Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.
The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).


Clinical significance of preoperative serum concentrations of interleukin-6 as a prognostic marker in patients with esophageal cancer.
Although the clinical outcome of esophageal cancer has recently improved, the relapse rate remains high for all disease stages. At present, there is no diagnostic method to predict the long-term outcome for esophageal cancer. In this study, we evaluated serum preoperative proinflammatory cytokine levels and investigated the correlation between preoperative interleukin-6 (IL-6) and IL-8 levels and survival of patients with esophageal cancer. Between 2008 and 2015, we evaluated preoperative serum cytokine levels in 122 patients who underwent esophagectomy for esophageal cancer. Serum IL-6 and IL-8 levels were measured by enzyme-linked immunosorbent assays. We investigated the relationship between serum cytokine levels and the response to chemotherapy and survival. The preoperative IL-6 levels were significantly associated with shorter recurrence-free survival (RFS, p = 0.001) and overall survival (OS, p = 0.001) after esophagectomy. Higher IL-8 levels were significantly associated with RFS (p = 0.018). In the multivariate analysis, age, preoperative chemotherapy, lymph node metastasis, serum C-reactive protein (CRP) levels and serum IL-6 levels (hazard ratio (HR), 2.888; p = 0.049) were significantly independent prognostic factors of RFS. Additionally, age, pathological stage, and serum IL-6 levels (HR, 3.247; p = 0.027) were shown to be significantly independent prognostic factors of OS. Serum IL-6 levels were significantly higher in the non-responder group (pathological response pGrade0 and pGrade1) after neoadjuvant therapy. High preoperative serum IL-6 levels are associated with a poor response to chemotherapy or chemoradiotherapy and poor prognosis after esophagectomy. Preoperative serum IL-6 levels may be a useful independent prognostic marker for esophageal cancer patients.


Stage-for-stage comparison of definitive chemoradiotherapy, surgery alone and neoadjuvant chemotherapy for oesophageal carcinoma.
Definitive chemoradiotherapy (dCRT) has been proposed as an alternative therapy for selected patients with oesophageal cancer. The aim of this study was to determine the outcomes of dCRT, surgery alone, and neoadjuvant chemotherapy followed by surgery (CS) in patients with oesophageal cancer. Consecutive patients diagnosed with oesophageal cancer and managed by a multidisciplinary team were staged by computed tomography and endoluminal ultrasonography. Those deemed unsuitable for surgery on the grounds of performance status, bulky local disease or personal choice received dCRT. The primary outcome measure was overall survival measured from date of diagnosis. Of 417 patients, 173 received dCRT, 126 underwent surgery alone and 118 received CS. The incidence of grade III/IV toxicity after dCRT and CS was 39.3 and 60.2 per cent respectively. Operative morbidity rates were 42.9 and 44.4 per cent after surgery alone and CS respectively. Thirty-day mortality rates were zero, 7.9 and 0.8 per cent after dCRT, surgery alone and CS respectively. Overall 2-year survival rates were 44.3, 56.2 and 42.4 per cent (P = 0.422). These findings support the need for a randomized trial of dCRT versus CS for resectable oesophageal cancer.


Non-Invasive Quantification of Cartilage Using a Novel In Vivo Bioluminescent Reporter Mouse.
Mouse models are common tools for examining post-traumatic osteoarthritis (OA), which involves cartilage deterioration following injury or stress. One challenge to current mouse models is longitudinal monitoring of the cartilage deterioration in vivo in the same mouse during an experiment. The objective of this study was to assess the feasibility for using a novel transgenic mouse for non-invasive quantification of cartilage. Chondrocytes are defined by expression of the matrix protein aggrecan, and we developed a novel mouse containing a reporter luciferase cassette under the inducible control of the endogenous aggrecan promoter. We generated these mice by crossing a Cre-dependent luciferase reporter allele with an aggrecan creERT2 knockin allele. The advantage of this design is that the targeted knockin retains the intact endogenous aggrecan locus and expresses the tamoxifen-inducible CreERT2 protein from a second IRES-driven open reading frame. These mice display bioluminescence in the joints, tail, and trachea, consistent with patterns of aggrecan expression. To evaluate this mouse as a technology for non-invasive quantification of cartilage loss, we characterized the relationship between loss of bioluminescence and loss of cartilage after induction with (i) ex vivo collagenase digestion, (ii) an in vivo OA model utilizing treadmill running, and (iii) age. Ex vivo experiments revealed that collagenase digestion of the femur reduced both luciferase signal intensity and pixel area, demonstrating a link between cartilage degradation and bioluminescence. In an in vivo model of experimental OA, we found decreased bioluminescent signal and pixel area, which correlated with pathological disease. We detected a decrease in both bioluminescent signal intensity and area with natural aging from 2 to 13 months of age. These results indicate that the bioluminescent signal from this mouse may be used as a non-invasive quantitative measure of cartilage. Future studies may use this reporter mouse to advance basic and preclinical studies of murine experimental OA with applications in synovial joint biology, disease pathogenesis, and drug delivery.


Immunoradiometric assay of insulin, intact proinsulin and 32-33 split proinsulin and radioimmunoassay of insulin in diet-treated type 2 (non-insulin-dependent) diabetic subjects.
Plasma insulin, intact proinsulin and 32-33 split proinsulin measured by specific immunoradiometric assays and insulin and C-peptide measured by radioimmunoassay were measured during a constant infusion of glucose test in ten diet-treated subjects with a history of Type 2 (non-insulin-dependent) diabetes (termed diabetic subjects), mean fasting plasma glucose 6.0 +/- 1.0 mmol/l (mean +/- SD), and 12 non-diabetic control subjects. Immunoreactive insulin concentrations measured by radioimmunoassay were 33% higher than insulin and 16% higher than the sum of insulin and its precursors by immunoradiometric assay. The diabetic and non-diabetic subjects had similar fasting concentrations of insulin, intact proinsulin and 32-33 split proinsulin. The ratio of fasting intact proinsulin to total insulin was greater in the diabetic than the non-diabetic group 12.0% (6.8-21.0%, 1 SD range) and 6.3% (4.0-9.8%), respectively, p less than 0.01), though the groups overlapped substantially. After glucose infusion, diabetic and non-diabetic subjects had similar intact proinsulin concentrations (geometric mean 4.9 and 5.2 pmol/l, respectively), but the diabetic group had impaired insulin secretion by immunoradiometric assay (geometric means 55 and 101 pmol/l, p less than 0.05) or by radioimmunoassay C-peptide (geometric means 935 and 1410 pmol/l, p less than 0.05), though not by radioimmunoassay insulin (87 and 144 pmol/l, p = 0.12), respectively. Individual immunoradiometric assay insulin responses to glucose expressed in terms of obesity were subnormal in nine of ten diabetic subjects. Radioimmunoassay insulin and C-peptide gave less complete discrimination (subnormal responses in six of ten and eight of ten, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


Failure of third ventriculostomy in the treatment of aqueductal stenosis in children.
The goal of this study was to analyze the types of failure and long-term efficacy of third ventriculostomy in children. The authors retrospectively analyzed clinical data obtained in 213 children affected by obstructive triventricular hydrocephalus who were treated by third ventriculostomy between 1973 and 1997. There were 120 boys and 93 girls. The causes of the hydrocephalus included: aqueductal stenosis in 126 cases; toxoplasmosis in 23 cases, pineal, mesencephalic, or tectal tumor in 42 cases; and other causes in 22 cases. In 94 cases, the procedure was performed using ventriculographic guidance (Group I) and in 119 cases by using endoscopic guidance (Group II). In 19 cases (12 in Group I and seven in Group II) failure was related to the surgical technique. Three deaths related to the technique were observed in Group I. For the remaining patients, Kaplan-Meier survival analysis showed a functioning third ventriculostomy rate of 72% at 6 years with a mean follow-up period of 45.5 months (range 4 days-17 years). No significant differences were found during long-term follow up between the two groups. In Group I, a significantly higher failure rate was seen in children younger than 6 months of age, but this difference was not observed in Group II. Thirty-eight patients required reoperation (21 in Group I and 17 in Group II) because of persistent or recurrent intracranial hypertension. In 29 patients shunt placement was necessary. In nine patients in whom there was radiologically confirmed obstruction of the stoma, the third ventriculostomy was repeated; this was successful in seven cases. Cine phase-contrast (PC) magnetic resonance (MR) imaging studies were performed in 15 patients in Group I at least 10 years after they had undergone third ventriculostomy (range 10-17 years, median 14.3 years); this confirmed long-term patency of the stoma in all cases. Third ventriculostomy effectively controls obstructive triventricular hydrocephalus in more than 70% of children and should be preferred to placement of extracranial cerebrospinal shunts in this group of patients. When performed using ventriculographic guidance, the technique has a higher mortality rate and a higher failure rate in children younger than 6 months of age and is, therefore, no longer preferred. When third ventriculostomy is performed using endoscopic guidance, the same long-term results are achieved in children younger than 6 months of age as in older children and, thus, patient age should no longer be considered as a contraindication to using the technique. Delayed failures are usually secondary to obstruction of the stoma and often can be managed by repeating the procedure. Midline sagittal T2-weighted MR imaging sequences combined with cine PC MR imaging flow measurements provide a reliable tool for diagnosis of aqueductal stenosis and for ascertaining the patency of the stoma during follow-up evaluation.


Collaborative Cross and Diversity Outbred data resources in the Mouse Phenome Database.
The Mouse Phenome Database was originally conceived as a platform for the integration of phenotype data collected on a defined collection of 40 inbred mouse strains--the "phenome panel." This model provided an impetus for community data sharing, and integration was readily achieved through the reproducible genotypes of the phenome panel strains. Advances in the development of mouse populations lead to an expanded role of the Mouse Phenome Database to encompass new strain panels and inbred strain crosses. The recent introduction of the Collaborative Cross and Diversity Outbred mice, which share an extensive pool of genetic variation from eight founder inbred strains, presents new opportunities and challenges for community data resources. A wide variety of molecular and clinical phenotypes are being collected across genotypes, tissues, ages, environmental exposures, interventions, and treatments. The Mouse Phenome Database provides a framework for retrieval, integration, analysis, and display of these data, enabling them to be evaluated in the context of existing data from standard inbred strains. Primary data in the Mouse Phenome Database are supported by extensive metadata on protocols and procedures. These are centrally curated to ensure accuracy and reproducibility and to provide data in consistent formats. The Mouse Phenome Database represents an established and growing community data resource for mouse phenotype data and encourages submissions from new mouse resources, enabling investigators to integrate existing data into their studies of the phenotypic consequences of genetic variation.


