Noncapsulated Klebsiella pneumoniae bearing mannose-containing O antigens is rapidly eradicated from mouse lung and triggers cytokine production by macrophages following opsonization with surfactant protein D.
To better understand the relationship between the surface polysaccharides of pulmonary pathogens and components of the lung innate immune system, we employed selected serotypes of Klebsiella pneumoniae expressing distinct capsular polysaccharides and/or O antigen in a murine model of K. pneumoniae infection. In addition, we examined the effect of surfactant protein D (SP-D) on the cytokine response of human monocyte-derived macrophages to these serotypes in vitro. Noncapsulated mannose-containing O3 serotypes (K50/n and K55/n), which react efficiently with SP-D in vitro, triggered high levels of interleukin-1beta (IL-1beta) and IL-6 production. In vivo, they were more efficiently cleared from the lungs of mice but not from macrophage-depleted mice. They also were more efficiently internalized by alveolar macrophages in vivo. In contrast, galactose-containing O1 serotypes (K2/n and K21a/n), which interact poorly with SP-D, exhibited significantly lower cytokine production and less efficient pulmonary clearance and were ineffectively internalized by alveolar macrophages. These findings are consistent with in vitro results showing that production of IL-1beta and IL-6 mRNA and IL-6 protein by human macrophages exposed to mannose-bearing Klebsiella O serotypes is significantly increased by SP-D. Thus, survival of inhaled bacteria in the lung depends partially on the lipopolysaccharide structure of the bacteria and their interactions with innate immunity components. We speculate that an imbalance of host SP-D and therefore cytokine levels may result in high susceptibility of the host to the pathogen.


Maintaining patients' dignity during clinical care: a qualitative interview study.
This article is a report of a study undertaken to understand how nurses maintain patients' dignity in clinical practice. Dignity is a core concept in nursing care and maintaining patients' dignity is critical to their recovery. In Western countries, measures to maintain dignity in patients' care include maintaining privacy of the body, providing spatial privacy, giving sufficient time, treating patients as a whole person and allowing patients to have autonomy. However, this is an under-studied topic in Asian countries. For this qualitative descriptive study, data were collected in Taiwan in 2009 using in-depth interviews with a purposive sample of 30 nurses from a teaching hospital in eastern Taiwan. The audiotaped interviews were transcribed verbatim and analysed using content analysis. Nurses' measures to maintain dignity in patient care were captured in five themes: respect, protecting privacy, emotional support, treating all patients alike and maintaining body image. Participants did not mention beneficence, a crucial element achieved through the professional care of nurses that can enhance the recovery of patients. In-service education to help nurses enhance dignity in patient care should emphasize emotional support, maintaining body image and treating all patients alike. Our model for maintaining dignity in patient care could be used to develop a clinical care protocol for nurses to use in clinical practice.


Improving Resident Feedback on Diagnostic Reasoning after Handovers: The LOOP Project.
Appropriate calibration of clinical reasoning is critical to becoming a competent physician. Lack of follow-up after transitions of care can present a barrier to calibration. This study aimed to implement structured feedback about clinical reasoning for residents performing overnight admissions, measure the frequency of diagnostic changes, and determine how feedback impacts learners' self-efficacy. Trainees shared feedback via a structured form within their electronic health record's secure messaging system. Forms were analyzed for diagnostic changes. Surveys evaluated comfort with sharing feedback, self-efficacy in identifying and mitigating cognitive biases' negative effects, and perceived educational value of night admissions-all of which improved after implementation. Analysis of 544 forms revealed a 43.7% diagnostic change rate spanning the transition from night-shift to day-shift providers; of the changes made, 29% (12.7% of cases overall) were major changes. This study suggests that structured feedback on clinical reasoning for overnight admissions is a promising approach to improve residents' diagnostic calibration, particularly given how often diagnostic changes occur.


Multi-layer microfluidic glass chips for microanalytical applications.
A new, versatile architecture is presented for microfluidic devices made entirely from glass, for use with reagents which would prove highly corrosive for silicon. Chips consist of three layers of glass wafers bonded together by fusion bonding. On the inside wafer faces a network of microfluidic channels is created by photolithography and wet chemical etching. Low dead-volume fluidic connections between the layers are fabricated by spark-assisted etching (SAE), a computer numerical controlled (CNC)-like machining technique new to microfluidic system fabrication. This method is also used to form a vertical, long path-length, optical cuvette through the middle wafer for optical absorbance detection of low-concentration compounds. Advantages of this technique compared with other, more standard, methods are discussed. When the new glass-based device for flow-injection analysis of ammonia was compared with our first-generation chips based on silicon micromachining, concentration sensitivity was higher, because of the longer path-length of the optical cuvette. The dependence of dispersion on velocity profile and on channel cross-sectional geometry is discussed. The rapid implementation of the devices for an organic synthesis reaction, the Wittig reaction, is also briefly described.


Invasive assessment of the coronary microcirculation: superior reproducibility and less hemodynamic dependence of index of microcirculatory resistance compared with coronary flow reserve.
A simple, reproducible invasive method for assessing the coronary microcirculation is lacking. A novel index of microcirculatory resistance (IMR) has been shown in animals to correlate with true microvascular resistance and, unlike coronary flow reserve (CFR), to be independent of the epicardial artery. We sought to compare the reproducibility and hemodynamic dependence of IMR with CFR in humans. Using a pressure-temperature sensor-tipped coronary wire, thermodilution-derived CFR and IMR were measured, along with fractional flow reserve (FFR), in 15 coronary arteries (15 patients) under the following hemodynamic conditions: (1) twice at baseline; (2) during right ventricular pacing at 110 bpm; (3) during intravenous infusion of nitroprusside; and (4) during intravenous dobutamine infusion. Mean CFR did not change during baseline measurements or during nitroprusside infusion but decreased during pacing (from 3.1+/-1.1 at baseline to 2.3+/-1.2 during pacing, P<0.05) and during dobutamine infusion (from 3.0+/-1.0 to 1.7+/-0.6 with dobutamine, P<0.0001). By comparison, mean values for IMR and FFR remained similar throughout all hemodynamic conditions. The mean coefficient of variation between 2 baseline measurements was significantly lower for IMR (6.9+/-6.5%) and FFR (1.6+/-1.6%) than for CFR (18.6+/-9.6%; P<0.01). Mean correlation between baseline measurements and each hemodynamic intervention was superior for IMR (r=0.90+/-0.05) and FFR (r=0.86+/-0.12) compared with CFR (r=0.70+/-0.05; P<0.05). Compared with CFR, IMR provides a more reproducible assessment of the microcirculation, which is independent of hemodynamic perturbations. Simultaneous measurement of FFR and IMR may provide a comprehensive and specific assessment of coronary physiology at both epicardial and microvascular levels, respectively.


Co-occurring mental illness, drug use, and medical multimorbidity among lesbian, gay, and bisexual middle-aged and older adults in the United States: a nationally representative study.
Older lesbian, gay, and bisexual (LGB) adults are an underserved and understudied population that experience specific health disparities. The intersection of aging and chronic medical disease with a higher risk for substance use and mental illness may place older LGB adults at risk for co-occurring conditions and resulting comorbidity. Understanding multimorbidity among older LGB adults may help inform interventions to reduce disparities in health outcomes. Data come from the 2015 to 2017 National Surveys on Drug Use and Health (n = 25,880). We first determined whether sexual orientation was associated with reporting: past-year drug use, mental illness, and/or 2 or more chronic medical diseases. We then determined whether sexual orientation was associated with reporting co-occurrence of these conditions. This was done using multivariable logistic regression. Analyses were stratified by gender. Compared to heterosexual men, gay men were at increased odds for reporting 2 or more chronic medical diseases (adjusted odds ratio [aOR] = 2.18, 95% confidence interval [CI] = 1.48, 3.21), and gay (aOR = 1.79, 95% CI = 1.09, 2.93) and bisexual men (aOR = 3.53, 95% CI = 2.03, 6.14) were at increased odds for reporting mental illness. Gay men (aOR = 2.95, 95CI = 1.60, 5.49) and bisexual men (aOR = 2.84, 95% CI = 1.58, 5.08) were at increased odds of reporting co-occurring conditions. Compared to heterosexual women, bisexual women were at increased odds for past-year drug use (aOR = 4.20, 95% CI = 2.55, 6.93), reporting mental illness (aOR = 1.94, 95% CI = 1.03, 3.67), and reporting co-occurring conditions (aOR = 3.25, 95% = 1.60, 6.62). Middle-aged and older LGB adults in the United States are at high risk for experiencing co-occurring drug use, mental illness, and/or medical multimorbidity. Interventions for older sexual minority populations are needed to reduce disparities.


Adipose tissue density, a novel biomarker predicting mortality risk in older adults.
Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics. VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4-13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics. Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36-2.80; Health ABC) and 1.88 (1.31-2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35-2.28; Health ABC) and 1.56 (1.15-2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12-2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21-2.07), and AGES-Reykjavik, 1.43 (1.07-1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs. VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.


Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
According to the World Health Organization, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neurological disease characterized by widespread inflammation and multi-systemic neuropathology. Aetiology and pathogenesis are unknown, and several agents have been proposed as causative agents or as factors perpetuating the syndrome. Exposure to heavy metals, with particular reference to mercury and gold in dental amalgams, has been considered among the triggers of ME/CFS. Here we hypothesize that cadmium, a widespread occupational and environmental heavy metal pollutant, might be associated with some of the neurological findings described in ME/CFS. In fact, ME/CFS patients show a decrease of the volume of the gray matter in turn associated with objective reduction of physical activity. Cadmium induces neuronal death in cortical neurons through a combined mechanism of apoptosis and necrosis and it could then be hypothesized that cadmium-induced neuronal cell death is responsible for some of the effects of cadmium on the central nervous system, i.e. a decrease in attention level and memory in exposed humans as well as to a diminished ability for training and learning in rats, that are symptoms typical of ME/CFS. This hypothesis can be tested by measuring cadmium exposure in a cohort of ME/CFS patients compared with matched healthy controls, and by measuring gray matter volume in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. In addition, we hypothesize that cadmium exposure could be associated with reduced cerebral blood flow in ME/CFS patients because of the disruptive effects of cadmium on angiogenesis. In fact, cadmium inhibits angiogenesis and low global cerebral flow is associated with abnormal brain neuroimaging results and brain dysfunction in the form of reduced cognitive testing scores in ME/CFS patients. This hypothesis can be tested by measuring cerebral cortex blood flow in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. If our hypothesis is demonstrated correct, the consequences could affect prevention, early diagnosis, and treatment of ME/CFS. Implications in early diagnosis could entail the evaluation of symptoms typical of ME/CFS in cadmium-exposed subjects as well as the search for signs of exposure to cadmium in subjects diagnosed with ME/CFS. Nutritional supplementation of magnesium and zinc could then be considered, since these elements have been proposed in the prophylaxis and therapy of cadmium exposure, and magnesium was demonstrated effective on ME/CFS patients' symptom profiles.


Genome-wide microsatellite characteristics of five human Plasmodium species, focusing on Plasmodium malariae and P. ovale curtisi.
Microsatellites can be utilized to explore genotypes, population structure, and other genomic features of eukaryotes. Systematic characterization of microsatellites has not been a focus for several species of Plasmodium, including P. malariae and P. ovale, as the majority of malaria elimination programs are focused on P. falciparum and to a lesser extent P. vivax. Here, five human malaria species (P. falciparum, P. vivax, P. malariae, P. ovale curtisi, and P. knowlesi) were investigated with the aim of conducting in-depth categorization of microsatellites for P. malariae and P. ovale curtisi. Investigation of reference genomes for microsatellites with unit motifs of 1-10 base pairs indicates high diversity among the five Plasmodium species. Plasmodium malariae, with the largest genome size, displays the second highest microsatellite density (1421 No./Mbp; 5% coverage) next to P. falciparum (3634 No./Mbp; 12% coverage). The lowest microsatellite density was observed in P. vivax (773 No./Mbp; 2% coverage). A, AT, and AAT are the most commonly repeated motifs in the Plasmodium species. For P. malariae and P. ovale curtisi, microsatellite-related sequences are observed in approximately 18-29% of coding sequences (CDS). Lysine, asparagine, and glutamic acids are most frequently coded by microsatellite-related CDS. The majority of these CDS could be related to the gene ontology terms "cell parts," "binding," "developmental processes," and "metabolic processes." The present study provides a comprehensive overview of microsatellite distribution and can assist in the planning and development of potentially useful genetic tools for further investigation of P. malariae and P. ovale curtisi epidemiology.


Epigenetic Regulation of ALS and CMT: A Lesson from Drosophila Models.
Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder and is sometimes associated with frontotemporal dementia. Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited peripheral neuropathies causing the slow progression of sensory and distal muscle defects. Of note, the severity and progression of CMT symptoms markedly vary. The phenotypic heterogeneity of ALS and CMT suggests the existence of modifiers that determine disease characteristics. Epigenetic regulation of biological functions via gene expression without alterations in the DNA sequence may be an important factor. The methylation of DNA, noncoding RNA, and post-translational modification of histones are the major epigenetic mechanisms. Currently, Drosophila is emerging as a useful ALS and CMT model. In this review, we summarize recent studies linking ALS and CMT to epigenetic regulation with a strong emphasis on approaches using Drosophila models.


Incidence and Predictors of Major Adverse Cardiovascular Events in Patients With Established Atherosclerotic Disease or Multiple Risk Factors.
Background There is a paucity of contemporary data estimating the incidence of major adverse cardiovascular events (MACE) in patients with established atherosclerotic disease or multiple risk factors managed in routine practice. We estimated 1- and 4-year incidences of MACE and the association between MACE and vascular beds affected in these patients. Methods and Results Using US IBM MarketScan data from January 1, 2013 to December 31, 2017, we identified patients ≥45 years old with established coronary artery disease, cerebrovascular disease, peripheral artery disease, or the presence of ≥3 risk factors for atherosclerosis during 2013 with a minimum of 4 years of follow-up. We calculated 1- and 4-year incidences of MACE (cardiovascular death or hospitalization for myocardial infarction or ischemic stroke). A Cox proportional hazards regression model adjusted for age and sex was used to evaluate the association between vascular bed number/location(s) affected and MACE. We identified 1 302 856 patients with established atherosclerotic disease or risk factors for atherosclerosis. Coronary artery disease was present in 16.9% of patients, cerebrovascular disease in 7.6%, peripheral artery disease in 13.6%, and risk factors for atherosclerosis only in 66.0%. The 1- and 4-year incidences of MACE were 1.4% and 6.9%, respectively. At 4 years, MACE was more frequent in patients with atherosclerotic disease in a single (hazard ratio=1.51, 95% CI=1.48-1.55), 2-(hazard ratio=2.35, 95% CI=2.27-2.44), or all 3 vascular beds (hazard ratio=3.30, 95% CI=2.97-3.68) compared with having risk factors for atherosclerosis. Conclusions Patients with established atherosclerotic disease or who have multiple risk factors and are treated in contemporary, routine practice carry a substantial risk for MACE at 1- and 4- years of follow-up. MACE risk was shown to vary based on the number and location of vascular beds involved.


Predictors of successful transition from school to employment for youth with disabilities.
This study examined data from the second National Longitudinal Transition Study to determine variables associated with post-high school competitive employment, and to develop a logistic regression model for predicting successful employment outcomes. A longitudinal survey design. Setting United States. A nationally representative sample (N = 2,900) of special education students who exited high school in the 2002/2003 school year. Any competitive employment during the 6-year study period. A number of predictors of competitive employment were confirmed, including high school employment experiences, parental expectations of post-high school employment, arrest record, and school type. The strongest predictors were high school employment experiences and parental expectations of a post-high school employment. The current study supports finding of several prior studies and fail to support others, such as the importance of self-determination for adult success. The findings highlight two aspects of the transition process that are critical for success: employment training and work experiences in high school, and high parental expectations for their child's future.


Acute respiratory illness in Adelaide children: breast feeding modifies the effect of passive smoking.
The aim was to investigate the relation between passive smoking and childhood acute respiratory illness. The study involved an initial postal survey on a random sample of children followed by a case-control study based on the survey. A respiratory illness score was calculated from maternal reports of episodes of illness in the previous 12 months. The study was a population survey based on Adelaide metropolitan area in South Australia. The reference population (n = 13,996) was all live born children registered in South Australia in 1983 whose parents lived in Adelaide metropolitan area. Of these, 4985 families were contacted by post and from 2125 respondents, 1218 (58%) gave consent for home interview. "Cases" were children with respiratory illness scores in the top 20%, controlling for age and time of year (n = 258); "controls" were taken in the bottom 20% (n = 231). Maternal smoking in the first year of life was associated with a doubling in relative odds of respiratory proneness in the child (odds ratio = 2.06, 95% CI 1.25-3.39) after adjustment for confounding by parental history of respiratory illness, other smokers in the home, use of group child care, parent's occupation, and levels of maternal stress and social support. There was no evidence that this association was attributable to differences in the way smoking and non-smoking parents perceived or managed childhood acute respiratory illness. Maternal smoking in the first year, without smoking in pregnancy, was also associated with increased risk of respiratory proneness (odds ratio 1.75, 95% CI 1.03-3.0), showing an effect of passive smoking independent of any in utero effect. There was a strong negative effect modification by breast feeding: relative odds of respiratory proneness with maternal smoking were seven times higher among children who were never breast fed than among those who were breast fed. The results suggest a relatively small but real effect of passive smoking on childhood acute respiratory illness. Effect modification by breast feeding may be due to a combination of behavioural and biological mechanisms.


Signal transduction pathways linking the activation of alveolar macrophages with the recruitment of neutrophils to lungs in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem. It is predicted by the World Health Organization to become the third most common cause of death and the fifth most common cause of disability in the world by 2020. COPD is a complex inflammatory disease involving several types of inflammatory cells and multiple inflammatory mediators. Although abnormal numbers of inflammatory cells such as macrophages, dendritic cells, neutrophils, and T lymphocytes have been documented in COPD, the relationship between these cell types and the sequence of their appearance and persistence is largely unknown. Alveolar macrophages have been identified as one of the major cell types that plays a key role in orchestrating the inflammatory events associated with the pathophysiology of COPD. One of the major functions of macrophages is the secretion of chemotactic factors and this function is markedly increased on exposure to cigarette smoke (CS). This enhanced release of chemoattractants results in increased lung neutrophil infiltration, which is thought to be a key event in the development of COPD. The molecular basis for this amplified inflammatory response is not very clear, but it could be due to an alteration in signal transduction pathways within the macrophage. Based on existing literature, an attempt has been made to create a comprehensive review of the signal transduction pathways that link the activation of macrophages with the increased recruitment of neutrophils into the airways. Some of the major stimuli that activate macrophages and cause them to secrete chemotactic factors have been identified as CS, wood smoke, ozone, bacterial endotoxin, and proinflammatory cytokines such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. These stimuli seem to activate mainly redox-sensitive transcription factors such as nuclear factor (NF)-kappa B and activator protein (AP)-1, both of which play a major role in the synthesis and secretion of chemotactic factors such as IL-8 and leukotriene B(4) (LTB(4)). The pathways involved in the synthesis and secretion of other factors such as macrophage chemotactic protein-1 (MCP-1) and growth-related oncogene-alpha (Gro-alpha) have also been reviewed.


