Using Machine Learning and Structural Neuroimaging to Detect First Episode Psychosis: Reconsidering the Evidence.
Despite the high level of interest in the use of machine learning (ML) and neuroimaging to detect psychosis at the individual level, the reliability of the findings is unclear due to potential methodological issues that may have inflated the existing literature. This study aimed to elucidate the extent to which the application of ML to neuroanatomical data allows detection of first episode psychosis (FEP), while putting in place methodological precautions to avoid overoptimistic results. We tested both traditional ML and an emerging approach known as deep learning (DL) using 3 feature sets of interest: (1) surface-based regional volumes and cortical thickness, (2) voxel-based gray matter volume (GMV) and (3) voxel-based cortical thickness (VBCT). To assess the reliability of the findings, we repeated all analyses in 5 independent datasets, totaling 956 participants (514 FEP and 444 within-site matched controls). The performance was assessed via nested cross-validation (CV) and cross-site CV. Accuracies ranged from 50% to 70% for surfaced-based features; from 50% to 63% for GMV; and from 51% to 68% for VBCT. The best accuracies (70%) were achieved when DL was applied to surface-based features; however, these models generalized poorly to other sites. Findings from this study suggest that, when methodological precautions are adopted to avoid overoptimistic results, detection of individuals in the early stages of psychosis is more challenging than originally thought. In light of this, we argue that the current evidence for the diagnostic value of ML and structural neuroimaging should be reconsidered toward a more cautious interpretation.


Modification of Helicobacter pylori Peptidoglycan Enhances NOD1 Activation and Promotes Cancer of the Stomach.
Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which translocates components of peptidoglycan into host cells. NOD1 is an intracellular immune receptor that senses peptidoglycan from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering peptidoglycan structure. We previously demonstrated that the H. pylori cag(+) strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. Using 2D-DIGE and mass spectrometry, we identified a novel mutation within the gene encoding the peptidoglycan deacetylase PgdA; therefore, we sought to define the role of H. pylori PgdA in NOD1-dependent activation of NF-κB, inflammation, and cancer. Coculture of H. pylori strain 7.13 or its pgdA(-) isogenic mutant with AGS gastric epithelial cells or HEK293 epithelial cells expressing a NF-κB reporter revealed that pgdA inactivation significantly decreased NOD1-dependent NF-κB activation and autophagy. Infection of Mongolian gerbils with an H. pylori pgdA(-) mutant strain led to significantly decreased levels of inflammation and malignant lesions in the stomach; however, preactivation of NOD1 before bacterial challenge reciprocally suppressed inflammation and cancer in response to wild-type H. pylori. Expression of NOD1 differs in human gastric cancer specimens compared with noncancer samples harvested from the same patients. These results indicate that peptidoglycan deacetylation plays an important role in modulating host inflammatory responses to H. pylori, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.


Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.
The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.


After-effects of pedaling exercise on spinal excitability and spinal reciprocal inhibition in patients with chronic stroke.
To evaluate the after-effects of pedaling on spinal excitability and spinal reciprocal inhibition in patients with post-stroke spastic hemiparesis. Twenty stroke patients with severe hemiparesis participated in this study and were instructed to perform 7 min of active pedaling and 7 min of passive pedaling with a recumbent ergometer at a comfortable speed. H reflexes and M waves of paretic soleus muscles were recorded at rest before, immediately after and 30 min after active and passive pedaling. The Hmax/Mmax ratio and H recruitment curve were measured. Reciprocal inhibition was assessed using the soleus H reflex conditioning test paradigm. The Hmax/Mmax ratio was significantly decreased after active and passive pedaling exercise. The decreased Hmax/Mmax ratio after active pedaling lasted at least for 30 min. The H recruitment curve and reciprocal inhibition did not change significantly after active or passive pedaling exercise. Pedaling exercise decreased spinal excitability in patients with severe hemiparesis. Pedaling may be effective in rehabilitation following stroke.


Snapshot of surgical activity in rural Ethiopia: is enough being done?
Surgical conditions are responsible for a significant burden of the disease prevalence in sub-Saharan Africa. However, there is a paucity of data surrounding the amount and availability of surgical care. Few surveys exist that document current rates of surgical activity in the low-income setting, and most figures rely on the country estimates. We aim to document accurately the rates of surgery at the district level. We performed a retrospective survey of surgical activity in 10 hospitals in the Southern Nation and Nationalities Peoples' Region of Ethiopia using a standardized data collection form. We also performed structured interviews with hospital directors. Surgical output varied across the hospitals from 56 to 421 operations per year per 100,000 catchment population. The most commonly performed operation was cesarean section (29% of major procedures). Emergency surgery accounted for 55% of operations, with the most frequent emergency operation being cesarean section. The overall cesarean section rate was alarmingly low at 0.6%. There are only 76 health workers that are providing a surgical service to this sample population of 12.9 million people. The rates of surgery found here were very low, consistent with the huge shortage of health workers providing a surgical service. The low cesarean section rate indicates that there is a large unmet surgical disease burden at the population level, and more comprehensive surveys are required to investigate this further. The most important steps to tackle the problem of deficiencies in global surgery are to increase access to surgical care and the surgical workforce capacity.


Mass media interventions for reducing mental health-related stigma.
Mental health-related stigma is widespread and has major adverse effects on the lives of people with mental health problems. Its two major components are discrimination (being treated unfairly) and prejudice (stigmatising attitudes). Anti-stigma initiatives often include mass media interventions, and such interventions can be expensive. It is important to know if mass media interventions are effective. To assess the effects of mass media interventions on reducing stigma (discrimination and prejudice) related to mental ill health compared to inactive controls, and to make comparisons of effectiveness based on the nature of the intervention (e.g. number of mass media components), the content of the intervention (e.g. type of primary message), and the type of media (e.g. print, internet). We searched eleven databases: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 7, 2011); MEDLINE (OvidSP),1966 to 15 August 2011; EMBASE (OvidSP),1947 to 15 August 2011; PsycINFO (OvidSP), 1806 to 15 August 2011; CINAHL (EBSCOhost) 1981 to 16 August 2011; ERIC (CSA), 1966 to 16 August 2011; Social Science Citation Index (ISI), 1956 to 16 August 2011; OpenSIGLE (http://www.opengrey.eu/), 1980 to 18 August 2012; Worldcat Dissertations and Theses (OCLC), 1978 to 18 August 2011; metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/mrct_about.asp), 1973 to 18 August 2011; and Ichushi (OCLC), 1903 to 11 November 2011. We checked references from articles and reviews, and citations from included studies. We also searched conference abstracts and websites, and contacted researchers. Randomised controlled trials (RCTs), cluster RCTs or interrupted time series studies of mass media interventions compared to inactive controls in members of the general public or any of its constituent groups (excluding studies in which all participants were people with mental health problems), with mental health as a subject of the intervention and discrimination or prejudice outcome measures. Two authors independently extracted data and assessed the risk of bias of included studies. We contacted study authors for missing information. Information about adverse effects was collected from study reports. Primary outcomes were discrimination and prejudice, and secondary outcomes were knowledge, cost, reach, recall, and awareness of interventions, duration/sustainability of media effects, audience reactions to media content, and unforeseen adverse effects. We calculated standardised mean differences and odds ratios. We conducted a primarily narrative synthesis due to the heterogeneity of included studies. Subgroup analyses were undertaken to examine the effects of the nature, content and type of mass media intervention. We included 22 studies involving 4490 participants. All were randomised trials (3 were cluster RCTs), and 19 of the 22 studies had analysable outcome data. Seventeen of the studies had student populations. Most of the studies were at unclear or high risk of bias for all forms of bias except detection bias.Findings from the five trials with discrimination outcomes (n = 1196) were mixed, with effects showing a reduction, increase or consistent with no evidence of effect. The median standardised mean difference (SMD) for the three trials (n = 394) with continuous outcomes was -0.25, with SMDs ranging from -0.85 (95% confidence interval (CI) -1.39 to -0.31) to -0.17 (95% CI -0.53 to 0.20). Odds ratios (OR) for the two studies (n = 802) with dichotomous discrimination outcomes showed no evidence of effect: results were 1.30 (95% CI 0.53 to 3.19) and 1.19 (95% CI 0.85 to 1.65).The 19 trials (n = 3176) with prejudice outcomes had median SMDs favouring the intervention, at the three following time periods: -0.38 (immediate), -0.38 (1 week to 2 months) and -0.49 (6 to 9 months). SMDs for prejudice outcomes across all studies ranged from -2.94 (95% CI -3.52 to -2.37) to 2.40 (95% CI 0.62 to 4.18). The median SMDs indicate that mass media interventions may have a small to medium effect in decreasing prejudice, and are equivalent to reducing the level of prejudice from that associated with schizophrenia to that associated with major depression.The studies were very heterogeneous, statistically, in their populations, interventions and outcomes, and only two meta-analyses within two subgroups were warranted. Data on secondary outcomes were sparse. Cost data were provided on request for three studies (n = 416), were highly variable, and did not address cost-effectiveness. Two studies (n = 455) contained statements about adverse effects and neither reported finding any. Mass media interventions may reduce prejudice, but there is insufficient evidence to determine their effects on discrimination. Very little is known about costs, adverse effects or other outcomes. Our review found few studies in middle- and low-income countries, or with employers or health professionals as the target group, and none targeted at children or adolescents. The findings are limited by the quality of the evidence, which was low for the primary outcomes for discrimination and prejudice, low for adverse effects and very low for costs. More research is required to establish the effects of mass media interventions on discrimination, to better understand which types of mass media intervention work best, to provide evidence about cost-effectiveness, and to fill evidence gaps about types of mass media not covered in this review. Such research should use robust methods, report data more consistently with reporting guidelines and be less reliant on student populations.


