The hormone resistin links obesity to diabetes.
Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.


An ecosystem-scale model for the spread of a host-specific forest pathogen in the Greater Yellowstone Ecosystem.
The introduction of nonnative pathogens is altering the scale, magnitude, and persistence of forest disturbance regimes in the western United States. In the high-altitude whitebark pine (Pinus albicaulis) forests of the Greater Yellowstone Ecosystem (GYE), white pine blister rust (Cronartium ribicola) is an introduced fungal pathogen that is now the principal cause of tree mortality in many locations. Although blister rust eradication has failed in the past, there is nonetheless substantial interest in monitoring the disease and its rate of progression in order to predict the future impact of forest disturbances within this critical ecosystem. This study integrates data from five different field-monitoring campaigns from 1968 to 2008 to create a blister rust infection model for sites located throughout the GYE. Our model parameterizes the past rates of blister rust spread in order to project its future impact on high-altitude whitebark pine forests. Because the process of blister rust infection and mortality of individuals occurs over the time frame of many years, the model in this paper operates on a yearly time step and defines a series of whitebark pine infection classes: susceptible, slightly infected, moderately infected, and dead. In our analysis, we evaluate four different infection models that compare local vs. global density dependence on the dynamics of blister rust infection. We compare models in which blister rust infection is: (1) independent of the density of infected trees, (2) locally density-dependent, (3) locally density-dependent with a static global infection rate among all sites, and (4) both locally and globally density-dependent. Model evaluation through the predictive loss criterion for Bayesian analysis supports the model that is both locally and globally density-dependent. Using this best-fit model, we predicted the average residence times for the four stages of blister rust infection in our model, and we found that, on average, whitebark pine trees within the GYE remain susceptible for 6.7 years, take 10.9 years to transition from slightly infected to moderately infected, and take 9.4 years to transition from moderately infected to dead. Using our best-fit model, we project the future levels of blister rust infestation in the GYE at critical sites over the next 20 years.


Mathematical modeling of growth of Salmonella in raw ground beef under isothermal conditions from 10 to 45 degrees C.
The objective of this study was to develop primary and secondary models to describe the growth of Salmonella in raw ground beef. Primary and secondary models can be integrated into a dynamic model that can predict the microbial growth under varying environmental conditions. Growth data of Salmonella at nine different isothermal conditions--10, 15, 20, 25, 28, 32, 35, 42, and 45 degrees C were first fitted into primary models, namely the logistic, modified Gompertz, Baranyi, and Huang models. Performances of these models were evaluated by using various statistical criteria, namely mean square error (MSE), pseudo-R(2), -2 log likelihood, Akaike's and Bayesian's information criteria. All the chosen models fitted well to the growth data of Salmonella based on these criteria. The results of statistical analysis showed that there was no significant difference in the performances of the four primary models, suggesting that the models were equally suitable for describing isothermal bacterial growth. The specific growth rates derived from each model was fitted to the Modified Ratkowsky equation, relating the specific growth rate to growth temperatures. It was also observed that the lag phase duration was an inverse function of specific growth rates. These models, if validated, can be used to construct dynamic models to predict potential Salmonella growth in raw ground beef.


Subcell misalignment in vertically cascaded metamaterial absorbers.
Metamaterial has demonstrated exotic electromagnetic (EM) properties and various applications, for example perfect absorbers. Cascaded perfect absorbers further extend the spectral engineering ability. Perfect alignment of subcells was usually presumed in previous studies. We numerically investigated the effect of lateral misalignments existing in the multiple lithography steps for vertically cascaded metamaterial absorbers and found that the position deviations of the subcells play an important role of the spectral response. As an example, near-unity absorbance reduces to only 30% for a λ/10 subcell misalignment. The detailed investigation of EM field and induced current distributions reveals that the relative position variations of strongly coupled subcells contribute to this phenomenon. The results give us an evaluation that how much registration accuracy is required in multi-step lithography for cascaded metamaterials and on the other side a hint of the potential application of this high position sensitivity.


Down-regulation of placental neuropilin-1 in fetal growth restriction.
Fetal growth restriction (FGR) is associated with adverse outcomes extending from fetal to adult life, and thus, constitutes a major health care challenge. Fetuses with progressive growth restriction show increasing impedance in the umbilical artery flow, which may become absent during end-diastole. Absent end-diastolic flow (AEDF) is associated with adverse perinatal outcomes including stillbirths and perinatal asphyxia. Placentas from such pregnancies demonstrate deficient fetoplacental vascular branching. Current evidence, moreover, indicates an antiangiogenic state in maternal circulation in several pregnancy complications including preeclampsia, small-for-gestational-age births, fetal death, and preterm labor. The angiogenic mediators in maternal circulation are predominantly of placental origin. Information, however, on the role of specific proangiogenic and antiangiogenic mechanisms operating at the placental level remains limited. Elucidation of these placenta-specific angiogenic mechanisms will not only extend our understanding of the causal pathway for restricted fetal growth but may also lead to the development of biomarkers that may allow early recognition of FGR. We sought to test the hypothesis that fetoplacental angiogenic gene expression is altered in pregnancies complicated with FGR and umbilical artery Doppler AEDF. Placental samples were collected from FGR pregnancies complicated with umbilical artery Doppler AEDF (study group, n = 7), and from uncomplicated pregnancies (control group, n = 7), all delivered by cesarean during the last trimester of pregnancy. Angiogenic oligonucleotide microarray analysis was performed and was corroborated by quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry. The Student t test with Bonferroni correction was used with P < .05 considered statistically significant. Independent groups t test was used to analyze the immunostain intensity scores with a P < .05 considered statistically significant. Our microarray results showed that among several differentially expressed angiogenic genes in the growth-restricted group, only the down-regulation of neuropilin (NRP)-1 was most significant (P < .0007). Quantitative real-time polymerase chain reaction confirmed a significantly lower NRP-1 gene expression in the FGR group than in the control group (mean ± SD (ˆ)cycle threshold: 0.624 ± 0.55 and 1.325 ± 0.84, respectively, P = .04). Western blot validated significantly lower NRP-1 protein expression in the FGR group than in the control group (mean ± SD NRP-1/β-actin ratio: 0.13 ± 0.04 and 0.34 ± 0.05, respectively, P < .001). Finally, immunohistochemistry of placental villi further corroborated a significantly decreased expression of NRP-1 in the FGR group (P = .006). The study demonstrated significant down-regulation of placental NRP-1 expression in FGR pregnancies complicated with AEDF in umbilical artery. As NRP-1 is known to promote sprouting angiogenesis, its down-regulation may be involved in the deficient vascular branching observed in FGR placentas suggesting the presence of an antiangiogenic state. Further studies may elucidate such a causal role and may lead to the development of novel diagnostic and therapeutic tools.


Multimeric scaffolds displaying the HIV-1 envelope MPER induce MPER-specific antibodies and cross-neutralizing antibodies when co-immunized with gp160 DNA.
Developing a vaccine that overcomes the diversity of HIV-1 is likely to require a strategy that directs antibody (Ab) responses toward conserved regions of the viral Envelope (Env). However, the generation of neutralizing Abs (NAbs) targeting these regions through vaccination has proven to be difficult. One conserved region of particular interest is the membrane proximal external region (MPER) of Env located within the gp41 ectodomain. In order to direct the immune response to this region, the MPER and gp41 ectodomain were expressed separately as N-terminal fusions to the E2 protein of Geobacillus stearothermophilus. The E2 protein acts as a scaffold by self-assembling into 60-mer particles, displaying up to 60 copies of the fused target on the surface. Rabbits were immunized with E2 particles displaying MPER and/or the gp41 ectodomain in conjunction with DNA encoding full-length gp160. Only vaccines including E2 particles displaying MPER elicited MPER-specific Ab responses. NAbs were elicited after two immunizations that largely targeted the V3 loop. To overcome V3 immunodominance in the DNA component, E2 particles displaying MPER were used in conjunction with gp160 DNA lacking hypervariable regions V2, V3, or combined V1V2V3. All rabbits had HIV binding Ab responses and NAbs following the second vaccination. Using HIV-2/HIV-1 MPER chimeric viruses as targets, NAbs were detected in 12/16 rabbits after three immunizations. Low levels of NAbs specific for Tier 1 and 2 viruses were observed in all groups. This study provides evidence that co-immunizing E2 particles displaying MPER and gp160 DNA can focus Ab responses toward conserved regions of Env.


The role of anti-Müllerian hormone in the classification of anovulatory infertility.
The World Health Organization (WHO) has defined three classes of anovulatory infertility, based on serum gonadotrophin and oestradiol levels: low gonadotrophin and oestradiol levels in women with WHO 1 anovulation, normal hormone levels in WHO 2 anovulation and high gonadotrophin but low oestradiol levels in WHO 3 anovulation. The number of follicles on the ovary also seems to be different in the three classes of anovulatory infertility. Serum anti-Müllerian hormone (AMH) levels correlate well with the number of pre-antral and small antral follicles. The objective of our study was to investigate whether a single AMH measurement might simplify the classification of the WHO classes of anovulatory dysfunction. In a tertiary hospital, 1863 patients with either oligomenorrhea or secondary amenorrhea were recruited. Standardized screening was performed, including transvaginal ultrasound and serum AMH measurement. Serum AMH levels were compared with those in 348 age-matched controls. Serum AMH levels were slightly elevated in women with hypogonadotropic anovulation (n=128) (P<0.001) as compared with controls. Normogonadotropic anovulatory women (n=1.465) had distinctly higher serum AMH levels than controls (P<0.001) and serum AMH levels were low in women with hypergonadotropic anovulation (n=270) (P<0.001). Although median AMH levels were distinctly different in each class of anovulatory dysfunction, serum AMH levels were comparable in hypogonadotropic women and normogonadotropic women without polycystic ovary syndrome. The clinical applicability of serum AMH as a diagnostic tool to differentiate between the different classes of anovulatory dysfunction seems to be limited to the prediction of hypergonadotropic anovulation.


