A New Method for Inducing a Depression-Like Behavior in Rats.
Contagious depression is a phenomenon that is yet to be fully recognized and this stems from insufficient material on the subject. At the moment, there is no existing format for studying the mechanism of action, prevention, containment, and treatment of contagious depression. The purpose of this study, therefore, was to establish the first animal model of contagious depression. Healthy rats can contract depressive behaviors if exposed to depressed rats. Depression is induced in rats by subjecting them to several manipulations of chronic unpredictable stress (CUS) over 5 weeks, as described in the protocol. A successful sucrose preference test confirmed the development of depression in the rats. The CUS-exposed rats were then caged with naïve rats from the contagion group (1 naïve rat/2 depressed rats in a cage) for an additional 5 weeks. 30 social groups were created from the combination of CUS-exposed rats and naïve rats. This proposed depression-contagion protocol in animals consists mainly of cohabiting CUS-exposed and healthy rats for 5 weeks. To ensure that this method works, a series of tests are carried out - first, the sucrose preference test upon inducing depression to rats, then, the sucrose preference test, alongside the open field and forced-swim tests at the end of the cohabitation period. Throughout the experiment, rats are given tags and are always returned to their cages after each test. A few limitations to this method are the weak differences recorded between the experimental and control groups in the sucrose preference test and the irreversible traumatic outcome of the forced swim test. These may be worth considering for suitability before any future application of the protocol. Nonetheless, following the experiment, naïve rats developed contagion depression after 5 weeks of sharing the same cage with the CUS-exposed rats.


In Vivo Hemin Conditioning Targets the Vascular and Immunologic Compartments and Restrains Prostate Tumor Development.
Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study, we assessed how hemin, a pharmacologic inducer of heme oxygenase-1 (HO-1), has an impact on prostate cancer development in an in vivo conditioning model.Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinical insight, we used prostate cancer patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes.Results: Conditioning resulted in increased tumor latency and decreased initial growth rate. Histologic analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated human umbilical vein endothelial cells (HUVEC) exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1-conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neovascularization in an in vivo Matrigel plug assay. In addition, hemin boosted CD8+ T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo A significant systemic increase in CD8+ T-cell frequency was observed in preconditioned tumor-bearing mice. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment. We also found a subset of prostate cancer patient-derived xenografts and prostate cancer patient samples with mild HO-1 and low Gal-1 expression levels.Conclusions: These results highlight a novel function of a human-used drug as a means of boosting the antitumor response. Clin Cancer Res; 23(17); 5135-48. ©2017 AACR.


Variation in simian immunodeficiency virus env is confined to V1 and V4 during progression to simian AIDS.
We have monitored changes in the simian immunodeficiency virus (SIV) envelope (env) gene in two macaques which developed AIDS after inoculation with a molecular clone of SIV. As the animals progressed to AIDS, selection occurred for viruses with variation in two discrete regions (V1 and V4) but not for viruses with changes in the region of SIV env that corresponds to the immunodominant, V3 loop of human immunodeficiency virus. Within the highly variable domains, the vast majority of nucleotide changes encoded an amino acid change (98%), suggesting that these envelope variants had evolved as a result of phenotypic selection. Analysis of the biological properties of these variants, which have been selected for in the host, may be useful in defining the mechanisms underlying viral persistence and progression to simian AIDS.


Differences in outcome between twins and singletons born very preterm: results from a population-based European cohort.
About 10% of twins are born before 32 weeks of gestation and very preterm birth rates are increasing. Preterm twins tend to have more favourable outcomes than singletons of the same gestational age, but fewer data are available for very preterm infants. This study aims to determine whether outcomes differ between very preterm twins and singletons. This study was of a population-based cohort of very preterm babies in 10 European regions in 2003. Mortality and morbidity to discharge from hospital were compared for twins and singletons between 24 and 31 weeks of gestation, who were alive at the onset of labour and without lethal congenital anomalies. Clinical characteristics, pregnancy complications and healthcare factors were taken into consideration. Between 28 and 31 weeks of gestation, mortality and oxygen dependency at 36 corrected weeks of gestation were lower for twins than singletons (3.9 versus 6.5% and 7.1 versus 10.4%, respectively), but this advantage disappeared after controlling for medical and healthcare factors. Hypertension, growth restriction and haemorrhaging were less frequent complications of twin birth and more twins received antenatal corticosteroids and were born in level III units. In contrast, between 24 and 27 weeks of gestation, twins had higher adjusted risks of mortality and Grade III/IV intraventricular haemorrhaging [adjusted ORs 1.5 (95% CI 1.1-2.2) and 1.5 (1.0-2.1)]. These adverse outcomes were concentrated among twins from same sex pairs with discordant birthweights. Between 24 and 27 weeks of gestation, risks of mortality and severe cranial haemorrhaging were higher for twins than singletons if they were from same sex pairs with discordant birthweights.


Machine learning for reparameterization of four-site water models: TIP4P-BG and TIP4P-BGT.
Parameterizing an effective water model is a challenging issue because of the difficulty in maintaining a comprehensive balance among the diverse physical properties of water with a limited number of parameters. The advancement in machine learning provides a promising path to search for a reliable set of parameters. Based on the TIP4P water model, hence, about 6000 molecular dynamics (MD) simulations for pure water at 1 atm and in the range of 273-373 K are conducted here as the training data. The back-propagation (BP) neural network is then utilized to construct an efficient mapping between the model parameters and four crucial physical properties of water, including the density, vaporization enthalpy, self-diffusion coefficient and viscosity. Without additional time-consuming MD simulations, this mapping operation could result in sufficient and accurate data for high-population genetic algorithm (GA) to optimize the model parameters as much as possible. Based on the proposed parameterizing strategy, TIP4P-BG (a conventional four-site water model) and TIP4P-BGT (an advanced model with temperature-dependent parameters) are established. Both the water models exhibit excellent performance with a reasonable balance among the four crucial physical properties. The relevant mean absolute percentage errors are 3.53% and 3.08%, respectively. Further calculations on the temperature of maximum density, isothermal compressibility, thermal expansion coefficient, radial distribution function and surface tension are also performed and the resulting values are in good agreement with the experimental values. Through this water modeling example, the potential of the proposed data-driven machine learning procedure has been demonstrated for parameterizing a MD-based material model.


Capilliposide C Sensitizes Esophageal Squamous Carcinoma Cells to Oxaliplatin by Inducing Apoptosis Through the PI3K/Akt/mTOR Pathway.
BACKGROUND Although platinum-based chemotherapy is the most effective strategy for esophageal cancer, toxicity and drug resistance limit the dose administration and the application of chemotherapy. Capilliposide C (CPS-C) is isolated from the Chinese herb Lysimachia capillipes Hemsl and is approved to be effective against carcinomas. However, the activity of CPS-C against esophageal cancer remains unclear. The present study was conducted to assess the chemosensitizing effects of CPS-C for enhancing the therapeutic efficacy of oxaliplatin in esophageal squamous carcinoma cells and explore the underlying mechanism. MATERIAL AND METHODS Human esophageal squamous cell carcinoma (ESCC) TE-1 and TE-2 were used. Several in vitro and in vivo analyses were carried out, including MTT, Annexin V/PI, Western blot, and TUNEL and immunohistochemistry in a xenograft model. RESULTS CPS-C significantly enhanced the proliferative inhibition and apoptotic effect of oxaliplatin in ESCC cells. Oxaliplatin combined with CPS-C decreased the expressions of PI3K, phospho-Akt, phospho-mTOR, Bcl-2, and Bcl-XL, and increased the expression of Bax and caspase-3 significantly compared to oxaliplatin-only treatment. Furthermore, in the ESCC xenograft model, CPS-C significantly enhanced the anti-cancer effects and apoptosis of oxaliplatin. CONCLUSIONS The results indicated that CPS-C enhanced the anti-proliferative and apoptotic effect of oxaliplatin by modulating the PI3K/Akt/mTOR pathway on ESCC in vitro and in vivo.


Risk of resource failure and toolkit variation in small-scale farmers and herders.
Recent work suggests that global variation in toolkit structure among hunter-gatherers is driven by risk of resource failure such that as risk of resource failure increases, toolkits become more diverse and complex. Here we report a study in which we investigated whether the toolkits of small-scale farmers and herders are influenced by risk of resource failure in the same way. In the study, we applied simple linear and multiple regression analysis to data from 45 small-scale food-producing groups to test the risk hypothesis. Our results were not consistent with the hypothesis; none of the risk variables we examined had a significant impact on toolkit diversity or on toolkit complexity. It appears, therefore, that the drivers of toolkit structure differ between hunter-gatherers and small-scale food-producers.


Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain.
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential of targeted therapies that protect the developing brain in the treatment of NEC in early childhood.