Interventions for the cessation of non-nutritive sucking habits in children.
Comforting behaviours, such as the use of pacifiers (dummies, soothers), blankets and finger or thumb sucking, are common in babies and young children. These comforting habits, which can be referred to collectively as 'non-nutritive sucking habits' (NNSHs), tend to stop as children get older, under their own impetus or with support from parents and carers. However, if the habit continues whilst the permanent dentition is becoming established, it can contribute to, or cause, development of a malocclusion (abnormal bite). A diverse variety of approaches has been used to help children with stopping a NNSH. These include advice, removal of the comforting object, fitting an orthodontic appliance to interfere with the habit, application of an aversive taste to the digit or behaviour modification techniques. Some of these interventions are easier to apply than others and less disturbing for the child and their parent; some are more applicable to a particular type of habit. The primary objective of the review was to evaluate the effects of different interventions for cessation of NNSHs in children. The secondary objectives were to determine which interventions work most quickly and are the most effective in terms of child and parent- or carer-centred outcomes of least discomfort and psychological distress from the intervention, as well as the dental measures of malocclusion (reduction in anterior open bite, overjet and correction of posterior crossbite) and cost-effectiveness. We searched the following electronic databases: the Cochrane Oral Health Group Trials Register (to 8 October 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 9), MEDLINE via OVID (1946 to 8 October 2014), EMBASE via OVID (1980 to 8 October 2014), PsycINFO via OVID (1980 to 8 October 2014) and CINAHL via EBSCO (1937 to 8 October 2014), the US National Institutes of Health Trials Register (Clinical Trials.gov) (to 8 October 2014) and the WHO International Clinical Trials Registry Platform (to 8 October 2014). There were no restrictions regarding language or date of publication in the searches of the electronic databases. We screened reference lists from relevant articles and contacted authors of eligible studies for further information where necessary. Randomised or quasi-randomised controlled trials in children with a non-nutritive sucking habit that compared one intervention with another intervention or a no-intervention control group. The primary outcome of interest was cessation of the habit. We used standard methodological procedures expected by The Cochrane Collaboration. Three review authors were involved in screening the records identified; two undertook data extraction, two assessed risk of bias and two assessed overall quality of the evidence base. Most of the data could not be combined and only one meta-analysis could be carried out. We included six trials, which recruited 252 children (aged two and a half to 18 years), but presented follow-up data on only 246 children. Digit sucking was the only NNSH assessed in the studies. Five studies compared single or multiple interventions with a no-intervention or waiting list control group and one study made a head-to-head comparison. All the studies were at high risk of bias due to major limitations in methodology and reporting. There were small numbers of participants in the studies (20 to 38 participants per study) and follow-up times ranged from one to 36 months. Short-term outcomes were observed under one year post intervention and long-term outcomes were observed at one year or more post intervention. Orthodontics appliance (with or without psychological intervention) versus no treatmentTwo trials that assessed this comparison evaluated our primary outcome of cessation of habit. One of the trials evaluated palatal crib and one used a mix of palatal cribs and arches. Both trials were at high risk of bias. The orthodontic appliance was more likely to stop digit sucking than no treatment, whether it was used over the short term (risk ratio (RR) 6.53, 95% confidence interval (CI) 1.67 to 25.53; two trials, 70 participants) or long term (RR 5.81, 95% CI 1.49 to 22.66; one trial, 37 participants) or used in combination with a psychological intervention (RR 6.36, 95% CI 0.97 to 41.96; one trial, 32 participants). Psychological intervention versus no treatmentTwo trials (78 participants) at high risk of bias evaluated positive reinforcement (alone or in combination with gaining the child's co-operation) or negative reinforcement compared with no treatment. Pooling of data showed a statistically significant difference in favour of the psychological interventions in the short term (RR 6.16, 95% CI 1.18 to 32.10; I(2) = 0%). One study, with data from 57 participants, reported on the long-term effect of positive and negative reinforcement on sucking cessation and found a statistically significant difference in favour of the psychological interventions (RR 6.25, 95% CI 1.65 to 23.65). Head-to-head comparisonsOnly one trial demonstrated a clear difference in effectiveness between different active interventions. This trial, which had only 22 participants, found a higher likelihood of cessation of habit with palatal crib than palatal arch (RR 0.13, 95% CI 0.03 to 0.59). This review found low quality evidence that orthodontic appliances (palatal arch and palatal crib) and psychological interventions (including positive and negative reinforcement) are effective at improving sucking cessation in children. There is very low quality evidence that palatal crib is more effective than palatal arch. This review has highlighted the need for high quality trials evaluating interventions to stop non-nutritive sucking habits to be conducted and the need for a consolidated, standardised approach to reporting outcomes in these trials.


Stability of implants and natural teeth as determined by the Periotest over 60 months of function.
Various methods for evaluating tooth mobility have been developed throughout the years, but their acceptance has been limited because of the subjectivity associated with their use. In recent years, the Periotest has been studied and used to evaluate the mobility of natural teeth and is claimed to b e potentially reliable in assessing the stability of the implant-bone interface. Few clinical implant studies have used natural teeth as controls to monitor changes in mobility associated with dental implants. The Dental Implant Clinical Research Group initiated a long-term clinical study in 1991 to assess the influence of design, application, and site of placement on clinical success and crestal bone height. As part of the study, Periotest values (PTVs) were recorded for 2,623 of the 2,998 implants placed and uncovered. For the statistical analysis, 2,623 implants were tested at second-stage surgery, with the number of implants tested varying at each follow-up visit. Data were collected from investigators at 32 study centers for periods ranging up to 60 months. A total of 975 natural teeth from 409 partially edentulous study subjects served as controls. FPVs on natural teeth and implants were combined, and the overall average Periotest values (OA-PTVs) were compared with values for individual subjects. The effect of implant and natural tooth locations on mobility were evaluated and compared with each other. The combined OA-PTV for all natural teeth was +1.8 and the OA-PTV for all implants was -3.4 PTVs. Compared with those in the maxillae, mandibular teeth and implants were found to be more stable Implants were found to be significantly more stable as compared with natural teeth. The recorded variations in PTVs for natural teeth and implants over the entire evaluation period were not found to be significantly different. This study developed the following conclusions: (1) implants were found to be significantly less mobile as compared with natural teeth for individual subjects; (2) the PTVs for natural teeth and implants did not exhibit significant variation over the evaluation period; (3) the Periotest can provide reproducible assessment of stability in a long-term clinical study; and (4) changes in PTVs may be helpful in evaluating improvement or degradation of the implant-bone complex.


Retina restored and brain abnormalities ameliorated by single-copy knock-in of human NR2E1 in null mice.
Nr2e1 encodes a stem cell fate determinant of the mouse forebrain and retina. Abnormal regulation of this gene results in retinal, brain, and behavioral abnormalities in mice. However, little is known about the functionality of human NR2E1. We investigated this functionality using a novel knock-in humanized-mouse strain carrying a single-copy bacterial artificial chromosome (BAC). We also documented, for the first time, the expression pattern of the human BAC, using an NR2E1-lacZ reporter strain. Unexpectedly, cerebrum and olfactory bulb hypoplasia, hallmarks of the Nr2e1-null phenotype, were not fully corrected in animals harboring one functional copy of human NR2E1. These results correlated with an absence of NR2E1-lacZ reporter expression in the dorsal pallium of embryos and proliferative cells of adult brains. Surprisingly, retinal histology and electroretinograms demonstrated complete correction of the retina-null phenotype. These results correlated with appropriate expression of the NR2E1-lacZ reporter in developing and adult retina. We conclude that the human BAC contained all the elements allowing correction of the mouse-null phenotype in the retina, while missing key regulatory regions important for proper spatiotemporal brain expression. This is the first time a separation of regulatory mechanisms governing NR2E1 has been demonstrated. Furthermore, candidate genomic regions controlling expression in proliferating cells during neurogenesis were identified.


Thiosulfate reduction in Salmonella enterica is driven by the proton motive force.
Thiosulfate respiration in Salmonella enterica serovar Typhimurium is catalyzed by the membrane-bound enzyme thiosulfate reductase. Experiments with quinone biosynthesis mutants show that menaquinol is the sole electron donor to thiosulfate reductase. However, the reduction of thiosulfate by menaquinol is highly endergonic under standard conditions (ΔE°' = -328 mV). Thiosulfate reductase activity was found to depend on the proton motive force (PMF) across the cytoplasmic membrane. A structural model for thiosulfate reductase suggests that the PMF drives endergonic electron flow within the enzyme by a reverse loop mechanism. Thiosulfate reductase was able to catalyze the combined oxidation of sulfide and sulfite to thiosulfate in a reverse of the physiological reaction. In contrast to the forward reaction the exergonic thiosulfate-forming reaction was PMF independent. Electron transfer from formate to thiosulfate in whole cells occurs predominantly by intraspecies hydrogen transfer.


