High Risk Research Articles

Age-specific prognosis of acute and steady minor elevations in cardiac troponin among non-acute myocardial infarction inpatients: a large real-world cohort study

BackgroundThe upper reference limit of normal (ULN) of cardiac troponin (cTn) for older adults can be higher than for young adults, while the same ULN is used for both older...

Prevalence, Incidence and Predictors of Anal HPV Infection and HPV-Related Squamous Intraepithelial Lesions in a Cohort of People Living with HIV

Background: Anal HPV infection can cause squamous intraepithelial lesions (SILs), which are precursors of anal squamous cell carcinoma (SCC). The early detection of HPV infections and improvement of effective screening programmes are, therefore, essential to prevent progression from pre-cancerous lesions to SCC, especially in people living with HIV (PLWH), who represent a population at higher risk of HPV infection and associated lesions. Among prevention strategies, HPV vaccination is relevant too, but its efficacy in persons already infected by HPV is still debated. Methods: This is a retrospective single-center study on a cohort of PLWH who performed longitudinal screening for anal dysplasia and HPV infection. The screening included cytological and molecular analyses. Results: A total of 110 PLWH performed at least one anal HPV screening, with an overall prevalence of HPV infection of 86.4% [23.6% low risk (LR)-HPV and 62.7% high risk (HR)-HPV genotypes]. Abnormal cytology was demonstrated in 39.1% of subjects, of whom ASCUS 6.4%, LSIL 30.9% and HSIL 1.8%. In total, 80 patients (72.7%) had an available longitudinal screening. No patient developed SCC during follow-up. However, a high incidence of new cytological abnormalities and new HPV infections was observed. On the other side, clearance of some HPV genotypes was also frequent, confirming that HPV infection is a dynamic process. A CD4 cell count > 500/mmc was an independent predictor of HPV clearance. HPV vaccination was performed on 30.9% of patients. A trend toward an increased clearance of HPV genotypes included in 9-valent vaccine was observed in vaccinated patients (40.6% versus 30.8% in unvaccinated, p = 0.079). Conclusions: A high prevalence of HPV infection and SILs was observed in our cohort of PLWH. A high incidence of new HPV infections and HPV-associated lesions was also observed in the longitudinal cohort, highlighting the need of strengthening immunization programs and continuous screening for anal HPV infection. Whether HPV vaccination may be efficacious in patients already infected by HPV remains to be determined.

Analysis of HIV transmission characteristics and intervention effects in Guangxi based on molecular networks

Objective: This study evaluates changes in HIV transmission and the effectiveness of interventions after two rounds of the Guangxi AIDS Conquering Project (GACP) in Guangxi, China. Methods: Samples and epidemiological data from newly diagnosed people living with HIV (PLWH) between 2014-2020 were analyzed. Molecular networks were constructed using nested PCR amplification and sequencing of the pol region, and multivariable logistic regression identified factors associated with clustering and high-degree nodes. Results: A total of 4,227 valid sequences (73.12% inclusion rate) were analyzed. Demographic changes included an increasing proportion of individuals aged ≥50 years (49.66%), with lower education (50.51%), peasants (76.82%), and heterosexual transmission (90.29%). The overall clustering rate was 86.89%, with higher clustering among individuals aged ≥50 (92.57%), those with primary school or below (89.09%), peasants (88.11%), and CRF08_BC infections (91.48%). Annual declines in cluster growth rate and clustering rates were observed, particularly among individuals aged <30, college graduates, men who have sex with men (MSM), and people who inject drugs (PWID). Key transmission hotspots were identified in Lingshan, particularly among older, less-educated individuals, and peasants. Factors associated with clustering included being male (aOR: 1.27), aged ≥50 (aOR: 3.84), and infected with CRF08_BC (aOR: 2.12). From 2017 to 2020, the risk of clustering and high-degree nodes was lower compared to 2014–2016, suggesting the effectiveness of interventions. Conclusion: Interventions in Guangxi effectively reduced HIV transmission among younger, high-degree populations. However, older, less-educated individuals remain at high risk, necessitating targeted strategies to address their specific needs and achieve better HIV control.

