Bactericidal activity and mechanism of action of copper-sputtered flexible surfaces against multidrug-resistant pathogens.
Using direct current magnetron sputtering (DCMS), we generated flexible copper polyester surfaces (Cu-PES) and investigated their antimicrobial activity against a range of multidrug-resistant (MDR) pathogens including eight Gram-positive isolates (three methicillin-resistant Staphylococcus aureus [MRSA], four vancomycin-resistant enterococci, one methicillin-resistant Staphylococcus epidermidis) and four Gram-negative strains (one extended-spectrum β-lactamase-producing [ESBL] Escherichia coli, one ESBL Klebsiella pneumoniae, one imipenem-resistant Pseudomonas aeruginosa, and one ciprofloxacin-resistant Acinetobacter baumannii). Bactericidal activity (≥3 log10 CFU reduction of the starting inoculum) was reached within 15-30 min exposure to Cu-PES. Antimicrobial activity of Cu-PES persisted in the absence of oxygen and against both Gram-positive and Gram-negative bacteria containing elevated levels of catalases, indicating that reactive oxygen species (ROS) do not play a primary role in the killing process. The decrease in cell viability of MRSA ATCC 43300 and Enterococcus faecalis V583 correlated with the progressive loss of cytoplasmic membrane integrity both under aerobic and anaerobic conditions, suggesting that Cu-PES mediated killing is primarily induced by disruption of the cytoplasmic membrane function. Overall, we here present novel antimicrobial copper surfaces with improved stability and sustainability and provide further insights into their mechanism of killing.


Physical activity and sedentary behavior patterns are associated with selected adolescent health risk behaviors.
Little is known about how physical activity (PA), sedentary behavior, and various adolescent health risk behaviors are associated. The objective of this study was to examine relationships between PA and sedentary behavior patterns and an array of risk behaviors, including leading causes of adolescent morbidity/mortality. Nationally representative self-reported data were collected (National Longitudinal Study of Adolescent Health; wave I: 1994-1995; II: 1996; N = 11957). Previously developed and validated cluster analyses identified 7 homogeneous groups of adolescents sharing PA and sedentary behaviors. Poisson regression predicted the relative risk of health risk behaviors, other weekly activities, and self-esteem across the 7 PA/sedentary behavior clusters controlling for demographics and socioeconomic status. Main outcome measures were adolescent risk behaviors (eg, truancy, cigarette smoking, sexual intercourse, delinquency), other weekly activities (eg, work, academic performance, sleep), self-esteem. Relative to high television (TV) and video viewers, adolescents in clusters characterized by skating and video gaming, high overall sports and sports participation with parents, using neighborhood recreation center, strict parental control of TV, reporting few activities overall, and being active in school were less likely to participate in a range of risky behaviors, ranging from an adjusted risk ratio (ARR) of 0.42 (outcome: illegal drug use, cluster: strict parental control of TV) to 0.88 (outcome: violence, cluster: sports with parents). Active teens were less likely to have low self-esteem (eg, adolescents engaging in sports with parents, ARR: 0.73) and more likely to have higher grades (eg, active in school, ARR: 1.20). Participation in a range of PA-related behaviors, particularly those characterized by high parental sports/exercise involvement, was associated with favorable adolescent risk profiles. Adolescents with high TV/video viewership were less likely to have positive risk behavior outcomes. Enhancing opportunities for PA and sport may have a beneficial effect on leading adolescent risk behaviors.


DNA repair gene XRCC1 polymorphisms and bladder cancer risk.
Cigarette smoking and chemical occupational exposure are the main known risk factors for bladder transitional cell carcinoma (TCC). Oxidative DNA damage induced by carcinogens present in these exposures requires accurate base excision repair (BER). The XRCC1 protein plays a crucial role in BER by acting as a scaffold for other BER enzymes. Variants in the XRCC1 gene might alter protein structure or function or create alternatively spliced proteins which may influence BER efficiency and hence affect individual susceptibility to bladder cancer. Recent epidemiological studies have shown inconsistent associations between these polymorphisms and bladder cancer. To clarify the situation, we conducted a comprehensive analysis of 14 XRCC1 polymorphisms in a case-control study involving more than 1100 subjects. We found no evidence of an association between any of the 14 XRCC1 polymorphisms and bladder cancer risk. However, we found carriage of the variant Arg280His allele to be marginally associated with increased bladder cancer risk compared to the wild-type genotype (adjusted odds ratio [95% confidence interval], 1.50 [0.98-2.28], p = 0.06). The association was stronger for current smokers such that individuals carrying the variant 280His allele had a two to three-fold increased risk of bladder cancer compared to those carrying the wildtype genotype (p = 0.09). However, the evidence for gene-environment interaction was not statistically significant (p = 0.45). We provide no evidence of an association between polymorphisms in XRCC1 and bladder cancer risk, although our study had only limited power to detect the association for low frequency variants, such as Arg280His.


Endocrine disrupters: the new players able to affect the epigenome.
Epigenetics represents the way by which the environment is able to program the genome; there are three main levels of epigenetic control on genome: DNA methylation, post-translational histone modification and microRNA expression. The term Epigenetics has been widened by NIH to include "both heritable changes in gene activity and expression but also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable." These changes might be produced mostly by the early life environment and might affect health influencing the susceptibility to develop diseases, from cancer to mental disorder, during the entire life span. The most studied environmental influences acting on epigenome are diet, infections, wasting, child care, smoking and environmental pollutants, in particular endocrine disrupters (EDs). These are environmental xenobiotics able to interfere with the normal development of the male and female reproductive systems of wildlife, of experimental animals and possibly of humans, disrupting the normal reproductive functions. Data from literature indicate that EDs can act at different levels of epigenetic control, in some cases transgenerationally, in particular when the exposure to these compounds occurs during the prenatal and earliest period of life. Some of the best characterized EDs will be considered in this review. Among the EDs, vinclozolin (VZ), and methoxychlor (MXC) promote epigenetic transgenerational effects. Polychlorinated biphenils (PCBs), the most widespread environmental EDs, affect histone post-translational modifications in a dimorphic way, possibly as the result of an alteration of gene expression of the enzymes involved in histone modification, as the demethylase Jarid1b, an enzyme also involved in regulating the interaction of androgens with their receptor.


Cryogenically preserved RBCs support gametocytogenesis of Plasmodium falciparum in vitro and gametogenesis in mosquitoes.
The malaria Eradication Research Agenda (malERA) has identified human-to-mosquito transmission of Plasmodium falciparum as a major target for eradication. The cornerstone for identifying and evaluating transmission in the laboratory is standard membrane feeding assays (SMFAs) where mature gametocytes of P. falciparum generated in vitro are offered to mosquitoes as part of a blood-meal. However, propagation of "infectious" gametocytes requires 10-12 days with considerable physico-chemical demands imposed on host RBCs and thus, "fresh" RBCs that are ≤ 1-week old post-collection are generally recommended. However, in addition to the costs, physico-chemical characteristics unique to RBC donors may confound reproducibility and interpretation of SMFAs. Cryogenic storage of RBCs ("cryo-preserved RBCs") is accepted by European and US FDAs as an alternative to refrigeration (4 °C) for preserving RBC "quality" and while cryo-preserved RBCs have been used for in vitro cultures of other Plasmodia and the asexual stages of P. falciparum, none of the studies required RBCs to support parasite development for > 4 days. Using the standard laboratory strain, P. falciparum NF54, 11 SMFAs were performed with RBCs from four separate donors to demonstrate that RBCs cryo-preserved in the gaseous phase of liquid nitrogen (- 196 °C) supported gametocytogenesis in vitro and subsequent gametogenesis in Anopheles stephensi mosquitoes. Overall levels of sporogony in the mosquito, as measured by oocyst and sporozoite prevalence, as well as oocyst burden, from each of the four donors thawed after varying intervals of cryopreservation (1, 4, 8, and 12 weeks) were comparable to using ≤ 1-week old refrigerated RBCs. Lastly, the potential for cryo-preserved RBCs to serve as a suitable alternative substrate is demonstrated for a Cambodian isolate of P. falciparum across two independent SMFAs. Basic guidelines are presented for integrating cryo-preserved RBCs into an existing laboratory/insectary framework for P. falciparum SMFAs with significant potential for reducing running costs while achieving greater reliability. Lastly, scenarios are discussed where cryo-preserved RBCs may be especially useful in enhancing the understanding and/or providing novel insights into the patterns and processes underlying human-to-mosquito transmission.


An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis.
Female patients (n = 20) with osteoporosis, aged 66 +/- 5 yr were studied during a 24-h infusion of parathyroid hormone (PTH [1-34]) at a rate of 0.5 IU equivalents/kg.h, and then during a 28-d period of subcutaneous injections, at a dose of 800 IU equivalents per day. Thereafter half the patients received subcutaneous injections of calcitonin, 75 U/d for 42 d, and all patients were followed to the end of a 90-d cycle. Biochemical markers of bone formation (serum alkaline phosphatase, osteocalcin, and the carboxy-terminal extension peptide of pro-collagen 1) and bone resorption (fasting urine calcium, hydroxyproline, and deoxypyridinoline) were compared during treatment by the intravenous and subcutaneous route of PTH administration, and subsequently during calcitonin therapy. During intravenous PTH infusion there were significant reductions in all three bone formation markers, despite expected rises in urinary calcium and hydroxyproline. By contrast, the circulating markers of bone formation increased rapidly by > 100% of baseline values during daily PTH injections (P < 0.001). Significant increases in bone resorption markers were only seen at the end of the 28 d of injections, but were < 100% over baseline values, (P < 0.05). Quantitative bone histomorphometry from biopsies obtained after 28 d of PTH treatment confirmed that bone formation at both the cellular and tissue levels were two to five times higher than similar indices measured in a control group of biopsies from untreated osteoporotic women. Subsequent treatment of these patients with calcitonin showed no significant changes in the biochemical markers of bone formation and only a modest attenuation of bone resorption. Thus, PTH infusion may inhibit bone formation, as judged by circulating biochemical markers, whereas daily injections confirm the potent anabolic actions of the hormone. Sequential calcitonin therapy does not appear to act synergistically with PTH in cyclical therapeutic protocols.


