Study Participants Research Articles

Retrospective Analysis of the Correlation between Umbilical Blood Flow Index and Maternal and Fetal Outcomes in Pregnant Women with Gestational Diabetes.

Aims/Background Gestational diabetes mellitus (GDM) is a common complication during pregnancy. This retrospective study investigates the correlation between umbilical blood flow index and maternal-fetal outcomes in pregnant women with GDM, aiming to contribute to evidence-based risk assessment and management strategy in this high-risk obstetric population. Methods This retrospective study recruited 119 pregnant women with GDM who were admitted to the Yichang Central People's Hospital, between January 2022 and January 2024. Based on the umbilical blood flow index, the study participants were divided into a normal umbilical blood flow (UBF) index group (n = 56) and a high UBF index group (n = 63). Colour Doppler ultrasound was used to assess umbilical blood flow, and relevant data on maternal, fetal, and neonatal outcomes were obtained from the hospital's electronic medical records. Results We observed that, compared to the normal UBF index group, the high UBF index group exhibited significantly higher rates of adverse pregnancy outcomes, including the cesarean section (p = 0.022), preterm delivery (p = 0.020), gestational hypertension (p = 0.019), neonatal hypoglycemia (p = 0.015), as well as increased incidence of neonatal complications such as respiratory distress syndrome (p = 0.009), neonatal jaundice (p = 0.022), neonatal intensive care unit (NICU) admission (p = 0.015), lower 5-minute Apgar scores (p = 0.013), and neonatal sepsis (p = 0.005). Furthermore, significant differences were observed in fetal biometric parameters and placental morphology between the two groups (fetal weight: p = 0.003; estimated fetal weight percentile: p = 0.017; femur length: p = 0.018; placental weight: p = 0.019; placental volume: p = 0.021). Additionally, correlation analyses indicated significant associations between umbilical blood flow index and maternal and fetal outcomes (p < 0.05). Conclusion We observed a significant correlation between umbilical blood flow indices and maternal and fetal outcomes in pregnant women with gestational diabetes mellitus, implying its utility as a non-invasive parameter for risk stratification and personalized management in this high-risk obstetric population.

Promoting student voice by involving vocational education students and staff in citizenship education development: a participatory action research study

Promoting student voice by involving vocational education students and staff in citizenship education development: a participatory action research study

Industrial air emissions and breast cancer incidence in a United States-wide prospective cohort.

We evaluated air emissions of industrial compounds, many of which have carcinogenic or endocrine disrupting properties, in relation to breast cancer incidence. Using the United States Environmental Protection Agency's Toxics Release Inventory, we quantified air emissions of 28 compounds near Sister Study participants' residences during the 10 years leading up to study enrollment (2003-2006; n=46,150). We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of residential emission levels of single pollutants with incident breast cancer. We assessed pollutant mixtures using an Exposure Continuum Mapping (ECM) framework and characterized associations using a joint-exposure response function. During follow-up (median=13.4 years), we identified 4,155 breast cancer cases. We observed non-monotonic but elevated associations with breast cancer for emissions within 3km of the residence for nickel compounds (HRquintile5vs.none = 1.3; 95% CI 1.0, 1.6) and trichloroethylene (HRquintile5vs.none = 1.3; 95% CI 1.0, 1.6). ECM identified 25 mixture profiles that explained 72% of the variance in emissions patterns, with most participants experiencing relatively low emissions profiles. The joint-exposure response function suggested that higher incidence of breast cancer occurred among individuals with relatively rare, high emissions profiles; however, the overall trend was not associated with breast cancer (p=0.09). In our study, breast cancer incidence was associated with air emissions of certain industrial carcinogens. Although the overall emissions mixture did not show a trend related to breast cancer, this may not reflect the importance of individual compounds or specific emissions sources.

The Benefits of Hearing Aids for Adults: A Systematic Umbrella Review.

