Longitudinal associations of polypharmacy and frailty with major cardiovascular events and mortality among more than half a million middle-aged participants of the UK Biobank.

BACKGROUND: Studies of the associations of polypharmacy and frailty with adverse health outcomes in middle-aged adults are limited. Furthermore, a potentially stronger association of polypharmacy with adverse health outcomes in frail than in non-frail adults is of interest. OBJECTIVE: To evaluate associations of frailty (assessed using a frailty index) and polypharmacy (defined as taking five or more drugs) with major cardiovascular events, cancer incidence, all-cause, cardiovascular disease-specific, and cancer-specific mortality. METHODS: Cox proportional hazards regression models were used to analyze 501,548 participants of the UK Biobank cohort study aged 40-69 years who were followed up for an average of 12 years. RESULTS: The prevalence of pre-frailty and frailty were 43.2 % and 2.3 %, respectively, and that of polypharmacy was 18.3 %. Although strongly associated with each other, frailty and polypharmacy were independently, statistically significantly associated with major cardiovascular events, cardiovascular disease-specific, and all-cause mortality. In addition, the hazard ratios of polypharmacy were stronger among (pre-)frail than non-frail study participants. No profound associations with cancer incidence and cancer mortality were observed. No sex and age differences were observed. CONCLUSIONS: This large cohort study showed that polypharmacy and frailty are independent risk factors for major cardiovascular events, cardiovascular disease-specific and all-cause mortality in both middle-aged (40-64 years) and older people (≥ 65 years). In addition, the hazard ratios of polypharmacy were stronger among (pre-)frail than non-frail study participants. This underlines the need to avoid polypharmacy as far as possible not only in older but also in middle-aged subjects (40-64 years), especially if they are pre-frail or frail.

MCL1 inhibition: a promising approach to augment the efficacy of sorafenib in NSCLC through ferroptosis induction.

Ferroptosis, an iron-dependent form of regulated cell death, plays a crucial role in modulating the therapeutic response in non-small cell lung cancer (NSCLC) patients. Studies have identified the signal transducer and activator of transcription 3 (STAT3) and myeloid cell leukemia-1 (MCL1) as potential targets for sorafenib, which exhibits activities in inducing ferroptosis. However, the role of STAT3-MCL1 axis in sorafenib-induced ferroptosis in NSCLC is still unclear. This study provided evidence that ferroptosis is a critical driver of sorafenib-induced cell death in NSCLC, supported by the accumulation of lipid peroxidation products, indicative of oxidative stress-induced cell death. Additionally, both in vitro and in vivo experiments showed that ferroptosis contributed to a significant portion of the anti-cancer effects elicited by sorafenib in NSCLC. The noticeable accumulation of lipid peroxidation products in sorafenib-treated mice underscored the significance of ferroptosis as a contributing factor to the therapeutic response of sorafenib in NSCLC. Furthermore, we identified the involvement of the STAT3/MCL1 axis in sorafenib-induced antitumor activity in NSCLC. Mechanistically, sorafenib inhibited endogenous STAT3 activation and downregulated MCL1 protein expression, consequently unleashing the ferroptosis driver BECN1 from the BECN1-MCL1 complex. Conversely, there is an augmented association of BECN1 with the catalytic subunit of system Xc-, SLC7A11, whose activity to import cystine and alleviate lipid peroxidation is hindered upon its binding with BECN1. Notably, we found that MCL1 upregulation correlated with ferroptosis resistance in NSCLC upon sorafenib treatment. Our findings highlight the importance of sorafenib-triggered ferroptosis in NSCLC and offer a novel strategy to treat advanced NSCLC patients: by downregulating MCL1 and, in turn, predispose NSCLC cells to ferroptosis.

Serum 25-Hydroxyvitamin D Status and Vitamin D Supplements Use Are Not Associated with Low Back Pain in the Large UK Biobank Cohort.

