The mutagenic forces shaping the genomic landscape of lung cancer in never smokers.

Lung cancer in never smokers (LCINS) accounts for up to 25% of all lung cancers and has been associated with exposure to secondhand tobacco smoke and air pollution in observational studies. Here, we evaluate the mutagenic exposures in LCINS by examining deep whole-genome sequencing data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 geographical locations within the Sherlock-Lung study. KRAS mutations were 3.8-fold more common in adenocarcinomas of never smokers from North America and Europe, while a 1.6-fold higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas from East Asia. Signature SBS40a, with unknown cause, was found in most samples and accounted for the largest proportion of single base substitutions in adenocarcinomas, being enriched in EGFR-mutated cases. Conversely, the aristolochic acid signature SBS22a was almost exclusively observed in patients from Taipei. Even though LCINS exposed to secondhand smoke had an 8.3% higher mutational burden and 5.4% shorter telomeres, passive smoking was not associated with driver mutations in cancer driver genes or the activities of individual mutational signatures. In contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations while exhibiting shorter telomeres and an increase in most types of somatic mutations, including a 3.9-fold elevation of signature SBS4 (q-value=3.1 × 10-5), previously linked mainly to tobacco smoking, and a 76% increase of clock-like signature SBS5 (q-value=5.0 × 10-5). A positive dose-response effect was observed with air pollution levels, which correlated with both a decrease in telomere length and an elevation in somatic mutations, notably attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

Pulse pressure is associated with decline in physical function in older adults.

OBJECTIVES: This study examined the associations between pulse pressure, hypertension, and the decline in physical function in a prospective framework. STUDY DESIGN: The Healthy Aging Longitudinal Study tracked a group of Taiwanese adults aged 55 or more over an average of 6.19 years to assess pulse pressure and decline in physical function, including in handgrip strength, gait speed, and 6-min walking distance, at baseline (2009-2013) and in the second phase of assessments (2013-2020). MAIN OUTCOME MEASURES: Pulse pressure was calculated as the difference between systolic and diastolic blood pressure values. Weakness, slowness, and low endurance were defined as decreases of ≥0.23 m/s (one standard deviation) in gait speed, ≥5.08 kg in handgrip strength, and ≥ 57.73 m in a 6-min walk, as determined from baseline to the second phase of assessment. Linear and logistic regressions were employed to evaluate the associations between pulse pressure, hypertension, and decline in physical function. RESULTS: Baseline pulse pressure was associated with future handgrip strength (beta = -0.017, p = 0.0362), gait speed (beta = -0.001, p < 0.0001), and 6-min walking distance (beta = -0.470, p < 0001). In multivariable models, only handgrip strength (beta = -0.016, p = 0.0135) and walking speed (beta = -0.001, p = 0.0042) remained significantly associated with future pulse pressure. Older adults with high systolic blood pressure (≥140 mmHg) and elevated pulse pressure (≥60 mmHg) exhibited a significantly increased risk of weakness (odds ratio: 1.30, 95 % confidence interval: 1.08-1.58), slowness (1.29, 1.04-1.59), and diminished endurance (1.25, 1.04-1.50) compared with the reference group, who exhibited systolic blood pressure of <140 mmHg and pulse pressure of <60 mmHg. CONCLUSIONS: Among older adults, pulse pressure is associated with a decline in physical function, especially in terms of strength and locomotion.

Subventricular zone stem cell niche injury is associated with intestinal perforation in preterm infants and predicts future motor impairment.

Brain injury is highly associated with preterm birth. Complications of prematurity, including spontaneous or necrotizing enterocolitis (NEC)-associated intestinal perforations, are linked to lifelong neurologic impairment, yet the mechanisms are poorly understood. Early diagnosis of preterm brain injuries remains a significant challenge. Here, we identified subventricular zone echogenicity (SVE) on cranial ultrasound in preterm infants following intestinal perforations. The development of SVE was significantly associated with motor impairment at 2 years. SVE was replicated in a neonatal mouse model of intestinal perforation. Examination of the murine echogenic subventricular zone (SVZ) revealed NLRP3-inflammasome assembly in multiciliated FoxJ1+ ependymal cells and a loss of the ependymal border in this postnatal stem cell niche. These data suggest a mechanism of preterm brain injury localized to the SVZ that has not been adequately considered. Ultrasound detection of SVE may serve as an early biomarker for neurodevelopmental impairment after inflammatory disease in preterm infants.

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity.