Heart transplantation in adult congenital heart disease.
Heart failure (HF) in adult congenital heart disease (ACHD) is vastly different to that observed in acquired heart disease. Unlike acquired HF in which pharmacological strategies are the cornerstone for protecting and improving ventricular function, ACHD-related HF relies heavily upon structural and other interventions to achieve these aims. patients with ACHD constitute a small percentage of the total adult heart transplant population (∼3%), although the number of ACHD heart transplant recipients is growing rapidly with a 40% increase over the last two decades. The worldwide experience to date has confirmed heart transplantation as an effective life-extending treatment option in carefully selected patients with ACHD with end-stage cardiac disease. Opportunities for improving outcomes in patients with ACHD-related HF include (i) earlier recognition and referral to centres with combined expertise in ACHD and HF, (ii) increased awareness of arrhythmia and sudden cardiac death risk in this population, (iii) greater collaboration between HF and ACHD specialists at the time of heart transplant assessment, (iv) expert surgical planning to reduce ischaemic time and bleeding risk at the time of transplant, (v) tailored immunosuppression in the post-transplant period and (vi) development and validation of ACHD-specific risk scores to predict mortality and guide patient selection. The purpose of this article is to review current approaches to diagnosing and treating advanced HF in patients with ACHD including indications, contraindications and clinical outcomes after heart transplantation.


Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea.
Olive tree (Olea europeaea) leaves are well known for their effect on metabolism in particular as a traditional anti-diabetic and anti-hypertensive herbal drug. These properties are until now only attributed to oleuropein, the major secoiridoid of olive leaves. Here we describe the isolation and the identification of another constituent implicated in the anti-diabetic effect of this plant, i.e. oleanolic acid. We show that this triterpene is an agonist for TGR5, a member of G-protein coupled receptor activated by bile acids and which mediates some of their various cellular and physiological effect. Oleanolic acid lowers serum glucose and insulin levels in mice fed with a high fat diet and it enhances glucose tolerance. Our data suggest that both oleuropein and oleanolic acid are involved in the anti-diabetic effect of olive leaves and further emphasize the potential role of TGR5 agonists to improve metabolic disorders.


Prevention of Antidrug Antibody Formation to Infliximab in Crohn's Patients With Prior Failure of Thiopurines.
Combination thiopurine-infliximab (IFX) therapy is associated with reduced generation of antidrug antibodies (ADA) compared with IFX monotherapy. Whether past clinical response to thiopurine therapy bears an effect on ADA prevention is unknown. This was a retrospective observational multicenter study of patients with Crohn's disease (CD) treated by IFX and thiopurines who had serial ADA measurements. Therapy was classified into past thiopurine response or its lack of, de novo combination, or IFX monotherapy. The primary endpoint was risk of ADA appearance. Out of 494 patients with serial ADA measurements 207 eligible patients were included in the final analysis. The 1-year cumulative risk of ADA development was similar in past thiopurine responders (19.3%) compared with past thiopurine failures (16.1%) (log rank P = .54). ADA was found in 46.6% of the monotherapy group and was significantly different compared with past thiopurine responders (P = .007) and past thiopurine failures (P = .007). The adjusted hazards for ADA development were significantly lower in past responders and past failures compared with the monotherapy group (hazard ratio, 0.47 [95% CI, 0.22-1.00] and 0.32 [95% CI, 0.11-0.93], respectively). Thiopurines-IFX cotherapy in patients with Crohn's disease is associated with reduced ADA formation compared with IFX monotherapy. This is probably regardless of initial thiopurine therapeutic effect.


The BET inhibitor JQ1 attenuates double-strand break repair and sensitizes models of pancreatic ductal adenocarcinoma to PARP inhibitors.
DNA repair deficiency accumulates DNA damage and sensitizes tumor cells to PARP inhibitors (PARPi). Based on our observation that the BET inhibitor JQ1 increases levels of DNA damage, we evaluated the efficacy of JQ1 + the PARPi olaparib in preclinical models of pancreatic ductal adenocarcinoma (PDAC). We also addressed the mechanism by which JQ1 increased DNA damage. The effect of JQ1 + olaparib on in vivo tumor growth was assessed with patient-derived xenograft (PDX) models of PDAC. Changes in protein expression were detected by immunohistochemistry and immunoblot. In vitro growth inhibition and mechanistic studies were done using alamarBlue, qRT-PCR, immunoblot, immunofluorescence, ChIP, and shRNA knockdown assays. Tumors exposed in vivo to JQ1 had higher levels of the DNA damage marker γH2AX than tumors exposed to vehicle only. Increases in γH2AX was concomitant with decreased expression of DNA repair proteins Ku80 and RAD51. JQ1 + olaparib inhibited the growth of PDX tumors greater than either drug alone. Mechanistically, ChIP assays demonstrated that JQ1 decreased the association of BRD4 and BRD2 with promoter loci of Ku80 and RAD51, and shRNA data showed that expression of Ku80 and RAD51 was BRD4- and BRD2-dependent in PDAC cell lines. The data are consistent with the hypothesis that JQ1 confers a repair deficient phenotype and the consequent accumulation of DNA damage sensitizes PDAC cells to PARPi. Combinations of BET inhibitors with PARPi may provide a novel strategy for treating PDAC. FUND: NIH grants R01CA208272 and R21CA205501; UAB CMB T32 predoctoral training grant.


Mechanisms of hemispheric lateralization: Asymmetric interhemispheric recruitment in the face perception network.
Perceiving human faces constitutes a fundamental ability of the human mind, integrating a wealth of information essential for social interactions in everyday life. Neuroimaging studies have unveiled a distributed neural network consisting of multiple brain regions in both hemispheres. Whereas the individual regions in the face perception network and the right-hemispheric dominance for face processing have been subject to intensive research, the functional integration among these regions and hemispheres has received considerably less attention. Using dynamic causal modeling (DCM) for fMRI, we analyzed the effective connectivity between the core regions in the face perception network of healthy humans to unveil the mechanisms underlying both intra- and interhemispheric integration. Our results suggest that the right-hemispheric lateralization of the network is due to an asymmetric face-specific interhemispheric recruitment at an early processing stage - that is, at the level of the occipital face area (OFA) but not the fusiform face area (FFA). As a structural correlate, we found that OFA gray matter volume was correlated with this asymmetric interhemispheric recruitment. Furthermore, exploratory analyses revealed that interhemispheric connection asymmetries were correlated with the strength of pupil constriction in response to faces, a measure with potential sensitivity to holistic (as opposed to feature-based) processing of faces. Overall, our findings thus provide a mechanistic description for lateralized processes in the core face perception network, point to a decisive role of interhemispheric integration at an early stage of face processing among bilateral OFA, and tentatively indicate a relation to individual variability in processing strategies for faces. These findings provide a promising avenue for systematic investigations of the potential role of interhemispheric integration in future studies.


Intracranial suppuration: Review of an 8-year experience at Umtata General Hospital and Nelson Mandela Academic Hospital, Eastern Cape, South Africa.
Intracranial suppuration (ICS) is a life-threatening condition caused by various disease processes and consisting of brain abscess and extradural and subdural empyema. The major causes have changed over the decades. To the author's knowledge, the incidence of ICS in South Africa (SA) has not been established. To determine the incidence of ICS, overall and according to age and gender, and to identify the source and distribution of ICS. The archive of the radiology departments at Umtata General Hospital and Nelson Mandela Academic Hospital in the Transkei region, Eastern Cape Province, SA, was searched retrospectively for computed tomography (CT) reports of patients diagnosed with ICS. Cases in which the CT images, patients' clinical information and CT reports were available for an uninterrupted period of at least 1 year were included. Five time frames were established, encompassing 8 years of data. The first time frame established an incidence of ICS of 1/100,000/year for the Transkei region. All the time frames were utilised to determine the incidence according to gender and age, and the source and distribution of ICS. The incidence of ICS was higher among males than females, and highest in the age groups 0-10 and 11-20 years. A seasonal variation in the incidence of sinusitis- and meningitis-related ICS was noted. Numbers of cases declined during the last 3 years of the study period. Sinusitis, head trauma, ear infection and meningitis were the major sources of ICS. A pulmonary source was not a major feature. In the last 4 years, trauma became the commonest source of ICS. A steady decline in ear infection- and meningitis-related ICS was noted.


Hemispheric differences in the surgical outcomes of patients with traumatic acute subdural hematoma.
Our assumption that prognosis of patients with traumatic acute subdural hematoma (ASDH) does not differ significantly according to the hemispheric laterality has never been verified. A review of the charts/radiographic images of 61 adult traumatic ASDH patients (33 left/28 right) was conducted. Intergroup comparison was made on the demographics, autonomic/laboratory data, and outcomes (90-day mortality rate). Based on the presence of concomitant brain contusion, patients were further quadrichotomized as: left ASDH with contusion (n = 14), right ASDH with contusion (n = 16), left ASDH without contusion (n = 19), and right ASDH without contusion (n = 12). Comparisons were made on demographic and outcome variables between the left ASDH with contusion and right ASDH with contusion, and between the left ASDH without contusion and right ASDH without contusion. Multivariate regression analysis was conducted to identify clinical variables correlated with fatality. There were no significant differences in the demographic, autonomic, and laboratory data between the left and right ASDH patients. However, 90-day mortality rate was significantly higher in the left ASDH patients when concomitant contusion was present (79% vs. 25%, p = 0.009). However, there were no significant hemispheric differences in the mortality rate among those without contusion (32% vs. 33%, p = 0.77). Multivariate regression analysis showed that left ASDH was correlated with fatality among those with contusion (OR: 6.620; 95% CI: 1.219-46.249). This study is probably the first to report that the left ASDH patients fared substantially worse than the right-sided counterparts. Future trials on traumatic ASDHs may benefit from considering hemispheric differences in the outcomes.


