Uncovering the roles of Mycobacterium tuberculosis melH in redox and bioenergetic homeostasis: implications for antitubercular therapy.

Mycobacterium tuberculosis (Mtb), the pathogenic bacterium that causes tuberculosis, has evolved sophisticated defense mechanisms to counteract the cytotoxicity of reactive oxygen species (ROS) generated within host macrophages during infection. The melH gene in Mtb and Mycobacterium marinum (Mm) plays a crucial role in defense mechanisms against ROS generated during infection. We demonstrate that melH encodes an epoxide hydrolase and contributes to ROS detoxification. Deletion of melH in Mm resulted in a mutant with increased sensitivity to oxidative stress, increased accumulation of aldehyde species, and decreased production of mycothiol and ergothioneine. This heightened vulnerability is attributed to the increased expression of whiB3, a universal stress sensor. The absence of melH also resulted in reduced intracellular levels of NAD+, NADH, and ATP. Bacterial growth was impaired, even in the absence of external stressors, and the impairment was carbon source dependent. Initial MelH substrate specificity studies demonstrate a preference for epoxides with a single aromatic substituent. Taken together, these results highlight the role of melH in mycobacterial bioenergetic metabolism and provide new insights into the complex interplay between redox homeostasis and generation of reactive aldehyde species in mycobacteria. IMPORTANCE: This study unveils the pivotal role played by the melH gene in Mycobacterium tuberculosis and in Mycobacterium marinum in combatting the detrimental impact of oxidative conditions during infection. This investigation revealed notable alterations in the level of cytokinin-associated aldehyde, para-hydroxybenzaldehyde, as well as the redox buffer ergothioneine, upon deletion of melH. Moreover, changes in crucial cofactors responsible for electron transfer highlighted melH's crucial function in maintaining a delicate equilibrium of redox and bioenergetic processes. MelH prefers epoxide small substrates with a phenyl substituted substrate. These findings collectively emphasize the potential of melH as an attractive target for the development of novel antitubercular therapies that sensitize mycobacteria to host stress, offering new avenues for combating tuberculosis.

Corrigendum: Safety assessment of poly-ε-caprolactone in the treatment of primary spontaneous pneumothorax.

[This corrects the article DOI: 10.3389/fsurg.2024.1335144.].

Safety assessment of poly-ε-caprolactone in the treatment of primary spontaneous pneumothorax.

Background/purpose: Biomaterial-based implants are gaining traction as an option for pleurodesis treatment, yet the search for the best biomaterial or the most suitable shape to handle spontaneous pneumothorax continues. This forward-looking research assessed the use of a poly-ε-caprolactone membrane for its safety when applied as a sclerosant in pleurodesis procedures in human patients. Methods: From July 2017 to February 2018, we conducted a Phase I trial in which 10 patients with primary spontaneous pneumothorax were treated using video-assisted thoracoscopic surgery with a poly-ε-caprolactone membrane. These procedures encompassed bleb resection and mechanical pleurodesis through parietal pleura scrubbing. After resection, a 150 × 150 mm poly-ε-caprolactone membrane was applied to the apex. The primary outcome measures were the adverse events and laboratory outcomes. Results: After surgery, we observed no cardiopulmonary-related adverse events or indications of systemic inflammation. Furthermore, no episodes of hypothermia or hyperthermia occurred. Chest radiographs showed no evident pneumonitis or effusion associated with tissue reactions. The average follow-up duration was 31.7 ± 17.7 months, during which two patients exhibited recurrence. Conclusion: This study is the first to show the biocompatibility of poly-ε-caprolactone in humans, suggesting its potential as a treatment option for patients with primary spontaneous pneumothorax. Despite the relatively small number of patients, we maintain confidence in the reliability and safety profile of the PCL membrane, bolstered by its previously established efficacy in applications involving other organs. Phase II and phase III clinical studies are needed to support these observations.

Mechanical and biological properties of poly-ε-caprolactone membrane for pleurodesis: A preclinical study in pigs.

