An integrated study of health, environmental and socioeconomic indicators in a mining-impacted community exposed to metal enrichment.
The occurrence of toxic metals and metalloids associated with mine tailings is a serious public health concern for communities living in mining areas. This work explores the relationship between metal occurrence (e.g., spatial distribution in street dusts), human health indicators (e.g., metals in urine samples, lifestyle and self-reported diseases) and socioeconomic status (SES) using Chañaral city (in northern Chile) as study site, where a copper mine tailing was disposed in the periurban area. This study model may shed light on the development of environmental and health surveillance plans on arid cities where legacy mining is a sustainability challenge. High concentrations of metals were found in street dust, with arsenic and copper concentrations of 24 ± 13 and 607 ± 911 mg/kg, respectively. The arsenic concentration in street dust correlated with distance to the mine tailing (r = - 0.32, p-value = 0.009), suggesting that arsenic is dispersed from this source toward the city. Despite these high environmental concentrations, urinary levels of metals were low, while 90% of the population had concentrations of inorganic arsenic and its metabolites in urine below 33.2 µg/L, copper was detected in few urine samples (< 6%). Our results detected statistically significant differences in environmental exposures across SES, but, surprisingly, there was no significant correlation between urinary levels of metals and SES. Despite this, future assessment and control strategies in follow-up research or surveillance programs should consider environmental and urinary concentrations and SES as indicators of environmental exposure to metals in mining communities.


Two structurally different dienelactone hydrolases (TfdEI and TfdEII) from Cupriavidus necator JMP134 plasmid pJP4 catalyse cis- and trans-dienelactones with similar efficiency.
In this study, dienelactone hydrolases (TfdEI and TfdEII) located on plasmid pJP4 of Cupriavidus necator JMP134 were cloned, purified, characterized and three dimensional structures were predicted. tfdEI and tfdEII genes were cloned into pET21b vector and expressed in E. coli BL21(DE3). The enzymes were purified by applying ultra-membrane filtration, anion-exchange QFF and gel-filtration columns. The enzyme activity was determined by using cis-dienelactone. The three-dimensional structure of enzymes was predicted using SWISS-MODEL workspace and the biophysical properties were determined on ExPASy server. Both TfdEI and TfdEII (Mr 25 kDa) exhibited optimum activity at 37°C and pH 7.0. The enzymes retained approximately 50% of their activity after 1 h of incubation at 50°C and showed high stability against denaturing agents. The TfdEI and TfdEII hydrolysed cis-dienelactone at a rate of 0.258 and 0.182 µMs(-1), with a Km value of 87 µM and 305 µM, respectively. Also, TfdEI and TfdEII hydrolysed trans-dienelactone at a rate of 0.053 µMs(-1) and 0.0766 µMs(-1), with a Km value of 84 µM and 178 µM, respectively. The TfdEI and TfdEII kcat/Km ratios were 0.12 µM(-1) s(-1) and 0.13 µM(-1) s(-1) and 0.216 µM(-1) s(-1) and 0.094 µM(-1) s(-1) for for cis- and trans-dienelactone, respectively. The kcat/Km ratios for cis-dienelactone show that both enzymes catalyse the reaction with same efficiency even though Km value differs significantly. This is the first report to characterize and compare reaction kinetics of purified TfdEI and TfdEII from Cupriavidus necator JMP134 and may be helpful for further exploration of their catalytic mechanisms.


Scrutinizing the SARS-CoV-2 protein information for designing an effective vaccine encompassing both the T-cell and B-cell epitopes.
Novel SARS coronavirus (SARS-CoV-2) has caused a pandemic condition worldwide. It has been declared as a public health emergency of international concern by WHO in a very short span of time. The community transmission of this highly infectious virus has severely affected various parts of China, Italy, Spain, India, and USA, among others. The prophylactic solution against SARS-CoV-2 infection is challenging due to the high mutation rate of its RNA genome. Herein, we exploited a next-generation vaccinology approach to construct a multi-epitope vaccine candidate against SARS-CoV-2 that is predicted to have high antigenicity, safety, and efficacy to combat this deadly infectious agent. The whole proteome was scrutinized for the screening of highly conserved, antigenic, non-allergen, and non-toxic epitopes having high population coverage that can elicit both humoral and cellular mediated immune response against COVID-19 infection. These epitopes along with four different adjuvants, were utilized to construct a multi-epitope-vaccine candidate that can generate strong immunological memory response having high efficacy in humans. Various physiochemical analyses revealed the formation of a stable vaccine product having a high propensity to form a protective solution against the detrimental SARS-CoV-2 strain with high efficacy. The vaccine candidate interacted with immunological receptor TLR3 with a high affinity depicting the generation of innate immunity. Further, the codon optimization and in silico expression show the plausibility of the high expression and easy purification of the vaccine product. Thus, this present study provides an initial platform for the rapid generation of an efficacious protective vaccine for combating COVID-19.


Response bias, weighting adjustments, and design effects in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).
The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi-component epidemiological and neurobiological study designed to generate actionable recommendations to reduce US Army suicides and increase knowledge about determinants of suicidality. Three Army STARRS component studies are large-scale surveys: one of new soldiers prior to beginning Basic Combat Training (BCT; n = 50,765 completed self-administered questionnaires); another of other soldiers exclusive of those in BCT (n = 35,372); and a third of three Brigade Combat Teams about to deploy to Afghanistan who are being followed multiple times after returning from deployment (n = 9421). Although the response rates in these surveys are quite good (72.0-90.8%), questions can be raised about sample biases in estimating prevalence of mental disorders and suicidality, the main outcomes of the surveys based on evidence that people in the general population with mental disorders are under-represented in community surveys. This paper presents the results of analyses designed to determine whether such bias exists in the Army STARRS surveys and, if so, to develop weights to correct for these biases. Data are also presented on sample inefficiencies introduced by weighting and sample clustering and on analyses of the trade-off between bias and efficiency in weight trimming.


Radiotherapy for stages I and II testicular seminoma: results and morbidity in 238 patients.
We have undertaken a retrospective analysis of 238 patients with Stages I and II seminoma of the testis treated with radiotherapy in Edinburgh between 1974 and 1989. There were five deaths from seminoma. Cause-specific survival for the whole group at 2 and 5 years was 99.2% and 98.1%, respectively. Cause-specific survival at 2 and 5 years by stage (Royal Marsden staging classification) was: Stage I, 99.5% and 98.7% and Stage II, 98.1% and 96.1%. Fourteen (5.9%) patients relapsed (one after treatment for his second testicular seminoma). Eight were given successful salvage treatment, five died of seminoma and one died of intercurrent disease. 13 (5.5%) patients developed World Health Organisation (WHO) grade 3 gastrointestinal or haematological toxicity and two developed grade 4 gastrointestinal toxicity as a result of abdominal radiotherapy. 22 patients (9.2%) developed problems ascribed to late morbidity of abdominal radiotherapy including 18 with peptic ulcer disease. Contralateral testicular tumours occurred in seven (2.9%) patients and five (2.1%) patients developed malignancies at other sites.


Nanomedicine: de novo design of nanodrugs.
Phenomenal advances in nanotechnology and nanoscience have been accompanied by exciting progress in de novo design of nanomedicines. Nanoparticles with their large space of structural amenability and excellent mechanical and electrical properties have become ideal candidates for high efficacy nanomedicines in both diagnostics and therapeutics. The therapeutic nanomedicines can be further categorized into nanocarriers for conventional drugs and nanodrugs with direct curing of target diseases. Here we review some of the recent advances in de novo design of nanodrugs, with an emphasis on the molecular level understanding of their interactions with biological systems including key proteins and cell membranes. We also include some of the latest advances in the development of nanocarriers with both passive and active targeting for completeness. These studies may shed light on a better understanding of the molecular mechanisms behind these nanodrugs, and also provide new insights and direction for the future design of nanomedicines.


Vortioxetine Treatment Reverses Subchronic PCP Treatment-Induced Cognitive Impairments: A Potential Role for Serotonin Receptor-Mediated Regulation of GABA Neurotransmission.
Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine's effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine's cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating vortioxetine's effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to vortioxetine treatment, and subchronic vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA's affinity for the GABAA receptor. These data suggest that vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that vortioxetine's GABAergic and glutamatergic effects are relevant for cognitive function.


Metabolic profiling based on two-dimensional J-resolved 1H NMR data and parallel factor analysis.
Metabolic profiling of natural products is used to map correlated concentration variances of known and unknown secondary metabolites in extracts. NMR-spectroscopy is in this respect regarded as a convenient and reproducible technique with the ability to detect a wide range of small organic compounds. Two-dimensional J-resolved NMR-spectra are used in this context to resolve overlapping signals by separating the effect of J-coupling from the effect of chemical shifts. Often one-dimensional projections of these data are used as input for standard multivariate statistical methods, and only the intensity variances along the chemical shift axis are taken into account. Here, we describe the use of parallel factor analysis (PARAFAC) as a tool to preprocess a set of two-dimensional J-resolved spectra with the aim of keeping the J-coupling information intact. PARAFAC is a mathematical decomposition method that fits three-way experimental data to a model whose parameters in this case reflect concentrations and individual component spectra along the chemical shift axis and corresponding profiles along the J-coupling axis. A set of saffron samples, directly extracted with methanol-d(4), were used as a model system to evaluate the feasibility and merits of the method. To successfully use PARAFAC, the two-dimensional spectra (n = 96) had to be aligned and processed in narrow windows (0.04 ppm wide) along the chemical shift axis. Selection of windows and number of components for each PARAFAC-model was done automatically by evaluating amount of explained variance and core consistency values. Score plots showing the distribution of objects in relation to each other, and loading plots in the form of two-dimensional pseudospectra with the same appearance as the original J-resolved spectra but with positive and negative contributions are presented. Loadings are interpreted not only in terms of signals with different chemical shifts but also the associated J-coupling profiles.


