Patient perspectives on integrated healthcare for HIV, hypertension and type 2 diabetes: a scoping review.
Antiretroviral therapy has reduced mortality and led to longer life expectancy in people living with HIV. These patients are now at an increased risk of non-communicable diseases (NCDs). Integration of care for HIV and NCDs has become a focus of research and policy. In this article, we aim to review patient perspectives on integration of healthcare for HIV, type 2 diabetes and hypertension. The framework for scoping reviews developed by Arksey and O'Malley and updated by Peter et al was applied for this review. The databases PubMed, Web of Science and Cochrane library were searched. Broad search terms for HIV, NCDs (specifically type 2 diabetes and hypertension) and healthcare integration were used. As the review aimed to identify definitions of patient perspectives, they were not included as an independent term in the search strategy. References of included publications were searched for relevant articles. Titles and abstracts for these papers were screened by two independent reviewers. The full texts for all the publications appearing to meet the inclusion criteria were then read to make the final literature selection. Of 5502 studies initially identified, 13 articles were included in this review, of which 11 had a geographical origin in sub-Saharan Africa. Nine articles were primarily focused on HIV/diabetes healthcare integration while four articles were focused on HIV/hypertension integration. Patient's experiences with integrated care were reduced HIV-related stigma, reduced travel and treatment costs and a more holistic person-centred care. Prominent concerns were long waiting times at clinics and a lack of continuity of care in some clinics due to a lack of healthcare workers. Non-integrated care was perceived as time-consuming and more expensive. Patient perspectives and experiences on integrated care for HIV, diabetes and hypertension were mostly positive. Integrated services can save resources and allow for a more personalised approach to healthcare. There is a paucity of evidence and further longitudinal and interventional evidence from a more diverse range of healthcare systems are needed.


Complete genome sequence and comparative genomics of the probiotic yeast Saccharomyces boulardii.
The probiotic yeast, Saccharomyces boulardii (Sb) is known to be effective against many gastrointestinal disorders and antibiotic-associated diarrhea. To understand molecular basis of probiotic-properties ascribed to Sb we determined the complete genomes of two strains of Sb i.e. Biocodex and unique28 and the draft genomes for three other Sb strains that are marketed as probiotics in India. We compared these genomes with 145 strains of S. cerevisiae (Sc) to understand genome-level similarities and differences between these yeasts. A distinctive feature of Sb from other Sc is absence of Ty elements Ty1, Ty3, Ty4 and associated LTR. However, we could identify complete Ty2 and Ty5 elements in Sb. The genes for hexose transporters HXT11 and HXT9, and asparagine-utilization are absent in all Sb strains. We find differences in repeat periods and copy numbers of repeats in flocculin genes that are likely related to the differential adhesion of Sb as compared to Sc. Core-proteome based taxonomy places Sb strains along with wine strains of Sc. We find the introgression of five genes from Z. bailii into the chromosome IV of Sb and wine strains of Sc. Intriguingly, genes involved in conferring known probiotic properties to Sb are conserved in most Sc strains.


Cancellation model of pitch perception.
A model of pitch perception is presented involving an array of delay lines and inhibitory gating neurons. In response to a periodic sound, a minimum appears in the pattern of outputs of the inhibitory neurons at a lag equal to the period of the sound. The position of this minimum is the cue to pitch. The model is similar to the autocorrelation model of pitch, multiplication being replaced by an operation similar to subtraction, and maxima by minima. The two models account for a wide class of pitch phenomena in very much the same way. The principal goal of this paper is to demonstrate this fact. Several features of the cancellation model may be to its advantage: it is closely related to the operation of harmonic cancellation that can account for segregation of concurrent harmonic stimuli, it can be generalized to explain the perception of multiple pitches, and it shows a greater degree of sensitivity to phase than autocorrelation, which may allow it to explain certain phenomena that autocorrelation cannot account for.


Hypothesis: Alpha-1-antitrypsin is a promising treatment option for COVID-19.
No definitive treatment for COVID-19 exists although promising results have been reported with remdesivir and glucocorticoids. Short of a truly effective preventive or curative vaccine against SARS-CoV-2, it is becoming increasingly clear that multiple pathophysiologic processes seen with COVID-19 as well as SARS-CoV-2 itself should be targeted. Because alpha-1-antitrypsin (AAT) embraces a panoply of biologic activities that may antagonize several pathophysiologic mechanisms induced by SARS-CoV-2, we hypothesize that this naturally occurring molecule is a promising agent to ameliorate COVID-19. We posit at least seven different mechanisms by which AAT may alleviate COVID-19. First, AAT is a serine protease inhibitor (SERPIN) shown to inhibit TMPRSS-2, the host serine protease that cleaves the spike protein of SARS-CoV-2, a necessary preparatory step for the virus to bind its cell surface receptor ACE2 to gain intracellular entry. Second, AAT has anti-viral activity against other RNA viruses HIV and influenza as well as induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes the Middle East Respiratory Syndrome. Third, AAT has potent anti-inflammatory properties, in part through inhibiting both nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as tumor necrosis factor-alpha converting enzyme), and thus may dampen the hyper-inflammatory response of COVID-19. Fourth, AAT inhibits neutrophil elastase, a serine protease that helps recruit potentially injurious neutrophils and implicated in acute lung injury. AAT inhibition of ADAM17 also prevents shedding of ACE2 and hence may preserve ACE2 inhibition of bradykinin, reducing the ability of bradykinin to cause a capillary leak in COVID-19. Fifth, AAT inhibits thrombin, and venous thromboembolism and in situ microthrombi and macrothrombi are increasingly implicated in COVID-19. Sixth, AAT inhibition of elastase can antagonize the formation of neutrophil extracellular traps (NETs), a complex extracellular structure comprised of neutrophil-derived DNA, histones, and proteases, and implicated in the immunothrombosis of COVID-19; indeed, AAT has been shown to change the shape and adherence of non-COVID-19-related NETs. Seventh, AAT inhibition of endothelial cell apoptosis may limit the endothelial injury linked to severe COVID-19-associated acute lung injury, multi-organ dysfunction, and pre-eclampsia-like syndrome seen in gravid women. Furthermore, because both NETs formation and the presence of anti-phospholipid antibodies are increased in both COVID-19 and non-COVID pre-eclampsia, it suggests a similar vascular pathogenesis in both disorders. As a final point, AAT has an excellent safety profile when administered to patients with AAT deficiency and is dosed intravenously once weekly but also comes in an inhaled preparation. Thus, AAT is an appealing drug candidate to treat COVID-19 and should be studied.


Isolated right ventricular infarction followed by posterior left ventricular infarction after a few days.
This report presents a rare case of isolated right ventricular infarction complicated by bilateral occlusive pulmonary embolism apparently due to right ventricular mural thrombus. Only 2 to 3 weeks later an infarct of the posterior wall of the left ventricle finally occurred. The clinical, pathological and electrocardiographic features of the case are discussed. This case shows that right ventricular infarct can occur without a preceding or simultaneous infarct of the left ventricle.


Differential gene expression analysis in early and late erythroid progenitor cells in β-thalassaemia.
β- thalassaemia is a disorder of globin gene synthesis resulting in reduced or absent production of the β-globin chain in red blood cells. In this study, haematopoietic stem cells were isolated from the peripheral blood of six transfusion dependent β-thalassaemia patients and six healthy controls. Following 7 and 14 d in culture, early- and late- erythroblasts were isolated and purified. No morphological difference in maturation was observed following 7 d in culture, while a delayed maturation was observed in the patient group after 14 d. Following RNA isolation and linear amplification, gene expression analyses were performed using microarray technology. The generated data were analysed by two methods: the BRB-ArrayTools platform and the Bioconductor platform using bead level data. Following 7 d culture, there was no difference in gene expression between the control and patient groups. Following 14 d culture, 384 differentially expressed genes were identified by either analysis. A subset of 90 genes was selected and the results were confirmed by Quantitative-Real-Time-polymerase chain reaction. Pathways shown to be significantly altered in the patient group include apoptosis, MAPKinase and the nuclear factor-κB pathway.


Extensive intrasubtype recombination in South African human immunodeficiency virus type 1 subtype C infections.
Recombinant human immunodeficiency virus type 1 (HIV-1) strains containing sequences from different viral genetic subtypes (intersubtype) and different lineages from within the same subtype (intrasubtype) have been observed. A consequence of recombination can be the distortion of the phylogenetic signal. Several intersubtype recombinants have been identified; however, less is known about the frequency of intrasubtype recombination. For this study, near-full-length HIV-1 subtype C genomes from 270 individuals were evaluated for the presence of intrasubtype recombination. A sliding window schema (window, 2 kb; step, 385 bp) was used to partition the aligned sequences. The Shimodaira-Hasegawa test detected significant topological incongruence in 99.6% of the comparisons of the maximum-likelihood trees generated from each sequence partition, a result that could be explained by recombination. Using RECOMBINE, we detected significant levels of recombination using five random subsets of the sequences. With a set of 23 topologically consistent sequences used as references, bootscanning followed by the interactive informative site test defined recombination breakpoints. Using two multiple-comparison correction methods, 47% of the sequences showed significant evidence of recombination in both analyses. Estimated evolutionary rates were revised from 0.51%/year (95% confidence interval [CI], 0.39 to 0.53%) with all sequences to 0.46%/year (95% CI, 0.38 to 0.48%) with the putative recombinants removed. The timing of the subtype C epidemic origin was revised from 1961 (95% CI, 1947 to 1962) with all sequences to 1958 (95% CI, 1949 to 1960) with the putative recombinants removed. Thus, intrasubtype recombinants are common within the subtype C epidemic and these impact analyses of HIV-1 evolution.


