Drug adherence and treatment duration for denosumab and mortality risk among hip fracture patients.

This study aimed to assess the impact of drug adherence and treatment duration for denosumab on mortality risk after hip fracture surgery. Lower all-cause mortality risk was associated with drug intervals of 7 months or less and longer treatment duration. The study highlights the importance of proper denosumab administration. PURPOSE: Prescription of anti-osteoporotic medications (AOMs) after osteoporotic hip fracture may increase bone mineral density (BMD) and decrease mortality risk. However, few studies have been conducted on drug adherence and treatment duration for denosumab, a popular choice among AOMs. This study aimed to assess the impact of denosumab adherence and treatment duration on the mortality risk of hip fracture patients after surgery. METHODS: We conducted a cohort study using nationwide population data from National Health Insurance Research Database (NHIRD) in Taiwan. Patients newly diagnosed with osteoporosis and hip fracture between 2008 and 2019 who used denosumab after surgery were included. We assessed drug adherence, treatment duration, and other parameters associated with patient outcomes. RESULTS: A total of 21,316 patients diagnosed with osteoporotic hip fractures were included. Compared with a > 7-month drug interval for denosumab, an interval of ≤ 7 months led to lower all-cause mortality risk (hazard ratio (HR): 0.60, 95% confidence interval (CI): 0.57 ~ 0.64). Patients with denosumab treatment for over 1, 2, and 3 years had lower all-cause mortality risk (HR&CI: 0.68 (0.64 ~ 0.73), 0.48 (0.43 ~ 0.53), 0.29 (0.26 ~ 0.33)) than those with treatment duration < 1 year. Analysis after excluding short-term death yielded similar results. Analysis of causes of death also showed that good adherence and longer duration were associated with reduced mortality due to cancer and cardiovascular disease. CONCLUSION: Better drug adherence and longer duration of denosumab treatment are associated with lower all-cause mortality risk among hip fracture patients after surgery. Our study highlights the benefits of a proper time interval of denosumab administration. These findings provide important insight into management of osteoporotic hip fractures and may inform clinical practice and development of guidelines.

Epidemiology and clinical impact of osteoporosis in Taiwan: A 12-year trend of a nationwide population-based study.

BACKGROUND: Osteoporosis increases the fracture and mortality risk of patients and has a higher disease burden than some cancers. Therefore, global concerns regarding the prevention and treatment of osteoporosis have been raised. However, fast-aging Taiwan lacks national epidemiological data on osteoporosis in recent years. We aimed to establish and update epidemiological data on osteoporosis by analyzing national data from 2008 to 2019. METHODS: We estimated the prevalence and incidence of osteoporosis in patients aged ≥50 years based on claims data from Taiwan's National Health Insurance database from 2008 to 2019. We also analyzed the key parameters of fracture care (anti-osteoporosis medication use, bone mineral density examination rate, and length of hospital stay) to understand the secular trend of management and related clinical outcomes (imminent refracture rate and mortality). RESULTS: The number of prevalent osteoporosis increased from 2008 to 2015 and remained constant until 2019; however, the age-standardized prevalence and incidence rates declined from 2008 to 2019 (3.77%-2.91% and 2.08%-1.02%, respectively). The overall incidence rates of hip and spine fractures decreased significantly by 34% and 27%, respectively. For patients with hip and spine fractures, the immanent refracture rates were 8.5% and 12.9% and the 1-year mortality rate remained stable at approximately 15% and 6%, respectively. CONCLUSION: The age-standardized prevalence and incidence rates decreased remarkably from 2008 to 2019, while the number of prevalent osteoporosis remained steady. Patients with hip fractures encountered a high 1-year mortality rate, while the risk of imminent refracture was notable for patients with spine fractures.

Natural history and survival rate of familial amyloidosis with polyneuropathy: A nationwide databank.