BACKGROUND/PURPOSE: Biomaterial implants are emerging as a treatment choice for pleurodesis; however, the optimal biomaterial and form for managing spontaneous pneumothorax, particularly post-video-assisted thoracic surgery, remain under investigation. This study evaluated the mechanical and biological properties of the poly-ε-caprolactone (PCL) membrane as a sclerosing agent for pleurodesis in Landrace pigs. METHODS: Twenty-four Landrace pigs were split into two groups for mechanical abrasion and PCL membrane pleurodesis, with the latter group's PCL meshes inserted using video-assisted thoracic surgery. The mechanical and biological properties of the PCL membrane were assessed in pigs at three, six, and 12 months after the procedure. This assessment involved a range of techniques, such as the T-Peel test, macroscopic evaluation with a scoring scale, microscopic examination, and biomechanical and molecular weight analysis. RESULTS: The PCL membrane group outperformed the traditional abrasion group, with stronger adhesions seen over longer implantation durations. This group also showed superior and more consistent results in both macroscopic and microscopic evaluations compared to the control group. The membrane-based method was easier and faster to perform than the control group's method, and importantly, no mortality occurred following membrane implantation. CONCLUSION: This study is the pioneering effort to present long-term findings regarding the mechanical and biological properties of the PCL membrane in an in vivo animal model. The membrane demonstrated better adhesion ability than that of traditional abrasion and showed reassuring biocompatibility in both the pig model, suggesting its potential as treatment for patients with primary spontaneous pneumothorax. Further clinical studies are needed to support these observations.

Coating-Free Culture Medium for Establishing and Maintaining Human Induced Pluripotent Stem Cells.

Cell expansion of human pluripotent stem cells (hPSCs) commonly depends on Matrigel as a coating matrix on two-dimensional (2D) culture plates and 3D microcarriers. However, the xenogenic Matrigel requires sophisticated quality-assurance processes to meet clinical requirements. In this study, we develop an innovative coating-free medium for expanding hPSCs. The xenofree medium supports the weekend-free culture and competitive growth of hPSCs on several cell culture plastics without an additional pre-coating process. The pluripotent stemness of the expanded cells is stably sustained for more than 10 passages, featured with high pluripotent marker expressions, normal karyotyping, and differentiating capacity for three germ layers. The expression levels of some integrins are reduced, compared with those of the hPSCs on Matrigel. This medium also successfully supports the clonal expansion and induced pluripotent stem cell establishment from mitochondrial-defective MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) patient's peripheral blood mononuclear cells. This innovative hPSC medium provides a straightforward scale-up process for producing clinical-orientated hPSCs by excluding the conventional coating procedure.

Reproductive outcomes of cesarean scar pregnancies treated with uterine artery embolization combined with curettage.

OBJECTIVE: The aim of this study was to review the reproductive outcomes of women with a cesarean scar pregnancy (CSP) treated with dilation and curettage (D&C) after uterine artery embolization (UAE). MATERIALS AND METHODS: This was a retrospective study to review women who received UAE followed by D&C for CSP between January 2010 and December 2019 at the Changhua Christian Hospital, Changhua in Taiwan. Data were collected from both electronic and paper medical records. Patients were contact via phone call to follow up reproductive outcomes between January 2021 and March 2021. These subsequent reproductive outcomes (including pregnancy rate, secondary infertility rate, miscarriage rate, live birth rate, and recurrent CSP rate) were recorded and analyzed. RESULTS: A total of 53 cases of women who received UAE followed by D&C for CSP were identified. The women's average age was 34.8 ± 5.1 years. The mean gestational age at diagnosis was 6.2 ± 1.1 weeks. The mean level for human chorionic gonadotropin was 23,407.7 ± 29,105.5 mIU/ml. The average of blood loss during D&C was 19.2 ± 43.6 ml. The average hospitalization time after D&C was 3.5 ± 1.1 days. Of the 53 cases, 10 patients were lost to follow-up and 43 patients agreed to follow-up on reproductive outcomes in 2021. Twenty-three patients who desired to conceive were analyzed. Nineteen out of these 23 women (82.6%) succeeded in conceiving again and gave birth to 15 healthy babies (78.9%). Only one woman (1/19, 5.3%) experienced recurrence of CSP. The average time interval between previous CSP treatment and subsequent conception was 10.4 ± 6.7 months. CONCLUSION: UAE combined with curettage treatment in CSP patients results in a positive rate of subsequent pregnancy outcomes. This minimally invasive procedure may be considered as one of the treatment options for CSP, as it enables preservation of fertility after treatment.

Prognostic Role of Subsequent Thrombocytopenia in Necrotizing Fasciitis Without Liver Disease.

