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Many clinical trials assess time‐to‐event endpoints. To describe the difference between groups in terms of time to event, we often employ hazard ratios. However, the hazard ratio is only informative in the case of proportional hazards (PHs) over time. There exist many other effect measures that do not require PHs. One of them is the average hazard ratio (AHR). Its core idea is to utilize a time‐dependent weighting function that accounts for time variation. Though propagated in methodological research papers, the AHR is rarely used in practice. To facilitate its application, we unfold approaches for sample size calculation of an AHR test. We assess the reliability of the sample size calculation by extensive simulation studies covering various survival and censoring distributions with proportional as well as nonproportional hazards (N‐PHs). The findings suggest that a simulation‐based sample size calculation approach can be useful for designing clinical trials with N‐PHs. Using the AHR can result in increased statistical power to detect differences between groups with more efficient sample sizes. [ABSTRACT FROM AUTHOR]

Background: The current endpoints for therapeutic trials of hospitalized COVID-19 patients capture only part of the clinical course of a patient and have limited statistical power and robustness. Methods: We specify proportional odds models for repeated measures of clinical status, with a common odds ratio of lower severity over time. We also specify the proportional hazards model for time to each level of improvement or deterioration of clinical status, with a common hazard ratio for overall treatment benefit. We apply these methods to Adaptive COVID-19 Treatment Trials. Results: For remdesivir versus placebo, the common odds ratio was 1.48 (95% confidence interval (CI) = 1.23–1.79; p < 0.001), and the common hazard ratio was 1.27 (95% CI = 1.09–1.47; p = 0.002). For baricitinib plus remdesivir versus remdesivir alone, the common odds ratio was 1.32 (95% CI = 1.10–1.57; p = 0.002), and the common hazard ratio was 1.30 (95% CI = 1.13–1.49; p < 0.001). For interferon beta-1a plus remdesivir versus remdesivir alone, the common odds ratio was 0.95 (95% CI = 0.79–1.14; p = 0.56), and the common hazard ratio was 0.98 (95% CI = 0.85–1.12; p = 0.74). Conclusions: The proposed methods comprehensively characterize the treatment effects on the entire clinical course of a hospitalized COVID-19 patient. [ABSTRACT FROM AUTHOR]

Background: Previous investigations into multiple sclerosis (MS) risk factors predominantly relied on retrospective studies, which do not consider different follow-up times and assume a constant risk effect throughout lifetime. Objective: We aimed to evaluate the impact of genetic and early life factors on MS diagnosis by employing a time-to-event analysis in a prospective cohort. Methods: We used the UK Biobank data, considering the observation period from birth up to 31 December 2022. We considered genetic risk, using a multiple sclerosis polygenic risk score (MS-PRS), and various early life factors. Tobacco smoking and infectious mononucleosis diagnosis were also considered as time-varying variables along the follow-up. Using a Cox proportional hazards model, we examined the associations between these factors and MS diagnosis instantaneous risk. Results: We analyzed 345,027 participants, of which 1669 had an MS diagnosis. Our analysis revealed age-dependent effects for sex (females vs males) and higher MS-PRS, with greater hazard ratios observed in young adults. Conclusion: The age-dependent effects suggest that retrospective studies could have underestimated sex and genetic variants' risk roles during younger ages. Therefore, we emphasize the importance of a time-to-event approach using longitudinal data to better characterize age-dependent risk effects. [ABSTRACT FROM AUTHOR]

Background: Drinking water at U.S. Marine Corps Base (MCB) Camp Lejeune, North Carolina was contaminated with trichloroethylene and other industrial solvents from 1953 to 1985. Methods: A cohort mortality study was conducted of Marines/Navy personnel who, between 1975 and 1985, began service and were stationed at Camp Lejeune (N = 159,128) or MCB Camp Pendleton, California (N = 168,406), and civilian workers employed at Camp Lejeune (N = 7,332) or Camp Pendleton (N = 6,677) between October 1972 and December 1985. Camp Pendleton's drinking water was not contaminated with industrial solvents. Mortality follow-up was between 1979 and 2018. Proportional hazards regression was used to calculate adjusted hazard ratios (aHRs) comparing mortality rates between Camp Lejeune and Camp Pendleton cohorts. The ratio of upper and lower 95% confidence interval (CI) limits, or CIR, was used to evaluate the precision of aHRs. The study focused on underlying causes of death with aHRs ≥ 1.20 and CIRs ≤ 3. Results: Deaths among Camp Lejeune and Camp Pendleton Marines/Navy personnel totaled 19,250 and 21,134, respectively. Deaths among Camp Lejeune and Camp Pendleton civilian workers totaled 3,055 and 3,280, respectively. Compared to Camp Pendleton Marines/Navy personnel, Camp Lejeune had aHRs ≥ 1.20 with CIRs ≤ 3 for cancers of the kidney (aHR = 1.21, 95% CI: 0.95, 1.54), esophagus (aHR = 1.24, 95% CI: 1.00, 1.54) and female breast (aHR = 1.20, 95% CI: 0.73, 1.98). Causes of death with aHRs ≥ 1.20 and CIR > 3, included Parkinson disease, myelodysplastic syndrome and cancers of the testes, cervix and ovary. Compared to Camp Pendleton civilian workers, Camp Lejeune had aHRs ≥ 1.20 with CIRs ≤ 3 for chronic kidney disease (aHR = 1.88, 95% CI: 1.13, 3.11) and Parkinson disease (aHR = 1.21, 95% CI: 0.72, 2.04). Female breast cancer had an aHR of 1.19 (95% CI: 0.76, 1.88), and aHRs ≥ 1.20 with CIRs > 3 were observed for kidney and pharyngeal cancers, melanoma, Hodgkin lymphoma, and chronic myeloid leukemia. Quantitative bias analyses indicated that confounding due to smoking and alcohol consumption would not appreciably impact the findings. Conclusion: Marines/Navy personnel and civilian workers likely exposed to contaminated drinking water at Camp Lejeune had increased hazard ratios for several causes of death compared to Camp Pendleton. [ABSTRACT FROM AUTHOR]

This article describes survivorship and explores factors affecting mortality risks in a captive colony of coppery titi monkeys (Plecturocebus cupreus) housed at the California National Primate Research Center (CNPRC), at UC Davis, in Davis, CA. We analyzed data collected on individuals since the colonys creation in the 1960s, with a sample of 600 animals with partially complete information (date of birth, age at death, body mass, parental lineage). We used three methods: (1) Kaplan-Meier regressions followed by a log-rank test to compare survival in male and female titi monkeys, (2) a breakpoint analysis to identify shifts in the survival curves, and (3) Cox regressions to test the effect of body mass change, parental pair tenure, and parental age on mortality risk. We found that males tend to have a longer median lifespan than females (14.9 and 11.4 years; p = 0.094) and that survival decreases earlier in males than in females during adulthood (9.8 and 16.2 years). A body mass loss of 10% from adulthood to the time of death led to a 26% higher risk of dying (p

Abstract Background Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. Methods Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. Results We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. Conclusions Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio.

Canada’s decentralized healthcare system may lead to regional disparities in survival among Canadians diagnosed with central nervous system (CNS) tumours. We identified 50,670 patients diagnosed with a first-ever primary CNS tumour between 2008 and 2017 with follow-up until 31 December 2017. We selected the four highest incidence histologies and used proportional hazard regression to estimate hazard ratios (HRs) for five regions (British Columbia, Prairie Provinces, Ontario, Atlantic Provinces and the Territories), adjusting for sex, tumour behaviour and patient age. Ontario had the best survival profile for all histologies investigated. The Atlantic Provinces had the highest HR for glioblastoma (HR = 1.26, 95% CI: 1.18–1.35) and malignant glioma not otherwise specified (NOS) (Overall: HR = 1.87, 95% CI:1.43–2.43; Pediatric population: HR = 2.86, 95% CI: 1.28–6.39). For meningioma, the Territories had the highest HR (HR = 2.44, 95% CI: 1.09–5.45) followed by the Prairie Provinces (HR = 1.52, 95% CI: 1.38–1.67). For malignant unclassified tumours, the highest HRs were in British Columbia (HR = 1.45, 95% CI: 1.22–1.71) and the Atlantic Provinces (HR = 1.40, 95% CI: 1.13–1.74). There are regional differences in the survival of CNS patients at the population level for all four specific histological types of CNS tumours investigated. Factors contributing to these observed regional survival differences are unknown and warrant further investigation.