Longitudinal studies assessing the association of vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels < 30 nmol/L, and vitamin D supplement (VDS) use with low back pain (LBP) are sparse. This investigation assessed the cross-sectional and longitudinal association of vitamin D status and VDS use with LBP among 135,934 participants from the UK Biobank cohort. Approximately 21.6% of the participants had vitamin D deficiency, while only 4% regularly took VDS. In the month before study enrollment, 3.8% of the population reported experiencing LBP. An additional 3.3% of the population were diagnosed with LBP by their general practitioners for the first time during a median follow-up of 8.5 years. Vitamin D deficiency and VDS use were cross-sectionally associated with LBP in age- and sex-adjusted models, but these associations were not evident in comprehensively adjusted models. In longitudinal analyses, both vitamin D deficiency and VDS use were not associated with LBP in any model after correction for multiple testing. In conclusion, not unexpectedly due to the fact that LBP is multifactorial, our findings provide no evidence for the role of the vitamin D status in the etiology of LBP.

The associations of serum vitamin D status and vitamin D supplements use with all-cause dementia, Alzheimer's disease, and vascular dementia: a UK Biobank based prospective cohort study.

BACKGROUND: Prior studies on vitamin D and dementia outcomes yielded mixed results and had several important limitations. OBJECTIVES: We aimed to assess the associations of both serum vitamin D status and supplementation with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) incidence. METHODS: With a prospective cohort study design, we comprehensively assessed the associations of vitamin D and multivitamin supplementation, as well as vitamin D deficiency {25-hydroxyvitamin D [25(OH)D] <30 nmol/L}, and insufficiency [25(OH)D 30 to <50 nmol/L], with the 14-year incidence of all-cause dementia, AD, and VD in 269,229 participants, aged 55 to 69, from the UK Biobank. RESULTS: Although 5.0% reported regular vitamin D use and 19.8% reported multivitamin use, the majority of participants exhibited either vitamin D deficiency (18.3%) or insufficiency (34.0%). However, vitamin D deficiency was less prevalent among users of vitamin D (6.9%) or multivitamin preparations (9.5%) than among nonusers (21.5%). Adjusted Cox regression models demonstrated 19% to 25% increased risk of all 3 dementia outcomes for those with vitamin D deficiency [hazard ratio (HR) 95% confidence interval (CI)]: 1.25 (1.16, 1.34) for all-cause dementia; 1.19 (1.07-1.31) for AD; 1.24 (1.08-1.43) for VD] and 10% to 15% increased risk of those with vitamin D insufficiency [HR (95% CI): 1.11 (1.05, 1.18) for all-cause dementia; 1.10 (1.02-1.19) for AD; 1.15 (1.03-1.29) for VD]. Regular users of vitamin D and multivitamins had 17% and 14% lower risk of AD [HR (95% CI): 0.83 (0.71, 0.98)] and VD [HR (95% CI): 0.86 (0.75, 0.98)] incidence, respectively. CONCLUSIONS: Although our findings indicate the potential benefits of vitamin D supplementation for dementia prevention, randomized controlled trials are essential for definitive evidence.

Associations of 25-hydroxyvitamin D status and vitamin D supplementation use with mortality due to 18 frequent cancer types in the UK Biobank cohort.

BACKGROUND: Although the associations of serum 25-hydroxyvitamin D (25(OH)D) levels and vitamin D supplementation with total cancer mortality are well-known, evidence regarding the association of 25(OH)D and cancer site-specific mortality is predominantly limited to common cancer types, and most studies on vitamin D supplementation use have limitations on sample size and the adjustment of important confounding factors. METHODS: We used cause-specific Cox regression models adjusted for 48 covariates to assess the associations of vitamin D deficiency, insufficiency, and vitamin D supplementation use with mortality from any cancer and 18 specific cancers in 411,436 United Kingdom Biobank participants, aged 40-69 years. RESULTS: The majority of the study population had either vitamin D deficiency (21.1%) or insufficiency (34.4%). Furthermore, 4.1% and 20.3% of the participants regularly took vitamin D or multivitamin supplements, respectively. During a median follow-up of 12.7 years, vitamin D deficiency was associated with significantly increased mortality from total cancer and four specific cancers: stomach (hazard ratio, 95% confidence interval: 1.42, 1.05-1.92), colorectal (1.27, 1.07-1.50), lung (1.24, 1.10-1.40), and prostate (1.36, 1.06-1.75). Vitamin D insufficiency was associated with increased colorectal (1.14, 1.00-1.30) and lung cancer mortality (1.19, 1.08-1.32). Compared to non-users, vitamin D use was associated with lower lung cancer (0.75, 0.60-0.95) and total cancer mortality. Multivitamin use was associated with lower mortality from melanoma (0.64, 0.43-0.97). CONCLUSION: Vitamin D deficiency and insufficiency were associated with increased mortality from multiple common cancers. The potential to reduce cancer mortality by vitamin D supplementation in populations with low 25(OH)D levels should be further explored.