A decision support system to determine optimal ventilator settings.
Choosing the correct ventilator settings for the treatment of patients with respiratory tract disease is quite an important issue. Since the task of specifying the parameters of ventilation equipment is entirely carried out by a physician, physician's knowledge and experience in the selection of these settings has a direct effect on the accuracy of his/her decisions. Nowadays, decision support systems have been used for these kinds of operations to eliminate errors. Our goal is to minimize errors in ventilation therapy and prevent deaths caused by incorrect configuration of ventilation devices. The proposed system is designed to assist less experienced physicians working in the facilities without having lung mechanics like cottage hospitals. This article describes a decision support system proposing the ventilator settings required to be applied in the treatment according to the patients' physiological information. The proposed model has been designed to minimize the possibility of making a mistake and to encourage more efficient use of time in support of the decision making process while the physicians make critical decisions about the patient. Artificial Neural Network (ANN) is implemented in order to calculate frequency, tidal volume, FiO2 outputs, and this classification model has been used for estimation of pressure support / volume support outputs. For the obtainment of the highest performance in both models, different configurations have been tried. Various tests have been realized for training methods, and a number of hidden layers mostly affect factors regarding the performance of ANNs. The physiological information of 158 respiratory patients over the age of 60 and were treated in three different hospitals between the years 2010 and 2012 has been used in the training and testing of the system. The diagnosed disease, core body temperature, pulse, arterial systolic pressure, diastolic blood pressure, PEEP, PSO2, pH, pCO2, bicarbonate data as well as the frequency, tidal volume, FiO2, and pressure support / volume support values suitable for use in the ventilator device have been recommended to the physicians with an accuracy of 98,44%. Performed experiments show that sequential order weight/bias training was found to be the most ideal ANN learning algorithm for regression model and Bayesian regulation backpropagation was found to be the most ideal ANN learning algorithm for classification models. This article aims at making independent of the choice of parameters from physicians in the ventilator treatment of respiratory tract patients with proposed decision support system. The rate of accuracy in prediction of systems increases with the use of data of more patients in training. Therefore, non-physician operators can use systems in determination of ventilator settings in case of emergencies.


Effect of Antihypertensive Medication Reduction vs Usual Care on Short-term Blood Pressure Control in Patients With Hypertension Aged 80 Years and Older: The OPTIMISE Randomized Clinical Trial.
Deprescribing of antihypertensive medications is recommended for some older patients with polypharmacy and multimorbidity when the benefits of continued treatment may not outweigh the harms. This study aimed to establish whether antihypertensive medication reduction is possible without significant changes in systolic blood pressure control or adverse events during 12-week follow-up. The Optimising Treatment for Mild Systolic Hypertension in the Elderly (OPTIMISE) study was a randomized, unblinded, noninferiority trial conducted in 69 primary care sites in England. Participants, whose primary care physician considered them appropriate for medication reduction, were aged 80 years and older, had systolic blood pressure lower than 150 mm Hg, and were receiving at least 2 antihypertensive medications were included. Participants enrolled between April 2017 and September 2018 and underwent follow-up until January 2019. Participants were randomized (1:1 ratio) to a strategy of antihypertensive medication reduction (removal of 1 drug [intervention], n = 282) or usual care (control, n = 287), in which no medication changes were mandated. The primary outcome was systolic blood pressure lower than 150 mm Hg at 12-week follow-up. The prespecified noninferiority margin was a relative risk (RR) of 0.90. Secondary outcomes included the proportion of participants maintaining medication reduction and differences in blood pressure, frailty, quality of life, adverse effects, and serious adverse events. Among 569 patients randomized (mean age, 84.8 years; 276 [48.5%] women; median of 2 antihypertensive medications prescribed at baseline), 534 (93.8%) completed the trial. Overall, 229 (86.4%) patients in the intervention group and 236 (87.7%) patients in the control group had a systolic blood pressure lower than 150 mm Hg at 12 weeks (adjusted RR, 0.98 [97.5% 1-sided CI, 0.92 to ∞]). Of 7 prespecified secondary end points, 5 showed no significant difference. Medication reduction was sustained in 187 (66.3%) participants at 12 weeks. Mean change in systolic blood pressure was 3.4 mm Hg (95% CI, 1.1 to 5.8 mm Hg) higher in the intervention group compared with the control group. Twelve (4.3%) participants in the intervention group and 7 (2.4%) in the control group reported at least 1 serious adverse event (adjusted RR, 1.72 [95% CI, 0.7 to 4.3]). Among older patients treated with multiple antihypertensive medications, a strategy of medication reduction, compared with usual care, was noninferior with regard to systolic blood pressure control at 12 weeks. The findings suggest antihypertensive medication reduction in some older patients with hypertension is not associated with substantial change in blood pressure control, although further research is needed to understand long-term clinical outcomes. EudraCT Identifier: 2016-004236-38; ISRCTN identifier: 97503221.


Ultrasound-guided subclavian venous catheterisation - is this the way forward? A narrative review.
Central venous catheterisation is a commonly performed procedure in anaesthesia, critical care, acute and emergency medicine. Traditionally, subclavian venous catheterisation has been performed using the landmark technique and because of the complications associated with this technique, it is not commonly performed in the United Kingdom - where the accepted practice is ultrasound-guided internal jugular vein catheterisation. Subclavian vein catheterisation offers particular advantages over the internal jugular and femoral vein sites such as reduced rates of line-related sepsis, improved patient comfort and swifter access in trauma situations where the internal jugular vein may not be easily accessible. There is a growing body of evidence to suggest a potential emerging role for ultrasound-guided subclavian vein catheterisation. Barriers to this approach include many physicians still believing that the clavicle obscures imaging of the vein. In this article, we review the evidence supporting ultrasound-guided subclavian vein catheterisation and ask the question whether, in view of it potential advantages, it could be the way forward?


Characterisation and selection of a Lactobacillus species to re-colonise the vagina of women with recurrent bacterial vaginosis.
This paper reports the results of characterising and selecting a strain of Lactobacillus for potential use as a probiotic in regenerating the vaginal flora of women with recurrent episodes of bacterial vaginosis (BV). BV is a condition characterised by a depletion of vaginal lactobacilli accompanied by an overgrowth of a mixed vaginal flora of aerobic, anaerobic and micro-aerophilic species in very large numbers. BV has been associated with various gynaecological and obstetric complications and has an extremely high recurrence rate, due in part to the failure to establish a normal vaginal flora after antimicrobial therapy. A total of 60 vaginal isolates of lactobacilli was assessed for characteristics considered important for vaginal re-colonisation. The characteristics studied were the in-vitro inhibitory activity of the lactobacilli against bacterial species isolated from women with recurrent BV, acid production after growth of the lactobacilli in liquid culture, production of hydrogen peroxide (H2O2) and adhesiveness of the lactobacilli to exfoliated vaginal epithelial cells (VEC). Four strains of lactobacilli, L. acidophilus (61701 and 61880), L. crispatus (55730) and L. delbrueckii subsp. delbrueckii (65407), demonstrated the greatest inhibitory activity against the BV-associated bacterial species. Two of these isolates (55730 and 61880) produced H2O2. All four isolates produced a highly acidic environment after growth in liquid medium (pH <4). Only one of these (strain 61701) was strongly adherent to VEC (>100 bacteria/VEC). A further isolate (L. acidophilus 48101) did not demonstrate maximum inhibitory activity against BV-associated bacteria, but was found to be a strong producer of H2O2 and was also highly adherent to VEC. Isolates 61701 and 48101 could be candidates for use as probiotics for vaginal re-colonisation.


Hepatocellular dysplastic nodules.
The multistep process of hepatic carcinogenesis is mirrored by the morphologic classification of lesions detectable in cirrhosis, that include large regenerative nodules (LRN), low grade dysplastic nodules (LGDN) and high grade dysplastic nodules (HGDN). The latter belong to the "bordeline malignancy" cathegory requiring an accurate distinction from well-differentiated and early hepatocellular carcinoma. Nodules in cirrhosis are usually detected by non-invasive imaging techniques, being the latter unable to discriminate malignant from non-malignant forms, particularly in the 1-2 cm sized group. Liver biopsy is essential in providing practical diagnostic information to hepathologists in the management of cirrhotic patients with US detectable nodules. The histologic diagnosis on liver samples is based on the accurate search of a set of cyto-architectural features (cell atypia, cell crowding, trabecular thickness, microacini etc) and by a supplement of histochemical (Gomori staining) and immunocytochemical stainings. The latter rely upon the search of both well established and novel markers, targeted to evaluate stromal invasion (CK7/19), the vascular pattern (ASMA and CD34) or tumor markers (HSP70 and Glipican 3 among others). Still, the diagnostic sensitivity is limited by the type and size of sampling and by its representativity of the entire lesion. The best diagnostic approach thus requires the integration of clinical, morphological and immunocytochemical information with imaging data (US pattern, perfusional pattern, helical CT/MR pattern). Molecular data are still under evaluation as to their diagnostic efficacy in this controversial field. Discrepancies have emerged recently between Eastern and Western interpretation of these lesions, particularly in the cathegory of "borderline" nodules, that are mostly labelled as early, well differentiated HCC by eastern pathologists and as HGDN by western pathologists. Novel and more objective phenotypical and molecular markers are needed to discriminate within the grey area of borderline lesions that, epidemiologically, are likely distinct between eastern and western geographic areas. These tools might allow a better understanding of the boundaries of the process going from high grade dysplasia to in situ HCC and from the latter to microinvasive HCC and advanced HCC, for a proper clinical management and optimal therapy.


