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Background Heart transplant volume varies significantly among centers. We hypothesized that centers where the transplant team routinely accepts organs previously declined by other centers and where operating room availability is unrestricted have higher transplant volumes. Methods and Results We used the potential transplant recipient sequence number in the United Network for Organ Sharing database as a surrogate for graft acceptance threshold and the number of transplantations occurring on weekends and 8 major holidays as a marker of center resource availability. Centers were classified as low-, medium-, or high-volume if the average annual number of transplants were, respectively, 30 over a 10-year period. From July 12, 2006, to December 31, 2015, 19,054 transplants were performed by 142 centers. There were 59 low-volume centers, 69 medium-volume centers, and 14 high-volume centers with median potential transplant recipient sequence numbers for transplanted candidates of 7 (interquartile range 3–11), 7 (5–10), and 15 (7–40), respectively (P = .002). The median proportion of off-hours transplantations performed by medium-volume centers was 28% (25%–31%) compared with 32% (29%–33%) by high-volume centers (P = .009). Five-year survival was equivalent among all centers (P = .053). Conclusions Transplants for candidates with high sequence numbers and unrestricted operating room availability are associated with increased center volume without sacrificing post-transplantation survival.

We present a theoretical analysis of the elastic stresses in a composite reinforced with beaded fibers by extending the classic Cox shear lag theory. The motivation for reinforcing a composite with beaded fibers is to improve both strength and toughness, two often conflicting properties. It is found that owing to their geometry beads intermittently placed on a fiber enhance fiber anchoring in the matrix, and can potentially dissipate energy by deforming the matrix during failure. The composite stiffness is shown to improve compared to a composite with beadless fibers, particularly when the beads are large and stiffer than the surrounding matrix. The stress profiles in the fiber, bead, matrix and along their respective interfaces incur periodic perturbations induced by the beads, modeled by Hill equation. For given elastic constants and bead geometry, these profiles reveal the weakest link loci in the structure, and consequently determine the composite strength and failure mode. A finite element analysis is presented that confirms our results. The bead-fiber and bead-matrix interfaces may be tuned by choice of materials and coatings to achieve desired mechanical properties.

Chronic graft-versus-host disease (cGVHD) targets include the oral mucosa and salivary glands after allogeneic hematopoietic stem cell transplant (HSCT). Without incisional biopsy, no diagnostic test exists to confirm oral cGVHD. Consequently, therapy is often withheld until severe manifestations develop. This proteomic study examined saliva and human salivary gland for a biomarker profile at first onset of oral cGVHD prior to initiation of topical steroid therapy. Whole saliva collected at onset of biopsy-proven oral GVHD was assessed using liquid chromatography coupled tandem mass spectrometry with identification of 569 proteins, of which 77 significantly changed in abundance. ZG16B, a secretory lectin protein, was reduced 2-fold in oral cGVHD saliva (p < 0.05), and significantly decreased in salivary gland secretory cells affected by cGVHD. Single-cell RNAseq analysis of healthy MSG localized ZG16B expression to two discreet acinar cell populations. Reduced ZG16B expression may indicate specific cGVHD activity and possibly general salivary gland dysfunction.

Older patients (aged 60 years or more) awaiting heart transplant often have comorbidities that may limit overall survival independent of cardiac status. We hypothesized that these comorbidities have a more-limiting impact on survival than age of donor heart and that older allografts might be utilized in these patients without compromising outcomes.We identified all transplant recipients aged more than 60 years in the United Network for Organ Sharing database. Local regression analysis detected the point above which increasing donor age incurred increasing risk of mortality, above and below which two cohorts were defined. Kaplan-Meier analysis compared cumulative 5-year survival between groups. Cox proportional hazard modeling was then used to determine the hazards of death in the two groups.An inflection point in posttransplant survival was detected near donor age 50 years. Of 14,113 older recipients studied, 86% received younger donor hearts (less than 50 years of age), and 14% received advanced age allografts (50 years of age or more). Baseline characteristics were comparable between groups except more recipients had left ventricular assist devices at time of transplant in the younger donor group (15% versus 9%, p 0.001). Five-year survival was significantly lower among recipients receiving advanced age hearts compared with those receiving younger hearts (67% versus 73%, log rank p0.001). Adjusting for relevant recipient baseline characteristics, patients receiving advanced age hearts were 30% more likely to die by 5 years compared with patients receiving younger hearts.Transplant recipients aged 60 years and more who receive advanced age donor hearts (50 years or more) have a significantly increased risk of mortality. With careful allograft selection, use of donor hearts to age 50 may be acceptable among older transplant recipients.

