Development and evaluation of a list of high-risk inpatient procedures in patients 65 years and older.

BACKGROUND: Inpatient procedures are common and important health events for older Americans. To facilitate surgical outcomes research, we sought to create and evaluate lists of International Classification of Disease, Tenth Revision (ICD-10) codes for high-risk inpatient procedures, defined as having at least a 1% inpatient mortality. METHODS: This retrospective national cohort study analyzes Medicare claims from 2018 for patients 65 years and older undergoing inpatient procedures. Surgical Diagnosis Related Group (DRG) codes in the inpatient claims were used to identify procedures. We identified the primary ICD-10 procedure code for each patient and then compiled all codes with at least a 1% inpatient mortality yielding three separate lists: one list that was blind to elective versus urgent/emergent status, and one each for urgent/emergent and elective procedures. Clinical review by three surgeons was used to remove procedures unlikely to be the proximate cause of mortality. For evaluation, we examined the mortality of each code among fee-for-service Medicare beneficiaries in 2017, 2019, and 2020 to determine how many of these satisfied the 1% mortality criterion. RESULTS: This study included 2,241,419 patients from 2018 undergoing inpatient procedures. The final result included 231 (blind to elective vs urgent/emergent status), 167 (urgent/emergent status), and 119 (elective status) ICD-10 procedure codes for the three lists. Our evaluation from 2017, 2019, and 2020 demonstrated that in our master list, which was blind to elective versus urgent/emergent status, 97.8% of procedures had an inpatient mortality of at least 1%. In our high-risk procedures lists for urgent/emergent and elective procedures, 100% and 94.1% of codes met this requirement. CONCLUSIONS: We developed and evaluated lists of ICD-10 codes representing high-risk procedures in patients 65 years and older. These lists will be powerful tools for researchers studying surgical outcomes.

The Association of Dialysis Facility Payer Mix With Access to Kidney Transplantation.

Importance: Insurance coverage for patients with end-stage kidney disease has shifted toward more commercially insured patients at dialysis facilities. The associations among insurance status, facility-level payer mix, and access to kidney transplantation are unclear. Objective: To determine the association of dialysis facility commercial payer mix and 1-year incidence of wait-listing for kidney transplantation, and to delineate the association of commercial insurance at the patient vs facility level. Design, Setting, and Participants: This retrospective population-based cohort study used data from the United States Renal Data System from 2013 to 2018. Participants included patients aged 18 to 75 years initiating chronic dialysis between 2013 and 2017, excluding patients with a prior kidney transplant or with major contraindications to kidney transplant. Data were analyzed from August 2021 and May 2023. Exposure: Dialysis facility commercial payer mix, calculated as the proportion of patients with commercial insurance per facility. Main Outcomes and Measures: The primary outcome was patients added to a waiting list for kidney transplant within 1 year of dialysis initiation. Multivariable Cox regression, censoring for death, was used to adjust for patient-level (demographic, socioeconomic, and medical) and facility-level factors. Results: A total of 233 003 patients (97 617 [41.9%] female patients; mean [SD] age, 58.0 [12.1] years) across 6565 facilities met inclusion criteria. Participants included 70 062 Black patients (30.1%), 42 820 Hispanic patients (18.4%), 105 368 White patients (45.2%), and 14 753 patients (6.3%) who identified as another race or ethnicity (eg, American Indian or Alaskan Native, Asian, Native Hawaiian or Pacific Islander, and multiracial). Of 6565 dialysis facilities, the mean (SD) commercial payer mix was 21.2% (15.6 percentage points). Patient-level commercial insurance was associated with increased incidence of wait-listing (adjusted hazard ratio [aHR], 1.86; 95% CI, 1.80-1.93; P < .001). At the facility-level and before covariate adjustment, higher commercial payer mix was associated with increased wait-listing (fourth vs first payer mix quartile [Q]: HR, 1.79; 95% CI, 1.67-1.91; P < .001). However, after covariate-adjustment, including adjusting for patient-level insurance status, commercial payer mix was not significantly associated with outcome (Q4 vs Q1: aHR, 1.02; 95% CI, 0.95-1.09; P = .60). Conclusions and Relevance: In this national cohort study of patients newly initiated on chronic dialysis, although patient-level commercial insurance was associated with higher access to the kidney transplant waiting lists, there was no independent association of facility-level commercial payer mix with patients being added to waiting lists for transplant. As the landscape of insurance coverage for dialysis evolves, the potential downstream impact on access to kidney transplant should be monitored.