Melatonin for pre-medication in children: a systematic review.
Melatonin's effectiveness as an anxiolytic medication has been confirmed in adults; however, its efficacy in a paediatric population is unclear. A number of small studies have assessed its use in children as a pre-operative anxiolytic, with conflicting results. We undertook a systematic review of pre-operative melatonin use in children. Four databases (MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Web of Science), and ' ClinicalTrials.gov ' were searched for ongoing and completed clinical trials of relevance. Citation tracking reference lists and relevant articles were also accessed. The review was unrestricted by comparator or outcomes. Eleven studies were judged eligible for inclusion. There were high levels of heterogeneity in melatonin administration (in terms of dose and timing). Variable outcomes were reported and included: anxiety; anaesthetic success; analgesia; sedation; post-operative recovery; and safety. Outcomes were not always assessed with the same measures. Evidence to support melatonin's anxiolytic properties in this setting is conflicting. Melatonin was associated with reduced sedative effects, post-operative excitement and improved emergence behaviour, compared to comparator drugs. One study reported the benefit of melatonin use on sleep disturbance at two weeks post-surgery. No adverse safety events were identified to be significantly associated with melatonin, affirming its excellent safety profile. Despite potential advantages, including improved emergence behaviour, based on current evidence we cannot confirm whether melatonin is non-inferior to current "usual care" pre-medications. Further consideration of melatonin as an anxiolytic pre-medication in paediatric surgery is needed.


Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging.
Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin (Ghrl), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that Ghrl(-/-) mice have impaired thermoregulatory responses to cold and fasting stresses, while Ghsr(-/-) mice are adaptive. To elucidate the mechanism, we analyzed the complete metabolic profiles of younger (3-4 months) and older (10-12 months) Ghrl(-/-) and Ghsr(-/-) mice. Food intake and locomotor activity were comparable for both null mice and their wild-type (WT) counterparts, regardless of age. There was also no difference in body composition between younger null mice and their WT counterparts. As the WT mice aged, as expected, the fat/lean ratio increased and energy expenditure (EE) decreased. Remarkably, however, older Ghsr(-/-) mice exhibited reduced fat/lean ratio and increased EE when compared to older WT mice, thus retaining a youthful lean and high EE phenotype; in comparison, there was no significant difference with EE in Ghrl(-/-) mice. In line with the EE data, the thermogenic regulator, uncoupling protein 1 (UCP1), was significantly up-regulated in brown adipose tissue (BAT) of Ghsr(-/-) mice, but not in Ghrl(-/-) mice. Our data therefore suggest that GHS-R ablation activates adaptive thermogenic function(s) in BAT and increases EE, thereby enabling the retention of a lean phenotype. This is the first direct evidence that the ghrelin signaling pathway regulates fat-burning BAT to affect energy balance during aging. This regulation is likely mediated through an as-yet-unidentified new ligand of GHS-R.


Sucralfate versus histamine 2 receptor antagonists for stress ulcer prophylaxis in adult critically ill patients: A meta-analysis and trial sequential analysis of randomized trials.
To determine the impact of using sucralfate versus H2RAs for SUP on patient important outcomes. We searched CENTRAL, MEDLINE, EMBASE, ACPJC, clinical trials registries, and conference proceedings through June 2016 for randomized controlled trials (RCTs) comparing sucralfate to H2RAs for SUP in adult critically ill patients. 21 RCTs enrolling 3121 patients met inclusion criteria. There was no significant difference between sucralfate compared to H2RAs in the risk of clinically important GI bleeding (risk ratio [RR] 1.19; 95% CI [confidence interval] 0.79, 1.80; P=0.42; I2=0%; low quality evidence). However, there was a statistically significant lower risk of ICU acquired pneumonia with sucralfate compared to H2RAs (RR 0.84; 95% CI 0.72, 0.98; P=0.03; I2=0%; moderate quality evidence). Sucralfate did not significantly affect the risk of death (RR 0.95; 95% CI 0.82, 1.10; P=0.51; I2=0%; high quality evidence), or duration of ICU stay in days (mean difference-0.39; 95% CI [-1.12, 0.34]; P=0.29; I2=0%; moderate quality evidence). Trial sequential analysis adjusted estimates were consistent with conventional estimates. Moderate quality evidence suggests that sucralfate reduced ICU acquired pneumonia compared to H2RAs in adult critically ill patients, with no significant impact on GI bleeding or death.


Evaluating the national multisite implementation of dialectical behaviour therapy in a community setting: a mixed methods approach.
The implementation of evidence-based interventions for borderline personality disorder in community settings is important given that individuals with this diagnosis are often extensive users of both inpatient and outpatient mental health services. Although work in this area is limited, previous studies have identified facilitators and barriers to successful DBT implementation. This study seeks to expand on previous work by evaluating a coordinated implementation of DBT in community settings at a national level. The Consolidated Framework for Implementation Research (CFIR) (Damschroder et al., Implementation Sci. 4:50, 2009) provided structural guidance for this national level coordinated implementation. A mixed methods approach was utilised to explore the national multisite implementation of DBT from the perspective of team leaders and therapists who participated in the coordinated training and subsequent implementation of DBT. Qualitative interviews with DBT team leaders (n = 8) explored their experiences of implementing DBT in their local service and was analysed using content analysis. Quantitative surveys from DBT therapists (n = 74) examined their experience of multiple aspects of the implementation process including orienting the system, and preparations and support for implementation. Frequencies of responses were calculated. Written qualitative feedback was analysed using content analysis. Five themes were identified from the interview data: team formation, implementation preparation, client selection, service level challenges and team leader role. Participants identified team size and support for the team leader as key points for consideration in DBT implementation. Key challenges encountered were the lack of system support to facilitate phone coaching and a lack of allocated time to focus on DBT. Implementation facilitators included having dedicated team members and support from management. The barriers and facilitators identified in this study are broadly similar to those reported in previous research. Barriers and facilitators were identified across several domains of the CFIR and are consistent with a recently published DBT implementation Framework (Toms et al., Borderline Personal Disord Emot Dysregul. 6: 2, 2019). Future research should pay particular attention to the domain of characteristics of individuals involved in DBT implementation. The results highlight the importance of a mandated service plan for the coordinated implementation of an evidence-based treatment in a public health service. ClinicalTrials.gov ID: NCT03180541; Registered June 7th 2017 'retrospectively registered'.


Size-related third-order optical nonlinearities of Au nanoparticle arrays.
We report a systematic study of the size-related nonlinear optical properties of triangular Au particles. The triangular Au nanoparticle arrays of four sizes (37 nm, 70 nm, 140 nm and 190 nm) were fabricated on quartz substrates using nanosphere lithography. By performing the Z-scan method with femtosecond laser (800 nm, 50 fs), the optical nonlinearities of Au nanoparticle arrays were determined. The results showed a size-related competition between two mechanisms of groundstate bleaching and two-photon absorption. As the size increased, the nonlinear absorption changed from two-photon absorption to saturated absorption, while the nonlinear refraction changed from self-defocusing to self-focusing. These size-tunable nonlinearities make it possible to optimize the one- and two-photon figures of merit, W and T, for all-optical switching.


Inherent optical properties of the ocean: retrieval of the absorption coefficient of chromophoric dissolved organic matter from airborne laser spectral fluorescence measurements.
The absorption coefficient of chromophoric dissolved organic matter (CDOM) at 355 nm has been retrieved from airborne laser-induced and water Raman-normalized CDOM fluorescence. Four combined airborne and ship field experiments have demonstrated that (1) the airborne CDOM fluorescence-to--water Raman ratio is linearly related to concurrent quinine-sulfate-standardized CDOM shipboard fluorescence measurements over a wide range of water masses (coastal to blue water); (2) the vicarious calibration of the airborne fluorosensor in units traceable to a fluorescence standard can be established and then maintained over an extended time period by tungsten lamp calibration; (3) the vicariously calibrated airborne CDOM fluorescence-to-water Raman ratio can be directly applied to previously developed shipboard fluorescence-to-absorption algorithms to retrieve CDOM absorption; and (4) the retrieval is not significantly affected by long-path multiple scattering, differences in attenuation at the excitation and emission wavelengths, or measurement in the 180° backscatter configuration. Airborne CDOM absorption measurements will find immediate application to (a) forward and inverse modeling of oceanic water-leaving radiance and (b) validation of satellite-retrieved products such as CDOM absorption.


Using WhatsApp messenger for health systems research: a scoping review of available literature.
Globally, the use of mobile phones for improving access to healthcare and conducting health research has gained traction in recent years as rates of ownership increase, particularly in low- and middle-income countries (LMICs). Mobile instant messaging applications, including WhatsApp Messenger, provide new and affordable opportunities for health research across time and place, potentially addressing the challenges of maintaining contact and participation involved in research with migrant and mobile populations, for example. However, little is known about the opportunities and challenges associated with the use of WhatsApp as a tool for health research. To inform our study, we conducted a scoping review of published health research that uses WhatsApp as a data collection tool. A key reason for focusing on WhatsApp is the ability to retain contact with participants when they cross international borders. Five key public health databases were searched for articles containing the words 'WhatsApp' and 'health research' in their titles and abstracts. We identified 69 articles, 16 of which met our inclusion criteria for review. We extracted data pertaining to the characteristics of the research. Across the 16 studies—11 of which were based in LMICs—WhatsApp was primarily used in one of two ways. In the eight quantitative studies identified, seven used WhatsApp to send hyperlinks to online surveys. With one exception, the eight studies that employed a qualitative (n = 6) or mixed-method (n = 2) design analysed the WhatsApp content generated through a WhatsApp-based programmatic intervention. We found a lack of attention paid to research ethics across the studies, which is concerning given the controversies WhatsApp has faced with regard to data protection in relation to end-to-end encryption. We provide recommendations to address these issues for researchers considering using WhatsApp as a data collection tool over time and place.


