing the need for mammalian models.

Orthostatic hypotension (OH) and the co-existence with supine hypertension (SH) are debilitating consequences of autonomic failure in Parkinson’s disease (PD) and multiple system atrophy (MSA). Head-up tilt sleeping (HUTS) has the potential to treat both simultaneously. Within the Heads-Up trial, 20 persons with PD or MSA and both SH and OH were assigned randomly to two HUTS schemes with gradually increasing angles: 1° (placebo), 6° and 12°; or 6°, 12° and 18°. The effect of increasing the head of the bed (per cm) was analyzed with linear mixed models. HUTS did not reduce nocturnal SBP but improved other indicators of blood pressure control, including early morning supine SBP, nocturnal dipping profile, diurnal SBP and SBP fall upon standing, coinciding with improved orthostatic tolerance. Adherence was 100% at 6°, 80% at 12°, and 60% at 18°. Higher angles were more effective, but at the cost of lower tolerability. The trial is registered at ClinicalTrials.gov (NCT05551377, 19-09-2022).

Context:Early prediction of ovarian reserve is essential to improve fertility counseling in girls with Turner syndrome (TS). Objective:This work aimed to examine the occurrence of puberty and longitudinal hormone patterns in girls with TS, and to take an initial step toward developing a prediction model for ovarian function. Main outcome measures included thelarche, menarche, and age of premature ovarian insufficiency (POI). Methods:A retrospective cohort study was conducted of girls with TS. Levels of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), antimüllerian hormone (AMH), inhibin B, and information on karyotype and puberty were extracted from the medical records. A joint model combining a Cox survival model and 2 linear mixed-effects models for FSH and AMH was used to model the association between POI and longitudinal hormone values. Results:A total of 365 girls were included, of whom 287 had available data on pubertal development. In this patient cohort, 43% had monosomy 45,X, 17% had mosaic 45,X/46,XX, 18% had an isochromosome X, and 22% had an "other" karyotype in lymphocytes. Girls with spontaneous puberty had lower FSH and higher AMH before age 8 years compared to girls without spontaneous puberty. The joint model showed that lower AMH is significantly related to POI, while FSH was not significantly related to POI. The individual predicted risks on POI come with large uncertainty. Conclusion:AMH and FSH patterns contribute to understanding ovarian reserve at an early age in girls with TS. Creating a prediction model remained challenging and more data are needed.

OBJECTIVE:Population-based information on variation in the delivery of first-line chemotherapy for epithelial ovarian cancer is scarce. This study aimed to evaluate chemotherapy delivery, reasons for chemotherapy modifications, and their associations with overall survival. METHODS:Patients with advanced-stage epithelial ovarian cancer diagnosed from January 2015 through December 2021 were identified in the Netherlands Cancer Registry. We included patients who underwent cytoreductive surgery with platinum- and taxane-based chemotherapy and categorized them as receiving chemotherapy without or with modifications (dose reduction, interruption, and/or fewer cycles). We assessed reasons for modifications and used Kaplan-Meier curves and Cox proportional hazards models to analyze overall survival. RESULTS:Among 3687 patients, 54% underwent chemotherapy modifications. Dose reduction (38%) was most common, followed by interruption (24%) and fewer cycles (9%). Patients with modifications more often had poorer performance scores, higher comorbidity indices, and primary cytoreductive surgery. Neurotoxicity and hematologic toxicity were the primary reasons for platinum (33% and 37%) and taxane (47% and 35%) modifications. Dose reduction and interruption were not associated with survival. Fewer cycles were associated with lower 5-year overall survival (32% [95% confidence interval 26% to 38%] vs 36% [95% confidence interval 34% to 38%]) after multi-variable adjustment (hazard ratio 1.36, 95% confidence interval 1.17 to 1.59). CONCLUSIONS:A substantial proportion of Dutch patients with advanced-stage epithelial ovarian cancer undergo chemotherapy modifications. Dose reduction and chemotherapy interruption did not appear to be associated with overall survival, warranting prospective studies. A reduction in the number of chemotherapy cycles was negatively associated with overall survival, possibly reflecting underlying treatment ineffectiveness. However, this association could also be explained by residual confounding (eg, underlying disease severity or treatment response not fully captured in our data) and warrants further confirmation.