Outcomes for patients with dementia undergoing emergency and elective colorectal surgery: A large multi-institutional comparative cohort study.

BACKGROUND: Alzheimer's Disease and Related Dementias (ADRD) may result in poor surgical outcomes. The current study aims to characterize the risk of ADRD on outcomes for patients undergoing colorectal surgery. METHODS: Colorectal surgery patients with and without ADRD from 2007 to 2017 were identified using electronic health record-linked Medicare claims data from two large health systems. Unadjusted and adjusted analyses were performed to evaluate postoperative outcomes. RESULTS: 5926 patients (median age 74) underwent colorectal surgery of whom 4.8% (n = 285) had ADRD. ADRD patients were more likely to undergo emergent operations (27.7% vs. 13.6%, p < 0.001) and be discharged to a facility (49.8% vs 28.9%, p < 0.001). After multi-variable adjustment, ADRD patients were more likely to have complications (61.1% vs 48.3%, p < 0.001) and required longer hospitalization (7.1 vs 6.1 days, p = 0.001). CONCLUSIONS: The diagnosis of ADRD is an independent risk factor for prolonged hospitalization and postoperative complications after colorectal surgery.

Brown adipose tissue-derived Nrg4 alleviates endothelial inflammation and atherosclerosis in male mice.

Brown adipose tissue (BAT) activity contributes to cardiovascular health by its energy-dissipating capacity but how BAT modulates vascular function and atherosclerosis through endocrine mechanisms remains poorly understood. Here we show that BAT-derived neuregulin-4 (Nrg4) ameliorates atherosclerosis in mice. BAT-specific Nrg4 deficiency accelerates vascular inflammation and adhesion responses, endothelial dysfunction and apoptosis and atherosclerosis in male mice. BAT-specific Nrg4 restoration alleviates vascular inflammation and adhesion responses, attenuates leukocyte homing and reduces endothelial injury and atherosclerosis in male mice. In endothelial cells, Nrg4 decreases apoptosis, inflammation and adhesion responses induced by oxidized low-density lipoprotein. Mechanistically, protein kinase B (Akt)-nuclear factor-κB signaling is involved in the beneficial effects of Nrg4 on the endothelium. Taken together, the results reveal Nrg4 as a potential cross-talk factor between BAT and arteries that may serve as a target for atherosclerosis.

Associations between dementia diagnosis and end-of-life care utilization.

BACKGROUND: Dementia is a leading cause of death for older adults and is more common among persons from racial/ethnic minoritized groups, who also tend to experience more intensive end-of-life care. This retrospective cohort study compared end-of-life care in persons with and without dementia and identified dementia's moderating effects on the relationship between race/ethnicity and end-of-life care. METHODS: Administrative claims data for 463,590 Medicare fee-for-service decedents from 2016 to 2018 were analyzed. Multivariable logistic and linear regression analyses examined the association of dementia with 5 intensive and 2 quality of life-focused measures. Intensity measures included hospital admission, ICU admission, receipt of any of 5 intensive procedures (CPR, mechanical ventilation, intubation, dialysis initiation, and feeding tube insertion), hospital death, and Medicare expenditures (last 30 days of life). Quality of life measures included timely hospice care (>3 days before death) and days at home (last 6 months of life). Models were adjusted for demographic and clinical factors. RESULTS: 54% of Medicare decedents were female, 85% non-Hispanic White, 8% non-Hispanic Black, and 4% Hispanic. Overall, 51% had a dementia diagnosis claim. In adjusted models, decedents with dementia had 16%-29% lower odds of receiving intensive services (AOR hospital death: 0.71, 95% CI: 0.70-0.72; AOR hospital admission: 0.84, 95% CI: 0.83-0.86). Patients with dementia had 45% higher odds of receiving timely hospice (AOR: 1.45, 95% CI: 1.42-1.47), but spent 0.74 fewer days at home (adjusted mean: -0.74, 95% CI: (-0.98)-(-0.49)). Compared to non-Hispanic White individuals, persons from racial/ethnic minoritized groups were more likely to receive intensive services. This effect was more pronounced among persons with dementia. CONCLUSIONS: Although overall dementia was associated with fewer intensive services near death, beneficiaries from racial/ethnic groups minoritized with dementia experienced more intensive service use. Particular attention is needed to ensure care aligns with the needs and preferences of persons with dementia and from racial/ethnic minoritized groups.

