Compatibility of Al-doped ZnO electron transport layer with various HTLs and absorbers in perovskite solar cells.

Perovskite solar cells (PSCs) have shown a significant improvement in cell performance in photovoltaics technology. The commonly used light absorbing material of halide-based perovskite in PSCs has produced high efficiency cells with low cost and a simple fabrication process. However, it contains the harmful substance of Pb, which affects the environment, and the cell still suffers from instability in the long run. Therefore, this work presents a theoretical study of the Pb-free absorber layer of CH3NH3SnI3 that is paired for compatibility with various types of hole transport layers (HTLs). Several key parameters of the absorbent layer and HTL have been optimized to produce the highest power conversion efficiency (PCE) using 1D-SCAPS software under AM 1.5 illumination. It was found that the combination of Cu2O and CH3NH3SnI3 used as the HTL and absorbent layer, respectively, has resulted in great PCE as high as 27.72%. These findings prove that the use of inorganic HTLs and Pb-free perovskite layers is promising for use in PSCs.

Trifolium repens and T. subterraneum modify their nodule microbiome in response to soil pH.

AIMS: The influence of soil edaphic factors on recruitment and composition of bacteria in the legume nodule is unknown. Typically, low (acidic) pH soils have a negative effect on the plant-rhizobia symbiosis and thereby reduce clover growth. However, the specific relationship between soil pH and the ecology of rhizobia is unknown, in either their free-living or nodule-inhabiting states. We used New Zealand pasture systems with soils of different pH, and white (WC) and subterranean (SC) clovers, to examine the relationship between soil pH and the diversity of bacteria that inhabit the nodules. METHODS AND RESULTS: Amplicon sequencing (16S rRNA) assessed the bacterial community in 5299 nodules recovered from both legume species grown in 47 soils of different edaphic (including pH) properties. Fewer nodules were formed on both clovers at low soil pH. As expected, rhizobia comprised ∼ 92% of the total reads in both clovers, however 28 non-rhizobia genera were also present. Soil pH influenced the community structure of bacteria within the nodule, and this was more evident in non-Rhizobium taxa than Rhizobium. Host strongly influenced the diversity of bacteria in the nodules. The alpha diversity of nodule microbiome in SC nodules was higher than in WC nodules and SC nodules also harbored a higher relative abundance of non-Rhizobium bacteria than WC. Beta diversity of Rhizobium and non-Rhizobium bacteria was influenced more by clover species rather than edaphic factors. CONCLUSIONS: The results indicate that these clover species modified their nodule biomes in response to pH-stress. SIGNIFICANCE AND IMPACT OF THE STUDY: The non-Rhizobium bacteria may have some functional significance (such as improved clover persistence in low pH soils) in legume nodules.

Risk Factors for De Novo Malignancy Following Lung Transplantation.

Risk factors for non-skin cancer de novo malignancy (DNM) after lung transplantation have yet to be identified. We queried the United Network for Organ Sharing database for all adult lung transplant patients between 1989 and 2012. Standardized incidence ratios (SIRs) were computed by comparing the data to Surveillance, Epidemiology, and End Results Program data after excluding skin squamous/basal cell carcinomas. We identified 18 093 adult lung transplant patients; median follow-up time was 1086 days (interquartile range 436-2070). DNMs occurred in 1306 patients, with incidences of 1.4%, 4.6%, and 7.9% at 1, 3, and 5 years, respectively. The overall cancer incidence was elevated compared with that of the general US population (SIR 3.26, 95% confidence interval [CI]: 2.95-3.60). The most common cancer types were lung cancer (26.2% of all malignancies, SIR 6.49, 95% CI: 5.04-8.45) and lymphoproliferative disease (20.0%, SIR 14.14, 95% CI: 9.45-22.04). Predictors of DNM following lung transplantation were age (hazard ratio [HR] 1.03, 95% CI: 1.02-1.05, p < 0.001), male gender (HR 1.20, 95% CI: 1.02-1.42, p = 0.03), disease etiology (not cystic fibrosis, idiopathic pulmonary fibrosis or interstitial lung disease, HR 0.59, 95% CI 0.37-0.97, p = 0.04) and single-lung transplantation (HR 1.64, 95% CI: 1.34-2.01, p < 0.001). Significant interactions between donor or recipient smoking and single-lung transplantation were noted. On multivariable survival analysis, DNMs were associated with an increased risk of mortality (HR 1.44, 95% CI: 1.10-1.88, p = 0.009).