About the associations of vitamin D deficiency and biomarkers of systemic inflammatory response with all-cause and cause-specific mortality in a general population sample of almost 400,000 UK Biobank participants.

It is unknown whether the well-known association between vitamin D deficiency and mortality could be explained by the immune system modulating effects of vitamin D, which may protect from a systemic inflammatory response (SIR) to adverse health conditions. This study aims to investigate the interrelationships of vitamin D deficiency, biomarkers of SIR, and mortality. We used multivariate logistic regression with adjustment for 51 covariates to assess the associations of vitamin D deficiency with disadvantageous levels of nine biomarkers of SIR in the UK Biobank cohort. Furthermore, we tested with Cox regression and mediation analysis whether biomarkers of SIR and vitamin D deficiency were independently associated with mortality. We included 397,737 participants aged 37-73 years. Vitamin D deficiency was associated with disadvantageous levels of all blood cell count-based biomarkers, but not with C-reactive protein (CRP)-based biomarkers after adjustment for body weight. Vitamin D deficiency and all biomarkers of SIR were significantly associated with all-cause mortality and mortality from cancer, cardiovascular and respiratory disease. The strength of these associations was unaltered if vitamin D deficiency and biomarkers of SIR were put in the same model. This finding was further supported by the mediation analyses. This study showed that vitamin D deficiency is associated with disadvantageous levels of blood cell count-based but not CRP-based biomarkers of SIR. Vitamin D deficiency and systemic inflammation were independently and strongly associated with mortality. The potential of clinical interventions against both vitamin D deficiency and underlying causes of systemic inflammation should be explored.

Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials.

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Protocol of the optimal study: Optimization of polypharmacy in geriatric oncology - A randomized controlled trial.

BACKGROUND: Polypharmacy is very common in older cancer patients and these patients are particularly vulnerable to drug-drug interactions and adverse drug reactions because they often receive chemotherapy and symptom-relieving agents. METHODS: The primary aim of the randomized, controlled Optimization of Polypharmacy in Geriatric Oncology (OPTIMAL) trial is to test whether an advisory letter with the results of a comprehensive medication review conducted with the Fit fOR The Aged (FORTA) list to the caring physician in rehabilitation clinics improves the quality of life (QoL) of older cancer patients exposed to polypharmacy more than usual care. The FORTA list detects medication overuse, underuse, and potentially inappropriate drug use among older adults. In the oncology departments of approximately 10 German rehabilitation clinics, we aim to recruit 514 cancer patients (22 common cancers; diagnosis or recurrence requiring treatment in the last 5 years; all stages) who are ≥ 65 years old, regularly take ≥ 5 drugs, and have ≥ 1 medication-related problem. All necessary information about the patients will be provided to a pharmacist at the coordinating center (German Cancer Research Center, Heidelberg), who will perform randomization (1:1) and conduct the medication review with the FORTA list. For the intervention group only, the results are sent by letter to the treating physician in the rehabilitation clinics, who shall discuss medication changes with the patient at the discharge visit, as well as implement them afterwards and disclose them in the discharge letter to the general practitioner. The control group gets the usual care provided in German rehabilitation clinics, which usually does not include a comprehensive medication review but can include medication changes. Patients will be blinded, as they cannot know whether proposed medication changes were part of the study or part of usual care. Study physicians cannot be blinded. The primary endpoint will be the EORTC-QLQ-C30 global health status/QoL score, assessed via self-administered questionnaires 8 months after baseline. DISCUSSION: If the planned study shows that a medication review with the FORTA list improves the QoL of older cancer patients in oncological rehabilitation more than usual care, it would provide the necessary evidence to translate the trial's findings into routine care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00031024.

SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma.

Ferroptosis is a type of iron-dependent cell death pertaining to an excess of lipid peroxidation. It has been suggested that sorafenib-an anti-angiogenic medication for hepatocellular carcinoma (HCC)-induces ferroptosis, but the underlying mechanism for this remains largely unknown. We employed siRNA-mediated gene silencing to investigate the role of Src homology region 2 domain-containing phosphatase-1 (SHP-1), following sorafenib treatment, in cystine/glutamate-antiporter-system-Xc--regulated cystine uptake. Co-immunoprecipitation was also performed to examine the interactions between MCL1, beclin 1 (BECN1), and solute carrier family 7 member 11 (SLC7A11), which functions as the catalytic subunit of system Xc-. The results of this study showed that sorafenib enhanced the activity of SHP-1, dephosphorylated STAT3, downregulated the expression of MCL1 and, consequently, reduced the association between MCL1 and BECN1. In contrast, increased binding between BECN1 and SLC7A11 was observed following sorafenib treatment. The elevated interaction between BECN1 and SLC7A11 inhibited the activity of system Xc-, whereas BECN1 silencing restored cystine intake and protected cells from ferroptosis. Notably, ectopic expression of MCL1 uncoupled BECN1 from SLC7A11 and rescued cell viability by attenuating lipid peroxidation. The results revealed that ferroptosis could be induced in HCC via SHP-1/STAT3-mediated downregulation of MCL1 and subsequent inhibition of SLC7A11 by increased BECN1 binding.

Work Stress and Willingness of Nursing Aides during the COVID-19 Pandemic.

OBJECTIVES: During the coronavirus disease 2019 (COVID-19) pandemic, nursing aides (NAs) experienced greater work stress than they do typically because they worked in highly contagious environments. This may have influenced their work morale and willingness to work, which can reduce patient satisfaction, influence their physical and mental health, and even endanger patient safety or cause medical system collapse. DESIGN: A cross-sectional survey with a structured self-report questionnaire was conducted. SETTING AND PARTICIPANTS: 144 NAs from a medical center in Central Taiwan participated. METHODS: We recruited NAs through convenience sampling to discuss their work stress, willingness to work, and patients' satisfaction with them during the COVID-19 pandemic. RESULT: Of the 144 recruited NAs, 115 (79.9%) were women and 29 (20.1%) were men, and 89 (61.8%) had completed COVID-19 training courses. NAs with different work tenure lengths exhibited significant differences in work stress (p = 0.022), willingness to work (p = 0.029), and patient satisfaction (p = 0.029) scores during the pandemic. CONCLUSION: The study findings provide crucial data for the management of NAs during pandemics to prevent them from neglecting patients due to excessive work stress or losing their willingness to work, which may cause the medical system to collapse.

Long-term low-dose acetylsalicylic use shows protective potential for the development of both vascular dementia and Alzheimer's disease in patients with coronary heart disease but not in other individuals from the general population: results from two large cohort studies.

