Haganriis0387

We particularly focus on the role of this peptide in the motivational effects of morphine, alcohol, nicotine, amphetamine, methamphetamine, and cocaine. Chronic lymphocytic leukemia (CLL) cells change their metabolic program between normoxia and hypoxia, possibly affecting cytotoxic drug potency by altering mitochondria-related cell stress responses (MRCSR) including mitophagy, mitochondrial biogenesis, and mitochondrial proteostasis. We evaluated in CLL cells from nine patients, the single and multiple-combined drug potency of arsenic trioxide (ATO), valproic acid (VPA), vincristine (VCR) and MG132 as four pharmacological sensors influencing mitochondrial apoptosis, mitochondrial biogenesis, mitophagy, and mitochondrial proteostasis respectively, under normoxia and hypoxia to force hypoxia-induced metabolic reprogramming (HMR). Untreated cells from all patients remained viable under O2 levels below 0.5% for 72 h. We obtained 21 measures of drug potency and interaction at 50% effect level that we denoted drug potency signature (DPS). Using the comparative DPS between normoxia and hypoxia, two non-supervised classification algorithms discriminated CLL patients with active disease (ADT) and stable disease (NAD) and showed complete consistency with their clinical characteristics. In ADT group under hypoxia, the potency of MG132 was increased, the interaction of ATO + VPA and ATO + VPA + VCR shifted towards antagonism, and ATO + VPA + VCR + MG132 shifted towards synergism, indicating a prominent role of mitochondrial proteostasis. Classification of patients based on DPS, depended on the contrasting response of drugs under hypoxia and normoxia, owing to HMR. Using these drugs as pharmacological sensors, we linked the metabolic arrangement of CLL cells under hypoxia, to potency of drugs targeting MRCSR, and to the clinical features of individual patients, therefore providing new sources of data on disease progression, drug response and risk prognosis. Aflatoxin G1 (AFG1), ochratoxin A (OTA), fumonisin B1 (FB1) and sterigmatocystin (ST) are very common toxic fungal metabolites with high detection rate and toxicity. The co-existence of many mycotoxins in animal feed has been reported worldwide, thus it is important to evaluate the combined cytotoxic effects among these mycotoxins. This study analysed the combined cytotoxic effects of the four mycotoxins in rat liver cells (BRL) and preliminary investigate their molecular mechanism. Cell viability assays were performed in accordance with the central composite design, and the combined index was analysed to estimate the combined effects. 4,6-Diamidino-2-phenylindole staining and flow cytometry analysis were performed, and Western blot analysis and quantitative real-time PCR were used to determine the molecular mechanism. The cytotoxicity of the mycotoxins on BRL was dose-dependent, following the order ST > OTA > FB1> AFG1. OTA and FB1 presented synergetic cytotoxic effect on BRL by inducing apoptosis. Caspase-3 and Bax expression were induced, whereas Bcl-2 was inhibited by treating with different concentrations of OTA and FB1. In addition, the Bax/Bcl-2 values were gradually increased, which indicated an increased degree of apoptosis. These results suggested that co-exposure of OTA and FB1 in agricultural products may be more hepatotoxic than OTA or FB1separately. Neurological disorders affecting human memory present a major scientific, medical, and societal challenge. Direct or indirect deep brain stimulation (DBS) of the entorhinal-hippocampal system, the brain's major memory hub, has been studied in people with epilepsy or Alzheimer's disease, intending to enhance memory performance or slow memory decline. Variability in the spatiotemporal parameters of stimulation employed to date notwithstanding, it is likely that future DBS for memory will employ closed-loop, nuanced approaches that are synergistic with native physiological processes. The potential for editing human memory-decoding, enhancing, incepting, or deleting specific memories-suggests exciting therapeutic possibilities but also raises considerable ethical concerns. Early career researchers (ECRs) are faced with a range of competing pressures in academia, making self-management key to building a successful career. The Organization for Human Brain Mapping undertook a group effort to gather helpful advice for ECRs in self-management. How does brain system organization evolve during development? Cui et al. (2020) combine big and higher-precision fMRI data to find that maturational processes and cognitive ability track individual differences in the refinement of borders between brain systems. In this issue of Neuron, Wu et al. (2020) provide evidence of a novel role for the premotor cortex in maintaining the context-dependent information necessary for mice to solve a delayed match to sample task. In this issue of Neuron, Gridchyn et al. (2020) show that by inhibiting memory reactivations of hippocampal place maps during rest, these maps are lost but re-emerge during re-learning, suggesting that alternative extrahippocampal representations can reinstate the original hippocampal map. In this issue of Neuron, Lahiri and Bevan (2020) investigate the effects of dopamine release on striatal projection neurons. Using perforated patch recordings and optogenetics, they show that dopamine release persistently enhances the intrinsic excitability of direct pathway striatal neurons. Homeostatic plasticity rules are well described for glutamatergic synapses but less clear for GABAergic synapses. In this issue of Neuron, Pan-Vazquez et al. (2020) leverage the precise targeting of chandelier-to-pyramidal cell connectivity to understand how homeostatic plasticity regulates GABAergic synapses, showing that these synapses maintain homeostatic rules even as they flip from exciting to inhibiting pyramidal cells. Bacteriophages must rapidly deploy anti-CRISPR proteins (Acrs) to inactivate the RNA-guided nucleases that enforce CRISPR-Cas adaptive immunity in their bacterial hosts. Listeria monocytogenes temperate phages encode up to three anti-Cas9 proteins, with acrIIA1 always present. AcrIIA1 