Electrode Mass Balancing as an Inexpensive and Simple Method to Increase the Capacitance of Electric Double-Layer Capacitors.
Symmetric electric double-layer capacitors (EDLCs) have equal masses of the same active material in both electrodes. However, having equal electrode masses may prevent the EDLC to have the largest possible specific capacitance if the sizes of the hydrated anions and cations in the electrolyte differ because the electrodes and the electrolyte may not be completely utilized. Here we demonstrate how this issue can be resolved by mass balancing. If the electrode masses are adjusted according to the size of the ions, one can easily increase an EDLC's specific capacitance. To that end, we performed galvanostatic cycling to measure the capacitances of symmetric EDLCs with different electrode mass ratios using four aqueous electrolytes- Na2SO4, H2SO4, NaOH, and KOH (all with a concentration of 1 M)-and compared these to the theoretical optimal electrode mass ratio that we calculated using the sizes of the hydrated ions. Both the theoretical and experimental values revealed lower-than-1 optimal electrode ratios for all electrolytes except KOH. The largest increase in capacitance was obtained for EDLCs with NaOH as electrolyte. Specifically, we demonstrate an increase of the specific capacitance by 8.6% by adjusting the electrode mass ratio from 1 to 0.86. Our findings demonstrate that electrode mass balancing is a simple and inexpensive method to increase the capacitance of EDLCs. Furthermore, our results imply that one can reduce the amount of unused material in EDLCs and thus decrease their weight, volume and cost.


Tumor cells in blood shed from the surgical field.
To analyze blood shed from the surgical field during oncologic surgery for tumor cells and to assess functional characteristics of these cells. Series of 61 patients with cancer who underwent surgery for an abdominal, orthopedic, urological, gynecological, or head and neck malignant tumor, and blinded comparison with 15 patients with benign diseases undergoing surgery. A 500-bed tumor center and a tertiary care hospital. Tumor cells were isolated from intraoperatively salvaged and washed blood by density gradient centrifugation. They were identified in cytospin specimens by their content of cytokeratins and nucleolar organizer regions with a sensitivity of 10 cells in 500 mL of blood. Clonogenicity was tested in a cell colony assay; invasiveness, in Boyden chambers; and tumorigenicity, in nude mice. In 57 of 61 patients, tumor cells were detected in the blood shed during oncologic surgery. They demonstrated proliferation capacity, invasiveness, and tumorigenicity. The total number of tumor cells identified ranged from 1 x 10(1) to 7 x 10(6), with no close correlation to the amount of blood loss. Circulating tumor cells were demonstrated in only 26% of these patients and in small numbers. Malignant cells identified regularly in the blood shed during tumor surgery and different from circulating tumor cells are of concern, since at the surgical site they may cause local tumor recurrence, or in the salvaged blood they may cause hematogenic metastasis after retransfusion. Therefore, the contraindication of intraoperative autotransfusion in tumor surgery is strongly supported, and a review of surgical procedures and adjuvant therapy may be indicated, as the passage of the identified cells to the shed blood is yet unknown.


Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.
In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.


Multiple signalling pathways trigger the exquisite sensitivity of yeast gluconeogenic mRNAs to glucose.
The transcription of the yeast FBP1 and PCK1 genes, which encode the gluconeogenic enzymes fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase, is repressed by glucose. Here, we show that this repression is both very strong and exceptionally sensitive to glucose, being triggered by glucose at concentrations less than 0.005% (0.27 mM). This repression remains operative in yeast mutants carrying any one of the three hexose kinases, but is lost in a triple hxk1, hxk2, glk1 mutant. In addition, 2-deoxyglucose can trigger the repression, but 6-deoxyglucose cannot, suggesting that internalization and phosphorylation of the glucose is essential for repression to occur. While gluconeogenic gene transcription is subject to the Mig 1p-dependent pathway of glucose repression, the exquisite response to glucose is maintained in hxk2 and mig1 mutants, suggesting that this pathway is not essential for the response. The response can also be triggered by the addition of exogenous cAMP, suggesting that the Ras/cAMP pathway can mediate repression of the FPB1 and PCK1 mRNAs. However, the response is not dependent upon this pathway because it remains intact in Ras, adenyl cyclase and protein kinase A mutants. The data show that yeast cells can detect very low glucose concentrations in the environment, and suggest that several distinct signalling pathways operate to repress FPB1 and PCK1 transcription in the presence of glucose.


Population mutation scanning of human GHR by meltMADGE and identification of a paucimorphic variant.
Current studies of human genetic diversity are focused in two areas: first, detection of rare mutations in highly selected clinical cases; and second, in common single-nucleotide polymorphism (SNP) and haplotype effects in the general population. Less frequent SNPs and "paucimorphisms" remain underexplored, although lower frequency coding SNPs are more likely to have functional impact. We have developed a cost-efficient mutation scanning technology, meltMADGE, for population mutation scanning. Previous research in GHR has explored its role in extreme (-3 SD) growth retardation and, subsequently, "moderate" (-2 SD) growth retardation cases. Here, we describe meltMADGE assays for the entire coding region of GHR. As a first step we have established long polymerase chain reaction subbanks for GHR from 2423 unselected subjects and have applied meltMADGE scanning assays of exons 4 and 5 to these subbanks. A novel paucimorphism present at 439+30A>C (allele frequency: 0.0021) in intron 5 (location chr5:42,695,221 in GRCh37/hg19) was identified in 10 individuals, confirmed by sequencing and analysis made for major phenotypic effects. This approach is relevant to the deep sampling of populations for less frequent sequence diversity, some of which is expected to exert significant phenotypic effects.


Multi-class motion-based semantic segmentation for ureteroscopy and laser lithotripsy.
Ureteroscopy with laser lithotripsy has evolved as the most commonly used technique for the treatment of kidney stones. Automated segmentation of kidney stones and the laser fiber is an essential initial step to performing any automated quantitative analysis, particularly stone-size estimation, that can be used by the surgeon to decide if the stone requires further fragmentation. However, factors such as turbid fluid inside the cavity, specularities, motion blur due to kidney movements and camera motion, bleeding, and stone debris impact the quality of vision within the kidney, leading to extended operative times. To the best of our knowledge, this is the first attempt made towards multi-class segmentation in ureteroscopy and laser lithotripsy data. We propose an end-to-end convolution neural network (CNN) based learning framework for the segmentation of stones and laser fiber. The proposed approach utilizes two sub-networks: (I) HybResUNet, a hybrid version of residual U-Net, that uses residual connections in the encoder path of the U-Net to improve semantic predictions, and (II) a DVFNet that generates deformation vector field (DVF) predictions by leveraging motion differences between the adjacent video frames which is then used to prune the prediction maps. We also present ablation studies that combine different dilated convolutions, recurrent and residual connections, atrous spatial pyramid pooling, and attention gate models. Further, we propose a compound loss function that significantly boosts the segmentation performance in our data. We have also provided an ablation study to determine the optimal data augmentation strategy for our dataset. Our qualitative and quantitative results illustrate that our proposed method outperforms state-of-the-art methods such as UNet and DeepLabv3+ showing a DSC improvement of 4.15% and 13.34%, respectively, in our in vivo test dataset. We further show that our proposed model outperforms state-of-the-art methods on an unseen out-of-sample clinical dataset with a DSC improvement of 9.61%, 11%, and 5.24% over UNet, HybResUNet, and DeepLabv3+, respectively in the case of the stone class and an improvement of 31.79%, 22.15%, and 10.42% over UNet, HybResUNet, and DeepLabv3+, respectively, in case of the laser class.


Research on symptoms versus research on syndromes. Arguments in favour of allocating more research time to the study of symptoms.
Research on symptoms may often be more fruitful than research on syndromes because: (a) the validities of psychiatric diagnoses remain questionable; (b) interview assessments of a large number of symptoms are inadequate; (c) the diagnostic approach results in problems of misclassification and confounding; (d) the dimensional/categorical issue may be more readily resolved with research using a symptom approach; (e) useful animal models of symptoms are more likely to be developed than useful animal models of syndromes; and (f) symptoms may be better phenotypes than syndromes in genetic research.


Spatial Restriction of Neural Activation Using Focused Multipolar Stimulation With a Retinal Prosthesis.
The resolution provided by present state-of-the-art retinal prostheses is severely limiting for recipients, partly due to the broad spread of activation in the retina in response to monopolar (MP) electrical stimulation. Focused multipolar (FMP) stimulation has been shown to restrict neural activation in the cochlea compared to MP stimulation. We extended the FMP stimulation technique to a two-dimensional electrode array and compared its efficacy to MP and hexapolar (HP) stimulation in the retina. Normally-sighted cats (n = 6) were implanted with a suprachoroidal electrode array containing 42 electrodes. Multichannel multiunit spiking activity was recorded from the visual cortex in response to MP, HP, and FMP retinal stimulation. When inferring retinal spread using voltage recordings off the stimulating array, FMP stimulation showed significantly reduced voltages in regions surrounding the primary stimulating electrode. When measuring the retinal and cortical selectivity of neural responses, FMP and HP stimulation showed significantly higher selectivity compared to MP stimulation (separate 2-way ANOVAs, P < 0.05). However, the lowest cortical thresholds for each stimulating electrode were higher for FMP and HP compared to MP stimulation (1-way ANOVA, P < 0.001). No significant differences were observed between FMP and HP stimulation in any measures. Focused multipolar and HP stimulation using a two-dimensional array are promising techniques to reduce the spread of activation for a retinal prosthesis. Clinical application would be expected to result in smaller phosphenes; thus, reducing phosphene overlap between electrodes and increasing the resolution at the expense of higher thresholds for activation.