BACKGROUND: No population-based cohort study investigated a potential inverse association between long-term low-dose acetylsalicylic acid (ASA) use and all-cause dementia and its two most common sub-types Alzheimer's disease (AD) and vascular dementia (VD) so far. METHODS: Cox regression models with inverse probability of treatment weighting to model the underlying cardiovascular risk were used to assess the associations of low-dose ASA use with all-cause dementia, AD, and VD incidence in community-dwelling older adults from the German ESTHER study (N = 5258) and the UK Biobank (N = 305,394). Inclusion criteria were age of 55 years or older and completed drug assessment. Meta-analyses of the individual participant data from the two prospective cohort studies were performed. RESULTS: Four hundred seventy-six cases of all-cause dementia, 157 cases of AD, and 183 cases of VD were diagnosed over a median of 14.3 years of follow-up in ESTHER. In the UK Biobank, 5584 participants were diagnosed with all-cause dementia, 2029 with AD, and 1437 with VD over a median of 11.6 years. The meta-analysis of both cohorts revealed a weak reduction in hazards for all-cause dementia (hazard ratio (HR) [95% confidence interval (CI)]: 0.96 [0.93 to 0.99]). The strongest protective effect of low-dose ASA was observed in participants with coronary heart disease (CHD) in both cohorts, and a significant interaction was detected. In particular, in meta-analysis, a 31% reduction in hazard for AD, 69% for VD and 34% for all-cause dementia were observed (HR [95% CI]: 0.69 [0.59 to 0.80], 0.31 [0.27 to 0.35], 0.46 [0.42 to 0.50], respectively). Furthermore, compared to non-users, users of low-dose ASA for 10 years or longer (who likely use it because they have CHD or a related diagnosis putting them at an increased risk for cardiovascular events) demonstrated a strong protective effect on all dementia outcomes, especially for VD (HR [95% CI]: 0.48 [0.42 to 0.56]) whereas no protective associations were observed with shorter low-dose ASA use. CONCLUSIONS: The protective potential of low-dose ASA for all-cause dementia, AD, and VD seems to strongly depend on pre-existing CHD and the willingness of patients to take it for a minimum of ten years.

Strongly increased risk of gastric and duodenal ulcers among new users of low-dose aspirin: results from two large cohorts with new-user design.

BACKGROUND: Low-dose aspirin is a risk factor for peptic ulcer disease but previous, population-based cohort studies may have underestimated the low-dose aspirin risk because they did not use a new-user design. Gastrointestinal bleeding occurs more frequently early after initiation of low-dose aspirin therapy than in later years. AIM: To assess the associations of low-dose aspirin with gastric and duodenal ulcer incidence in prevalent- and new-user design. METHODS: Multivariate Cox regression models in the German ESTHER study (N = 7737) and the UK Biobank (N = 213,598) with more than 10 years of follow-up. RESULTS: In the prevalent-user design, there was no significant association between low-dose aspirin and gastric ulcer observed in both cohorts. Furthermore, low-dose aspirin was weakly, statistically significantly associated with prevalent duodenal ulcer in the UK Biobank (hazard ratio [95% confidence interval]: 1.27 [1.07-1.51]) but not in the ESTHER study (1.33 [0.54-3.29]). When restricting the exposure to only new users, the hazard ratios for incident gastric and duodenal ulcer disease were 1.82 [1.58-2.11] and 1.66 [1.36-2.04] in the UK Biobank, respectively, and 2.83 [1.40-5.71] and 3.89 [1.46-10.42] in the ESTHER study, respectively. CONCLUSIONS: This study shows that low-dose aspirin is an independent risk factor for both gastric and duodenal ulcers. The associations were not significant or weak in the prevalent-user design and strong and statistically significant in the new-user design in both cohorts. Thus, it is important to weigh risks against benefits when low-dose aspirin treatment shall be initiated and to monitor adverse gastrointestinal symptoms after the start of low-dose aspirin therapy.

Incorporation of functional status, frailty, comorbidities and comedication in prediction models for colorectal cancer survival.

Limitations in functional status, frailty, multiple comorbidities and comedications are common among older colorectal cancer (CRC) patients. We investigated whether adding these factors could improve the predictive value of a reference model containing age, sex, tumor stage and location for prediction of 5-year overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), recurrence-free survival (RFS) and nondisease-specific survival (nDSS) for all CRC patients as well as for younger (<65 years) and older patients (≥65 years). Overall, 3410 CRC patients from the DACHS study were analyzed and area under receiver operating characteristic curves (AUC) and net reclassification improvements (NRI) were assessed. In prediction of OS, the reference model plus functional status was identified as the best model among all CRC patients (AUC: 0.762) and younger CRC patients (AUC: 0.820). In older CRC patients, comorbidity should additionally be added (AUC: 0.747). For nDSS, the reference model plus comorbidity and frailty had the best predictive performance in all CRC patients (AUC: 0.776). For the outcomes DFS (AUC: 0.727), DSS (AUC: 0.838) and RFS (AUC: 0.784), the reference model was already the best model in all CRC patients because no significant NRIs were observed. The pattern "The less CRC-specific the survival outcome and the older the CRC patients, the more relevant the inclusion of functional status, comorbidity, and frailty in CRC prognostic scores is" was observed. Thus, different nomograms for younger and older CRC patients for 1-, 3- and 5-year OS prognosis estimation are being suggested.