OBJECTIVE: Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy, a rare autosomal-dominant disease, has gained attention in recent years owing to treatment improvements. However, epidemiological real-world mega database of nationwide natural history and survival rates, especially with the specific mutation of Ala97Ser, are limited. METHODS: Taiwan National Health Insurance Research Database contains data from over 23 million individuals; Among them, 175 ATTRv amyloidosis patients validated by rare disease registry were enrolled. Multivariable Cox proportional hazard analyses were applied to investigate the association between baseline characteristics and all-cause mortality. FINDINGS: From 2008 to 2020, the annual incidence and prevalence rates of specific mutations (Ala97Ser) leading to ATTRv amyloidosis with polyneuropathy were 0.04-1.14 and 0.04-4.79 per million in Taiwan, respectively. In Taiwan, these patients exhibited male predominance with a mean age at validation of 62.75 years. At the 5th year after validation, patients exhibited a survival rate of approximately 50%, with higher mortality in male patients (hazard ratio [HR]: 2.22, 95% confidence interval [CI]: 1.15-4.31) and patients older at validation (HR: 1.10, 95% CI: 1.06-1.15). The two most common departments in outpatient were neurology and family medicine, and neurology and cardiology in inpatient. The three most common causes of death registered were unspecified amyloidosis (30.6%), organ-limited amyloidosis (20.9%), and neuropathic heredofamilial amyloidosis (9.7%). INTERPRETATION: The annual prevalence rate of specific mutation (Ala97Ser)-dominant ATTRv amyloidosis with polyneuropathy in Taiwan is comparable to the mid- to high-prevalence country level of the research by Schmidt et al. The extraordinarily high mortality, especially among patients older at validation, may reflect the inadequate awareness and the necessity of early intervention with novel disease-modifying regimens.

Label-free and de-conjugation-free workflow to simultaneously quantify trace amount of free/conjugated and protein-bound estrogen metabolites in human serum.

Different chemical forms of sex hormones including free/conjugated metabolites as well as their protein/DNA adducts in human serum are a panel of important indicators of health conditions. It is, however, hard to quantify all species simultaneously due to the lack of general extraction, derivatization, and de-conjugation methods. Here we developed a label-free and de-conjugation-free workflow to quantify 11 free/conjugated estrogen metabolites including depurinating DNA and protein adduct forms of 4-hydroxyestradiol (4OHE2) in human serum. Acetonitrile acts as an excellent solvent to purify adducted and non-adducted human serum albumin (HSA) by precipitation as well as to extract free/conjugated metabolites and depurinating DNA adducts from the supernatant by salting-out effect. The adduction level of 4OHE2 on HSA was determined by proteomics; free/conjugated metabolites were quantified by a newly developed microflow liquid chromatography (microflow LC)-nanoelectrospray ionization (nanoESI)-multiple reaction monitoring (MRM) method with high reproducibility (7-22% RSD, n > 3) and sub-picogram levels (0.6-20 pg/mL) of quantification limits (S/N = 8) by using non-pulled capillary as nano-ESI emitter. This workflow was demonstrated to reveal endogenous adduction level of 4OHE2 on HSA as well as circulation levels of free/conjugated metabolites in clinical samples. 4OHE2 in human serum were solely detected as protein-bound form, indicating the merit of such integrated platform covering unstable or active metabolites. Compared to traditional methods using labeling or de-conjugation reaction, this workflow is much simplier, more sensitive, and more specific. Moreover, it can be widely applied in omics to concurrently access various bio-transformed known and un-known markers or drugs.

The Impact of Various Anti-Osteoporosis Drugs on All-Cause Mortality After Hip Fractures: A Nationwide Population Study.

