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Age-related neurodegenerative diseases involving amyloid aggregation remain one of the biggest challenges of modern medicine. Alterations in the gastrointestinal microbiome play an active role in the aetiology of neurological disorders. Here, we dissect the amyloidogenic properties of biofilm-associated proteins (BAPs) of the gut microbiota and their implications for synucleinopathies. We demonstrate that BAPs are naturally assembled as amyloid-like fibrils in insoluble fractions isolated from the human gut microbiota. We show that BAP genes are part of the accessory genomes, revealing microbiome variability. Remarkably, the abundance of certain BAP genes in the gut microbiome is correlated with Parkinson's disease (PD) incidence. Using cultured dopaminergic neurons and Caenorhabditis elegans models, we report that BAP-derived amyloids induce α-synuclein aggregation. Our results show that the chaperone-mediated autophagy is compromised by BAP amyloids. Indeed, inoculation of BAP fibrils into the brains of wild-type mice promote key pathological features of PD. Therefore, our findings establish the use of BAP amyloids as potential targets and biomarkers of α-synucleinopathies. The microbiota of the intestinal tract is considered a large biofilm formed by myriads bacteria that have a considerable impact in health and disease. Here, the authors show that biofilm-associated proteins from intestinal microbiota form amyloid-like structures that exacerbate alpha-synuclein pathologies. [ABSTRACT FROM AUTHOR]

Introduction: Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor approved to treat type 2 diabetes mellitus (T2DM), among other conditions. When dapagliflozin was approved in Europe for treating T2DM (2012), potential safety concerns regarding its effect on kidney function resulted in this post-authorization safety study to assess hospitalization for acute kidney injury (hAKI) among dapagliflozin initiators in a real-world setting. Objective: The aim of this study was to evaluate the incidence of hAKI in adults with T2DM initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). Methods: This noninterventional cohort study identified new users of dapagliflozin and comparator GLDs from November 2012 to February 2019 from three longitudinal, population-based data sources: Clinical Practice Research Datalink (CPRD; United Kingdom), the HealthCore Integrated Research Database (HIRD; United States [US]), and Medicare (US). Electronic algorithms identified occurrences of hAKI, from which a sample underwent validation. Incidence rates for hAKI were calculated, and incidence rate ratios (IRRs) compared hAKI in dapagliflozin with comparator GLDs. Propensity score trimming and stratification were conducted for confounding adjustment. Results: In all data sources, dapagliflozin initiators had a lower hAKI incidence rate than comparator GLD initiators (adjusted IRRs: CPRD, 0.44 [95% confidence interval (CI), 0.22–0.86]; HIRD, 0.76 [95% CI, 0.62–0.93]; Medicare, 0.69 [95% CI, 0.59–0.79]). The adjusted IRR pooled across the data sources was 0.70 (95% CI, 0.62–0.78). Results from sensitivity and stratified analyses were consistent with the primary analysis. Conclusions: This study, with > 34,000 person-years of real-world dapagliflozin exposure, suggests a decreased risk of hAKI in patients with T2DM exposed to dapagliflozin, aligning with results from dapagliflozin clinical trials. Study registration: European Union Post-Authorisation Studies Register, EUPAS 11684; ClinicalTrials.gov, NCT02695082. [ABSTRACT FROM AUTHOR]

Introduction: At the time of dapagliflozin's approval in Europe (2012) to treat patients with type 2 diabetes mellitus, concerns regarding acute liver injury and severe complications of urinary tract infection (sUTI) led to two post-authorization safety (PAS) studies of these outcomes to monitor the safety of dapagliflozin in real-world use. Objective: To investigate the incidence of hospitalization for acute liver injury (hALI) or sUTI (pyelonephritis or urosepsis) among patients initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). Methods: These two noninterventional cohort studies identified initiators of dapagliflozin and comparator GLDs in November 2012–February 2019 using data from three longitudinal, population-based data sources: Clinical Practice Research Datalink (UK), the HealthCore Integrated Research Database (USA), and the Medicare database (USA). Outcomes (hALI and sUTI) were identified with electronic algorithms. Incidence rates were estimated by exposure group. Incidence rate ratios (IRRs) were calculated comparing dapagliflozin to comparator GLDs, using propensity score trimming and stratification to address confounding. The sUTI analyses were conducted separately by sex. Results: In all data sources, hALI and sUTI incidence rates were generally lower in dapagliflozin initiators than comparator GLD initiators. The adjusted IRR (95% confidence interval) pooled across data sources for hALI was 0.85 (0.59–1.24) and for sUTI was 0.76 (0.60–0.96) in females and 0.74 (0.56–1.00) in males. Findings from sensitivity analyses were largely consistent with the primary analyses. Conclusions: These real-world studies do not suggest increased risks of hALI or sUTI, and they suggest a potential decreased risk of sUTI with dapagliflozin exposure compared with other GLDs. [ABSTRACT FROM AUTHOR]

