Predicting the risk for major bleeding in elderly patients with venous thromboembolism using the Charlson index. Findings from the RIETE.

Old patients receiving anticoagulant therapy for venous thromboembolism (VTE) are at an increased risk for bleeding. We used data from the RIETE registry to assess the prognostic ability of the Comorbidity Charlson Index (CCI) to predict the risk for major bleeding in patients aged > 75 years receiving anticoagulation for VTE beyond the third month. We calculated the area under the receiver-operating characteristic curve (AUC), the category-based net reclassification index (NRI) and the net benefit (NB). We included 4303 patients with a median follow-up of 706 days (interquartile range [IQR] 462-1101). Of these, 147 (3%) developed major bleeding (27 died of bleeding). The AUC was 0.569 (95% CI 0.524-0.614). Patients with CCI ≤ 4 points were at a lower risk for adverse outcomes than those with CCI > 10 (major bleeding 0.81 (95% CI 0.53-1.19) vs. 2.21 (95% CI 1.18-3.79) per 100 patient-years; p < 0.05; all-cause death 1.9 (95% CI 1.45-2.44) vs. 15.67 (95% CI 12.63-19.22) per 100 patient-years; p < 0.05). A cut-off point of 4 points (CCI4) had a sensitivity of 82% (95% CI 75-89) and a specificity of 30% (95% CI 29-31) to predict major bleeding beyond the third month. CCI4 reclassification improved the NB of the RIETE bleeding score to predict bleeding beyond the third month (CCI4 NB 1.78% vs. RIETE NB 0.44%). Although the AUC of the CCI to predict major bleeding was modest, it could become an additional help to select patients aged > 75 years that obtain more benefit of extended anticoagulation, due to a lower risk for bleeding and better survival.

Bacteroides expand the functional versatility of a universal transcription factor and transcribed DNA to program capsule diversity.

Human gut Bacteroides species encode numerous (eight or more) tightly regulated capsular polysaccharides (CPS). Specialized paralogs of the universal transcription elongation factor NusG, called UpxY (Y), and an anti-Y UpxZ (Z) are encoded by the first two genes of each CPS operon. The Y-Z regulators combine with promoter inversions to limit CPS transcription to a single operon in most cells. Y enhances transcript elongation whereas Z inhibits noncognate Ys. How Y distinguishes among cognate CPS operons and how Z inhibits only noncognate Ys are unknown. Using in-vivo nascent-RNA sequencing and promoter-less in vitro transcription (PIVoT), we establish that Y recognizes a paused RNA polymerase via sequences in both the exposed non-template DNA and the upstream duplex DNA. Y association is aided by novel 'pause-then-escape' nascent RNA hairpins. Z binds non-cognate Ys to directly inhibit Y association. This Y-Z hierarchical regulatory program allows Bacteroides to create CPS subpopulations for optimal fitness.

Phosphorothioate DNA modification by BREX Type 4 systems in the human gut microbiome.

Among dozens of microbial DNA modifications regulating gene expression and host defense, phosphorothioation (PT) is the only known backbone modification, with sulfur inserted at a non-bridging oxygen by dnd and ssp gene families. Here we explored the distribution of PT genes in 13,663 human gut microbiome genomes, finding that 6.3% possessed dnd or ssp genes predominantly in Bacillota, Bacteroidota, and Pseudomonadota. This analysis uncovered several putative new PT synthesis systems, including Type 4 Bacteriophage Exclusion (BREX) brx genes, which were genetically validated in Bacteroides salyersiae. Mass spectrometric analysis of DNA from 226 gut microbiome isolates possessing dnd, ssp, and brx genes revealed 8 PT dinucleotide settings confirmed in 6 consensus sequences by PT-specific DNA sequencing. Genomic analysis showed PT enrichment in rRNA genes and depletion at gene boundaries. These results illustrate the power of the microbiome for discovering prokaryotic epigenetics and the widespread distribution of oxidation-sensitive PTs in gut microbes.

A pervasive large conjugative plasmid mediates multispecies biofilm formation in the intestinal microbiota increasing resilience to perturbations.

Although horizontal gene transfer is pervasive in the intestinal microbiota, we understand only superficially the roles of most exchanged genes and how the mobile repertoire affects community dynamics. Similarly, little is known about the mechanisms underlying the ability of a community to recover after a perturbation. Here, we identified and functionally characterized a large conjugative plasmid that is one of the most frequently transferred elements among Bacteroidales species and is ubiquitous in diverse human populations. This plasmid encodes both an extracellular polysaccharide and fimbriae, which promote the formation of multispecies biofilms in the mammalian gut. We use a hybridization-based approach to visualize biofilms in clarified whole colon tissue with unprecedented 3D spatial resolution. These biofilms increase bacterial survival to common stressors encountered in the gut, increasing strain resiliency, and providing a rationale for the plasmid's recent spread and high worldwide prevalence.

Distant relatives of a eukaryotic cell-specific toxin family evolved a complement-like mechanism to kill bacteria.