Simulated Regionalization of Heart and Lung Transplantation in the United States.

We simulated the impact of regionalization of isolated heart and lung transplantation within United Network for Organ Sharing (UNOS) regions. Overall, 12 594 orthotopic heart transplantation (OHT) patients across 135 centers and 12 300 orthotopic lung transplantation (OLT) patients across 67 centers were included in the study. An algorithm was constructed that "closed" the lowest volume center in a region and referred its patients to the highest volume center. In the unadjusted analysis, referred patients were assigned the highest volume center's 1-year mortality rate, and the difference in deaths per region before and after closure was computed. An adjusted analysis was performed using multivariable logistic regression using recipient and donor variables. The primary outcome was the potential number of lives saved at 1 year after transplant. In adjusted OHT analysis, 10 lives were saved (95% confidence interval [CI] 9-11) after one center closure and 240 lives were saved (95% CI 209-272) after up to five center closures per region, with the latter resulting in 1624 total patient referrals (13.2% of OHT patients). For OLT, lives saved ranged from 29 (95% CI 26-32) after one center closure per region to 240 (95% CI 224-256) after up to five regional closures, but the latter resulted in 2999 referrals (24.4% of OLT patients). Increased referral distances would severely limit access to care for rural and resource-limited populations.

Weight loss surgery in adolescents corrects high-density lipoprotein subspecies and their function.

BACKGROUND/OBJECTIVE: Youth with obesity have an altered high-density lipoprotein (HDL) subspecies profile characterized by depletion of large apoE-rich HDL particles and an enrichment of small HDL particles. The goal of this study was to test the hypothesis that this atherogenic HDL profile is reversible and that HDL function would improve with metabolic surgery. METHODS: Serum samples from adolescent males with severe obesity mean±s.d. age of 17.4±1.6 years were studied at baseline and 1 year following vertical sleeve gastrectomy (VSG). HDL subspecies and HDL function were evaluated pre and post VSG using paired t-tests. A lean group of adolescents was included as a reference group. RESULTS: After VSG, body mass index decreased by 32% and insulin resistance as estimated by homeostatic model assessment of insulin resistance decreased by 75% (both P<0.01). Large apoE-rich HDL subspecies increased following VSG (P<0.01) and approached that of lean adolescents despite participants with considerable residual obesity. In addition, HDL function improved compared with baseline (cholesterol efflux capacity increased by 12%, HDL lipid peroxidation potential decreased by 30% and HDL anti-oxidative capacity improved by 25%, all P<0.01). CONCLUSIONS: Metabolic surgery results in a significant improvement in the quantity of large HDL subspecies and HDL function. Our data suggest metabolic surgery may improve cardiovascular risk in adolescents and young adults.

Lipid changes 8 years post gastric bypass in adolescents with severe obesity (FABS-5+ study).

OBJECTIVE: Severe obesity in adolescents is increasing and few effective treatments exist. Bariatric surgery is one option, but the extent to which surgery influences cardiovascular risk factors over time in youth is not clear. We hypothesized that Roux-en Y gastric bypass (RYGB) would be associated with sustained improvements in lipids over time (>5 years). PARTICIPANTS/METHODS: Youth who underwent RYGB from 2001 to 2007 were recruited for the Follow-up of Adolescent Bariatric Surgery-5+ (FABS-5+) in 2011-2014. Baseline body mass index (BMI) and lipids were abstracted from medical records. Follow-up data were obtained at a research visit. Analyses included paired t-tests to assess changes in BMI and lipids over time. General linear models were used to evaluate predictors of high-density lipoprotein (HDL) and non-HDL-cholesterol at follow-up. A non-operative group was recruited for comparison. RESULTS: Surgical participants (n=58) were a mean±s.d. age of 17±2 years at baseline and 25±2 years at long-term follow-up. Eighty-six percent were Caucasian and 64% were female. At long-term follow-up BMI decreased by 29% and all lipids (except total cholesterol) significantly improved (P<0.01). Female sex was a significant predictor of non-HDL-cholesterol level at 1 year, while change in BMI from 1 year to long-term follow-up was a significant predictor of non-HDL-cholesterol and HDL-cholesterol during the same interval (P<0.05). In the non-operative group, BMI increased by 8% and lipid parameters were unchanged. CONCLUSIONS: This is the longest and most complete follow-up of youth following RYGB. Weight loss maintenance over time was significantly associated with improvements in lipid profile over 5 years.

