Contemporary colorectal cancer (CRC) epidemiology reveals evolving risk factors have reconfigured CRC as a societally-modulated, quasi-age-dependent disease. Nevertheless, temporal drivers of incidence/incidence-based mortality (IBM) patterns and longitudinal trends in clinicopathological profiles, therapeutic modalities, and 5-year survival (5-YS) remain incompletely defined, necessitating methodologically rigorous studies. The Surveillance, Epidemiology, and End Results Program data (1975-2019) were analyzed using the National Cancer Institute's (NCI's) Age-Period-Cohort Analysis Tool to examine temporal drivers of US CRC epidemiology. Longitudinal trends in clinicopathological profiles, therapeutic modalities, and 5-YS were further assessed via NCI's Joinpoint Regression Program. The relative risk (RR) of incidence increased exponentially in sequentially younger birth cohort, with the annual percentage change (APC) peaking at 6.11% in 20 - 24 years, while the RR of IBM declined in successively older birth cohorts and showed no improvement in younger birth cohorts. Early-onset CRC with regional- or distant-predominant disease (notably hepatic) showed a marked shift from adjuvant to neoadjuvant therapy, including a notable increase in preoperative radiotherapy for regional rectal cancer from 19.7% (2000) to 53.8% (2019), and preoperative systemic therapy for distant colon cancer from 5.5% (2007) to 17.6% (2019). Correspondingly, stage-specific 5-YS was also superior in early-onset CRC (e.g., regional rectal cancer: 82.5% vs. 67.8%; distant colon cancer: 22.9% vs. 14.7%), with greater annual improvement (e.g., APC for regional rectal cancer: 1.60% vs. 1.46%; APC for distant colon cancer: 3.59% vs. 2.55%). However, over 50% of distant metastatic patients, especially those with late-onset disease, still received no effective treatment. While overall CRC burden decreased in the US, extreme early-onset CRC surged with poor prognosis. Despite higher regional/metastatic burden, early-onset CRC showed better survival owing to aggressive treatment and adherence. Urgent actions are needed to address the rising risk in youth and therapeutic gaps in metastatic disease.
Post-traumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder that develops after exposure to a severe traumatic event. PTSD is characterized by intrusive re-experiencing of traumatic memories, avoidance of trauma reminders, negative alterations in cognition and mood, and changes in arousal and reactivity. PTSD is prevalent, with tens of millions of patients in the USA alone affected. The lifetime prevalence worldwide is estimated to be about 4-6%, but it can occur in up to 25-30% of people who experience severe psychological trauma, such as combat veterans, refugees and assault victims. PTSD is highly comorbid with major depressive disorder, anxiety disorders and substance use disorders, and it is a leading cause of suicide. PTSD also increases the risk of multiple medical problems including cardiovascular and metabolic disorders. We review the epidemiology and diagnostic aspects of PTSD in adults, the mechanistic and neurobiological understanding of the syndrome - from neural circuitry to genetic mechanisms - as well as medication, psychotherapy and other trauma-informed treatment approaches to PTSD and trauma-related syndromes.
Lung cancer is the leading cause of death worldwide, and about 40% to 70% of lung cancer patients have chronic obstructive pulmonary disease (COPD). The aim of this study is to analyze lung cancer and COPD-related mortality trends among older adults in the U.S. and to assess shifts in trends across different divisions of demographics and geographics. We assessed CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiology Research) death certificates on which both lung cancer and COPD were listed as either underlying or contributing cause of death from 1999 to 2024. Age-adjusted mortality rates (AAMRs) per 100,000 and annual percent changes (APCs) were calculated and measured across different demographic and geographic subdivisions. Overall, 582,373 deaths were recorded with AAMR declining from 58.7 in 1999 to 43.8 in 2024, showing significant falls between 2006-2018 (APC -1.96*; p < 0.05) and later from 2021 to 2024 (APC -2.66*; p < 0.05). Males (68.1) persistently had higher AAMRs than females (41.1). From races/ ethnicities, the highest AAMR was reported in NH whites (58.3), while non-metropolitan areas (67.2) and the region of the Midwest (60.8) represented the highest rates among geographics. Although AAMR declined from 1999 to 2024, significant disparities persist, highlighting the need for targeted interventions and resource distributions among males, NH Whites, and non-metropolitan areas in the U.S.
