The prevalence of disability in elderly in India - Analysis of 2011 census data.
Advancing age leads to physical and sensory impairment with varying degrees of disability. There is lack of publication focusing on disability of elderly in India with a countrywide state-based analysis of all types of disabilities. To measure the prevalence of disability and describe the types of disability in the elderly Indian population by gender, advancing age, states and geographical regions. The 2011 Census cross-sectional survey data restricted to elderly in India was analyzed. 'Elderly' is defined as a person who is of age 60 years or above. Disability rates per 100,000 elderly population and age-adjusted disability rates were calculated. A total of 5,376,205 elderly individuals were disabled in India in 2011; disability rate of 5178 per 100,000 elderly population. Movement and seeing disabilities individually accounted for 25% of total disabilities and disability in hearing was 19%. Disability rates in 17 Indian States and Union Territories were above the national average. Disability rates increased as age advanced with the highest disability rate of 8409 per 100,000 among people aged 80 yrs or above. The disability rates were higher in males than females (5314 vs. 5045 per 100,000) and in rural compared to urban areas (5593 vs. 4181 per 100,000). Currently married and working populations had lower disability rates. One in every twenty Indian citizens aged 60 yrs and above is either physically or mentally disabled. Identification of the underlying causes, employing effective and focused preventive strategies will help to reduce the prevalence of disability in the elderly.


Transition from parenteral to enteral nutrition induces immediate diet-dependent gut histological and immunological responses in preterm neonates.
Necrotizing enterocolitis (NEC) in preterm infants develops very rapidly from a mild intolerance to enteral feeding into intestinal mucosal hemorrhage, inflammation, and necrosis. We hypothesized that immediate feeding-induced gut responses precede later clinical NEC symptoms in preterm pigs. Fifty-six preterm pigs were fed total parenteral nutrition (TPN) for 48 h followed by enteral feeding for 0, 8, 17, or 34 h with either colostrum (Colos, n = 20) or formula (Form, n = 31). Macroscopic NEC lesions were detected in Form pigs throughout the enteral feeding period (20/31, 65%), whereas most Colos pigs remained protected (1/20, 5%). Just 8 h of formula feeding induced histopathological lesions, as evidenced by capillary stasis and necrosis, epithelial degeneration, edema, and mucosal hemorrhage. These immediate formula-induced changes were paralleled by decreased digestive enzyme activities (lactase and dipeptidylpeptidase IV), increased nutrient fermentation, and altered expression of innate immune defense genes such as interleukins (IL-1α, IL-6, IL-18), nitric oxide synthetase, tight junction proteins (claudins), Toll-like receptors (TLR-4), and TNF-α. In contrast, the first hours of colostrum feeding induced no histopathological lesions, increased maltase activity, and induced changes in gene expressions related to tissue development. Total bacterial density was high after 2 days of parenteral feeding and was not significantly affected by diet (colostrum, formula) or length of enteral feeding (8-34 h), except that a few bacterial groups (Clostridium, Enterococcus, Streptococcus species) increased with time. We conclude that a switch from parenteral to enteral nutrition rapidly induces diet-dependent histopathological, functional, and proinflammatory insults to the immature intestine. Great care is required when introducing enteral feeds to TPN-fed preterm infants, particularly when using formula, because early feeding-induced insults may predispose to NEC lesions that are difficult to revert by later dietary or medical interventions.


Evaluation of the relationship between Orthopedic Foundation for Animals' hip joint scores and PennHIP distraction index values in dogs.
To compare 2 screening methods for detecting evidence of hip dysplasia (Orthopedic Foundation for Animals [OFA] and PennHIP) in dogs. Diagnostic test evaluation study. Animals-439 dogs >or= 24 months of age that received routine hip joint screening from June 1987 through July 2008. Dogs were sedated, and PennHIP radiography was performed (hip joint- extended [HE], compression, and distraction radiographic views). The HE radiographic view was submitted for OFA evaluation. A copy of the HE radiographic view plus the compression and distraction radiographic views were submitted for routine PennHIP evaluation, including quantification of hip joint laxity via the distraction index (DI). 14% (60/439) of dogs had hip joints scored as excellent by OFA standards; however, 52% (31/60) of those had a DI >or= 0.30 (range, 0.14 to 0.61). Eighty-two percent of (183/223) dogs with OFA-rated good hip joints had a DI >or= 0.30 (range, 0.10 to 0.77), and 94% (79/84) of dogs with OFA-rated fair hip joints had a DI >or= 0.30 (range, 0.14 to 0.77). Of all dogs with fair to excellent hip joints by OFA standards, 80% (293/367) had a DI >or= 0.30. All dogs with OFA-rated borderline hip joints or mild, moderate, or severe hip dysplasia had a DI >or= 0.30 (range, 0.30 to 0.83). Dogs judged as phenotypically normal by the OFA harbored clinically important passive hip joint laxity as determined via distraction radiography. Results suggested that OFA scoring of HE radiographs underestimated susceptibility to osteoarthritis in dogs, which may impede progress in reducing or eliminating hip dysplasia through breeding.


Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections.
Newborn screening for cystic fibrosis (CF) provides a model to investigate the implications of applying multiple-mutation DNA testing in screening for any disorder in a pediatric population-based setting, where detection of affected infants is desired and identification of unaffected carriers is not. Widely applied 2-tiered CF newborn screening strategies first test for elevated immunoreactive trypsinogen (IRT) with subsequent analysis for a single CFTR mutation (DeltaF508), systematically missing CF-affected infants with any of the >1000 less common or population-specific mutations. Comparison of CF newborn screening algorithms that incorporate single- and multiple-mutation testing may offer insights into strategies that maximize the public health value of screening for CF and other genetic disorders. The objective of this study was to evaluate technical feasibility and practical implications of 2-tiered CF newborn screening that uses testing for multiple mutations (multiple-CFTR-mutation testing). We implemented statewide CF newborn screening using a 2-tiered algorithm: all specimens were assayed for IRT; those with elevated IRT then had multiple-CFTR-mutation testing. Infants who screened positive by detection of 1 or 2 mutations or extremely elevated IRT (>99.8%; failsafe protocol) were then referred for definitive diagnosis by sweat testing. We compared the number of sweat-test referrals using single- with multiple-CFTR-mutation testing. Initial physician assessments and diagnostic outcomes of these screened-positive infants and any affected infants missed by the screen were analyzed. We evaluated compliance with our screening and follow-up protocols. All Massachusetts delivery units, the Newborn Screening Program, pediatric health care providers who evaluate and refer screened-positive infants, and the 5 Massachusetts CF Centers and their affiliated genetic services participated. A 4-year cohort of 323 506 infants who were born in Massachusetts between February 1, 1999, and February 1, 2003, and screened for CF at approximately 2 days of age was studied. A total of 110 of 112 CF-affected infants screened (negative predictive value: 99.99%) were detected with IRT/multiple-CFTR-mutation screening; 2 false-negative screens did not show elevated IRT. A total of 107 (97%) of the 110 had 1 or 2 mutations detected by the multiple- CFTR-mutation screen, and 3 had positive screens on the basis of the failsafe protocol. In contrast, had we used single-mutation testing, only 96 (87%) of the 110 would have had 1 or 2 mutations detectable by single-mutation screen, 8 would have had positive screens on the basis of the failsafe protocol, and an additional 6 infants would have had false-negative screens. Among 110 CF-affected screened-positive infants, a likely "genetic diagnosis" was made by the multiple-CFTR-mutation screen in 82 (75%) versus 55 (50%) with DeltaF508 alone. Increased sensitivity from multiple-CFTR-mutation testing yielded 274 (26%) more referrals for sweat testing and carrier identifications than testing with DeltaF508 alone. Use of multiple-CFTR-mutation testing improved sensitivity and postscreening prediction of CF at the cost of increased referrals and carrier identification.


PilG is Involved in the Regulation of Twitching Motility and Antifungal Antibiotic Biosynthesis in the Biological Control Agent Lysobacter enzymogenes.
Lysobacter enzymogenes strain C3 is a gliding bacterium which produces the antifungal secondary metabolite heat-stable antifungal factor (HSAF) and type IV pilus (T4P) as important mechanisms in biological control activity against fungal pathogens. To date, the regulators that control HSAF biosynthesis and T4P-dependent twitching motility in L. enzymogenes are poorly explored. In the present study, we addressed the role of pilG in the regulation of these two traits in L. enzymogenes. PilG of L. enzymogenes was found to be a response regulator, commonly known as a component of a two-component transduction system. Mutation of pilG in strain C3 abolished its ability to display spreading colony phenotype and cell movement at the colony margin, which is indicative of twitching motility; hence, PilG positively regulates twitching motility in L. enzymogenes. Mutation of pilG also enhanced HSAF production and the transcription of its key biosynthetic gene hsaf pks/nrps, suggesting that PilG plays a negative regulatory role in HSAF biosynthesis. This finding represents the first demonstration of the regulator PilG having a role in secondary metabolite biosynthesis in bacteria. Collectively, our results suggest that key ecological functions (HSAF production and twitching motility) in L. enzymogenes strain C3 are regulated in opposite directions by the same regulatory protein, PilG.


Effectiveness and Acceptability of Cognitive Behavior Therapy Delivery Formats in Adults With Depression: A Network Meta-analysis.
Cognitive behavior therapy (CBT) has been shown to be effective in the treatment of acute depression. However, whether CBT can be effectively delivered in individual, group, telephone-administered, guided self-help, and unguided self-help formats remains unclear. To examine the most effective delivery format for CBT via a network meta-analysis. A database updated yearly from PubMed, PsycINFO, Embase, and the Cochrane Library. Literature search dates encompassed January 1, 1966, to January 1, 2018. Randomized clinical trials of CBT for adult depression. The 5 treatment formats were compared with each other and the control conditions (waiting list, care as usual, and pill placebo). PRISMA guidelines were used when extracting data and assessing data quality. Data were pooled using a random-effects model. Pairwise and network meta-analyses were conducted. Severity of depression and acceptability of the treatment formats. A total of 155 trials with 15 191 participants compared 5 CBT delivery formats with 2 control conditions. In half of the studies (78 [50.3%]), patients met the criteria for a depressive disorder; in the other half (77 [49.7%]), participants scored above the cutoff point on a self-report measure. The effectiveness of individual, group, telephone, and guided self-help CBT did not differ statistically significantly from each other. These formats were statistically significantly more effective than the waiting list (standardized mean differences [SMDs], 0.87-1.02) and care as usual (SMDs, 0.47-0.72) control conditions as well as the unguided self-help CBT (SMDs, 0.34-0.59). In terms of acceptability (dropout for any reason), individual (relative risk [RR] = 1.44; 95% CI, 1.09-1.89) and group (RR = 1.38; 95% CI, 1.06-1.80) CBT were significantly better than guided self-help. Guided self-help was also less acceptable than being on a waiting list (RR = 0.63; 95% CI, 0.52-0.75) and care as usual (RR = 0.72; 95% CI, 0.57-0.90). Sensitivity analyses supported the overall findings. For acute symptoms of depression, group, telephone, and guided self-help treatment formats appeared to be effective interventions, which may be considered as alternatives to individual CBT; although there were few indications of significant differences in efficacy between treatments with human support, guided self-help CBT may be less acceptable for patients than individual, group, or telephone formats.