Anti-osteoporosis treatment following hip fractures may reduce the overall mortality rate. However, the effects of different drugs on mortality is still unclear. This population-based cohort study aimed to identify the degree of reduced mortality after various anti-osteoporosis regimens following hip fracture surgery. We conducted this cohort study to identify patients with newly diagnosed osteoporosis and hip fractures from 2009 to 2017 using the Taiwan National Health Insurance Research Database (NHIRD). The subsequent use of anti-osteoporosis medication following hip fracture surgery was collected and analyzed. National death registration records were retrieved to determine mortality. A total of 45,226 new cases of osteoporotic hip fracture were identified. Compared with patients who did not receive further treatment, patients who had ever used oral bisphosphonates (alendronate and risedronate, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.78-0.84), ibandronate (HR 0.76; 95% CI, 0.67-0.86), zoledronic acid (HR 0.70; 95% CI, 0.64-0.76), and denosumab (HR 0.64; 95% CI, 0.60-0.68) showed lower all-cause mortality rates. Patients treated with bisphosphonates had a lower mortality risk than those treated with selective estrogen receptor modulators (HR 0.81; 95% CI, 0.75-0.87). Patients treated with zoledronic acid showed a lower mortality risk than those treated with oral bisphosphonates (HR 0.89; 95% CI, 0.82-0.97). However, patients receiving denosumab and zoledronic acid did not show a significant difference in mortality (HR 0.94; 95% CI, 0.85-1.03). Different anti-osteoporosis treatments for postsurgical patients were associated with different levels of decline in mortality. Generally, longer durations of drug use were associated with lower mortality. © 2022 American Society for Bone and Mineral Research (ASBMR).

Multiple in-hospital counseling increases six-month smoking abstinence among individuals participating in a hospital-initiated smoking cessation program.

BACKGROUND: A cessation program for hospitalized smokers is an effective strategy to achieve smoking abstinence. The effects of multiple in-hospital counseling sessions on 6-month smoking abstinence require further investigation. METHODS: We retrospectively analyzed the data of smokers who participated in hospital-initiated cessation programs at a medical center between 2017 and 2019. Data on age, sex, comorbidities, daily number of cigarettes, cessation motivation, nicotine dependence, cessation medications, discharge diagnosis, length of hospitalization, and intensive care unit admission were collected. We conducted multiple logistic regression analysis to investigate the effect of multiple in-hospital counseling sessions on 6-month sustained smoking abstinence. Sensitivity analyses were carried out excluding participants who underwent post-discharge cessation programs and assuming that the loss to follow-up participants had failure in 6-month smoking abstinence. RESULTS: A total of 1943 participants aged ≥ 20 years were analyzed. Compared with single in-hospital counseling session, the adjusted odds ratios (ORs) for 2 and ≥ 3 counseling sessions were 1.44 (95% confidence interval [CI] 1.05 to 1.98) and 2.02 (95% CI 1.27 to 3.22), respectively, with a significant trend for increasing the number of counseling sessions (P < 0.001). The results remained significant after excluding participants who underwent a post-discharge cessation program or when assuming that lost to follow-up participants had failure in smoking abstinence. CONCLUSION: Multiple in-hospital counseling sessions were associated with a higher 6-month sustained smoking abstinence rate. This strategy could be used to reduce the prevalence of smoking.

The association between osteoporosis medications and lowered all-cause mortality after hip or vertebral fracture in older and oldest-old adults: a nationwide population-based study.

BACKGROUND: Osteoporotic fracture is a common public-health problem in ageing societies. Although post-fracture usage of osteoporosis medications may reduce mortality, recent results have been inconsistent. We aimed to examine associations between osteoporosis medication and mortality in older adults, particularly oldest-old adults (>=85 years old). METHODS: Participants aged 65 years old and older newly diagnosed with both osteoporosis and hip or vertebral fractures within 2009-2017 were recruited from the records of 23,455,164 people in Taiwan National Health Insurance Research Database (NHIRD). Osteoporosis medication exposure was calculated after the first-time ambulatory visit with newly diagnosed osteoporosis. Mortality and its specific causes were ascertained from Cause of Death Data. Patients were followed until death or censored at the end of 2018. RESULTS: A total of 87,935 participants aged 65 years old and over (73.4% female), with a mean 4.13 follow-up years, were included. Taking medication was associated with significantly lower risk of mortality (hip fracture HR 0.75, vertebral fracture HR 0.74), even in the oldest-old adults (hip fracture HR 0.76, vertebral fracture HR 0.72), where a longer duration of taking osteoporosis medication was associated with lower all-cause mortality. Specific causes of mortality were also significantly lower for participants taking osteoporosis medication (cancer HR 0.84 in hip fracture, 0.75 in vertebral fracture; cardiovascular disease HR 0.85 in hip fracture, 0.91 in vertebral fracture). CONCLUSIONS: Osteoporosis medication after hip or vertebral fracture may reduce mortality risk in older adults, notably in oldest-old adults. Encouraging the use of post-fracture osteoporosis medication in healthcare policies is warranted.

