Category: Statistics

Mol Pharm. 2025 Nov 10. doi: 10.1021/acs.molpharmaceut.5c00799. Online ahead of print.

ABSTRACT

A spray-dried powder formulation of 5-azacytidine (5-AZA) recently showed significantly improved tumor reduction and systemic exposure for the potential treatment of metastatic lung cancer. To support clinical use, the target product profile required double the active loading. Here, a series of powders were spray dried to increase 5-AZA loading in the formulation, and process parameters were varied to identify variables controlling powder properties. Formulations were sprayed via in-line mixing, where separate dimethyl sulfoxide (DMSO) and aqueous solutions were mixed immediately upstream of atomization. A core-shell structure was observed matching previous reports of spray-dried l-leucine with sugar from water and ethanol. To the best of our knowledge, this is the first study investigating the process and structure of spray-dried l-leucine and trehalose using DMSO and water as processing solvents. Powders with glass transition temperatures (T_g) below room temperature were successfully manufactured with high yields, attributed to the crystalline l-leucine shell surrounding the low T_g core. The residual DMSO was controlled by the DMSO:water ratio and the composition of the core. Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) was employed to understand droplet drying processes by developing ternary phase diagrams and drying trajectories. This work enables the manufacture of both dry inhalable 5-AZA powder for the treatment of lung cancer and low T_g materials previously thought to be unmanufacturable via spray drying. It also highlights the importance of aligning experimental data and theoretical models to improve our understanding of complex processes.

PMID:41213010 | DOI:10.1021/acs.molpharmaceut.5c00799

Circulation. 2025 Nov 10. doi: 10.1161/CIRCULATIONAHA.125.077304. Online ahead of print.

ABSTRACT

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive disease caused by the deposition of transthyretin as amyloid in the myocardium. Current therapies may slow disease progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets misfolded transthyretin, designed to promote clearance of transthyretin amyloid through antibody-mediated phagocytosis.

METHODS: This phase 2, double-blind, placebo-controlled trial randomized participants with ATTR-CM to receive infusions every 4 weeks of either coramitug at two dosages (10 mg/kg or 60 mg/kg) or placebo in a 1:1:1 ratio for 52 weeks. The primary endpoints were the change from baseline to week 52 in the six-minute walk test (6MWT) and N-terminal pro-brain type natriuretic peptide (NT-proBNP) levels. Safety was assessed for up to 64 weeks by assessing treatment-emergent adverse events, all-cause mortality, and number of cardiovascular (CV) events comprising hospitalization due to CV events or urgent heart failure visits.

RESULTS: In total, 104 participants (median age 77 years; 93% men; 84% New York Heart Association class II; 13% with variant ATTR-CM) were randomized and dosed: 34 to coramitug 10 mg/kg, 35 to coramitug 60 mg/kg, 35 to placebo. Median NT-proBNP was 1985 pg/mL (interquartile range: 1224, 3406 pg/mL). In total, 90% of participants were on disease-modifying therapy; 84% were treated with tafamidis and 7 (6.7%) with TTR silencers (patisiran, n=4; vutrisiran, n=3). From baseline to week 52, coramitug 60 mg/kg significantly reduced NT-proBNP levels compared with placebo (-48%; 95% CI: -65%, -22%; P=0.0017). The change in 6MWT from baseline to week 52 was not statistically different from placebo with either dose. Coramitug 60 mg/kg was associated with improved functional echocardiographic parameters and was well tolerated.

CONCLUSIONS: This phase 2 trial showed that coramitug, an antibody targeting misfolded transthyretin in ATTR-CM, was well tolerated and at a dose of 60 mg/kg resulted in a statistically significant reduction in NT-proBNP, a validated marker of disease progression, with no statistically significant effect on 6MWT within 52 weeks.

PMID:41212997 | DOI:10.1161/CIRCULATIONAHA.125.077304

J Speech Lang Hear Res. 2025 Nov 10:1-16. doi: 10.1044/2025_JSLHR-24-00736. Online ahead of print.

ABSTRACT

PURPOSE: Reproducibility is a core principle of science, and access to a study’s data is essential to reproduce its findings. However, data sharing is uncommon in the discipline of communication sciences and disorders (CSD), often due to concerns related to privacy and disclosure risks. Synthetic data offer a potential solution to this barrier by generating artificial data sets that do not represent real individuals yet retain statistical properties and relationships from the original data. This study aimed to explore the feasibility and preliminary utility of synthetic data to promote transparency and reproducibility in the discipline of CSD.