Childhood socio-economic status, school failure and drug abuse: a Swedish national cohort study.
To investigate whether socio-economic status (SES) in childhood and school failure at 15 years of age predict illicit drug abuse in youth and young adulthood. Register study in a Swedish national cohort born 1973-88 (n = 1,405,763), followed from age 16 to 20-35 years. Cox regression analyses were used to calculate hazard ratios (HR) for any indication of drug abuse. Our outcomes were hospital admissions, death and criminality associated with illicit drug abuse. Data on socio-demographics, school grades and parental psychosocial problems were collected from censuses (1985 and 1990) and national registers. School failure was defined as having mean school grades from the final year in primary school lower than -1 standard deviation and/or no grades in core subjects. School failure was a strong predictor of illicit drug abuse with an HR of 5.87 (95% CI: 5.76-5.99) after adjustment for age and sex. Childhood SES was associated with illicit drug abuse later in life in a stepwise manner. The lowest stratum had a HR of 2.28 (95% CI: 2.20-2.37) compared with the highest stratum as the reference, when adjusted for other socio-demographic variables. In the fully adjusted model, the effect of SES was greatly attenuated to an HR of 1.23 (95% CI: 1.19-1.28) in the lowest SES category, while the effect of school failure remained high with an HR of 4.22 (95% CI: 4.13-4.31). School failure and childhood socio-economic status predict illicit drug abuse independently in youth and young adults in Sweden.


Long-lasting pro-ictogenic effects induced in vivo by rat brain exposure to serum albumin in the absence of concomitant pathology.
Dysfunction of the blood-brain barrier (BBB) is a common finding during seizures or following epileptogenic brain injuries, and experimentally induced BBB opening promotes seizures both in naive and epileptic animals. Brain albumin extravasation was reported to promote hyperexcitability by inducing astrocytes dysfunction. To provide in vivo evidence for a direct role of extravasated serum albumin in seizures independently on the pathologic context, we did the following: (1) quantified the amount of serum albumin extravasated in the rat brain parenchyma during status epilepticus (SE); (2) reproduced a similar concentration in the hippocampus by intracerebroventricular (i.c.v.) albumin injection in naive rats; (3) measured electroencephalography (EEG) activity in these rats, their susceptibility to kainic acid (KA)-induced seizures, and their hippocampal afterdischarge threshold (ADT). Brain albumin concentration was measured in the rat hippocampus and other forebrain regions 2 and 24 h after SE by western blot analysis. Brain distribution of serum albumin or fluorescein isothiocyanate (FITC)-albumin was studied by immunohistochemistry and immunofluorescence, respectively. Naive rats were injected with rat albumin or FITC-albumin, i.c.v., to mimic the brain concentration attained after SE, or with dextran used as control. Inflammation was evaluated by immunohistochemistry by measuring glial induction of interleukin (IL)-1β. Western blot analysis was used to measure inward rectifying potassium channel subunit Kir4.1 protein levels in the hippocampus. Seizures were induced in rats by intrahippocampal injection of 80 ng KA and quantified by EEG analysis, 2 or 24 h after rat albumin or dextran administration. ADT was measured by electrical stimulation of the hippocampus 3 months after albumin injection. In these rats, EEG was continuously monitored for 2 weeks to search for spontaneous seizures. The hippocampal serum albumin concentration 24 h post-SE was 0.76 ± 0.21 μm. Similar concentrations were measured in other forebrain regions, whereas no changes were found in cerebellum. The hippocampal albumin concentration was similarly reproduced in naive rats by i.c.v. administration of 500 μg/4 μl rat albumin: albumin was predominantly detected extracellularly 2 h after injection, whereas at 24 h it was visible inside pyramidal neurons and in only a few scattered chondroitin sulphate proteoglycan (NG2)-positive cells, but not in glial fibrillary acidic protein (GFAP)-positive astrocytes or CR-3 complement receptor (OX-42)-positive microglia. The presence of albumin in naive rat hippocampus was associated with induced IL-1β in GFAP-positive astrocytes and a concomitant tissue down-regulation of Kir4.1. Spiking activity was evoked by albumin in the hippocampus lasting for 2 h. When KA was intrahippocampally applied either 2 or 24 h after albumin injection, the number of total interictal spikes in 3 h EEG recording was significantly increased by twofold on average. Three months after albumin injection, neither albumin nor inflammation was detected in brain tissue; at this time, the ADT was reduced by 50% but no spontaneous seizures were observed. Transient hippocampal exposure to albumin levels similar to those attained after prominent BBB breakdown resulted in increased seizure susceptibility and long-term reduction in seizure threshold, but it did not evoke spontaneous seizures. These effects may be mediated by albumin-induced astrocytes dysfunction and the associated induction of proinflammatory molecules.


Symptom burden among head and neck cancer patients in the first year after diagnosis: Association with primary treatment modality.
Head and neck cancer (HNC) and its treatment affects quality of life, with significant symptom burden. The main objectives of this study were to examine symptom trajectories of HNC patients by treatment and to identify factors associated with high ESAS scores. We conducted a retrospective cohort study in patients diagnosed with HNC in Ontario, Canada from 2007 to 2015 using linked health administrative databases. The primary outcome was a monthly patient self-reported moderate-to-severe (≥4) symptom score in the year following diagnosis. Multivariable Modified Poisson regression analyses with robust variance were used to investigate factors associated with moderate-to-severe scores. Of 13,827 HNC patients identified, 4793 had ≥1 ESAS assessment within 12 months of cancer diagnosis. Overall, 60% (n = 2708) and 65% (n = 2903) of patients reported moderate-to-severe pain and poor appetite, respectively. The proportion of patients reporting a score ≥4 increased significantly during treatment and was most pronounced for those who received chemoradiation (CRT). On multivariable analysis, patients who were female (Relative Risk (RR) 1.15, 95% CI 1.08-1.23, received CRT, had a higher comorbidity burden (RR 1.31, 1.23-1.39), and had a diagnosis of oropharyngeal (1.10, 1.02-1.19), or oral cavity cancer (1.31, 1.19-1.45), were at an increased risk of reporting severe pain scores (p < 0.01 for all). The majority of HNC patients report high pain scores, with symptom burden highest during the treatment phase, and especially for patients who received radiation or chemoradiation. This large study highlights the need for proactive symptom management during the HNC patients' cancer journey.


Preclinical studies of human immunodeficiency virus/AIDS vaccines: inverse correlation between avidity of anti-Env antibodies and peak postchallenge viremia.
A major challenge for human immunodeficiency virus (HIV)/AIDS vaccines is the elicitation of anti-Env antibodies (Ab) capable of neutralizing the diversity of isolates in the pandemic. Here, we show that high-avidity, but nonneutralizing, Abs can have an inverse correlation with peak postchallenge viremia for a heterologous challenge. Vaccine studies were conducted in rhesus macaques using DNA priming followed by modified vaccinia Ankara boosting with HIV type 1 (HIV-1) immunogens that express virus-like particles displaying CCR5-tropic clade B (strain ADA) or clade C (IN98012) Envs. Rhesus granulocyte-macrophage colony-stimulating factor was used as an adjuvant for enhancing the avidity of anti-Env Ab responses. Challenge was with simian/human immunodeficiency virus (SHIV)-162P3, a CCR5-tropic clade B chimera of SIV and HIV-1. Within the groups receiving the clade B vaccine, a strong inverse correlation was found between the avidity of anti-Env Abs and peak postchallenge viremia. This correlation required the use of native but not gp120 or gp140 forms of Env for avidity assays. The high-avidity Ab elicited by the ADA Env had excellent breadth for the Envs of incident clade B but not clade C isolates, whereas the high-avidity Ab elicited by the IN98012 Env had excellent breadth for incident clade C but not clade B isolates. High-avidity Ab elicited by a SHIV vaccine with a dual-tropic clade B Env (89.6) had limited breadth for incident isolates. Our results suggest that certain Envs can elicit nonneutralizing but high-avidity Ab with broad potential for blunting incident infections of the same clade.


Soluble antigen traffics rapidly and selectively from the corneal surface to the eye draining lymph node and activates T cells when codelivered with CpG oligonucleotides.
The transport of antigen to the secondary lymphoid tissue is a central component in the initiation of the adaptive immune response. The mechanism of antigen delivery to the DLN from the avascular cornea has not been fully explored. Previous studies in the mouse have shown that cell-associated corneal antigen is delivered within 6 h to the eye draining SM DLN via DCs and macrophages. In this study, we used a system in which antigen and the processed p-MHCII complexes derived from the antigen could be tracked in vivo. We report that soluble antigen applied to an abraded cornea in the mouse is transported rapidly (within 30 min) to the SM DLN, where a proportion is taken up by resident DCs and presented as p-MHCII complexes, while the larger part is cleared by 8 h. At a later time, a second wave of antigen transport in migratory DCs enters the DLN and participates in further continued antigen presentation. With the use of an antigen-specific TCR transgenic mouse system, we demonstrate that T cell activation does not occur during the early stages of soluble antigen delivery to LN, even though p-MHCII complexes are generated. Antigen-specific T cell activation occurs in the later, presumed cell-associated phase but requires codelivery of a "danger" signal, such as the TLR ligand CpG. We suggest that the early delivery of soluble antigen is more likely to induce T cell nonresponsiveness (anergy) unless presented in the context of an innate-immune cell activation (danger) signal.


The role of nutraceuticals in prevention and treatment of hypertension: An updated review of the literature.
Hypertension (HTN) is a worldwide epidemic in both developed and developing countries. It is one of the leading causes of major health problems such as cardiovascular disease, stroke, and heart attack. In recent years, several studies have reported associations between specific dietary ingredients and improving HTN. Nutraceuticals are natural food components with pharmacological properties. Reports suggest that functional foods and nutraceutical ingredients might support patients to obtain the desired therapeutic blood pressure (BP) goals and reduce cardiovascular risks by modulating various risk factors such as oxidative stress, renin-angiotensin system hyperactivity, inflammation, hyperlipidemia, and vascular resistance. We review the recent clinical experiments that have evaluated the biological and pharmacological activities of several types of nutraceuticals, including sour tea, cocoa, common spices, vitamin C, vitamin E, lycopene, flavonoids, coenzyme Q10, milk's tripeptides, calcium, magnesium, polyunsaturated fatty acids, and prebiotics in preventing and treating HTN. This review summarizes recent knowledge about the impact of common nutraceuticals for the regulation of BP.


Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?
In human pregnancy, placental cytotrophoblasts that invade the uterus downregulate the expression of adhesion receptors that are characteristic of their epithelial origin, and upregulate the expression of adhesion receptors that are expressed by vascular cells. We suggest that this transformation could be critical to endovascular invasion, the process whereby cytotrophoblasts invade the uterine spiral arterioles and line their walls (Zhou et al. J. Clin. Invest. 1997. 99: 2139-2151.). To better understand the in vivo significance of these findings, we tested the hypothesis that in preeclampsia, an important disease of pregnancy in which endovascular invasion is abrogated, cytotrophoblasts fail to adopt a vascular adhesion phenotype. In experiments described here we stained placental bed biopsy specimens from age-matched control pregnancies and from those complicated by preeclampsia with antibodies that recognize adhesion molecules that are normally modulated during this transformation. In preeclampsia, differentiating/invading cytotrophoblasts fail to express properly many of these molecules, including integrin, cadherin, and Ig superfamily members. These results suggest that preeclampsia is associated with failure of cytotrophoblasts to mimic a vascular adhesion phenotype. The functional consequences of this abnormality are unknown, but are likely to affect negatively cytotrophoblast endovascular invasion and uterine arteriole remodeling, thereby compromising blood flow to the maternal-fetal interface.


Quasi-optimum pseudo-Lambertian reflecting concentrators: an analysis.
In this work we analyze a two-stage concentrator in which the first stage is reflective and the second stage considers the first one as a Lambertian source in order to obtain the highest possible gain. We determine the profile and the position of this first stage, which happens to be a parabola, and we calculate the value of the gain as a function of the acceptance angle and the focal length of the first stage.


Finding gene-expression patterns in bacterial biofilms.
The production of biofilms by bacteria is a lifestyle that is thought to require or involve a differential gene expression compared with that of planktonic bacteria. Recently, we have witnessed a change of focus from the simple hunt for hypothetical essential biofilm genes to the identification of late and more complex biofilm functions. However, finding common bacterial biofilm gene-expression patterns through global expression analysis remains difficult. Owing to the apparently minimal overlap between functions involved in biofilm formation by different bacteria, exploring the biofilm lifestyle could prove to be a case-by-case task for which global approaches show their limits.


Comparing Survival Outcomes and Costs Associated With Radical Cystectomy and Trimodal Therapy for Older Adults With Muscle-Invasive Bladder Cancer.
Radical cystectomy is the guidelines-recommended treatment of muscle-invasive bladder cancer, but a resurgence of trimodal therapy has occurred. Limited comparative data are available on outcomes and costs attributable to these 2 treatments. To compare the survival outcomes and costs between trimodal therapy and radical cystectomy in older adults with muscle-invasive bladder cancer. This population-based cohort study used data from the Surveillance, Epidemiology, and End Results-Medicare linked database. A total of 3200 older adults (aged ≥66 years) with clinical stage T2 to T4a bladder cancer diagnosed from January 1, 2002, to December 31, 2011, and with claims data available through December 31, 2013, were included in the analysis. Patients who received radical cystectomy underwent either only surgery or surgery in combination with radiotherapy or chemotherapy. Patients who received trimodal therapy underwent transurethral resection of the bladder followed by radiotherapy and chemotherapy. Propensity score matching by sociodemographic and clinical characteristics was used. Data analysis was performed from August 1, 2017, to March 11, 2018. Overall survival and cancer-specific survival were evaluated using the Cox proportional hazards regression model and the Fine and Gray competing risk model. All Medicare health care costs for inpatient, outpatient, and physician services within 30, 90, and 180 days of treatment were compared. The total amount spent nationwide was estimated, using 180-day medical costs between treatments, by the total number of new cases of muscle-invasive bladder cancer in the United States in 2011. Of the 3200 patients who met the inclusion criteria, 2048 (64.0%) were men and 1152 (36.0%) were women, with a mean (SD) age of 75.8 (6.0) years. After propensity score matching, 687 patients (21.5%) underwent trimodal therapy and 687 patients (21.5%) underwent radical cystectomy. Patients who underwent trimodal therapy had significantly decreased overall survival (hazard ratio [HR], 1.49; 95% CI, 1.31-1.69) and cancer-specific survival (HR, 1.55; 95% CI, 1.32-1.83). No differences in costs at 30 days were observed between trimodal therapy ($15 233 in 2002 vs $18 743 in 2011) and radical cystectomy ($17 990 in 2002 vs $21 738 in 2011). However, median total costs were significantly higher with trimodal therapy than with radical cystectomy at 90 days ($80 174 vs $69 181; median difference, $8964; Hodges-Lehmann 95% CI, $3848-$14 079) and at 180 days ($179 891 vs $107 017; median difference, $63 771; Hodges-Lehmann 95% CI, $55 512-$72 029). Extrapolating these figures to the total US population revealed $335 million in excess spending for trimodal therapy compared with the less costly radical cystectomy ($492 million) for patients who received a muscle-invasive bladder cancer diagnosis in 2011. Trimodal therapy was associated with significantly decreased overall survival and cancer-specific survival as well as $335 million in excess spending in 2011. These findings have important health policy implications regarding the appropriate use of high value-based care among older adults with invasive bladder cancer who are candidates for either radical cystectomy or trimodal therapy.


Immunohistochemical analysis of ezrin-radixin-moesin-binding phosphoprotein 50 in prostatic adenocarcinoma.
Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is an adapter protein which has been shown to play an active role in a wide variety of cellular processes, including interactions with proteins related to both tumor suppression and oncogenesis. Here we use immunohistochemistry to evaluate EBP50's expression in normal donor prostate (NDP), benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets). Tissue microarrays were immunohistochemically stained for EBP50, with the staining intensities quantified using automated image analysis software. The data were statistically analyzed using one-way ANOVA with subsequent Tukey tests for multiple comparisons. Eleven cases of NDP, 37 cases of NAC, 15 cases of BPH, 35 cases of HGPIN, 103 cases of PCa, and 36 cases of Mets were analyzed in the microarrays. Specimens of PCa and Mets had the lowest absolute staining for EBP50. Mets staining was significantly lower than NDP (p = 0.027), BPH (p = 0.012), NAC (p < 0.001), HGPIN (p < 0.001), and PCa (p = 0.006). Additionally, HGPIN staining was significantly higher than NAC (p < 0.009) and PCa (p < 0.001). To our knowledge, this represents the first study comparing the immunohistochemical profiles of EBP50 in PCa and Mets to specimens of HGPIN, BPH, NDP, and NAC and suggests that EBP50 expression is decreased in Mets. Given that PCa also had significantly higher expression than Mets, future studies are warranted to assess EBP50's potential as a prognostic biomarker for prostate cancer.


Population regulation and character displacement in a seasonal environment.
Competition has negative effects on population size and also drives ecological character displacement, that is, evolutionary divergence to utilize different portions of the resource spectrum. Many species undergo an annual cycle composed of a lean season of intense competition for resources and a breeding season. We use a quantitative genetic model to study the effects of differential reproductive output in the summer or breeding season on character displacement in the winter or nonbreeding season. The model is developed with reference to the avian family of Old World leaf warblers (Phylloscopidae), which breed in the temperate regions of Eurasia and winter in tropical and subtropical regions. Empirical evidence implicates strong winter density-dependent regulation driven by food shortage, but paradoxically, the relative abundance of each species appears to be determined by conditions in the summer. We show how population regulation in the two seasons becomes linked, with higher reproductive output by one species in the summer resulting in its evolution to occupy a larger portion of niche space in the winter. We find short-term ecological processes and longer-term evolutionary processes to have comparable effects on a species population size. This modeling approach can also be applied to other differential effects of productivity across seasons.


Anorectal contractility under basal conditions and during rectal infusion of saline in ulcerative colitis.
Pressure activity in the rectum and anal canal was measured with a multilumen probe in 29 patients with ulcerative colitis (12 active, 11 quiescent, six studied during both phases) and 18 normal controls under resting conditions and during rectal infusion of saline. Resting motor activity was significantly decreased in patients with active colitis compared with quiescent colitis (p less than 0.005) and normal controls (p less than 0.001). Forty per cent of active colitics showed a featureless record compared with only one patient with quiescent colitis and one normal subject. The volume of saline infused before leakage occurred, and the total volume retained were significantly lower (p less than 0.001) in patients with active and quiescent colitis compared with normal controls. Rectal infusion of saline provoked regular rectal contractions, of significantly higher (p less than 0.05) amplitude in patients with active colitis, than in quiescent colitis or controls. These rectal contractions were associated with simultaneous anal relaxations. During saline infusion, peak and pressures were lower in patients with ulcerative colitis than in normal subjects, but there were no significant differences in relaxation pressures. In normal subjects, the rectal pressures remained below the anal pressures throughout the saline infusion. Peak rectal pressures exceeded the anal relaxation pressures during the last five minutes of saline infusion in patients with ulcerative colitis and throughout the infusion in those patients who complained of incontinence. Results suggest that although the resting rectal motor activity is diminished in patients with ulcerative colitis, luminal distension causes the inflamed rectum to generate abnormally strong contractions that may threaten continence.


Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy.
Purpose Childhood cancer survivors (CCSs) are at increased risk for subsequent malignant neoplasms (SMNs). We evaluated the long-term risk of SMNs in a well-characterized cohort of 5-year CCSs, with a particular focus on individual chemotherapeutic agents and solid cancer risk. Methods The Dutch Childhood Cancer Oncology Group-Long-Term Effects After Childhood Cancer cohort includes 6,165 5-year CCSs diagnosed between 1963 and 2001 in the Netherlands. SMNs were identified by linkages with the Netherlands Cancer Registry, the Dutch Pathology Registry, and medical chart review. We calculated standardized incidence ratios, excess absolute risks, and cumulative incidences. Multivariable Cox proportional hazard regression analyses were used to evaluate treatment-associated risks for breast cancer, sarcoma, and all solid cancers. Results After a median follow-up of 20.7 years (range, 5.0 to 49.8 years) since first diagnosis, 291 SMNs were ascertained in 261 CCSs (standardized incidence ratio, 5.2; 95% CI, 4.6 to 5.8; excess absolute risk, 20.3/10,000 person-years). Cumulative SMN incidence at 25 years after first diagnosis was 3.9% (95% CI, 3.4% to 4.6%) and did not change noticeably among CCSs treated in the 1990s compared with those treated earlier. We found dose-dependent doxorubicin-related increased risks of all solid cancers ( Ptrend < .001) and breast cancer ( Ptrend < .001). The doxorubicin-breast cancer dose response was stronger in survivors of Li-Fraumeni syndrome-associated childhood cancers (leukemia, CNS, and non-Ewing sarcoma) versus survivors of other cancers ( Pdifference = .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner ( Ptrend = .01). Conclusion The results strongly suggest that doxorubicin exposure in CCSs increases the risk of subsequent solid cancers and breast cancer, whereas cyclophosphamide exposure increases the risk of subsequent sarcomas. These results may inform future childhood cancer treatment protocols and SMN surveillance guidelines for CCSs.


A scarcity mindset alters neural processing underlying consumer decision making.
Not having enough of what one needs has long been shown to have detrimental consequences for decision making. Recent work suggests that the experience of insufficient resources can create a "scarcity" mindset; increasing attention toward the scarce resource itself, but at the cost of attention for unrelated aspects. To investigate the effects of a scarcity mindset on consumer choice behavior, as well as its underlying neural mechanisms, we used an experimental manipulation to induce both a scarcity and an abundance mindset within participants and examined the effects of both mindsets on participants' willingness to pay for familiar food items while being scanned using fMRI. Results demonstrated that a scarcity mindset affects neural mechanisms related to consumer decision making. When in a scarcity mindset compared with an abundance mindset, participants had increased activity in the orbitofrontal cortex, a region often implicated in valuation processes. Moreover, again compared with abundance, a scarcity mindset decreased activity in dorsolateral prefrontal cortex, an area well known for its role in goal-directed choice. This effect was predominant in the group of participants who experienced scarcity following abundance, suggesting that the effects of scarcity are largest when they are compared with previous situations when resources were plentiful. More broadly, these data suggest a potential neural locus for a scarcity mindset and demonstrate how these changes in brain activity might underlie goal-directed decision making.


Application of Wavelet Entropy to predict atrial fibrillation progression from the surface ECG.
Atrial fibrillation (AF) is the most common supraventricular arrhythmia in clinical practice, thus, being the subject of intensive research both in medicine and engineering. Wavelet Entropy (WE) is a measure of the disorder degree of a specific phenomena in both time and frequency domains, allowing to reveal underlying dynamical processes out of sight for other methods. The present work introduces two different WE applications to the electrocardiogram (ECG) of patients in AF. The first application predicts the spontaneous termination of paroxysmal AF (PAF), whereas the second one deals with the electrical cardioversion (ECV) outcome in persistent AF patients. In both applications, WE was used with the objective of assessing the atrial fibrillatory (f) waves organization. Structural changes into the f waves reflect the atrial activity organization variation, and this fact can be used to predict AF progression. To this respect, results in the prediction of PAF termination regarding sensitivity, specificity, and accuracy were 95.38%, 91.67%, and 93.60%, respectively. On the other hand, for ECV outcome prediction, 85.24% sensitivity, 81.82% specificity, and 84.05% accuracy were obtained. These results turn WE as the highest single predictor of spontaneous PAF termination and ECV outcome, thus being a promising tool to characterize non-invasive AF signals.


Safety evaluation of food contact paper and board using chemical tests and in vitro bioassays: role of known and unknown substances.
In vitro toxicological tests have been proposed as an approach to complement the chemical safety assessment of food contact materials, particularly those with a complex or unknown chemical composition such as paper and board. Among the concerns raised regarding the applicability of in vitro tests are the effects of interference of the extractables on the outcome of the cytotoxicity and genotoxicity tests applied and the role of known compounds present in chemically complex materials, such as paper and board, either as constituents or contaminants. To answer these questions, a series of experiments were performed to assess the role of natural substances (wood extracts, resin acids), some additives (diisopropylnaphthalene, phthalates, acrylamide, fluorescent whitening agents) and contaminants (2,4-diaminotoluene, benzo[a]pyrene) in the toxicological profile of paper and board. These substances were individually tested or used to spike actual paper and board extracts. The toxic concentrations of diisopropylnaphthalenes and phthalates were compared with those actually detected in paper and board extracts showing conspicuous toxicity. According to the results of the spiking experiments, the extracts did not affect the toxicity of tested chemicals nor was there any significant metabolic interference in the cases where two compounds were used in tests involving xenobiotic metabolism by the target cells. While the identified substances apparently have a role in the cytotoxicity of some of the project samples, their presence does not explain the total toxicological profile of the extracts. In conclusion, in vitro toxicological testing can have a role in the safety assessment of chemically complex materials in detecting potentially harmful activities not predictable by chemical analysis alone.


Structural mechanism of WASP activation by the enterohaemorrhagic E. coli effector EspF(U).
During infection, enterohaemorrhagic Escherichia coli (EHEC) takes over the actin cytoskeleton of eukaryotic cells by injecting the EspF(U) protein into the host cytoplasm. EspF(U) controls actin by activating members of the Wiskott-Aldrich syndrome protein (WASP) family. Here we show that EspF(U) binds to the autoinhibitory GTPase binding domain (GBD) in WASP proteins and displaces it from the activity-bearing VCA domain (for verprolin homology, central hydrophobic and acidic regions). This interaction potently activates WASP and neural (N)-WASP in vitro and induces localized actin assembly in cells. In the solution structure of the GBD-EspF(U) complex, EspF(U) forms an amphipathic helix that binds the GBD, mimicking interactions of the VCA domain in autoinhibited WASP. Thus, EspF(U) activates WASP by competing directly for the VCA binding site on the GBD. This mechanism is distinct from that used by the eukaryotic activators Cdc42 and SH2 domains, which globally destabilize the GBD fold to release the VCA. Such diversity of mechanism in WASP proteins is distinct from other multimodular systems, and may result from the intrinsically unstructured nature of the isolated GBD and VCA elements. The structural incompatibility of the GBD complexes with EspF(U) and Cdc42/SH2, plus high-affinity EspF(U) binding, enable EHEC to hijack the eukaryotic cytoskeletal machinery effectively.


Gene expression and effects of orally active derivatives of fluoropyrimidine on gastric and colorectal cancer.
The effects of chemotherapy on gastrointestinal cancer are influenced by the chemotherapeutic sensitivity of the cancer cells. Determining the expression of genes related to chemotherapeutic sensitivity has been used as a molecular method. The aim of the study was to clarify the relationships between the expression of genes related to chemotherapeutic sensitivity and the effects of orally active derivatives of fluoropyrimidine on gastric and colorectal cancer. Forty-five patients who underwent adjuvant chemotherapy containing orally active derivatives of fluoropyrimidine after undergoing curative surgery for gastric or colorectal cancer were enrolled. Twenty-four patients had colorectal cancer and 21 patients had gastric cancer. Total RNA was extracted from formalin-fixed, paraffin-embedded specimens of the resected tumors, and the expression of 11 genes was measured using the RT-PCR method. We then analyzed the relationships between the gene expression and the postoperative relapse rate as well as the relationships between clinicopathological factors and postoperative relapse rate. The median observation period of the subjects was 41 months. Twelve out of the 21 gastric cancer patients (57%) and 11 out of the 24 colorectal cancer patients (46%) relapsed. Although the results of a univariate analysis revealed that expression of none of the evaluated genes was related to relapse in the gastric cancer patients, excision repair cross-complementing gene 1 (ERCC1) overexpression was related to the relapse rate in colorectal cancer patients (p=0.023). When 1.295 was set as the cut-off value for ERCC1 overexpression using the receiver operating characteristic (ROC) curve, 67% of patients with ERCC1 overexpression and 25% of patients without ERCC1 overexpression relapsed. The relapse-free survival rate was lower in the group with ERCC1 overexpression than in the group without ERCC1 overexpression (p=0.046). ERCC1 overexpression appears to be a useful predictor of relapse in colorectal cancer patients receiving adjuvant therapy with regimens including orally active derivatives of fluoropyrimidine.


The betaretrovirus Mason-Pfizer monkey virus selectively excludes simian APOBEC3G from virion particles.
The APOBEC3 protein family can constitute a potent barrier to the successful infection of mammalian species by retroviruses. Therefore, any retrovirus that has evolved the ability to replicate in a given animal must have developed mechanisms that allow it to avoid or inhibit the APOBEC3 proteins expressed in that animal. Here, we demonstrate that Mason-Pfizer monkey virus (MPMV) is resistant to inhibition by the APOBEC3G protein expressed in its normal host, the rhesus macaque, but highly susceptible to inhibition by murine APOBEC3 (mA3). MPMV virion particles fail to package rhesus APOBEC3G (rA3G), and MPMV Gag binds rA3G poorly in coexpressing cells. In contrast, MPMV virions package mA3 efficiently and MPMV Gag-mA3 complexes are readily detected. Moreover, mA3, but not rA3G, partially colocalizes with MPMV Gag in the cytoplasm of coexpressing cells. Previously, we have demonstrated that murine leukemia virus also escapes inhibition by APOBEC3 proteins by avoiding virion incorporation of its cognate APOBEC3 protein, mA3, yet is inhibited by primate APOBEC3G proteins, which it packages effectively (B. P. Doehle, A. Schäfer, H. L. Wiegand, H. P. Bogerd, and B. R. Cullen, J. Virol. 79:8201-8207, 2005). The finding that two essentially unrelated beta- and gammaretroviruses use similar mechanisms to escape inhibition by the APOBEC3 proteins found in their normal host species suggests that the selective exclusion of APOBEC3 proteins from virion particles may be a general mechanism used by simple mammalian retroviruses.


