Category: Statistics

CPT Pharmacometrics Syst Pharmacol. 2025 Jul 4. doi: 10.1002/psp4.70051. Online ahead of print.

ABSTRACT

Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist approved for acute and preventive migraine treatment in adults, administered as an orally disintegrating tablet (ODT). A population pharmacokinetic analysis was performed to describe rimegepant’s plasma concentration-time course and to estimate covariate effects on rimegepant exposure. The model was developed/evaluated in 3 stages using data from 11 phase 1 clinical studies, wherein rimegepant was administered orally to healthy adults, elderly people with stable chronic illness(es), adults with renal or hepatic dysfunction, and healthy adults with Japanese or Chinese ethnicity. Plasma concentration-time data were analyzed using nonlinear mixed effects modeling. A 2-compartment model with 4 transit compartments and a first-order absorption best described the rimegepant plasma concentration-time course. Estimated typical values (%relative standard error) were apparent clearance (CL/F) = 24.1 L/h (4.86%), apparent central volume of distribution (V_c/F) = 114.0 L (5.36%), apparent inter-compartmental clearance (Q/F) = 3.94 L/h (6.37%), apparent peripheral volume of distribution (V_p/F) = 46.0 L (5.30%), absorption rate constant (k_a) = 3.86 h^-1 (28.4%), and transit absorption rate constant (ktr) = 8.23 h^-1 (8.24%). Statistically significant covariates included empirical allometric body weight-based scaling exponents (0.75 for CL/F and Q/F and 1 for V_c/F and V_p/F); severe/moderate hepatic impairment and fluconazole/itraconazole co-administration on CL/F; fed status, dose on relative bioavailability; and fed status, itraconazole co-administration, and capsule and ODT formulations on transition absorption rate constant. Only severe hepatic impairment and co-administration of itraconazole resulted in a clinically significant decrease in rimegepant CL/F, supporting the recommendation to avoid rimegepant administration in patients with severe hepatic impairment or with a strong CYP3A4 inhibitor.

PMID:40614133 | DOI:10.1002/psp4.70051

CPT Pharmacometrics Syst Pharmacol. 2025 Jul 4. doi: 10.1002/psp4.70063. Online ahead of print.

ABSTRACT

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening thrombotic microangiopathy caused by a severe inherited deficiency of ADAMTS13, a von Willebrand factor (VWF) cleaving enzyme. Inadequate clinical endpoint data often make it challenging to statistically power clinical trials in ultra-rare diseases. Therefore, utilizing in vitro, adamts13-knockout mouse, literature-based, and clinical data, a quantitative systems pharmacology (QSP) model was developed to describe the mechanistic relationship between ADAMTS13, VWF, and platelet count, and to supplement evidence from clinical trials of recombinant ADAMTS13 (rADAMTS13) for the treatment of cTTP. The effect of long-term prophylaxis with rADAMTS13 versus plasma-based therapies (PBT) on platelet count in patients with cTTP was investigated. One-year clinical trial simulations of thrombocytopenia occurrences in 1000 virtual patients, phenotype-matched to a cTTP Phase 3 study population (NCT03393975), were produced. Simulations suggested that once-weekly (Q1W) or once every 2 weeks (Q2W) rADAMTS13 administered over 1 year resulted in fewer patients experiencing thrombocytopenia versus patients treated with PBT (e.g., Q2W [rADAMTS13] relative to Q2W [PBT], HR = 0.47 [platelet count drop to < 150 × 10⁹/L], HR = 0.41 [< 100 × 10⁹/L]). These results provide confirmative evidence to support the use of rADAMTS13 in cTTP by integrating the current mechanistic understanding of interactions between ADAMTS13 and VWF multimers as its substrate, as well as key downstream parameters, primarily platelet count. Virtual patient clinical simulations from the QSP model supported the regulatory approval of rADAMTS13 in cTTP, highlighting the significant potential of QSP modeling to supplement clinical trial data in rare disease drug development.