Abstract Background As is known, CD4 cell count is a significant parameter predicting HIV progression, opportunistic infections and death in HIV-infected individuals, as well was an important indicator for initiating antiretroviral therapy (ART). In China’s National Free Antiretroviral Treatment Program, people with HIV (PWH) on ART can receive a CD4 count test at least once every six months. Importantly, the baseline CD4 count (before ART initiation) is significantly correlated with ART and even prognosis, but the influence of the peak CD4 cell count on ART and/or clinical outcomes is still unknown. Methods A retrospective study was conducted among 7965 PWH who received ART from October 2003 to September 2022 at Yunnan Infectious Disease Hospital. Clinical features and laboratory data were collected and analyzed by Chi-square test, univariate and multivariate Cox regression analysis. After elimination of confounding variables, multivariate Cox regression analysis was performed to identify survival-related factors. Results Of a total of 7965 PWH in the ART treatment cohort who met the inclusion and exclusion criteria, 7939 were finally included in the subsequent analyses. First, it was found that the proportion of clinical variables, including sex, age distribution, interval from diagnosis to ART initiation, marital status, and others, was significantly different between the living and dead groups (P

Abstract Background Periodontitis represents the foremost oral condition in young men, strongly correlated with socioeconomic elements and oral health behaviors. This research aimed to assess the prevalence of periodontitis and associated associations with socio-demographics and oral health practices for subsequent Hazard Ratio (HR) estimation. Methods A total of 46,476 young men were recruited to the study between August 2022 and October 2023. A questionnaire on socio-demographic factors and oral health-related behaviors related to periodontitis was completed. The standard procedure was used for oral examination. Logistic regression and hazard ratios were used to estimate the influencing factors, whereas the nomogram was used to predict the risk of periodontitis in young men. Results A total of 46,476 young men were surveyed and completed the questionnaire. The overall prevalence of periodontitis among young men was 1.74%. Out of these, 1.7% had mild periodontitis and 0.6% had moderate periodontitis. Age and dental calculus were important factors in the periodontal health of young men. This nomogram, which includes 7 easily obtainable clinical characteristics routinely collected during periodontitis risk assessment, provides clinicians with a user-friendly tool to assess the risk of periodontal disease in young men. Conclusions Regular dental prophylaxis is crucial for young men to maintain their gingival health and prevent the onset of periodontitis. Dental calculus plays a prominent role in this matter, as it serves as a significant contributing factor.

Background: Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. Methods: Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. Results: We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. Conclusions: Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio. [ABSTRACT FROM AUTHOR]

Most US dairy calves are raised in individual hutches for biocontainment purposes and to facilitate monitoring and handling of calves. However, individual hutches typically restrict calves' activity and social interactions. Previous studies showed that group housing (GH) is beneficial to calf welfare and is associated with social benefits. The adoption of GH on dairies is hindered by several concerns, with the primary concern being the potential for increased transmission of diseases due to heightened calf-to-calf contact. In light of this, our study aimed to compare the behavior, health, and growth outcomes of calves housed in groups of 3 to individually housed (IH) calves during the preweaning period. A total of 42 Holstein heifer calves on a commercial dairy in Northern California were enrolled in groups of 3 to different housing treatments; IH (n = 21) or GH (n = 21) between July and October 2020. Each treatment was composed of 7 groups of 3 calves each. Calves in the GH treatment were housed in groups of 3 from 6 to 10 d until 70 d of age. Individual pens consisted of one polyethylene hutch with a 1.5 m × 1.2 m outside exercise area. Group pens were constructed by assembling 3 polyethylene hutches with a 1.5 m × 3.6 m outside exercise area of wire panel fencing. Calves were weighed and measured for height at birth and weaning. Diarrhea and bovine respiratory disease (BRD) scores were recorded daily throughout the preweaning period. Cumulative incidence and hazard ratios were estimated for BRD and diarrhea for GH and IH. A mixed model with pen as a random effect was specified to evaluate the effect of treatment. Group-housed calves gained 0.64 ± 0.02 kg/d while IH calves gained 0.65 ± 0.02 kg/d. Similarly, there was no evidence for treatment differences in withers height gain in GH calves (0.22 ± 0.01 cm/d) compared with IH calves (0.21 ± 0.01 cm/d). The cumulative incidence of BRD based on the California scoring system in GH calves was 75 ± 9.68% compared with 66.66 ± 10.28% in IH calves. Group-housed calves had a BRD hazard of 1.14 times that of IH calves (95% CI: 1.21–2.40). The cumulative incidence of diarrhea (fecal score 3) in GH calves was 100% in comparison to 95.20% ± 4.66% in IH calves. The mean proportion of scan observations of calves feeding on concentrates was significantly higher in GH (0.145 ± 0.004/h) compared with IH calves (0.076 ± 0.003/h) during the preweaning period. The study results provide evidence that this simplified GH system provides benefits of GH without detrimental short-term effects on calf growth and health during the preweaning period. [ABSTRACT FROM AUTHOR]

Canada's decentralized healthcare system may lead to regional disparities in survival among Canadians diagnosed with central nervous system (CNS) tumours. We identified 50,670 patients diagnosed with a first-ever primary CNS tumour between 2008 and 2017 with follow-up until 31 December 2017. We selected the four highest incidence histologies and used proportional hazard regression to estimate hazard ratios (HRs) for five regions (British Columbia, Prairie Provinces, Ontario, Atlantic Provinces and the Territories), adjusting for sex, tumour behaviour and patient age. Ontario had the best survival profile for all histologies investigated. The Atlantic Provinces had the highest HR for glioblastoma (HR = 1.26, 95% CI: 1.18–1.35) and malignant glioma not otherwise specified (NOS) (Overall: HR = 1.87, 95% CI:1.43–2.43; Pediatric population: HR = 2.86, 95% CI: 1.28–6.39). For meningioma, the Territories had the highest HR (HR = 2.44, 95% CI: 1.09–5.45) followed by the Prairie Provinces (HR = 1.52, 95% CI: 1.38–1.67). For malignant unclassified tumours, the highest HRs were in British Columbia (HR = 1.45, 95% CI: 1.22–1.71) and the Atlantic Provinces (HR = 1.40, 95% CI: 1.13–1.74). There are regional differences in the survival of CNS patients at the population level for all four specific histological types of CNS tumours investigated. Factors contributing to these observed regional survival differences are unknown and warrant further investigation. [ABSTRACT FROM AUTHOR]

Depression and anxiety may be significant prognostic factors after myocardial infarction (MI). Thus, we investigated depression and anxiety prevalence among older MI survivors and their impact on mortality, stroke, and recurrent MI. This population-based cohort study used the Korean National Health Insurance Service database for data concerning individuals aged 66 years who participated in the National Screening Program from 2009 to 2016. Overall, 11,721 individuals with MI history and 58,605 age- and sex-matched controls were included and followed up until 2019. The presence of depression and anxiety was assessed 2 years before and after participation in the program. Mortality and major adverse outcomes, defined as a composite outcome comprising mortality, stroke, and recurrent MI, were analyzed. Depression and anxiety prevalence among MI survivors was 20.4 % and 30.3 %, respectively. Crude odds ratios for depression and anxiety, compared with the control group, were 1.207 (1.148–1.269) and 1.078 (1.032–1.126), respectively. During the follow-up, individuals with depression, anxiety, or both showed increased hazard ratios (HRs) for mortality and major adverse outcomes; after adjustments, their HRs were 1.442 (1.182–1.759), 1.129 (0.960–1.328), and 1.498 (1.263–1.776), respectively, for mortality and 1.505 (1.289–1.758), 1.158 (1.021–1.314), and 1.530 (1.337–1.751), respectively, for major adverse outcomes. Although this was a nationwide cohort study, the MI, depression, and anxiety diagnoses were based on diagnostic codes. Higher depression and anxiety prevalence was observed among older MI survivors. Depression and anxiety occurrence correlated with increased adverse clinical outcomes after adjustments. [Display omitted] • A higher prevalence of depression and anxiety was observed in older myocardial infarction (MI) survivors. • The presence of depression and anxiety was associated with adverse clinical outcomes. • Cardiac rehabilitation models should prioritize the identification and management of depression and anxiety after MI. [ABSTRACT FROM AUTHOR]

Background: Patients with hidradenitis suppurativa (HS) often suffer from comorbid diabetes, metabolic syndrome, and hyperlipidemia and, therefore, are susceptible to the development of cardiovascular diseases (CVDs). Moreover, systemic inflammation plays a vital role in the development of atherosclerosis. The creation of atherosclerotic plaque is characterized by endothelial dysfunction driven by elevated concentrations of interleukin (IL)‐1, IL‐6, and IL‐18 among others, as well as tumor necrosis factor (TNF) alpha. Methods: This study aimed to assess the risk of HS patients developing CVDs. We performed a large‐scale, propensity‐matched global retrospective cohort study analyzing the risk of development of CVDs in patients suffering from HS. The analysis included 144,100 HS patients with 144,100 healthy controls (HC). The cohorts were matched regarding demographics and history of diseases relevant to CVDs, e.g., diabetes, obesity, and nicotine dependence. A total of 90 cardiovascular disorders were identified. The identification of cardiovascular disorders was based on ≥1% appearance of the event, based on absolute numbers, in both cohorts. Results: Before the matching, HS patients displayed a higher frequency in excess weight or obesity (25 vs. 14.4%, respectively), nicotine dependence, and diabetes mellitus, but lower odds of primary hypertension in comparison to healthy controls. A total of 47 CVDs are associated with an increased risk of onset in HS patients. Although the highest hazard ratio (HR; 2.1; 95% CI: 1.95–2.269) was found for unspecified heart failure, the HS cohort was exceptionally predisposed to developing myocardial infarction (HR: 2.06; 95% CI: 1.88–2.27) and an acute embolism and deep vein thrombosis of the lower extremity (HR: 1.93; 95% CI: 1.74–2.14). Conclusions: This is the most extensive study on the association of HS with CVDs. We demonstrated that HS patients are at significantly greater risk of developing various CVDs compared to matched controls, with heart failure being the most common one. [ABSTRACT FROM AUTHOR]