Background BRCA1/2 pathogenic variant (PV) carriers have an increased risk of tubo-ovarian cancer. They are recommended to have a risk-reducing salpingo-oophorectomy around age 40, resulting in premature menopause. The alternative risk-reducing salpingectomy (RRS) with delayed oophorectomy (DO) postpones this. We present the 5-year results of a nationwide preference trial (TUBA study) comparing menopause-related quality of life (QoL) after RRS/DO with salpingo-oophorectomy.Methods Premenopausal BRCA1/2-PV carriers aged 25-40 (BRCA1) or 25-45 (BRCA2) chose RRS/DO or salpingo-oophorectomy with or without hormonal replacement therapy (HRT). We compared QoL (Greene Climacteric Scale) between RRS/DO and salpingo-oophorectomy without HRT 5 years after surgery using linear mixed models. Secondarily, RRS/DO was compared with salpingo-oophorectomy with HRT. Women who underwent oophorectomy in the RRS/DO group were excluded in a sensitivity analysis.Results In total, 410 (71.9%) participants chose RRS/DO and 160 (28.1%) salpingo-oophorectomy. Seventy-three (17.8%) participants underwent oophorectomy within 5 years after salpingectomy. The adjusted mean difference (aMD) in QoL was 1.8 (95% CI = -0.6 to 4.3) after salpingo-oophorectomy without HRT and 1.4 (95% CI = -0.4 to 3.1) after salpingo-oophorectomy with HRT compared with RRS (with and without oophorectomy) at 5 years follow-up. The sensitivity analysis showed that QoL decreased less after RRS before oophorectomy compared with salpingo-oophorectomy without (aMD = 2.4, 95% CI = 0.1 to 4.8) and with HRT (aMD = 1.9, 95% CI = 0.1 to 3.7).Conclusion Postponing oophorectomy is key in preventing deterioration of QoL. QoL was similar 5 years after salpingectomy (with and without oophorectomy) compared with salpingo-oophorectomy (regardless of HRT use). However, QoL was higher when comparing salpingectomy without oophorectomy to salpingo-oophorectomy (regardless of HRT use).

In the context of clinical research, computational models have received increasing attention over the past decades. In this systematic review, we aimed to provide an overview of the role of so-called in silico clinical trials (ISCTs) in medical applications. Exemplary for the broad field of clinical medicine, we focused on in silico (IS) methods applied in drug development, sometimes also referred to as model informed drug development (MIDD). We searched PubMed and ClinicalTrials.gov for published articles and registered clinical trials related to ISCTs. We identified 202 articles and 48 trials, and of these, 76 articles and 19 trials were directly linked to drug development. We extracted information from all 202 articles and 48 clinical trials and conducted a more detailed review of the methods used in the 76 articles that are connected to drug development. Regarding application, most articles and trials focused on cancer and imaging-related research while rare and pediatric diseases were only addressed in 14 articles and 5 trials, respectively. While some models were informed combining mechanistic knowledge with clinical or preclinical (in-vivo or in-vitro) data, the majority of models were fully data-driven, illustrating that clinical data is a crucial part in the process of generating synthetic data in ISCTs. Regarding reproducibility, a more detailed analysis revealed that only 24

OBJECTIVE:To determine whether established heart rate parameters of exercise, related to cardiac autonomic function, are associated with incident Parkinson's disease, independent of both clinical and autonomic prodromal features. METHODS:A study of UK Biobank participants who performed a standardized bicycle exercise test (2009-2013), followed until November 2022, and analyzed in January 2024, was carried out. Heart rate increase from rest to exercise, and heart rate decrease from peak exercise to recovery were associated with incident Parkinson's disease. Multivariable adjustment was performed both for clinical characteristics and for prodromal non-cardiac autonomic features. RESULTS:A total of 69,288 eligible participants (men 48%, mean age 56.8 years [SD 8.2 years]) were followed for 12.5 years: among the 319 (0.5%) who developed Parkinson's disease, recognized prodromal markers (constipation, bladder dysfunction) were more common at baseline. The median lag time to diagnosis was 9.3 years (interquartile range 4.4). Both heart rate increase (37.5 [SD 11.5] vs 40.8 [SD 12.4] b.p.m., p < 0.001) and recovery (23.4 [SD 8.8] vs. 27.8 [SD 10.3] b.p.m., p < 0.001) were significantly lower in incident cases compared with controls. Heart rate recovery was independently associated with incident Parkinson's disease, whereas heart rate increase was not. Specifically, a blunted heart rate lowering during recovery was associated with a 30% higher risk of incident Parkinson's disease (HR 1.3; 95% CI 1.1-1.4; p < 0.001 per 10 beats less recovery). INTERPRETATION:Collectively, this suggests that cardiac autonomic involvement precedes clinically manifest Parkinson's disease, and that heart rate recovery might serve as a quantitative prodromal marker. ANN NEUROL 2025;98:1004-1013.