Anaemia stimulates aquaporin 1 expression in the fetal sheep heart.
Interstitial fluid fluxes are much greater in the fetus than in the adult, and filtration rates are increased over control in most tissues of the anaemic fetus. Increased capillary filtration may lead to cardiac oedema which, in turn, severely impacts cardiac function. Mechanisms that underlie these differences in flux are incompletely understood. One possible mechanism is an increase in capillary water permeability. Therefore, the goal of our study was to determine the level of expression of the water channel aquaporin 1 (AQP1) during cardiac development and in the anaemic fetal sheep heart. Hearts from chronically instrumented anaemic sheep fetuses and hearts from normal early fetal, late fetal, neonatal and adult sheep were used for Northern and Western analyses and immunohistochemistry. We found that AQP1 mRNA levels were lower in the young fetal left ventricle than in the adult left ventricle (P < 0.05). We also found that cardiac AQP1 expression was increased in anaemic fetuses compared to age-matched controls (P < 0.05). Expression of AQP1 in all groups was greatest in the microvascular endothelium. These data suggest that AQP1 plays an important role in the physiological accommodation to fetal anaemia.


Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness.
Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug's efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File - Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug interaction claims linked to the Drug Interactions section for a drug were potentially novel. The baseline performance characteristics of the proof-of-concept will enable further technical and user-centered research on robust methods for scaling the approach to the many thousands of product labels currently on the market.


Decreased progesterone levels and progesterone receptor antagonists promote apoptotic cell death in bovine luteal cells.
We tested the hypothesis that progesterone (P(4)) acts at a local level to inhibit luteal apoptosis. Initial experiments employed aminoglutethimide, a P450 cholesterol side-chain cleavage inhibitor, to inhibit steroid synthesis. Cultured bovine luteal cells were treated with aminoglutethimide (0.15 mM) +/- P(4) (500 ng/ml) for 48 h. Luteal cells were recovered and snap frozen for isolation and analysis of oligonucleosomal DNA fragmentation or fixed for morphological analysis. Medium was collected for analysis of P(4) levels by RIA. Aminoglutethimide inhibited P(4) synthesis by > 95% and increased the level of apoptosis as evidenced by (32)P-labeled oligonucleosomal DNA fragmentation (> 40%). P(4) supplementation inhibited the onset of apoptosis that was induced by aminoglutethimide. These data were further supported by morphological assessment of apoptotic cells utilizing a Hoechst staining technique and together strongly suggest that P(4) has anti-apoptotic capacity. Using reverse transcription-polymerase chain reaction, we were able to isolate a 380-base pair cDNA from the bovine corpus luteum (CL) that was 100% homologous to the progesterone receptor (PR) previously found in bovine oviductal tissue. Furthermore, PR transcripts were present in large and small luteal cells. Immunohistochemistry also revealed that PR protein was present in both large and small luteal cells. To determine whether the anti-apoptotic effect of P(4) was regulated at the receptor level, luteal cells were cultured in the presence of PR antagonists, RU-486 and onapristone, for 48 h. Both antagonists caused approximately a 40% increase in (32)P-labeled oligonucleosomal DNA fragmentation. Interestingly, there was no difference (P >/= 0.05) in P(4) levels after treatment with PR antagonists. These observations support the concept that P(4) represses the onset of apoptosis in the CL by a PR-dependent mechanism.


The formation of leaves.
The past year has seen major advances in our understanding of the mechanisms through which leaf pattern is elaborated. It has been suggested that developmental subcompartments are delimited within the leaf and that homeobox genes are involved in specifying these domains in compound leaves. Importantly, peptide signaling has emerged as a novel component of leaf developmental pathways.


Long-range electron transfer in myoglobin.
The distance and driving-force dependences of electron transfer (ET) in a set of four surface-ruthenated myoglobins, in which the heme prosthetic group has been systematically replaced by a series of metalloporphyrins of differing excited-state redox potentials, have provided information on the magnitude [Hab(12.7 A) approximately 6.3 x 10(-3) cm-1] and decay [beta approximately 0.8 A-1, where kET alpha exp [-beta(d - do)]] of protein-mediated donor-acceptor electronic coupling. A reorganization energy lambda approximately 1.3 eV, due to coordination and solvation changes both at and between the ET sites, has been estimated using a rate expression that allows electron-vibration coupling to classical and quantum mechanical modes. The contribution to lambda from the porphyrin and peptide matrix is approximately 0.7 eV. Specific electron-tunneling pathways in the protein have been evaluated.


Effects of U74006F on multifocal cerebral blood flow and metabolism after cardiac arrest in dogs.
Lipid peroxidation reactions during reperfusion after cardiac arrest may contribute to postischemic cerebral hypoperfusion, which in turn can contribute to permanent neurological dysfunction. We designed this study to determine whether the aminosteroid U74006F, a putative inhibitor of lipid peroxidation, mitigates cerebral multifocal hypoperfusion after cardiac arrest. We used our established dog model of ventricular fibrillation cardiac arrest (no blood flow) of 12.5 minutes, reperfusion by cardiopulmonary bypass of less than or equal to 5 minutes, and control of extracerebral variables during 4 hours postarrest. Cerebral blood flow was monitored by the stable xenon computed tomography method. Changes in cerebral oxygen consumption were obtained from mean blood flow values of coronal slices and the cerebral arteriovenous (sagittal sinus) oxygen content difference. A treatment group (n = 5) received U74006F starting with reperfusion (1.5 mg/kg i.a. plus 1.5 mg/kg i.v.) and three additional (graded) doses over 4 hours (total dose 4.5, 7.5, or 14.5 mg/kg). The U74006F-treated group showed the same postarrest transient hyperemia and protracted hypoperfusion in terms of global (computed tomography slice), regional, and local (multifocal) cerebral blood flow values and the same global cerebral oxygen consumption pattern as a concurrent control group (n = 5). At 1-4 hours postarrest, in both groups there was mismatching of global cerebral oxygen consumption, which reached baseline values, in relation to global cerebral blood flow and oxygen delivery, which remained at 50% of baseline. We conclude that treatment with U74006F after prolonged cardiac arrest causes no deleterious side effects and does not seem to alter multifocal postarrest cerebral blood flow and oxygen consumption.


Early Oral Tongue Squamous Cell Carcinoma: Sampling of Margins From Tumor Bed and Worse Local Control.
Positive margins are associated with poor prognosis among patients with oral tongue squamous cell carcinoma (SCC). However, wide variation exists in the margin sampling technique. To determine the effect of the margin sampling technique on local recurrence (LR) in patients with stage I or II oral tongue SCC. A retrospective study was conducted from January 1, 1986, to December 31, 2012, in 5 tertiary care centers following tumor resection and elective neck dissection in 280 patients with pathologic (p)T1-2 pN0 oral tongue SCC. Analysis was conducted from June 1, 2013, to January 20, 2015. In group 1 (n = 119), tumor bed margins were not sampled. In group 2 (n = 61), margins were examined from the glossectomy specimen, found to be positive or suboptimal, and revised with additional tumor bed margins. In group 3 (n = 100), margins were primarily sampled from the tumor bed without preceding examination of the glossectomy specimen. The margin status (both as a binary [positive vs negative] and continuous [distance to the margin in millimeters] variable) and other clinicopathologic parameters were compared across the 3 groups and correlated with LR. Local recurrence. Age, sex, pT stage, lymphovascular or perineural invasion, and adjuvant radiation treatment were similar across the 3 groups. The probability of LR-free survival at 3 years was 0.9 and 0.8 in groups 1 and 3, respectively (P = .03). The frequency of positive glossectomy margins was lowest in group 1 (9 of 117 [7.7%]) compared with groups 2 and 3 (28 of 61 [45.9%] and 23 of 95 [24.2%], respectively) (P < .001). Even after excluding cases with positive margins, the median distance to the closest margin was significantly narrower in group 3 (2 mm) compared with group 1 (3 mm) (P = .008). The status (positive vs negative) of margins obtained from the glossectomy specimen correlated with LR (P = .007), while the status of tumor bed margins did not. The status of the tumor bed margin was 24% sensitive (95% CI, 16%-34%) and 92% specific (95% CI, 85%-97%) for detecting a positive glossectomy margin. The margin sampling technique affects local control in patients with oral tongue SCC. Reliance on margin sampling from the tumor bed is associated with worse local control, most likely owing to narrower margin clearance and greater incidence of positive margins. A resection specimen-based margin assessment is recommended.


The presence of multiple prothrombotic risk factors is associated with a higher risk of thrombosis in individuals with anticardiolipin antibodies.
To explore the effect of multiple prothrombotic risk factors in individuals with anticardiolipin antibodies (aCL), we evaluated immunologic, coagulation, and genetic prothrombotic abnormalities in a cohort of individuals with different aCL titers. We recruited 87 individuals into 4 categories (normal, low, intermediate, or high) based on their baseline IgG aCL (aCL-IgG) titers. We measured at followup: repeat aCL-IgG, IgM aCL (aCL-IgM), antibodies to beta2-glycoprotein I (anti-beta2-GPI), lupus anticoagulant (LAC) antibodies, protein C, protein S, activated protein C resistance, factor V506 Leiden mutation, methyl tetrahydrofolate reductase (MTHFR) C677T genotype, and prothrombin 20210A gene mutation. Thrombotic events were confirmed. At recruitment, 20 individuals were negative for aCL-IgG and 67 were positive (22 low, 20 intermediate, and 25 high titer). Twenty of the 87 participants had experienced a previous thrombotic event: 4 in the aCL-IgG negative group and 16 in the aCL-IgG positive group. Among the 87 individuals, the number of those with concomitant prothrombotic risk factors was as follows: 5 had no other prothrombotic risk factors, 32 had 1 risk factor, 24 had 2 risk factors, 10 had 3 risk factors, 10 had 4 risk factors, and 6 had 5 risk factors. Thrombotic events were observed in 20%, 13%, 33%, 10%, 30%, and 50% of these groups, respectively, and the odds ratio associated with a previous thrombotic event was 1.46 per each additional prothrombotic risk factor (95% confidence interval: 1.003-2.134). In individuals with positive aCL-IgG, we observed an association between the number of prothrombotic risk factors and history of thrombotic events.