How should nets be dried after insecticide treatment in the field?
Different procedures for drying polyamide (nylon) hammock nets (approximately 10 m2) posttreatment were evaluated. Forty-three nets were soaked for 10 min in a plastic bowl containing a solution of water and lambdacyhalothrin 0.05% (target dose of 10 mg/m2). Twenty-two freshly treated nets were put to dry in the sun: 13 of them hung vertically with the roof of the hammock net at the top and the hem at the bottom, and the other 9 were folded and laid flat on a plastic sheet. The rest of the nets (21) were dried in the shade: 11 of them hung vertically and 10 were folded flat on a plastic sheet. After 6-7 h, 2 15-cm2 samples of each net were cut, one on top of the lateral side and one 40 cm from the edge. Concentrations of lambdacyhalothrin were determined by gas chromatography-mass spectrometry on subsamples of netting (1 cm2). The mean insecticide concentrations of samples were compared between nets that were dried in the sun or in the shade, and placed to dry either hanging vertically or folded flat. In general, no differences were found between the mean insecticide concentrations of nets that were dried vertically in the sun or in the shade, or those dried flat in the shade. However, the mean dose was considerably lower in the remaining nets, which were dried flat in the sun. The reason for this is unclear but is hypothesized to be an effect of temperature. Results indicated that nets hung vertically either in the sun or shade dried faster than those laid flat. Based on the time to dry and mean insecticide extracted, it is recommended to hang treated nets vertically in the sun for drying.


Long-term effects of cognitive training on everyday functional outcomes in older adults.
Cognitive training has been shown to improve cognitive abilities in older adults but the effects of cognitive training on everyday function have not been demonstrated. To determine the effects of cognitive training on daily function and durability of training on cognitive abilities. Five-year follow-up of a randomized controlled single-blind trial with 4 treatment groups. A volunteer sample of 2832 persons (mean age, 73.6 years; 26% black), living independently in 6 US cities, was recruited from senior housing, community centers, and hospitals and clinics. The study was conducted between April 1998 and December 2004. Five-year follow-up was completed in 67% of the sample. Ten-session training for memory (verbal episodic memory), reasoning (inductive reasoning), or speed of processing (visual search and identification); 4-session booster training at 11 and 35 months after training in a random sample of those who completed training. Self-reported and performance-based measures of daily function and cognitive abilities. The reasoning group reported significantly less difficulty in the instrumental activities of daily living (IADL) than the control group (effect size, 0.29; 99% confidence interval [CI], 0.03-0.55). Neither speed of processing training (effect size, 0.26; 99% CI, -0.002 to 0.51) nor memory training (effect size, 0.20; 99% CI, -0.06 to 0.46) had a significant effect on IADL. The booster training for the speed of processing group, but not for the other 2 groups, showed a significant effect on the performance-based functional measure of everyday speed of processing (effect size, 0.30; 99% CI, 0.08-0.52). No booster effects were seen for any of the groups for everyday problem-solving or self-reported difficulty in IADL. Each intervention maintained effects on its specific targeted cognitive ability through 5 years (memory: effect size, 0.23 [99% CI, 0.11-0.35]; reasoning: effect size, 0.26 [99% CI, 0.17-0.35]; speed of processing: effect size, 0.76 [99% CI, 0.62-0.90]). Booster training produced additional improvement with the reasoning intervention for reasoning performance (effect size, 0.28; 99% CI, 0.12-0.43) and the speed of processing intervention for speed of processing performance (effect size, 0.85; 99% CI, 0.61-1.09). Reasoning training resulted in less functional decline in self-reported IADL. Compared with the control group, cognitive training resulted in improved cognitive abilities specific to the abilities trained that continued 5 years after the initiation of the intervention. clinicaltrials.gov Identifier: NCT00298558.


Crystal structure of the specificity domain of ribonuclease P.
RNase P is the only endonuclease responsible for processing the 5' end of transfer RNA by cleaving a precursor and leading to tRNA maturation. It contains an RNA component and a protein component and has been identified in all organisms. It was one of the first catalytic RNAs identified and the first that acts as a multiple-turnover enzyme in vivo. RNase P and the ribosome are so far the only two ribozymes known to be conserved in all kingdoms of life. The RNA component of bacterial RNase P can catalyse pre-tRNA cleavage in the absence of the RNase P protein in vitro and consists of two domains: a specificity domain and a catalytic domain. Here we report a 3.15-A resolution crystal structure of the 154-nucleotide specificity domain of Bacillus subtilis RNase P. The structure reveals the architecture of this domain, the interactions that maintain the overall fold of the molecule, a large non-helical but well-structured module that is conserved in all RNase P RNA, and the regions that are involved in interactions with the substrate.


Some historical and methodological developments in early clinical trials at the National Institutes of Health.
This paper reviews five randomized clinical trials with unusual design or analysis features from institutes other than the National Cancer Institute or the National Heart, Lung and Blood Institute. These are: a Cooperative Study of Retrolental Fibroplasia sponsored by the National Institute of Neurological Diseases and Blindness; the Diabetic Retinopathy Study sponsored by the National Eye Institute; the University Group Diabetes Program sponsored by the National Institute of Arthritis and Metabolic Diseases; a Clinical Trial of the Extracranial to Intracranial Arterial Anastomosis (EC/IC bypass) by the National Institute of Neurological and Communicative Disorders and Stroke; and the Clinical Trial of Hereditary Angioedema by the National Institute of Allergy and Infectious Diseases.


[Control of visceral leishmaniasis in the town of Porteirinha, state of Minas Gerais, Brazil, from 1998 to 2003].
In the town of Porteirinha, State of Minas Gerais, 23 human cases of visceral leishmaniasis (VL) in 1998 and 1999 were recorded. A study was conducted involving the triad of action recommended for the control of VL. Patients were treated and serologically positive dogs were euthanized quarterly. The pyrethroid insecticide α-cypermethrin was applied in the neighborhoods where human cases were recorded. A reduction in canine seroprevalence and sand flies occurred following the implementation of control measures, reflecting in a reduction in human cases of VL. The results show the efficiency of such control measures when used in association.


Acquired C1 Inhibitor Deficiency.
Acquired angioedema due to C1-INH deficiency (C1-INH-AAE) can occur when there are acquired (not inherited) deficiencies of C1-INH. A quantitative or functional C1-INH deficiency with negative family history and low C1q is diagnostic of C1-INH-AAE. The most common conditions associated with C1-INH-AAE are autoimmunity and B-cell lymphoproliferative disorders. A diagnosis of C1-INH-AAE can precede a diagnosis of lymphoproliferative disease and confers an increased risk for developing non-Hodgkin lymphoma. Treatment focuses on symptom control with therapies that regulate bradykinin activity (C1-INH concentrate, icatibant, ecallantide, tranexamic acid, androgens) and treatment of any underlying conditions.


Targeting EZH2 regulates tumor growth and apoptosis through modulating mitochondria dependent cell-death pathway in HNSCC.
EZH2 is a negative prognostic factor and is overexpressed or activated in most human cancers including head and neck squamous cell carcinoma (HNSCC). Analysis of The Cancer Genome Atlas (TCGA) HNSCC data indicated that EZH2 over-expression was associated with high tumor grade and conferred poor prognosis. EZH2 inhibition triggered cell apoptosis, cell cycle arrest and decreased cell growth in vitro. MICU1 (mitochondrial calcium uptake1) was shown to be down regulated when EZH2 expression was inhibited in HNSCC. When the EZH2 and MICU1 were inhibited, HNSCC cells became susceptible to cell cycle arrest and apoptosis. Mitochondrial membrane potential and cytosolic Ca2+ concentration analysis suggested that EZH2 and MICU1 were required to maintain mitochondrial membrane potential stability. A xenograft tumor model was used to confirm that EZH2 depletion inhibited HNSCC cell growth and induced tumor cell apoptosis. In summary, EZH2 is a potential anti-tumor target in HNSCC.


Changes in motor network expression related to moulting behaviour in lobster: role of moult-induced deep hypoxia
The well known rhythmically active pyloric neural network in intact and freely behaving lobsters Homarus gammarus was monitored prior to and following ecdysis. Despite long-lasting hormonal and metabolic alterations associated with this process, spontaneous pyloric network activity remained largely unaltered until the last 12-48 h before exuviation. At this time, the most notable change was a progressive lengthening of pyloric cycle period, which eventually attained 500-600 % of control values. It was only in the very last minutes before ecdysis that burst patterning became irregular and the otherwise strictly alternating motor sequence broke down. After the moult, coordinated rhythmicity was re-established within 10 min. Concomitant with these final changes in motor network expression at ecdysis was a drastic reduction in blood oxygen levels which led to a temporary near-anoxia. By imposing similarly deep hypoxic conditions both on intermoult animals and on the pyloric network in vitro, we mimicked to a large extent the moult-induced changes in pyloric network performance. Our data suggest that, despite major surrounding physiological perturbations, the pyloric network in vivo retains stable pattern-generating properties throughout much of the moulting process. Moreover, some of the most significant modifications in motor expression just prior to ecdysis can be related to a substantial reduction in oxygen levels in the blood.


Use of Mobile Clinical Decision Support Software by Junior Doctors at a UK Teaching Hospital: Identification and Evaluation of Barriers to Engagement.
Clinical decision support (CDS) tools improve clinical diagnostic decision making and patient safety. The availability of CDS to health care professionals has grown in line with the increased prevalence of apps and smart mobile devices. Despite these benefits, patients may have safety concerns about the use of mobile devices around medical equipment. This research explored the engagement of junior doctors (JDs) with CDS and the perceptions of patients about their use. There were three objectives for this research: (1) to measure the actual usage of CDS tools on mobile devices (mCDS) by JDs, (2) to explore the perceptions of JDs about the drivers and barriers to using mCDS, and (3) to explore the perceptions of patients about the use of mCDS. This study used a mixed-methods approach to study the engagement of JDs with CDS accessed through mobile devices. Usage data were collected on the number of interactions by JDs with mCDS. The perceived drivers and barriers for JDs to using CDS were then explored by interviews. Finally, these findings were contrasted with the perception of patients about the use of mCDS by JDs. Nine of the 16 JDs made a total of 142 recorded interactions with the mCDS over a 4-month period. Only 27 of the 114 interactions (24%) that could be categorized as on-shift or off-shift occurred on-shift. Eight individual, institutional, and cultural barriers to engagement emerged from interviews with the user group. In contrast to reported cautions and concerns about the impact of clinicians' use of mobile phone on patient health and safety, patients had positive perceptions about the use of mCDS. Patients reported positive perceptions toward mCDS. The usage of mCDS to support clinical decision making was considered to be positive as part of everyday clinical practice. The degree of engagement was found to be limited due to a number of individual, institutional, and cultural barriers. The majority of mCDS engagement occurred outside of the workplace. Further research is required to verify these findings and assess their implications for future policy and practice.


