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In patients with cirrhosis with severe thrombocytopenia (platelet count [PC] 100 × 109/L), intermediate (51‐100 × 109/L), and low (≤50 × 109/L). PC was also analyzed as a continuous covariate on multivariable analysis. The primary endpoint was major perioperative bleeding. The overall event rate of major perioperative bleeding was 8.9% and was not found to differ significantly between the high, intermediate, and low platelet groups (8.1% vs. 10.2% vs. 10.8%, P = 0.48). On multivariable analysis, greater age, aspartate aminotransferase, lower hemoglobin, and treatment with LR (vs. RFA) were found to be significant independent predictors of major perioperative bleeding, with associations with disease etiology and year of surgery also observed. After adjusting for these factors, the association between PC and major perioperative bleeding remained nonsignificant. Conclusion: Major perioperative bleeding was not significantly associated with PC in patients with cirrhosis undergoing surgical treatment of HCC, even when their PC was

The frequency of total knee arthroplasty (TKA) is increasing, particularly in younger and more active patients. In these patients, there may be greater functional demands, with an expectation to return to sporting activities (RTS) following TKA. There is a paucity of data on the time to RTS following TKA and the aim of this meta-analysis is to determine the time to RTS following TKA. Using the PRISMA guidelines, an electronic search of PUBMED, MEDLINE, EMBASE, and the Cochrane Library for trails was performed on TKA and RTS in English language, published since the inception of the database to 31st October 2020. Data evaluating the time to RTS and functional outcomes were recorded by two authors independently that were included in the analysis. Pooled analysis using random effect model on overall proportions at the different time intervals and at the end of the follow-up was carried out for all studies. In total, 1,611 studies were retrieved from literature search. Of these, nine studies met the inclusion criteria with 1,307 patients. Two studies with 148 patients demonstrated an overall pooled proportion of 18.7% (95% CI 8.2–32.3%) of patients RTS at 3 month post-TKA; Three studies reported RTS rate at 6 months 70.% (95% CI 48–88.4). Two studies with 123 patients demonstrated an overall pooled proportion of 84.0% (95% CI 77.1–89.9%) patients RTS at 12 months. 986 patients returned to sport from total of 1307, with an overall adjusted proportion return to sport of 87.9 (95% CI 80.5–93.8%) at the end of follow-up; mean 14 months (range 3–36 months). Patients undergoing TKA were found to successfully RTS, pooled proportion analysis showed an increasing rate of RTS with time, at a mean of 14 months following TKA, where 87.9% of patients had returned to sports. The findings of this study will enable more informed discussions and rehabilitation planning between patients and clinicians on RTS following TKA.

Introduction: Total Hip Arthroplasty (THA) is being increasingly undertaken in younger and more active patients, with many of these patients wanting to return to sport (RTS) after surgery. However, the percentage of patients RTS and time at which they are able to get back to sport following surgery remains unknown. The objective of this meta-analysis was to determine the time patients RTS after THA. Methods: A search was performed on PUBMED, MEDLINE, EMBASE, and the Cochrane Library for trials on THA and RTS, in the English language, published from the inception of the database to October 2020. All clinical trials reporting on to RTS following THA were included. Data relating to patient demographics, methodological quality, RTS, clinical outcomes and complications were recorded. The PRISMA guidelines were used to undertake this study. Results: The initial literature search identified 1720 studies. Of these, 11 studies with 2297 patients matched the inclusion criteria. 3 studies with 154 patients demonstrated an overall pooled proportion of 40.0% (95% CI, 32.5–47.9%) of patients RTS between 2 and 3 months after surgery. 4 studies with 242 patients demonstrated an overall pooled proportion of 76.9% (95% CI, 71.5–82.0) of patients RTS by 6 months after surgery. Pooled proportion analysis from 7 trials with 560 patients demonstrated 93.9% (95% CI, 82.7–99.5%) of patients RTS between 6 and 12 months after surgery. Conclusions: Pooled proportion analysis showed increasingly more patients were able to RTS after THA over the first 1 year after surgery. There remains marked inter and intra-study variations in time for RTS but the pooled analysis shows that over 90% of patients were able to RTS at 6–12 months after THA. These finding will enable more informed discussions between patients and healthcare professionals about time for RTS following THA.

To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial.Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).Patients with GA secondary to age-related macular degeneration (AMD), n = 246.Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period.Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity.Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy.Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.

Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that affects all ages, including women of childbearing age. Optimal management during pregnancy is poorly defined. We aimed to explore the clinical and biochemical course of AIH in the antenatal and postpartum periods, and assess factors associated with premature birth and postpartum flares. Pregnant women with AIH reviewed in the autoimmune liver disease clinic at the Queen Elizabeth Hospital Birmingham between 2009 and 2020 were identified retrospectively, and clinical, biochemical, and immunological data 1 year before conception to 1 year postpartum were collected. Analysis was performed to identify trends in blood markers over the antenatal period, with an interrupted time series approach used to assess postpartum trends. Data were available for n = 27 pregnancies (n = 20 women), with median gestation of 38 weeks (30% premature) and most having type 1 AIH (78%) and delivering via caesarean section (63%). Levels of alanine transaminase, aspartate transaminase, and immunoglobulin G all declined significantly during gestation, followed by significant step-change increases after delivery. Postpartum flare developed in 58% of pregnancies. AIH type 2 was associated with a higher rate of premature births (67% vs. 19%, P = 0.044), and a trend toward a higher rate of postpartum flare (100% vs. 48%, P = 0.053). Although not significant, medication nonadherence was associated with almost double the risk of prematurity (40% vs. 24%, P = 0.415) and postpartum flare (80% vs. 44%, P = 0.109). Conclusion: Biochemical and immunological remission of AIH occurs during pregnancy, although subsequent postpartum flare is common. Type 2 AIH is associated with a higher risk of premature birth and postpartum flare, although further research is required to validate and explain this finding.