Meta-analyses, embedded in systematic reviews, are pivotal in today's scientific landscape for reconciling conflicting findings, increasing statistical power, and charting new research directions. However, poor reporting practices that conceal technical details and potential limitations often need to be revised to maintain their reliability. Despite existing reporting guidelines, a comprehensive tool has yet to be tailored to appraise the reporting quality of the quantitative aspects of meta-analysis in environmental sciences. To bridge this gap, we introduce the Meta-analysis Appraisal Tool for Environmental Sciences (MATES), a checklist of items to assess the reporting quality of meta-analyses. To develop MATES, we used an adapted Delphi process involving workshops (11-16 participants), a survey (193 participants), and validation (30 participants). This process resulted in a 14-item checklist, encompassing the environmental science communities view of important reporting elements. The validation, across 50 meta-analyses, indicated that the tool is repeatable (an average intra-class correlation of 88.97%) and time-efficient (17.00 ± 11.77 min) to implement. To enhance the accessibility and usability of MATES, we created an interactive web-based app that features training and implementation modules https://kylemorrisonisshiny99.shinyapps.io/MATES_shiny/. We also discuss how to interpret the MATES results, potential use cases of MATES and evaluate the development methodology. Overall, MATES provides authors, readers, reviewers, and editors with a reliable and user-friendly tool to assess the reporting quality of meta-analyses in the environmental sciences.

OBJECTIVES:The feasibility, generalizability, and validity of randomized controlled trials (RCTs) may be compromised when patients have preferences for specific trial arms. The patient preference trial (PPT) design, which assigns at least a subset of the patients based on their preference rather than randomization, has been proposed as an alternative. The aim of this review was to provide an overview of the application of the PPT design in oncological research, with a particular focus on PPTs designed to assess the effectiveness of an intervention and provide recommendations on reporting. STUDY DESIGN AND SETTING:We performed a scoping review including all prospective oncological studies where trial arm allocation for part or all of the patients was based on patients' preferences. Retrieved information included research objectives, motivation for the design choice, baseline covariate adjustments, and sample size calculations. RESULTS:We identified 44 PPTs, of which 34 (77%) aimed to investigate intervention effectiveness and were reviewed in more detail. Of these 34 effectiveness PPTs, 24 (71%) studies were completed trials, while 10 were protocols. The most frequently indicated rationale behind opting for the PPT design was the perceived infeasibility of an RCT (17 [50%] studies). Baseline covariate adjustment was performed in 18 (53%) studies. Fourteen out of 24 completed trials reported an unequal allocation ratio across trial arms not anticipated during the design. CONCLUSION:This review identified several challenges for PPTs in oncology. Future PPTs should take bias due to confounding and unequal group sizes arising from the preferential allocation into account and report on these issues, as these aspects are crucial for the validity and statistical power of the study.

