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Analytical development experts from nine pharmaceutical companies share their collective experience and perspective on the minimum expectations when establishing scientifically sound practices (SSP) during technical development of pharmaceuticals; some companies use the equivalent expression 'good scientific practices'. The authors describe the SSP framework as a comprehensive set of best practices and recommendations for analytical development activities focused on a flexible and "fit for purpose" approach supporting the different development phases as well as post commercialization life-cycle management. It covers scientific and technical activities not performed under current Good Manufacturing Practices (cGMP) yet resulting in data or information that may become regulatorily relevant by submitting to health authorities, particularly in CMC documentation during clinical development, NDA/BLA/MAA filings or post-approval changes. These activities include for example analytical development activities related to product characterization, comparability assessments, forced degradation studies, cell line development, manufacturing process development, (pre-)formulation studies, device development, or investigations related to cGMP activities. Data requires good documentation practice ensuring that all records are accurate, complete, legible, and traceable, supporting data integrity and regulatory compliance in scientific and clinical work. Analytical developmental activities significantly impact the control of manufacturing processes and overall control strategies. They provide rationales and justifications for controls, such as specifications, that are subsequently maintained under cGMP. Therefore, these activities require appropriate scientific scrutiny to ensure high data quality. This ensures continual improvement across the entire product lifecycle by promoting a science- and risk-based approach during each lifecycle stage. As described in ICH Q10, such an approach fosters an integrated and effective pharmaceutical quality system, enhances innovation, and connects development and manufacturing activities through quality risk management.

Identifying patients with glaucoma who are at risk of rapid disease progression is crucial to preventing vision loss. We aimed to develop and externally validate G-PROG, a deep learning model that predicts 2-5-year glaucoma progression from baseline colour fundus photographs (CFPs). G-PROG was trained and validated on data from a single centre (UZ Leuven, Leuven, Belgium); the other datasets (Brussels, Belgium; Liège, Belgium; Tampere, Finland; Mainz, Germany; and Hangzhou, China) served as external test sets. Across six glaucoma departments, we analysed 161 827 fundus images from 127 962 visits (13 913 patients), totalling 128 021 eye-years of follow-up. Progression was defined by the G-RISK slope, calculated via within-eye linear regression on longitudinal G-RISK predictions over follow-up intervals of 2-5 years. G-RISK is a previously validated deep learning model that quantifies glaucomatous optic nerve damage from CFPs. We trained 20 G-PROG configurations with varying inclusion criteria applied to the number of visits, image quality, time between visits, and G-RISK at baseline. Performance was evaluated using the area under the receiver operating characteristic curve (AUC), the coefficient of determination (R2), and explained variance score (EVS). G-RISK slope as a progression biomarker was validated against the visual field mean deviation (MD) slope and average retinal nerve fibre layer thickness (RNFL) slope. Significant AUC values were obtained in 18 out of 20 model configurations, with internal validation reaching a maximum AUC of 0·98 (95% CI 0·97-1·00) across follow-up intervals (2-5 years). In glaucomatous eyes with a baseline G-RISK exceeding 0·6, the maximum AUC was 0·92 (0·85-0·98). For external validation, the predictions from the eight top-performing configurations (selected based on positive R2 and minimal discrepancy between R2 and EVS in internal validation) were averaged. Maximum AUC values ranged from 0·74 to 0·86 across the five test datasets. G-RISK slope showed significant agreement with established progression markers, with maximum AUCs of 0·82 for MD slope and 1·00 for average RNFL slope. Externally validated across five international cohorts, G-PROG predicts 2-5-year glaucoma progression from baseline CFPs. Prospective evaluation is warranted to assess whether G-PROG can improve risk stratification and resource allocation in glaucoma care. This work was funded and supported by grants from the National Medical Research Council, National Research Foundation Singapore, National Health Innovation Centre Singapore, SingHealth and Duke-NUS, Duke-NUS, the Singapore Eye Research Institute and Nanyang Technological University and the Singapore Eye Research Institute, the Competitive Research Funding of the Pirkanmaa Wellbeing Services County, the LUX-Foundation for Glaucoma Research, state funding for university-level health research at Tampere University Hospital, Wellbeing Services County of Pirkanmaa, the Tampere University Hospital Support Foundation, and the Belgian Ophthalmology Cooperation in Clinical Sciences initiative hosted by the Funds for Research in Ophthalmology.