Reorienting Norwegian mental healthcare services: listen to patients' learning appetite.
Reorientation of healthcare services towards more efficient health promotion interventions is an urgent matter. Despite policies and guidelines being in place, it is the least developed key action area of the Ottawa charter. User involvement, or the voice of the patient, is missing from the knowledge base of health promotion in the mental healthcare services. The aim of this study was to add experiential knowledge from former patients. We explored the lived experience of 12 former inpatients at a mental healthcare hospital. We describe what they perceive as mental health promoting efforts. A salutogenic theoretical framework and the methodology of interpretative phenomenological analysis were used. The analysis revealed an appetite for learning in order to develop an in depth understanding of their former experiences. This was motivated by a desire to master daily life despite living with an illness and to increase health and well-being. The participants perceived the learning processes within the healthcare setting as mental health promoting. This craving for a better life is compatible with health promotion. It may turn out to be an opportunity to complement the curative activity of healthcare services with health promotion educational activities.


Hydrology Affects Environmental and Spatial Structuring of Microalgal Metacommunities in Tropical Pacific Coast Wetlands.
The alternating climate between wet and dry periods has important effects on the hydrology and therefore on niche-based processes of water bodies in tropical areas. Additionally, assemblages of microorganism can show spatial patterns, in the form of a distance decay relationship due to their size or life form. We aimed to test spatial and environmental effects, modulated by a seasonal flooding climatic pattern, on the distribution of microalgae in 30 wetlands of a tropical dry forest region: the Pacific coast of Costa Rica and Nicaragua. Three surveys were conducted corresponding to the beginning, the highest peak, and the end of the hydrological year during the wet season, and species abundance and composition of planktonic and benthic microalgae was determined. Variation partitioning analysis (as explained by spatial distance or environmental factors) was applied to each seasonal dataset by means of partial redundancy analysis. Our results show that microalgal assemblages were structured by spatial and environmental factors depending on the hydrological period of the year. At the onset of hydroperiod and during flooding, neutral effects dominated community dynamics, but niche-based local effects resulted in more structured algal communities at the final periods of desiccating water bodies. Results suggest that climate-mediated effects on hydrology can influence the relative role of spatial and environmental factors on metacommunities of microalgae. Such variability needs to be accounted in order to describe accurately community dynamics in tropical coastal wetlands.


Behavioral and neurochemical alterations evoked by p-Chlorophenylalanine application in rats examined in the light-dark crossing test.
The aim of the present study is to examine the effects of serotonin synthesis inhibition with p-Chlorophenylalanine (p-CPA) in rats on (1) anxiety behavior examined in the light-dark crossing test and, (2) regional brain concentration of monoamines (NA, DA and 5-HT) and their metabolites (MHPG, DOPAC, HVA and 5-HIAA) as well as GABA in the hypothalamus, amygdala, hippocampus, midbrain central gray matter and the frontal cortex. Treatment of animals with p-CPA produced a significant increase in time out from the illuminated part of the chamber and in time of locomotor activity in the illuminated part of the chamber. HPLC analysis showed a significant reduction of 5-HT and 5-HIAA concentration in all examined brain regions with the exception of the frontal cortex. Additionally, a significant decrease in DA and its metabolites, DOPAC and HVA occurred in the hypothalamus and amygdala. Moreover, we observed a significant decrease in frontal cortex NA concentration after p-CPA administration. The results of our study suggest that administration of p-CPA is effective in reduction of anxiety through depletion of 5-HT accompanied by diminution of catecholamines, especially DA and its metabolites in the main emotional brain regions.


Effect of Glycemic Index of a Pre-exercise Meal on Endurance Exercise Performance: A Systematic Review and Meta-analysis.
Low glycemic index (GI) pre-exercise meals may enhance endurance performance by maintaining euglycemia and altering fuel utilization. However, evidence for performance benefits is equivocal. To evaluate the effect of a low GI (LGI) versus a high GI (HGI) pre-exercise meal on endurance performance using meta-analyses. Data sources included MEDLINE, SPORTDiscus, AUSPORT, AusportMed, Web of Science, and Scopus. Eligibility criteria were randomized, crossover trials with an endurance exercise (≥60 min) component, e.g., time trial (TT), time to exhaustion (TTE) test, or submaximal bout followed by TT or TTE. Participants were healthy, active individuals aged ≥16 years. Interventions included a LGI (≤55) and HGI (≥70) meal ingested 30-240 min before exercise. Study quality was assessed using an adapted version of the validated Downs and Black tool. Effect size (ES) and 95 % confidence interval were calculated for each study and pooled according to performance test type and whether exogenous carbohydrate (CHO) was given during exercise. Potential effect modifiers including exercise duration, pre-exercise meal timing, glycemic load (GL), and fitness were assessed using meta-regression. The search netted 3431 citations with 19 studies eligible for inclusion (totaling 188 participants; 91 % male; VO2max: >50 ml/kg/min). Meals with 0.18-2 g CHO/kg body mass, and a mean GI and glycemic load of 82 (GL: 72) and 35 (GL: 32) for HGI and LGI, respectively, were given between 30 and 210 min before exercise. All test types without CHO ingestion during exercise showed slightly improved performance with LGI, but no significant pooled effects were observed (ES: -0.17 to -0.36; p > 0.05). Studies where exogenous CHO was ingested during exercise showed conflicting results (ES: -0.67 to 0.11; p = 0.04 to 0.94). No significant relationship was observed with any of the effect modifiers (p > 0.05). No consistent metabolic responses (glucose, insulin, lactate, respiratory exchange ratio) during exercise were observed with either meal type. There were small numbers of studies within each exercise testing protocol and limited statistical power within studies. Pre-exercise meal timing, GL, meal composition and participant fitness varied across studies, limiting the capacity to assess the influence of these factors on study outcomes. There was no clear benefit of consuming a LGI pre-exercise meal for endurance performance regardless of carbohydrate ingestion during exercise.


Neuroimmune disorders of the central nervous system in children in the molecular era.
Immune-mediated disorders of the CNS in children are a complex group of demyelinating, inflammatory, parainfectious and postinfectious disorders with heterogeneous pathobiological mechanisms and clinical manifestations, often associated with fundamental derangement in immune regulation. In this Review, we aim to provide an update on our knowledge of neuroimmune disorders and highlight areas of research that are priorities for improving clinical management. We outline the clinical features of neuroimmune disorders, the current approaches to their treatment and new approaches in development. We then consider the pathological features, including biomarkers, pathological mechanisms and genetics, and discuss the value of immune assays in clinical investigation and basic research. On the basis of current knowledge and techniques, we propose four research priorities: rigorous and consistent collection of core clinical data, cooperative investigation of treatments, development of biological assays and genetic studies. These priorities should help us to achieve the shared goal of precision medicine for neuroimmune disorders. However, multicentre research and the creation of clinical consortia for these rare disorders will be necessary, and we hope that this Review serves as a call to action that is timely given current exciting advances in neuroimmune therapeutics.


Current hydration guidelines are erroneous: dehydration does not impair exercise performance in the heat.
Laboratory studies that support the hydration guidelines of leading governing bodies have shown that dehydration to only -2% of body mass can lead to increase in body temperature and heart rate during exercise, and decrease in performance. These studies, however, have been conducted in relatively windless environments (ie, wind speed <12.9 km/h), without participants being blinded to their hydration status. To investigate the effect of blinded hydration status on cycling time-trial performance in the heat with ecologically valid facing wind speed conditions. During three experimental trials, 10 cyclists were dehydrated to -3% body mass by performing 2 h of submaximal exercise (walking and cycling) in the heat, before being reinfused with saline to replace 100%, 33% or 0% of fluid losses, leaving them 0%, -2% or -3% hypohydrated, respectively. Participants then completed a 25 km time trial in the heat (33°C, 40% relative humidity; wind speed 32 km/h) during which their starting hydration status was maintained by infusing saline at a rate equal to their sweat rate. The treatment was participant-blinded and the order was randomised. Completion time, power output, heart rate, rectal temperature and perceptual variables were measured. While rectal temperature was higher beyond 17 km of the time trial in the -3% vs 0% conditions (38.9±0.3°C vs 38.6±0.3°C; p<0.05), no other differences between trials were shown. When well-trained cyclists performed a 25 km cycling time trial under ecologically valid conditions and were blinded to their hydration status, performance, physiological and perceptual variables were not different between trials. These data do not support the residing basis behind many of the current hydration guidelines.


Generation of simian-tropic HIV-1 by restriction factor evasion.
Because HIV-1 does not infect most nonhuman primates, animal modeling of human HIV infection and AIDS has primarily consisted of experimentally infecting macaques with related simian immunodeficiency viruses (SIVMAC). However, the usefulness of such models is limited by the substantial divergence between SIVMAC and HIV-1. We derived an HIV-1-based virus that includes only small portions of SIVMAC yet replicates robustly in both transformed and primary rhesus macaque T cells. Derivation of simian-tropic HIV-1 (stHIV-1) has important implications for understanding primate lentivirus zoonosis and should allow the development of improved animal models for studies of AIDS and the evaluation of vaccines and treatments.