Treatment of osteoporosis after hip fracture is associated with lower all-cause mortality: A nationwide population study.

PURPOSE: Mortality after osteoporotic hip fractures is high. Postoperative care is as important as surgery itself to prevent a second fracture and improve outcomes, and the effect of anti-osteoporosis treatment after hip fractures on overall mortality is controversial. This nationwide population study aimed to determine whether anti-osteoporosis treatment might reduce overall mortality after hip fracture surgery. METHODS: We conducted this cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan to identify patients admitted for surgery due to hip fractures from 2008 to 2018. The subsequent use and duration of anti-osteoporotic medication and other parameters were analyzed, and national death registration records were retrieved to investigate mortality. RESULTS: A total of 59,943 patients admitted for hip fracture surgery were identified. The 22,494 patients (37.5%) who received anti-osteoporotic medication showed a lower all-cause mortality rate compared with the 37,449 patients (62.5%) who did not receive further treatment (hazard ratio (HR): 0.69, 95% confidence interval (CI): 0.67-0.70, p < 0.0001). Patients who received anti-osteoporotic medication for more than 1, 2, and 3 years exhibited propotional reductions in all-cause mortality (HR & 95%CI: 0.57 (0.54-0.60), 0.42 (0.38-0.46), and 0.29 (0.26-0.33) respectively). CONCLUSION: Anti-osteoporosis treatment was associated with lower all-cause mortality after hip fracture surgery. A longer duration of treatment was also associated with lower mortality. Postoperative treatment for osteoporosis is crucial for patients with hip fracture.

The Pathophysiologic Role of Gelsolin in Chronic Kidney Disease: Focus on Podocytes.

Chronic kidney disease (CKD) is normally related to proteinuria, a common finding in a compromised glomerular filtration barrier (GFB). GFB is a structure composed of glomerular endothelial cells, the basement membrane, and the podocytes. CKD with podocyte damage may be associated with actin cytoskeleton reorganization, resulting in podocyte effacement. Gelsolin plays a critical role in several diseases, including cardiovascular diseases and cancer. Our current study aimed to determine the connection between gelsolin and podocyte, and thus the mechanism underlying podocyte injury in CKD. Experiments were carried out on Drosophila to demonstrate whether gelsolin had a physiological role in maintaining podocyte. Furthermore, the survival rate of gelsolin-knocked down Drosophila larvae was extensively reduced after AgNO3 exposure. Secondly, the in vitro podocytes treated with puromycin aminonucleoside (PAN) enhanced the gelsolin protein expression, as well as small GTPase RhoA and Rac1, which also regulated actin dynamic expression incrementally with the PAN concentrations. Thirdly, we further demonstrated in vivo that GSN was highly expressed inside the glomeruli with mitochondrial dysfunction in a CKD mouse model. Our findings suggest that an excess of gelsolin may contribute to podocytes damage in glomeruli.

Quantification of the Endogenous Adduction Level on Hemoglobin and Correlation with Albumin Adduction via Proteomics: Multiple Exposure Markers of Catechol Estrogen.