Molecular characterization of extended-spectrum beta-lactamases in clinical Escherichia coli and Klebsiella pneumoniae isolates from Surabaya, Indonesia.
No detailed reports regarding extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are currently available from Indonesia, the fourth most populous country in the world. A survey was carried out to investigate the molecular epidemiology and genetic characteristics of clinical ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates originating from the Dr. Soetomo Academic Hospital in Surabaya, Indonesia, over a 4 month period (January to April 2005). ESBLs were characterized by isoelectric focusing and PCR assays. Clonality of the isolates was assessed by PFGE and repetitive-sequence-based PCR (rep-PCR). Phylogenetic grouping was performed among CTX-M-15-producing E. coli. In total, 73 consecutive non-duplicate ESBL-positive E. coli and 72 K. pneumoniae strains were isolated. The bla(CTX-M-15) gene was found to be highly prevalent (69/73 strains, 94.5%) among the 73 ESBL-positive E. coli isolates. The gene was detected in both clonal and non-clonal isolates, as defined by PFGE and rep-PCR. Sixteen CTX-M-15-positive E. coli could be assigned to a single rep-PCR type and phylogenetic group B2 and belonged to the well-known O25b-ST131 clone. Among the 72 ESBL-positive K. pneumoniae isolates, bla(CTX-M-15) was again the most prevalent ESBL (40/72, 55.6%). Several SHV-type enzymes were also frequently detected: SHV-5 (n = 28); SHV-12 (n = 13); and SHV-2 (n = 6). TEM-type ESBLs were not detected in any of the isolates. Indonesia is another developing country affected by the emergence and spread of bacterial strains harbouring ESBL genes, including the CTX-M-15-producing B2-E. coli O25b-ST131 clone.


Outcomes of aggressive treatment in esophageal cancer patients with synchronous solitary brain metastasis.
The aim of the present study was to investigate the outcomes of esophageal cancer (EC) patients with isolated synchronous brain oligometastasis (oligo-BM) treated with chemoradiotherapy (CRT) of the primary site and localized treatment of the BM with surgery, radiotherapy (RT) or radiosurgery. Of 125 EC patients investigated, seven patients (6%) had solitary BM. Six patients were diagnosed prior to, and one patient was diagnosed during, treatment. All patients were treated with neoadjuvant chemotherapy and whole-brain RT (WBRT) for BM. All but one patient received definitive CRT with a median RT dose of 50.4 Gy using conventional fractionation RT. The median age at diagnosis was 59 years (range, 48-77 years). Six patients succumbed to mortality, and one continued to receive systemic chemotherapy at the last visit. The median survival time of the patients was 18.9 months (range, 10.0-27.2 months). Median time to progression after completion of the treatments was 8 months (range, 3-9 months). Two patients had progression of the primary tumor, and one patient had progression of the BM. The neurological status of three patients with BM who were identified during the staging work-up did not deteriorate as a consequence of WBRT. In conclusion, the present study has demonstrated that aggressive treatment of the primary tumor and oligo-BM in patients with EC may prolong the survival time.


Influence of surface groups on poly(propylene imine) dendrimers antiprion activity.
Prion diseases are characterized by the accumulation of PrP(Sc), an aberrantly folded isoform of the host protein PrP(C). Specific forms of synthetic molecules known as dendrimers are able to eliminate protease-resistant PrP(Sc) in both an intracellular and in vitro setting. The properties of a dendrimer which govern this ability are unknown. We addressed the issue by comparing the in vitro antiprion ability of numerous modified poly(propylene-imine) dendrimers, which varied in size, structure, charge, and surface group composition. Several of the modified dendrimers, including an anionic glycodendrimer, reduced the level of protease resistant PrP(Sc) in a prion strain-dependent manner. This led to the formulation of a new working model for dendrimer/prion interactions which proposes dendrimers eliminate PrP(Sc) by destabilizing the protein and rendering it susceptible to proteolysis. This ability is not dependent on any particular charge of dendrimer, but does require a high density of reactive surface groups.


Improved results of lung transplantation for patients with cystic fibrosis.
Patients with cystic fibrosis pose particular challenges for lung transplant surgeons. Earlier reports from North American centers suggested that patients with cystic fibrosis were at greater risk for heart-lung or isolated lung transplantation than other patients with end-stage pulmonary disease. During a 3 1/2 year period, 44 patients with end-stage lung disease resulting from cystic fibrosis underwent double lung transplantation at this institution. During the same interval, 18 patients with cystic fibrosis died while waiting for lung transplantation. The ages of the recipients ranged from 8 to 45 years, and mean forced expiratory volume in 1 second was 21% predicted. Seven patients had Pseudomonas cepacia bacteria before transplantation. Bilateral sequential implantation with omentopexy was used in all patients. There were no operative deaths, although two patients required urgent retransplantation because of graft failure. Cardiopulmonary bypass was necessary in six procedures in five patients and was associated with an increased blood transfusion requirement, longer postoperative ventilation, and longer hospital stay. Actuarial survival was 85% at 1 year and 67% at 2 years. Infection was the most common cause of death within 6 months of transplantation (Pseudomonas cepacia pneumonia was the cause of death in two patients), and bronchiolitis obliterans was the most common cause of death after 6 months. Actuarial freedom from development of clinically significant bronchiolitis obliterans was 59% at 2 years. Results of pulmonary function tests improved substantially in survivors, with forced expiratory volume in 1 second averaging 78% predicted 2 years after transplantation. Double lung transplantation can be accomplished with acceptable morbidity and mortality in patients with cystic fibrosis.


Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice.
IkappaB kinase-alpha and -beta (IKK-alpha and IKK-beta), the catalytic subunits of the IKK complex, phosphorylate IkappaB proteins on specific serine residues, thus targeting IkappaB for degradation and activating the transcription factor NF-kappaB. To elucidate the in vivo function of IKK-beta, we generated IKK-beta-deficient mice. The homozygous mouse embryo dies at approximately 14.5 days of gestation due to liver degeneration and apoptosis. IKK-beta-deficient embryonic fibroblasts have both reduced basal NF-kappaB activity and impaired cytokine-induced NF-kappaB activation. Similarly, basal and cytokine-inducible kinase activities of the IKK complex are greatly reduced in IKK-beta-deficient cells. These results indicate that IKK-beta is crucial for liver development and regulation of NF-kappaB activity and that IKK-alpha can only partially compensate for the loss of IKK-beta.


Patient specific modeling of palpation-based prostate cancer diagnosis: effects of pelvic cavity anatomy and intrabladder pressure.
Computational modeling has become a successful tool for scientific advances including understanding the behavior of biological and biomedical systems as well as improving clinical practice. In most cases, only general models are used without taking into account patient-specific features. However, patient specificity has proven to be crucial in guiding clinical practice because of disastrous consequences that can arise should the model be inaccurate. This paper proposes a framework for the computational modeling applied to the example of the male pelvic cavity for the purpose of prostate cancer diagnostics using palpation. The effects of patient specific structural features on palpation response are studied in three selected patients with very different pathophysiological conditions whose pelvic cavities are reconstructed from MRI scans. In particular, the role of intrabladder pressure in the outcome of digital rectal examination is investigated with the objective of providing guidelines to practitioners to enhance the effectiveness of diagnosis. Furthermore, the presence of the pelvic bone in the model is assessed to determine the pathophysiological conditions in which it has to be modeled. The conclusions and suggestions of this work have potential use not only in clinical practice and also for biomechanical modeling where structural patient-specificity needs to be considered. © 2015 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.


Application and Uses of Electronic Noses for Clinical Diagnosis on Urine Samples: A Review.
The electronic nose is able to provide useful information through the analysis of the volatile organic compounds in body fluids, such as exhaled breath, urine and blood. This paper focuses on the review of electronic nose studies and applications in the specific field of medical diagnostics based on the analysis of the gaseous headspace of human urine, in order to provide a broad overview of the state of the art and thus enhance future developments in this field. The research in this field is rather recent and still in progress, and there are several aspects that need to be investigated more into depth, not only to develop and improve specific electronic noses for different diseases, but also with the aim to discover and analyse the connections between specific diseases and the body fluids odour. Further research is needed to improve the results obtained up to now; the development of new sensors and data processing methods should lead to greater diagnostic accuracy thus making the electronic nose an effective tool for early detection of different kinds of diseases, ranging from infections to tumours or exposure to toxic agents.


Predicting motor, cognitive & functional impairment in Parkinson's.
We recently demonstrated that 998 features derived from a simple 7-minute smartphone test could distinguish between controls, people with Parkinson's and people with idiopathic Rapid Eye Movement sleep behavior disorder, with mean sensitivity/specificity values of 84.6-91.9%. Here, we investigate whether the same smartphone features can be used to predict future clinically relevant outcomes in early Parkinson's. A total of 237 participants with Parkinson's (mean (SD) disease duration 3.5 (2.2) years) in the Oxford Discovery cohort performed smartphone tests in clinic and at home. Each test assessed voice, balance, gait, reaction time, dexterity, rest, and postural tremor. In addition, standard motor, cognitive and functional assessments and questionnaires were administered in clinic. Machine learning algorithms were trained to predict the onset of clinical outcomes provided at the next 18-month follow-up visit using baseline smartphone recordings alone. The accuracy of model predictions was assessed using 10-fold and subject-wise cross validation schemes. Baseline smartphone tests predicted the new onset of falls, freezing, postural instability, cognitive impairment, and functional impairment at 18 months. For all outcome predictions AUC values were greater than 0.90 for 10-fold cross validation using all smartphone features. Using only the 30 most salient features, AUC values greater than 0.75 were obtained. We demonstrate the ability to predict key future clinical outcomes using a simple smartphone test. This work has the potential to introduce individualized predictions to routine care, helping to target interventions to those most likely to benefit, with the aim of improving their outcome.