"Brain health" encompasses key functions such as cognition, emotion, and behaviour, and is increasingly relevant given its role across neurological and psychiatric conditions. One of these, depression is the most common psychiatric comorbidity in people with epilepsy (PWE). When unrecognized and untreated, depression is associated with increased seizure severity and poorer treatment response, significantly impacting patients' prognosis and quality of life; conversely, the rate of epilepsy is 2-fold higher in individuals with incident depression compared to those without depression. Several studies have confirmed a strong bidirectional relationship between epilepsy and depression; an advisory panel of psychiatrists and neurologists with expertise in epilepsy and mood disorders convened for a virtual meeting held in 2024 to assess the impact of the interplay between these two conditions. A comprehensive, interdisciplinary approach to discussion was adopted to address challenges in diagnosing and managing depression in PWE, focusing on early intervention, patient education, and tailored treatments strategies; additionally, the meeting emphasized the importance of integrated care between neurologists and psychiatrists to address this unmet medical need. The authors identified depression in PWE as being underdiagnosed due to overlapping symptoms, stigma, and limited psychiatric care integration. Management is challenging as some antiseizure medication worsen depression and certain antidepressants may lower the seizure threshold, requiring careful selection and monitoring to balance efficacy and safety. Potential interactions between these medicines underscore the importance of carefully selecting therapeutic combinations to minimize adverse effects. Effective management involves an interdisciplinary approach, integrating neurologists and psychiatrists. Key strategies include early screening, psychoeducation, a personalized approach to pharmacological and nonpharmacological treatment, and increased awareness among healthcare providers, patients, and caregivers regarding the overlap of neurological and psychiatric disorders. Furthermore, educational resources, as well as digital tools, can help inform and educate patients and caregivers on holistic brain health management.

To evaluate the impact of timing of aggressive joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) piperacillin-tazobactam on early clinical response in pediatric hematopoietic stem cell (HSCT) recipients with febrile neutropenia (FN). This prospective, monocentric, observational study included pediatric HSCT recipients receiving at least 72 hours of TDM-guided CI piperacillin-tazobactam monotherapy for treating FN episodes. Plasma C-reactive protein, procalcitonin, and interleukin-6 levels were assessed at the onset of febrile neutropenia episodes and at day +1 and +3 after starting antibiotic therapy, together with steady-state piperacillin-tazobactam concentrations (Css). Aggressive piperacillin-tazobactam joint PK/PD target attainment was calculated at each timepoint. Multivariate logistic regression analyses were performed for identifying at each timepoint independent predictors significantly associated with the attainment of aggressive PK/PD target. Overall, 42 patients who received CI piperacillin-tazobactam for 49 documented FN episodes were enrolled. The proportion of aggressive joint PK/PD target attainment was 46.7% at day +1 and increased to 67.3% at day +3 (p=0.04). Clinical response at day +3 was reported in 35 FN episodes (71.4%). Aggressive PK/PD target attainment occurred more frequently in cases having lower baseline creatinine clearance values at day +1 (OR 1.01; 95%CI 1.00-1.02; p=0.018), and was an independent predictor of >50% reduction of baseline plasma interleukin-6 levels at day +3 (OR 4.62; 95%CI 1.22-17.45; p=0.024). Attaining aggressive piperacillin-tazobactam joint PK/PD target in pediatric HSCT recipients with FN was significantly associated with reduction >50% in interleukin-6 levels at day +3, although no significant impact on early clinical response was found.

