Nevin Manimala

Pharm Stat. 2025 Nov-Dec;24(6):e70044. doi: 10.1002/pst.70044.

ABSTRACT

The initiation of dose optimization has driven a paradigm shift in oncology clinical trials to determine the optimal biological dose (OBD). Early-phase trials with randomized doses can facilitate additional investigation of the identified OBD in targeted populations by incorporating safety, efficacy, and biomarker data. To support dose comparison in such settings, we propose to extend the utility score-based approach (U-MET) to account for multiple endpoints and doses. The utility-based dose optimization approach for multiple-dose randomized trial designs accounting for multiple (≤ 3) endpoints and doses (U-MET-m) extends the U-MET, using a utility score to account for multiple endpoints jointly (e.g., toxicity-efficacy trade-off). When there are > 3 endpoints, assigning weights jointly is quite complicated; therefore, we suggest an alternative approach with CUI-MET (clinical utility index dose optimization approach for multiple-dose randomized trial designs), which uses a utility index to account for multiple endpoints marginally. We demonstrate the relationship between U-MET-m and CUI-MET to offer a guide in weight selection for U-MET-m when there are up to three endpoints. U-MET-m and (extended) CUI-MET use Bayesian inference within a hypothesis framework to compare utility metrics across doses to identify the OBD. Here we describe simulation studies and present examples to compare both the U-MET-m and CUI-MET designs with the empirical design. The U-MET-m design and CUI-MET were shown to have satisfactory operating characteristics for selecting the OBD. Based on these findings, we recommend the U-MET-m with ≤ 3 endpoints and CUI-MET with > 3 endpoints as the primary dose comparison approach to select the OBD.

PMID:41111350 | DOI:10.1002/pst.70044

Cancer. 2025 Nov 1;131(21):e70067. doi: 10.1002/cncr.70067.

ABSTRACT

BACKGROUND: There are suspected disparities in clinical research (CR) development among low- and middle-income countries (LMICs). This study investigated differences in number and complexity of clinical trials (CTs) and how economic growth (EG) might contribute to these disparities.

METHODS: For countries classified as LMICs in 2000, number, proportion of phase 1-2/3 and independent/pharma-sponsored CTs were documented. For correlations with EG, correlation coefficients (CC) were produced, indicating very weak, weak, moderate, strong, and very strong correlation.

RESULTS: A total of 16,977 CTs were identified. Asian countries China and South Korea experienced strong EG and increases in CTs (very strong CC). South/Southeast Asian countries had strong EG but modest increases in CTs (variable CC). Most East European countries and West Asian/Southeast European Turkey experienced robust EG and increases in CTs (moderate to strong and very strong CC, respectively). South/North American Argentina, Brazil, and Mexico had inconsistent EG but increases in CTs (weak to moderate CC). Among African countries, Egypt showed strong EG with a corresponding increase in CTs (strong CC), whereas South Africa had a weak CC. Most LMICs, except for China and South Korea, relied heavily on pharma-sponsored CTs, with a persistently low proportion of early-phase (1-2) compared to late-phase (3) CTs.

CONCLUSION: CR development has been unequal among LMICs. Strong EG could be a contributing factor but only to some extent. Only China and South Korea meaningfully developed independent and high-complexity CR. These data reinforce the need for initiatives to support cancer research in LMICs.

PMID:41111348 | DOI:10.1002/cncr.70067

Disaster Med Public Health Prep. 2025 Oct 20;19:e299. doi: 10.1017/dmp.2025.10218.

ABSTRACT

BACKGROUND: Preparation for mass casualty incidents (MCIs) requires knowledge of the number of victims to be treated on site and transferred to hospitals. The objective was to collect this information for MCIs with hospital admissions in Europe over the last 30 years.

METHOD: This was a scoping review of MCIs with hospital admissions in Europe between 1991 and 2023. The study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Scoping Review (PRISMA-ScR) guidelines with PubMed, the Web of Science, Industrial and Transport Accident Reports, and two global databases on terrorism and disasters. Events with ten victims transferred to hospitals were included.