Metaphors of a shifting sense of self in men recovering from substance abuse and suicidal behavior.
The purpose of this descriptive study was to explore and interpret men's experience of sense of self within the context of recovery from substance abuse and suicidal behavior. A secondary analysis of data from a previous study of four young Norwegian men revealed how a shifting sense of self was constructed through the use of metaphors. The analysis identified three themes related to the participants' sense of self: The Meaning of Being Isolated, The Meaning of Being Close to the Point of No Return, and The Meaning of Still Being on the Edge. By acknowledging metaphorical expressions as a source of important knowledge, this study reflects on how mental health professionals can use metaphors in the recovery process. As part of the' treatment alliance and therapeutic communication, we suggest that metaphors may aid the assessment of suicidal ideation, promote a sense of a more active self, and signal acceptance and recognition of subjectivity.


Non-osseous uptake on Tc99m methylene diphosphonate in multiple muscles confirmed on SPECT/computed tomography.
A 55-year-old female presented with complaints of pain in the left hip radiating to the left lower limb since 1 year. Computed tomography (CT) abdomen and pelvis revealed bony destruction of pubic symphysis with associated soft tissue component suspicious of infective or metastatic etiology. Magnetic resonance imaging Lumbo-sacral spine performed later revealed altered bone marrow signal in sacral 1-3 vertebrae. Wholebody bone scan with 25 mCi of Tc-99m methylene diphosphonate (MDP) was performed, which revealed multiple skeletal metastases and extraosseous soft tissue uptake was seen involving multiple muscles. We performed single photon emission tomography single photon emission computed tomography (SPECT)/computed tomography (CT) images to precisely delineate the muscle involved and noted calcification on CT images in one of the muscle at site of Tc-99m MDP uptake, no definite calcification was noted in the other muscles. Thus, the final diagnosis was multiple skeletal metastasis with metastatic calcification in multiple muscle from an unknown primary.


Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.
The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.


Case management of childhood pneumonia in developing countries.
Pneumonia is a leading cause of morbidity and mortality in children worldwide. Appropriate management depends on accurate assessment of disease severity, and for the majority of children in developing countries the assessment is based on clinical signs alone. This article reviews recent evidence on clinical assessment and severity classification of pneumonia and reported results on the effectiveness of currently recommended treatments. Potential studies for inclusion were identified by Medline (1990-2006) search. The Oxford Center for Evidence Based Medicine criteria were used to describe the methodologic quality of selected studies. In the included studies the sensitivity of current definitions of tachypnea for diagnosing radiologic pneumonia ranged from 72% to 94% with specificities between 38% and 99%; chest indrawing had reported sensitivities of between 46% and 78%. Data provide some support for the value of current clinical criteria for classifying pneumonia severity, with those meeting severe or very severe criteria being at considerably increased risk of death, hypoxemia or bacteremia. Results of randomized controlled trials report clinically defined improvement at 48 hours in at least 80% of children treated using recommended antibiotics. However, a limitation of these data may include inappropriate definitions of treatment failure. Particularly with regard to severe pneumonia, issues that specifically need to be addressed are the adequacy of penicillin monotherapy, or oral amoxicillin or alternative antibiotics; the timing of introduction of high-dose trimethoprim-sulfamethoxazole in children at risk for or known to be infected by HIV and the value of pulse oximetry.


Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis.
Which types of exercise intervention are most effective in relieving pain and improving function in people with lower limb osteoarthritis? As of 2002 sufficient evidence had accumulated to show significant benefit of exercise over no exercise. An approach combining exercises to increase strength, flexibility, and aerobic capacity is most likely to be effective for relieving pain and improving function. Current international guidelines recommend therapeutic exercise (land or water based) as "core" and effective management of osteoarthritis. Evidence from this first network meta-analysis, largely based on studies in knee osteoarthritis, indicates that an intervention combining strengthening exercises with flexibility and aerobic exercise is most likely to improve outcomes of pain and function. Further trials of exercise versus no exercise are unlikely to overturn this positive result.


The TLX2 homeobox gene is a transcriptional target of PHOX2B in neural-crest-derived cells.
The TLX2 (HOX11L1, Ncx, Enx) and PHOX2B genes encode transcription factors crucial in the development of neural-crest-derived cells, leading to ANS (autonomic nervous system) specific neuronal lineages. Moreover, they share a similar expression pattern and are both involved in downstream steps of BMP (bone morphogenetic protein) signalling. In an attempt to reconstruct the gene network sustaining the correct development of the ANS, we have undertaken an in vitro experimental strategy to identify direct upstream regulators of the TLX2 gene. After characterizing a sequence displaying enhancer property in its 5' flanking region, we confirmed the functional link between the human PHOX2B and TLX2 genes. Transient transfections and electrophoretic-mobility-shift assays suggested that PHOX2B is able to bind the cell-specific element in the 5' regulatory region of the TLX2 gene, determining its transactivation in neuroblastoma cells. Such interaction was also confirmed in vivo by means of chromatin immunoprecipitation assay and, in addition, up-regulation of endogenous TLX2 mRNA level was demonstrated following PHOX2B over-expression, by quantitative real-time PCR. Finally, PHOX2B proteins carrying mutations responsible for CCHS (congenital central hypoventilation syndrome) development showed a severe impairment in activating TLX2 expression, both in vitro and in vivo. Taken together, these results support the PHOX2B-TLX2 promoter interaction, suggesting a physiological role in the transcription-factor cascade underlying the differentiation of neuronal lineages of the ANS during human embryogenesis.


Helicobacter hepaticus polysaccharide induces an anti-inflammatory response in intestinal macrophages.
A high density of microbes inhabits the intestine, helping with food digestion, vitamin synthesis, xenobiotic detoxification, pathogen resistance and immune system maturation. Crucial for human health, communities of commensal bacteria (collectively termed microbiota) benefit in return from a nutrient-rich environment. Host-microbiota mutualism results from a long-term co-adaptation. At barrier surfaces, immune cells distinguish harmful from commensal bacteria and tolerate non-self organisms at close proximity to the mucosa; gut inhabitants have developed strategies to ensure beneficial conditions in their preferred niche. So far, the complex dialogue of host-microbial mutualism is poorly understood. Helicobacter hepaticus is a member of the mouse microbiota that colonizes the lower intestine without inducing immune pathology. However, when there is a host maladaptation such as the absence of the anti-inflammatory cytokine interleukin 10 (IL-10) or its receptor IL-10R, H. hepaticus triggers aberrant IL-23-driven intestinal inflammation. This response results in major changes in the intestinal innate cell compartment, with the accumulation of inflammatory macrophages. Relying both on a bacterial trigger and on an immune defect, H. hepaticus-induced colitis in the context of IL-10/IL-10R axis deficiency shares many features of human inflammatory bowel diseases (IBD). In our study [Danne et al, Cell Host Microbe 22(6):733-745], we questioned the interactions between H. hepaticus and intestinal macrophages that promote mutualism. Our results show that H. hepaticus produces a large polysaccharide that triggers IL-10 production without a corresponding inflammatory response in macrophages. Moreover, H. hepaticus polysaccharide specifically induces an anti-inflammatory gene signature in vitro and in vivo, including transcriptional factors known as repressors of immune activation. This anti-inflammatory program depends on the TLR2/MSK/CREB pathway, which might be crucial to maintain mutualistic relationships at the intestinal interface.


The old and familiar meets the new and unknown: patient and clinician perceptions on e-cigarettes for smoking reduction in UK general practice, a qualitative interview study.
Clinicians could promote e-cigarettes for harm reduction to people who smoke but cannot stop, but many clinicians feel uneasy doing so. In a randomized controlled trial (RCT), primary care clinicians offered free e-cigarettes and encouraged people with chronic diseases who were unwilling to stop smoking to switch to vaping. We interviewed clinicians and patients to understand how to adopt harm reduction in routine practice. Qualitative analysis nested within an RCT, comprising thematic analysis of semi-structured interviews with primary care clinicians who delivered the trial intervention, and patients who took part. Primary care clinics in England. Twenty-one patients and 11 clinicians, purposively sampled from an RCT. We qualitatively explored patients' and clinicians' experiences of: being offered/offering an e-cigarette, past and current perceptions about e-cigarettes and applying a harm reduction approach. Four themes captured clinicians' and patients' reported perspectives. These were: (1) concepts of safety/risk, with clinicians concerned about recommending a product with unknown long-term risks and patients preferring the known risks of cigarettes; (2) clinicians felt they were going out on a limb by offering these as though they were prescribing them, whereas patients did not share this view; (3) equating quitting with success, as both patients and clinicians conceptualized e-cigarettes as quitting aids; and (4) unchanged views, as clinicians reported that training did not change their existing views about e-cigarettes. These themes were united by the higher-order concept: 'The old and familiar meets the new and unknown', as a contradiction between this new approach and long-established methods underpinned these concerns. A qualitative analysis found barriers obstructing clinicians and patients from easily accepting e-cigarettes for harm reduction, rather than as aids to support smoking cessation: clinicians had difficulty reconciling harm reduction with their existing ethical models of practice, even following targeted training, and patients saw e-cigarettes as quitting aids.