This umbrella review aims to summarize the major benefits of hearing aid usage in adults by synthesizing findings from published review articles. A comprehensive search of databases, including MEDLINE, EMBASE, PsycINFO, and Google Scholar, was conducted. The search was limited to English-language review articles published between 1990 and 2023, focusing on hearing aid outcomes in at least 5 adults (aged ≥18 years). Two researchers independently screened titles, abstracts, and full-text articles, and conducted a quality assessment using the Joanna Briggs Checklist for Systematic Reviews and Research Syntheses. A third researcher was involved in discussions with the 2 researchers to resolve conflicts during the screening and quality assessment stages. Eleven articles were included in this review. There were three systematic reviews with meta-analysis and eight systematic reviews without meta-analysis. The quality assessment indicated that articles scored between 6 and 11 out of a total of 11 criteria. Three articles met all quality criteria. Study participants tended to be middle-aged (≥40 years) or older adults (≥65 years). Participant gender was less clear as this was not consistently reported but appeared to favor men. This umbrella review found that speech perception, communication function, hearing handicap, and self-assessed hearing aid benefit were consistently positively associated with hearing aid use in the analysis of included studies. Hearing handicap was the most frequently reported outcome with evidence from four different studies supporting its mitigation with hearing aid use. There was insufficient evidence in terms of benefit on balance, cognitive function, depression, tinnitus, loneliness, and social isolation. There was conflicting evidence on the impact of hearing aid use on quality of life. Among eligible studies, there were no reports of negative impacts of hearing aid use. There are a number of potential benefits associated with hearing aid use. However, this review found that there was a clear lack of high-quality evidence and limited use of robust study design to support the benefits of hearing aids on other outcomes such as quality of life and cognition. Inconsistent use and interpretation of various outcome measures makes it difficult to produce homogenous data which is needed to make more conclusive statements about the benefits of hearing aids.

Culturally appropriate terminologies in health research: a participatory study with pregnant and breastfeeding mothers in Uganda

Culturally appropriate terminologies in health research: a participatory study with pregnant and breastfeeding mothers in Uganda

Participatory research towards the control of snakebite envenoming and other illnesses in a riverine community of the Western Brazilian Amazon.

Riverine communities face various health problems, which involve geographical and cultural barriers to accessing care, in addition to a lack of financial investments in services aimed at these communities, resulting in a process of invisibility for the population living in these regions. In this scenario, the significant burden of snakebite envenoming (SBE) highlights the need for participatory research to address ways to minimize this situation. Thus, this study aimed to describe the priority health problems identified by this population and the ranking of SBEs in that context, mapping solutions according to the local reality. This study was conducted in Limeira, a riverine community located in Tabatinga, in the extreme Western Brazilian Amazonia, on the borders with Peru and Colombia. The research lasted approximately one year, from 2021 to 2022.It is a participatory study that followed three steps: baseline assessment of the community, community assembly, and final data analysis. The study included a total of 42 participants in the sociodemographic survey, which served as the basis for the subsequent stages of data collection. Of these 42 individuals, 32 participated in the qualitative interviews, and 20 took part in the community assembly. Participants emphasized snakebite envenoming as a significant health issue, though not the only one, and reported frequent encounters with snakes, underscoring its severity as a concern. The qualitative analysis identified three main themes: Snakebites in the Community, which focused on personal experiences with snakes; Common Health Problems, which addressed other health issues faced by community members; and Community Defining Solutions, which discussed strategies and solutions proposed by the community to address these challenges. Improvements in health care delivery to populations living in Amazonian communities are possible with the judicious use of tested integrated interventions, particularly when the community identifies various concurrent health problems. SBE control programs in remote areas of the Brazilian Amazon should be planned with a multidisciplinary and intercultural approach, preferably integrated with broader interventions that address the population's needs for a range of health issues.

Ambient Air Pollution and COPD: The Multiethnic Cohort Study.