BACKGROUND: Necrotizing fasciitis (NF) is a life-threatening disease with a fulminant presentation. Although early diagnosis can be aided by combining physical examination, the Laboratory Risk Indicator for Necrotizing Fasciitis score, and computed tomography, a mortality rate of 30% is still reported. In the modern times, an economical and efficient biomarker for predicting mortality in NF patients is still lacking. Platelet count is typically measured in routine blood tests and aids in predicting disease severity. We aimed to clarify the role of platelet count as a predictive factor for aspects of prognosis, such as mortality and surgical outcomes, in patients with NF. METHODS: We identified 285 patients with NF between 2018 and 2020 in a single medical center in southern Taiwan. Medical records were collected for the evaluation of patients with thrombocytopenia. Univariate and multivariate analyses were performed for different outcomes. RESULTS: We included 115 patients with confirmed diagnoses of NF. Twelve patients died with a mortality rate of 10.4%. Patients with thrombocytopenia exhibited a higher mortality rate (20.9% vs 4.2%, P = 0.006), more shock episodes (51.2% vs 11.1%, P < 0.001), higher intensive care unit admission rate (46.5% vs 13.9%, P < 0.001), and longer hospital length of stay (37.49 ± 24.12 days vs 28.82 ± 14.63 days, P = 0.037) than those without thrombocytopenia. All patients infected with Vibrio species exhibited thrombocytopenia. In multivariate analysis, independent risk factors for mortality were thrombocytopenia (odds ratio, 4.57; 95% confidence interval, 1.08-19.25) and single gram-negative bacterial culture from the wound (odds ratio 6.88; 95% confidence interval, 1.58-29.96). CONCLUSIONS: In patients with NF and subsequent thrombocytopenia, a higher mortality rate, greater numbers of shock episodes, higher demand for intensive care unit, and longer hospital length of stay were observed than in those without thrombocytopenia. In patients with NF, platelet count is a valuable and economic indicator of prognosis. Once thrombocytopenia developed in patients with necrotizing fasciitis, aggressive antibiotic treatment and surgical management are required to improve the chances of recovery.

Prognostic factors and population-based analysis of melanoma with sentinel lymph node biopsy.

Cutaneous malignant melanoma is a rare but fatal disease in East Asia. Despite its increasing incidence, a general lack of awareness about the disease was noted. This study aims to provide population-based prognostic analysis of melanoma with sentinel lymph node biopsy (SLNB) in Taiwan. We conducted this retrospective cohort study using the data from Taiwan National Health Insurance Research Database during 1997-2013. The study cohort contains 3284 patients. The 5-year survival rates of patients undergoing SLNB and not undergoing SLNB were 45.5% and 33.6%. In multivariate analysis, age ≥ 80 years [adjusted hazard ratio (aHR) = 2.15] and male (aHR = 1.19) were associated with a poorer prognosis, while high social economic status (SES) (aHR = 0.69) and undergoing SLNB (aHR = 0.84) were good prognostic factors. Old age and low SES were associated with lower percentages of patients undergoing SLNB (P < 0.001). E-value analysis suggested robustness to unmeasured confounding. In conclusion, undergoing SLNB was associated with a better prognosis. The poor prognosis of old age and low SES may be due to decreased percentages of patients undergoing SLNB. Therefore, we recommend that SLNB should be performed on patients, especially in old age or low SES, who are candidates for SLNB according to current guidelines to achieve maximal survival.

Tumor location on MRI determines outcomes of patients with prostate cancer after total prostate cryoablation.

We investigated the association between tumor location on multiparametric magnetic resonance imaging (mpMRI) and outcomes of prostate cancer patients after primary total prostate cryoablation (PTPC). Between March 2010 and December 2012, consecutive 192 prostate cancer patients receiving PTPC were enrolled. Tumor locations were determined and classified as anterior apex (AA), anterior midgland (AM), anterior base (AB), posterior apex (PA), posterior midgland (PM) and posterior base (PB) using mpMRI. Midline location, central location, seminal vesicle invasion, extraprostatic extension, multiple tumors, and tumor volume were also identified. Prostate local recurrence and biochemical failure were considered as primary and secondary endpoints, respectively. Tumors on mpMRI were identified in 148 (77.1%) patients. Tumor locations were most frequently noted in PM (89, 46.4%), followed by AM (55, 28.6%), PB (53, 27.6%), PA (46, 24%), AA (35, 18.2%) and AB (31, 16.1%). Midline and central tumors were observed in 34 (17.7%) and 14 (7.3%) patients, respectively. During a median follow-up duration of 81 months (range, 2-114 months), 71 (37.0%) and 29 (40.8%) patients experienced biochemical failure and local recurrence, respectively. Multivariable analyses revealed only AA tumors increased the risk of local recurrences (HR = 2.98, 95% CI. 1.36-6.49). None of location-related parameters was associated with biochemical failure. Tumor location on mpMRI has a significant association with local tumor recurrence in patients receiving PTPC. Physicians should be cautious when conducting cryoablation for prostate tumors in AA location.