Protective mechanical ventilation does not exacerbate lung function impairment or lung inflammation following influenza A infection.
The degree to which mechanical ventilation induces ventilator-associated lung injury is dependent on the initial acute lung injury (ALI). Viral-induced ALI is poorly studied, and this study aimed to determine whether ALI induced by a clinically relevant infection is exacerbated by protective mechanical ventilation. Adult female BALB/c mice were inoculated with 10(4.5) plaque-forming units of influenza A/Mem/1/71 in 50 microl of medium or medium alone. This study used a protective ventilation strategy, whereby mice were anesthetized, tracheostomized, and mechanically ventilated for 2 h. Lung mechanics were measured periodically throughout the ventilation period using a modification of the forced oscillation technique to obtain measures of airway resistance and coefficients of tissue damping and tissue elastance. Thoracic gas volume was measured and used to obtain specific airway resistance, tissue damping, and tissue elastance. At the end of the ventilation period, a bronchoalveolar lavage sample was collected to measure inflammatory cells, macrophage inflammatory protein-2, IL-6, TNF-alpha, and protein leak. Influenza infection caused significant increases in inflammatory cells, protein leak, and deterioration in lung mechanics that were not exacerbated by mechanical ventilation, in contrast to previous studies using bacterial and mouse-specific viral infection. This study highlighted the importance of type and severity of lung injury in determining outcome following mechanical ventilation.


1H NMR-Based Chemometrics to Gain Insights Into the Bran of Radiation-Induced Colored Wheat Mutant.
Recently, wheat has attracted attention as a functional food, rather than a simple dietary energy source. Accordingly, whole-grain intake increases with an understanding of bioactive phytochemicals in bran. The development of colored wheat has drawn more attention to the value of bran owing to its nutritional quality, as well as the antioxidant properties of the colorant. The present 1H NMR-based chemometric study evaluated the compositional improvement of radiation-induced mutants in purple wheat by focusing on the predominant metabolites with high polarity. A total of 33 metabolites, including three choline derivatives, three sugar alcohols, four sugars, 13 amino acids, eight organic acids, and two nucleosides, were identified throughout the 1H NMR spectra, and quantification data were obtained for the identified metabolites via peak shape-based quantification. Principal component and hierarchical cluster analyses were conducted for performing multivariate analyses. The colored original wheat was found to exhibit improvements compared to yellow wheat in terms of the contents of primary metabolites, thus highlighting the importance of conducting investigations of polar metabolites. The chemometrics studies further revealed mutant lines with a compositional enhancement for metabolites, including lysine, proline, acetate, and glycerol.


Development of a comprehensive health-risk prediction tool for postmenopausal women.
The aim of the study was to develop a web-based calculator that predicts the likelihood of experiencing multiple, competing outcomes prospectively over 5, 10, and 15 years. Baseline demographic and medical data from a healthy and racially and ethnically diverse cohort of 161,808 postmenopausal women, aged 50 to 79 at study baseline, who participated in the Women's Health Initiative (WHI), were used to develop and evaluate a risk-prediction calculator designed to predict individual risk for morbidity and mortality outcomes. Women were enrolled from 40 sites arranged in four regions of the United States. The calculator predicts all-cause mortality, adjudicated outcomes of health events (ie, myocardial infarction [MI], stroke, and hip fracture), and disease (lung, breast, and colorectal cancer). A proportional subdistribution hazards regression model was used to develop the calculator in a training dataset using data from three regions. The calculator was evaluated using the C-statistic in a test dataset with data from the fourth region. The predictive validity of our calculator measured by the C-statistic in the test dataset for a first event at 5 and 15 years was as follows: MI 0.77, 0.61, stroke 0.77, 0.72, lung cancer 0.82, 0.79, breast cancer 0.60, 0.59, colorectal cancer 0.67, 0.60, hip fracture 0.79, 0.76, and death 0.74, 0.72. This study represents the first large-scale study to develop a risk prediction calculator that yields health risk prediction for several outcomes simultaneously. Development of this tool is a first step toward enabling women to prioritize interventions that may decrease these risks. : Video Summary:http://links.lww.com/MENO/A463.


The potential use of propolis as a cariostatic agent and its actions on mutans group streptococci.
Propolis is a resinous substance made by bees. It possesses many biological activities, and many studies have reported its potential application in the control of dental caries. However, variability in the chemical composition of propolis is a potential problem in its quality control, especially since propolis has already been incorporated into products for oral use. Therefore, a critical analysis of the available data on propolis is warranted. The present review discusses the in vitro and in vivo studies published in the period between 1978 and 2008 regarding the effects of propolis on Streptococcus mutans growth, bacterial adherence, glucosyltransferase activity, and caries indicators. Several investigations carried out with crude propolis extracts, isolated fractions, and purified compounds showed reductions in Streptococcus mutans counts and interference with their adhesion capacity and glucosyltransferase activity, which are considered major properties in the establishment of the cariogenic process. Data from in vivo studies have demonstrated reductions in Streptococcus mutans counts in saliva, the plaque index, and insoluble polysaccharide formation. These findings indicate that propolis and/or its compounds are promising cariostatic agents. However, the variation in the chemical composition of propolis due to its geographical distribution is a significant drawback to its routine clinical use. Thus, further studies are needed to establish the quality and safety control criteria for propolis in order for it to be used in accordance with its proposed activity.


Reflections on the tissue kallikrein and kallikrein-related peptidase family - from mice to men - what have we learnt in the last two decades?
The genes encoding the kininogenase, glandular tissue kallikrein, in rodents and man were first described in the mid-1980s. Remarkably, they appeared to be part of a much larger highly conserved family of genes (GK) in rodents, but only had two paralogs in man. This discrepancy was not rectified until the late 1990s/2000 with the identification of a cluster of 12 more kallikrein-related (KLK) genes in the human 19q13 locus and the subsequent identification of their rodent homologs. Interestingly, there are remarkable similarities in expression patterns, hormonal regulation and functional attributes of the old (GK) and new (KLK) families which underscore the evolutionary conservation across these loci and species. This historical perspective focuses on the lessons learned from earlier studies on the rodent GK gene families and the striking similarities of some attributes, yet uniqueness, of others. These earlier findings have all contributed to the current status of the KLK serine peptidase-encoding gene family as an exciting source of new biomarkers and therapeutic targets.


Does the Impact of the Tobacco Epidemic Explain Structural Changes in the Decline of Mortality?
Since 1950, most developed countries have exhibited structural changes in mortality decline. This complicates extrapolative forecasts, such as the commonly used Lee-Carter model, that require the presence of a steady long-term trend. This study tests whether the impact of the tobacco epidemic explains the structural changes in mortality decline, as it is presumed in earlier studies. For this purpose, the time index of the Lee-Carter model in males was investigated in 20 developed countries between 1950 and 2011 for possible structural changes. It was found that removing the impact of smoking from mortality trends took away more than half of the 12 detected trend breaks. For the remaining trend breaks, adjusting for smoking attenuated the degree of change in mortality decline. Taking the tobacco epidemic into account should become standard procedure in mortality forecasts to avoid a misleading extrapolation of trends. Nevertheless, more research is needed to identify additional factors, such as health-care policies and innovations in medical treatment, to explain the remaining structural changes.


Social influences on clinical outcomes of patients with ovarian cancer.
Previous research has demonstrated relationships of social support with disease-related biomarkers in patients with ovarian cancer. However, the clinical relevance of these findings to patient outcomes has not been established. This prospective study examined how social support relates to long-term survival among consecutive patients with ovarian cancer. We focused on two types of social support: social attachment, a type of emotional social support reflecting connections with others, and instrumental social support reflecting the availability of tangible assistance. Patients were prospectively recruited during a presurgical clinic visit and completed surveys before surgery. One hundred sixty-eight patients with histologically confirmed epithelial ovarian cancer were observed from the date of surgery until death or December 2010. Clinical information was obtained from medical records. In a Cox regression model, adjusting for disease stage, grade, histology, residual disease, and age, greater social attachment was associated with a lower likelihood of death (hazard ratio [HR], 0.87; 95% CI, 0.77 to 0.98; P = .018). The median survival time for patients with low social attachment categorized on a median split of 15 was 3.35 years (95% CI, 2.56 to 4.15 years). In contrast, by study completion, 59% of patients with high social attachment were still alive after 4.70 years. No significant association was found between instrumental social support and survival, even after adjustment for covariates. Social attachment is associated with a survival advantage for patients with ovarian cancer. Clinical implications include the importance of screening for deficits in the social environment and consideration of support activities during adjuvant treatment.


Type 2 diabetes mellitus--an autoimmune disease?
Inflammation-induced inhibition of the insulin signalling pathway can lead to insulin resistance and contribute to the development of type 2 diabetes mellitus (T2DM). Obesity and insulin resistance are associated with a chronic but subclinical inflammatory process that impairs insulin action in most tissues and could also hamper pancreatic β-cell function. The involvement of monocytic cells and the profiles of the chemokines and cytokines induced by this inflammation suggest an innate immune response. However, emerging data indicate that elements of the adaptive immune system could also be involved. As activation of an adaptive response requires antigen specificity, some researchers have hypothesized that T2DM evolves from an innate immune response to an autoimmune condition. In this Perspectives article, we present the arguments for and against this hypothesis and discuss which mechanisms could be involved in a putative switch from innate immunity to autoimmunity.


Resolution of strongly competitive product channels with optimal dynamic discrimination: application to flavins.
Fundamental molecular selectivity limits are probed by exploiting laser-controlled quantum interferences for the creation of distinct spectral signatures in two flavin molecules, erstwhile nearly indistinguishable via steady-state methods. Optimal dynamic discrimination (ODD) uses optimally shaped laser fields to transiently amplify minute molecular variations that would otherwise go unnoticed with linear absorption and fluorescence techniques. ODD is experimentally demonstrated by combining an optimally shaped UV pump pulse with a time-delayed, fluorescence-depleting IR pulse for discrimination amongst riboflavin and flavin mononucleotide in aqueous solution, which are structurally and spectroscopically very similar. Closed-loop, adaptive pulse shaping discovers a set of UV pulses that induce disparate responses from the two flavins and allows for concomitant flavin discrimination of ∼16σ. Additionally, attainment of ODD permits quantitative, analytical detection of the individual constituents in a flavin mixture. The successful implementation of ODD on quantum systems of such high complexity bodes well for the future development of the field and the use of ODD techniques in a variety of demanding practical applications.