Human Papillomavirus (HPV) Infection in Early Pregnancy: Prevalence and Implications.
Young women (20-35 years) are at high risk of HPV infection, although the majority of the infections are asymptomatic and are cleared spontaneously by the host immune system. These are also the group of women who are sexually active and are in the population of pregnant women. During pregnancy, the changes in the hormonal milieu and immune response may favor persistence of HPV infection and may aid in transgenerational transmission thereby furthering the cancer risk. In the present study, we determined the prevalence of vaginal HPV infection in early pregnancy and attempted to relate with pregnancy outcome. Vaginal cytology samples were collected from the condoms used to cover the vaginal sonography probe during a routine first trimester visit to the hospital. All women were followed up throughout pregnancy and childbirth. Maternal and neonatal outcomes were recorded. We found a prevalence of HPV infection around 39.4% in our population. Interestingly all HPV positive women were infected with one or more high risk HPV viruses with an overlap of intermediate and low risk in 43% and 7.3%, respectively. Women with preterm prelabor rupture of membranes (PPROM) showed a statistically higher incidence in HPV positive (7.3%) group as compared to the HPV negative (3.2%) group. The prevalence of genital HPV infection is high during pregnancy (around 40%) and was associated with higher incidence of PPROM.


Mortality among residents of Uravan, Colorado who lived near a uranium mill, 1936-84.
A cohort mortality study was conducted of all adult residents who ever lived in Uravan, Colorado, a company town built around a uranium mill. Vital status was determined through 2004 and standardised mortality analyses conducted for 1905 men and women alive after 1978 who lived for at least 6 months between 1936 and 1984 in Uravan. Overall, mortality from all causes (standardised mortality ratio (SMR) 0.90) and all cancers (SMR 1.00) was less than or as expected based on US mortality rates. Among the 459 residents who had worked in underground uranium mines, a significant increase in lung cancer was found (SMR 2.00; 95% CI 1.39-2.78). No significant elevation in lung cancer was seen among the 767 female residents of Uravan or the 622 uranium mill workers. No cause of death of a priori interest was significantly increased in any group, i.e. cancers of the kidney, liver, breast, lymphoma or leukaemia or non-malignant respiratory disease, renal disease or liver disease. This community cohort study revealed a significant excess of lung cancer among males who had been employed as underground miners. We attribute this excess to the historically high levels of radon in uranium mines of the Colorado Plateau, coupled with the heavy use of tobacco products. There was no evidence that environmental radiation exposures above natural background associated with the uranium mill operations increased the risk of cancer. Although the population studied was relatively small, the follow-up was long, extending up to 65 years after first residence in Uravan, and nearly half of the study subjects had died.


Positron emission tomography-computed tomography compared with invasive mediastinal staging in non-small cell lung cancer: results of mediastinal staging in the early lung positron emission tomography trial.
Patients with non-small cell lung cancer (NSCLC) require careful preoperative staging to define resectability for potential cure. Fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET-CT) is widely used to stage NSCLC. If the mediastinum is positive on PET-CT examination, some practitioners conclude that the patient is inoperable and refer the patient for nonsurgical treatment. In this analysis of a previously reported trial comparing PET-CT with conventional imaging in the diagnostic work-up of patients with clinical stage I, II, or IIIA NSCLC, we determined the accuracy of PET-CT in mediastinal staging compared with invasive mediastinal staging either by mediastinoscopy alone or by mediastinoscopy combined with thoracotomy. All 149 patients had mediastinal nodal staging at mediastinoscopy alone (14), thoracotomy alone (64), or both (71). The sensitivity of PET-CT was 70% (95% confidence interval [CI], 48-85%), and specificity was 94% (95% CI, 88-97%). Of 22 patients with a PET-CT interpreted as positive for mediastinal nodes, 8 did not have tumor. The positive predictive value and negative predictive value were 64% (95% CI, 43-80%) and 95% (95% CI, 90-98%), respectively. Based on PET-CT alone, eight patients would have been denied potentially curative surgery if the mediastinal abnormalities detected by PET-CT had not been evaluated with an invasive mediastinal procedure. PET-CT assessment of the mediastinum is associated with a clinically relevant false-positive rate. Our study confirms the need for pathologic confirmation of mediastinal lymph node abnormalities detected by PET-CT.


State of the APC/C: organization, function, and structure.
The ubiquitin-proteasome protein degradation system is involved in many essential cellular processes including cell cycle regulation, cell differentiation, and the unfolded protein response. The anaphase-promoting complex/cyclosome (APC/C), an evolutionarily conserved E3 ubiquitin ligase, was discovered 15 years ago because of its pivotal role in cyclin degradation and mitotic progression. Since then, we have learned that the APC/C is a very large, complex E3 ligase composed of 13 subunits, yielding a molecular machine of approximately 1 MDa. The intricate regulation of the APC/C is mediated by the Cdc20 family of activators, pseudosubstrate inhibitors, protein kinases and phosphatases and the spindle assembly checkpoint. The large size, complexity, and dynamic nature of the APC/C represent significant obstacles toward high-resolution structural techniques; however, over the last decade, there have been a number of lower resolution APC/C structures determined using single particle electron microscopy. These structures, when combined with data generated from numerous genetic and biochemical studies, have begun to shed light on how APC/C activity is regulated. Here, we discuss the most recent developments in the APC/C field concerning structure, substrate recognition, and catalysis.


Meta-analyses with industry involvement are massively published and report no caveats for antidepressants.
To identify the impact of industry involvement in the publication and interpretation of meta-analyses of antidepressant trials in depression. Using MEDLINE, we identified all meta-analyses evaluating antidepressants for depression published in January 2007-March 2014. We extracted data pertaining to author affiliations, conflicts of interest, and whether the conclusion of the abstract included negative statements on whether the antidepressant(s) were effective or safe. We identified 185 eligible meta-analyses. Fifty-four meta-analyses (29%) had authors who were employees of the assessed drug manufacturer, and 147 (79%) had some industry link (sponsorship or authors who were industry employees and/or had conflicts of interest). Only 58 meta-analyses (31%) had negative statements in the concluding statement of the abstract. Meta-analyses including an author who were employees of the manufacturer of the assessed drug were 22-fold less likely to have negative statements about the drug than other meta-analyses [1/54 (2%) vs. 57/131 (44%); P < 0.001]. There is a massive production of meta-analyses of antidepressants for depression authored by or linked to the industry, and they almost never report any caveats about antidepressants in their abstracts. Our findings add a note of caution for meta-analyses with ties to the manufacturers of the assessed products.


Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment.
The NGFI-B (Nur77) subfamily of orphan nuclear receptors (NRs), which also includes Nurr1 and NOR1, bind the NurRE regulatory element as either homo- or heterodimers formed between subfamily members. These NRs mediate the activation of pituitary proopiomelanocortin (POMC) gene transcription by the hypothalamic hormone corticotropin-releasing hormone (CRH), an important link between neuronal and endocrine components of the hypothalamo-pituitary-adrenal axis. CRH effects on POMC transcription do not require de novo protein synthesis. We now show that CRH signals activate Nur factors through the cyclic AMP/protein kinase A (PKA) pathway. CRH and PKA rapidly increase nuclear DNA binding activity of NGFI-B dimers but not monomers. Accordingly, CRH- or PKA-activated Nur factors enhance dimer (but not monomer) target response elements. We also show that p160/SRC coactivators are recruited to Nur dimers (but not to monomers) and that coactivator recruitment to the NurRE is enhanced in response to CRH. Moreover, PKA- and coactivator-induced potentiation of NGFI-B activity are primarily exerted through the N-terminal AF-1 domain of NGFI-B. The TIF2 (SRC-2) glutamine-rich domain is required for this activity. Taken together, these results indicate that Nur factors behave as endpoint effectors of the PKA signaling pathway acting through dimers and AF-1-dependent recruitment of coactivators.


The Hippo size control pathway--ever expanding.
An important regulator of organ size and tumorigenesis is the Hippo pathway. Recent studies have unveiled increasing complexity in regulation of Hippo pathway activity at the level of the oncoprotein Yes-associated protein (YAP). The protein tyrosine phosphatase 14 (PTPN14, known as Pez in Drosophila) was identified as a protein that antagonizes the function of the key Hippo pathway protein YAP by promoting its cytoplasmic localization under high cell density conditions. In Drosophila, Pez was identified as a repressor of epithelial proliferation in vivo. Studies in mammalian cells showed that a family of G protein-coupled receptors, the protease-activated receptors, functioned as activators of YAP. These studies shed light on the intricate regulation of the Hippo pathway and also highlight the importance of investigating these newly discovered regulatory links in physiological and pathological settings to fully appreciate their importance.