Developmental Timing of High-Fat Diet Exposure Impacts Glucose Homeostasis in Mice in a Sex-Specific Manner.
We previously demonstrated that male, but not female, Swiss Webster mice are susceptible to diabetes, with incidence increased by early overnutrition and high-fat diet (HFD). In this study, we investigated how HFD in Swiss Webster males and females during preweaning, peripubertal, and postpubertal periods alters glucose homeostasis and diabetes susceptibility. In males, HFD throughout life resulted in the highest diabetes incidence. Notably, switching to chow postpuberty was protective against diabetes relative to switching to chow at weaning, despite the longer period of HFD exposure. Similarly, HFD throughout life in males resulted in less liver steatosis relative to mice with shorter duration of postpubertal HFD. Thus, HFD timing relative to weaning and puberty, not simply exposure length, contributes to metabolic outcomes. Females were protected from hyperglycemia regardless of length or timing of HFD. However, postpubertal HFD resulted in a high degree of hepatic steatosis and adipose fibrosis, but glucose regulation and insulin sensitivity remained unchanged. Interestingly, peri-insulitis was observed in the majority of females but was not correlated with impaired glucose regulation. Our findings reveal critical periods of HFD-induced glucose dysregulation with striking sex differences in Swiss Webster mice, highlighting the importance of careful consideration of HFD timing relative to critical developmental periods.


Microbial ecology of biological invasions.
Invasive microbes, plants and animals are a major threat to the composition and functioning of ecosystems; however, the mechanistic basis of why exotic species can be so abundant and disruptive is not well understood. Most studies have focused on invasive plants and animals, although few have considered the effects of invasive microbes, or interactions of invasive plant and animal species with microbial communities. Here, we review effects of invasive plants on soil microbial communities and discuss consequences for plant performance, plant community structure and ecosystem processes. In addition, we briefly discuss effects of invasive soil microbes on plant communities, which has been less well studied, and effects of invasive animals on soil decomposers and ecosystem functioning. We do this by considering each of three important functional groups of microbes, namely soil microbial parasites and pathogens, mutualistic symbionts and decomposers. We conclude that invasive plants, pathogenic and symbiotic soil microbes will have strongest effects on the abundance of individual species, community diversity and ecosystem functioning. Invasive decomposer microbes probably have little impact, because of limited specificity and great functional redundancy. However, invasive plants and animals can have major effects on microbial decomposition in soil. We propose that understanding, predicting and counteracting consequences of enhanced global homogenization of natural communities through introducing exotic plants, animals and microbes will require future studies on how pathogenic, symbiotic and decomposer soil microbes interact, how they are influenced by higher trophic level organisms and how their combined effects are influencing the composition and functioning of ecosystems.


Type I toxin-antitoxin systems contribute to the maintenance of mobile genetic elements in Clostridioides difficile.
Toxin-antitoxin (TA) systems are widespread on mobile genetic elements and in bacterial chromosomes. In type I TA, synthesis of the toxin protein is prevented by the transcription of an antitoxin RNA. The first type I TA were recently identified in the human enteropathogen Clostridioides difficile. Here we report the characterization of five additional type I TA within phiCD630-1 (CD0977.1-RCd11, CD0904.1-RCd13 and CD0956.3-RCd14) and phiCD630-2 (CD2889-RCd12 and CD2907.2-RCd15) prophages of C. difficile strain 630. Toxin genes encode 34 to 47 amino acid peptides and their ectopic expression in C. difficile induces growth arrest that is neutralized by antitoxin RNA co-expression. We show that type I TA located within the phiCD630-1 prophage contribute to its stability and heritability. We have made use of a type I TA toxin gene to generate an efficient mutagenesis tool for this bacterium that allowed investigation of the role of these widespread TA in prophage maintenance.


Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis.
The impact of transfusing fresher vs older red blood cells (RBCs) on patient-important outcomes remains controversial. Two recently published large trials have provided new evidence. We summarized results of randomized trials evaluating the impact of the age of transfused RBCs. We searched MEDLINE, EMBASE, CINAHL, the Cochrane Database for Systematic Reviews, and Cochrane CENTRAL for randomized controlled trials enrolling patients who were transfused fresher vs older RBCs and reported outcomes of death, adverse events, and infection. Independently and in duplicate, reviewers determined eligibility, risk of bias, and abstracted data. We conducted random effects meta-analyses and rated certainty (quality or confidence) of evidence using the GRADE approach. Of 12 trials that enrolled 5229 participants, 6 compared fresher RBCs with older RBCs and 6 compared fresher RBCs with current standard practice. There was little or no impact of fresher vs older RBCs on mortality (relative risk [RR], 1.04; 95% confidence interval [CI], 0.94-1.14; P = .45; I(2) = 0%, moderate certainty evidence) or on adverse events (RR, 1.02; 95% CI, 0.91-1.14; P = .74; I(2) = 0%, low certainty evidence). Fresher RBCs appeared to increase the risk of nosocomial infection (RR, 1.09; 95% CI, 1.00-1.18; P = .04; I(2) = 0%, risk difference 4.3%, low certainty evidence). Current evidence provides moderate certainty that use of fresher RBCs does not influence mortality, and low certainty that it does not influence adverse events but could possibly increase infection rates. The existing evidence provides no support for changing practices toward fresher RBC transfusion.


The KCNQ5 potassium channel from mouse: a broadly expressed M-current like potassium channel modulated by zinc, pH, and volume changes.
The KCNQ proteins compose a sub-group of the voltage-activated potassium channel family. The family consists of five members (KCNQ1 to 5--also named Kv7.1 to Kv7.5) encoded by single genes, which all give rise to proteins forming slowly activating potassium-selective ion channels. The physiological importance of the KCNQ channel family is emphasized by the fact that mutations in four of the five genes have been linked to human pathologies (KCNQ1 to 4). Here, we present the cloning and characterization of a novel KCNQ5 ortholog from mouse isolated by homology cloning from total mouse brain RNA (GenBank accession number: AY679158). The predicted protein is 95% identical to human KCNQ5. Upon expression in Xenopus oocytes, these proteins form voltage-dependent slowly activating channels with half-maximal activation at -21 mV. Our functional characterization revealed three novel modes of modulation: pH-dependent potentiation by Zn2+ (EC50 = 21.8 microM at pH 7.4), inhibition by acidification (IC50 = 0.75 microM; pKa = 6.1), and regulation by small changes in cell volume. Furthermore, the channels are activated by the anti-convulsant drug retigabine (EC50 = 2.0 microM) and inhibited by the M-current blockers linopiridine and XE-991. Finally, real-time RT-PCR was used to quantify the expression profile in a wide range of mouse tissues. These experiments revealed a relatively broad expression pattern in the nervous system but also expression in other tissues. Highest overall expression levels were observed in cortex and hippocampus. This study shows that murine KCNQ5 channels, in addition to sharing biophysical and pharmacological characteristics with the human ortholog, are tightly regulated by physiological stimuli such as changes in extracellular Zn2+, pH, and tonicity, thus adding to the complex regulation of these channels.


Left unilateral neglect as a disconnection syndrome.
Unilateral spatial neglect is a disabling neurological condition that typically results from right hemisphere damage. Neglect patients are unable to take into account information coming from the left side of space. The study of neglect is important for understanding the brain mechanisms of spatial cognition, but its anatomical correlates are currently the object of intense debate. We propose a reappraisal of the contribution of disconnection factors to the pathophysiology of neglect based on a review of animal and patient studies. These indicate that damage to the long-range white matter pathways connecting parietal and frontal areas within the right hemisphere may constitute a crucial antecedent of neglect. Thus, neglect would not result from the dysfunction of a single cortical region but from the disruption of large networks made up of distant cortical regions. In this perspective, we also reexamined the possible contribution to neglect of interhemispheric disconnection. The reviewed evidence, often present in previous studies but frequently overlooked, is consistent with the existence of distributed cortical networks for orienting of attention in the normal brain, has implications for theories of neglect and normal spatial processing, opens perspectives for research on brain-behavior relationships, and suggests new possibilities for patient diagnosis and rehabilitation.


Photocatalytic Degradation of Dyes Using Titania Nanoparticles Supported in Metal-Organic Materials Based on Iron.
Composite materials based on titania nanoparticles (TiO2 NPs) and three metal-organic frameworks (MOFs) called MIL-53 (Fe) ((Fe (III) (OH) (1,4-BDC)), MILs (Materials Institute Lavoisier)), MIL-100 (Fe) (Fe3O(H2O)2OH(BTC)2), and Fe-BTC (iron-benzenetricarboxylate) with different percentages of TiO2 NPs (0.5, 1, and 2.5% wt.) were synthesized using the solvothermal method and used as photocatalytic materials in the degradation of two dyes (Orange II and Reactive Black 5 (RB5)). The pristine and composite materials were characterized with X-ray diffraction, Raman, UV-Vis and Fourier transform infrared spectroscopy and scanning electron microscopy techniques. The 2.5TiO2/MIL-100 composite material showed the best results for the degradation of both dyes (Reactive Black 5 and Orange II dye, 99% and 99.5% degradation in 105 and 150 min, respectively). The incorporation of TiO2 NPs into MOFs can decrease the recombination of the change carrier in the MOF, increasing the photocatalytic activity of a pristine MOF. Results therefore indicated that the synthesized MOF nanocomposites have good potential for wastewater treatment.


A single-molecule stretching method for lateral and normal AFM lever calibration.
A novel method for quantitative lateral force measurement (LFM) calibration has been developed. Using a single-molecule spectroscopy approach it is possible to calibrate the AFM levers for both lateral and normal spring constants with a single image scan. Moreover, our method does not involve tip modifications. Dextran molecules were chosen for testing our calibration procedure due to their characteristic plateau feature in the force-elongation curve which enables an easy identification of single-molecule stretching events. Using a non-standard (tilted) geometry of AFM scanning, it is possible to observe different components of the stretching force on both normal and lateral force signals. These signals can be further compared to the values obtained by standard (normal) spectroscopic measurements. The values of the normal spring constant obtained with our method are in good agreement with the results obtained from the method exploiting the energy equipartition theorem. The statistical analysis shows that the approach proposed in our paper gives reproducible results of the lateral sensitivity with a relative standard deviation less than 15%.