Birth defects can cause significant morbidity and mortality. We examined the prevalence of maternal characteristics and risk factors associated with birth defects and examined their associations with prepregnancy multivitamin/folic acid (MVF) intake and diabetes. Data from 22 jurisdictions participating in the Pregnancy Risk Assessment Monitoring System (PRAMS) survey (2017-2022) of women with recent live births were used. Distributions were calculated for: prepregnancy health factors (MVF intake, diabetes status, obesity, smoking, alcohol use) and for participant characteristics (age, race/ethnicity, educational attainment, pregnancy intention, federal poverty level). Log-binomial regression was used to calculate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) for the associations between selected characteristics and MVF intake and diabetes. Associations between pregnancy intention and MVF intake stratified by selected characteristics were also examined. Finally, differences in longitudinal MVF intake across jurisdictions were assessed. Almost half (48.2%) of women reported no prepregnancy MVF intake; before pregnancy, 52.0% were overweight or had obesity, 57.9% used alcohol, 15.2% smoked, and 3.1% had diabetes. Prepregnancy MVF intake was associated with increased age (≥ 30 years vs. 25-29: aPRs > 1.10), higher educational attainment (graduate degree vs. ≤ high school: aPR = 1.32, 95% CI: 1.17, 1.49), and intended pregnancies (aPR: 1.50, 95% CI: 1.42, 1.58). Diabetes status was not associated with MVF intake or pregnancy intention. Prevalence of risk factors for birth defects was high, and differences exist across groups of women. Findings from this study can help inform public health interventions on risk factors that may help improve birth outcomes.
Numeracy and math skills in the US, key predictors of academic and vocational success, are low and decreasing. Numeracy is not captured by general developmental screening, and no efficient, direct measure feasible for pediatric settings currently exists. In this pediatric primary care pilot, The Number Farm performed well in terms of psychometric validity, family acceptance, and relationships with home reading and math routines. The book-based approach of The Number Farm is family-centered, inexpensive, and scalable within existing literacy and early childhood education programs. These findings align with AAP recommendations to conduct developmental screening during clinic visits and promote school readiness.
The cholera burden in Yemen is the highest in the world, with the country facing recurrent outbreaks. It is worsened by the ongoing conflict, limited access to clean water, and the deteriorated sanitation and health systems. In November 2023, a cholera outbreak started in Shabwah governorate and seemed to be controlled in January 2024. However, in March 2024, cholera spread westward, causing 40,000 suspected cases in South Yemen. Routinely collected data were used to provide descriptive statistics of the 2023-2024 cholera outbreak of patients managed in the Médecins Sans Frontières (MSF)-supported cholera treatment centers (CTCs) and units (CTUs) of Aden, Ataq, Mafraq and Mocha. There were 10,252 suspected cholera cases admitted to MSF-supported facilities. Of these, 52.5% were male, and 41.4% were aged 15-44 years and 24.1% 0 to 4 years. Most cases were managed in Aden (56.2%) and Mocha (24.8%). Of these, 43.1% were classified as non-dehydrated (plan A), 41.9% had moderate dehydration (plan B), and 15.0% had severe dehydration (plan C). The overall case fatality rate in MSF-supported facilities was 0.2% compared to 0.52% across South Yemen. Aden's Sadaqa CTC treated 80.3% of all Plan C cases, reflecting its role as a referral hub. The 2023-2024 cholera outbreak highlighted persistent challenges in South Yemen, such as conflict, inconsistent laboratory testing and surveillance, and limited access to healthcare, despite a low case fatality rate. Outbreak preparedness must shift from reactive to anticipatory, including strategic storage of medicines, vaccines and diagnostics and clear guidelines on how to use them.