Background & aims Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Non-invasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis at disease presentation in PBC. Approach & results We collected data from 167 consecutive treatment-naive PBC patients who underwent liver biopsy(LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves(AUROCs) for advanced fibrosis (Ludwig stage≥III). The effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. Derivation cohort consisted of 126 patients with valid LSM and LB, VCTE identified patients with advanced fibrosis with AUROC of 0.89. LSM cut-offs ≤6.5kPa and >11.0kPa enabled to exclude and confirm, respectively, advanced fibrosis (negative predictive value[NPV]=0.94, positive predictive value[PPV]=0.89, error rate=5.6%). These values were externally validated in an independent cohort of 91 PBC patients(NPV=0.93, PPV=0.89, error rate=8.6%). Multivariable analysis found the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. Conclusions In a multicenter study of treatment-naive PBC patients, we identified two cut-offs (LSM≤6.5kPa and>11.0kPa) able to discriminate at diagnosis the presence or the absence, respectively, of advanced fibrosis in PBC patients, with external validation. In patients with LSM between these two cut-offs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

Background & aims Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. Methods Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. Results We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). Conclusions Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. Lay summary Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis., Graphical abstract, Highlights • Under real-world conditions, OCA was effective in ~43% of patients who were non-responders to UDCA, according to Poise criteria. • Patients with cirrhosis showed lower efficacy (29.5%), mainly attributed to reduced tolerability and higher discontinuation rate. • Patients with overlap AIH-PBC showed a comparable efficacy to pure PBC, with a higher ALT reduction at 6 months. • Most patients with PBC are still in need of additional therapy if aiming to normalise liver biochemistry.

For many years the one-size-fits-all approach has been the only one available to manage patients affected by primary biliary cholangitis. The introduction of obeticholic acid in 2016 as a second-line treatment, together with the creation and validation of several biochemically based scores to stratify the risk of progressive disease, has opened up the need to redefine clinical practice by changing the actual paradigm. The precision medicine initiative is a model of patient-centered health care that aims to improve medicine based on genotypic and molecular characteristics that correlate to specific phenotypic, individual characteristics. In summary, the aim of the precision medicine is to define the right treatment for the right person at the right time. The availability of a second-line disease-modifying drug and new molecules in phase 2 or 3 trials makes this an exciting time for the precision medicine initiative in primary biliary cholangitis. In this review we describe the current risk stratification tools and we track a possible path towards the application of precision medicine in clinical daily life.

Background Although general practitioners (GPs) are generally considered as the first point of contact for care, this may be different for persons with complex conditions, such as those with spinal cord injury (SCI). The objective of this study is to understand the differences in long-term care provision by GPs and SCI-specialists, by examining (1) the first contact of care for SCI health problems, (2) the morbidity profile and use of health-care services in relation to first contact, and (3) the factors associated with the choice of first contact. Methods In this cross-sectional study based on data derived from the Swiss Spinal Cord Injury Cohort Study Community Survey 2017, the main outcome measure was the reported first contact for SCI-specific care. This information was analysed using the chi-square test and logistic regression analysis of groups based on patient characteristics, use of health-care services and secondary health conditions assessed using the Spinal Cord Injury Secondary Conditions Scale (SCI-SCS). Results Out of 1294 respondents, 1095 reported their first contact for SCI-specific care; 56% indicated SCI-specialists and 44% specified GPs. On average, participants who first contacted a GP reported higher number of GP consultations (5.1 ± 5.2 vs. 3.9 ± 7.2), planned visits to ambulatory clinics (3.7 ± 7.3 vs. 3.6 ± 6.7) and hospital admissions (GP, 1.9 ± 1.7 vs. 1.5 ± 1.3), but lower number of visits to SCI-specialists (1.7 ± 1.8 vs. 2.6 ± 1.7) and of hospital days (22.8 ± 43.2 vs. 31.0 ± 42.8). The likelihood to contact a GP first was significantly higher in persons ≥75 years old (OR = 4.44, 95% CI = 1.85–10.69), Italian speakers (OR = 5.06, 95% CI = 2.44–10.47), had incomplete lesions (OR = 2.39, 95% CI = 1.71–3.35), experiencing pain (OR = 1.47, 95% CI = 1.04–2.09) or diabetes mellitus (OR = 1.85, 95% CI = 1.05–3.27), but lower for those situated closer to SCI centres (OR = 0.69, 95% CI = 0.51–0.93) or had higher SCI-SCS scores (OR = 0.92, 95% CI = 0.86–0.99). Conclusion Age, language region, travel distance to SCI centres, lesion completeness, and occurrence of secondary conditions play a significant role in determining the choice of first contact of care, however there is still some unwarranted variation that remains unclear and requires further research.

Introduction: Studies on the epidemiology of primary sclerosing cholangitis (PSC) are mainly based on tertiary referral centers, and are retrospective case series susceptible to selection bias. The aim of this study was to estimate incidence, survival and cause of mortality of PSC in Italy, using population-based data. Methods: Data collected from the National Rare Diseases Registry (RNMR) and the National Mortality Database (NMD) were integrated and analyzed. Results: We identified 502 PSC incident cases. The crude incidence rate between 2012 and 2014 was 0.10 per 100,000 individuals. Sixty percent were male, mean age at disease onset and at diagnosis were 33 and 37 years, respectively, highlighting a mean diagnostic delay of 4 years. The rate of interregional mobility was 12%. Ten-year survival was 92%. In 32% of cases the cause of death was biliary-related, 12% died of biliary or gallbladder cancer. Conclusions: For rare diseases such as PSC, population-based cohort&rsquo, s studies are of paramount importance. Incidence rates of PSC in Italy are markedly lower and survival much longer than the ones reported from tertiary, single-centre series. Moreover, the diagnostic delay and the patient interregional mobility highlights the need for increasing awareness on the disease and for resource reallocation among Italian regions within the National Health Service

International audience; Air Traffic Control (ATC) has been classified as the fourth most stressful job. In this regard, sixteen controllers were asked to perform ecological ATC simulation during which behavioral (Radio Communications with pilots - RCs), subjective (stress perception) and neurophysiological signals (brain activity and skin conductance - SC) were collected. All the considered parameters reported significant changes under high stress conditions. In particular, the theta, alpha, and beta brain rhythms increased significantly (all p