First Report of Potato Stem Canker Caused by Rhizoctonia solani AG4 HGII in Gansu Province, China.
Black scurf and stem canker on potato (Solanum tuberosum L.), caused by Rhizoctonia solani, is an important disease throughout the world. Isolates of R. solani AG3 are the principal cause of these diseases on potato (2). In August 2011, at the tuber bulking growth stage, symptoms typically associated stem canker, including dark brown stem lesions, were observed on 20% of potato plants collected from 23 locations (about 2,000 ha) in Gansu Province, northwest China. Stem pieces (each 5 mm long) taken from the margins of the healthy and diseased tissues were surface-disinfected with 0.5% NaOCl for 2 min, rinsed with sterilized water, dried, then placed on potato dextrose agar (PDA) at 25°C in the dark. Twenty-nine fungal isolates taken from single hyphal tips were identified as R. solani based on morphological traits, including mycelium branched at right angles with a septum near the branch and a slight constriction at the branch base. Hyphal cells were determined to be multinucleate (4 to 10 nuclei/cell) when stained with 4'-6-diamidino-2-phenylindole (DAPI). Anastomosis groups were determined by pairing with reference strains (kindly provided by N. Kondo, Hokkaido University, Japan), and three isolates (designed GS-15, GS-24, and GS-25) anastomosed with isolates of R. solani AG4. The internal transcribed spacer (ITS) region of rDNA was amplified from genomic DNA of each of the three isolates with primers ITS1 and ITS4. The resulting sequences (GenBank Accession Nos. JX843818, JX843819, and JX843820) were 100% identical to those of >10 R. solani AG4 HGII isolates (e.g., HQ629873.1; isolate ND13). Therefore, based on the anastomosis assay and molecular characteristics, the three isolates were identified as R. solani AG4 HGII. To determine pathogenicity of the AG4 HGII isolates, potato seed tubers (cv. Favorita) with 3 to 5 mm long sprouts were inoculated with wheat seeds (sterilized by autoclaving twice at 121°C for 1 h with a 24 h interval between autoclavings) colonized with each isolate (1). One sprouted tuber was planted in a sterilized plastic pot (1 liter) with a single colonized wheat seed placed 10 mm above the uppermost sprout tip in a sand/sawdust mixture (1:2 v/v, with dry heat sterilization at 161°C for 4 h before use). Plants were incubated in a glasshouse maintained at 25 to 27°C. The test was performed on 20 plants for each isolate, and the experiment was repeated. After 3 weeks, control plants inoculated with sterilized wheat seeds remained asymptomatic, and no Rhizoctonia spp. were isolated from these plants, whereas all inoculated plants showed symptoms of stem canker. R. solani AG4 HGII was reisolated consistently from symptomatic stems, and the identity of the reisolates confirmed by the morphological and molecular characteristics mentioned above, fulfilling Koch's postulates. Potato stem canker caused by R. solani AG4 HGII was reported previously in the United States (3). To our knowledge, this is the first report of R. solani AG4 HGII causing stem canker on potato in Gansu Province, the main potato-producing area of China. R. solani AG4 HGII can cause sheath blight on corn in China (4), which is commonly grown in rotation with potato. This rotation could increase the risk of soilborne infection to either crop by R. solani AG4 HGII. References: (1) M. J. Lehtonen et al. Plant Pathol. 57:141, 2008. (2) L. Tsror. J. Phytopathol. 158:649, 2010. (3) J. W. Woodhall et al. Plant Dis. 96:1701, 2012. (4) X. Zhou et al. J. Shenyang Agric. Univ. 43:33, 2012.


Prognostic stratification in critically ill patients with acute renal failure requiring dialysis.
Despite the widespread availability of dialytic and intensive care unit technology, the probability of early mortality in critically ill persons with acute renal failure is distressingly high. Previous efforts to predict outcome in this population have been limited by small sample size and the absence of uniform exclusion criteria. Additionally, data obtained decades ago may not apply today owing to changes in case mix. The medical records of 132 consecutive patients in the intensive care unit with acute renal failure who required dialysis from 1991 through 1993 were evaluated by a blinded reviewer. The overall in-hospital mortality rate was 70%. Twelve readily available historical, clinical, and laboratory variables were significantly associated with in-hospital mortality. Multivariate logistic regression analysis showed that mechanical ventilation, malignancy, and nonrespiratory organ system failure were independently associated with in-hospital mortality. Using a 95% positivity criterion, this model identified 24% of high-risk patients who died, without misclassification of any survivors. Of those who survived to hospital discharge, 33% were dialysis dependent and 28% were institutionalized long-term. Among critically ill patients, acute renal failure requiring dialysis is an ominous condition with a high risk of in-hospital mortality. This risk appears to depend largely on comorbid conditions, such as the need for mechanical ventilation and underlying malignancy. While this prognostic model requires prospective validation, it appears to identify a substantial fraction of patients for whom dialysis may be of limited or no benefit.


Inhibition of kinesin motor proteins by adociasulfate-2.
Kinesin motor proteins are involved in cell division and intracellular transport of vesicles and organelles, and as such, they play a role in neurological disease, cancer, and developmental disorders. Inhibitors of kinesin would be valuable as probes of cell physiology and as potential therapeutics. Adociasulfate-2 (AS-2) is the only known natural product inhibitor of kinesins, but its mechanism of action is unknown. We utilized kinetic studies, dynamic light scattering, and transmission electron microscopy to investigate the inhibitory action of AS-2. Our data suggest that AS-2 is not a classical 1:1 inhibitor. Instead, a rodlike aggregate that mimics microtubules is complexed with kinesin and inhibits its ATPase activity. An intriguing implication of this hypothesis is that aggregates of a chiral natural product can have interesting and biologically relevant properties. This mode of action might represent one way in which a small molecule can disrupt a protein-protein interaction.


A Biomechanical Examination of Prefabricated Total Contact Cast Kits: Relevance to Patients With Diabetic Neuropathy.
The traditional Total Contact Cast (TCC) is considered the gold standard for treating plantar diabetic ulcers. A number of prefabricated TCC kits have been introduced, which offer a user-friendly casting process for health care providers. Our objective was to evaluate pressure reduction and gait characteristics after application of a TCC kit (TCC-EZ) and traditional TCC. Fifteen individuals (9 males, 6 females; median age of 51.5 years [range = 40.5-71.2 years]) completed 30-m walking trials while fitted with TCC-EZ and TCC in a randomized order. A pair of automated wireless photogate sensors captured time to traverse the distance and pedobarographic insoles measured and recorded plantar pressures. Paired t tests were used to compare peak pressure, gait speed, and cast weights across the 2 modalities. Peak pressure and cast weight were significantly lower in the TCC-EZ arm (169.6 ± 41.3 kPa vs 214.9 ± 63.2 kPa, P = .0048; and 1.79 ± 0.17 kg vs 2.11 ± 0.25 kg, P = .0004). Contact area and gait speed were not significantly different between the 2 modalities (140.4 ± 25.8 cm2 vs 126.9 ± 37.8 cm2, P = .0228, Cohen's d = 0.40; and 0.94 ± 0.19 m/s vs 0.83 ± 0.26 m/s, P = .0532, Cohen's d = .48). TCC-EZ was found to provide more favorable pressure distributions compared with TCC. TCC-EZ is also lighter and may be a preferred treatment modality for patients. More research is necessary to reveal the clinical effectiveness of prefabricated total contact kits.


Assembling the 20 Gb white spruce (Picea glauca) genome from whole-genome shotgun sequencing data.
White spruce (Picea glauca) is a dominant conifer of the boreal forests of North America, and providing genomics resources for this commercially valuable tree will help improve forest management and conservation efforts. Sequencing and assembling the large and highly repetitive spruce genome though pushes the boundaries of the current technology. Here, we describe a whole-genome shotgun sequencing strategy using two Illumina sequencing platforms and an assembly approach using the ABySS software. We report a 20.8 giga base pairs draft genome in 4.9 million scaffolds, with a scaffold N50 of 20,356 bp. We demonstrate how recent improvements in the sequencing technology, especially increasing read lengths and paired end reads from longer fragments have a major impact on the assembly contiguity. We also note that scalable bioinformatics tools are instrumental in providing rapid draft assemblies. The Picea glauca genome sequencing and assembly data are available through NCBI (Accession#: ALWZ0100000000 PID: PRJNA83435). http://www.ncbi.nlm.nih.gov/bioproject/83435.


Association between PM10 and respiratory hospital admissions in different seasons in heavily polluted Lanzhou City.
Exposure-response relationship between particulate matter less than 10 μm in diameter (PM10) and human health in different seasons from 2001 to 2005 was examined based on hospital admissions data of respiratory system diseases from four major hospitals in Lanzhou, China. To quantify associations of respiratory system diseases with multiple air pollutants and meteorological conditions, a semiparametric generalized additive model was used in the authors' study by implementing daily ambient sulfur dioxide, nitrogen dioxide, and PM10 data collected from the Lanzhou Environmental Monitoring Station and daily meteorological data from Lanzhou Meteorological Bureau. Results showed that daily averaged PM10 increased per interquartile range the hospital admissions number of respiratory diseases by 3.3% in spring, 1.4% in summer, 3.6% in autumn, and 4.0% in winter from a single-pollutant model, or 3.1%, 1.4%, 3.0%, and 4.0% from a multi-pollutant model, respectively. The effect of PM10 on respiratory hospital admissions was lowest in summer and highest in winter. The relative risks of PM10 on female or the elderly (≥ 65 yrs.) were higher, showing a stronger association of PM10 with respiratory diseases in female and elderly groups than in males and people younger than 65.


N-cadherin is differentially expressed in histological subtypes of papillary renal cell carcinoma.
Papillary renal cell carcinoma (RCC) represents a rare tumor, which is divided, based on histological criteria, into two subtypes. In contrast to type I papillary RCC type II papillary RCC shows a worse prognosis. So far, reliable immunohistochemical markers for the distinction of these subtypes are not available. In the present study the expression of N(neural)-, E(epithelial)-, P(placental)-, and KSP(kidney specific)-cadherin was examined in 22 papillary RCC of histological type I and 18 papillary RCC of histological type II (n = 40). All papillary RCC type II displayed a membranous expression for N-cadherin, whereas type I did not show any membranous positivity for N-cadherin. E-cadherin exhibited a stronger, but not significant, membranous as well as cytoplasmic expression in type II than in type I papillary RCC. A diagnostic relevant expression of P- and KSP-cadherin could not be demonstrated in both tumor entities. Thus N-cadherin represents the first immunhistochemical marker for a clear cut differentiation between papillary RCC type I and type II and could be a target for therapy and diagnostic in the future. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2011556982761733.


