The pathogenesis of severe fever with thrombocytopenia syndrome virus infection in alpha/beta interferon knockout mice: insights into the pathologic mechanisms of a new viral hemorrhagic fever.
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered Phlebovirus causing an emerging hemorrhagic fever in East Asia, with reported case fatality rates up to 30%. Despite the high case fatality rate and large number of persons at risk of infection, the pathobiology of the disease is unknown, and no effective animal model has been available for investigating its pathogenesis. We have studied mice and hamsters as potential small-animal models of SFTSV infection following subcutaneous, intraperitoneal, or intracerebral inoculation. Animal tissues were processed for viral load determination, histopathology, immunohistochemistry, and confocal microscopic studies. We found that immunocompetent adult mice and hamsters did not become ill after SFTSV infection. However, alpha/beta interferon receptor knockout (IFNAR(-/-)) mice were highly susceptible to SFTSV infection, and all mice died within 3 to 4 days after subcutaneous inoculation of 10(6) focus-forming units of SFTSV. Histologic examination of tissues of IFNAR(-/-) mice infected with SFTSV showed no detectable lesions. In contrast, by immunohistochemistry virus antigen was found in liver, intestine, kidney, spleen, lymphoid tissue, and brain, but not in the lungs. Mesenteric lymph nodes and spleen were the most heavily infected tissues. Quantitative reverse transcription-PCR (RT-PCR) confirmed the presence of virus in these tissues. Confocal microscopy showed that SFTSV colocalized with reticular cells but did not colocalize with dendritic cells, monocytes/macrophages, neutrophils, or endothelium. Our results indicate that SFTSV multiplied in all organs except for lungs and that mesenteric lymph nodes and spleen were the most heavily infected tissues. The major target cells of SFTSV appear to be reticular cells in lymphoid tissues of intestine and spleen.


Surgical technique: posterior cruciate ligament (PCL) reconstruction using double posteromedial arthroscopic portals.
The posterior cruciate ligament (PCL) reconstruction is a technically demanding surgical procedure that requires optimal identification of both the femoral and the tibial anatomical footprints. To aid the tibial tunnel placement and many authors recommend creating a posteromedial (PM) portal. The further addition of a second PM portal, which could be used as a "working portal", may further allow a more straightforward reconstruction by improving the identification of the anatomical footprint, the clearing of the stump, and the graft passage.


Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model.
Breast cancer is the most common malignancy in women of the Western world. Doxorubicin (DOX) continues to be used extensively to treat early-stage or node-positive breast cancer, human epidermal growth factor receptor-2 (HER2)-positive breast cancer, and metastatic disease. We have previously demonstrated in a mouse model that sulforaphane (SFN), an isothiocyanate isolated from cruciferous vegetables, protects the heart from DOX-induced toxicity and damage. However, the effects of SFN on the chemotherapeutic efficacy of DOX in breast cancer are not known. Present studies were designed to investigate whether SFN alters the effects of DOX on breast cancer regression while also acting as a cardioprotective agent. Studies on rat neonatal cardiomyocytes and multiple rat and human breast cancer cell lines revealed that SFN protects cardiac cells but not cancer cells from DOX toxicity. Results of studies in a rat orthotopic breast cancer model indicated that SFN enhanced the efficacy of DOX in regression of tumor growth, and that the DOX dosage required to treat the tumor could be reduced when SFN was administered concomitantly. Additionally, SFN enhanced mitochondrial respiration in the hearts of DOX-treated rats and reduced cardiac oxidative stress caused by DOX, as evidenced by the inhibition of lipid peroxidation, the activation of NF-E2-related factor 2 (Nrf2) and associated antioxidant enzymes. These studies indicate that SFN not only acts synergistically with DOX in cancer regression, but also protects the heart from DOX toxicity through Nrf2 activation and protection of mitochondrial integrity and functions.


Predictors of hangover during a week of heavy drinking on holiday.
To investigate predictors of hangover during a week of heavy drinking in young adults. Design Observational prospective study. A total of 112 young Danish tourists were interviewed on three occasions during their holiday. They completed the Acute Hangover Scale and answered questions about their alcohol consumption and rest duration. The incidence of hangover was analysed as the proportion of heavy drinkers (i.e. those reporting drinking more than 12 standard units of alcohol during the night before) scoring above the 90th percentile of light drinkers (i.e. those who had consumed fewer than seven standard units the night before). We estimated the course and predictors of hangover using random effects regression. The incidence of hangover was 68% after drinking more than 12 standard units in the whole sample. The severity of hangover increased significantly during a week of heavy drinking and there was a time x number of drinks interaction, indicating that the impact of alcohol consumed on hangover became more pronounced later in the week. Levels of drinking before the holiday did not predict hangover. Hangovers after heavy drinking during holidays appear to be related both to amount drunk and time into the holiday.


The Impact of Baseline User Characteristics on the Benefits of Real-Time Versus Intermittently Scanned Continuous Glucose Monitoring in Adults With Type 1 Diabetes: Moderator Analyses of the ALERTT1 Trial.
ALERTT1 showed that switching from intermittently scanned continuous glucose monitoring (isCGM) without alerts to real-time CGM (rtCGM) with alert functionality improved time in range (TIR; 70-180 mg/dL), glycated hemoglobin (HbA1c), time <54 mg/dL, and Hypoglycemia Fear Survey version II worry subscale (HFS-worry) score after six months in adults with type 1 diabetes (T1D). Moderator analyses aimed to identify certain subgroups that would benefit more from switching to rtCGM than others. Post hoc analyses of ALERTT1 evaluated the impact of 14 baseline characteristics on the difference (delta) in mean TIR, HbA1c, time <54 mg/dL, and HFS-worry score at six months between rtCGM and isCGM. Therefore, the delta was allowed to depend on each of these variables by including interactions in the moderator analysis model. Analyses were performed separately for each variable; variables with P < .10 in the univariable analysis were combined into a single model. Univariable analyses showed no dependency of delta TIR, HbA1c, or time <54 mg/dL on variables other than CGM type. Only delta HFS-worry score depended on baseline HbA1c (P = .0059), indicating less worries with rtCGM in people with baseline HbA1c <6.5% or ≥8%. Given P < .10 for dependency of delta TIR on insulin therapy type (favoring multiple daily injections), baseline HbA1c, and baseline TIR, these variables were combined into a multivariable analysis; interactions were not statistically significant. Except for HFS-worry score, no interactions between 14 baseline characteristics and the six-month intervention effect of rtCGM on TIR, HbA1c, or time <54 mg/dL were observed, supporting the conclusion of ALERTT1 that switching from isCGM without alerts to rtCGM with alert functionality is beneficial for a wide range of people with T1D.


Specific release of membrane-bound annexin II and cortical cytoskeletal elements by sequestration of membrane cholesterol.
Annexin II is an abundant protein which is present in the cytosol and on the cytoplasmic face of plasma membrane and early endosomes. It is generally believed that this association occurs via Ca(2+)-dependent binding to lipids, a mechanism typical for the annexin protein family. Although previous studies have shown that annexin II is involved in early endosome dynamics and organization, the precise biological role of the protein is unknown. In this study, we found that approximately 50% of the total cellular annexin was associated with membranes in a Ca(2+)-independent manner. This binding was extremely tight, since it resisted high salt and, to some extent, high pH treatments. We found, however, that membrane-associated annexin II could be quantitatively released by low concentrations of the cholesterol-sequestering agents filipin and digitonin. Both treatments released an identical and limited set of proteins but had no effects on other membrane-associated proteins. Among the released proteins, we identified, in addition to annexin II itself, the cortical cytoskeletal proteins alpha-actinin, ezrin and moesin, and membrane-associated actin. Our biochemical and immunological observations indicate that these proteins are part of a complex containing annexin II and that stability of the complex is sensitive to cholesterol sequestering agents. Since annexin II is tightly membrane-associated in a cholesterol-dependent manner, and since it seems to interact physically with elements of the cortical actin cytoskeleton, we propose that the protein serves as interface between membranes containing high amounts of cholesterol and the actin cytoskeleton.


Analyzing the effects of platelet gel on knee osteoarthritis in the rat model.
Platelet gel (PG) includes concentrated dose of growth factors which plays role in physiological processes of healing. The goal of this study is to evaluate repairing effects of intra-articular injection of PG use in a rat model of knee osteoarthritis (OA). A total of 20 rats were randomly distributed into a PG group and a control group. Both the groups were induced OA in knee joints with intra-articular formaline injection. The rats in the PG group and the control group were injected in the knee joint with PG and 0.9% NaCl solution, respectively. Two weeks after last injections, all rats were sacrificed by ether asphyxiation. Tissue samples were obtained from the knee joints and were examined histopathologically. No statistically significant differences were found between the groups regarding cartilage healing (P > .05). We were unable to determine any beneficial or harmful effects of PG on joint cartilage healing in OA.


Review of water reuse practices and development in China.
The paper reviews existing urban water reuse schemes in north China including existing policies, institutional, technical and financial practices, summarises the data of nine water reclamation plants in six case study cities, highlights key issues and constraints, and presents development trend in water reuse sector. It is based on an intensive study programme financed by the World Bank in 2004/2005.


Host and Microbial Characteristics Associated with Recurrent Prosthetic Joint Infections.
Approximately 20% of patients after resection arthroplasty and antibiotic spacer placement for prosthetic joint infection develop repeat infections, requiring an additional antibiotic spacer before definitive reimplantation. The host and bacterial characteristics associated with the development of recurrent infection is poorly understood. A case-control study was conducted for 106 patients with intention to treat by two-stage revision arthroplasty for prosthetic joint infection at a single institution between 2009-2020. Infection was defined according to the 2018 Musculoskeletal Infection Society criteria. Thirty-nine cases ("recurrent-PJI") received at least two antibiotic spacers before clinical resolution of their infection, and 67 controls ("single-PJI") received a single antibiotic cement spacer prior to infection-free prosthesis reimplantation. Patient demographics, McPherson host grade, and culture results including antibiotic susceptibilities were compared. Fifty-two (78%) single-PJI and 32 (82%) recurrent-PJI patients had positive intraoperative cultures at the time of their initial spacer procedure. The odds of polymicrobial infections were 11-fold higher among recurrent-PJI patients, and the odds of significant systemic compromise (McPherson host-grade C) were more than double. Recurrent-PJI patients were significantly more likely to harbor Staphylococcus aureus. We found no differences between cases and controls in pathogen resistance to the six most tested antibiotics. Among recurrent-PJI patients, erythromycin-resistant infections were more prevalent at the final than initial spacer, despite no erythromycin exposure. Our findings suggest that McPherson host grade, polymicrobial infection, and S. aureus infection are key indicators of secondary or persistent joint infection following resection arthroplasty and antibiotic spacer placement, while bacterial resistance does not predict infection-related arthroplasty failure. This article is protected by copyright. All rights reserved.