Malaria parasite development in a Drosophila model.
Malaria is a devastating public health menace, killing over one million people every year and infecting about half a billion. Here it is shown that the protozoan Plasmodium gallinaceum, a close relative of the human malaria parasite Plasmodium falciparum, can develop in the fruit fly Drosophila melanogaster. Plasmodium gallinaceum ookinetes injected into the fly developed into sporozoites infectious to the vertebrate host with similar kinetics as seen in the mosquito host Aedes aegypti. In the fly, a component of the insect's innate immune system, the macrophage, can destroy Plasmodia. These experiments suggest that Drosophila can be used as a surrogate mosquito for defining the genetic pathways involved in both vector competence and part of the parasite sexual cycle.


Student perceptions of empowerment in their graduate program.
Empowerment is a critical aspect of the education of the Advanced Practice Nurse (APN). This paper reports a study which asked for feedback from APN students about their experience of feelings of empowerment and powerlessness in their graduate program. Learning which was driven by the student's interest, which respected and valued their experience and which guided them in defining and pursuing individual goals was empowering. Powerlessness was experienced when faculty controlled the process, were demeaning about students' abilities and when learning was not connected to their goals. Advanced Practice Nurses (APN) are in great demand for the emerging health care system. It is critical that students graduate well prepared to face the challenge of today's health care environment. An overarching objective of advanced practice is to enable patients to take control and be responsible for their own health needs, to empower them to care for themselves. The connection between the empowerment of APNs and their ability to empower their patients is unclear. The relationship between the way APN students are treated and how they treat their patients when they graduate is also not known. This investigation looked at what elicited feelings of powerlessness and empowerment in students as a first step in understanding the process. This paper describes a pilot study which elicited student experiences in their graduate program which engendered feelings of empowerment or powerlessness. The study was a replication of Chandler's previous work with staff nurses. It is hoped that this information will provide a framework for a knowledge base to develop educational strategies which will empower the APN student.


Fast, global, and entrepreneurial: supply chain management, Hong Kong style. An interview with Victor Fung. Interview by Joan Magretta.
Li & Fung, Hong Kong's largest export trading company, has been an innovator in supply chain management--a topic of increasing importance to many senior executives. In this interview, chairman Victor Fung explains both the philosophy behind supply chain management and the specific practices that Li & Fung has developed to reduce costs and lead times, allowing its customers to buy "closer to the market." Li & Fung has been a pioneer in "dispersed manufacturing." It performs the higher-value-added tasks such as design and quality control in Hong Kong, and outsources the lower-value-added tasks to the best possible locations around the world. The result is something new: a truly global product. To produce a garment, for example, the company might purchase yarn from Korea that will be woven and dyed in Taiwan, then shipped to Thailand for final assembly, where it will be matched with zippers from a Japanese company. For every order, the goal is to customize the value chain to meet the customer's specific needs. To be run effectively, Victor Fung maintains, trading companies have to be small and entrepreneurial. He describes the organizational approaches that keep the company that way despite its growing size and geographic scope: its organization around small, customer-focused units; its incentives and compensation structure; and its use of venture capital as a vehicle for business development. As Asia's economic crisis continues, chairman Fung sees a new model of companies emerging--companies that are, like Li & Fung, narrowly focused and professionally managed.


In Vitro Activity of Minocycline against U.S. Isolates of Acinetobacter baumannii-Acinetobacter calcoaceticus Species Complex, Stenotrophomonas maltophilia, and Burkholderia cepacia Complex: Results from the SENTRY Antimicrobial Surveillance Program, 2014 to 2018.
We evaluated the activity of minocycline and comparator agents against a large number of Stenotrophomonas maltophilia (n = 1,289), Acinetobacter baumannii-Acinetobacter calcoaceticus species complex (n = 1,081), and Burkholderia cepacia complex (n = 101) isolates collected from 2014 to 2018 from 87 U.S. medical centers spanning all 9 census divisions. The isolates were collected primarily from hospitalized patients with pneumonia (1,632 isolates; 66.0% overall), skin and skin structure infections (354 isolates; 14.3% overall), bloodstream infections (266 isolates; 10.8% overall), urinary tract infections (126 isolates; 5.1% overall), intra-abdominal infections (61 isolates; 2.5% overall), and other infections (32 isolates; 1.3% overall). Against the A. baumannii-A. calcoaceticus species complex, colistin was the most active agent, exhibiting MIC50/90 values at ≤0.5/2 μg/ml and 92.4% susceptibility. Minocycline ranked second in activity, with MIC50/90 values at 0.25/8 μg/ml and susceptibility at 85.7%. Activity for these two agents was reduced against extensively drug-resistant and multidrug-resistant isolates of the Acinetobacter baumannii-Acinetobacter calcoaceticus species complex. Only two agents showed high levels of activity (susceptibility, >90%) against S. maltophilia, minocycline (MIC50/90, 0.5/2 μg/ml; 99.5% susceptible) and trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/1 μg/ml; 94.6% susceptible). Minocycline was active against 92.8% (MIC90, 4 μg/ml) of trimethoprim-sulfamethoxazole-resistant S. maltophilia isolates. Various agents exhibited susceptibility rates of nearly 90% against the B. cepacia complex isolates; these were trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/2 μg/ml; 93.1% susceptible), ceftazidime (MIC50/90, 2/8 μg/ml; 91.0% susceptible), meropenem (MIC50/90, 2/8 μg/ml; 89.1% susceptible), and minocycline (MIC50/90, 2/8 μg/ml; 88.1% susceptible). These results indicate that minocycline is among the most active agents for these three problematic potential pathogen groups when tested against U.S. isolates.


WHO guidance on mental health training: a systematic review of the progress for non-specialist health workers.
To assess existing literature on the effectiveness of mental health training courses for non-specialist health workers, based on the WHO guidelines (2008). A systematic review was carried out, complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. After examination of key studies in the literature, a comprehensive search was performed within the following electronic databases on 31 May 2017: PubMed, PsycINFO, CINAHL (using EBSCOHost interface), Cochrane, Web of Science. Searches were conducted for articles published in English from January 2008 to May 2017, using search terms related to mental health, training, community care and evaluation/outcome, following the Participants, Interventions, Comparators and Outcomes process for evidence-based practice. Data were collected across the following categories: trainees (number and background), training course (curriculum, teaching method, length), evaluation method (timing of evaluation, collection method and measures assessed) and evaluation outcome (any improvement recorded from baseline). In addition, studies were assessed for their methodological quality using the framework established by Liu et al (2016). 29 studies with relevant training courses met the inclusion criteria. These were implemented across 16 countries since 2008 (over half between 2014 and 2017), with 10 in three high-income countries. Evaluation methods and outcomes showed high variability across studies, with courses assessing trainees' attitude, knowledge, clinical practice, skills, confidence, satisfaction and/or patient outcome. All 29 studies found some improvement after training in at least one area, and 10 studies found this improvement to be significant. Training non-specialist workers in mental healthcare is an effective strategy to increase global provision and capacity, and improves knowledge, attitude, skill and confidence among health workers, as well as clinical practice and patient outcome. Areas for future focus include the development of standardised evaluation methods and outcomes to allow cross-comparison between studies, and optimisation of course structure. CRD42016033269.


A standardized clinical evaluation of phenotypic diversity in diabetic polyneuropathy.
Diabetic polyneuropathy (DPN) is a major cause of neuropathic pain and a frequent target condition in analgesic treatment trials. Differences in the clinical symptoms and signs associated with DPN suggest distinct pathophysiological mechanisms underlying nerve damage and dysfunction that are likely to have therapeutic relevance. The aim of this study was to develop a tool for the bedside assessment of painful neuropathies such as DPN that captures the diversity of phenotypes. Sixty-one patients with type 2 diabetes and painful neuropathy, 19 patients with painless DPN, 25 patients with type 2 diabetes but no clinical evidence of neuropathy, and 20 healthy control subjects completed a structured interview (47 items) and a standardized physical examination (39 items). After analyzing critical features of pain and painless symptoms and examining the outcome of physical tests of sensory function, we determined principal components of the phenotypic variance among patients. Increased sensitivity to mechanical or thermal stimuli and, to a lesser extent, the sensory quality of pain or paresthesia were the most discriminating elements of DPN phenotypes. Correlation patterns of symptoms and signs indicated the involvement of functionally distinct nerve fiber populations. We combined interview questions and physical tests identifying these differences in a shortened assessment protocol that we named Standardized Evaluation of Pain and Somatosensory Function (StEPS). The protocol StEPS generates a phenotypic profile of patients with neuropathy. Separate intensity ratings for spontaneous painful symptoms and pain evoked by standard stimuli support a detailed documentation of neuropathic pain and its response to analgesic treatment.


Rare Papillary Breast Carcinoma Incidentally Discovered After Trauma-Induced Hematoma.
Papillary carcinoma of the breast is rare, comprising only 0.5% incidence of all breast cancers. Clinically the disease presents in postmenopausal women as a painless breast lump with possible bloody nipple discharge. Prognosis is favorable due to its slow growth. We present a 61-year-old woman incidentally diagnosed with papillary breast carcinoma after presenting with a trauma-induced hematoma of the right breast. The patient presented to our surgery oncology clinic for persistent right breast swelling secondary to a fall, despite initial incision and drainage (I&D) six weeks prior. She had no history of breast cancer. On presentation, her right breast was distended demonstrating an approximately 20cm ill-defined solid mass with skin changes consistent with a tense hematoma. CT scan demonstrated a large complex cystic and solid breast mass measuring 15.2cmx11.8cmx15.2cm with irregular peripheral solid hyperdense polypoid components. She then underwent a right breast incisional biopsy and hematoma evacuation. Frozen sections of the mass outer cavity wall and papillary projections were consistent with encapsulated papillary carcinoma (EPC). The patient was lost to follow-up and did not obtain definitive treatment. Breast cancer rarely presents as a breast hematoma. However, as in this case, if the hematoma fails to resolve, further investigation is warranted. The prognosis of EPC is excellent when identified and treated appropriately.


MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape.
Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems.


Quality of initial HIV care in Canada: extension of a composite programmatic assessment tool for HIV therapy.
To document the quality of initial HIV care in Canada using the Programmatic Compliance Score (PCS), to explore the association of the PCS with mortality, and to identify factors associated with higher quality of care. We analysed data from the Canadian Observational Cohort Collaboration (CANOC), a multisite Canadian cohort of HIV-positive adults initiating combination antiretroviral therapy (ART) from 2000 to 2011. PCS indicators of noncompliance with HIV treatment guidelines include: fewer than three CD4 count tests in the first year of ART; fewer than three viral load tests in the first year of ART; no drug resistance testing before initiation; baseline CD4 count < 200 cells/mm3 ; starting a nonrecommended ART regimen; and not achieving viral suppression within 6 months of initiation. Indicators are summed for a score from 0 to 6; higher scores indicate poorer care. Cox regression was used to assess the association between PCS and mortality and ordinal logistic regression was used to explore factors associated with higher quality of care. Of the 7460 participants (18% female), the median score was 1.0 (Q1-Q3 1.0-2.0); 21% scored 0 and 8% scored ≥ 4. In multivariable analysis, compared with a score of 0, poorer PCS was associated with mortality for scores > 1 [score = 2: adjusted hazard ratio (AHR) 1.64; 95% confidence interval (CI) 1.13-2.36; score = 3: AHR 2.02; 95% CI 1.38-2.97; score ≥ 4: AHR 2.14; 95% CI 1.43-3.21], after adjustments for age, sex, province, ART start year, hepatitis C virus (HCV) coinfection, and baseline viral load. Women, individuals with HCV coinfection, younger people, and individuals starting ART earlier (2000-2003) had poorer scores. Our findings further validate the PCS as a predictor of all-cause mortality. Disparities identified suggest that further efforts are needed to ensure that care is equitably accessible.


Chronic toxicological evaluation of dietary NovaSil clay in Sprague-Dawley rats.
NovaSil (NS) clay, a common anti-caking agent in animal feeds, has been shown to sorb aflatoxins in the GI tract and diminish their bioavailability and adverse effects in short-term animal studies. Based on this evidence, it is hypothesized that clay-based enterosorption of aflatoxins may be a useful strategy for the prevention of aflatoxicosis in human populations. However, the potential toxicity of long-term dietary exposure to NS has not been determined. In this research, 5-6-week-old male and female Sprague-Dawley rats were fed rations containing 0, 0.25, 0.5, 1.0, or 2.0% (w/w) levels of NS for 28 weeks. Analysis of the NS showed negligible levels of dioxin and furan contaminants. Total feed consumption, cumulative feed consumption, body weight, total body weight gain, feed conversion efficiency, cumulative feed conversion efficiency, and relative organ weights were unaffected in either sex at the doses tested. No NS-dependent differences in relative organ weights or gross or histopathological changes were observed. Analysis of hematological parameters, clinical chemistry, and selected vitamin and mineral levels revealed isolated significant differences between some treatments and control groups (mean corpuscular hemoglobin, serum Ca, serum vitamin A, and serum Fe). However, the differences observed in each case were not dose-dependent. These results suggest that dietary inclusion of NS at levels as high as 2.0% (w/w) does not result in overt toxicity. These findings (as well as others) support the use of NS clay for dietary intervention studies in human populations at high risk for aflatoxicosis.


Mechanisms of anti-inflammatory property of Anacardium occidentale stem bark: inhibition of NF-κB and MAPK signalling in the microglia.
Anacardium occidentale is used in traditional African medicine for the treatment of arthritis, fever, aches, pains, and inflammation of the extremities. In this study, we investigated the molecular mechanisms responsible for anti-inflammatory effects of a stem bark extract of A. occidentale (ANE) in LPS-stimulated microglia. Nitric oxide (NO), prostaglandin E(2) and cytokine (TNFα and IL-6) production were evaluated in supernatants from LPS-stimulated BV-2 cells. Cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and microsomal prostaglandin E2 synthase (mPGES-1) protein expressions in rat primary microglia were measured using western blot. The effects of ANE on NF-κB activation and nuclear translocation were evaluated in the luciferase reporter gene assay and ELISA, while ability of ANE to influence IκB phosphorylation was determined using ELISA specific for phospho-IκB. The involvement of MAPK phosphorylation in the anti-inflammatory actions of ANE was evaluated using specific ELISA for phospho-p38, phospho-p42/44 and phospho-JNK. The MTT assay was used to determine the effect of ANE on BV-2 microglia viability. ANE (25-100 μg/ml) produced significant (p<0.05) reduction in the production of NO, PGE(2), TNFα and IL-6 in BV-2 microglia stimulated with LPS for 24h. Pre-treatment with ANE caused a significant (p<0.05) inhibition of COX-2, iNOS and mPGES-1 protein expressions in the rat primary microglia. Further experiments showed that ANE inhibited COX-2 and iNOS protein expression via IκB-mediated nuclear translocation and transactivation of NF-κB. Our studies also revealed that ANE produced significant (p<0.05) and dose-dependent inhibition of p38, p42/44 and JNK MAPK phosphorylation in LPS-activated BV-2 microglia. We conclude that ANE has an anti-inflammatory property related to inhibition of inflammation-associated cytokine production as well as iNOS and COX-2 gene expression by blocking NF-κB and MAPK pathways in the microglia. It is also suggested that mPGES-1 inhibition contributes to the effect of ANE on PGE(2) production in the microglia.


Genomic predictions based on haplotypes fitted as pseudo-SNP for milk production and udder type traits and SCS in French dairy goats.
The development of statistical methods aiming to improve the accuracy of genomic predictions is of utmost value for dairy goat breeding programs. In this context, the use of haplotypes, instead of individual SNP, could improve the accuracy of genomic predictions by better capturing the effect of causal variants, instead of relying solely on linkage disequilibrium with individual SNP. Haplotypes can be included in genomic evaluation models in various ways, such as fitting them as pseudo-SNP (i.e., haplotypes converted into biallelic SNP format). This can be easily incorporated in the software already available for single-step genomic predictions (ssGBLUP). Therefore, the aim of this study was to compare the predictive performances of ssGBLUP and weighted ssGBLUP (WssGBLUP) based on individual SNP or on haplotypes fitted as pseudo-SNP. Performance was compared in terms of accuracy, bias, and weights for SNP versus pseudo-SNP. Genomic predictions were performed on 5 milk production traits, 5 udder type traits, and somatic cell score (SCS). The training population was formed by 307 Alpine and 247 Saanen progeny-tested bucks, genotyped using the Illumina Goat SNP50 BeadChip (Illumina, San Diego, CA). The validation population included 205 Alpine and 146 Saanen young bucks. The accuracy of genomic predictions was evaluated in the validation population as the Pearson correlation between genomic estimated breeding values (GEBV), predicted based on various methods, and daughter deviation (DD) based on the official genetic evaluation of January 2016. Haplotype-based models were shown to improve the performance of genomic predictions for some traits. Gains in accuracy of up to +19% (0.310 to 0.368 for fat yield) in Alpine and up to +3% (0.361 to 0.373 for udder shape) in Saanen were observed with ssGBLUP. The ssGBLUP accuracies averaged across all traits and methods were equal to 0.467 (SNP) versus 0.471 (pseudo-SNP) in Alpine and 0.528 (SNP) versus 0.523 (pseudo-SNP) in Saanen. With WssGBLUP, gains in accuracy of up to 24% (0.298 to 0.370 for fat yield) in Alpine and 14% (0.431 to 0.490 for SCS) in Saanen were observed with WssGBLUP. Accuracies of WssGBLUP averaged across all traits and methods were equal to 0.455 (SNP and pseudo-SNP) in Alpine and 0.542 (SNP) versus 0.528 (pseudo-SNP) in Saanen. The average (±SD) slope of the regression of DD on GEBV for the validation animals, across all breeds, traits and scenarios, were equal to 0.82 ± 0.20 (SNP) and 0.83 ± 0.18 (pseudo-SNP) for ssGBLUP and 0.67 ± 0.16 (SNP) and 0.65 ± 0.16 (pseudo-SNP) for WssGBLUP, which suggest that haplotype-based models and ssGBLUPSNP were similarly biased. However, WssGBLUP was more biased than ssGBLUP, and its gains in accuracies were limited to milk production traits. Despite the fact that genomic predictions based on haplotypes require additional steps and time, the observed gains in GEBV predictive performance indicate that haplotype-based methods could be recommended for some traits.


Ciliate diversity, community structure, and novel taxa in lakes of the McMurdo Dry Valleys, Antarctica.
We report an in-depth survey of next-generation DNA sequencing of ciliate diversity and community structure in two permanently ice-covered McMurdo Dry Valley lakes during the austral summer and autumn (November 2007 and March 2008). We tested hypotheses on the relationship between species richness and environmental conditions including environmental extremes, nutrient status, and day length. On the basis of the unique environment that exists in these high-latitude lakes, we expected that novel taxa would be present. Alpha diversity analyses showed that extreme conditions-that is, high salinity, low oxygen, and extreme changes in day length-did not impact ciliate richness; however, ciliate richness was 30% higher in samples with higher dissolved organic matter. Beta diversity analyses revealed that ciliate communities clustered by dissolved oxygen, depth, and salinity, but not by season (i.e., day length). The permutational analysis of variance test indicated that depth, dissolved oxygen, and salinity had significant influences on the ciliate community for the abundance matrices of resampled data, while lake and season were not significant. This result suggests that the vertical trends in dissolved oxygen concentration and salinity may play a critical role in structuring ciliate communities. A PCR-based strategy capitalizing on divergent eukaryotic V9 hypervariable region ribosomal RNA gene targets unveiled two new genera in these lakes. A novel taxon belonging to an unknown class most closely related to Cryptocaryon irritans was also inferred from separate gene phylogenies.