Utilization of [15N]glutamate by cultured astrocytes.
The metabolism of 0.25 mM-[15N]glutamic acid in cultured astrocytes was studied with gas chromatography-mass spectrometry. Almost all 15N was found as [2-15N]glutamine, [2-15N]glutamine, [5-15N]glutamine and [15N]alanine after 210 min of incubation. Some incorporation of 15N into aspartate and the 6-amino position of the adenine nucleotides also was observed, the latter reflecting activity of the purine nucleotide cycle. After the addition of [15N]glutamate the ammonia concentration in the medium declined, but the intracellular ATP concentration was unchanged despite concomitant ATP consumption in the glutamine synthetase reaction. Some potential sources of glutamate nitrogen were identified by incubating the astrocytes for 24 h with [5-15N]glutamine, [2-15N]glutamine or [15N]alanine. Significant labelling of glutamate was noted with addition of glutamine labelled on either the amino or the amide moiety, reflecting both glutaminase activity and reductive amination of 2-oxoglutarate in the glutamate dehydrogenase reaction. Alanine nitrogen also is an important source of glutamate nitrogen in this system.


[Clinical observation of preventing and treating constipation by electroacupuncture intervention in ischemic stroke patients at acute stage].
To observe the efficacy of preventing constipation by electroacupuncture intervention in ischemic stroke patients at acute stage. Three hundred and forty ischemic stroke patients who matched the inclusive criteria were randomly divided into an electroacupuncture (EA) group and a routine treatment group, 170 cases in each one. In the EA group, based on routine western treatment, rehabilitation training and common acupuncture, Tianshu (ST 25) and Zusanli (ST 36) were selected and connected to SDZ-V Hwato brand electric acupuncture apparatus respectively, given stimulation of dense-disperse wave (10 Hz/50 Hz) with electric current of 0.1 to 1.0 mA, once every day and 5 times a week in the first 2 weeks, 2 times a week in the latter 2 weeks. In the routine treatment group, only basic treatment was applied. In the two groups, the course of treatment was 4 weeks and 8 weeks' follow-up was required after treatment. The actual numbers who independently defecated less than 3 times a week after 1 to 4 weeks' treatment and in the 4th and the 8th weeks' follow-up and condition taking laxative medicines during the 12 weeks in the two groups were observed and compared. Compared on the numbers of constipation cases after 1 to 4 weeks' treatment, those in the EA group were all less than those in the routine treatment group [24.7% (42/170) vs. 36.5%(62/170), 18.8% (32/170) vs. 30.6% (52/170), 10.5% (17/162) vs. 27.5% (44/160), 9.3% (15/162) vs. 19.4% (31/160),P<0.05, P<0.001]. In the 4th and the 8th weeks' follow-up, numbers in the EA group were still less than those in the routine treatment group [9.0% (14/156) vs. 18.1% (28/155), 7.7% (12/155) vs. 16.9 (26/154) both P<0.05)]. During the 12 weeks, the number of cases who took laxative medicines in the EA group was less than that in the routine treatment group [21.2% (36/170) vs. 34.7% (59/170), P<0.05]. There is clinical significance to electroacupuncture at Tian-shui (ST 25) and Zusanli (ST 36) coibined with basic comprehensive treatment for preventing and treating constipation symptom in ischemic stroke acute stage.


The paternal age at conception effect on offspring telomere length: mechanistic, comparative and adaptive perspectives.
Telomeres are repeating DNA found at the ends of chromosomes that, in the absence of restorative processes, shorten with cell replications and are implicated as a cause of senescence. It appears that sperm telomere length (TL) increases with age in humans, and as a result offspring of older fathers inherit longer telomeres. We review possible mechanisms underlying this paternal age at conception (PAC) effect on TL, including sperm telomere extension due to telomerase activity, age-dependent changes in the spermatogonial stem cell population (possibly driven by 'selfish' spermatogonia) and non-causal confounding. In contrast to the lengthening of TL with PAC, higher maternal age at conception appears to predict shorter offspring TL in humans. We review evidence for heterogeneity across species in the PAC effect on TL, which could relate to differences in statistical power, sperm production rates or testicular telomerase activity. Finally, we review the hypothesis that the PAC effect on TL may allow a gradual multi-generational adaptive calibration of maintenance effort, and reproductive lifespan, to local demographic conditions: descendants of males who reproduced at a later age are likely to find themselves in an environment where increased maintenance effort, allowing later reproduction, represents a fitness improving resource allocation.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.


Use and acceptance of long lasting insecticidal net screens for dengue prevention in Acapulco, Guerrero, Mexico.
Dengue, recognized by the WHO as the most important mosquito-borne viral disease in the world, is a growing problem. Currently, the only effective way of preventing dengue is vector control. Standard methods have shown limited effect, and there have been calls to develop new integrated vector management approaches. One novel tool, protecting houses with long lasting insecticidal screens on doors and windows, is being trialled in a cluster randomised controlled trial by a joint UADY/WHO TDR/IDRC study in various districts of Acapulco, Mexico, with exceptionally high levels of crime and insecurity.This study investigated the community's perspectives of long lasting insecticidal screens on doors and windows in homes and in schools, in order to ascertain their acceptability, to identify challenges to further implementation and opportunities for future improvements. This was a sequential mixed-methods study. The quantitative arm contained a satisfaction survey administered to 288 houses that had received the intervention examining their perspectives of both the intervention and dengue prevention in general. The qualitative arm consisted of Focus Group Discussions (FGDs) with those who had accepted the intervention and key informant interviews with: schoolteachers to discuss the use of the screens in schools, program staff, and community members who had refused the intervention. Overall satisfaction and acceptance of the screens was very high, with only some operational and technical complaints relating to screen fragility and the installation process. However, the wider social context of urban violence and insecurity was a major barrier to screen acceptance. Lack of information dissemination and community collaboration were identified as project weaknesses. The screens are widely accepted by the population, but the project implementation could be improved by reassuring the community of its legitimacy in the context of insecurity. More community engagement and better information sharing structures are needed.The screens could be a major new dengue prevention tool suitable for widespread use, if further research supports their entomological and epidemiological effectiveness and their acceptability in different social and environmental contexts. Further research is needed looking at the impact of insecurity of dengue prevention programmes.


Varicella and varicella vaccination in South Korea.
With continuing occurrence of varicella despite increasing vaccine coverage for the past 20 years, a case-based study, a case-control study, and an immunogenicity and safety study were conducted to address the impact of varicella vaccination in South Korea. Varicella patients under the age of 16 years were enrolled for the case-based study. For the case-control study, varicella patients between 12 months and 15 years of age were enrolled with one control matched for each patient. For the immunogenicity and safety study, otherwise healthy children from 12 to 24 months old were immunized with Suduvax (Green Cross, South Korea). Fluorescent antibody to membrane antigen (FAMA) varicella-zoster virus (VZV) antibody was measured before and 6 weeks after immunization. In the case-based study, the median age of the patients was 4 years. Among 152 patients between 1 and 15 years of age, 139 children received varicella vaccine and all had breakthrough infections. Clinical courses were not ameliorated in vaccinated patients, but more vaccinated patients received outpatient rather than inpatient care. In the case-control study, the adjusted overall effectiveness of varicella vaccination was 54%. In the immunogenicity and safety study, the seroconversion rate and geometric mean titer for FAMA antibody were 76.67% and 5.31. Even with increasing varicella vaccine uptake, we illustrate no upward age shift in the peak incidence, a high proportion of breakthrough disease, almost no amelioration in disease presentation by vaccination, and insufficient immunogenicity of domestic varicella vaccine. There is need to improve the varicella vaccine used in South Korea.


Regional paleoclimates and local consequences: Integrating GIS analysis of diachronic settlement patterns and process-based agroecosystem modeling of potential agricultural productivity in Provence (France).
Holocene climate variability in the Mediterranean Basin is often cited as a potential driver of societal change, but the mechanisms of this putative influence are generally little explored. In this paper we integrate two tools-agro-ecosystem modeling of potential agricultural yields and spatial analysis of archaeological settlement pattern data-in order to examine the human consequences of past climatic changes. Focusing on a case study in Provence (France), we adapt an agro-ecosystem model to the modeling of potential agricultural productivity during the Holocene. Calibrating this model for past crops and agricultural practices and using a downscaling approach to produce high spatiotemporal resolution paleoclimate data from a Mediterranean Holocene climate reconstruction, we estimate realistic potential agricultural yields under past climatic conditions. These serve as the basis for spatial analysis of archaeological settlement patterns, in which we examine the changing relationship over time between agricultural productivity and settlement location. Using potential agricultural productivity (PAgP) as a measure of the human consequences of climate changes, we focus on the relative magnitudes of 1) climate-driven shifts in PAgP and 2) the potential increases in productivity realizable through agricultural intensification. Together these offer a means of assessing the scale and mechanisms of the vulnerability and resilience of Holocene inhabitants of Provence to climate change. Our results suggest that settlement patterns were closely tied to PAgP throughout most of the Holocene, with the notable exception of the period from the Middle Bronze Age through the Early Iron Age. This pattern does not appear to be linked to any climatically-driven changes in PAgP, and conversely the most salient changes in PAgP during the Holocene cannot be clearly linked to any changes in settlement pattern. We argue that this constitutes evidence that vulnerability and resilience to climate change are strongly dependent on societal variables.