Globally, in 2019, chronic obstructive pulmonary disease (COPD) was the third leading cause of death. While tobacco smoking is the predominant risk factor, the role of long-term air pollution exposure in increasing risk of COPD remains unclear. Moreover, there are few studies that have been conducted in racial and ethnic minoritized and socioeconomically diverse populations, while accounting for smoking history and other known risk factors. To evaluate the association for ambient air pollution and COPD in a multiethnic population in California. Among 38,654 African American, Japanese American, Latino and White California participants in the Multiethnic Cohort study enrolled in the fee-for-service component of Medicare, we used Cox proportional hazards regression to estimate the association of time-varying ambient air pollutants: particulate matter with diameter ≤2.5 μm or 10 μm (PM2.5, PM10), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), benzene and ultrafine particles (UFP) with COPD risk (n=10,915 cases; 8.8 years of follow-up). Subgroup analyses were conducted by race and ethnicity, sex, smoking status at MEC baseline questionnaire, and neighborhood socioeconomic status (nSES). We observed positive associations for NOx (per 50 ppb) with risk of COPD (hazards ratios (HR)=1.45; 95% CI: 1.35-1.55). The associations for NO2 (per 20 ppb), PM2.5 (10ug/m3), PM10 (10ug/m3), CO (1000 ppb), and UFP (IQR=5241.7 particles/cm3) with risk of COPD were in similar directions as these air pollutants are highly correlated with NOx. These associations were found in African American, Latino, and Japanese American participants, but not in whites (p-heterogeneity across race and ethnicity<0.04). These associations also differed by nSES with effects being stronger in racial and ethnic minoritized populations and residents of low SES neighborhoods. Long-term ambient air pollutant exposure is associated with COPD risk in a multiethnic, older adult (>65 years of age), population.

Potential Therapeutic drug Targets for Hypertension Identified using Proteomics and Mendelian Randomization.

Hypertension (HT) is the most prevalent risk factor for cardiovascular disease (CVD) worldwide. Despite being a highly heritable trait, the underlying mechanisms of HT remain elusive due to its complex genetic architecture. Discovering disease-associated proteins with causal genetic evidence offers a potential strategy for identifying therapeutic targets for HT. We analyzed the plasma proteome of 4,657 plasma proteins from 7,213 European American (EA) participants in the ARIC study. Genome-wide association study (GWAS) data for HT were sourced from FinnGen R10, which includes 102,864 cases and 289,117 controls. Cis-Mendelian randomization (MR) was conducted to assess the causal effect of circulating proteins on the risk of HT. A multiverse sensitivity analysis was performed to evaluate the robustness of these causal relationships. Colocalization analysis was conducted to determine whether these features share the same associated single nucleotide polymorphisms (SNPs). The causal effects of HT-associated proteins were then validated using cis-protein quantitative trait loci (Cis-pQTL) genetic instruments from the deCODE database. Among 1,788 proteins, genetically predicted levels of 18 plasma proteins were associated with HT in the discovery stage. Seven of these proteins showed strong support for colocalization. After replication, only ERAP1 and ACVRL1 were validated as therapeutic candidates for HT, demonstrating a negative correlation with the risk of HT. By combining cis-MR analysis with colocalization analysis, we identified ERAP1 and ACVRL1 as potential targets for interventions in the primary prevention of HT, with ERAP1 emerging as a particularly promising drug target after further validation.

Demographic disparities in access to COVID-19 clinical trial sites across the United States: a geospatial analysis

Throughout the COVID-19 pandemic, underserved populations, such as racial and ethnic minority communities, were disproportionately impacted by illness and death. Ensuring people from diverse backgrounds have the ability to participate in clinical trials is key to advancing health equity. We sought to analyze the spatial variability in locations of COVID-19 trials sites and to test associations with demographic correlates. All available and searchable COVID-19 studies listed on ClinicalTrials.gov until 04/04/2022 and conducted in the United States were extracted at the trial-level, and locations were geocoded using the Microsoft Bing API. Publicly available demographic data were available at the county level for national analysis and the census tract level for local analysis. Independent variables included eight racial and ethnic covariates, both sexes, and twelve age categories, all of which were population-normalized. The county-level, population-normalized count of study site locations, by type, was used as the outcome for national analysis, thereby enabling the determination of demographic associations with geospatial availability to enroll as a participant in a COVID-19 study. Z-scores of the Getis-Ord Gi statistic were used as the outcome for local analysis in order to account for areas close to those with clinical study sites. For both national (p < 0.001) and local analysis (p = 0.006 for Los Angeles, p = 0.030 for New York), areas with greater proportions of men had significantly fewer studies. Sites were more likely to be found in counties with higher proportions of Asian (p < 0.001) and American Indian or Alaska Native residents (p < 0.001). Areas with greater concentrations of Black or African American residents had significantly lower concentrations of observational (p < 0.001) and government-sponsored COVID-19 studies (p = 0.003) in national analysis and significantly fewer concentrations of study sites in both Los Angeles (p < 0.001) and New York (p = 0.007). Though there appear to be a large number of COVID-19 studies that commenced in the US, they are distributed unevenly, both nationally and locally.