Time‐to‐event analysis often relies on prior parametric assumptions, or, if a semiparametric approach is chosen, Cox's model. This is inherently tied to the assumption of proportional hazards, with the analysis potentially invalidated if this assumption is not fulfilled. In addition, most interpretations focus on the hazard ratio, that is often misinterpreted as the relative risk (RR), the ratio of the cumulative distribution functions. In this paper, we introduce an alternative to current methodology for assessing a treatment effect in a two‐group situation, not relying on the proportional hazards assumption but assuming proportional risks. Precisely, we propose a new nonparametric model to directly estimate the RR of two groups to experience an event under the assumption that the risk ratio is constant over time. In addition to this relative measure, our model allows for calculating the number needed to treat as an absolute measure, providing the possibility of an easy and holistic interpretation of the data. We demonstrate the validity of the approach by means of a simulation study and present an application to data from a large randomized controlled trial investigating the effect of dapagliflozin on all‐cause mortality. [ABSTRACT FROM AUTHOR]

Background: The prevalence of TNBC in India is higher compared to western countries. There is a multitude of biomarkers associated with different clinical outcomes of TNBC with contradictory reports. Identification of a set of specific biomarkers from the very many number of proteins reported in the literature to predict prognosis of TNBC is an urgent clinical need. Methodology: A systematic review of key molecular biomarkers in cohort studies that have been investigated for their role in breast cancer prognosis was conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was followed. A meta-analysis was used to evaluate their pooled hazard ratio (HR) and the corresponding 95% confidence interval (95% CI) statistically. Immunohistochemical characterization of the meta-analyzed markers were performed in a cohort of 200 retrospective TNBC and 100 non TNBC patient tissues. Kaplan–Meier plot were used to evaluate disease free survival (DFS), and overall survival (OS). Cox regression models were used to evaluate predictors of DFS and OS. Results: Using a meta-analytical approach, we consolidated the biomarker signatures associated with survival outcomes in breast cancers. The promising markers that emerged for the prediction of DFS and OS included E-Cadherin, Survivin, p53, MTA1, HIF1A, CD133, Vimentin and CK5/6. Evaluation of these markers in tumor tissue revealed that subcellular localization of p53, MTA1 and HIF1A had a significant association in predicting TNBC prognosis. Kaplan Meier plot revealed that p53 (OS p = 0.007, DFS p = 0.004), HIF 1 A (OS p = 0.054, DFS p = 0.009) and MTA1 (OS p = 0.043, DFS = p = 0.001) expression in the primary tumor tissue were found to be significantly correlated with poor OS and DFS, whereas expression of Survivin (DFS p = 0.024) and E Cadherin (DFS p = 0.027) correlated with DFS alone in TNBC. Univariate analysis revealed that p53, HIF1A and MTA1 could be independent prognostic markers. Conclusion: Our study suggests cytoplasmic over expression of HIF1A, nuclear over expression of MTA1 and mutated p53 in the primary tumor tissue of TNBC have significance as markers predicting survival of TNBC patients. [ABSTRACT FROM AUTHOR]

Breast cancer is the fifth-ranked cancer globally. Despite early diagnosis and advances in treatment, breast cancer mortality is increasing. This meta-analysis aims to examine all possible prognostic factors that improve/deteriorate breast cancer-specific survival. MEDLINE, PubMed, ScienceDirect, Ovid, and Google Scholar were systematically searched until September 16, 2023. The retrieved studies from 1995 to 2022 accumulated 1,386,663 cases from 30 countries. A total of 13 out of 22 prognostic factors were significantly associated with breast cancer-specific survival. A random-effects model provided a pooled estimate of the top five poorest prognostic factors, including Stage 4 (HR = 12.12; 95% CI: 5.70, 25.76), followed by Stage 3 (HR = 3.42, 95% CI: 2.51, 4.67), a comorbidity index ≥ 3 (HR = 3.29; 95% CI: 4.52, 7.35), the poor differentiation of cancer cell histology (HR = 2.43; 95% CI: 1.79, 3.30), and undifferentiated cancer cell histology (HR = 2.24; 95% CI: 1.66, 3.01). Other survival-reducing factors include positive nodes, age, race, HER2-receptor positivity, and overweight/obesity. The top five best prognostic factors include different types of mastectomies and breast-conserving therapies (HR = 0.56; 95% CI: 0.44, 0.70), medullary histology (HR = 0.62; 95% CI: 0.53, 0.72), higher education (HR = 0.72; 95% CI: 0.68, 0.77), and a positive estrogen receptor status (HR = 0.78; 95% CI: 0.65, 0.94). Heterogeneity was observed in most studies. Data from developing countries are still scarce. [ABSTRACT FROM AUTHOR]

Objectives: Small nucleolar RNAs (snoRNAs) form clusters within the genome, representing a mysterious category of small non-coding RNAs. Research has demonstrated that aberrant snoRNAs can contribute to the development of various types of cancers. Recent studies have identified snoRNAs as potentially valuable biomarkers for the diagnosis or/and prognosis of cancers. However, there has been a lack of comprehensive reviews on prognostic and diagnostic snoRNAs across different types of cancers. Methods: We conducted a systematic search of various databases including Google Scholar, Medline, Cochrane, Scopus, PubMed, Embase, ScienceDirect, Ovid-Medline, Chinese National Knowledge Infrastructure, WanFang, and SinoMed with a time frame reception to December 30, 2022. A total of 49 relevant articles were included in our analysis, consisting of 21 articles focusing on diagnostic aspects and 41 articles focusing on prognostic aspects. Pooled odds ratio, 95% confidence intervals (CIs), and hazard ratio (HR) were utilized to evaluate clinical parameters and overall survival (OS), respectively. Result: The findings indicated that area under the curve, sensitivity, and specificity were 0.85, 75%, and 80% in cancer, respectively. There was a possibility that snoRNAs had a positive impact on the diagnosis (risk ratio, RR = 2.95, 95% CI: 2.75-3.16, P = 0.000) and OS (HR = 1) in cancer. Additionally, abnormally expressed snoRNAs were associated with a positive impact on OS time for chronic lymphocytic leukemia (HR: 0.88, 95%Cl: 0.69-1.11, P < 0.00001), colon adenocarcinoma (HR: 0.97, 95%Cl: 0.91-1.03, P < 0.0001), and ovarian cancer (HR: 0.98, 95%Cl: 0.98-0.99, P < 0.00001). However, dysregulated snoRNAs of colon cancer and colorectal cancer had a negative impact on OS time (HR = 3.01 and 1.01 respectively, P < 0.0001). Conclusion: The results strongly suggested that snoRNAs could serve as potential novel indicators for prognosis and diagnosis in cancers. This systematic review followed the guidelines of the Transparent Reporting of Systematic Review and Meta-Analyses (PROSPERO register: CRD42020209096). [ABSTRACT FROM AUTHOR]

Background: Periodontitis represents the foremost oral condition in young men, strongly correlated with socioeconomic elements and oral health behaviors. This research aimed to assess the prevalence of periodontitis and associated associations with socio-demographics and oral health practices for subsequent Hazard Ratio (HR) estimation. Methods: A total of 46,476 young men were recruited to the study between August 2022 and October 2023. A questionnaire on socio-demographic factors and oral health-related behaviors related to periodontitis was completed. The standard procedure was used for oral examination. Logistic regression and hazard ratios were used to estimate the influencing factors, whereas the nomogram was used to predict the risk of periodontitis in young men. Results: A total of 46,476 young men were surveyed and completed the questionnaire. The overall prevalence of periodontitis among young men was 1.74%. Out of these, 1.7% had mild periodontitis and 0.6% had moderate periodontitis. Age and dental calculus were important factors in the periodontal health of young men. This nomogram, which includes 7 easily obtainable clinical characteristics routinely collected during periodontitis risk assessment, provides clinicians with a user-friendly tool to assess the risk of periodontal disease in young men. Conclusions: Regular dental prophylaxis is crucial for young men to maintain their gingival health and prevent the onset of periodontitis. Dental calculus plays a prominent role in this matter, as it serves as a significant contributing factor. [ABSTRACT FROM AUTHOR]