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

Develop and Validate a Prognostic Index With Laboratory Tests to Predict Mortality in Middle-Aged and Older Adults Using Machine Learning Models: A Prospective Cohort Study.

BACKGROUND: Prognostic indices can enhance personalized predictions of health burdens. However, a simple, practical, and reproducible tool is lacking for clinical use. This study aimed to develop a machine learning-based prognostic index for predicting all-cause mortality in community-dwelling older individuals. METHODS: We utilized the Healthy Aging Longitudinal Study in Taiwan (HALST) cohort, encompassing data from 5 663 participants. Over the 5-year follow-up, 447 deaths were confirmed. A machine learning-based routine blood examination prognostic index (MARBE-PI) was developed using common laboratory tests based on machine learning techniques. Participants were grouped into multiple risk categories by stratum-specific likelihood ratio analysis based on their MARBE-PI scores. The MARBE-PI was subsequently externally validated with an independent population-based cohort from Japan. RESULTS: Beyond age, sex, education level, and BMI, 6 laboratory tests (low-density lipoprotein, albumin, aspartate aminotransferase, lymphocyte count, high-sensitivity C-reactive protein, and creatinine) emerged as pivotal predictors via stepwise logistic regression (LR) for 5-year mortality. The area under curves of MARBE-PI constructed by LR were 0.799 (95% confidence interval [95% CI]: 0.778-0.819) and 0.756 (95% CI: 0.694-0.814) for the internal and external validation data sets, and were 0.801 (95% CI: 0.790-0.811) and 0.809 (95% CI: 0.774-0.845) for the extended 10-year mortality in both data sets, respectively. Risk categories stratified by MARBE-PI showed a consistent dose-response association with mortality. The MARBE-PI also performed comparably with indices constructed with clinical health deficits and/or laboratory results. CONCLUSIONS: The MARBE-PI is considered the most applicable measure for risk stratification in busy clinical settings. It holds potential to pinpoint older individuals at elevated mortality risk, thereby aiding clinical decision-making.

Impact of physical activity on disability-free and disabled life expectancies in middle-aged and older adults: Data from the healthy aging longitudinal study in Taiwan.

AIM: Leisure-time physical activity (LTPA) promotes healthy aging; however, data on work-related physical activity (WPA) are inconsistent. This study was conducted to examine the disability-free life expectancy (DFLE) and disabled life expectancy (DLE) across physical activity levels, with a focus on WPA, in middle-aged and older adults. METHODS: Data from 5663 community-dwelling participants aged ≥55 years and enrolled in the Healthy Aging Longitudinal Study in Taiwan were evaluated. Energy expenditures from LTPA and WPA were calculated from baseline questionnaires and categorized into sex-specific cutoffs. Disability was based on repeat measures of participants' activities of daily living and instrumental activities of daily living. Mortality was confirmed via data linkage with the Death Certificate database. DFLE and DLE were estimated from discrete-time multistate life-table models. RESULTS: At age 65, women with low WPA had a DLE of 2.88 years (95% confidence interval [CI], 1.67-4.08), which was shorter than that of women without WPA (DLE, 5.24 years; 95% CI, 4.65-5.83) and with high WPA (DLE, 4.01 years; 95% CI, 2.69-5.34). DFLE and DLE were similar across WPA levels in men. DFLE tended to increase as the LTPA increased in men and women. CONCLUSION: Women with low WPA had shorter DLE than did those with no or high WPA. To reduce the risks of disability associated with physical activity, public policy should advocate for older people to watch the type, amount, and intensity of their activities as these may go ignored during WPA. Geriatr Gerontol Int 2024; 24: 229-239.

Examining the role of living alone and loneliness in predicting health-related quality of life: results from the Healthy Aging Longitudinal Study in Taiwan (HALST).

PURPOSE: This study aimed to investigate the distinct yet interconnected aspects of social isolation, namely living alone and loneliness, and their individual and combined effects on predicting health-related quality of life (HRQoL). METHODS: A comprehensive analysis, encompassing both cross-sectional and longitudinal approaches, was conducted using a nationally representative sample of 5644 community-dwelling adults aged 55 and older from the Healthy Aging Longitudinal Study in Taiwan (HALST). RESULTS: Baseline data revealed that 9% of the sample reported living alone, while 10.3% reported experiencing loneliness, with 2.5% reporting both living alone and feeling lonely. Regression analyses consistently demonstrated that loneliness was significantly associated with concurrent and subsequent lower physical (PCS) and mental (MCS) component of HRQoL. Conversely, additional analyses indicated that living alone could indirectly exacerbate the adverse effects of loneliness or contribute to prolonged feelings of loneliness, subsequently predicting lower HRQoL after 3.2 year. CONCLUSION: In terms of practical implications, interventions and policies aiming to enhance HRQoL in older adults should give particular attention to those who report feelings of loneliness, especially individuals living alone.

Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.

BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. FUNDING: Ministry of Health and Welfare of Taiwan.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan.

Importance: Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. Objectives: To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. Design, Setting, and Participants: The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. Exposures: A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. Main Outcomes and Measures: The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Results: Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. Conclusions and Relevance: This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

20-αHydroxycholesterol, an oxysterol in human breast milk, reverses mouse neonatal white matter injury through Gli-dependent oligodendrogenesis.

White matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment. Neonates present a unique opportunity to repair WMIs due to a transient abundance of neural stem/progenitor cells (NSPCs) present in the germinal matrix with oligodendrogenic potential. We identified an endogenous oxysterol, 20-αHydroxycholesterol (20HC), in human maternal breast milk that induces oligodendrogenesis through a sonic hedgehog (shh), Gli-dependent mechanism. Following WMI in neonatal mice, injection of 20HC induced subventricular zone-derived oligodendrogenesis and improved myelination in the periventricular white matter, resulting in improved motor outcomes. Targeting the oligodendrogenic potential of postnatal NSPCs in neonates with WMIs may be further developed into a novel approach to mitigate this devastating complication of preterm birth.

Mortality rate and its determinants among people with dementia receiving home healthcare: a nationwide cohort study.

People with dementia (PwD) who receive home healthcare (HHC) may have distressing symptoms, complex care needs and high mortality rates. However, there are few studies investigating the determinants of mortality in HHC recipients. To identify end-of-life care needs and tailor individualized care goals, we aim to explore the mortality rate and its determinants among PwD receiving HHC. We conducted a retrospective cohort study using a Taiwanese national population database. People with new dementia diagnosis in 2007-2016 who received HHC were included. We calculated the accumulative mortality rate and applied Poisson regression model to estimate the risk of mortality for each variable (adjusted risk ratios, aRR) with a 95% confidence interval (CI). We included 95,831 PwD and 57,036 (59.5%) of them died during the follow-up period (30.5% died in the first-year). Among comorbidities, cirrhosis was associated with the highest mortality risks (aRR 1.65, 95% CI 1.49-1.83). Among HHC-related factors, higher visit frequency of HHC (> 2 versus ≦1 times/month, aRR 3.52, 95% CI 3.39-3.66) and higher level of resource utilization group (RUG, RUG 4 versus 1, aRR = 1.38, 95% CI 1.25-1.51) were risk factor of mortality risk. Meanwhile, HHC provided by physician and nurse was related to reduced mortality risk (aRR 0.79, 95% CI 0.77-0.81) compared to those provided by nurse only. Anticipatory care planning and timely end-of life care should be integrated in light of the high mortality rate among PwD receiving HHC. Determinants associated with increased mortality risk facilitate the identification of high risk group and tailoring the appropriate care goals. Trial registration number: ClinicalTrials.gov Identifier is NCT04250103 which has been registered on 31st January 2020.

Maternal and peripartum risk factors for acute funisitis among term deliveries complicated by intraamniotic infection.