National Healthcare Delivery Systems Influence Lung Transplant Outcomes for Cystic Fibrosis.

Successful lung transplantation (LTx) depends on multiple components of healthcare delivery and performance. Therefore, we conducted an international registry analysis to compare post-LTx outcomes for cystic fibrosis (CF) patients using the UNOS registry in the United States and the National Health Service (NHS) Transplant Registry in the United Kingdom. Patients with CF who underwent lung or heart-lung transplantation in the United States or United Kingdom between January 1, 2000 and December 31, 2011 were included. The primary outcome was all-cause mortality. Kaplan-Meier analysis and Cox proportional hazards regression evaluated the effect of healthcare system and insurance on mortality after LTx. 2,307 US LTx recipients and 451 individuals in the United Kingdom were included. 894 (38.8%) US LTx recipients had publically funded Medicare/Medicaid insurance. US private insurance and UK patients had improved median predicted survival compared with US Medicare/Medicaid recipients (p < 0.001). In multivariable Cox regression, US Medicare/Medicaid insurance was associated with worse survival after LTx (US private: HR0.78,0.68-0.90,p = 0.001 and UK: HR0.63,0.41-0.97, p = 0.03). This study in CF patients is the largest comparison of LTx in two unique health systems. Both the United States and United Kingdom have similar early survival outcomes, suggesting important dissemination of best practices internationally. However, the performance of US public insurance is significantly worse and may put patients at risk.

Perioperative myocardial injury in patients receiving cardiac output-guided haemodynamic therapy: a substudy of the OPTIMISE Trial.

BACKGROUND: Evidence suggests that cardiac output-guided haemodynamic therapy algorithms improve outcomes after high-risk surgery, but there is some concern that this could promote acute myocardial injury. We evaluated the incidence of myocardial injury in a perioperative goal-directed therapy trial. METHODS: Patients undergoing major gastrointestinal surgery (n=723) were randomly assigned to cardiac output-guided haemodynamic therapy (intervention group) or usual care as part of the OPTIMISE trial. At four participating sites, 288 patients were enrolled in a biomarker substudy. Serum high-sensitivity cardiac troponin I (TnI) concentration and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration were measured before and at 24 and 72 h after surgery. RESULTS: Median preoperative TnI and NT-ProBNP concentrations were 4.3 ng litre(-1) and 144 pg ml(-1), respectively. After surgery, 67 (46%) patients in the intervention group and 68 (48%) patients receiving usual care had TnI concentrations above the 99th centile upper reference limit (P=0.82). Peak serum TnI concentration was similar in the intervention and usual care groups (median [interquartile range]: 10.0 [5.3-21.5] vs 7.8 [5.0-21.8] ng litre(-1); P=0.85), and no differences were observed in serum TnI concentrations over 72 h (repeated-measures anova, P=0.51). Likewise, there were no differences in peak NT-proBNP concentration between intervention and usual care groups (645 [362-1169] vs 659 [381-1028] pg ml(-1); P=0.86) or in serial NT-proBNP concentrations over 72 h (P=0.20). CONCLUSIONS: Myocardial injury is common among patients undergoing major gastrointestinal surgery. In this study, the frequency was not affected by cardiac output-guided fluid and low-dose inotropic therapy.

Dopant engineering for ZnO electron transport layer towards efficient perovskite solar cells.

The conventional electron transport layer (ETL) TiO2 has been widely used in perovskite solar cells (PSCs), which have produced exceptional power conversion efficiencies (PCE), allowing the technology to be highly regarded and propitious. Nevertheless, the recent high demand for energy harvesters in wearable electronics, aerospace, and building integration has led to the need for flexible solar cells. However, the conventional TiO2 ETL layer is less preferred, where a crystallization process at a temperature as high as 450 °C is required, which degrades the plastic substrate. Zinc oxide nanorods (ZnO NRs) as a simple and low-cost fabrication material may fulfil the need as an ETL, but they still suffer from low PCE due to atomic defect vacancy. To delve into the issue, several dopants have been reviewed as an additive to passivate or substitute the Zn2+ vacancies, thus enhancing the charge transport mechanism. This work thereby unravels and provides a clear insight into dopant engineering in ZnO NRs ETL for PSC.