The effect of genetic variants in SERPING1 on the risk of neovascular age-related macular degeneration.
Genetic factors influence an individual's risk for developing age-related macular degeneration (AMD), a leading cause of irreversible vision loss. Previous studies investigating the potential association between all AMD subtypes and the SERPING1 gene, which encodes a key regulator of the classic complement pathway, have yielded conflicting results. The purpose of this study is to determine whether variations in SERPING1 are associated with neovascular AMD. A total of 556 patients with neovascular AMD and 256 ethnically matched controls were genotyped for polymorphisms in SERPING1. A tagging single nucleotide polymorphism (tSNP) approach was used to cover the SERPING1 gene plus 2 kb on each side, spanning the promoter and the 3' untranslated regions. Ten SNPs with a minor allele frequency of 0.10 were covered by three tSNPs (rs1005510, rs11603020, rs2511989). SERPING1 SNPs rs1005510 and rs2511989 were significantly associated with neovascular AMD in our cohort, with rs1005510 conferring an adverse risk effect (OR 1.49, 95% CI 1.18 to 1.88) and rs2511989 conferring a protective effect (OR 0.73, 95% CI 0.59 to 0.90). For both tSNPs, logistic regression of individual genotypes demonstrated statistically significant stepwise changes in the risk of developing AMD. Combined analysis of rs1005510 with variants in CFH and HTRA1 confirmed an independent risk effect. The rs11603020 variant had no effect on AMD susceptibility in this study (OR 0.98, 95% CI 0.78 to 1.24). The SERPING1 gene is comprehensively investigated in this study (using three tSNPs), and its genetic variants are evaluated in the largest neovascular AMD cohort to date. The hypothesis that SERPING1 has a modest effect on the risk of neovascular AMD is supported by our results.


The antidepressant effect of running is associated with increased hippocampal cell proliferation.
A common trait of antidepressant drugs, electroconvulsive treatment and physical exercise is that they relieve depression and up-regulate neurotrophic factors as well as cell proliferation and neurogenesis in the hippocampus. In order to identify possible biological underpinnings of depression and the antidepressant effect of running, we analysed cell proliferation, the level of the neurotrophic factor BDNF in hippocampus and dynorphin in striatum/accumbens in 'depressed' Flinders Sensitive Line rats (FSL) and Flinders Resistant Line (FRL) rats with and without access to running-wheels. The FRL strain exhibited a higher daily running activity than the FSL strain. Wheel-running had an antidepressant effect in the 'depressed' FSL rats, as indicated by the forced swim test. In the hippocampus, cell proliferation was lower in the 'depressed' rats compared to the control FRL rats but there was no difference in BDNF or dynorphin levels in striatum/accumbens. After 5 wk of running, cell proliferation increased in FSL but not in FRL rats. BDNF and dynorphin mRNA levels were increased in FRL but not to the same extent in the in FSL rats; thus, increased BDNF and dynorphin levels were correlated to the running activity but not to the antidepressant effect of running. The only parameter that was associated to basal level of 'depression' and to the antidepressant effect was cell proliferation in the hippocampus. Thus, suppression of cell proliferation in the hippocampus could constitute one of the mechanisms that underlie depression, and physical activity might be an efficient antidepressant.


Performance of fetal ultrasound and magnetic resonance imaging in predicting birthweight according to the test-to-delivery interval: A cohort study.
To assess the influence of the test-to-delivery interval (TDI) on the performance of ultrasound (US) and magnetic resonance imaging (MRI) for predicting birthweight (BW). This is a secondary analysis of a prospective, single center, blinded cohort study that compared MRI and US for the prediction of BW ≥ 95th percentile in singleton pregnancies. Patients that were included in the initial study underwent US and MRI for estimation of fetal weight between 36 + 0/7 and 36 + 6/7 weeks of gestation (WG). The primary outcome of the current study was to report the changes of US and MRI sensitivity and specificity in the prediction of BW > 95th percentile, BW > 90th percentile, BW < 10th percentile, and BW < 5th percentile, according to the TDI. The secondary outcome was to represent the performance of both tools in the prediction of BW > 90th percentile when TDI is<2 weeks, between 2 and 4 weeks, and>4 weeks. Receiver operating characteristic (ROC) curves were constructed accordingly. 2378 patients were eligible for final analysis. For the prediction of BW > 95th or 90th percentile, the sensitivity of MRI remains high until 2 weeks, and it decreases slowly between 2 and 4 weeks, in contrast to the sensitivity of US which decreases rapidly 2 weeks after examination (p < 0.001). For the prediction of BW < 10th or 5th percentile, the sensitivity of both tools decreases in parallel between 1 and 2 weeks. The specificities of both tools remain high from examination till delivery. These findings are reproducible with the use of the antenatal customized and the postnatal national growth charts. The performance of MRI in the prediction of BW, especially in large-for-gestational age, is maximal when delivery occurs within two weeks of the examination, decreasing slightly thereafter, in contrast with the performance of US which decreases drastically over time.


Endoscopic cranial base surgery: classification of operative approaches.
Endoscopic cranial base surgery is a minimal access, maximally aggressive alternative to traditional transfacial, transcranial, or combined open cranial base approaches. Previous descriptions of endoscopic approaches have used varying terminology, which can be confusing to the new practitioner. Indications for surgery are not well defined. Our objective was to create a comprehensive classification system of the various approaches and describe their indications with case examples. We prospectively compiled a comprehensive database of our endonasal endoscopic operations, detailing the nasal sinus transgressed, the cranial base approach, and the intracranial target for the first 150 consecutive cases performed at our institution. All cases were performed collaboratively by a neurosurgeon and an otolaryngologist. We categorized the endonasal endoscopic cranial base operations into four nasal corridors, nine cranial base approaches, and 13 intracranial targets. Each of the various approaches is described in detail and illustrated with case examples. Pathology encountered included pituitary tumor (50%), meningocele/encephalocele (14%), craniopharyngioma and Rathke cleft cyst (10%), meningioma (8%), chordoma (5%), esthesioneuroblastoma (2%), and other (11%). Endonasal endoscopic cranial base surgery is a minimal access, maximally invasive alternative to open transcranial cranial base approaches for specific indications. A clear understanding of the possible approaches is facilitated by an awareness of the nasal corridors and intracranial targets.


DUB3 Facilitates Growth and Inhibits Apoptosis Through Enhancing Expression of EZH2 in Oral Squamous Cell Carcinoma.
Here, we probed the action mechanism of ubiquitin-specific processing proteases 17 (DUB3) in the evolution of oral squamous cell carcinoma (OSCC). The expression of genes were calculated by qRT-PCR, and proteins were assessed by Western blot and immunohistochemistry. The cells viability and proliferation were checked by MTT and EdU assay, respectively. Flow cytometry was implemented to detect the cell cycle and apoptosis. The activity of EZH2 gene promoter was measured by luciferase reporter assay. Co-immunoprecipitation assay was used to ensure the ubiquitination of bromodomain-containing protein 4 (BRD4). The cell apoptosis of tumor tissues was assessed by TUNEL assay. DUB3 was overexpressed in OSCC tissues and cell lines, and negatively correlated with patient's survival time. DUB3 downregulation could effectively curb OSCC cells viability and proliferation, promote cell apoptosis and the expression of cleaved-caspase-3, cleaved PARP and p21, while inhibit cyclin D1. Besides, DUB3 production was positivity correlated with enhancer of zeste homolog-2 (EZH2) and BRD4. BRD4 downregulation could repress DUB3-induced EZH2 production, and MG132 reversed DUB3 decreasing-mediated BRD4 downregulation. Downregulation of DUB3 promoted BRD4 ubiquitination. DUB3 promoted OSCC cells proliferation, while suppressing apoptosis via facilitating EZH2 production. At last, in vivo experiment indicated that the downregulation of DUB3 significantly inhibited the growth of xenograft tumor. In summary, we found that DUB3 enhanced OSCC cells proliferation and xenograft tumor growth, while inhibited their apoptosis via promoting BRD4-mediated upregulation of EZH2. Our study indicated that DUB3 may be an effective anti-cancer target for OSCC therapy.


Randomized clinical trial examining the effect of music therapy in stress response to day surgery.
Music therapy could reduce stress and the stress response. The aim of this study was to investigate the role of music therapy in alleviating stress during day surgery. Sixty patients undergoing day surgery were randomized to one of three groups, each containing 20 patients. Before and during surgery, patients in group 1 listened to new age music and those in group 2 listened to a choice of music from one of four styles. Patients in group 3 (control group) heard the normal sounds of the operating theatre. Plasma levels of cortisol and subpopulations of lymphocytes were evaluated before, during and after operation. Plasma cortisol levels decreased during operation in both groups of patients who listened to music, but increased in the control group. Postoperative cortisol levels were significantly higher in group 1 than in group 2 (mean(s.d.) 14.21(6.96) versus 8.63(2.72) ng/dl respectively; P < 0.050). Levels of natural killer lymphocytes decreased during surgery in groups 1 and 2, but increased in controls. Intraoperative levels of natural killer cells were significantly lower in group 1 than in group 3 (mean(s.d.) 212.2(89.3) versus 329.1(167.8) cells/microl; P < 0.050). Perioperative music therapy changed the neurohormonal and immune stress response to day surgery, especially when the type of music was selected by the patient.