Orally administered small-molecule programmed death ligand 1 (PD-L1) inhibitors may have the potential to improve patient outcomes in the treatment of a range of cancers compared with their antibody-based counterparts. A small molecule might achieve better tumor tissue penetration, and oral administration could significantly improve convenience and access for patients. Three phase 1 open-label, non-randomized, dose escalation, and expansion studies evaluated the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of three agents in patients with advanced solid tumors: INCB086550 (NCT03762447), INCB099280 (NCT04242199), and INCB099318 (NCT04272034). Overall, 138, 182, and 104 patients received INCB086550, INCB099280, and INCB099318, respectively. Most had previously received ≥2 lines of cancer therapy for advanced or metastatic disease; 9.6%-16.5% had received prior immunotherapy. All three agents were rapidly absorbed and showed stable dose-dependent PK. With INCB086550, 88 patients (63.8%) had ≥1 treatment-related treatment-emergent adverse event (TEAE), and 19 (13.8%) had ≥1 treatment-related grade ≥3 TEAE. In total, 14 patients (10.1%) had a nervous system-associated TEAE for which an immune-mediated etiology could not be ruled out; events were predominantly peripheral sensory and motor neuropathies. With INCB099280 and INCB099318, 144 (79.1%) and 69 (66.3%) of patients had ≥1 treatment-related TEAE, and 25 (13.7%) and 12 (11.5%) had ≥1 treatment-related grade ≥3 TEAE, respectively. The most frequent immune-related adverse events were skin reactions (INCB099280 and INCB099318) and hepatitis (INCB099280). No dose-limiting toxicities (DLTs) occurred during dose escalation with INCB086550 or INCB099318; two DLTs occurred in two patients with INCB099280 (grade 2 vomiting with 600 mg once daily and grade 2 maculopapular rash with 800 mg two times per day). Overall objective response rates for INCB086550, INCB099280, and INCB099318 were 10.9% (95% CI 6.2% to 17.3%; n=15), 8.8% (95% CI 5.1% to 13.9%; n=16), and 8.7% (95% CI 4.0% to 15.8%; n=9), respectively. Target engagement and PD activity were demonstrated, including PD-L1 binding, and increases in cytokine and chemokine production, as well as T-cell activation and proliferation. Both INCB099280 and INCB099318 had an acceptable safety profile, with preliminary evidence of antitumor activity. The risk of immune-mediated neuropathy led to discontinuation of the clinical program for INCB086550.

To systematically evaluate the certainty of evidence for treatment strategies across age groups and mood phases in bipolar disorder, and develop an open access web platform to facilitate shared decision making. Living umbrella review, evaluation, analysis, and communication hub (U-REACH) project. PubMed, PsycInfo, and Cochrane library databases, from inception to 19 November 2024. Systematic reviews with network or pairwise meta-analyses of randomised controlled trials of pharmacological, nutraceutical, psychosocial, brain stimulation, or circadian rhythm based treatments, administered as monotherapy (without concurrent interventions), augmentation treatment (interventions added to an ongoing treatment regimen), or combination treatment (simultaneous initiation of two different interventions), examining any age group, bipolar disorder phase (ie, acute bipolar depression, mania or mixed episodes, or maintenance), treatment, control, or outcome. 77 studies met the inclusion criteria (21 network meta-analyses and 56 pairwise meta-analyses), including 116 unique pharmacological (n=74), brain stimulation (n=18), nutraceutical (n=13), psychosocial (n=8), and circadian rhythm based (n=3) treatments as monotherapy, augmentation, or combination therapy, along with five control interventions. These studies covered 133 unique outcomes (45 efficacy outcomes and 88 safety outcomes) resulting in 2510 meta-analyses with Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) ratings of the certainty of the evidence as high (n=236), moderate (n=827), low (n=986), and very low (n=461). A communication hub, the Evidence Based Interventions for Bipolar Disorder (EBI-BD) platform, was developed and the full results are freely available (https://ebibd-database.org), including the preference based tool (12 interventions and 17 safety outcomes). Interventions effective across outcomes varied by phases. For bipolar depression, effective interventions in adults were cariprazine, divalproex or valproate, fluoxetine, ketamine (augmentation), lamotrigine, lumateperone, lurasidone, olanzapine, olanzapine with fluoxetine, and quetiapine, whereas effective interventions in children and adolescents were lurasidone and olanzapine with fluoxetine. For mania episodes, effective interventions in adults were aripiprazole, asenapine, carbamazepine, cariprazine, divalproex or valproate, haloperidol, lithium, olanzapine, paliperidone, quetiapine (also augmentation), risperidone (also as augmentation), tamoxifen, and ziprasidone, whereas effective interventions in children and adolescents were aripiprazole, asenapine, olanzapine, quetiapine, and risperidone. For maintenance, interventions effective across outcomes in adults were aripiprazole (also the long acting injectable formulation), asenapine, divalproex or valproate, lithium, olanzapine, group psychoeducation (augmentation), quetiapine, and risperidone long acting injectable formulation. Interventions effective across phases were aripiprazole (also as augmentation and as a long acting injectable formulation), asenapine, cariprazine, cognitive behavioural therapy (augmentation), divalproex or valproate, lamotrigine, lithium, olanzapine (also as augmentation), paliperidone, quetiapine (also as augmentation), and risperidone (also as augmentation and the long acting injectable formulation) (adults). Treatment effects by neuroscience based nomenclature classes are also reported. The EBI-BD tool can help clinicians make evidence based, personalised treatment decisions for bipolar disorder. This resource can inform clinical guidelines and provides a foundation for continuously improving bipolar disorder care as new evidence emerges. Open Science Framework https://osf.io/pjmvn/ READERS' NOTE: This is a living systematic review and may be updated in the next two years if additional evidence emerges.