Did the severity of appendicitis increase during the COVID-19 pandemic?

BACKGROUND: This study aimed to assess the severity of appendicitis during the coronavirus disease 2019 (COVID-19) pandemic, as patients with appendicitis may procrastinate seeking medical attention during the pandemic. METHODS: Information on patients with appendicitis who were treated at the Taipei City Hospital during the COVID-19 pandemic (January 1, 2020 to June 30, 2020) was retrieved. Patients who were diagnosed with appendicitis and treated at the same hospital from January 1, 2019 to July 1, 2019 were designated as the control group. Multivariate logistic regression analysis was conducted to assess changes in the severity of appendicitis (at a 2-week interval) between the two groups. RESULTS: We identified 307 (study group: 149; control group: 158) consecutive patients with appendicitis. The mean age was 46.2 +- 19.8 years. Between the two groups, there were no significant differences in age, sex, comorbidity, surgery type (laparoscopic or open appendectomy) or surgery time. The number of patients in the study group decreased between January 29, 2020 and April 21, 2020, which paralleled the period of spikes in the confirmed COVID-19 cases and restricted daily activities. The percentage of uncomplicated and complicated appendicitis (excluding mild appendicitis or normal appendix) in the study group increased between February 26 and March 10, as well as between April 8 and April 21. In the multivariate regression analysis, the odds of uncomplicated and complicated appendicitis increased in three bi-weeks for the study group but not in the control group. CONCLUSION: The severity of acute appendicitis might increase during the COVID-19 pandemic, because patients with mild appendicitis (or abdominal pain) may hesitate to seek help.

Age and sex differences in associations between self-reported health, physical function, mental function and mortality.

OBJECTIVES: To explore how age and sex affect the impacts of self-rated health, self-reported physical activities, physical function, and depressive symptoms on long-term mortality among community-dwelling middle-aged and older adults using a nationally representative population-based cohort study. METHODS: Data from 1550 study participants from the Social Environment and Biomarkers of Aging Study (SEBAS) were retrieved for analysis, and all participants were divided into four groups based on their age and gender. Middle aged participants were aged 53 to 64 years, and elderly subjects were ≥ 65 years old. Multivariate logistic regression models were applied to investigate the associations between age, sex, and self-reported disabilities of physical activities, physical function (activities of daily living (ADL) and instrumental activities of daily living (IADL) and depression. RESULTS: Although the self-reported health status was similar across different age- and sex-stratified subgroups, older women were at the highest risk in self-reported difficulty with physical activities (aOR 2.58 [1.55-4.28]) and difficulty with IADL (aOR 3.32 [2.20-5.03]) compared to men. After adjusting for living arrangement, residence locale, education levels, occupation, socioeconomic status, self-reported health, multimorbidity, impairments in daily activities, and depressive symptoms, older men were found to display the highest risk of mortality (aHR 2.06 [95% CI 1.45-2.93]). CONCLUSIONS: Although self-reported health was similar across different age and sex stratified subgroups, women (particularly older women) are significantly more likely to have worse physical and functional health than men. After adjusting for all confounding factors, men are at substantially greater risk for mortality despite reporting better health and functional performance.

Association of Comedication Quality With Chemotherapy-Related Adverse Drug Reactions and Survival in Older Colorectal Cancer Patients.