Detection and Modulation of DNA Translocations During Multi-Gene Genome Editing in T Cells.
Multiplexed genome editing with DNA endonucleases has broad application, including for cellular therapies, but chromosomal translocations, natural byproducts of inducing simultaneous genomic breaks, have not been explored in detail. Here we apply various CRISPR-Cas nucleases to edit the T cell receptor alpha and beta 2 microglobulin genes in human primary T cells and comprehensively evaluate the frequency and stability of the resulting translocations. A thorough translocation frequency analysis using three orthogonal methods (droplet digital PCR, unidirectional sequencing, and metaphase fluorescence in situ hybridization) yielded comparable results and an overall translocation rate of ∼7% between two simultaneous CRISPR-Cas9 induced edits. In addition, we show that chromosomal translocations can be reduced when using different nuclease combinations, or by the presence of a homologous single stranded oligo donor for multiplexed genome editing. Importantly, the two different approaches for translocation reduction are compatible with cell therapy applications.


Registration of MR and SPECT without using external fiducial markers.
The aim of our work is to present, test and validate an automated registration method used for matching brain SPECT scans with corresponding MR scans. The method was applied on a data set consisting of ten brain IDEX SPECT scans and ten T1- and T2-weighted MR scans of the same subjects. Of two subjects a CT scan was also made. (Semi-) automated algorithms were used to extract the brain from the MR, CT and SPECT images. Next, a surface registration technique called chamfer matching was used to match the segmented brains. A perturbation study was performed to determine the sensitivity of the matching results to the choice of the starting values. Furthermore, the SPECT segmentation threshold was varied to study its effect on the resulting parameters and a comparison between the use of MR T1- and T2-weighted images was made. Finally, the two sets of CT scans were used to estimate the accuracy by matching MR to CT and comparing the MR-SPECT match to the SPECT-CT match. The perturbation study showed that for initial perturbations up to 6 cm the algorithm fails in less than 4% of the cases. A variation of the SPECT segmentation threshold over a realistic range (25%) caused an average variation in the optimal match of 0.28 cm vector length. When T2 is used instead of T1 the stability of the algorithm is comparable but the results are less realistic due the large deformations. Finally, a comparison of the direct SPECT-MR match and the indirect match with CT as intermediate yields a discrepancy of 0.4 cm vector length. We conclude that the accuracy of our automatic matching algorithm for SPECT and MR, in which no external markers were used, is comparable to the accuracies reported in the literature for non-automatic methods or methods based on external markers. The proposed method is efficient and insensitive to small variations in SPECT segmentation.


'Turning the tide' on hyperglycemia in pregnancy: insights from multiscale dynamic simulation modeling.
Hyperglycemia in pregnancy (HIP, including gestational diabetes and pre-existing type 1 and type 2 diabetes) is increasing, with associated risks to the health of women and their babies. Strategies to manage and prevent this condition are contested. Dynamic simulation models (DSM) can test policy and program scenarios before implementation in the real world. This paper reports the development and use of an advanced DSM exploring the impact of maternal weight status interventions on incidence of HIP. A consortium of experts collaboratively developed a hybrid DSM of HIP, comprising system dynamics, agent-based and discrete event model components. The structure and parameterization drew on a range of evidence and data sources. Scenarios comparing population-level and targeted prevention interventions were simulated from 2018 to identify the intervention combination that would deliver the greatest impact. Population interventions promoting weight loss in early adulthood were found to be effective, reducing the population incidence of HIP by 17.3% by 2030 (baseline ('business as usual' scenario)=16.1%, 95% CI 15.8 to 16.4; population intervention=13.3%, 95% CI 13.0 to 13.6), more than targeted prepregnancy (5.2% reduction; incidence=15.3%, 95% CI 15.0 to 15.6) and interpregnancy (4.2% reduction; incidence=15.5%, 95% CI 15.2 to 15.8) interventions. Combining targeted interventions for high-risk groups with population interventions promoting healthy weight was most effective in reducing HIP incidence (28.8% reduction by 2030; incidence=11.5, 95% CI 11.2 to 11.8). Scenarios exploring the effect of childhood weight status on entry to adulthood demonstrated significant impact in the selected outcome measure for glycemic regulation, insulin sensitivity in the short term and HIP in the long term. Population-level weight reduction interventions will be necessary to 'turn the tide' on HIP. Weight reduction interventions targeting high-risk individuals, while beneficial for those individuals, did not significantly impact forecasted HIP incidence rates. The importance of maintaining interventions promoting healthy weight in childhood was demonstrated.


Poloxamer-188 and d-α-Tocopheryl Polyethylene Glycol Succinate (TPGS-1000) Mixed Micelles Integrated Orodispersible Sublingual Films to Improve Oral Bioavailability of Ebastine; In Vitro and In Vivo Characterization.
Orodispersible sublingual films (OSFs) composed of hydrophilic polymers were loaded with poloxamer-188 and d-α-tocopheryl polyethylene glycol succinate (TPGS-1000) mixed micelles to improve the oral bioavailability of a poorly soluble drug, ebastine (EBT). Mixed micelles formed by thin-film hydration method were incorporated into orodispersible sublingual film, consisting of HPMC and glycerol, using solvent casting technique. The mixed micelles and films were thoroughly evaluated for physicochemical characterization (size, polydispersity index, zeta potential, entrapment efficiency, thickness, weight, surface pH studies, disintegration time, swelling indices, mechanical properties, FTIR, PXRD, DSC, SEM, AFM, in vitro drug release, in vivo bioavailability, and toxicological studies). The results showed that the average particle size of mixed micelles was 73 nm. The mean zeta potential and PDI of the optimal mixed micelles formulation were -26 mV and 0.16, respectively. Furthermore, the maximum entrapment efficiency 82% was attained. The film's disintegration time was in the range of 28 to 102 s in aqueous media. The integrity of micelles was not affected upon incorporation in films. Importantly, the micelles-loaded films revealed rapid absorption, high permeability, and increased bioavailability of EBT as compared to the pure drug. The existence of ebastine loaded mixed micelles in the films enhanced the bioavailability about 2.18 folds as compared to pure drug. Further, the results evidently established in-vitro and in-vivo performance of bioavailability enhancement, biocompatibility, and good safety profile of micelles-loaded orodispersible EBT films. Finally, it was concluded that film loaded with poloxamer-188/TPGS-1000 mixed micelles could be an effective carrier system for enhancing the bioavailability of ebastine.


Involvement of CONSTANS-like Proteins in Plant Flowering and Abiotic Stress Response.
The process of flowering in plants is a pivotal stage in their life cycle, and the CONSTANS-like (COL) protein family, known for its photoperiod sensing ability, plays a crucial role in regulating plant flowering. Over the past two decades, homologous genes of COL have been identified in various plant species, leading to significant advancements in comprehending their involvement in the flowering pathway and response to abiotic stress. This article presents novel research progress on the structural aspects of COL proteins and their regulatory patterns within transcription complexes. Additionally, we reviewed recent information about their participation in flowering and abiotic stress response, aiming to provide a more comprehensive understanding of the functions of COL proteins.


Prophylaxis of endocarditis.
For a long time it has been known that bacteraemias caused by medical or dental procedures may cause endocarditis in patients with specific types of congenital or acquired heart disease. In the 1940s it was thought that the administration of antibiotics before such procedures would prevent endocarditis. However, the beneficial effect of this preventive measure on the incidence of endocarditis did not live up to its expectations. Quite soon it became obvious that prophylaxis was not 100% efficacious in man, although it did prevent endocarditis in animals. A controlled study into the protective effect of prophylaxis in humans has never been carried out. In the last decade it has become dear from case-control studies that endocarditis prophylaxis is not a very effective preventive measure but that it reduces an already small risk even further. In this article the theoretical background of endocarditis prophylaxis and possible explanations for its lack of effect are discussed.


Deciphering the Roles of Thiazolidinediones and PPARγ in Bladder Cancer.
The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγ may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγ in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.


Persistence of benzo(a)pyrene metabolite:DNA adducts in lung and liver of mice.
The persistence of benzo(a)pyrene (BP) metabolite:DNA adducts has been studied in lung and liver of A/HeJ and C57BL/6J mice after a dose of BP (6 mg/mouse) which induces pulmonary adenomas in A/HeJ mice but not in C57BL/6J mice. BP is not a hepatic carcinogen in either strain. Following p.o. administration of [3H]BP, animals were killed at times ranging from 10 hr to 28 days, and BP metabolite:DNA adducts were analyzed by high-pressure liquid chromatography. The major adduct identified in each tissue was the (+)-7 beta-8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene:deoxyguanosine adduct. A 7 beta, 8 alpha-dihydroxy-9 beta,10 beta,epoxy-7,8,9, 10-tetrahydrobenzo(a)pyrene:deoxyguanosine adduct, a (-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene:deoxyguanosine adduct, and an unidentified adduct were also observed. The disappearance of (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydro-BP adduct in A/HeJ mice followed first-order kinetics over the time period examined, with a half-life of 18 and 9 days in lung and liver, respectively. The decay of this adduct in C57BL/6J mice was biphasic in both tissues. Our data on cell turnover suggest that there is active removal of adducts in liver, but that normal DNA turnover can account for the partial or possibly total observed disappearance of adducts in lung. These results suggest that the tissue specificity for BP-induced neoplasia in A/HeJ mice may be related to the relative persistence of adducts and high cell turnover rates in lung. In contrast, the results on formation and persistence of adducts and cell turnover do not provide an explanation for the strain difference in susceptibility to BP-induced pulmonary adenomas. It was also shown that the rates of removal of BP metabolite:DNA adducts in A/HeJ mice are not significantly different at a 500-fold lower BP dose.