Earthquake and typhoon trigger unprecedented transient shifts in shallow hydrothermal vents biogeochemistry.
Shallow hydrothermal vents are of pivotal relevance for ocean biogeochemical cycles, including seawater dissolved heavy metals and trace elements as well as the carbonate system balance. The Kueishan Tao (KST) stratovolcano off Taiwan is associated with numerous hydrothermal vents emitting warm sulfur-rich fluids at so-called White Vents (WV) and Yellow Vent (YV) that impact the surrounding seawater masses and habitats. The morphological and biogeochemical consequences caused by a M5.8 earthquake and a C5 typhoon ("Nepartak") hitting KST (12th May, and 2nd-10th July, 2016) were studied within a 10-year time series (2009-2018) combining aerial drone imagery, technical diving, and hydrographic surveys. The catastrophic disturbances triggered landslides that reshaped the shoreline, burying the seabed and, as a consequence, native sulfur accretions that were abundant on the seafloor disappeared. A significant reduction in venting activity and fluid flow was observed at the high-temperature YV. Dissolved Inorganic Carbon (DIC) maxima in surrounding seawater reached 3000-5000 µmol kg-1, and Total Alkalinity (TA) drawdowns were below 1500-1000 µmol kg-1 lasting for one year. A strong decrease and, in some cases, depletion of dissolved elements (Cd, Ba, Tl, Pb, Fe, Cu, As) including Mg and Cl in seawater from shallow depths to the open ocean followed the disturbance, with a recovery of Mg and Cl to pre-disturbance concentrations in 2018. The WV and YV benthic megafauna exhibited mixed responses in their skeleton Mg:Ca and Sr:Ca ratios, not always following directions of seawater chemical changes. Over 70% of the organisms increased skeleton Mg:Ca ratio during rising DIC (higher CO2) despite decreasing seawater Mg:Ca ratios showing a high level of resilience. KST benthic organisms have historically co-existed with such events providing them ecological advantages under extreme conditions. The sudden and catastrophic changes observed at the KST site profoundly reshaped biogeochemical processes in shallow and offshore waters for one year, but they remained transient in nature, with a possible recovery of the system within two years.


Effect of obesity on asthma phenotype is dependent upon asthma severity.
We recently reported that obese and non-obese patients with asthma have similar airflow limitation and bronchodilator responsiveness, but obese patients have more symptoms overall. There is limited information on the effect of obesity on asthmatics of varying severity measured by objective physiological parameters. Understanding how obesity affects asthmatics of differing severity can provide insights into the pathogenesis of asthma in the obese and a rationale for the therapeutic approach to such patients. Participants with asthma from two American Lung Association--Asthma Clinical Research Center (ALA-ACRC) studies were grouped by tertiles of airflow obstruction (forced expiratory volume in one second (FEV(1)%) predicted, FEV(1)/forced vital capacity (FVC)) and methacholine reactivity (PC(20)FEV(1)). Within each tertile, we examined the independent effect of body mass index (BMI), divided into normal weight, overweight, and obese categories, on lung function, airway reactivity, and symptoms. Overall, both FEV(1) and FVC decreased and symptoms worsened with increasing BMI; airway reactivity was unchanged. When stratified by the degree of airflow obstruction, higher BMI was not associated with greater airway reactivity to methacholine. Higher BMI was associated with more asthma symptoms only in the least obstructed FEV(1)/FVC tertile. When stratified by degree of airway reactivity, BMI was inversely associated with FVC in all PC(20)FEV(1) tertiles. BMI was directly associated with asthma symptoms only in those with the least airway reactivity. Obesity does not influence airway reactivity in patients with asthma and it is associated with more symptoms only in those with less severe disease.


CYP2D6 polymorphisms influence the efficacy of adjuvant tamoxifen in Thai breast cancer patients.
We evaluated single nucleotide polymorphisms (SNPs) of CYP2D6 to identify those that influence the efficiency of tamoxifen in adjuvant treatment of breast cancer through a matched case-control study. Peripheral blood DNA was collected from 20 patients with disease recurrence during adjuvant tamoxifen treatment and from 19 patients who had completed 5 years of tamoxifen therapy without recurrence of breast cancer. CYP2D6*4 (1846G > A; rs3892097), CYP2D6*10 (100C > T, rs1065852), and CYP2D6*5 (deletion) were genotyped. The correlation between disease-free survival (DFS) and genotype and clinical outcome were assessed using Kaplan-Meier analysis and a log-rank test. We found the allelic frequency of CYP2D6*10 during this study. Patients with the CYP2D6*10 homozygous variant T/T genotype had a significantly shorter median of DFS than those with C/T (P = 0.036), but DFS was not significantly different from that of patients with the C/C genotype (P = 0.316). One patient who was a carrier both of CYP2D6 G/A (1846G > A) and T/T (100C > T) had DFS of 22.7 months. This study demonstrated that CYP2D6*10/*10 was significantly associated with shorter DFS in Thai breast cancer patients receiving tamoxifen. This was a pilot study investigating the correlation of CYP2D6 polymorphisms and their influence on clinical outcomes in Thai estrogen receptor-positive breast cancer patients.


Safety of Vitamin D2 mushroom powder (Agaricus bisporus) as a Novel food pursuant to Regulation (EU) 2015/2283.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on vitamin D2 mushroom powder as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The NF is an ingredient produced from Agaricus bisporus mushroom powder that has been exposed to ultraviolet (UV) irradiation to induce the conversion of provitamin D2 (ergosterol) to vitamin D2 (ergocalciferol). The NF contains concentrations of vitamin D provided by vitamin D2 in the ranges of 580-595 μg/g. The information provided on the manufacturing process, composition and specifications of the NF does not raise safety concerns. The applicant intends to add the NF in a variety of foods and beverages, including food for special medical purposes and food supplements. The target population is the general population except for food supplements and Foods for Special Medical Purposes (FSMPs), for which the target population is individuals above 1 year of age. The Panel concludes that the NF, used as an ingredient, is safe for the general population at the proposed condition of use in foods and beverages and that the NF used as a food supplement, is safe for individuals above 1 year.


Visuospatial Attention and Saccadic Inhibitory Control in Children With Cerebral Palsy.
Cerebral palsy (CP) is a non-progressive syndrome due to a pre-, peri- or post-natal brain injury, which frequently involves an impairment of non-motor abilities. The aim of this article was to examine visuospatial attention and inhibitory control of prepotent motor responses in children with CP showing a normal IQ or mild cognitive impairment, measuring their performance in oculomotor tasks. Ten children (9-16-year-old) with spastic CP and 13 age-matched, typically developing children (TDC) participated in the study. Subjects performed a simple visually-guided saccade task and a cue-target task, in which they performed a saccade towards a peripheral target, after a non-informative visual cue was flashed 150 ms before the imperative target, either at the same (valid) or at a different (invalid) spatial position. Children with CP showed severe executive deficits in maintaining sustained attention and complying with task instructions. Furthermore, saccadic inhibitory control appeared to be significantly impaired in the presence of both stimulus-driven and goal-directed captures of attention. In fact, patients showed great difficulties in suppressing saccades not only to the cue stimuli but also to the always-present target placeholders, which represented powerful attentional attractors that had to be covertly attended throughout the task execution. Moreover, impairment did not affect in equal manner the whole visual field but showed a marked spatial selectivity in each individual subject. Saccade latencies in the cue-target task were faster in the valid than in the invalid condition in both child groups, indicating the preservation of low-level visuospatial attentive capabilities. Finally, this study provides evidence that these impairments of executive skills and in inhibitory control, following early brain injuries, manifest in childhood but recover to virtually normal level during adolescence.


Effects of valve geometry and tissue anisotropy on the radial stretch and coaptation area of tissue-engineered heart valves.
Tissue engineering represents a promising technique to overcome the limitations of the current valve replacements, since it allows for creating living autologous heart valves that have the potential to grow and remodel. However, also this approach still faces a number of challenges. One particular problem is regurgitation, caused by cell-mediated tissue retraction or the mismatch in geometrical and material properties between tissue-engineered heart valves (TEHVs) and their native counterparts. The goal of the present study was to assess the influence of valve geometry and tissue anisotropy on the deformation profile and closed configuration of TEHVs. To achieve this aim, a range of finite element models incorporating different valve shapes was developed, and the constitutive behavior of the tissue was modeled using an established computational framework, where the degree of anisotropy was varied between values representative of TEHVs and native valves. The results of this study suggest that valve geometry and tissue anisotropy are both important to maximize the radial strains and thereby the coaptation area. Additionally, the minimum degree of anisotropy that is required to obtain positive radial strains was shown to depend on the valve shape and the pressure to which the valves are exposed. Exposure to pulmonary diastolic pressure only yielded positive radial strains if the anisotropy was comparable to the native situation, whereas considerably less anisotropy was required if the valves were exposed to aortic diastolic pressure.


Two-dimensional imaging of soot volume fraction by the use of laser-induced incandescence.
A recently developed laser-induced incandescence technique is used to make novel planar measurements of soot volume fraction within turbulent diffusion flames and droplet flames. The two-dimensional imaging technique is developed and assessed by systematic experiments in a coannular laminar diffusion flame, in which the soot characteristics have been well established. With a single point calibration procedure, agreement to within 10% was found between the values of soot volume fraction measured by this technique and those determined by conventional laser scattering-extinction methods in the flame. As a demonstration of the wide range of applicability of the technique, soot volume fraction images are also obtained from both turbulent ethene diffusion flames and from a freely falling droplet flame that burns the mixture of 75% benzene and 25% methanol. For the turbulent diffusion flames, approximately an 80% reduction in soot volume fraction was found when the Reynolds number of the fuel jet increased from 4000 to 8000. In the droplet flame case, the distribution of soot field was found to be similar to that observed in coannular laminar diffusion flames.