Structure and stability of helices in square-well homopolymers.
Recently, it has been demonstrated [Magee, Phys. Rev. Lett. 96, 207802 (2006)] that isolated square-well homopolymers can spontaneously break chiral symmetry and "freeze" into helical structures at sufficiently low temperatures. This behavior is interesting because the square-well homopolymer is itself achiral. In this work, we use event-driven molecular dynamics combined with an optimized parallel tempering scheme to study this polymer model over a wide range of parameters. We examine the conditions where the helix structure is stable and determine how the interaction parameters of the polymer govern the details of the helix structure. The width of the square well (proportional to lambda) is found to control the radius of the helix, which decreases with increasing well width until the polymer forms a coiled sphere for sufficiently large wells. The helices are found to be stable for only a "window" of molecular weights. If the polymer is too short, the helix will not form. If the polymer is too long, the helix is no longer the minimum energy structure, and other folded structures will form. The size of this window is governed by the chain stiffness, which in this model is a function of the ratio of the monomer size to the bond length. Outside this window, the polymer still freezes into a locked structure at low temperature; however, unless the chain is sufficiently stiff, this structure will not be unique and is similar to a glassy state.


Development and Validation of a Real-Time PCR Assay for the Quantification of Verticillium dahliae in Potato.
An increase in the stringency for higher quality potato tubers and restrictions on the use of soil fumigants, among other factors, has garnered renewed interest in Verticillium wilt, particularly in russet-skinned cultivars grown for processing. In response to the needs of producers, breeders have increased efforts in the development of potato cultivars with resistance to Verticillium dahliae Kleb., the primary cause of Verticillium wilt. These efforts have resulted in the release of numerous russet-skinned cultivars with purported resistance to the pathogen. However, because efficient and effective methods to screen germplasm for true resistance do not exist, breeders typically have reported resistance based on the development of wilt symptoms alone. The studies reported here demonstrate the efficiency and practicality of a QPCR method for quantification of V. dahliae in potato stem tissue. This method, developed to detect the target trypsin protease gene of the pathogen, was compared with traditional methods for V. dahliae quantification which involve plating stem tissue or sap onto semi-selective media, as well as to a recently developed QPCR assay which amplifies a region of the β-tubulin gene of V. dahliae. The QPCR assay developed in the studies reported here was demonstrated to be sensitive to 0.25 pg of DNA. Use of the duplex real-time PCR assay, utilizing the potato actin gene to normalize quantification, resulted in clearer differentiation of levels of resistance among eight russet-skinned potato cultivars inoculated in greenhouse trials when compared with traditional plating assays. However, relative levels of resistance among cultivars were similar between traditional plating and QPCR methods, resulting in correlation coefficients greater than 0.93. The assay described here also detected the pathogen in inoculated stem tissue at higher frequencies than both traditional plating assays and a previously developed QPCR assay. The QPCR assay developed here demonstrates rapid, efficient, and accurate quantification of V. dahliae, providing a tool amenable for use by breeding programs on large numbers of clones and selections, and will aid researchers evaluating other control strategies for Verticillium wilt.


Prevalence of selected cardiotropic pathogens in the myocardium of adult dogs with unexplained myocardial and rhythm disorders or with congenital heart disease.
To determine the prevalence of nucleic acid from selected cardiotropic pathogens in endomyocardial biopsy samples from dogs with unexplained myocardial and rhythm disorders (UMRD) and compare prevalence with that for a group of control dogs with congenital heart disease (CHD). 47 client-owned dogs. Right ventricular endomyocardial biopsy was performed in dogs with UMRD (dilated cardiomyopathy [n = 25], atrioventricular block [6], and nonfamilial ventricular [4] and supraventricular arrhythmias [2]) or CHD (10) that required right ventricular catheterization. Biopsy samples were evaluated histologically, and PCR assays were used for detection of nucleic acid from 12 pathogens. 197 biopsy samples were collected from dogs with UMRD (n = 172) or CHD (25). At least 1 pathogen was detected in 21 of 37 (57%; 95% confidence interval [CI], 41% to 71%) dogs with UMRD, and canine coronavirus was detected in 1 of 10 (10%; 95% CI, 2% to 40%) dogs with CHD. Dogs with UMRD were significantly more likely than dogs with CHD to have pathogens detected in biopsy samples (OR, 11.8; 95% CI, 1.3 to 103.0). The most common pathogens in dogs with UMRD were canine distemper virus, canine coronavirus, canine parvovirus 2, and Bartonella spp. No pathogens were detected in available blood samples from dogs with pathogens detected in biopsy samples. Detection of nucleic acids from selected cardiotropic pathogens in myocardial tissue from dogs with UMRD suggested a possible association between the 2. Further studies are needed to explore whether this association is causative or clinically important. (J Am Vet Med Assoc 2019;255:1150-1160).


Accidental ingestion of concentrated white vinegar in Hatay children in Turkey.
White vinegar which contains high concentrations (~85 %) of acetic acid is a staple ingredient used in food preparation in many Mediterranean cuisines but in small amounts. Being corrosive, it can cause ulcerative injury to the oropharynx and oesophagus and upset the stomach with resulting nausea and vomiting. This study presents 11 cases of paediatric patients (five boys and six girls, aged between 11 and 89 months) with oesophageal strictures who drank white vinegar by accident. They all received endoscopic oesophageal dilation (with a bougie) ranging from one to 28 per patient, depending on the severity of the injury. Follow-up showed uneventful healing in eight patients, who at the time of the telephone call were able to swallow solids and liquids normally. Two patients who could not be reached by telephone were found healthy by consulting the national database (e-Nabız). Unfortunately, one patient, who was discharged without any symptoms after the first dilation, suffered massive gastrointestinal bleeding 24 hours after the dilation and died. The loss of this patient shows that ingesting white vinegar can be very dangerous in children, especially if parents delay seeking medical help. We believe that controlling the production and sales of highly concentrated white vinegar and selling it in child-proof containers can help to prevent accidental ingestions by children and tragic outcomes such as the one reported here.


[Compliance with the partner notification of HIV/STI patients in the counties of Lleida].
The partner notification is one of the main activities of epidemiological surveillance in Public Health. The primary objective was to estimate the compliance of the partner notification by health professionals who reported sexually transmitted diseases (HIV, Gonorrhoea, Syphilis and Chlamydia) during 2017 in Lleida's regions. We carried out a descriptive epidemiological study of prevalence about the compliance of partner notification. Data collection was done by epidemiological surveys of these notifiable diseases and additional information was recovered through medical record and interview with professionals. The factors associated with the lack of partner notification were studied through the odds ratio (OR) and its 95% confidence interval (CI). ORs were adjusted (ORa) with multivariate logistic regression models. We studied 203 STD cases with an average age of 30.6 years (SD=11.1); 32.5% were women. There was 46.3% without partner notification. The main cause of this absence was the lack of patient cooperation (23.4%). The variables associated with the lack of partner notification were the male sex (aOR-3.5; CI95%=1.6-7.5), gonococcal infection (aOR-4.9; CI95%=1.2-19.8), chlamydia infection (aOR-3.9; CI95%=0.9-16.1) and homosexual/bisexual sexual orientation (aOR-2.2; CI95%=0.9-5.4). Compliance of partner notification is low and it is related to male sex, sexual orientation (homosexual/bisexual/transsexual) and type of infection (Gonorrhoea and Chlamydia). Reducing the social stigma associated with sexual orientation and improving the information of health professionals could favour the contact studies.


[Tuberculosis in Rio de Janeiro prisons, Brazil: an urgent public health problem].
The tuberculosis incidence rate in prisons in Rio de Janeiro State, Brazil, was 30 times higher in 2004 than in the general population and is probably underestimated, particularly given the difficult access to care in the prison setting. To obtain a better estimate, a survey used systematic X-ray screening and showed a prevalence rate of 4.6% in one such detention facility, A (n = 1,052). Two additional surveys, in facilities B (n = 590) and C (n = 1,372), showed even higher prevalence rates (6.3% and 8.6% respectively). A comparison of socio-demographic characteristics between A, B, and C showed a heterogeneous prison population. As compared to facility A, inmates in B and C come from poorer urban communities and have more frequent histories of incarceration and tuberculosis. These differences, consistent with the prevalence data, imply the necessary adaptation of tuberculosis control programs to each detention facility's epidemiological and socio-demographic profile.


Physical activity assessment in American Indian schoolchildren in the Pathways study.
The objective of the Pathways physical activity feasibility study was to develop methods for comparing type and amount of activity between intervention and control schools participating in a school-based obesity prevention program. Two methods proved feasible: 1) a specially designed 24-h physical activity recall questionnaire for assessing the frequency and type of activities and 2) use of a triaxial accelerometer for assessing amount of activity. Results from pilot studies supporting the use of these methods are described. Analyses of activity during different segments of the day showed that children were most active after school. The activities reported most frequently (e.g., basketball and mixed walking and running) were also the ones found to be most popular in the study population on the basis of formative assessment surveys. Both the physical activity recall questionnaire and the triaxial accelerometer methods will be used to assess the effects of the full-scale intervention on physical activity.


Forensic applications of DART-MS: A review of recent literature.
The need for rapid chemical analyses and new analytical tools in forensic laboratories continues to grow due to case backlogs, difficult-to-analyze cases, and identification of previously unseen materials such as new psychoactive substances. To adapt to these needs, the forensics community has been pursuing the use of ambient ionization mass spectrometry, and more specifically direct analysis in real time mass spectrometry (DART-MS), for a wide range of applications. From the inception of DART-MS forensic applications have been researched with demonstrations ranging from drugs of abuse to inorganic gunshot residue to printer inks to insect identification. This article presents a review of research demonstrating the use of DART-MS for forensically relevant samples over the past five years. To provide more context, background on the technique, sampling approaches, and data analysis methods are presented along with a discussion on the potential future and research needs of the technology.