BACKGROUND: Evidence about the clinical relevance of appropriate comedication among older colorectal cancer (CRC) patients is sparse. METHODS: A cohort study was conducted with 3239 CRC patients aged 65 years and older. To assess comedication quality, we calculated the total Fit fOR The Aged (FORTA) score and its subscores for medication overuse, underuse, and potentially inappropriate medication use. Multivariable Cox proportional hazards or logistic regression models were performed to evaluate the association of comedication quality with up to 5-year overall survival, CRC-specific survival, and chemotherapy-related adverse drug reactions. RESULTS: Overall, 3239 and 1209 participants were included in analyses on survival and adverse drug reactions, respectively. The hazard ratios [95% confidence intervals] for the total FORTA score ≥ 7 versus 0-1 points were 1.83 [1.40-2.40] and 1.76 [1.22-2.52] for up to 5-year overall and CRC-specific survival, respectively. Worse up to 5-year overall survival and CRC-specific survival was also evident for FORTA subscores for potentially inappropriate medication use and overuse, whereas no association was observed for underuse. Although results for the total FORTA and potentially inappropriate medication score were much stronger among patients receiving chemotherapy, no significant associations with chemotherapy-related adverse drug reactions were observed. Moreover, associations were particularly strong among men and rectal cancer patients as compared to women and colon cancer patients. CONCLUSIONS: Poor total comedication quality was significantly associated with worse up to 5-year overall and CRC-specific survival. Randomized controlled trials are needed to test whether improved cancer comedication management in older CRC patients prolongs survival.

Association of F2-isoprostane levels with Alzheimer's disease in observational studies: A systematic review and meta-analysis.

INTRODUCTION: The association between F2-isoprostanes and Alzheimer's disease (AD) has been controversially discussed in the literature since the 1990s. However, no systematic review has been performed so far. METHODS: A systematic review of observational studies on the associations of F2-isoprostanes and the specific biomarker 8-iso-prostaglandin F2α with AD were conducted. Random-effects model meta-analyses were performed. RESULTS: 29 studies were included in the systematic review, including four longitudinal studies. In an overall meta-analysis of the 25 cross-sectional studies, F2-isoprostane levels were statistically significantly associated with AD (Hedge's g [95% confidence interval]: 1.00 [0.69-1.32]). When studies were grouped by biomarker and sample specimen, F2-isoprostane and 8-iso-prostaglandin F2α levels were statistically significantly elevated in tissue samples of the frontal lobe of AD patients. Moreover, F2-isoprostane levels in cerebrospinal fluid and 8-iso-prostaglandin F2α levels in blood samples of AD patients were significantly increased. Meta-analyses of the few longitudinal studies did not reach statistical significance. DISCUSSION: Increased concentrations of F2-isoprostanes were found in AD patients. However, due to the lack of adjustment in most cross-sectional case-control studies, results must be interpreted carefully. In addition, the causality of the association is uncertain because evidence from well-conducted longitudinal studies was conflicting, and further longitudinal studies are required to reinforce the results.

Association of Polypharmacy with Colorectal Cancer Survival Among Older Patients.

BACKGROUND: In geriatric oncology, polypharmacy is often assessed during a comprehensive geriatric assessment. Previous studies about its association with survival among patients with colorectal cancer (CRC) were inconclusive and had high risk for indication bias. PATIENTS AND METHODS: A cohort study was conducted with 3,239 patients with CRC, aged ≥65 years, who were recruited in Germany between 2003 and 2016, while being hospitalized for CRC surgery. We defined polypharmacy as the concurrent use of five or more drugs, and excessive polypharmacy (EPP) as concurrent use of eight or more drugs. Cox proportional hazards regression models were performed to assess the associations of polypharmacy with 5-year overall (OS), CRC-specific (CSS), and non-cancer-specific survival (NCS) with rigorous adjustment for morbidity to minimize indication bias (e.g., for cancer stage, functional status, and 13 common diseases/conditions). RESULTS: The prevalence of polypharmacy was 54.7% and that of EPP was 24.2%. During up to 5 years of follow-up, 1,070 participants died, among whom 615 died of CRC and 296 died of other causes than cancer. EPP was statistically significantly associated with poorer up-to-5-year OS (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.02-1.47) and CSS (HR, 1.31; 95% CI, 1.03-1.68). HR point estimate for NCS was higher than 1 (1.22) but not statistically significant. CONCLUSION: Polypharmacy was very common and EPP was a weak risk factor for mortality in this large cohort of older patients with CRC. Clinical trials are needed to address the causality of this relationship because older patients with CRC might benefit from deprescribing drugs without an indication. IMPLICATIONS FOR PRACTICE: The results of this study support the hypothesis that excessive polypharmacy, defined as use of eight or more concurrently used active substances, has a negative impact on the prognosis of older patients with colorectal cancer (CRC). This study suggests to oncologists that performing a medication review for older patients with CRC with eight drugs or more is indicated (especially when a broader comprehensive geriatric assessment is being performed). Such a medication review should not only focus on reducing the number of medications (by deprescribing drugs without an indication) but also check the appropriateness of indicated drugs for older patients with cancer.