Early detection of breast cancer rectifies inequality of breast cancer outcomes.

OBJECTIVES: To explain apparent differences among mammography screening services in Sweden using individual data on participation in screening and with breast cancer-specific survival as an outcome. METHODS: We analysed breast cancer survival data from the Swedish Cancer Register on breast cancer cases from nine Swedish counties diagnosed in women eligible for screening. Data were available on 38,278 breast cancers diagnosed and 4312 breast cancer deaths. Survival to death from breast cancer was estimated using the Kaplan-Meier estimate, for all cases in each county, and separately for cases of women participating and not participating in their last invitation to screening. Formal statistical comparisons of survival were made using proportional hazards regression. RESULTS: All counties showed a reduction in the hazard of breast cancer death with participation in screening, but the reductions for individual counties varied substantially, ranging from 51% (95% confidence interval 46-55%) to 81% (95% confidence interval 74-85%). Survival rates in nonparticipating women ranged from 53% (95% confidence interval 40-65%) to 74% (95% confidence interval 72-77%), while the corresponding survival in women participating in screening varied from 80% (95% confidence interval 77-84%) to 86% (95% confidence interval 83-88%), a considerably narrower range. CONCLUSIONS: Differences among counties in the effect of screening on breast cancer outcomes were mainly due to variation in survival in women not participating in screening. Screening conferred similarly high survival rates in all counties. This indicates that the performance of screening services was similar across counties and that detection and treatment of breast cancer in early-stage reduces inequalities in breast cancer outcome.

Mammography screening reduces rates of advanced and fatal breast cancers: Results in 549,091 women.

BACKGROUND: It is of paramount importance to evaluate the impact of participation in organized mammography service screening independently from changes in breast cancer treatment. This can be done by measuring the incidence of fatal breast cancer, which is based on the date of diagnosis and not on the date of death. METHODS: Among 549,091 women, covering approximately 30% of the Swedish screening-eligible population, the authors calculated the incidence rates of 2473 breast cancers that were fatal within 10 years after diagnosis and the incidence rates of 9737 advanced breast cancers. Data regarding each breast cancer diagnosis and the cause and date of death of each breast cancer case were gathered from national Swedish registries. Tumor characteristics were collected from regional cancer centers. Aggregated data concerning invitation and participation were provided by Sectra Medical Systems AB. Incidence rates were analyzed using Poisson regression. RESULTS: Women who participated in mammography screening had a statistically significant 41% reduction in their risk of dying of breast cancer within 10 years (relative risk, 0.59; 95% CI, 0.51-0.68 [P < .001]) and a 25% reduction in the rate of advanced breast cancers (relative risk, 0.75; 95% CI, 0.66-0.84 [P < .001]). CONCLUSIONS: Substantial reductions in the incidence rate of breast cancers that were fatal within 10 years after diagnosis and in the advanced breast cancer rate were found in this contemporaneous comparison of women participating versus those not participating in screening. These benefits appeared to be independent of recent changes in treatment regimens.

Different histopathologic profiles and outcomes between sun-exposed BCC and non-sun-exposed BCC.

Asian population is a low-risk group for basal cell carcinoma (BCC) and there is little data available in this setting. Sun-exposed BCC (SEBCC) may possess a different pathogenic mechanism from non-sun-exposed BCC (NSEBCC). To compare the histopathological profiles and outcomes between SEBCC and NSEBCC, and to assess the risk factors for tumor recurrences. Retrospective cohort study on 372 patients with pathologically diagnosed BCC from January 1, 1990 to August 31, 2017. Data were derived from a single medical center in Taiwan. SEBCC presented with higher Clark level and more high-risk factors for recurrence than NSEBCC. Nodular, micronodular, infiltrating/mixed infiltrating, basosquamous, and adenoid types were predominant in SEBCC, as superficial type in NSEBCC. Risk factors for recurrence included infiltrating/mixed-infiltrating subtypes and synchronous basosquamous cell carcinoma. No recurrence events were observed in NSEBCC. Our study showed an acceptable recurrence rate (4.2%) of the whole population after excision even under a smaller surgical margin width than suggested by current guidelines. SEBCC had a higher recurrence rate with a significantly different tumor characteristic from NSEBCC and a greater tumor depth than NSEBCC. A wider surgical margin in SEBCC than NSEBCC is suggested.