The Role of Systemic Health Indicators, Including C-Reactive Protein and eGFR, in Predicting Periodontal Disease: A Longitudinal Study

C-reactive protein (CRP) and estimated glomerular filtration rate (eGFR) are key biomarkers reflecting systemic inflammation and metabolic dysfunction. This study explored systemic and oral health indicators, including CRP and eGFR, as potential factors associated with periodontitis, using a longitudinal clinical dataset comprising 23,742 records from patients identified by ICD-10 codes between 2015 and 2022. Univariate Cox analysis and Gompertz models, selected based on AIC and BIC after evaluating alternative models, were employed to assess the predictive roles of CRP and eGFR in periodontitis incidence, adjusting for oral and systemic health factors. Elevated CRP (>15 mg/L) and reduced eGFR (<60 mL/min/1.73 m2) were significant predictors of periodontitis, with hazard ratios (HR) of 1.36 [1.05–1.77] and 1.39 [1.08–1.78], respectively. Atherosclerosis (HR: 2.12 [1.11–4.06]), diseases of the hard tissues of the teeth (HR: 7.30 [5.45–9.78]), and disorders of the teeth and supporting structures (HR: 3.02 [2.05–4.43]) also demonstrated strong predictive associations. CRP and eGFR emerged as potential biomarkers for predicting periodontitis, enabling early interventions to prevent tooth loss and systemic complications. Patients with chronic kidney disease, atherosclerotic heart disease, and lipid metabolism disorders are at higher risk, emphasizing the need for integrated care addressing both systemic and oral health factors.

Rare and common genetic variants underlying the risk of Hirschsprung’s disease

Abstract Hirschsprung’s disease (HSCR) is a congenital enteric neuropathic disorder characterized by high heritability (>80%) and polygenic inheritance (>20 genes). The previous genome-wide association studies (GWAS) identified several common variants associated with HSCR and demonstrated increased predictive performance for HSCR risk in Europeans using a genetic risk score, there remains a notable gap in knowledge regarding Chinese populations. We conducted whole exome sequencing in a HSCR case cohort in Chinese. By using the common controls (505 controls from 1KG EAS and 10 588 controls from ChinaMAP), we conducted GWAS for the common variants in the exome and gene-based association for rare variants. We further validated the associated variants and genes in replicated samples and in vitro and vivo experiments. We identified one novel gene PLK5 by GWAS and suggested 45 novel putative genes based the gene-based test. By using genetic variant at RET and PLK5, we constructed a genetic risk score that could identify the individuals with very high genetic risk for HSCR. Compared with patients with zero or one risk allele from the three variants, the risk for HSCR was 36.61 times higher with six alleles. In addition, we delineated a HSCR risk gene landscape that encompasses 57 genes, which explains 88.5% and 54.5% of HSCR in Chinese and European, respectively. In summary, this study improved the understanding of genetic architecture of HSCR and provided a risk prediction approach for HSCR in the Chinese.

Association of Alzheimer’s Disease Polygenic Risk Score with Concussion Severity and Recovery Metrics

Abstract Background Identification of genetic alleles associated with both Alzheimer’s disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed. Objective We used AD polygenic risk scores (PRS) and APOE genotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset. Methods We assessed six concussion outcomes in 931 participants, including two recovery measures (number of days to asymptomatic and to return to play (RTP)) and four severity measures (scores on SAC and BESS, SCAT symptom severity and total number of symptoms). We calculated the PRS using a published score and performed multiple linear regression to assess the relationship of the PRS with outcomes. We also used ANOVAs, t-tests, and chi-square tests to examine outcomes by APOE genotype. Results Higher PRS was associated with longer injury to RTP time in the normal RTP (< 24 days) subgroup (p = 0.024). A one standard deviation increase in the PRS resulted in a 9.89 hour increase to RTP time. This result was no longer significant after inclusion of covariates. There were no other consistently significant effects. Conclusions Our findings suggest high AD genetic risk is not associated with more severe concussions or poor recovery in young adults. Future studies should attempt to replicate these findings in larger samples with longer follow-up using PRS calculated from diverse populations.

Impact of different glycoprotein IIb/IIIa inhibitor infusion routes on infarct size and microvascular obstruction in patients with high thrombotic risk ST elevation myocardial infarction

Impact of different glycoprotein IIb/IIIa inhibitor infusion routes on infarct size and microvascular obstruction in patients with high thrombotic risk ST elevation myocardial infarction

Can digital transformation decrease the debt concentration?