Resource utilization pattern and cost of tuberculosis treatment from the provider and patient perspectives in the state of Penang, Malaysia.
Studies from both developed and developing countries have demonstrated a considerable fluctuation in the average cost of TB treatment. The objective of this study was to analyze the medical resource utilization among new smear positive pulmonary tuberculosis patients. We also estimated the cost of tuberculosis treatment from the provider and patient perspectives, and identified the significant cost driving factors. All new smear positive pulmonary tuberculosis patients who were registered at the chest clinic of the Penang General Hospital, between March 2010 and February 2011, were invited to participate in the study. Provider sector costs were estimated using bottom-up, micro-costing technique. For the calculation of costs from the patients' perspective, all eligible patients who agreed to participate in the study were interviewed after the intensive phase and subsequently at the end of the treatment by a trained nurse. PASW was used to analyze the data (Predictive Analysis SoftWare, version 19.0, Armonk, NY: IBM Corp.). During the study period, 226 patients completed the treatment. However, complete costing data were available for 212 patients. The most highly utilized resources were chest X-ray followed by sputum smear examination. Only a smaller proportion of the patients were hospitalized. The average provider sector cost was MYR 992.34 (i.e., USD 325.35 per patient) whereby the average patient sector cost was MYR 1225.80 (i.e., USD 401.90 per patient). The average patient sector cost of our study population accounted for 5.7% of their annual family income. In multiple linear regression analysis, prolonged treatment duration (i.e., > 6 months) was the only predictor of higher provider sector costs whereby higher patient sector costs were determined by greater household income and persistent cough at the end of the intensive phase of the treatment. In relation to average provider sector cost, our estimates are substantially higher than the budget allocated by the Ministry of Health for the treatment of a tuberculosis case in Malaysia. The expenses borne by the patients and their families on the treatment of the current episode of tuberculosis were not catastrophic for them.


Rapid antimicrobial susceptibility tests for sepsis; the road ahead.
Current methods for antimicrobial susceptibility testing (AST) are too slow to affect initial treatment decisions in the early stages of sepsis, when the prescriber is most concerned to select effective therapy immediately, rather than finding out what will not work 1 or 2 days later. There is a clear need for much faster differentiation between viral and bacterial infection, and AST, linked to earlier aetiological diagnosis, without sacrificing either the accuracy of quantitative AST or the low cost of qualitative AST. Truly rapid AST methods are eagerly awaited, and there are several candidate technologies that aim to improve the targeting of our limited stock of effective antimicrobial agents. However, none of these technologies are approaching the point of care and nor can they be described as truly culture-independent diagnostic tests. Rapid chemical and genomic methods of resistance detection are not yet reliable predictors of antimicrobial susceptibility and often rely on prior bacterial isolation. In order to resolve the trade-off between diagnostic confidence and therapeutic efficacy in increasingly antimicrobial-resistant sepsis, we propose a series of three linked decision milestones: initial clinical assessment (e.g. qSOFA score) within 10 min, initial laboratory tests and presumptive antimicrobial therapy within 1 h, and definitive AST with corresponding antimicrobial amendment within an 8 h window (i.e. the same working day). Truly rapid AST methods therefore must be integrated into the clinical laboratory workflow to ensure maximum impact on clinical outcomes of sepsis, and diagnostic and antimicrobial stewardship. The requisite series of development stages come with a substantial regulatory burden that hinders the translation of innovation into practice. The regulatory hurdles for the adoption of rapid AST technology emphasize technical accuracy, but progress will also rely on the effect rapid AST has on prescribing behaviour by physicians managing the care of patients with sepsis. Early adopters in well-equipped teaching centres in close proximity to large clinical laboratories are likely to be early beneficiaries of rapid AST, while simplified and lower-cost technology is needed to support poorly resourced hospitals in developing countries, with their higher burden of AMR. If we really want the clinical laboratory to deliver a specific, same-day diagnosis underpinned by definitive AST results, we are going to have to advocate more effectively for the clinical benefits of bacterial detection and susceptibility testing at critical decision points in the sepsis management pathway.


Diet, ageing and genetic factors in the pathogenesis of diverticular disease.
Diverticular disease (DD) is an age-related disorder of the large bowel which may affect half of the population over the age of 65 in the UK. This high prevalence ranks it as one of the most common bowel disorders in western nations. The majority of patients remain asymptomatic but there are associated life-threatening co-morbidities, which, given the large numbers of people with DD, translates into a considerable number of deaths per annum. Despite this public health burden, relatively little seems to be known about either the mechanisms of development or causality. In the 1970s, a model of DD formulated the concept that diverticula occur as a consequence of pressure-induced damage to the colon wall amongst those with a low intake of dietary fiber. In this review, we have examined the evidence regarding the influence of ageing, diet, inflammation and genetics on DD development. We argue that the evidence supporting the barotrauma hypothesis is largely anecdotal. We have also identified several gaps in the knowledge base which need to be filled before we can complete a model for the etiology of diverticular disease.


The Importance of Sleep: Attentional Problems in School-Aged Children With Down Syndrome and Williams Syndrome.
In typically developing (TD) children, sleep problems have been associated with day-time attentional difficulties. Children with developmental disabilities often suffer with sleep and attention problems, yet their relationship is poorly understood. The present study investigated this association in school-aged children with Down syndrome (DS) and Williams syndrome (WS). Actigraphy and pulse oximetry assessed sleep and sleep-disordered breathing respectively, and attention was tested using a novel visual Continuous Performance Task (CPT).Attentional deficits were evident in both disorder groups. In the TD group, higher scores on the CPT were related to better sleep quality, higher oxyhemoglobin saturation (SpO2), and fewer desaturation events. Sleep quality, duration, and SpO2 variables were not related to CPT performance for children with DS and WS.


Long-term weight patterns and risk for cholecystectomy in women.
Obesity and rapid weight loss in obese persons are known risk factors for gallstones. However, the effect of intentional, long-term, moderate weight changes on the risk for gallstones is unclear. To study long-term weight patterns in a cohort of women and to examine the relation between weight pattern and risk for cholecystectomy. Prospective cohort study. 11 U.S. states. 47,153 female registered nurses who did not undergo cholecystectomy before 1988. Cholecystectomy between 1988 and 1994 (ascertained by patient self-report). During the exposure period (1972 to 1988), there was evidence of substantial variation in weight due to intentional weight loss during adulthood. Among cohort patients, 54.9% reported weight cycling with at least one episode of intentional weight loss associated with regain. Of the total cohort, 20.1% were light cyclers (5 to 9 lb of weight loss and gain), 18.8% were moderate cyclers (10 to 19 lb of weight loss and gain), and 16.0% were severe cyclers (> or = 20 lb of weight loss and gain). Net weight gain without cycling occurred in 29.3% of women; net weight loss without cycling was the least common pattern (4.6%). Only 11.1% of the cohort maintained weight within 5 lb over the 16-year period. In the study, 1751 women had undergone cholecystectomy between 1988 and 1994. Compared with weight maintainers, the relative risk for cholecystectomy (adjusted for body mass index, age, alcohol intake, fat intake, and smoking) was 1.20 (95% CI, 0.96 to 1.50) among light cyclers, 1.31 among moderate cyclers (CI, 1.05 to 1.64), and 1.68 among severe cyclers (CI, 1.34 to 2.10). Weight cycling was highly prevalent in this large cohort of middle-aged women. The risk for cholecystectomy associated with weight cycling was substantial, independent of attained relative body weight.


Antibody-dependent enhancement of dengue virus infection mediated by bispecific antibodies against cell surface molecules other than Fc gamma receptors.
It is known that antibodies to dengue viruses at subneutralizing concentrations enhance dengue virus infection of Fc gamma R+ cells. This phenomenon called antibody-dependent enhancement (ADE) occurs when virus-antibody complexes bind to the Fc gamma R via the Fc portion of the Ig. It has been hypothesized that ADE may be responsible for the pathogenesis of the severe manifestations of dengue virus infection including dengue hemorrhagic fever/dengue shock syndrome. To further analyze the mechanisms of ADE, we prepared bispecific antibodies by chemically cross-linking antidengue virus antibodies to antibodies specific for Fc gamma RI or Fc gamma RII and the non-Fc R molecules beta2 microglobulin, CD15 or CD33 and examined whether these bispecific antibodies could enhance infection. Bispecific antibodies targeting dengue virus to Fc gamma RI or Fc gamma RII enhanced dengue virus infection, consistent with previous reports using conventional antibodies. Furthermore, bispecific antibodies targeting dengue virus to beta2 microglobulin, CD15 or CD33 also enhanced dengue virus infection. Bispecific antibody mediated ADE was inhibited by pretreating the cells with the appropriate blocking mAb. These results indicate that cell surface molecules other than Fc gamma R can mediate ADE and suggest that the Fc gamma R does not provide a unique signal necessary for enhanced infection. We hypothesize that directing dengue virus to the cell surface by a bispecific antibody facilitates the interaction between dengue virus and its receptor, thereby increasing its infectivity.


Selling Gender: Associations of Box Art Representation of Female Characters With Sales for Teen- and Mature-rated Video Games.
Content analysis of video games has consistently shown that women are portrayed much less frequently than men and in subordinate roles, often in "hypersexualized" ways. However, the relationship between portrayal of female characters and videogame sales has not previously been studied. In order to assess the cultural influence of video games on players, it is important to weight differently those games seen by the majority of players (in the millions), rather than a random sample of all games, many of which are seen by only a few thousand people. Box art adorning the front of video game boxes is a form of advertising seen by most game customers prior to purchase and should therefore predict sales if indeed particular depictions of female and male characters influence sales. Using a sample of 399 box art cases from games with ESRB ratings of Teen or Mature released in the US during the period of 2005 through 2010, this study shows that sales were positively related to sexualization of non-central female characters among cases with women present. In contrast, sales were negatively related to the presence of any central female characters (sexualized or non-sexualized) or the presence of female characters without male characters present. These findings suggest there is an economic motive for the marginalization and sexualization of women in video game box art, and that there is greater audience exposure to these stereotypical depictions than to alternative depictions because of their positive relationship to sales.