BACKGROUND: Acute funisitis-the histologic diagnosis of inflammation within the umbilical cord-represents a fetal inflammatory response and has been associated with adverse neonatal outcomes. Little is known regarding the maternal and intrapartum risk factors associated with the development of acute funisitis among term deliveries complicated by intraamniotic infection. OBJECTIVE: This study aimed to identify the maternal and intrapartum risk factors associated with developing acute funisitis among term deliveries complicated by intraamniotic infection. STUDY DESIGN: After institutional review board approval, we conducted a retrospective cohort study of term deliveries affected by clinical intraamniotic infection at a single tertiary center between 2013 and 2017, with placental pathology consistent with histologic chorioamnionitis. The exclusion criteria included intrauterine fetal demise, missing delivery information or placental pathology, and documented congenital fetal abnormalities. Maternal sociodemographic, antepartum, and intrapartum factors were compared among patients with acute funisitis on pathology to those without acute funisitis using bivariate statistics. Regression models were developed to estimate the adjusted odds ratios. RESULTS: Of 123 patients meeting the inclusion criteria, 75 (61%) had acute funisitis on placental pathology. Compared with placental specimens without acute funisitis, acute funisitis was observed more frequently among patients with maternal BMI ≥30 kg/m2 (58.7% vs 39.6%, P=.04) and labor courses with increased rupture of membrane duration (17.3 vs 9.6 hours, P=.001). Use of fetal scalp electrode was observed less frequently in acute funisitis (5.3% vs 16.7%, P=.04) than cases without acute funisitis. In regression models, maternal BMI ≥30 kg/m2 (adjusted odds ratio, 2.67; 95% confidence interval, 1.21-5.90) and rupture of membrane >18 hours (adjusted odds ratio, 2.48; 95% confidence interval, 1.07-5.75) were significantly associated with acute funisitis. Fetal scalp electrode use (adjusted odds ratio, 0.18; 95% confidence interval, 0.04-0.71) was negatively associated with acute funisitis. CONCLUSION: In term deliveries with intraamniotic infection and histologic chorioamnionitis, maternal BMI ≥30 kg/m2, and rupture of membrane>18 hours were associated with acute funisitis on placental pathology. As insight into the clinical impact of acute funisitis grows, the ability to predict which pregnancies are at the greatest risk for its development may allow for a tailored approach to predicting neonatal risk for sepsis and related comorbidity.

Dietary Inflammatory Patterns Are Associated With Serum TGs and Insulin in Adults: A Community-Based Study in Taiwan.

BACKGROUND: Dietary patterns related to inflammation have become a focus of disease prevention but the patterns may vary among populations. OBJECTIVES: The study was conducted to determine Taiwanese dietary inflammatory patterns and evaluate their associations with biomarkers of lipid and glucose. METHODS: Data were taken from 5664 community-dwelling individuals aged ≥55 y recruited in 2009-2013 in the Healthy Aging Longitudinal Study in Taiwan (HALST). Dietary data were obtained from an FFQ. An empirical dietary inflammatory pattern (EDIP) was derived from reduced rank regression models that explained the serum high-sensitivity CRP, plasma IL-6, and TNF receptor 1. Cross-sectional associations between dietary scores and biomarkers of total cholesterol (TC); HDL cholesterol; LDL cholesterol; TG; and ratios of TG/HDL cholesterol, TG/TC, fasting glucose, insulin, and HbA1c were analyzed via multiple linear regression and adjusted for major confounders. The false-discovery rate (FDR)-adjusted P < 0.05 was considered statistically significant. Abdominal obesity was defined as a waist circumference of ≥90 cm for men and ≥80 cm for women. RESULTS: Higher EDIP-HALST scores were associated with higher TG (per score increment: 1.62%, 95% CI: 0.58%, 2.76%; PFDR = 0.01), TG/HDL cholesterol (2.01%, 95% CI: 0.67%, 3.37%; PFDR = 0.01), and TG/TC (1.42%, 95% CI: 0.41%, 2.43%; PFDR = 0.01) and nonlinearly associated with insulin, with those in the middle tertile had the highest serum insulin concentrations (means: 5.12 µIU/mL, 95% CI: 4.78, 5.78; PFDR = 0.04) in men, but not in women. No heterogeneity was detected between sexes. The associations with TG (1.23%, 95% CI: 0.19, 2.23%; Ptrend = 0.02), TG/HDL cholesterol (1.62%, 95% CI: 0.30%, 2.96%; Ptrend = 0.02), and TG/TC (1.11%, 95% CI: 0.11%, 2.13%; Ptrend = 0.03) were stronger in participants with abdominal obesity, but were borderline associated in participants with normal abdominal circumferences (all Ptrend = 0.05). CONCLUSIONS: Inflammatory diets, as measured via EDIP-HALST, are associated with serum TG concentration, particularly in participants with abdominal obesity. These findings may suggest that developing disease prevention strategies using dietary inflammatory patterns may be different by populations. J Nutr 20xx;x:xx.

Interactions of Insomnia and Sedative-Hypnotic Drug Use Associated with Frailty Over Time Among Older Adults.