AbstractDigital transformation affects a firm's financial decisions. This study examines the relationship between digital transformation and debt concentration. Higher‐level corporate digital transformation significantly decreases debt concentration (i.e., firms prefer to choose multiple debt types). Moreover, this relationship is more pronounced for firms with lower accounting information quality, higher default risk, and higher bankruptcy costs. Additional analyses reveal that digital and institutional environments affect the relationship between digital transformation and debt concentration. This study contributes to existing literature by showing the impact of the integration of digital technology on firms' debt structures and the economy.

Hermetia illucens in the Process of Kitchen Waste Biodegradation: The Effect of Different Approaches to Waste Storage on the Microbiological Profile and Nutritional Parameters of the Larvae

This study assessed the bioconversion efficiency of Hermetia illucens larvae (BSFL) fed on food waste stored under different conditions, focusing on the nutritional and microbial quality of the resulting larval biomass. Food waste was prepared as a fresh diet (FD) or naturally contaminated and stored at 20–22 °C (OS-T, opened storage-tempered) or under refrigeration, at 5–8 °C (CS-C, closed storage-cooled). Refrigerated, closed storage (CS-C) led to the highest rates of waste reduction (91.0%) and bioconversion efficiency (30.2%), with larvae exhibiting the highest protein content (36.83%) compared to the FD (35.5%) and OS-T (34.71%) groups. Microbiome analysis revealed that the CS-C condition promoted beneficial yeasts like Pichia and Diutia, which correlated positively with improved protein content and microbial safety. In contrast, OS-T storage supported spoilage fungi (Mucor, Rhizopus) and elevated total aerobic counts (7.28 log CFU/g), indicating higher microbial risks. The observed trends in waste reduction and protein content most probably relate to differences in microbial profiles, as controlled cooling affected microbial dynamics, preserving substrate quality and supporting larval growth. These findings emphasize the importance of refrigerated, closed storage to optimize bioconversion, improve larval nutritional value, and minimize microbiological hazards.

Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer

BackgroundPatients with human epidermal growth factor receptor 2 (HER2)–positive early breast cancer with residual invasive disease after neoadjuvant systemic therapy have a high risk of recurrence and death. The primary analysis of KATHERINE, a phase 3, open-label trial, showed that the risk of invasive breast cancer or death was 50% lower with adjuvant trastuzumab emtansine (T-DM1) than with trastuzumab alone.MethodsWe randomly assigned patients with HER2-positive early breast cancer with residual invasive disease in the breast or axilla after neoadjuvant systemic treatment with taxane-based chemotherapy and trastuzumab to receive T-DM1 or trastuzumab for 14 cycles. Here, we report the prespecified final analysis of invasive disease–free survival and the second interim analysis of overall survival.ResultsWith a median follow-up of 8.4 years, T-DM1 sustained the improvement in invasive disease–free survival over trastuzumab (unstratified hazard ratio for invasive disease or death, 0.54; 95% confidence interval [CI], 0.44 to 0.66). Seven-year invasive disease–free survival was 80.8% with T-DM1 and 67.1% with trastuzumab (difference, 13.7 percentage points). T-DM1 also led to a significantly lower risk of death than trastuzumab (unstratified hazard ratio, 0.66; 95% CI, 0.51 to 0.87; P=0.003). Seven-year overall survival was 89.1% with T-DM1 and 84.4% with trastuzumab (difference, 4.7 percentage points). Adverse events of grade 3 or higher were noted in 26.1% of the patients in the T-DM1 group and 15.7% of those in the trastuzumab group.ConclusionsAs compared with trastuzumab, T-DM1 improved overall survival with sustained improvement in invasive disease–free survival among patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. (Funded by F. Hoffmann–La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472.)