Risk prediction modelling is important to better understand the determinants of the course and outcome of PBC and to inform the risk across the disease continuum in PBC enabling risk-stratified follow-up care and personalised therapy. Current prognostic models in PBC are based on treatment response to ursodeoxycholic acid because of the well-established relationship between alkaline phosphatase on treatment and long-term outcome. In addition, serum alkaline phosphatase correlates with ductular reaction and biliary metaplasia, which are hallmark of biliary injury. Considering the waiting time for treatment failure in high-risk patients is not inconsequential, efforts are focused on bringing forward risk stratification at diagnosis by predicting treatment response at onset. There is a need for better prognostic variables that are central to the disease process. We should take an integrative approach that incorporates multiple layers of information including genetic and environmental influences, host characteristics, clinical data, and molecular alterations for risk assessments. Biomarker discovery has an accelerated pace taking advantage of the emergence of large-scale omics platforms (genomics, epigenomics, transcriptomics, proteomics, metabolomics, and others) and whole-genome sequencing. In the digital era, applications of artificial intelligence, such as machine learning, can support the computing power required to analyse the vast amount of data produced by omics. The information is then used for the development of personalised risk prediction models that through clinical trials and hopefully industry partnerships can guide risk management strategies. We are facing an unprecedented opportunity for the integration of molecular diagnostics into the clinic, which promotes progress toward the personalised management of patients with PBC.

Cross-sectional survey. To evaluate the annual influenza vaccination coverage rate (IVCR) among community-dwelling individuals with spinal cord injury (SCI). SCI community in Switzerland. Participants were responders to the influenza vaccination question (n = 492) in the 2012 community survey of the Swiss Spinal Cord Injury (SwiSCI) cohort study. IVCR of SwiSCI participants were compared to the normative Swiss population, sampled in the Swiss Health Survey of 2012 using direct standardization, logistic regression standardization, and a genetic matching approach to control for differences in age, sex, and quarterly period of survey response. Individuals with SCI showed higher crude (26%, 95% confidence interval (CI): 22–30%) and age- and sex-standardized (24%, CI: 23–24%) IVCR than observed in the general population (15% CI, 14–15%). The adjustment for age and sex as well as quarterly period of survey response showed that the standardized IVCR of individuals with SCI (17%; CI: 12–23%) approached that of the general population. Low IVCR of about 10% were found among individuals with SCI younger than 45 years. IVCR were similar between men and women and between individuals with incomplete and complete paraplegia and tetraplegia. The IVCR in individuals with chronic SCI was not higher than in the general population and much lower than guidelines recommend. The improvement of the IVCR is an important target of health policy in SCI in Switzerland as to reduce the evidenced excess burden in respiratory-disease related morbidity and mortality.

Human liver possesses a persistent and tightly regulated immune response. Maintaining this homeostatic state is the key to prevent pathological processes, as a failure in clearing dangerous stimuli, is associated with tissue damage. A dysregulation of the liver immune homeostasis is involved in many disease processes and the use of the immunosuppression aims to control the inflammatory response, where the physiologic mechanisms failed. The use of steroids which targets broadly the inflammatory cascade and the immune system activation have been extensively employed in both acute and chronic liver diseases. They currently are the backbone of the treatment of autoimmune diseases such as autoimmune hepatitis or IgG4 sclerosing cholangitis. The steroid use in acute liver injury, especially alcohol mediated and drug induced liver injury (DILI), have been debated, despite the biological rationale. The immunosuppression molecules currently employed in liver diseases target the immune system broadly, causing multiple side effects either intrinsic in the mechanisms of the drug or secondary to off-target toxicity. The future of immunosuppressant treatment is moving towards more selective strategies, targeting disease specific pathways. This review aims to explore the rationale of use of immunosuppression in non-transplant hepatology. A broad summary of the immune biology of liver immune mediated diseases will be provided to the readers in order to highlight the potential therapeutic targets. An extensive description of the molecules employed in liver diseases will follow and the clinical evidences in AIH, IgG4 related cholangitis, alcoholic hepatitis and DILI will be reviewed.

BackgroundNearly every individual sustaining traumatic spinal cord injury receives multiple types and classes of medications to manage a litany of secondary complications. Prior clinical studies and evidence from animal models suggest that several of these medications could enhance or impede endogenous neurological recovery. However, there is a knowledge gap surrounding the spectrum of pharmacologic agents typically administered in the routine management of spinal cord injury.ObjectiveTo systematically determine the types of medications commonly administered, alone or in combination, in the acute to subacute phase of spinal cord injury.MethodsWe conducted an analysis of two largescale cohorts (the Sygen interventional trial and the SCIRehab observational cohort study) to determine what constitutes “ standards of acute pharmacological care” after spinal cord injury. Concomitant medication use, including dosage, timing and reason for administration, was tracked. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury.ResultsAcross 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in the Sygen trial received 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Patients enrolled in the SCIRehab cohort study received on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections).ConclusionsTo our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, with potential to both positively and negatively impact neurological recovery. This data may provide key insight to achieve better understanding of how the acute pharmacological management of spinal cord injury affects long-term recovery. All results can be interactively explored on theRXSCIweb site (https://jutzelec.shinyapps.io/RxSCI/) and GitHub repository (https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/).

Background:Ex situ donor liver machine perfusion is a promising tool to assess organ viability prior to transplantation and platform to investigate novel therapeutic interventions. However, the wide variability in donor and graft characteristics between individual donor livers limits the comparability of results. We investigated the hypothesis that the development of a split liver ex situ machine perfusion protocol provides the ideal comparative controls in the investigation of machine perfusion techniques and therapeutic interventions, thus leading to more comparable results.Methods: Four discarded human donor livers were surgically split following identification and separation of right and left inflow and outflow vessels. Each lobe, on separate perfusion machines, was subjected to normothermic perfusion using an artificial hemoglobin-based oxygen carrier solution for 6 h. Metabolic parameters as well as hepatic artery and portal vein perfusion parameters monitored.Results: Trends in hepatic artery and portal vein flows showed a general increase in both lobes throughout each perfusion experiment, even when normalized for tissue weight. Progressive decreases in perfusate lactate and glucose levels exhibited comparable trends in between lobes.Conclusion: Our results demonstrate comparability between right and left lobes when simultaneously subjected to normothermic machine perfusion. In the pre-clinical setting, this model provides the ideal comparative controls in the investigation of therapeutic interventions.