Differentiation of cellular reaction to alloantigens and bacterial infection in human skin graft--immunosuppressive drugs or antibiotics.
The human hand transplantations prompted revival of interest in evaluation of the rejection process of the grafted skin and its control with the antirejection drugs [1-3]. In case of first hand transplantation a combined immunosuppressive regimen was applied with currently available drugs resulting in acceptance of the entire composite graft. No major untoward systemic effects of antirejection therapy were observed. The most important clinical conclusion was that allogeneic skin can be accepted and function as in a normal extremity, although the attack of host cells on the graft can not be totally eliminated. Chronic perivascular and subepidermal infiltrates with recipient cells could be seen [4]. Another problem connected with skin transplantation is graft infection. Skin is inhabited by a specific spectrum of bacteria [5]. Allografted skin is more sensitive to bacterial penetration than normal skin due to local damage by the host-versus-graft cellular reaction and compromised immune reactivity to bacterial antigens by the immunosuppressive therapy. The histological pictures of rejecting skin represent a mixture of cellular reaction against the graft and penetrating microbes. Alloreaction requires modification of immunosuppressive regimen and infection is an indication for prolonged antibiotic therapy against skin bacterial flora. The question arises how to discriminate the alloreactive and bacterial changes in the skin graft. We studied the histological pictures of rejecting and infected human skin after transplantion to scid mice.


Cumulative adversity sensitizes neural response to acute stress: association with health symptoms.
Cumulative adversity (CA) increases stress sensitivity and risk of adverse health outcomes. However, neural mechanisms underlying these associations in humans remain unclear. To understand neural responses underlying the link between CA and adverse health symptoms, the current study assessed brain activity during stress and neutral-relaxing states in 75 demographically matched, healthy individuals with high, mid, and low CA (25 in each group), and their health symptoms using the Cornell Medical Index. CA was significantly associated with greater adverse health symptoms (P=0.01) in all participants. Functional magnetic resonance imaging results indicated significant associations between CA scores and increased stress-induced activity in the lateral prefrontal cortex, insula, striatum, right amygdala, hippocampus, and temporal regions in all 75 participants (p<0.05, whole-brain corrected). In addition to these regions, the high vs low CA group comparison revealed decreased stress-induced activity in the medial orbitofrontal cortex (OFC) in the high CA group (p<0.01, whole-brain corrected). Specifically, hypoactive medial OFC and hyperactive right hippocampus responses to stress were each significantly associated with greater adverse health symptoms (p<0.01). Furthermore, an inverse correlation was found between activity in the medial OFC and right hippocampus (p=0.01). These results indicate that high CA sensitizes limbic-striatal responses to acute stress and also identifies an important role for stress-related medial OFC and hippocampus responses in the effects of CA on increasing vulnerability to adverse health consequences.


[Hair growth effect of minoxidil].
The length and size of hair are depend on the anagen term in its hair cycle. It has been reported that the some cell growth factors, such as VEGF, FGF-5S, IGF-1 and KGF, induce the proliferation of cells in the matrix, dermal papilla and dermal papillary vascular system and increase the amount of extra cellular matrix in dermal papilla and then maintain follicles in the anagen phase. On the other hand, negative factors, like FGF-5, thrombospondin, or still unknown ones, terminate the anagen phase. If the negative factors become dominant against cell proliferation factors according to fulfilling some time set by the biological clock for hair follicles, TGF beta induced in the matrix tissues evokes apoptosis of matrix cells and shifts the follicles from anagen to catagen. Androgenetic alopecia is caused by miniaturizing of hair follicles located in the frontal or crown part of scalp and are hereditarily more sensitive to androgen. In their hair cycles, the androgen shortens the anagen phase of follicles and shifts them to the catagen phase earlier than usual. The mode of action of hair growth effect of minoxidil is not completely elucidated, but the most plausible explanation proposed here is that minoxidil works as a sulfonylurea receptor (SUR) activator and prolongs the anagen phase of hair follicles in the following manner: minoxidil (1) induces cell growth factors such as VEGF, HGF, IGF-1 and potentiates HGF and IGF-1 actions by the activation of uncoupled SUR on the plasma membrane of dermal papilla cells, (2) inhibits of TGF beta induced apoptosis of hair matrix cells by opening the Kir 6.0 channel pore coupled with SUR on the mitochondrial inner membrane, and (3) dilates hair follicle arteries and increases blood flow in dermal papilla by opening the Kir 6.0 channel pore coupled with SUR on the plasma membrane of vascular smooth muscle cells.


Structure of the C-terminal domain of the prokaryotic sodium channel orthologue NsvBa.
Crystallographic and electrophysiological studies have recently provided insight into the structure, function, and drug binding of prokaryotic sodium channels. These channels exhibit significant sequence identities, especially in their transmembrane regions, with human voltage-gated sodium channels. However, rather than being single polypeptides with four homologous domains, they are tetramers of single domain polypeptides, with a C-terminal domain (CTD) composed of an inter-subunit four helix coiled coil. The structures of the CTDs differ between orthologues. In NavBh and NavMs, the C-termini form a disordered region adjacent to the final transmembrane helix, followed by a coiled-coil region, as demonstrated by synchrotron radiation circular dichroism (SRCD) and double electron-electron resonance electron paramagnetic resonance spectroscopic measurements. In contrast, in the crystal structure of the NavAe orthologue, the entire C-terminus is comprised of a helical region followed by a coiled coil. In this study, we have examined the CTD of the NsvBa from Bacillus alcalophilus, which unlike other orthologues is predicted by different methods to have different types of structures: either a disordered region adjacent to the transmembrane region, followed by a helical coiled coil, or a fully helical CTD. To discriminate between the two possible structures, we have used SRCD spectroscopy to experimentally determine the secondary structure of the C-terminus of this orthologue and used the results as the basis for modeling the open and closed conformations of the channel.


[Analysis of mortality in relation to various demographic phenomena: migration and marital status].
This paper analyzes the mortality of major respiratory cancers, certified in Italy in the years 1981-84, by two demographic phenomena: migration and civil status. Direct standardized rates were computed using the total population as reference; a partial analysis of mortality by all causes was also performed. Because of the industrial development in some areas of Italy, great migrations took place in the past within the country, with specific and well known geographic and time patterns. This paper mainly considers migrations towards the industrialized regions of the north-west both from the north-east, occurring between the two world wars, and from the south regions, occurring from the fifties to the seventies. Various studies have shown that cancer mortality decreases with the geographic latitude of the area studied, and that there is a protective effect associated with being born in the southern part of the country. Italian regions were grouped into five areas: north-west, north-east, north-central, south-central and south. Individuals born in the same area of the last residence were defined as "stable", while "migrant" indicates that the area of birth differed from the last residence; for "internal migrant" both regions of birth and last residence are in the same area. For migrants to the north-west, rates by age are reported. For larynx cancer, only mortality of males is discussed. Our study's results confirm that lung cancer mortality is always higher for migrants than it is for stables from the same birth area. Immigrants also show higher rates of lung cancer mortality than the stables in the host areas. The rate ratio of emigrants versus stables in the birth area increases towards the south. The increasing protective role of birth area with decreasing latitude is confirmed for both stables and immigrants. Subjects in the north-west who emigrated from the north-east show age-specific mortality rates higher than stables, both in host and birth areas. Immigrants from southern areas show rates equal to the stables of the host area with increasing age. Results for lung cancer mortality suggest that migrants differed from the stables in socio-economic characteristics not only in the birth areas but also in the host regions. For larynx cancer, migrants and stables show similar rates. Mortality rates for internal migrants and stables decrease with latitude; the protective role of birth area in immigrants is less evident.(ABSTRACT TRUNCATED AT 400 WORDS)


Some aspects of balance disorder in patients with multiple sclerosis.
The aim of this study was to analyze: frequency of balance disorder (vertigo and disequilibrium), frequency of abnormalities in auditory evoked potentials (AEP) and magnetic resonance imaging (MRI) changes of the brain in multiple sclerosis (MS) patients with balance disorder, relation of patient's disability status to balance disorder and relation of the changes in MRI of the brainstem to AEP abnormalities. It was analyzed 60 patients with relapsing-remitting form of MS. Two groups of patients were made consecutively under Expanded Disability Status Scale score (EDSS): A (EDSS < or =4,5) and B (EDSS > or =5,0). The study was retrospective-prospective. After the neurological exam AEP and MRI of the brain have been done. Balance disorder has been verified as initial symptom in 29 (48,4%) and out of them disequilibrium experienced 24 (83,4%) patients. During the relapses balance disorder experienced 48 (80%) patients and in 37 (77,1%) it was disequilibrium. Among them 33 (68,7%) were with lower EDSS (< or =4,5) and 15 (31,3%) with higher EDSS score (> or =5). There is no correlation between disability status and vertigo which means that vertigo is not more frequent in more disabled patients and vice-versa. The AEP were pathological in 57 (95%) patients. Of all 29 patients with vertigo AEP were pathological in 28 (96,5%) while in 31 patients without vertigo pathological AEP were in 29 (93,5%) but it is not statistical significant. The most frequent characteristic of AEP changes were prolonged inter-peak latency III-V waves (48 patients or 80%). The plaque in brainstem visualized by MRI was found in 41 (71,8%) of patients (38 or 92,6% of them had pathological AEP and in three patients AEP were normal). In group of patients with pathological AEP, 38 (66,6%) of them had plaque in brainstem. In other three patients with normal AEP it was visualized plaque in brainstem. In the group of 29 patients with balance disorder, 20 (68,9%) had plaque in brainstem as well as 21 (67,7%) out of 31 patients without balance disorder had plaque in the brainstem. This difference is not statistical significant. It is concluded that the vertigo (including disequilibrium) is relatively often (48,4%) initial symptom of MS. Vertigo is not more frequent in patients with higher EDSS score and vice-versa. Pathological AEP are frequent neurophysiologic finding in both (95%) patients with (96,5%) and without (93,5%) vertigo. The most often pathological characteristic of AEP are prolonged interpeak latency of III-V waves (78,5%), as well as abnormalities of V and than IV wave. MS plaques in brainstem visualized by MRI technique are frequent in both groups of patients with and without pathological finding of the AEP.