Human rights violations are associated with forcibly displaced population’s mental health—a systematic review and meta-analysis

BackgroundLittle is known about the mental health consequences of human rights violations in forcibly displaced populations. Objective: The objectives of this systematic review are to examine: (1) the prevalence of mental health conditions among forcibly displaced persons; (2) to investigate methodological factors contributing to mental health conditions; and (3) associations between mental health conditions and human rights violations.MethodsWe conducted a systematic review with meta-analyses on the prevalence of anxiety, depression, and posttraumatic stress disorder among forcibly displaced populations and factors contributing to it by searching in databases MEDLINE (Ovid), Embase, Web of Science Core Collection (Clarivate), PsycINFO (EBSCO), Sociological Abstracts (ProQuest), and PTSDPubs (ProQuest). Additionally, we assessed the Global Peace Index. Pooled associations were calculated using a random-effects meta-analysis model. Subgroup analyses were performed for the Global Peace Index, sampling methodology, also we assessed risk of bias.ResultsOf the 4,175 records screened, 55 with n = 31,573 participants met the inclusion criteria (n = 15,714 males, females, n = 15,859 females). Most studies were cross-sectional (n = 49). The pooled prevalence rates were 38.90% (95% CI: 29.63; 48.17) for anxiety, 38.16% (95% CI: 32.16; 44.15) for depression and 39.62% (95% CI: 32.87; 46.36) for posttraumatic stress disorder. Analyses by level of human rights violations show anxiety, and depression prevalence rates were higher in countries with low Global Peace Index than countries with high, moderate and low Global Peace Index (39.84% vs. 16.09%; 41.07% vs. 26.67%). Analyses by risk of bias indicate that the prevalence rate of PTSD was higher in studies with a high risk of bias compared to those with a very high risk of bias (49.27% vs. 29.79%). For anxiety, the prevalence rate was greater with random sampling compared to convenience sampling (44.71% vs. 36.87%). Depression and PTSD prevalence rates were higher with convenience sampling than with random sampling (38.67% vs. 37.70%; 42.83% vs. 35.50%).ConclusionOur review suggests that systematic continuous human rights violations are associated with mental health conditions in forcibly displaced persons. To prevent mental health conditions, it is necessary to reduce exposure to human rights violations in the countries forcibly displaced persons come from.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017076535, PROSPERO registration: CRD42017076535.

Influence of Mesalazine on Ferroptosis-Related Gene Expression in In Vitro Colorectal Cancer Culture

Background/Objectives: Colorectal cancer (CRC) is one of the most common oncological disorders. Its fundamental treatments include surgery and chemotherapy, predominantly utilizing 5-fluorouracil (5-FU). Despite medical advances, CRC continues to present a high risk of recurrence, metastasis and low survival rates. Consequently, significant emphasis has been directed towards exploring novel types of cell death, particularly ferroptosis. Ferroptosis is characterized by iron imbalance and the accumulation of lipid peroxides and reactive oxygen species (ROS), leading to cellular damage and death. Thus, the discovery of safe inducers of ferroptosis, offering new hope in the struggle against CRC, remains crucial. In this study, we applied the concept of drug repositioning, selecting mesalazine (MES), a non-steroidal anti-inflammatory drug (NSAID), for investigation. Methods: The study was conducted on the colon cancer cell line DLD-1 and normal intestinal epithelial cells from the CCD 841 CoN cell line. Both cell lines were treated with MES solutions at concentrations of 10, 20, 30, 40, and 50 mM. Cytotoxicity was assessed using the MTT assay, while ferroptosis-related gene expression analysis was performed using oligonucleotide microarrays, with RT-qPCR used for validation. Results: MES effectively reduces the viability of DLD-1 cells while minimally affecting normal intestinal cells. Subsequent oligonucleotide microarray analysis revealed that MES significantly alters the expression of 56 genes associated with ferroptosis. Conclusion: Our results suggest that MES may induce ferroptosis in CRC, providing a foundation for further research in this area.

Early menarche is associated with disordered eating—results from a National Youth Survey