PMID:40614125 | DOI:10.1002/psp4.70063

Chembiochem. 2025 Jul 4:e2500172. doi: 10.1002/cbic.202500172. Online ahead of print.

ABSTRACT

Intrinsically disordered and artificially denatured foldable proteins have many properties in common, even though the distribution of amino acid residues generally differ. Both are traditionally described as either adopting molten globule or random coil-like structure, depending on their amino acid composition. For a long period of time, it was believed that with the exception of glycine and proline, conformational preferences of individual amino acid residues are very similar, and therefore, not of great concern. This article discusses experimental and bioinformatical data which show that individual Ramachandran plot distributions in unfolded proteins depend on the characteristics of side chains. Furthermore, ample experimental evidence suggests the presence of nearest neighbor interactions between residues which are ignored in the classical random coil model. The article reviews and discusses work that emphasizes the necessity of a thorough understanding of the local behavior of disordered and unfolded proteins alike for an understanding of the coiled state of proteins. Unresolved issues are delineated and research perspectives suggested.

PMID:40614117 | DOI:10.1002/cbic.202500172

JMIR Form Res. 2025 Jul 4;9:e68316. doi: 10.2196/68316.

ABSTRACT

BACKGROUND: People experiencing homelessness have worse oral health outcomes and a notable health informational asymmetry compared to the general population. Screening programs present a viable option for this population; however, barriers to access, such as lower levels of health literacy, lack of information, and mistrust, narrow their chances to participate in such programs.

OBJECTIVE: The aim of this study is to investigate the applicability of generative artificial intelligence (AI) in designing a homeless health screening program fact sheet with experts by experience using co-design principles.

METHODS: Six fact sheet text variants were created by the open-access version of ChatGPT 3.5 for an oral cancer screening program targeting people experiencing homelessness in Budapest, Hungary. Clients of homeless social services (N=23) were invited to a short questionnaire survey and 3 semistructured focus group discussions between May and July 2024. General opinions regarding generative AI technology and direct feedback on the text variants were obtained. Additionally, a standardized readability assessment of the text variants was completed via the Sydney Health Literacy Lab Editor.

RESULTS: Almost two-thirds of participants (17/23) stated that they had previously heard about AI; however, their self-assessment regarding the extent of their knowledge resulted in an average of 2.38 (n=16) on a 5-point Likert scale. During the first focus group discussion, all 6 variants received a high score (between 4.63 and 4.92 on a 5-point Likert scale). In the next sessions, participants remained positive when the pool was narrowed to 4 versions, although they scored the texts lower. During open discussions, text variants were considered understandable, while difficulties with medical expressions, lengthiness of sentences, and references to a stereotypical homeless subgroup (rough sleepers) were also reported. The health literacy editor showed that most AI-generated text variants were difficult to read and too complex for the target group.

CONCLUSIONS: The co-design process revealed that focus group participants actively wanted to shape the fact sheet drafts. They shared their insights on how to make the text variants more appealing for the target audience. Moreover, the involvement of generative AI technology revealed that the participants have heard about the concept of AI and text generation as a potential function, and they have not rejected its use in health care settings.

PMID:40614110 | DOI:10.2196/68316

JMIR Mhealth Uhealth. 2025 Jul 4;13:e60426. doi: 10.2196/60426.

ABSTRACT

BACKGROUND: Air pollution is a major environmental cause of premature deaths, responsible for around 7 million deaths annually. In this context, personal air pollution exposure (PAPE), the product of pollutant concentration and minute ventilation (V’m), is a crucial measure for understanding individual health risks. Standard exposure techniques do not address the space-time variability of air pollution, both indoor and outdoor, and the intra- and intersubject variability in V’m.

OBJECTIVE: This study evaluates the feasibility of using a wearable body sensor network (BSN) to estimate PAPE in real-life settings, assess its capability to detect spatiotemporal variations in pollution levels, and compare inhaled dose estimates from the BSN with those from fixed monitoring stations and standard V’m values. The study also examines the system’s usability.