CD14++CD16- classical monocyte subset secreting IL-1ß and IL-10 is associated with 'Tuberculosis Resisters' phenotype.

Mycobacterium tuberculosis (M.tb) infection can lead to various outcomes, including active tuberculosis or latent tuberculosis infection (LTBI). Household contacts of TB cases have a high risk of acquiring LTBI. However, some contacts exposed to M.tb remain negative for tuberculin skin test (TST) and interferon-gamma release assay (IGRA) tests and are called 'TB resisters'. Characterization of immune responses in 'TB resisters' may help to understand correlates of protection against M.tb. Based on the TST and IGRA tests, household contacts were divided into 'LTBI' and 'TB Resisters'. Peripheral blood mononuclear cells (PBMCs) of the study participants were isolated and processed to characterize the monocyte subsets based on CD14 and CD16 expression in flow cytometry. Monocyte intracellular cytokine expression (IL-10, IL-6, TNF-α and IL-1ß) was assessed after Lipopolysaccharide (LPS) stimulation. LTBI and active TB patients showed a higher frequency of intermediate and non-classical monocyte subsets depicting the infectious stage. Higher frequency of classical monocyte subsets was associated with 'TB resisters'. Marked expression of IL-1ß and a higher monocyte to lymphocytes (M/L) ratio was seen in PTB, LTBI and TB resister groups compared to healthy controls indicating active disease or exposure to M.tb. Classical Monocytes (CM) were further found to be associated with higher expression of IL-1ß and IL-10 in the 'TB resister group', which might help in the clearance of infection at an early stage. LTBI and PTB showed significantly higher TNF-α producing monocytes than healthy controls and 'TB Resisters'. IL6-producing monocytes were significantly higher in LTBI compared to other study groups. These findings could further be explored with follow-up in cohort of 'TB resisters'. Also, the role of IL-1ß and IL10 secreting classical monocytes in early clearance of infection could be explored with in vitro mechanistic studies.

Residual C-peptide secretion is associated with better CGM-metrics in adults with short-lasting type 1 diabetes.

To investigate whether the risk of hypoglycemia is associated with residual β-cell function in adults with type 1 diabetes (T1D). This cross-sectional study included 61 subjects with T1D of <15 years' duration using continuous glucose monitoring (CGM). Random C-peptide levels were compared between participants with time below range (TBR) ≥3 % (n = 15) and TBR <3 % (n = 45). The associations of C-peptide levels with other CGM metrics and clinical characteristics of the study participants were also tested. Analyses were adjusted for disease duration. Median [25th - 75th percentiles] C-peptide levels were generally low: 49.3 [15.7-152] pmol/l. Participants in the low-TBR group had significantly higher C-peptide levels compared to those in the high-TBR group (52.9 [19.5-176.3] vs. 21.0 [9.4-106.6] pmol/L, p = 0.036), independently from disease duration. Higher C-peptide levels were associated with better CGM-metrics (p < 0.05). A C-peptide threshold of 15.1 pmol/l was the best cut-off to distinguish people at high risk of hypoglycemia. C-peptide microsecretion is associated with a low risk of hypoglycemia and improved CGM metrics. Therapeutic approaches aimed at preserving minimal C-peptide secretion could potentially enhance glycemic outcomes and reduce hypoglycemic risk in individual with T1D.