METHOD: Ten open data sets were obtained from previously published research within the American Speech-Language-Hearing Association “Big Nine” domains (articulation, cognition, communication, fluency, hearing, language, social communication, voice and resonance, and swallowing) across a range of study outcomes and designs. Synthetic data sets were generated with the synthpop R package. General utility was assessed visually and with the standardized ratio of the propensity mean squared error (S_pMSE). Specific utility assessed whether inferential relationships from the original data were preserved in the synthetic data set by comparing model fit indices, coefficients, and p values.

RESULTS: All synthetic data sets showed strong general utility, maintaining univariate and bivariate distributions. Six of nine synthetic data sets that used inferential statistics showed strong specific utility, maintaining inferential relationships from the original analysis. Specific utility was low in three data sets with hierarchical structures.

CONCLUSIONS: Findings suggest that synthetic data can effectively maintain statistical properties and relationships across a wide range of nonhierarchical data commonly seen in the discipline of CSD. Other approaches for hierarchical data need to be explored in future work. Researchers who use synthetic data should assess its utility in preserving their results for their own data and use-case.

OPEN SCIENCE FORM: https://doi.org/10.23641/asha.30569957.

PMID:41212974 | DOI:10.1044/2025_JSLHR-24-00736

Nutr Neurosci. 2025 Nov 10:1-11. doi: 10.1080/1028415X.2025.2587076. Online ahead of print.

ABSTRACT

BACKGROUND: Recent research highlights the central role of emotion in psychopathology, with Panksepp’s Affective Neuroscience Theory identifying seven primary emotional systems critical for mammalian survival. Although this framework has advanced understanding of disorders such as depression and addiction, its application to eating pathology remains limited.

OBJECTIVE: The present study integrates affective neuroscience with behavioural analysis, conceptualizing emotions not merely as neural activations but as classes of behaviour shaped by phylogenetic selection and ontogenetic contingencies.

METHODS: Eating disorders, characterized by maladaptive eating patterns that impair physical and psychological functioning, are examined here as emotional-behavioural phenomena maintained by reinforcement processes. This cross-sectional, correlational study investigated associations between emotional systems and disordered eating.

RESULTS: Weak but statistically significant correlations were found between negative emotional systems (FEAR, PANIC/GRIEF, RAGE) and disordered eating (r ≈ .15-.25, 95% CI [.07, .35]), suggesting that difficulties in emotion regulation may act as antecedents and reinforcers of maladaptive coping behaviours. Positive emotional systems (PLAY, CARE, SEEKING) showed no significant relationships, indicating heterogeneous reward contingencies among individuals with eating pathology. Exploratory gender-stratified analyses revealed small differences in emotional correlates but no moderation effects, underscoring similar functional mechanisms across sexes.

CONCLUSIONS: Findings are interpreted within a functional-analytic framework, proposing that disordered eating is maintained by negative reinforcement, reducing aversive private events such as shame, fear, or panic. Clinically, results highlight the need for integrated, context-sensitive interventions that target emotion regulation and avoidance mechanisms across genders.

PMID:41212971 | DOI:10.1080/1028415X.2025.2587076

J Refract Surg. 2025 Nov;41(11):e1162-e1167. doi: 10.3928/1081597X-20250821-03. Epub 2025 Nov 1.

ABSTRACT

PURPOSE: To investigate the ultrastructure and apoptosis of small incision lenticule extraction (SMILE) lenticules under different preservation conditions.

METHODS: A total of 104 corneal stromal lenticules of 52 patients (13 men and 39 women, age 28.85 ± 6.45 years, mean spherical error -4.27 ± 1.34 diopters [D]) were collected from small incision lenticule extraction (SMILE) surgeries, and were immediately preserved using glycerol, silicone oil, Optisol (Bausch & Lomb), and cryopreservation for 1 day, 1 week, and 1 month. Fresh lenticules were taken as control groups. Hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) were applied for evaluation of ultrastructure and terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) for cell apoptosis ratio. Changes of quantity of collagen in TEM were evaluated in each group among all time points.