Introduction: During clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder.Objective: The purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use.Methods: We conducted an observational post-marketing safety study utilising real-world data. The study population was identified within five sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (USA) and Humana (USA). Episodes of time when patients were new users of mirabegron or antimuscarinics (October 2012-December 2018) were sourced from prescriptions and matched on propensity scores. Occurrences of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, CV mortality and all-cause mortality were identified. Outcome incidence rates and hazard ratios from Cox models were estimated.Results: Overall, 152,026 mirabegron and 152,026 antimuscarinic episodes were matched. The population consisted of 63.1% women and 72.6% were ≥ 65 years old. There were no appreciable differences in the incidence rates of MACE, AMI or stroke between users of mirabegron and antimuscarinics. Incidence rates of CV mortality (hazard ratio 0.83, 95% confidence interval 0.73-0.95) and all-cause mortality (hazard ratio 0.80, 95% confidence interval 0.76-0.84) were no higher with mirabegron vs antimuscarinics. Results restricted to episodes at high risk for CV events or stratified by age (< 65 years, ≥ 65 years) or prior overactive bladder medication use were consistent with overall findings.Conclusions: This large, multinational study found no higher risk of MACE, AMI, stroke, CV mortality or all-cause mortality among users of mirabegron relative to users of antimuscarinics. [ABSTRACT FROM AUTHOR]

Purpose: Laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) offers better short-term results than open surgery with similar long-term results although it is technically difficult due to the risk of bleeding. Methods: This study included patients with HCC in Child A cirrhosis who underwent TACE before LLR between 2009 and 2019. The primary endpoint was to analyze the intraoperative and early results of this technique. We also analyzed the long-term outcomes. Patients with and without clinically significant portal hypertension (CSPH) were compared. Results: A total of 44 cirrhotic patients with HCC were included (24 CSPH and 20 non-CSPH). The Pringle maneuver was used in two cases (4.5%), mean blood losses was 100 ml (range 50–200), and three patients (6.8%) required a blood transfusion. The degree of necrosis achieved was greater than 90% in 27 patients (61.4%). At 1, 3, and 5 years, overall survival was 97.7%, 81.5%, and 63.4%, respectively, and disease-free survival was 85.2%, 52.5%, and 34.5%, respectively. There were no statistically significant differences between non-CSPH and CSPH groups regarding intraoperative, early, and long-term outcomes. Conclusion: In our experience, TACE could be beneficial to perform LLR in HCC Child–Pugh A patients with and without CSPH without serious complications and similar oncological outcomes. [ABSTRACT FROM AUTHOR]

Bacteria use two-component systems (TCSs) to sense and respond to environmental changes. The core genome of the major human pathogen Staphylococcus aureus encodes 16 TCSs, one of which (WalRK) is essential. Here we show that S. aureus can be deprived of its complete sensorial TCS network and still survive under growth arrest conditions similarly to wild-type bacteria. Under replicating conditions, however, the WalRK system is necessary and sufficient to maintain bacterial growth, indicating that sensing through TCSs is mostly dispensable for living under constant environmental conditions. Characterization of S. aureus derivatives containing individual TCSs reveals that each TCS appears to be autonomous and self-sufficient to sense and respond to specific environmental cues, although some level of cross-regulation between non-cognate sensor-response regulator pairs occurs in vivo. This organization, if confirmed in other bacterial species, may provide a general evolutionarily mechanism for flexible bacterial adaptation to life in new niches. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to explore the cardiovascular safety of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark. Methods: This was a cohort study using data recorded in Danish registries from patients newly exposed to darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium in 2004-2012. We estimated crude and standardized incidence rates (IRs) for acute myocardial infarction (AMI); stroke; cardiovascular mortality; major adverse cardiac events (MACE, a combined endpoint of the previous three outcomes); and all-cause death for the individual and combined drugs. We also estimated crude, standardized, and propensity score-stratified incidence rate ratios (IRRs) comparing individual antimuscarinic drugs to tolterodine as the reference. Results: Among 72,917 new users of OAB drugs (mean age, 66 years; 60% women), the standardized IR (95% confidence interval) per 1000 person-years for current use of any OAB drug was 2.7 (2.5-2.9) for AMI, 1.3 (1.2-1.5) for stroke, 7.8 (7.5-8.1) for MACE, 4.8 (4.5-5.0) for cardiovascular mortality, and 15.2 (14.8-15.6) for all-cause mortality. Propensity score-stratified IRRs for current use (reference, tolterodine) were close to the null for all drugs and endpoints. Conclusions: We did not identify differences in the risk of cardiovascular events or mortality among users of individual antimuscarinic OAB drugs. [ABSTRACT FROM AUTHOR]

