RNA G-quadruplexes inhibit translation of the PE/PPE transcripts in Mycobacterium tuberculosis.

The role of RNA G-quadruplexes (rG4s) in bacteria remains poorly understood. High G-quadruplex densities have been linked to organismal stress. Here we investigate rG4s in mycobacteria, which survive highly stressful conditions within the host. We show that rG4-enrichment is a unique feature exclusive to slow-growing pathogenic mycobacteria, and Mycobacterium tuberculosis (Mtb) transcripts contain an abundance of folded rG4s. Notably, the PE/PPE family of genes, unique to slow-growing pathogenic mycobacteria, contain over 50% of rG4s within Mtb transcripts. We found that RNA oligonucleotides of putative rG4s in PE/PPE genes form G-quadruplex structures in vitro, which are stabilized by the G-quadruplex ligand BRACO19. Furthermore, BRACO19 inhibits the transcription of PE/PPE genes and selectively suppresses the growth of Mtb but not Mycobacterium smegmatis or other rapidly growing bacteria. Importantly, the stabilization of rG4s inhibits the translation of Mtb PE/PPE genes (PPE56, PPE67, PPE68, PE_PGRS39, and PE_PGRS41) ectopically expressed in M. smegmatis or Escherichia coli. In addition, the rG4-mediated reduction in PE/PPE protein levels attenuates proinflammatory response upon infection of THP-1 cells. Our findings shed new light on the regulation of PE/PPE genes and highlight a pivotal role for rG4s in Mtb transcripts as regulators of post-transcriptional translational control. The rG4s in mycobacterial transcripts may represent potential drug targets for newer therapies.

Identifying PE2 and PE5 Proteins from Existing Mass Spectrometry Data Using pFind.

The Chromosome-Centric Human Proteome Project (C-HPP) aims to identify all proteins encoded by the human genome. Currently, the human proteome still contains approximately 2000 PE2-PE5 proteins, referring to annotated coding genes that lack sufficient protein-level evidence. During the past 10 years, it has been increasingly difficult to identify PE2-PE5 proteins in C-HPP approaches due to the limited occurrence. Therefore, we proposed that reanalyzing massive MS data sets in repository with newly developed algorithms may increase the occurrence of the peptides of these proteins. In this study, we downloaded 1000 MS data sets via the ProteomeXchange database. Using pFind software, we identified peptides referring to 1788 PE2-PE5 proteins. Among them, 11 PE2 and 16 PE5 proteins were identified with at least 2 peptides, and 12 of them were identified using 2 peptides in a single data set, following the criteria of the HPP guidelines. We found translation evidence for 16 of the 11 PE2 and 16 PE5 proteins in our RNC-seq data, supporting their existence. The properties of the PE2 and PE5 proteins were similar to those of the PE1 proteins. Our approach demonstrated that mining PE2 and PE5 proteins in massive data repository is still worthy, and multidata set peptide identifications may support the presence of PE2 and PE5 proteins or at least prompt additional studies for validation. Extremely high throughput could be a solution to finding more PE2 and PE5 proteins.

The 2023 Report on the Proteome from the HUPO Human Proteome Project.

Since 2010, the Human Proteome Project (HPP), the flagship initiative of the Human Proteome Organization (HUPO), has pursued two goals: (1) to credibly identify the protein parts list and (2) to make proteomics an integral part of multiomics studies of human health and disease. The HPP relies on international collaboration, data sharing, standardized reanalysis of MS data sets by PeptideAtlas and MassIVE-KB using HPP Guidelines for quality assurance, integration and curation of MS and non-MS protein data by neXtProt, plus extensive use of antibody profiling carried out by the Human Protein Atlas. According to the neXtProt release 2023-04-18, protein expression has now been credibly detected (PE1) for 18,397 of the 19,778 neXtProt predicted proteins coded in the human genome (93%). Of these PE1 proteins, 17,453 were detected with mass spectrometry (MS) in accordance with HPP Guidelines and 944 by a variety of non-MS methods. The number of neXtProt PE2, PE3, and PE4 missing proteins now stands at 1381. Achieving the unambiguous identification of 93% of predicted proteins encoded from across all chromosomes represents remarkable experimental progress on the Human Proteome parts list. Meanwhile, there are several categories of predicted proteins that have proved resistant to detection regardless of protein-based methods used. Additionally there are some PE1-4 proteins that probably should be reclassified to PE5, specifically 21 LINC entries and ∼30 HERV entries; these are being addressed in the present year. Applying proteomics in a wide array of biological and clinical studies ensures integration with other omics platforms as reported by the Biology and Disease-driven HPP teams and the antibody and pathology resource pillars. Current progress has positioned the HPP to transition to its Grand Challenge Project focused on determining the primary function(s) of every protein itself and in networks and pathways within the context of human health and disease.