Synthetic manipulations of polyunsaturated fatty acids as a convenient strategy for the synthesis of bioactive compounds.
Stereoselective synthesis of Z-configured double bonds is central in organic synthesis due to the presence of such motifs in polyunsaturated fatty acids and many natural products. Traditionally, reductions of internal alkynes or Wittig, Ando or Still-Gennari reactions, are often used for preparing such compounds. The substrate scope is limited for both the Ando and the Still-Gennari reactions, while the Wittig reaction often gives low Z-selectivity for the synthesis of polyunsaturated Z-configured methylene interrupted (skipped) double bonds. Reductions of internal alkynes are challenging due to diminished Z-selectivity, poor catalyst reproducibility and over-reductions. An alternative and highly attractive approach is to employ naturally occurring and commercially available polyunsaturated fatty acids as starting materials. The main advantage of this strategy is the conservation of the multiple Z-configured double bonds present in the starting material, allowing a precise incorporation of the desired double bonds into the final product. In particular, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid have been used for the stereoselective synthesis of polyunsaturated fatty acids, their derivatives and other polyunsaturated natural products. Herein, such efforts are reviewed.


Dental implants in patients affected by systemic diseases.
Several systemic diseases (and relative medications) have been reported to impair or in some cases complicate dental implant surgery. In broader terms, when dealing with patients suffering from systemic diseases, the monitoring of the medical condition and of the related post-operative complications is of great importance in order to avoid risks which could jeopardise the health of the patient. In this review, the available evidence on implant survival/success, as well as relevant surgical recommendations in patients affected by systemic diseases, are evaluated and when possible, practical suggestions for the clinician are provided.


Endoscope-Assisted Surgery for Petrous Bone Cholesteatoma with Hearing Preservation.
Petrous bone cholesteatoma is a rare pathologic entity and may be a difficult surgical challenge because of potential involvement of the facial nerve, carotid artery, dura mater, otic capsule and superior petrosal or lateral sinus. The objective of this article is to present the endoscope-assisted surgery for petrous bone cholesteatoma. Eight patients (nine ears) who underwent endoscope-assisted petrous bone surgery for cholesteatoma. Pure tone audiogram, magnetic resonance imaging were performed at preoperatively, and at approximately 12 months postoperatively. Endoscope assisted surgery was performed in 8 patients and 9 ears. Of these patients, 6 were male and 2 were females. Median age was 19,5 (range 7-52) years. Hearing was able to preserved in 8 ears (8/9). Recurrence disease was observed one ear in long term follow up (1/9). In another one patient, cholesteatoma pearl was removed in the office. Endoscope-assisted surgery can allow removal of cholesteatoma of petrous apex with preserving hearing. It also provides to remove the cholesteatoma via transmastoid approach for perilabyrinthine space as "minimally invasive surgery" instead of middle fossa approach that is standard surgical procedure. In apical and peri-labyrinthine cholesteatomas, endoscopes allow to preserve hearing with middle fossa approach instead of trans-otic/ trans-labyrinthine/trans-cochlear approach.


The Ankle Injury Management (AIM) trial: a pragmatic, multicentre, equivalence randomised controlled trial and economic evaluation comparing close contact casting with open surgical reduction and internal fixation in the treatment of unstable ankle fractures in patients aged over 60 years.
Close contact casting (CCC) may offer an alternative to open reduction and internal fixation (ORIF) surgery for unstable ankle fractures in older adults. We aimed to (1) determine if CCC for unstable ankle fractures in adults aged over 60 years resulted in equivalent clinical outcome compared with ORIF, (2) estimate cost-effectiveness to the NHS and society and (3) explore participant experiences. A pragmatic, multicentre, equivalence randomised controlled trial incorporating health economic evaluation and qualitative study. Trauma and orthopaedic departments of 24 NHS hospitals. Adults aged over 60 years with unstable ankle fracture. Those with serious limb or concomitant disease or substantial cognitive impairment were excluded. CCC was conducted under anaesthetic in theatre by surgeons who attended training. ORIF was as per local practice. Participants were randomised in 1 : 1 allocation via remote telephone randomisation. Sequence generation was by random block size, with stratification by centre and fracture pattern. Follow-up was conducted at 6 weeks and, by blinded outcome assessors, at 6 months after randomisation. The primary outcome was the Olerud-Molander Ankle Score (OMAS), a patient-reported assessment of ankle function, at 6 months. Secondary outcomes were quality of life (as measured by the European Quality of Life 5-Dimensions, Short Form questionnaire-12 items), pain, ankle range of motion and mobility (as measured by the timed up and go test), patient satisfaction and radiological measures. In accordance with equivalence trial US Food and Drug Administration guidance, primary analysis was per protocol. We recruited 620 participants, 95 from the pilot and 525 from the multicentre phase, between June 2010 and November 2013. The majority of participants, 579 out of 620 (93%), received the allocated treatment; 52 out of 275 (19%) who received CCC later converted to ORIF because of loss of fracture reduction. CCC resulted in equivalent ankle function compared with ORIF at 6 months {OMAS 64.5 points [standard deviation (SD) 22.4 points] vs. OMAS 66.0 points (SD 21.1 points); mean difference -0.65 points, 95% confidence interval (CI) -3.98 to 2.68 points; standardised effect size -0.04, 95% CI -0.23 to 0.15}. There were no differences in quality of life, ankle motion, pain, mobility and patient satisfaction. Infection and/or wound problems were more common with ORIF [29/298 (10%) vs. 4/275 (1%)], as were additional operating theatre procedures [17/298 (6%) vs. 3/275 (1%)]. Malunion was more common with CCC [38/249 (15%) vs. 8/274 (3%); p < 0.001]. Malleolar non-union was lower in the ORIF group [lateral: 0/274 (0%) vs. 8/248 (3%); p = 0.002; medial: 3/274 (1%) vs. 18/248 (7%); p < 0.001]. During the trial, CCC showed modest mean cost savings [NHS mean difference -£644 (95% CI -£1390 to £76); society mean difference -£683 (95% CI -£1851 to £536)]. Estimates showed some imprecision. Incremental quality-adjusted life-years following CCC were no different from ORIF. Over common willingness-to-pay thresholds, the probability that CCC was cost-effective was very high (> 95% from NHS perspective and 85% from societal perspective). Experiences of treatments were similar; both groups endured the impact of fracture, uncertainty regarding future function and the need for further interventions. Assessors at 6 weeks were necessarily not blinded. The learning-effect analysis was inconclusive because of limited CCC applications per surgeon. CCC provides a clinically equivalent outcome to ORIF at reduced cost to the NHS and to society at 6 months. Longer-term follow-up of trial participants is under way to address concerns over potential later complications or additional procedures and their potential to impact on ankle function. Further study of the patient factors, radiological fracture patterns and outcomes, treatment responses and prognosis would also contribute to understanding the treatment pathway. Current Controlled Trials ISRCTN04180738. The National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 75. See the NIHR Journals Library website for further project information. This report was developed in association with the National Institute for Health Research Oxford Biomedical Research Unit funding scheme. The pilot phase was funded by the AO Research Foundation.


Obstacle avoidance during online corrections.
The dorsal visual stream codes information crucial to the planning and online control of target-directed reaching movements in dynamic and cluttered environments. Two specific dorsally mediated abilities are the avoidance of obstacles and the online correction for changes in target location. The current study was designed to test whether or not both of these abilities can be performed concurrently. Participants made reaches to touch a target that, on two-thirds of the trials, remained stationary and on the other third "jumped" at movement onset. Importantly, on target-jump trials, a single object (in one of four positions) sometimes became an obstacle that interfered with the reach. When a target jump caused an object to suddenly become an obstacle, we observed clear spatial avoidance behavior, an effect that was not present when the target jumped but the object did not become an obstacle. This automatic spatial avoidance was accompanied by significant velocity reductions only when the risk for collision with the obstacle was high, suggesting an "intelligent" encoding of potential obstacle locations. We believe that this provides strong evidence that the entire workspace is encoded during reach planning and that the representation of all objects in the workspace is available to the automatic online correction system.


Working towards widening participation in nurse education.
The widening participation agenda has particular significance for worldwide nursing since it is a profession which is under increasing scrutiny in its recruitment and retention practices. Debate about this agenda within nurse education is strengthened by careful scrutiny of the research within the wider context of higher education, some of which challenges commonly held assumptions. This paper examines four areas of relevance to the UK widening participation agenda: disability, ethnicity, socioeconomic status and family responsibilities. Taken together, they indicate that nurse education operates within a particularly complex context with some important implications for the future design of pre-registration programmes. These complexities should be debated in depth by educational commissioners and providers, in tandem with regulatory bodies.


Stereoscopy in Dental Education: An Investigation.
The aim of this study was to investigate whether stereoscopy can play a meaningful role in dental education. The study used an anaglyph technique in which two images were presented separately to the left and right eyes (using red/cyan filters), which, combined in the brain, give enhanced depth perception. A positional judgment task was performed to assess whether the use of stereoscopy would enhance depth perception among dental students at Osaka University in Japan. Subsequently, the optimum angle was evaluated to obtain maximum ability to discriminate among complex anatomical structures. Finally, students completed a questionnaire on a range of matters concerning their experience with stereoscopic images including their views on using stereoscopy in their future careers. The results showed that the students who used stereoscopy were better able than students who did not to appreciate spatial relationships between structures when judging relative positions. The maximum ability to discriminate among complex anatomical structures was between 2 and 6 degrees. The students' overall experience with the technique was positive, and although most did not have a clear vision for stereoscopy in their own practice, they did recognize its merits for education. These results suggest that using stereoscopic images in dental education can be quite valuable as stereoscopy greatly helped these students' understanding of the spatial relationships in complex anatomical structures.


Olanzapine-induced diabetic ketoacidosis in a Chinese man.
We present a case report of a 22-year-old Chinese man with schizophrenia and dissocial personality disorder who was normoglycaemic before taking olanzapine. After commencing olanzapine he developed diabetic ketoacidosis and was managed in the intensive care unit of a general hospital. Olanzapine was stopped and replaced by haloperidol 5 mg/day. He was put on a strict 1500 kcal diabetic diet and required insulin injections to maintain a normal blood sugar level despite cessation of olanzapine for 4 months. Doctors prescribing olanzapine should be aware of the risk of diabetes mellitus. Baseline and regular monitoring of body weight, body mass index, and fasting blood glucose are essential to prevent serious consequences.