[Visceral leishmaniasis: clinical sensitivity and resistance to various therapeutic agents].
Visceral leishmaniasis is present in 61 countries but 90% of the 500,000 new cases that arise annually occur in five countries, i.e., India, Bangladesh, Nepal, Sudan, and Brazil. Annual mortality is approximately 59000 cases. Agents based on pentavalent antimony have been the mainstay of treatment for the last 60 years. In recent years, however, clinical resistance to these agents has been reported especially in the state of Bihar in India. Pentamidine and amphotericin B were introduced in the 1950s and 1960s. More recent additions to the therapeutic arsenal include liposomal amphotericin B, miltefosine, and paromomycin. Among these recent molecules, miltefosine, i.e., the only oral agent, appears most vulnerable because it involves long-term treatment and has a long half-life. The main therapeutic problems now being encountered are the emergence of acquired resistance to antimonials, the high cost of treatment, and failure of therapy in immunocompromised patients mainly due to concurrent human immunodeficiency virus (HIV) infection. For eradication initiatives such as the one aimed at eliminating leishmaniasis on the Indian subcontinent, the appearance of drug resistance increases the risk associated to parasite infection and, as for malaria, tuberculosis and HIV infection, raises fears that the problems in the implementation of public health policies will lead to highly refractory forms.


Transition from Collisional to Collisionless Regimes in Interpenetrating Plasma Flows on the National Ignition Facility.
A study of the transition from collisional to collisionless plasma flows has been carried out at the National Ignition Facility using high Mach number (M>4) counterstreaming plasmas. In these experiments, CD-CD and CD-CH planar foils separated by 6-10 mm are irradiated with laser energies of 250 kJ per foil, generating ∼1000 km/s plasma flows. Varying the foil separation distance scales the ion density and average bulk velocity and, therefore, the ion-ion Coulomb mean free path, at the interaction region at the midplane. The characteristics of the flow interaction have been inferred from the neutrons and protons generated by deuteron-deuteron interactions and by x-ray emission from the hot, interpenetrating, and interacting plasmas. A localized burst of neutrons and bright x-ray emission near the midpoint of the counterstreaming flows was observed, suggesting strong heating and the initial stages of shock formation. As the separation of the CD-CH foils increases we observe enhanced neutron production compared to particle-in-cell simulations that include Coulomb collisions, but do not include collective collisionless plasma instabilities. The observed plasma heating and enhanced neutron production is consistent with the initial stages of collisionless shock formation, mediated by the Weibel filamentation instability.


Vitamin B12: unique metalorganic compounds and the most complex vitamins.
The chemistry and biochemistry of the vitamin B(12) compounds (cobalamins, XCbl) are described, with particular emphasis on their structural aspects and their relationships with properties and function. A brief history of B(12), reveals how much the effort of chemists, biochemists and crystallographers have contributed in the past to understand the basic properties of this very complex vitamin. The properties of the two cobalamins, the two important B(12) cofactors Ado- and MeCbl are described, with particular emphasis on how the Co-C bond cleavage is involved in the enzymatic mechanisms. The main structural features of cobalamins are described, with particular reference to the axial fragment. The structure/property relationships in cobalamins are summarized. The recent studies on base-off/base-on equilibrium are emphasized for their relevance to the mode of binding of the cofactor to the protein scaffold. The absorption, transport and cellular uptake of cobalamins and the structure of the B(12) transport proteins, IF and TC, in mammals are reviewed. The B(12) transport in bacteria and the structure of the so far determined proteins are briefly described. The currently accepted mechanisms for the catalytic cycles of the AdoCbl and MeCbl enzymes are reported. The structure and function of B(12) enzymes, particularly the important mammalian enzymes methyltransferase (MetH) and methyl-malonyl-coenzyme A mutase (MMCM), are described and briefly discussed. Since fast proliferating cells require higher amount of vitamin B(12) than that required by normal cells, the study of B(12 )conjugates as targeting agents has recently gained importance. Bioconjugates have been studied as potential agents for delivering radioisotopes and NMR probes or as various cytotoxic agents towards cancer cells in humans and the most recent studies are described. Specifically, functionalized bioconjugates are used as "Trojan horses" to carry into the cell the appropriate antitumour or diagnostic label. Possible future developments of B(12) work are summarized.


A survey of the quality and accuracy of information leaflets about skin cancer and sun-protective behaviour available from UK general practices and community pharmacies.
Better information promotes sun protection behaviour and is associated with earlier presentation and survival for malignant melanoma. Aim To assess the quality of patient information leaflets about skin cancer and sun-protective behaviour available from general practices and community pharmacies. A structured review of patient information leaflets. Setting All community pharmacies and general practices in one Primary Care Trust were invited to supply leaflets. Readability was assessed using the SMOG scoring system. Presentation and content were reviewed using the Ensuring Quality Information for Patients (EQIP) guidelines. Three consultant dermatologists assessed each leaflet for accuracy. Thirty-one different patient information leaflets were returned. Thirteen (42%) were published in the previous 2 years, but 10 (32%) were over 5 years old. Nine (29%) leaflets were produced by the NHS or Health Education Authority, and 8 (27%) were linked to a commercial organization. One leaflet had readability in the primary education range (SMOG score = 6), and none with the recommended range for health education material (SMOG score < or = 5). Two leaflets (6%) were in the highest quartile of EQIP score for presentation and content. Five leaflets (17%) had a major inaccuracy such as over-reliance on sun screen products instead of shade and clothing. Leaflets were of variable quality in presentation and content. All required a reading age higher than recommended. All leaflets with major inaccuracies had links with commercial organizations. This study raises important issues about the potential conflict between marketing and health messages in the way sun creams are promoted.


Independent association between preoperative cognitive status and discharge location after cardiac surgery.
Among cardiac surgery patients, those with impaired cognitive status before surgery may have longer postoperative stays than do patients with normal status and may require additional care upon discharge. To determine if preoperative scores on a screening measure for cognitive status (the Clock-in-the-Box), were associated with postoperative length of stay and discharge to a location other than home in patients who had cardiac surgery. A total of 181 consecutive patients scheduled for cardiac surgery at a single site were administered the Clock-in-the-Box as part of the preoperative evaluation. Scores on the Clock-in-the-Box tool, demographic and operative information, postoperative length of stay, and discharge location were collected retrospectively from medical records. The mean age of the patients was 68.1 years (SD, 0.7), and 99% were men. Mean postoperative length of stay was 10.5 days (SD, 8.2), and 35 patients (19%) were discharged to a facility. Scores on the Clock-in-the-Box assessment were not associated with postoperative length of stay. Increasing age, living alone before surgery, and duration of cardiopulmonary bypass were associated with discharge to a facility and were used as covariates in adjusted analyses. After adjustment, better preoperative cognitive status reduced the risk of being discharged to a facility (adjusted relative risk, 0.93; 95% confidence interval, 0.89-0.98) after cardiac surgery. Cognitive screening before cardiac surgery can identify patients with impaired cognitive status who are less likely than patients with normal cognitive status to return home after cardiac surgery.


Thiol isomerases negatively regulate the cellular shedding activity of ADAM17.
ADAM17 (where ADAM is 'a disintegrin and metalloproteinase') can rapidly modulate cell-surface signalling events by the proteolytic release of soluble forms of proligands for cellular receptors. Many regulatory pathways affect the ADAM17 sheddase activity, but the mechanisms for the activation are still not clear. We have utilized a cell-based ADAM17 assay to show that thiol isomerases, specifically PDI (protein disulfide isomerase), could be responsible for maintaining ADAM17 in an inactive form. Down-regulation of thiol isomerases, by changes in the redox environment (for instance as elicited by phorbol ester modulation of mitochondrial reactive oxygen species) markedly enhanced ADAM17 activation. On the basis of ELISA binding studies with novel fragment antibodies against ADAM17 we propose that isomerization of the disulfide bonds in ADAM17, and the subsequent conformational changes, form the basis for the modulation of ADAM17 activity. The shuffling of disulfide bond patterns in ADAMs has been suggested by a number of recent adamalysin crystal structures, with distinct disulfide bond patterns altering the relative orientations of the domains. Such a mechanism is rapid and reversible, and the role of thiol isomerases should be investigated further as a potential factor in the redox regulation of ADAM17.


Cycling to Meet Fate: Connecting Pluripotency to the Cell Cycle.
Pluripotent stem cells are characterized by their high proliferative rates, their ability to self-renew and their potential to differentiate to all the three germ layers. This rapid proliferation is brought about by a highly modified cell cycle that allows the cells to quickly shuttle from DNA synthesis to cell division, by reducing the time spent in the intervening gap phases. Many key regulators that define the somatic cell cycle are either absent or exhibit altered behavior, allowing the pluripotent cell to bypass cell cycle checkpoints typical of somatic cells. Experimental analysis of this modified stem cell cycle has been challenging due to the strong link between rapid proliferation and pluripotency, since perturbations to the cell cycle or pluripotency factors result in differentiation. Despite these hurdles, our understanding of this unique cell cycle has greatly improved over the past decade, in part because of the availability of new technologies that permit the analysis of single cells in heterogeneous populations. This review aims to highlight some of the recent discoveries in this area with a special emphasis on different states of pluripotency. We also discuss the highly interlinked network that connects pluripotency factors and key cell cycle genes and review evidence for how this interdependency may promote the rapid cell cycle. This issue gains translational importance since disruptions in stem cell proliferation and differentiation can impact disorders at opposite ends of a spectrum, from cancer to degenerative disease.


meCLICK-Seq, a Substrate-Hijacking and RNA Degradation Strategy for the Study of RNA Methylation.
The fates of RNA species in a cell are controlled by ribonucleases, which degrade them by exploiting the universal structural 2'-OH group. This phenomenon plays a key role in numerous transformative technologies, for example, RNA interference and CRISPR/Cas13-based RNA editing systems. These approaches, however, are genetic or oligomer-based and so have inherent limitations. This has led to interest in the development of small molecules capable of degrading nucleic acids in a targeted manner. Here we describe click-degraders, small molecules that can be covalently attached to RNA species through click-chemistry and can degrade them, that are akin to ribonucleases. By using these molecules, we have developed the meCLICK-Seq (methylation CLICK-degradation Sequencing) a method to identify RNA modification substrates with high resolution at intronic and intergenic regions. The method hijacks RNA methyltransferase activity to introduce an alkyne, instead of a methyl, moiety on RNA. Subsequent copper(I)-catalyzed azide-alkyne cycloaddition reaction with the click-degrader leads to RNA cleavage and degradation exploiting a mechanism used by endogenous ribonucleases. Focusing on N6-methyladenosine (m6A), meCLICK-Seq identifies methylated transcripts, determines RNA methylase specificity, and reliably maps modification sites in intronic and intergenic regions. Importantly, we show that METTL16 deposits m6A to intronic polyadenylation (IPA) sites, which suggests a potential role for METTL16 in IPA and, in turn, splicing. Unlike other methods, the readout of meCLICK-Seq is depletion, not enrichment, of modified RNA species, which allows a comprehensive and dynamic study of RNA modifications throughout the transcriptome, including regions of low abundance. The click-degraders are highly modular and so may be exploited to study any RNA modification and design new technologies that rely on RNA degradation.