Escaping the blame spiral: student-centered teaching reform in Vietnam

ABSTRACT This present study in-depth investigates how higher education (HE) instructors and leaders in Vietnam are implementing student-centered orientation of teaching (SCOT) to help them escape the Confucian culture-caused blaming spiral: leaders blame instructors for failures, instructors blame students and institutional communities blame everyone. This study had a twofold aim: identifying how Vietnamese university instructors are implementing SCOT and identifying whether leaders support the academics staff’s SCOT adoption. The focus of the first aim was both authenticity – how well the study participants’ practices aligned with their SCOT conceptions – and comprehensiveness – how thoroughly they were incorporating the three central SCOT tenets of curriculum, instruction, and assessment. The findings revealed that the study participants neither comprehensively incorporate SCOT principles into practice nor authentically student-oriented by adhering to their conceptions, and that they obtained no comprehensive support from institutional administrators for their SCOT efforts.

The Association Between the Presence of Human Facial Mites Demodex (Acari, Demodicidae) and Dermatological Symptoms in Rosacea Patients in Central Anatolia, Türkiye.

This study aimed to investigate the potential relationship between the presence of Demodex mites and dermatological symptoms in patients with rosacea in the Central Anatolian Region of Türkiye. A total of 63 patients diagnosed with rosacea were enrolled in the study. Skin samples were obtained using a standardized skin surface biopsy technique, and a questionnaire was administered to assess skin symptoms. Statistical analysis was performed to evaluate the association between Demodex infestation and specific skin symptoms. Among the study participants, 65.1% exhibited Demodex infestation. Statistical analysis revealed significant associations between the presence of Demodex and skin burning (p=0.018), skin pain (p=0.012), and skin stinging (p=0.001). However, no statistically significant associations were observed between Demodex presence and gender, skin dryness, itching, irritation, skin rash or the presence of red/pink bumps on the skin. This study provides evidence suggesting a potential role for Demodex mites in the pathogenesis of rosacea, specifically in relation to skin symptoms such as burning, pain, and stinging. The findings underscore the complexity of the relationship between Demodex infestation and rosacea and highlight the need for further research, including longitudinal and mechanistic studies, to better understand this association and its clinical implications. Ultimately, understanding the role of Demodex mites in rosacea may lead to innovative therapeutic approaches, offering hope for improved management of this challenging dermatological condition.

Estimating mortality attributable to alcohol or tobacco – a cohort study from Germany

BackgroundLittle is known about mortality from four disorder combinations: fully attributable to alcohol or tobacco, partly attributable to both alcohol and tobacco, to tobacco only, to alcohol only.AimTo analyze whether residents who had disclosed risky alcohol drinking or daily tobacco smoking had a shorter time to death than non-risky drinkers and never daily smokers twenty years later according to the disorder combinations.MethodsA random adult general population sample (4,075 study participants) of a northern German area had been interviewed in the years 1996–1997. Vital status and death certificate data were gathered 2017–2018. The data analysis included estimates of alcohol- or tobacco-attributable mortality using all conditions given in the death certificate and alternatively the underlying cause of death only.ResultsAmong 573 deaths, 71.9–94.1% had any alcohol- or tobacco-attributable disorder depending on the estimate. Risky alcohol consumption and daily tobacco smoking at baseline were related to disorders in the death certificate according to the combinations. Deaths with an alcohol- and tobacco-attributable disorder were related to risky alcohol consumption (subhazard ratio 1.57; 95% confidence interval 1.25–1.98) and to daily tobacco smoking at baseline (subhazard ratio 1.85; 95% confidence interval 1.42–2.41).ConclusionFirst, more than 70% of the deceased persons had one or more alcohol- or tobacco-attributable disorders. This finding suggests that total mortality seems to be the suitable outcome if potential effects of alcohol or tobacco consumption in a general population are to be estimated. Second, the relations of risky alcohol consumption and tobacco smoking with time to death speak in favor of the validity of alcohol- and of tobacco-attributable disorders in death certificates and of considering both alcohol consumption and tobacco smoking if attributable deaths are to be estimated.