Neuronal spike train entropy estimation by history clustering.
Neurons send signals to each other by means of sequences of action potentials (spikes). Ignoring variations in spike amplitude and shape that are probably not meaningful to a receiving cell, the information content, or entropy of the signal depends on only the timing of action potentials, and because there is no external clock, only the interspike intervals, and not the absolute spike times, are significant. Estimating spike train entropy is a difficult task, particularly with small data sets, and many methods of entropy estimation have been proposed. Here we present two related model-based methods for estimating the entropy of neural signals and compare them to existing methods. One of the methods is fast and reasonably accurate, and it converges well with short spike time records; the other is impractically time-consuming but apparently very accurate, relying on generating artificial data that are a statistical match to the experimental data. Using the slow, accurate method to generate a best-estimate entropy value, we find that the faster estimator converges to this value more closely and with smaller data sets than many existing entropy estimators.


Obesity Is Not Associated with Antimicrobial Treatment Failure for Intra-Abdominal Infection.
Obesity and commonly associated comorbidities are known risk factors for the development of infections. However, the intensity and duration of antimicrobial treatment are rarely conditioned on body mass index (BMI). In particular, the influence of obesity on failure of antimicrobial treatment for intra-abdominal infection (IAI) remains unknown. We hypothesized that obesity is associated with recurrent infectious complications in patients treated for IAI. Five hundred eighteen patients randomized to treatment in the Surgical Infection Society Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial were evaluated. Patients were stratified by obese (BMI ≥30) versus non-obese (BMI≥30) status. Descriptive comparisons were performed using Chi-square test, Fisher exact test, or Wilcoxon rank-sum tests as appropriate. Multivariable logistic regression using a priori selected variables was performed to assess the independent association between obesity and treatment failure in patients with IAI. Overall, 198 (38.3%) of patients were obese (BMI ≥30) versus 319 (61.7%) who were non-obese. Mean antibiotic d and total hospital d were similar between both groups. Unadjusted outcomes of surgical site infection (9.1% vs. 6.9%, p = 0.36), recurrent intra-abdominal infection (16.2% vs. 13.8, p = 0.46), death (1.0% vs. 0.9%, p = 1.0), and a composite of all complications (25.3% vs. 19.8%, p = 0.14) were also similar between both groups. After controlling for appropriate demographics, comorbidities, severity of illness, treatment group, and duration of antimicrobial therapy, obesity was not independently associated with treatment failure (c-statistic: 0.64). Obesity is not associated with antimicrobial treatment failure among patients with IAI. These results suggest that obesity may not independently influence the need for longer duration of antimicrobial therapy in treatment of IAI versus non-obese patients.


Dynamic habitat models: using telemetry data to project fisheries bycatch.
Fisheries bycatch is a recognized threat to marine megafauna. Addressing bycatch of pelagic species however is challenging owing to the dynamic nature of marine environments and vagility of these organisms. In order to assess the potential for species to overlap with fisheries, we propose applying dynamic habitat models to determine relative probabilities of species occurrence for specific oceanographic conditions. We demonstrate this approach by modelling habitats for Laysan (Phoebastria immutabilis) and black-footed albatrosses (Phoebastria nigripes) using telemetry data and relating their occurrence probabilities to observations of Hawaii-based longline fisheries in 1997-2000. We found that modelled habitat preference probabilities of black-footed albatrosses were high within some areas of the fishing range of the Hawaiian fleet and such preferences were important in explaining bycatch occurrence. Conversely, modelled habitats of Laysan albatrosses overlapped little with Hawaii-based longline fisheries and did little to explain the bycatch of this species. Estimated patterns of albatross habitat overlap with the Hawaiian fleet corresponded to bycatch observations: black-footed albatrosses were more frequently caught in this fishery despite being 10 times less abundant than Laysan albatrosses. This case study demonstrates that dynamic habitat models based on telemetry data may help to project interactions with pelagic animals relative to environmental features and that such an approach can serve as a tool to guide conservation and management decisions.


Conformational switch-defective X174 internal scaffolding proteins kinetically trap assembly intermediates before procapsid formation.
Conformational switching is an overarching paradigm in which to describe scaffolding protein-mediated virus assembly. However, rapid morphogenesis with small assembly subunits hinders the isolation of early morphogenetic intermediates in most model systems. Consequently, conformational switches are often defined by comparing the structures of virions, procapsids and aberrantly assembled particles. In contrast, X174 morphogenesis proceeds through at least three preprocapsid intermediates, which can be biochemically isolated. This affords a detailed analysis of early morphogenesis and internal scaffolding protein function. Amino acid substitutions were generated for the six C-terminal, aromatic amino acids that mediate most coat-internal scaffolding protein contacts. The biochemical characterization of mutant assembly pathways revealed two classes of molecular defects, protein binding and conformational switching, a novel phenotype. The conformational switch mutations kinetically trapped assembly intermediates before procapsid formation. Although mutations trapped different particles, they shared common second-site suppressors located in the viral coat protein. This suggests a fluid assembly pathway, one in which the scaffolding protein induces a single, coat protein conformational switch and not a series of sequential reactions. In this model, an incomplete or improper switch would kinetically trap intermediates.


Altered methylprednisolone pharmacodynamics in healthy subjects with histamine N-methyltransferase C314T genetic polymorphism.
This study investigated the potential differences in methylprednisolone pharmacodynamics between healthy subjects with different histamine N-methyltransferase (HNMT) C314T genotypes. Six individuals with C/C genotype and 4 with C/T genotype were administered a single intravenous dose of methylprednisolone 0.6 mg/kg ideal body weight in a randomized 2-period manner. Methylprednisolone plasma concentrations were fitted with a 1-compartment model. Cortisol and whole blood histamine suppression were assessed by indirect response models, with circadian baseline cortisol analyzed by Fourier analysis. The area between the baseline and effect curve and the area under the effect versus time curve suppression ratio were used to characterize plasma histamine suppression. Methylprednisolone pharmacokinetics and plasma and whole blood histamine suppression were similar between the 2 genotype groups. Median nadir of cortisol and the 50% inhibitory concentration for cortisol were significantly higher in subjects with C/T genotype than those with C/C genotype (P=.031 and .033, respectively, Wilcoxon rank sum test). Subjects who are heterozygous for the T314 variant allele thus appeared less sensitive to the suppressive effects of methylprednisolone on cortisol secretion.


COVID-19 and immunosuppression: a review of current clinical experiences and implications for ophthalmology patients taking immunosuppressive drugs.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 in Wuhan city, Hubei province, China. This is the third and largest coronavirus outbreak since the new millennium after SARS in 2002 and Middle East respiratory syndrome (MERS) in 2012. Over 3 million people have been infected and the COVID-19 has caused more than 217 000 deaths. A concern exists regarding the vulnerability of patients who have been treated with immunosuppressive drugs prior or during this pandemic. Would they be more susceptible to infection by the SARS-CoV-2 and how would their clinical course be altered by their immunosuppressed state? This is a question the wider medical fraternity-including ophthalmologists, rheumatologists, gastroenterologist and transplant physicians among others-must answer. The evidence from the SARS and MERS outbreak offer some degree of confidence that immunosuppression is largely safe in the current COVID-19 pandemic. Preliminary clinical experiences based on case reports, small series and observational studies show the morbidity and mortality rates in immunosuppressed patients may not differ largely from the general population. Overwhelmingly, current best practice guidelines worldwide recommended the continuation of immunosuppression treatment in patients who require them except for perhaps high-dose corticosteroid therapy and in patients with associated risk factors for severe COVID-19 disease.


Consultation on the feasibility and ethics of specific, probable Controlled Human Infection Model study scenarios in India: A report.
On March 6, 2019, a workshop was held as part of a larger public consultation exercise to evaluate the perceptions of participants from diverse backgrounds of studies involving Controlled Human Infection Models (CHIMs) (1,2) in India, through three specific case scenarios. This workshop was organised by the Health and Humanities Division of the St. John's Research Institute, Bangalore with funding from the Translational Health Science and Technology Institute (TSHTI), Faridabad (www.thsti.res.in), an autonomous institute of the Department of Biotechnology, Government of India This was an on-going effort of the Division to bring public discourse centre stage in the discussion on the use, ethics and regulations related to CHIM studies, and the introduction of such studies in India. Participants included epidemiologists, community/public health experts, microbiologists, infectious disease specialists, basic and translational scientists, ethicists, journalists and lawyers.


A curated collection of tissue microarray images and clinical outcome data of prostate cancer patients.
Microscopy image data of human cancers provide detailed phenotypes of spatially and morphologically intact tissues at single-cell resolution, thus complementing large-scale molecular analyses, e.g., next generation sequencing or proteomic profiling. Here we describe a high-resolution tissue microarray (TMA) image dataset from a cohort of 71 prostate tissue samples, which was hybridized with bright-field dual colour chromogenic and silver in situ hybridization probes for the tumour suppressor gene PTEN. These tissue samples were digitized and supplemented with expert annotations, clinical information, statistical models of PTEN genetic status, and computer source codes. For validation, we constructed an additional TMA dataset for 424 prostate tissues, hybridized with FISH probes for PTEN, and performed survival analysis on a subset of 339 radical prostatectomy specimens with overall, disease-specific and recurrence-free survival (maximum 167 months). For application, we further produced 6,036 image patches derived from two whole slides. Our curated collection of prostate cancer data sets provides reuse potential for both biomedical and computational studies.


Dynamics of excited-state intramolecular proton-transfer in 2-amino-3-(2'-benzazolyl)quinoline cations.
It was found that cations formed by the protonation of 2-amino-3-(2'-benzoxazolyl)-quinoline (ABO) and 2-amino-3-(2'-benzothiazolyl)-quinoline (ABT) at the nitrogen atom of the quinoline ring exhibit excited-state intramolecular proton transfer (ESIPT). The two-band fluorescence of these cations is due to the emission from two species: the initial tautomer (short-wavelength band) and the ESIPT product (long-wavelength band). The relative intensity of the long-wavelength band depends on the basicity of the proton-accepting moiety and temperature. Quantum-chemical calculations demonstrated that ESIPT in cations involves overcoming a significant potential barrier, which increases with the decreasing basicity of the proton-accepting benzazole moiety. Using femtosecond absorption spectroscopy and nanosecond fluorescence spectroscopy, the effective ESIPT time in the studied cations was determined, which increased with decreasing temperature.


Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment.
Polycystic ovarian syndrome (PCOS) is a common reproductive disorder frequently associated with a substantial risk factor for ovarian hyperstimulation syndrome (OHSS). Dopamine receptor 2 (D2) agonists, like cabergoline (Cb2), have been used to reduce the OHSS risk. However, lutein granulosa cells (LGCs) from PCOS patients treated with Cb2 still show a deregulated dopaminergic tone (decreased D2 expression and low dopamine production) and increased vascularization compared to non-PCOS LGCs. Therefore, to understand the PCOS ovarian physiology, it is important to explore the mechanisms that underlie syndrome based on the therapeutic effects of Cb2. Here, LGCs from non-PCOS and PCOS patients were cultured with hCG in the absence/presence of Cb2 (n = 12). Subsequently, a transcriptomic-paired design that compared untreated vs treated LGCs within each patient was performed. After transcriptomic analysis, functions and genes were prioritized by systems biology approaches and validated by RT-qPCR. We identified that similar functions were altered in both PCOS and non-PCOS LGCs treated with Cb2; however, PCOS-treated LGCs exhibited more significant changes than non-PCOS. Among the prioritized functions, dopaminergic synapse, vascular endothelial growth factor (VEGF) signaling, apoptosis and ovarian steroidogenesis were highlighted. Finally, network modeling showed CASP9, VEGFA, AKT1, CREB, AIF, MAOA, MAPK14 and BMAL1 as key genes implicated in these pathways in Cb2 response, which might be potential biomarkers for further studies in PCOS.


Use of Saline as a Placebo in Intra-articular Injections in Osteoarthritis: Potential Contributions to Nociceptive Pain Relief.
Osteoarthritis of the knee (OAK) is a severe debilitating condition characterized by joint pain, stiffness, and resultant limited mobility. In recent years, intra-articular (IA) injections have been used to relieve symptoms and have succeeded to varying degrees either with sodium hyaluronate preparations or with a biologic. The objective of this review is to evaluate multiple studies that demonstrate some relief from the symptoms of OAK in the saline arm of various clinical trials. A thorough literature search (PubMed) was performed assessing the pain efficacy of various compounds compared to saline injections in clinical trials. A total of 73 studies were identified in the literature search including a total of 5,816 patients. These clinical trials all involved the IA injection of a viscosupplement (hyaluronate, platelet rich plasma (PRP), etc.) or a biologic (the low molecular weight fraction (< 5kDa) of human serum albumin (LMWF-5A)). For all of these studies, the control arm was injection of sterile physiological saline that approximates the salt concentration and total solute concentration of blood and most tissues. Based on our review of the current literature, the tested compounds performed with mixed results when compared to saline injections. Moreover, OAK is a variable disease, with severity measured on the Kellgren and Lawrence (KL) scale where various hyaluronate preparations have a therapeutic effect mostly on KL 2-3 patients while a biologic works best on KL 3-4 patients. Since the effect of saline injection is always greater than no treatment, the evaluations of these treatments can be confounded in clinical trials. Therefore, the question of whether there are known therapeutic effects of saline injections might explain these results.


Three-Element Fractional-Order Viscoelastic Arterial Windkessel Model.
Arterial hemodynamic assessment has always been essential for clinical Cardiovascular System (CVS) diagnosis. Using Windkessel (WK) lumped parametric model as non-invasive measurement tool provides the potential of achieving a very convenient, computational inexpensive and accurate prediction of the arterial parameters. Many versions of WK models have been proposed and extensively studied, over the last century. In general, they can be classified into two categories: elastic and viscoelastic models. Recently, several studies have discussed the potential of describing the arterial wall viscoelasticity using fractional order models, reducing the number of parameters and exposing a natural response. Hence, a key missing item in the arterial Windkessel modeling is a fractional-order analog component that can provide a reliable, realistic and reduced representation of the fractional viscoelasticity behavior. In this paper, we present, for the first time, a three-element fractional-order viscoelastic Windkessel model. The proposed model incorporates a fractional-order capacitor that substitutes the ideal capacitor of standard three-elements WK model. The latter non-ideal element combines both resistive and capacitive properties which displays viscoelastic behavior of the arterial vessel. The contribution of both properties is controlled by the fractional differentiation order α enabling an accurate and reliable physiological description.


Juxtaglomerular cell tumor of kidney with CD34 and CD117 immunoreactivity: report of 5 cases.
Juxtaglomerular cell tumor is a rare renal neoplasm. Renin immunohistochemistry and electron microscopic documentation of rhomboid crystals are the primary methods of diagnosing this benign tumor. In this retrospective study, we evaluated the morphologic, immunohistochemical, and ultrastructural features of 5 cases of juxtaglomerular cell tumor to determine the effectiveness of CD34 and CD117 immunohistochemistry for the diagnosis of this tumor. We reviewed 5 cases with clinical, histologic, immunohistochemical, and ultrastructural aspects. Three women and 2 men with a mean age of 37.8 years (range, 16-60 years) were included in this study. All patients presented with severe hypertension. All tumors were well circumscribed and ranged from 1.5 cm to 8.5 cm (mean, 4.4 cm). On light microscopic examination, we found solid sheets and nests of tumor cells with oval-to-round nuclei and eosinophilic cytoplasm. Low-power microscopic examination disclosed a hemangiopericytic vascular pattern. Immunohistochemistry results were as follows: vimentin (positive), renin (weakly positive), smooth muscle actin (focal immunoreactivity), and cytokeratin (negative). All 5 tumors were immunoreactive for CD34 and CD117. Electron microscopy revealed rhomboid crystals in the cytoplasm. Postoperatively, 4 patients were normotensive and 1 patient experienced persistent mild hypertension. Our findings indicate that immunohistochemistry for CD34 and CD117 are effective at diagnosing juxtaglomerular cell tumor. Juxtaglomerular cell tumor should be considered in the diagnosis of any renal tumors with epithelioid cells and negative initial cytokeratin immunohistochemistry.


Variation of the superelastic properties and nickel release from original and reused NiTi orthodontic archwires.
Reuse of NiTi orthodontic wires has become increasingly common in dental clinics. For sterilization and recovery of the original superelastic properties of the wires, a heat treatment is usually performed between 500 and 600 °C. The aim of this study was to analyze the effect of these thermal treatments on the mechanical behavior and the microstructure of NiTi archwires of different compositions. A reduction of the Ni content was observed in the matrix of the thermally treated archwires, due to the formation of Ti(3)Ni(4) precipitates. The nickel-rich precipitates were observed and characterized by Transmission Electron Microscopy (TEM) and electron diffraction. They were found to alter the mechanical properties of the wires, decreasing the transformation stresses, and causing a loss of activation of the NiTi archwires. The release of nickel was higher in the original archwires than in the reused ones, due to the matrix nickel depletion caused by the precipitation of Ti(3)Ni(4).


Uncertainty in QSAR predictions.
It is relevant to consider uncertainty in individual predictions when quantitative structure-activity (or property) relationships (QSARs) are used to support decisions of high societal concern. Successful communication of uncertainty in the integration of QSARs in chemical safety assessment under the EU Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) system can be facilitated by a common understanding of how to define, characterise, assess and evaluate uncertainty in QSAR predictions. A QSAR prediction is, compared to experimental estimates, subject to added uncertainty that comes from the use of a model instead of empirically-based estimates. A framework is provided to aid the distinction between different types of uncertainty in a QSAR prediction: quantitative, i.e. for regressions related to the error in a prediction and characterised by a predictive distribution; and qualitative, by expressing our confidence in the model for predicting a particular compound based on a quantitative measure of predictive reliability. It is possible to assess a quantitative (i.e. probabilistic) predictive distribution, given the supervised learning algorithm, the underlying QSAR data, a probability model for uncertainty and a statistical principle for inference. The integration of QSARs into risk assessment may be facilitated by the inclusion of the assessment of predictive error and predictive reliability into the "unambiguous algorithm", as outlined in the second OECD principle.


Risk of musculoskeletal injury among cleaners during vacuuming.
This study aimed to examine the risk of work-related upper-limb musculoskeletal disorders in cleaning workers during the work task of vacuuming. In total, 24 cleaning workers were observed while they performed vacuum cleaning tasks in the normal course of their employment in government schools, hospitality and commercial office space sectors. Risk of upper-limb musculoskeletal disorders were rated using three observational assessment tools: Manual Task Risk Assessment (ManTRA); Quick Exposure Check (QEC); the Rapid Upper Limb Assessment (RULA). Mean results (e.g. ManTRA wrist/hand cumulative wrist score 18.67 ± 1.27, QEC neck score 13 ± 1.77, RULA score 6.54 ± 0.509) demonstrated that cleaning workers who perform the task of vacuum cleaning are at risk of work-related upper-limb musculoskeletal injury, regardless of whether they use a back-pack or canister machine. Government school cleaners experienced greater risk of work-related upper-limb musculoskeletal disorders than workers in either the hospitality or commercial office space sectors. Cleaning workers in Australia are mostly female, ageing and of non-English-speaking backgrounds and involved in repetitive manual tasks. Their occupation is low status. This research confirms that vacuuming tasks are a risk for cleaning workers and highlights the need for further research to improve conditions for these workers.