binds and inhibits Cas9 with its C-terminal domain; however, the function of its highly conserved N-terminal domain (NTD) is unknown. Here, we report that the AcrIIA1NTD is a critical transcriptional repressor of the strong anti-CRISPR promoter. A rapid burst of anti-CRISPR transcription occurs during phage infection and the subsequent negative feedback by AcrIIA1NTD is required for optimal phage replication, even in the absence of CRISPR-Cas immunity. In the presence of CRISPR-Cas immunity, full-length AcrIIA1 uses its two-domain architecture to act as a "Cas9 sensor," tuning acr expression according to Cas9 levels. Finally, we identify AcrIIA1NTD homologs in other Firmicutes and demonstrate that they have been co-opted by hosts as "anti-anti-CRISPRs," repressing phage anti-CRISPR deployment. Bacterial CRISPR-Cas systems employ RNA-guided nucleases to destroy phage (viral) DNA. Phages, in turn, have evolved diverse "anti-CRISPR" proteins (Acrs) to counteract acquired immunity. In Listeria monocytogenes, prophages encode two to three distinct anti-Cas9 proteins, with acrIIA1 always present. However, the significance of AcrIIA1's pervasiveness and its mechanism are unknown. Here, we report that AcrIIA1 binds with high affinity to Cas9 via the catalytic HNH domain. During lysogeny in Listeria, AcrIIA1 triggers Cas9 degradation. During lytic infection, however, AcrIIA1 fails to block Cas9 due to its multi-step inactivation mechanism. Thus, phages encode an additional Acr that rapidly binds and inactivates Cas9. AcrIIA1 also uniquely inhibits a highly diverged Cas9 found in Listeria (similar to SauCas9) and Type II-C Cas9s, likely due to Cas9 HNH domain conservation. In summary, Listeria phages inactivate Cas9 in lytic growth using variable, narrow-spectrum inhibitors, while the broad-spectrum AcrIIA1 stimulates Cas9 degradation for protection of the lysogenic genome. Rift Valley fever (RVF) is a mosquito-borne zoonosis that severely impacts livelihoods, national and international economies, and human health. Few studies have investigated the prevalence of this infection in Tunisian livestock. The present report aimed to update the epidemiological status and identify the risk factors associated with this RVF virus infection in the one-humped dromedary camel from arid areas. A total of 470 sera of apparently healthy camels (Camelus dromedarius) were collected from six governorates from southern and central Tunisia. Samples were tested by a competitive Enzyme Linked Immunosorbent Assay (ELISA). An overall, 162 camels (34%, 95%CI 0.1-0.4) were seropositive to RVF virus antigen. Logistic regression model revealed three potential risk factors associated with the infection. A meaningful high seropositivity was observed among aged camels (>10 years-old) (40%) (P=0.001; OR=3.367). Besides, camels raised in small flocks particularly intended for meat production showed a high level of seropositivity (37%) (P=0.013; OR=13.173). Animals having close contact with other ruminants showed high seroprevalence (37%) (P=0.022; OR=10.919). This report indicated that Tunisian one-humped dromedaries were exposed to this virus and may contribute to its dissemination among farmers and other livestock. Furthers studies are urgently required to isolate and characterize this virus, evaluate the potential risk of human infection particularly in farmers, veterinarians and slaughterhouse workers and finally to program a serious strategy for RVF control. Tobacco consumption (predominantly cigarettes) is the leading preventable cause of mortality worldwide. While the major focus of strategies to reduce mortality from tobacco must include prevention of future generations from initially gaining access, some smokers are unwilling/ unable to quit. Can the higher risk chronic smoker be identified and can their risk be reduced? The risk of adverse events in cigarette smokers is influenced by the intensity/duration of cigarette smoking or second hand exposure, associated conventional risk factors, environmental stressors and certain genetic variants and epigenetic modifiers. Recent data suggest that inflammatory markers such as hs C-RP and targeted imaging can identify some smokers at higher risk. As smoking is prothrombotic, aspirin initiation and expanded statin use might reduce cardiovascular risk in those who don`t presently meet criteria for these therapies but further study is required. Thus, while advocacy for smoking cessation should always be the primary approach, increased efforts are needed to identify and potentially treat those who are unable/unwilling to quit. BACKGROUND The purpose of this study was to identify predictors of mortality and potentially modifiable factors related to arrhythmias in patients that undergo transcatheter aortic valve replacement (TAVR). Patients that undergo TAVR are at risk for complete heart block requiring pacemaker implant. Additionally, other arrhythmias, specifically atrial fibrillation, are common in this population. It is unclear how arrhythmias and their management contribute to mortality risk. METHODS The study analyzed 176 patients who underwent TAVR at a single center. Factors associated with pacemaker implantation within 30 days were analyzed by logistic regression. Factors associated with mortality were analyzed by Kaplan-Meier and Cox regression analyses. RESULTS Mean age was 80 ± 8.5 years. Atrial fibrillation was present in 69 patients, and 39 received anticoagulation. Post TAVR, a pacemaker was implanted within 30 days in 25 patients. Over a follow up of 566 ± 496 days, 49 patients died. In multivariable analysis, right bundle branch block remained significant (odds ratio 4.212, p=0.012) for pacemaker implant within 30 days. The presence of atrial fibrillation (hazard ratio (HR) 3.905, p= 0.001), albumin level (HR 0.316, p=0.034), and diabetes (HR 2.323, p = 0.027) were predictors of death in a multivariate analysis while pacemaker implant within 30 days was not. Atrial fibrillation patients who were anticoagulated had improved survival in a stratified Kaplan-Meier analysis compared to those who were not anticoagulated (p=0.0001). CONCLUSION AF, diabetes, and low