Equation of state for random sphere packings with arbitrary adhesion and friction.
We systematically generate a large set of random micro-particle packings over a wide range of adhesion and friction by means of adhesive contact dynamics simulation. The ensemble of generated packings covers a range of volume fractions ϕ from 0.135 ± 0.007 to 0.639 ± 0.004, and of coordination numbers Z from 2.11 ± 0.03 to 6.40 ± 0.06. We determine ϕ and Z at four limits (random close packing, random loose packing, adhesive close packing, and adhesive loose packing), and find a universal equation of state ϕ(Z) to describe packings with arbitrary adhesion and friction. From a mechanical equilibrium analysis, we determine the critical friction coefficient μf,c: when the friction coefficient μf is below μf,c, particles' rearrangements are dominated by sliding, otherwise they are dominated by rolling. Because of this reason, both ϕ(μf) and Z(μf) change sharply across μf,c. Finally, we generalize the Maxwell counting argument to micro-particle packings, and show that the loosest packing, i.e., adhesive loose packing, satisfies the isostatic condition at Z = 2.


Transcriptome analysis reveals new insights into the modulation of endometrial stromal cell receptive phenotype by embryo-derived signals interleukin-1 and human chorionic gonadotropin: possible involvement in early embryo implantation.
The presence of the conceptus in uterine cavity necessitates an elaborate network of interactions between the implanting embryo and a receptive endometrial tissue. We believe that embryo-derived signals play an important role in the remodeling and the extension of endometrial receptivity period. Our previous studies provided original evidence that human Chorionic Gonadotropin (hCG) modulates and potentiates endometrial epithelial as well as stromal cell responsiveness to interleukin 1 (IL1), one of the earliest embryonic signals, which may represent a novel pathway by which the embryo favors its own implantation and growth within the maternal endometrial host. The present study was designed to gain a broader understanding of hCG impact on the modulation of endometrial cell receptivity, and in particular, cell responsiveness to IL1 and the acquisition of growth-promoting phenotype capable of receiving, sustaining, and promoting early and crucial steps of embryonic development. Our results showed significant changes in the expression of genes involved in cell proliferation, immune modulation, tissue remodeling, apoptotic and angiogenic processes. This points to a relevant impact of these embryonic signals on the receptivity of the maternal endometrium, its adaptation to the implanting embryo and the creation of an environment that is favorable for the implantation and the growth of this latter within a new and likely hostile host tissue. Interestingly our data further identified a complex interaction between IL1 and hCG, which, despite a synergistic action on several significant endometrial target genes, may encompass a tight control of endogenous IL1 and extends to other IL1 family members.


Learning to appreciate others: neural development of cognitive perspective taking.
Neuroimaging studies have thoroughly investigated brain regions that are recruited when we put ourselves in another person's shoes. Taking a third-person perspective (3PP) as opposed to a first-person perspective (1PP) has been associated with brain activation in the inferior parietal cortex, the medial posterior cortex and the prefrontal cortex. Here we investigate for the first time the development of the neural network that yields cognitive perspective taking. Twelve adults (aged 25-32 years) and twelve school-aged children (aged 8-10 years) were investigated using functional magnetic resonance imaging (fMRI). Behaviorally, we found a decrease of reaction time differences between 3PP and 1PP with age indicating that adults were more efficient in processing a 3PP. Despite the reaction time differences both groups were equally accurate in their judgments. Brain imaging data indicated neural activity in the left inferior parietal cortex and precuneus for adults during 3PP as compared with 1PP judgments. Children additionally showed enhanced activity in the dorsolateral prefrontal cortex and the right inferior perietal cortex. We found a significant interaction between groups and brain activation in the right dorsolateral prefrontal cortex and in the right inferior parietal cortex. These results suggest that the development of the ability to reason about another person's mind accompanies a shift in activity from frontal to posterior brain regions and from bilateral to unilateral left inferior parietal cortex.


The influence of the optimization starting conditions on the robustness of intensity-modulated proton therapy plans.
In this paper the influence of varying the starting conditions on intensity-modulated proton therapy (IMPT) plans has been studied. In particular IMPT plans have been optimized based on four different starting conditions of initial beamlet fluences: (a) all beamlets with an initial constant weight, delivering a gradient from the proximal to the distal edge of the target (forward wedge approach); (b) beamlet weights reduced from the distal to the proximal aspect of the target such as to deliver a flat 'spread-out-Bragg-peak' (SOBP approach); (c) beamlet weights calculated to deliver a gradient from the distal (maximal dose) to the proximal edge (inverse wedge); (d) beamlet weights set universally to zero except the most distal one, for each given lateral direction (i.e. distal-edge-tracking, DET). An analysis of robustness to range errors has been performed by recalculating plans, assuming a systematic 3% error in CT values. Results showed that IMPT plans optimized with the forward wedge approach were very sensitive to range errors, since organs-at-risk (OAR) were spared by patching single-field lateral and distal fall-offs, the last ones being strongly sensitive to range errors. In addition a plan robust to range errors can be achieved by starting the optimization process in the case of low-dose constraints to OAR, with the initial flat SOBP approach, and with either the DET or the inverse wedge approaches, in the case of stringent dose-volume constraints to OAR. 'Starting condition-based optimization' as proposed here can therefore provide a tool to transparently 'steer' the optimization outcome to solutions more robust to uncertainties.


Assessment of myocardial viability.
The prevalence of left ventricular (LV) dysfunction and resultant congestive heart failure is increasing. Patients with this condition are at high risk for cardiac death and usually have significant limitations in their lifestyles. Although there have been advances in medical therapy resulting in improved survival and well being, the best and most definitive therapy, when appropriate, is revascularization. In the setting of coronary artery disease, accounting for approximately two thirds of cases of congestive heart failure, LV dysfunction often is not the result of irreversible scar but rather caused by impairment in function and energy use of still viable-myocytes, with the opportunity for improved function if coronary blood flow is restored. Patients with LV dysfunction who have viable myocardium are the patients at highest risk because of the potential for ischemia but at the same time benefit most from revascularization. It is important to identify viable myocardium in these patients, and radionuclide myocardial scintigraphy is an excellent tool for this. Single-photon emission computed tomography perfusion scintigraphy, whether using thallium-201, Tc-99m sestamibi, or Tc-99m tetrofosmin, in stress and/or rest protocols, has consistently been shown to be an effective modality for identifying myocardial viability and guiding appropriate management. Metabolic imaging with positron emission tomography radiotracers frequently adds additional information and is a powerful tool for predicting which patients will have an improved outcome from revascularization, including some patients referred instead for cardiac transplantation. Other noninvasive modalities, such as stress echocardiography, also facilitate the assessment of myocardial viability, but there are advantages and disadvantages compared with the nuclear techniques. Nuclear imaging appears to require fewer viable cells for detection, resulting in a higher sensitivity but a lower specificity than stress echocardiography for predicting post-revascularization improvement of ventricular function. Nevertheless, it appears that LV functional improvement may not always be necessary for clinical improvement. Future directions include use of magnetic resonance imaging, as well as larger, multicenter trials of radionuclide techniques. The increasing population of patients with LV dysfunction, and the increased benefit afforded by newer therapies, will make assessment of myocardial viability even more essential for proper patient management.


A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group.
A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.


The 1999 Fresno particulate matter exposure studies: comparison of community, outdoor, and residential PM mass measurements.
Two collaborative studies have been conducted by the U.S. Environmental Protection Agency (EPA) National Exposure Research Laboratory (NERL) and National Health and Environmental Effects Research Laboratory to determine personal exposures and physiological responses to particulate matter (PM) of elderly persons living in a retirement facility in Fresno, CA. Measurements of PM and other criteria air pollutants were made inside selected individual residences within the retirement facility and at a central outdoor site on the premises. In addition, personal PM exposure monitoring was conducted for a subset of the participants, and ambient PM monitoring data were available for comparison from the NERL PM research monitoring platform in central Fresno. Both a winter (February 1-28, 1999) and a spring (April 19-May 16, 1999) study were completed so that seasonal effects could be evaluated. During the spring study, a more robust personal exposure component was added, as well as a more detailed evaluation of physical factors, such as air-exchange rate, that are known to influence the penetration of particles into the indoor environment. In this paper, comparisons are made among measured personal PM exposures and PM mass concentrations measured at the NERL Fresno Platform site, outside on the premises of the retirement facility, and inside selected residential apartments at the facility during the two 28-day study periods. The arithmetic daily mean personal PM2.5 exposure during the winter study period was 13.3 micrograms/m3, compared with 9.7, 20.5, and 21.7 micrograms/m3 for daily mean overall apartment, outdoor, and ambient (i.e., platform) concentrations, respectively. The daily mean personal PM2.5 exposure during the spring study period was 11.1 micrograms/m3, compared with 8.0, 10.1, and 8.6 micrograms/m3 for the daily mean apartment, outdoor, and ambient concentrations, respectively.