Anastomosis Time and Outcomes after Donation after Circulatory Death Kidney Transplantation.

BACKGROUND: At every stage in the transplantation process for a deceased-donor kidney, time means ischemia. Donation after circulatory death (DCD) kidneys are already subject to warm ischemia in the donor, but another underappreciated component of warm ischemia time is the time required for anastomosis prior to reperfusion. We studied the effect of anastomosis time (AT) on outcomes after DCD kidney transplantation. STUDY DESIGN: This is a retrospective study of the Scientific Registry of Transplant Recipients, including all US adult DCD kidney transplantation recipients from 2009 to 2015 (N = 6,397). Our exposure was AT (time out of cold storage until reperfusion, quartiles). Outcomes included delayed graft function (DGF), death-censored graft survival, and overall patient survival. Multivariable logistic and Cox regression quantified the association of AT with outcomes, adjusting for donor and recipient factors (including donor warm ischemia time). RESULTS: AT accounted for 67% of total warm ischemia time on average, with a median AT of 38 minutes (median total warm ischemia 56 minutes). Longer AT (fourth [≥48min] vs first quartile [≤30min]) was associated with increased DGF (odds ratio = 1.19, p = 0.024) and increased graft failure (hazard ratio = 1.21, p = 0.043) but was not associated with patient survival. Comparing patients with the longest vs shortest AT, adjusted DGF incidence was 44.0% vs 36.7% (p = 0.024), and 5-year graft survival was 84.8% vs 88.2% (p = 0.004). CONCLUSION: Prolonged AT is associated with worse graft outcomes in DCD kidney transplant recipients. Efforts to minimize rewarming during implantation and optimize AT may improve graft outcomes.

Evolving Metrics of Quality for Kidney Transplant Candidates: Transplant Center Variability in Delisting and 1-Year Mortality.

BACKGROUND: Management of patients on the kidney transplant waitlist lacks oversight, and transplant centers can delist candidates without consequence. To better understand between-center differences in waitlist management, we examined delisting rates and mortality after delisting within 3 years of removal from the kidney transplant waitlist. STUDY DESIGN: This is a retrospective cohort study using data from the Scientific Registry of Transplant Recipients of adults listed for deceased donor kidney transplant in 2015 and followed until the end of 2018. Patients of interest were those delisted for reasons other than transplant, death, or transfer. Centers were excluded if they had fewer than 20 waitlisted patients per year. We calculated probability of delisting and death after delisting using multivariable competing risk models. RESULTS: During follow-up, 14.2% of patients were delisted. The median probability of delisting within 3 years, adjusted for center-level variability, was 7.0% (interquartile range [IQR]: 3.9% to 10.6%). Median probability of death was 58.2% (IQR: 40% to 73.4%). There was no meaningful correlation between probability of delisting and death (τ = -0.05, p = 0.34). CONCLUSIONS: There is significant variability in the rate of death after delisting across kidney transplant centers. Likelihood of transplant is extremely important to candidates, and improved data collection efforts are needed to inform whether current delisting practices are successfully removing patients who could not meaningfully benefit from transplant, or whether certain populations may benefit from remaining on the list and maintaining eligibility.

Patients living with dementia have worse outcomes when undergoing high-risk procedures.