Rondaptivon pegol (BT200) is a PEGylated RNA aptamer that prolongs von Willebrand factor (VWF) and factor VIII half-lives in patients with hemophilia A and von Willebrand disease (VWD) type 2B. Embryo-fetal safety is particularly relevant given the disproportionate disease burden in women with VWD. Data on placental transfer and developmental safety of PEGylated aptamers remain limited. An embryo-fetal development study was conducted in pregnant rabbits. Animals received rondaptivon pegol subcutaneously (0, 1.5, 5, or 15 mg/kg/day) from gestational days (GDs) 7-19. Maternal toxicokinetic samples and pooled fetal plasma concentrations were collected during gestation to quantify transplacental exposure. Rondaptivon pegol was well tolerated, with no maternal toxicity, no effects on implantation, and no treatment-related fetal malformations. Dose-related reductions in mean fetal body weight (<11%) were considered adverse only at the highest dose level. Maternal systemic exposure was supratherapeutic, with mean Cmax ranging from 133 to 807 &#xb5;g/mL on GD19, far exceeding the human target concentration (&#x223c;1.2 &#xb5;g/mL). Fetal plasma concentrations were <0.25% of maternal levels across all dose groups, confirming minimal placental transfer. The no-observed-adverse-effect level was 5 mg/kg/day. At maternal systemic exposures ranging from 110- to 670-fold above anticipated clinical levels, rondaptivon pegol did not adversely affect implantation, embryonic viability, or fetal development. These findings provide the first quantitative maternal-fetal pharmacokinetic and developmental safety data for a PEGylated aptamer, supporting further clinical evaluation of rondaptivon pegol in women of reproductive age.

Psilocybin has demonstrated promising antidepressant effects in depression and treatment-resistant depression (TRD) in controlled clinical trials. However, its effectiveness and safety in real-world therapeutic settings remain largely unknown. Although psilocybin is not yet approved as an antidepressant treatment, Switzerland's unique legal framework allows its limited medical use for TRD. We aimed to examine antidepressant outcomes, safety, and feasibility of real-world psilocybin therapy for TRD, including repeated dosing sessions. We conducted a retrospective analysis of medical records from 19 TRD patients treated with psilocybin (20-35 mg) across one to four dosing sessions at the Psychiatric University Hospital Zurich. Depression severity was assessed using the Montgomery-&#xc5;sberg Depression Rating Scale (MADRS) and the Beck Depression Inventory II (BDI). Changes from baseline to interim and post-treatment were analysed, including response and remission. MADRS scores decreased from baseline (M = 30.78) to post-treatment (M = 19.89), with a large effect size (Hedges' g = 1.37, 95% CI [0.90, 1.84]). BDI scores also decreased (M = 32.33-M = 23.28), with a medium-to-large effect (Hedges' g = .77, 95% CI [0.46, 1.09]). Response and remission rates were 33.3% and 22.2% (MADRS), and 27.8% and 27.8% (BDI). No serious adverse events were documented. This study provides some of the first evidence on psilocybin outside controlled trials. Psilocybin was associated with a clinically meaningful reduction in depressive symptoms, with response and remission rates below those reported in previous trials. Findings suggest feasibility of psilocybin in real-world TRD care and should be interpreted within the limitations of small sample size, retrospective uncontrolled design, heterogeneous treatment conditions, and concomitant psychopharmacology. This research did not receive any funding.