ERCP and laparoscopic cholecystectomy in a combined (one-step) procedure: a random comparison to the standard (two-step) procedure.
Current treatment of complicated calculous biliary disease typically involves a two-step procedure consisting of preoperative endoscopic retrograde cholangiopancreatography (ERCP) followed by laparoscopic cholecystectomy. Alternatively, laparoscopic cholecystectomy with intraoperative cholangiogram (IOC) and intraoperative common bile duct exploration or ERCP at a later date may be performed. This study compared the benefits of the traditional two-step procedure to the novel one-step procedure for the management of calculous biliary disease. A retrospective review of 20 patients was conducted comparing one-step to two-step procedures for the management of choledocholithiasis. We define the one-step procedure to be a laparoscopic cholecystectomy with IOC to confirm the presence or absence of stones. Intraoperative ERCP with stone extraction was conducted if necessary as part of the one-step procedure. A statistically significant difference existed between hospital charges for one-step ($58,145.30, SD $17,963.09) and two-step ($78,895.53, SD $21,954.78) procedures (p = 0.033). Other parameters (length of stay, preoperative days) trended toward significance; however, statistical significance was not achieved. There appears to be a significant cost reduction with implementation of the one-step treatment of calculous biliary disease. Further research with a larger study population is necessary to determine the additional benefits of this procedure and to help augment the surgical endoscopists' armamentarium.


Case report of neonatal ductus venosus atresia.
In the fetus, the ductus venosus (DV) connects the umbilical vein and the portal veins to the inferior vena cava in order to bypass the high-resistance hepatic vascular network. Via the Eustachian valve, the DV directs umbilical venous blood with the highest oxygen content preferentially towards the myocardium and the brain. An absence (agenesis) or a secondary obliteration of an initially normally developed DV (atresia) is associated with various shunt types and may lead to severe hydrops. A routine check-up of a healthy 34-year-old woman at 27 5/7 wks GA revealed a severe hydrops fetalis with pleural effusions and ascites. After birth at 28 0/7 wks GA, the bilateral pleural effusions needed drainage via thoracic drains. Arterial hypotension was initially treated with volume replacement and dopamine, later on adrenaline and hydrocortisone were added. The initial echocardiography showed normal anatomic structures and normal bi-ventricular function. Despite maximal intensive care treatment, a global respiratory and cardiovascular insufficiency developed. The girl died on fourth day of life. At autopsy, a secondary atresia of the DV was identified, and moreover a pathogenic de novo heterozygous mutation in the KRAS gene was found in the chorion biopsy probe. For all cases of non-haemolytic hydrops fetalis, a prenatal or postnatal sonography with Doppler examination of the venous system and of the heart should be performed. Furthermore, testing for RASopathies should be recommended especially in presence of increased nuchal translucency thickness and polyhydramnios.


A simplified, low-cost method for polarized light microscopy.
Malaria pigment is an intracellular inclusion body that appears in blood and tissue specimens on microscopic examination and can help in establishing the diagnosis of malaria. In simple light microscopy, it can be difficult to discern from cellular background and artifacts. It has long been known that if polarized light microscopy is used, malaria pigment can be much easier to distinguish. However, this technique is rarely used because of the need for a relatively costly polarization microscope. We describe a simple and economical technique to convert any standard light microscope suitable for examination of malaria films into a polarization microscope.


Differences in Coaching Needs Among Underrepresented Minority Medical Students.
Little is known about how the academic coaching needs of medical students differ between those who are racially, ethnically, and socially underrepresented minority (RES-URM) and those who represent the majority. This single-site exploratory study investigated student perceptions and coaching needs associated with a mandatory academic coaching program, and coaches' understanding of and preparedness to address these potentially differing needs. Coaching needs of second- and third-year medical students were assessed using two initial focus groups and two validation focus groups, one consisting of RES-URM students and the other majority medical students. Coaches were assessed using a cross-sectional self-administered survey designed to determine their perceptions of differing coaching needs of students Results: Seven themes emerged from the student focus groups. Three of these reflected the coaching relationship, and four reflected the coaching process. RES-URM students expressed stress around sharing vulnerability that was not expressed among majority students. Sixty-eight percent of coaches expressed that RES-URM students would not have differing needs of their coaches. Coaches self-rated as being somewhat (45%), moderately (29%), or very (13%) skilled at coaching RES-URM students. RES-URM students cite different coaching needs than majority students that most coaches do not recognize. Faculty and program development regarding these unique needs is warranted.


Efficacy of phosphodiesterase type 5 inhibitors in univentricular congenital heart disease: the SV-INHIBITION study design.
In univentricular hearts, selective lung vasodilators such as phosphodiesterase type 5 (PDE5) inhibitors would decrease pulmonary resistance and improve exercise tolerance. However, the level of evidence for the use of PDE5 inhibitors in patients with a single ventricle (SV) remains limited. We present the SV-INHIBITION study rationale, design, and methods. The SV-INHIBITION trial is a nationwide multicentre, randomized, double blind, placebo-controlled, Phase III study, aiming to evaluate the efficacy of sildenafil on the ventilatory efficiency during exercise, in teenagers and adult patients (>15 years old) with an SV. Patients with a mean pulmonary arterial pressure >15 mmHg and a trans-pulmonary gradient >5 mmHg, measured by cardiac catheterization, will be eligible. The primary outcome is the variation of the VE/VCO2 slope, measured by a cardiopulmonary exercise test, between baseline and 6 months of treatment. A total of 50 patients are required to observe a decrease of 5 ± 5 points in the VE/VCO2 slope, with a power of 90% and an alpha risk of 5%. The secondary outcomes are clinical outcomes, oxygen saturation, 6 min walk test, SV function, NT-proBNP, peak VO2 , stroke volume, mean pulmonary arterial pressure, trans-pulmonary gradient, SF36 quality of life score, safety, and acceptability. The SV-INHIBITION study aims to answer the question whether PDE5 inhibitors should be prescribed in patients with an SV. This trial has been built focusing on the three levels of research defined by the World Health Organization: disability (exercise tolerance), deficit (SV function), and handicap (quality of life).


Two typical time scales of the piston effect.
The existence of a fourth mode of heat transfer near the critical point, named the piston effect, has been known for more than a decade. The typical time scale of temperature relaxation due to this effect was first predicted by Onuki [Phys. Rev A 41, 2256 (1990)], and this author's formula has been extensively used since then to predict the thermal behavior of near-critical fluids. Recent studies, however, pointed out that the critical divergence of the bulk viscosity could have a strong influence on piston-effect-related processes. In this paper, we conduct a theoretical analysis of near-critical temperature relaxation showing that the piston effect is not governed by one (as was until now believed) but by two typical time scales. These two time scales exhibit antagonistic asymptotic behaviors as the critical point is approached: while the classical piston-effect time scale (as predicted by Onuki ) goes to zero at the critical point (critical speeding up), the second time scale (related to bulk viscosity) goes to infinity (critical slowing down). Based on this property, an alternative method for measuring near-critical bulk viscosity is proposed.


Enhancing Light Fields through Ray-Space Stitching.
Light fields (LFs) have been shown to enable photorealistic visualization of complex scenes. In practice, however, an LF tends to have a relatively small angular range or spatial resolution, which limits the scope of virtual navigation. In this paper, we show how seamless virtual navigation can be enhanced by stitching multiple LFs. Our technique consists of two key components: LF registration and LF stitching. To register LFs, we use what we call the ray-space motion matrix (RSMM) to establish pairwise ray-ray correspondences. Using Plücker coordinates, we show that the RSMM is a 5 ×6 matrix, which reduces to a 5 ×5 matrix under pure translation and/or in-plane rotation. The final LF stitching is done using multi-resolution, high-dimensional graph-cut in order to account for possible scene motion, imperfect RSMM estimation, and/or undersampling. We show how our technique allows us to create LFs with various enhanced features: extended horizontal and/or vertical field-of-view, larger synthetic aperture and defocus blur, and larger parallax.


Feasibility and validity of accelerometer measurements to assess physical activity in toddlers.
Accelerometers are considered to be the most promising tool for measuring physical activity (PA) in free-living young children. So far, no studies have examined the feasibility and validity of accelerometer measurements in children under 3 years of age. Therefore, the purpose of the present study was to examine the feasibility and validity of accelerometer measurements in toddlers (1- to 3-year olds). Forty-seven toddlers (25 boys; 20 ± 4 months) wore a GT1M ActiGraph accelerometer for 6 consecutive days and parental perceptions of the acceptability of wearing the monitor were assessed to examine feasibility. To investigate the validity of the ActiGraph and the predictive validity of three ActiGraph cut points, accelerometer measurements of 31 toddlers (17 boys; 20 ± 4 months) during free play at child care were compared to directly observed PA, using the Observational System for Recording Physical Activity in Children-Preschool (OSRAC-P). Validity was assessed using Pearson and Spearman correlations and predictive validity using area under the Receiver Operating Characteristic curve (ROC-AUC). The feasibility examination indicated that accelerometer measurements of 30 toddlers (63.8%) could be included with a mean registration time of 564 ± 62 min during weekdays and 595 ± 83 min during weekend days. According to the parental reports, 83% perceived wearing the accelerometer as 'not unpleasant and not pleasant' and none as 'unpleasant'. The validity evaluation showed that mean ActiGraph activity counts were significantly and positively associated with mean OSRAC-P activity intensity (r = 0.66; p < 0.001; n = 31). Further, the correlation among the ActiGraph activity counts and the OSRAC-P activity intensity level during each observation interval was significantly positive (ρ = 0.52; p < 0.001; n = 4218). Finally, the three sedentary cut points exhibited poor to fair classification accuracy (ROC-AUC: 0.56 to 0.71) while the three light PA (ROC-AUC: 0.51 to 0.62) and the three moderate-to-vigorous PA cut points (ROC-AUC: 0.53 to 0.57) demonstrated poor classification accuracy with respect to detecting sedentary behavior, light PA and moderate-to-vigorous PA, respectively. The present findings suggest that ActiGraph accelerometer measurements are feasible and valid for quantifying PA in toddlers. However, further research is needed to accurately identify PA intensities in toddlers using accelerometry.