BACKGROUND: Insomnia and frailty are prevalent in older adults. This study aimed to elucidate the impact of insomnia and sedative-hypnotic use on the frailty rate over time. METHODS: We used data from community-dwelling older adults (mean ± SD age = 69.4 ± 8.2 years) from the Healthy Aging Longitudinal Study in Taiwan (HALST). A total of 4,744 participants were included in the study and were followed up for an average of 3.2 years. Frailty was assessed using the Fried criteria. Self-reported sleep problems, sedative-hypnotic use, and claims records from the National Health Insurance database were used. The generalized equation estimation (GEE) approach was applied to account for correlations between repeated measures. The average impact of insomnia and drug use on frailty over time was estimated by adjusting for potential confounding factors using the logic link in the GEE approach. RESULTS: The adjusted odds ratio (OR) of frailty was 1.41 (95% CI: [1.16, 1.72], Z-test statistics Z = 3.39, p <0.001) for insomnia and 1.52 ([1.16, 2.00], Z = 3.00, p = 0.0027) for sedative-hypnotic use. Interactions between insomnia and sedative-hypnotic use with frailty were not statistically significant. Long sleep duration > 8 hours, daytime sleepiness, and sleep apnea was also associated with an increased likelihood of developing frailty. Notably, a dose-response relationship between sedative-hypnotic drug use and frailty was observed. CONCLUSIONS: Insomnia and sedative-hypnotic use were independently associated with increased frailty. The implementation of nonpharmacological treatments to attenuate insomnia may reduce frailty rates.

Does acute funisitis predict worse neonatal outcomes among term newborns?

BACKGROUND: Acute funisitis-the histologic diagnosis of inflammation within the umbilical cord-represents a fetal inflammatory response to infection. Although acute funisitis has been associated with an increased risk of adverse outcomes among preterm neonates, there are limited and conflicting data with term deliveries. OBJECTIVE: This study aimed to evaluate the association between acute funisitis and neonatal morbidity in neonates born at term to pregnant patients with a clinical diagnosis of intraamniotic infection. STUDY DESIGN: This was a retrospective cohort study of pregnant patients who had clinically diagnosed intraamniotic infection at term, delivered vaginally at a single tertiary institution from 2013 to 2019, and had histologic chorioamnionitis on placental pathology. Patients with intrauterine fetal demise or missing neonatal/placental pathology data were excluded. The primary outcome was a neonatal sepsis composite, defined as culture-positive bacteremia, neutropenia (absolute neutrophil count<3500/µL), or immature-to-total neutrophil ratio>0.2. The secondary outcomes included composite neonatal morbidity, defined as neonatal intensive care unit admission, 5-minute Apgar score <7, bacteremia, endotracheal intubation or need for continuous positive airway pressure, intraventricular hemorrhage (grade 3 or 4), necrotizing enterocolitis (stage 3 or 4), umbilical artery pH<7.1, umbilical artery base excess>12, and neonatal mortality. The components of these composites, neonatal intensive care unit length of stay, and Kaiser early-onset sepsis score were also measured. Neonates with acute funisitis on pathology were compared with those without acute funisitis using bivariate statistics. Regression was used to estimate the relative risk of outcomes. RESULTS: Of 184 neonates with deliveries complicated by intraamniotic infection, acute funisitis was present in 109 (59%) placental specimens. Composite neonatal sepsis was significantly higher among neonates with acute funisitis (relative risk, 1.85; 95% confidence interval, 1.13-3.03) than in those without acute funisitis. As a marker for sepsis, acute funisitis has a sensitivity of 39.4%, negative predictive value of 47.2%, specificity of 78.7%, and positive predictive value of 72.9%. An immature-to-total neutrophil ratio>0.2 (relative risk, 1.83; 95% confidence interval, 1.09-3.08) was also significantly associated with acute funisitis. Neonatal morbidity composite, intraventricular hemorrhage, necrotizing enterocolitis, neonatal intensive care unit admission, higher Kaiser early-onset sepsis scores, and other examined outcomes were not statistically associated with acute funisitis. CONCLUSION: In term deliveries complicated by intraamniotic infection, acute funisitis was associated with increased neonatal sepsis. Current approaches for estimating neonatal sepsis risk are limited by their reliance on indirect maternal factors such as maximum maternal temperature and intrapartum antibiotic use. This study suggests that acute funisitis may serve as a marker that could be utilized to augment risk stratification at birth if a protocol for evaluating the umbilical cord in real-time were widely adopted.

Sleep habits are associated with cognition decline in physically robust, but not in frail participants: a longitudinal observational study.