BACKGROUND: Patients with Alzheimer's Disease and Related Dementias (ADRD) undergoing inpatient procedures represent a population at elevated risk for adverse outcomes including postoperative complications, mortality, and discharge to a higher level of care. Outcomes may be particularly poor in patients with ADRD undergoing high-risk procedures. We sought to determine traditional (e.g., 30-day mortality) and patient-centered (e.g., discharge disposition) outcomes in patients with ADRD undergoing high-risk inpatient procedures. METHODS: This retrospective cohort study analyzed electronic health records linked to fee-for-service Medicare claims data at a tertiary care academic health system. All patients from a large multi-hospital health system undergoing high-risk inpatient procedures from October 1, 2015 to September 30, 2017 with continuous Medicare Parts A and B enrollment in the 12 months prior to and 90 days following the procedure were included. RESULTS: This study included 6779 patients. 536 (7.9%) had ADRD. A multivariable analysis of outcomes demonstrated higher risks for postoperative complications (OR 1.49, 95% CI 1.23-1.81) and 90-day mortality (OR 1.44 [95% CI 1.09-1.91]) in patients with ADRD compared to those without. Patients with ADRD were more likely to be discharged to a higher level of care (OR 1.70, 95% CI 1.32-2.18) and only 37.3% of patients admitted from home were discharged to home. CONCLUSIONS: Compared to those without ADRD, patients living with ADRD undergoing high-risk procedures have poor traditional and patient-centered outcomes including increased risks for 90-day mortality, postoperative complications, longer hospital lengths of stay, and discharge to a higher level of care. These data may be used by patients, their surrogates, and their physicians to help align surgical decision-making with health care goals.

Initial Home Dialysis Is Increased for Rural Patients by Accessing Urban Facilities.

Background: The 240,000 rural patients with end stage kidney disease in the United States have less access to nephrology care and higher mortality than those in urban settings. The Advancing American Kidney Health initiative aims to increase the use of home renal replacement therapy. Little is known about how rural patients access home dialysis and the availability and quality of rural dialysis facilities. Methods: Incident dialysis patients in 2017 and their facilities were identified in the United States Renal Data System. Facility quality and service availability were analyzed with descriptive statistics. We assessed the availability of home dialysis methods, depending on rural versus urban counties, and then we used multivariate logistic regression to identify the likelihood of rural patients with home dialysis as their initial modality and the likelihood of rural patients changing to home dialysis within 90 days. Finally, we assessed mortality after dialysis initiation on the basis of patient home location. Results: Of the 97,930 dialysis initiates, 15,310 (16%) were rural. Rural dialysis facilities were less likely to offer home dialysis (51% versus 54%, P<0.001). Although a greater proportion of rural patients (9% versus 8%, P<0.001) were on home dialysis, this was achieved by traveling to urban facilities to obtain home dialysis (OR=2.74, P<0.001). After adjusting for patient and facility factors, rural patients had a higher risk of mortality (HR=1.06, P=0.004). Conclusions: Despite having fewer facilities that offer home dialysis, rural patients were more often on home dialysis methods because they traveled to urban facilities, representing an access gap. Even if rural patients accessed home dialysis at urban facilities, rural patients still suffered worse mortality. Future dialysis policy should address this access gap to improve care and overall mortality for rural patients.

Myeloid-derived growth factor (MYDGF) protects bone mass through inhibiting osteoclastogenesis and promoting osteoblast differentiation.

Whether bone marrow regulates bone metabolism through endocrine and paracrine mechanism remains largely unknown. Here, we found that (i) myeloid cell-specific myeloid-derived growth factor (MYDGF) deficiency decreased bone mass and bone strength in young and aged mice; (ii) myeloid cell-specific MYDGF restoration prevented decreases in bone mass and bone strength in MYDGF knockout mice; moreover, myeloid cell-derived MYDGF improved the progress of bone defects healing, prevented ovariectomy (OVX)-induced bone loss and age-related osteoporosis; (iii) MYDGF inhibited osteoclastogenesis and promoted osteoblast differentiation in vivo and in vitro; and (iv) PKCß-NF-κB and MAPK1/3-STAT3 pathways were involved in the regulation of MYDGF on bone metabolism. Thus, we concluded that myeloid cell-derived MYDGF is a positive regulator of bone homeostasis by inhibiting bone resorption and promoting bone formation. MYDGF may become a potential novel therapeutic drug for osteoporosis, and bone marrow may become a potential therapeutic target for bone metabolic disorders.