Long-Term Survival of Combined Hepatocellular-Cholangiocarcinoma: A Nationwide Study.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (HCC-CC) is an aggressive primary liver cancer. However, the clinical features are not clearly understood because of limited literature and the complex nature of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). METHODS: The records of 100,754 patients with newly diagnosed liver cancer between 2004 and 2013 were obtained from the Taiwan Cancer Registry. The primary outcome measures were overall survival and local recurrence-free survival. The median follow-up time was 60 months (29-120 months). RESULTS: HCC-CC tended to share some characteristics with HCC, including increased frequency of stage I cases, high individual tumor rates, and similar patterns of viral hepatitis B and hepatitis C infections. In contrast, HCC-CC showed malignant behavior similar to that of CC, as high-grade tumor cell differentiation and presentation of jaundice were predominant in HCC-CC and CC compared with HCC. Overall survival and local recurrence-free survival rates of HCC-CC were between HCC and CC rates. The mortality rate of HCC-CC was 79.2% (HCC, 77.5%; CC, 93.5%) and the local recurrence rate of HCC-CC was 65.3% (HCC, 74.6%; CC, 88.4%). Surgical treatment was an independent factor for the long-term prognosis of HCC-CC, whereas transarterial chemoembolization (TAcE) promoted survival in both surgical and nonsurgical groups. CONCLUSION: Our data confirmed that, although it reflects the malignant behavior of CC, HCC-CC should mainly be characterized as a subtype of HCC. With careful selection of patients, curative resection and TAcE might benefit the survival of patients with HCC-CC. IMPLICATIONS FOR PRACTICE: Combined hepatocellular-cholangiocarcinoma (HCC-CC) is a rare cancer that shares demographic characteristics, as well as survival probabilities, with both hepatocellular carcinoma and cholangiocarcinoma. It occurs frequently in patients with hepatitis B virus infection, cirrhotic liver background, and early-stage disease. Compared with 20% of initial resection rates of its counterparts, HCC-CC has higher initial resection rate (55%). Although short-term overall survival is inferior to HCC, its long-term overall survival is similar with HCC.

Relationship between practices of eye protection against solar ultraviolet radiation and cataract in a rural area.

BACKGROUND: Cataract is a public health concern worldwide that differentially affects rural residents of outlying islands where ultraviolet radiation (UVR) may have greater penetration because of less shading. OBJECTIVES: To assess the relationships between attitudes and practices of eye protection and eye diseases for residents of an offshore island of Taiwan. METHODS: Questionnaire survey was administered to local residents (age > 50 years) regarding socio-demographic information, attitudes/practices of eye protection under sun exposure and eye diseases. RESULTS: A total of 816 participants (response rate 90.7%, 816/900) completed the questionnaires. Mean age was 63.7 (+ 10.8) years. Among these participants, 44.4%, 15.1% and 8.3% had cataract, dry eye and glaucoma, respectively. Although 86.3% and 88.2% of participants agreed that they should avoid outdoor activities and wear glasses/broad-brimmed hats in harsh daylight, 69.4% and 48.3% of participants never/rarely used glasses or hats/umbrellas in harsh daylight, respectively. Predictors of less practices of eye protection against solar UVR included residents who were male, with lower education level, with longer residence and lack of commercial health insurance. Multivariate logistic regression revealed that practices of eye protection under sun exposure were significantly associated with less cataract, but not glaucoma or dry eye. Participants who did not wear glasses, broad-brimmed hats/use umbrellas or both in harsh sunlight (almost) every time were respectively associated with a 57% (P = 0.028), 45% (P = 0.027) or 70% (P = 0.026) increase of cataract than those who did in harsh sunlight (almost) every time. CONCLUSIONS: Practices of eye protection under sun exposure is associated with lower risk of cataract.