Data on the impact of environmental pollution on the homeostasis of sea turtles remains scarce, particularly in the Southern Gulf of Mexico. As many municipalities along the coastline of the Yucatan Peninsula do not rely on a waste treatment plant, these organisms could be particularly vulnerable. We searched for relationships between the presence of organochlorine pesticides (OCP) and the level of several oxidative and pollutant stress indicators of the hawksbill sea turtle ( Eretmochelys imbricata) during the 2010 nesting season at Punta Xen (Campeche, Mexico). Of the 30 sampled sea turtles, endosulfans, aldrin related (aldrin, endrin, dieldrin, endrin ketone, endrin aldehyde) and dichlorodiphenyldichloroethylene (DDT) families were detected in 17, 21 and 26, respectively. Significant correlation existed between the size of sea turtles with the concentration of methoxychlor, cholinesterase activity in plasma and heptachlors family, and catalase activity and hexachlorohexane family. Cholinesterase activity in washed erythrocytes and lipid peroxidation were positively correlated with glutathione reductase activity. Antioxidant enzyme actions seem adequate as no lipids damages were correlated with any OCPs. Future studies are necessary to evaluate the effect of OCPs on males of the area due to the significant detection of methoxychlor, which target endocrine functioning and increases its concentration with sea turtles size. [ABSTRACT FROM AUTHOR]

Background: The ascertainment of sudden cardiac death (SCD) in electronic health databases is challenging. Objectives: Our objective was to evaluate the applicability of the validated computer definition of SCD developed by Chung et al. in a retrospective study of SCD and domperidone exposure in the Clinical Practice Research Datalink (CPRD). Methods: We assessed out-of-hospital SCD by applying the validated computer definition and linking data with Hospital Episode Statistics and death certificates. We developed a separate algorithm to identify end-of-life care in noninstitutionalized patients and excluded associated deaths from the analysis to address their misclassification as SCD. Results: Of the 681,104 patients in the study cohort, 3444 were initially classified as out-of-hospital SCD. Next, 163 deaths were identified as expected deaths by our algorithm for end-of-life home care. After review of patient profiles, 162 were classified as expected deaths because of evidence that the patient received palliative or end-of-life care, but one was a false negative. The exclusion of such cases appreciably changed the odds ratio for current exposure to domperidone compared with non-use of study medications from 2.09 (95 % confidence interval [CI] 1.16-3.74) to 1.71 (95 % CI 0.92-3.18). A similar effect on the odds ratio was observed for current exposure to metoclopramide but not to proton pump inhibitors. Conclusions: Our algorithm to identify end-of-life care at home in the CPRD performed well, with only one false negative. The exclusion of misclassified cases of SCD reduced the magnitude of the odds ratios for SCD associated with domperidone and metoclopramide exposure by controlling protopathic bias. [ABSTRACT FROM AUTHOR]