Association of Public Reporting of Medicare Dialysis Facility Quality Ratings With Access to Kidney Transplantation.

Importance: Improving the quality of dialysis care and access to kidney transplantation for patients with end-stage kidney disease is a national clinical and policy priority. The role of dialysis facility quality in increasing access to kidney transplantation is not known. Objective: To determine whether patient, facility, and kidney transplant waitlisting characteristics are associated with variations in dialysis center quality. Design, Setting, and Participants: This population-based cohort study is an analysis of US Renal Data System data and Medicare Dialysis Facility Compare (DFC) data from 2013 to 2018. Participants included all adult (aged ≥18 years) patients in the US Renal Data System beginning long-term dialysis in the US from 2013 to 2017 with follow-up through the end of 2018. Patients with a prior kidney transplant and matched Medicare DFC star ratings to each annual cohort of recipients were excluded. Patients at facilities without a star rating in that year were also excluded. Data analysis was performed from January to April 2021. Exposures: Dialysis center quality, as defined by Medicare DFC star ratings. Main Outcomes and Measures: The primary outcome was the proportion of patients undergoing incident dialysis who were waitlisted within 1 year of dialysis initiation. Secondary outcomes were patient and facility characteristics. Results: Of 507 581 patients beginning long-term dialysis in the US from 2013 to 2017, 291 802 (57.4%) were male, 266 517 (52.5%) were White, and the median (interquartile range) age was 65 (55-75) years. Of 5869 dialysis facilities in 2017, 132 (2.2%) were 1-star, 436 (7.4%) were 2-star, 2047 (34.9%) were 3-star, 1660 (28.3%) were 4-star, and 1594 (27.2%) were 5-star. Higher-quality dialysis facilities were associated with 47% higher odds of transplant waitlisting (odds ratio [OR], 1.47; 95% CI, 1.39-1.57 for 5-star facilities vs 1-star facilities; P < .001). Black patients were less likely than White patients to be waitlisted for transplantation (OR, 0.74; 95% CI, 0.72-0.76). In addition, patients at for-profit (OR, 0.78; 95% CI, 0.74-0.81) and rural (OR, 0.63; 95%, CI 0.58-0.68) facilities were less likely to be waitlisted for transplantation compared with those at nonprofit and urban facilities, respectively. Conclusions and Relevance: In this cohort study, patients at higher-quality dialysis facilities had higher odds than patients at lower-quality facilities of being waitlisted for kidney transplantation within 1 year. Waitlisting rates for kidney transplantation should be considered for integration into the current Centers for Medicare & Medicaid Services DFC star ratings to incentivize dialysis facility referral to transplant centers, inform patient choice, and drive quality improvement by increasing transplant waitlisting rates.

Myeloid-derived growth factor inhibits inflammation and alleviates endothelial injury and atherosclerosis in mice.

Whether bone marrow modulates systemic metabolism remains unknown. Here, we found that (i) myeloid cell-specific myeloid-derived growth factor (MYDGF) deficiency exacerbated vascular inflammation, adhesion responses, endothelial injury, and atherosclerosis in vivo. (ii) Myeloid cell-specific MYDGF restoration attenuated vascular inflammation, adhesion responses and leukocyte homing and alleviated endothelial injury and atherosclerosis in vivo. (iii) MYDGF attenuated endothelial inflammation, apoptosis, permeability, and adhesion responses induced by palmitic acid in vitro. (iv) MYDGF alleviated endothelial injury and atherosclerosis through mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4)/nuclear factor κB (NF-κB) signaling. Therefore, we concluded that MYDGF inhibits endothelial inflammation and adhesion responses, blunts leukocyte homing, protects against endothelial injury and atherosclerosis in a manner involving MAP4K4/NF-κB signaling, and serves as a cross-talk factor between bone marrow and arteries to regulate the pathophysiology of arteries. Bone marrow functions as an endocrine organ and serves as a potential therapeutic target for metabolic disorders.