Neonatal care in Brazil: hospital structure and adequacy according to newborn obstetric risk.
In Brazil, hospital birth care is available to all, but there are important differences between hospitals in the public and private sectors, geographical regions and capitals/inland cities, resulting in inequalities of infant health. To assess the hospital structure for birth care in Brazil and analyze hospital adequacy to care for newborns according to levels of risk. Data were collected as part of a nationwide hospital-based cohort study, 'Birth in Brazil'. The hospitals were classified according to whether they had a neonatal intensive care unit and divided into two models of governance: public and private financing. Three structure domains were assessed: human resources, medications and equipment for post-natal women and newborn emergency care. Newborns were classified according to the obstetric risk. There are more NICUs in private hospitals and they cater mostly for low obstetric risk newborns; the public sector serves 50% of at-risk patients in hospitals without an NICU. The differences between hospital service structures according to geographic region and capital/inland cities were evident. Hospitals in less developed regions and inland cities had poorer adequacy in the three domains. The distribution of neonatal care to Brazilian infants varied between the public and private sectors. The public sector offered less complex services for newborns at risk, and infants without obstetric risk were born in facilities with an NICU, creating the possibility of unnecessary intervention, especially in the private sector.


Antibiotics protect against EAE by increasing regulatory and anti-inflammatory cells.
A seven day pretreatment course of an oral antibiotic cocktail (Ampicillin, Metronidazole, Neomycin Sulfate, and Vancomycin) was shown to induce changes in peripheral immune regulation and protect mice from signs of experimental autoimmune encephalomyelitis (EAE). To determine if a shorter course of antibiotic pretreatment could also protect the mice from EAE and induce regulatory immune cells, studies were conducted using the same oral antibiotic cocktail for three days. In addition, the CNS was examined to determine the effects of antibiotic pretreatment on EAE disease course and immune modulation within the affected tissue. The shorter three day pretreatment course was also significantly protective against severe EAE in C57BL/6 mice. Moreover, our study found increased frequencies of regulatory cells and a decrease in the frequency of anti-inflammatory macrophages in the spleen of EAE protected mice. Additionally, a chemokine and chemokine receptor array run on mRNA from spinal cords revealed that genes associated with regulatory T cells and macrophage recruitment were strongly upregulated in the antibiotic pretreated mice. Additional RT-PCR data showed genes associated with anti-inflammatory microglia/macrophages were upregulated and pro-inflammatory genes were downregulated. This suggests the macrophages recruited to the spinal cord by chemokines are subsequently polarized toward an anti-inflammatory phenotype. These results lend strong support to the conclusion that a three day course of antibiotic treatment given prior to the induction of severe EAE profoundly protected the mice by inducing regulatory lymphocytes in the periphery and an anti-inflammatory milieu in the affected spinal cord tissue.


Measurement of the presampled two-dimensional modulation transfer function of digital imaging systems.
The purpose of this work was to develop methods to measure the presampled two-dimensional modulation transfer function (2D MTF) of digital imaging systems. A custom x-ray "point source" phantom was created by machining 256 holes with diameter 0.107 mm through a 0.5-mm-thick copper plate. The phantom was imaged several times, resulting in many images of individual x-ray "spots." The center of each spot (with respect to the pixel matrix) was determined to subpixel accuracy by fitting each spot to a 2D Gaussian function. The subpixel spot center locations were used to create a 5 x oversampled system point spread function (PSF), which characterizes the optical and electrical properties of the system and is independent of the pixel sampling of the original image. The modulus of the Fourier transform of the PSF was calculated. Next, the Fourier function was normalized to the zero frequency value. Finally, the Fourier transform function was divided by the first-order Bessel function that defined the frequency content of the holes, resulting in the presampled 2D MTF. The presampled 2D MTF of a 0.1 mm pixel pitch computed radiography system and 0.2 mm pixel pitch flat panel digital imaging system that utilized a cesium iodide scintillator was measured. Comparison of the axial components of the 2D MTF to one-dimensional MTF measurements acquired using an edge device method demonstrated that the two methods produced consistent results.


Genotype-dependent behavioral sensitivity to mu vs. kappa opiate agonists. I. Acute and chronic effects on mouse locomotor activity.
The locomotor activity (LMA) effects of morphine (MRP) and (+/-)-ethylketocyclazocine (EKC) were studied in two inbred mouse strains, C57B1/6J (C57) and DBA/2J (DBA). MRP (3.2-100 mg/kg) caused a monophasic stimulation, a "running fit," in naive C57 mice and a biphasic, depression-stimulation in DBA mice. In contrast, EKC (3.2-100 mg/kg) elicited a biphasic, catalepsy-stereotypy in both strains. The later stereotypic actions of acute EKC, although including sporadic running, were clearly unlike the persistent circling of MRP-stimulation. The LMA responses to MRP and EKC were stereoselective and antagonized by naloxone. Tolerance to the initial depression of activity by MRP in DBA mice developed after chronic administration of either MRP or EKC (32 mg/kg s.c., b.i.d. for 1 week); the intensity of MRP-stimulation, however, increased in both strains. This sensitization to MRP was not overcome with a chronic treatment schedule of 100 mg/kg t.i.d. for 10 days of MRP or EKC. Mice treated chronically with EKC were completely tolerant to its cataleptic and stereotypic effects. Moreover, in these mice EKC elicited a vigorous, MRP-like running fit. Prolonged MRP administration, on the other hand, conferred no tolerance whatsoever to the cataleptic effect of EKC. Taken together with the genetic differences in the acute actions of MRP, this lack of cross-tolerance indicates that distinct neural mechanisms mediate the acute LMA responses to the two narcotics in these mice.


Subsaxibacter sediminis sp. nov., isolated from Arctic glacial sediment and emended description of the genus Subsaxibacter.
A Gram-stain-negative, yellowish-orange pigmented, rod-shaped, motile bacterium, designated strain ARC111T, was isolated from sediment of Arctic permafrost at Midtre Lovénbreen glacier, Svalbard. 16S rRNA gene based identification of strain ARC111T demonstrated highest sequence similarities to Subsaxibacter broadyi P7T (97.8 %) and Subsaxibacter arcticus JCM30334T (97.5 %) and ≤95.2 % with all other members of the family Flavobacteriaceae. Phylogenetic analysis revealed the distinct positioning of strain ARC111T within the genus Subsaxibacter. The G+C content of ARC111T was 37.8±0.5 mol% while DNA-DNA hybridization depicted 35.6 % relatedness with S. arcticus JCM30334T. Strain ARC111T had C15 : 0iso, C16 : 0iso 3-OH, C15 : 1iso G, C15 : 0anteiso, C16 : 1iso H and C17 : 0iso 3-OH as major (>5 % of the total) cellular fatty acids and MK-6 was the predominant respiratory quinone. The polar lipid profile of strain ARC111T consisted of phosphatidylethanolamine, aminolipid and an unidentified lipid. Strain ARC111T harboured sym-homospermidine as the major polyamine. Characteristic differences obtained using polyphasic analysis of strain ARC111T and its closest relatives suggested that strain ARC111T is a novel species of genus Subsaxibacter, for which the name Subsaxibacter sediminis sp. nov. has been proposed. The type strain is ARC111T (=MCC 3191T=KCTC 42965T=LMG 29783T=GDMCC 1.1201T).


eggNOG v4.0: nested orthology inference across 3686 organisms.
With the increasing availability of various 'omics data, high-quality orthology assignment is crucial for evolutionary and functional genomics studies. We here present the fourth version of the eggNOG database (available at http://eggnog.embl.de) that derives nonsupervised orthologous groups (NOGs) from complete genomes, and then applies a comprehensive characterization and analysis pipeline to the resulting gene families. Compared with the previous version, we have more than tripled the underlying species set to cover 3686 organisms, keeping track with genome project completions while prioritizing the inclusion of high-quality genomes to minimize error propagation from incomplete proteome sets. Major technological advances include (i) a robust and scalable procedure for the identification and inclusion of high-quality genomes, (ii) provision of orthologous groups for 107 different taxonomic levels compared with 41 in eggNOGv3, (iii) identification and annotation of particularly closely related orthologous groups, facilitating analysis of related gene families, (iv) improvements of the clustering and functional annotation approach, (v) adoption of a revised tree building procedure based on the multiple alignments generated during the process and (vi) implementation of quality control procedures throughout the entire pipeline. As in previous versions, eggNOGv4 provides multiple sequence alignments and maximum-likelihood trees, as well as broad functional annotation. Users can access the complete database of orthologous groups via a web interface, as well as through bulk download.


The role of the peridomiciliary area in the elimination of Triatoma infestans from rural Argentine communities.
The purpose of this study was to identify the origin of Triatoma infestans reinfestation and study its dynamics following spraying with deltamethrin inside and around 94 houses in three rural communities in northwestern Argentina. The effectiveness of the spraying was evaluated immediately after the houses were sprayed and two months later. In addition, five residual peridomiciliary foci were found and sprayed, as well as three preexisting ones that had not been sprayed. To monitor reinfestation, biosensors were placed in the houses and each family was also asked to capture triatomines and keep them in plastic bags; in addition, triatomines were searched for in and around houses, using an aerosol that dislodged them from their hiding places. Selective sprayings were carried out only where a colony of T. infestans was found. During the 30 months of follow-up, the percentage of houses in which any T. infestans were captured varied between 3% and 9%. In six houses, T. infestans were captured during more than one evaluation. The number of peridomiciliary areas found to be infested (19) was double the number of infested houses (9). Colonies of T. infestans were found only in the peridomiciliary areas, where the number of T. infestans captured was six times higher than in the houses. Chickens were the host most frequently associated with peridomiciliary foci. This area was the origin and principal source of reinfestation. To reduce the speed of reinfestation and the frequency with which sprayings are needed, the following environmental and chemical control methods must be combined in the peridomiciliary area: reduce the number of hiding places of triatomines; restrict the raising of birds to structures that cannot be colonized by triatomines; apply an insecticide that is less likely to be degraded by exposure to the elements, or perform a second spraying 6 to 12 months after the first; and employ a device for early detection of the presence of T. infestans around houses.