Risk of chemotherapy-induced febrile neutropenia in patients with metastatic cancer not receiving granulocyte colony-stimulating factor prophylaxis in US clinical practice.
To evaluate the use of granulocyte colony-stimulating factor (G-CSF) prophylaxis in US patients with selected metastatic cancers and chemotherapy-induced febrile neutropenia (FN) incidence and associated outcomes among the subgroup who did not receive prophylaxis. This retrospective cohort study was conducted at four US health systems and included adults with metastatic cancer (breast, colorectal, lung, non-Hodgkin lymphoma [NHL]) who received myelosuppressive chemotherapy (2009-2017). Patients were stratified by FN risk level based on risk factors and chemotherapy (low/unclassified risk, intermediate risk without any risk factors, intermediate risk with ≥ 1 risk factor [IR + 1], high risk [HR]). G-CSF use was evaluated among all patients stratified by FN risk, and FN/FN-related outcomes were evaluated among patients who did not receive first-cycle G-CSF prophylaxis. Among 1457 metastatic cancer patients, 20.5% and 28.1% were classified as HR and IR + 1, respectively. First-cycle G-CSF prophylaxis use was 48.5% among HR patients and 13.9% among IR + 1 patients. In the subgroup not receiving first-cycle G-CSF prophylaxis, FN incidence in cycle 1 was 7.8% for HR patients and 4.8% for IR + 1 patients; during the course, corresponding values were 16.9% and 15.9%. Most (> 90%) FN episodes required hospitalization, and mortality risk ranged from 7.1 to 26.9% across subgroups. In this retrospective study, the majority of metastatic cancer chemotherapy patients for whom G-CSF prophylaxis is recommended did not receive it; FN incidence in this subgroup was notably high. Patients with elevated FN risk should be carefully identified and managed to ensure appropriate use of supportive care.


The Social Ecology of School-Age Child Care.
The goal of this longitudinal study was to examine variations in school-age child care arrangements across the elementary school years as a function of child, family, and contextual factors. Pre-kindergarten family background measures were collected through parent questionnaires and interviews. Follow-up interviews with 466 parents provided information on children's care experiences in grades 1 through 5. Some care arrangements (e.g., self care) showed considerable continuity, whereas other arrangements (e.g., school programs) changed substantially from year-to-year. Increases in use were found for self-care, sibling care, neighbor care, and activity-based care; use of day care decreased across years. Children living with working and/or single mothers spent more time in non-parent care, as did boys with behavior problems. Time spent in specific care arrangements varied as a function of child sex, behavioral adjustment, ethnicity, family socio-economic status, mothers' employment, and parents' marital status. These findings underscore the importance of developmental and ecological-contextual factors in families' choices of care arrangements.


S1P receptor 1-Mediated Anti-Renin-Angiotensin System Cardioprotection: Pivotal Role of Mast Cell Aldehyde Dehydrogenase Type 2.
In the ischemic-reperfused (I/R) heart, renin-containing mast cells (MC) release enzymatically active renin, activating a local renin-angiotensin system (RAS), causing excessive norepinephrine release and arrhythmic dysfunction. Activation of Gi-receptors on MC and/or ischemic preconditioning (IPC) prevent renin release, thus providing anti-RAS cardioprotection. We questioned whether sphingosine-1-phosphate (S1P), a sphingolipid produced in the I/R heart, might afford anti-RAS cardioprotection by activating Gi-coupled S1P1 receptors (S1P1R) on MC. We report that activation of Gi-coupled S1P1R in cardiac MC confers IPC-like anti-RAS cardioprotection due to S1P1R-mediated inhibition of I/R-induced cardiac MC degranulation and renin release. This results from an initial translocation of protein kinase C subtype-ε and subsequent activation of aldehyde dehydrogenase type 2 (ALDH2), culminating in the elimination of the MC-degranulating effects of acetaldehyde and other toxic species produced during I/R. Inhibition of toxic aldehydes-induced MC-renin release prevents local RAS activation, reduces infarct size, and alleviates arrhythmias. Notably, these cardioprotective effects are lacking in hearts and MC from gene-targeted knock-in mice (ALDH2*2) in which ALDH2 enzymatic activity is maximally reduced. Thus, ALDH2 appears to play a pivotal role in this protective process. Our findings suggest that MC S1P1R may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.


Assessment of concurrent stereotactic radiosurgery and bevacizumab treatment of recurrent malignant gliomas using multi-modality MRI imaging and radiomics analysis.
To assess the response and predict the overall survival (OS) of recurrent malignant gliomas (MG) patients treated with concurrent BVZ/SRS using multi-modality MRI imaging and radiomics analysis.Methods and materials: SRS was delivered in a single fraction (18/24Gy) or 25Gy in 5 fractions. BVZ was administered immediately before SRS and 2 weeks after. MRI scans were performed before SRS, 1 week and 2 months after SRS. The MR protocol included 2 anatomical (T1w and T2w) and 2 functional (dynamic contrast-enhanced DCE-MRI and diffusion weighted DW-MRI) modalities. Functional biomarkers including apparent diffusion coefficient (ADC), micro-vascular transfer constant Ktrans, brain blood flow FB, and blood volume VB were analyzed. Radiomics analysis was performed to extract imaging features from anatomical MRI images and functional biomarker maps. Wicoxon signed rank tests were performed to evaluate treatment-induced changes, and Mann-Whitney U tests were performed to compare the differences of treatment-induced changes between different patient groups. Selected biomarkers and radiomics features were used to predict the OS after treatment using Support Vector Regression (SVR) with leave-one-out cross validation (LOOCV). Twelve patients with recurrent MG were studied. The median OS was 13.8 months post SRS. DCE results showed that Ktrans (p=0.035) and VB (p=0.035) showed significant decrease 2 months after SRS, and FB showed significant decrease as early as 1 week (p=0.017) after SRS. No functional parameters reflected statistically significant treatment response 1 week after SRS. A total of 888 radiomics features were extracted. 31/126 features demonstrated significant changes 1 week/2 months after SRS, respectively. 9 features' changes were significantly different between WHO Grade III vs IV patient groups, and 6 features' changes were found to be linearly correlated with OS. Using 5 selected features, 9 patients' survival time could be accurately predicted (Mean absolute error = 1.47 months, RMSE = 2.10 months). The results of this work demonstrate the potential of combined radiomics analysis and functional MR imaging in quantitatively identifying early treatment response of concurrent SRS/BVZ.


Abnormal access of axial vibrotactile input to deafferented somatosensory cortex in human upper limb amputees.
We studied two human subjects with total deafferentation of one upper limb secondary to traumatic multiple cervical root avulsions. Both subjects developed a phantom limb and underwent elective amputation of the paralyzed, deafferentated limb. Psychophysical study revealed in each subject an area of skin in the pectoral region ipsilateral to the amputation where vibrotactile stimulation (VS) elicited referred sensations (RS) in the phantom limb. Positron emission tomography was then used to measure regional cerebral blood flow changes during VS of the pectoral region ipsilateral to the amputation with RS and during VS of a homologous part of the pectoral region adjacent to the intact arm without RS. A voxel-based correlation analysis was subsequently used to study functional connectivity. VS of the pectoral region adjacent to the intact arm was associated with activation of the dorsal part of the contralateral primary somatosensory cortex (S1) in a position consistent with the S1 trunk area. In contrast, VS of the pectoral region ipsilateral to the amputation with RS was associated with activation of the contralateral S1 that extended from the level of the trunk representation ventrally over distances of 20 and 12 mm, respectively, in the two subjects. The area of S1 activated during VS of the digits in a normal control subject was coextensive with the ventral S1 region abnormally activated during VS of the ectopic phantom representation in the two amputees, suggesting that the deafferented digit or hand/arm area had been activated by sensory input from the pectoral region. Correlation analysis showed an abnormal pattern of intrinsic connectivity within the deafferented S1 hand/arm area of both amputees. In one subject, the deafferented S1 was functionally connected with 3 times as many S1 voxels as the normally afferented S1. This abnormal functional connectivity extended in both the rostrocaudal and ventrodorsal dimensions. The results demonstrate that sensory input delivered to the axial body surface may gain access to the S1 hand/arm area in some humans who have suffered extensive deafferentation of this area. The findings are consistent with the hypothesis that deafferentation of an area of S1 may result in activation of previously dormant inputs from body surfaces represented in immediately adjacent parts of S1. The results also provide evidence that changes in functional connectivity between these adjacent areas of the cortex play a role in the somatotopic reorganization.


Macrophage-endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa.
Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here, we describe what we believe to be a new mechanism where vessel-associated macrophages through localized interactions primed EC responses to form ICAM-1 "hot spots" to support PMN TEM. Using real-time intravital microscopy of LPS-inflamed intestines in CX3CR1-EGFP macrophage-reporter mice, complemented by whole-mount tissue imaging and flow cytometry, we found that macrophage vessel association is critical for the initiation of PMN-EC adhesive interactions, PMN TEM, and subsequent accumulation in the intestinal mucosa. Anti-colony stimulating factor 1 receptor Ab-mediated macrophage depletion in the lamina propria and at the vessel wall resulted in elimination of ICAM-1 hot spots impeding PMN-EC interactions and TEM. Mechanistically, the use of human clinical specimens, TNF-α-KO macrophage chimeras, TNF-α/TNF receptor (TNF-α/TNFR) neutralization, and multicellular macrophage-EC-PMN cocultures revealed that macrophage-derived TNF-α and EC TNFR2 axis mediated this regulatory mechanism and was required for PMN TEM. As such, our findings identified clinically relevant mechanisms by which macrophages regulate PMN trafficking in inflamed mucosa.