TGF-ß causes Docetaxel resistance in Prostate Cancer via the induction of Bcl-2 by acetylated KLF5 and Protein Stabilization.

Prostate cancer is the second leading cause of cancer-related death in the United States. As a first line treatment for hormone-refractory prostate cancer, docetaxel (DTX) treatment leads to suboptimal effect since almost all patients eventually develop DTX resistance. In this study, we investigated whether and how TGF-ß affects DTX resistance of prostate cancer. Methods: Cytotoxicity of DTX in DU 145 and PC-3 cells was measured by CCK-8 and Matrigel colony formation assays. Resistance to DTX in DU 145 cells was examined in a xenograft tumorigenesis model. A luciferase reporter system was used to determine transcriptional activities. Gene expression was analyzed by RT-qPCR and Western blotting. Results: We found that KLF5 is indispensable in TGF-ß-induced DTX resistance. Moreover, KLF5 acetylation at lysine 369 mediates DTX resistance in vitro and in vivo. We showed that the TGF-ß/acetylated KLF5 signaling axis activates Bcl-2 expression transcriptionally. Furthermore, DTX-induced Bcl-2 degradation depends on a proteasome pathway, and TGF-ß inhibits DTX-induced Bcl-2 ubiquitination. Conclusion: Our study demonstrated that the TGF-ß-acetylated KLF5-Bcl-2 signaling axis mediates DTX resistance in prostate cancer and blockade of this pathway could provide clinical insights into chemoresistance of prostate cancer.

MYDGF attenuates podocyte injury and proteinuria by activating Akt/BAD signal pathway in mice with diabetic kidney disease.

AIMS/HYPOTHESIS: Myeloid-derived growth factor (MYDGF), mainly secreted by bone marrow-derived cells, has been known to promote glucagon-like peptide-1 production and improve glucose/lipid metabolism in mouse models of diabetes, but little is known about the functions of MYDGF in diabetic kidney disease (DKD). Here, we investigated whether MYDGF can prevent the progression of DKD. METHODS: In vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of MYDGF on albuminuria and pathological glomerular lesions. We used streptozotocin-treated Mydgf knockout and wild-type mice on high fat diets to induce a model of DKD. Then, albuminuria, glomerular lesions and podocyte injury were evaluated in Mydgf knockout and wild-type DKD mice treated with adeno-associated virus-mediated Mydgf gene transfer. In vitro and ex vivo experiments, the expression of slit diaphragm protein nephrin and podocyte apoptosis were evaluated in conditionally immortalised mouse podocytes and isolated glomeruli from non-diabetic wild-type mice treated with recombinant MYDGF. RESULTS: MYDGF deficiency caused more severe podocyte injury in DKD mice, including the disruption of slit diaphragm proteins (nephrin and podocin) and an increase in desmin expression and podocyte apoptosis, and subsequently caused more severe glomerular injury and increased albuminuria by 39.6% compared with those of wild-type DKD mice (p < 0.01). Inversely, MYDGF replenishment attenuated podocyte and glomerular injury in both wild-type and Mydgf knockout DKD mice and then decreased albuminuria by 36.7% in wild-type DKD mice (p < 0.01) and 34.9% in Mydgf knockout DKD mice (p < 0.01). Moreover, recombinant MYDGF preserved nephrin expression and inhibited podocyte apoptosis in vitro and ex vivo. Mechanistically, the renoprotection of MYDGF was attributed to the activation of the Akt/Bcl-2-associated death promoter (BAD) pathway. CONCLUSIONS/INTERPRETATION: The study demonstrates that MYDGF protects podocytes from injury and prevents the progression of DKD, providing a novel strategy for the treatment of DKD. Graphical abstract.

Myeloid-Derived Growth Factor Promotes Intestinal Glucagon-Like Peptide-1 Production in Male Mice With Type 2 Diabetes.