Solid-organ transplantation in older adults: current status and future research.

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

The effects of obesity and type 2 diabetes mellitus on cardiac structure and function in adolescents and young adults.

AIMS/HYPOTHESIS: We sought to evaluate the effects of obesity and obesity-related type 2 diabetes mellitus on cardiac geometry (remodelling) and systolic and diastolic function in adolescents and young adults. METHODS: Cardiac structure and function were compared by echocardiography in participants who were lean, obese or obese with type 2 diabetes (obese diabetic), in a cross sectional study. Group differences were assessed using ANOVA. Independent determinants of cardiac outcome measures were evaluated with general linear models. RESULTS: Adolescents with obesity and obesity-related type 2 diabetes were found to have abnormal cardiac geometry compared with lean controls (16% and 20% vs <1%, p < 0.05). These two groups also had increased systolic function. Diastolic function decreased from the lean to obese to obese diabetic groups with the lowest diastolic function observed in the obese diabetic group (p < 0.05). Regression analysis showed that group, BMI z score (BMIz), group × BMIz interaction and systolic BP z score (BPz) were significant determinants of cardiac structure, while group, BMIz, systolic BPz, age and fasting glucose were significant determinants of the diastolic function (all p < 0.05). CONCLUSIONS/INTERPRETATION: Adolescents with obesity and obesity-related type 2 diabetes demonstrate changes in cardiac geometry consistent with cardiac remodelling. These two groups also demonstrate decreased diastolic function compared with lean controls, with the greatest decrease observed in those with type 2 diabetes. Adults with diastolic dysfunction are known to be at increased risk of progressing to heart failure. Therefore, our findings suggest that adolescents with obesity-related type 2 diabetes may be at increased risk of progressing to early heart failure compared with their obese and lean counterparts.

Elevated plasma long pentraxin-3 levels and primary graft dysfunction after lung transplantation for idiopathic pulmonary fibrosis.

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

Time-Driven activity-based costing identifies opportunities for process efficiency and cost optimization for robot-assisted laparoscopic pyeloplasty.

BACKGROUND: Robot-assisted laparoscopic pyeloplasty (RALP) is a commonly performed procedure in children, but its actual cost implications on the healthcare ecosystem have not been adequately defined. Time-driven activity-based costing (TDABC) is a novel cost accounting method derived from value based healthcare systems that may offer one pathway to assess institutional costs. OBJECTIVE: To determine the true cost of a robot-assisted laparoscopic pyeloplasty (RALP) in the pediatric population using TDABC, and compare it to traditional cost accounting. And to utilize TDABC to minimize cost and improve time-flow efficiency. SUBJECTS/PATIENTS AND METHODS: The RALP care pathway was defined from patient arrival to the pre-operative suite to discharge from the post-anesthesia care unit (PACU). Process maps were created with an interdisciplinary team to survey RALP activities. Retrospective time stamps were obtained from the electronic medical record for fiscal year 2016 (FY16) RALP cases, and were validated by prospectively stopwatch timing additional RALP cases. Male and female pediatric patients undergoing a unilateral RALP during FY16 and during the prospective study period (June 2017-October 2017) were included. Procedure costs were calculated using TDABC after determining the capacity cost rate for all personnel and assets, and multiplying them with the time stamps. RESULTS: 25 RALP cases were analyzed for FY16. TDABC determined a total cost of $15 319/case, when direct, indirect and capital robot cost are included. Traditional cost accounting amounted to a total of $16 158/case. The current robot utilization rate is 22% of total capacity, effectively increasing the total RALP cost by 16%. Time stamps with the most variance were pre-operative services (115 ± 27.5 min), robotic console (142 min ±30.7 min) and PACU times (145 ± 101.1 min) (Figure) DISCUSSION: This study represents the first TDABC implementation in robot-assisted pediatric procedures. Previous TDABC in other areas of urology similarly revealed discrepancies between traditional cost accounting and TDABC. The present study demonstrates a higher total cost than previous cost accounting studies for the RALP, however, this is the first effort to include indirect costs in the final calculations. This study does convey the limitations of a retrospective analysis and those inherent to a single institution study. CONCLUSION: TDABC defined the magnitude of cost variation based on robot utilization of a RALP. Traditional cost accounting overestimates the actual costs of a RALP. TDABC also identified high-cost and high variability loci in the RALP process map that will be targeted for process and quality improvement while further reducing assessed costs.