Metabolomics profiles from blood, urine, or other body fluids have the potential to assess intakes of foods and nutrients objectively, thereby strengthening nutritional epidemiology research. Metabolomics platforms may include targeted components that estimate the relative concentrations for individual metabolites in a predetermined set, or global components, typically involving mass spectrometry, that estimate relative concentrations more broadly. While a specific metabolite concentration usually correlates with the intake of a single food or food group, multiple metabolites may be correlated with the intake of certain foods or with specific nutrient intakes, each of which may be expressed in absolute terms or relative to total energy intake. Here, I briefly review the progress over the past 20 years on the development and application intake biomarkers for foods/food groups, nutrients, and dietary patterns, primarily by drawing from several recent reviews. In doing so, I emphasize the criteria and study designs for candidate biomarker identification, biomarker validation, and intake biomarker application. The use of intake biomarkers for diet and chronic disease association studies is still infrequent in nutritional epidemiology research. My comments here will derive primarily from our research group's recent contributions to the Women's Health Initiative cohorts. I will complete the contribution by describing some opportunities to build on the collective 20 years of effort, including opportunities related to the metabolomics profiling of blood and urine specimens from human feeding studies that approximate habitual diets. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to quantify the severity of metabolic syndrome (MetS) and investigate its association with cardiovascular disease(CVD) risk on Chinese adults. Methods: 13,500 participants from the Zhejiang Adult Chronic Disease Study were followed up between 2010 and 2021. A continuous MetS severity score derived from the five components of MetS was used to quantify MetS severity, and the association between MetS severity and the risk of incident CVD was assessed using Cox proportional hazard and restricted cubic spline regression. Results: Both the presence and severity of MetS were strongly associated with CVD risk. MetS was related to an increased risk of CVD (hazard ratio(HR):1.700, 95% confidence interval(CI): 1.380–2.094). Compared with the hazard ratio for CVD in the lowest quartile of the MetS severity score, that in the second, third, and highest quartiles were 1.812 (1.329–2.470), 1.746 (1.265–2.410), and 2.817 (2.015–3.938), respectively. A linear and positive dose-response relationship was observed between the MetS severity and CVD risk (P for non-linearity = 0.437). Similar results were found in various sensitivity analyses. Conclusion: The MetS severity score was significantly associated with CVD risk. Assessing MetS severity and further ensuring intervention measures according to the different severities of MetS may be more useful in preventing CVD. [ABSTRACT FROM AUTHOR]

BackgroundRank preserving structural failure time (RPSFT) is a statistical method to correct or adjust for crossover in clinical trials, by estimating the counterfactual effect on overall survival (OS) when control arm patients do not receive the interventional drug when their tumor progresses. We sought to examine the strength of correlation between differences in uncorrected and corrected OS hazard ratios and percentage of crossover, and characterize instances of fundamental and sequential efficacy.MethodsIn a cross-sectional analysis (2003-2023), we reviewed oncology randomized trials that used RPSFT analysis to adjust the OS hazard ratio for patients who crossed over to an anti-cancer drug. We calculated the percentage of RPSFT studies evaluating a drug for fundamental efficacy (with or without a standard of care (SOC)) or sequential efficacy and the correlation between the OS hazard ratio difference (unadjusted and adjusted) and the percentage of crossover.ResultsAmong 65 studies, the median difference between the uncorrected and corrected OS hazard ratio was -0.1 (quartile 1, quartile 3 : -0.3 to -0.06). The median percentage of crossover was 56% (quartile 1, quartile 3: 37% to 72%). All studies were funded by the industry or had authors who were employees of the industry. Twelve studies (19%) tested a drug's fundamental efficacy when there was no SOC; 34 studies (52%) tested a drug's fundamental efficacy when there was already a SOC; and 19 studies (29%) tested a drug's sequential efficacy. The correlation between the uncorrected and corrected OS hazard ratio difference and the percentage of crossover was 0.44 (95% CI: 0.21 to 0.63).ConclusionsRPSFT is a common tactic used by the industry to reinterpret trial results. Nineteen percent of RPSFT use is appropriate. We recognize that while crossover can bias OS results, the allowance and handling of crossover in trials should be limited to appropriate circumstances.

Long-term exposure to ambient PM2.5 is known associated with cardiovascular and respiratory health effects. However, the heterogeneous concentrationresponse function (CRF) between PM2.5 exposure across different concentration range and cardiopulmonary disease and diabetes mellitus (DM) incidence, and their implications on attributable years lived with disability (YLD) and regulation policy has not been well-studied. In this retrospective longitudinal cohort study, disease-free participants (approximately 170,000 individuals, aged ≥ 30 years) from the MJ Health Database were followed up (2007–2017) regarding incidents of coronary heart disease (CHD), ischemic stroke, chronic obstructive pulmonary disease (COPD), lower respiratory tract infections (LRIs), and DM. We used a time-dependent nonlinear weight-transformation Cox regression model for the CRF with an address-matched 3-year mean PM2.5 exposure estimate. Town/district-specific PM2.5-attributable YLD were calculated by multiplying the disease incidence rate, population attributable fraction, disability weight, and sex-age group specific subpopulation for each disease separately. The estimated CRFs for cardiopulmonary diseases were heterogeneously with the hazard ratios (HRs) increased rapidly for CHD and ischemic stroke at PM2.5 concentration lower than 10 μg/m3, whereas the HRs for DM (LRIs) increased with PM2.5 higher than 15 (20) μg/m3. Women had higher HRs for ischemic stroke and DM but not CHD. Relative to the lowest observed PM2.5 concentration of 6 μg/m3 of the study population, the PM2.5 level with an extra risk of 0.1 % (comparable to the disease incidence) for CHD, ischemic stroke, DM, and LRIs were 8.59, 11.85, 22.09, and 24.23 μg/m3, respectively. The associated attributable YLD decreased by 51.4 % with LRIs reduced most (83.6 %), followed by DM (63.7 %) as a result of PM2.5 concentration reduction from 26.10 to 16.82 μg/m3 during 2011–2019 in Taiwan. The proportion of YLD due to CHD and ischemic stroke remained dominant (56.4 %-69.9 %). The cost-benefit analysis for the tradeoff between avoidable YLD and mitigation cost suggested an optimal PM2.5 exposure level at 12 μg/m3. CRFs for cardiopulmonary diseases, attributable YLD, and regulation level, may vary depending on the national/regional background and spatial distribution of PM2.5 concentrations, as well as demographic characteristics.

A recent study conducted by Hui et al. analyzed the cost-effectiveness of different treatment options for advanced non-small cell lung cancer (NSCLC). However, there are concerns about the methodological approach used in the study. The authors did not provide evidence of testing for proportional hazards (PH), which is crucial for determining the appropriateness of using hazard ratios (HRs) in the analysis. Additionally, the study applied the PH assumption throughout the network, which may not be suitable for comparing treatment regimens with different mechanistic properties. Furthermore, the selection of the log-logistic model for estimating treatment effects contradicts the assumption of PH. The study also made assumptions about costs and quality-adjusted life years that may not be representative of other cost-effectiveness analyses. Overall, the study has methodological flaws that may lead to substantial error and bias in the conclusions. Alternative methodologies and considerations should be discussed to ensure robustness in the analysis. [Extracted from the article]

Background To investigate the association between gestational diabetes mellitus (GDM) without subsequent overt diabetes and long-term all-cause and cardiac mortality. Methods This prospective cohort study included 10,327 women (weighted population: 132,332,187) with a pregnancy history from the National Health and Nutrition Examination Survey (2007 to 2018). Participants were divided into three groups (GDM alone, overt diabetes, and no diabetes). Mortality data was linked from the National Death Index up to December 31, 2019. Multivariable Cox regression analysis was performed to examine the association between GDM alone and overt diabetes with all-cause mortality and cardiac mortality. Data analysis was performed from October 2022 to April 2023. Results Among the participants, 510 (weighted 5.3%) had GDM alone and 1862 (weighted 14.1%) had overt diabetes. Over a median follow-up period of 6.7 years (69,063 person-years), there were 758 deaths. The GDM group did not show an increased risk of all-cause mortality (hazard ratio [HR] 0.67; 95% CI, 0.25–1.84), while the overt diabetes group had a significantly higher risk (HR 1.95; 95% CI, 1.62–2.35). Similarly, the GDM group did not exhibit an elevated risk of cardiac mortality (HR 1.48; 95% CI, 0.50–4.39), whereas the overt diabetes group had a significantly higher risk (HR 2.37; 95% CI, 1.69–3.32). Furthermore, sensitivity analysis focusing on women aged 50 or above showed that the HR of GDM history for all-cause mortality was 1.14 (95% CI, 0.33–3.95) and the HR for cardiac mortality was 1.74 (95% CI, 0.49–6.20). Conclusions GDM alone was not associated with an increased risk of all-cause and cardiac mortality, while overt diabetes was significantly associated with both types of mortality.