Both vaccine and therapeutic approaches to malaria are based on conventional paradigms; whole organism or single antigen epitope-based vaccines administered with or without an adjuvant, and chemotherapeutics (anti-malaria drugs) that are toxic to the parasite. Two major problems that limit the effectiveness of these approaches are i) high levels of antigenic variation within parasite populations rendering vaccination efficacy against all variants difficult, and ii) the capacity of the parasite to quickly evolve resistance to drugs. We describe a new approach to both protection from and treatment of malaria parasites that involves the direct stimulation of the host innate immune response through the administration of a Toll-Like Receptor-2 (TLR2) agonist. The activity of PEG-Pam2Cys against the hepatocytic stages, erythrocytic stages and gametocytes of the rodent malaria parasite Plasmodium yoelii was investigated in laboratory mice. We show that administration of PEG-Pam2Cys, a soluble form of the TLR2 agonist S-[2,3-bis(palmitoyloxy)propyl] cysteine (Pam2Cys), significantly and dramatically reduces the numbers of malaria parasites that grow in the livers of mice following subsequent challenge with sporozoites. We also show that treatment can also clear parasites from the liver when administered subsequent to the establishment of infection. Finally, PEG-Pam2Cys can reduce the numbers of mosquitoes that are infected, and the intensity of their infection, following blood feeding on gametocytaemic mice. These results suggest that this compound could represent a novel liver stage anti-malarial that can be used both for the clearance of parasites following exposure and for the prevention of the establishment of infection., Graphical abstract Image 1, Highlights • TLR-2 agonist Pam2Cys reduces malaria parasite burden in the liver when administered prior to sporozoite challenge. • It also reduces malaria parasite burden in the liver when administered 24 h after sporozoite challenge. • It reduces the transmissibility of a malaria infection to mosquitoes.

Summary Chronic graft-versus-host disease (cGVHD) targets include the oral mucosa and salivary glands after allogeneic hematopoietic stem cell transplant (HSCT). Without incisional biopsy, no diagnostic test exists to confirm oral cGVHD. Consequently, therapy is often withheld until severe manifestations develop. This proteomic study examined saliva and human salivary gland for a biomarker profile at first onset of oral cGVHD prior to initiation of topical steroid therapy. Whole saliva collected at onset of biopsy-proven oral GVHD was assessed using liquid chromatography–coupled tandem mass spectrometry with identification of 569 proteins, of which 77 significantly changed in abundance. ZG16B, a secretory lectin protein, was reduced 2-fold in oral cGVHD saliva (p, Graphical abstract, Highlights • Salivary glands are targets of chronic graft-versus-host disease (cGVHD) • Saliva and salivary glands at onset of oral cGVHD have reduced ZG16B protein • ZG16b gene expression localizes to two types of salivary gland excretory cells • ZG16B expression loss may indicate cGVHD activity or general salivary gland damage, Pathophysiology; Proteomics; Transcriptomics

The geometric modification of fibre-matrix interfaces is a promising approach for simultaneous improvement of strength and toughness of composites. In this study, we investigate the effect of discrete epoxy droplets deposited on glass fibres embedded in an epoxy matrix, using single fibre experiments. Pullout tests reveal increases in both the pullout force and work in beaded fibre samples compared to beadless ones. This is somewhat unexpected as the bead and the matrix are made of the same material (cured epoxy) and possess the same mechanical properties. Interestingly, upon pullout, only the fibres are extracted from the matrix whereas the beads remain within the matrix, indicating that failure occurs at the fibre-bead interface. The simultaneous improvement in pullout force and work seen during the pullout of beaded fibres is explained by a conceptual anchoring mechanism based on friction lock, which agrees well with the experimental results. Smaller beads yield higher increases in pullout force and work, leading to the possibility of denser packing of multiple beaded fibres in a practical composite.