The pregnancy outcomes of intrauterine insemination with husband's sperm in natural cycles versus ovulation stimulated cycles: A retrospective study.
To compare the clinical outcomes of intrauterine insemination (IUI) with or without ovulation induction (OI), IUI cycles from January 2008 to December 2017 in Zhoushan Maternity and Child Healthcare Hospital were included, consisting of 455 natural cycles and 536 OI cycles. The overall clinical pregnancy rate did not differ between the two groups (P > 0.05). Stratified by OI medications such as clomiphene (CC), human menopausal gonadotropin (HMG) and follicle stimulating hormone (FSH), the pregnancy rates in HMG, CC, CC+HMG, and FSH/FSH+HMG groups were 11.70%, 13.58%, 15.95%, and 13.46%, respectively, but the difference was not significant compared with natural cycles (P > 0.05). Stratified by infertility etiology, the pregnancy rate was significantly higher in stimulated cycles than natural cycles with ovulation disorders (P < 0.01) and unexplained factors (P < 0.01) while it was significantly lower regarding cervical factors (P < 0.01), endometriosis (P < 0.05), male factor (P < 0.01) and other female factors. There was no strong difference of pregnancy rate for biparental causes (P > 0.05). Stratified by age category, women over 35 had higher pregnancy rate in stimulated cycles compared with natural cycles (18.75 vs. 12.24%; P < 0.05), while women under 35 had no significant difference of pregnancy rate between the two groups (13.65 vs 13.05%; P > 0.05). However, there was no significant difference between each ovarian stimulation group and natural cycle group regardless of the infertility causes or age categories. To conclude, IUI-OI could achieve a higher overall pregnancy rate for women over 35 and infertile patients with ovulation disorders and unexplained factors.


Morphometric changes of the corpus callosum in congenital blindness.
We examined the effects of visual deprivation at birth on the development of the corpus callosum in a large group of congenitally blind individuals. We acquired high-resolution T1-weighted MRI scans in 28 congenitally blind and 28 normal sighted subjects matched for age and gender. There was no overall group effect of visual deprivation on the total surface area of the corpus callosum. However, subdividing the corpus callosum into five subdivisions revealed significant regional changes in its three most posterior parts. Compared to the sighted controls, congenitally blind individuals showed a 12% reduction in the splenium, and a 20% increase in the isthmus and the posterior part of the body. A shape analysis further revealed that the bending angle of the corpus callosum was more convex in congenitally blind compared to the sighted control subjects. The observed morphometric changes in the corpus callosum are in line with the well-described cross-modal functional and structural neuroplastic changes in congenital blindness.


Comparative efficacy and safety of anticoagulants for prevention of venous thromboembolism after hip and knee arthroplasty.
Background and purpose - New oral anticoagulants have been developed to prevent venous thromboembolism (VTE) after knee or hip arthroplasty. Although there have been several network meta-analyses (NMA) to compare different regimens, an NMA including 2 different enoxaparin doses and edoxaban has not been performed. Methods - Standard NMA for fondaparinux, dabigatran, rivaroxaban, apixaban, edoxaban, and enoxaparin was performed. Outcome variables included a composite of total VTE and major/clinically relevant bleeding. The rank probabilities of each treatment outcome were summarized by the surface under the cumulative ranking curve. Results - Fondaparinux, rivaroxaban, and apixaban were associated with a reduced risk of VTE compared with enoxaparin, while dabigatran was not. None of these 3 drugs increased bleeding compared with enoxaparin 30 mg twice daily. However, fondaparinux and rivaroxaban increased bleeding compared with enoxaparin 40 mg once daily, while apixaban did not. Apixaban was even associated with decreased major/clinically relevant bleeding compared with enoxaparin 30 mg twice daily or 40 mg once daily. When edoxaban was included in the NMA, edoxaban decreased VTE and did not increase bleeding compared with enoxaparin. Interpretation - A higher efficacy of fondaparinux and rivaroxaban compared with enoxaparin was associated with increased bleeding tendency, while apixaban was superior to enoxaparin regarding both efficacy and safety. A clustered ranking plot showed that apixaban might be the most preferred regarding efficacy and safety. However, our results were driven by indirect statistical inference and were limited by the heterogeneity of the bleeding outcome definitions, drug initiation and continuation, and different surgery types.


2018 update of the EULAR recommendations for the role of the nurse in the management of chronic inflammatory arthritis.
To update the European League Against Rheumatism (EULAR) recommendations for the role of the nurse in the management of chronic inflammatory arthritis (CIA) using the most up to date evidence. The EULAR standardised operating procedures were followed. A task force of rheumatologists, health professionals and patients, representing 17 European countries updated the recommendations, based on a systematic literature review and expert consensus. Higher level of evidence and new insights into nursing care for patients with CIA were added to the recommendation. Level of agreement was obtained by email voting. The search identified 2609 records, of which 51 (41 papers, 10 abstracts), mostly on rheumatoid arthritis, were included. Based on consensus, the task force formulated three overarching principles and eight recommendations. One recommendation remained unchanged, six were reworded, two were merged and one was reformulated as an overarching principle. Two additional overarching principles were formulated. The overarching principles emphasise the nurse's role as part of a healthcare team, describe the importance of providing evidence-based care and endorse shared decision-making in the nursing consultation with the patient. The recommendations cover the contribution of rheumatology nursing in needs-based patient education, satisfaction with care, timely access to care, disease management, efficiency of care, psychosocial support and the promotion of self-management. The level of agreement among task force members was high (mean 9.7, range 9.6-10.0). The updated recommendations encompass three overarching principles and eight evidence-based and expert opinion-based recommendations for the role of the nurse in the management of CIA.


Carbamazepine-induced angioedema.
Angioedema is a rare adverse reaction of carbamazepine, which causes localized tissue edema in submucosal and subcutaneous tissue mediated by histamine, serotonin, and kinins (bradykinin). We report a case of 34-year-old female who developed angioedema, 24 h after administration of carbamazepine for treating bipolar disorder. Patient's symptoms responded rapidly with antihistamine therapy and with the withdrawal of carbamazepine, the offending drug. Carbamazepine-induced angioedema is a life-threatening reaction which requires immediate treatment and monitoring in order to avoid morbidity and mortality.


Swan-Ganz catheter: comparison of insertion techniques.
One hundred eighty-nine Swan-Ganz catheters were inserted in 165 critically ill patients with different techniques. Percutaneous catheterization through the subclavian, internal jugular, and antecubital veins and antecubital venous cutdown with or without fluoroscopy were compared. The antecubital approach, percutaneously or through a venous cutdown, was associated with most complications. We conclude that the method of choice is the percutaneous insertion of the balloon-tipped catheter through the subclavian or internal jugular veins and that fluoroscopy is unnecessary.


Non-human primates in HIV research: Achievements, limits and alternatives.
An ideal model for HIV-1 research is still unavailable. However, infection of non-human primates (NHP), such as macaques, with Simian Immunodeficiency Virus (SIV) recapitulates most virological, immunological and clinical hallmarks of HIV infection in humans. It has become the most suitable model to study the mechanisms of transmission and physiopathology of HIV/AIDS. On the other hand, natural hosts of SIV, such as African green monkeys and sooty mangabeys that when infected do not progress to AIDS, represent an excellent model to elucidate the mechanisms involved in the capacity of controlling inflammation and disease progression. The use of NHP-SIV models has indeed enriched our knowledge in the fields of: i) viral transmission and viral reservoirs, ii) early immune responses, iii) host cell-virus interactions in tissues, iv) AIDS pathogenesis, v) virulence factors, vi) prevention and vii) drug development. The possibility to control many variables during experimental SIV infection, together with the resemblance between SIV and HIV infections, make the NHP model the most appropriate, so far, for HIV/AIDS research. Nonetheless, some limitations in using these models have to be considered. Alternative models for HIV/AIDS research, such as humanized mice and recombinant forms of HIV-SIV viruses (SHIV) for NHP infection, have been developed. The improvement of SHIV viruses that mimic even better the natural history of HIV infection and of humanized mice that develop a greater variety of human immune cell lineages, is ongoing. None of these models is perfect, but they allow contributing to the progress in managing or preventing HIV infection.


Caveolin-3 directly interacts with the C-terminal tail of beta -dystroglycan. Identification of a central WW-like domain within caveolin family members.
Caveolin-3, the most recently recognized member of the caveolin gene family, is muscle-specific and is found in both cardiac and skeletal muscle, as well as smooth muscle cells. Several independent lines of evidence indicate that caveolin-3 is localized to the sarcolemma, where it associates with the dystrophin-glycoprotein complex. However, it remains unknown which component of the dystrophin complex interacts with caveolin-3. Here, we demonstrate that caveolin-3 directly interacts with beta-dystroglycan, an integral membrane component of the dystrophin complex. Our results indicate that caveolin-3 co-localizes, co-fractionates, and co-immunoprecipitates with a fusion protein containing the cytoplasmic tail of beta-dystroglycan. In addition, we show that a novel WW-like domain within caveolin-3 directly recognizes the extreme C terminus of beta-dystroglycan that contains a PPXY motif. As the WW domain of dystrophin recognizes the same site within beta-dystroglycan, we also demonstrate that caveolin-3 can effectively block the interaction of dystrophin with beta-dystroglycan. In this regard, interaction of caveolin-3 with beta-dystroglycan may competitively regulate the recruitment of dystrophin to the sarcolemma. We discuss the possible implications of our findings in the context of Duchenne muscular dystrophy.


Model-driven engineering of RNA devices to quantitatively program gene expression.
The models and simulation tools available to design functionally complex synthetic biological devices are very limited. We formulated a design-driven approach that used mechanistic modeling and kinetic RNA folding simulations to engineer RNA-regulated genetic devices that control gene expression. Ribozyme and metabolite-controlled, aptazyme-regulated expression devices with quantitatively predictable functions were assembled from components characterized in vitro, in vivo, and in silico. The models and design strategy were verified by constructing 28 Escherichia coli expression devices that gave excellent quantitative agreement between the predicted and measured gene expression levels (r = 0.94). These technologies were applied to engineer RNA-regulated controls in metabolic pathways. More broadly, we provide a framework for studying RNA functions and illustrate the potential for the use of biochemical and biophysical modeling to develop biological design methods.