The role of the peripheral and central nervous systems in rotator cuff disease.
Rotator cuff (RC) disease is an extremely common condition associated with shoulder pain, reduced functional capacities, and impaired quality of life. It primarily involves alterations in tendon health and mechanical properties that can ultimately lead to tendon failure. RC tendon tears induce progressive muscle changes that have a negative impact on surgical reparability of the RC tendons and clinical outcomes. At the same time, a significant base of clinical data suggests a relatively weak relationship between RC integrity and clinical presentation, emphasizing the multifactorial aspects of RC disease. This review aims to summarize the potential contribution of peripheral, spinal, and supraspinal neural factors that may (1) exacerbate structural and functional muscle changes induced by tendon tear, (2) compromise the reversal of these changes during surgery and rehabilitation, (3) contribute to pain generation and persistence of pain, (4) impair shoulder function through reduced proprioception, kinematics, and muscle recruitment, and (5) help explain interindividual differences and response to treatment. Given the current clinical and scientific interest in peripheral nerve injury in the context of RC disease and surgery, we carefully reviewed this body of literature with a particular emphasis on suprascapular neuropathy that has generated a large number of studies in the past decade. Within this process, we highlight the gaps in current knowledge and suggest research avenues for scientists and clinicians.


Mechanistic investigation of the NH-sulfoximination of sulfide. Evidence for λ6-sulfanenitrile intermediates.
We report a new procedure for the preparation of NH-sulfoximines from sulfides using PIDA as an oxidant and ammonium carbamate as the ammonia source. Excellent yields were obtained with a wide range of sulfides. The formation of acetoxy- and methoxy-λ6-sulfanenitrile as intermediates was proposed, both of which were converted to the NH-sulfoximine by the action of the solvent. The structure of these intermediates was confirmed by 1H, 13C and 15N NMR and HRMS analysis.


The expression of squalene epoxidase in human gastric cancer and its clinical significance.
Squalene epoxidase (SQLE) is overexpressed in a variety of tumors, which may play an important role in their tumorigenesis, development, and prognosis. The aim of this study is to investigate the expression of SQLE and explore its clinicopathological significance in gastric cancer. The correlation between its positive expression and the pathological characteristics of patients (such as sex, age, tumor size, survival, tumor differentiation, TNM staging, and lymph node metastasis) was analyzed. Immunohistochemical method was used to detect its expression in 107 cases of gastric carcinoma and 34 cases of tumor-adjacent tissues. Counting data were analyzed by Chi-square test. Its overall survival was analyzed by Kaplan-Meier method and log-rank test. Its hazard factors were analyzed by Cox multivariate analysis. The positive rate of SQLE in gastric cancer is 67.3%, which is higher than that in tumor-adjacent tissues (17.6%), <0.001. Expression of SQLE is closely related to tumor differentiation, TNM staging and lymph node metastasis (P = 0.030, P = 0.009, and P = 0.011, respectively). Furthermore, compared with those low expression of SQLE, the patients of overexpression had worse overall survival by Kaplan-Meier analysis (P = 0.025). Cox multivariate analysis shows that lymph node metastasis, tumor differentiation, SQLE, and TNM staging are independent factors for prognosis of gastric cancer (P = 0.003, 0.020, 0.018, and P = 0.001 respectively). SQLE is overexpressed in gastric cancer. It could be used for the diagnosis and prognosis of the gastric cancer patients.


Fall-related injuries in the elderly in Tehran.
During 13 months of data gathering, all injury-related information concerning trauma patients was gathered according to International Classification of Diseases, 10th revision (ICD-10). The severity of the injury was calculated according to Abbreviated Injury Scale (AIS-90) in six major university hospitals in Tehran. Twelve percent of 8000 hospitalised trauma patients were elderly (65 years or older) and 70% of them (675 patients) had suffered from fall-related injuries. Falling on the ground and falling on stairs were the most common kinds of injury (with 462 (68%) and 122 (18%) cases, respectively). In the home and on the street were the most common sites of fall occurrence (with 520 cases (77%) and 91 cases (13.5%), respectively). After adjustment for the gender, kind of fall and Injury Severity Score, it was shown that the elderly were more prone to death than their younger counterparts (odds ratio=5.8, 95% CI for odds ratio: 2.3-7.2), but there was no significant difference in mortality rate between elderly men and women. Further studies are needed to evaluate personal and environmental risk factors for falls in our population. Furthermore, significantly higher mortality rate in our elderly trauma victims necessitates prudent attention to elderly trauma care in our teaching hospitals.


Early intervention with suplatast tosilate for prophylaxis of pediatric atopic asthma: a pilot study.
The onset of asthma may be related to Th2 cytokine dominance at the time when food allergies occur several months after birth. This study investigated the effectiveness of early intervention with a Th2 cytokine inhibitor (suplatast tosilate) for prevention of asthma in infants with food allergies and atopic dermatitis. Suplatast tosilate dry syrup (6 mg/kg daily) or a histamine H(1)-blocker (ketotifen fumarate dry syrup: 0.06 mg/kg daily) was administered randomly to 53 infants with atopic dermatitis caused by food allergies. The primary endpoints were the incidence of asthma and the time to the onset of wheezing. The peripheral blood Th1/Th2 ratio, total IgE level, and eosinophil count were measured before and after treatment. After 24 months of treatment, the prevalence of asthma was significantly lower in the suplatast group (20.8%) than in the ketotifen group (65.6%, p < 0.01). Additionally, the time from the start of treatment to the initial episode of wheezing for infants who developed asthma was significantly longer in the suplatast group than the ketotifen group (p < 0.01). Furthermore, the eosinophil count was significantly decreased by suplatast treatment (p < 0.05), and there was a significant difference between the suplatast and ketotifen groups with respect to both the eosinophil count (p < 0.01) and the Th1/Th2 ratio (p < 0.05). The results of the present pilot study suggest that suplatast tosilate is useful for the primary prevention of wheezing and asthma in children.


METASTATIC NODULAR MELANOMA DEVELOPING ON NEVUS SPILUS DURING INTAKE OF BETA BLOCKERS (BISOPROLOL/NEBIVOLOL) AND ACE INHIBITORS (PERINDOPRIL). POTENTIAL LINKS TО THE DRUG RELATED NITROSOGENESIS/CARCINOGENESIS, DUNNING-KRUGER EFFECT AND GENETIC WEAPONS OF THE NEW GENERATION.
Drug-induced Nitrosogenesis/Carcinogenesis turns out to be a ubiquitous, pervasive, large-scale, poorly controllable concept for the academic community, which underlies the long-term, permanent modification of the human genome by contact with nitrosamines/NDSRIs, which ultimately leads to the generation of diverse cancers, but also melanoma in particular. The discovery of a (currently) unclassifiable number of nitroso derivatives/genome modifiers in the most commonly distributed drugs worldwide (in about 300 preparations according to the FDA/includes beta blockers/bisoprolol/nebivolol and ACE inhibitors/perindopril), their forced tolerability, attributed as a necessity or lack of alternative also to the present (but also to future periods), and their proven carcinogenicity (already 70 years ago), suggest a kind of creepy form of experiment to which public health is subjected worldwide. The creation of a universal nitroso-comfort of pharmaceutical companies and the regulation of a permanent intake of carcinogens in drugs for years to come, but also decades back, suggest possible cartel agreements between the regulation/distribution unit and that of production cycles. These "agreements" are becoming increasingly evident and in all likelihood position nitrosogenesis from a until recently unknown element, to a pathogenetic factor of paramount importance. Melanoma could be viewed precisely as the controlled end gene-modified product of drug-mediated nitrosogenesis/carcinogenesis, proven to be a locoregional (but not only) phenomenon hundreds if not thousands of times. The dilemma stays: Are the nitrosamines in drugs genetic weapons, ethnic bioweapons for silent war ? The nitrosogenesis concerning melanoma leads to the logical conclusion that cancer is in fact a largely controlled set event or, according to others, a forced necessity of evolutionary globalization processes to purge the population in certain regions. In favor of this statement indicative are namely: 1) lack of regulatory control/results of such conducted, 2) complete information veil for the end user regarding contamination with carcinogens/nitrosamines in certain batches or all batches of drugs, 3) misinformation and lack of transparency regarding the concept of nitrosogenesis also for the academic community, as well as 4) the impunity to pharmaceutical conglomerates after criminal negligence/controlled criminogenicity proven thousands of times by the FDA/EMA leading to regulatory controlled drug mediated genocide of the human population in certain areas on a daily basis. And most important of all: 5) the lack of refusal to eliminate these drugs, i.e. - the imposition of forced tolerance at any cost. It is extremely unfortunate that the mentioned and identified grotesque/situation, its tolerance on a global scale, lead to a misjudgement of the significance of real tumor inducers within the global health map//statistics as well as melanoma. The focus of prevention is being displaced, while the incidence of cancer in general and that of melanoma is skyrocketing. Nitrosamines could be defined as the newest, modern, until recently invisible and unknown, but -controllable form of genetic weapon to modify the human genome. Because of these very facts, the likelihood that clinicians and the academic community are in the frozen and permanent state of the Dunning-Kruger effect is very real. Certain globalization regulatory elements create problems and assignments that must be solved ˝competently˝ by incompetent, fully regulatable compartments. As their state of competence depends again and entirely on ˝their incompetence˝. Until now. After the formalization of the concept of Nitrosogenesis (as a form of genetic weapon) and melanoma for example, but not only, it remains to be seen whether universal incompetence will become a guarantee of competence and the survival. Or- will it remain again at the level of globalized, criminally conditioned, appointed and regulated from above "competent incompetence". The dilemmas to regulators and manufacturers remain open : Is it competent to take drugs that contain carcinogens/nitrosamines? Is it competent for this issue to continue for decades with impunity? Is it competent for regulators not to inform consumers about the presence of carcinogens/genome modifiers in medicines for decades? Is it competent for certain regions to be affected by nitrosamine contamination and not others? Is it competent not to reflect this in regional and global health bulletins on side effects? Is it competent to make thousands of times the profits from the modified genetic map business, regulated and legally initiated through the intake of carcinogens? Is it competent to have the concentration of carcinogens within polymedication exceeding many times the daily allowable doses of carcinogens and have no solution for this? Is it competent, when the intake of nitrosamines in medicines is associated with the generation of melanomas and heterogeneous cancers- to have no alternative to this or when one is available- to conceal it skillfully? Is it competent to determine carcinogenic activity based on mutagenic tests? Is it competent to be polyincompetent within a framework of mass (in)competence? We report systemically administered drugs for the treatment of high blood pressure from the group of beta blockers (bisoprolol/nebivolol) and ACE inhibitors (perindopril) that have been identified by regulators in the face of FDA as hypothetically contaminated with nitrosamines/NDSRIs with a carcinogenic potency between 4 and 5, respectively. Within this cumulative intake, (which according to the regulators was not at risk of developing cancerous forms), similar to other cases in the world literature, the patient developed a relatively short-term, metastatic nevus spilus-based nodular melanoma. The paper analyses not only the role of nitrosogenesis, but also that of two pregnancies and painful sunburns as potential cofactors for melanoma genesis. Academic attention is drawn to the potential impact of drug-mediated nitrosogenesis/carcinogenesis. Nitrosamines in the framework of polycontamination and polymedication could also be identified as one of the most effective, until recently unknown, modern generation genetic weapons for modifying the human genome and controlling cancer. Moreover, they could be controllably applied and skillfully targeted. At least until now. The officialization of carcinogens in more than 250 of the most common drugs and the clinico-pathological correlations concerning the development of cancer/melanoma in poorly controlled geographical regions represent a kind of in vivo prospective study to determine precisely the real carcinogenic role of nitrosamines to date.