Sorafenib with Transarterial Chemoembolization Achieves Improved Survival vs. Sorafenib Alone in Advanced Hepatocellular Carcinoma: A Nationwide Population-Based Cohort Study.

We hypothesized that sorafenib plus transarterial chemoembolization (TACE) would confer survival benefits over sorafenib alone for advanced hepatocellular carcinoma (aHCC). We investigated this while using the population-based All-Cancer Dataset to assemble a cohort (n = 3674; median age, 60; 83% men) of patients receiving sorafenib for aHCC (Child-Pugh A) with macro-vascular invasion or nodal/distant metastases. The patients were classified into the sorafenib-TACE group (n = 426) or the propensity score-matched sorafenib-alone group (n = 1686). All of the participants were followed up until death or the end of the study. Time-dependent Cox model and the Mantel-Byar test were used for survival analysis. During the median follow-ups of 221 and 133 days for the sorafenib-TACE and sorafenib-alone groups, 164 (39%) and 916 (54%) deaths occurred, respectively; the corresponding median overall survivals (OS) were 381 and 204 days, respectively (hazard ratio, HR: 0.74; 95% confidence interval, CI, 0.63-0.88; p = 0.021). The one-year and six-month OS were 53.5% and 80.3% in the sorafenib-TACE group and 32.4% and 54.4% in the sorafenib-alone group, respectively. The major complications were comparable between the two groups. The addition of TACE to sorafenib improves survival, with a 26% reduction in mortality. These findings provide strong real-world evidence that supports this combination strategy for eligible Child-Pugh A aHCC patients.

Association between blood pressure and postoperative hematomas in the patients undergoing head and neck cancer reconstruction.

BACKGROUND: Postoperative hematoma is one of the most common complications of free flap reconstruction and compromises the perfusion of pedicles and perforators. Therefore, we reviewed our patients to analyze the associated risk factors. METHOD: This study involved a retrospective chart review from 2014 to 2016. We identified the patients undergoing free flap reconstructions for head and neck cancer. Patients with postoperative hematoma requiring surgical intervention were included. RESULT: We enlisted 289 patients undergoing head and neck reconstructions. Eighteen patients (6.2%) had postoperative hematomas of which 12 hematomas occurred within the first 3 days and 9 in the first 24 hours. Elevated systolic blood pressure increased the risk of hematoma formation, but hematoma was not associated with higher failure rate. Tachycardia was observed in the patients with hematoma. CONCLUSIONS: Transient elevated blood pressure increased the risk of hematoma. We suggest controlling systolic blood pressure below 150 mm Hg for prevention of hematoma.

The incidence of fatal breast cancer measures the increased effectiveness of therapy in women participating in mammography screening.

BACKGROUND: Women and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice improve her chances of avoiding a death from breast cancer compared with women who choose not to participate? METHODS: To answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease-specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39-year period (1977-2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958-1976). All patients received stage-specific therapy according to the latest national guidelines, irrespective of the mode of detection. RESULTS: The benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34-0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44-0.63) compared with the corresponding risks for nonparticipants. CONCLUSIONS: Although all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated.

Risk and clinical predictors of osteoporotic fracture in East Asian patients with chronic obstructive pulmonary disease: a population-based cohort study.