Artificial intelligence (AI)-based risk prediction is increasingly implemented in clinical care, but randomized evidence on communication and shared decision-making (SDM) outcomes is limited. In the single-center PRIMA-AI trial, 76 kidney transplant recipients with estimated glomerular filtration rate <30 mL/min/1.73 m² were randomized 1:1 to usual care or usual care plus an electronic health record (EHR)-integrated machine-learning model predicting 1-year graft loss risk. The primary outcome was patient-reported conversations about treatment options after graft loss during 12 months. Conversation frequency did not differ between groups (intervention 14/36 [39%] vs control 16/40 [40%]; chi-square p = 1.00). No significant between-group differences were observed for secondary clinical, SDM-related, relationship, or distress outcomes. Post-study user feedback suggested low and variable tool uptake with workflow barriers. Passive EHR availability of AI risk estimates did not improve communication or SDM-related outcomes. Future interventions should strengthen workflow integration and directly support SDM. Trial Registration: ClinicalTrials.gov number, NCT0605651, registered 2023-09-21.
Clozapine is the most effective and only approved drug for treatment-resistant schizophrenia (TRS). Studies based on data up to 2014 concluded that it is underutilized in most industrialized countries, including Germany. Since 2019, national guidelines have explicitly been recommending clozapine as first-line therapy in TRS. We aimed to assess whether clozapine use in Germany has increased in recent years and to examine regional variations. Using claims data covering about 20% of the German population (GePaRD), we calculated the yearly prescription prevalence and incidence of clozapine among individuals aged 0-64 years based on outpatient dispensations. For 2022, we also assessed regional variations in clozapine prescription prevalence at the district level (restricted to N = 202 districts with ≥20,000 individuals). From 2012 to 2022, the overall (age- and sex-standardized) prescription prevalence of clozapine continuously decreased by 16% (from 77.6 to 65.5 per 100,000). The relative decline was greatest in women aged 30-39 years (-51%) and in men aged 30-34 years (-57%), in urban areas (large urban cities: -23%; urban districts: -16%), and in regions with high socioeconomic status (-22%). Over the same period, the overall prescription incidence of clozapine decreased by 41%. In 2022, regional clozapine prescription prevalence differed up to 39-fold. In conclusion, clozapine prescribing in Germany did not increase from 2012 to 2022, despite new clozapine-favoring guidelines, and showed substantial regional variation. Our results suggest a persisting underutilization of clozapine in most of Germany. Further research on barriers and facilitators for clozapine use in Germany is needed.
Autism diagnoses have increased over the past decade, prompting debate on potential causes. In September 2025, US President Donald Trump claimed that paracetamol is a 'big factor' in autism, citing a systematic review based solely on observational studies. The review's selective reporting, methodological flaws (including applying an environmental health rather than evidence-based medicine framework) and lack of causal evidence provided weak justifications for its conclusions and have fuelled public confusion about paracetamol safety in pregnancy. This article critically appraises the review and examines how scientific uncertainty can be manipulated and amplified within broader public health domains.
Early-life gut microbiota development is critical for orchestrating mucosal barrier function and immune priming, as disruptions in this process can increase susceptibility to life-threatening diseases such as necrotizing enterocolitis (NEC) and sepsis. This longitudinal multi-omics study of 186 preterm infants (<32 weeks of gestation or <1500 g birth weight) explores the impact of early-life exposures in the neonatal intensive care units (NICUs) on gut microbiota, metabolism, and immune responses. We analyzed 1153 stool samples using quantitative microbial profiling, untargeted metabolomics, and fecal S100A8/A9 (calprotectin) levels. Antibiotic exposure suppressed anaerobic colonization and microbial diversity in a cumulative exposure-dependent manner, with breastmilk feeding partially mitigating these effects. The stool metabolome correlated with microbial colonization, showing antibiotic-driven disruptions in polyamine metabolism linked to anaerobe abundance. Host calprotectin levels followed a biphasic pattern, correlating with microbial diversity and polyamine metabolites. Mediation analysis identified anaerobe suppression and polyamine depletion as key drivers of antibiotic-associated reductions in calprotectin. This study reveals that NICU interventions, particularly antibiotics, reprogram the preterm gut ecosystem and immune response, with anaerobes and polyamines being key mediators linking microbial ecology to immune maturation during early life.