A tale of two ages: fluid reasoning as a predictor of working memory training efficacy in middle-aged and older adults

ABSTRACT Research on working memory (WM) training reveals significant variability in training effects, indicating that pretraining cognitive abilities might account for these differences. However, consensus on whether higher (magnification account) or lower (compensation account) pretraining abilities predict greater training effects remains elusive. Our study aimed to clarify the role of fluid reasoning in predicting training performance (i.e. training scores at each session) and gains on near transfer WM tasks. We conducted two studies: Study 1 focused on middle-aged adults (47–65 years) and Study 2 on older adults (65–83 years). Participants in both studies were randomly assigned to either adaptive n-back training or an active control group and have all completed three WM tasks before and after 20 training sessions – the trained n-back task and two structurally different untrained tasks. Generally, greater average training scores were found in individuals with higher fluid reasoning for both age groups, although this trend did not reach statistical significance in older adults. Similarly, higher fluid reasoning predicted greater training gains only in the sample of middle-aged adults. Further analysis showed that both, middle-aged and older participants in the training groups exhibited higher gains on the trained n-back task but not on two other WM tasks. Additionally, fluid reasoning predicted n-back gains in both the training and control group. Consistent with a growing body of research, our results show limited generalization of training effects across untrained tasks. It seems that factors beyond pretraining ability should be considered when explaining between-participant differences in training performance.

Association of environmental, demographic and clinical parameters with physical activity in children with asthma

Personal characteristics, unfavorable weather conditions and air pollution have been linked with reduced physical activity in children. However, among children with asthma the effects of these parameters remain unclear. This study objectively quantified the physical activity of children with asthma and evaluated its association with environmental, personal, and clinical parameters. Participants of the prospective LIFE-MEDEA asthma study wore the EMRACE™ smartwatch daily for continuous monitoring of physical activity and acquisition of global positioning system data. Daily physical activity, personal and clinical data were combined with daily temperature, precipitation, and air pollution levels in adjusted mixed effect regression models to examine the relationship between physical activity and the examined parameters. For a follow-up period of 4 months, 186 children with asthma demonstrated a decrease of 796 steps (95% CI: -1080, -512) on days with precipitation compared to non-precipitation days and a decrease of 96 steps (95% CI: -182, -9) for every 10 µg/m3 increase in PM10. The relationship between temperature and daily steps was characterized by an inverted U-shape. There was also evidence that gender and age-adjusted BMI z-score were negatively associated with daily steps. These results can further inform the design of physical activity interventions targeting children with asthma.

Cohort profile: the BangladEsh Longitudinal Investigation of Emerging Vascular and nonvascular Events (BELIEVE) cohort study

PurposeBangladesh has experienced a rapid epidemiological transition from communicable to non-communicable diseases (NCDs) in recent decades. There is, however, limited evidence about multidimensional determinants of NCDs in this population. The...

Insights into youth nutritional status in Serbia: assessing prevalence and trend in the context of social determinants

BackgroundThe study aimed to assess the prevalence and distribution of different levels of nutritional status among young people, to examine its association with social determinants of health, and to analyse its trend over time.MethodThe research was a secondary analysis of the data from four national health surveys of the Serbian population. The research sample included 11,243 respondents, aged 15 to 29, both genders. A multivariate logistic regression model was applied to examine the association between socio-demographic characteristics, lifestyle, health status, and the level of respondents’ nutritional status. The trend analysis of the levels of nutritional status by the research years was done using multiple linear regression in adjusted models.ResultsA total of 63.3% of respondents had body mass index (BMI) in the normal weight range, 11.7% were underweight, 18.5% were pre-obese, and 6.2% were obese. The average BMI of the study participants was 23.01 ± 6.01. The female respondents were more frequently underweight, and the male respondents were pre-obese and obese. Different factors were associated with different nutritional status levels - for underweight: female gender (OR: 5.29), age 15–19 (OR: 0.06), being married/ in a relationship (OR: 0.69), living in Belgrade region (OR: 1.35), presence of chronic diseases (OR: 0.56), consumption of psychoactive substances (OR:0.56) and non-smoking (OR: 0.70); for pre-obesity: female gender (OR: 0.38), ages 15–19 (OR:0.36) and 20–24 (OR:0.65), being married/ in a relationship (OR: 1.39), having high wealth index (OR:1.30) and non-smoking status (OR:1.32); for obesity: female gender (OR: 0.36), ages 15–19 (OR:0.35) and 20–24 (OR:0.51), being married/ in a relationship (OR:2.31) and primary education level (OR:2.17). The trend analysis of nutritional status level in the research period showed an increase in the average value of the BMI of the respondents in the entire sample, as well as the prevalence of obesity, while the prevalence of underweight and pre-obesity decreased.ConclusionThe research provided insight into the specific factors associated with and trends of levels of nutritional status of the young, leading to the conclusion that preventive and interventional public health programs and strategies must be fully adapted to their specific needs.