Cord pilot trial - immediate versus deferred cord clamping for very preterm birth (before 32 weeks gestation): study protocol for a randomized controlled trial.
Preterm birth is the most important single determinant of adverse outcome in the United Kingdom; one in every 70 babies (1.4%) is born before 32 weeks (very preterm), yet these births account for over half of infant deaths.Deferring cord clamping allows blood flow between baby and placenta to continue for a short time. This often leads to increased neonatal blood volume at birth and may allow longer for transition to the neonatal circulation. Optimal timing for clamping the cord remains uncertain, however. The Cochrane Review suggests that deferring umbilical cord clamping for preterm births may improve outcome, but larger studies reporting substantive outcomes and with long-term follow-up are needed. Studies of the physiology of placental transfusion suggest that flow in the umbilical cord at very preterm birth may continue for several minutes. This pilot trial aims to assess the feasibility of conducting a large randomised trial comparing immediate and deferred cord clamping in the UK. Women are eligible for the trial if they are expected to have a live birth before 32 weeks gestation. Exclusion criteria are known monochorionic twins or clinical evidence of twin-twin transfusion syndrome, triplet or higher order multiple pregnancy, and known major congenital malformation. The interventions will be cord clamping within 20 seconds compared with cord clamping after at least two minutes. For births with cord clamping after at least two minutes, initial neonatal care is at the bedside. For the pilot trial, outcomes include measures of recruitment, compliance with the intervention, retention of participants and data quality for the clinical outcomes.Information about the trial is available to women during their antenatal care. Women considered likely to have a very preterm birth are approached for informed consent. Randomisation is close to the time of birth. Follow-up for the women is for one year, and for the children to two years of age (corrected for gestation at birth). The target sample size is 100 to 110 mother-infant pairs recruited over 12 months at eight sites. ISRCTN21456601, registered on 28 February 2013.


Online Learning and Sequential Anomaly Detection in Trajectories.
Detection of anomalous trajectories is an important problem in the surveillance domain. Various algorithms based on learning of normal trajectory patterns have been proposed for this problem. Yet, these algorithms typically suffer from one or more limitations: They are not designed for sequential analysis of incomplete trajectories or online learning based on an incrementally updated training set. Moreover, they typically involve tuning of many parameters, including ad-hoc anomaly thresholds, and may therefore suffer from overfitting and poorly-calibrated alarm rates. In this article, we propose and investigate the Sequential Hausdorff Nearest-Neighbor Conformal Anomaly Detector (SHNN-CAD) for online learning and sequential anomaly detection in trajectories. This is a parameter-light algorithm that offers a well-founded approach to the calibration of the anomaly threshold. The discords algorithm, originally proposed by Keogh et al. , is another parameter-light anomaly detection algorithm that has previously been shown to have good classification performance on a wide range of time-series datasets, including trajectory data. We implement and investigate the performance of SHNN-CAD and the discords algorithm on four different labeled trajectory datasets. The results show that SHNN-CAD achieves competitive classification performance with minimum parameter tuning during unsupervised online learning and sequential anomaly detection in trajectories.


Association between vitamin D and pressure ulcers in older ambulatory adults: results of a matched case-control study.
Pressure ulcers are common among older adults, but knowledge about nutritional risk factors is still developing. Vitamin D deficiency is common in the elderly population and is required for normal skin proliferation. The role of vitamin D in pressure ulceration and wound healing is not known. The purpose of this case-control study was to determine the association between vitamin D levels and pressure ulceration in an older community-dwelling cohort. All cases and controls were community-dwelling elderly older than 60 years in a primary care panel in Olmsted County, MN. Pressure ulcer cases were defined clinically. The controls were age-matched and gender-matched to controls without pressure ulceration. The main exposure variable was 25-hydroxyvitamin D levels in both groups. The other exposure variable was the Charlson Comorbidity Index used to measure medical comorbidity. The analysis included univariate and conditional logistic regression for 25-hydroxyvitamin D levels. The average (standard deviation) age of the study participants with a pressure ulcer was 80.46 years (±8.67), and the average vitamin D level was 30.92 ng/mL (±12.46). In univariate analysis, Vitamin D deficiency (levels < 25 ng/mL) was associated with pressure ulcers (odds ratio: 1.871, P = 0.0154). Comorbidities of the subjects calculated using the Charlson Comorbidity Index were also associated with pressure ulcers (odds ratio: 1.136, P < 0.001). In the final conditional logistical regression model, the association of Vitamin D and pressure ulcers became nonsignificant after adjustment for comorbid illness. Medical comorbidities increased the risk of pressure ulceration. Vitamin D deficiency was not an independent risk factor for pressure ulceration, and may be a marker of comorbid illness.


Selective one- and two-electron reductions of a haloborane enabled by a π-withdrawing carbene ligand.
A carbene-stabilised neutral boryl radical and a boryl anion are isolated via selective one- and two-electron reduction of a diamidocarbene (DAC) adduct of dibromo(pentafluorophenyl)borane. Both the radical and the anion have been characterised by various spectroscopic techniques in solution, while the structures have been ascertained by single-crystal X-ray diffraction. In contrast, the reduction of the analogous cyclic (alkyl)(amino) carbene (CAAC) adduct yields a C-H activation product.


Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer's Disease.
Finding a therapy for Alzheimer's disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates. Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain. This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive. Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal. Pairwise combinations of THC and CBN lead to a synergistic neuroprotective interaction. Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potential lead drug candidates for AD and other neurodegenerative diseases.


Seasonality in pain, sleep and mental distress in patients with chronic musculoskeletal pain at latitude 69° N.
Seasonality is evident in several aspects of human health and behavior, whereas seasonality in chronic pain is less well studied. We examined seasonal variation in pain severity and pain dissemination, as well as in pain-associated conditions, such as sleep impairment, sleep timing, mental distress, fatigue and physical activity. We also examined if any of these associated conditions moderated the seasonality in pain. This prospective study was conducted in the subarctic municipality of Tromsø, Norway (69º North), on a sample of patients with chronic musculoskeletal pain (N = 56). Data were collected with self-report questionnaires and objective actigraphy measures (7 days) twice: winter and summer. Mixed linear regression models were fitted. A modest seasonality effect was observed in pain severity (highest in summer), but not in pain dissemination. Seasonality with increased physical activity and delayed sleep timing in the summer was also present. The remaining pain-associated self-report or objective measures indicated no seasonality. The season-pain association was not significantly moderated by any of the pain-associated conditions. Previous studies on healthy individuals residing in polar areas have suggested an opposite seasonal effect with delay of the sleep-wake rhythm in winter. Our results based on a clinical sample thus represent a novel finding that needs to be examined further with regard to seasonal circadian entrainment and alignment in pain populations. These results may have clinical value for the treatment of patients with musculoskeletal pain as seasonality may require seasonal adjustments of pain treatment strategies.


Effects of a music therapy voice protocol on speech intelligibility, vocal acoustic measures, and mood of individuals with Parkinson's disease.
This study examined the effects of a Music Therapy Voice Protocol (MTVP) on speech intelligibility, vocal intensity, maximum vocal range, maximum duration of sustained vowel phonation, vocal fundamental frequency, vocal fundamental frequency variability, and mood of individuals with Parkinson's disease. Four female patients, who demonstrated voice and speech problems, served as their own controls and participated in baseline assessment (study pretest), a series of MTVP sessions involving vocal and singing exercises, and final evaluation (study posttest). In study pre and posttests, data for speech intelligibility and all acoustic variables were collected. Statistically significant increases were found in speech intelligibility, as rated by caregivers, and in vocal intensity from study pretest to posttest as the results of paired samples t-tests. In addition, before and after each MTVP session (session pre and posttests), self-rated mood scores and selected acoustic variables were collected. No significant differences were found in any of the variables from the session pretests to posttests, across the entire treatment period, or their interactions as the results of two-way ANOVAs with repeated measures. Although not significant, the mean of mood scores in session posttests (M = 8.69) was higher than that in session pretests (M = 7.93).


Angiotensin II-Induced Hypertension Is Attenuated by Overexpressing Copper/Zinc Superoxide Dismutase in the Brain Organum Vasculosum of the Lamina Terminalis.
Angiotensin II (AngII) can access the brain via circumventricular organs (CVOs), including the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), to modulate blood pressure. Previous studies have demonstrated a role for both the SFO and OVLT in the hypertensive response to chronic AngII, yet it is unclear which intracellular signaling pathways are involved in this response. Overexpression of copper/zinc superoxide dismutase (CuZnSOD) in the SFO has been shown to attenuate the chronic hypertensive effects of AngII. Presently, we tested the hypothesis that elevated levels of superoxide (O2 (∙-)) in the OVLT contribute to the hypertensive effects of AngII. To facilitate overexpression of superoxide dismutase, adenoviral vectors encoding human CuZnSOD or control adenovirus (AdEmpty) were injected directly into the OVLT of rats. Following 3 days of control saline infusion, rats were intravenously infused with AngII (10 ng/kg/min) for ten days. Blood pressure increased 33 ± 8 mmHg in AdEmpty rats (n = 6), while rats overexpressing CuZnSOD (n = 8) in the OVLT demonstrated a blood pressure increase of only 18 ± 5 mmHg after 10 days of AngII infusion. These results support the hypothesis that overproduction of O2 (∙-) in the OVLT plays an important role in the development of chronic AngII-dependent hypertension.