The COVID-19 pandemic has had a profound impact on public health and human cognitive functioning, with studies highlighting deficits in attention, executive function, and working memory. In this study, we examine the relationship between working memory performance and anxiety, psychosomatic symptoms, and psychological distress-variables known to influence cognitive functioning. Our findings reveal that psychological distress accounted for a significant portion of the variance in visual working memory performance, particularly during the early stages of the disease when distress levels were at their peak. These results underscore the importance of distinguishing the direct effects of COVID-19 on brain structures from the broader psychological toll. These findings highlight the need for rehabilitation programs to address not only cognitive impairments but also the psychological burden faced by patients, ensuring a more holistic approach to recovery.
The utility of antiretroviral therapy (ART) in the management of human immunodeficiency virus (HIV) is being challenged by growing HIV drug resistance (HIVDR). Although simulation modelling is useful for understanding complex problems, the extent to which it is used in HIVDR is unknown. This review aimed to determine how modelling has been used to inform HIVDR interventions and how its use can align with the World Health Organization (WHO) Global Action Plan (GAP) for HIVDR 2017-2021. This review involved a literature search across PubMed, Scopus, Web of Science, and Embase databases. Articles published after the introduction of ART, 1997 to 28th November 2025, were considered. Relevant information, including metadata, model descriptions, interventions, and their outcomes, was extracted. Findings from included papers were categorized according to their area of focus within the five strategic objectives of the WHO GAP for HIVDR 2017-2021. A total of 2346 articles were screened, and 17 articles were included in the final analysis. Most studies modelled HIVDR in sub-Saharan Africa (n = 13). Acquired resistance (n = 15) was assessed in most of the studies, followed by transmitted resistance (n = 7) and pretreatment resistance (n = 3). Most of the models were stochastic models(n = 11), with about one third of them analyzing cost effectiveness(n = 6). Ten models focused on the WHO GAP HIVDR strategic objective of prevention and response, four aligned with the objective of monitoring and surveillance, while the remaining three assessed a combination of the two objectives. None of the models assessed the remaining three objectives: research and innovation, laboratory capacity, or governance and enabling mechanisms. This review identifies a need for more cross-cutting analyses of multiple strategic objectives for HIVDR, including system-wide models to provide holistic insights into the complexity surrounding HIVDR. Employing patient and public involvement (PPI) in model development and intervention design would further strengthen model validity and transition to real-world settings (PROSPERO ID: CRD42024553557).
Objective: To examine the association between the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) and the occurrence of dementia in patients undergoing maintenance hemodialysis (MHD). Methods: A multicenter cross-sectional study was conducted, involving MHD patients from 10 hemodialysis centers in Guizhou Province between May 2019 and November 2023. Cognitive function was assessed using the mini-mental state examination (MMSE), and the presence of dementia was determined according to the corresponding criteria based on the patient's educational level. NHHR was used as a marker of lipid metabolism. Patients were categorized into four groups (Q1-Q4) according to NHHR quartiles: Q1 group (NHHR<1.89), Q2 