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Polycythemia vera is characterized by erythrocytosis and increased risk of thrombosis. Sapablursen is an antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6), increases hepcidin production, and reduces iron availability for erythropoiesis. IMPRSSION; an ongoing phase 2a, randomized, open-label study includes patients meeting 2016 WHO criteria for polycythemia vera, requiring ≥3 phlebotomies within 6 months of screening and ≥1 phlebotomy within the last 12 weeks. Cohort A (120 or 80 mg) and Cohort B (40 mg) received sapablursen subcutaneously once every 4 weeks (Q4W). The primary efficacy endpoint was the reduction in phlebotomy frequency from baseline to weeks 17-37 in patients who received ≥1 dose. Forty-nine patients received ≥1 sapablursen dose (median age 61 years; 82% male). The baseline mean±SD weekly phlebotomy rate was 0.15±0.07 in Cohort A; 0.17±0.07 in Cohort B and was reduced by -0.10 (95%CI, -0.13, -0.07; n=32;p<0.0001) in Cohort A; -0.10 (95%CI, -0.14, -0.06; n=17;p=0.0001) in Cohort B. Sapablursen reduced the median (IQR) number of phlebotomies from 5.0 (3.0-6.0,Cohort A; 3.5-6.5,Cohort B) at baseline (26-weeks) to 0 (0-1.0) in the efficacy evaluation window (20-weeks) in Cohort A and 1.5 (0-2.5) in Cohort B. Most adverse events were mild or moderate; anemia and fatigue were most common. The mean change in MPN-SAF-TSS at week 37 was -6.21 points (95%CI: -10.56, -1.85, p=0.0052) in Cohort A; -2.71 points in Cohort B (95% CI: -8.33, 2.91, p=0.34). Sapablursen reduced phlebotomy need, improved symptoms, and was safe and well-tolerated in patients with polycythemia vera. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov: NCT05143957)

ABSTRACT Objectives To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross‐regional practices across North America, Europe, and the Pacific. Methods Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta‐analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. Results The sample ( N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention‐deficit/hyperactivity disorder (ADHD), post‐traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first‐generation antipsychotic prescriptions varied, with higher rates observed in Europe. Conclusions Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context‐specific guidelines. Gaps in data on medication‐assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

Abstract Objectives 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. Design Living umbrella review, evaluation, analysis, and communication hub (U-REACH) project. Data sources PubMed, PsycInfo, and Cochrane library databases, from inception to 19 November 2024. Eligibility criteria for selecting studies 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. Results 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. Conclusions 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. Trial registration 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.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) TPMT/NUDT15 Pharmacogene Curation Expert Panel (PCEP) conducted a comprehensive review of clinical, laboratory, and computational evidence to determine the clinical function assignments for TPMT and NUDT15 star alleles. These genes are critical for the metabolism of thiopurines, which are widely used in the treatment of cancer and autoimmune disorders. Standardized allele function assignment is essential for predicting metabolizer phenotypes and pharmacogenetics‐guided thiopurine dosing. The work presented here includes the first designation of decreased function alleles for both TPMT and NUDT15 , reflecting new clinical data that demonstrate partial loss of enzymatic activity and reduced dose tolerance. The panel also reclassified several alleles previously assigned uncertain or unknown function. The functional assignments were informed by a standardized framework incorporating clinical data, such as thiopurine tolerance and toxicity, as well as in vitro protein activity, ex vivo enzymatic measurements, and in silico variant effect prediction tools. These updates enhance the precision of genotype‐to‐phenotype mapping and support more personalized thiopurine therapy across diverse patient populations.

ABSTRACT Background Higher time in sedentary behavior and insufficient physical activity are very common in bipolar disorder (BD). Whereas physical activity and exercise offer significant benefits across mental health, brain health, and heart health in BD. The International Society for Bipolar Disorders Nutrition and Exercise Task Force (NExT) synthesized evidence to evaluate the impacts of sedentary behavior, physical activity, and exercise on illness course, physical health, and treatment outcomes. Methods A best‐evidence synthesis was conducted using a question‐and‐answer format. We searched PsycINFO, SPORTDiscus, Embase, PubMed, and Web of Science from inception to March 1st, 2026, supplemented by reference lists and existing guidelines. Search terms included combinations of physical activity, exercise, sedentary behavior, and bipolar disorder‐related terms. Results Observational studies show that individuals with BD exhibit significantly higher sedentary behavior and lower physical activity compared to the general population, with notable discrepancies between self‐reported and objective measurements. Evidence on physical activity's protective role against BD onset is mixed, with some prospective and Mendelian randomization studies suggesting reduced risk, while others report bidirectional or null associations. Preliminary findings from clinical trials indicate that exercise improves overall functioning, reduces mood episode frequency and hospitalizations, and alleviates depressive symptoms, with one pilot study showing an 82% antidepressant response rate. Exercise also shows potential to reduce anxiety and improve sleep, though robust data are limited. Conclusions Despite limited high‐quality evidence, physical activity and exercise demonstrate promising physical and mental health benefits for individuals with BD. Future research should prioritize multicenter randomized controlled trials, enhanced assessment tools, and accessible, tailored programs to integrate physical activity into routine BD management.