Statin prescription rates and their facility-level variation in patients with peripheral artery disease and ischemic cerebrovascular disease: Insights from the Department of Veterans Affairs.
The 2013 American College of Cardiology/American Heart Association cholesterol guideline recommends moderate to high-intensity statin therapy in patients with peripheral artery disease (PAD) and ischemic cerebrovascular disease (ICVD). We examined frequency and facility-level variation in any statin prescription and in guideline-concordant statin prescriptions in patients with PAD and ICVD receiving primary care in 130 facilities across the Veterans Affairs (VA) health care system between October 2013 and September 2014. Guideline-concordant statin intensity was defined as the prescription of high-intensity statins in patients with PAD or ICVD ≤75 years and at least moderate-intensity statins in those >75 years. We calculated median rate ratios (MRR) after adjusting for patient demographic factors to assess the magnitude of facility-level variation in statin prescribing patterns independent of patient characteristics. Among 194,151 PAD patients, 153,438 patients (79.0%) were prescribed any statin and 79,435 (40.9%) were prescribed a guideline-concordant intensity of statin. PAD patients without ischemic heart disease were prescribed any statin and a guideline-concordant intensity of statin therapy less frequently (69.1% and 28.9%, respectively). Among 339,771 ICVD patients, 265,491 (78.1%) were prescribed any statin and 136,430 (40.2%) were prescribed a guideline-concordant intensity of statin. ICVD patients without ischemic heart disease were prescribed any statin and a guideline-concordant intensity of statin less frequently (70.9% and 30.5%, respectively). MRRs for both PAD and ICVD patients demonstrated a 20% and 28% variation among two facilities in treating two identical patients with statin therapy and guideline-concordant intensity of statin therapy, respectively. The prescription of statins, especially guideline-recommended intensity of statin therapy, is suboptimal in PAD and ICVD patients, with significant facility-level variation not explained by patient-level factors.


The Effects of Cost Sharing on Adherence to Medications Prescribed for Concurrent Use: Do Definitions Matter?
Accurate estimates of the effects of cost sharing on adherence to medications prescribed for use together, also called concurrent adherence, are important for researchers, payers, and policymakers who want to reduce barriers to adherence for chronic condition patients prescribed multiple medications concurrently. But measure definition consensus is lacking, and the effects of different definitions on estimates of cost-related nonadherence are unevaluated. To (a) compare estimates of cost-related nonadherence using different measure definitions and (b) provide guidance for analyses of the effects of cost sharing on concurrent adherence. This is a retrospective cohort study of Medicare Part D beneficiaries aged 65 years and older who used multiple oral antidiabetics concurrently in 2008 and 2009. We compared patients with standard coverage, which contains cost-sharing requirements in deductible (100%), initial (25%), and coverage gap (100%) phases, to patients with a low-income subsidy (LIS) and minimal cost-sharing requirements. Data source was the IMS Health Longitudinal Prescription Database. Patients with standard coverage were propensity matched to controls with LIS coverage. Propensity score was developed using logistic regression to model likelihood of Part D standard enrollment, controlling for sociodemographic and health status characteristics. For analysis, 3 definitions were used for unadjusted and adjusted estimates of adherence: (1) patients adherent to All medications; (2) patients adherent on Average; and (3) patients adherent to Any medication. Analyses were conducted using the full study sample and then repeated in analytic subgroups where patients used (a) 1 or more costly branded oral antidiabetics or (b) inexpensive generics only. We identified 12,771 propensity matched patients with Medicare Part D standard (N = 6,298) or LIS (N = 6,473) coverage who used oral antidiabetics in 2 or more of the same classes in 2008 and 2009. In this sample, estimates of the effects of cost sharing on concurrent adherence varied by measure definition, coverage type, and proportion of patients using more costly branded drugs. Adherence rates ranged from 37% (All: standard patients using 1+ branded) to 97% (Any: LIS using generics only). In adjusted estimates, standard patients using branded drugs had 0.63 (95% CI = 0.57-0.70) and 0.70 (95% CI = 0.63-0.77) times the odds of concurrent adherence using All and Average definitions, respectively. The Any subgroup was not significant (OR = 0.89, 95% CI = 0.87-1.17). Estimates also varied in the full-study sample (All: OR = 0.79, 95% CI = 0.74-0.85; Average: OR = 0.83, 95% CI = 0.77-0.89) and generics-only subgroup, although cost-sharing effects were smaller. The Any subgroup generated no significant estimates. Different concurrent adherence measure definitions lead to markedly different findings of the effects of cost sharing on concurrent adherence, with All and Average subgroups sensitive to these effects. However, when more study patients use inexpensive generics, estimates of these effects on adherence to branded medications with higher cost-sharing requirements may be diluted. When selecting a measure definition, researchers, payers, and policy analysts should consider the range of medication prices patients face, use a measure sensitive to the effects of cost sharing on adherence, and perform subgroup analyses for patients prescribed more medications for which they must pay more, since these patients are most vulnerable to cost-related nonadherence.


Associations of lipoprotein lipase gene polymorphisms with longitudinal plasma lipid trends in young adults: The Coronary Artery Risk Development in Young Adults (CARDIA) study.
Genome-wide association studies in European Americans have reported several single-nucleotide polymorphisms (SNPs) in the lipoprotein lipase gene associated with plasma levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides. However, the influences of the lipoprotein lipase SNPs on longitudinal changes of these lipids have not been systematically examined. On the basis of data from 2045 African Americans and 2116 European Americans in the Coronary Artery Risk Development in Young Adults study, we investigated cross-sectional and longitudinal associations of lipids with 8 lipoprotein lipase SNPs, including the 2 that have been reported in genome-wide association studies. Plasma levels of HDL-C and triglycerides were measured at 7 examinations during 20 years of follow-up. In European Americans, rs328 (Ser447Stop), rs326, and rs13702 were significantly associated with cross-sectional interindividual variations in triglycerides and HDL-C (P<0.005) and with their longitudinal changes over time (P<0.05). The minor alleles in rs326, rs328, and rs13702 that predispose an individual to lower triglycerides and higher HDL-C levels at young adulthood further slow down the trajectory increase in triglycerides and decrease in HDL-C during 20 years of follow-up. In African Americans, these 3 SNPs were significantly associated with triglycerides, but only rs326 and rs13702 were associated with HDL-C (P<0.008). Rs328 showed a stronger association in European Americans than in African Americans, and adjustment for it did not remove all of the associations for the other SNPs. Longitudinal changes in either trait did not differ significantly by SNP genotypes in African Americans. Our data suggest that aging interacts with LPL gene variants to influence the longitudinal lipid variations, and there is population-related heterogeneity in the longitudinal associations.


School Food and Physical Activity Environment: A Longitudinal Analysis of Four School Districts in New Jersey.
Exposures to favorable environments in childhood, including those in schools, are associated with healthy habits among children. In this study, we developed a series of indices aimed at measuring students' exposure to different dimensions of the school food and physical activity (PA) environment. We implemented these indices to investigate how different aspects of the school food and PA environment changed over time and examined their correspondence with known changes in relevant policies and programs. All public schools (n= 141) in four school districts in New Jersey provided detailed food and PA environment data for each school year from 2010-2011 to 2015-2016. Seven food environment indices, three PA environment indices, and two additional indices that capture health-promoting initiatives at the school level and at the state or federal level were developed. Although the school PA environment largely remained unchanged, several dimensions of the school food environment changed between 2010-2011 and 2015-2016. Overall, the number of healthy items increased over time in vending machines (p < .001), a la carte (p < .05), or through reimbursable school lunches (p < .001); decreases in number of unhealthy items were only detected in school lunches (p < .05). For most food indices, both the number of items offered and the trend over time varied across school levels. Schools are a key venue for implementing policy and environment interventions aimed to promote healthy behaviors. Indices developed from easy-to-use survey questions captured multiple dimensions of the school food and PA environments and were sensitive to policy changes over time.


Fibrolipomatous hamartoma of nerve arising in the brachial plexus.
Fibrolipomatous hamartoma of nerve is a rare benign infiltrating condition of peripheral nerves leading to progressive functional loss. Previous descriptions have virtually all been confined to the distal part of the upper limb, with the median nerve being the commonest reported site. Most cases occur in the first 3 decades of life and a third are associated with macrodactyly. A case is described in a 63-year-old woman, involving the whole of the brachial plexus, a previously unreported site for this particular lesion.


The effect of age on short-term outcomes after pancreatic resection: a population-based study.
To use a large population-based cohort to determine age-dependent short-term outcomes after pancreatic resection. We identified all pancreatic resections in Texas from 1999 to 2005. Patients were stratified into 4 age groups (<60, 60-69, 70-79, and 80+ years). Bivariate and multivariate analyses were performed to determine the effect of age on mortality, discharge to home versus requiring inpatient nursing care, and length of stay. Three thousand seven hundred and thirty-six patients underwent pancreatic resection. Unadjusted in-hospital mortality increased with each increasing age group from 2.4% in patients <60 to 11.4% in patients 80 years and older (P < 0.0001). Likewise, postoperative lengths of stay increased with each increasing age group (P = 0.02). Age group independently predicted the need for discharge to an inpatient nursing unit rather than home (P < 0.0001), with the odds ration (OR) increasing with each increasing age group. With each increasing age group, patients were less likely to be resected at high-volume (H-V) hospitals (>10 pancreatic resections/y). Whereas low-volume (L-V) hospitals (< or =10 pancreatic resections/y) had higher mortality rates (3.2% versus 7.3%, P < 0.0001), the difference in mortality between H- and L-V hospitals was more striking in older patients. With increasing age group, mortality increased from 3.0% to 9.5% to 11.4% to 14.7% at L-V hospitals. It increased from 2.0% to 3.5% to 4.5% to 8.7% at H-V hospitals (P < 0.0001). In the multivariate model controlling for gender, race, hospital volume, year of surgery, diagnosis, risk of mortality, severity of illness, admission status, and procedure type, older age group independently predicted increased mortality. The OR for patients 60-69 years was 2.5 (P = 0.0003), the OR for patients 70-79 years was 1.8 (P = 0.02), and the OR for patients 80+ years was 4.4 (P < 0.0001) when compared with patients <60 years. In contrast to some previous single-institution studies, we found that increased age is an independent risk factor for mortality after pancreatic resection. For all ages, mortality rates were higher at L-V hospitals, but the difference worsened significantly with increasing age. Older patients had longer lengths of stay, were less likely to be discharged home, and more likely to require care at an inpatient nursing or acute care facility at the time of discharge.