Introduction: Epidemiological studies have linked domperidone use with serious cardiac arrhythmias, including sudden cardiac death, but data on age, dose, and duration of use are limited.Objectives: The aim of this study was to assess the risk of out-of-hospital sudden cardiac death associated with domperidone use versus proton pump inhibitors (PPIs), metoclopramide, or non-use of all three medications, and to evaluate the risk of sudden cardiac death in relation to age and domperidone dose.Methods: This was a population-based case-control study nested in a cohort of subjects aged ≥2 years in the Clinical Practice Research Datalink with one or more prescriptions for domperidone, any PPI, or metoclopramide from 2005 to 2011. Out-of-hospital sudden cardiac death was assessed by linkage with Hospital Episode Statistics and death certificates. Controls were matched on age, sex, and medical practice. The risk of sudden cardiac death in domperidone users versus risk in users of PPIs or metoclopramide was evaluated with multivariable conditional logistic regression; case-crossover analysis addressed possible residual confounding.Results: From the study cohort (n = 681,104), 3239 sudden cardiac death cases were matched to 12,572 controls. The adjusted odds ratio (95 % confidence interval) for sudden cardiac death with current use of domperidone alone was 1.71 (0.92-3.18) versus non-use of study medications, 1.26 (0.68-2.34) versus current PPI use, and 0.40 (0.17-0.94) current metoclopramide use. The adjusted odds ratio (95 % confidence interval) relative to exposure to no study drug for domperidone >30 mg/day (eight cases, five controls) was 3.20 (0.59-17.3) and 1.65 (0.89-3.07) for age ≥61 years (27 cases, 49 controls). The odds ratio (95 % confidence interval) was 3.17 (1.72-5.83) for within-person periods of domperidone use versus non-use in the case-crossover analysis.Conclusions: Compared with non-use of any study drug, current domperidone use was associated with sudden cardiac death in nested case-control and case-crossover analyses, with a suggestion of higher risk in older persons and users of higher daily doses. [ABSTRACT FROM AUTHOR]

RNA-based pathways that regulate protein expression are much more widespread than previously thought. Regulatory RNAs, including 5′ and 3′ untranslated regions next to the coding sequence, cis-acting antisense RNAs and trans-acting small non-coding RNAs, are effective regulatory molecules that can influence protein expression and function in response to external cues such as temperature, pH and levels of metabolites. This Review discusses the mechanisms by which these regulatory RNAs, together with accessory proteins such as RNases, control the fate of mRNAs and proteins and how this regulation influences virulence in pathogenic bacteria. [ABSTRACT FROM AUTHOR]

Background: The infliximab (Remicade; Schering-Plough, Kenilworth, NJ, USA) Risk Management Plan included the development, execution and tracking of an education programme directed towards prescribers of infliximab for patients with paediatric Crohn's disease (the Infliximab Paediatric Crohn's Disease Educational Plan). The programme content consisted of educational materials and communications aimed at educating prescribers on the risks associated with infliximab use.Objective: To evaluate the effectiveness of the risk minimization plan.Methods: Evaluation focused on two components: documentation of training of sponsors' personnel, and evaluation of awareness among prescribing physicians in European countries. Treating physicians, identified both independently of the sponsor (6 countries) and by the sponsor (24 countries), were surveyed using a structured questionnaire.Results: Training of internal staff on the educational programme was performed and completed by every person designated an appropriate candidate for the programme in all European countries. The independent survey conducted in Germany, France, Italy, Spain, Sweden and the UK indicated that around 90% of the physicians were either paediatric gastroenterologists (57%) or paediatricians (33%). The great majority (96%) of the interviewed physicians were currently treating paediatric Crohn's disease, and most were currently using infliximab in their treatment of the disease. More specifically, 82% of gastroentrologists treating paediatric Crohn's disease were using infliximab; among paediatricians, the proportion was lower (42%). Ninety-six percent of paediatric gastroenterologists or gastroenterologists declared themselves aware of the benefits and risks of using infliximab for the treatment of paediatric Crohn's disease; in comparison, fewer paediatricians (82%) declared themselves aware of these benefits and risks. The majority initially gained awareness through congresses and workshops, and at the time of the survey only 25% declared that they were made aware of the benefits and risks through the educational programme. However, the majority of physicians reported that they had been approached by the sponsor's personnel in France (98%), Italy (100%), Spain (83%) and Sweden (70%). In Germany and the UK this proportion was 42%. Almost all physicians were aware of the need to perform tuberculosis (TB) and cancer screening prior to initiating therapy with infliximab, and to screen for hypersensitivity reactions before, during and after treatment. Ninety percent of the physicians were aware of the need to update immunization therapy before initiating therapy and, except in Italy (92% aware), around 50% of the physicians were aware of the need to provide patients with the infliximab Patient Alert Card. In the other European countries where the survey took place among physicians identified by the sponsor, 99% of paediatric gastroenterologists and 90% of gastroenterologists or paediatricians declared themselves aware of the benefits and risks of using infliximab for the treatment of paediatric Crohn's disease, and all of them were aware of the risk of TB and opportunistic infections and the need to perform TB and cancer screening prior to initiating therapy with infliximab.Conclusions: Overall, the results of the evaluation of the Infliximab Paediatric Crohn's Disease Educational Plan were satisfactory. The objective of education of internal personnel of the pharmaceutical companies distributing infliximab was completely achieved; over 90% of physicians reported being aware of the benefits and risks of infliximab for the treatment of paediatric Crohn's disease. Further work should be carried out across all countries to educate physicians on providing patients with the infliximab Patient Alert Card. In Germany and the UK in particular, where <50% of physicians reported having been approached by the sponsor's personnel, further work is needed to raise awareness of the educational programme. [ABSTRACT FROM AUTHOR]