Comparison of manual and automatic segmentation methods for brain structures in the presence of space-occupying lesions: a multi-expert study.
The purpose of this work was to characterize expert variation in segmentation of intracranial structures pertinent to radiation therapy, and to assess a registration-driven atlas-based segmentation algorithm in that context. Eight experts were recruited to segment the brainstem, optic chiasm, optic nerves, and eyes, of 20 patients who underwent therapy for large space-occupying tumors. Performance variability was assessed through three geometric measures: volume, Dice similarity coefficient, and Euclidean distance. In addition, two simulated ground truth segmentations were calculated via the simultaneous truth and performance level estimation algorithm and a novel application of probability maps. The experts and automatic system were found to generate structures of similar volume, though the experts exhibited higher variation with respect to tubular structures. No difference was found between the mean Dice similarity coefficient (DSC) of the automatic and expert delineations as a group at a 5% significance level over all cases and organs. The larger structures of the brainstem and eyes exhibited mean DSC of approximately 0.8-0.9, whereas the tubular chiasm and nerves were lower, approximately 0.4-0.5. Similarly low DSCs have been reported previously without the context of several experts and patient volumes. This study, however, provides evidence that experts are similarly challenged. The average maximum distances (maximum inside, maximum outside) from a simulated ground truth ranged from (-4.3, +5.4) mm for the automatic system to (-3.9, +7.5) mm for the experts considered as a group. Over all the structures in a rank of true positive rates at a 2 mm threshold from the simulated ground truth, the automatic system ranked second of the nine raters. This work underscores the need for large scale studies utilizing statistically robust numbers of patients and experts in evaluating quality of automatic algorithms.


Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP.
K46J B lymphomas express a T cell costimulatory activity that is not inhibited by CTLA-4Ig, anti-B7-1, anti-B7-2, anti-intercellular adhesion molecule 1 or antibodies to heat stable antigen. In this paper we report that this costimulatory activity is mediated at least in part by 4-1BB ligand, a member of the tumor necrosis factor (TNF) gene family that binds to 4-1BB, a T cell activation antigen with homology to the TNF/nerve growth factor receptor family. A fusion protein between 4-1BB and alkaline phosphatase (4-1BB-AP) blocks T cell activation by K46J lymphomas in both an antigen-specific system and with polyclonally (anti-CD3) activated T cells. 4-1BB-AP also blocks antigen presentation by normal spleen cells. When the antigen-presenting cells express B7 molecules as well as 4-1BB ligand, we find that B7 molecules and 4-1BB-AP both contribute to T cell activation. These data suggest that 4-1BB ligand plays an important role in costimulation of IL-2 production and proliferation by T cells. The B lymphoma M12 expresses low levels of 4-1BB-L but can be induced to express higher levels by treatment of the B cells with cAMP, which also induces B7-1 and B7-2 in these cells. Thus cAMP appears to coordinately induce several costimulatory molecules on B cells.


Involvement of ion channels and transporters in carcinoma angiogenesis and metastasis.
Angiogenesis is a finely tuned process, which is the result of the equilibrium between pro- and antiangiogenic factors. In solid tumor angiogenesis, the balance is highly in favor of the production of new, but poorly functional blood vessels, initially intended to provide growing tumors with nutrients and oxygen. Among the numerous proteins involved in tumor development, several types of ion channels are overexpressed in tumor cells, as well as in stromal and endothelial cells. Ion channels thus actively participate in the different hallmarks of cancer, especially in tumor angiogenesis and metastasis. Indeed, from their strategic localization in the plasma membrane, ion channels are key operators of cell signaling, as they sense and respond to environmental changes. This review aims to decipher how ion channels of different families are intricately involved in the fundamental angiogenesis and metastasis hallmarks, which lead from a nascent tumor to systemic dissemination. An overview of the possible use of ion channels as therapeutic targets will also be given, showing that ion channel inhibitors or specific antibodies may provide effective tools, in the near future, in the treatment of carcinomas.


Nanocluster superstructures or nanoparticles? The self-consuming scaffold decides.
We show that using the same reaction procedure, by hindering or allowing the formation of a reaction intermediate, the Ag+dodecanethiolate polymeric complex, it is possible to selectively obtain Ag dodecanethiolate nanoparticles or Ag dodecanethiolate nanoclusters in the size range 4-2 nm. Moreover, the Ag dodecanethiolate nanoclusters display a lamellar superstructure templated from the precursor Ag+dodecanethiolate polymeric complex. A plausible formation mechanism is illustrated where, starting from the precursor and scaffold lamellar Ag+ thiolate polymeric complex, first the nanocluster Agn0 core is formed by reduction of isoplanar Ag+ ions, followed by Ag+ thiolate units that build protection, the nanocluster shell, around the core. The nanoclusters are characterized by elemental analyses, XRD, ATR-FTIR, XPS, XAS, MALDI, ESI, UV-Vis and fluorescence measurements. The luminescent Ag15(dodecanethiolate)11·2H2O nanocluster is achieved in good yield after 4 hours of reaction whereas after 2 hours, the luminescent Ag35(dodecanethiolate)16 is isolated. Both Ag nanoclusters present emission bands in the range 330-450 nm, the shifting depending on the excitation wavelength. This phenomenon is attributed to a possible dipolar state causing distribution in energies due to variability of dipole-dipole interactions. Moreover, both nanoclusters further present a NIR emission at about 700 nm independent from the excitation wavelength. Thanks to their optical and structural properties, the synthesized nanoclusters, perfect molecular/nanoparticle hybrids, have great potentiality for new applications in nanotechnologies.


[Scientific evidence of sensory integration as an approach to occupational therapy in autism].
This article briefly presents the theoretical and practical background of Ayres Sensory Integration (ASI) and its application in autism spectrum disorder (ASD). Historical criticisms on the evidence of ASI as a therapeutic intervention are reviewed and contemporary evidence is presented. According to standards established by the Council for Exceptional Children (CEC), an international organization that develops criteria for categorizing evidence-based practices, ASI is an evidence-based practice.


COVID-19 Biomarkers and Advanced Sensing Technologies for Point-of-Care (POC) Diagnosis.
COVID-19, also known as SARS-CoV-2 is a novel, respiratory virus currently plaguing humanity. Genetically, at its core, it is a single-strand positive-sense RNA virus. It is a beta-type Coronavirus and is distinct in its structure and binding mechanism compared to other types of coronaviruses. Testing for the virus remains a challenge due to the small market available for at-home detection. Currently, there are three main types of tests for biomarker detection: viral, antigen and antibody. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) remains the gold standard for viral testing. However, the lack of quantitative detection and turnaround time for results are drawbacks. This manuscript focuses on recent advances in COVID-19 detection that have lower limits of detection and faster response times than RT-PCR testing. The advancements in sensing platforms have amplified the detection levels and provided real-time results for SARS-CoV-2 spike protein detection with limits as low as 1 fg/mL in the Graphene Field Effect Transistor (FET) sensor. Additionally, using multiple biomarkers, detection levels can achieve a specificity and sensitivity level comparable to that of PCR testing. Proper biomarker selection coupled with nano sensing detection platforms are key in the widespread use of Point of Care (POC) diagnosis in COVID-19 detection.


Optimization of a DPP-BOTDA sensor with 25 cm spatial resolution over 60 km standard single-mode fiber using Simplex codes and optical pre-amplification.
Sub-meter distributed optical fiber sensing based on Brillouin optical time-domain analysis with differential pulse-width pairs (DPP-BOTDA) is combined with the use of optical pre-amplification and pulse coding. In order to provide significant measurement SNR enhancement and to avoid distortions in the Brillouin gain spectrum due to acoustic-wave pre-excitation, the pulse width and duty cycle of Simplex coding based on return-to-zero pulses are optimized through simulations. In addition, the use of linear optical pre-amplification increases the receiver sensitivity and the overall dynamic range of DPP-BOTDA measurements. Experimental results demonstrate for first time a spatial resolution of ~25 cm over a 60 km standard single-mode fiber (equivalent to ~240 k discrete sensing points) with temperature resolution of 1.2°C and strain resolution of 24 με.


Linkage of posterior polymorphous corneal dystrophy to 20q11.
Posterior polymorphous dystrophy (PPMD) is an autosomal dominant disorder of the cornea that is clinically recognized by the presence of vesicles on the endothelial surface of the cornea. The corneal endothelium is normally a single layer of cells that lose their mitotic potential after development is complete. In PPMD, the endothelium is often multi-layered and has several other characteristics of an epithelium including the presence of desmosomes, tonofilaments, and microvilli. These abnormal cells retain their ability to divide and extend onto the trabecular meshwork to cause glaucoma in up to 40% of cases. A large family with 21 members affected with PPMD was genotyped with short tandem repeat polymorphisms distributed across the autosomal genome. Linkage was established with markers on the long arm of chromosome 20. The highest observed LOD score was 5.54 (theta = 0) with marker D20S45. Analysis of recombination events in four affected individuals revealed that the disease gene lies within a 30cM interval between markers D20S98 and D20S108.


Direct evidence for a xylose metabolic pathway in Saccharomyces cerevisiae.
Xylose transport, xylose reductase, and xylitol dehydrogenase activities are demonstrated in Saccharomyces cerevisiae. The enzymes in the xylose catabolic pathway necessary for the conversion of xylose to xylulose are present, although S. cerevisiae cannot grow on xylose as a sole carbon source. Xylose transport is less efficient than glucose transport, and its rate is dependent upon aeration. Xylose reductase appears to be a xylose inducible enzyme and xylitol dehydrogenase activity is constitutive, although both are repressed by glucose. Both xylose reductase and xylitol dehydrogenase activities are five- to tenfold lower in S. cerevisiae as compared to Candida utilis. In vivo conversion of (14)C-xylose in S. cerevisiae is demonstrated and xylitol is detected, although no significant levels of any other (14)C-labeled metabolites (e. g., ethanol) are observed.