The Implementation and Validation of a Virtual Environment for Training Powered Wheelchair Manoeuvres.
Navigating a powered wheelchair and avoiding collisions is often a daunting task for new wheelchair users. It takes time and practice to gain the coordination needed to become a competent driver and this can be even more of a challenge for someone with a disability. We present a cost-effective virtual reality (VR) application that takes advantage of consumer level VR hardware. The system can be easily deployed in an assessment centre or for home use, and does not depend on a specialized high-end virtual environment such as a Powerwall or CAVE. This paper reviews previous work that has used virtual environments technology for training tasks, particularly wheelchair simulation. We then describe the implementation of our own system and the first validation study carried out using thirty three able bodied volunteers. The study results indicate that at a significance level of 5 percent then there is an improvement in driving skills from the use of our VR system. We thus have the potential to develop the competency of a wheelchair user whilst avoiding the risks inherent to training in the real world. However, the occurrence of cybersickness is a particular problem in this application that will need to be addressed.


Assessment of Genetic Diversity and Symbiotic Efficiency of Selected Rhizobia Strains Nodulating Lentil (Lens culinaris Medik.).
A total of 14 Rhizobium strains were isolated from lentil accessions grown at the ICARDA experimental research station at Marchouch in Morocco and used for molecular characterization and symbiotic efficiency assessment. Individual phylogenetic analysis using the 16S rRNA gene, house-keeping genes rpoB, recA, and gyrB, and symbiotic genes nodD and nodA along with Multilocus Sequence Analysis (MLSA) of the concatenated genes (16S rRNA-rpoB-recA-gyrB) was carried out for the identification and clustering of the isolates. The symbiotic efficiency of the strains was assessed on three Moroccan lentil cultivars (Bakria, Chakkouf, and Zaria) based on the number of nodules, plant height, plant dry weight, and total nitrogen content in leaves. The results showed that the individual phylogenetic analysis clustered all the strains into Rhizobium laguerreae and Rhizobium leguminosarum with sequence similarity ranging from 94 to 100%, except one strain which clustered with Mesorhizobium huakuii with sequence similarity of 100%. The MLSA of the concatenated genes and the related percentages of similarity clustered these strains into two groups of Rhizobium species, with one strain as a new genospecies when applying the threshold of 96%. For symbiotic efficiency, the Bakria variety showed the best association with 10 strains compared to its non-inoculated control (p-value ≤ 0.05), followed by Chakkouf and Zaria. The present study concluded that the genetic diversity and the symbiotic efficiency of Rhizobium strains appeared to be mainly under the control of the lentil genotypes.


Rice Galaxy: an open resource for plant science.
Rice molecular genetics, breeding, genetic diversity, and allied research (such as rice-pathogen interaction) have adopted sequencing technologies and high-density genotyping platforms for genome variation analysis and gene discovery. Germplasm collections representing rice diversity, improved varieties, and elite breeding materials are accessible through rice gene banks for use in research and breeding, with many having genome sequences and high-density genotype data available. Combining phenotypic and genotypic information on these accessions enables genome-wide association analysis, which is driving quantitative trait loci discovery and molecular marker development. Comparative sequence analyses across quantitative trait loci regions facilitate the discovery of novel alleles. Analyses involving DNA sequences and large genotyping matrices for thousands of samples, however, pose a challenge to non-computer savvy rice researchers. The Rice Galaxy resource has shared datasets that include high-density genotypes from the 3,000 Rice Genomes project and sequences with corresponding annotations from 9 published rice genomes. The Rice Galaxy web server and deployment installer includes tools for designing single-nucleotide polymorphism assays, analyzing genome-wide association studies, population diversity, rice-bacterial pathogen diagnostics, and a suite of published genomic prediction methods. A prototype Rice Galaxy compliant to Open Access, Open Data, and Findable, Accessible, Interoperable, and Reproducible principles is also presented. Rice Galaxy is a freely available resource that empowers the plant research community to perform state-of-the-art analyses and utilize publicly available big datasets for both fundamental and applied science.


The use of routinely collected patient data for research: a critical review.
Over recent years in the UK there has been growing interest in the potential for routinely collected NHS (National Health Service) patient data to be used for secondary purposes, facilitated by the potential of increasingly sophisticated electronic databases. This article is based on a critically reflective literature review which analyses the key debates pertaining to this issue. The work arose in the context of a programme of research concerning routine patient data use in neonatal care. The article includes analysis of commentary (opinion and ethical inquiry) as well as empirically derived claims. It aims to deconstruct the knowledge assumptions on which relevant research studies have been based or are proposed and it also incorporates ontological position and moral argument. Results are presented according to three predominant debates: the prevailing claim that all health research benefits civic society; the varieties of informed consent and choices open to patients regarding secondary uses of their data; and the 'rights and responsibilities' of patients when it comes to their data being used for research purposes. It examines the relevance of these themes specifically to the neonatal context and the implications for our own research, concluding that employing an alternative ethical model to the traditional professional one might be useful in order to provide a further perspective on the issue.


Flat Monolayer Graphene Cathodes for Li-Oxygen Microbatteries.
Miniature batteries can accelerate the development of mobile electronics by providing sufficient energy to power small devices. Typical microbatteries commonly use thin-film inorganic electrodes based on Li-ion insertion reaction. However, they rely on the complicated thin-film synthesis method of inorganics containing many elements. Graphene, one atomic layer thick carbon sheet, has diverse physical and chemical properties and is compatible with conventional micron-scale device fabrication. Here, we study the use of chemical vapor deposition (CVD) grown monolayer graphene in a two-dimensional configuration, as a future Li-oxygen microbattery cathode. By maximizing the dissolution of discharge intermediates, we obtain 2610 Ah/ggraphene of capacity corresponding to 20% higher areal cathode energy density and 2.7 times higher cathode specific energy than that can be derived from the same volume or mass of conventional Li-ion battery cathode material. Furthermore, a clear observation on the discharge reaction on composite electrodes and their role in the charging reaction was made, thanks to the two-dimensional monolayer graphene Li-oxygen battery cathode. We demonstrate an easy integration of two-dimensional CVD graphene cathode into microscale devices by simply transferring or coating the target device substrate with flexible graphene layers. The ability to integrate and use monolayer graphene on arbitrary device substrates as well as precise control over a chemical derivation of the carbon interface can have a radical impact on future energy-storage devices.


Endohedral Metallofullerene as Molecular High Spin Qubit: Diverse Rabi Cycles in Gd2@C79N.
An anisotropic high-spin qubit with long coherence time could scale the quantum system up. It has been proposed that Grover's algorithm can be implemented in such systems. Dimetallic aza[80]fullerenes M2@C79N (M = Y or Gd) possess an unpaired electron located between two metal ions, offering an opportunity to manipulate spin(s) protected in the cage for quantum information processing. Herein, we report the crystallographic determination of Gd2@C79N for the first time. This molecular magnet with a collective high-spin ground state (S = 15/2) generated by strong magnetic coupling (JGd-Rad = 350 ± 20 cm-1) has been unambiguously validated by magnetic susceptibility experiments. Gd2@C79N has quantum coherence and diverse Rabi cycles, allowing arbitrary superposition state manipulation between each adjacent level. The phase memory time reaches 5 μs at 5 K by dynamic decoupling. This molecule fulfills the requirements of Grover's searching algorithm proposed by Leuenberger and Loss.


Biological monitoring of cadmium exposure--an Italian experience.
Studies carried out over the last 12 years in northern Italy on a case list of 105 cadmium (Cd) workers showed that blood levels (B-Cd) were influenced not only by current exposure but also by body burden, while urinary levels (U-Cd) were influenced predominantly by body burden. Moreover, no advantages were gained by adjusting U-Cd for creatinine or specific gravity. The urinary beta 2-microglobulin levels were within the reference values when B-Cd and U-Cd were below the current threshold values. However, some indicators of early renal effect appeared to be altered. An increase in chromosome-type aberrations in lymphocytes occurred in workers with a heavy cadmium burden. Studies carried out on more than 600 subjects from the general population showed higher B-Cd levels in smokers than in nonsmokers. B-Cd levels were higher in men and in higher age groups. Identifying reference values for B-Cd through meta-analysis studies seems useful.


High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9.
High mobility group box 1 (HMGB1) is a nuclear protein that involves the binding with DNA and influences chromatin regulation and transcription. HMGB1 is also a cytokine that can activate monocytes and neutrophils involved in inflammation. In this study, we investigated the role of HMGB1 on cellular activation using human fibroblast cell line WI-38. After treatment with 1, 10, and 100 ng/mL of HMGB1 for 24 h, we did not find obviously cytotoxicity and cellular proliferation of WI-38 cells by MTT and BrdU incorporation assay, respectively. However, we found that treatment with 10 and 100 ng/mL of HMGB1 induced the differentiation of lung fibroblasts into myofibroblasts and myofibroblasts showed higher migration ability through activation of matrix metalloproteinase (MMP)-9 activation. To delineate the mechanism underlying HMGB1-induced cellular migration, we examined HMGB1-induced mitogen activated protein kinases (MAPKs), including extracellular signal related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen activated protein kinase (p38) phosphorylation, as well as nuclear factor (NF)-κB nuclear translocation. Using specific inhibitors and shRNAs of protein kinases, we observed that repression of ERK, JNK, p38, and NF-κB all inhibited HMGB1-induced cellular differentiation, migration and MMP-9 activation in WI-38 cells. In addition, knocking down of RAGE but not TLR2 and TLR4 by shRNAs attenuated HMGB1-induced myofibroblast differentiation and migration. In conclusion, our study demonstrated that HMGB1 induced lung fibroblasts' differentiation into myofibroblasts and enhanced cell migration through induction of MMP-9 activation and the RAGE-MAPK and NF-κB interaction signaling pathways. Targeting HMGB1 might be a potential therapeutic approach for alleviation of airway remodeling seen in chronic airway inflammatory diseases.