albumin levels are independently associated with mortality after TAVR. In particular, patients with AF who are not anticoagulated are at highest risk for death. Efforts to identify AF and consider anticoagulation should be emphasized. Artificial intelligence is a fast-growing field and its applications to diabetes, a global pandemic, can reform the approach to diagnosis and management of this chronic condition.. Principles of machine learning have been utilized to build algorithms to support predictive models for the risk of developing diabetes or its consequent complications.. Digital therapeutics has proven to be an established intervention for lifestyle therapy in the management of diabetes. Patients are increasingly being empowered for self-management of diabetes and both patients and healthcare professionals are benefitting from clinical decision support. Artificial intelligence allows a continuous and burden-free remote monitoring of the patient's symptoms and biomarkers. Further, social media and online communities enhance patient engagement in diabetes care. Technical advances have helped to optimize resource utilization in diabetes. Together, these intelligent technical reforms have produced better glycemic control with reductions in fasting and postprandial glucose levels, glucose excursions, and glycosylated hemoglobin. Artificial intelligence will introduce a paradigm shift in diabetes care from conventional management strategies to building targeted data-driven precision care. BACKGROUND Cancer and cardiovascular disease are the two leading causes of death in most developed countries, making up the majority of national healthcare expenditures. In this study we aim to investigate nationwide trends of cardiovascular disease and cancer drug expenditure in relation to concomitant trends in cardiovascular disease and cancer death rates. METHODS We obtained cardiovascular and cancer drug expenditure data in Denmark through the Danish Register of Medical Product Statistics. Trends in cancer deaths and cardiovascular disease deaths were observed by linkage to the Cancer statistics for the Nordic Countries and Danish Heart Foundation databases. RESULTS Our data show that introduction and rapid uptake of generic versions of most cardiovascular disease drugs have resulted in a remarkable cost-neutral development in cardiovascular disease drug expenditure from 1995 to 2018 despite increased drug utilization. This development is contrasted to cancer drug expenditure which has increased more than 15-fold in the same period. Since 2006, expenditure for cancer drugs has exceeded the expenditure for cardiovascular disease drugs and is now more than triple as high. However, death rates for cancer have dropped a fraction as much as for cardiovascular disease. CONCLUSION Our results points to a disproportionate high mortality-adjusted expenditure for cancer drugs compared to cardiovascular disease drugs, and demonstrate an enormous potential for national health care savings when cheaper versions like biosimilars of many cancer drugs are introduced. BACKGROUND The safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) have been established in randomized controlled trials, but limited data are available on their use in clinical practice across geographical regions. METHODS In the international RE-COVERY DVT/PE™ observational study (enrollment January 2016 to May 2017), we sought to characterize the patient population and describe the prescribed anticoagulant. Patient characteristics and anticoagulants administered after objective diagnosis of venous thromboembolism were recorded at the baseline visit and again at hospital discharge or at 14 days after the diagnosis, whichever was later. RESULTS A total of 6095 patients were included, 50.2% were male, and the mean age was 61.5 years. The most common comorbidities were hypertension (35%), diabetes mellitus (11%), cancer (11%), prior venous thromboembolism (11%), and trauma/surgery (7%). Overall, 77% of patients received oral anticoagulants, with 54% on NOACs and 23% on vitamin K antagonists (VKAs); 20% received parenteral anticoagulation only. NOACs comprised about 60% of anticoagulant treatment in Europe and Asia but substantially less in Latin America (29%) and the Middle East (21%). For NOAC therapies, the distribution (as a percentage of the total cohort) was rivaroxaban 25.6%, dabigatran 15.5%, apixaban 11.3%, and edoxaban 1.7%. Treatment with NOACs was less frequent in patients who had cancer, chronic renal disease, heart failure, or stroke. CONCLUSIONS These findings enhance our understanding of venous thromboembolism patient baseline characteristics and the initial management of venous thromboembolism patients in routine practice. TRIAL REGISTRATION NUMBER NCT02596230 (ClinicalTrials.gov). BACKGROUND Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans. METHODS This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18-50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses the low-dose group received 5 × 109 viral particles, theto the MERS-CoV spike antigen was observed at all doses. Neutralising antibodies against live MERS-CoV were observed in four (44% [95% CI 19-73]) of nine participants in the high-dose group 28 days after vaccination, and 19 (79% [58-93]) of 24 participants had antibodies capable of neutralisation in a pseudotyped virus neutralisation assay. INTERPRETATION ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials. FUNDING UK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research. BACKGROUND The Middle East respiratory syndrome coronavirus (MERS-CoV) causes a respiratory disease with a case fatality rate of up to 35%. Given its potential to cause a public health emergency and the absence of efficacious drugs or vaccines, MERS is one of the WHO priority diseases warranting urgent research and development of countermeasures. We aimed to assess safety and tolerability of an anti-MERS-CoV modified vaccinia virus Ankara (MVA)-based vaccine candidate that expresses the MERS-CoV spike glycoprotein, MVA-MERS-S, in healthy adults. METHODS This open-label, phase 1 trial was done at