Frail older adults are vulnerable to stressors; thus, sleep related cognition impairment might more greatly affect frail than healthy older adults. In the present study, we investigated whether the association between sleep problems and cognition varies with physical frailty status (modified from Fried et al.). Participants 55 years and older who completed a baseline and follow-up questionnaire (median follow-up: 5.5 years), were included in the analysis. Sleep parameters were evaluated in an interview at the baseline. Cognitive decline was defined as a loss of 3 or more points on the Mini-Mental State Examination (MMSE) at follow-up. Associations between sleep problems and cognitive decline were examined using logistic regression and were stratified by baseline physical frailty status, adjusted for potential confounders. A short total sleep duration (< 5 vs. 7-9 h, odds ratio (OR) = 1.88, 95% confidence interval (CI) 1.18-3.00), excessive daytime sleepiness (OR = 1.49, 95% CI 1.04-2.13), low sleep efficiency (< 65% vs. ≥ 85%, OR = 1.62, 95% CI 1.07-2.46), and insomnia complaints (OR = 2.34, 95% CI 1.23-4.43) were associated with MMSE decline in physically robust. The association was stronger for the sleep summary score, which summarized abnormal sleep duration, excessive daytime sleepiness, and insomnia complaints ([Formula: see text] 2 vs. 0, OR = 3.79, 95% CI 2.10-6.85, p < 0.0001). Due to the low prevalence of frailty in this community-dwelling population, the statistical power to detect an association was low. More evidence is needed to clarify the role of sleep in the progression of cognitive decline in frail individuals.

Metformin and the Risk of Anemia of Advanced Chronic Kidney Disease in Patients With Type 2 Diabetes Mellitus.

This retrospective cohort study determines whether metformin monotherapy or combination therapies can decrease anemia risk in the progress of advanced chronic kidney disease for patients with type 2 diabetes mellitus. The data set was obtained from the National Health Insurance Research Database, containing 1 million randomly selected beneficiaries. After matching, 9303 pairs (1:1) of metformin users and nonusers were acquired. Every patient was individually recorded from 1997 to 2012 to identify anemia incidence (hemoglobin <9 gm/dL). Cox regression models were used to compute hazard ratios and 95% confidence intervals (CIs). There were 305 (0.7%) and 76 (0.8%) erythropoietin-stimulating agent cases in the metformin and non-metformin cohorts over a mean follow-up period of 6.8 and 5.6 years. After matching, the use of metformin decreased the risk of usage of erythropoietin-stimulating agents with an adjusted hazard ratio of 0.76 (95%CI, 0.45-1.29) for dosage of <357 g to 0.30 (95%CI, 0.17-0.56) for >1368 g. The combination of metformin and dipeptidyl peptidase-4 inhibitors decreased with a hazard ratio of 0.42 (95%CI, 0.18-0.99), compared to metformin alone. Metformin combined with dipeptidyl peptidase-4 inhibitors is superior to metformin monotherapy or non-metformin antidiabetic therapies for reducing the risk of anemia in the progress of advanced chronic kidney disease among patients with type 2 diabetes.

Reliability and Validity of the Traditional Chinese Version of the Advance Care Planning Engagement Survey: A Pilot Evaluation in Taiwanese Outpatients.

Objective: The Advance Care Planning Engagement Survey (ACP-ES) has proven effective in evaluating individuals' engagement in advance care planning (ACP). However, a Traditional Chinese version of ACP-ES (ACPES-TC) has not yet been developed. Therefore, this study aimed to translate and preliminarily validate the ACPES-TC in the Taiwanese context. Material and Methods: A forward and backward translation process was conducted. The translated questionnaire was confirmed by clinical and academic experts. The ACPES-TC was then evaluated for its reliability and validity with participants in the community and from an outpatient clinic in a medical center in Northern Taiwan. The participants comprised healthy people aged 20 to 30 years and patients ≥55 years old, recruited from September 17 to October 28, 2019. Results: Seventy people were recruited, including 20 people aged 20 to 30 years in the community and 50 patients ≥ 55 years old from clinics. The ACPES-TC scores are significantly higher among those of older age, having financial independence, and under long-term medication (p < .05). The patients' preference for health-related decision-making is significantly correlated with the ACPES-TC score; the point-biserial correlation coefficient is 0.46 (p < .001). The discriminant and criterion-related validities are verified. The ACPES-TC demonstrated a good internal consistency (Cronbach's α .97), acceptable one-week test-retest reliability (overall intraclass correlation coefficient 0.86), and low practice effect between the test and retest (Cohen's d .43). Conclusion: The overall reliability and validity of the ACPES-TC are fair, which could be used to evaluate the patients' engagement in ACP in Taiwan. However, further studies with a full-scale psychometric evaluation are needed.