Health Promotion and Wellness for All Students: School-Based Occupational Therapy as a Preventive Approach.
The coronavirus disease 2019 pandemic accelerated the impending youth mental health crisis in the United States, necessitating a comprehensive approach to providing mental health education and interventions. School-based occupational therapy practitioners' scope of practice includes wellness promotion, early detection, and evidence-based interventions for mental health challenges. Given the rise of school-based wellness programs, the growing legislation supporting the formation of such programs, and the burgeoning burden of pediatric mental health concerns, occupational therapy practitioners are uniquely positioned to create and implement interventions to support student access to the general education curriculum and can do so by using both prepandemic funding sources and pandemic response funds. This Health Policy Perspectives column is a call to action to refocus the occupational therapy practitioner's role in school settings to include providing high-quality, evidence-based preventive mental health education and interventions. In this column, we examine prevention-based occupational therapy services in Mason City Schools, Mason, Ohio, as a model of success in the execution of this vision for school-based practice. In addition, we outline the importance of expanding the role of occupational therapy practitioners in schools, which will in turn increase the visibility and relevancy of the profession and broaden its impact on mitigating the youth mental health crisis.


Should We Screen HIV-Positive Migrants for Strongyloidiasis?
Strongyloides stercoralis, a nematode endemic in all (sub)tropical regions, can cause life-threatening disease, especially in immunosuppressed patients. Many countries with high HIV-prevalence rates are also highly S. stercoralis endemic, and co-infection may occur. Retrospective study based on serological testing for S. stercoralis in all HIV-infected migrants followed at the Institute of Tropical Medicine, Antwerp, Belgium. If untested, serologic testing was performed on stored samples, dating from the first HIV viral load determination. The epidemiological, clinical and laboratory features of patients with and without strongyloidiasis were retrieved from the electronic medical files. Of the 2846 HIV patients in active follow-up, 723 (25.4%) had a migration background. Thirty-six patients (5.1%) were diagnosed with Strongyloides co-infection, including 29 during their medical evaluation and seven retrospectively. Patients had a median age of 35.3 years (IQR 30.3-44.4), 28 patients (78%) originated from Sub-Saharan Africa and median time in Belgium was 3.5 years (IQR 0.8-5.7). Symptoms compatible with strongyloidiasis were present in 17 (47%) patients, of whom two were diagnosed retrospectively. Eosinophilia (eosinophil cell count > 450/µL) was observed in 19 (53%) participants. Median CD4 level was 386 /µL (IQR 299-518) at diagnosis of co-infection. Of note, 8 (22%) patients with strongyloidiasis had no reported symptoms nor eosinophilia. None of the patients developed hyperinfection syndrome. There were no differences in age, gender, geographic origin, clinical presentation, CD4 level or viral load between patients with and without strongyloidiasis. Only eosinophilia was strongly correlated with the presence of Strongyloides in multivariate analysis (OR 10.74 (95% CI 5.19-22.25), p < 0.001); the positive likelihood ratio (LR+) of eosinophilia for strongyloidiasis was 5.38 (95% CI 3.66-7.91). Strongyloidiasis was diagnosed in 5.1% of HIV-infected migrants. Eosinophilia had good confirming power for the presence of the disease. However, a sizeable proportion (22%) of co-infected individuals were asymptomatic and had normal eosinophil count, supporting universal screening of all HIV-positive patients native to tropical countries.


Assessing the scalability of healthy eating interventions within the early childhood education and care setting: secondary analysis of a Cochrane systematic review.
Early childhood education and care (ECEC) is a recommended setting for the delivery of health eating interventions 'at scale' (i.e. to large numbers of childcare services) to improve child public health nutrition. Appraisal of the 'scalability' (suitability for delivery at scale) of interventions is recommended to guide public health decision-making. This study describes the extent to which factors required to assess scalability are reported among ECEC-based healthy eating interventions. Studies from a recent Cochrane systematic review assessing the effectiveness of healthy eating interventions delivered in ECEC for improving child dietary intake were included. The reporting of factors of scalability was assessed against domains outlined within the Intervention Scalability Assessment Tool (ISAT). The tool recommends decision makers consider the problem, the intervention, strategic and political context, effectiveness, costs, fidelity and adaptation, reach and acceptability, delivery setting and workforce, implementation infrastructure and sustainability. Data were extracted by one reviewer and checked by a second reviewer. ECEC. Children 6 months to 6 years. Of thirty-eight included studies, none reported all factors within the ISAT. All studies reported the problem, the intervention, effectiveness and the delivery workforce and setting. The lowest reported domains were intervention costs (13 % of studies) and sustainability (16 % of studies). Findings indicate there is a lack of reporting of some key factors of scalability for ECEC-based healthy eating interventions. Future studies should measure and report such factors to support policy and practice decision makers when selecting interventions to be scaled-up.


Paper-based analytical devices for environmental analysis.
The field of paper-based microfluidics has experienced rapid growth over the past decade. Microfluidic paper-based analytical devices (μPADs), originally developed for point-of-care medical diagnostics in resource-limited settings, are now being applied in new areas, such as environmental analyses. Low-cost paper sensors show great promise for on-site environmental analysis; the theme of ongoing research complements existing instrumental techniques by providing high spatial and temporal resolution for environmental monitoring. This review highlights recent applications of μPADs for environmental analysis along with technical advances that may enable μPADs to be more widely implemented in field testing.


The simulation research of dissolved nitrogen and phosphorus non-point source pollution in Xiao-Jiang watershed of Three Gorges Reservoir area.
Xiao-jiang, with a basin area of almost 5,276 km(2) and a length of 182.4 km, is located in the center of the Three Gorges Reservoir Area, and is the largest tributary of the central section in Three Gorges Reservoir Area, farmland accounts for a large proportion of Xiao-jiang watershed, and the hilly cropland of purple soil is much of the farmland of the watershed. After the second phase of water storage in the Three Gorges Reservoir, the majority of sub-rivers in the reservoir area experienced eutrophication phenomenon frequently, and non-point source (NPS) pollution has become an important source of pollution in Xiao-jiang Watershed. Because dissolved nitrogen and phosphorus non-point source pollution are related to surface runoff and interflow, using climatic, topographic and land cover data from the internet and research institutes, the Semi-Distributed Land-use Runoff Process (SLURP) hydrological model was introduced to simulate the complete hydrological cycle of the Xiao-jiang Watershed. Based on the SLURP distributed hydrological model, non-point source pollution annual output load models of land use and rural residents were respectively established. Therefore, using GIS technology, considering the losses of dissolved nitrogen and phosphorus in the course of transport, a dissolved non-point source pollution load dynamic model was established by the organic coupling of the SLURP hydrological model and land-use output model. Through the above dynamic model, the annual dissolved non-point source nitrogen and phosphorus pollution output as well as the load in different types were simulated and quantitatively estimated from 2001 to 2008, furthermore, the loads of Xiao-jiang Watershed were calculated and expressed by temporal and spatial distribution in the Three Gorges Reservoir Area. The simulation results show that: the temporal changes of dissolved nitrogen and phosphorus load in the watershed are close to the inter-annual changes of rainfall runoff, and the different land-use type distribution has great impacts on the spatial changes of dissolved nitrogen and phosphorus load in the watershed; The nitrogen and phosphorus load of different land-use types in size with descending order is, glebe and mixed land, paddy, grassland, urban land, forestland; however, for the phosphorus load, the unit area output load of glebe and mixed land is almost the same as for paddy fields; The output contribution of nitrogen and phosphorus pollution load from land-use accounts for 78%-85%, while the output contribution from livestock and poultry occupies 13%-20%. The established load model was verified by observation data, simulation results show that the established model is reasonable, simulation accuracy is higher.


Educating grade school children using a structured bicycle safety program.
Prevention is understudied in trauma care. Furthermore, the effectiveness of prevention outreach programs is not well documented. We attempted to verify that elementary school educational programs effectively create retained knowledge. Three hundred fifty-one students (grades 1-3) viewed a bicycle safety videotape and then listened to a structured discussion of bicycle safety rules. Coded pretests were given before and identical posttests were given immediately after the session. Tests were readministered 1 month later to evaluate retained knowledge. Two hundred fifty-one students completed all three tests. Students showed significant (p < 0.01) improvement in retained knowledge about riding with traffic, wearing a bicycle helmet, warning pedestrians when riding on sidewalks, and stopping before riding into the street. We conclude that prevention programs are effective and result in retained knowledge. Further analysis is recommended to evaluate retained knowledge at greater intervals after the original education.


Epithelioid sarcoma of the hand.
Twenty-eight patients were treated for a primary epithelioid sarcoma of the hand. Twenty-seven patients (96%) had excisions before evaluation, including 11 (39%) with multiple prior excisions with varying diagnoses before epithelioid sarcoma, and all had surgical treatment after referral. The patients' surgical management included three patients with amputation at the forearm, three patients with wide excision, and 21 patients with a partial amputation of the hand. The followup period averaged 120 months (range, 24-276 months). Eighteen patients have no evidence of disease at last followup. Treatment failures included one local recurrence, four regional metastases, and five distant metastases. Five patients died secondary to disease. Two patients are alive with disease, and three are alive with no evidence of disease after additional treatment. After aggressive surgical management with negative margins, 71% of the patients were alive without evidence of disease at the last followup, with a 5- and 10-year survivorship of 85%. Our goal is to review: (1) the effectiveness of preoperative imaging, (2) the role of adjuvant therapy, (3) survival after alternative resections, and (4) function after resection.