Background The coronavirus disease 2019 (COVID-19) has caused substantial morbidity and mortality on a global scale. A strong correlation has been found between COVID-19 treatment outcomes and noncommunicable diseases such as cancers. However, there is limited information on the outcomes of cancer patients who were hospitalised for COVID-19. Methods We conducted an analysis on data collected in a large prospective cohort study set-up by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). All patients with laboratory-confirmed or clinically-diagnosed SARS-CoV-2 infection were included. Cancer was defined as having a current solid organ or haematological malignancy. The following outcomes were assessed; 30-day in-hospital mortality, intensive care unit (ICU) admission, length of hospitalization and receipt of higher-level care. Results Of the 560,547 hospitalised individuals who were analysed, 27,243 (4.9%) had cancer. Overall, cancer patients were older and had more comorbidities than non-cancer patients. Patients with cancer had higher 30-day in-hospital mortality than non-cancer patients (29.1.3% vs 18.0%) and longer hospital stays (median of 12 days vs 8 days). However, patients with cancer were admitted less often to intensive care units than non-cancer patients (12.6% vs 17.1%) and received less invasive mechanical ventilation than non-cancer patients (4.5% vs 7.6%). The hazard ratio of dying from cancer, adjusted for age, sex and country income level was 1.18 (95%CI: 1.15-1.2). Conclusions This study’s findings underscore the heightened vulnerability of hospitalized COVID-19 patients with cancer, revealing a higher mortality rate, longer hospital stays, and an unstructured pattern of care that reflects the complexity of managing severely ill patients during a public health crisis like the COVID-19 pandemic.

ABSTRACTEffectiveness of heterologous booster regimes with ad5 vectored COVID-19 vaccine in a large, diverse population during the national-scale outbreak of SARS-CoV-2 omicron predominance in China has not been reported, yet. We conducted a large-scale cohort-control study in six provinces in China, and did a retrospective survey on the COVID-19 attack risk during this outbreak. Participant aged ≥18 years in five previous trials who were primed with 1 to 3 doses of ICV received heterologous booster with either intramuscular or orally inhaled ad5 vectored COVID-19 vaccine were included in the heterologous-trial cohort. We performed propensity score-matching at a ratio of 1:4 to match participants in the heterologous-trial cohort individually with the community individuals who received three-dose of ICV as a control (ICV-community cohort). From February 4 to April 10, 2023, 41504 (74.5%) of 55710 individuals completed the survey. The median time since the most recent vaccination to the onset of the symptoms of COVID-19 was 303.0 days (IQR 293.0-322.0). The attack rate of COVID-19 in the heterologous-trial cohort was 55.8%, while that in the ICV-community cohort was 64.6%, resulting in a relative effectiveness of 13.7% (95% CI 11.9 to 15.3). In addition, a higher relative effectiveness against COVID-19 associated outpatient visits, and admission to hospital was demonstrated, which was 25.1% (95% CI 18.9 to 30.9), and 48.9% (95% CI 27.0 to 64.2), respectively. The heterologous booster with ad5 vectored COVID-19 vaccine still offered some additional protection in preventing COVID-19 breakthrough infection versus homologous three-dose regimen with ICV, 10 months after vaccination.

Background Having multiple sleep problems is common in adulthood. Yet, most studies have assessed single sleep variables at one timepoint, potentially misinterpreting health consequences of co-occurring sleep problems that may change over time. We investigated the relationship between multidimensional sleep health across adulthood and mortality. Methods Participants from the Midlife in the United States Study reported sleep characteristics in 2004–2006 (MIDUS-2; M2) and in 2013–2014 (MIDUS-3; M3). We calculated a composite score of sleep health problems across 5 dimensions: Regularity, Satisfaction, Alertness, Efficiency, and Duration (higher = more problems). Two separate models for baseline sleep health (n  = 5 140; median follow-up time = 15.3 years) and change in sleep health (n  = 2 991; median follow-up time = 6.4 years) to mortality were conducted. Cox regression models controlled for sociodemographics and key health risk factors (body mass index, smoking, depressive symptoms, diabetes, and hypertension). Results On average, 88% of the sample reported having one or more sleep health problems at M2. Each additional sleep health problem at M2 was associated with 12% greater risk of all-cause mortality (hazard ratio [HR] = 1.12, 95% confidence interval [CI] = 1.04–1.21), but not heart disease-related mortality (HR = 1.14, 95% CI = 0.99–1.31). An increase in sleep health problems from M2 to M3 was associated with 27% greater risk of all-cause mortality (HR = 1.27, 95% CI = 1.005–1.59), and 153% greater risk of heart disease mortality (HR = 2.53, 95% CI = 1.37–4.68). Conclusions More sleep health problems may increase the risk of early mortality. Sleep health in middle and older adulthood is a vital sign that can be assessed at medical checkups to identify those at greater risk. [ABSTRACT FROM AUTHOR]

Inference for the conditional association between an exposure and a time-to-event endpoint, given covariates, is routinely based on partial likelihood estimators for hazard ratios indexing Cox proportional hazards models. This approach is flexible and makes testing straightforward, but is nonetheless not entirely satisfactory. First, there is no good understanding of what it infers when the model is misspecified. Second, it is common to employ variable selection procedures when deciding which model to use. However, the bias and uncertainty that imperfect variable selection adds to the analysis is rarely acknowledged, rendering standard inferences biased and overly optimistic. To remedy this, we propose a nonparametric estimand which reduces to the main exposure effect parameter in a (partially linear) Cox model when that model is correct, but continues to capture the (conditional) association of interest in a well understood way, even when this model is misspecified in an arbitrary manner. We achieve an assumption-lean inference for this estimand based on its influence function under the nonparametric model. This has the further advantage that it makes the proposed approach amenable to the use of data-adaptive procedures (e.g., variable selection, machine learning), which we find to work well in simulation studies and a data analysis. for this article are available online. [ABSTRACT FROM AUTHOR]

The best treatments for the clinically node-negative (cN0) neck in early-stage oral squamous cell carcinoma (OSCC) patients are a subject of ongoing debate and there is no consensus. A network meta-analysis (NMA) of randomized clinical trials (RCTs) was conducted to determine the most effective treatment and to rank treatments based on their effectiveness. A systematic search was performed in accordance with the PRISMA guidelines to retrieve RCTs that compared therapeutic neck dissection (TND), sentinel lymph node biopsy (SLNB), and elective neck dissection (END). The outcomes analysed were overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and nodal recurrence. Hazard ratios and risk ratios were calculated by direct meta-analysis and NMA. Ten RCTs with a total of 1858 patients were eligible for inclusion. Direct meta-analysis showed END to be superior to TND and comparable to SLNB. The NMA revealed no statistically significant difference between END and SLNB (very low quality evidence) regarding OS, DSS, DFS, and nodal recurrence. However, END was found to significantly improve OS and DFS, and reduce nodal recurrence when compared to TND (moderate quality evidence). END ranked as probably the top treatment option for maximizing OS and DSS, and reducing nodal recurrence in early-stage OSCC, followed by SLNB and TND. There was very low quality evidence supporting SLNB as non-inferior to END for patients with early-stage OSCC. This NMA yielded favourable results for the use of END (with moderate quality evidence) in early-stage OSCC patients, although excellent results have also been obtained with SLNB. However, data in the literature for SLNB are scarce, as this technique has not yet been formalized in many countries. There is a need to further explore SLNB for early-stage OSCC patients, as well as its value in detecting occult lymph node metastases on the contralateral side. More studies comparing morbidity, quality of life, and costs between the different management strategies for the clinically negative neck in early-stage OSCC patients are needed. [ABSTRACT FROM AUTHOR]

Background: To investigate the association between gestational diabetes mellitus (GDM) without subsequent overt diabetes and long-term all-cause and cardiac mortality. Methods: This prospective cohort study included 10,327 women (weighted population: 132,332,187) with a pregnancy history from the National Health and Nutrition Examination Survey (2007 to 2018). Participants were divided into three groups (GDM alone, overt diabetes, and no diabetes). Mortality data was linked from the National Death Index up to December 31, 2019. Multivariable Cox regression analysis was performed to examine the association between GDM alone and overt diabetes with all-cause mortality and cardiac mortality. Data analysis was performed from October 2022 to April 2023. Results: Among the participants, 510 (weighted 5.3%) had GDM alone and 1862 (weighted 14.1%) had overt diabetes. Over a median follow-up period of 6.7 years (69,063 person-years), there were 758 deaths. The GDM group did not show an increased risk of all-cause mortality (hazard ratio [HR] 0.67; 95% CI, 0.25–1.84), while the overt diabetes group had a significantly higher risk (HR 1.95; 95% CI, 1.62–2.35). Similarly, the GDM group did not exhibit an elevated risk of cardiac mortality (HR 1.48; 95% CI, 0.50–4.39), whereas the overt diabetes group had a significantly higher risk (HR 2.37; 95% CI, 1.69–3.32). Furthermore, sensitivity analysis focusing on women aged 50 or above showed that the HR of GDM history for all-cause mortality was 1.14 (95% CI, 0.33–3.95) and the HR for cardiac mortality was 1.74 (95% CI, 0.49–6.20). Conclusions: GDM alone was not associated with an increased risk of all-cause and cardiac mortality, while overt diabetes was significantly associated with both types of mortality. [ABSTRACT FROM AUTHOR]