Catechol estrogens (CEs) are genotoxic metabolites whose detection is challenging due to their low concentrations and high variability in the blood. By intact protein and free CE measurement of the spiked hemolysate, endogenous CEs were revealed to mainly (>99%) exist as hemoglobin (Hb) adducts in red blood cells. In order to detect endogenous CE-Hb adducts, we developed a two-step method that involved protein precipitation and solid phase extraction to purify Hb from red blood cells, and the method was coupled with proteomics using liquid chromatography-tandem mass spectrometry. Using bottom-up proteomics and standard additions, we identified C93 and C112 of Hb-ß as the main adduction sites of Hb, and this accounted for CE-induced oxidization of adducted peptides by sample preparation. The non-adducted, adducted, and oxidized tryptic peptides that covered the same Hb-ß sequences were targeted by parallel reaction monitoring to determine the adduction level in red blood cells. A quantification limit (S/N < 8) below the endogenous CE-Hb adduction level with relative standard errors that ranged from 5 to 22% was achieved and applied to clinical samples. The human serum albumin (HSA) adduction levels from the same patient were also determined using a previously developed method (Anal. Chem.2019,91, 15922-15931). A positive correlation (R2 = 0.673) between the CE-HSA and CE-Hb adduction level was obtained from all clinical samples, and both levels were significantly (p < 0.005) higher for patients with breast cancer compared to healthy controls. However, double indexes derived from the red blood cell and the serum, respectively, provide higher precision and confidence in predicting cancer risk than the single index. This study reported an efficient sample preparation for proteomics-based Hb adducts and revealed the potential of using multiple blood proteins for developing more reliable and specific markers based on protein adductomics.

IL-20 is involved in obesity by modulation of adipogenesis and macrophage dysregulation.

IL-20 is a proinflammatory cytokine of the IL-10 family and involved in several diseases. However, the regulatory role of IL-20 in obesity is not well understood. We explored the function of IL-20 in the pathogenesis of obesity-induced insulin resistance by ELISA, Western blotting and flow cytometry. The therapeutic potential of IL-20 monoclonal antibody 7E for ameliorating diet-induced obesity was analysed in murine models. Higher serum IL-20 levels were detected in obese patients. It was upregulated in leptin-deficient (ob/ob), leptin-resistant (db/db) and high-fat diet (HFD)-induced murine obesity models. In vitro, IL-20 regulated the adipocyte differentiation and the polarization of bone marrow-derived macrophages into proinflammatory M1 type. It also caused inflammation and macrophage retention in adipose tissues by upregulating TNF-α, monocyte chemotactic protein 1 (MCP-1), netrin 1 and unc5b (netrin receptor) expression in macrophages and netrin 1, leptin and MCP-1 in adipocytes. IL-20 promoted insulin resistance by inhibiting glucose uptake in mature adipocytes through the SOCS-3 pathway. In HFD-induced obesity in mice, 7E treatment reduced body weight and improved glucose tolerance and insulin sensitivity; it also reduced local inflammation and the number of M1-like macrophages in adipose tissues. We have identified a critical role of IL-20 in obesity-induced inflammation and insulin resistance, and we conclude that IL-20 may be a novel target for treating obesity and insulin resistance in patients with metabolic disorders.

No association between alcohol consumption and pancreatic cancer even among individuals genetically susceptible to the carcinogenicity of alcohol.

Inconsistent results have been reported for the association between alcohol use and pancreatic cancer, particularly at low levels of alcohol consumption. Individuals genetically susceptible to the carcinogenic effect of alcohol might have higher pancreatic cancer risk after drinking alcohol. The current study investigated the association between alcohol use and pancreatic cancer with 419 pancreatic cancer cases and 963 controls recruited by a hospital-based case-control study in Taiwan. Gene-environment interaction between alcohol use and polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2, on pancreatic risk was evaluated. Our results showed no significant association between alcohol drinking and an increased pancreatic cancer risk, even at high levels of alcohol consumption. Even among those genetically susceptible to the carcinogenic effect of alcohol (carriers of ADH1B*2/*2(fast activity) combined with ALDH2*1/*2(slow activity) or ALDH2*2/*2(almost non-functional)), no significant association between alcohol use and pancreatic cancer was observed. Overall, our results suggested that alcohol drinking is not a significant contributor to the occurrence of pancreatic cancer in Taiwan.

Systematic review and meta-analysis of lean mass and mortality: Rationale and study description.