the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Participants were healthy men and women aged 18-55 years with no clinically significant health problems as determined during medical history and physical examination, a body-mass index of 18·5-30·0 kg/m2 and weight of more than 50 kg at screening, and a negative pregnancy test for women. A key exclusion criterion was a previous MVA vaccination. For thhumoral and cell-mediated responses against MERS-CoV. A dose-effect relationship was demonstrated for reactogenicity, but not for vaccine-induced immune responses. The data presented here support further clinical testing of MVA-MERS-S in larger cohorts to advance MERS vaccine development. FUNDING German Center for Infection Research. Non-genetic transcriptional variability is a potential mechanism for therapy resistance in melanoma. Specifically, rare subpopulations of cells occupy a transient pre-resistant state characterized by coordinated high expression of several genes and survive therapy. How might these rare states arise and disappear within the population? It is unclear whether the canonical models of probabilistic transcriptional pulsing can explain this behavior, or if it requires special, hitherto unidentified mechanisms. We show that a minimal model of transcriptional bursting and gene interactions can give rise to rare coordinated high expression states. These states occur more frequently in networks with low connectivity and depend on three parameters. While entry into these states is initiated by a long transcriptional burst that also triggers entry of other genes, the exit occurs through independent inactivation of individual genes. Together, we demonstrate that established principles of gene regulation are sufficient to describe this behavior and argue for its more general existence. A record of this paper's transparent peer review process is included in the Supplemental Information. Connectivity webs mediate the unique biology of the mammalian brain. Yet, while cell circuit maps are increasingly available, knowledge of their underlying molecular networks remains limited. Here, we applied multi-dimensional biochemical fractionation with mass spectrometry and machine learning to survey endogenous macromolecules across the adult mouse brain. We defined a global "interactome" comprising over one thousand multi-protein complexes. These include hundreds of brain-selective assemblies that have distinct physical and functional attributes, show regional and cell-type specificity, and have links to core neurological processes and disorders. Using reciprocal pull-downs and a transgenic model, we validated a putative 28-member RNA-binding protein complex associated with amyotrophic lateral sclerosis, suggesting a coordinated function in alternative splicing in disease progression. This brain interaction map (BraInMap) resource facilitates mechanistic exploration of the unique molecular machinery driving core cellular processes of the central nervous system. It is publicly available and can be explored here https//www.bu.edu/dbin/cnsb/mousebrain/. Cell proliferation and inflammation are two metabolically demanding biological processes. How these competing processes are selectively executed in the same cell remains unknown. Here, we report that the enzyme carbamoyl-phosphate synthetase, aspartyl transcarbamoylase, and dihydroorotase (CAD) deamidates the RelA subunit of NF-κB in cancer cells to promote aerobic glycolysis and fuel cell proliferation in tumorigenesis. This post-translational modification switches RelA function from mediating the expression of NF-κB-responsive genes to that of glycolytic enzymes, thus shunting the cell's inflammatory response to aerobic glycolysis. Further, we profiled diverse human cancer cell lines and found that high CAD expression and a subset of RELA mutations correlated with RelA deamidation. And by use of inhibitors of key glycolytic enzymes, we validated the pivotal role of RelA deamidation in tumorigenesis of cancer cell lines. This work illuminates a mechanism by which protein deamidation selectively specifies gene expression and consequent biological processes. Mechanotransduction channels have been proposed as force sensors in various physiological processes, such as hearing and touch. In particular, TMC1 has been shown to constitute the pore of hair cell mechanotransduction channels, but little is known about how force is sensed by TMC channels. Here, we identify UNC-44/ankyrin as an essential component of the TMC-1 mechanotransduction channel complex in the sensory cilia of Caenorhabditis elegans mechanoreceptor neurons. Ankyrin binds indirectly to TMC-1 via evolutionarily conserved CIB proteins, which are required for TMC-1-mediated mechanosensation in C. elegans OLQ neurons and body wall muscles. Mechanosensory activity conferred by ectopically expressed TMCs in mechanoinsensitive neurons depends on both ankyrin and CIB proteins, indicating that the ankyrin-CIB subcomplex is required for TMC mechanosensitivity. Our work indicates that ankyrin is a long-sought intracellular tether that transmits force to TMC mechanotransduction channels. A nurse explores the unique grief of losing a child. Studying posttranslational modifications classically relies on experimental strategies that oversimplify the complex biosynthetic machineries of living cells. Protein glycosylation contributes to essential biological processes, but correlating glycan structure, underlying protein, and disease-relevant biosynthetic regulation is currently elusive. Here, we engineer living cells to tag glycans with editable chemical functionalities while providing information on biosynthesis, physiological context, and glycan fine structure. We introduce a non-natural substrate biosynthetic pathway and use engineered glycosyltransferases to incorporate chemically tagged sugars into the cell surface glycome of the living cell. We apply the strategy to a particularly redundant yet disease-relevant human glycosyltransferase family, the polypeptide N-acetylgalactosaminyl transferases. This approach bestows a gain-of-chemical-functionality modification on cells, where the products of individual glycosyltransferases can be selectively characterized or manipulated to understand glycan contribution to major physiological processes. Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis. PURPOSE This systematic review aims to describe objective sleep parameters for athletes under different conditions and address potential sleep issues in this specific population. METHODS PubMed and Scopus were searched from inception to April 2019. Included studies measured sleep only via objective evaluation tools such as polysomnography or actigraphy. The modified version of the Newcastle-Ottawa Scale was used for the quality assessment of the studies. RESULTS Eighty-one studies were included, of which 56 were classified as medium quality, 5 as low, and 20 as high quality. A total of 1830 athletes were monitored over 18,958 nights. Average values for sleep-related parameters were calculated for all athletes according to sex, age, athletic expertise level, training season, and type of sport. Athletes slept on average 7.2 ± 1.1 h/night, with 86.3% ± 6.8% sleep efficiency (SE). In all datasets, the athletes' mean total sleep time was less then 8 h. SE was low for young athletes (80.3% ± 8.8%). Reduced SE was attributed to high wake after sleep onset rather than sleep onset latency. During heavy training periods, sleep duration and SE were on average 36 min and 0.8% less compared to pre-season and 42 min and 3.0% less compared to in-season training periods, respectively. CONCLUSION Athletes' sleep duration was found to be short with low SE, in comparison to the general consensus for non-athlete healthy adults. Notable sleep issues were revealed in young athletes. Sleep quality and architecture tend to change across different training periods. V.Microfluidic technologies are commonly used for the manipulation of red blood cell (RBC) suspensions and analyses of flow-mediated biomechanics. To enhance the performance of microfluidic devices, understanding the dynamics of the suspensions processed within is crucial. We report novel, to our knowledge, aspects of the spatiotemporal dynamics of RBC suspensions flowing through a typical microchannel at low Reynolds number. Through experiments with dilute RBC suspensions, we find an off-center two-peak (OCTP) profile of cells contrary to the centralized distribution commonly reported for low-inertia flows. This is reminiscent of the well-known "tubular pinch effect," which arises from inertial effects. However, given the conditions of negligible inertia in our experiments, an alternative explanation is needed for this OCTP profile. Our massively parallel simulations of RBC flow in real-size microfluidic dimensions using the immersed-boundary-lattice-Boltzmann method confirm the experimental findings and elucidate the underlying mechanism for the counterintuitive RBC pattern. By analyzing the RBC migration and cell-free layer development within a high-aspect-ratio channel, we show that such a distribution is co-determined by the spatial decay of hydrodynamic lift and the global deficiency of cell dispersion in dilute suspensions. We find a cell-free layer development length greater than 46 and 28 hydraulic diameters in the experiment and simulation, respectively, exceeding typical lengths of microfluidic designs. Our work highlights the key role of transient cell distribution in dilute suspensions, which may negatively affect the reliability of experimental results if not taken into account. In developed countries that protect core aspects of the fundamental human right to the highest attainable standard of health, how does that right intersect with intellectual property rights? Here, the human rights implication of providing access to all cancer drugs recommended by experts in a developed country is considered in the context of conflict between the incentive to invent and the rights of others to access medicines. Effective incentives to innovate in developed countries can lead to global improvements in access to medicine if the intellectual property system is calibrated to permit this. This depends partly on the usefulness of compulsory licensing and alternative mechanisms facilitating global access to drugs. This review considers tensions between fundamental rights to access essential medicines and rights of the inventor and investors, including the pharmaceutical industry. INTRODUCTION Carbapenem resistance in members of order Enterobacterales is a growing public health problem causing high mortality in developing and industrialized countries. Its emergence and rapid propagation worldwide was due to both intercontinental spread of pandemic strains and horizontal dissemination via mobile genetic elements (MGE) such as plasmids and transposons. OBJECTIVE To describe MGE carrying carbapenem resistance genes in Enterobacterales which have been reported in South America. SEARCH STRATEGY AND SELECTION CRITERIA A search of the literature in English or Spanish published until 2019 in PubMed, Google Scholar, LILACS and SciELO databases was performed for studies of MGE in Enterobacterales reported in South American countries. RESULTS Seven South American countries reported MGE related to carbapenemases. Carbapenemase-producing Klebsiella pneumoniae belonging to clonal complex 258 were the most prevalent pathogens reported; others carbapenemase-producing Enterobacterales such as Escherichia coli, Serratia marcescens, and Providencia rettgeri also have been reported. The MGE implicated in the spread of the most prevalent carbapenemase genes are Tn4401 and non-Tn4401 elements for blaKPC and ISAba125 for blaNDM, located in different plasmid incompatibility groups, i.e. L/M, A/C, FII and bacterial clones. CONCLUSION This review indicates that, like in other parts of the world, the most commonly reported carbapenemases in Enterobacterales from South America are being disseminated through clones, plasmids, and transposons which have been previously reported in other parts of the world. L.U.BACKGROUND Previous studies have found that mechanical bowel preparation with oral antibiotics can reduce the incidence of surgical-site infections, but no randomised controlled trial has