Family-focused prevention programs have been shown to effectively reduce a range of negative behavioral health outcomes but have had limited reach. Three key barriers must be overcome to expand the reach of family-focused prevention programs and thereby achieve a significant public health impact. These barriers are (1) current social norms and perceptions of parenting programs; (2) concerns about the expertise and legitimacy of sponsoring organizations to offer parenting advice; and (3) a paucity of stable, sustainable funding mechanisms. Primary healthcare settings are well positioned to overcome these barriers. Recent changes within health care make primary care settings an increasingly favorable home for family-focused prevention and suggest possibilities for sustainable funding of family-focused prevention programs. This paper discusses the existing advantages of primary care settings and lays out a plan to move toward realizing the potential public health impact of family-focused prevention through widespread implementation in primary healthcare settings.

The aim of this study was to examine the feasibility (accessibility, engagement and impact) of adding social media and gaming features (e.g., social sharing with anonymity, badges to incentivize skills practice, an accredited facilitator for support) and access via smartphones to an evidenced-based parenting program, Triple P Online. The highly vulnerable population included 155 disadvantaged, high-risk parents (e.g., 76% had a family annual income of less than $15,000; 41% had been incarcerated; 38% were in drug/alcohol treatment; and 24% had had a child removed due to maltreatment). The ethnic groups most commonly identified were African American (24%) and Hispanic (66%). Respondents were primarily mothers (86%) from five community programs in Los Angeles. The study used a single group repeated measures design (pre, post, 6-month follow-up). Data collected included standardized self-report measures, post-intervention focus groups and interviews, website usage reports, and Google Analytics. Significant multivariate ANOVA time effects were found, demonstrating reductions in child behavioral problems, reduced lax/permissive and over-reactive parenting, and decreased parental stress. No effects were found for parental confidence, attributions, or depression and anxiety (which were in the normal range at baseline). Positive effects were maintained or improved at 6-month follow-up. The participants engaged in the online community and valued its flexibility, anonymity, and shared learning. This foundational implementation trial provides support for future rigorous evaluation of social media and gaming features as a medium for increasing parental engagement in evidence-based parenting programs online--a public health approach to protect and improve the development of vulnerable children.

Maintenance of lung function is an often underappreciated, yet critical component of healthy aging. Given the unprecedented shift in the average age of Canadians over the next half century, it will be important to investigate the determinants of lung function in the elderly. In the following study, we estimated the association between lung function and a broad array of factors related to sociodemographics, lifestyle, chronic medical conditions and psychosocial factors in older adults aged 45–86 years old using cross-sectional data from the Canadian Longitudinal Study of Aging (n = 21,338). In addition to examining the entire cohort, we also performed stratified analyses within men/women, adults aged 45–64/65+, and healthy/comorbid. In multivariable regression, our explanatory factors (excluding age, sex, height and ethnicity) were able to explain 17% and 11% of the total variance in FEV1 and FEV1/FVC, respectively. Notable and significant contributions were observed for respiratory disease, smoking, obesity, income, and physical activity, while psychosocial factors mainly exhibited non-significant associations. Generally, these associations were stronger for males than females, and adults 65 and older as compared to those aged 45–64. Our findings indicate that there are pervasive and generally under-recognized sociodemographic and lifestyle factors that exhibit significant associations with FEV1 and FEV1/FVC in older adults. While implication of causality in these relationships is not possible due to the cross-sectional nature of the study, future work aiming to investigate determinants of lung health in older adults may choose to target these factors, given that many are modifiable.