OBJECTIVES: Muscle mass is one of the key components in defining sarcopenia and is known to be important for locomotion and body homeostasis. Lean mass is commonly used as a surrogate of muscle mass and has been shown to be associated with increased mortality. However, the relationship of lean mass with mortality may be affected by different clinical conditions, modalities used, cut-off point to define low or normal lean mass, and even types of cancer among cancer patients. Thus, we aim to perform a comprehensive meta-analysis of lean mass with mortality by considering all these factors. METHODS: Systematic search was done in PubMed, Cochrane Library and Embase for articles related to lean mass and mortality. Lean mass measured by dual X-ray absorptiometry, bioelectrical impedance analysis, and computerized tomography were included. RESULTS: The number of relevant studies has increased continuously since 2002. A total of 188 studies with 98 468 people were included in the meta-analysis. The association of lean mass with mortality was most studied in cancer patients, followed by people with renal diseases, liver diseases, elderly, people with cardiovascular disease, lung diseases, and other diseases. The meta-analysis can be further conducted in subgroups based on measurement modalities, site of measurements, definition of low lean mass adopted, and types of cancer for studies conducted in cancer patients. CONCLUSIONS: This series of meta-analysis provided insight and evidence on the relationship between lean mass and mortality in all directions, which may be useful for further study and guideline development.

Sarcopenia and mortality in cancer: A meta-analysis.

OBJECTIVES: The aim of this meta-analysis is to comprehensively evaluate the effects of lean mass on all-cause mortality across different cancer types. METHODS: This is a meta-analysis. Cohort studies on lean mass and mortality published before December 20, 2017 were obtained by systematic search on PubMed, Cochrane Library, and Embase. Inclusion criteria were cohort studies reporting lean mass measurements by dual-energy X-ray absorptiometry, bioimpedance analysis or computed tomography, and with all-cause mortality as the study outcome. Exclusion criteria were studies using muscle mass surrogates, anthropometric measurement of muscle, rate of change in muscle mass, and sarcopenia defined by composite criteria. Hazard ratios (HRs) and 95% confidence intervals (CIs) of low/reduced lean mass on cancer mortality were pooled with a random-effects model. Subgroup analysis stratifying studies according to cancer type and measurement index was performed. RESULTS: Altogether 100 studies evaluated the association between lean mass and cancer mortality. The overall pooled HR on cancer mortality was 1.41 (95% CI, 1.24 to 1.59) for every standard deviation decrease in lean mass and 1.69 (95% CI, 1.56 to 1.83) for patients with sarcopenia (binary cutoffs). Overall mortality was also significantly associated with sarcopenia in across various cancer types, except for hematopoietic, breast, ovarian and endometrial, and prostate cancer. CONCLUSIONS: The robust association of decreased lean mass with increased mortality further justified the importance of developing clinical guidelines for managing sarcopenia in cancer patients. Public health initiatives aiming at promoting awareness of muscle health in susceptible individuals are urgently needed.

Different definition of sarcopenia and mortality in cancer: A meta-analysis.

OBJECTIVES: Sarcopenia has been an emerging theme in clinical oncology. Various definitions of sarcopenia have been proposed, but their prognostic performance have yet to be evaluated and compared. The aim of this meta-analysis is to comprehensively evaluate the performance of different cutoff definitions of sarcopenia in cancer mortality prognostication. METHODS: This is a meta-analysis. Cohort studies on lean mass and mortality published before December 20, 2017 were obtained by systematic search on PubMed, Cochrane Library, and Embase. Inclusion criteria were cohort studies reporting binary lean mass categorized according to clearly defined cutoffs, and with all-cause mortality as study outcome. Studies were stratified according to the cutoff(s) used in defining low lean mass. The cutoff-specific hazard ratios (HRs) and 95% confidence intervals (CIs) of low lean mass on cancer mortality were pooled with a random-effects model and compared. RESULTS: Altogether 81 studies that studied binary lean mass were included. The pooled HRs on cancer mortality using the 3 most used definitions were: 1.74 (95% CI, 1.46-2.07) using the definition proposed by International Consensus of Cancer Cachexia, 1.45 (95% CI, 1.21-1.75) using that by Martin, and 1.58 (95% CI, 1.35-1.84) using that by Prado. The associations between sarcopenia and cancer mortality using other definitions were all statistically significant, despite different estimates were observed. CONCLUSIONS: The association of low lean mass with increased mortality was consistent across different definitions; this provides further evidence on the poorer survival in cancer patients with sarcopenia. However, further studies evaluating the performance of each definition are warranted.