assessed oral antibiotics alone without mechanical bowel preparation. The aim of this study was to determine whether prophylaxis with oral antibiotics the day before elective colon surgery affects the incidence of postoperative surgical-site infections. METHODS In this multicentre, pragmatic, randomised controlled trial (ORALEV), patients undergoing colon surgery were recruited from five major hospitals in Spain and 47 colorectal surgeons at these hospitals participated. Patients were eligible for inclusion if they were diagnosed with neoplasia or diverticular disease and if a partial colon resection or total colectomy was indicated. Participants were randomly assigned (11) using online randomisation tables to either administration of oral antibiotics the day before surgery (experimental group) or no administration of oral ashould be routinely adopted before elective colon surgery. FUNDING Fundación Asociación Española de Coloproctología. OBJECTIVE This study aims to describe the epidemiological characteristics and survival rates of children with acute myeloid leukemia treated in hospitals in southern Brazil and compare them with international data. METHODS A multicenter cohort study was conducted with retrospective data collection of all new patients with acute myeloid leukemia under 18 treated at five referral centers in pediatric hematology-oncology in southern Brazil between January 2005 and December 2015. RESULTS Of the 149 patients with acute myeloid leukemia, 63.0% (n=94) were male. The median age at diagnosis was 10.5 years (range 0-18 years) and 40.3% (n=60) had a white blood cell count below 50,000/mm2. The most common Franco-American-British (FAB) subtype was M3 (n=43, 28.9%). Nine (6.0%) patients had central nervous system disease. In M3 patients, overall survival (OS) was 69.2% and 3-year event-free survival was 67.7%; in non-M3 patients, these rates were 45.3% and 36.7%, respectively. In non-M3 patients, OS was significantly different between transplanted (61.8%) and non-transplanted (38.2%) patients (p=0.031). CONCLUSIONS These results show a higher prevalence of the Franco-American-British M3 subtype than that reported in the international literature, as well as a decreased OS compared with that of developed countries. Further multicenter Brazilian studies with a larger sample size are encouraged to better understand the characteristics of acute myeloid leukemia, and to improve the treatment and prognosis in this population. Previous research has identified a critical role of executive function and memory in self-awareness, a metacognitive capacity often impaired in acquired brain injury. Through this observational study, we aimed to explore the effect of cognitive rehabilitation on the predictive value of these variables, as also whether any of them can predict the level of self-awareness once the cognitive rehabilitation is completed. 69 patients underwent a neuropsychological assessment, including self-awareness, at admission to and discharge from a cognitive rehabilitation process. Regression analysis was performed at these two moments and a third one was conducted to evaluate whether any of the variables at admission predicted the level of self-awareness at discharge. Verbal fluency was found to be the best predictor of self-awareness, both at admission and discharge. In addition, inhibition and cognitive flexibility, as well as episodic memory, appeared as significant predictors of post-rehabilitation self-awareness. Finally, verbal fluency was revealed as the unique pre-rehabilitation predictor of subsequent level of self-awareness following rehabilitation. While post-acute self-awareness is predicted by non-specific executive measures, the cognitive improvement putatively induced by neuropsychological rehabilitation reveals the contribution of more specific executive and memory functions. Importantly, pre-rehabilitation verbal fluency scores predicted the level of self-awareness after cognitive rehabilitation.The clinical outcome of oral squamous cell carcinoma (OSCC) has not improved in recent years, mainly due to the limited effective targeted therapy that has been applied. Recently, a transcriptional coactivator, YAP, has been shown to have a key regulatory role in malignant progression in multiple cancers, including OSCC. But pharmacologically targeting YAP or the Hippo pathway, which is the main signaling pathway regulating YAP, has been proven to be challenging. Therefore, uncovering YAP upstream regulators in cancer would identify novel therapeutic targets for treatment of YAP-sustained cancers. Here, we showed that YAP was overactivated in OSCC and that high YAP activity in patients with OSCC was associated with malignant progression and poor survival. We uncovered that GPR39 (a G protein-coupled receptor) was overexpressed in OSCC, that the expression level of GPR39 was correlated with the activity level of YAP, and that the high GPR39 expression was associated with malignant progression and poor survival in patients with OSCC. Moreover, we found that GPR39 regulated YAP through a Gαq/11-RhoA-dependent signaling pathway. Importantly, inhibition of GPR39 resulted in YAP-sustained OSCC growth inhibition. Our findings suggest that GPR39 is a potential therapeutic target for OSCC treatment with itself as a biomarker.In the United States, state Medicaid programs pay for medical and dental care for children from low-income families and support nondental primary care providers delivering preventive oral health services (POHS) to young children in medical offices ("medical POHS"). Despite the potential of these policies to expand access to care, there is concern that they may replace dental visits with medical POHS. Using Medicaid claims from 38 states from 2006 to 2014, we conducted a repeated cross-sectional study and used linear probability regression to estimate the association between the annual proportion of children in a county receiving medical POHS and the probability that a child received 1) dental POHS and 2) a dental visit in a given year. Models included county and year fixed effects and controlled for child- and county-level factors, and standard