The bacterium Listeria monocytogenes is ubiquitous in the environment and can lead to severe food-borne infections. It has recently emerged as a multifaceted model in pathogenesis. However, how this bacterium switches from a saprophyte to a pathogen is largely unknown. Here, using tiling arrays and RNAs from wild-type and mutant bacteria grown in vitro, ex vivo and in vivo, we have analysed the transcription of its entire genome. We provide the complete Listeria operon map and have uncovered far more diverse types of RNAs than expected: in addition to 50 small RNAs (<500 nucleotides), at least two of which are involved in virulence in mice, we have identified antisense RNAs covering several open-reading frames and long overlapping 5′ and 3′ untranslated regions. We discovered that riboswitches can act as terminators for upstream genes. When Listeria reaches the host intestinal lumen, an extensive transcriptional reshaping occurs with a SigB-mediated activation of virulence genes. In contrast, in the blood, PrfA controls transcription of virulence genes. Remarkably, several non-coding RNAs absent in the non-pathogenic species Listeria innocua exhibit the same expression patterns as the virulence genes. Together, our data unravel successive and coordinated global transcriptional changes during infection and point to previously unknown regulatory mechanisms in bacteria. [ABSTRACT FROM AUTHOR]

When the marginal utility of money is positive even at very high levels of the asset (Yoshiyasu Ono's, 1994, assumption), the relationship between inflation and the public deficit at full employment may result in a unique perverse equilibrium where higher deficits reduce inflation. If there are two equilibria, the low inflation equilibrium is one where the perverse effect between inflation and the public deficit prevails; while in the high inflation equilibrium higher public deficits increase inflation. These results contrast sharply with traditional results found in the literature. [ABSTRACT FROM AUTHOR]

Pathogenic bacteria must rapidly adapt to ever‐changing environmental signals resulting in metabolism remodeling. The carbon catabolite repression, mediated by the catabolite control protein A (CcpA), is used to express genes involved in utilization and metabolism of the preferred carbon source. Here, we have identified RsaI as a CcpA‐repressed small non‐coding RNA that is inhibited by high glucose concentrations. When glucose is consumed, RsaI represses translation initiation of mRNAs encoding a permease of glucose uptake and the FN3K enzyme that protects proteins against damage caused by high glucose concentrations. RsaI also binds to the 3′ untranslated region of icaR mRNA encoding the transcriptional repressor of exopolysaccharide production and to sRNAs induced by the uptake of glucose‐6 phosphate or nitric oxide. Furthermore, RsaI expression is accompanied by a decreased transcription of genes involved in carbon catabolism pathway and an activation of genes involved in energy production, fermentation, and nitric oxide detoxification. This multifaceted RNA can be considered as a metabolic signature when glucose becomes scarce and growth is arrested. Synopsis: A small non‐coding RNA in Staphylococcus aureus, called RsaI, adapts carbohydrate metabolism in response to glucose starvation. RsaI is repressed by catabolite control protein A in presence of glucose.RsaI inhibits translation initiation of mRNAs for glucose entry and detoxification upon decreased glucose concentration.RsaI blocks translation through interactions with ribosome binding sites on several mRNA targets.RsaI inhibits the repressor of biofilm formation icaR.RsaI forms duplexes with other non‐coding RNAs. A small non‐coding RNA RsaI represses translation initiation of mRNAs to adapt carbohydrate metabolism in response to glucose starvation. [ABSTRACT FROM AUTHOR]