The dogma of the sterile uterus revisited: does microbial seeding occur during fetal life in humans and animals?
Opposing conclusions have been drawn regarding the presence of viable bacteria in the healthy pregnant uterus. Current evidence in humans and animals suggests that fetomaternal tissues present only traces of bacteria whose viability is still to be proven. The debate about the pioneer colonization of the fetus is still open, being the 'in utero colonization' hypothesis versus the 'sterile womb paradigm' the two opposing sides. The seed in this field of research sprouted in human medicine in the last decade and became a central topic in other mammals as well. We aimed to review the literature on bacterial colonization of the healthy placenta, amniotic fluid, and meconium as representatives of the fetal environment. What emerges is that confirming the colonization of fetomaternal tissues by viable bacteria is challenging in humans as well as in animals. Contamination represents the major risk in this type of research as it can be related to different parts of the study design. Sampling at natural parturition or postpartum introduces risk for colonization by the vaginal microbiome of the mother or from the environment. Culture does not reveal the presence of unculturable microorganisms, and sequencing does not allow confirming bacterial viability, while also introducing the variability associated with the data analysis. Therefore, on the basis of the present review, we provide some guidelines on the best practices when performing this type of studies. What emerges from the current literature in humans and animals is that fetomaternal tissues are characterized by a very low biomass, that the viability of bacteria eventually present is still to be confirmed, while massive colonization happens at birth, priming the individual, regardless of the species.


Cascaded amplifying circuits enable ultrasensitive cellular sensors for toxic metals.
Cell-based biosensors have great potential to detect various toxic and pathogenic contaminants in aqueous environments. However, frequently they cannot meet practical requirements due to insufficient sensing performance. To address this issue, we investigated a modular, cascaded signal amplifying methodology. We first tuned intracellular sensory receptor densities to increase sensitivity, and then engineered multi-layered transcriptional amplifiers to sequentially boost output expression level. We demonstrated these strategies by engineering ultrasensitive bacterial sensors for arsenic and mercury, and improved detection limit and output up to 5,000-fold and 750-fold, respectively. Coupled by leakage regulation approaches, we developed an encapsulated microbial sensor cell array for low-cost, portable and precise field monitoring, where the analyte can be readily quantified via displaying an easy-to-interpret volume bar-like pattern. The ultrasensitive signal amplifying methodology along with the background regulation and the sensing platform will be widely applicable to many other cell-based sensors, paving the way for their real-world applications.


Assessment of respiratory symptoms and lung function among textile workers at Kano Textile Mills, Kano, Nigeria.
The number of textile industries in Nigeria with large work force is on the rise. There is thus the need to assess medical challenges of its workers, one of which is respiratory ailments. Although much has been written about the subject globally, only few studies have been done in Nigeria. This study aims to address this gap. A cross-sectional study was undertaken to determine the prevalence of respiratory symptoms and pulmonary functions among Textile Workers in Kano, Nigeria. A cross sectional study was done, Two hundred male workers exposed to raw cotton dust and its end products in a Textile Company and 200 unexposed workers with similar age- and gender-matched were investigated. Their forced vital capacity (FVC), forced expiratory volume in one second (FEV11), and peak expiratory flow rate (PEFR) were determined with a flow-sensing spirometer and Wright's peak flow meter. Exposed workers generally complained of cough, phlegm production, rhinitis, wheezing, chest pain, and breathlessness. Unexposed worker has a significant lower frequency (P < 0.001) of symptoms as well as higher (P < 0.001) forced vital capacity (FVC), forced expiratory volume in one second (FEV11), and peak expiratory flow rate (PEFR) than exposed workers. The reduction in ventilatory function of exposed from predicted values for Nigerian men was significantly higher (P < 0.001) than unexposed workers. The smokers among the exposed and unexposed workers had significantly lower lung function values than nonsmokers. Respiratory symptoms were more prevalent among workers in most dusty sections of the factory. Use of protective mask should be enforced. Workers in the spinning and weaving sections of the company compared with workers in other sections had the lowest lung function indices.


Invisible Scars: Comparing the Mental Health of LGB and Heterosexual Intimate Partner Violence Survivors.
Intimate partner violence (IPV) affects countless women and men in lesbian, gay, and bisexual (LGB) as well as heterosexual relationships, but few studies have examined how such abuse is associated with the mental health of LGB victims. The present study addresses this issue using data from the 2006 Behavioral Risk Factor Surveillance System (BRFSS) survey to examine differences in depression and anxiety among IPV victims in LGB and heterosexual partnerships. The findings indicate LGB IPV victims are much more likely to have a history of depression (OR 1.70, p < .05) and anxiety (OR 1.70, p < .05) than heterosexual victims. These differences are slightly mediated by the victim's perceived emotional support but not the type of abuse experienced. Our findings accentuate the need for greater inclusion of LGB persons in the IPV and mental health discourse, as well as the importance of social support for IPV victims. Policy implications for members of the LGB community are discussed.


A mutation in the canine gene encoding folliculin-interacting protein 2 (FNIP2) associated with a unique disruption in spinal cord myelination.
Novel mutations in myelin and myelin-associated genes have provided important information on oligodendrocytes and myelin and the effects of their disruption on the normal developmental process of myelination of the central nervous system (CNS). We report here a mutation in the folliculin-interacting protein 2 (FNIP2) gene in the Weimaraner dog that results in hypomyelination of the brain and a tract-specific myelin defect in the spinal cord. This myelination disruption results in a notable tremor syndrome from which affected dogs recover with time. In the peripheral tracts of the lateral and ventral columns of the spinal cord, there is a lack of mature oligodendrocytes. A genome-wide association study of DNA from three groups of dogs mapped the gene to canine chromosome 15. Sequencing of all the genes in the candidate region identified a frameshift mutation in the FNIP2 gene that segregated with the phenotype. While the functional role of FNIP2 is not known, our data would suggest that production of truncated protein results in a delay or failure of maturation of a subpopulation of oligodendrocytes.


When nanocellulose meets diffraction grating: freestanding photonic paper with programmable optical coupling.
Photonic crystals based on plasmonic or dielectric periodic structures have attracted considerable interest owing to their capabilities to control light-matter interactions with tailored precision. By using a nanocellulose derived chiral liquid crystal as a building block, here we demonstrate a bio-inspired dual photonic structure that contains the combination of microscopic periodic 1D surface grating and nanoscopic helical organization, giving rise to programmable colour mixing and polarization rotation. We show that a variation in the photonic band-gap in the bulk matrix leads to simultaneous control over the reflection and diffraction of light with controllable iridescence.


Effect of electronic time monitors on children's television watching: pilot trial of a home-based intervention.
This pilot study evaluated the feasibility (recruitment, retention, and acceptability) and preliminary efficacy of a six-week home-based electronic time monitor intervention on New Zealand children's television watching in 2008. Twenty-nine children aged 9 to 12 years who watched more than 20 h of television per week (62% male, mean age 10.4 years) were randomised to either the intervention or the control group. The intervention group received an electronic TV time monitor for 6 weeks and advice to restrict TV watching to 1 h per day or less. The control group was given verbal advice to restrict TV watching. Participant retention at 6 weeks was 93%. Semi-structured interviews with intervention families confirmed moderate acceptability of TV time monitors and several perceived benefits including better awareness of household TV viewing and improved time planning. Drawbacks reported included disruption to parents' TV watching and increased sibling conflict. Time spent watching television decreased by 4.2 h (mean change [SD]: -254 [536] min) per week in the intervention group compared with no change in the control group (-3 [241] min), but the difference between groups was not statistically significant, p=0.77. Both groups reported decreases in energy intake from snacks and total screen time and increases in physical activity measured by pedometer and between-group differences were not statistically significant. Electronic TV time monitors are feasible to use for home-based TV watching interventions although acceptability varies between families. Preliminary findings from this pilot suggest that such devices have potential to decrease children's TV watching but a larger trial is needed to confirm effectiveness. Future research should be family-orientated; take account of other screen time activities; and employ TV time monitors as just one of a range of strategies to decrease sedentary behaviour.


The biomechanical characteristics of a feline distal forelimb: A finite element analysis study.
As a typical digitigrade mammal, the uniquely designed small distal limbs of the feline support two to three times of its body weight during daily movements. To understand how force transmission occurs in relation to the distal joint in a feline limb, which transfers bodyweight to the ground, it is necessary to examine the internal stress distribution of the distal joint limb in detail. Therefore, finite element models (FEM) of a healthy feline were established to predict the internal stress distribution of the distal limb. The FEM model included 23 bony components, various cartilaginous ligaments, as well as the encapsulated soft tissue of the paw. The FEM model was validated by comparison of paw pressure distribution, obtained from an experiment for balance standing. The results demonstrated a good agreement between the experimentally measured and numerically predicted pressure distribution in the feline paw. Additionally, higher stress levels were noted in the metacarpal segment, with smaller stresses observed in the phalanges portion including the proximal, middle, and distal segments. The raised metacarpal segment plays an important role in creating a stiff junction between the metacarpophalangeal (MCP) and wrist joint, stabilizing the distal limb. The paw pads help to optimize stress distribution in phalanx region. Findings from this study contribute to our understanding of feline distal forelimb biomechanical behavior. This information can be applied to bionic design of footwear since an optimal stiff junction and pressure distribution can be adapted to enhance injury relief and sports activities. Further developments may include progress, evaluation, and treatment of metatarsophalangeal joint injuries in human populations.