Abstract Background Disordered eating (DE) is highly prevalent among adolescents, though its definition varies. The association between DE and early pubertal maturation (EPM) remains underexplored in Israel, and has not been sufficiently examined using the widely-used SCOFF questionnaire. This study examines these associations in adolescents. Methods Participants (n = 2415 girls, 2095 boys; ages 12–18 years) in a nationally-representative, cross-sectional Youth Health and Nutrition Survey (2015–2016) completed self-administered questionnaires, including the SCOFF questionnaire, and underwent anthropometric measurements. EPM was determined by menarcheal age <11.5 years in girls, and facial hair appearance <12.5 years in boys. Respondents affirming ≥2 SCOFF items were classified as DE cases. Multivariable logistic regression analyses examined the associations between EPM and DE. Results Among the participants, 12.7% of the girls and 20.4% of the boys met EPM criteria; 55.5% and 33.7%, respectively, were categorized as having DE. Following adjustment for age, socioeconomic status, ethnic background, and weight status, EPM was significantly associated with DE in girls (OR 1.47, 95%CI: 1.12–1.93) and with 3/5 SCOFF items. No such association was found in boys (OR 1.00, 95%CI: 0.77–1.28). Conclusion EPM in girls was associated with DE. Identifying high risk groups for DE in adolescents is crucial for early intervention and prevention. Impact This study included a large, nationally representative sample of Israeli adolescents and utilized the SCOFF questionnaire, a widely used screening measure for disordered eating (DE). Following comprehensive analyses, a significant association between early pubertal maturation (EPM), defined as early menarche, and DE was documented in Israeli adolescent girls. Identifying girls with EPM and screening for disordered eating will allow for early interventions, potentially improving physical and mental health, and preventing progression to eating disorders.

Predicting financial distress in high-dimensional imbalanced datasets: a multi-heterogeneous self-paced ensemble learning framework

Financial distress prediction (FDP) is a critical area of study for researchers, industry stakeholders, and regulatory authorities. However, FDP tasks present several challenges, including high-dimensional datasets, class imbalances, and the complexity of parameter optimization. These issues often hinder the predictive model’s ability to accurately identify companies at high risk of financial distress. To mitigate these challenges, we introduce FinMHSPE—a novel multi-heterogeneous self-paced ensemble (MHSPE) FDP learning framework. The proposed model uses pairwise comparisons of data from multiple time frames combined with the maximum relevance and minimum redundancy method to select an optimal subset of features, effectively resolving the high dimensionality issue. Furthermore, the proposed framework incorporates the MHSPE model to iteratively identify the most informative majority class data samples, effectively addressing the class imbalance issue. To optimize the model’s parameters, we leverage the particle swarm optimization algorithm. The robustness of our proposed model is validated through extensive experiments performed on a financial dataset of Chinese listed companies. The empirical results demonstrate that the proposed model outperforms existing competing models in the field of FDP. Specifically, our FinMHSPE framework achieves the highest performance, achieving an area under the curve (AUC) value of 0.9574, considerably surpassing all existing methods. A comparative analysis of AUC values further reveals that FinMHSPE outperforms state-of-the-art approaches that rely on financial features as inputs. Furthermore, our investigation identifies several valuable features for enhancing FDP model performance, notably those associated with a company’s information and growth potential.

Endotracheal tube as chest tube: a back-up alternative in resource limited settings

Thoracostomies, and subsequent placements of chest tubes (CTs), are a standard procedure in several domains of medicine. In emergency medicine, thoracostomies are indicated to release a relevant hemothorax or pneumothorax,...

Emergency department early mortality model for patients admitted after presenting to a tertiary medical center emergency department

AbstractObjectivesIdentifying patients in the emergency department (ED) at higher risk for in‐hospital mortality can inform shared decision making and goals‐of‐care discussions. Electronic health record systems allow for integrated multivariable logistic regression (LR) modeling, which can provide early predictions of mortality risk in time for crucial decision making during a patient's initial care. Many commonly used LR models require blood gas analysis values, which are not frequently obtained in the ED. The goal of this study was to develop an all‐cause mortality prediction model, derived from commonly collected ED data, which can assess mortality risk early in ED care.MethodsData were obtained for all patients, age 18 and older, admitted from the ED to Atrium Health Wake Forest Baptist from April 1, 2016, through March 31, 2020. Initial vital signs including heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, pulse oximetry, weight, body mass index, comprehensive metabolic panel, and a complete blood count were electronically retrieved for all patients. The prediction model was developed using LR. The ED early mortality (EDEM) model was compared with the rapid Emergency Medicine Score (REMS) for performance analysis.ResultsA total of 45,004 patients met inclusion criteria, comprising a total of 77,117 admissions. In this cohort, 52.8% of patients were male and 47.2% were female. The model used 35 variables and yielded an area under the receiver operating characteristic curve (AUC) of 0.889 (95% CI 0.874–0.905) with a sensitivity of 0.828 (95% CI 0.791–0.860), a specificity of 0.788 (95% CI 0.783–0.794), a negative predictive value of 0.995 (95% CI 0.994–0.996), and a positive predictive value of 0.084 (95% CI 0.076–0.092). This outperformed REMS in this data set, which yielded an AUC of 0.500 (95% CI 0.455–0.545).ConclusionsThe EDEM model was predictive of in‐hospital mortality and was superior to REMS.