Objective Chronic graft-versus-host disease (cGVHD) targets the oral mucosa and salivary glands in 30-70% of cGVHD patients after allogeneic hematopoietic stem cell transplant (HSCT). In the absence of an incisional biopsy, no diagnostic test exists to confirm clinical suspicion of cGVHD processes in oral tissues. Consequently, therapy is often withheld until severe manifestations, such as ulceration, develop. This proteomic study examined whole saliva for the presence of a diagnostic biomarker profile at first onset of oral cGVHD prior to initiation of topical steroid therapy. Methods Patients from NIH protocols (NCT00331968, NCT00520130, or NCT01851382) were sampled at oral cGVHD onset. All cases had biopsy-proven oral GVHD. Five-minute unstimulated whole saliva from 3 individual oral cGVHD patients, 3 post-transplant controls and 2 healthy volunteers was processed, iTRAQ-tagged, HPLC-fractionated, and analyzed via liquid chromatography coupled tandem mass spectrometry. High confidence protein identifications were tested using a Kruskal-Wallis test with Bonferroni correction. Selected proteins were validated by Western blot (WB) using two independent cohorts. Cohort 1: post-HSCT patients with (n=10) and without (n=10) oral cGVHD; Cohort 2: post-HSCT patients with (n=12) and without (n=12) oral cGVHD, controlled for recipient sex and prior total-body irradiation. Fluorescent immunohistochemistry (IHC) was used to further analyze zymogen granule protein 16B (ZG16B) in patient labial minor salivary glands (MSG). Results The discovery dataset contained 569 confidently-identified proteins, with 77 significantly differentially expressed at onset of cGVHD. A 6-protein panel was selected for WB validation in two independent sample cohorts; proteins were selected based on Ingenuity Pathway Analysis, biological function, and protein level. In WB analysis, MMP9, Ezrin, PIP and alpha-1-antichymotrypsin displayed similar abundance levels as in the iTRAQ screen but were not significantly different. ZG16B, a secretory lectin protein associated with the tear release in the lacrimal gland, was reduced 2-fold in saliva of post-HSCT patients with oral cGVHD (898.1 ± 371.8 AU) compared with post-HSCT patients without oral cGVHD (1905 ± 598.6 AU; p Conclusion Taken together, results indicate that ZG16B is present in lower amounts in unstimulated whole saliva and within the salivary gland acinar units at oral cGVHD onset. Reduction in this protein may indicate cGVHD activity and/or salivary gland damage and further investigation of its biological function and potential utility as a clinical biomarker of oral cGVHD onset is needed.

Between 2004 and 2010, 189 adult patients were enrolled on the National Cancer Institute's cross-sectional chronic graft-versus-host disease (cGVHD) natural history study. Patients were evaluated by multiple disease scales and outcome measures, including the 2005 National Institutes of Health (NIH) Consensus Project cGVHD severity scores. The purpose of this study was to assess the validity of the NIH scoring variables as determinants of disease severity in severely affected patients in efforts to standardize clinician evaluation and staging of cGVHD. Out of 189 patients enrolled, 125 met the criteria for severe cGVHD on the NIH global score, 62 of whom had moderate disease, with a median of 4 (range, 1-8) involved organs. Clinician-assigned average NIH organ score and the corresponding organ scores assigned by subspecialists were highly correlated (r = 0.64). NIH global severity scores showed significant associations with nearly all functional and quality of life outcome measures, including the Lee Symptom Scale, Short Form-36 Physical Component Scale, 2-minute walk, grip strength, range of motion, and Human Activity Profile. Joint/fascia, skin, and lung involvement affected function and quality of life most significantly and showed the greatest correlation with outcome measures. The final Cox model with factors jointly predictive for survival included the time from cGVHD diagnosis (>49 versus ≤49 months, hazard ratio [HR] = 0.23; P = .0011), absolute eosinophil count at the time of NIH evaluation (0-0.5 versus >0.5 cells/μL, HR = 3.95; P = .0006), and NIH lung score (3 versus 0-2, HR = 11.02; P < .0001). These results demonstrate that NIH organs and global severity scores are reliable measures of cGVHD disease burden. The strong association with subspecialist evaluation suggests that NIH organ and global severity scores are appropriate for clinical and research assessments, and may serve as a surrogate for more complex subspecialist examinations. In this population of severely affected patients, NIH lung score is the strongest predictor of poor overall survival, both alone and after adjustment for other important factors.