Honokiol enhances temozolomide-induced apoptotic insults to malignant glioma cells via an intrinsic mitochondrion-dependent pathway.
Temozolomide (TMZ) is a first-line chemotherapeutic drug for malignant gliomas. Nonetheless, TMZ-induced side effects and drug resistance remain challenges. Our previous study showed the suppressive effects of honokiol on growth of gliomas. This study was further aimed to evaluate if honokiol could enhance TMZ-induced insults toward malignant glioma cells and its possible mechanisms. Human U87 MG glioma cells were exposed to TMZ, honokiol, and a combination of TMZ and honokiol. Cell survival, apoptosis, necrosis, and proliferation were successively assayed. Fluorometric substrate assays were conducted to determine activities of caspase-3, -6, -8, and -9. Levels of Fas ligand, Bax, and cytochrome c were immunodetected. Translocation of Bax to mitochondria were examined using confocal microscopy. Mitochondrial function was evaluated by assaying the mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and complex I enzyme activity. Caspase-6 activity was suppressed using specific peptide inhibitors. The honokiol-induced effects were further confirmed using human U373 MG and murine GL261 cells. Exposure of human U87 MG glioma cells to honokiol significantly increased TMZ-induced DNA fragmentation and cell apoptosis. Interestingly, honokiol enhanced intrinsic caspase-9 activity without affecting extrinsic Fas ligand levels and caspase-8 activity. Sequentially, TMZ-induced changes in Bax translocation, the MMP, mitochondrial complex I enzyme activity, intracellular ROS levels, and cytochrome c release were enhanced by honokiol. Consequently, honokiol amplified TMZ-induced activation of caspases-3 and -6 in human U87 MG cells. Fascinatingly, suppressing caspase-6 activity concurrently decreased honokiol-induced DNA fragmentation and cell apoptosis. The honokiol-involved improvement in TMZ-induced intrinsic apoptosis was also confirmed in human U373 MG and murine GL261 glioma cells. This study showed that honokiol can enhance TMZ-induced apoptotic insults to glioma cells via an intrinsic mitochondrion-dependent mechanism. Our results suggest the therapeutic potential of honokiol to attenuate TMZ-induced side effects.


A simple Schiff base as dual-responsive fluorescent sensor for bioimaging recognition of Zn2+ and Al3+ in living cells.
A simple Schiff base fluorescent sensor (BDNOL) was synthesized from the reaction of picolinohydrazide and 4-(diethylamino)salicylaldehyde, and developed for selective detection of Al3+ and Zn2+. This non-fluorescent sensor displayed obvious fluorescence enhancement after binding to Al3+/Zn2+ ions with high sensitivity and selectivity, accompanied by obvious fluorescence emission enhancement (504 nm for Al3+ and 575 nm for Zn2+). The detection limits were found to be 8.30 × 10-8 M for Al3+ and 1.24 × 10-7 M for Zn2+. The binding mechanisms between BDNOL and Al3+/Zn2+ ions were supported by 1H NMR and HR-MS analysis, and a density functional theory (DFT) study. The sensing behavior was also studied with molecular logic functions of OR, AND, and NOT gates. Furthermore, the fluorescent sensor was successfully used to recognize Al3+ and Zn2+ in living cells, suggesting that this simple biosensor has great potential in biological imaging applications.


Determination of 4-hydroxyproline-2-epimerase activity by capillary electrophoresis: A stereoselective platform for inhibitor screening of amino acid isomerases.
Isomerases involved in the metabolism of D/L-amino acids represent promising therapeutic targets for treatment of disease. Herein, we report a tunable platform for the assessment of enzymatic kinetics involving amino acid isomerization by CE that offers improved selectivity and sensitivity over traditional methods. Enzyme activity and competition assays were evaluated for various hydroxyproline diastereoisomers, proline enantiomers and their structural analogs using 4-hydroxyproline-2-epimerase as a model system. In this work, pyrrole 2-carboxylic acid was found to be a selective inhibitor of 4-hydroxyproline-2-epimerase with a half-maximal inhibition concentration of (2.3 + or - 0.1) mM. Reliable methods for unambiguous characterization of amino acid isomerases are required for the screening of novel inhibitors with epimerase and/or racemase activity.


Recent Research on the Health Benefits of Blueberries and Their Anthocyanins.
Awareness of the human health benefits of blueberries is underpinned by a growing body of positive scientific evidence from human observational and clinical research, plus mechanistic research using animal and in vitro models. Blueberries contain a large number of phytochemicals, including abundant anthocyanin pigments. Of their various phytochemicals, anthocyanins probably make the greatest impact on blueberry health functionality. Epidemiological studies associate regular, moderate intake of blueberries and/or anthocyanins with reduced risk of cardiovascular disease, death, and type 2 diabetes, and with improved weight maintenance and neuroprotection. These findings are supported by biomarker-based evidence from human clinical studies. Among the more important healthful aspects of blueberries are their anti-inflammatory and antioxidant actions and their beneficial effects on vascular and glucoregulatory function. Blueberry phytochemicals may affect gastrointestinal microflora and contribute to host health. These aspects have implications in degenerative diseases and conditions as well as the aging process. More evidence, and particularly human clinical evidence, is needed to better understand the potential for anthocyanin-rich blueberries to benefit public health. However, it is widely agreed that the regular consumption of tasty, ripe blueberries can be unconditionally recommended.


Eye-like ocelloids are built from different endosymbiotically acquired components.
Multicellularity is often considered a prerequisite for morphological complexity, as seen in the camera-type eyes found in several groups of animals. A notable exception exists in single-celled eukaryotes called dinoflagellates, some of which have an eye-like 'ocelloid' consisting of subcellular analogues to a cornea, lens, iris, and retina. These planktonic cells are uncultivated and rarely encountered in environmental samples, obscuring the function and evolutionary origin of the ocelloid. Here we show, using a combination of electron microscopy, tomography, isolated-organelle genomics, and single-cell genomics, that ocelloids are built from pre-existing organelles, including a cornea-like layer made of mitochondria and a retinal body made of anastomosing plastids. We find that the retinal body forms the central core of a network of peridinin-type plastids, which in dinoflagellates and their relatives originated through an ancient endosymbiosis with a red alga. As such, the ocelloid is a chimaeric structure, incorporating organelles with different endosymbiotic histories. The anatomical complexity of single-celled organisms may be limited by the components available for differentiation, but the ocelloid shows that pre-existing organelles can be assembled into a structure so complex that it was initially mistaken for a multicellular eye. Although mitochondria and plastids are acknowledged chiefly for their metabolic roles, they can also be building blocks for greater structural complexity.


Challenges in conducting natural experiments in parks-lessons from the REVAMP study.
Experimental evidence on the role of the built environment for promoting physical activity is important for informing how to create cities that promote active living. Parks provide opportunities for physical activity; however, there is little robust evidence on the impact of park refurbishment. Government agencies often modify parks, providing opportunities for natural experiment studies of these interventions. Such an opportunity was provided by the modification of a large park in Victoria, Australia in 2013 when the Recording and EValuating Activity in a Modified Park (REVAMP) study was established. Based on insights from the REVAMP study, this paper discusses challenges involved in conducting natural experiments in park settings, focussing on issues that may help design more effective future evaluations of the impact of park refurbishment. Natural experiments offer unique opportunities to evaluate the impact of large-scale changes to the built environment. They provide valuable data that might not otherwise be possible to gather, because of the costs associated with modification of the environment. However, factors beyond the control of the study team contribute to the complexity of both organising and conducting natural experiments, with potential flow-on effects to the quality of data. Therefore many extraneous factors need to be considered when designing, costing and conducting natural experiments; studies should identify opportunities to include key partners from the inception of the project, be flexible yet robust, and allow sufficient funding to accommodate unexpected changes in the research protocol. Current controlled trial ISRCTN50745547 , registration date 11.1.2014.


Supersoft lithography: candy-based fabrication of soft silicone microstructures.
We designed a fabrication technique able to replicate microstructures in soft silicone materials (E < 1 kPa). Sugar-based 'hard candy' recipes from the confectionery industry were modified to be compatible with silicone processing conditions, and used as templates for replica molding. Microstructures fabricated in soft silicones can then be easily released by dissolving the template in water. We anticipate that this technique will be of particular importance in replicating physiologically soft, microstructured environments for cell culture, and demonstrate a first application in which intrinsically soft microstructures are used to measure forces generated by fibroblast-laden contractile tissues.


Risk factors for suicide, attitudes toward mental illness, and practice-related stressors among US veterinarians.
To evaluate the prevalence of suicide risk factors, attitudes toward mental illness, and practice-related stressors among US veterinarians. Cross-sectional survey. 11,627 US veterinarians. Between July 1 and October 20, 2014, a Web-based questionnaire was made available through the Veterinary Information Network (VIN), VIN News Service, JAVMA News, and email messages to US veterinarians sent by a veterinary medical association, agriculture or livestock department, or health department of each state (except Maine) and Puerto Rico. Of 11,627 respondents, 3,628 (31%) were male. Modal age category was 30 to 39 years, and modal range for years practicing veterinary medicine was 10 to 19 years. There were 7,460 (64%) respondents who primarily practiced small animal medicine, and 4,224 (36%) who were practice owners. There were 1,077 (9%) respondents with current serious psychological distress. Since leaving veterinary school, 3,655 (31%) respondents experienced depressive episodes, 1,952 (17%) experienced suicidal ideation, and 157 (1%) attempted suicide. Currently, 2,228 (19%) respondents were receiving treatment for a mental health condition. Only 3,250 of 10,220 (32%) respondents somewhat or strongly agreed that people are sympathetic toward persons with mental illness. The most commonly reported practice-related stressor was demands of practice. In this survey, approximately 1 in 11 veterinarians had serious psychological distress and 1 in 6 experienced suicidal ideation since leaving veterinary school. Implementing measures to help veterinarians cope with practice-related stressors and reducing barriers veterinarians face in seeking mental health treatment might reduce the risk for suicide among veterinarians.