Acute and chronic intakes of fallout radionuclides by Marshallese from nuclear weapons testing at Bikini and Enewetak and related internal radiation doses.
Annual internal radiation doses resulting from both acute and chronic intakes of all important dose-contributing radionuclides occurring in fallout from nuclear weapons testing at Bikini and Enewetak from 1946 through 1958 have been estimated for the residents living on all atolls and separate reef islands of the Marshall Islands. Internal radiation absorbed doses to the tissues most at risk to cancer induction (red bone marrow, thyroid, stomach, and colon) have been estimated for representative persons of all population communities for all birth years from 1929 through 1968, and for all years of exposure from 1948 through 1970. The acute intake estimates rely on a model using, as its basis, historical urine bioassay data, for members of the Rongelap Island and Ailinginae communities as well as for Rongerik residents. The model also utilizes fallout times of arrival and radionuclide deposition densities estimated for all tests and all atolls. Acute intakes of 63 radionuclides were estimated for the populations of the 20 inhabited atolls and for the communities that were relocated during the testing years for reasons of safety and decontamination. The model used for chronic intake estimates is based on reported whole-body, urine, and blood counting data for residents of Utrik and Rongelap. Dose conversion coefficients relating intake to organ absorbed dose were developed using internationally accepted models but specifically tailored for intakes of particulate fallout by consideration of literature-based evidence to choose the most appropriate alimentary tract absorption fraction (f1) values. Dose estimates were much higher for the thyroid gland than for red marrow, stomach wall, or colon. The highest thyroid doses to adults were about 7,600 mGy for the people exposed on Rongelap; thyroid doses to adults were much lower, by a factor of 100 or more, for the people exposed on the populated atolls of Kwajalein and Majuro. The estimates of radionuclide intake and internal radiation dose to the Marshallese that are presented in this paper are the most complete available anywhere and were used to make projections of lifetime cancer risks to the exposed populations, which are presented in a companion paper in this volume.


Synergistic effect of allyl isothiocyanate (AITC) on cisplatin efficacy in vitro and in vivo.
Although in vitro studies have shown that isothiocyanates (ITCs) can synergistically sensitize cancer cells to cisplatin treatment, the underlying mechanisms have not been well defined, and there are no in vivo demonstrations of this synergy. Here, we report the in vitro and in vivo data for the combination of allyl isothiocyanate (AITC), one of the most common naturally occurring ITCs, with cisplatin. Our study revealed that cisplatin and AITC combination synergistically inhibits cancer cell growth and colony formation, and enhances apoptosis in association with the downregulation of antiapoptotic proteins Bcl-2 and survivin. Importantly, the in vivo combination treatment suppresses human tumor growth in animal models without observable increases in toxicity (body weight loss) in comparison with single agent treatment. Furthermore, our data revealed that addition of AITC to cisplatin treatment changes the profile of G2/M arrest (e.g. increase in M phase cell number) and significantly extends the duration of G2/M arrest in comparison with cisplatin treatment alone. To explore the underlying mechanism, we found that AITC treatment rapidly depletes b-tubulin. Combination of AITC and cisplatin inhibits the expression of G2/M checkpoint-relevant proteins including CDC2, cyclin B1 and CDC25. Together, our findings reveal a novel mechanism for AITC enhancing cisplatin efficacy and provides the first in vivo evidence to support ITCs as potential candidates for developing new regimens to overcome platinum resistance.


Novel gene cassettes and integrons in antibiotic-resistant bacteria isolated from urban wastewaters.
In this study, the occurrence and diversity of integrons were evaluated in 697 isolates belonging to Enterobacteriaceae and Aeromonas spp. isolated from urban wastewaters. Screening of integrons was performed by dot blot hybridization and intI-positive strains were further characterized. The global prevalence of integrons was 3.73%. Three new gene cassettes were identified: a novel aadA variant (aadA17), a gene putatively involved in cell signaling (dcyA) and an open reading frame of unknown function interrupted by a novel insertion sequence (orfER.17::ISAs12). In total, thirteen different gene cassette arrays were detected, 4 representing novel integrons: intI1-dcyA-tniC, intI1-orfER.1.7::ISAs12-aadA13-qacEΔ1-sul1, intI1-aacA4-catB3-bla(OxA-10)-aadA1-qacEΔ1-sul1 and intI1-catB8-aadA17-qacEΔ1-sul1. Approximately 80% of strains were resistant to at least 3 antibiotics of different classes. The presence of novel integron structures in treated effluents suggests that domestic wastewaters may favor the formation of novel combinations of gene cassettes. Moreover, the high prevalence of multiresistant strains highlights the urgent need to employ effective means of effluent disinfection to avoid dissemination of antibiotic-resistant bacteria.


Seizing Control: From Current Treatments to Optogenetic Interventions in Epilepsy.
The unpredictability and severity of seizures contribute to the debilitating nature of epilepsy. These factors also render the condition particularly challenging to treat, as an ideal treatment would need to detect and halt the pathological bursts of hyperactivity without disrupting normal brain activity. Optogenetic techniques offer promising tools to study and perhaps eventually treat this episodic disorder by controlling specific brain circuits in epileptic animals with great temporal precision. Here, we briefly review the current treatment options for patients with epilepsy. We then describe the many ways optogenetics has allowed us to untangle the microcircuits involved in seizure activity, and how it has, in some cases, changed our perception of previous theories of seizure generation. Control of seizures with light is no longer a dream, and has been achieved in numerous different animal models of epilepsy. Beyond its application as a seizure suppressor, we highlight another facet of optogenetics in epilepsy, namely the ability to create "on-demand" seizures, as a tool to systematically probe the dynamics of networks during seizure initiation and propagation. Finally, we look into the future to discuss the possibilities and challenges of translating optogenetic techniques to clinical use.


A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death.
The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with the disease (p < 0.0001). We demonstrate here the identification of a variant in the titin gene highly associated with the disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.


Complement and Cardiovascular Disease--The Missing Link in Haemodialysis Patients.
Patients on haemodialysis (HD) have high rates of cardiovascular (CV) disease and activation of the complement system. Despite evidence in non-renal patients that these may be linked, this association has received little attention in HD patients to date. In the setting of a randomised controlled trial we evaluated the relationships between baseline complement levels and subsequent CV events and mortality, in addition to the effects of HD with a vitamin E (VE)-coated dialysis membrane on circulating complement levels. A total of 260 HD patients were randomised to dialysis with a VE-coated dialysis membrane or non-VE coated equivalent for 12 months. Blood samples were taken at baseline, 6 and 12 months for measurement of C3, factor D, factor H and SC5b-9 levels. Data were collected prospectively on deaths and CV events. Higher C3 levels at baseline were associated with subsequent CV events (hazard ratio 1.20 (1.01-1.42) per 0.1 mg/ml). Patients with intermediate SC5b-9 levels had significantly lower CV event rates and mortality than those with either high or low levels (p < 0.01). There were no effects of the VE-membranes on the complement components measured nor the clinical endpoints considered. The levels of C3 and SC5b-9 may have prognostic utility for predicting future CV events and/or mortality in HD patients - a relationship that requires further investigation. Dialysing prevalent HD patients with VE-bonded polysulfone membranes for a period of 12 months did not alter the circulating levels of the alternative complement pathway components considered here.


A Patient Centric Nursing Mobile App Redesign.
Sanatorio Finochietto has a nursing mobile app that allows safely preparing and administering medications. Hospitalized patients care experience is influenced by the system, the care process and nurse response, in this context, technology acts as a facilitator for care and humanized treatment. A "Patient-Centered Management System" would assist caregivers and patients to make individualized decisions about optimal care. This paper describe a paradigm shift to a mobile patient centered nursing application.


Time to Surgery and Breast Cancer Survival in the United States.
Time to surgery (TTS) is of concern to patients and clinicians, but controversy surrounds its effect on breast cancer survival. There remains little national data evaluating the association. To investigate the relationship between the time from diagnosis to breast cancer surgery and survival, using separate analyses of 2 of the largest cancer databases in the United States. Two independent population-based studies were conducted of prospectively collected national data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database and the National Cancer Database (NCDB). The SEER-Medicare cohort included Medicare patients older than 65 years, and the NCDB cohort included patients cared for at Commission on Cancer-accredited facilities throughout the United States. Each analysis assessed overall survival as a function of time between diagnosis and surgery by evaluating 5 intervals (≤30, 31-60, 61-90, 91-120, and 121-180 days) and disease-specific survival at 60-day intervals. All patients were diagnosed with noninflammatory, nonmetastatic, invasive breast cancer and underwent surgery as initial treatment. Overall and disease-specific survival as a function of time between diagnosis and surgery, after adjusting for patient, demographic, and tumor-related factors. The SEER-Medicare cohort had 94 544 patients 66 years or older diagnosed between 1992 and 2009. With each interval of delay increase, overall survival was lower overall (hazard ratio [HR], 1.09; 95% CI, 1.06-1.13; P < .001), and in patients with stage I (HR, 1.13; 95% CI, 1.08-1.18; P < .001) and stage II disease (HR 1.06; 95% CI, 1.01-1.11; P = .01). Breast cancer-specific mortality increased with each 60-day interval (subdistribution hazard ratio [sHR], 1.26; 95% CI, 1.02-1.54; P = .03). The NCDB study evaluated 115 790 patients 18 years or older diagnosed between 2003 and 2005. The overall mortality HR was 1.10 (95% CI, 1.07-1.13; P < .001) for each increasing interval, significant in stages I (HR, 1.16; 95% CI, 1.12-1.21; P < .001) and II (HR, 1.09; 95% CI, 1.05-1.13; P < .001) only, after adjusting for demographic, tumor, and treatment factors. Greater TTS is associated with lower overall and disease-specific survival, and a shortened delay is associated with benefits comparable to some standard therapies. Although time is required for preoperative evaluation and consideration of options such as reconstruction, efforts to reduce TTS should be pursued when possible to enhance survival.