Spatiotemporal Distribution and Evolution of the A/H1N1 2009 Pandemic Influenza Virus in Pigs in France from 2009 to 2017: Identification of a Potential Swine-Specific Lineage.
The H1N1 influenza virus responsible for the most recent pandemic in 2009 (H1N1pdm) has spread to swine populations worldwide while it replaced the previous seasonal H1N1 virus in humans. In France, surveillance of swine influenza A viruses in pig herds with respiratory outbreaks led to the detection of 44 H1N1pdm strains between 2009 and 2017, regardless of the season, and findings were not correlated with pig density. From these isolates, 17 whole-genome sequences were obtained, as were 6 additional hemagglutinin (HA)/neuraminidase (NA) sequences, in order to perform spatial and temporal analyses of genetic diversity and to compare evolutionary patterns of H1N1pdm in pigs to patterns for human strains. Following mutation accumulation and fixation over time, phylogenetic analyses revealed for the first time the divergence of a swine-specific genogroup within the H1N1pdm lineage. The divergence is thought to have occurred around 2011, although this was demonstrated only through strains isolated in 2015 to 2016 in the southern half of France. To date, these H1N1pdm swine strains have not been related to any increased virulence in swine herds and have not exhibited any antigenic drift compared to seasonal human strains. However, further monitoring is encouraged, as diverging evolutionary patterns in these two species, i.e., swine and humans, may lead to the emergence of viruses with a potentially higher risk to both animal and human health.IMPORTANCE Pigs are a "mixing vessel" for influenza A viruses (IAVs) because of their ability to be infected by avian and human IAVs and their propensity to facilitate viral genomic reassortment events. Also, as IAVs may evolve differently in swine and humans, pigs can become a reservoir for old human strains against which the human population has become immunologically naive. Thus, viruses from the novel swine-specific H1N1pdm genogroup may continue to diverge from seasonal H1N1pdm strains and/or from other H1N1pdm viruses infecting pigs and lead to the emergence of viruses that would not be covered by human vaccines and/or swine vaccines based on antigens closely related to the original H1N1pdm virus. This discovery confirms the importance of encouraging swine IAV monitoring because H1N1pdm swine viruses could carry an increased risk to both human and swine health in the future as a whole H1N1pdm virus or gene provider in subsequent reassortant viruses.


Mixed versus Focused Resistance Training during an Australian Football Pre-Season.
The purpose of this investigation was to determine the effect of a focused versus mixed-methods strength-power training plan on athletes undertaking high volumes of concurrent training. Fourteen junior elite male Australian football players were randomly assigned into either the focused or mixed group. Both training groups undertook a sequenced training intervention consisting of a four-week mesocycle emphasising heavy strength followed by a four-week mesocycle of high velocity emphasis. Training differed between groups by way of the degree of emphasis placed on the targeted attribute in each cycle and occurred during the preseason. Testing occurred pre- and post-training and consisted of the unloaded and loaded (+20 kg) countermovement jump (CMJ). Focused training elicited practical (non-trivial) improvements in flight time to contraction ratio (FT:CT) (g = 0.45, ±90% confidence interval 0.49) underpinned by a small reduction in contraction time (g = -0.46, ±0.45) and a small increase in braking (g = 0.36, ±0.42) and concentric phase mean force (g = 0.22, ±0.39). Conversely, the mixed group demonstrated an unchanged FT:CT (g = -0.13, ±0.56). Similar respective changes occurred in the loaded condition. Preferential improvements in FT:CT occur when a greater focus is placed on a targeted physical quality in a sequenced training plan of junior elite Australian football players during preseason training.


A hierarchical Bayesian approach for combining pharmacokinetic/pharmacodynamic modeling and Phase IIa trial design in orphan drugs: Treating adrenoleukodystrophy with Lorenzo's oil.
X-linked adrenoleukodystrophy (X-ALD) is a rare, progressive, and typically fatal neurodegenerative disease. Lorenzo's oil (LO) is one of the few X-ALD treatments available, but little has been done to establish its clinical efficacy or indications for its use. In this article, we analyze data on 116 male asymptomatic pediatric patients who were administered LO. We offer a hierarchical Bayesian statistical approach to understand LO pharmacokinetics (PK) and pharmacodynamics (PD) resulting from an accumulation of very long-chain fatty acids. We experiment with individual- and observational-level errors and various choices of prior distributions and deal with the limitation of having just one observation per administration of the drug, as opposed to the more usual multiple observations per administration. We link LO dose to the plasma erucic acid concentrations by PK modeling, and then link this concentration to a biomarker (C26, a very long-chain fatty acid) by PD modeling. Next, we design a Bayesian Phase IIa study to estimate precisely what improvements in the biomarker can arise from various LO doses while simultaneously modeling a binary toxicity endpoint. Our Bayesian adaptive algorithm emerges as reasonably robust and efficient while still retaining good classical (frequentist) operating characteristics. Future work looks toward using the results of this trial to design a Phase III study linking LO dose to actual improvements in health status, as measured by the appearance of brain lesions observed via magnetic resonance imaging.


Effect of lymphatic and splenic pump techniques on the antibody response to hepatitis B vaccine: a pilot study.
Osteopathic manipulative treatment (OMT) facilitates the movement of lymphatic fluid and may enhance the immunologic response to infection or injected antigen. In this investigation, two groups of volunteers were vaccinated with recombinant hepatitis B vaccine, given at 0, 5, and 25 weeks. The experimental group (n = 20) received OMT (lymphatic and splenic pump) three times per week for 2 weeks after each vaccination. Control subjects (n = 19) received vaccine but no OMT. Resultant serum antibody levels were measured by enzyme immunoassay. Fifty percent of subjects in the treatment group achieved protective antibody titers (> or = 10 mIU/mL) on the 13th week with an average titer of 374 mIU/mL. Only 16% of the control subjects had positive antibody responses, with average titers of 96 mIU/mL. At all time points from week 6 on, the average anti-hepatitis B titer was higher in the treatment group than in the control group. These data suggest an enhanced immunologic response in subjects who received OMT.


Non-pharmacological interventions for restless legs syndrome: a systematic review of randomised controlled trials.
Introduction: Restless legs syndrome (RLS) is a sensorimotor disorder characterised by an uncomfortable urge to move the legs. Management is primarily pharmacological. Effects for non-pharmacological, non-surgical options are published but lack systematic examination. Objectives: To synthesise results of non-pharmacological/non-surgical treatment compared to no-treatment controls or alternative treatment for RLS on any relevant outcome. Methods: Databases and reference lists of reviews were searched for randomised controlled trials (RCTs) comparing non-pharmacological treatment to alternative or no treatment controls for idiopathic RLS. Search results were independently screened for inclusion by two researchers; disagreements regarding eligibility were resolved with discussion. Outcomes were summarised, and pooled where possible in meta-analysis. Results: The search yielded 442 articles. Eleven trials met inclusion criteria. Repetitive transcranial magnetic stimulation, exercise, compression devices, counterstrain manipulation, infrared therapy, and standard acupuncture were significantly more effective for RLS severity than control conditions. Vibration pads, cryotherapy, and transcranial direct current stimulation were ineffective in reducing RLS severity. Vibration pads, cryotherapy, yoga, compression devices, and acupuncture significantly improved some sleep-related outcomes. Conclusions: Few studies were identified and quality of evidence was not high. Some non-pharmacological interventions may be beneficial for reducing RLS severity and enhancing sleep. Implications for Rehabilitation The current management of restless leg syndrome is primarily pharmacological, and medications can have unwanted side effects. Repetitive transcranial magnetic stimulation, exercise, compression devices, counterstrain manipulation, infrared therapy, and standard acupuncture may reduce restless leg syndrome severity. Vibration pads, cryotherapy, yoga, compression devices, and acupuncture may improve some sleep-related outcomes in restless leg syndrome. Non-pharmacological interventions for RLS may cause placebo effects and rehabilitation professionals should control for this possibility in future investigations.


Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture.
Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. Large-scale meta-analysis of genome-wide association data. 5 international, multicenter, population-based studies. Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.