Risks and benefits of a multidrug approach to mild-to-moderate heart failure.
Multidrug therapy offers several advantages in the management of mild-to-moderate heart failure. Treatment with a combination of agents, such as diuretics, digoxin, angiotensin-converting enzyme inhibitors, and beta blockers, can provide relief of symptoms while also addressing specific pathophysiologic factors. By allowing therapy to be tailored to the individual, the multidrug approach can slow progression of the disease, reduce or prevent the need for hospitalization, and decrease health-care costs. Evidence of the benefit of the multidrug approach has come from numerous trials in which newer treatments for heart failure have been evaluated in the context of the background therapy considered standard at the time of the trial. Compliance may be a challenge with multidrug therapy, particularly for patients who generally feel well and do not experience symptoms that interfere with normal daily function. The clinician must ensure that patients understand the need to comply with the prescribed regimen to prevent more serious problems in the future. Multidrug therapy may also require that patients be more closely monitored so that dosages of the individual medications can be adjusted to provide maximum benefit with a minimum of side effects.


[Construction of System for Support of Multifacility IVR Dose Analysis and Research].
Although measurement and management of angiographic entrance skin dose (ESD) are deemed extremely important, accurate determination of maximum ESD and its location is generally difficult because of the dependence on therapeutic technique and position. Following our development of body-mounted gear bearing radiophotoluminescence glass dosimeter (RPLD) arrays for direct measurement of ESD in cranial and cardiovascular angiography and interventional radiology (IVR), our focus next turned to the limited number of facilities equipped to read RPLD outputs and the need for methods to effectively provide feedback to clinical facilities. As described here, we first constructed an RPLD reading facility capable of sending and receiving RPLDs by post, offering the potential to enable utilization of the developed gear at all hospitals in Japan that perform angiography and IVR. We next developed specialized web-based system to generate dose maps from RPLD dose data, thereby enabling any facility to perform trial system analysis, evaluation, and implementation; and investigated the results and related problems.


Application of Data Mining to "Big Data" Acquired in Audiology: Principles and Potential.
The ubiquity and cheapness of miniature low-power sensors, digital processing, and large amounts of storage contained in small packages has heralded the ability to acquire large amounts of data about systems during their course of operation. The size and complexity of the data sets so generated have colloquially been labeled "big data." The computer science field of "data mining" has arisen with the purpose of extracting meaning from such data, expressly looking for patterns that not only link historic observations but also predict future behavior. This overview article considers the process, techniques, and interpretation of data mining, with specific focus on its application in audiology. Modern hearing instruments contain data-logging technology to record data separate from the audio stream, such as the acoustic environments in which the device was being used and how the signal processing was consequently operating. Combined with details about the patient, such as the audiogram, the variety of data generated lends itself to a data mining approach. To date, reports of the use and interpretation of these data have been mostly constrained to questions such as looking for changes in patterns of daily use, or the degree and direction of volume control manipulation as the patient's experience with a hearing aid changes. In this, and an accompanying results paper, the practical applications of some data mining techniques are described as applied to a large data set of examples of real-world device usage, as supplied by a hearing aid manufacturer.


Characterising the binding specificities of the subunits associated with the KMT2/Set1 histone lysine methyltransferase.
KMT2/Set1 is the catalytic subunit of the complex of proteins associated with Set1 (COMPASS) that is responsible for the methylation of lysine 4 of histone H3 (H3K4) in Saccharomyces cerevisiae. Whereas monomethylated H3K4 (H3K4me1) is found throughout the genome, di- (H3K4me2) and tri- (H3K4me3) methylated H3K4 are enriched at specific loci, which correlates with the promoter and 5'-ends of actively transcribed genes in the case of H3K4me3. The COMPASS subunits contain a number of domains that are conserved in homologous complexes in higher eukaryotes and are reported to interact with modified histones. However, the exact organization of these subunits and their role within the complex have not been elucidated. In this study we showed that: (1) subunits Swd1 and Swd3 form a stable heterodimer that dissociates upon binding to a modified H3K4me2 tail peptide, suggesting a regulatory role in COMPASS; (2) the affinity of the subunit Spp1 for modified histone H3 substrates is much higher than that of Swd1 and Swd3; (3) Spp1 has a preference for H3K4me2/3 methylation state; and (4) Spp1 contains a high-affinity DNA-binding domain in the previously uncharacterised C-terminal region. These data allow us to suggest a mechanism for the regulation of COMPASS activity at an actively transcribed gene.


Emergence of a distinct HIV-specific IL-10-producing CD8+ T-cell subset with immunomodulatory functions during chronic HIV-1 infection.
Interleukin-10 (IL-10) plays a key role in regulating proinflammatory immune responses to infection but can interfere with pathogen clearance. Although IL-10 is upregulated throughout HIV-1 infection in multiple cell subsets, whether this is a viral immune evasion strategy or an appropriate response to immune activation is unresolved. Analysis of IL-10 production at the single cell level in 51 chronically infected subjects (31 antiretroviral (ART) naïve and 20 ART treated) showed that a subset of CD8(+) T cells with a CD25(neg) FoxP3(neg) phenotype contributes substantially to IL-10 production in response to HIV-1 gag stimulation. The frequencies of gag-specific IL-10- and IFN-γ-producing T cells in ART-naïve subjects were strongly correlated and the majority of these IL-10(+) CD8(+) T cells co-produced IFN-γ; however, patients with a predominant IL-10(+) /IFN-γ(neg) profile showed better control of viraemia. Depletion of HIV-specific CD8(+) IL-10(+) cells from PBMCs led to upregulation of CD38 on CD14(+) monocytes together with increased IL-6 production, in response to gag stimulation. Increased CD38 expression was positively correlated with the frequency of the IL-10(+) population and was also induced by exposure of monocytes to HIV-1 in vitro. Production of IL-10 by HIV-specific CD8(+) T cells may represent an adaptive regulatory response to monocyte activation during chronic infection.


Structural and functional changes by ethanol on in vitro guinea pig gastric mucosa.
Relationships between morphological and electrophysiological changes with low concentrations of ethanol on in vitro guinea pig gastric mucosa were investigated. Tissues mounted in Ussing chambers allowed recording of transepithelial potential difference (PD), resistance (R), short-circuit current (Isc), and acid secretion (H+). At selected times the mucosae were processed for morphological analysis. With luminal 10% ethanol there was a decrease in PD, R, Isc, and H+ within 1 min, and they eventually went to low steady-state values between 10 and 40 min. At 1 min many surface epithelial cells lifted off from the basal lamina but were still anchored by thin basal cell processes. After 10 min in ethanol many surface cells had completely detached from the basal lamina but remained connected to adjacent cells by their junctions. Numerous cytoplasmic blebs formed on both apical and basal cell surfaces. Concurrently, there was a significant increase in microvillus length. After 40 min most of the surface cells were detached from the basal lamina as sheets forming epithelial blisters. Upon ethanol washout there was epithelial cell reattachment to the basal lamina and a return of the PD, R, and Isc to control values within 40 min. Incubation of the luminal surface with 10% ethanol for 5 h resulted in a gradual rise of the PD, R, Isc, and H+ to control values by 4 h with a coincident return of the normal mucosal morphology. These studies indicate that ethanol has reversible and possibly adaptable effects on the in vitro guinea pig gastric mucosa and that the morphological changes are closely correlated with the decline and recovery of the electrical and secretory activity of the tissue.


The ciliary pocket: a once-forgotten membrane domain at the base of cilia.
The PC (primary cilium) is present on most cell types in both developing and adult tissues in vertebrates. Despite multiple reports in the 1960s, the PC was almost forgotten for decades by most of the cell biology community, mainly because its function appeared enigmatic. This situation changed 10 years ago with the key discovery that this fascinating structure is the missing link between complex genetic diseases and key signalling pathways during development and tissue homoeostasis. A similar misfortune might have happened to an original membrane domain found at the base of PC in most cell types and recently termed the 'ciliary pocket'. A morphologically related structure has also been described at the connecting cilium of photoreceptors and at the flagellum in spermatids. Its organization is also reminiscent of the flagellar pocket, a plasma membrane invagination specialized in uptake and secretion encountered in kinetoplastid protozoa. The exact function of the ciliary pocket remains to be established, but the recent observation of endocytic activity coupled to the fact that vesicular trafficking plays important roles during ciliogenesis brought excitement in the ciliary community. Here, we have tried to decipher what this highly conserved membrane domain could tell us about the function and/or biogenesis of the associated cilium.


Making sense of street chaos: an ethnographic exploration of homeless people's health service utilization.
Homeless people have poor health and mortality indices. Despite this they make poor usage of health services. This study sought to understand why they use health services differently from the domiciled population. Ethnographic observations were conducted at several homeless services, in Dublin. This was supplemented with 47 semi-structured interviews with homeless people and two focus groups of homeless people and hospital doctors. A critical-realist approach was adopted for interpretation of the data. Homeless people tended to present late in their illness; default early from treatment; have low usage of primary-care, preventative and outpatient services; have high usage of Emergency and Inpatient services; and poor compliance with medication. They tended to avoid psychiatric services. A number of external barriers were identified. These were classified as physical (distance) administrative (application process for medical care; appointments; queues; the management of addiction in hospital; rules of service; and information providing processes); and attitudinal (stigma; differing attitudes as to appropriate use of services. A new form of barrier, Conversations of Exclusion was identified and described. Internalised barriers were identified which were in nature, either cognitive (fatalistic, denial, deferral to future, presumption of poor treatment or discrimination, self blame and survival cognitions) or emotional (fear; embarrassment, hopelessness and poor self-esteem). Generative mechanisms for these factors were identified which either affected participants prior to homelessness (marginalization causing hopelessness, familial dysfunction, substance misuse, fear of authority, illiteracy; mental health; and poor English) or after becoming homeless (homelessness; ubiquity of premature death; substance misuse; prioritization of survival over health; threat of violence; chaotic nature of homelessness; negative experiences of authority; and stigma. An explanatory critical realist model integrating the identified generative mechanisms, external and internalised barriers was developed to explain why the Health service Utilization of homeless people differs from the domiciled populations. This new model has implications for health service policy makers and providers in how they design and deliver accessible health services to homeless people.