METHODS: The system, a BSN capturing physiological (pulse rate [PR] and respiratory rate [RR]) and environmental data, including health-affecting pollutants (particulate matter [PM] 1, PM2.5, PM10, CO2, CO, total volatile organic compounds, and NO2), was tested in a 4.5 km walk in Milan by 20 healthy volunteers. PR and RR collected by the system were used, together with biometric data and forced vital capacity estimations, in a model for V’m estimation to compute PAPE. Pollution levels were compared between morning and afternoon measurements, as well as between indoor and outdoor settings.

RESULTS: Variations in RR were found among volunteers and at different locations for the same participant. Significant differences (P<.001) in pollutant concentrations were observed between morning and afternoon for CO2 (higher in the morning) and PM (higher in the afternoon). Spatial variability along the walking path was also detected, highlighting the system’s high spatiotemporal resolution. Indoor environments showed high variability in CO2 and total volatile organic compounds, while outdoor settings exhibited elevated and variable PM levels. The mean PAPE to PM2.5 estimated with tabulated V’m and fixed station data was 13.31 (SD 4.16) μg while the one estimated with the BSN was 16.27 (SD 9.78) μg, 2.96 μg higher (22.3%; 95% CI -6.55 to 0.63; P=.05) than the former one, and with a broader IQR. Nevertheless, the 2 estimation methods show a good and strongly significant correlation (r=0.665; P<.001). The system’s usability was generally rated as good.

CONCLUSIONS: The BSN provides high-resolution spatiotemporal data on personal exposure, capturing differences in pollution levels dependent on time, location, and surrounding environment, along with individual physiological variations. It offers a more accurate estimation of inhaled dose in real-life settings, supporting personalized exposure assessments and potential applications in activity planning and complementing epidemiological research.

PMID:40614107 | DOI:10.2196/60426

JMIR Mhealth Uhealth. 2025 Jul 4;13:e64622. doi: 10.2196/64622.

ABSTRACT

BACKGROUND: Mental health is an essential element of life. However, existing mental health services face challenges in utilization due to issues such as societal prejudices and a shortage of counselors. Mobile health is gaining attention as an alternative approach to improving mental health by addressing the shortcomings of traditional services. As a result, various mental health apps are being developed, but there is a lack of evaluation research on whether these apps meet users’ needs.

OBJECTIVE: This study aims to evaluate the content and quality of mental health apps from the user’s perspective and identify the content features that influence evaluation scores. We also aim to guide future updates and improvements in mental health apps to deliver high-quality solutions to users.

METHODS: We searched the Google Play Store and iOS App Store using Korean keywords “mental health,” “mental health care,” “depression,” and “stress.” Apps meeting the following criteria were selected for the study: relevance to the topic, written in Korean, more than 700 reviews (Android) or more than 200 reviews (iOS), updated within the past 365 days, available for free, nonduplicate, and currently operational. After identifying and defining the primary contents of the apps, 7 users evaluated their quality using the user version of the Mobile Application Rating Scale (uMARS). Correlation analysis was performed to examine the relationships among app content, uMARS scores, star ratings, and the number of reviews. Multiple regression analysis was conducted to identify the factors influencing uMARS scores and each evaluation item.

RESULTS: The analysis included a total of 41 mental health apps. Content analysis revealed that reminders (n=29, 71%), recording and statistics features (n=29, 71%), and diaries (n=24, 59%) were the most common app components. The top-rated apps, as determined by uMARS evaluations, consistently provided information about counselors and counseling agencies, and included counseling services. uMARS scores were significantly correlated with the presence of health care provider information (r=0.53; P<.001) and counseling/question and answer services (r=0.55; P<.001). Multiple regression analysis indicated that providing more relevant information was associated with higher uMARS scores (β=.361; P=.02).

CONCLUSIONS: The quality of mental health apps was evaluated from the user’s perspective using a validated scale. To deliver a high-quality mental health app, it is essential to incorporate app technologies such as generative artificial intelligence during development and to continuously monitor app quality from the user’s perspective.

PMID:40614100 | DOI:10.2196/64622

Orv Hetil. 2025 Apr 27;166(17):658-668. doi: 10.1556/650.2025.33284. Print 2025 Apr 27.