Fibrocartilaginous embolism--an uncommon cause of spinal cord infarction: a case report and review of the literature.
Fibrocartilaginous embolism is a rare cause of spinal cord infarction. It is postulated that an acute vertical disk herniation of the nucleus pulposus material can lead to spinal cord infarction by a retrograde embolization to the central artery. An increased intradiskal pressure resulting from axial loading of the vertebral column with a concomitant Valsalva maneuver is thought to be the initiating event for the embolus. We present a previously healthy 16-year-old boy with sudden onset of back pain and progressive paraparesis within 36 hours after lifting exercises in a squat position. His clinical presentation and neuroimaging studies were consistent with spinal cord infarction resulting from a central artery embolus at the T8 spinal cord level. Laboratory investigation showed no evidence of infectious, autoimmune, inflammatory, or neoplastic causes. Although no histologic confirmation was obtained, lack of evidence for other plausible diagnoses in the setting of his clinical presentation and in the magnetic resonance imaging findings made fibrocartilaginous embolism myelopathy the most likely diagnosis. We postulated that some cases of transverse myelitis might actually be fibrocartilaginous embolism, making it a more prevalent cause of an acute myelopathy than commonly recognized. Relevant literature and current theories regarding the pathogenesis of fibrocartilaginous embolism myelopathy are reviewed.


Effect of hypoxia on tert-butylhydroperoxide-induced oxidative injury in hepatocytes.
Toxicity of t-butylhydroperoxide (t-BuOOH) was studied at different steady state O2 concentrations under conditions at which O2 deficiency alone did not cause cell death. t-BuOOH-induced cell death was more rapid in hypoxic than normoxic cells; the maximal rate of cell death occurred in anoxic cells. t-BuOOH elimination was independent of O2 concentration and was complete within 15 min; t-Butanol was produced at the same rate and was the only product detected by gas chromatography. Measurement of radical production by formation of adducts of the spin-trapping agent N-tert-butylphenylnitrone showed that the amount of radicals trapped was 0.02% of the amount of peroxide added and was the same under anoxic and oxygenated (214 microM O2) conditions. These results show that the O2 dependence of t-BuOOH-induced toxicity is not related to quantitative alterations in its metabolism. Lipid peroxidation was lowest in anoxic cells and increased as the O2 concentration was increased to 1.07 mM O2, showing that enhanced toxicity during hypoxia and anoxia was not due to enhanced lipid peroxidation. In contrast, O2 deficiency impaired the ability of cells to maintain and recovery GSH and NADPH pools after addition of t-BuOOH. GSH was decreased to a greater extent in anoxic cells than in normoxic cells, and the GSH content remained lower in these cells for up to 30 min. This decrease was due both to a decrease in the rate of synthesis and to decreased supply of the NADPH needed for the reduction of GSSG. Taken together, these results show that O2 deficiency has little effect on metabolism of t-BuOOH but impairs the ability of cells to maintain cellular GSH and renders them more susceptible to injury from oxidizing agents. This suggests that oxidative injury under hypoxia or following ischemia may not require a marked stimulation in generation of oxidative species but may occur as a consequence of the impaired ability to tolerate or repair oxidative injury.


Automated PCR detection of BRAF mutations in colorectal adenocarcinoma: a diagnostic test accuracy study.
Testing for BRAF mutations in colorectal carcinoma (CRC) is important in the screening pathway for Lynch syndrome and is of prognostic value to guide management. This is a diagnostic accuracy study of the Idylla system, a novel and automated alternative PCR system. 100 consecutive formalin-fixed, paraffin-embedded CRC resection cases were tested for BRAF mutations using the Idylla automated platform and compared with standard (Cobas) PCR. The sensitivity of the Idylla BRAF test was 100% and the specificity was 96%. Only one discordant Idylla positive/standard PCR negative result occurred and on Droplet Digital PCR demonstrated a mutation not identified by traditional PCR in this case. This study has validated the Idylla system for BRAF testing in CRC and demonstrated a possibly greater sensitivity, in addition to cost effectiveness and shorter turnaround time, when compared with standard PCR.


Dissociation of renin--aldosterone and renal prostaglandin E during volume expansion induced by immersion in normal man.
The relationship of the renin--angiotensin--aldosterone axis with renal prostaglandin E is complex. Although studies have suggested that these two hormonal systems respond to experimental manipulations in a parallel manner, their interdependence has not been assessed fully during volume expansion. Since studies have demonstrated that in normal man the central hypervolaemia induced by water immersion to the neck produces a prompt and profound suppression of plasma renin activity and plasma aldosterone concentration without concomitant alteration of plasma composition, immersion afforded a unique opportunity to assess simultaneously the effects of central hypervolaemia on plasma renin activity, plasma aldosterone concentration and prostaglandin E excretion. 2. Seven normal subjects were studied twice while in balance on a diet containing 10 mmol of sodium/day, 100 mmol of potassium/day: with indomethacin administration (50 mg given every 6 h for five doses) and without indomethacin. Urinary prostaglandin E excretion was measured hourly and plasma renin activity and plasma aldosterone concentration at 30 min intervals. 3. Immersion was associated with a marked suppression of plasma renin activity (59 +/- 7%) and plasma aldosterone concentration (55 +/- 3%) with a return to pre-study values during the recovery hour. Concomitantly, urinary prostaglandin E excretion increased from 4.7 to a peak of 10.9 ng/min. Although administration of indomethacin lowered the basal rate of urinary prostaglandin E excretion and plasma renin activity, it did not prevent the subsequent augmentation of urinary prostaglandin E or the suppression of plasma renin activity and plasma aldosterone during the subsequent 4 h of immersion. 4. These results demonstrate a dissociation of renin--aldosterone and prostaglandin E during hypervolaemia and suggest that whereas prostaglandin E may constitute one of the major determinants of renin release clinically and experimentally, these two hormonal systems can be dissociated from each other in response to central volume expansion in man.


State-of-the-art of wearable EEG for personalized health applications.
Despite the proliferation of low-cost wearable sensors, until recently we have not been able to monitor our brain activity in our daily lives with affordable and wearable devices. In this paper we provide an overview of the state-of-the-art of wearable electroencephalographic (EEG) devices after determining the key characteristics that enable wider adoption. Furthermore, we explore their potential applications, which suggest that wearable EEG devices can become a major enabler for personalized health. This review can serve as a reference on the state-of-the-art at the beginning of 2013.


PAH and OPAH Flux during the Deepwater Horizon Incident.
Passive sampling devices were used to measure air vapor and water dissolved phase concentrations of 33 polycyclic aromatic hydrocarbons (PAHs) and 22 oxygenated PAHs (OPAHs) at four Gulf of Mexico coastal sites prior to, during and after shoreline oiling from the Deepwater Horizon oil spill (DWH). Measurements were taken at each site over a 13 month period, and flux across the water-air boundary was determined. This is the first report of vapor phase and diffusive flux of both PAHs and OPAHs during the DWH. Vapor phase sum PAH and OPAH concentrations ranged between 6.6 and 210 ng/m(3) and 0.02 and 34 ng/m(3) respectively. PAH and OPAH concentrations in air exhibited different spatial and temporal trends than in water, and air-water flux of 13 individual PAHs was shown to be at least partially influenced by the DWH incident. The largest PAH volatilizations occurred at the sites in Alabama and Mississippi at nominal rates of 56 000 and 42 000 ng/m(2) day(-1) in the summer. Naphthalene was the PAH with the highest observed volatilization rate of 52 000 ng/m(2) day(-1) in June 2010. This work represents additional evidence of the DWH incident contributing to air contamination, and provides one of the first quantitative air-water chemical flux determinations with passive sampling technology.


Seroprevalence of Brucellosis among General Population in Famenin City, Western Iran in 2016: The Famenin Brucellosis Cohort Study.
Brucellosis is endemic in Iran with a higher level of endemicity in western areas, including the Hamadan province. This study aims to define the seroprevalence of brucellosis and it,s risk factors in general the population of Famenin, Hamadan province, in western Iran. This survey was conducted on 2367 participants in Famenin and its villages from September to November 2016. After receiving written consent from subjects, demographic information was obtained through questionnaires and 10cc blood samples were taken from the participants. Blood samples were sent to the Core facility of Hamadan University of Medical Sciences and were tested using Wright and 2ME kits (Pasteur Institute, Iran) for serological detection of brucellosis. The seroprevalence of brucellosis was reported as percentage with 95% confidence interval (CI). Totally, 2367 individuals with the mean age (SD) of 34.6 (20.9) (range: 2 to 95) years were enrolled. Of these, 1060 (44.8%) were men and 1610 (68.0%) lived in rural areas. The seroprevalence of brucellosis according to the Wright titer (equal to or greater than 1:80) was 6.6% (95% CI: 5.62%, 7.66%). The corresponding prevalence based on 2ME titers (equal to or greater than 1:40) in subjects with positive Wright test was 37.2% (95% CI: 29.5%, 44.84%). We saw a significant association between the incidence of brucellosis and occupation (P < 0.001) and type of contact with livestock (P = 0.009) as two important risk factors. The seroprevalence of brucellosis in Famenin population was considerable. Contact with livestock, animal husbandry, farming and history of brucellosis were risk factors for brucellosis infection.


Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia.
Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove active primarily in lymphoproliferative diseases, early reports suggested unexpected high activity of this drug in heavily pretreated children with acute myeloblastic leukemia (AML) at a maximally tolerated dose of 8.9 mg/m2/day for 5 days. In view of these findings, we conducted an escalating dose trial of 2-CdA in adult patients with relapsed or resistant AML. Thirty-six patients who had received extensive prior therapy were treated at 9 dose levels of 2-CdA at daily doses ranging from 5 to 21 mg/m2 for 5 days. 2-CdA eliminated leukemic blasts from the peripheral blood in 32 of 36 cases; however, bone marrow hypoplasia was seen only at daily dose levels > or = 15 mg/m2. We observed a total of 3 complete remissions: 1 at the 15 mg/m2/d dose level and 2 at the 21 mg/m2/d dose level; these responses persisted for 3, 2, and 3 months, respectively. Although prolonged myelosuppression would have been dose-limiting at 21 mg/m2/d for 5 days, the most important adverse effect was the development of a sensorimotor peripheral neuropathy. This reaction, whose onset was substantially delayed after completion of drug treatment, was observed in 2 of 5 patients at the 19 mg/m2/d level and in 4 of 4 evaluable patients at the 21 mg/m2/d level. Pathologically, this process was characterized by axonal degeneration and secondary demyelination. Other side effects included reactivation of a posttransplant Epstein-Barr virus-related lymphoma in 1 patient and tumor lysis syndrome. We conclude that the maximally tolerable dose of 2-CdA in adult patients (17 mg/m2/d for 5 days) in approximately twofold in excess of that previously reported in children and that the limiting toxic effect is a degenerative neuropathic disorder. We confirm that this drug has definite activity in AML, but the magnitude of this effect needs to be determined in larger numbers of patients who have received less extensive therapy. This agent deserves further evaluation in patients with both AML and acute lymphoblastic leukemia at these higher doses and perhaps as part of a preparative regimen for patients undergoing bone marrow transplantation.