Objective: Probucol is a cholesterol-lowering agent whose ability to prevent atherosclerosis is currently under study. Herein, we investigate the putative mechanism of probucol by observation of changes in cellular cholesterol efflux and lipid droplet morphology in macrophages. Results: The inhibitory activity of probucol was assessed in non-foam or foam cell macrophages expressing ABCA1 generated by treatment with fetal calf serum (FCS) alone or in combination with acetylated LDL, respectively. Probucol inhibited cholesterol efflux to apolipoprotein A-I (apoA-I) by 31.5±0.1% in THP-1 non-foam cells and by 18.5±0.2% in foam cells. In probucol-treated non-foam THP-1 cells, nascent high density lipoprotein (nHDL) particles with a diameter < 7 nm were generated, while in probucol-treated THP-1 foam cells nHDL particles of > 7 nm in diameter containing cholesterol were produced. Foam cells also displayed a significant accumulation of free cholesterol at the plasma membrane, as measured by percent cholestenone formed. Intracellularly, there was a significant decrease in lipid droplet number and an increase in size in probucol-treated THP-1 foam cells when compared to non-treated cells. Conclusions: We report for the first time that probucol is unable to completely inhibit cholesterol efflux in foam cells to the same extent as in non-foam cells. Indeed, functional nHDL is released from foam cells in the presence of probucol. This difference in inhibitory effect could potentially be explained by changes in the plasma membrane pool as well as intracellular cholesterol storage independently of ABCA1.

Gun violence is a public health crisis plaguing the United States, deeply affecting individuals, communities, and the nation as a whole—a crisis that is garnering increasing attention in public and political discourse. In order to better understand and thus mitigate the effects of gun violence, it is vital to understand where it is happening and why. The United States suffers from uniquely high rates of gun violence compared to other developed nations, and adolescents shoulder a disproportionately large share of morbidity and mortality. The adolescent gun violence epidemic is characterized by two parallel tragedies: gun homicide deaths among boys in urban areas and gun suicide deaths among teen boys in rural areas. By understanding the epidemiology of gun violence and the most vulnerable populations it affects, the United States can move toward thoughtful policies and solutions to decrease the devastation it brings to the children and families of the United States.

Introduction: Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by chronic inflammation of the intrahepatic bile ducts, causing progressive ductopenia, cholestasis and fibrosis, and leading to liver failure. Ursodeoxycholic acid (UDCA) is the first-line therapy for the treatment of PBC patients. This is effective in majority of patients; however, up to 20 percent of patients have an incomplete response to UDCA therapy and have a reduced prognosis as compared to healthy individuals. Obeticholic acid (OCA) has been recently registered as second-line therapy for patients with incomplete response to UDCA, with plans to demonstrate the long-term clinical efficacy. Areas covered: Recent evolution in our understanding of disease mechanisms is leading to the advent of new and re-purposed therapeutic agents targeting key processes in the etiopathogenesis. Several therapeutic targets have been proposed which can be categorized into three compartments: immune, biliary and fibrosis. In this review we describe the main biological mechanisms underpinning disease development and progression in PBC and the new targeted therapies on the horizon. Expert commentary: Testing new drugs towards hard clinical endpoints is challenging in PBC due to its low prevalence and the slow progression of the disease. Novel promising biomarkers are under study and should be evaluated as surrogate endpoints in clinical trials.

Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p

Autoimmune Hepatitis (AIH) can present under clinical profile as acute hepatitis of unexplained cause. We analyzed clinical, therapeutical and prognostic implications of AIH presenting as acute hepatitis in a cohort of patients admitted to 3 referral Centres in Italy. AIH onset was considered acute when transaminases were higher than 10 times the normal limit and/or bilirubin higher than 5 mg/ml (irrespectively from the histology, available only in 62% of cases). Among 479 patients diagnosed as AIH, 202 (43%) met the criteria of acute onset. This former group of patients on the basis of the histology has been subdivided in the "genuine" acute onset (83 pts) and acute "on chronic" onset (45 pts) At onset, clinical acute AIH showed significantly higher ALT, bilirubin and INR levels (p < 0.001 for all), lower albumin values (p = 0.001), similar IgG levels; Response to treatment was similar between the two groups. The progression to liver cirrhosis or its complications was significantly less frequent in acute onset AIH (13% vs. 22%, p = 0.02). The "genuine" acute patients showed a higher albumin serum levels (40 vs. 36, p = 0.001), lower INR levels (1.12 vs. 1.26, p = 0.002) and less tendency to the progression of liver disease (7% vs. 12%, p = NS) with respect to acute "on chronic" onset patients. Clinical acute hepatitis represents a common presentation of AIH, responds to standard immunosuppression regimen and would seem to be correlated with a better long-term prognosis.

Liver transplantation (LT) is the only recognized effective treatment for end-stage liver disease (ESLD) and acute fulminant liver failure [...]

Cirrhosis has been long considered a risk factor for bleeding due to the co-existence of the so-called ‘coagulopathy’. More recently, however, compelling evidences have been provided on the occurrence of thrombotic events in the portal and systemic circulation.3–5 Portal vein thrombosis (PVT) is predominantly observed in patients with moderate to severe liver failure with a variable prevalence ranging from 0.6 to 25%. Only fewstudies have provided a longitudinal assessment of the PVT incidence and its sequelae, including recurrence and survival.9–14 Due to the variability of PVT incidence and the paucity of data regarding recurrence and survival,15–20 we prospectively analysed the incidence and the recurrence of PVT in the population of Portal vein thrombosis Relevance On Liver cirrhosis: ItalianVenous thromboticEventsRegistry (PROLIVER), a multi-centre study,8 which involved 43 enrolling centres in Italy (ClinicalTrials.gov Identifier: NCT01470547).