ABSTRACT

Bevezetés: Az elmúlt években az egészségügyi rendszerben észlelhető szerkezeti és jogi változások következtében a magánegészségügy szerepe hangsúlyosabbá vált, aminek következtében a Maternity Szülészeti és Nőgyógyászati Magánklinikán az éves szülésszám jelentős növekedése volt megfigyelhető. A klinika alapvető törekvése már a kezdetektől fogva az, hogy magas szintű, szakmai protokollokon nyugvó perinatológiai ellátást nyújtson minden páciens számára, a betegforgalomtól függetlenül. Célkitűzés: A jelen vizsgálat célja a Maternity Szülészeti és Nőgyógyászati Magánklinikán nyújtott 2023. évi neonatológiai ellátás mennyiségi és minőségi mutatóinak elemzése és összegzése. Módszer: Retrospektív vizsgálatunkban a 2023. január 1. és 2023. december 31. között a Maternity Szülészeti és Nőgyógyászati Magánklinikán élve született újszülöttek adatait elemeztük, a releváns eredményeket grafikonon ábrázoltuk. Eredmények: A Maternity Szülészeti és Nőgyógyászati Magánklinikán 2023-ban 1461 újszülött született élve, az újszülöttek túlnyomó többsége a 38–39. héten (n = 1010, 69%). A betöltött 37. terhességi hét előtt 34 újszülött jött a világra (ebből 5 újszülött 35 hetes koraszülött volt). A császármetszések aránya 78% volt. A klinikán született újszülöttek 92%-át eseménytelen kórházi bent fekvést követően 2, illetve 3 nap után haza tudtuk engedni. A hazamenetel napján a kizárólagos anyatejes táplálásban részesülő újszülöttek aránya 71% volt (n = 1027). Újszülöttkori sárgaság miatt 85 újszülött részesült kékfény-kezelésben, mely a kórházi tartózkodást 1–2 nappal hosszabbította meg. A vizsgált időszakban összesen 12 újszülöttnél kezdtünk antibiotikumkezelést újszülöttkori szepszis gyanúja miatt, közülük 5 újszülött részesült komplett 5 napos antibiotikumterápiában. Újszülöttkori légzészavar miatt 32 esetben volt szükség az osztályon NCPAP- (nasalis folyamatos pozitív légúti nyomású) légzéstámogatás alkalmazására, ezek közül 15 alkalommal néhány órás kezelést követően sikeresen el tudtuk hagyni a légzéstámogatást, 17 esetben történt áthelyezés légzészavar miatt. Az 1461 újszülött közül összesen csupán 36 alkalommal (2,4%) volt szükség magasabb progresszivitási szintű intézménybe való áthelyezésre. Két újszülöttnek volt kisebb fejlődési rendellenessége (egy kamrai septumdefektus és egy hypospadiasis). Egyetlen újszülöttet sem veszítettünk el. Megbeszélés: A Maternity Szülészeti és Nőgyógyászati Magánklinika neonatológiai ellátási modellje a 21. századi követelményeknek megfelelően, a betegbiztonságot figyelembe véve, szakmai protokollok alapján működik. Biztosítja az újszülöttek és családok részére a háborítatlan, biztonságos környezetet az anya-újszülött kapcsolat kialakulásához és az anyatejes táplálás elindításához a szülést követő órákban és napokban. Orv Hetil. 2025; 166(17): 658–668.

PMID:40614089 | DOI:10.1556/650.2025.33284

Hepatol Int. 2025 Jul 4. doi: 10.1007/s12072-025-10841-3. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Large-volume paracentesis (LVP), a therapeutic procedure for cirrhosis patients with refractory ascites, is associated with paracentesis-induced circulatory dysfunction (PICD). While albumin infusion is known to prevent PICD, it is unknown whether the addition of vasoconstrictors to albumin reduces complications of LVP.