ABSTRACT Beta‐lactam antibiotics (beta‐lactams) are first‐line treatments for most major infectious syndromes in acutely ill patients, with in vitro activity against common pathogens, demonstrated efficacy in trials, and a perceived low risk of adverse effects. The current dosing approach, informed by population‐level data, tends to be simplistically reduced to a “one size fits all” dosing method which only accounts for body weight (i.e., in pediatrics) and end organ function to estimate drug clearance (e.g., estimated glomerular filtration rate); this approach results in substantial variability in observed serum concentrations in acutely ill patients, which can compromise real‐world effectiveness and safety. Beta‐lactam dose individualization, therefore, defined as a dosing regimen for one patient informed by measured concentrations from that patient, has been recommended in international clinical guidelines. Comprehensive guidance on best practices for beta‐lactam dose individualization is lacking. To address this knowledge gap and develop guidance, a multidisciplinary panel of international experts was assembled from the disciplines of infectious diseases, critical care, pharmacometrics, and laboratory medicine, representing both adults and pediatrics. The panel systematically evaluated the literature, using the GRADE approach where feasible, to address broad thematic questions pertaining to whether beta‐lactam dose individualization should be pursued, for what indications beta‐lactam dose individualization is warranted, and the most critical considerations and best practices for implementation of beta‐lactam individualization. The resultant consensus recommendations will equip healthcare professionals caring for acutely ill patients treated with beta‐lactam therapy with the evidence and tools necessary to guide optimal use of beta‐lactam dose individualization.

Background: By 2030, nearly one-quarter of the U.S. population will be over age 65, emphasizing the need to understand factors that promote healthy aging. Vitality is often reduced to physical indicators in clinical frameworks, overlooking its multidimensional nature. Methods: This qualitative descriptive study explored how independently living older adults define and experience vitality, focusing on physical, emotional, cognitive, and social dimensions. Guided by Self-Determination Theory, semi-structured interviews were conducted with 10 participants aged 61–83 years purposively recruited from community and faith-based settings in Northeast Florida. Results: Thematic analysis revealed four interconnected themes: (1) Make Adjustments, Keep Going; (2) Being Mentally Jubilant; (3) Bonds that Keep Me Going; and (4) Thriving Amid Uncertainty. Conclusions: Findings suggest that participants perceived vitality as a dynamic, multidimensional process shaped by adaptation, purpose, and connection rather than physical health alone. These insights underscore the need for holistic approaches to vitality assessment and interventions that support autonomy, competence, and relatedness in later life.

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

BACKGROUND: Primary aldosteronism (PA) is a common and treatable cause of hypertension, yet data on the durability of medical treatment response beyond the first year are limited. Using the PA medical treatment outcomes framework, we evaluated long-term biochemical and clinical outcomes and factors associated with treatment response. METHODS: We conducted an international, multicenter, observational cohort study across 27 centers on 4 continents. Adults with PA treated with mineralocorticoid receptor antagonists and/or epithelial sodium channel blockers between 2016 and 2021 were included if follow-up data were available at ≥12 months. Biochemical and clinical responses were classified as complete, partial, or absent using PA medical treatment outcomes criteria. Ordinal logistic regression identified determinants of a favorable treatment response. RESULTS: The cohort included 1292 patients (47.5% women, mean age 52 years) with a median follow-up of 34 months (interquartile range, 21–51). At ≥12 months, 58.3% achieved a complete biochemical response, and 20.8% achieved a complete clinical response, with only 5% showing no response. Determinants of a favorable biochemical response included lower aldosterone and lateralization index, and higher renin and potassium levels at baseline. In those taking spironolactone, a higher daily dose was also associated with a favorable biochemical response. Determinants of a favorable clinical response included female sex, lower body mass index, shorter duration of hypertension, and absence of hypertension-mediated organ damage. CONCLUSIONS: Targeted medical therapy for PA can deliver sustained biochemical and clinical benefits. Early disease detection and adequate dose titration are highly actionable determinants of long-term treatment success.