Postoperative respiratory depression after hysterectomy.
To investigate if sex-specific physiologic characteristics could impact postoperative respiratory depression risks in women, we studied incidence and risk factors associated with postoperative respiratory depression in a gynecologic surgical cohort. Only hysterectomies performed under general anesthesia from 2012 to 2017 were included to minimize interprocedural variability. Respiratory depression was defined as episodes of apnea, hypopnea, hypoxemia, pain-sedation mismatch, unplanned positive airway pressure device application, or naloxone administration in the post-anesthesia care unit. Multivariable logistic regression was used to explore the association with clinical characteristics. From 1,974 hysterectomies, 253 had postoperative respiratory depression, yielding an incidence of 128 (95% confidence interval, 114-144) per 1,000 surgeries. Risk factors associated with respiratory depression were older age (odds ratio 1.22 [95% confidence interval 1.02-1.46] per decade increase, p = 0.03), lower body weight (0.77 [0.62-0.94] per 10 kg/m2, p = 0.01), and higher intraoperative opioid dose (1.05 [1.01-1.09] per 10 mg oral morphine equivalents, p = 0.01); while sugammadex use was associated with a reduced risk (0.48 [0.30-0.75], p = 0.002). Respiratory depression was not associated with increased hospital stay, postoperative complications, or mortality. Postoperative respiratory depression risk in women increased with age, lower weight, and higher intraoperative opioids and decreased with sugammadex use; however, it was not associated with postoperative pulmonary complications.


The impact of body armor on physical performance of law enforcement personnel: a systematic review.
The law enforcement officer profession requires performance of arduous occupational tasks while carrying an external load, consisting of, at minimum, a chest rig, a communication system, weaponry, handcuffs, personal protective equipment and a torch. The aim of this systematic review of the literature was to identify and critically appraise the methodological quality of published studies that have investigated the impacts of body armour on task performance and to synthesize and report key findings from these studies to inform law enforcement organizations. Several literature databases (Medline, CINAHL, SPORTDiscus, EMBAS) were searched using key search words and terms to identify appropriate studies. Studies meeting the inclusion criteria were critically evaluated using the Downs and Black protocol with inter-rater agreement determined by Cohen's Kappa. Sixteen articles were retained for evaluation with a mean Downs and Black score of 73.2 ± 6.8% (k = 0.841). Based on the research quality and findings across the included studies, this review determined that while effects of body armour on marksmanship and physiological responses have not yet been adequately ascertained, body armour does have significant physical performance and biomechanical impacts on the wearer, including: a) increased ratings of perceived exertion and increased time to complete functional tasks, b) decreased work capability (indicated by deterioration in fitness test scores), c) decreased balance and stability, and d) increased ground reaction forces. Given the physical performance and biomechanical impacts on the wearer, body armour should be carefully selected, with consideration of the physical fitness of the wearers and the degree to which the armour systems can be ergonomically optimized for the specific population in question.


[UDP-glucuronyltransferases in detoxification and activation metabolism of endogenous compounds and xenobiotics].
Glucuronidation is a crucial pathway of metabolism and excretion of endogenous compounds and xenobiotics. UDP-glucuronyltransferases, UGT, catalyse transformations of bilirubine, steroids and thyroid hormones, bile acids as well as exogenous compounds, including drugs, carcinogens, environmental pollutants and nutrient components. From therapeutic point of view, the participation of UGTs in drug metabolism is of particular significance. Polymorphism of UGT1A and UGT2B genes resulted in various susceptibility of substrates to conjugation with glucuronic acid. Deactivation of xenobiotics and the following excretion of hydrophilic conjugates is a common task of glucuronidation, which should lead to detoxification. However, a lot of glucuronides were known, which expressed the comparable or even higher reactivity than that of the native compound. There are, among others, acyl glucuronides of carboxylic acids, morphine 6-O-glucuronide or retinoid glucuronides. They are able to bind cellular macromolecules with low or high strength and, as a consequence, their toxicity is saved or even increased, respectively.


Ipsilateral Molar Clenching Induces Less Pain and Discomfort than Contralateral Molar Clenching in Patients with Unilateral Anterior Disc Displacement of the Temporomandibular Joint.
To assess the influence of clenching side and location (ie, tooth) on the bite force necessary to induce pain or discomfort in patients with unilateral anterior disc displacement (ADD) of the temporomandibular joint (TMJ). A total of 17 patients with unilateral ADD diagnosed clinically and with magnetic resonance imaging were included. A bite force meter was positioned at each of four experimental positions: the mandibular first premolars and first molars, bilaterally. Subjects were instructed to clench on the bite force meter until they felt pain or discomfort in the orofacial area and to report the location of the pain. Differences in pain location (ADD side versus contralateral side) and in the bite force thresholds for eliciting pain or discomfort were assessed by means of the paired t test and Wilcoxon signed-rank test. Only 18% of subjects (3 out of 17) reported pain in the TMJ with ADD during clenching at the ipsilateral molar, whereas 65% (11 out of 17) reported joint pain during clenching on the contralateral molar (P = .005). At the molars, the mean ± standard deviation bite force necessary to induce pain was 241.2 ± 135.5 N on the side with ADD and 160.9 ± 78.0 N on the contralateral side. The mean molar bite force necessary to induce pain on the side with ADD was significantly higher than that on the contralateral side (P = .002). Patients with unilateral ADD had fewer reports of TMJ pain and discomfort when they were molar clenching on the ipsilateral side compared to molar clenching on the contralateral side.


Immunological fate of Schwann cell-populated acellular basal lamina nerve allografts.
Acellular basal lamina allografts are known to exhibit reduced immunogenicity, but the extent of host axonal regeneration through such grafts is reduced in comparison to the cellular isografts. The present study was designed to determine both the ability of cultured Schwann cells to populate acellular allografts, and the effects of Schwann cells on immunogenicity and regenerative potential. Isogeneic and allogeneic Schwann cell-populated acellular allografts of 2.0 cm length were used to repair a surgically created gap in the host rat peroneal nerve. Transplanted nerves were analyzed at 1, 2, 4, and 8 weeks later to determine their fate and ability to support axonal regeneration. Acellular allografts cocultured with isogeneic Schwann cells survived and supported axonal regeneration through them. In contrast, acellular allografts cocultured with allogeneic Schwann cells underwent rejection and were unsuccessful. The results show that cultured Schwann cells continue to exhibit immunogenicity and are a critical factor in allograft survival. It is thus important to use host-matched (isogeneic or autologous) Schwann cells to populate acellular basal lamina grafts in order to enhance their axonal growth-supporting function.


Cognition and health in African American men.
Despite high rates of poor health outcomes, little attention has been focused on associations between prominent health factors and cognitive function in African American men, exclusively. The objective was to examine relationships between cardiovascular and pulmonary health, and cognitive function in African American men. Data from 257 men were pooled from two studies of African American aging. The mean age of participants was 58.15 and mean educational attainment was 11.78 years. Participants provided self-reported health and demographic information, completed cognitive measures, and had their blood pressure and peak expiratory flow assessed. After adjustment, significant relationships were found between average peak expiratory flow rate (APEFR) and cognitive performance measures. Results suggest that lung function is important to consider when examining cognitive function in African American men. Understanding the role of health in cognition and implications for quality of life in this population will be critical as life expectancies increase.


A comparison of patient clinical and social outcomes before and after the introduction of an extended-hours community mental health team.
The aim of this study was to assess the effectiveness of the addition of standard community treatment to a hospital-based service in a regional district of Australia. The study was a naturalistic investigation of a routine clinical service and utilized a longitudinal panel design. Two matched groups of seriously mentally ill patients were recruited,one before the addition of the community mental health team (CMHT)and one after. Each sample was followed up for one year using a semistructured questionnaire and instruments including the Brief Psychiatric Rating Scale, the Global Assessment Scale, the Life Skills Profile and the Rosenberg Self-Esteem Scale as well as hospital records. Patients in both groups showed similar patterns of improvements. Although the aims of the new service included reducing in-patient utilization and improving social functioning,there were few significant differences between the two groups. While the number of admissions and length of stay were lower in the post-CMHTsample most were admitted rather than treated in their homes by the CMHT. The study concludes that better outcomes might have been achieved if the aims of the CMHT had been limited to either crisis or rehabilitation interventions, but not both. More attention needs to be paid to the service context in which model programmes are introduced so that new developments can be more closely tailored to the realities of what is likely to be achievable.


Theoretical characterization of end-on and side-on peroxide coordination in ligated Cu2O2 models.
The relative energetics of mu-eta1:eta1 (trans end-on) and mu-eta2:eta2 (side-on) peroxo isomers of Cu2O2 fragments supported by 0, 2, 4, and 6 ammonia ligands have been computed with various density functional, coupled-cluster, and multiconfigurational protocols. There is substantial disagreement between the different levels for most cases, although completely renormalized coupled-cluster methods appear to offer the most reliable predictions. The significant biradical character of the end-on peroxo isomer proves problematic for the density functionals, while the demands on active space size and the need to account for interactions between different states in second-order perturbation theory prove challenging for the multireference treatments. In the latter case, it proved impossible to achieve any convincing convergence.