AbstractGradient boosting methods become popular in recent years to analyze right-censored survival data where Cox’s proportional hazards model is the widely used statistical model. However, there are very limited studies on the differences between the two approaches for right-censored survival data. We compare two boosting methods with Cox’s proportional hazards model in this paper: one is the gradient boosting decision tree and the other is gradient boosting with component-wise linear models. The differences between the two boosting methods are presented. A simulation study is conducted to investigate the performance of the three methods in practice where only the main effects of covariates are included. The results show that the boosting methods outperform Cox’s proportional hazards model in both the relative and absolute risk estimation in the proportional hazards model except when Cox’s proportional hazards model is fully specified with nonlinear and interaction covariates effects. It indicates that the boosting methods, particularly the gradient boosting decision tree, is a very competitive method for right-censored survival data if complicated covariate effects may exist but are unknown to the investigator. We illustrate an application of the boosting methods with real data analysis. [ABSTRACT FROM AUTHOR]

AbstractNonproportional hazards (NPH) have been observed in confirmatory clinical trials with time to event outcomes. Under NPH, the hazard ratio does not stay constant over time and the log rank test is no longer the most powerful test. The weighted log rank test (WLRT) has been introduced to deal with the presence of nonproportionality. We focus our attention on the WLRT and the complementary Cox model based on time varying treatment effect proposed by Lin and León. We investigate whether the proposed weighted hazard ratio (WHR) approach is unbiased in scenarios where the WLRT statistic is the most powerful test. In the diminishing treatment effect scenario where the WLRT statistic would be most optimal, the time varying treatment effect estimated by the Cox model estimates the treatment effect very close to the true one. However, when the true hazard ratio is large the proposed model overestimates the treatment effect and the treatment profile over time. In the delayed treatment scenario, the estimated treatment effect profile over time is typically close to the true profile. For both scenarios, we have demonstrated analytically that the hazard ratio functions are approximately equal under small treatment effects. When the assumed rate of how quickly the treatment effect profile is diminishing or delaying differs in the analysis from that in the true data generating mechanism, the estimated hazard ratio profile from the WHR approach is biased. Since in practice the true HR time profile may differ from that assumed in the WHR analysis, it may be preferable to use alternative approaches for effect estimation. [ABSTRACT FROM AUTHOR]

Introduction: blood centres are often faced with the problem of donor lapsing resulting in loss of donors from the already strained donor pool. In Zimbabwe, 70% of the donated blood comes from younger donors aged 40 years and below, who at the same time, have high attrition rates. This study seeks to apply the concept of survival analysis in analysing blood donor lapsing rates. Methods: in analysing the donor lapsing and retention rates, data on 450 first-time blood donors at the National Blood Service Zimbabwe, in Harare's blood bank for the period 2014 to 2017 was extracted from the donors' database. The Cox proportional hazards (Cox PH) and Kaplan-Meier methods were applied in the analysis. Donor demographic characteristics suspected of having effect on donor lapsing and retention were identified and analysed. Results: the study findings show that 56.9% of the donors had lapsed by the end of the four-year study period. Results from the multiple Cox PH model indicate that donor age had a significant effect on blood donor retention time (p = 0.000918 < 0.05). The Hazard Ratio (HR) = 0.615 with 95% CI: (0.461; 0.820) shows that the relatively older donors had a lower hazard (38.5% lower) of lapsing compared to the hazard for younger donors. The effect of gender, blood donor group and donation time interval on donor retention and attrition were not statistically significant. Male donors had HR = 1.03; 95% CI (0.537; 1.99) with (p = 0.922 > 0.05) and donors with a 4-month interval between donations had HR = 1.31; 95% CI (0.667; 2.59) with (p = 0.430 > 0.05). Conclusion: the study confirmed the problem of donor attrition faced by blood centres. The age of the donor had a significant effect on the retention time of blood donors before lapsing. The older the blood donor, the lower the risk of lapsing. The Zimbabwe National Blood Service (NBSZ) Blood Centre authorities should have a critical mass of individuals above 40 years as potential blood donors because of their reliability in blood donation according to the study findings. [ABSTRACT FROM AUTHOR]

Purpose: To explore the association between chronic prostatitis (CP) and the subsequent development of benign prostatic hyperplasia (BPH). Methods: Data analyzed were medical claims of Taiwan’s National Health Insurance program. From 2010 to 2017, 3571 patients ≧20 years with CP diagnosed by certified urologists were enrolled. Patients with past BPH diagnosis and diagnosis of prostate cancer, inguinal hernia, interstitial cystitis, and urethritis in the past and within one year after the first CP diagnosis were excluded. Age-matched controls were randomly selected from all non-CP individuals of the same exclusion criteria in the study period with a CP/non-CP ratio of 1:4. The follow-up was made from the first CP diagnosis to death or the end of 2018. The endpoint was the newly diagnosed BPH. Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of BPH in association with CP. Results: Over a maximum of 8 years of follow-up, 287 (8.03%) and 258 (0.43%) BPH events were noted for the CP and non-CP group, respectively, representing a covariate adjusted HR (aHR) of 4.30 (95% CI, 3.61–5.13). Younger patients tended to suffer from higher aHRs, especially those aged 20–39 years (aHR: 11.45, 95% CI, 5.12–25.64). Conclusion: The Taiwan national health database indicated that CP patients had a significantly higher risk of developing BPH later than non-CP patients. Interestingly, the younger the CP is diagnosed (under 40), the greater the risk. [ABSTRACT FROM AUTHOR]

BackgroundNonalcoholic fatty liver disease (NAFLD) is common among patients with type 2 diabetes mellitus (T2DM) and is associated with increased risk for coronary atherosclerosis and acute cardiovascular (CV) events. We employed the validated, non-invasive Angulo NAFLD fibrosis score (FS) in an intervention study in patients with T2DM and recent acute coronary syndrome (ACS) to determine the association of FS with CV risk and treatment response to apabetalone. Apabetalone is a novel selective inhibitor of the second bromodomain of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression.MethodsThe Phase 3 BETonMACE trial compared apabetalone with placebo in 2,425 patients with T2DM and recent ACS. In this post hoc analysis, we evaluated the impact of apabetalone therapy on CV risk, defined as a composite of major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction [MI], or stroke) and hospitalization for heart failure (HHF) in two patient categories of FS that reflect the likelihood of underlying NAFLD. Patients were initially classified into three mutually exclusive categories according to a baseline Angulo FS 0.675 (F3-F4), where F0 through F4 connote fibrosis severity none, mild, moderate, severe, and cirrhosis, respectively. The composite of ischemic MACE and HHF in the placebo group was higher in indeterminant and F3-F4 categories compared to the F0-F2 category (17.2% vs 15.0% vs 9.7%). Therefore, for the present analysis, the former two categories were combined into an elevated NAFLD CVD risk group (FS+) that was compared with the F0-F2 group (lower NAFLD risk, FS0-2).ResultsIn 73.7% of patients, FS was elevated and consistent with a moderate-to-high likelihood of advanced liver fibrosis (FS+); 26.3% of patients had a lower FS (FS0-2). In the placebo group, FS+ patients had a higher incidence of ischemic MACE and HHF (15.4%) than FS0-2 patients (9.7%). In FS+ patients, addition of apabetalone to standard of care treatment lowered the rate of ischemic MACE compared with placebo (HR = 0.79; 95% CI 0.60-1.05; p=0.10), HHF (HR = 0.53; 95% CI 0.33-0.86; p=0.01), and the composite of ischemic MACE and HHF (HR = 0.76; 95% CI 0.59-0.98; p=0.03). In contrast, there was no apparent benefit of apabetalone in FS0-2 patients (HR 1.24; 95% CI 0.75-2.07; p=0.40; HR 1.12; 95% CI 0.30-4.14; p=0.87; and HR 1.13; 95% CI 0.69-1.86; p=0.62, respectively). Over a median duration of 26.5 months, FS increased from baseline in both treatment groups, but the increase was smaller in patients assigned to apabetalone than to placebo (p=0.04).ConclusionsAmongst patients with T2DM, recent ACS, and a moderate-to-high likelihood of advanced liver fibrosis, apabetalone was associated with a significantly lower rate of ischemic MACE and HHF and attenuated the increase in hepatic FS over time.