Combined chemotherapy and radiotherapy improves survival in 1897 testicular Lymphoma patients from a contemporary cohort.
The standard of care (SOC) for primary testicular lymphoma (PTL) is orchiectomy, chemotherapy (CHT), and radiotherapy (RT). We hypothesized that men may not receive SOC and may have worse outcomes. To assess this, we queried the National Cancer Database (NCDB) to analyze treatment patterns and survival in PTL patients. The NCDB was queried (2006-2016) for men diagnosed with extranodal lymphoma with primary site testis. Patients were placed in 2 treatment groups (1) orchiectomy with chemotherapy plus radiotherapy (CHT + RT), named the SOC group; and 2) CHT + orchiectomy, or RT + orchiectomy, or orchiectomy alone, grouped as non-SOC. Propensity score matching and Kaplan-Meier analysis were used to investigate 5-year overall survival (OS). Two thousand two hundred thirty-two men with PTL underwent orchiectomy. After exclusions, 891 men were included in the SOC group and 1,006 men were included in the non-SOC group. KM analysis showed 5-year OS was significantly higher in the SOC group vs. non-SOC for all stages (hazard ratio = 0.54, with 95% confidence interval 0.45 to 0.65, P < 0.0001). This study represents one of the largest PTL cohort reported to date reflecting current treatments and shows men receiving standard of care treatment have significantly improved survival. Additionally, analysis reveals that most men included in the NCDB do not receive the standard of care.


A dynamic network population model with strategic link formation governed by individual preferences.
Historically most evolutionary models have considered infinite populations with no structure. Recently more realistic evolutionary models have been developed using evolutionary graph theory, which considered the evolution of structured populations. The structures involved in these populations are typically fixed, however, and real populations change their structure over both long and short time periods. In this paper we consider the dynamics of such a population structure. The timescales involved are sufficiently short that no individuals are born or die, but the links between individuals are in a constant state of flux, being actively governed by the preferences of the members of the population. The process is modelled using a Markov chain over the possible structures. We find that under the specified process the population evolves to a closed class of structures, and we show a method to find the stationary distribution on this class. We also consider some special cases of interest.


Dietary antioxidants remodel DNA methylation patterns in chronic disease.
Chronic diseases account for over 60% of all deaths worldwide according to the World Health Organization reports. Majority of cases are triggered by environmental exposures that lead to aberrant changes in the epigenome, specifically, the DNA methylation patterns. These changes result in altered expression of gene networks and activity of signalling pathways. Dietary antioxidants, including catechins, flavonoids, anthocyanins, stilbenes and carotenoids, demonstrate benefits in the prevention and/or support of therapy in chronic diseases. This review provides a comprehensive discussion of potential epigenetic mechanisms of antioxidant compounds in reversing altered patterns of DNA methylation in chronic disease. Antioxidants remodel the DNA methylation patterns through multiple mechanisms, including regulation of epigenetic enzymes and chromatin remodelling complexes. These effects can further contribute to antioxidant properties of the compounds. On the other hand, decrease in oxidative stress itself can impact DNA methylation delivering additional link between antioxidant mechanisms and epigenetic effects of the compounds. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.


Assessment of ocular biomechanics using dynamic ultra high-speed Scheimpflug imaging in keratoconic and normal eyes.
To introduce several new ocular biomechanical parameters for comparison between keratoconic and normal eyes using an analysis method based on corneal dynamic deformation video recorded by corneal visualization Scheimpflug technology (Corvis ST; Oculus Optikgeräte GmbH, Wetzlar, Germany). This comparative study comprised 52 keratoconic eyes of 43 patients with keratoconus and 52 normal eyes of 52 controls. An analysis method (PolyU [Labview 2009; National Instrument, Austin, TX]) was developed to introduce several new ocular biomechanical parameters and to compare the difference between keratoconic and normal eyes. The repeatability of the new parameters measurement was evaluated and compared with the Corvis ST measurement. Receiver operating characteristic curves were used to establish a cutoff value for the new biomechanical parameters. Intraclass correlation coefficients of the deformation amplitude, peak distance, corneal concave radius of curvature, maximum deformation area, maximum corneal inward velocity and outward velocity (Vin, max and Vout, max) were high in both the keratoconic and normal eyes (all intraclass correlation coefficients > 0.75). The measurement agreement of the PolyU analysis method and Corvis ST was good. Most of the biomechanical parameters of patients with keratoconus were significantly different from those of the controls. In the receiver operating characteristic analysis, the Vin, max was the best predictive parameter with an area under the curve of 0.79. The corneal deformation video recorded by the Corvis ST provides useful information for the study of ocular biomechanics. Most of the new ocular biomechanical parameters were significantly different between keratoconic and normal eyes. Further research is needed to develop more comprehensive clinical applications with these new ocular biomechanical parameters.


[Driver's licence: responsibility, ethics and deontology].
The new law enacted on march 23rd 1998 regarding driving-licence, which became effective on october 1st 1998, modifies the method for obtaining the different types of driving-licences. Its 6th annex enumerates a list of physical impairments and pathologies implying the denial, the limitation or the withdrawal of the driving-licence; it determines if a medical advice, and if the case which kind of medical advice, is required. This leads to new situations, for which no jurisprudence has been established to date, where not only the responsibility of the licence's applicant but also that of the examining physician could be suspected. The physicians are also confronted to ethical an deontological problems on which the medical authorities have not always given an opinion. This paper examines them in order to give some bases for reflexion and discussion.


Actin Turnover in Lamellipodial Fragments.
Actin turnover is the central driving force underlying lamellipodial motility. The molecular components involved are largely known, and their properties have been studied extensively in vitro. However, a comprehensive picture of actin turnover in vivo is still missing. We focus on fragments from fish epithelial keratocytes, which are essentially stand-alone motile lamellipodia. The geometric simplicity of the fragments and the absence of additional actin structures allow us to characterize the spatiotemporal lamellipodial actin organization with unprecedented detail. We use fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, and extraction experiments to show that about two-thirds of the lamellipodial actin diffuses in the cytoplasm with nearly uniform density, whereas the rest forms the treadmilling polymer network. Roughly a quarter of the diffusible actin pool is in filamentous form as diffusing oligomers, indicating that severing and debranching are important steps in the disassembly process generating oligomers as intermediates. The remaining diffusible actin concentration is orders of magnitude higher than the in vitro actin monomer concentration required to support the observed polymerization rates, implying that the majority of monomers are transiently kept in a non-polymerizable "reserve" pool. The actin network disassembles and reassembles throughout the lamellipodium within seconds, so the lamellipodial network turnover is local. The diffusible actin transport, on the other hand, is global: actin subunits typically diffuse across the entire lamellipodium before reassembling into the network. This combination of local network turnover and global transport of dissociated subunits through the cytoplasm makes actin transport robust yet rapidly adaptable and amenable to regulation.


Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases.
Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson's disease (PD), and Friedreich's ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.


CD49d associates with nodal presentation and subsequent development of lymphadenopathy in patients with chronic lymphocytic leukaemia.
CD49d is a surface integrin that is expressed on chronic lymphocytic leukaemia (CLL) cells, and strongly correlates with more aggressive disease. Given its association with cell-cell adhesion and leucocyte trafficking, we hypothesized that patients with high CD49d expression would experience a clinical course dominated by lymphadenopathy. CD49d expression was measured by flow cytometry and considered positive if expressed by ≥30% of CLL cells. The study included 797 newly diagnosed CLL/small lymphocytic leukaemia patients; 279 (35%) were CD49d positive. CD49d-positive patients were more likely to present with lymphadenopathy (P < 0·001); a finding that persisted after adjusting for fluorescence in situ hybridisation (FISH) and IGHV mutation status [odds ratio (OR) 2·51; 95% confidence interval (CI) 1·64-3·83; P < 0·001]. Among CLL Rai 0 patients, CD49d positivity was associated with shorter time to development of lymphadenopathy (3·2 years vs not reached, P < 0·01). This association was maintained after adjusting for either FISH [hazard ratio (HR) 2·18; 95% CI 1·25-3·81; P = 0·006) or IGHV status (HR 2·02; 95% CI 1·11-3·69; P = 0·02) individually, but was attenuated when adjusting by both (HR 1·72; 95% CI 0·88-3·38; P = 0·11).These data demonstrate that CD49d-positive CLL patients experience a disease course dominated by lymphadenopathy. These findings could have implications for therapy selection and disease monitoring.