Comment on "Isomerization of the methoxy radical revisited: the impact of water dimers" by B. Bandyopadhyay et al., Phys. Chem. Chem. Phys., 2016, 18, 27728 and "Isomerization of methoxy radical in the troposphere: competition between acidic, neutral and basic catalysts" by P. Kumar, B. Bandyopadhyay et al., Phys. Chem. Chem. Phys., 2017, 19, 278.
In two recent papers Bandyopadhyay and co-workers studied how atmospheric trace gases catalyze the isomerization of methoxy radical (CH3O˙) to hydroxymethyl radical (˙CH2OH). Their second paper extensively discussed the altitude dependence of this catalyzed isomerization. Unfortunately, they did not compare their computed isomerization rates with the abundant kinetic data on the long-established fate of CH3O˙: reaction with O2. This Comment shows that the fastest rate they compute for catalyzed isomerization is over one million times slower than the O2 reaction at all altitudes considered in those papers. Furthermore, we argue that, even if the reaction CH3O˙ → ˙CH2OH were to occur, it would not have any atmospheric consequence. This is because the near-exclusive atmospheric fate of both ˙CH2OH and CH3O˙ is reaction with O2 to produce CH2[double bond, length as m-dash]O + HOO.


Effects of calcium antagonists in multidrug resistant primary human renal cell carcinomas.
Human renal cell carcinomas display a characteristically high degree of intrinsic chemoresistance to a multitude of chemotherapeutic agents. It was suggested previously, that P-170 glycoprotein contributes to this phenomenon in renal cell carcinoma indicated by elevated MDR-1 gene mRNA levels and by the expression of this specific resistance characteristic. The P-170-related efflux mechanism can be inactivated by certain calcium antagonists. P-170 was traced immunohistochemically using monoclonal antibody C 219. Concomitantly, we studied the enhancement of vinblastine cytotoxicity with 4 major classes of calcium-blocking agents in a microculture tetrazolium assay. Seven different calcium antagonists were selected: verapamil (VPM, racemic form), its R-stereoisomer (R-VPM), diltiazem, flunarizine, nifedipine, and its derivatives nimodipine and nitrendipine. Verapamil or R-verapamil causes a significant decrease of viable tumor cells as compared to vinblastine alone (P less than 0.001). Similar effects were found with diltiazem, nifedipine, and its derivatives reaching approximately 70% of the VPM/R-VPM activity. Flunarizine showed only minor enhancement of cytotoxicity. P-170 expression was demonstrated in 18 of 32 tumors, and a relation to chemoresistance was evident. None of the chemoresponders, but 18 of 25 (72%) of the highly resistant tumors, revealed this resistance factor. It was concluded that certain calcium antagonists in combination with chemotherapy may well offer therapeutic options in renal cell carcinoma as they apparently inactivate the underlying mechanism conferring resistance. The new stereoisomer R-VPM, in particular, may be used in clinical trials since it combines strong enhancement of vinblastine drug responsiveness with a 10-fold lower cardiovascular activity as compared to racemic VPM, thus allowing higher concentrations to be applied.


Effects of practicing tandem gait with and without vibrotactile biofeedback in subjects with unilateral vestibular loss.
Subjects with unilateral vestibular loss exhibit motor control impairments as shown by body and limb deviation during gait. Biofeedback devices have been shown to improve stance postural control, especially when sensory information is limited by environmental conditions or pathologies such as unilateral vestibular loss. However, the extent to which biofeedback could improve motor performance or learning while practicing a dynamic task such as narrow gait is still unknown. In this cross-over design study, 9 unilateral vestibular loss subjects practiced narrow gait with and without wearing a trunk-tilt, biofeedback device in 2 practice sessions. The biofeedback device informed the subjects of their medial-lateral angular tilt and tilt velocity during gait via vibration of the trunk. From motion analysis and tilt data, the performance of the subjects practicing tandem gait were compared over time with and without biofeedback. By practicing tandem gait, subjects reduced their trunk-tilt, center of mass displacement, medial-lateral feet distance, and frequency of stepping error. In both groups, use of tactile biofeedback consistently increased postural stability during tandem gait, beyond the effects of practice alone. However, one single session of practice with biofeedback did not result in conclusive short-term after-effects consistent with short-term retention of motor performance without this additional biofeedback. Results from this study support the hypothesis that tactile biofeedback acts similar to natural sensory feedback to improve dynamic motor performance but does not facilitate a recalibration of motor performance to improve function after short-term use.


SARS-CoV-2 Papain-Like Protease Potential Inhibitors-In Silico Quantitative Assessment.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC50 values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC50 values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs.


Differences in Explicit Stereotype Activation among Social Groups Based on the Stereotype Content Model: Behavioral and Electrophysiological Evidence in Chinese Sample.
The stereotype content model (SCM; Fiske, Cuddy, Glick and Xu, 2002) identifies four basic categories of stereotyped social groups: high warmth-high competence (HW-HC), high warmth-low competence (HW-LC), low warmth-high competence (LW-HC), and low warmth-low competence (LW-LC). However, many of these groups have not been directly examined in stereotype activation research. The purpose of the present research was to extend stereotype activation research to groups that more fully represent those identified under the SCM. Employing explicit sequential priming task, participants responded to prime-target stimulus pairs that were either congruent or incongruent with stereotypes of social groups from all four SCM quadrants in two studies in the current investigation. Study 1 was to determine the behavioral pattern of explicit stereotype activation among four quadrants (the sample included 60 Chinese undergraduate students, 51%-female). Study 2 further employed event-related brain potentials (ERPs) technique to track the time course and electrophysiological underpinnings of explicit stereotype activation (the sample included 22 right-handed Chinese undergraduate students, 76%-female). In Study 1, participants responded more quickly and accurately on stereotype congruent trials than incongruent trials for all social groups except LW-LC groups. This reverse priming effect on LW-LC social groups in RTs was also replicated in Study 2. ERPs findings further showed that incongruent targets elicited larger N400 amplitudes than congruent targets for all four SCM quadrants. Moreover, congruent targets elicited larger P2 than incongruent targets, but only found for the LW-LC social groups. In addition, congruent targets elicited larger amplitudes of late positive component than incongruent targets for the low warmth (LW-LC and LW-HC) groups. Together, these results highlight the unique processing that LW-LC groups receive throughout the cognitive stream, ultimately manifesting in distinctive behavioral responses. Unconscious activation of egalitarian goals, disgust, and distrust accounts are discussed.


Automated quality assessment of large digitised histology cohorts by artificial intelligence.
Research using whole slide images (WSIs) of histopathology slides has increased exponentially over recent years. Glass slides from retrospective cohorts, some with patient follow-up data are digitised for the development and validation of artificial intelligence (AI) tools. Such resources, therefore, become very important, with the need to ensure that their quality is of the standard necessary for downstream AI development. However, manual quality control of large cohorts of WSIs by visual assessment is unfeasible, and whilst quality control AI algorithms exist, these focus on bespoke aspects of image quality, e.g. focus, or use traditional machine-learning methods, which are unable to classify the range of potential image artefacts that should be considered. In this study, we have trained and validated a multi-task deep neural network to automate the process of quality control of a large retrospective cohort of prostate cases from which glass slides have been scanned several years after production, to determine both the usability of the images at the diagnostic level (considered in this study to be the minimal standard for research) and the common image artefacts present. Using a two-layer approach, quality overlays of WSIs were generated from a quality assessment (QA) undertaken at patch-level at [Formula: see text] magnification. From these quality overlays the slide-level quality scores were predicted and then compared to those generated by three specialist urological pathologists, with a Pearson correlation of 0.89 for overall 'usability' (at a diagnostic level), and 0.87 and 0.82 for focus and H&E staining quality scores respectively. To demonstrate its wider potential utility, we subsequently applied our QA pipeline to the TCGA prostate cancer cohort and to a colorectal cancer cohort, for comparison. Our model, designated as PathProfiler, indicates comparable predicted usability of images from the cohorts assessed (86-90% of WSIs predicted to be usable), and perhaps more significantly is able to predict WSIs that could benefit from an intervention such as re-scanning or re-staining for quality improvement. We have shown in this study that AI can be used to automate the process of quality control of large retrospective WSI cohorts to maximise their utility for research.


Geriatric trauma patients-are they receiving trauma center care?
The primary purpose of this study was to evaluate whether severely injured geriatric patients were as likely to be treated at designated trauma centers (TCs) within the statewide trauma system. The secondary objective was to compare the demographic and injury characteristics of severely injured older and young patients who received care in TCs with the characteristics of those patients cared for in non-TCs. The authors reviewed files for all acute injury discharges in Pennsylvania for 1997. Injury diagnoses were mapped to Abbreviated Injury Scale (AIS) scores using ICDMAP software; the Injury Severity Score (ISS) was computed. The frequency of hospital discharges for injury from TC and non-TC hospitals in both the older (E) (>/=65 years) and younger (Y) (<65 years) groups were computed, and compared using chi-square testing for significance. Logistic regression was performed to assess the influence of various factors. Severity of injury was controlled for with both ISS and Maximum AIS (MAIS). 107,358 patients were admitted to hospitals in the state because of injury; 8,980 had an ISS > 15; 5,855 were Y and 3,125 were E. Forty-seven percent of the Y patients received TC care compared with only 36.6% of the E patients (p < 0.001). Logistic regression analysis showed that age was a strongly negative predictor for TC care when injury severity was controlled. Seriously injured older patients were less likely to receive care in a trauma center than younger patients.