OBJECTIVE:To externally validate the published postoperative and BRCA models predictive of early relapse in patients with advanced-stage epithelial ovarian cancer (EOC) using independent Australian and Dutch cohorts. METHODS:Advanced-stage EOC patients diagnosed between January 1, 2002, and June 1, 2006, in Australia, and between January 1, 2016, and December 31, 2017, in the Netherlands were included. Data from patients who underwent cytoreductive surgery and platinum-based chemotherapy were used to validate both models. Missing data were addressed through multiple imputation. Model updates included recalibration-in-the-large, recalibration, and model revision, with a closed testing procedure to identify the most suitable approach. Model performance was assessed for calibration, discrimination, and the Brier score. RESULTS:The Australian cohort (N = 1334) included 457 early relapsers and 859 late or non-relapsers, showing baseline differences compared to the development cohort. Discrimination was adequate for both the postoperative and BRCA models (c-statistics: 0.69 and 0.70, respectively). The postoperative model required full revision, while recalibration-in-the-large was sufficient for the BRCA model in the Australian cohort. The Dutch cohort (N = 1212) included 283 early relapsers and 929 late or non-relapsers, with baseline characteristics similar to those of the development cohort. Both models demonstrated adequate discrimination (c-statistics: 0.71 and 0.70, respectively). Recalibration-in-the-large corrected miscalibration in the Dutch cohort. CONCLUSION:The postoperative and BRCA model were successfully validated for predicting early relapse in advanced-stage EOC patients, confirming their robustness. However, local data updates are advised to enhance accuracy across clinical settings. Online calculators were built for clinical use (Link 1; Link 2).

Objectives: The aim of this study is to validate a uniform method for measuring perineal descent which can be used for different imaging methods, to establish cut-off values for this measurement, and to assess diagnostic test accuracy (DTA) of imaging techniques using these cut-off values. Secondly, the study aims to correlate perineal descent to symptoms, signs and imaging findings in women with obstructed defaecation syndrome (ODS) to assess its clinical relevance. Methods: Cross-sectional study of 131 women with symptoms of ODS. Symptoms and signs were assessed using validated methods. These women underwent evacuation proctography (EP), magnetic resonance imaging (MRI), transperineal ultrasound (TPUS) and endovaginal ultrasound (EVUS). Perineal descent was measured on EP and MRI as the position of anorectal junction (ARJ) with respect to the pubococcygeal line (PCL) at rest (i.e., static descent) and during evacuation (i.e., descent at Valsalva). Dynamic perineal descent was measured on all four imaging techniques as the difference between the position of the ARJ at rest and Valsalva. DTA of dynamic perineal descent was estimated using Latent Class Analysis in the absence of a reference standard. Results: Interobserver agreement of dynamic perineal descent measurements was good for MRI and EVUS (ICC 0.86 and 0.85) and moderate for EP and TPUS (ICC 0.61 and 0.59). The systematic differences in measurements between imaging techniques show the need for individual cut-off values. New established cut-off values for dynamic descent are for EP 20 mm, MRI 35 mm, TPUS 15 mm and EVUS 15 mm. Sensitivity was moderate for EP (0.78) and MRI (0.74), fair for TPUS (0.65) and poor for EVUS (0.58). Specificity was similar for all imaging techniques (0.73–0.77). Static perineal descent correlated with symptoms of pelvic organ prolapse (POP) (r = 0.19), prolapse of all three compartments (r = 0.19–0.36), presence of levator ani muscle avulsion (p = 0.01) and increased hiatal area (r = 0.51). Dynamic perineal descent correlated with excessive straining (r = 0.24) and use of laxatives (r = 0.24). Classic symptoms of ODS (incomplete evacuation and digitation) did not correlate with perineal descent measurements. Static and dynamic perineal descent were associated with presence of rectocele, enterocele, intussusception, and absence of anismus. Conclusions: Dynamic perineal descent is a reliable measurement that can be applied to different imaging techniques to allow standardisation. Static descent is more often present in women with POP and dynamic descent is more often present in women with constipation. Perineal descent does not correlate with typical symptoms of ODS. Specificity of TPUS and EVUS is comparable to EP and MRI, hence ultrasound could be used for the initial assessment of pelvic floor dysfunction.