Purpose Positive emotions have been found to be analgesic and can be induced by positive psychology exercises. This study tested if positive psychology exercises provide beneficial effects on pain, responses to pain, physical (pain interference), and emotional function. Methods Randomized parallel-group controlled single-blinded superiority-trial including community-dwelling individuals with chronic pain secondary to spinal cord injury. Participants in the intervention group were instructed to practice 4 personalized positive psychology exercises for 8 weeks. Participants in the control group were asked to be mindful and write about current life events. Results 108 (64%) completed the study. At post-treatment, the intervention participants reported significant reductions in pain intensity and improvements in pain catastrophizing and pain control, relative to baseline. Both groups reported significant decreases in pain interference and negative emotions. Significant between-group differences emerged for pain intensity at post-treatment. At 3-months follow-up, improvements maintained for the intervention group and improvements in positive emotions reached statistical significance. Between-group differences were identified for pain intensity at post-treatment. Conclusion Positive psychology exercises represent a potential effective complementary treatment that result in benefits on pain which can be readily implemented into daily living. Trials designed with an inactive control condition should be conducted to further address efficacy. Trial registration Swiss ethics committee (EKNZ 2014-317)/clinicaltrials.gov (NCT02459028) Registration date: Ethics approval 25.10.2014/Study start date: May 2015 URL of the record: https://clinicaltrials.gov/ct2/show/NCT02459028?term=NCT02459028&cntry=CH&draw=2&rank=1IMPLICATIONS FOR REHABILITATIONPain engenders negative emotions (e.g., fear, anger, sadness) which can negatively affect psychological, social, and physical function.Positive emotions have been found to be analgesic and can be induced by practicing positive psychology exercises.The findings of the current randomized controlled trial provide support for practicing positive psychology exercises (beyond the effects of pain medication intake), in particular on the reduction of pain intensity, but also in improving pain catastrophizing and pain control.The majority of the positive psychology exercises are brief and self-administered positive activities that have no known negative side effects nor financial cost, can be tailored to a person's preferences in activities and can be readily implemented into daily living with chronic pain, complementing standard treatment of pain.

Background: Ex-situ donor liver machine perfusion is a promising tool to assess organ viability prior to transplantation and a platform to investigate novel therapeutic interventions. However, the wide variability in donor and graft characteristics between individual donor livers limits the comparability of results. We investigated the hypothesis that the development of a split liver ex-situ machine perfusion protocol provides the ideal comparative controls in the investigation of machine perfusion techniques and therapeutic interventions, thus leading to more comparable results. Methods: Four discarded human donor livers were surgically split following identification and separation of right and left inflow and outflow vessels. Each lobe, on separate perfusion machines, was subjected to normothermic perfusion using an artificial haemoglobin-based oxygen carrier solution for six hours. Metabolic parameters as well as hepatic artery and portal vein perfusion parameters monitored. Results: Trends in hepatic and portal vein flows showed a general increase in both lobes throughout each perfusion experiment, even when normalised for tissue weight. Progressive decreases in perfusate lactate and glucose levels exhibited comparable trends in between lobes. Conclusion: Our results demonstrate comparability between right and left lobes when simultaneously subjected to normothermic machine perfusion. In the pre-clinical setting, this model provides the ideal comparative controls in the investigation of therapeutic interventions for GMP cellular therapies.

BACKGROUND Direct oral anticoagulants (DOACs) are recommended for stroke prevention in patients with atrial fibrillation (AF) or for treatment of deep vein thrombosis, although some concerns about safety and efficacy were raised on the use of these drugs in patients with advanced liver disease (ALD). We want to investigate the association of DOACs use with the bleeding and ischaemic risk. MATERIAL AND METHODS We performed a systematic review and metanalysis of clinical studies retrieved from PubMed (via MEDLINE) and Cochrane (CENTRAL) databases addressing the impact of DOACs therapy on bleeding events including intracranial haemorrhage (ICH), gastrointestinal and major bleeding. Secondary end points were all-cause death, ischaemic stroke/systemic embolism (IS/SE) and recurrence/progression of vein thrombosis (rDVT). RESULTS 12 studies were included in the meta-analysis: a total of 43 532 patients with ALD or cirrhosis, of whom 27 574 (63.3%) were on treatment with DOACs and 15 958 were in warfarin/low molecular weight heparin. DOACs reduced the incidence of major bleeding by 61% (pooled Hazard Ratio [HR] 0.39, 95% Confidence Interval [CI] 0.21-0.70), ICH by 52% (HR 0.48, 95% CI 0.40-0.59), while no difference in the reduction of any and gastrointestinal bleeding were observed. DOACs reduced also rDVT by 82% (HR 0.18, 95%CI 0.06-0.57), but did not reduce death and IS/SE. No difference was shown according to oesophageal varices and Child Pugh score in the meta-regression analysis between warfarin/heparin and DOACs performed on each outcome. CONCLUSIONS DOACs are associated with a lower incidence of bleeding and may be an attractive therapeutic option in patients with cirrhosis.

Liver transplantation is the only recognized effective treatment for end-stage liver disease. However, organ shortages have become the main challenge for patients and physicians within the transplant community. Waiting list mortality remains an issue with around 10% of patients dying whilst waiting for an available organ. The post-transplantation period is also associated with an adverse complication rate for these specific cohorts of high-risk patients, particularly regarding patient and graft survival. Ischaemia reperfusion injury (IRI) has been highlighted as the mechanism of injury that increases parenchymal damage, which eventually lead to significant graft dysfunction and other poor outcome indicators. The consequences of IRI in clinical practice such as reperfusion syndrome, primary non-function of graft, allograft dysfunction, ischaemic biliary damage and early biliary complications can be life-threatening. IRI dictates the development of a significant inflammatory response that drives the pathway to eventual cell death. The main mechanisms of IRI are mitochondrial damage due to low oxygen tension within the hepatic micro-environment and severe adenosine triphosphate (ATP) depletion during the ischaemic period. After the restoration of normal blood flow, this damage is further enhanced by reoxygenation as the mitochondria respond to reperfusion by releasing reactive oxygen species (ROS), which in turn activate Kupffer cells within the hepatic micro-environment, leading to a pro-inflammatory response and eventual parenchymal cell apoptosis and associated tissue degradation. Machine perfusion (MP) is one emergent strategy considered to be one of the most important advances in organ preservation, restoration and transplantation. Indeed, MP has the potential to rescue frequently discarded organs and has been shown to limit the extent of IRI, leading to suppression of the deleterious pro-inflammatory response. This immunomodulation reduces the prevalence of allograft rejection, the use of immunosuppression therapy and minimizes post-transplant complications. This review aims to update the current knowledge of MP with a focus on normothermic machine liver perfusion (NMLP) and its potential role in immune response pathways.