RESULTS: In total, 2,498 documents were identified, and 82 documents covering 62 MCIs were selected. In Europe, there was a median of 73 MCI: 9 victims died on site (12%), 48 were transferred to hospitals (66%), and 13 with serious casualties (17%). MCI is divided into 7 categories: explosion, ballistic, fire, road, ram raid, railway, and industrial accident.

CONCLUSIONS: By improving our knowledge of past MCIs and their casualty figures, we can now train more realistically and be better prepared to respond to future MCIs.

PMID:41111321 | DOI:10.1017/dmp.2025.10218

Ren Fail. 2025 Dec;47(1):2570817. doi: 10.1080/0886022X.2025.2570817. Epub 2025 Oct 20.

ABSTRACT

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy in severe respiratory and/or cardiovascular failure. Acute kidney injury (AKI) is a frequent complication of ECMO that increases morbidity and mortality. We report the outcomes of patients with AKI who received ECMO.

METHODS: Clinical, management, and 30-d kidney and patient outcome data of adult inpatients with AKI who received ECMO in seven public hospitals in Kuwait from 1 January to 31 December 2021, were prospectively collected and analyzed.

RESULTS: There were 3,744 AKI referrals to nephrology during study period, of which 121 received ECMO (3.2%). Patients with AKI on ECMO had a mean age of 56.3 years and a mean baseline eGFR of 81.6 mL/min. Preexisting chronic kidney disease was reported in 21.5% of patients, diabetes in 58.7%, and hypertension in 48%. COVID-19 infection contributed to AKI in 69% of the cases. AKI developed before ECMO initiation in 62% of cases. ECMO was veno-venous in 90% of cases. Dialysis was performed in 92% of cases, 97% of which was continuous modality. Mechanical ventilation was required in 94.2% of patients (all on inotropic support). At 30 d, 86.8% of the cohort died (91% of the deceased were on dialysis), 5% remained on dialysis, and only 3.3% recovered kidney function completely.

CONCLUSIONS: AKI in patients receiving ECMO was associated with a high need for dialysis, and a high mortality rate. COVID-19 pandemic may have contributed to this outcome. ECMO modality, and whether AKI was pre or post ECMO did not affect the outcome.

PMID:41111310 | DOI:10.1080/0886022X.2025.2570817

SAR QSAR Environ Res. 2025 Oct 20:1-25. doi: 10.1080/1062936X.2025.2569865. Online ahead of print.

ABSTRACT

Enhancer of Zeste Homolog 2 (EZH2) inhibitors have demonstrated selective efficacy, but their broader therapeutic potential remains limited, highlighting the need to clarify the structural basis of their activity. The central aim of our study is to systematically analyse the structural diversity and activity patterns of known EZH2 inhibitors to provide insights that may guide incremental scaffold optimization. We examined 531 potential EZH2 inhibitors retrieved from ChEMBL through a cheminformatics workflow encompassing clustering, scaffold identification, activity cliff detection, and chemical space visualization. Using RDKit and NetworkX, 94 clusters were generated, of which 13 contained ten or more compounds. Notably, clusters 6, 16, 20, 21, and 31 exhibited favourable balances of structural homogeneity and enrichment scores, suggesting chemical cohesiveness and biological relevance for structure – activity relationship (SAR) prioritization. Statistical analyses revealed significant differences in mean pIC₅₀ values across clusters, underscoring distinct activity distributions linked to structural groups. Scaffold analysis highlighted pyrrole – benzamide derivatives, particularly those incorporating morpholine and piperidine motifs, as enriched among potent inhibitors. Substructure evaluation further indicated that aromatic rings and aromatic amine groups were positively correlated with bioactivity. These findings delineate key SAR features of EZH2 inhibitors and provide guidance for scaffold refinement, hit identification, and lead optimization.

PMID:41111308 | DOI:10.1080/1062936X.2025.2569865

Philos Trans R Soc Lond B Biol Sci. 2025 Oct 20;380(1937):20240222. doi: 10.1098/rstb.2024.0222. Epub 2025 Oct 20.