Disease-related disability burden: a comparison of seven chronic conditions in middle-aged and older adults.

BACKGROUND: Although previous studies have explored the effect of chronic conditions on physical disability, little is known about the levels and rates of change in physical disability after a chronic condition diagnosis in middle-aged and older adults in the Asian population. The aim of this study is to ascertain the average levels and rates of change in the development of disability after disease diagnosis, as well as to determine the influences of sociodemographic and health-related correlates in the development of disability. METHODS: This is a retrospective cohort study analyzing data of nationally representative participants aged 50 and over with a chronic condition or having developed one during follow-ups based on data from the 1996-2011 Taiwan Longitudinal Study on Aging (TLSA) (n = 5131). Seven chronic conditions were examined. Covariates included age at initial diagnosis, gender, education level, number of comorbidities, and depression status. Physical disability was measured by combining self-reported ADL, IADL, and strength and mobility activities with 17 total possible points, further analyzed with multilevel modeling. RESULTS: The results showed that (1) physical disability was highest for stroke, followed by cancer and diabetes at the time of the initial disease diagnosis. (2) The linear rate of change was highest for stroke, followed by lung disease and heart disease, indicating that these diseases led to higher steady increases in physical disability after the disease diagnosis. (3) The quadratic rate of change was highest in diabetes, followed by cancer and hypertension, indicating that these diseases had led to higher increments of physical disability in later stage disease. After controlling for sociodemographic and comorbidity, depression status accounted for 39.9-73.6% and 37.9-100% of the variances in the physical disability intercept and change over time, respectively. CONCLUSIONS: Despite the fact that a comparison across conditions was not statistically tested, an accelerated increase in physical disabilities was found as chronic conditions progressed. While stroke and cancer lead to disability immediately, conditions such as diabetes, cancer, and hypertension give rise to higher increments of physical disability in later stage disease. Mitigating depressive symptoms may be beneficial in terms of preventing disability development in this population.

Inhibitory effect of PPARγ on NLRP3 inflammasome activation.

Rationale: Stimulation of the NLRP3 inflammasome by metabolic byproducts is known to result in inflammatory responses and metabolic diseases. However, how the host controls aberrant NLRP3 inflammasome activation remains unclear. PPARγ, a known regulator of energy metabolism, plays an anti-inflammatory role through the inhibition of NF-κB activation and additionally attenuates NLRP3-dependent IL-1ß and IL-18 production. Therefore, we hypothesized that PPARγ serves as an endogenous modulator that attenuates NLRP3 inflammasome activation in macrophages. Methods: Mouse peritoneal macrophages with exposure to a PPARγ agonist at different stages and the NLRP3 inflammasome-reconstituted system in HEK293T cells were used to investigate the additional anti-inflammatory effect of PPARγ on NLRP3 inflammasome regulation. Circulating mononuclear cells of obese patients with weight-loss surgery were used to identify the in vivo correlation between PPARγ and the NLRP3 inflammasome. Results: Exposure to the PPARγ agonist, rosiglitazone, during the second signal of NLRP3 inflammasome activation attenuated caspase-1 and IL-1ß maturation. Moreover, PPARγ interfered with NLRP3 inflammasome formation by decreasing NLRP3-ASC and NLRP3-NLRP3 interactions as well as NLRP3-dependent ASC oligomerization, which is mediated through interaction between the PPARγ DNA-binding domain and the nucleotide-binding and leucine-rich repeat domains of NLRP3. Furthermore, PPARγ was required to limit metabolic damage-associated molecular pattern-induced NLRP3 inflammasome activation in mouse macrophages. Finally, the mature caspase-1/PPARγ ratio was reduced in circulating mononuclear cells of obese patients after weight-loss surgery, which we define as an "NLRP3 accelerating index". Conclusions: These results revealed an additional anti-inflammatory role for PPARγ in suppressing NLRP3 inflammasome activation through interaction with NLRP3. Thus, our study highlights that PPARγ agonism may be a therapeutic option for targeting NLRP3-related metabolic diseases.