Abstract Background This research aims to determine the incidence of calf morbidity, mortality and its potential predisposing factors in the first six months of life. Morbidity and mortality of dairy calves are persistent problems for dairy farmers worldwide. For effective control and prevention programs on calf health, it is imperative to estimate the extent of calf morbidity and mortality, and associated risk factors. Although few studies have investigated the epidemiology of calf morbidity and mortality in Ethiopia, comprehensive information is scarce in this area. Methods Data were collected through a cross-sectional survey and longitudinal follow-up on purposively selected dairy farms. A longitudinal study was conducted on 235 calves from birth to 6 months of age. Survival analysis methods using the Kaplan–Meier (K-M) method, and mixed effect Cox proportional hazard regression were employed to compute the life-to-event data on morbidity and mortality. Results From the 235 calves studied, 53 morbidity and 15 mortality events were recorded. This gives an overall morbidity and mortality incidence rate of 55 per 100-calf 6-months at risk (risk rate of 42.07%) and 14 per 100-calf 6-months at risk (risk rate of 12.97%), respectively. Diarrhea (13.84%) followed by pneumonia (8.97%) were the most common diseases that occurred in calves, respectively. Similarly, diarrhea (33.3%) and pneumonia (26.7%) were the leading causes of death. Dam parity (p

The material is devoted to the distribution of mobile forms of heavy metals in the ground cover urban landscapes of the Mykolaiv industrial urban agglomeration, which is a complex multifunctional system. The authors of the study collected soil samples in different places of agglomeration sand and measured the levels of mobile forms of heavy metals in these samples. The purpose of the study is a determination of the migration levels of heavy metals in the locations of missile strikes by the Russian aggressors. The objectives of the research are developing a strategy for testing the Mykolaiv Urban Industrial Agglomeration (MUIA) soil cover; estimating the migration level of HM (Cr, Zn, Hg, Pb, Ni, Cu, Mn) of the MUIA soil cover at the maximum permissible levels. The research data revealed that the concentration of heavy metals (Cr, Zn, Hg, Pb, Ni, Cu, Mn) is in three forms - ion exchange, available, and fixed - in the soil. The average concentration of heavy metals in the ion exchange form ranges from 0.9 mg/kg for Cr to 60.3 mg/kg for Mn. In available form, the average concentration of metals varies from 0.4 mg/kg for Cr to 57.9 mg/kg for Hg. In fixed form, the average concentration of metals ranges from 8.7 mg/kg for Cr to 582.9 mg/kg for Mn. The analysis of the study showed that the content of mobile forms in soil agglomerations differs significantly depending on the place of heavy metals of sampling. In some places, the content of heavy metals exceeds the permissible standards, which can harm human health and the ecosystem.

Abstract Background Stroke is one of the top causes of functional disability around the world. The main objective was to identify stroke-related functional outcomes and risk factors. A good functional outcome is defined as the absence of problems secondary to the stroke event, a poor functional outcome as the presence of complications, and mortality as the existence of complications. Method A retrospective cohort analysis was used to observe factors in 298 eligible adult (18 or older) stroke patients who attend outpatient clinics every three months at Felege Hiwot Referral Hospital between September 2019 and August 2021 to predict outcomes. Result The likelihood of dying from a poor outcome was 9%, and the likelihood of recovering was 24%. The average time spent on good and poor outcomes for different levels of independent variables varies according to their risk. During the first three years of follow-up, the instantaneous risk with a 95% confidence interval of transitioning from good to poor outcome in the women, aged 60 or older, with hypertension, atrial fibrillation, and hemorrhage stroke versus men stroke patients, aged 18 to 59, without hypertension, atrial fibrillation, and ischemic stroke were 1.54 (1.10, 2.15), 1.73 (1.19, 2.52), 2.34 (1.55, 3.53), 2.74 (1.64, 4.56), and 1.52 (1.10, 2.19) respectively. The hazard ratio of transitioning from poor outcome to death for patients with diabetes mellitus and atrial fibrillation versus those without diabetes mellitus and atrial fibrillation was estimated to be 1.95 (1.10, 3.46) and 3.39 (1.67, 6.89), respectively. Conclusion Women over 60 with hypertension, atrial fibrillation, and hemorrhagic stroke were more likely to progress from a good to a poor outcome. Diabetes and atrial fibrillation were also risk factors for progressing from a poor outcome to death. The states and transitions, as well as a clinical control of the hazards for the transition through states, should improve the physician’s decision-making process. Since gender and age are difficult to control, early intervention by patients and the hospital may be critical in influencing functional outcomes.

Abstract Background Atmospheric pollution has been recognized as the greatest environmental threat to human health. The population of the Venafro Valley, southern Italy, is exposed to emissions from a Waste-To-Energy (WTE) and a cement plant and potentially also to another WTE located in the neighboring region of Lazio; also, the vehicular atmospheric pollution situation is critical. In order to assess the environmental health risk of residents in eight municipalities of the Venafro Valley, a retrospective residential cohort study during 2006–2019 was carried out. Methods Four exposure classes were defined by natural-break method, using a dispersion map of nitrogen dioxides (chosen as proxy of industrial pollution). The association between the industrial pollution and cause-specific mortality/morbidity of the cohort was calculated using the Hazard Ratio (HR) through a multiple time-dependent and sex-specific Cox regression adjusting for age, proximity to main roads and socio-economic deprivation index. Results Results showed, for both sexes, mortality and morbidity excesses in the most exposed class for diseases of the circulatory system and some signals for respiratory diseases. Particularly, mortality excesses in both sexes in class 3 for diseases of the circulatory system [men: HR = 1.37 (1.04–1.79); women: HR = 1.27 (1.01–1.60)] and for cerebrovascular diseases [men: HR = 2.50 (1.44–4.35); women: HR = 1.41 (0.92–2.17)] were observed and confirmed by morbidity analyses. Mortality excesses for heart diseases for both sexes [men-class 3: HR = 1.32 (0.93–1.87); men-class 4: HR = 1.95 (0.99–3.85); women-class 3: HR = 1.49 (1.10–2.04)] and for acute respiratory diseases among women [HR = 2.31 (0.67-8.00)] were observed. Morbidity excesses in both sexes for ischemic heart diseases [men-class 3: HR = 1.24 (0.96–1.61); women-class 4: HR = 2.04 (1.04–4.02)] and in class 4 only among men for respiratory diseases [HR = 1.43 (0.88–2.31)] were also found. Conclusions The present study provides several not-negligible signals indicating mitigation actions and deserve further investigations. For future studies, the authors recommend enriching the exposure and lifestyle profile using tools such as questionnaires and human biomonitoring.

In clinical development, it is useful to characterize the causal relationship between individual drug concentrations and clinical outcomes in large phase III trials of new therapeutic agents because it can provide insights on whether increasing the currently administered drug dose may lead to better outcomes. However, estimating causal effects of drug concentration is complicated by the fact that drug concentration is a continuous measure and it is usually influenced by patient-level prognostic characteristics such as body weight and sex. In this article, we compare two approaches to estimate causal effects of continuous point exposures on time-to-event outcomes: (a) outcome regression (OR) and (b) weighting. In particular, we make the first direct comparison of the balancing weights, inverse probability weighting and OR methods for estimating the effects of continuous exposures on time-to-event outcomes in simulations and demonstrate that these methods can exhibit markedly different behaviours that subsequently lead to a change in the conclusions. To improve weighted exposure effect estimators, we also propose a new simple-to-apply diagnostic to detect when such estimators might be subject to severe bias, and demonstrate its effectiveness in simulations. Finally, we apply these methods to an example of multiple sclerosis drug development by providing causal effect estimates of average ocrelizumab concentrations on time-to-event disability progression outcomes. [ABSTRACT FROM AUTHOR]

Background: The population-level summary measure is a key component of the estimand for clinical trials with time-to-event outcomes. This is particularly the case for non-inferiority trials, because different summary measures imply different null hypotheses. Most trials are designed using the hazard ratio as summary measure, but recent studies suggested that the difference in restricted mean survival time might be more powerful, at least in certain situations. In a recent letter, we conjectured that differences between summary measures can be explained using the concept of the non-inferiority frontier and that for a fair simulation comparison of summary measures, the same analysis methods, making the same assumptions, should be used to estimate different summary measures. The aim of this article is to make such a comparison between three commonly used summary measures: hazard ratio, difference in restricted mean survival time and difference in survival at a fixed time point. In addition, we aim to investigate the impact of using an analysis method that assumes proportional hazards on the operating characteristics of a trial designed with any of the three summary measures. Methods: We conduct a simulation study in the proportional hazards setting. We estimate difference in restricted mean survival time and difference in survival non-parametrically, without assuming proportional hazards. We also estimate all three measures parametrically, using flexible survival regression, under the proportional hazards assumption. Results: Comparing the hazard ratio assuming proportional hazards with the other summary measures not assuming proportional hazards, relative performance varies substantially depending on the specific scenario. Fixing the summary measure, assuming proportional hazards always leads to substantial power gains compared to using non-parametric methods. Fixing the modelling approach to flexible parametric regression assuming proportional hazards, difference in restricted mean survival time is most often the most powerful summary measure among those considered. Conclusion: When the hazards are likely to be approximately proportional, reflecting this in the analysis can lead to large gains in power for difference in restricted mean survival time and difference in survival. The choice of summary measure for a non-inferiority trial with time-to-event outcomes should be made on clinical grounds; when any of the three summary measures discussed here is equally justifiable, difference in restricted mean survival time is most often associated with the most powerful test, on the condition that it is estimated under proportional hazards. [ABSTRACT FROM AUTHOR]