STUDY DESIGN Questionnaire survey conducted in 2017 as part of the Swiss Spinal Cord Injury Cohort Study (SwiSCI). OBJECTIVES To elucidate the use of outpatient health care providers by individuals with chronic spinal cord injury in a situation of free choice and ample supply. SETTING Community, nationwide. METHODS The frequency of visits was compared to that of a survey conducted five years earlier. Using regression tree analysis, the characteristics of individuals with extensive use of health care providers' services were investigated. Substitution effects, where health care users replace one provider type by another, were quantified using likelihood ratios for positive outcomes. RESULTS The questionnaire was returned by 1,294 persons (response rate 33%). Participants reported visits to 14 different health care providers within the previous 12 months. Most often visited was the general practitioner (GP) by 82%. Older individuals used fewer health care providers than younger participants. Individuals with spasticity and females visited a broader variety of health care providers than the average user. The participants used fewer providers than they did five years ago. Health care users were not found to be substituting one provider type with another. CONCLUSIONS Individuals with spinal cord injury in Switzerland use a wide array of medical service providers. All providers were used complementary to each other without redundancies between providers. The use of providers is driven by health-related factors and gender. Old age was not as much a driver for high utilization as described in other settings.

In recent years, 3D printing gained considerable attention in the orthopedic sector. This work evaluates the feasibility of producing orthopedic scoliosis braces by 3D printing, comparing performance and costs with classical thermoforming procedures. Critical parameters, such as manufacture time, mechanical properties, weight, and comfort are carefully considered. Polyethylene terephthalate glycol-modified (PETG) was selected among the several filaments materials present on the market. Printed samples were analyzed with electronic microscope, tensile, and impact tests and compared with thermoformed polyethylene (PE) and polypropylene (PP) samples. Moreover, a cost analysis was carried out for the specific application. The thermoformed brace of a volunteer patient affected by scoliosis was reproduced using reverse-engineering techniques. The model was then printed as a single piece and postprocessed by an expert orthotist. Subsequently, the patient wore the brace in a pilot case to compare comfort and mechanical effectiveness. Results show that the 3D printing fabrication method is able to provide a valid alternative to the current fabrication methods, being also very competitive in terms of costs. The morphological analysis does not show critical defects in 3D printed samples, while the mechanical tests highlighted their anisotropy, with an overall brittleness of PETG samples in the direction orthogonal to the fibers. However, in terms of mechanical stresses, a back brace should never reach the polymer yield stress, otherwise the shape would be modified and the therapeutic effect could be compromised. Finally, the patient reported the perception of improved support and no significant comfort differences compared with the thermoformed brace.

The Normal Delivery Center (CPN) of São Sebastião / DF, also named the House of Delivery in São Sebastião, is a unit of the Unified Health System (SUS) that provides care to low-risk pregnant women in the Eastern Health Region of the Federal District who want a humanized birth in the public health network. Created in 2001, with the objective of attending and conducting normal delivery, it is composed of 4 PPP rooms (pre-delivery, delivery and postpartum) and aims to meet the entire gestation demand by giving birth to the proposed line of care by the Stork Network. In 2011, the Ministry of Health (MS) created this care network as a public policy strategy that systematizes and institutionalizes a model of care for childbirth and birth. However, the lack of support infrastructure makes the actions proposed by the network unfeasible. Therefore, it is necessary to evaluate and implement viable solutions. Based on the post-occupation evaluation (APO) of the House of Delivery in São Sebastião, the existing project from the architectural point of view, considering the physical space and its environmental comfort (thermal, light and sound), the users' perception, companions and employees) through the application of a questionnaire and compliance with current legislation. In view of the information obtained, the intention is to identify the main aspects that need improvement, aiming at a sustainable architecture, that qualifies the environment., O Centro de Parto Normal (CPN) de São Sebastião/DF, também nominado Casa de Parto de São Sebastião, é uma unidade do Sistema Único de Saúde (SUS) que oferece atendimento às gestantes de baixo risco da Região de Saúde Leste do Distrito Federal que desejam um parto humanizado na rede pública de saúde. Criada em 2001, com o objetivo de assistir e conduzir o parto normal, é composta por 4 quartos PPP (pré-parto, parto e pós-parto) e tem o intuito de atender toda a demanda da gestação ao parir, seguindo a linha de cuidados propostos pela Rede Cegonha. Em 2011, o Ministério da Saúde (MS) criou essa rede de cuidados como uma estratégia de política pública que sistematiza e institucionaliza um modelo de atenção ao parto e ao nascimento. No entanto, a ausência de infraestrutura de apoio inviabiliza as ações propostas pela rede. Sendo assim, faz-se necessária a avaliação e implementação de soluções viáveis.Com base na avaliação pós-ocupação (APO) da Casa de Parto de São Sebastião, serão avaliados o projeto existente do ponto de vista arquitetônico considerando o espaço físico e seu conforto ambiental (térmico, luminoso e sonoro), a percepção dos usuários (puérperas, acompanhantes e funcionários) por meio de aplicação de questionário e a conformidade com a legislação vigente. Tendo em vista as informações obtidas, a intenção é identificar os principais aspectos que necessitam de melhoria, visando uma arquitetura sustentável, que qualifique o ambiente.

Using reported case data from ArboNET and previous seroprevalence data stratified by age and sex, we conservatively estimate that ≈7 million persons in the United States have been infected with West Nile virus since its introduction in 1999. Our data support the need for public health interventions and improved surveillance.