Cholesterol-dependent cytolysins (CDCs) comprise a large family of pore-forming toxins produced by Gram-positive bacteria, which are used to attack eukaryotic cells. Here, we functionally characterize a family of 2-component CDC-like (CDCL) toxins produced by the Gram-negative Bacteroidota that form pores by a mechanism only described for the mammalian complement membrane attack complex (MAC). We further show that the Bacteroides CDCLs are not eukaryotic cell toxins like the CDCs, but instead bind to and are proteolytically activated on the surface of closely related species, resulting in pore formation and cell death. The CDCL-producing Bacteroides is protected from the effects of its own CDCL by the presence of a surface lipoprotein that blocks CDCL pore formation. These studies suggest a prevalent mode of bacterial antagonism by a family of two-component CDCLs that function like mammalian MAC and that are wide-spread in the gut microbiota of diverse human populations.

Real world use of dolutegravir two drug regimens.

BACKGROUND: Since 2015, we prescribed dolutegravir (DTG)-based two drug regimens (DTG-2DR) for 620 people [total cohort 3133 (19.8%)]. METHOD: Clinic database search 1 January 15 to 31 October 21. Demographic, tolerability and HIV related data analysed. RESULTS: In total, 620 people identified; 561 had complete data. 446 male (79.5%); median age 54 years (interquartile range 46, 59). 343 (61.1%) MSM. Nine people who initiated naïvely achieved viral suppression (100%). 546/552 (99.0%) switched or continued and were suppressed at data censor. 460/552 (83.3%) received DTG-lamivudine (DTG/3TC), 74/552 (13.4%) received DTG-rilpivirine (DTG/RPV) and 18/552 (3.3%) received DTG-emtricitabine (DTG/FTC). 70 (12.5%) switched off DTG-2DR (55 DTG/3TC, 13 DTG/RPV, two DTG/FTC) due to side-effects. 41 episodes of blip (1 off >50 copies/ml) occurred in 30 people (5.3%). 11/41 on DTG-RPV [ n  = 7 multi-tablet regimen (MTR), n  = 4 single tablet regimen (STR)]. 27/41 DTG-3TC, 3/41 DTG/FTC ( n  = 26 MTR, n  = 4 STR). Six people (1.1%) failed (confirmed viral load >200 copies/ml or persistent low level viraemia) ( n  = 4 DTG-3TC STR, n  = 1 DTG-3TC MTR, n  = 1 DTG-RPV MTR). Four failures due to low level viraemia, one due to non-adherence and one due to high viral load. Resistance tests performed for 5/6 - mutations detected only in latter person with high viral load failure (on DTG-3TC MTR) who developed triple class resistance. CONCLUSION: Majority of experience is in DTG/3TC stable switch. Minority of patients developed side-effects. Low number of virological failures, one developed integrase inhibitor resistance. Viral failure associated with MTR, commensurate with trial data showing no failure with resistance if DTG/3TC STR used. Overall DTG-2DR demonstrates high efficacy in real-world setting.

Edoxaban Versus Low-Molecular-Weight Heparin in Hospitalized COVID-19 Patients With Atrial Fibrillation.

OBJECTIVE: During the first wave of the SARS-CoV-2 pandemic, management of anticoagulation therapy in hospitalized patients with atrial fibrillation (AF) was simplified to low-molecular-weight heparin (LMWH) followed by oral anticoagulation, mainly owing to the risk of drug-drug interactions. However, not all oral anticoagulants carry the same risk. METHODS: Observational, retrospective, and multicenter study that consecutively included hospitalized patients with AF anticoagulated with LMWH followed by oral anticoagulation or edoxaban concomitantly with empirical COVID-19 therapy. Time-to-event (mortality, total bleeds, and admissions to ICU) curves, using an unadjusted Kaplan-Meier method and Cox regression model adjusted for potential confounders were constructed. RESULTS: A total of 232 patients were included (80.3 ± 7.7 years, 50.0% men, CHA2DS2-VASc 4.1 ± 1.4; HAS-BLED 2.6 ± 1.0). During hospitalization, patients were taking azithromycin (98.7%), hydroxychloroquine (89.7%), and ritonavir/lopinavir (81.5%). The mean length of hospital stay was 14.6 ± 7.2 days, and total follow-up was 31.6 ± 13.4 days; 12.9% of patients required admission to ICU, 18.5% died, and 9.9% had a bleeding complication (34.8% major bleeding). Length of hospital stay was longer in patients taking LMWH (16.0 ± 7.7 vs 13.3 ± 6.5 days; P = .005), but mortality and total bleeds were similar in patients treated with edoxaban and those treated with LMWH followed by oral anticoagulation. CONCLUSIONS: Mortality rates, arterial and venous thromboembolic complications, and bleeds did not significantly differ between AF patients receiving anticoagulation therapy with edoxaban or LMWH followed by oral anticoagulation. However, the duration of hospitalization was significantly lower with edoxaban. Edoxaban had a similar therapeutic profile to LMWH followed by oral anticoagulation and may provide additional benefits.