Outcomes of chronic limb-threatening ischemia revascularization in patients with chronic kidney disease in the BEST-CLI trial.

Chronic limb-threatening ischemia (CLTI) in patients with chronic kidney disease (CKD) has a high risk of poor outcomes. We aimed to compare the outcomes of lower extremity revascularization in patients with CLTI stratified by CKD severity in patients enrolled in the prospective, randomized Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial. The BEST-CLI trial dataset was queried to categorize patients into three groups according to CKD stage. Group A includes non-CKD and CKD stages<3; group B includes stage 3 and stage 4 CKD patients; and group C includes stage 5 CKD and dialysis-dependent patients. Furthermore, spline modeling was performed across the range of estimated glomerular filtration rate (eGFR, mL/min/1.73m2) observed in study participants to identify a threshold eGFR that impacted the primary trial outcomes: major adverse limb events (MALEs; defined as above-ankle amputation or major reintervention) or all-cause mortality, by surgical or endovascular revascularization (as-treated analysis). Kaplan-Meier and multivariate Cox regression analyses were used to assess association of CKD risk groups with the outcomes. A total of 1797 patients were included. Group C patients had double the risk of amputation (hazard ratio [HR], 2.13; P< .001), MALE, or all-cause mortality (HR, 2.05; P< .001) and more than triple the risk of all-cause mortality (HR, 3.40; P<.001) compared with group A. In dialysis-dependent patients, endovascular therapy was associated with better survival, but twice the risk of reintervention compared with surgical revascularization. According to spline model analysis, hazard of MALE or all-cause mortality increased sharply at eGFR<30. The hazard ratios for eGFR<30 vs ≥60 were 2.03 (95% confidence interval [CI], 1.68-2.43; P< .001) and 3.46 (95% CI, 2.80-4.27; P< .001) for MALE and mortality, respectively. At eGFR<30, there was no difference in the primary outcome by treatment received (surgical or endovascular revascularization). The progressive nature of renal impairment in patients with CLTI threatens their survival and limb salvage and may reduce the relative benefit of open vs endovascular revascularization seen in the overall BEST-CLI trial population. In dialysis-dependent patients, endovascular therapy was associated with lower mortality but increased reintervention rate.

Operating Characteristics of the Simulated Healthy Participant Approach in Impaired Clearance Studies.

Minimizing harm is a cornerstone of ethical research practices. A drug that has undergone extensive clinical pharmacological testing in healthy participants (HPs) and a diverse selection of patients can be described with a sufficiently predictive population pharmacokinetic (PopPK) model. In impaired clearance trials, recruitment is minimized and underpowered for all but major exposure differences. Virtual HP arms have been reported to support similar conclusions to conventional impaired clearance studies, and further minimize potential harm of drug exposure without medical benefit by eliminating an arm of the study. However, the extent to which the conventional analysis of impairment studies compare to the simulation approach is unknown. Here we assess the operating characteristics of the virtual cohort approach along with the conventional approach through controlled simulations. These simulations included a simple, widely accessible PopPK model and several internal models that have been used in a previous meta-analysis of the virtual cohort approach. In the pairwise comparisons assessed, the virtual cohort simulation approach had greater power per sample size than the conventional approach and the same power under the null hypothesis. Given key methodological differences, it is recommended that the simulation and conventional approaches be treated as having approximately the same power under equivalent conditions. These results provide a strong justification for the use of the virtual cohort approach when an adequate PopPK model is available, minimizing unnecessary exposure to study drugs that will not benefit healthy study participants.