RESULTS: HE staining showed that collagen in the fresh lenticules had an orderly arrangement with few vacuoles. In each preservation group, vacuoles and changes in arrangement of collagen were observed. TEM showed that the mean density of collagen was lowest at 1 month in the glycerol, silicone oil, and cryopreservation groups and highest at 1 month in the Optisol group. Quantities of collagen of lenticules preserved for 1 day and 1 week in the Optisol group were not statistically significantly different from those in the fresh group. At the same storage time, the mean density of collagen was the highest in the cryopreservation group at 1 day and the Optisol group at 1 month, and there was no statistically significant difference among the other groups. There was no statistically significant difference in apoptotic cell ratio among groups.

CONCLUSIONS: SMILE lenticules preserved using glycerol, silicone oil, Optisol, and cryopreservation within 1 month maintain a similar cell viability level as fresh lenticules.

PMID:41212966 | DOI:10.3928/1081597X-20250821-03

J Neurophysiol. 2025 Nov 10. doi: 10.1152/jn.00067.2025. Online ahead of print.

ABSTRACT

Predictive control enables humans to anticipate future events by combining sensory feedback with internal models. In interception tasks, such mechanisms could allow the visual system to estimate future target positions, supporting timely and accurate motor responses. Here, we investigated predictive gaze behavior in a visuomotor task where participants used a joystick to intercept a moving target that rebounded within a circular arena. Eye movements were classified into fixations, smooth pursuit, and saccades using a velocity-based method. The arena’s geometry constrained rebound angles and facilitated standardized trajectory analysis. Participants consistently deployed fixations aligned with the target’s anticipated post-rebound path, as confirmed by fixations that were closer to future than to current target positions. Moreover, saccade and fixation onsets were time-locked to the rebound event, reflecting anticipatory adjustments based on the statistical regularities of the task. Gaze alignment was modulated by the target’s entry angle and velocity: steeper entries and higher speeds compressed fixation timing but increased spatial variability. Visual masking of the target disrupted predictive gaze, highlighting the critical role of target visibility in guiding anticipatory behavior. These findings demonstrate the crucial role of predictive fixations in visuomotor coordination, offering a broader understanding of anticipatory behaviors and their applications. Our task design offers a controlled platform to study anticipatory gaze strategies, with potential applications for clinical diagnostics, skill training, and human-computer interaction.

PMID:41212615 | DOI:10.1152/jn.00067.2025

J Appl Physiol (1985). 2025 Nov 10. doi: 10.1152/japplphysiol.00834.2025. Online ahead of print.

ABSTRACT

Background: Night-shift work is prevalent among healthcare workers and disrupt circadian rhythms, potentially influencing blood pressure (BP) regulation. Pregnancy itself causes significant BP fluctuations, and night shifts may exacerbate these changes, increasing the risk of hypertension disorders. However, studies on the impact of shift work on BP patterns in pregnancy in a free-living environment is currently lacking. Method: We recruited 25 pregnant nurses in their second trimester, comprising 13 on day shifts (DS) and 12 on night shifts (NS), from eight urban hospitals in Edmonton, Alberta, Canada. Resting BP (systolic – SBP; diastolic – DBP; mean arterial pressure – MAP; and pulse pressure – PP) was assessed before and after shift work. Data were analyzed to compare pre- and post- shift measurements between DS and NS workers using a Linear Mixed-Effects Model, with statistical significance set at p < 0.05. Results: NS workers showed significantly higher post-shift DBP and MAP compared to DS workers (p < 0.001). In contrast, NS workers exhibited a significant post-shift decrease in pulse pressure (PP) than the DS group (p < 0.001), indicating distinct acute hemodynamic responses to NS work. Conclusions: NS work in pregnant nurses is associated with acute elevations in DBP and MAP, along with a significant reduction in PP following the shift. These findings suggest that NS may trigger distinct hemodynamic stress responses during pregnancy, potentially increasing short-term cardiovascular load.

PMID:41212601 | DOI:10.1152/japplphysiol.00834.2025

JAMA Intern Med. 2025 Nov 10. doi: 10.1001/jamainternmed.2025.5917. Online ahead of print.

ABSTRACT

IMPORTANCE: Although risk-based payment contracts to health care organizations can reduce health care utilization, there is limited evidence on how these contracts influence the value of health care services delivered, whether effects depend on contract design features, and what these contracts achieve in Medicare Advantage, the segment of US health insurance with the most adoption of risk-based contracts.