Anxiety is correlated with running in adolescent female mice undergoing activity-based anorexia.
Activity-based anorexia (ABA) is a widely used animal model for identifying the biological basis of excessive exercise and starvation, 2 hallmarks of anorexia nervosa (AN). Anxiety is correlated with exercise in AN. Yet the anxiety level of animals in ABA has not been reported. We asked: Does food restriction as part of ABA induction change the anxiety level of animals? If so, is the degree of anxiety correlated with degree of hyperactivity? We used the open field test before food restriction and the elevated plus maze test (EPM) during food restriction to quantify anxiety among singly housed adolescent female mice and determined whether food restriction alone or combined with exercise (i.e., ABA induction) abates or increases anxiety. We show that food restriction, with or without exercise, reduced anxiety significantly, as measured by the proportion of entries into the open arms of EPM (35.73%, p = .04). Moreover, ABA-induced individuals varied in their open arm time measure of anxiety and this value was highly and negatively correlated to the individual's food restriction-evoked wheel activity during the 24 hr following the anxiety test (R = -.75, p = .004, N = 12). This correlation was absent among the exercise-only controls. In addition, mice with higher increase in anxiety ran more following food restriction. Our data suggest that food restriction-evoked wheel running hyperactivity can be used as a reliable and continuous measure of anxiety in ABA. The parallel relationship between anxiety level and activity in AN and ABA-induced female mice strengthens the animal model.


Biochemistry of neuromodulation in primary headaches: focus on anomalies of tyrosine metabolism.
Recent studies have suggested that abnormalities of dopamine and trace amines (tyramine, octopamine, and synephrine), products of tyrosine metabolism, may constitute the metabolic events that predispose to the occurrence of cluster headache (CH) and migraine attacks. This hypothesis is supported by the following evidences: the discovery of trace amine associated receptors (TAARs), expressed on the olfactory epithelium, amigdala, hypothalamus, periacqueductal gray, and the biochemical anomalies of dopamine and trace amines. The possible effects of these biochemical abnormalities on TAARs and dopamine receptors, located in different areas of CNS, may explain the behaviour (restlessness, anxiety and, at times, hypersexuality) and the autonomic signs during the painful attacks of CH, and the premonitory symptoms of migraine crisis (thirst, craving, yawning, alteration of smell, depression etc.).


The role of cytochrome P450-dependent metabolism in the regulation of mouse hepatic growth hormone signaling components and target genes by 3-methylcholanthrene.
3-Methylcholanthrene (MC) is a readily metabolized aryl hydrocarbon receptor (AHR) agonist. MC disrupts expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). To determine if these effects of MC depend on hepatic microsomal P450-mediated activity, we examined biologic responses to MC treatment in liver Cpr-null (LCN) mice with hepatocyte-specific conditional deletion of NADPH-cytochrome P450 oxidoreductase (POR). MC caused mild induction of Por and a hepatic inflammatory marker in wild-type mice, whereas MC caused strong induction of AHR target genes, Cyp1a1, Cyp1a2, and Cyp1b1 in wild-type and LCN mice. Two mouse hepatic STAT5b target genes, Cyp2d9 and major urinary protein 2 (Mup2), were suppressed by MC in wild-type mice, and the CYP2D9 mRNA response was maintained in LCN mice. In wild-type mice only, MC decreased hepatic GH receptor (GHR) mRNA but increased GHR protein levels. There was an apparent impairment of STAT5 phosphorylation by MC in wild-type and LCN mice, but large interanimal variation prevented achievement of statistical significance. In vehicle-treated mice, basal levels of MUP2 mRNA, GHR mRNA, GHR protein, and the activation status of extracellular signal-regulated kinase 2 and Akt were influenced by hepatic Por genetic status. These results indicate that the effects of MC on hepatic GH signaling components and target genes are complex, involving aspects that are both dependent and independent of hepatic microsomal P450-mediated activity.


Effect of ouabain on arteriolar responses to norepinephrine in chronic, benign, volume-expanded hypertension.
We have reported increases in ouabain-sensitive Rb+ uptake by freshly excised conduit arteries from volume-expanded Dahl salt-sensitive (S) rats and also from rats with chronic (4 to 6 weeks), benign (serum creatinine less than 1.4 mg%) one-kidney, one clip ( 1K1C ) hypertension on high NaCl intake. To assess in vivo arteriolar function in this latter model, and a role for putative circulating ouabain-like factors, we perfused the maximally vasodilated (nitroprusside, 0.015 mg/ml limb blood), vascularly isolated, innervated hindlimb vascular beds of chloralose-anesthetized, water- or saline-drinking 1K1C hypertensive rats with their own blood at 1 ml/min, and measured limb responses to i.a. norepinephrine 0.004 to 128 micrograms, before and during local infusion of ouabain (achieving 2.5 X 10(-5) M in limb blood). Complete dose-response curves in eight 1K1C hypertensive rats were steeper and higher than those in five uninephrectomized (1K) normotensive control rats. However, threshold and ED50 were unchanged. Thus, alterations in the curve in the hypertensive rats represented only structural vascular changes. Ouabain evoked a leftward shift of the dose-response curve in an additional 18 1K1C hypertensive rats and 13 1K normotensive controls. In the hypertensive rats as compared to the controls, there were trends for increases, rather than decreases, in the ouabain-induced shift of the curve. Shifts in 14 rats with chronic 2K1C hypertension did not differ from those in the 1K1C hypertensive rats. Together, these studies in chronic, presumably volume-expanded, low-renin hypertension unaccompanied by renal insufficiency provide no evidence for physiologically significant inotropic effects of circulating ouabain-like pump inhibitor.


CAMITAX: Taxon labels for microbial genomes.
The number of microbial genome sequences is increasing exponentially, especially thanks to recent advances in recovering complete or near-complete genomes from metagenomes and single cells. Assigning reliable taxon labels to genomes is key and often a prerequisite for downstream analyses. We introduce CAMITAX, a scalable and reproducible workflow for the taxonomic labelling of microbial genomes recovered from isolates, single cells, and metagenomes. CAMITAX combines genome distance-, 16S ribosomal RNA gene-, and gene homology-based taxonomic assignments with phylogenetic placement. It uses Nextflow to orchestrate reference databases and software containers and thus combines ease of installation and use with computational reproducibility. We evaluated the method on several hundred metagenome-assembled genomes with high-quality taxonomic annotations from the TARA Oceans project, and we show that the ensemble classification method in CAMITAX improved on all individual methods across tested ranks. While we initially developed CAMITAX to aid the Critical Assessment of Metagenome Interpretation (CAMI) initiative, it evolved into a comprehensive software package to reliably assign taxon labels to microbial genomes. CAMITAX is available under Apache License 2.0 at https://github.com/CAMI-challenge/CAMITAX.


Co-expression of human calreticulin significantly improves the production of HIV gp140 and other viral glycoproteins in plants.
Plant molecular farming (PMF) is rapidly gaining traction as a viable alternative to the currently accepted paradigm of producing biologics. While the platform is potentially cheaper and more scalable than conventional manufacturing systems, expression yields and appropriate post-translational modifications along the plant secretory pathway remain a challenge for certain proteins. Viral fusion glycoproteins in particular are often expressed at low yields in plants and, in some cases, may not be appropriately processed. Recently, however, transiently or stably engineering the host plant has shown promise as a strategy for producing heterologous proteins with more complex maturation requirements. In this study we investigated the co-expression of a suite of human chaperones to improve the production of a human immunodeficiency virus (HIV) type 1 soluble gp140 vaccine candidate in Nicotiana benthamiana plants. The co-expression of calreticulin (CRT) resulted in a dramatic increase in Env expression and ameliorated the endoplasmic reticulum (ER) stress response - as evidenced by lower transcript abundance of representative stress-responsive genes. The co-expression of CRT similarly improved accumulation of glycoproteins from Epstein-Barr virus (EBV), Rift Valley fever virus (RVFV) and chikungunya virus (CHIKV), suggesting that the endogenous chaperone machinery may impose a bottleneck for their production. We subsequently successfully combined the co-expression of human CRT with the transient expression of human furin, to enable the production of an appropriately cleaved HIV gp140 antigen. These transient plant host engineering strategies are a promising approach for the production of high yields of appropriately processed and cleaved viral glycoproteins.


Examining relationships among dialect variation, literacy skills, and school context in first grade.
This study examined relationships between the use of nonmainstream American English dialects, literacy skills, and school environment among typically developing first graders (n = 617), of whom 48% were African American and 52% were White, in order to describe and better understand the difficulties many children from linguistically diverse backgrounds experience while learning to read. Using hierarchical linear modeling, the authors examined the linear and quadratic relationships between students' dialect variation (DVAR) and their vocabulary, phonological awareness, and word reading skills, taking into account school environment, specifically schoolwide socioeconomic status (SES). The relationships between DVAR and literacy outcomes depended on the outcome of interest and school SES. However, children's race did not generally affect the trajectory or strength of the relationships between outcomes and dialect variation. For vocabulary and word reading, the association was nonlinear, that is, U-shaped, but this depended on school SES. For phonological awareness, a negative linear relationship was observed that did not depend on school SES. The results inform theories on the relationship between DVAR and literacy achievement and suggest a more complex explanation of how nonmainstream American English dialect use might influence how young children learn to read.