INTRODUCTION: Osteoporosis is becoming an impending epidemic in the Asia-Pacific region. The association between risk of osteoporotic fracture (OTPF) and chronic obstructive pulmonary disease (COPD) in East Asian patients is yet to be fully examined. We conducted a nationwide population-based retrospective cohort study of 98,700 patients aged ≥50 years with or without COPD using a national administrative claims dataset. MATERIALS AND METHODS: The patients were divided into COPD and comparison groups comprising 19,740 and 78,960 patients, respectively. The groups were 1 to 4 matched for age, gender, index date, diabetes mellitus, pre-existing osteoporosis and chronic kidney disease. Information such as the geographic area where southern part represented more sunshine exposure, smoking-related diagnoses, alcohol use disorder, whether there was regular use of inhaled corticosteroids and oral corticosteroids, vitamin D prescriptions, Charlson-Deyo comorbidity index score, and other relevant medical comorbidities were extracted for analysis. They were followed up until OTPF or the end of the year 2013. The outcome measure was an osteoporotic vertebral fracture and other long-bone fractures. A multivariate Cox model was constructed to derive adjusted hazard ratios (aHR) for OTPF with corresponding 95% confidence intervals (CI) after controlling for age, sex, insurance premium category, vitamin D prescription, osteoporosis, and coronary heart disease (CHD). Kaplan-Meier curves of the probability of OTPF-free survival for each cohort were compared using the log-rank test. Patients with OTPF during the first follow-up year were excluded from the overall risk calculation. Contributing factors to the increased risk of OTPF in COPD patients were examined in a sensitivity analysis. RESULTS: After a total follow-up of 68,743 patient-years for the COPD group and 278,051 patient-years for the matched comparison group, the HR for OTPF was 1.24 (95% CI [1.02-1.51]; P = 0.0322) in COPD patients. The aHR was increased by 30% for vertebral OTPF (aHR = 1.297, 95% CI [1.020-1.649]; P = 0.0339). Differential lag time sensitivity analysis revealed a progressively elevated risk up to 8-fold increase in women (aHR = 8.0 (95% CI [1.81-35.4]; P < 0.01)) during the fifth follow-up year. COPD patients with pre-existing osteoporosis or given vitamin D prescription harbor a sustained increased risk up to the 5th (aHR, 4.1; 95% CI [1.61-10.35]) and third (aHR, 2.97; 95% CI [1.48-5.97]) follow-up year, respectively. CONCLUSIONS: Our nationwide population-based cohort study demonstrates that East Asian COPD patients aged 50 and beyond do harbor a modestly increased risk for osteoporotic vertebral fractures particularly for those who are female, have pre-existing osteoporosis or require vitamin D prescription.

Impact of pay-for-performance on mortality in diabetes patients in Taiwan: A population-based study.

BACKGROUND: The impact of pay-for-performance (P4P) programs on long-term mortality for chronic illnesses, especially diabetes mellitus, has been rarely reported. Several studies described the favorable impact of P4P for diabetes mellitus on medical utilizations or intermediate outcomes. Therefore, this study aimed to investigate the impact of a P4P program on mortality in patients with type 2 diabetes. METHODS: The P4P group in this population-based cohort study was 2090 individuals with a primary diagnosis of type 2 diabetes who had been newly enrolled in the P4P program of Taiwan between January 1, 2004 and December 31, 2004. Matched by 1:1 ratio, patients in the non-P4P group were selected by propensity score matching (PSM) for sex, age, the first year of diagnosis as diabetes, and 32 other potential confounding factors. Mean (SD) age was 60.91 (12.04) years when diabetes was first diagnosed and mean (SD) duration of diabetes was 4.3 (1.9) years at baseline. The time-dependent Cox regression model was used to explore the impact of P4P on all-cause mortality. RESULTS: During a mean of 5.13 years (SD = 1.07 years) of follow-up, 206 and 263 subjects died in the P4P group and the non-P4P group, respectively. After adjusting for the potential confounding factors at baseline, survival was significantly longer in the P4P group than in the non-P4P group (hazard ratio, 0.76 [95% confidence interval, 0.64-0.92], P = 0.004, by log-rank test). This decrease in mortality is equivalent to one less death for every 37 patients who were treated in the P4P program for 5.13 years. In this study, the P4P program significantly increased the medical utilization of physician visits and diabetes-related examinations, improved the adherence of oral hypoglycemic drugs during the first 3 years and that of insulin during the second 3 years, and was negatively associated with risk of cancer and chronic kidney disease. In annual health expense, there was no significant difference between P4P and non-P4P groups, P = 0.430. CONCLUSIONS: As compared with control, pay-for-performance program significantly improved survival in patients with diabetes without increasing the medical cost. The P4P group had significantly lower risk of cancer and chronic kidney disease.

Finding a Potential Dipeptidyl Peptidase-4 (DPP-4) Inhibitor for Type-2 Diabetes Treatment Based on Molecular Docking, Pharmacophore Generation, and Molecular Dynamics Simulation.