Genetic analysis of extracellular proteins of Serratia marcescens.
Serratia marcescens, a gram-negative enteric bacterium, is capable of secreting a number of proteins extracellularly. The types of activity found in the growth media include proteases, chitinases, a nuclease, and a lipase. Genetic studies have been undertaken to investigate the mechanisms used for the extracellular secretion of these exoproteins by S. marcescens. Many independent mutations affecting the extracellular enzymes were isolated after chemical and transposon mutagenesis. Using indicator media, we have identified loci involved in the production or excretion of extracellular protease, nuclease, or chitinase by S. marcescens. None of the mutations represented general extracellular-excretion mutants; in no case was the production or excretion of multiple exoproteins affected. A variety of loci were identified, including regulatory mutations affecting nuclease and chitinase expression. A number of phenotypically different protease mutants arose. Some of them may represent different gene products required for the production and excretion of the major metalloprotease, a process more complex than that for the other S. marcescens exoproteins characterized to date.


The prevalence of hazardous and harmful drinking in the UK Police Service, and their co-occurrence with job strain and mental health problems.
Due to the stressful nature of policing, police employees are at risk of mental health problems and problematic alcohol use. We aim to determine the prevalence of hazardous and harmful alcohol use in the UK Police Service, and to explore the associations with job strain and mental health problems. Cross-sectional data from the Airwave Health Monitoring Study (N = 40 986) included measures of alcohol consumption (total units in past week), mental health (depression, anxiety and post-traumatic stress disorder [PTSD]) and job strain. The associations between mental health and job strain with alcohol consumption (i.e. abstinence, low-risk [<14 units per week, reference group], hazardous [>14 to 35 units for women, >14 to 50 units for men], harmful [>35 units for women, >50 units for men]), were analysed using multinomial logistic regressions, adjusting for potential confounders (i.e. age, gender, ethnicity, marital status, children under 18, income and smoking status). A total of 32.6% of police employees reported hazardous drinking, with 3.0% drinking at harmful levels. Compared to those without a mental health problem, police employees with depression, anxiety or PTSD were twice as likely to be harmful drinkers and were also 1.3 times more likely to report abstinence. Those reporting low strain (reference group) were more likely to drink hazardously compared to those reporting high strain, which was statistically moderated by mental health. When the sample was stratified by mental health status, the association between low strain (compared to all other categories) and hazardous drinking, was significant only in those without a mental health problem. These findings indicate that police employees may be an occupational group at risk of alcohol harm, with one-third drinking hazardously. The J-shaped relationship between mental health and alcohol use highlights a need for an integration of mental health and alcohol services, tailored for the UK Police Service.


Synthesis of oligo(poly(ethylene glycol) fumarate).
This protocol describes the synthesis of oligo(poly(ethylene glycol) fumarate) (OPF; 1-35 kDa; a polymer useful for tissue engineering applications) by a one-pot reaction of poly(ethylene glycol) (PEG) and fumaryl chloride. The procedure involves three parts: dichloromethane and PEG are first dried; the reaction step follows, in which fumaryl chloride and triethylamine are added dropwise to a solution of PEG in dichloromethane; and finally, the product solution is filtered to remove by-product salt, and the OPF product is twice crystallized, washed and dried under vacuum. The reaction is affected by the molecular weight of PEG and reactant molar ratio. The OPF product is cross-linked by radical polymerization by either a thermally induced or ultraviolet-induced radical initiator, and the physical properties of the OPF oligomer and resulting cross-linked hydrogel are easily tailored by varying PEG molecular weight. OPF hydrogels are injectable, they polymerize in situ and they undergo biodegradation by hydrolysis of ester bonds. The expected time required to complete this protocol is 6 d.


Modeling Kidney Disease with iPS Cells.
Induced pluripotent stem cells (iPSCs) are somatic cells that have been transcriptionally reprogrammed to an embryonic stem cell (ESC)-like state. iPSCs are a renewable source of diverse somatic cell types and tissues matching the original patient, including nephron-like kidney organoids. iPSCs have been derived representing several kidney disorders, such as ADPKD, ARPKD, Alport syndrome, and lupus nephritis, with the goals of generating replacement tissue and 'disease in a dish' laboratory models. Cellular defects in iPSCs and derived kidney organoids provide functional, personalized biomarkers, which can be correlated with genetic and clinical information. In proof of principle, disease-specific phenotypes have been described in iPSCs and ESCs with mutations linked to polycystic kidney disease or focal segmental glomerulosclerosis. In addition, these cells can be used to model nephrotoxic chemical injury. Recent advances in directed differentiation and CRISPR genome editing enable more specific iPSC models and present new possibilities for diagnostics, disease modeling, therapeutic screens, and tissue regeneration using human cells. This review outlines growth opportunities and design strategies for this rapidly expanding and evolving field.


Does changing from mercury to electronic blood pressure measurement influence recorded blood pressure? An observational study.
Mercury sphygmomanometers have been commonly used in primary care to measure blood pressure but are associated with bias. Electronic blood pressure machines are being introduced in many practices and have anecdotally been associated with higher recorded blood pressure. This study examined recorded blood pressure in four practices before and after electronic blood pressure machine introduction. No consistent change in mean blood pressure was apparent following their introduction, but there was a large and significant fall in terminal digit preference suggesting improved precision of recording.


Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy.
Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.


Enhancement to the RANKPEP resource for the prediction of peptide binding to MHC molecules using profiles.
We introduced previously an on-line resource, RANKPEP that uses position specific scoring matrices (PSSMs) or profiles for the prediction of peptide-MHC class I (MHCI) binding as a basis for CD8 T-cell epitope identification. Here, using PSSMs that are structurally consistent with the binding mode of MHC class II (MHCII) ligands, we have extended RANKPEP to prediction of peptide-MHCII binding and anticipation of CD4 T-cell epitopes. Currently, 88 and 50 different MHCI and MHCII molecules, respectively, can be targeted for peptide binding predictions in RANKPEP. Because appropriate processing of antigenic peptides must occur prior to major histocompatibility complex (MHC) binding, cleavage site prediction methods are important adjuncts for T-cell epitope discovery. Given that the C-terminus of most MHCI-restricted epitopes results from proteasomal cleavage, we have modeled the cleavage site from known MHCI-restricted epitopes using statistical language models. The RANKPEP server now determines whether the C-terminus of any predicted MHCI ligand may result from such proteasomal cleavage. Also implemented is a variability masking function. This feature focuses prediction on conserved rather than highly variable protein segments encoded by infectious genomes, thereby offering identification of invariant T-cell epitopes to thwart mutation as an immune evasion mechanism.


The catalytic domains of Clostridium sordellii lethal toxin and related large clostridial glucosylating toxins specifically recognize the negatively charged phospholipids phosphatidylserine and phosphatidic acid.
Clostridium sordellii lethal toxin (TcsL) is a potent virulence factor belonging to the large clostridial glucosylating toxin family. TcsL enters target cells via receptor-mediated endocytosis and delivers the N-terminal catalytic domain (TcsL-cat) into the cytosol upon an autoproteolytic process. TcsL-cat inactivates small GTPases including Rac and Ras by glucosylation with uridine-diphosphate (UDP)-glucose as cofactor leading to drastic changes in cytoskeleton and cell viability. TcsL-cat was found to preferentially bind to phosphatidylserine (PS)-containing membranes and to increase the glucosylation of Rac anchored to lipid membrane. We here report binding affinity measurements of TcsL-cat for brain PS-containing membranes by surface plasmon resonance and enzyme-linked immunosorbent assay (ELISA). In addition, TcsL-cat bound to phosphatidic acid (PA) and, to a lesser extent, to other anionic lipids, but not to neutral lipids, sphingolipids or sterol. We further show that the lipid unsaturation status influenced TcsL-cat binding to phospholipids, PS with unsaturated acyl chains and PA with saturated acyl chains being the preferred bindingsubstrates. Phospholipid binding site is localized at the N-terminal four helical bundle structure (1-93 domain). However, TcsL-1-93 bound to a broad range of substrates, whereas TcsL-cat, which is the active domain physiologically delivered into the cytosol, selectively bound to PS and PA. Similar findings were observed with the other large clostridial glucosylating toxins from C. difficile, C. novyi and C. perfringens.


Systematic review with network meta-analysis: pharmacological prophylaxis against post-ERCP pancreatitis.
The efficacy of many pharmacological agents for preventing post-ERCP pancreatitis (PEP) has been evaluated in randomised controlled trials (RCTs), but it is unclear which agent(s) should be used in clinical practice. Network meta-analyses of RCTs are used to simultaneously compare several agents to determine their relative efficacy and identify priority agents for comparison in future RCTs. To evaluate pharmacological agents for the prevention of PEP by conducting a network meta-analysis of RCTs. We searched MEDLINE, EMBASE and Cochrane Library databases for RCTs that evaluated the efficacy of agents for preventing PEP. RCTs were simultaneously analysed using random-effects network meta-analysis under the Bayesian framework to identify the best agents. The efficacy of agents was ordered according to the probability of being ranked as any of the top three best performing agents. The network meta-analysis included 99 RCTs evaluating 16 agents in 25 313 patients. Topical epinephrine (adrenaline) was the most efficacious agent with 85.9% probability of ranking among the top three agents, followed by nafamostat (51.4%), antibiotics (44.5%) and NSAIDs (42.8%). However, in a sensitivity analysis including only rectal NSAIDs, NSAIDs moved from fourth rank to second (58.1%). Patients receiving topical epinephrine, compared with placebo, had a 75% reduced risk of PEP (OR 0.25, 95% probability interval 0.06-0.66). Topical epinephrine and rectal NSAIDs are the most efficacious agents for preventing post-ERCP pancreatitis, based on existing RCTs. Combinations of these agents, which act on different steps in the pathogenesis of post-ERCP pancreatitis, should be evaluated in future trials.