Background: This research aims to determine the incidence of calf morbidity, mortality and its potential predisposing factors in the first six months of life. Morbidity and mortality of dairy calves are persistent problems for dairy farmers worldwide. For effective control and prevention programs on calf health, it is imperative to estimate the extent of calf morbidity and mortality, and associated risk factors. Although few studies have investigated the epidemiology of calf morbidity and mortality in Ethiopia, comprehensive information is scarce in this area. Methods: Data were collected through a cross-sectional survey and longitudinal follow-up on purposively selected dairy farms. A longitudinal study was conducted on 235 calves from birth to 6 months of age. Survival analysis methods using the Kaplan–Meier (K-M) method, and mixed effect Cox proportional hazard regression were employed to compute the life-to-event data on morbidity and mortality. Results: From the 235 calves studied, 53 morbidity and 15 mortality events were recorded. This gives an overall morbidity and mortality incidence rate of 55 per 100-calf 6-months at risk (risk rate of 42.07%) and 14 per 100-calf 6-months at risk (risk rate of 12.97%), respectively. Diarrhea (13.84%) followed by pneumonia (8.97%) were the most common diseases that occurred in calves, respectively. Similarly, diarrhea (33.3%) and pneumonia (26.7%) were the leading causes of death. Dam parity (p < 0.001) and pen cleaning (p < 0.001) were significant predictors of calf morbidity. Dam parity (p = 0.007), calving status (p = 0.005), pen cleaning (p = 0.04), and floor type (p = 0.001) of houses were significantly associated with mortality. The hazard of diarrhea was significantly associated with sex (p = 0.003), first colostrum feeding time (p = 0.028), pen cleaning (p = 0.010), and breeding method (p = 0.013). Conclusion: The rates of morbidity and mortality reported in the study were higher than the economically acceptable, also affecting the welfare of the animals. The risk factors found need due attention in the management practices of dairy calves in Ethiopia. [ABSTRACT FROM AUTHOR]

Purpose: Hyperandrogenic intrauterine environment may lead to the development of metabolic disorders in offspring in their later life. In this study, we aimed to determine the impact of maternal hyperandrogenism (MHA) on metabolic syndrome (MetS) risk in female offspring in their later life. Methods: In this cohort study conducted in Tehran, Iran, female offspring with MHA (n = 323) and without MHA (controls) (n = 1125) were selected. Both groups of female offspring were followed from the baseline to the date of the incidence of events, censoring, or end of the study period, whichever came first. We used age-scaled unadjusted and adjusted Cox regression models to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MHA and MetS in female offspring. The software package STATA was used for statistical analysis, and the significance level was set at P < 0.05. Results: We observed a higher risk of MetS (unadjusted HR (95% CI), 1.36 (1.05–1.77)), (P = 0.02) and (adjusted HR (95% CI), 1.34 (1.00–1.80)), (P = 0.05, borderline)), in female offspring with MHA, compared to controls. The results were adjusted for the potential confounders including body mass index (BMI) at baseline, net changes of BMI, physical activity, education status, and birth weight. Conclusion: Our results suggest that MHA increases the risk of developing MetS in female offspring in their later life. Screening of these female offspring for MetS may be recommended. [ABSTRACT FROM AUTHOR]

The material is devoted to the distribution of heavy metals mobile forms in the ground cover urban landscapes of the Mykolaiv industrial urban agglomeration, which is a complex multifunctional system. The authors of the research collected soil samples from different places of agglomeration and measured the levels of heavy metals mobile forms in these samples. The purpose is a determination of the heavy metals migration levels in the missile strikes locations by the Russian aggressors. The objectives of the research are developing a strategy for testing the Mykolaiv Urban Industrial Agglomeration (MUIA) soil cover; estimating the migration level of heavy metals (HM) (Cr, Zn, Hg, Pb, Ni, Cu, Mn) of the MUIA soil cover according to the maximum permissible levels. The research data revealed that the HM concentration (Cr, Zn, Hg, Pb, Ni, Cu, Mn) is in three forms - ion exchange, available and fixed. The HM average concentration in the ion exchange form ranges from 0.9 mg/kg for Cr to 60.3 mg/kg for Mn. In available form, the HM average concentration varies from 0.4 mg/kg for Cr to 57.9 mg/kg for Hg. In fixed form, the HM average concentration ranges from 8.7 mg/kg for Cr to 582.9 mg/kg for Mn. The analysis of the study showed that the mobile forms content in soils agglomerations differs significantly depending on the place heavy metals of sampling. In some places, the content of heavy metals exceeds the permissible standards, which can harm on the ecosystem and human health. [ABSTRACT FROM AUTHOR]

In this study, the long-term mortality effects associated with exposure to PM10 (particles with an aerodynamic diameter smaller than or equal to 10 µm), PM2.5 (particles with an aerodynamic diameter smaller than or equal to 2.5 µm), BC (black carbon), and NOx (nitrogen oxides) were analyzed in a cohort in southern Sweden during the period from 1991 to 2016. Participants (those residing in Malmö, Sweden, born between 1923 and 1950) were randomly recruited from 1991 to 1996. At enrollment, 30,438 participants underwent a health screening, which consisted of questionnaires about lifestyle and diet, a clinical examination, and blood sampling. Mortality data were retrieved from the Swedish National Cause of Death Register. The modeled concentrations of PM10, PM2.5, BC, and NOx at the cohort participants' home addresses were used to assess air pollution exposure. Cox proportional hazard models were used to estimate the associations between long-term exposure to PM10, PM2.5, BC, and NOx and the time until death among the participants during the period from 1991 to 2016. The hazard ratios (HRs) associated with an interquartile range (IQR) increase in each air pollutant were calculated based on the exposure lag windows of the same year (lag0), 1–5 years (lag1–5), and 6–10 years (lag6–10). Three models were used with varying adjustments for possible confounders including both single-pollutant estimates and two-pollutant estimates. With adjustments for all covariates, the HRs for PM10, PM2.5, BC, and NOx in the single-pollutant models at lag1–5 were 1.06 (95% CI: 1.02–1.11), 1.01 (95% CI: 0.95–1.08), 1.07 (95% CI: 1.04–1.11), and 1.11 (95% CI: 1.07–1.16) per IQR increase, respectively. The HRs, in most cases, decreased with the inclusion of a larger number of covariates in the models. The most robust associations were shown for NOx, with statistically significant positive HRs in all the models. An overall conclusion is that road traffic-related pollutants had a significant association with mortality in the cohort. [ABSTRACT FROM AUTHOR]

Background: Stroke is one of the top causes of functional disability around the world. The main objective was to identify stroke-related functional outcomes and risk factors. A good functional outcome is defined as the absence of problems secondary to the stroke event, a poor functional outcome as the presence of complications, and mortality as the existence of complications. Method: A retrospective cohort analysis was used to observe factors in 298 eligible adult (18 or older) stroke patients who attend outpatient clinics every three months at Felege Hiwot Referral Hospital between September 2019 and August 2021 to predict outcomes. Result: The likelihood of dying from a poor outcome was 9%, and the likelihood of recovering was 24%. The average time spent on good and poor outcomes for different levels of independent variables varies according to their risk. During the first three years of follow-up, the instantaneous risk with a 95% confidence interval of transitioning from good to poor outcome in the women, aged 60 or older, with hypertension, atrial fibrillation, and hemorrhage stroke versus men stroke patients, aged 18 to 59, without hypertension, atrial fibrillation, and ischemic stroke were 1.54 (1.10, 2.15), 1.73 (1.19, 2.52), 2.34 (1.55, 3.53), 2.74 (1.64, 4.56), and 1.52 (1.10, 2.19) respectively. The hazard ratio of transitioning from poor outcome to death for patients with diabetes mellitus and atrial fibrillation versus those without diabetes mellitus and atrial fibrillation was estimated to be 1.95 (1.10, 3.46) and 3.39 (1.67, 6.89), respectively. Conclusion: Women over 60 with hypertension, atrial fibrillation, and hemorrhagic stroke were more likely to progress from a good to a poor outcome. Diabetes and atrial fibrillation were also risk factors for progressing from a poor outcome to death. The states and transitions, as well as a clinical control of the hazards for the transition through states, should improve the physician's decision-making process. Since gender and age are difficult to control, early intervention by patients and the hospital may be critical in influencing functional outcomes. [ABSTRACT FROM AUTHOR]