OBJECTIVE: To assess whether voluntary transition to risk-based contracts (either upside-only, with financial bonuses possible, or 2-sided with both bonuses and penalties possible) was associated with changes in either broad domains of health care utilization or use of low-value services.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study analyzed claims from January 1, 2015, through December 31, 2021, for beneficiaries enrolled in health maintenance organization plans from Humana, a large, national Medicare Advantage insurer. A difference-in-differences analysis measured changes in outcomes for health care organizations that newly transitioned to upside-only or 2-sided risk contracts compared with organizations with stable fee-for-service (FFS) or upside-only risk contracts, respectively. Statistical analysis was conducted between April 4 and June 23, 2025.

MAIN OUTCOMES AND MEASURES: Nine utilization measures in 3 domains (inpatient encounters, outpatient visits, testing) and 26 measures of low-value service use in 6 domains (cancer screening, diagnostic and preventive testing, preoperative testing, imaging, cardiovascular testing and procedures, and other surgeries).

RESULTS: The sample included 658 organizations transitioning from FFS to upside-only risk contracts (1 042 272 beneficiary-years), 114 organizations transitioning from upside-only to 2-sided risk contracts (706 303 beneficiary-years), and 3385 control organizations (2 491 985 beneficiary-years). In difference-in-differences analyses, transitioning to upside-only risk contracts was associated with differential reductions in 4 of 9 utilization outcomes (emergency department visits, primary care visits, advanced imaging, and cardiovascular stress testing); however, when analyses accounted for differential temporal trends in outcomes prior to contract transitions, differential reductions were only detected for emergency department visits (-8.4% of baseline use; 95% CI, -15.5% to -1.3%; P = .02) and cardiovascular stress testing (-12.1%; 95% CI -23.4% to -0.7% P = .04). Transitioning to 2-sided risk contracts was associated with differential reductions in specialty visits and advanced imaging; however, neither association was detected after accounting for pretransition outcome trends. Neither type of contract adoption was associated with differential changes in total use of low-value services or differential reductions in any domain of low-value service use.

CONCLUSIONS AND RELEVANCE: This study found that voluntary transition to upside-only or 2-sided risk payment contracts in Medicare Advantage was not associated with consistent changes in health care utilization or low-value service use. It is uncertain what factors account for the lack of apparent changes.

PMID:41212579 | DOI:10.1001/jamainternmed.2025.5917

JAMA Netw Open. 2025 Nov 3;8(11):e2542147. doi: 10.1001/jamanetworkopen.2025.42147.

ABSTRACT

IMPORTANCE: Colorectal cancer (CRC) survivors frequently report bowel-related symptoms, but longitudinal data are scarce and diet has not been extensively investigated in relation to bowel-related symptoms.

OBJECTIVE: To investigate the prevalence of bowel-related symptoms as well as their association with dietary fiber intake until 5 years after CRC diagnosis.

DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study using data from the Colorectal Cancer: Longitudinal, Observational Study on Nutritional and Lifestyle Factors (COLON) study included CRC survivors with stage I-IV disease recruited at diagnosis from 11 hospitals in the Netherlands between August 2010 and February 2020. CRC survivors were followed up until 5 years after diagnosis. Data were analyzed between April 2024 and March 2025.

EXPOSURES: Clinical data including CRC treatment strategy, retrieved from hospital records and national registries, and habitual dietary fiber intake, assessed by a food frequency questionnaire, at 6 months, 2 years, and 5 years after CRC diagnosis.

MAIN OUTCOMES AND MEASURES: Prevalence of self-reported diarrhea, constipation, flatulence or bloating, frequent stools, mucus in stools, or false urgency at 6 months, 2 years, and 5 years after diagnosis, obtained via a questionnaire. The validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was also used to evaluate prevalence of moderate-to-severe diarrhea or constipation and health-related quality of life (HRQOL) at these time points. Odds ratios (ORs) for associations between fiber intake and bowel-related symptoms (yes or no) were calculated using multivariable logistic regression.