errors were clustered at the state level. In a weighted population of 45.1 million child-years (age, 6 mo to less then 6 y), we found no significant nor substantively important association between the proportion of children in a county receiving medical POHS and the probability that a child received dental POHS or a dental visit. Additionally, we found an almost zero probability ( less then 0.001) that the reduction in dental POHS was at least as large as the expansion in medical POHS (full substitution) and a 0.50 probability that increased medical POHS was associated with an increase in dental POHS of at least 6.6% of the expansion of medical POHS. Results were similar when receipt of dental visits was examined. This study failed to find evidence that medical POHS replaced dental visits for young children enrolled in Medicaid and, in fact, offers evidence that increased medical POHS was associated with increased utilization of dental care. Given lower-than-desired rates of dental visits for this population, delivery of medical POHS should be expanded.Background Individuals with mental illness use social media to share treatment experiences and anecdotal information. Despite the significant impact of social media on individuals with mental illness, posts related to antidepressants have not been studied systematically.Aims This study evaluates public sentiments and content posted on Instagram regarding the use of antidepressants.Methods Instagram posts from July 2010 to June 30, 2018 containing hashtags of commonly prescribed antidepressants and anxiety/depression-related terms were gathered (n = 13,096). Approximately 1,000 posts were randomly selected and evaluated for photo content, anecdotal experiences, sentiments towards antidepressants, and mentions of psychotherapy, comorbidities, polypharmacy, or adverse effects.Results Instagram posts describing antidepressant use have increased exponentially from 2010, and 43% provided anecdotal experiences. Among these posts, 58% expressed negative sentiments towards antidepressant usage, citing adverse effects and lack of improvement. Posts that also mentioned psychotherapy, comorbidities, or polypharmacy differed in their collective sentiments. Misinformation was present in analyzed posts, and none mentioned recovery-oriented materials (i.e., mental health facility, hotline, etc.).Conclusions Instagram is a useful resource for exploring public sentiments related to antidepressant use. Mental health professionals should be cognizant of these sentiments/perceptions in order to tailor communication with patients and should consider increasing their social media presence.RATIONALE Idiopathic pulmonary fibrosis (IPF) is a deadly disease with increasingly impaired health-related quality of life (HRQOL). EHealth technologies facilitate collection of physiological outcomes and patient reported-outcomes (PROMs) at home, but randomized controlled trials (RCTs) on the effects of eHealth are scarce. We investigated whether a home monitoring program improved HRQOL and medication use for IPF patients. METHODS We performed a multicenter RCT in newly treated patients with IPF. Patients were randomly assigned to standard care or a home monitoring program on top of standard care for 24 weeks. The home monitoring program included home spirometry, reporting of symptoms and side-effects, PROMs, information, a medication coach and eConsultations. The primary endpoint was between-group difference in change in Kings Brief Interstitial Lung disease (K-BILD) questionnaire score at 24 weeks. RESULTS 90 patients were randomized (46 patients home monitoring, 44 standard care). After 24 weeks, no statistically significant differences were found in K-BILD total score (home monitoring group+2.7 points, standard care+0.03, p=0.24) and psychological domain score (home monitoring group+5.1, standard care-0.5, p=0.1). In the home monitoring group medication was more often adjusted (1 vs 0.3 adjustments per patient, p=0.027). Patient satisfaction with the home monitoring program was high. Home-based spirometry was highly correlated with hospital-based spirometry over time. CONCLUSIONS The results of this first-ever eHealth RCT in IPF showed that a comprehensive home monitoring program did not improve overall HRQOL measured with K-BILD, but tended to improve psychological wellbeing. Home monitoring was greatly appreciated by patients and allowed for individually-tailored medication adjustments. Clinical trial registration available at www.clinicaltrials.gov, ID NCT03420235.RATIONALE The role of inspiratory effort has still to be determined as a potential predictors of non-invasive mechanical ventilation (NIV) failure in acute hypoxic de novo respiratory failure (AHRF). OBJECTIVES We explore the hypothesis that inspiratory effort might be a major determinant of NIV failure in these patients. METHODS Thirty consecutive patients with AHRF admitted to a single center and candidates for a 24-hour NIV trial were enrolled. Clinical features, tidal changes in esophageal (ΔPes) and dynamic transpulmonary pressure (ΔPL), expiratory tidal volume, and respiratory rate were recorded on admission and 2-4-12-24 hours after NIV start, and were tested for correlation with outcomes. MEASUREMENTS AND MAIN RESULTS ΔPes and ΔPes/ΔPL were significantly lower 2 hours after NIV start in patients who successfully completed the NIV trial (n=18) compared to those who needed endotracheal intubation (n=12) [median=11 (IQR=8-15) cmH2O vs 31.5 (30-36) cmH2O, p less then 0.0001] while other variables differed later. ΔPes was not related to other predictors of NIV failure at baseline. NIV-induced reduction in ΔPes of 10 cmH2O or more after 2 hours of treatment was strongly associated to avoidance of intubation, and represented the most accurate predictor of treatment success (OR=15, 95%CI 2.8-110, p=0.001, AUC=0.97, 95%CI 0.91-1, p less then 0.0001). CONCLUSIONS The magnitude of inspiratory effort relief as assessed by ΔPes variation within the first 2 hours of NIV was an early and accurate predictor of NIV outcome at 24 hours. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http//creativecommons.org/licenses/by-nc-nd/4.0/).Background The devastation of the Syrian war can lead to a drastic re-evaluation of oneself and alteration in self-capacities. Yet, little is known regarding its impact on these domains among Syrian refugees.Aims To investigate the inter-relationship between trauma characteristics, trauma centrality, self-efficacy, emotional suppression, PTSD and psychiatric co-morbidity among Syrian refugees.Methods 1197 refugees from Turkey and Sweden completed the Harvard Trauma Questionnaire, General Health Questionnaire-28, Centrality of Event Scale, Generalized Self-Efficacy Scale and Courtauld Emotional Control Scale.Results Using the DSM-IV criteria for PTSD from the Harvard Trauma Questionnaire, 43% met the criteria. The PTSD group reported significantly higher levels of trauma characteristics, trauma centrality and psychiatric co-morbidity but a lower level of self-efficacy than the non-PTSD group. Trauma characteristics were positively associated with trauma centrality; trauma centrality was negatively correlated with self-efficacy. Contrary to hypothesis, self-efficacy was positively correlated with emotional suppression which was positively correlated with psychiatric co-morbidity but not PTSD.Conclusions The experience of war can lead to the emergence of PTSD among Syrian refugees. Exposure to war can alter self-perception, belief of personal mastery over one's future and the way emotion is expressed, all of which can have specific effects on general psychological symptoms.The criterion to distinguish a simple eutectic mixture from a deep eutectic solvent (DES) lies in the deviations to thermodynamic ideality presented by the components in the system. In this work, the current knowledge of the molecular interactions in types III and V DES is explored to liquefy a set of three fatty acids and three fatty alcohols, here used as model compounds for carboxyl and hydroxyl containing solid compounds. This work shows that thymol, a stronger than usual hydrogen bond donor, is able to form deep eutectic solvents of type V with the fatty alcohols studied. This is particularly interesting, since these DES formed are hydrophobic. Regarding type III DES, the results suggest that the prototypical DES hydrogen bond acceptor, cholinium chloride, is unable to induce negative deviations to ideality in the model molecules studied. By substituting choline with tetramethylammonium chloride, it is shown that the choline hydroxyl group is responsible for the difficulty in forming choline-based deep eutectic solvents and that its absence induces strong negative deviations to ideality in the alkylammonium side. Finally, it is demonstrated that tetrabutylammonium chloride acts as a chloride donning agent, causing significant negative deviations to ideality in both fatty acids and alcohols and leading to the formation of deep eutectic solvents of type III.Disordered proteins play important roles in cell signaling and are frequently involved in protein-protein interactions. They also have a larger proportion of charged and polar residues than their folded counterparts. Here, we developed a structure-based model and applied molecular dynamics simulations to examine the presence and importance of electrostatic interactions in the binding processes of two differently charged intrinsically disordered ligands of the KIX domain of CBP. We observed non-native opposite-charged contacts in the encounter complexes for both ligands with KIX, and this may be a general feature of coupled folding and binding reactions. The ensemble of successful encounter complexes is a diverse set of structures, and in the case of the highly charged ligand, this ensemble was found to be malleable with respect to ionic strength. There are only minor differences between encounter complex ensembles for successful and unsuccessful collisions with no key interactions that appear to make the process far more productive. The energy landscape at this early stage in the process does not appear highly funneled. Strikingly we observed many native interactions that appear to reduce chances of an encounter complex being productive. Instead it appears that collectively non-native electrostatic interactions in the encounter complex increase the likelihood of productivity by holding the proteins together long enough for folding to take place. This mechanism is more effective for the more highly charged ligand.Engineering of supramolecular topologies offers potential opportunities for tailoring their properties to various function and applications. However, the synthesis of interlocked or intertwined compounds, catenanes, links or knots, is a challenge. Previously, we used coordination-driven self-assembly and noncovalent interactions (NCIs) between metal-based acceptors and multipyridyl donors to create supramolecular topologies with increasing complexity. Self-assembling components of fixed length and geometry have been utilized for the production of topologies such as Borromean rings, Solomon links, Hopf's link, "rectangle in rectangle", and an 818 molecular knot. However, recent synthesis of a linear [3]catenane by us witnessed the importance of flexible ligands along with coordination-driven self-assembly and NCIs in self-assembling units. This flexibility provides distinctive angularity for the recognition of various NCIs and thus offers tremendous possibilities for realizing complex supramolecular topologies. This study proposed a selective and quantitative synthesis, and also the first X-ray characterization of a closed three-link chain (a prime link of [3]catenane with 6 crossings) via two component coordination-driven self-assembly. The experiments based upon concentration, guest template, and solvent effects were systematically presented. Furthermore, the experimental finding was supported by density functional theory calculations, which highlighted the necessity of the multiple NCIs along with appropriate geometry of the [2 + 2] rings.The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (∼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound 27 demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound 46 (ABBV-744).