Descriptive qualitative and quantitative study using cross-sectional data from the Swiss Spinal Cord Injury Cohort Study (SwiSCI).To determine the key demands and characteristics of occupations performed by individuals with spinal cord injury (SCI).Swiss community.Job titles indicated by SwiSCI participants were linked to occupational titles from the Occupational Information Network (O*NET) and then frequency-analyzed across sociodemographic and injury-related factors. Subsequently, average O*NET relevance values ranging from 0 to 100 were calculated for the occupations' demands and characteristics, both in general and stratified by injury-related factors.The 1549 study participants indicated a total of 717 job titles and were primarily employed in administrative and management occupations (22.1% and 16.4%, respectively). The participants' occupations predominantly required verbal abilities (average relevance [AR]=68.4) and complex problem solving skills (AR=55.8) and were characterized by conventional work tasks (AR=62.9) and social relationships (AR=58.6). Both the occupations' frequency distribution as well as the average relevance levels of their demands and characteristics differed by SCI severity.Individuals with SCI perform a broad range of occupations that are mainly characterized by cognitive and communicative demands, while physical demands are of minor importance. By informing the development of job matching profiles for vocational guidance, our study facilitates the determination of well-matching jobs for persons with SCI and may contribute to a more sustainable return to work of the affected persons.

// Roberto Ronca 1 , Roberto Tamma 2, 3 , Daniela Coltrini 1 , Simona Ruggieri 2 , Marco Presta 1 and Domenico Ribatti 2, 3 1 Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy 2 Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy 3 National Cancer Institute “Giovanni Paolo II”, Bari, Italy Correspondence to: Domenico Ribatti, email: domenico.ribatti@uniba.it Marco Presta, email: marco.presta@unibs.it Keywords: angiogenesis, fibroblast growth factor-2, long pentraxin-3, mast cell, prostate cancer Received: June 15, 2017 Accepted: June 28, 2017 Published: August 01, 2017 ABSTRACT Mast cells are important modifiers of prostate tumor microenvironment. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system plays a non-redundant autocrine/paracrine role in the growth, vascularization and progression of prostate tumors. Accordingly, the FGF antagonist long pentraxin-3 (PTX3) and the PTX3-derived small molecule FGF-trap NSC12 have been shown to inhibit the growth and vascularization of different FGF-dependent tumor types, including prostate cancer. In this study, we show that recombinant FGF2 is able to cause mast cell recruitment in vivo in the Matrigel plug assay. Conversely, PTX3 overexpression in transgenic mice or treatment with the FGF inhibitor NSC12 result in a significant inhibition of the growth and vascularization of TRAMP-C2 tumor grafts, a murine model of prostate cancer, that were paralleled by a decrease of mast cell infiltrate into the lesion. These data confirm and extend previous observations about the capacity of mast cells to respond chemotactically to FGF2 stimulation and provide evidence about a relationship among mast cell recruitment, angiogenesis, and tumor growth in human prostate adenocarcinoma.

This was a cross-sectional questionnaire survey. The objective of this study was to identify the care-seeking behavior of persons with spinal cord injury (SCI) with respect to the various health care providers and ascertain circumstances that lead to situations where required care was not received. This study was conducted in the entire country of Switzerland. Statistical analysis of frequency of annual visits to health care providers by 17 specialties, and description of situations where health care was required but not received, in persons with chronic SCI living in the community. Main medical contact person was the general practitioner (GP; visited by 88% during last 12 months). The physiotherapist (visited by 72%) was the health care provider with the most visits (average of 30 visits in 12 months). GPs, physiotherapists, urologists and spinal medicine specialists were often contacted in combination, by many participants, often for check-up visits. A situation where care was required but not received was reported by 53 (11%) of participants, with a substantially higher rate in migrants (29%). Main problems why care was not received were bladder and bowel problems and main reasons of care not received were regional or temporal unavailability. Individuals with SCI are frequent users of medical services. There is no group of medical specialists that covers all needs of persons with SCI, what emphasizes health care provision from a comprehensive perspective including a wide array of services. Instances with care required but not received appeared to be rare and more likely in participants with migration background.

Background Mesangiogenic progenitor cells (MPCs) have shown the ability to differentiate in-vitro toward mesenchymal stromal cells (MSCs) as well as angiogenic potential. MPCs have so far been described in detail as progenitors of the mesodermal lineage and appear to be of great significance in tissue regeneration and in hemopoietic niche regulation. On the contrary, information regarding the MPC angiogenic process is still incomplete and requires further clarification. In particular, genuine MPC angiogenic potential should be confirmed in-vivo. Methods In the present article, markers and functions associated with angiogenic cells have been dissected. MPCs freshly isolated from human bone marrow have been induced to differentiate into exponentially growing MSCs (P2-MSCs). Cells have been characterized and angiogenesis-related gene expression was evaluated before and after mesengenic differentiation. Moreover, angiogenic potential has been tested by in-vitro and in-vivo functional assays. Results MPCs showed a distinctive gene expression profile, acetylated-low density lipoprotein uptake, and transendothelial migration capacity. However, mature endothelial markers and functions of endothelial cells, including the ability to form new capillaries, were absent, thus suggesting MPCs to be very immature endothelial progenitors. MPCs showed marked 3D spheroid sprouting activating the related molecular machinery, a clear in-vitro indication of early angiogenesis. Indeed, MPCs applied to chicken chorioallantoic membrane induced and participated in neovessel formation. All of these features were lost in mesengenic terminally differentiated P2-MSCs, showing definite separation of the two differentiation lineages. Conclusion Our results confirm the bona-fide angiogenic potential of MPCs and suggest that the high variability reported for MSC cultures, responsible for the controversies regarding MSC angiogenic potential, could be correlated to variable percentages of co-isolated MPCs in the different culture conditions so far used. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0562-x) contains supplementary material, which is available to authorized users.

Background and Purpose: Prior to thrombectomy for proximal anterior circulation large vessel occlusion (LVO) stroke, recent trials have utilized CT angiography (CTA) for vascular imaging immediately following noncontrast CT (NCCT) for decision-making, but thin-section NCCT with automated maximum intensity projection (MIP) reconstruction also has high accuracy in demonstrating the site of an occluding thrombus. We hypothesized that performing thin-section NCCT with MIP alone prior to thrombectomy improves the time to groin puncture (GP) compared to performing CTA after NCCT. Materials and Methods: We performed a retrospective cohort study of anterior circulation LVO thrombectomy at our tertiary care academic medical center. All stroke patients evaluated with thin-section NCCT (0.625 mm) with automated MIP reconstructions alone and those who had additional CTA were included. We excluded transfer patients, in-hospital strokes, posterior circulation strokes, and patients that were evaluated with stroke imaging other than NCCT or CTA prior to thrombectomy. The study groups were compared for duration from NCCT to GP and total stroke imaging duration. Results: From March 2008 through August 2015, 34 thrombectomy patients met the inclusion/exclusion criteria - 13 in the NCCT and 20 in the NCCT+CTA group. The total stroke imaging duration was shorter in the NCCT group than in the NCCT+CTA group (2 min [1-6] vs. 28 min [23-65]; p < 0.001). The NCCT-only group had a shorter time from NCCT to GP (68 min [32-99] vs. 104 min [79-128]; p = 0.030). Conclusion: Avoiding advanced imaging for patients with anterior circulation LVO in whom thin-section NCCT with MIPs reveals a hyperdense sign significantly shortens the imaging-to-GP time.