RESULTS: Among 1751 CRC survivors who underwent surgery and were included in the analysis, median age at diagnosis was 66 years (IQR, 61-71 years), and 1115 (63.7%) were men. Bowel-related symptoms were reported by 817 of 1751 survivors (46.7%) at 6 months, 614 of 1511 (40.6%) at 2 years, and 290 of 812 (35.7%) at 5 years after diagnosis. At 6 months after diagnosis, symptoms were predominantly reported by survivors who had received chemotherapy (260 of 446 [58.3%]), whereas symptoms at 2 and 5 years occurred mostly in those who received radiotherapy (86 of 160 [53.8%] at 2 years and 47 of 92 [51.1%] at 5 years). Of the studied bowel-related symptoms, diarrhea was associated with the lowest HRQOL score (B, -9.6; 95% CI, -14.0 to -5.2) at 5 years after diagnosis. In multivariable logistic regression analyses, higher fiber intake (per 10-g/d increment) was associated with a significantly lower prevalence of moderate-to-severe diarrhea at 6 months (OR, 0.44; 95% CI, 0.28-0.70) and 2 years (OR, 0.53; 95% CI, 0.30-0.94) after diagnosis, but the association was not statistically significant at 5 years (OR, 0.43; 95% CI, 0.16-1.13).

CONCLUSIONS AND RELEVANCE: In this cohort study of CRC survivors, the prevalence of bowel-related symptoms was considerably high during the 5 years after diagnosis, highlighting a need for effective symptom management. Higher dietary fiber intake was associated with a lower prevalence of diarrhea, suggesting a potential role of diet in management of bowel-related symptoms in CRC survivors.

PMID:41212563 | DOI:10.1001/jamanetworkopen.2025.42147

JAMA Netw Open. 2025 Nov 3;8(11):e2542668. doi: 10.1001/jamanetworkopen.2025.42668.

ABSTRACT

IMPORTANCE: Gestational diabetes (GD) is a heterogeneous condition that predisposes both mother and offspring to metabolic disorders. GD subtypes defined by antepartum testing results have been associated with adverse perinatal outcomes, but little is known about their relationship to maternal metabolic outcomes soon after pregnancy.

OBJECTIVE: To evaluate early postpartum glucose tolerance reclassification of GD subtypes.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study examined women from the Study of Women, Infant Feeding, and Type 2 Diabetes Mellitus After GD Pregnancy (SWIFT), who were recruited within the Kaiser Permanente Northern California integrated health care system between 2008 and 2011. All women were diagnosed with GD using Carpenter and Coustan criteria with complete glucose measurements at all 4 time points of the diagnostic 3-hour 100-gram oral glucose tolerance test (OGTT). Data analyses were conducted from January to July 2025.

EXPOSURE: Three subtypes of GD based on the diagnostic OGTT: (1) postload glucose intolerance (GD-P), as having elevations only at 2 or more postload time points; (2) fasting hyperglycemia (GD-F), as having elevations at fasting and 1 postload time point; and (3) both (GD-M), as having elevations at fasting and 2 or more post-load time points.

MAIN OUTCOMES AND MEASURES: At 6 to 9 weeks after delivery, glucose tolerance classification was evaluated using 2-hour, 75-g OGTTs. Modified Poisson regression models were used to estimate adjusted prevalence ratios (PRs) of postpartum prediabetes associated with GD subtypes, without and with adjustments for age, race and ethnicity, prepregnancy body mass index, educational level, and gestational weight gain.

RESULTS: This study included 1005 women with GD (median [IQR] age, 33.2 [29.8-36.7] years; 368 [36.6%] Asian, 78 [7.8%] Black, 308 [30.6%] Hispanic, 16 [1.6%] multiracial, and 235 [23.4%] White). Prevalence of postpartum prediabetes was 34.5% (347 women), with wide variation across GD subtypes; 23.9% (147 of 616), 41.9% (52 of 124), and 55.8% (148 of 265) for GD-P, GD-F, and GD-M, respectively. Compared with women with GD-P, the adjusted PR for GD-F was 1.74 (95% CI, 1.36-2.24), and for GD-M, it was 2.23 (95% CI, 1.85-2.68) (both P < .001). Pairwise comparisons between GD-F and GD-M were also statistically significant (adjusted PR, 1.28; 95% CI, 1.01-1.61; P = .04).

CONCLUSIONS AND RELEVANCE: In this cohort study, GD subtypes had distinct postpartum prediabetes risks. Early action and intervention to address dysglycemia may be most beneficial for women with fasting or mixed defects.

PMID:41212558 | DOI:10.1001/jamanetworkopen.2025.42668