Mobility Skills With Exoskeletal-Assisted Walking in Persons With SCI: Results From a Three Center Randomized Clinical Trial.
Background: Clinical exoskeletal-assisted walking (EAW) programs for individuals with spinal cord injury (SCI) have been established, but many unknown variables remain. These include addressing staffing needs, determining the number of sessions needed to achieve a successful walking velocity milestone for ambulation, distinguishing potential achievement goals according to level of injury, and deciding the number of sessions participants need to perform in order to meet the Food and Drug Administration (FDA) criteria for personal use prescription in the home and community. The primary aim of this study was to determine the number of sessions necessary to achieve adequate EAW skills and velocity milestones, and the percentage of participants able to achieve these skills by 12 sessions and to determine the skill progression over the course of 36 sessions. Methods: A randomized clinical trial (RCT) was conducted across three sites, in persons with chronic (≥6 months) non-ambulatory SCI. Eligible participants were randomized (within site) to either the EAW arm first (Group 1), three times per week for 36 sessions, striving to be completed in 12 weeks or the usual activity arm (UA) first (Group 2), followed by a crossover to the other arm for both groups. The 10-meter walk test seconds (s) (10MWT), 6-min walk test meters (m) (6MWT), and the Timed-Up-and-Go (s) (TUG) were performed at 12, 24, and 36 sessions. To test walking performance in the exoskeletal devices, nominal velocities and distance milestones were chosen prior to study initiation, and were used for the 10MWT (≤ 40s), 6MWT (≥80m), and TUG (≤ 90s). All walking tests were performed with the exoskeletons. Results: A total of 50 participants completed 36 sessions of EAW training. At 12 sessions, 31 (62%), 35 (70%), and 36 (72%) participants achieved the 10MWT, 6MWT, and TUG milestones, respectively. By 36 sessions, 40 (80%), 41 (82%), and 42 (84%) achieved the 10MWT, 6MWT, and TUG criteria, respectively. Conclusions: It is feasible to train chronic non-ambulatory individuals with SCI in performance of EAW sufficiently to achieve reasonable mobility skill outcome milestones.


NiPTUNE: an automated pipeline for noninvasive prenatal testing in an accurate, integrative and flexible framework.
Noninvasive prenatal testing (NIPT) consists of determining fetal aneuploidies by quantifying copy number alteration from the sequencing of cell-free DNA (cfDNA) from maternal blood. Due to the presence of cfDNA of fetal origin in maternal blood, in silico approaches have been developed to accurately predict fetal aneuploidies. Although NIPT is becoming a new standard in prenatal screening of chromosomal abnormalities, there are no integrated pipelines available to allow rapid, accurate and standardized data analysis in any clinical setting. Several tools have been developed, however often optimized only for research purposes or requiring enormous amount of retrospective data, making hard their implementation in a clinical context. Furthermore, no guidelines have been provided on how to accomplish each step of the data analysis to achieve reliable results. Finally, there is no integrated pipeline to perform all steps of NIPT analysis. To address these needs, we tested several tools for performing NIPT data analysis. We provide extensive benchmark of tools performances but also guidelines for running them. We selected the best performing tools that we benchmarked and gathered them in a computational pipeline. NiPTUNE is an open source python package that includes methods for fetal fraction estimation, a novel method for accurate gender prediction, a principal component analysis based strategy for quality control and fetal aneuploidies prediction. NiPTUNE is constituted by seven modules allowing the user to run the entire pipeline or each module independently. Using two cohorts composed by 1439 samples with 31 confirmed aneuploidies, we demonstrated that NiPTUNE is a valuable resource for NIPT analysis.


Coronary vasculitis. A review in the current scheme of classification of vasculitis.
Coronary artery disease is overwhelmingly atherosclerotic in nature, but inflammatory disease of the coronary arteries can be just as life-threatening a cause of ischemic heart disease in all age groups. Coronary vasculitis is not short in variety; as a clinicopathologic entity it spans the entire spectrum of systemic vasculitides. Coronary vasculitis is most closely associated with the polyarteritis group of necrotizing angiitis, vasculitis of collagen-vascular disease, and granulomatous giant cell arteritis. This article provides an overview of coronary vasculitis as an independent entity as well as a manifestation of systemic vasculitis, both the common and the uncommon varieties.


Detailed analysis of pro-apoptotic signaling and metabolic adaptation triggered by a N-heterocyclic carbene-gold(I) complex.
Due to their broad spectrum of biological activity and antiproliferative effect on different human cancer cell lines, gold compounds have been in the focus of drug research for many years. Gold(I)-N-heterocyclic carbene complexes are of particular interest, because of their stability, ease of derivatization and clear cytotoxicity in cancer cells. To obtain a more detailed view of the molecular mechanisms underlying their cellular activity, we used a novel gold(I)-N-heterocyclic carbene complex, [triphenylphosphane-(1,3-diethyl-5-methoxy-benzylimidazol-2-ylidene)]gold(I) iodide and investigated changes in cellular signaling pathways using quantitative signal transduction protein microarray analysis. We also analyzed changes in cell metabolism in a time-dependent manner by on-line metabolic measurements and used isolated mitochondria to elucidate the direct effects on this cell organelle. We found strong cytotoxic effects in cancer cells, accompanied by an immediate and irreversible loss of mitochondrial respiration as well as by a crucial imbalance of the intracellular redox state, resulting in apoptotic cell death. ELISA microarray analysis of signal transduction pathways revealed a time-dependent up-regulation of pro-apoptotic signaling proteins, e.g. p38 and JNK, whereas pro-survival signals that are directly linked to the thioredoxin system were down-regulated, which pinpoints to thioredoxin reductase as a central target of the compound. Further results suggest that DNA is an indirect target of the compound. Based on our findings, we outline a signaling model for the molecular mechanism underlying the antiproliferative activity of the gold(I)-N-heterocyclic carbene complex investigated, which provides a good general model for the known pattern of cell death induced by this class of substances.


Perioperative corticosteroids administration as a risk factor for pressure ulcers in cardiovascular surgical patients: a retrospective study.
The aim of this study was to investigate the relationship between perioperative corticosteroids administration and the incidence of pressure ulcers (PUs) in cardiovascular surgical patients. A retrospective analysis was performed on data from consecutive patients who had cardiac surgery in 2012. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between perioperative corticosteroid administration and the incidence of surgery-related PU (SRPU). A total of 286 cardiac surgery patients were included in this study; of these, 47 patients developed 57 SRPUs, an incidence of 16·4% [95% confidence interval (CI): 12·3-21·2%). The SRPU incidence was significantly higher in corticosteroid-administered group compared with groups not receiving corticosteroids (43·8% versus 14·8%, Pearson's χ(2) = 9·209, P = 0·002). The crude odds ratio (OR) was 4·472 (95% CI: 1·576-12·694). After performing multivariate logistic regression analysis, the adjusted OR was 2·808 (95% CI: 1·062-11·769). This result showed that perioperative corticosteroid administration was an independent risk factor for PUs in cardiovascular surgical patients. Therefore, it is recommended that in order to prevent PU perioperative corticosteroids should be administered with caution to cardiovascular surgical patients.


In Situ Proteome Profiling and Bioimaging Applications of Small-Molecule Affinity-Based Probes Derived From DOT1L Inhibitors.
DOT1L is the sole protein methyltransferase that methylates histone H3 on lysine 79 (H3K79), and is a promising drug target against cancers. Small-molecule inhibitors of DOT1L such as FED1 are potential anti-cancer agents and useful tools to investigate the biological roles of DOT1L in human diseases. FED1 showed excellent in vitro inhibitory activity against DOT1L, but its cellular effect was relatively poor. In this study, we designed and synthesized photo-reactive and "clickable" affinity-based probes (AfBPs), P1 and P2, which were cell-permeable and structural mimics of FED1. The binding and inhibitory effects of these two probes against DOT1L protein were extensively investigated in vitro and in live mammalian cells (in situ). The cellular uptake and sub-cellular localization properties of the probes were subsequently studied in live-cell imaging experiments, and our results revealed that, whereas both P1 and P2 readily entered mammalian cells, most of them were not able to reach the cell nucleus where functional DOT1L resides. This offers a plausible explanation for the poor cellular activity of FED1. Finally with P1/P2, large-scale cell-based proteome profiling, followed by quantitative LC-MS/MS, was carried out to identify potential cellular off-targets of FED1. Amongst the more than 100 candidate off-targets identified, NOP2 (a putative ribosomal RNA methyltransferase) was further confirmed to be likely a genuine off-target of FED1 by preliminary validation experiments including pull-down/Western blotting (PD/WB) and cellular thermal shift assay (CETSA).


Intravascular activation of complement and acute lung injury. Dependency on neutrophils and toxic oxygen metabolites.
Intravascular activation of the complement system with cobra venom factor results in acute lung injury, which has been quantitated by increases in lung vascular permeability. Cobra venom factor preparations devoid of phospholipase A2 activity retain full lung-damaging capacity. The lung injury is associated with the preceding appearance of chemotactic activity in the serum coincident with the development of a profound neutropenia. The chemotactic activity is immunochemically related to human C5a. Morphologic studies have revealed discontinuities in the endothelial cell lining of lung alveolar capillaries, damage and/or destruction of endothelial cells in these areas, plugging of pulmonary capillaries with neutrophils that are in direct contact with vascular basement membrane, the presence of fibrin in alveolar spaces and in areas adjacent to damaged endothelial cells, and intraalveolar hemorrhage. Lung injury is dramatically attenuated in animals that have been previously neutrophil depleted. Teh intravenous injection of superoxide dismutase or catalase also provides significant protection from the pulmonary damage. Very little protection from the pulmonary damage. Very little protection is afforded by pretreatment of rats with antihistamine. These studies suggest that intravascular activation of the complement system leads to neutrophil aggregation and activation, intrapulmonary capillary sequestration of neutrophils, and vascular injury, which may be related to production of toxic oxygen metabolites by complement-activated neutrophils.


Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
Objective To assess risk of cancer in patients with childhood onset inflammatory bowel disease in childhood and adulthood.Design Cohort study with matched general population reference individuals using multivariable Cox regression to estimate hazard ratios.Setting Swedish national patient register (both inpatient and non-primary outpatient care) 1964-2014.Participants Incident cases of childhood onset (<18 years) inflammatory bowel disease (n=9405: ulcerative colitis, n=4648; Crohn's disease, n=3768; unclassified, n=989) compared with 92 870 comparators from the general population matched for sex, age, birth year, and county.Main outcome measures Any cancer and cancer types according to the Swedish Cancer Register.Results During follow-up through adulthood (median age at end of follow-up 27 years), 497 (3.3 per 1000 person years) people with childhood onset inflammatory bowel disease had first cancers, compared with 2256 (1.5 per 1000 person years) in the general population comparators (hazard ratio 2.2, 95% confidence interval 2.0 to 2.5). Hazard ratios for any cancer were 2.6 in ulcerative colitis (2.3 to 3.0) and 1.7 in Crohn's disease (1.5 to 2.1). Patients also had an increased risk of cancer before their 18th birthday (2.7, 1.6 to 4.4; 20 cancers in 9405 patients, 0.6 per1000 person years). Gastrointestinal cancers had the highest relative risks, with a hazard ratio of 18.0 (14.4 to 22.7) corresponding to 202 cancers in patients with inflammatory bowel disease. The increased risk of cancer (before 25th birthday) was similar over time (1964-1989: 1.6, 1.0 to 2.4; 1990-2001: 2.3, 1.5 to 3.3); 2002-06: 2.9, 1.9 to 4.2; 2007-14: 2.2, 1.1 to 4.2).Conclusion Childhood onset inflammatory bowel disease is associated with an increased risk of any cancer, especially gastrointestinal cancers, both in childhood and later in life. The higher risk of cancer has not fallen over time.


Intrahepatic Toll-Like Receptor 3 in Chronic HBV Infection Subjects: Asymptomatic Carriers, Active Chronic Hepatitis, Cirrhosis, and Hepatocellular Carcinoma.
The entire disease spectrum of chronic HBV infection (CHB) includes asymptomatic carriers (AC), active chronic hepatitis (ACH), cirrhosis (Cir), and hepatocellular carcinoma (HCC). Previous study have demonstrated that the costimulation profiles from the livers of patients influenced immune responses and played various immunological roles in AC, ACH, Cir, and HCC. In addition, activation of TLR3 signaling in the liver may contribute to HBV clearance, although some HBV components are able to block TLR3 signaling and counteract HBV clearance through positive or negative feedback loops. Previous clinical studies have demonstrated that different TLR3 expressions are present in ACH patients, but no studies investigated the expression of TLR3 proteins in the livers of patients with AC, Cir, or HCC. This study investigated intrahepatic TLR3 expression throughout the entire disease spectrum of CHB patients and assessed the interrelations between TLR3 and costimulation proteins. Patients with ACH, Cir, HCC, and AC and healthy donors (HD) were recruited. TLR3 expression in the livers of patients were investigated using western blot analysis and immunohistochemistry. Correlations between TLR3 and costimulation proteins, including CD80, CD86, CD83, CD28, CTLA-4, CD40, and ICAM-1, were assessed. The TLR3 protein in the ACH group tended toward reduction although the P Value of the comparison between the ACH group and HD group was not statistically significant. The TLR3 levels in the HCC, AC, and Cir groups were higher than those in the HD and ACH groups. TLR3 was not interrelated with all costimulation proteins in the DCs and T cells in all five groups. No group presented any interrelation between TLR3 and CD40, except the AC group. The AC, HCC, and Cir patients displayed increased levels of the intrahepatic TLR3 protein compared to the HD and AC patients. Both activation of TLR3/INF-β signaling and inhibition of TLR3/INF-β signaling by HBV components influenced TLR3 expression in the AC, ACH, Cir, and HCC subjects. However, TLR3 signaling did not influence the expression of costimulatory protein in the ACH, Cir, or HCC patients. TLR3/ IFN-β signaling did influence immune responses in the livers of CHB patients.


The structural, compositional and mechanical features of the calcite shell of the barnacle Tetraclita rufotincta.
The microstructure and chemical composition of the calcite shell of the sea barnacle Tetraclita rufotincta (Pilsbry, 1916) were investigated using microscopic and analytical methods. The barnacle shell was separated mechanically into its three substructural units: outer, interior, and inner layers. The organic matrices of these structural parts were further separated into soluble and insoluble constituents and their characteristic functional groups were studied by FTIR. Investigation of the mechanical properties of the interior mass of the shell reveals remarkable viscoelastic behavior. In general, the mechanical behavior of the shell is a function of its geometry as well as of the material, of which it is constructed. In the case of T. rufotincta, as calcite is a brittle material, the elastic behavior of the shell is apparently related to its micro- and macroarchitecture. The latter enables the shell to fulfill its primary function which is to protect the organism from a hostile environment and enables its survival. Our detailed identification of the similarities and differences between the various structural components of the shell in regard to the composition and properties of the organic component will hopefully throw light on the role of organic matrices in biomineralization processes.


Systematic biological prioritization after a genome-wide association study: an application to nicotine dependence.
A challenging problem after a genome-wide association study (GWAS) is to balance the statistical evidence of genotype-phenotype correlation with a priori evidence of biological relevance. We introduce a method for systematically prioritizing single nucleotide polymorphisms (SNPs) for further study after a GWAS. The method combines evidence across multiple domains including statistical evidence of genotype-phenotype correlation, known pathways in the pathologic development of disease, SNP/gene functional properties, comparative genomics, prior evidence of genetic linkage, and linkage disequilibrium. We apply this method to a GWAS of nicotine dependence, and use simulated data to test it on several commercial SNP microarrays. A comprehensive database of biological prioritization scores for all known SNPs is available at http://zork.wustl.edu/gin. This can be used to prioritize nicotine dependence association studies through a straightforward mathematical formula-no special software is necessary. Supplementary data are available at Bioinformatics online.


[Results of endovascular interventions (embolization and chemoembolization) in the treatment of operable and extensive kidney cancer].
The results of an all-round examination and complex treatment of 323 patients with renal cell carcinoma were evaluated. Locally advanced tumors were diagnosed in 143 (44.3%) and extended ones--in 180 (66.7%). In patients with locally advanced tumor who had undergone nephrectomy after embolization or chemoembolization, 12-, 24- and 36-month survival rates showed no significant difference. In patients with extended renal carcinoma, 2- and 3-year survival was significantly higher after chemoembolization than after standard embolization of the renal artery.


Divalent minerals decrease micellarization and uptake of carotenoids and digestion products into Caco-2 cells.
Carotenoids are lipophilic, dietary antioxidants with the potential to prevent chronic and age-related diseases. Prior to their availability for physiological functions, carotenoids require micellarization and intestinal uptake, both constituting marginally understood processes. Based on an in vitro digestion model coupled to Caco-2 cells, we assessed the effect of dietary abundant divalent ions on spinach-derived carotenoid micellarization and cellular uptake: Ca and Mg ranging from 7.5 to 25 mmol/L in the digesta and Zn and Fe ranging from 3.8 to 12.5 mmol/L. Both micellarization and uptake were significantly inhibited by minerals in a concentration-dependent manner, with stronger effects for Fe and Zn compared to Ca and Mg. Compared to controls (no mineral addition), fractional micellarization and uptake were decreased to the greatest extent (to 22.5 and 5.0%, respectively; P < 0.001) by 12.5 mmol/L Fe. Effects of Mg were of the least magnitude; at 25 mmol/L, only uptake was decreased significantly to 69.2% of the control value (P < 0.001). Total cellular carotenoid uptake from test meals decreased similarly compared to micellarization; however, decreased β-carotene micellarization was counterbalanced by improved fractional cellular uptakes from the micelles for all ions. Compared to controls, fractional β-carotene uptake from the micelles was greater in samples digested in the presence of Fe, Ca, and Zn, by up to 5-10 times at the highest concentrations of each ion (P < 0.001). Like for the above carotenoids, a high cellular uptake of the epoxycarotenoid conversion products neochrome (from neoxanthin) and luteoxanthin+auroxanthin (from violaxanthin) was also observed. The present results indicate that divalent ions may inhibit carotenoid micellarization and uptake.


Phycocomes zhengii gen. nov., sp. nov., a marine bacterium of the family Rhodobacteraceae isolated from the phycosphere of Chlorella vulgaris.
A Gram-stain-negative, motile with flagellum, ovoid- or rod-shaped, aerobic bacterium, was isolated from the phycosphere of the microalga Chlorellavulgaris and designated as strain LMIT002T. The bacterium formed white, circular and smooth colonies on marine agar 2216 after 48 h incubation at 25 °C. On the basis of 16S rRNA gene sequence analysis, strain LMIT002T was found to be affiliated with the family Rhodobacteraceae of the order Rhodobacterales, and formed a distinct group. The 16S rRNA gene sequence similarities between strain LMIT002T and type strains in the family including Poseidonocella pacifica DSM 29316T, Roseobacter litoralis and Rhodovulum sulfidophilum were 95.1, 95.0 and 95.0 %, respectively. Strain LMIT002Tgrew optimally at 25 °C, pH 6.0 and in the presence of 2.0 % (w/v) NaCl. The genomic DNA G+C content was 67.0 mol% (the thermal denaturation method) or 66.9 % (genome sequencing). The sole respiratory quinone was ubiquinone-8, while the major fatty acids were summed feature 8 (C18 : 1 ω7с/C18 : 1 ω6с). The draft genome of strain LMIT002T was sequenced and annotated, with the results showing that it had a total size of 4 607 780 bp and comprised 4557 genes. Functional genes encoding the production of vitamin B12, indole-3-acetic acid and transform dimethylsulphoniopropionate were detected. Given its distinct genomic, morphological and physiological differences from previously described type strains, strain LMIT002T is proposed as a representative of a novel genus of the family Rhodobacteraceae, with the name Phycocomes zhengii gen. nov., sp. nov. The type strain is LMIT002T (=KCTC 62390T=CICC 24357T).