ABSTRACT

Most of the world’s languages have numeral systems with a decimal base, but in some areas, such systems are rare. This article focuses on languages with either restricted numeral systems or systems featuring compositional anchors that are not bases, examining how they are used in the creation of non-atomic numerals. We investigate anchor choice from an explicitly diachronic perspective by modelling it on phylogenetic trees for language families from two areas: northern lowland South America (Arawakan, Pano-Tacanan, Tucanoan and Tupian) and Papuan languages of New Guinea (Nuclear Torricelli, Nuclear Trans New Guinea, Ramu and Sepik). We find languages with restricted numeral systems lacking anchors, as well as systems with anchor 2 or 5. Phylogenetic analyses suggest that the proto-languages of these families likely had restricted or anchor 2 systems, with shifts to anchor 5 occurring in specific groups, indicating some time depth, although statistical power is limited by small family sizes. Further research should study linguistic systems alongside cultural counting practices, reconstruct both linguistic forms and cultural practices and model the impact of contact, especially given the global dominance of decimal systems.This article is part of the theme issue ‘A solid base for scaling up: the structure of numeration systems’.

PMID:41111297 | DOI:10.1098/rstb.2024.0222

Diagn Interv Radiol. 2025 Oct 20. doi: 10.4274/dir.2025.253585. Online ahead of print.

ABSTRACT

PURPOSE: This study aims to present our institutional experience with the use of percutaneous balloon-expandable biodegradable magnesium biliary stents (MBS) in the treatment of benign, refractory anastomotic strictures (AS), where initial percutaneous or endoscopic approaches fail or are ineffective, after liver transplantation (LT).

METHODS: In this retrospective single-center study, 13 patients with clinically refractory AS who underwent MBS placement between July 2021 and August 2024 were evaluated. Statistical analyses included Kaplan-Meier survival analysis for patency and Spearman’s correlation for recurrence risk. Primary outcomes included stricture recurrence and time to reintervention during follow-up.

RESULTS: The median age of patients was 35 years [interquartile range (IQR): 22-48], and 11 were male (85%). Living donor LT was performed in 12 (92%). The MBS were placed at a median of 8 months post-transplant (IQR: 5-44), with a technical success in all cases (100%). Before MBS placement, patients underwent a median of one endoscopic retrograde cholangiopancreatography (IQR: 0-3) and three percutaneous transhepatic biliary drainage procedures (IQR: 1-8). The median follow-up was 25 months (IQR: 15-33). The MBS patency rates were 93%, 85%, and 67% at 6, 12, and 24 months, respectively. Stricture recurrence occurred at a median of 30 months post-placement (95% confidence interval: 23.6-36.3). A moderate positive correlation was observed between the number of pre-stent interventions and recurrence risk (rho: 0.582, P = 0.023). Post-procedural complications (cholangitis) occurred in 1 patient.

CONCLUSION: Balloon-expandable biodegradable MBS may provide a safe and effective treatment for refractory AS following LT. Early placement of MBS, particularly after fewer prior interventions, appears to be associated with improved patency and longer stricture-free survival.

CLINICAL SIGNIFICANCE: Early use of biodegradable magnesium stents after LT may reduce the need for multiple interventions and improve long-term biliary patency.

PMID:41111279 | DOI:10.4274/dir.2025.253585

J Educ Eval Health Prof. 2025;22:32. doi: 10.3352/jeehp.2025.22.32. Epub 2025 Oct 20.

ABSTRACT

PURPOSE: Interprofessional education (IPE) is increasingly recognized as critical to preparing health professionals for collaborative practice, yet rigorous assessment remains limited by a lack of psychometrically sound instruments. Building on a previously developed questionnaire for physicians, this study aimed to expand the scale to include allied health professionals and to evaluate whether the factor structure remained consistent across professions. We hypothesized that a similar factor structure would emerge from the combined dataset, thereby supporting the scale’s generalizability.

METHODS: This observational study included 930 healthcare professionals in the United States (379 physicians, 419 nurses, 76 pharmacists, and others) who completed a 35-item questionnaire addressing IPE competency domains. Data were collected between December 2019 and May 2020. Exploratory factor analysis was employed to examine the factor structure, followed by item response theory (IRT) analyses to assess item fit, reliability, and validity. Raw data are available upon request.