Seasonality selects for more acutely virulent parasites when virulence is density dependent.
Host condition is often likely to influence parasite virulence. Furthermore, condition may often be correlated with host density, and therefore, it is important to understand the role of density-dependent virulence (DDV). We examine the consequences of DDV to the evolution of parasites in both seasonal and non-seasonal environments. In particular, we consider seasonality in host birth rate that results in a fluctuating host density and therefore a variable virulence. We show that parasites are selected for lower exploitation, and therefore lower transmission and virulence as the strength of DDV increases without seasonality. This is an important insight from our models; DDV has the opposite effect on the evolution of parasites to that of higher baseline mortality. Our key result is that although seasonality does not affect the evolution of virulence in classical models, with DDV parasites in seasonal environments are predicted to evolve to be more acute. This suggests that in more seasonal environments wildlife disease is likely to be more rather than less virulent if DDV is widespread.


The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial.
Current asthma guidelines recommend adjusting antiinflammatory treatment on the basis of the results of lung function tests and symptom assessment, neither of which are closely associated with airway inflammation. We tested the hypothesis that titrating corticosteroid dose using the concentration of exhaled nitric oxide in exhaled breath (Fe(NO)) results in fewer asthma exacerbations and more efficient use of corticosteroids, when compared with traditional management. One hundred eighteen participants with a primary care diagnosis of asthma were randomized to a single-blind trial of corticosteroid therapy based on either Fe(NO) measurements (n = 58) or British Thoracic Society guidelines (n = 60). Participants were assessed monthly for 4 months and then every 2 months for a further 8 months. The primary outcome was the number of severe asthma exacerbations. Analyses were by intention to treat. The estimated mean (SD) exacerbation frequency was 0.33 per patient per year (0.69) in the Fe(NO) group and 0.42 (0.79) in the control group (mean difference, -21%; 95% confidence interval [CI], -57 to 43%; p = 0.43). Overall the Fe(NO) group used 11% more inhaled corticosteroid (95% CI, -17 to 42%; p = 0.40), although the final daily dose of inhaled corticosteroid was lower in the Fe(NO) group (557 vs. 895 microg; mean difference, 338 microg; 95% CI, -640 to -37; p = 0.028). An asthma treatment strategy based on the measurement of exhaled nitric oxide did not result in a large reduction in asthma exacerbations or in the total amount of inhaled corticosteroid therapy used over 12 mo, when compared with current asthma guidelines. Clinical trial registered with www.controlled-trials.com (ISRCTN08067387).


Functional analysis of the three major PGRPLC isoforms in the midgut of the malaria mosquito Anopheles coluzzii.
Peptidoglycan recognition proteins (PGRPs) constitute the primary means of bacterial recognition in insects. Recent work in the model organism Drosophila has revealed the mechanisms by which the complement of PGRPs refine the sensitivity of different tissues to bacterial elicitors, permitting the persistence of commensal bacteria in the gut whilst maintaining vigilance against bacterial infection. Here, we use in vivo knockdowns and in vitro pull-down assays to investigate the role of the three major isoforms of the transmembrane receptor of the Imd pathway, PGRPLC, in basal immunity in the Anopheles coluzzii mosquito midgut. Our results indicate that the mosquito midgut is regionalized in its expression of immune effectors and of PGRPLC1. We show that PGRPLC1 and PGRPLC3 are pulled down with polymeric DAP-type peptidoglycan, while PGRPLC2 and PGRPLC3 co-precipitate in the presence of TCT, a peptidoglycan monomer. These data suggest that, as found in Drosophila, discrimination of polymeric and monomeric PGN by Anopheles PGRPLC participates in the regulation of the Imd pathway.


How does infliximab work in rheumatoid arthritis?
Since the initial characterization of tumor necrosis factor alpha (TNFalpha), it has become clear that TNFalpha has diverse biologic activity. The realization that TNFalpha plays a role in rheumatoid arthritis (RA) has led to the development of anti-TNF agents for the treatment of RA. Infliximab, a chimeric monoclonal antibody that specifically, and with high affinity, binds to TNFalpha and neutralizes the cytokine, is currently approved for the treatment of RA and Crohn's disease, another immune-inflammatory disorder. In addition to establishing the safety and efficacy of infliximab, clinical research has also provided insights into the complex cellular and cytokine-dependent pathways involved in the pathophysiology of RA, including evidence that supports TNFalpha involvement in cytokine regulation, cell recruitment, angiogenesis, and tissue destruction.


Helicobacter pylori stimulates gastric epithelial cell MMP-1 secretion via CagA-dependent and -independent ERK activation.
Because the mechanisms of Helicobacter pylori-induced gastric injury are incompletely understood, we examined the hypothesis that H. pylori induces matrix metalloproteinase-1 (MMP-1) secretion, with potential to disrupt gastric stroma. We further tested the role of CagA, an H. pylori virulence factor, in MMP-1 secretion. Co-incubation of AGS cells with Tx30a, an H. pylori strain lacking the cagA virulence gene, stimulated MMP-1 secretion, confirming cagA-independent secretion. Co-incubation with strain 147C (cagA(+)) resulted in CagA translocation into AGS cells and increased MMP-1 secretion relative to Tx30a. Transfection of cells with the recombinant 147C cagA gene also induced MMP-1 secretion, indicating that CagA can independently stimulate MMP-1 secretion. Co-incubation with strain 147A, containing a cagA gene that lacks an EPIYA tyrosine phosphorylation motif, as well as transfection with 147A cagA, yielded an MMP-1 secretion intermediate between no treatment and 147C, indicating that CagA tyrosine phosphorylation regulates cellular signaling in this model system. H. pylori induced activation of the MAP kinase ERK, with CagA-independent (early) and dependent (later) components. MEK inhibitors UO126 and PD98059 inhibited both CagA-independent and -dependent MMP-1 secretion, whereas p38 inhibition enhanced MMP-1 secretion and ERK activation, suggesting p38 negative regulation of MMP-1 and ERK. These data indicate H. pylori effects on host epithelial MMP-1 expression via ERK, with p38 playing a potential regulatory role.


Anterior segment dysgenesis (Peters' anomaly) in two snow leopard (Panthera uncia) cubs.
Two sibling snow leopards, a male and a female, with bilateral anterior segment dysgenesis (ASD), are reported. Both snow leopards also had colobomas of both upper eyelids. All eyes exhibited a central corneal opacity associated with a defect in posterior corneal stroma, endothelium and Descemet's membrane. Iris strands were present attached to the termination of Descemet's membrane and to the periphery of the posterior corneal defect. The iris was hypoplastic, and cataract was present in all four eyes. The left eye of the female was microphthalmic, with no trabecular meshwork and with persistent remnant of the hyaloid artery. The male had hydrocephalus and thus some of the features of Peters' plus syndrome (Peters' anomaly in addition to systemic malformations). The histological findings in the eyes of these snow leopard siblings are identical with those described in humans with Peters' anomaly.


Cell based assay identifies TLR2 and TLR4 stimulating impurities in Interferon beta.
Immunogenicity can have devastating consequences on the safety and efficacy of therapeutic proteins. Therefore, evaluating and mitigating the risk of product immunogenicity is critical for the development these products. This study, showed that Betaseron and Extavia, which are reported to be more immunogenic among IFNβ products in clinical usage, contain residual innate immune response modulating impurities (IIRMIs) capable of activating NF-κB and induced expression of inflammatory mediators. These IIRMIs were undetectable in Rebif or Avonex. The stimulatory effect was attributed solely to IIRMIs because it was evident in murine cells lacking the interferon receptor (IFNAR). The IIRMIs in Betaseron and Extavia triggered NF-κB activation in HEK-293 cells bearing TLR2 and TLR4 in MyD88 dependent manner. Importantly, the IIRMIs in Betaseron induced up-regulation of IL-6, IL-1β, and ccl5 in the skin of IFNAR knock out mice following subcutaneous administration. This indicates that trace level IIRMIs in Betaseron could contribute to the higher immunogenicity rates seen in clinics. Together these data suggest that cell based assays can reveal subtle but clinically relevant differences in IIRMIs following manufacturing changes or between products with the same active ingredients but different manufacturing processes. Appreciating these differences may inform immunogenicity risk assessments.


Temperature adaptation in Dictyostelium: role of Delta5 fatty acid desaturase.
Membrane fluidity is critical for proper membrane function and is regulated in part by the proportion of unsaturated fatty acids present in membrane lipids. The proportion of these lipids in turn varies with temperature and may contribute to temperature adaptation in poikilothermic organisms. The fundamental question posed in this study was whether the unsaturation of fatty acids contributes to the ability to adapt to temperature stress in Dictyostelium. First, fatty acid composition was analysed and it was observed that the relative proportions of dienoic acids changed with temperature. To investigate the role of dienoic fatty acids in temperature adaptation, null mutants were created in the two known Delta5 fatty acid desaturases (FadA and FadB) that are responsible for the production of dienoic fatty acids. The fadB null mutant showed no significant alteration in fatty acid composition or in phenotype. However, the disruption of fadA resulted in a large drop in dienoic fatty acid content from 51.2 to 4.1 % and a possibly compensatory increase in monoenoic fatty acids (40.9-92.4 %). No difference was detected in temperature adaptation with that of wild-type cells during the growth phase. However, surprisingly, mutant cells developed more efficiently than the wild-type at elevated temperatures. These results show that the fatty acid composition of Dictyostelium changes with temperature and suggest that the regulation of dienoic fatty acid synthesis is involved in the development of Dictyostelium at elevated temperatures, but not during the growth phase.


Favorable effect on acute and chronic graft-versus-host disease with cyclophosphamide and in vivo anti-CD52 monoclonal antibodies for marrow transplantation from HLA-identical sibling donors for acquired aplastic anemia.
Between August 1989 and November 2003, 33 patients at our center with acquired aplastic anemia underwent bone marrow transplantation (BMT) from HLA-identical sibling donors with cyclophosphamide and in vivo anti-CD52 monoclonal antibodies (MoAb) for conditioning. The median age at BMT was 17 years (range, 4-46 years). Before BMT, 58% were heavily transfused (>50 transfusions), and 42% had previously experienced treatment failure with antithymocyte globulin-based immunosuppressive therapy. Unmanipulated bone marrow was used as the source of stem cells in all patients except 1. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine alone in 19 (58%) patients; 14 received anti-CD52 MoAb in addition to cyclosporine. The conditioning regimen was well tolerated without significant acute toxicity. Graft failure was seen in 8 patients (primary, n = 4; secondary, n = 4). Of those whose grafts failed, 4 survived long-term (complete autologous recovery, n = 2; rescue with previously stored marrow, n = 1; second allograft, n = 1). The cumulative incidence of graft failure and grade II to IV acute and chronic GVHD was 24%, 14%, and 4%, respectively. None developed extensive chronic GVHD. With a median follow-up of 59 months, the 5-year survival was 81% (95% confidence interval, 68%-96%). No unexpected early or late infectious or noninfectious complications were observed. We conclude that the conditioning regimen containing cyclophosphamide and anti-CD52 MoAb is well tolerated and effective for acquired aplastic anemia with HLA-matched sibling donors. The favorable effect on the incidence and severity of GVHD is noteworthy in this study and warrants further investigation.