Assembly and patterning of the vascular network of the vertebrate hindbrain.
The cranial vasculature is essential for the survival and development of the central nervous system and is important in stroke and other brain pathologies. Cranial vessels form in a reproducible and evolutionarily conserved manner, but the process by which these vessels assemble and acquire their stereotypic patterning remains unclear. Here, we examine the stepwise assembly and patterning of the vascular network of the zebrafish hindbrain. The major artery supplying the hindbrain, the basilar artery, runs along the ventral keel of the hindbrain in all vertebrates. We show that this artery forms by a novel process of medial sprouting and migration of endothelial cells from a bilateral pair of primitive veins, the primordial hindbrain channels. Subsequently, a second wave of dorsal sprouting from the primordial hindbrain channels gives rise to angiogenic central arteries that penetrate into and innervate the hindbrain. The chemokine receptor cxcr4a is expressed in migrating endothelial cells of the primordial hindbrain channels, whereas its ligand cxcl12b is expressed in the hindbrain neural keel immediately adjacent to the assembling basilar artery. Knockdown of either cxcl12b or cxcr4a results in defects in basilar artery formation, showing that the assembly and patterning of this crucial artery depends on chemokine signaling.


Luminescent chemosensors by using cyclometalated iridium(iii) complexes and their applications.
Luminescent metal complexes have found increasing use in multiple areas of science and technology, including in chemosensing, light-emitting devices and photochemistry. In particular, the use of cyclometalated iridium(iii) complexes as chemosensors has received increasing attention in the recent literature. Phosphorescent metal complexes enjoy a number of advantages (e.g., long-lived phosphorescence, high quantum efficiency and modular syntheses) that render them as suitable alternatives to organic dyes for sensing a variety of analytes. This review describes recent examples of cyclometalated iridium(iii) complexes that act as luminescent chemosensors for cations, anions or small molecules.


Can you get the magic back? The moderating effect of passion decay beliefs on relationship commitment.
The present research introduces the construct of a decay theory of passion-a lay belief that romantic passion decline is irreversible-and investigates how this construct interacts with existing levels of passion for one's romantic partner to predict lower relationship commitment and greater pursuit of romantic alternatives. Across three studies employing experimental and nonexperimental procedures-and a set of meta-analytic syntheses including additional studies-results generally supported the hypotheses that, although low passion is linked to lower commitment and greater pursuit of romantic alternatives, such effects are stronger when adherence to decay beliefs is high rather than low. These effects tended to be independent of effects of destiny and growth theories (Knee, 1998), a related set of lay theories in the domain of relationships. Mediated moderation analyses revealed that the moderating effect of decay theories on relationship commitment mediates the moderating effect of decay theories on the link between low passion and the pursuit of romantic alternatives. Discussion addresses the possibility that changing one's beliefs surrounding the nature of romantic passion may be an important, but previously overlooked, means for preventing one from prematurely abandoning an otherwise satisfying relationship. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Perception of global facial geometry in the inversion effect and prosopagnosia.
We investigated how efficiently combinations of positional shifts in facial features were perceived and whether the effects of combinations on the overall geometry of the face were reflected in discriminative performance. We moved the eyes closer together or further apart, and moved the mouth up or down. Trials with combinations of changes to both the mouth and the eyes were contrasted with trials with single changes to either the mouth or the eyes. As a contrast, we also examined combinations of changes in eye colour (brightness) and the same spatial manipulations. In addition, we specifically contrasted spatial combinations that more severely distorted the original triangular relation of the mouth and eyes (e.g. eyes closer and mouth down) to those that better preserved the original aspect ratio (e.g. eyes farther and mouth down). This we termed the "geometric context effect". We found that combinations of two spatial changes were detected more quickly and accurately by normal subjects viewing upright faces but not when faces were inverted. In contrast, combinations of spatial shifts and eye colour changes showed no advantage over faces with only one type of change. Combinations of spatial changes that distorted overall facial geometry more were detected more efficiently than less distorting combinations, showing that the spatial shifts were perceived in the context of the global facial structure. Again, this was found for upright but not inverted faces. We also tested a prosopagnosic patient, who showed the advantage for two spatial changes over one but lacked this geometric context effect, implying that she did not integrate local spatial information into overall facial structure.


Involvement of estrogen receptor alpha, beta and oxytocin in social discrimination: A detailed behavioral analysis with knockout female mice.
Social recognition, processing, and retaining information about conspecific individuals is crucial for the development of normal social relationships. The neuropeptide oxytocin (OT) is necessary for social recognition in male and female mice, with its effects being modulated by estrogens in females. In previous studies, mice whose genes for the estrogen receptor-alpha (alpha-ERKO) and estrogen receptor-beta (beta-ERKO) as well as OTKO were knocked out failed to habituate to a repeatedly presented conspecific and to dishabituate when the familiar mouse is replaced by a novel animal (Choleris et al. 2003, Proc Natl Acad Sci USA 100, 6192-6197). However, a binary social discrimination assay, where animals are given a simultaneous choice between a familiar and a previously unknown individual, offers a more direct test of social recognition. Here, we used alpha-ERKO, beta-ERKO, and OTKO female mice in the binary social discrimination paradigm. Differently from their wild-type controls, when given a choice, the KO mice showed either reduced (beta-ERKO) or completely impaired (OTKO and alpha-ERKO) social discrimination. Detailed behavioral analyses indicate that all of the KO mice have reduced anxiety-related stretched approaches to the social stimulus with no overall impairment in horizontal and vertical activity, non-social investigation, and various other behaviors such as, self-grooming, digging, and inactivity. Therefore, the OT, ER-alpha, and ER-beta genes are necessary, to different degrees, for social discrimination and, thus, for the modulation of social behavior (e.g. aggression, affiliation).


A comprehensive descriptor of shape: method and application to content-based retrieval of similar appearing lesions in medical images.
We have developed a method to quantify the shape of liver lesions in CT images and to evaluate its performance for retrieval of images with similarly-shaped lesions. We employed a machine learning method to combine several shape descriptors and defined similarity measures for a pair of shapes as a weighted combination of distances calculated based on each feature. We created a dataset of 144 simulated shapes and established several reference standards for similarity and computed the optimal weights so that the retrieval result agrees best with the reference standard. Then we evaluated our method on a clinical database consisting of 79 portal-venous-phase CT liver images, where we derived a reference standard of similarity from radiologists' visual evaluation. Normalized Discounted Cumulative Gain (NDCG) was calculated to compare this ordering with the expected ordering based on the reference standard. For the simulated lesions, the mean NDCG values ranged from 91% to 100%, indicating that our methods for combining features were very accurate in representing true similarity. For the clinical images, the mean NDCG values were still around 90%, suggesting a strong correlation between the computed similarity and the independent similarity reference derived the radiologists.


Alliance Against Cancer, the network of Italian cancer centers bridging research and care.
Alliance Against Cancer (ACC) was established in Rome in 2002 as a consortium of six Italian comprehensive cancer centers (Founders). The aims of ACC were to promote a network among Italian oncologic institutions in order to develop specific, advanced projects in clinical and translational research. During the following years, many additional full and associate members joined ACC, that presently includes the National Institute of Health, 17 research-oriented hospitals, scientific and patient organizations. Furthermore, in the last three years ACC underwent a reorganization process that redesigned the structure, governance and major activities. The present goal of ACC is to achieve high standards of care across Italy, to implement and harmonize principles of modern personalized and precision medicine, by developing cost effective processes and to provide tailored information to cancer patients. We herein summarize some of the major initiatives that ACC is currently developing to reach its goal, including tumor genetic screening programs, establishment of clinical trial programs for cancer patients treated in Italian cancer centers, facilitate their access to innovative drugs under development, improve quality through an European accreditation process (European Organization of Cancer Institutes), and develop international partnerships. In conclusion, ACC is a growing organization, trying to respond to the need of networking in Italy and may contribute significantly to improve the way we face cancer in Europe.


Genome-wide DNA methylation patterns in discordant sib pairs with alcohol dependence.
Alcohol dependence is a complex disease caused by a confluence of environmental and genetic factors. Epigenetic mechanisms have been shown to play an important role in the pathogenesis of alcohol dependence. To determine if alterations in gene-specific methylation were associated with alcohol dependence, a genome-wide DNA methylation analysis was performed on peripheral blood mononuclear cells from alcohol-dependent patients and siblings without alcohol dependence as controls. The Illumina Infinium Human Methylation450 BeadChip was used and gene-specific methylation of DNA isolated from peripheral blood mononuclear cells was assessed. Genes ALDH1L2, GAD1, DBH and GABRP were selected to validate beadchip results by pyrosequencing. Compared to normal controls, 865 hypomethylated and 716 hypermethylated CG sites in peripheral blood mononuclear cell DNA in alcohol-dependent patients were identified. The most hypomethylated CG site is located in the promoter of SSTR4 (somatostatin receptor 4) and the most hypermethylated CG site is GABRP (gamma-aminobutyric acid A receptor). The results from beadchip analysis were consistent with that of pyrosequencing. DNA methylation might be associated with alcohol dependence. Genes SSTR4, ALDH1L2, GAD1, DBH and GABRP may participate in the biological process of alcohol dependence.