A ubiquitous mobile genetic element disarms a bacterial antagonist of the gut microbiota.

DNA transfer is ubiquitous in the gut microbiota, especially among species of Bacteroidales. In silico analyses have revealed hundreds of mobile genetic elements shared between these species, yet little is known about the phenotypes they encode, their effects on fitness, or pleiotropic consequences for the recipient's genome. Here, we show that acquisition of a ubiquitous integrative and conjugative element encoding an antagonistic system shuts down the native contact-dependent antagonistic system of Bacteroides fragilis . Despite inactivating the native antagonism system, mobile element acquisition increases fitness of the B. fragilis transconjugant over its progenitor by arming it with a new weapon. This DNA transfer causes the strain to change allegiances so that it no longer targets ecosystem members containing the same element yet is armed for communal defense.

Rivaroxaban or apixaban in fragile patients with acute venous thromboembolism.

INTRODUCTION: The efficacy and safety of the direct oral anticoagulants (DOACs) in fragile patients (age ≥ 75 years and/or creatinine clearance [CrCl] levels ≤50 mL/min and/or body weight ≤50kg) with venous thromboembolism (VTE) have not been consistently compared. MATERIAL AND METHODS: We used the RIETE database to compare the rates of the composite of VTE recurrences or major bleeding during anticoagulation in fragile patients with VTE, according to the use of rivaroxaban or apixaban for initial and long-term therapy. RESULTS: From January 2013 to October 2019, 36,889 patients were recruited, of whom 14,831 (40%) were fragile. Overall, 999 fragile patients (15%) received DOACs starting within the first 48 h: rivaroxaban 711 and apixaban 288. Median duration of therapy was: 113 vs. 111 days. A substantial amount of patients in both subgroups (25% vs. 40%) received non-recommended doses of DOACs. During anticoagulation, 13 patients developed VTE recurrences, 18 had major bleeding and 36 died. When only considering patients receiving recommended doses (n = 705), there were no differences between drugs in the rate of the composite outcome (rate ratio [RR]: 1.08; 95%CI: 0.35-3.30) or all-cause death (RR: 0.99; 95%CI: 0.32-3.08). On multivariable analysis, patients receiving rivaroxaban or apixaban at recommended doses had a similar risk for the composite outcome (hazard ratio: 1.34; 95%CI: 0.35-5.06). CONCLUSION: The use of rivaroxaban or apixaban at recommended doses in fragile patients with VTE was associated with a similar risk for VTE recurrences or major bleeding.

Panorámica de la atención estomatológica a pacientes discapacitados o especiales / Panorama of stomatological attention to disabled or special patients

Se realizó una revisión bibliográfica para caracterizar la situación actual de la atención estomatológica al paciente discapacitado o especial durante los meses de marzo y abril de 2012. Se consultaron libros, revistas, tesis etc.; tanto en formato digital como impreso, bases de datos bibliográficas en la BVS de Infomed, y en el buscador google académico; se empleó la estrategia de búsqueda avanzada y la vía de los descriptores del MeSH y el DeCS. Las enfermedades que provocan discapacidad se pueden clasificar en cuatro grupos, enfermedades crónicas degenerativas, las que provocan déficit motor o sensorial y retraso mental. La prevalencia de las enfermedades bucales es alta, destacándose la periodontitis y la caries dental, condicionada por una deficiente higiene bucal, que se traduce en una mala educación para la salud bucal en pacientes y padres o tutores. La promoción y prevención constituyen las herramientas fundamentales en el tratamiento estomatológico de estos pacientes. Se concluyó que a nivel mundial la mayoría de los discapacitados no reciben tratamientos estomatológicos acorde a sus necesidades, que el odontólogo necesita más familiarización y capacitación sobre este tipo de paciente, para brindar una atención con calidad, y que gran parte de ellos pueden ser atendidos en la atención primaria por el especialista, con buena preparación técnico-profesional, correcta integración con el equipo multidisciplinario de salud y manejo de aspectos psicológicos con enfoque familiar y social

A bibliographical review was conducted to characterize the current state of stomatological attention to disabled or special patients during the months of March and April 2012. It was consulted books, journals, theses etc., both in digital and printed format, bibliographic databases at INFOMED VHL, and in Google Scholar search engine. It was used the advanced search strategy and MeSH/DeCS descriptors. The diseases that cause disability can be classified into four groups, chronic degenerative diseases, which cause motor or sensory deficits and mental retardation. The prevalence of oral diseases is high, standing periodontitis and dental caries, conditioned by poor buccal hygiene, resulting in poor buccal health education for patients and parents or guardians. Promotion and prevention are the key tools in the dental treatment of these patients. It was concluded that most disabled persons worldwide do not receive dental treatments according to their needs, odontologists need more familiarization and training on this type of patient, to provide quality care, and that most of them can be treated in primary care by the specialist, with good technical and professional training, proper integration with the multidisciplinary team and managing of psychological aspects with family and social approach