Evidence for NMDA and mGlu receptor-dependent long-term potentiation of mossy fiber-granule cell transmission in rat cerebellum.
Long-term potentiation (LTP) is a form of synaptic plasticity that can be revealed at numerous hippocampal and neocortical synapses following high-frequency activation of N-methyl--aspartate (NMDA) receptors. However, it was not known whether LTP could be induced at the mossy fiber-granule cell relay of cerebellum. This is a particularly interesting issue because theories of the cerebellum do not consider or even explicitly negate the existence of mossy fiber-granule cell synaptic plasticity. Here we show that high-frequency mossy fiber stimulation paired with granule cell membrane depolarization (-40 mV) leads to LTP of granule cell excitatory postsynaptic currents (EPSCs). Pairing with a relatively hyperpolarized potential (-60 mV) or in the presence of NMDA receptor blockers [5-amino--phosphonovaleric acid (APV) and 7-chloro-kynurenic acid (7-Cl-Kyn)] prevented LTP, suggesting that the induction process involves a voltage-dependent NMDA receptor activation. Metabotropic glutamate receptors were also involved because blocking them with (+)-alpha-methyl-4-carboxyphenyl-glycine (MCPG) prevented potentiation. At the cytoplasmic level, EPSC potentiation required a Ca2+ increase and protein kinase C (PKC) activation. Potentiation was expressed through an increase in both the NMDA and non-NMDA receptor-mediated current and by an NMDA current slowdown, suggesting that complex mechanisms control synaptic efficacy during LTP. LTP at the mossy fiber-granule cell synapse provides the cerebellar network with a large reservoir for memory storage, which may be needed to optimize pattern recognition and, ultimately, cerebellar learning and computation.


Machine Learning the Voltage of Electrode Materials in Metal-Ion Batteries.
Machine-learning (ML) techniques have rapidly found applications in many domains of materials chemistry and physics where large data sets are available. Aiming to accelerate the discovery of materials for battery applications, in this work, we develop a tool ( http://se.cmich.edu/batteries ) based on ML models to predict voltages of electrode materials for metal-ion batteries. To this end, we use deep neural network, support vector machine, and kernel ridge regression as ML algorithms in combination with data taken from the Materials Project database, as well as feature vectors from properties of chemical compounds and elemental properties of their constituents. We show that our ML models have predictive capabilities for different reference test sets and, as an example, we utilize them to generate a voltage profile diagram and compare it to density functional theory calculations. In addition, using our models, we propose nearly 5000 candidate electrode materials for Na- and K-ion batteries. We also make available a web-accessible tool that, within a minute, can be used to estimate the voltage of any bulk electrode material for a number of metal ions. These results show that ML is a promising alternative for computationally demanding calculations as a first screening tool of novel materials for battery applications.


A comparison of the psychosocial aspects of AIDS and cancer-related bereavement.
This study compares the psychological symptoms and bereavement distress of individuals bereaved by AIDS with a group bereaved by a cancer death, and addresses the question of whether an AIDS death is associated with a higher rate of adverse psychosocial factors that may increase risk of psychological morbidity in the bereaved individuals. AIDS (n = 28) and cancer (n = 30) bereaved individuals (all within 3 months of the bereavement) completed measures of psychological morbidity and measures addressing a range of other adverse factors, e.g., number of losses, levels of social support and stigma. The cancer and AIDS bereaved were essentially similar on all psychological symptom measures. The AIDS group reported lower levels of social support in response to the bereavement than cancer bereaved individuals; a greater number of bereavements, were more likely to conceal the cause of death from significant others including their own family and perceived, in some instances, a greater level of rejection from others. The AIDS group reported higher levels of social support from friends than from family. At three months following bereavement, AIDS and cancer bereaved were similar in levels of distress. While this may change with the progress of grief over time, it suggests essentially similar early bereavement responses. Those bereaved by AIDS reported a range of other adverse factors such as a greater number of losses, lower social support, stigma, and less open disclosure of the cause of death.


Feasibility and Acceptability of Adapting the Eating in the Absence of Hunger Assessment for Preschoolers in the Classroom Setting.
Eating in the Absence of Hunger (EAH) represents a failure to self-regulate intake leading to overconsumption. Existing research on EAH has come from the clinical setting, limiting our understanding of this behavior. The purpose of this study was to describe the adaptation of the clinical EAH paradigm for preschoolers to the classroom setting and evaluate the feasibility and acceptability of measuring EAH in the classroom. The adapted protocol was implemented in childcare centers in Houston, Texas (N=4) and Phoenix, Arizona (N=2). The protocol was feasible, economical, and time efficient, eliminating previously identified barriers to administering the EAH assessment such as limited resources and the time constraint of delivering the assessment to participants individually. Implementation challenges included difficulty in choosing palatable test snacks that were in compliance with childcare center food regulations and the limited control over the meal that was administered prior to the assessment. The adapted protocol will allow for broader use of the EAH assessment and encourage researchers to incorporate the assessment into longitudinal studies in order to further our understanding of the causes and emergence of EAH.


Antidepressants use is associated with overall survival improvement of patients with gastric cancer after surgery and adjuvant chemotherapy in Taiwan: A large population-based cohort study.
To determine whether exposure to antidepressants (ATDs) results in improved overall survival (OS) of patients with gastric cancer (GC) after surgery, we conducted a large cohort study and considered confounding factors that might affect the research outcomes.Patients who received a new diagnosis of GC and received surgery and chemotherapy between 1999 and 2008 were recruited and were classified into different groups based on the ATD level used. The association between the OS of patients with GC after surgery with different levels of ATD use, and the hazard ratio with comorbidities at different ATD use levels were compared.According to Kaplan-Meier method, the more of an ATD was taken, the longer the OS and a dose-dependent relationship was discovered in the OS curve; the adjusted HRs were 0.76 (95% confidence interval [CI] = 0.68-0.84) and 0.48 (95% CI = 0.41-0.57) for ATD users taking a cumulative defined daily dose (cDDD) of 28-167 and ≧168, respectively. Sensitivity analyzes were performed to investigate the effect of various comorbidities on OS with different degrees of ATD use and the results remained consistent among the varying models. Additionally, the effect of ATD use still exhibited a dose-dependent relationship in distinct stratifications for sex and age.The OS for patients with GC after surgery and chemotherapy improved with ATD use, and a dose-dependent relationship was discovered in this study. Further studies on the association between OS of GC and ATD use are required.


Out of sight, out of mind: a prospective observational study to estimate the duration of the Hawthorne effect on hand hygiene events.
Human auditing has been the gold standard for evaluating hand hygiene (HH) compliance but is subject to the Hawthorne effect (HE), the change in subjects' behaviour due to their awareness of being observed. For the first time, we used electronic HH monitoring to characterise the duration of the HE on HH events after human auditors have left the ward. Observations were prospectively conducted on two transplant wards at a tertiary centre between May 2018 and January 2019. HH events were measured using the electronic GOJO Smartlink Activity Monitoring System located throughout the ward. Non-covert human auditing was conducted in 1-hour intervals at random locations on both wards on varying days of the week. Two adjusted negative binomial regression models were fit in order to estimate an overall auditor effect and a graded auditor effect. In total, 365 674 HH dispensing events were observed out of a possible 911 791 opportunities. In the adjusted model, the presence of an auditor increased electronic HH events by approximately 2.5-fold in the room closest to where the auditor was standing (9.86 events per hour/3.98 events per hour; p<0.01), an effect sustained across only the partial hour before and after the auditor was present but not beyond the first hour after the auditor left. This effect persisted but was attenuated in areas distal from the auditor (total ward events of 6.91*6.32-7.55, p<0.01). Additionally, there was significant variability in the magnitude of the HE based on temporal and geographic distribution of audits. The HE on HH events appears to last for a limited time on inpatient wards and is highly dynamic across time and auditor location. These findings further challenge the validity and value of human auditing and support the need for alternative and complementary monitoring methods.


The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis.
Fatty liver disease involves the accumulation of triglycerides in hepatocytes, necrosis of hepatocytes, inflammation, and often fibrosis with progression to cirrhosis. The two-hit model summarizes the important early metabolic events leading to hepatocellular necrosis in nonalcoholic steatohepatitis (NASH). In this article, we provide evidence of lipid release from hepatocytes in posttransplant fat necrosis and in NASH and quantify vascular obliteration in a series of biopsies with NASH. Obliteration of small hepatic veins (<30 microm) in small numbers is compensated by collateral flow. Obliteration of larger hepatic veins (>30 microm) is associated with fibrotic collapse lesions that are not easily resorbed. Based on these observations, we propose a new four-step model that includes the later events that lead to cirrhosis after necrosis has occurred. This model is applicable to nonalcoholic fatty liver disease (NAFLD), alcoholic disease, postjejunoileal bypass disease, and posttransplant fat necrosis. The first step is steatosis facilitated by insulin, and the second is necrosis induced by intracellular lipid toxicity or lipid peroxidation, or both, modified by alcohol, drugs, and ischemia. The third step is release of bulk lipid from hepatocytes into the interstitium leading to direct and inflammatory injury to hepatic veins. The fourth step is venous obstruction with secondary collapse and ultimately fibrous septation and cirrhosis.


Idiopathic Granulomatous Mastitis: Comparison of Wide Local Excision with or without Corticosteroid Therapy.
Idiopathic granulomatous mastitis (IGM) is an uncommon chronic inflammatory disease of the breast with uncertain optimal treatment regimen. In this study, our purpose was to report our clinical experience with 74 IGM patients who were treated wide local excision with or without steroid therapy. 74 cases diagnosed histologically as IGM were identified from surgical and pathological records between January 1995 and January 2012. Group 1 (surgery-only group) comprised 53 patients, and the 21 patients in group 2 were treated with corticosteroids prior to surgical treatment (steroid-and-surgery group). Follow-up data were complete for 67 (91.7%) of the 73 patients. Recurrence developed in 4 (7.5%) patients in the surgery-only group, while there was no recurrence in the steroid-and-surgery group; the difference was not statistically significant (p = 0.19). Systemic steroid therapy with surgical resection is the recommended first-line treatment strategy for IGM.


Cloning of the glucokinase gene in Escherichia coli B.
A gene for glucokinase (Glk) in Escherichia coli B was cloned onto vector plasmid pBR322, and the hybrid plasmid obtained was designated pGK100. The gene for Glk was located in the central MluI fragment (0.82 megadalton) of the 6.0-megadalton chromosomal DNA inserted in the HindIII site of the vector. The introduction of pGK100 into E. coli 112L having a decreased level of Glk activity resulted in the about 15-fold increase in this enzyme activity. The poor growth rate of 112L cells on glucose or mannose was also improved by the introduction of pGK100. However, removal of some portion near the glk gene prevented the growth of 112L cells, although Glk activity was high enough to support growth. Therefore, some function of Glk may be regulated by a gene(s) near the glk gene.