High incidence of restenosis/reocclusion of stents in the percutaneous treatment of long-segment superficial femoral artery disease after suboptimal angioplasty.
To evaluate the efficacy of intravascular stents used to treat long-segment stenoses and occlusions of the superficial femoral artery (SFA) after suboptimal angioplasty. Fifty-eight limbs in 55 patients who underwent stenting of the SFA were identified from a vascular registry. Indications for stent placement after suboptimal PTA included flow-limiting dissection, residual pressure gradient (>15 mm Hg) or stenosis (>30%), or failure to establish initial patency. Lesion length ranged from 6 to 35 cm (mean, 16.5 cm). Endpoints for primary patency were: restenosis of >50%, reocclusion, or diminution of the postprocedure ankle-brachial index greater than 0.15. The mean ankle-brachial index improved from 0.48 +/- 0.19 to 0.71 +/- 0.23 (p = 0.001). Primary patency rates by Kaplan-Meier estimates at 1 month, 6 months, and 1 year were 88%, 47%, and 22%, respectively. Secondary patency rates were 94% at 1 month, 59% at 6 months, and 46% at 1 year. The median time to reaching an endpoint of restenosis or reocclusion was 6 months primarily and 9 months secondarily. Clinical improvement at the time of latest follow-up occurred in 56% of patients (mean, 13.8 months). Periprocedural complications occurred in 24.5% of patients with the first intervention. The only factor that favorably influenced outcome was improvement in clinical category after the procedure (p = 0.001). There was a high incidence of restenosis and reocclusion with long-segment SFA disease that required stents to achieve initial success. Despite close surveillance and reintervention, anatomic patency at 1 year was poor. However, clinical benefit was maintained in the majority of patients. The outcome was similar in the claudication population compared with those who had limb-threatening ischemia. Percutaneous revascularization of long-segment SFA disease requiring stents should be reserved for patients with critical limb ischemia for which no reasonable surgical alternative exists.


Hypnotic modulation of pain perception and of brain activity triggered by nociceptive laser stimuli.
Neuroimaging studies indicate that hypnotic suggestions of increased and decreased pain intensity and unpleasantness may modulate somatosensory and cingulate cortex activity, respectively. Using a within subject design and a strict subject selection procedure, we tested in High (Highs) and Low (Lows) hypnotically suggestible individuals whether hypnotic suggestions of sensory and affective hypoalgesia or hyperalgesia differentially affected subjective ratings of laser-induced pain and nociceptive-related brain activity in the time- and time-frequency domain. Hypnotic modulation of pain intensity and unpleasantness affected subjective ratings of laser-induced pain only in Highs. Such modulation was more specific for unpleasantness manipulation and more evident for suggestions of hyperalgesia. Importantly, Highs and Lows showed increase and decrease of P2a and P2b wave amplitudes and gamma band power, respectively. Hypnotic suggestions exerted a top-down modulatory effect on both evoked and induced-cortical brain responses triggered by selective nociceptive laser inputs. Furthermore, correlation analyses indicated that gamma power modulation and suggestions of hyperalgesia may reflect the process of allocating control resources to salient and threatening sensory-affective dimensions of pain.


The Fatality Assessment and Control Evaluation program's role in the prevention of occupational fatalities.
The objective of the Fatality Assessment and Control Evaluation (FACE) program is to prevent traumatic occupational fatalities in the United States by identifying and investigating work situations at high risk for injury and formulating and disseminating prevention strategies to those who can intervene in the workplace. The FACE program is a research program located in the Division of Safety Research, a division of the National Institute for Occupational Safety and Health (NIOSH). NIOSH is an agency of the United States government and is part of the Centers for Disease Control and Prevention. NIOSH is responsible for conducting research and making recommendations for prevention of work related illnesses and injuries. FACE investigators conduct traumatic occupational fatality investigations throughout the United States and provide technical assistance to 15 state health or labor departments who have cooperative agreements with NIOSH to conduct traumatic fatality surveillance, targeted investigations, and prevention activities at the state level. Investigations are conducted at the worksite using the FACE model, an approach derived from the research conducted by William Haddon Jr. This approach reflects the public health perspective that the etiology of injuries is multifactorial and largely preventable. FACE investigators gather information on multiple factors that may have contributed to traumatic occupational fatalities. Information on factors associated with the agent (energy exchange, for example, thermal energy, mechanical energy, electrical energy, chemical energy), host (worker who died), and the environment (the physical and social aspects of the workplace), during the pre-event, event, and post-event time phases of the fatal incident are collected and analyzed. Organizational, behavioral, and environmental factors contributing to the death are detailed and prevention recommendations formulated and disseminated to help prevent future incidents of a similar nature. Between 1982 and the present, more than 1,500 fatality investigations have been conducted and reports with prevention recommendations distributed. Findings have been published in scientific and trade journals; safety professionals and policy makers have used FACE findings for prevention efforts; and working partnerships have been formed to address newly emerging safety concerns. FACE investigations identify multiple factors contributing to fatal occupational injuries, which lead to the formulation and dissemination of diverse strategies for preventing deaths of a similar nature.


Modulation of epithelial cell growth by intraepithelial gamma delta T cells.
The role played in immune surveillance by gamma delta T cells residing in various epithelia has not been clear. It is shown here that activated gamma delta T cells obtained from skin and intestine express the epithelial cell mitogen keratinocyte growth factor (KGF). In contrast, intraepithelial alpha beta T cells, as well as all lymphoid alpha beta and gamma delta T cell populations tested, did not produce KGF or promote the growth of cultured epithelial cells. These results suggest that intraepithelial gamma delta T cells function in surveillance and in repair of damaged epithelial tissues.


Yield prediction in parallel homogeneous assembly.
We investigate the parallel assembly of two-dimensional, geometrically-closed modular target structures out of homogeneous sets of macroscopic components of varying anisotropy. The yield predicted by a chemical reaction network (CRN)-based model is quantitatively shown to reproduce experimental results over a large set of conditions. Scaling laws for parallel assembling systems are then derived from the model. By extending the validity of the CRN-based modelling, this work prompts analysis and solutions to the incompatible substructure problem.


Flush Rate Oxygen for Emergency Airway Preoxygenation.
Recent data suggest that emergency airway preoxygenation with a bag-valve-mask (BVM) device (held with a tight mask seal but without squeezing the bag) is superior to a nonrebreather (NRB) mask at standard oxygen flow rates. We seek to determine whether preoxygenation with an NRB mask with flush rate oxygen (>40 L/min by fully opening a standard oxygen flowmeter) is noninferior to BVM device with standard-flow oxygen (15 L/min). We also seek to compare the efficacy of preoxygenation with NRB mask at flush rate oxygen with both NRB mask with oxygen at 15 L/min and simple mask at flush rate oxygen. We performed a crossover trial using healthy volunteers. In random sequence, subjects underwent 3-minute trials of preoxygenation with nonrebreather mask with oxygen at 15 L/min (NRB-15), nonrebreather mask with flush rate oxygen (NRB-Flush), BVM device with oxygen at 15 L/min (BVM-15), and simple mask with flush rate oxygen. The primary outcome measure was the FeO2 in a single exhaled breath. We compared the FeO2 of NRB-Flush to other study groups, using a prespecified noninferiority margin of 10%. We enrolled 26 subjects. Mean FeO2 values for NRB-15, NRB-Flush, BVM-15, and simple mask with flush rate oxygen were 54% (95% confidence interval [CI] 50% to 57%), 86% (95% CI 84% to 88%), 77% (95% CI 74% to 81%), and 72% (95% CI 69% to 76%), respectively. FeO2 for NRB-Flush was noninferior to BVM-15 (difference 8%; 95% CI 5% to 11%). FeO2 for NRB-Flush was higher than both NRB-15 (FeO2 difference 32%; 95% CI 29% to 35%) and simple mask with flush rate oxygen (FeO2 difference 13%; 95% CI 10% to 17%). Preoxygenation with NRB-Flush was noninferior to BVM-15. NRB with flush rate oxygen may be a reasonable preoxygenation method for spontaneously breathing patients undergoing emergency airway management.


Repairing the broken market for antibiotic innovation.
Multidrug-resistant bacterial diseases pose serious and growing threats to human health. While innovation is important to all areas of health research, it is uniquely important in antibiotics. Resistance destroys the fruit of prior research, making it necessary to constantly innovate to avoid falling back into a pre-antibiotic era. But investment is declining in antibiotics, driven by competition from older antibiotics, the cost and uncertainty of the development process, and limited reimbursement incentives. Good public health practices curb inappropriate antibiotic use, making return on investment challenging in payment systems based on sales volume. We assess the impact of recent initiatives to improve antibiotic innovation, reflecting experience with all sixty-seven new molecular entity antibiotics approved by the Food and Drug Administration since 1980. Our analysis incorporates data and insights derived from several multistakeholder initiatives under way involving governments and the private sector on both sides of the Atlantic. We propose three specific reforms that could revitalize innovations that protect public health, while promoting long-term sustainability: increased incentives for antibiotic research and development, surveillance, and stewardship; greater targeting of incentives to high-priority public health needs, including reimbursement that is delinked from volume of drug use; and enhanced global collaboration, including a global treaty.


The Pathologic Point of View of Laparoscopic Adrenalectomy in the Era of Radiologic Imaging: A Multicenter Retrospective Study.
This study aimed to determine if laparoscopic adrenalectomy (LA) is feasible for the treatment of adrenal malignancies and metastasis, and to review the final pathology findings in order to clarify the indications for surgery. The medical records of all patients that underwent LA at 3 university hospitals between January 1, 2008, and May 1, 2015, were retrospectively reviewed. In total, 189 laparoscopic adrenalectomies were completed successfully. Mean duration of surgery was 79.3 ± 38.6 min and mean estimated intraoperative blood loss was 39.9 ml. Intraoperatively, 4 patients had major complications: spleen injury (n = 1), renal vein injury (n = 2) and diaphragm injury (n = 2). Histopathological examination showed that there were 20 different types of lesions. Surgical margins (SMs) were tumor free in 95.2% of the patients. Moreover, SMs were tumor free in all patients with adrenocortical carcinomas; however, positive margins were noted in 7 of 23 patients (30.4%) with malignant adrenal tumors. The present findings support the use of laparoscopy for metastatic adrenal masses, despite a high positive margin rate. LA is a safe, feasible and cost-effective procedure for the management of benign and malignant adrenal masses.