OBJECTIVE:To compare menopause-related quality of life (QoL) after risk-reducing salpingectomy (RRS) versus risk-reducing salpingo-oophorectomy (RRSO) until 3 years of post-surgery. DESIGN:A prospective study (TUBA study) with treatment allocation based on patients' preference. Data were collected pre-surgery and at 3 months, 1 and 3 years of post-surgery. SETTING:Multicentre prospective preference trial in thirteen hospitals in the Netherlands. POPULATION:BRCA1/2 pathogenic variant (PV) carriers aged 25-40 (BRCA1) or 25-45 (BRCA2), who were premenopausal, without a future child wish and without current (treatment for) malignancy. METHODS:Treatment allocation was based on patients' preference: either RRS from the age of 25 years with delayed oophorectomy at the maximum age of 45 (BRCA1) or 50 (BRCA2), or RRSO between the ages of 35-40 (BRCA1) or 40-45 (BRCA2). After RRSO, hormone replacement therapy (HRT) was recommended, if not contraindicated. Primarily, menopause-related QoL as measured with the Greene Climacteric Scale (GCS) was compared between the RRS and RRSO without HRT group. Secondarily, GSC-scores of the RRS group were compared with the scores of the RRSO with HRT after surgery group. A higher GSC-score reflects more climacteric symptoms. RESULTS:Until April 2023, 410 participants had undergone RRS and 160 RRSO. The BRCA1/BRCA2 proportions were 51.4%/48.6%. The mean age at surgery (SD) was 37.9 (3.5) years. Participants 3 years after RRSO without HRT had a 4.3 (95% CI 2.1-6.5; p < 0.001) point higher increase in GCS-score from baseline compared to those after RRS, while the difference was 7.9 (95% CI 5.9-9.8) and 8.5 (95% CI 6.5-10.5) points at 3 and 12 months, respectively. Among participants with HRT after surgery, the RRSO group had a 2.4 (95% CI 0.8-3.9; p = 0.002) point higher increase in GCS-score from baseline compared to the RRS group. CONCLUSIONS:In this multicentre preference trial, menopause-related QoL was better after RRS than after RRSO, even with HRT after RRSO. Differences between arms were most pronounced until one-year post-surgery.

Introduction/Background Since most tubo-ovarian cancers originate in the fallopian tubes, the risk-reducing salpingectomy (RRS) with delayed oophorectomy (DO) was proposed as an alternative to risk-reducing salpingo-oophorectomy (RRSO). Compared to RRSO, menopause-related quality of life (QoL) appeared better after RRS up to one year post-surgery. We compare menopause-related QoL after RRS versus RRSO until three years post-surgery. Methodology We performed a prospective multicenter preference study (TUBA study) among BRCA1/2 pathogenic variant (PV) carriers aged 25–40 (BRCA1) or 25–45 (BRCA2), who were premenopausal and without a future child wish. RRS could be performed from the age of 25 with DO at the maximum age of 45 (BRCA1) or 50 (BRCA2). RRSO could be performed between the ages of 35–40 (BRCA1) or 40–45 (BRCA2). After RRSO, hormone replacement therapy (HRT) was recommended, if not contraindicated. Menopause-related QoL as measured with the Greene Climacteric Scale (GCS) was compared between the RRS and RRSO without HRT group. Secondarily, GSC-scores of the RRS group were compared with the scores of the RRSO with HRT after surgery group. A higher GSC-score reflects more climacteric symptoms. Results Until April 2023, 410 participants had undergone RRS and 160 RRSO. The BRCA1/BRCA2 proportions were 51.4%/48.6%. The mean age at surgery (SD) was 37.9 (3.5) years. Participants three years after RRSO without HRT had a 4.3 (95% CI 2.1–6.5; p<.001) point higher increase in GCS-score from baseline compared to those after RRS, while the difference was 7.9 (5.9–9.8) and 8.5 (6.5–10.5) points at three and twelve months, respectively. Among participants with HRT after surgery, the RRSO group had a 2.4 (95% CI 0.8–3.9; p0.002) point higher increase in GCS-score from baseline compared to the RRS group. Conclusion Menopause-related QoL is better after RRS than after RRSO, even with HRT after RRSO. Differences between arms were most pronounced until one year post-surgery. Disclosures None of the authors have anything to disclose.