Active Play Network Influences on Physical Activity Among Children Living in Texas Colonias.
Physical activity (PA) is beneficial for child health; however, few children meet PA guidelines. Social relationships impact child PA behaviors; however, little is known about this effect in Mexican-heritage populations. This study aims to understand associations between self-reported play networks and PA among Mexican-heritage children. Mexican-heritage children from colonias along the Texas-Mexico border (n = 44; 54.5% girls; mean age = 9.89 years, SD = 0.97) reported information on up to 5 people they played with most often. Linear regression was used to analyze the relationship between composition of children's social network and minutes of moderate- to vigorous-intensity PA (MVPA) and sedentary minutes per day measured by accelerometers. Children who reported a higher percentage of friends as opposed to family members attained significantly more minutes of MVPA per day (β = .27, P = .04). Children who reported playing with individuals in their network more often (β = ‒.28, P = .03) were sedentary for fewer minutes per day. Increasing the connections between children in the neighborhood or community, as well as increasing a child's frequency of active play, may be promising approaches to increasing MVPA and decreasing sedentary behaviors among Mexican-heritage children.


Occupational safety and health in India: now and the future.
India, a growing economy and world's largest democracy, has population exceeding 1.2 billion. Out of this huge number, 63.6% form working age group. More than 90% work in the informal economy, mainly agriculture and services. Less than 10% work in the organized sector; mainly industry, mining and some services. New service industries like Information Technology (IT), Business Process Outsourcing (BPO) are increasing rapidly; so is the proportion of females in the workforce. The occupational safety and health (OSH) scenario in India is complex. Unprecedented growth and progress go hand in hand with challenges such as huge workforce in unorganized sector, availability of cheap labor, meager public spending on health, inadequate implementation of existing legislation, lack of reliable OSH data, shortage of OSH professionals, multiplicity of statutory controls, apathy of stakeholders and infrastructure problems. The national policy on OSH at workplace, adopted by the government in 2009, is yet to be implemented. Some of the major occupational risks are accidents, pneumoconiosis, musculoskeletal injuries, chronic obstructive lung diseases; pesticide poisoning and noise induced hearing loss. The three most important OSH needs are: 1. legislation to extend OSH coverage to all sectors of working life including the unorganized sector; 2. spreading the awareness about OSH among stakeholders; 3. development of OSH infrastructure and OSH professionals. Other issues include integration of occupational health with primary health care.


Ceramides bind VDAC2 to trigger mitochondrial apoptosis.
Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity.


First report of the emergence of CTX-M-type extended-spectrum beta-lactamases (ESBLs) as the predominant ESBL isolated in a U.S. health care system.
CTX-M-type extended-spectrum beta-lactamases (ESBLs) have become increasingly common worldwide, with the notable exception of the United States, where TEM- and SHV-type ESBLs have appeared to predominate. We have noted the emergence of ESBLs in our health care system (the University Health System in San Antonio, TX), especially in Escherichia coli isolates, that preferentially hydrolyze cefotaxime rather than ceftazidime, suggesting the possibility of CTX-M-type enzymes. Microbiology laboratory records were reviewed to identify ESBL-producing isolates and to compare the diameters of ceftazidime disk diffusion zones of inhibition to cefotaxime zone diameters. All isolates had been initially detected and confirmed using the procedures recommended by the Clinical and Laboratory Standards Institute. A total of 94 stored ESBL-producing isolates recovered between January 2000 and June 2006 (predominately from blood and normally sterile fluids) were retrieved for further study and screened using PCR primers specific for the presence of CTX-M, TEM, and SHV ESBLs. Only small numbers of retained ESBL-producing isolates were available for study in 2000 and 2002. The percentages of available ESBL-producing organisms in the following years were found to produce CTX-M enzymes: 2000, 25%; 2001, 10%; 2002, 0%; 2003, 60%; 2004, 69%; 2005, 89%; and 2006, 70%. The most common CTX-M-type ESBL was CTX-M-15, followed by CTX-M-16, CTX-M-8, and CTX-M-14. Comparing the disk diffusion zone diameters of cefotaxime and ceftazidime was helpful with the initial recognition of CTX-M-producing E. coli, which had an average cefotaxime zone diameter 7 mm smaller than the ceftazidime zone. However, comparing ceftazidime and cefotaxime zones for CTX-M-producing Klebsiella spp. was not helpful with initial recognition. CTX-M enzymes were also identified in Proteus mirabilis, Enterobacter spp., and Morganella morganii. Based on pulsed-field gel electrophoresis typing of the E. coli isolates, the CTX-M-producing isolates did not represent the spread of a single clone in the institution or in the community. In conclusion, CTX-M-type ESBLs are now the most common ESBL type isolated from patients in our health care system and may also be present but unrecognized in other U.S. locales.


Effects of ethnic density on the risk of compulsory psychiatric admission for individuals attending secondary care mental health services: evidence from a large-scale study in England.
Black, Asian and minority ethnicity groups may experience better health outcomes when living in areas of high own-group ethnic density - the so-called 'ethnic density' hypothesis. We tested this hypothesis for the treatment outcome of compulsory admission. Data from the 2010-2011 Mental Health Minimum Dataset (N = 1 053 617) was linked to the 2011 Census and 2010 Index of Multiple Deprivation. Own-group ethnic density was calculated by dividing the number of residents per ethnic group for each lower layer super output area (LSOA) in the Census by the LSOA total population. Multilevel modelling estimated the effect of own-group ethnic density on the risk of compulsory admission by ethnic group (White British, White other, Black, Asian and mixed), accounting for patient characteristics (age and gender), area-level deprivation and population density. Asian and White British patients experienced a reduced risk of compulsory admission when living in the areas of high own-group ethnic density [odds ratios (OR) 0.97, 95% credible interval (CI) 0.95-0.99 and 0.94, 95% CI 0.93-0.95, respectively], whereas White minority patients were at increased risk when living in neighbourhoods of higher own-group ethnic concentration (OR 1.18, 95% CI 1.11-1.26). Higher levels of own-group ethnic density were associated with an increased risk of compulsory admission for mixed-ethnicity patients, but only when deprivation and population density were excluded from the model. Neighbourhood-level concentration of own-group ethnicity for Black patients did not influence the risk of compulsory admission. We found only minimal support for the ethnic density hypothesis for the treatment outcome of compulsory admission to under the Mental Health Act.


Molecular Characterization of Carbapenem-Resistant Acinetobacter baumannii in the Intensive Care Unit of Uruguay's University Hospital Identifies the First rmtC Gene in the Species.
Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are an increasing concern in intensive care units (ICUs) worldwide. The combination of carbapenemases and 16S rRNA-methyltransferases (16S-RMTases) further reduces the therapeutic options. OXA-carbapenemase/A. baumannii clone tandems in Latin America have already been described; however, no information exists in this region regarding the occurrence of 16S-RMTases in this microorganism. In addition, the epidemiology of A. baumannii in ICUs and its associated resistance profiles are poorly understood. Our objectives were as follows: to study the clonal relationship and antibiotic resistance profiles of clinical and digestive colonizing A. baumannii isolates in an ICU, to characterize the circulating carbapenemases, and to detect 16S-RMTases. Patients admitted between August 2010 and July 2011 with a clinically predicted hospital stay > 48 hr were included. Pharyngeal and rectal swabs were obtained during the first fortnight after hospitalization. Resistance profiles were determined with MicroScan® and VITEK2 system. Carbapenemases and 16S-RMTases were identified by PCR and sequencing, and clonality was assessed by pulsed-field gel electrophoresis and multilocus sequence typing. Sixty-nine patients were studied and 63 were diagnosed with bacterial infections. Among these, 29 were CRAB isolates; 49 A. baumannii were isolated as digestive colonizers. These 78 isolates were clustered in 7 pulsetypes, mostly belonging to ST79. The only carbapenemase genes detected were blaOXA-51 (n = 78), blaOXA-23 (n = 62), and blaOXA-58 (n = 3). Interestingly, two clinical isolates harbored the rmtC 16S-RMTase gene. To the best of our knowledge, this is the first description of the presence of rmtC in A. baumannii.


Geriatric Consultation Reduces High-risk Medication Usage at Discharge in Elderly Trauma Patients.
Background Traumatic injury in a growing geriatric population is associated with higher mortality and complication rates. Geriatric consultation (GC) is vital in reducing risk factors that contribute to adverse outcomes. This study aims to determine if receiving a GC had an impact on high-risk medication usage. Methods Patients eligible for a GC, age ≥ 65, and length of stay > two days, were identified via a chart review from July 2013 to July 2014 at a Level II trauma center. This population was divided into those with and without a GC. Data collected included demographics, injury severity, medications, delirium, mortality, and readmissions. High-risk medications were defined using the Beers Criteria. Statistical analysis involved using appropriate standard tests to compare groups, including multivariate logistic regression. Results Forty-nine of a total of 104 patients received a GC. Groups were comparable on injury severity score, co-morbidities, and high-risk medication use upon admissions. The GC group was 74% less likely to be discharged on high-risk medications than the non-GC group. Conclusion GC in elderly trauma patients reduces high-risk medication use upon discharge. Further studies are needed to explore how GC impacts readmission rates and mortality. A multidisciplinary trauma team, including a geriatrician, must exist to address the unique medical, psychological, functional, and social issues of a growing, aged trauma population.


Quantitative susceptibility mapping by inversion of a perturbation field model: correlation with brain iron in normal aging.
There is increasing evidence that iron deposition occurs in specific regions of the brain in normal aging and neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's disease. Iron deposition changes the magnetic susceptibility of tissue, which alters the MR signal phase, and allows estimation of susceptibility differences using quantitative susceptibility mapping (QSM). We present a method for quantifying susceptibility by inversion of a perturbation model, or "QSIP." The perturbation model relates phase to susceptibility using a kernel calculated in the spatial domain, in contrast to previous Fourier-based techniques. A tissue/air susceptibility atlas is used to estimate B0 inhomogeneity. QSIP estimates in young and elderly subjects are compared to postmortem iron estimates, maps of the Field-Dependent Relaxation Rate Increase, and the L1-QSM method. Results for both groups showed excellent agreement with published postmortem data and in vivo FDRI: statistically significant Spearman correlations ranging from Rho=0.905 to Rho=1.00 were obtained. QSIP also showed improvement over FDRI and L1-QSM: reduced variance in susceptibility estimates and statistically significant group differences were detected in striatal and brainstem nuclei, consistent with age-dependent iron accumulation in these regions.