Chagas disease, caused by the vector-borne parasite Trypanosoma cruzi, remains one of the most significant neglected tropical diseases affecting the Americas. Identifying high-risk populations is important for understanding Chagas disease transmission and directing public health resources. We recently hypothesized that Texas hunters may be at an elevated risk for contracting Chagas disease because of opportunities for vector exposure and contact with blood of infected reservoirs. To assess their unique exposure risks, we conducted a statewide screening program of Texas hunters. A total of 885 study participants were interviewed and tested for T. cruzi infection; 18 screened positive on a rapid, point-of-care test; however, none were found positive through confirmatory testing. We did find a high prevalence of reported direct contact with wildlife blood as well as triatomine and other arthropod disease vectors. This large-scale screening program represents a novel approach to better understand the vector-borne disease risk in this unique population.

Aims: Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) promote atherogenesis via innate immune receptors, and may impair cellular cholesterol homeostasis (CH). We explored the presence of anti-ApoA-1 IgG in children (5–15 years old) with or without familial hypercholesterolemia (FH), analyzing their association with lipid profiles, and studied their in vitro effects on foam cell formation, gene regulation, and their functional impact on cholesterol passive diffusion (PD). Methods: Anti-ApoA-1 IgG and lipid profiles were measured on 29 FH and 25 healthy children. The impact of anti-ApoA-1 IgG on key CH regulators (SREBP2, HMGCR, LDL-R, ABCA1, and miR-33a) and foam cell formation detected by Oil Red O staining were assessed using human monocyte-derived macrophages. PD experiments were performed using a validated THP-1 macrophage model. Results: Prevalence of high anti-ApoA-1 IgG levels (seropositivity) was about 38% in both study groups. FH children seropositive for anti-ApoA-1 IgG had significant lower total cholesterol LDL and miR-33a levels than those who were seronegative. On macrophages, anti-ApoA-1 IgG induced foam cell formation in a toll-like receptor (TLR) 2/4-dependent manner, accompanied by NF-kB- and AP1-dependent increases of SREBP-2, LDL-R, and HMGCR. Despite increased ABCA1 and decreased mature miR-33a expression, the increased ACAT activity decreased membrane free cholesterol, functionally culminating to PD inhibition. Conclusions: Anti-ApoA-1 IgG seropositivity is frequent in children, unrelated to FH, and paradoxically associated with a favorable lipid profile. In vitro, anti-ApoA-1 IgG induced foam cell formation through a complex interplay between innate immune receptors and key cholesterol homeostasis regulators, functionally impairing the PD cholesterol efflux capacity of macrophages.

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound‐detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross‐sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, −0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40‐ligand (P = 0.0238), soluble Nox2‐derived peptide (sNox2‐dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD40L (Spearman’s rank correlation coefficient [rs], −0.33; P < 0.001), sNox2‐dp (rs, −0.57; P < 0.0001), and urinary excretion of isoprostanes (rs, −0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2‐dp, and urinary 8‐iso prostaglandin F2α‐III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2‐dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation.

West Nile virus (WNV) is a widespread and devastating disease, especially in those who develop neuroinvasive disease. A growing body of evidence describes sequelae years after infection, including neurological complications and chronic kidney disease (CKD). Eighty-nine out of 373 WNV-positive cases were followed for approximately two years and compared to 127 WNV-negative controls with and without CKD. Adjusted risk ratios (aRRs) were calculated via a log binomial regression to determine the impact of WNV exposure and other possible confounders on the likelihood of developing CKD. Cytokine profiles of WNV patients and controls were evaluated to characterize differences and describe potential underlying pathophysiological mechanisms. The associated risk for developing CKD was significantly associated with history of WNV infection (aRR = 1.91, 95% CI 1.13–3.25). Additionally, five distinct cytokines were found to be significantly associated with WNV infection (eotaxin, IL-8, IL-12p70, IP-10, and TNFα) after the p-value was adjusted to &lt, 0.0019 due to the Bonferroni correction. These data support that WNV infection is an independent risk factor for CKD, even after accounting for confounding comorbidities. WNV participants who developed CKD had high activity of proinflammatory markers, indicating underlying inflammatory disease. This study provides new insights into CKD resultant of WNV infection.

chlorpyrifos (CPF) is an organophosphate insecticide used to control pests on a variety of food and feed crops. In mammals, maternal exposure to CPF has been reported to induce cerebral cortex thinning, alteration of long-term brain cognitive function, and Parkinson-like symptoms, but the mechanisms of these processes are not fully understood. In this study, we aimed to gain a deeper understanding of the alterations induced in the brains of mice chronically exposed to CPF by dietary intake. For our purpose, we analysed F1 offspring (sacrificed at 3 and 8 months) of Mus musculus, treated in utero and postnatally with 3 different doses of CPF (0.1-1-10 mg/kg/day). Using RT² Profiler PCR Arrays, we evaluated the alterations in the expression of 84 genes associated with neurodegenerative diseases. In the brains of exposed mice, we evidenced a clear dose-response relationship for AChE inhibition and alterations of gene expression. Some of the genes that were steadily down-regulated, such as Pink1, Park 2, Sv2b, Gabbr2, Sept5 and Atxn2, were directly related to Parkinson's onset. Our experimental results shed light on the possibility that long-term CPF exposure may exert membrane signalling alterations which make brain cells more susceptible to develop neurodegenerative diseases.