Selection criteria for durable left ventricular assist device (LVAD) implantation remain unclear. One such criterion is renal function. In this study we evaluated outcomes of LVAD implantation in patients with preoperative renal dysfunction.Patients with implanted LVADs as destination therapy (DT) or bridge to transplantation (BTT) at a single institution between 2006 and 2015 were included. Primary stratification was according to pre-implantation glomerular filtration rate (GFR):60 mL/min versus60 mL/min or dialysis dependence. The primary outcome was post-LVAD implantation overall survival.Two hundred thirty-eight patients underwent LVAD implantation during the study period as DT (60%; n = 142) or BTT (40%; n = 96). Reduced GFR was present in 56% (n = 132), with 8% (n = 18) being dialysis-dependent. Normal versus reduced GFR cohorts were well matched except for a higher incidence of coronary artery disease in the patients with reduced GFR (61% vs 48%; P = .04). Mean follow-up was 13.5 ± 17.0 months. Unadjusted and risk-adjusted survival at 1, 3, 6, and 12 months after LVAD implantation were similar between the cohorts for DT and BTT. Rates of transplantation were comparable in BTT patients (61% normal vs 53% reduced GFR; P = .43). Recovery of renal function to a GFR60 mL/min occurred in 43% (n = 17) and 57% (n = 42) of patients with reduced GFR in the BTT and DT cohorts, respectively, by 1 year post implantation.Well selected patients with preexisting renal dysfunction can undergo LVAD implantation with acceptable outcomes. Approximately half of LVAD recipients with preimplantation renal dysfunction will recover normal renal function within the first postoperative year. Renal dysfunction alone should not serve as an absolute contraindication to LVAD therapy.

Life sciences and healthcare enterprises represent the largest industry in the U.S. economy. Given the importance of this sector, there is increasing demand for financial valuation of both publicly and privately held companies. At the same time, accurate valuation is particularly difficult in light of shifting business models, the current economy, intellectual property rights issues, continuous innovation in the sector, changing population demographics, quality issues, and government involvement in healthcare debate, discussion, and regulation. Herein, we examine the changing and increasingly problematic valuation of life sciences and healthcare enterprises that have obvious importance from a social welfare perspective.

The number of foodborne illnesses traced to improper food handling in restaurants indicates a need for research to improve food safety in these establishments. Therefore, this 2-year longitudinal study investigated the effectiveness of traditional ServSafe (National Restaurant Association Educational Foundation, Chicago, IL) food-safety training and a Theory of Planned Behavior intervention program targeting employees' perceived barriers and attitudes toward important food-safety behaviors. The effectiveness of the training and intervention was measured by knowledge scores and observed behavioral compliance rates related to food-safety practices. Employees were observed for handwashing, thermometer usage, and proper handling of work surfaces at baseline, after receiving ServSafe training, and again after exposure to the intervention targeting barriers and negative attitudes about food-safety practices. Repeated-measures analyses of variance indicated training improved handwashing knowledge, but the intervention was necessary to improve overall behavioral compliance and handwashing compliance. Results suggest that registered dietitians; dietetic technicians, registered; and foodservice managers should implement a combination of training and intervention to improve knowledge and compliance with food-safety behaviors, rather than relying on training alone. Challenges encountered while conducting this research are discussed, and recommendations are provided for researchers interested in conducting this type of research in the future.