group (NHHR 1.89-<2.55), Q3 group (NHHR 2.55-<3.42), and Q4 group (NHHR≥3.42). The association between NHHR and the risk of dementia was assessed through multivariate logistic regression, multiple linear regression, restricted cubic splines (RCS), subgroup analysis, and interaction testing. Results: A total of 2 279 MHD patients (1 385 males and 894 females) aged 58 (49, 68) years were included in the study. Among these patients, 179 cases (7.9%) (103 males and 76 females) were diagnosed with dementia, with the age of 69 (60, 77) years. Multivariate logistic regression analysis revealed that, after adjusting for relevant confounding factors, the risk of dementia in the Q3 group was 1.98 times greater than that in the Q1 group (OR=1.98, 95%CI: 1.20-3.27, P=0.007). Furthermore, the risk of dementia in the Q4 group was 2.56 times that of the Q1 group (OR=2.56, 95%CI: 1.56-4.20, P<0.001). Multiple linear regression analysis indicated a negative correlation between NHHR and the total MMSE score (β=-0.25, 95%CI:-0.38--0.12, P<0.001). Subgroup analysis demonstrated an interaction between gender and NHHR (Pinteraction=0.005). Among female MHD patients, the risk of dementia in the NHHR Q4 group was 6.04 times that of the Q1 group (OR=6.04, 95%CI: 2.59-16.54), whereas no significant correlation was observed between NHHR and dementia in male MHD patients (all P>0.05). Restricted cubic splines analysis indicated a linear relationship between NHHR and the risk of dementia (Pnonlinearity=0.240). Conclusion: Elevated NHHR levels areassociated with an increased risk of dementia in MHD patients, with a more pronounced effect observed in female patients. 目的： 探讨非高密度脂蛋白胆固醇与高密度脂蛋白胆固醇比值（NHHR）和维持性血液透析（MHD）患者发生痴呆的相关性。 方法： 采用多中心横断面研究，纳入2019年5月至2023年11月贵州省10家血液透析中心的MHD患者，使用简易精神状态检查（MMSE）量表评估认知功能，并根据患者文化程度，采用相应标准判定是否存在痴呆。以NHHR作为反映脂质代谢的指标，根据NHHR四分位数将患者分为4组（Q1~Q4组），其中，Q1组NHHR<1.89，Q2组NHHR 1.89~<2.55，Q3组NHHR 2.55~<3.42，Q4组NHHR≥3.42。采用多因素logistic回归模型、多重线性回归模型、限制立方样条（RCS）、亚组分析及交互作用检验等方法分析NHHR与痴呆风险的关系。 结果： 共纳入2 279例MHD患者，男1 385例，女894例，年龄58（49，68）岁。179例（7.9%）存在痴呆，男103例，女76例，年龄69（60，77）岁。多因素logistic回归分析结果显示，在调整相关混杂因素后，Q3组患者发生痴呆的风险为Q1组的1.98倍（OR=1.98，95%CI：1.20~3.27，P=0.007），Q4组患者发生痴呆的风险为Q1组的2.56倍（OR=2.56，95%CI：1.56~4.20，P<0.001）。多重线性回归分析结果显示，NHHR与MMSE总分呈负相关（β=-0.25，95%CI：-0.38~-0.12，P<0.001）。亚组分析结果显示，性别与NHHR存在交互作用（P交互=0.005），女性MHD患者中NHHR Q4组痴呆风险是Q1组的6.04倍（OR=6.04，95%CI：2.59~16.54），而男性MHD患者中NHHR 与痴呆无明显相关性（均P>0.05）；RCS分析显示NHHR与痴呆风险呈线性关系（P非线性=0.240）。 结论： NHHR水平升高与MHD患者痴呆风险增加相关，且在女性患者中更加明显。.
Postpartum psychosis is a severe psychiatric condition marked by the abrupt onset of psychosis, mania, or psychotic depression following childbirth. Despite evidence for a strong genetic basis, the roles of common and rare genetic variation remain poorly understood. Leveraging data from Swedish national registers and genomic data from the All of Us Research Program, we estimated family-based heritability at 55% and whole-genome sequencing-based heritability at 46%. Rare coding variant analysis identified HMGCR as a gene in which rare damaging variants confer risk for postpartum psychosis (FDR < 0.05). Analyses of 240,009 participants from the All of Us Research Program and 58,990 participants from the Mount Sinai BioMe Biobank identified significant associations linking deleterious rare variants in HMGCR to vascular dementia and mental disorder, not otherwise specified, supporting the gene's broader psychiatric relevance. Additionally, among the top 200 genes ranked by association statistics, 17% of bipolar disorder, 21% of schizophrenia, and 16-25% of multiple autoimmune disorders exhibit a possible association with postpartum psychosis. These findings reveal unique genetic contributions and shared pathways, providing a foundation for understanding pathophysiology and advancing therapeutic strategies.
Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) is the cornerstone in the prevention of coronary artery disease (CAD) but may also increase risk of type 2 diabetes (T2D). A comprehensive examination of the genetic evidence of T2D related side-effects of all current lipid-modifying drugs, including those in development, has not yet been performed. This cis-Mendelian randomization study used individual level data from the UK Biobank, Lifelines, and publicly available genome-wide association data. We identified loci that are either targeted directly with drugs, or alternatively, targeting their gene products (mRNA and/or protein). Included are, in alphabetical order, the loci ACLY, ANGPTL3, ANGPTL4, APOB, APOC3, CETP, HMGCR, LDLR, LIPG, LPA, MTTP, NPC1L1, and PCSK9. We used cis-genetic instruments weighted for LDL-C, HDL-C, triglycerides, and apolipoproteins as downstream proxies for the drug targets. Main outcomes were prevalent and incident T2D, with CAD as a contrast outcome. Lipid modification through HMGCR is predicted to reduce CAD risk and increase T2D risk. Modification through targeting APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 is predicted to reduce CAD risk without a change in T2D risk. Modification through ANGPTL4 and CETP is predicted to reduce risk of both CAD and T2D. For ACLY, ANGPTL3, APOB, and LIPG, we found evidence for neither CAD nor T2D. This study provides genetic evidence for variation in diabetes-related side-effects of different lipid-modifying drugs, with potential relevance for future clinical trials and individual treatment decisions.
Malaria caused by Plasmodium falciparum remains a leading cause of childhood mortality in sub-Saharan Africa. The intraerythrocytic parasite can evade complement-mediated destruction through recruitment of human Factor H (FH). In vitro, Factor H-Related Protein 1 (FHR-1) competes with FH for binding sites, suggesting a potential role in modulating complement activation during infection. Because one-third of Africans carry a CFHR3/1 deletion, we examined the impact of FHR-1 deficiency on malaria severity. We analyzed plasma from 500 Ghanaian children presenting with different clinical manifestations. One-third of plasma samples lacked detectable FHR-1 protein, but logistic regression analysis revealed no association between FHR-1 deficiency and risk of severe malaria. In contrast, FHR-1 deficiency was overrepresented among children presenting with anemia and multiple syndromes and affected children exhibited markedly lower hemoglobin levels. These findings indicate that FHR-1 deficiency does not affect overall progression of severe falciparum malaria, but correlates with severe malaria anemia.
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Clinical implementation of patient cell-based drug testing is hampered by inconsistencies and irreproducible results. Using linear mixed models and drug response data from four cohorts of patients with acute myeloid leukemia (n = 993 samples), we identified sources of variability in ex vivo drug sensitivity testing across the studies. We identified several experimental factors, including the time until sample was tested, the type of culture media and viability assay, which led to systematic differences in drug sensitivity profiles. We further investigated the effects of sample types (fresh or frozen) and disease status (diagnosis, relapse, or refractory), and observed that peripheral blood samples resulted in higher drug sensitivity levels, compared to those derived from bone marrow. Technical factors, such as the type of plate reader and centrifugation procedure, further contributed to the response variability depending on the chosen drug response metric. These factors need to be standardized for improved consistency in functional precision medicine studies.
Joint models offer an unbiased statistical approach for analyzing the effects of longitudinal biomarkers on time-to-event outcomes, providing an alternative to time-varying Cox proportional-hazards regression and the two-stage approach. However, whether available implementations of these methods perform reliably across different practically relevant scenarios remains insufficiently studied. We conducted a simulation study based on the Berlin Initiative Study examining kidney function and survival in older adults. In a manner comparable to phase IV studies in clinical research, our evaluation aims to provide insights into the practical performance of commonly used R package implementations of these methods, mostly under their default settings. By varying data generating scenarios, we assessed how different numbers of events and longitudinal measurements affect performance of Bayesian (JMbayes2) and frequentist joint model implementations (JM and joineRML), time-varying Cox PH regression (survival), and the two-stage approach (nlme and survival), focusing on bias in parameter estimates. Results revealed substantial variability across implementations. The JM package exhibited considerable bias and frequent convergence issues. In contrast, joineRML performed robustly with approximately unbiased estimates for association parameters and high convergence frequencies comparable to the implementations of the simpler methods across diverse scenarios. However, both frequentist packages systematically underestimated the effects of baseline covariates in the survival model. The Bayesian JMbayes2 was largely unbiased, but performance deteriorated under two conditions: with few events (< 70), convergence was low and bias persisted even in converged models; and with observation-to-event ratios below 2, convergence declined, although estimates from converged models remained approximately unbiased. Time-varying Cox PH regression and the two-stage approach showed more bias than JMbayes2 in certain settings but tended to achieve more robust performance and convergence across most scenarios.
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