Head injury from falls in children younger than 6 years of age.
The risk of serious head injury (HI) from a fall in a young child is ill defined. The relationship between the object fallen from and prevalence of intracranial injury (ICI) or skull fracture is described. Cross-sectional study of HIs from falls in children (<6 years) admitted to UK hospitals, analysed according to the object fallen from and associated Glasgow Coma Score (GCS) or alert, voice, pain, unresponsive (AVPU) and CT scan results. Of 1775 cases ascertained (median age 18 months, 54.7% boys), 87% (1552) had a GCS=15/AVPU=alert. 19.3% (342) had a CT scan: 32% (110/342) were abnormal; equivalent to 5.9% of the overall population, 16.9% (58) had isolated skull fractures and 13.7% (47) had ICI (49% (23/47) had an associated skull fracture). The prevalence of ICI increased with neurological compromise; however, 12% of children with a GCS=15/AVPU=alert had ICI. When compared to falls from standing, falls from a person's arms (233 children (mean age 1 year)) had a significant relative OR for a skull fracture/ICI of 6.94 (95% CI 3.54 to 13.6), falls from a building (eg, window or attic) (mean age 3 years) OR 6.84 (95% CI 2.65 to 17.6) and from an infant or child product (mean age 21 months) OR 2.75 (95% CI 1.36 to 5.65). Most HIs from a fall in these children admitted to hospital were minor. Infants, dropped from a carer's arms, those who fell from infant products, a window, wall or from an attic had the greatest chance of ICI or skull fracture. These data inform prevention and the assessment of the likelihood of serious injury when the object fallen from is known.


Expression of GPR17, a regulator of oligodendrocyte differentiation and maturation, in Nasu-Hakola disease brains.
The G protein-coupled receptor 17 (GPR17), a Gi-coupled GPCR, acts as an intrinsic timer of oligodendrocyte differentiation and myelination. The expression of GPR17 is upregulated during differentiation of oligodendrocyte precursor cells (OPCs) into premyelinating oligodendrocytes (preoligodendrocytes), whereas it is markedly downregulated during terminal maturation of myelinating oligodendrocytes. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2. Pathologically, the brains of NHD patients exhibit extensive demyelination designated leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and activation of microglia predominantly in the white matter of frontal and temporal lobes. Although GPR17 is a key regulator of oligodendrogenesis, a pathological role of GPR17 in NHD brains with relevance to development of leukoencephalopathy remains unknown. We studied the expression of GPR17 in five NHD brains and eight control brains by immunohistochemistry. We identified GPR17-immunoreactive preoligodendrocytes with a multipolar ramified morphology distributed in the white matter and the grey matter of all cases examined. However, we did not find statistically significant differences in the number of GPR17-expressing cells between NHD and control brains both in the white matter and the grey matter due to great variability from case to case. These observations do not support the view that GPR17-positive preoligodendrocytes play a central role in the development of leukoencephalopathy in NHD brains.


[Effects of polypharmacy and anticholinergic/sedative drugs on the physical/cognitive/mental related outcomes of community-dwelling elderly people: The Kawasaki Wellbeing Project].
To assess the burdens of polypharmacy and the drug burden index in community-dwelling elder people. The survey was conducted on 396 participants who participated in The Kawasaki Wellbeing Project from March to December 2017. We investigated the associations between the drug burden and the physical/cognitive/mental outcomes. The drug burden was determined by calculating the number of medications and the drug burden index (DBI) based on the use of anticholinergic and sedative drugs. A multivariate regression analysis was conducted for the outcome measures ADL, IADL, MMSE, J-CHS, and EQ5D5L after adjusting for the sex, age, number of diseases, education level, smoking history, and alcohol history. A total of 389 subjects were analyzed, the mean age of the population was 86 years old, and 187 people (48%) were male. Polypharmacy was reported in 243 people (62%), and DBI exposure was reported for 142 people (36.5%). We found that this population was physically healthy, with a median ADL of 100, and had high quality of life, with a median EQ5D5L of 0.895. Polypharmacy was found to be related to the J-CHS (β: 0.04) and EQ5D5L (-0.01). The DBI was also related to the EQ5D5L (-0.04). These results showed that even though this population was healthier than the general Japanese elderly population, the drug burden of polypharmacy and high dosages of anticholinergic/sedative drugs exerted significant negative effects on frailty and the quality of life. Additional research should be conducted to investigate the long-term effects of polypharmacy and anticholinergic/sedative drugs on elderly people.


Autoimmune Diseases in Children and Adults With Type 1 Diabetes From the T1D Exchange Clinic Registry.
Type 1 diabetes (T1D) is associated with other autoimmune diseases (AIDs), but the prevalence and associated predictive factors for these comorbidities of T1D across all age groups have not been fully characterized. Data obtained from 25 759 participants with T1D enrolled in the T1D Exchange Registry were used to analyze the types and frequency of AIDs as well as their relationships to gender, age, and race/ethnicity. Diagnoses of autoimmune diseases, represented as ordinal categories (0, 1, 2, 3, or more AIDs) were obtained from medical records of Exchange Registry participants. Among the 25 759 T1D Exchange participants, 50% were female, 82% non-Hispanic white, mean age was 23.0 ± 16.9 years and mean duration of diabetes was 11 years. Of these participants, 6876 (27%) were diagnosed with at least one AID. Frequency of two or more AIDs increased from 4.3% in participants aged younger than 13 years to 10.4% in those aged 50 years or older. The most common AIDs were thyroid (6097, 24%), gastrointestinal (1530, 6%), and collagen vascular diseases (432, 2%). Addison's disease was rare (75, 0.3%). The prevalence of one or more AIDs was increased in females and non-Hispanic whites and with older age. In the T1D Exchange Clinic Registry, a diagnosis of one or more AIDs in addition to T1D is common, particularly in women, non-Hispanic whites, and older individuals. Results of this study have implications for both primary care and endocrine practice and will allow clinicians to better anticipate and manage the additional AIDs that develop in patients with T1D.


What buffers ethnic homophily? Explaining the development of outgroup contact in adolescence.
Although literature provides strong evidence for the beneficial role of outgroup contact, longitudinal knowledge regarding the formation and change of outgroup contact remains improvable. Using a longitudinal, large-scale data set including 6,726 majority and minority participants (Mage = 14.98 years at Wave 1; 55% female) from 4 western European countries that were followed in 3 waves over 2 years, we systematically examined the development of outgroup contact during adolescence and tested the role of hypothesized predictors (i.e., intergroup attitudes and social identity) for explaining this development. In the majority, growth curve models revealed consistent patterns of ethnic homophily characterized by a continuous decline of outgroup contact, whereas this negative growth was buffered by a positive change of intergroup attitudes and a negative change of national identity during adolescence. In contrast, in the minority, outgroup contact was characterized by higher mean levels and a nonlinear development (i.e., no systematic decline or increase) of outgroup contact. Findings highlight the developmental importance of adolescence for promoting positive intergroup relations, especially for the majority, and emphasize the usefulness of contact interventions with adolescent students in school. (PsycINFO Database Record


Hablo Inglés y Español: Cultural Self-Schemas as a Function of Language.
Research has demonstrated that bilingual individuals experience a "double personality," which allows them to shift their self-schemas when they are primed with different language modes. In this study, we examine whether self-schemas change in Mexican-American (N = 193) bilinguals living in the U.S. when they provide open-ended personality self-descriptions in both English and Spanish. We used the Meaning Extraction Helper (MEH) software to extract the most salient self-schemas that influence individuals' self-defining process. Following a qualitative-inductive approach, words were extracted from the open-ended essays and organized into semantic clusters, which were analyzed qualitatively and named. The results show that as expected, language primed bilinguals to think about different self-schemas. In Spanish, their Mexican self-schemas were more salient; whereas, in English their U.S. American self-schemas were more salient. Similarities of self-schemas across languages were assessed using a quantitative approach. Language differences and similarities in theme definition and implications for self-identity of bilinguals are discussed.


The status of pharmacometrics in pregnancy: highlights from the 3(rd) American conference on pharmacometrics.
Physiological changes during pregnancy may alter drug pharmacokinetics. Therefore, mechanistic understanding of these changes and, ultimately, clinical studies in pregnant women are necessary to determine if and how dosing regimens should be adjusted. Because of the typically limited number of patients who can be recruited in this patient group, efficient design and analysis of these studies is of special relevance. This paper is a summary of a conference session organized at the American Conference of Pharmacometrics in April 2011, around the topic of applying pharmacometric methodology to this important problem. The discussion included both design and analysis of clinical studies during pregnancy and in silico predictions. An overview of different pharmacometric methods relevant to this subject was given. The impact of pharmacometrics was illustrated using a range of case examples of studies around pregnancy.


Removing the confounding effect of habitat specialization reveals the stabilizing contribution of diversity to species variability.
Earlier studies have found that diversity, S, stabilizes the relative variability of combined biomass or abundance of species making up a community. However, the effect of S on variability of constituent species has been elusive. We hypothesize that the proportion of specialists increases with S and, because specialists are more variable, this shift in composition will mask the stabilizing effect of S on populations of species making up a community. The test uses data on variability and ecological specialization of species in 49 natural rock pool invertebrate communities. Initial analyses produced inconclusive results similar to earlier studies. However, when variability owing to species' specialization was factored out, S reduced species' abundance variability, although not in all communities. Our study explains why the stabilizing effect of diversity on populations has not been found earlier.


Safeguarding people living in vulnerable conditions in the COVID-19 era through universal health coverage and social protection.
The COVID-19 pandemic is unprecedented. The pandemic not only induced a public health crisis, but has led to severe economic, social, and educational crises. Across economies and societies, the distributional consequences of the pandemic have been uneven. Among groups living in vulnerable conditions, the pandemic substantially magnified the inequality gaps, with possible negative implications for these individuals' long-term physical, socioeconomic, and mental wellbeing. This Viewpoint proposes priority, programmatic, and policy recommendations that governments, resource partners, and relevant stakeholders should consider in formulating medium-term to long-term strategies for preventing the spread of COVID-19, addressing the virus's impacts, and decreasing health inequalities. The world is at a never more crucial moment, requiring collaboration and cooperation from all sectors to mitigate the inequality gaps and improve people's health and wellbeing with universal health coverage and social protection, in addition to implementation of the health in all policies approach.