Myeloid-derived growth factor (MYDGF), which is produced by bone marrow-derived cells, mediates cardiac repair following myocardial infarction by inhibiting cardiac myocyte apoptosis to subsequently reduce the infarct size. However, the function of MYDGF in the incretin system of diabetes is still unknown. Here, loss-of-function and gain-of-function experiments in mice revealed that MYDGF maintains glucose homeostasis by inducing glucagon-like peptide-1 (GLP-1) production and secretion and that it improves glucose tolerance and lipid metabolism. Treatment with recombinant MYDGF increased the secretion and production of GLP-1 in STC-1 cells in vitro. Mechanistically, the positive effects of MYDGF are potentially attributable to the activation of protein kinase A/glycogen synthase kinase 3ß/ß-catenin (PKA/GSK-3ß/ß-catenin) and mitogen-activated protein kinase (MAPK) kinases/extracellular regulated protein kinase (MEK/ERK) pathways. Based on these findings, MYDGF promotes the secretion and production of GLP-1 in intestinal L-cells and potentially represents a potential therapeutic medication target for type 2 diabetes.

Alogliptin improves survival and health of mice on a high-fat diet.

Alogliptin is a commonly prescribed drug treating patients with type 2 diabetes. Here, we show that long-term intervention with alogliptin (0.03% w/w in diet) improves survival and health of mice on a high-fat diet. Alogliptin intervention takes beneficial effects associated with longevity, including increased insulin sensitivity, attenuated functionality decline, decreased organ pathology, preserved mitochondrial function, and reduced oxidative stress. Autophagy activation is proposed as an underlying mechanism of these beneficial effects. We conclude that alogliptin intervention could be considered as a potential strategy for extending lifespan and healthspan in obesity and overweight.

Prevalence of Chlamydia trachomatis-Specific Antibodies before and after Mass Drug Administration for Trachoma in Community-Wide Surveys of Four Communities in Nepal.

The target end date for the global elimination of trachoma as a public health problem is 2020. As countries begin the process for submitting their dossier for the validation of elimination of trachoma as a public health problem, strategies for post-validation surveillance must be considered. Seroprevalence of antibodies against antigens from the causative bacteria Chlamydia trachomatis (Ct) in young children has been shown to reflect trachomatous inflammation-follicular (TF) rates in both endemic and previously endemic settings. However, none of these studies has directly compared age seroprevalence in the same communities before and after mass drug administration (MDA) for trachoma. Here we report a marked shift in age seroprevalence curves in four villages in Kapilvastu District, Nepal, before and after MDA. Clinical examinations were performed and blood was taken before (N = 659) and 5 years after (N = 646) MDA. Rates of TF decreased from 17.6% in ≤ 9-year-olds before MDA (N = 52) to 0% in ≤ 9-year-olds (N = 73) after MDA. Positive antibody responses to Ct in the entire population decreased from 82.1% pre-MDA to 35.8% post-MDA, whereas those among ≤ 9-year-olds decreased from 59.6% to 4.1%. These data show that the postintervention decrease in TF was reflected in a drop in anti-Ct antibody responses, suggesting that antibody responses could be useful indicators for post-validation surveillance.

GDF11 Attenuates Development of Type 2 Diabetes via Improvement of Islet ß-Cell Function and Survival.

Growth differentiation factor 11 (GDF11) has been implicated in the regulation of islet development and a variety of aging conditions, but little is known about the physiological functions of GDF11 in adult pancreatic islets. Here, we showed that systematic replenishment of GDF11 not only preserved insulin secretion but also improved the survival and morphology of ß-cells and improved glucose metabolism in both nongenetic and genetic mouse models of type 2 diabetes (T2D). Conversely, anti-GDF11 monoclonal antibody treatment caused ß-cell failure and lethal T2D. In vitro treatment of isolated murine islets and MIN6 cells with recombinant GDF11 attenuated glucotoxicity-induced ß-cell dysfunction and apoptosis. Mechanistically, the GDF11-mediated protective effects could be attributed to the activation of transforming growth factor-ß/Smad2 and phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-FoxO1 signaling. These findings suggest that GDF11 repletion may improve ß-cell function and mass and thus may lead to a new therapeutic approach for T2D.