METHODS: Cirrhosis patients undergoing LVP for refractory ascites were randomized to receive albumin alone (Gr. I), terlipressin with albumin (Gr.II), or midodrine with albumin (Gr. III). The primary endpoint was the incidence of PICD, and the secondary endpoints were the incidence of new-onset complications (hyponatremia, acute kidney injury, and encephalopathy), 28-day survival and adverse events to therapy.

RESULTS: One hundred and sixty-fifty cirrhosis patients with refractory ascites undergoing LVP were equally randomized to 3 groups. The incidence of PICD in Gr. I (14%), II (7%), and III (11%) was similar (p = 0.46). Mean arterial pressure (MAP) reduced in Gr.I and II compared to the rise in Gr. III on day 3 (ΔMAP: Gr.I = – 8.2 ± 5.01; Gr.II = – 4.34 ± 5.82; Gr. III = 9.16 ± 5.14 mmHg; p < 0.001), with a statistically significant rise in PRA (ng/ml/hour) at day 6 in Gr. I and II than in Gr. III. The incidence of new-onset complications was significantly higher in Gr.I (52.72%) and Gr.II (45.46%) than Gr.III (23.63%) (p = 0.005). Overall mortality on day 28 was not different between the groups.

CONCLUSIONS: PICD remains a challenge even in hospitalized settings. The addition of oral midodrine to albumin prevents hypotensive response on day 3, thereby reducing the incidence of new-onset complications following LVP.

PMID:40614032 | DOI:10.1007/s12072-025-10841-3

Lifetime Data Anal. 2025 Jul 4. doi: 10.1007/s10985-025-09663-0. Online ahead of print.

ABSTRACT

Analyses of multi-source data, such as data from multi-center randomized trials, individual participant data meta-analyses, or pooled analyses of observational studies, combine information to estimate an overall average treatment effect. However, if average treatment effects vary across data sources, commonly used approaches for multi-source analyses may not have a clear causal interpretation with respect to a target population of interest. In this paper, we provide identification and estimation of average treatment effects in a target population underlying one of the data sources in a point treatment setting for failure time outcomes potentially subject to right-censoring. We do not assume the absence of effect heterogeneity and hence our results are valid, under certain assumptions, when average treatment effects vary across data sources. We derive the efficient influence functions for source-specific average treatment effects using multi-source data under two different sets of assumptions, and propose a novel doubly robust estimator for our estimand. We evaluate the finite-sample performance of our estimator in simulation studies, and apply our methods to data from the HALT-C multi-center trials.

PMID:40614027 | DOI:10.1007/s10985-025-09663-0

Odontology. 2025 Jul 4. doi: 10.1007/s10266-025-01143-z. Online ahead of print.

ABSTRACT

This study assessed the biological and antimicrobial properties of a calcium silicate-based material and calcium hydroxide (CH) when used as intracanal medications. MTT assay, osteogenic differentiation of human periodontal stem cells (hPDLSCs), cell mineralization-assay, and determination of ALP activity were assessed to investigate the biological properties. While the agar well diffusion, crystal violet (CRV) assay and LIVE/DEAD staining of dentin slices infected with a mature E. faecalis biofilm were used to assess the antimicrobial properties. Normally distributed data were analyzed using one and two-way ANOVA and post hoc Tukey test, while for non-normally distributed data Kruskal Wallis and Dunn’s tests were used. The results showed that both materials were cytocompatible, but BioC-Temp showed statistically higher hPDLSCs viability (P < 0.05). hPDLSCs cultured with BioC-Temp extract demonstrated a significantly higher mineralization and more mineralized nodules than CH extract (P < 0.05). Both BioC-Temp and CH had similar antibacterial potential against E. faecalis in radicular dentin. BioC-Temp has higher mineralization potentials than CH. For the antimicrobial properties, BioC-Temp caused significantly higher inhibition zones than CH (P = 0.0001). The biofilm biomass reduction of BioC-Temp was significantly higher than for CH (P < 0.05). Regarding the percentage of live E. faecalis in biofilm, both BioC-Temp and CH caused significant reductions with no significant difference between them (P > 0.05).

PMID:40614024 | DOI:10.1007/s10266-025-01143-z