Importance:Previous studies indicated that female sex might be a modifier in Stargardt disease, which is an ABCA4-associated retinopathy. Objective:To investigate whether women are overrepresented among individuals with ABCA4-associated retinopathy who are carrying at least 1 mild allele or carrying nonmild alleles. Data Sources:Literature data, data from 2 European centers, and a new study. Data from a Radboudumc database and from the Rotterdam Eye Hospital were used for exploratory hypothesis testing. Study Selection:Studies investigating the sex ratio in individuals with ABCA4-AR and data from centers that collected ABCA4 variant and sex data. The literature search was performed on February 1, 2023; data from the centers were from before 2023. Data Extraction and Synthesis:Random-effects meta-analyses were conducted to test whether the proportions of women among individuals with ABCA4-associated retinopathy with mild and nonmild variants differed from 0.5, including subgroup analyses for mild alleles. Sensitivity analyses were performed excluding data with possibly incomplete variant identification. χ2 Tests were conducted to compare the proportions of women in adult-onset autosomal non-ABCA4-associated retinopathy and adult-onset ABCA4-associated retinopathy and to investigate if women with suspected ABCA4-associated retinopathy are more likely to obtain a genetic diagnosis. Data analyses were performed from March to October 2023. Main Outcomes and Measures:Proportion of women per ABCA4-associated retinopathy group. The exploratory testing included sex ratio comparisons for individuals with ABCA4-associated retinopathy vs those with other autosomal retinopathies and for individuals with ABCA4-associated retinopathy who underwent genetic testing vs those who did not. Results:Women were significantly overrepresented in the mild variant group (proportion, 0.59; 95% CI, 0.56-0.62; P < .001) but not in the nonmild variant group (proportion, 0.50; 95% CI, 0.46-0.54; P = .89). Sensitivity analyses confirmed these results. Subgroup analyses on mild variants showed differences in the proportions of women. Furthermore, in the Radboudumc database, the proportion of adult women among individuals with ABCA4-associated retinopathy (652/1154 = 0.56) was 0.10 (95% CI, 0.05-0.15) higher than among individuals with other retinopathies (280/602 = 0.47). Conclusions and Relevance:This meta-analysis supports the likelihood that sex is a modifier in developing ABCA4-associated retinopathy for individuals with a mild ABCA4 allele. This finding may be relevant for prognosis predictions and recurrence risks for individuals with ABCA4-associated retinopathy. Future studies should further investigate whether the overrepresentation of women is caused by differences in the disease mechanism, by differences in health care-seeking behavior, or by health care discrimination between women and men with ABCA4-AR.

OBJECTIVES:Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials. METHODS:We performed a prospective 1-year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient-reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1-year progression and evaluated the potential predictive value of several baseline markers on 1-year disease progression. RESULTS:At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non-ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA). Longer disease duration, longer non-expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1-year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N-acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase. INTERPRETATION:Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024;96:774-787.

Epithelial ovarian cancer (EOC) is the most lethal type of gynaecological cancer, due to lack of effective screening possibilities and because the disease tends to metastasize before onset of symptoms. Women with an increased inherited risk for EOC are advised to undergo a risk-reducing salpingo-oophorectomy (RRSO), which decreases their EOC risk by 96% when performed within guideline ages. However, it also induces premature menopause, which has harmful consequences. There is compelling evidence that the majority of EOCs originate in the fallopian tube. Therefore, a risk-reducing salpingectomy with delayed oophorectomy (RRS with DO) has gained interest as an alternative strategy. Previous studies have shown that this alternative strategy has a positive effect on menopause-related quality of life and sexual health when compared to the standard RRSO. It is hypothesized that the alternative strategy is non-inferior to the standard RRSO with respect to oncological safety (EOC incidence). Three prospective studies are currently including patients to compare the safety and/or quality of life of the two distinct strategies. In this article we discuss the background, opportunities, and challenges of the current and alternative strategy.

Objective: To assess the association between pretreatment thrombocytosis, anemia, and leukocytosis and overall survival (OS) of advanced-stage EOC. Furthermore, to develop nomograms using established prognostic factors and pretreatment hematologic parameters to predict the OS of advanced EOC patients. Methods: Advanced-stage EOC patients treated between January 1996 and January 2010 in eastern Netherlands were included. Survival outcomes were compared between patients with and without pretreatment thrombocytosis (≥450,000 platelets/µL), anemia (hemoglobin level of <7.5 mmol/L), or leukocytosis (≥11.0 × 109 leukocytes/L). Three nomograms (for ≤3-, ≥5-, and ≥10-year OS) were developed. Candidate predictors were fitted into multivariable logistic regression models. Multiple imputation was conducted. Model performance was assessed on calibration, discrimination, and Brier scores. Bootstrap validation was used to correct for model optimism. Results: A total of 773 advanced-stage (i.e., FIGO stages IIB–IV) EOC patients were included. The median [interquartile range, IQR] OS was 2.3 [1.3–4.2] and 3.0 [1.4–7.0] years for patients with and without pretreatment thrombocytosis (p < 0.01). The median OS was not notably different for patients with and without pretreatment leukocytosis (p = 0.58) or patients with and without pretreatment anemia (p = 0.07). The final nomograms comprised established predictors with either pretreatment leukocyte or platelet count. The ≥5- and ≥10-year OS models demonstrated good calibration and adequate discrimination with optimism-corrected c-indices [95%-CI] of 0.76 [0.72–0.80] and 0.78 [0.73–0.83], respectively. The ≤3-year OS model demonstrated suboptimal performance with an optimism-corrected c-index of 0.71 [0.66–0.75]. Conclusions: Pretreatment thrombocytosis is associated with poorer EOC survival. Two well-performing models predictive of ≥5-year and ≥10-year OS in advanced-stage EOC were developed and internally validated.