1,N2-ethenodeoxyguanosine as a potential marker for DNA adduct formation by trans-4-hydroxy-2-nonenal.
The reaction of trans-4-hydroxy-2-nonenal, a major alpha, beta-unsaturated aldehyde released during lipid peroxidation, with deoxyguanosine under physiological conditions was investigated in order to assess its DNA damaging potential. This aldehyde was dissolved in tetrahydrofuran (THF) prior to addition to the reaction mixture. The results showed that structurally different adducts were formed in these reactions depending on the THF used. Using THF unprotected from light, reactions yielded adducts 1 to 6. Adduct 1 was characterized as 1,N2-ethenodeoxyguanosine (5,9-dihydro-9-oxo-3-beta-D-deoxyribofuranosylimidazo[1,2-alpha]pu rine) by its UV, proton nuclear magnetic resonance, and mass spectrum and by comparison to the corresponding guanosine and guanine adducts reported in the literature. The UV spectrum of adduct 4 was indicative of a substituted 1,N2-etheno derivative. Adducts 2,3,5, and 6 were essentially identical in UV spectra and appeared to be N2-substituted deoxyguanosine diastereomers. At room temperature adducts 2,3,5, and 6 were converted quantitatively to a single product at pH 10.5. This product was shown to be identical to 1,N2-ethenodeoxyguanosine (adduct 1). Analogous conversions to 1,N2-ethenoguanine were also observed for the corresponding guanine adducts. Using THF that had been protected from the light, however, the reactions of trans-4-hydroxy-2-nonenal with deoxyguanosine gave three major adducts, 7,8, and 9. These adducts possessed UV spectra similar to that of 1,N2-propanodeoxyguanosine and were not converted to 1,N2-ethenodeoxyguanosine upon base treatment. Evidence obtained suggests that adducts 1 to 6 were formed from the reaction of deoxyguanosine with the epoxide of trans-4-hydroxy-2-nonenal generated in the presence of hydroperoxide in the light unprotected THF, whereas adducts 7 to 9 were formed by direct Michael addition. Adducts 1 to 6 were formed presumably as a result of nucleophilic addition of the exo-amino of deoxyguanosine to the aldehydic group of the epoxide of trans-4-hydroxy-2-nonenal. Base treatment of these adducts facilitated subsequent cyclization and eliminations and finally gave 1,N2-ethenodeoxyguanosine. These results demonstrated that trans-4-hydroxy-2-nonenal readily forms adducts with deoxyguanosine either by direct Michael addition or via its epoxide formation. The facile conversion of some of these adducts to a single adduct suggests that 1,N2-ethenodeoxyguanosine may provide a simple and useful marker for assessing potential DNA damage by trans-4-hydroxy-2-nonenal and related alkenals associated with lipid peroxidation.


Access to physicians' services for vulnerable Medicare beneficiaries.
This article examines whether changes in physician reimbursement under the Medicare Fee Schedule (MFS) had differential impacts on access to care for vulnerable and nonvulnerable Medicare beneficiaries. The quasi-experimental research design takes advantage of cross-sectional differences in the magnitude of the MFS impact on payments. We selected a stratified random sample to ensure adequate representation of vulnerable group members and constructed service-specific measures of the MFS payment change. While we found few effects on access attributable to the MFS, we did find substantial utilization gaps between vulnerable and nonvulnerable subpopulations for primary care services, as well as for high-cost procedures during episodes of care for acute myocardial infarctions.


A deep learning framework to predict binding preference of RNA constituents on protein surface.
Protein-RNA interaction plays important roles in post-transcriptional regulation. However, the task of predicting these interactions given a protein structure is difficult. Here we show that, by leveraging a deep learning model NucleicNet, attributes such as binding preference of RNA backbone constituents and different bases can be predicted from local physicochemical characteristics of protein structure surface. On a diverse set of challenging RNA-binding proteins, including Fem-3-binding-factor 2, Argonaute 2 and Ribonuclease III, NucleicNet can accurately recover interaction modes discovered by structural biology experiments. Furthermore, we show that, without seeing any in vitro or in vivo assay data, NucleicNet can still achieve consistency with experiments, including RNAcompete, Immunoprecipitation Assay, and siRNA Knockdown Benchmark. NucleicNet can thus serve to provide quantitative fitness of RNA sequences for given binding pockets or to predict potential binding pockets and binding RNAs for previously unknown RNA binding proteins.


Evidence for phenotypic plasticity among multihost Campylobacter jejuni and C. coli lineages, obtained using ribosomal multilocus sequence typing and Raman spectroscopy.
Closely related bacterial isolates can display divergent phenotypes. This can limit the usefulness of phylogenetic studies for understanding bacterial ecology and evolution. Here, we compare phenotyping based on Raman spectrometric analysis of cellular composition to phylogenetic classification by ribosomal multilocus sequence typing (rMLST) in 108 isolates of the zoonotic pathogens Campylobacter jejuni and C. coli. Automatic relevance determination (ARD) was used to identify informative peaks in the Raman spectra that could be used to distinguish strains in taxonomic and host source groups (species, clade, clonal complex, and isolate source/host). Phenotypic characterization based on Raman spectra showed a degree of agreement with genotypic classification using rMLST, with segregation accuracy between species (83.95%), clade (in C. coli, 98.41%), and, to some extent, clonal complex (86.89% C. jejuni ST-21 and ST-45 complexes) being achieved. This confirmed the utility of Raman spectroscopy for lineage classification and the correlation between genotypic and phenotypic classification. In parallel analysis, relatively distantly related isolates (different clonal complexes) were assigned the correct host origin irrespective of the clonal origin (74.07 to 96.97% accuracy) based upon different Raman peaks. This suggests that the phenotypic characteristics, from which the phenotypic signal is derived, are not fixed by clonal descent but are influenced by the host environment and change as strains move between hosts.


Molecular dissection of the CD2-CD58 counter-receptor interface identifies CD2 Tyr86 and CD58 Lys34 residues as the functional "hot spot".
The heterophilic CD2-CD58 adhesion interface contains interdigitating residues that impart high specificity and rapid binding kinetics. To define the hot spot of this counter-receptor interaction, we characterized CD2 adhesion domain variants harboring a single mutation of the central Tyr86 or of each amino acid residue forming a salt link/hydrogen bond. Alanine mutations at D31, D32 and K34 on the C strand and K43 and R48 on the C' strand reduce affinity for CD58 by 47-127-fold as measured by isothermal titration calorimetry. The Y86A mutant reduces affinity by approximately 1000-fold, whereas Y86F is virtually without effect, underscoring the importance of the phenyl ring rather than the hydroxyl moiety. The CD2-CD58 crystal structure offers a detailed view of this key functional epitope: CD2 D31 and D32 orient the side-chain of CD58 K34 such that CD2 Y86 makes hydrophobic contact with the extended aliphatic component of CD58 K34 between CD2 Y86 and CD58 F46. The elucidation of this hot spot provides a new target for rational design of immunosuppressive compounds and suggests a general approach for other receptors.


The Distributed Nature of Working Memory.
Studies in humans and non-human primates have provided evidence for storage of working memory contents in multiple regions ranging from sensory to parietal and prefrontal cortex. We discuss potential explanations for these distributed representations: (i) features in sensory regions versus prefrontal cortex differ in the level of abstractness and generalizability; and (ii) features in prefrontal cortex reflect representations that are transformed for guidance of upcoming behavioral actions. We propose that the propensity to produce persistent activity is a general feature of cortical networks. Future studies may have to shift focus from asking where working memory can be observed in the brain to how a range of specialized brain areas together transform sensory information into a delayed behavioral response.


Carbon footprint and nutritional quality of different human dietary choices.
Apart from industrial activities, our eating habits also have a significant environmental cost associated with crop cultivation, manufacturing processes, packaging, refrigeration, transport cooking and waste management. In a context of growing social awareness of the role of different dietary choices in the environment, the review of different alternatives on the road to a healthy and sustainable diet should integrate relevant information on the nutritional quality of different eating habits. Since dietary choices have an effect on environmental sustainability and human health, a literature review on different dietary choices has been conducted to determine the differences in carbon footprint and nutritional quality identifying the main hotspots trying to give advice towards the identification of sustainable diets. After applying a set of criteria for reference selection, 21 peer-reviewed studies have been analysed in detail, allowing the comparison of 66 dietary scenarios. We identified that the so-called Mediterranean and Atlantic diets present high nutritional scores and low carbon footprints. On the contrary, the dietary choices identified in northern and Western Europe, as well as in the United States, have the highest carbon footprints, highlighting the contribution of dairy products as a basic source of high-quality nutrients and protein. Broadly speaking, dietary choices rich in vegetables (e.g., vegan, vegetarian as well as Indian and Peruvian) have a better environmental profile than those rich in meat (mainly ruminant meat). In line with these findings, the shift in meat consumption habits from beef and veal to chicken, pork and poultry, the introduction of alternative foods to animal protein (e.g. quinoa) and the consumption of olive oil as a major source of vegetable oil may be compatible with a healthier and more environmentally friendly diet. However, the complete elimination of meat and dairy products from the daily diet may not be feasible in case the supply of some micronutrients (e.g., calcium and vitamin D) is not guaranteed. Limitations were identified in the consulted studies related to the consideration of the different system boundaries, as well as underlying uncertainties related to data sources. Therefore, efforts should be made to develop consistent and agreed-upon methods for estimating both the carbon footprint and nutritional quality scores.


Trophic downgrading of planet Earth.
Until recently, large apex consumers were ubiquitous across the globe and had been for millions of years. The loss of these animals may be humankind's most pervasive influence on nature. Although such losses are widely viewed as an ethical and aesthetic problem, recent research reveals extensive cascading effects of their disappearance in marine, terrestrial, and freshwater ecosystems worldwide. This empirical work supports long-standing theory about the role of top-down forcing in ecosystems but also highlights the unanticipated impacts of trophic cascades on processes as diverse as the dynamics of disease, wildfire, carbon sequestration, invasive species, and biogeochemical cycles. These findings emphasize the urgent need for interdisciplinary research to forecast the effects of trophic downgrading on process, function, and resilience in global ecosystems.