Incidence of insulin dependent diabetes in children aged under 15 years in the British Isles during 1988.
To ascertain the annual incidence rate of insulin dependent diabetes diagnosed in children under the age of 15 years in the British Isles during 1988, and to compare the results with an earlier study carried out in 1973-4. Active monthly reporting of cases by consultant paediatricians, with additional input from diabetologists and all specialist diabetes nurses and health visitors. British Isles (England, Wales, Scotland, Northern Ireland, Republic of Ireland) with a total population at risk of 11,819,000 children. All children diagnosed under the age of 15 years with primary insulin dependent diabetes from 1 January to 31 December 1988 and resident in the British Isles at diagnosis. National incidence rate of insulin dependent diabetes; differences in incidence rates between regions and between three age groups: 4 and under, 5-9, and 10-14 year olds. 1600 children (837 boys and 763 girls) had a confirmed diagnosis of insulin dependent diabetes, giving a national incidence rate of 13.5/100,000/year (95% confidence interval 12.9 to 14.2/100,000/year). This was considerably higher than the incidence rate of 7.7/100,000/year in children under the age of 16 years reported in the British Diabetic Association's study of 1973-4. The age-sex adjusted rates varied between regions, ranging from 6.8/100,000/year (Republic of Ireland) to 19.8/100,000/year (Scotland). There were considerable differences in the numbers of cases diagnosed each month, with the 10-14 year age group showing the most seasonal variation. A quarter of the children (404/1600) were under 5 years old. Case ascertainment was estimated as 90%. Insulin dependent diabetes in the British Isles does not seem to occur uniformly over time or geographical area. Even allowing for differences in ascertainment between the 1973-4 and 1988 studies, there seems to have been an increase in the incidence rate of insulin dependent diabetes in children under the age of 15 years during the 15 year time period. If diabetes is becoming more common in this age group, possibly by developing earlier in susceptible children, this would be a matter of considerable public health concern.


Lipid nanobilayers to host biological nanopores for DNA translocations.
We characterize a recently introduced novel nanobilayer technique [Gornall, J. L., Mahendran, K. R., Pambos, O. J., Steinbock, L. J., Otto, O., Chimerel, C., Winterhalter, M., and Keyser, U. F. Simple reconstitution of protein pores in nano lipid bilayers. Nano Lett. 2011, 11 (8), 3334-3340] and its practical aspects for incorporating the biological nanopore α-hemolysin from Staphylococcus aureus and subsequent studies on the translocation of biomolecules under various conditions. This technique provides advantages over classical bilayer methods, especially the quick formation and extended stability of a bilayer. We have also developed a methodology to prepare a uniform quality of giant unilamellar vesicles (GUVs) in a reproducible way for producing nanobilayers. The process and the characteristics of the reconstitution of α-hemolysin in nanobilayers were examined by exploiting various important parameters, including pH, applied voltage, salt concentration, and number of nanopores. Protonation of α-hemolysin residues in the low pH region affects the translocation durations, which, in turn, changes the statistics of event types as a result of electrostatics and potentially the structural changes in DNA. When the pH and applied voltage were varied, it was possible to investigate and partly control the capture rates and type of translocation events through α-hemolysin nanopores. This study could be helpful to use the nanobilayer technique for further explorations, particularly owing to its advantages and technical ease compared to existing bilayer methods.


Evaluating the impact of spatio-temporal smoothness constraints on the BOLD hemodynamic response function estimation: an analysis based on Tikhonov regularization.
Recently we have proposed the use of Tikhonov regularization with temporal smoothness constraints to estimate the BOLD fMRI hemodynamic response function (HRF). The temporal smoothness constraint was imposed on the estimates by using second derivative information while the regularization parameter was selected based on the generalized cross-validation function (GCV). Using one-dimensional simulations, we previously found this method to produce reliable estimates of the HRF time course, especially its time to peak (TTP), being at the same time fast and robust to over-sampling in the HRF estimation. Here, we extend the method to include simultaneous temporal and spatial smoothness constraints. This method does not need Gaussian smoothing as a pre-processing step as usually done in fMRI data analysis. We carried out two-dimensional simulations to compare the two methods: Tikhonov regularization with temporal (Tik-GCV-T) and spatio-temporal (Tik-GCV-ST) smoothness constraints on the estimated HRF. We focus our attention on quantifying the influence of the Gaussian data smoothing and the presence of edges on the performance of these techniques. Our results suggest that the spatial smoothing introduced by regularization is less severe than that produced by Gaussian smoothing. This allows more accurate estimates of the response amplitudes while producing similar estimates of the TTP. We illustrate these ideas using real data.


Real-time inversion of polarization gate frequency-resolved optical gating spectrograms.
Frequency-resolved optical gating (FROG) is a technique used to measure the intensity and phase of ultrashort laser pulses through the optical construction of a spectrogram of the pulse. To obtain quantitative information about the pulse from its spectrogram, an iterative two-dimensional phase retrieval algorithm must be used. Current algorithms are quite robust but retrieval of all the pulse information can be slow. Previous real-time FROG trace inversion work focused on second-harmonic-generation FROG, which has an ambiguity in the direction of time, and required digital signal processors (DSPs). We develop a simplified real-time FROG device based on a single-shot geometry that no longer requires DSPs. We use it and apply the principal component generalized projections algorithm to invert polarization gate FROG traces at rates as high as 20 Hz.


Invited review: Intergovernmental Panel on Climate Change, agriculture, and food-A case of shifting cultivation and history.
Since 1990, the Intergovernmental Panel on Climate Change (IPCC) has produced five Assessment Reports (ARs), in which agriculture as the production of food for humans via crops and livestock have featured in one form or another. A constructed database of the ca. 2,100 cited experiments and simulations in the five ARs was analyzed with respect to impacts on yields via crop type, region, and whether adaptation was included. Quantitative data on impacts and adaptation in livestock farming have been extremely scarce in the ARs. The main conclusions from impact and adaptation are that crop yields will decline, but that responses have large statistical variation. Mitigation assessments in the ARs have used both bottom-up and top-down methods but need better to link emissions and their mitigation with food production and security. Relevant policy options have become broader in later ARs and included more of the social and nonproduction aspects of food security. Our overall conclusion is that agriculture and food security, which are two of the most central, critical, and imminent issues in climate change, have been dealt with an unfocussed and inconsistent manner between the IPCC five ARs. This is partly a result of not only agriculture spanning two IPCC working groups but also the very strong focus on projections from computer crop simulation modeling. For the future, we suggest a need to examine interactions between themes such as crop resource use efficiencies and to include all production and nonproduction aspects of food security in future roles for integrated assessment models.


Self-assembling toxin-based nanoparticles as self-delivered antitumoral drugs.
Loading capacity and drug leakage from vehicles during circulation in blood is a major concern when developing nanoparticle-based cell-targeted cytotoxics. To circumvent this potential issue it would be convenient the engineering of drugs as self-delivered nanoscale entities, devoid of any heterologous carriers. In this context, we have here engineered potent protein toxins, namely segments of the diphtheria toxin and the Pseudomonas aeruginosa exotoxin as self-assembling, self-delivered therapeutic materials targeted to CXCR4+ cancer stem cells. The systemic administration of both nanostructured drugs in a colorectal cancer xenograft mouse model promotes efficient and specific local destruction of target tumor tissues and a significant reduction of the tumor volume. This observation strongly supports the concept of intrinsically functional protein nanoparticles, which having a dual role as drug and carrier, are designed to be administered without the assistance of heterologous vehicles.


Pitfalls in the pathological diagnosis of lymphoma.
Since the publication of the 2008 World Health Organization classifications of lymphoma, additional immunohistochemical tests and other ancillary methods such as flow cytometry, cytogenetic and other molecular biology techniques, have been applied in routine clinical work. Due to the utilization of these methodologies, there has been great progress in the pathological diagnosis and classification of lymphomas in the mainland of China. Nonetheless, lymphoma pathology still remains very challenging in the field of diagnostic pathology. Ten percent of pathologist's annual consultation cases are lymphomas, thus reflecting the difficulty of this field. Here, we summarize the common misdiagnoses and pitfalls when dealing with lymphoma cases, the cause of the errors and strategies to avoid inaccurate diagnoses.


Spontaneous cortical activity is transiently poised close to criticality.
Brain activity displays a large repertoire of dynamics across the sleep-wake cycle and even during anesthesia. It was suggested that criticality could serve as a unifying principle underlying the diversity of dynamics. This view has been supported by the observation of spontaneous bursts of cortical activity with scale-invariant sizes and durations, known as neuronal avalanches, in recordings of mesoscopic cortical signals. However, the existence of neuronal avalanches in spiking activity has been equivocal with studies reporting both its presence and absence. Here, we show that signs of criticality in spiking activity can change between synchronized and desynchronized cortical states. We analyzed the spontaneous activity in the primary visual cortex of the anesthetized cat and the awake monkey, and found that neuronal avalanches and thermodynamic indicators of criticality strongly depend on collective synchrony among neurons, LFP fluctuations, and behavioral state. We found that synchronized states are associated to criticality, large dynamical repertoire and prolonged epochs of eye closure, while desynchronized states are associated to sub-criticality, reduced dynamical repertoire, and eyes open conditions. Our results show that criticality in cortical dynamics is not stationary, but fluctuates during anesthesia and between different vigilance states.