One of the fundamental challenges with human nutrition research is the difficulty of knowing what people actually eat. Asking people to live in the laboratory enables precise control and measurement of food intake, but the environment does not reflect real-world conditions. Here, we present a bedside-to-outside model, which aims to address this gap by combining controlled feeding studies (prioritizing efficacy) with free-living intervention studies (incorporating effectiveness) within the same cohort. This approach will enable translation of the efficacy and effectiveness of dietary interventions with causal inference within the same cohort, offering novel insights into the real-world impact of controlled dietary interventions.

Postoperative delirium (POD) and perioperative neurocognitive disorders (PND) are among the most common and clinically relevant complications following surgical procedures. Older and vulnerable patients are particularly affected, with reported delirium incidences ranging from 20% to 50%, depending on patient risk profile, surgical procedure, and screening methodology. Beyond increased morbidity and mortality, postoperative neurocognitive complications are associated with functional decline, reduced quality of life, prolonged hospital stays, and substantial healthcare costs.The evidence base for the prevention, early detection, and management of perioperative neurocognitive disorders includes preoperative risk stratification, structured delirium screening, EEG-guided anesthesia, and multimodal perioperative care pathways. These measures are supported by contemporary international recommendations, including the European Society of Anaesthesiology and Intensive Care (ESAIC) guideline on postoperative delirium in adult patients. Despite the growing body of evidence, the successful implementation of these strategies into routine clinical practice remains challenging.This CME article summarizes the current evidence regarding the assessment, prevention, and follow-up of perioperative neurocognitive disorders and discusses the Safe Brain Initiative (SBI) together with its Patient-Centered Precision Care - (PC)2 - framework as an example of a structured implementation strategy for evidence-based perioperative care. Three clinical case studies illustrate the practical application of guideline-based recommendations throughout the perioperative pathway. Statements supported by published evidence are clearly distinguished from working hypotheses and implementation concepts whose effectiveness remains the subject of ongoing scientific investigation.

Granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA) are recognized subtypes of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Their clinical boundaries, however, may be more dynamic than assumed. We describe 2 patients illustrating sequential phenotype transitions with prominent respiratory involvement. The first patient was initially diagnosed with GPA, presenting with neuropathy, purpura, epistaxis, renal disease, and myeloperoxidase (MPO)-ANCA positivity. Six years later, she developed asthma, marked eosinophilia, and eosinophilic myocarditis, consistent with evolution toward EGPA despite stable ANCA serology. The second patient was first classified as EGPA based on eosinophilic asthma, chronic rhinosinusitis with nasal polyps, and MPO-ANCA with borderline proteinase 3 (PR3)-ANCA. After SARS-CoV-2 infection, he developed GPA-like disease with strongly positive PR3-ANCA and destructive airway involvement, including tracheobronchomalacia requiring tracheostomy and stenting. These cases highlight that recognizing this dynamic nature is essential for the timely reassessment of disease classification, prognosis, and therapeutic approach in AAV.

To evaluate the association between baseline optical coherence tomography (OCT) biomarkers and 2-year disease progression from intermediate age-related macular degeneration (iAMD) to advanced atrophic AMD, defined by OCT, with emphasis on ellipsoid zone (EZ) attenuation/loss and other quantitative structural features. Retrospective cohort study. 502 eyes with iAMD and no evidence of atrophy (i.e., RPE loss with associated outer retinal atrophy) or exudation at baseline, each with 2-year follow-up OCT imaging. Baseline and 2-year spectral-domain OCT scans were analyzed using a validated, machine learning-enhanced multilayer segmentation platform with subsequent certified reader review and correction. Quantitative OCT parameters included EZ-RPE thickness, partial and total EZ attenuation, drusen volume, hyperreflective foci (HRF) count, total RPE loss, and outer nuclear layer-RPE (ONL-RPE) thickness. Fully automated deep-learning models quantified hypertransmission and EZ at-risk (i.e., a model developed to identify areas of abnormal EZ-RPE thinning in the absence of RPE loss). A random forest classifier was trained using baseline features, with performance assessed using 5-fold stratified cross-validation. Development of OCT-defined advanced atrophic AMD defined by total RPE loss with associated outer retinal atrophy with an area &#x2265;0.05 mm2 (i.e., cRORA equivalent) at 2 years and baseline OCT biomarkers associated with progression. Eyes that developed advanced atrophic AMD showed significantly greater partial and total EZ attenuation, reduced EZ-RPE and ONL-RPE thickness, higher drusen volume, and greater HRF counts than non-converters (all p<0.05). Deep-learning-derived EZ at-risk and hypertransmission metrics were also significantly higher in converters. The cross-validated predictive model incorporating all baseline features achieved a mean area-under-the-ROC curve (AUC) of 0.85 &#xb1; 0.02. EZ integrity metrics and HRF count ranked as the most influential predictors of progression. Quantitative OCT biomarkers, particularly EZ integrity measures and HRF count, are strongly associated with 2-year progression to advanced atrophic AMD in iAMD. These findings support the role of quantitative EZ integrity metrics and hyperreflective foci features for early disease risk stratification and may inform the design of prevention-focused or early-intervention clinical trials aimed at delaying the onset of atrophic changes.