RESULTS: Factor analysis of 22 retained items confirmed a 5-factor solution: teamwork and communication, patient-centered care, roles and responsibilities, ethics and attitudes, and reflective practice, explaining 59% of the variance. Subscale reliabilities ranged from α=0.65 to 0.87. IRT analyses supported construct validity and measurement precision, while identifying areas for refinement in reflective practice.

CONCLUSION: This study demonstrates that the scale is reliable, valid, and generalizable across diverse health professions. It provides a robust tool for assessing attitudes toward IPE, offering value for curriculum evaluation, institutional benchmarking, and future longitudinal research on professional identity formation and collaborative practice.

PMID:41111278 | DOI:10.3352/jeehp.2025.22.32

BJU Int. 2025 Oct 19. doi: 10.1111/bju.70041. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate two new prognostic risk models aimed at improving clinical decision-making in patients with clinical stage (cS) I seminomatous testicular germ cell tumours (GCTs), 5%-30% of whom experience recurrence during surveillance after orchiectomy and may benefit from adjuvant therapy.

METHODS: In this exploratory study, patients with unilateral cS I seminoma, normalised serum tumour markers after orchiectomy, no adjuvant therapy and at least 12 months of follow-up were included. Cox regression analysis was applied to evaluate the prognostic factors proposed by the Danish Testicular Cancer Database (DaTeCa) and the European Association of Urology (EAU), and recurrence probabilities were estimated using the Kaplan-Meier method.

RESULTS: Among 139 patients, 25 (18%) experienced recurrence within a median follow-up of 37 months (95% confidence interval 47.9-63.1 months). Multivariable analysis confirmed only rete testis infiltration as an independent predictor of recurrence (P = 0.039), while other prognostic factors included in the DaTeCa risk model (i.e. hilar soft tissue invasion, rete testis infiltration, lymphovascular invasion, and elevated pre-orchiectomy human chorionic gonadotropin and lactate dehydrogenase) and the EAU model (i.e. tumour size, rete testis infiltration and lymphovascular invasion) were not. However, 5-year recurrence risks for the different risk groups, defined by the combination of prognostic factors, aligned well with the DaTeCa (no risk factors: 4% vs 6%; all risk factors: 67% vs 62%) and the EAU risk models (low [13% vs 8%] and intermediate risk [22% vs 20%]). A discrepancy was observed in EAU high-risk cases (67% vs 44%), which was probably attributable to the very small number of patients in our high-risk subgroup (n = 6 [4.3%]).

CONCLUSION: The DaTeCa and EAU risk classification models demonstrated overall consistency in our exploratory cohort and may aid in identifying patients with cS I seminoma who are at high risk for recurrence and who might be candidates for adjuvant therapy. Further multicentre validation studies are needed.

PMID:41111273 | DOI:10.1111/bju.70041

J Evol Biol. 2025 Oct 16:voaf120. doi: 10.1093/jeb/voaf120. Online ahead of print.

ABSTRACT

This paper models the genetical evolution of individual behavioral rules that guide the choice of strategies in pairwise assortative interactions under incomplete information. Building on results at the crossroads of evolutionary theory and game theory, it is first shown that in an uninvadable population state of behavioral rule evolution, individuals are compelled to use strategies that are Nash equilibria of a lineage fitness game. Thus, choice behavior evolves to be representable as the maximization of a utility function, as if each individual holds a personal preference that orders both their own and their interaction partner’s strategies. Second, the paper contrasts two representations of personal utility that are found to be uninvadable. The first is semi-Kantian in form. This preference averages a fitness self-interest with a relatedness weighted Kantian interest. The latter interest evaluates the consequence of own behavior for own fitness, assuming the interaction partner adopts the same behavior as self. The second preference is a personal inclusive fitness. This preference combines a self-regarding interest with a relatedness weighted other-regarding interest. Each such interest takes the form of an average effect, which evaluates the consequence of expressing own behavior, instead of average population behavior, on a statistical average fitness to self and the interaction partner.

PMID:41100163 | DOI:10.1093/jeb/voaf120