Rainbow trout Oncorhynchus mykiss skin responses to salmon louse Lepeophtheirus salmonis: From copepodid to adult stage.
The marine crustacean Lepeophtheirus salmonis (salmon louse) is a common ectoparasite of wild and farmed salmonids. The parasite has a complex ontogeny comprising eight instars. The planktonic copepodid stage settles on host skin and pass through five instars to reach the adult stage. The present study comprises an experimental infestation of Oncorhynchus mykiss (rainbow trout) with salmon lice and describes histopathology and host immune responses in skin beneath the louse at multiple time points encompassing all louse developmental stages. Each fish was exposed to 80 infective copepodids, a mean no. of 32 parasites reached the preadult I stage whereas a mean no. of 11 parasites reached the adult stage. A progression in the severity of cutaneous lesions was observed, and levels of immune gene transcripts at the attachment site revealed a dynamic response, initially related to innate immunity. Later, immune cells accumulated in the dermis concomitant with a moderate decrease in levels of transcripts characteristic of both innate and adaptive immune responses. The present study also demonstrates that the cutaneous immune response was mainly induced at lice affected sites, while non-affected skin resembled the skin of untreated control. This indicates that the skin cannot be regarded as a uniform organ and requires careful sampling at all salmon louse stages.


Musical Preferences Predict Personality: Evidence From Active Listening and Facebook Likes.
Research over the past decade has shown that various personality traits are communicated through musical preferences. One limitation of that research is external validity, as most studies have assessed individual differences in musical preferences using self-reports of music-genre preferences. Are personality traits communicated through behavioral manifestations of musical preferences? We addressed this question in two large-scale online studies with demographically diverse populations. Study 1 ( N = 22,252) shows that reactions to unfamiliar musical excerpts predicted individual differences in personality-most notably, openness and extraversion-above and beyond demographic characteristics. Moreover, these personality traits were differentially associated with particular music-preference dimensions. The results from Study 2 ( N = 21,929) replicated and extended these findings by showing that an active measure of naturally occurring behavior, Facebook Likes for musical artists, also predicted individual differences in personality. In general, our findings establish the robustness and external validity of the links between musical preferences and personality.


Paediatric cervical lymphadenopathy: when to biopsy?
Cervical lymphadenopathy is common in the paediatric population and persistent lymphadenopathy of unknown cause is a frequent reason for otolaryngology referral. Diagnostic work-up is variable among physicians and deciding when excisional biopsy is necessary remains a challenge. This update reviews the recent literature on the work-up and diagnosis of paediatric cervical lymphadenopathy, with a focus on factors that may influence the need for excisional biopsy. The majority of paediatric cervical lymphadenopathy cases are benign, with infection and reactive lymphoid hyperplasia being far more common than malignancy. Ultrasound is the initial imaging modality of choice for paediatric cervical lymphadenopathy and can provide critical information to aid in diagnosis. Clinical factors that may predict malignancy include lymph node size greater than 2 cm, multiple levels of adenopathy and supraclavicular location. Biopsy should be strongly considered in patients with a combination of these factors or other suspicious findings such as severe systemic symptoms. Paediatric cervical lymphadenopathy is commonly encountered in general and paediatric otolaryngology practice; however, absolute guidelines for biopsy do not exist. Careful consideration of history, physical examination, laboratory work-up and diagnostic imaging must be used to guide the clinician in decision-making for biopsy.


Consequences of biotransformation of plant secondary metabolites on acid-base metabolism in mammals-A final common pathway?
Regulation of acid-base homeostasis is essential for mammals and birds. Biotransformation and metabolism of absorbed plant secondary metabolites (PSMs) results in the production of organic acids that threaten acid-base homeostasis. Consequently these acids must be buffered and excreted from the body. The production of an acid load from detoxified PSMs should occur in herbivorous mammals and birds and with most PSMs and so may provide a unifying theme to explain many effects of PSMs on animal metabolism. Since the organic acids will be largely ionized at physiological pH, disposal of the hydrogen ion and the organic anion may proceed independently. Most hydrogen ions (H(+)) from organic acids are eliminated by one or more of three ways: (1) when they react with bicarbonate in the extracellular fluid to form carbon dioxide and the carbon dioxide is exhaled, (2) when they bind to dibasic phosphate and are excreted by the kidney as monobasic phosphate, and (3) when they are buffered and retained in the skeletal system. The secretion of phosphate ions and ammonium excretion are two ways in which the kidney replaces bicarbonate ions that have been eliminated as carbon dioxide. Secretion in the kidney tubule is an important means of excreting excessive organic anions rapidly. This process is saturable and may be subject to competition from a variety of different metabolites. Lagomorphs have limited capacity to form new bicarbonate from ammonium excretion and may therefore be obliged to excrete other cations such as sodium to balance the excretion of organic anions from PSMs. Acidemia has wide-ranging impacts on animals but browsing mammals and birds may have to break down muscle tissues to provide for urinary ammonium in order to generate bicarbonate for buffering. Acidemia also can affect the extent of urea recycling. Animals consuming browse diets may have to regulate feeding so that the rate of formation of hydrogen ions does not exceed the rate of disposal. The mechanisms by which this could occur are unknown.


Drug use among college students--an interim report.
A survey was conducted at Agra (India) to study the extent and pattern of the non-medical use of dependence producing drugs among the post-graduate students of the local colleges and a number of medical students of other colleges of the state of Uttar Pradesh who were posted for training at the Mental Hospital. The study was confined to the academic year 1975-76 and covered 1,200 students. The present interim report is based on a sample of 564 students covered during 1975 (1st stage). The data on the total sample of 1200 (2nd and the final stage) are still being analysed. The results reveal that 73.88 per cent male, and 25.96 per cent female students had a drug experience at some time or another. Drug use was highest (80.66 per cent) among male medical students. The substances commonly used by males were: alcohol, barbiturates, Mandrax (methaqualone diphenhydramine hydrochloride). Vesparax (hydroxyzine hydrochloride), Equanil (meprobamate). Librium (chlordiazeproxide), pain killers (minor analgesics such as aspirin, and cannabis (bhang, ganja, and charas). The female students mainly used Equanil and pain killers. Among the 23 reasons offered for the use of drugs, the majority of students (50-59 per cent) stated that their main reason for drug use was "to relieve tension and facilitate relaxation". The next motivating factor for indulgence was "for the sake of fun" (30-39 per cent). The student drug users reported a number of effects produced by various substances. The most commonly mentioned effects were: excessive sleepiness, sluggishness, giddiness, inability to concentrate on studies, poor physical co-ordination. They expressed their opinion on various aspects of the drug use problem and favoured stringent measures to curb it.


The effects of hormonal contraceptives on glycemic regulation.
A number of side effects have been linked to the use of hormonal contraceptives, among others, alterations in glucose levels. Hence, the objective of this mini-review is to show the main effects of hormonal contraceptive intake on glycemic regulation. First, the most relevant studies on this topic are described, then the mechanisms that might be accountable for this glycemic regulation impairment as exerted by hormonal contraceptives are discussed. Finally, we briefly discuss the ethical responsibility of health professionals to inform about the potential risks on glycemic homeostasis regarding hormonal contraceptive intake.


The role of lysine-132 and arginine-136 in the receptor-binding domain of the K99 fibrillar subunit.
The gene encoding the K99 fibrillar adhesin of Escherichia coli has been modified by oligonucleotide-directed, site-specific, mutagenesis. The tryptophan-67, lysine-132, lysine-133 or arginine-136 were replaced by leucine, threonine, threonine and serine, respectively. The threonine-133 mutant fibrillae were indistinguishable from wild-type fibrillae. In contrast, replacement of lysine-132 or arginine-136 by threonine or serine, respectively, resulted in mutant fibrillae which had completely lost adhesive capacity, suggesting that the positive charges of these residues are essential for the interaction with the negatively charged sialic acid residue of the receptor molecules. After the replacement of tryptophan-67 with leucine neither fibrillae nor subunits were detectable, indicating that the mutant product is unstable and that tryptophan-67 has an essential structural role in the K99 subunit.


Integrative single-cell omics analyses reveal epigenetic heterogeneity in mouse embryonic stem cells.
Embryonic stem cells (ESCs) consist of a population of self-renewing cells displaying extensive phenotypic and functional heterogeneity. Research towards the understanding of the epigenetic mechanisms underlying the heterogeneity among ESCs is still in its initial stage. Key issues, such as how to identify cell-subset specifically methylated loci and how to interpret the biological meanings of methylation variations remain largely unexplored. To fill in the research gap, we implemented a computational pipeline to analyze single-cell methylome and to perform an integrative analysis with single-cell transcriptome data. According to the origins of variation in DNA methylation, we determined the genomic loci associated with allelic-specific methylation or asymmetric DNA methylation, and explored a beta mixture model to infer the genomic loci exhibiting cell-subset specific methylation (CSM). We observed that the putative CSM loci in ESCs are significantly enriched in CpG island (CGI) shelves and regions with histone marks for promoter and enhancer, and the genes hosting putative CSM loci show wide-ranging expression among ESCs. More interestingly, the putative CSM loci may be clustered into co-methylated modules enriching the binding motifs of distinct sets of transcription factors. Taken together, our study provided a novel tool to explore single-cell methylome and transcriptome to reveal the underlying transcriptional regulatory networks associated with epigenetic heterogeneity of ESCs.


Sub-harmonic entrainment of cortical gamma oscillations to deep brain stimulation in Parkinson's disease: Model based predictions and validation in three human subjects.
The exact mechanisms of deep brain stimulation (DBS) are still an active area of investigation, in spite of its clinical successes. This is due in part to the lack of understanding of the effects of stimulation on neuronal rhythms. Entrainment of brain oscillations has been hypothesised as a potential mechanism of neuromodulation. A better understanding of entrainment might further inform existing methods of continuous DBS, and help refine algorithms for adaptive methods. The purpose of this study is to develop and test a theoretical framework to predict entrainment of cortical rhythms to DBS across a wide range of stimulation parameters. We fit a model of interacting neural populations to selected features characterising PD patients' off-stimulation finely-tuned gamma rhythm recorded through electrocorticography. Using the fitted models, we predict basal ganglia DBS parameters that would result in 1:2 entrainment, a special case of sub-harmonic entrainment observed in patients and predicted by theory. We show that the neural circuit models fitted to patient data exhibit 1:2 entrainment when stimulation is provided across a range of stimulation parameters. Furthermore, we verify key features of the region of 1:2 entrainment in the stimulation frequency/amplitude space with follow-up recordings from the same patients, such as the loss of 1:2 entrainment above certain stimulation amplitudes. Our results reveal that continuous, constant frequency DBS in patients may lead to nonlinear patterns of neuronal entrainment across stimulation parameters, and that these responses can be predicted by modelling. Should entrainment prove to be an important mechanism of therapeutic stimulation, our modelling framework may reduce the parameter space that clinicians must consider when programming devices for optimal benefit.