Invasive pneumococcal disease in Kanti Children's Hospital, Nepal, as observed by the South Asian Pneumococcal Alliance network.

BACKGROUND: Pneumonia accounts for approximately 2 million deaths annually among children aged <5 years, with most of these deaths occurring in Africa and southern Asia. The South Asian Pneumococcal Alliance (SAPNA) network in Nepal is generating local epidemiological data to assist in the development of national and regional policies for prevention of pneumococcal and Haemophilus influenzae (Hib) disease. METHODS: Children aged 2 months to 5 years with suspected invasive bacterial disease were recruited from Kanti Children Hospital, Kathmandu, Nepal. Specimens of blood, CSF, and normally sterile body fluids were cultured, and analysis of antimicrobial susceptibility patterns and serotyping of Streptococcus pneumoniae isolates were performed. CSF specimens were also tested for S. pneumoniae and Hib antigens by a latex agglutination test and an immunochromatographic test of pneumococcal antigen (NOW S. pneumoniae Antigen Test; Binax). RESULTS: A total of 2528 children with suspected invasive bacterial disease were recruited, of whom 82% had pneumonia, 9.6% had meningitis, 2% had very severe disease, and 0.4% had bacteremia; the remainder received another diagnosis. Before hospitalization, 26.7% had received antibiotic treatment. Fifty children had S. pneumoniae identified as the etiological agent of invasive disease. Of 2461 blood cultures performed, 22 were positive for S. pneumoniae. Of 33 cases of S. pneumoniae meningitis, 11 were detected by CSF culture, and 21 were detected by latex agglutination and pneumococcal antigen tests. The rate of detection of S. pneumoniae in CSF was 3.6% by culture, compared with 7.8% by latex agglutination and 10% by pneumococcal antigen testing. The rate of detection of H. influenzae in CSF was 1.7% by culture and 6.5% by latex agglutination. The most common serotypes found were 1, 5, 2, and 7F, followed by 12A, 19B, and 23F. Of all the invasive isolates, 3.8% were resistant to penicillin, and 68% were resistant to trimethoprim-sulfamethoxazole. CONCLUSIONS: The SAPNA network has identified Hib and pneumococci as causes of significant disease in Nepal.

Kidney transplantation in previous heart or lung recipients.

Outcomes after heart and lung transplants have improved, and many recipients survive long enough to develop secondary renal failure, yet remain healthy enough to undergo kidney transplantation. We used national data reported to United Network for Organ Sharing (UNOS) to evaluate outcomes of 568 kidney after heart (KAH) and 210 kidney after lung (KAL) transplants performed between 1995 and 2008. Median time to kidney transplant was 100.3 months after heart, and 90.2 months after lung transplant. Renal failure was attributed to calcineurin inhibitor toxicity in most patients. Outcomes were compared with primary kidney recipients using matched controls (MC) to account for donor, recipient and graft characteristics. Although 5-year renal graft survival was lower than primary kidney recipients (61% KAH vs. 73.8% MC, p < 0.001; 62.6% KAL vs. 82.9% MC, p < 0.001), death-censored graft survival was comparable (84.9% KAH vs. 88.2% MC, p = 0.1; 87.6% KAL vs. 91.8% MC, p = 0.6). Furthermore, renal transplantation reduced the risk of death compared with dialysis by 43% for KAH and 54% for KAL recipients. Our findings that renal grafts function well and provide survival benefit in KAH and KAL recipients, but are limited in longevity by the general life expectancy of these recipients, might help inform clinical decision-making and allocation in this population.

Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery.

Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy approaches to alter cardiac function can be realized, efficient and reproducible in vivo gene techniques must be established to efficiently transfer transgenes globally to the myocardium. We have been testing the hypothesis that genetic manipulation of the myocardial beta-adrenergic receptor (beta-AR) system, which is impaired in HF, can enhance cardiac function. We have delivered adenoviral transgenes, including the human beta2-AR (Adeno-beta2AR), to the myocardium of rabbits using an intracoronary approach. Catheter-mediated Adeno-beta2AR delivery produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. A total of 5 x 10(11) viral particles of Adeno-beta2AR reproducibly produced 5- to 10-fold beta-AR overexpression in the heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic function compared with control rabbits that received an empty adenovirus. Several physiological parameters, including dP/dtmax as a measure of contractility, were significantly enhanced basally and showed increased responsiveness to the beta-agonist isoproterenol. Our results demonstrate that global myocardial in vivo gene delivery is possible and that genetic manipulation of beta-AR density can result in enhanced cardiac performance. Thus, replacement of lost receptors seen in HF may represent novel inotropic therapy.

Wavelet transform analysis predicts outcome of DC cardioversion for atrial fibrillation patients.

The aim of this study was to examine whether wavelet transform analysis of the electrocardiogram (ECG) can improve the prediction of the maintenance of sinus rhythm in patients with atrial fibrillation (AF) after external DC cardioversion. We examined a variety of wavelet transform-based statistical markers as potential candidates for the prediction of patient status post-cardioversion. Considering a 'success' as a patient who remains in normal sinus rhythm for one month post cardioversion and 'failure' as a patient who does not, it was shown the proposed non-parametric classification system can achieve 89% specificity at 100% sensitivity using a non-parametric classification method.

Late-Life Body Mass Index, Rapid Weight Loss, Apolipoprotein E ε4 and the Risk of Cognitive Decline and Incident Dementia.

OBJECTIVES: To examine the effect of late-life body mass index (BMI) and rapid weight loss on incident mild cognitive impairment (MCI) and Alzheimer's disease (AD). DESIGN: Prospective longitudinal cohort study. SETTING: National Alzheimer's Coordinating Center (NACC) Uniform Data Set, including 34 past and current National Institute on Aging-funded AD Centers across the United States. PARTICIPANTS: 6940 older adults (n=5061 normal cognition [NC]; n=1879 MCI). MEASUREMENTS: BMI (kg/m2) and modified Framingham Stroke Risk Profile (FSRP) score (sex, age, systolic blood pressure, anti-hypertension medication, diabetes mellitus, cigarette smoking, prevalent cardiovascular disease, atrial fibrillation) were assessed at baseline. Cognition and weight were assessed annually. RESULTS: Multivariable binary logistic regression, adjusting for age, sex, race, education, length of follow-up, and modified FSRP related late-life BMI to risk of diagnostic conversion from NC to MCI or AD and from MCI to AD. Secondary analyses related late-life BMI to diagnostic conversion in the presence of rapid weight loss (>5% decrease in 12 months) and apolipoprotein E (APOE) ε4. During a mean 3.8-year follow-up period, 12% of NC participants converted to MCI or AD and 49% of MCI participants converted to AD. Higher baseline BMI was associated with a reduced probability of diagnostic conversion, such that for each one-unit increase in baseline BMI there was a reduction in diagnostic conversion for both NC (OR=0.977, 95%CI 0.958-0.996, p=0.015) and MCI participants (OR=0.962, 95%CI 0.942-0.983, p<0.001). The protective effect of higher baseline BMI did not persist in the setting of rapid weight loss but did persist when adjusting for APOE ε4. CONCLUSIONS: Higher late-life BMI is associated with a lower risk of incident MCI and AD but is not protective in the presence of rapid weight loss.

In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.

BACKGROUND: Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo beta-adrenergic receptor kinase (betaARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI). METHODS AND RESULTS: Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5x10(11) viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of betaARK1 (Adeno-betaARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-betaARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the betaARKct. Baseline in vivo LV systolic performance was improved in Adeno-betaARKct-treated animals compared with their individual pre-gene delivery values and compared with EV-treated rabbits. Total beta-AR density and betaARK1 levels were unchanged between treatment groups; however, beta-AR-stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-betaARKct-treated rabbits compared with EV-treated animals. CONCLUSIONS: In vivo delivery of Adeno-betaARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of betaARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of betaARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.