Dipeptidyl peptidase-4 (DPP-4) is the vital enzyme that is responsible for inactivating intestinal peptides glucagon like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP), which stimulates a decline in blood glucose levels. The aim of this study was to explore the inhibition activity of small molecule inhibitors to DPP-4 following a computational strategy based on docking studies and molecular dynamics simulations. The thorough docking protocol we applied allowed us to derive good correlation parameters between the predicted binding affinities (pKi) of the DPP-4 inhibitors and the experimental activity values (pIC50). Based on molecular docking receptor-ligand interactions, pharmacophore generation was carried out in order to identify the binding modes of structurally diverse compounds in the receptor active site. Consideration of the permanence and flexibility of DPP-4 inhibitor complexes by means of molecular dynamics (MD) simulation specified that the inhibitors maintained the binding mode observed in the docking study. The present study helps generate new information for further structural optimization and can influence the development of new DPP-4 inhibitors discoveries in the treatment of type-2 diabetes.

Risk of Autoimmune Disease in Adults with Chronic Insomnia Requiring Sleep-Inducing Pills: A Population-Based Longitudinal Study.

BACKGROUND: Recent studies indicate that chronic insomnia is associated with the development of certain somatic diseases. Whether it would be associated with the development of an autoimmune disease (AID) was unknown. OBJECTIVE: We aimed to examine the association and quantify the magnitude of risk for AID in individuals suffering from chronic insomnia requiring sleep-inducing pills. DESIGN: This was a population-based, nationwide longitudinal study. PARTICIPANTS: Using a claims data set containing 1 million randomly sampled, insured subjects derived from the National Health Insurance Research Database, we assembled a chronic insomnia group and a 1:3 propensity score-matched comparison group (CP), which were balanced in terms of sex, age, insurance premium, urbanization, alcohol use disorder, smoking-related diagnoses, and morbid obesity. MAIN MEASURES: Person-time data with incidence rate, adjusted hazard ratios (aHR) by the Cox model, AID-free survival functions compared with the log-rank test, and a sensitivity analysis on the time lag effect were presented. Incident AID within the first year of follow-up were excluded. The error rate was controlled using the Benjamini-Hochberg procedure. KEY RESULTS: With 39,550 and 129,914 person-years' follow-up for the chronic insomnia and CP groups (n = 5,736 and 17,208), respectively, we found an increased risk for subsequent AID, representing a 70 % increase in the aHR (1.7; 95 % confidence interval [CI], 1.5-1.9, p < 0.0001). A positive association between chronic insomnia and primary Sjögren's syndrome (pSS) was observed (aHR, 1.3; 95 % CI, 1.1-1.6). Sensitivity analysis disclosed that AID risk was even stronger after 5 years of follow-up (aHR, 2.0; 95 % CI, 1.7-2.4). CONCLUSION: Chronic insomnia requiring sleep-inducing pills may be associated with a 70 % increased risk for future AID, particularly pSS.

High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells.

Epithelial-mesenchymal transition (EMT) is implicated in bronchial remodeling and loss of lung function in chronic inflammatory airway diseases. Previous studies showed the involvement of the high mobility group box 1 (HMGB1) protein in the pathology of chronic pulmonary inflammatory diseases. However, the role of HMGB1 in EMT of human airway epithelial cells is still unclear. In this study, we used RNA sequencing to show that HMGB1 treatment regulated EMT-related gene expression in human primary-airway epithelial cells. The top five upregulated genes were SNAI2, FGFBP1, VIM, SPARC (osteonectin), and SERPINE1, while the downregulated genes included OCLN, TJP1 (ZO-1), FZD7, CDH1 (E-cadherin), and LAMA5. We found that HMGB1 induced downregulation of E-cadherin and ZO-1, and upregulation of vimentin mRNA transcription and protein translation in a dose-dependent manner. Additionally, we observed that HMGB1 induced AKT phosphorylation, resulting in GSK3ß inactivation, cytoplasmic accumulation, and nuclear translocation of ß-catenin to induce EMT in human airway epithelial cells. Treatment with PI3K inhibitor (LY294006) and ß-catenin shRNA reversed HMGB1-induced EMT. Moreover, HMGB1 induced expression of receptor for advanced glycation products (RAGE), but not that of Toll-like receptor (TLR) 2 or TLR4, and RAGE shRNA inhibited HMGB1-induced EMT in human airway epithelial cells. In conclusion, we found that HMGB1 induced EMT through RAGE and the PI3K/AKT/GSK3ß/ß-catenin signaling pathway.