Genetic Predisposition to Hippocampal Atrophy and Risk of Amnestic Mild Cognitive Impairment and Alzheimer’s Dementia

Background: There is a paucity of evidence on the association between genetic propensity for hippocampal atrophy with cognitive outcomes. Therefore, we examined the relationship of the polygenic risk score for hippocampal atrophy (PRShp) with the incidence of amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) as well as the rates of cognitive decline. Methods: Participants were drawn from the population-based HELIAD cohort. Comprehensive neuropsychological assessments were performed at baseline and at follow-up. PRShp was derived from the summary statistics of a large genome-wide association study for hippocampal volume. Cox proportional hazards models as well as generalized estimating equations (GEEs) were used to evaluate the association of PRShp with the combined incidence of aMCI/AD and cognitive changes over time, respectively. All models were adjusted for age, sex, education, and apolipoprotein E (APOE) genotype. Results: Our analysis included 618 older adults, among whom 73 developed aMCI/AD after an average follow-up of 2.96 ± 0.8 years. Each additional SD of PRShp elevated the relative hazard for incident aMCI/AD by 46%. Participants at the top quartile of PRShp had an almost three times higher risk of converting to aMCI/AD compared to the lowest quartile group. Higher PRShp scores were also linked to steeper global cognitive and memory decline. The impact of PRShp was greater among women and younger adults. Conclusions: Our findings support the association of PRShp with aMCI/AD incidence and with global cognitive and memory decline over time. The PRS association was sex- and age-dependent, suggesting that these factors should be considered in genetic modelling for AD.

Non-Indexed vs. Body Surface Area Indexed Measured Glomerular Filtration Rate Determinations as a Criterion of Living Donor Acceptance

Introduction: When GFR is measured (mGFR) using iohexol plasma clearance, results are reported both as a “non-indexed” (mL/min) and “body-surface area (BSA) indexed” to 1.73 m2. When these two values differ, there is no consensus as to which is preferable to use to determine suitability for living kidney donation (LKD). We sought to compare the difference between non-indexed and BSA indexed mGFR in LKDs and the association with postdonation estimated GFR (eGFR). Methods: Between 1/1/2007-1/1/2023, 627 adult LKDs at the University of Minnesota had predonation mGFR by iohexol plasma clearance and a minimum six-month follow-up. LKD acceptance was based on a non-indexed mGFR ≥80 ml/min (age <60) or ≥75 ml/min (age ≥60). Primary outcomes included eGFR at one-year postdonation and sustained eGFR <45 mL/min/1.73m2. Results: Among 627 LKDs, 561 (90%) had both a non-indexed and BSA indexed mGFR above the age-based threshold (concordant), while 66 (11%) had non-indexed measurements above and BSA indexed below (discordant). Compared to concordant LKDs, discordant LKDs were older (median: 54.1 years vs. 42.8 years, p <0.001) and had higher body mass indices (28.0 vs. 26.1, p <0.001). At one-year postdonation, mean eGFR was higher among concordant LKDs, although the difference in relative change from pre-donation eGFR measurements was similar. During a median follow up of 2.3 years, six out of 66 (9%) discordant LKDs experienced sustained eGFR <45 mL/min/1.73m2 compared to five out of 561 (0.9%) concordant LKDs (hazard ratio: 10.7, 95% confidence intervals: 3.21 to 35.6). Conclusion: Discordant LKDs had lower eGFR measurements postdonation and experienced a higher risk for eGFR <45 mL/min/1.73m2.