Current national food safety training programs appear ineffective at improving food safety practices in foodservice operations, given the substantial number of Americans affected by foodborne illnesses after eating in restaurants each year. The Theory of Planned Behavior (TpB) was used to identify important beliefs that may be targeted to improve foodservice employees' intentions for three food safety behaviors that have the most substantial affect on public health: hand washing, using thermometers, and proper handling of food contact surfaces. In a cross-sectional design, foodservice employees (n=190) across three midwestern states completed a survey assessing TpB components and knowledge for the three food safety behaviors. Multiple regression analyses were performed on the TpB components for each behavior. Independent-samples t tests identified TpB beliefs that discriminated between participants who absolutely intend to perform the behaviors and those with lower intention. Employees' attitudes were the one consistent predictor of intentions for performing all three behaviors. However, a unique combination of important predictors existed for each separate behavior. Interventions for improving employees' behavioral intentions for food safety should focus on TpB components that predict intentions for each behavior and should bring all employees' beliefs in line with those of the employees who already intend to perform the food safety behaviors. Registered dietitians; dietetic technicians, registered; and foodservice managers can use these results to enhance training sessions and motivational programs to improve employees' food safety behaviors. Results also assist these professionals in recognizing their responsibility for enforcing and providing adequate resources for proper food safety behaviors.

c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU11274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers.

Telomere elongation is cell-cycle regulated and requires the coordinated activity of proteins involved in the DNA damage response. We used an assay that detects de novo telomere addition to examine the role of the cyclin-dependent kinase Cdk1 (Cdc28) in cell-cycle-specific telomere elongation. Inhibition of an ATP analog-sensitive allele of Cdk1 completely blocked the addition of telomere repeats. Mutations in Rif2 and DNA polymerase alpha that cause increased telomere elongation were unable to compensate for the loss of Cdk1 activity, suggesting Cdk1 activity is required for an early step in telomere addition. Mutations in DNA repair proteins that act with Cdk1 at double-strand breaks also prevented telomere elongation. Cdk1 activity was required for the generation of 3' single-strand overhangs at both native and de novo telomeres. We propose Cdk1 activity controls the timing of telomere elongation by regulating the single-strand overhang at chromosome ends.

Eukaryotic cells undergo arrest and enter apoptosis in response to short telomeres. T cells from late generation mTR(-/-) mice that lack telomerase show increased apoptosis when stimulated to enter the cell cycle. The increased apoptosis was not inhibited by colcemid, indicating that the response did not result from breakage of dicentric chromosomes at mitosis. The damage response protein gamma-H2AX localized to telomeres in metaphases from T cells and fibroblasts from mTR(-/-) cells with short telomeres. These data suggest that the major mechanism for induction of apoptosis in late generation mTR(-/-) cells is independent of chromosome segregation and that loss of telomere function through progressive telomere shortening in the absence of telomerase leads to recognition of telomeres as DNA breaks.

By proactively setting and driving a esearch agenda that scientifically roves the value of dietetic services, he nearly 70,000 members of the merican Dietetic Association (ADA) re making sure that the future of ietetics will be a bright one. “Priorities for Research: Agenda to upport the Future of Dietetics” will rovide key input or answers to all of he above questions (1). The Research ommittee developed the Priorities ver the past 2 years with input from any members throughout the ADA nd researchers who are not ADA embers (Figure). The impetus for evelopment of the Priorities is the

Telomerase RNA is an intrinsic component of the telomerase enzyme. A short template sequence in the telomerase RNA is copied by the catalytic telomerase reverse transcriptase (TERT) to synthesize telomere repeats to chromosome ends. In addition to the template, other conserved RNA structural elements play important parts in catalysis as well as localization, maturation and assembly of telomerase. Telomerase RNA is mutated in the autosomal dominant form of the disease dyskeratosis congenita. Recent studies of telomerase RNA function and telomerase biogenesis have provided a basis for understanding the role of telomerase in this disease.