Evidence to guide (neo)adjuvant chemotherapy choices in carriers of germline BRCA1/BRCA2 pathogenic variants (BRCA carriers) with early breast cancer (BC) is limited. We evaluated the association of different chemotherapy regimens with survival outcomes in this population. The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, retrospective cohort study of BRCA carriers diagnosed with stage I-III BC at age &#x2264;&#x202f;40 years, between 2000 and 2020. Disease-free survival (DFS) and overall survival (OS) were assessed among patients with HER2-negative disease treated with anthracycline-taxane, anthracycline-no-taxane, or non-anthracycline (neo)adjuvant chemotherapy. The association of platinum use with outcomes was evaluated in triple-negative breast cancer (TNBC). Among 4200 young BRCA carriers from 109 centres who received (neo)adjuvant chemotherapy for HER2-negative BC, 58.7% had TNBC. Median follow-up was 8.1 years (IQR, 4.7-12.6 years). Anthracycline-taxane, anthracycline-no-taxane, and non-anthracycline regimens were used in 74.4%, 19.3%, and 6.3% of patients, respectively. Platinum agents were administered in 19.8% of TNBC cases. After multivariable adjustment, no significant differences in DFS or OS were observed between anthracycline-no-taxane and anthracycline-taxane regimens (DFS adjusted hazard ratio [aHR] 0.88, 95% CI 0.73-1.05; OS aHR 1.20, 95% CI 0.87-1.67) or non-anthracycline regimens (DFS aHR 1.07, 95% CI 0.82-1.38; OS aHR 1.16, 95% CI 0.68-2.0). In TNBC, platinum use was not associated with improved outcomes. In young BRCA carriers with HER2-negative early BC, no statistically significant differences in survival outcomes were detected across different chemotherapy regimens. Our findings may inform future prospective studies evaluating chemotherapy de-escalation strategies in this genetically defined population.

Based on the principle that increased airway resistance prolongs the expiratory time constant (TC), we investigated whether TC patterns could serve as a signature for obstruction. In this cross-sectional multicenter study of 19,937 validated spirometry records, we divided the descending expiratory flow-volume curve into five equal volume segments and derived consecutive TCs for each. A K-means algorithm trained on the normal subset defined data-driven patterns, which were then used to classify the entire cohort. We quantified pattern prevalence and used propensity score matching to assess spirometric differences between patterns within each spirometric category. Two distinct patterns were identified: a 'normal' pattern (stable consecutive TCs) and an 'obstructive' pattern (progressively prolonging TCs). The obstructive pattern was present in 7% of normal spirometry, 13% of possible restriction, and 33% of nonspecific FEV1 reduction, while 9% of patients meeting obstruction criteria had a normal TC pattern. In normal spirometry group, the obstructive pattern group showed lower forced expiratory volume in 1 second (FEV1) (males: 2.7 vs 3.0 L; females: 1.8 vs 2.0 L), reduced FEV1/forced vital capacity (FVC) (males: 67% vs 76%; females: 68% vs 78%), and impaired small airway metrics, including maximal mid-expiratory flow (MMEF25-75) (males: 1.6 vs 2.6 L/s; females: 1.0 vs 1.8 L/s) and FEV3/FEV6 (males: 91% vs 94%; females: 91% vs 95%), all p&#x2009;<&#x2009;0.001. Other spirometric groups mirrored these findings. The obstructive TC pattern represents a distinct physiological phenotype suggestive of obstructive lung mechanics and is highly prevalent across common spirometric categories.