Validation of genome-wide association study-identified single nucleotide polymorphisms in a case-control study of pancreatic cancer from Taiwan.

BACKGROUND: Due to differences in genetic background, it is unclear whether the genetic loci identified by the previous genome-wide association studies (GWAS) of pancreatic cancer also play significant roles in the development of pancreatic cancer among the Taiwanese population. METHODS: This study aimed to validate the 25 pancreatic cancer GWAS-identified single nucleotide polymorphisms (SNPs) in a case-control study (278 cases and 658 controls) of pancreatic cancer conducted in Taiwan. Statistical analyses were conducted to determine the associations between the GWAS-identified SNPs and pancreatic cancer risk. Gene-environment interaction analysis was conducted to evaluate the interactions between SNPs and environmental factors on pancreatic cancer risk. RESULTS: Among the 25 GWAS-identified SNPs, 7 (rs2816938 (~ 11 kb upstream of NR5A2), rs10094872 (~ 28 kb upstream of MYC), rs9581943 (200 bp upstream of PDX1) and 4 chromosome 13q22.1 SNPs: rs4885093, rs9573163, rs9543325, rs9573166) showed a statistically significant association with pancreatic cancer risk in the current study. Additional analyses showed two significant gene-environment interactions (between poor oral hygiene and NR5A2 rs2816938 and between obesity and PDX1 rs9581943) on the risk of pancreatic cancer. CONCLUSIONS: The current study confirmed the associations between 7 of the 25 GWAS-identified SNPs and pancreatic risk among the Taiwanese population. Furthermore, pancreatic cancer was jointly influenced by lifestyle and medical factors, genetic polymorphisms, and gene-environment interaction. Additional GWAS is needed to determine the genetic polymorphisms that are more relevant to the pancreatic cancer cases occurring in Taiwan.

Sex differences in fracture outcomes within Taiwan population: A nationwide matched study.

BACKGROUND AND AIMS: Because the sex difference in outcomes of fracture was incompletely understood, we evaluated the post-fracture complications and mortality of female and male patients. METHODS: We conducted a nationwide study of 498,586 fracture patients who received inpatient care using Taiwan's National Health Insurance Research Database 2008-2013 claims data. Female and male fracture patients were selected for comparison by using a propensity-score matching procedure. Age, low income, types of fracture, fracture with surgery, several medical conditions, number of hospitalization and emergency visits were considered as potential confounding factors. Multivariate logistic regressions were used to calculate the adjusted odds ratios (OR), the 95% CI of post-fracture complications and 30-day in-hospital mortality differences between women and men. RESULTS: Male patients had a higher risk of post-fracture pneumonia (OR 1.96, 95% CI 1.83-2.11), acute renal failure (OR 1.85, 95% CI 1.60-2.15), deep wound infection (OR 1.63, 95% CI 1.51-1.77), stroke (OR 1.58, 95% CI 1.49-1.67), septicemia (OR 1.51, 95% CI 1.42-1.61), acute myocardial infarction (OR 1.38, 95% CI 1.09-1.75) and 30-day in-hospital mortality (OR 1.69, 95% CI 1.48-1.93) compared with female patients. However, a lower risk of post-fracture urinary tract infection (OR 0.69, 95% CI 0.65-0.72) was found in men than in women. Male patients also had longer hospital stays and higher medical expenditures due to fracture admission than did the female patients. Higher rates of post-fracture adverse events in male patients were noted in all age groups and all types of fractures. CONCLUSION: We raised the possibility that male patients showed more complications and higher mortality rates after fracture admission compared with female patients, with the exception of urinary tract infections.