Microbial Communities in Sediments From Four Mildly Acidic Ephemeral Salt Lakes in the Yilgarn Craton (Australia) - Terrestrial Analogs to Ancient Mars.
The Yilgarn Craton in Australia has a large number of naturally occurring shallow ephemeral lakes underlain by a dendritic system of paleodrainage channels. Processes like evaporation, flooding, erosion, as well as inflow of saline, often acidic and ion-rich groundwater contribute to the (dynamic) nature of the lakes and the composition of the sediments. The region has previously been described as an analog environment for early Mars due to its geological and geophysical similarities. Here, we investigated sediment samples of four lake environments aimed at getting a fundamental understanding of the native microbial communities and the mineralogical and (bio)chemical composition of the sediments they are associated with. The dominant mineral phases in the sediments were quartz, feldspars and amphiboles, while halite and gypsum were the only evaporites detected. Element analysis revealed a rich and complex image, in which silicon, iron, and aluminum were the dominant ions, but relative high concentrations of trace elements such as strontium, chromium, zirconium, and barium were also found. The concentrations of organic carbon, nitrogen, and phosphorus were generally low. 16S amplicon sequencing on the Illumina platform showed the presence of diverse microbial communities in all four lake environments. We found that most of the communities were dominated by extremely halophilic Archaea of the Halobacteriaceae family. The dynamic nature of these lakes appears to influence the biological, biochemical, and geological components of the ecosystem to a large effect. Inter- and intra-lake variations in the distributions of microbial communities were significant, and could only to a minor degree be explained by underlying environmental conditions. The communities are likely significantly influenced by small scale local effects caused by variations in geological settings and dynamic interactions caused by aeolian transport and flooding and evaporation events.


The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis.
Tafenoquine is a newly licensed antimalarial drug for the radical cure of Plasmodium vivax malaria. The mechanism of action and optimal dosing are uncertain. We pooled individual data from 1102 patients and 72 healthy volunteers studied in the pre-registration trials. We show that tafenoquine dose is the primary determinant of efficacy. Under an Emax model, we estimate the currently recommended 300 mg dose in a 60 kg adult (5 mg/kg) results in 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5 mg/kg (i.e. 450 mg) would result in 90% reduction in the risk of P. vivax recurrence. After adjustment for dose, the tafenoquine terminal elimination half-life, and day 7 methaemoglobin concentration, but not the parent compound exposure, were also associated with recurrence. These results suggest that the production of oxidative metabolites is central to tafenoquine's hypnozoiticidal efficacy. Clinical trials of higher tafenoquine doses are needed to characterise their efficacy, safety and tolerability.


High-quality draft assemblies of mammalian genomes from massively parallel sequence data.
Massively parallel DNA sequencing technologies are revolutionizing genomics by making it possible to generate billions of relatively short (~100-base) sequence reads at very low cost. Whereas such data can be readily used for a wide range of biomedical applications, it has proven difficult to use them to generate high-quality de novo genome assemblies of large, repeat-rich vertebrate genomes. To date, the genome assemblies generated from such data have fallen far short of those obtained with the older (but much more expensive) capillary-based sequencing approach. Here, we report the development of an algorithm for genome assembly, ALLPATHS-LG, and its application to massively parallel DNA sequence data from the human and mouse genomes, generated on the Illumina platform. The resulting draft genome assemblies have good accuracy, short-range contiguity, long-range connectivity, and coverage of the genome. In particular, the base accuracy is high (≥99.95%) and the scaffold sizes (N50 size = 11.5 Mb for human and 7.2 Mb for mouse) approach those obtained with capillary-based sequencing. The combination of improved sequencing technology and improved computational methods should now make it possible to increase dramatically the de novo sequencing of large genomes. The ALLPATHS-LG program is available at http://www.broadinstitute.org/science/programs/genome-biology/crd.


Marked reduction in mortality in patients with severe traumatic brain injury.
In spite of evidence that use of the Brain Trauma Foundation Guidelines for the Management of Severe Traumatic Brain Injury (Guidelines) would dramatically reduce morbidity and mortality, adherence to these Guidelines remains variable across trauma centers. The authors analyzed 2-week mortality due to severe traumatic brain injury (TBI) from 2001 through 2009 in New York State and examined the trends in adherence to the Guidelines. The authors calculated trends in adherence to the Guidelines and age-adjusted 2-week mortality rates between January 1, 2001, and December 31, 2009. Univariate and multivariate logistic regression analyses were performed to evaluate the effect of time period on case-fatality. Intracranial pressure (ICP) monitor insertion was modeled in a 2-level hierarchical model using generalized linear mixed effects to allow for clustering by different centers. From 2001 to 2009, the case-fatality rate decreased from 22% to 13% (p < 0.0001), a change that remained significant after adjusting for factors that independently predict mortality (adjusted OR 0.52, 95% CI 0.39-0.70; p < 0.0001). Guidelines adherence increased, with the percentage of patients with ICP monitoring increasing from 56% to 75% (p < 0.0001). Adherence to cerebral perfusion pressure treatment thresholds increased from 15% to 48% (p < 0.0001). The proportion of patients having an ICP elevation greater than 25 mm Hg dropped from 42% to 29% (p = 0.0001). There was a significant reduction in TBI mortality between 2001 and 2009 in New York State. Increase in Guidelines adherence occurred at the same time as the pronounced decrease in 2-week mortality and decreased rate of intracranial hypertension, suggesting a causal relationship between Guidelines adherence and improved outcomes. Our findings warrant future investigation to identify methods for increasing and sustaining adherence to evidence-based Guidelines recommendations.


Corner cutting compromises clinical trials: the inherent problems with up-front randomisation and a common standard arm.
To minimise bias, clinical trials must be randomised, and all patients analysed by allocated treatment. With several separate randomisations, patients should be analysed only within the randomisation they entered, and not compared against patients in different randomisations. Some people worry that randomised trials result in many patients receiving an inferior treatment. Accordingly, several suggestions have been made, including a combined control arm for many trials, and performing several randomisations at the same up-front time point. These approaches fundamentally contradict the above statistical principles, and can lead to wrong conclusions. We explore these problems, with reference to one such recent proposal.


A UV-Raman spectrometry method for quality control of anticancer preparations: Results after 18 months of implementation in hospital pharmacy.
In France, chemotherapy preparation units of hospital pharmacy compound cytotoxic infusion bags adapted to each patient. The narrow therapeutic index of these preparations led us to implement qualitative and quantitative control for patients' safety. To this aim, we calibrated an equipment combining UV-vis spectrometry and Raman spectroscopy (QC Prep+) and monitored 14 different molecule-solvent combinations over a 18 months period. This rapid and specific method allowed the qualitative and quantitative analysis of 1 mL sample tests in less than 2 min. On 5742 anticancer preparations, we obtained accepted results with more than 99.4% solvent identification, 99.6% drug identification and only 1.52% of preparations not matching quantitative specifications (±15% of theoretical concentration). This quantitative control enabled us to pinpoint some critical points of production for two of the most common preparations. We thus updated the procedures of reconstitution and preparation, increasing the quality of final product. UV-Raman spectrometry is thus an effective tool to control chemotherapy infusions and to improve good practices of preparation.


Identification of neonatal hearing impairment: characteristics of infants in the neonatal intensive care unit and well-baby nursery.
The objective of this study was to describe the demographic data, medical status, and incidence of risk factors for hearing impairment in the neonatal intensive care unit (NICU) and well-baby populations in a multicenter prospective study designed to assess neonatal hearing impairment and to evaluate factors that might affect neonatal hearing test performance. This was a prospective multicenter study funded by the National Institutes of Health-National Institute on Deafness and Other Communication Disorders to evaluate the effectiveness of auditory brain stem response, transient evoked otoacoustic emissions, and distortion product otoacoustic emissions for newborn hearing screening. Research staff at each site obtained informed consent and detailed demographic and medical data, including information on established risk factors for hearing loss on 4478 high-risk infants cared for in the NICU, 2348 infants from the well-baby nurseries with no risk factor, and 353 infants from the well-baby nurseries with risk factors. For follow-up purposes the sample was divided further to include a subgroup called selects. Selects were either infants from the well-baby nursery who had an established risk factor for hearing impairment (N = 353) or did not pass the neonatal hearing screen protocol (N = 80). In this study, we focus on the distribution of infants by nursery and risk factors only. Particular effort was made to enroll infants with risk factors for hearing loss in both the NICU and well-baby nurseries. Descriptive analyses are used to describe characteristics of this sample. All 10 of the risk factors established by the Joint Committee on Infant Hearing in 1994 were identified in the NICU population. The four most common were ototoxic medications (44.4%), very low birth weight (17.8%), assisted ventilation > 5 days (16.4%), and low Apgar scores at 1 or 5 min (13.9%). In contrast, only six risk factors were present in the well-baby nurseries: family history (6.6%), craniofacial abnormalities (3.4%), low Apgar scores (2.8%), syndromes (0.5%), ototoxic medications (0.2%), and congenital infection (0.1%). These descriptive risk factor data reflect both the newborn populations at the study sites and the bias for enrolling infants at risk for hearing loss. The high-risk NICU sample reflects the characteristics typically found in graduates of the NICU. The data summarized in this study will be used to assess the relationships between risk factor and hearing test outcome.


GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.
Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.


Defective expression of the DNA mismatch repair protein, MLH1, alters G2-M cell cycle checkpoint arrest following ionizing radiation.
A role for the Mut L homologue-1 (MLH1) protein, a necessary component of DNA mismatch repair (MMR), in G2-M cell cycle checkpoint arrest after 6-thioguanine (6-TG) exposure was suggested previously. A potential role for MLH1 in G1 arrest and/or G1-S transition after damage was, however, not discounted. We report that MLH1-deficient human colon carcinoma (HCT116) cells showed decreased survival and a concomitant deficiency in G2-M cell cycle checkpoint arrest after ionizing radiation (IR) compared with genetically matched, MMR-corrected human colon carcinoma (HCT116 3-6) cells. Similar responses were noted between murine MLH1 knockout compared to wild-type primary embryonic fibroblasts. MMR-deficient HCT116 cells or embryonic fibroblasts from MLH1 knockout mice also demonstrated classic DNA damage tolerance responses after 6-TG exposure. Interestingly, an enhanced p53 protein induction response was observed in HCT116 3-6 (MLH1+) compared with HCT116 (MLH1-) cells after IR or 6-TG. Retroviral vector-mediated expression of the E6 protein did not, however, affect the enhanced G2-M cell cycle arrest observed in HCT116 3-6 compared with MLH1-deficient HCT116 cells. A role for MLH1 in G2-M cell cycle checkpoint control, without alteration in G1, after IR was also suggested by similar S-phase progression between irradiated MLH1-deficient and MLH1-proficient human or murine cells. Introduction of a nocodazole-induced G2-M block, which corrected the MLH1-mediated G2-M arrest deficiency in HCT116 cells, clearly demonstrated that HCT116 and HCT116 3-6 cells did not differ in G1 arrest or G1-S cell cycle transition after IR. Thus, our data indicate that MLH1 does not play a major role in G1 cell cycle transition or arrest. We also show that human MLH1 and MSH2 steady-state protein levels did not vary with damage or cell cycle changes caused by IR or 6-TG. MLH1-mediated G2-M cell cycle delay (caused by either MMR proofreading of DNA lesions or by a direct function of the MLH1 protein in cell cycle arrest) may be important for DNA damage detection and repair prior to chromosome segregation to eliminate carcinogenic lesions (possibly brought on by misrepair) in daughter cells.


Multi-nutrient supplement improves hormone ratio associated with cancer risk.
Gynecological cancers are among the most common in women and are directly related to a variety of hormonal factors. One potential risk factor associated with developing a gynecological malignancy is the ratio of two hormone metabolites, 2-Hydroxyestrone (2-HE) and 16alpha-Hydroxyestrone (16alpha-HE). A number of botanical constituents such as indoles, flavonoids, and resveratrol have been shown to have a favorable effect on the metabolic pathways that affect this ratio. The present study was designed to evaluate if a multi-nutrient supplement containing targeted botanical constituents would affect the 2-HE/16 alpha-HE ratio in middle-aged women. A retrospective analysis was performed on 76 female patients (mean age 54 years) who received 2-HE/16 alpha-HE ratio assessments at two separate time points. The ratio assessment was part of standard care for women who presented with risk indicators associated with a high proliferative state. All patients who completed pre and post assessments were included. Sixty-five of the patients received a multi-nutrient supplement, Lucentia Peak, during the study period. Eleven patients chose not to take the supplement, but did receive ratio assessments at similar time points as the treatment group, allowing for between group comparisons. Paired t-tests were used to compare the changes in the 2-HE and 16alpha-HE measures as well as their ratio, both within groups and between groups. The results demonstrated a significant increase in the 2-HE/16alpha-HE ratio in the treated group (pre 0.38 to post 0.57, p<0.0001), and was significantly different (p=0.02) compared to the change in the control group (pre 0.65 to post 0.64). This change appears to be mediated primarily by an increase in the 2-HE level. Individually, 54 patients given Lucentia Peak had increased ratios while 11 patients had a decrease. In the control group, 3 patients had an increase in their ratio and 8 patients had a decrease. The results demonstrated that women receiving the Lucentia Peak multi-nutrient supplement had significant increases in their 2-HE:16alpha-HE ratio, which appears to be mediated primarily by increasing the 2-HE levels. These results suggest further research on phytonutrients that might positively affect estrogen metabolism is warranted.


Death on the job: The Great Recession and work-related traffic fatalities.
In light of recent discussions about shifting employees from traditional workplaces to virtual employment, we are motivated by the question of whether this phenomenon will end up saving lives even in the absence of an infectious disease outbreak. Motor vehicle incidents are the leading cause of work-related fatalities in the US, killing more than 1200 workers each year, which make up about a quarter of all work-related deaths. Not only are motor vehicle crashes the top killer at work, but economic expansions can further increase occupational and traffic deaths as they both tend to be procyclical. In this paper, we examine the effects of business cycles on traffic fatalities in the US with a special focus on work-related deaths. Specifically, we implement a longitudinal design across all 50 states by compiling quarterly data for 2004-2012 and consider macroeconomic fluctuations around the Great Recession. Our findings show that traffic deaths during prosperous times are not solely due to an increase in risky behaviors such as drunk driving, but directly related to work. Given the highly preventable nature of traffic crashes, policy makers, public health advocates, and employers can develop effective strategies, including remote work arrangements, to improve both occupational and traffic safety.


Transport of amino acids in the kidney.
Amino acids are the building blocks of proteins and key intermediates in the synthesis of biologically important molecules, as well as energy sources, neurotransmitters, regulators of cellular metabolism, etc. The efficient recovery of amino acids from the primary filtrate is a well-conserved key role of the kidney proximal tubule. Additionally, renal metabolism participates in the whole body disposition of amino acids. Therefore, a wide array of axially heterogeneously expressed transporters is localized on both epithelial membranes. For transepithelial transport, luminal uptake, which is carried out mainly by active symporters, is coupled with a mostly passive basolateral efflux. Many transporters require partner proteins for appropriate localization, or to modulate transporter activity, and/or increase substrate supply. Interacting proteins include cell surface antigens (CD98), endoplasmic reticulum proteins (GTRAP3-18 or 41), or enzymes (ACE2 and aminopeptidase N). In the past two decades, the molecular identification of transporters has led to significant advances in our understanding of amino acid transport and aminoacidurias arising from defects in renal transport. Furthermore, the three-dimensional crystal structures of bacterial homologues have been used to yield new insights on the structure and function of mammalian transporters. Additionally, transgenic animal models have contributed to our understanding of the role of amino acid transporters in the kidney and other organs and/or at critical developmental stages. Progress in elucidation of the renal contribution to systemic amino acid homeostasis requires further integration of kinetic, regulatory, and expression data of amino acid transporters into our understanding of physiological regulatory networks controlling metabolism.


Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.
Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD.


Community health centers and community development financial institutions: joining forces to address determinants of health.
Community health centers and community development financial institutions share similar origins and missions and are increasingly working together to meet community needs. Addressing the social and economic determinants of health is a common focus. The availability of new federal grants and tax credits has led these financial institutions to invest in the creation and expansion of community health centers. This article reviews the most recent trends in these two sectors and explores opportunities for further collaboration to transform the health and well-being of the nation's low-income communities.


The size of the loading dose as an important determinant of the results of the oral glucose tolerance test: a study in subjects with slightly impaired glucose tolerance.
In the oral glucose tolerance test (OGTT), divergent doses of glucose remain in use by virtue of the prevailing conviction that the size of the loading dose hardly affects the outcome of the test. We compared the results of OGTTs with 100-gm. and 50-gm. loads in 85 patients, who were selected for slightly impaired glucose tolerance (plasma glucose at 120 minutes after 100 gm. of glucose was between 130 and 200 mg./dl.) The mean between-load difference in this group appeared to be nearly three times as great (54 mg./dl. at 120 minutes) as reported in the literature for normal subjects. The small impact of the dose in normal subjects could be confirmed in a group of 22 controls. As subjects with normal and with slightly impaired glucose tolerance react divergently to a change in the glucose dose, tests with different loads are not comparable and select different populations. The results can therefore also not be converted to one another by conversion formulas. The finding might be explained by the delay of the additional rise of the plasma insulin in patients after the higher load.


Metal-organic frameworks based on flexible ligands (FL-MOFs): structures and applications.
Metal-organic frameworks (MOFs), also known as coordination polymers (CPs), are crystalline materials constructed from metal ions or clusters bridged by organic ligands to form one-, two-, or three-dimensional infinite networks. In contrast with the prolific production of MOFs based on rigid ligands (RL-MOFs), the design, syntheses and applications of MOFs based on flexible ligands (FL-MOFs) are somewhat overlooked. Although sacrificing a measure of control, the use of flexible ligands may provide unique opportunities to obtain novel crystalline framework materials exhibiting desirable attributes. In this review, emphasis has been placed on the design and the structural diversity of FL-MOFs. Homochiral FL-MOFs and dynamic frameworks induced by flexible ligands are also briefly outlined. An overview is also shown for the applications of FL-MOFs as platforms for gas adsorption, heterogeneous catalysis, proton conduction etc.