Interleukin (IL)17 and IL23 inhibitors (i) for psoriasis are highly effective but not all patients may need the registered dose. Dose reduction (DR) could contribute to prevent unnecessary drug exposure and lower healthcare expenditures. The aim of this study was to evaluate whether DR through stepwise interval prolongation is effective and safe in patients with psoriasis with stable low disease activity. This pragmatic, open-label, controlled, non-inferiority randomised clinical trial was performed in 19 (non-)academic hospitals in the Netherlands and Belgium. Patients were randomised (2:1) to stepwise DR or usual care (UC) by block randomisation with random allocation sequence, stratified by biologic. Patients with stable low disease activity on registered dosages of IL17i (secukinumab, ixekizumab, bimekizumab, brodalumab) or IL23i (guselkumab, risankizumab, tildrakizumab) were eligible. In DR, injection intervals were prolonged stepwise to 67.0% and 50.0% of the original dose if disease activity permitted. The primary aim was to assess non-inferiority of this DR strategy compared to UC regarding the incidence proportion of persistent flares (Psoriasis Area and Severity Index (PASI) > 5 for &#x2265;3 months) after 18 months, with a non-inferiority margin of 15.0%. Patients were analysed by intention-to-treat (ITT) and per-protocol (PP) with imputation of missings. ClinicalTrials.gov Identifier NCT04340076; status: closed. Between June 30, 2020 and September 14, 2023, 244 patients were included (mean age 51 &#xb1; 15 years; 67.0% male; DR N = 164, UC N = 80). After 18 months, a difference of 2.4% (95% CI -2.0% to 6.8%) in incidence proportion of persistent flares (DR (4.0%) and UC (1.6%) in ITT) showed non-inferiority of DR. No serious adverse events/deaths related to DR were reported. Disease-activity guided, stepwise interval prolongation of IL17i and IL23i in patients with controlled psoriasis is an effective and safe strategy to reduce unnecessary exposure to these expensive drugs. ZonMw (the Netherlands Organization for Health Research and Development), KCE Trials (the Belgian Health Care Knowledge Centre).

Childhood suicide attempts requiring pediatric intensive care unit (PICU) admission represent some of the most severe forms of self-harm and are associated with substantial morbidity and mortality. This study aimed to identify potential psychosocial factors and clinical warning signs preceding severe suicide attempts in children and adolescents. This retrospective study was conducted in the PICU of Van Regional Training and Research Hospital between January 2017 and January 2025. Children aged 8-18 years admitted following intentional self-harm or suicide attempts were eligible. Survivors participated in structured face-to-face interviews. For deceased patients, information was obtained from at least three first-degree relatives and corroborated using medical records and reports from treating physicians. During the study period, 256 individual patients accounted for 289 suicide-related PICU admissions, of whom 116 met the inclusion criteria. The cohort included 81 females (69.8%) and 35 males (30.2%), with a mean age of 15.5 &#xb1; 2.1 years. Patients were classified according to the presence of documented healthcare encounters within the preceding year: Group 1 (80/116, 69.0%) had at least one prior healthcare contact for potential warning signs, whereas Group 2 (36/116, 31.0%) had none. Group 2 patients were younger, more frequently aged 8-13 years, and experienced significantly higher morbidity and mortality. Mortality was significantly higher among boys aged 8-13 years. The highest mortality rates were observed among patients with gender identity-related distress (3/3) and pregnant adolescents reporting violations of sexual consent (3/4), although these findings were based on very small subgroups. Nearly 70% of children who attempted suicide had prior healthcare encounters for potentially recognizable warning signs, including psychosomatic complaints, humiliation or bullying, exposure to violence, and gynecological presentations. These findings highlight opportunities for earlier recognition of psychosocial distress during routine clinical encounters. Given the retrospective single-center design and absence of a non-suicidal comparison group, the results should be considered exploratory and hypothesis-generating rather than predictive.