Nurse-initiation and maintenance of patients on antiretroviral therapy: are nurses in primary care clinics initiating ART after attending NIMART training?
To determine the percentage of nurses initiating new HIV-positive patients on therapy within 2 months of attending the Nurse Initiation and Maintenance of Antiretroviral Therapy(NIMART) course, and to identify possible barriers to nurse initiation. A brief telephonic interview using a structured questionnaire of a randomly selected sample (126/1736) of primary care nurses who had attended the NIMART course facilitated by the Foundation for Professional Development (FPD) between October 2010 and 31 March 2011 at primary care clinics in 7 provinces. Outcome measures were the number of nurses initiating ART within 2 months of attending the FPD-facilitated NIMART course. Of the nurses surveyed, 62% (79/126) had started initiating new adult patients on ART, but only 7% (9/126) were initiating ART in children. The main barrier to initiation was allocation to other tasks in the clinic as a result of staff shortages. Despite numerous challenges, many primary care nurses working in the 7 provinces surveyed have taken on the responsibility of sharing the task of initiating HIV-positive patients on ART. The barriers preventing more nurses initiating ART include the shortage of primary care nurses and the lack of sufficient consulting rooms. Expanding clinical mentoring and further training in clinical skills and pharmacology would assist in reaching the target of initiating a further 1.2 million HIV-positive patients on ART by 2012.


Comparison of healthcare experiences in autistic and non-autistic adults: a cross-sectional online survey facilitated by an academic-community partnership.
Little is known about the healthcare experiences of adults on the autism spectrum. Moreover, autistic adults have rarely been included as partners in autism research. To compare the healthcare experiences of autistic and non-autistic adults via an online survey. We used a community-based participatory research (CBPR) approach to adapt survey instruments to be accessible to autistic adults and to conduct an online cross-sectional survey. We assessed preliminary psychometric data on the adapted scales. We used multivariate analyses to compare healthcare experiences of autistic and non-autistic participants. Four hundred and thirty-seven participants completed the survey (209 autistic, 228 non-autistic). All adapted scales had good to excellent internal consistency reliability (alpha 0.82-0.92) and strong construct validity. In multivariate analyses, after adjustment for demographic characteristics, health insurance, and overall health status, autistic adults reported lower satisfaction with patient-provider communication (beta coefficient -1.9, CI -2.9 to -0.9), general healthcare self-efficacy (beta coefficient -11.9, CI -14.0 to -8.6), and chronic condition self-efficacy (beta coefficient -4.5, CI -7.5 to -1.6); higher odds of unmet healthcare needs related to physical health (OR 1.9 CI 1.1-3.4), mental health (OR 2.2, CI 1.3-3.7), and prescription medications (OR 2.8, CI 2.2-7.5); lower self-reported rates of tetanus vaccination (OR 0.5, CI 0.3-0.9) and Papanicolaou smears (OR 0.5, CI 0.2-0.9); and greater odds of using the emergency department (OR 2.1, CI 1.8-3.8). A CBPR approach may facilitate the inclusion of people with disabilities in research by increasing researchers' ability to create accessible data collection instruments. Autistic adults who use the Internet report experiencing significant healthcare disparities. Efforts are needed to improve the healthcare of autistic individuals, including individuals who may be potentially perceived as having fewer disability-related needs.


MALT Lymphomas.
Mucosa-associated lymphoid tissue (MALT) lymphomas occur in a variety of organs, including the orbit, conjunctiva, salivary glands, skin, thyroid gland, lungs, stomach, and intestine. These tumors are often localized and of indolent clinical behavior. Diagnosis is made by pathologic evaluation of a tissue biopsy. Careful staging is mandatory and tailored to the initial presentation. Staging includes a history and physical, chemistries, computed tomography scan, and bone marrow biopsy. This information is supplemented with an ear, nose, and throat consultation, esophagogastro-duodenoscopy, colonoscopy, endoscopic ultrasound of the stomach, and cytogenetic/immunohistochemical analysis of the tumors. Treatment is tailored to organ involvement and stage at presentation. Eradication of Helicobacter pylori using a triple anti-H. pylori regimen approved by the US Food and Drug Administration is standard therapy for all H. pylori-positive gastric MALT lymphomas. Endoscopic ultrasound- and computed tomography-staged gastric MALT stage IE tumors will achieve a complete response with this approach in approximately 60% to 90% of patients (the more superficial the tumor, the better the response). Patients with tumors that are T4 node-positive Musshoff stage IIE1 and IIE2 or tumors with adverse cytogenetics should receive radiotherapy or surgery with or without radiotherapy. Tumors with a significant high-grade component or large cell tumors with a minor low-grade MALT component should receive CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based chemotherapy. Localized MALT lymphomas of the orbit, conjunctiva, salivary glands, and thyroid gland are treated successfully with radiotherapy. Surgery as first-line therapy for gastric MALT lymphomas was replaced by attempts at organ preservation. In the past, margin-free surgical excision or tumor debulking followed by radiation therapy and chemotherapy has been highly effective for gastric MALT lymphomas. Therefore, surgical excision of large cell or bulky tumors of the stomach, thyroid, lung, and salivary gland, followed by adjuvant radiotherapy or chemotherapy, may still be an important consideration in selected patients. Surgery still has a role for patients with relapsed or refractory low-grade disease and life-threatening hemorrhage. Disseminated MALT lymphomas are incurable and are treated primarily with chemotherapy according to symptoms.


Intraoperative fluid restriction improves outcome after major elective gastrointestinal surgery.
Fluid therapy is one of the most controversial topics in perioperative management. There is continuing debate with regard to the quantity and the type of fluid resuscitation during elective major surgery. However, there are increasing reports of perioperative excessive intravascular volume leading to increased postoperative morbidity and mortality. Recent evidence suggests that judicious perioperative fluid therapy improves outcome after major elective gastrointestinal surgery. The observed benefits may not be solely attributable to crystalloid restriction but also to the use of colloids instead. Some clinically useful guidelines based on the studies discussed in this review include avoidance of deep general anesthesia and elimination of preload for patients who receive epidural analgesia. A balanced approach to fluid management is recommended, with colloids administered to provide hemodynamic stability and maintain urine output of 0.5 mL x kg(-1) x h(-1) and crystalloids administered only for maintenance. In addition, blood loss may be replaced with colloid on a volume-to-volume basis. Furthermore, predetermined algorithms that suggest replacement of third space losses and losses through diuresis are unnecessary. Significant reduction in crystalloid volume can be achieved without encountering intraoperative hemodynamic instability or reduced (i.e., < 0.5 mL x kg(-1) x h(-1)) urinary output just by avoiding replacement of third space losses and preloading. Finally, there is a need for well-controlled studies in a well-defined patient population using clear criteria or end-points for perioperative fluid therapy.


Abnormal Myocardial Function Is Related to Myocardial Steatosis and Diffuse Myocardial Fibrosis in HIV-Infected Adults.
Impaired cardiac function persists in the era of effective human immunodeficiency virus (HIV) therapy, although the etiology is unclear. We used magnetic resonance imaging (MRI) to measure intramyocardial lipid levels and fibrosis as possible contributors to HIV-associated myocardial dysfunction. A cross-sectional study of 95 HIV-infected and 30 matched-healthy adults, without known cardiovascular disease (CVD) was completed. Intramyocardial lipid levels, myocardial fibrosis, and cardiac function (measured on the basis of strain) were quantified by MRI. Systolic function was significantly decreased in HIV-infected subjects as compared to controls (mean radial strain [±SD], 21.7 ± 8.6% vs 30.5 ± 14.2%; P = .004). Intramyocardial lipid level and fibrosis index were both increased in HIV-infected subjects as compared to controls (P ≤ .04 for both) and correlated with the degree of myocardial dysfunction measured by strain parameters. Intramyocardial lipid levels correlated positively with antiretroviral therapy duration and visceral adiposity. Further, impaired myocardial function was strongly correlated with increased monocyte chemoattractant protein 1 levels (r = 0.396, P = .0002) and lipopolysaccharide binding protein levels (r = 0.25, P = .02). HIV-infected adults have reduced myocardial function as compared to controls in the absence of known CVD. Decreased cardiac function was associated with abnormal myocardial tissue composition characterized by increased lipid levels and diffuse myocardial fibrosis. Metabolic alterations related to antiretroviral therapy and chronic inflammation may be important targets for optimizing long-term cardiovascular health in HIV-infected individuals.


Patients' and clinicians' views on the optimum schedules for self-monitoring of blood pressure: a qualitative focus group and interview study.
Self-monitoring of blood pressure is common but guidance on how it should be carried out varies and it is currently unclear how such guidance is viewed. To explore patients' and healthcare professionals' (HCPs) views and experiences of the use of different self-monitoring regimens to determine what is acceptable and feasible, and to inform future recommendations. Thirteen focus groups and four HCP interviews were held, with a total of 66 participants (41 patients and 25 HCPs) from primary and secondary care with and without experience of self-monitoring. Standard and shortened self-monitoring protocols were both considered. Focus groups and interviews were recorded, transcribed verbatim, and analysed using the constant comparative method. Patients generally supported structured schedules but with sufficient flexibility to allow adaptation to individual routine. They preferred a shorter (3-day) schedule to longer (7-day) regimens. Although HCPs could describe benefits for patients of using a schedule, they were reluctant to recommend a specific schedule. Concerns surrounded the use of different schedules for diagnosis and subsequent monitoring. Appropriate education was seen as vital by all participants to enable a self-monitoring schedule to be followed at home. There is not a 'one size fits all approach' to developing the optimum protocol from the perspective of users and those implementing it. An approach whereby patients are asked to complete the minimum number of readings required for accurate blood pressure estimation in a flexible manner seems most likely to succeed. Informative advice and guidance should incorporate such flexibility for patients and professionals alike.


Nuk controls pathfinding of commissural axons in the mammalian central nervous system.
Eph family receptor tyrosine kinases have been proposed to control axon guidance and fasciculation. To address the biological functions of the Eph family member Nuk, two mutations in the mouse germline have been generated: a protein null allele (Nuk1) and an allele that encodes a Nuk-beta gal fusion receptor lacking the tyrosine kinase and C-terminal domains (Nuk(lacZ)). In Nuk1 homozygous brains, the majority of axons forming the posterior tract of the anterior commissure migrate aberrantly to the floor of the brain, resulting in a failure of cortical neurons to link the two temporal lobes. These results indicate that Nuk, a receptor that binds transmembrane ligands, plays a critical and unique role in the pathfinding of specific axons in the mammalian central nervous system.