Sensitive and frequent identification of high avidity neo-epitope specific CD8 + T cells in immunotherapy-naive ovarian cancer.
Immunotherapy directed against private tumor neo-antigens derived from non-synonymous somatic mutations is a promising strategy of personalized cancer immunotherapy. However, feasibility in low mutational load tumor types remains unknown. Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neo-epitope specific CD8+ T cells has allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naive patients with advanced epithelial ovarian cancer studied. Neo-epitope recognition is discordant between circulating T cells and TILs, and is more likely to be found among TILs, which display higher functional avidity and unique TCRs with higher predicted affinity than their blood counterparts. Our results imply that identification of neo-epitope specific CD8+ T cells is achievable even in tumors with relatively low number of somatic mutations, and neo-epitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.


Nicotine intake by snuff users.
Blood nicotine and cotinine concentrations were measured in 27 volunteers before and after taking snuff. Within 10 minutes after snuffing blood nicotine concentrations were comparable to those obtained after the 10 minutes or so that it takes to smoke a cigarette. Nicotine intake from snuffing was related to the experience of the snuffer. In daily and occasional snuffers increases in plasma nicotine concentrations averaged 77.7 and 12.3 nmol/l (12.6 and 2.0 ng/ml) respectively, while the novices showed no appreciable increase. The increase shown by thea daily snuffers was comparable to the average increase of 62.3 nmol/l (10.1 ng/ml) obtained from a single cigarette by a group of heavy smokers. The peak nicotine concentrations in the daily snuffers were also similar to the peak values in 136 heavy smokers--222.6 and 226-3 nmol/l (36.1 and 36.7 ng/ml), respectively. Unusual multiple-dose snuffing produced massive increases in plasma nicotine to concentrations that have never been recorded in smokers. The similarity of the concentrations produced by regular daily snuffing and regular daily smoking suggests that the plasma nicotine concentration has some controlling influence over the self-regulation of these two quite different forms of tobacco use. The rapid absorption of nicotine from snuff confirms its potential as an acceptable and relatively harmless substitute for smoking.


Particularities of coronary artery disease in hypertensive patients with left bundle branch block.
We mean to investigate whether the presence of hypertension could be associated with a more severe atherosclerotic coronary artery disease in patients with left bundle branch block. To assess the current incidence and meaning of hypertension associated with atherosclerotic coronary artery disease we performed a cross-sectional analysis that included 402 patients with left bundle branch block, admitted between January 2011 and June 2013 in the Cardiovascular Diseases Institute Iasi, Romania. Of these, 194 were hypertensive, especially grade 1 and 2; 272 patients had new or presumably new left bundle branch block on their presenting electrocardiograms. The median follow up was 7 days (hospitalization period). The results of our study show that hypertensive patients were more likely to have a prior history of cardiovascular events, including myocardial infarction, angina pectoris, diabetes and obesity, with statistically significant differences. On the other hand, the normotensive patients had higher rates of current and previous smoking and congestive heart failure. Conventional coronary angiography was performed in 130 (67.01%) hypertensive patients and demonstrated that almost half (41.76%) of them have coronary artery disease, one in five patients being diagnosed with acute coronary syndromes. The majority of hypertensive patients evaluated by coronary angiography had either one or two coronary lesions (28.86%); in contrast, from 110 normotensive patients evaluated by coronary angiography, 78.36% had no vessel disease (p = 0.001). When coronary artery disease was present it was frequently localized on the left descendent artery in both groups, but with statistically significant differences (16.82% in normotensives vs. 32.47% in hypertensives, p = 0.001). With regards to systolic left ventricular function, normotensive patients were more likely to have a decreased ejection fraction (EF) <50% (p <0.001), almost half of them having an EF <30%. We have found that hypertensive patients with left bundle branch block and a clinical context suggestive of acute coronary syndrome have an elevated risk of coronary artery disease, especially one and two coronary lesions. The association of hypertension with left bundle branch block is a high probability criterion for the diagnosis of coronary artery disease, even in asymptomatic patients.


Effectiveness of osteopathic manipulative treatment for carpal tunnel syndrome: a pilot project.
Osteopathic manipulative treatment (OMT) has been recognized as a management option for carpal tunnel syndrome (CTS), although limited research exists to substantiate its effectiveness. To evaluate the effectiveness of OMT in the management of CTS. This single-blinded quasi-controlled trial was conducted at an academic institution. Participants with CTS underwent weekly OMT sessions for 6 consecutive weeks. The main outcome measures were the Boston Carpal Tunnel Syndrome Questionnaire (BCTQ), a sensory symptom diagram (SSD), patient estimate of overall change, electrophysiologic testing of the median nerve (trans-carpal tunnel motor and sensory nerve conduction velocity and amplitude ratio), and carpal tunnel ultrasound imaging of the cross-sectional area of the median nerve and transverse carpal ligament length and bowing. All outcome measures were administered to participants before the first OMT session. Immediately after the first session, electrophysiologic testing of the median nerve and ultrasound imaging of the carpal tunnel were repeated. After 6 weeks of OMT, all outcome measures were readministered. Results of the BCTQ revealed statistically significant improvements in symptoms and function after 6 weeks of OMT (F=11.0; P=.004), and the improvements tended to be more pronounced on the treated side. The drop in SSD scores after 6 weeks of treatment was statistically significant (F=4.19; P=.0002). Patient estimate of overall improvement of symptoms was statistically significant for the treated side. No statistically significant changes in electrophysiologic function of the median nerve, cross-sectional area of the median nerve, or transverse carpal ligament bowing were observed. After treatment, the increase in transverse carpal ligament length was statistically significant, but no side-to-side difference was detected. Osteopathic manipulative treatment resulted in patient-perceived improvement in symptoms and function associated with CTS. However, median nerve function and morphology at the carpal tunnel did not change, possibly indicating a different mechanism by which OMT acted, such as central nervous system processes.


Functional MRI in human somatosensory cortex activated by touching textured surfaces.
MRI revealed activation foci in human somatosensory cortex during protocols involving stimulation of the fingertips with a textured surface. A 2D T2*-weighted gradient echo sequence was used to acquire images. The imaging protocol included acquiring images while subjects performed specific tactile stimulation paradigms (activation scans) or rested. Three different paradigms were used to produce functional activation using a textured surface to rub the fingertips of one hand. First, motor sensory activation was produced by rubbing the textured surface held in one hand against the fingertips of the opposite hand only during the activation scans. Second, the hand holding the textured surface moved throughout the experiment but touched the fingertips of the opposite hand only during the activation scans. Third, subjects remained still in the magnet throughout the entire study while an investigator rubbed the textured surface against the subjects' fingertips during the activation scans. Images were postprocessed using a cross-correlation scheme. The results revealed multiple foci of motor sensory activation near the central sulcus, postcentral sulcus, and prefrontal cortex.


A pilot randomized trial comparing long-term effects of red and white wines on biomarkers of atherosclerosis (in vino veritas: IVV trial).
Since early 90', growing body of evidence indicates that the Mediterranean diet with mild to moderate consumption of wine, mostly red wine, has a protective effect on cardiovascular diseases. Several mechanisms have been discussed to participate in the beneficial effect of red wine, such as antioxidant or vasodilating activity. However, later it has been shown that also other alcoholic beverages have a protective effect on atherosclerosis. Up to now, data from the prospective, long-term, head-to-head comparisons of the effects of different drinks on markers of atherosclerosis are insufficient. The IVV (in vino veritas) study is a long-term, prospective, multicenter, randomized trial comparing the effect of red and white wines on the markers of atherosclerosis. One hundred and twenty healthy subjects with mild to moderate risk of atherosclerosis will be randomized to regular consumption of red wine (Pinot Noir) or white wine (Chardonnay-Pinot) for one year. The primary endpoint is the level of HDL-cholesterol at one year, while secondary endpoints are levels of other markers of atherosclerosis (LDL-cholesterol, C-reactive protein, myeloperoxidase, advanced oxidation protein product, interleukins 6 and 18, matrix metalloproteinases, glutathione s-transferase, monocyte chemoattractant protein 1, soluble CD40L). The IVV trial is the first study focusing on the long-term prospective comparison of the effects of red and white wines consumption on HDL-cholesterol and other markers of atherosclerosis. Results of the IVV trial may extend our understanding of the widely discussed "French paradox" (Tab. 1, Ref. 21)


Lanthanide complexes with aromatic o-phosphorylated ligands: synthesis, structure elucidation and photophysical properties.
Lanthanide complexes LnL3 (Ln = Sm, Eu, Tb, Dy, Tm, Yb, Lu) with aromatic o-phosphorylated ligands (HL(1) and HL(2)) have been synthesized and identified. Their molecular structure was proposed on the basis of a new complex approach, including DFT calculations, Sparkle/PM3 modelling, EXAFS spectroscopy and luminescent probing. The photophysical properties of all of the complexes were investigated in detail to obtain a deeper insight into the energy transfer processes.


Discriminating the earliest stages of mammary carcinoma using myoepithelial and proliferative markers.
Mammographic screening has led to increased detection of breast cancer at a pre-invasive state, hence modelling the earliest stages of breast cancer invasion is important in defining candidate biomarkers to predict risk of relapse. Discrimination of pre-invasive from invasive lesions is critically important for such studies. Myoepithelial cells are the barrier between epithelial cells and the surrounding stroma in the breast ductal system. A number of myoepithelial immunohistochemistry markers have been identified and validated in human tissue for use by pathologists as diagnostic tools to distinguish in situ carcinoma from invasive breast cancer. However, robust myoepithelial markers for mouse mammary tissue have been largely under-utilised. Here, we investigated the utility of the myoepithelial markers smooth muscle actin (SMA), smooth muscle myosin heavy chain (SMMHC), cytokeratin-14 (CK14) and p63 to discriminate mammary intraepithelial neoplasia (MIN) from invasive disease in the C57BL/6J MMTV-PyMT transgenic model of mammary carcinoma. We identified that SMMHC and CK14 are retained in early in situ neoplasia and are appropriate markers for distinguishing MIN from invasive disease in this model. Additionally, the proliferation marker Ki67 is a superior marker for differentiating between normal and hyperplastic ducts, prior to the development of MIN. Based on this, we developed a scoring matrix for discriminating normal, hyperplasia, MIN and invasive lesions in this spontaneous mammary tumorigenesis model. This study demonstrates heterogeneous expression of myoepithelial proteins throughout tumour development, and highlights the need to characterise the most appropriate markers in other models of early breast cancer to allow accurate classification of disease state.


Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 × 2 factorial, double-blind, randomised controlled trial.
Standard treatment for thyroid eye disease is with systemic corticosteroids. We aimed to establish whether orbital radiotherapy or antiproliferative immunosuppression would confer any additional benefit. CIRTED was a multicentre, double-blind, randomised controlled trial with a 2 × 2 factorial design done at six centres in the UK. Adults with active moderate-to-severe thyroid eye disease associated with proptosis or ocular motility restriction were recruited to the trial. Patients all received a 24 week course of oral prednisolone (80 mg per day, reduced to 20 mg per day by 6 weeks, 10 mg per day by 15 weeks, and 5 mg per day by 21 weeks) and were randomly assigned via remote computerised randomisation to receive either radiotherapy or sham radiotherapy and azathioprine or placebo in a 2 × 2 factorial design. Randomisation included minimisation to reduce baseline disparities in potential confounding variables between trial interventions. Patients and data analysts were masked to assignment, whereas trial coordinators (who monitored blood results), pharmacists, and radiographers were not. The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in ten to 12 fractions over 2 to 3 weeks. Azathioprine treatment was provided for 48 weeks at 100-200 mg per day (dispensed as 50 mg tablets), depending on bodyweight (100 mg for <50 kg, 150 mg 50-79 kg, 200 mg for ≥80 kg). The primary outcomes were a binary composite clinical outcome score and an ophthalmopathy index at 48 weeks, and a clinical activity score at 12 weeks. The primary analysis was based on the intention-to-treat allocation and safety was assessed in all participants. This study is registered with ISRCTN, number 22471573. Between Feb 15, 2006, and Oct 3, 2013, 126 patients were recruited and randomly assigned to groups: 31 patients to radiotherapy plus azathioprine, 31 to sham radiotherapy and azathioprine, 32 to radiotherapy and placebo, and 32 to sham radiotherapy and placebo. Outcome data were available for 103 patients (54 for sham radiotherapy vs 49 for radiotherapy and 53 for placebo vs 50 for azathioprine), of whom 84 completed their allocated treatment of radiotherapy or sham radiotherapy and 57 continued to take azathioprine or placebo up to 48 weeks. There was no interaction betweeen azathioprine and radiotherapy (pinteraction=0·86). The adjusted odds ratio (ORadj) for improvement in the binary clinical composite outcome measure was 2·56 (95% CI 0·98-6·66, p=0·054) for azathioprine and 0·89 (0·36-2·23, p=0·80) for radiotherapy. In a post-hoc analysis of patients who completed their allocated therapy the ORadj for improvement was 6·83 (1·66-28·1, p=0·008) for azathioprine and 1·32 (0·30-4·84, p=0·67) for radiotherapy. The ophthalmopathy index, clinical activity score, and numbers of adverse events (161 with azathioprine and 156 with radiotherapy) did not differ between treatment groups. In both groups, the most common adverse events were mild infections. No patients died during the study. In patients receiving oral prednisolone for 24 weeks, radiotherapy did not have added benefit. We also did not find added benefit for addition of azathioprine in the primary analysis; however, our conclusions are limited by the high number of patients who withdrew from treatment. Results of post-hoc analysis of those who completed the assigned treatment suggest improved clinical outcome at 48 weeks with azathioprine treatment. National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.


Clinical Effectiveness of Co-trimoxazole vs. Amoxicillin in the Treatment of Non-Severe Pneumonia in Children in India: A Randomized Controlled Trial.
Acute respiratory infection (ARI) in young children is responsible for an estimated 4.1 million deaths worldwide of which approximately 90% are due to pneumonia. To study the clinical effectiveness of co-trimoxazole versus amoxicillin in the treatment of non-severe pneumonia, as defined by WHO, in children in the age group of 02 months to 5 years. Randomized Control Trial study was conducted in out patient department of a large tertiary care hospital after taking consent from parents and ethical committee clearance. Children in study group were treated with amoxicillin (40 mg/kg/day in 3 divided doses) and those in control group were treated with co-trimoxazole (8 mg/kg/day of trimethoprim in 2 divided doses). All cases were reviewed on second and fifth day. The effectiveness and therapy failure were decided on the basis of clinical, radiological and complete blood count results. Two hundred and four cases of non severe pneumonia were studied. All cases were diagnosed on the basis of clinical criteria, as defined by WHO. Treatment failure was seen in 8.09% cases with amoxicillin and 39.05% cases with co-trimoxazole. Cost of one complete course with amoxicillin was 2.3 times higher than with co-trimoxazole. Compliance of therapy to co-trimoxazole (90.47%) was better than to amoxicillin (83.84%). The response to treatment with amoxicillin is faster, however, compliance is slightly poorer and cost of treatment high. In order to improve the compliance, better counseling and more studies are required to ascertain the efficacy of amoxicillin in higher dosage over a shorter period of time.


Evidence for the effectiveness of police-based pre-booking diversion programs in decriminalizing mental illness: A systematic literature review.
People with mental illnesses are at a significantly greater risk of police arrest than the general population. This pattern of arrests has been associated with a phenomenon referred to as the criminalization of mental illness such that people with mental illnesses are inappropriately diverted to the criminal justice system rather than to treatment. To decrease arrests of people with mental illnesses experiencing a crisis, pre-booking diversion programs have been developed to intervene at the point of police contact. This systematic literature review examines the state of knowledge regarding the effectiveness of police-based pre-booking diversion programs by addressing the question, "What is the evidence for the effectiveness of police-based pre-booking diversion programs in reducing arrests (i.e., reducing criminalization) of people with mental illnesses?" Systematic literature searches of seven databases were performed during May 2017. The searches sought to identify studies that examined the effectiveness of pre-booking diversion programs in decreasing arrests. A multi-phase screening process was completed independently by two pairs of reviewers as well as a risk of bias review. A total of 2,750 unique citations were identified. Of these, 4 met the inclusion/exclusion criteria; all were from the US. Three of the studies examined the effectiveness of Crisis Intervention Teams and one study looked at a mobile crisis program. Two of the studies were at moderate risk of bias and two at high risk. This review indicates that this line of inquiry is still developing. There are a number of gaps yet to be filled. The current evidence for the effectiveness of police-based pre-booking diversion programs in reducing arrests (i.e., reducing criminalization) of people with mental illnesses is limited. However, these studies indicate there is moderate evidence that these programs increase linkages to mental health services.


The effects of erythropoiesis-stimulating agents on the short-term and long-term survivals in metastatic breast cancer patients receiving chemotherapy: a SEER population-based study.
Current clinical guidelines state that the use of erythropoiesis-stimulating agents (ESAs) may be considered to treat chemotherapy-induced anemia in the non-curative setting to alleviate anemia-related symptoms. However, no convincing survival benefit has been demonstrated to support the use of ESAs in these patients. Using the comprehensive data collected in the National Cancer Institute (NCI)-surveillance epidemiology and end results (SEER) and Medicare-linked database, we analyzed the effect of ESA use on the short-term (18-month) and long-term (60-month) survival rates of chemotherapy-treated metastatic breast cancer patients. Confounding variables were adjusted using a propensity score approach. We also analyzed the effects of ESA on the survival of patients receiving trastuzumab, a commonly prescribed targeted therapy agent in treating HER2-positive tumors. Metastatic breast cancer patients who received ESA treatment exhibited similar 60-month survival rate to those without ESA treatment (22.8 vs. 24.9%, p = 0.8). ESA-treated patients had a trend toward better 18-month survival [crude hazard ratio (HR) 0.86, 95% confidence intervals (CI) 0.68-1.09, p = 0.21]. This protective effect during the first 18 months of chemotherapy became marginally significant after adjusting for the propensity of receiving ESAs (HR 0.80, 95% CI 0.63-1.01, p = 0.070). An interaction effect between ESA and trastuzumab on patient survival was noticeable but not statistically significant. ESAs did not negatively affect the long-term survival of metastatic breast cancer patients. Moreover, ESAs improved patients' survival during the first 18 months of chemotherapy treatment. These findings endorse the current clinical guideline. Given the short survival of these patients, the potential short-term beneficial effects of ESAs are clinically meaningful.


Home exposure to Arabian incense (bakhour) and asthma symptoms in children: a community survey in two regions in Oman.
Incense burning has been reported to adversely affect respiratory health. The aim of this study was to explore whether exposure to bakhour contributes to the prevalence of asthma and/or triggers its symptoms in Omani children by comparing two Omani regions with different prevalence of asthma. A randomly selected sample of 10 years old schoolchildren were surveyed using an Arabic version of ISAAC Phase II questionnaires with the addition of questions concerning the use and effect of Arabian incense on asthma symptoms. Current asthma was defined as positive response to wheeze in the past 12 months or positive response to "ever had asthma" together with a positive response to exercise wheeze or night cough in the past 12 months. Simple and multivariable logistic regression analyses were performed to estimate the effect of bakhour exposure and other variables on current asthma diagnosis and parents' response to the question: "Does exposure to bakhour affect your child breathing?" Of the 2441 surveyed children, 15.4% had current asthma. Bakhour use more than twice a week was three times more likely to affect child breathing compared to no bakhour use (adjusted OR 3.01; 95% CI 2.23-4.08) and this effect was 2.55 times higher in asthmatics (adjusted OR 2.55; 95% CI 1.97-3.31) compared to non-asthmatics. In addition, bakhour caused worsening of wheeze in 38% of the asthmatics, making it the fourth most common trigger factor after dust (49.2%), weather (47.6%) and respiratory tract infections (42.2%). However, there was no significant association between bakhour use and the prevalence of current asthma (adjusted OR 0.87; 95% CI 0.63-1.20). Arabian incense burning is a common trigger of wheezing among asthmatic children in Oman. However, it is not associated with the prevalence asthma.