Crowdsourcing hypothesis tests: Making transparent how design choices shape research results.
To what extent are research results influenced by subjective decisions that scientists make as they design studies? Fifteen research teams independently designed studies to answer five original research questions related to moral judgments, negotiations, and implicit cognition. Participants from 2 separate large samples (total N > 15,000) were then randomly assigned to complete 1 version of each study. Effect sizes varied dramatically across different sets of materials designed to test the same hypothesis: Materials from different teams rendered statistically significant effects in opposite directions for 4 of 5 hypotheses, with the narrowest range in estimates being d = -0.37 to + 0.26. Meta-analysis and a Bayesian perspective on the results revealed overall support for 2 hypotheses and a lack of support for 3 hypotheses. Overall, practically none of the variability in effect sizes was attributable to the skill of the research team in designing materials, whereas considerable variability was attributable to the hypothesis being tested. In a forecasting survey, predictions of other scientists were significantly correlated with study results, both across and within hypotheses. Crowdsourced testing of research hypotheses helps reveal the true consistency of empirical support for a scientific claim. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Mechanical Cell Competition in Heterogeneous Epithelial Tissues.
Mechanical cell competition is important during tissue development, cancer invasion, and tissue ageing. Heterogeneity plays a key role in practical applications since cancer cells can have different cell stiffness and different proliferation rates than normal cells. To study this phenomenon, we propose a one-dimensional mechanical model of heterogeneous epithelial tissue dynamics that includes cell-length-dependent proliferation and death mechanisms. Proliferation and death are incorporated into the discrete model stochastically and arise as source/sink terms in the corresponding continuum model that we derive. Using the new discrete model and continuum description, we explore several applications including the evolution of homogeneous tissues experiencing proliferation and death, and competition in a heterogeneous setting with a cancerous tissue competing for space with an adjacent normal tissue. This framework allows us to postulate new mechanisms that explain the ability of cancer cells to outcompete healthy cells through mechanical differences rather than an intrinsic proliferative advantage. We advise when the continuum model is beneficial and demonstrate why naively adding source/sink terms to a continuum model without considering the underlying discrete model may lead to incorrect results.


Simple technique for measuring the Goos-Hänchen effect with polarization modulation and a position-sensitive detector.
An original approach to directly measuring the Goos-Hänchen longitudinal shift between TE and TM polarization states during a total internal reflection is introduced. The technique is based on the modulation of the polarization state of a laser by an electro-optic modulator combined with a precise measurement of the resulting spatial displacement with a position-sensitive detector. This method presents many advantages over other techniques and allows measurements at different wavelengths over a broad range for the incident angle.


A Systematic Review Evaluating the Use of the interRAI Home Care Instrument in Research for Older People.
Objective: To summarize studies that used the international Resident Assessment home care instrument (interRAI HC) to examine study outcomes for older people. Methods: A comprehensive systematic search was performed to identify relevant studies, using five databases from 1990 until October 2016. The Cochrane Risk-Bias assessment tool and Newcastle-Ottawa Scale was used to assess the quality of RCTs and non-RCTs, respectively. Results: Based on the full-text analysis, 40 studies met the inclusion criteria out of 506 total records. The review included 6 RCTs, 2 quasi-experimental, 17 prospective and retrospective studies, 13 cross-sectional and 2 longitudinal studies. A series of interventions and/or applications were identified from this review that employed the use of interRAI HC instrument: (a) in health services, (b) as a new integrated care model and for implementing machine learning algorithm, (c) as a comprehensive geriatric assessment tool, (d) in case management, (e) for care planning and screening, (f) in drug therapy assessment, (g) to assess caregiver burden, and (h) for various risk assessments. Studies that employed the interRAI HC instrument reported an array of health-outcome measures mostly related to functional, cognition, hospitalization and mortality. Conclusions: Application of the interRAI HC tool varied markedly across all studies, and the outcomes measures were heterogeneous. Future research directions are discussed. Clinical Implications: The results from this study facilitate the use of interRAI HC as a tool to measure an intervention's effect that leads to improvements in specific geriatric-related health outcome measures emphasizes on functional status and quality of life and ascertain its utility as a quality indicator for the care of older individuals.


Rehydration with sodium-enriched coconut water after exercise-induced dehydration.
This crossover study assessed the effectiveness of plain water (PW), sports drink (SD), fresh young coconut water (CW) and sodium-enriched fresh young coconut water (SCW) on whole body rehydration (R) and plasma volume (PV) restoration after exercise-induced dehydration. Ten healthy male subjects ran at 65% of VO2max in an environmental temperature of 32.06 +/- 0.02 degree C with a relative humidity (rh) of 53.32 +/- 0.17% for 90 minutes to lose 3% body weight (BW). During the 2-hour rehydration period, subjects drank, in randomized order, PW, SD, CW or SCW equivalent to 120% of BW lost in three boluses representing 50, 40 and 30% of the fluid lost at 0, 30, and 60 minutes, respectively. In all trials subjects were still somewhat dehydrated even after the 2-hour rehydration period. Indexes of percent rehydration with PW, SD, CW and SCW were 58 +/- 2, 68 +/- 2, 65+/- 2 and 69 +/- 1%, respectively, with significantly better rehydration with SD and SCW. The rehydration indexes for SD and SCW were significantly lower than PW (p < 0.01). PV was restored to euhydration levels after 2 hours of rehydration with SD, CW and SCW but not with PW. The plasma glucose concentration were significantly higher when SD, CW and SCW were ingested. SCW was similar in sweetness to CW and SD but caused less nausea and stomach upset compared to SD and PW. In conclusion, ingesting SCW was as good as ingesting a commercial sports drink for whole body rehydration after exercise-induced dehydration but with better fluid tolerance.


Plasma 1,3-β-d-glucan levels predict adverse clinical outcomes in critical illness.
BACKGROUNDThe fungal cell wall constituent 1,3-β-d-glucan (BDG) is a pathogen-associated molecular pattern that can stimulate innate immunity. We hypothesized that BDG from colonizing fungi in critically ill patients may translocate into the systemic circulation and be associated with host inflammation and outcomes.METHODSWe enrolled 453 mechanically ventilated patients with acute respiratory failure (ARF) without invasive fungal infection and measured BDG, innate immunity, and epithelial permeability biomarkers in serially collected plasma samples.RESULTSCompared with healthy controls, patients with ARF had significantly higher BDG levels (median [IQR], 26 pg/mL [15-49 pg/mL], P < 0.001), whereas patients with ARF with high BDG levels (≥40 pg/mL, 31%) had higher odds for assignment to the prognostically adverse hyperinflammatory subphenotype (OR [CI], 2.88 [1.83-4.54], P < 0.001). Baseline BDG levels were predictive of fewer ventilator-free days and worse 30-day survival (adjusted P < 0.05). Integrative analyses of fungal colonization and epithelial barrier disruption suggested that BDG may translocate from either the lung or gut compartment. We validated the associations between plasma BDG and host inflammatory responses in 97 hospitalized patients with COVID-19.CONCLUSIONBDG measurements offered prognostic information in critically ill patients without fungal infections. Further research in the mechanisms of translocation and innate immunity recognition and stimulation may offer new therapeutic opportunities in critical illness.FUNDINGUniversity of Pittsburgh Clinical and Translational Science Institute, COVID-19 Pilot Award and NIH grants (K23 HL139987, U01 HL098962, P01 HL114453, R01 HL097376, K24 HL123342, U01 HL137159, R01 LM012087, K08HK144820, F32 HL142172, K23 GM122069).


Temporal trends in the use of parenteral nutrition in critically ill patients.
Clinical practice guidelines recommend enteral over parenteral nutrition in critical illness and do not recommend early initiation. Few data are available on parenteral nutrition use or timing of initiation in the ICU or how this use may have changed over time. We used the Project IMPACT database to evaluate temporal trends in parenteral nutrition use (total and partial parenteral nutrition and lipid supplementation) and timing of initiation in adult ICU admissions from 2001 to 2008. We used χ2 tests and analysis of variance to examine characteristics of patients receiving parenteral nutrition and multilevel multivariate logistic regression models to assess parenteral nutrition use over time, in all patients and in specific subgroups. Of 337,442 patients, 20,913 (6.2%) received parenteral nutrition. Adjusting for patient characteristics, the use of parenteral nutrition decreased modestly over time (adjusted probability, 7.2% in 2001-2002 vs 5.5% in 2007-2008, P<.001). Enteral nutrition use increased simultaneously (adjusted probability, 11.5% in 2001-2002 vs 15.3% in 2007-2008, P<.001). Use of parenteral nutrition declined most rapidly in emergent surgical patients, patients with moderate illness severity, patients in the surgical ICU, and patients admitted to an academic facility (P≤.01 for all interactions with year). When used, parenteral nutrition was initiated a median of 2 days (interquartile range, 1-3), after ICU admission and >90% of patients had parenteral nutrition initiated within 7 days; timing of initiation of parenteral nutrition did not change from 2001 to 2008. Use of parenteral nutrition in US ICUs declined from 2001 through 2008 in all patients and in all examined subgroups, with the majority of parenteral nutrition initiated within the first 7 days in ICU; enteral nutrition use coincidently increased over the same time period.