Thyromimetics and MASLD: Unveiling the Novel Molecules Beyond Resmetirom

ABSTRACTBackgroundResmetirom, the first FDA‐approved drug for nonalcoholic steatohepatitis (NASH) with fibrosis in obese patients, when combined with lifestyle modifications, improves NASH resolution and reduces fibrosis by at least one stage. Low thyroid hormone (T3) levels are linked to a higher risk of developing metabolic dysfunction‐associated steatotic liver disease (MASLD). Epidemiological studies have confirmed the positive correlation between hypothyroidism and MASLD. Unraveling the molecular mechanisms of T3 signaling pathways in MASLD will enhance the prospects of identifying effective and specific targets. Therefore, this review discusses the significant role of thyroid hormones in the homeostasis of fat metabolism and describes the possible molecular mechanisms of thyromimetics in the treatment of MASLD.MethodsA comprehensive search in PubMed and EMBASE was conducted using the keywords “thyromimetics and liver diseases,” “thyroid hormone and liver diseases,” “hypothyroidism and liver diseases,” “T3, T4 and liver disease,” and “resmetirom and liver disease.” Relevant papers published before October 2024 were included.ResultsT3 treatment enhances mitochondrial respiration, biogenesis, β‐oxidation, and mitophagy, reducing liver lipid accumulation. However, T3 treatment causes cardiotoxicity through thyroid hormone receptor (THR)α agonistic activity. To address this, molecules with high THRβ agonistic but lower THRα activity have been developed. Besides resmetirom, other THRβ agonists like TG68, CS27109, MB07811, and KB‐141 show promising results in experimental studies. These molecules upregulate THRβ target genes, activate genes for fatty acid β‐oxidation in mitochondria and fatty acid breakdown in peroxisomes, downregulate the genes involved in de novo lipogenesis, reduce inflammation by downregulating NF‐κB/JNK/STAT3 signaling pathways, and accelerate fibrosis resolution by downregulating the expressions of fibrosis marker genes in NASH liver tissue.ConclusionFuture clinical studies should thoroughly investigate THRβ agonists, including TG68, CS27109, MB07811, and KB‐141.

Personalized Dynamic Prediction Model for Biopsy Timing in Patients With Prostate Cancer During Active Surveillance

ImportanceActive surveillance (AS) for patients with prostate cancer (PC) often includes fixed repeat prostate biopsies that do not account for the varying risk of reclassification to significant disease. Given the invasive nature and potential complications of biopsies, a personalized approach is needed to balance the burden of biopsies with the risk of missing disease progression.ObjectiveTo develop and externally validate a dynamic model that predicts an individual’s risk of PC reclassification during AS.Design, Setting, and ParticipantsThis prognostic study developed a dynamic prediction model using data from the Prostate Cancer Research International: Active Surveillance (PRIAS) study, which was initiated in 2006. Follow-up was truncated until April 2023. External validation was conducted using cohorts from the world’s largest centralized AS database, the Global Action Plan Prostate Cancer Active Surveillance initiative database. The PRIAS study is a multicenter, prospective, web-based cohort study monitoring patients undergoing AS, involving more than 175 academic, nonacademic, and private centers across 23 countries worldwide. For the development and external validation of the model, all patients diagnosed with Grade Group 1 PC who underwent at least 1 baseline or follow-up magnetic resonance imaging (MRI) and 1 follow-up biopsy were included. Data were analyzed from September 2023 to January 2024.ExposuresAS, including prostate-specific antigen (PSA) tests, MRI, and prostate biopsies according to a fixed follow-up schedule.Main Outcomes and MeasuresA joint model for longitudinal and time-to-event data was used to predict reclassification to Grade Group 2 or greater on repeat biopsy using predefined baseline and repeated clinical characteristics. Performance was assessed using time-dependent area under the receiver operating characteristic curve and negative predictive value.ResultsThe development cohort included 2512 patients (median [IQR] age, 65 [59-69] years). Characteristics significantly associated with a higher risk of reclassification were increased age, higher PSA and velocity, lower prostate volume, a suspicious lesion on MRI, and no previous negative biopsy findings. Depending on the threshold and time point used, the model demonstrated a negative predictive value of 86% to 97%. External validation included 3199 patients from 9 other cohorts. The time-dependent area under the curve ranged from 0.81 to 0.84 in the development cohort and 0.52 to 0.90 at external validation.Conclusions and RelevanceIn this prognostic study, the developed dynamic risk model effectively identified patients at low risk of PC reclassification during AS. After prospective validation, this model may support personalized, risk-based AS and reduce the burden of unnecessary biopsies.