PURPOSE/BACKGROUND:Antipsychotic polypharmacy (APP) is controversial yet applied in 20% of patients with psychotic disorders. We investigated indications for initiating and continuing APP, including the contribution of unfinished cross-titrations. METHODS/PROCEDURES:This 2-month study was part of a prospective study to reduce inappropriate APP in inpatients. With each new prescription resulting in APP, we asked the prescriber for the indication (eg, switching antipsychotics, sedation for agitation/sleep disorders, treatment refractoriness, other) and repeated this at 30 and 60 days. Secondary outcome was unfinished cross-titration at 60 days. FINDINGS/RESULTS:In a consecutive cohort of 55 patients, 80% diagnosed with schizophrenia, switching antipsychotics was the primary initial indication for APP in 31 of 55 patients (56%), followed by sedation in 12 of 55 patients (22%), and treatment refractoriness in 10 of 55 patients (18%). Overall, APP was discontinued after 30 days in 25 of 55 patients (45%) and after 60 days in 28 of 55 patients (51%). At 60 days, APP initiated for switching antipsychotics was ongoing in 9 of 31 patients (29%), APP initiated for sedation was ongoing in 8 of 12 patients (66%), and APP initiated for refractoriness was ongoing in 9 of 10 patients (90%). The initial indication for APP was maintained at 60 days in 21 of 27 patients (78%). Unfinished cross-titration occurred in 9 of 31 patients (29%) with APP initiated for switching antipsychotics. IMPLICATIONS/CONCLUSIONS:APP was initiated primarily because of cross-titration switching of antipsychotics. The reason for APP was generally maintained consistently over time, particularly when initiated for treatment refractoriness. Of all patients with APP initiated to switch antipsychotics, 29% ended in unfinished cross-titration.

Purpose/BackgroundAntipsychotic polypharmacy (APP) is controversial yet applied in 20% of patients with psychotic disorders. We investigated indications for initiating and continuing APP, including the contribution of unfinished cross-titrations.Methods/ProceduresThis 2-month study was part of a prospective study to reduce inappropriate APP in inpatients. With each new prescription resulting in APP, we asked the prescriber for the indication (eg, switching antipsychotics, sedation for agitation/sleep disorders, treatment refractoriness, other) and repeated this at 30 and 60 days. Secondary outcome was unfinished cross-titration at 60 days.Findings/ResultsIn a consecutive cohort of 55 patients, 80% diagnosed with schizophrenia, switching antipsychotics was the primary initial indication for APP in 31 of 55 patients (56%), followed by sedation in 12 of 55 patients (22%), and treatment refractoriness in 10 of 55 patients (18%). Overall, APP was discontinued after 30 days in 25 of 55 patients (45%) and after 60 days in 28 of 55 patients (51%). At 60 days, APP initiated for switching antipsychotics was ongoing in 9 of 31 patients (29%), APP initiated for sedation was ongoing in 8 of 12 patients (66%), and APP initiated for refractoriness was ongoing in 9 of 10 patients (90%). The initial indication for APP was maintained at 60 days in 21 of 27 patients (78%). Unfinished cross-titration occurred in 9 of 31 patients (29%) with APP initiated for switching antipsychotics.Implications/ConclusionsAPP was initiated primarily because of cross-titration switching of antipsychotics. The reason for APP was generally maintained consistently over time, particularly when initiated for treatment refractoriness. Of all patients with APP initiated to switch antipsychotics, 29% ended in unfinished cross-titration.