Astrocytic uptake of posttranslationally modified amyloid-ß leads to endolysosomal system disruption and induction of pro-inflammatory signaling.

The disruption of astrocytic catabolic processes contributes to the impairment of amyloid-ß (Aß) clearance, neuroinflammatory signaling, and the loss of synaptic contacts in late-onset Alzheimer's disease (AD). While it is known that the posttranslational modifications of Aß have significant implications on biophysical properties of the peptides, their consequences for clearance impairment are not well understood. It was previously shown that N-terminally pyroglutamylated Aß3(pE)-42, a significant constituent of amyloid plaques, is efficiently taken up by astrocytes, leading to the release of pro-inflammatory cytokine tumor necrosis factor α and synapse loss. Here we report that Aß3(pE)-42, but not Aß1-42, gradually accumulates within the astrocytic endolysosomal system, disrupting this catabolic pathway and inducing the formation of heteromorphous vacuoles. This accumulation alters lysosomal kinetics, lysosome-dependent calcium signaling, and upregulates the lysosomal stress response. These changes correlate with the upregulation of glial fibrillary acidic protein (GFAP) and increased activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Treatment with a lysosomal protease inhibitor, E-64, rescues GFAP upregulation, NF-κB activation, and synapse loss, indicating that abnormal lysosomal protease activity is upstream of pro-inflammatory signaling and related synapse loss. Collectively, our data suggest that Aß3(pE)-42-induced disruption of the astrocytic endolysosomal system leads to cytoplasmic leakage of lysosomal proteases, promoting pro-inflammatory signaling and synapse loss, hallmarks of AD-pathology.

PE/PPE mutations in the transmission of Mycobacterium tuberculosis in China revealed by whole genome sequencing.

OBJECTIVE: This study aims to examine the impact of PE/PPE gene mutations on the transmission of Mycobacterium tuberculosis (M. tuberculosis) in China. METHODS: We collected the whole genome sequencing (WGS) data of 3202 M. tuberculosis isolates in China from 2007 to 2018 and investigated the clustering of strains from different lineages. To evaluate the potential role of PE/PPE gene mutations in the dissemination of the pathogen, we employed homoplastic analysis to detect homoplastic single nucleotide polymorphisms (SNPs) within these gene regions. Subsequently, logistic regression analysis was conducted to analyze the statistical association. RESULTS: Based on nationwide M. tuberculosis WGS data, it has been observed that the majority of the M. tuberculosis burden in China is caused by lineage 2 strains, followed by lineage 4. Lineage 2 exhibited a higher number of transmission clusters, totaling 446 clusters, of which 77 were cross-regional clusters. Conversely, there were only 52 transmission clusters in lineage 4, of which 9 were cross-regional clusters. In the analysis of lineage 2 isolates, regression results showed that 4 specific gene mutations, PE4 (position 190,394; c.46G > A), PE_PGRS10 (839,194; c.744 A > G), PE16 (1,607,005; c.620T > G) and PE_PGRS44 (2,921,883; c.333 C > A), were significantly associated with the transmission of M. tuberculosis. Mutations of PE_PGRS10 (839,334; c.884 A > G), PE_PGRS11 (847,613; c.1455G > C), PE_PGRS47 (3,054,724; c.811 A > G) and PPE66 (4,189,930; c.303G > C) exhibited significant associations with the cross-regional clusters. A total of 13 mutation positions showed a positive correlation with clustering size, indicating a positive association. For lineage 4 strains, no mutations were found to enhance transmission, but 2 mutation sites were identified as risk factors for cross-regional clusters. These included PE_PGRS4 (338,100; c.974 A > G) and PPE13 (976,897; c.1307 A > C). CONCLUSION: Our results indicate that some PE/PPE gene mutations can increase the risk of M. tuberculosis transmission, which might provide a basis for controlling the spread of tuberculosis.

Role of PE/PPE proteins of Mycobacterium tuberculosis in triad of host mitochondria, oxidative stress and cell death.

The PE and PPE family proteins of Mycobacterium tuberculosis (Mtb) is exclusively found in pathogenic Mycobacterium species, comprising approximately 8-10 % of the Mtb genome. These emerging virulent factors have been observed to play pivotal roles in Mtb pathogenesis and immune evasion through various strategies. These immunogenic proteins are known to modulate the host immune response and cell-death pathways by targeting the powerhouse of the cell, the mitochondria to support Mtb survival. In this article, we are focused on how PE/PPE family proteins target host mitochondria to induce mitochondrial perturbations, modulate the levels of cellular ROS (Reactive oxygen species) and control cell death pathways. We observed that the time of expression of these proteins at different stages of infection is crucial for elucidating their impact on the cell death pathways and eventually on the outcome of infection. This article focuses on understanding the contributions of the PE/PPE proteins by unravelling the triad of host mitochondria, oxidative stress and cell death pathways that facilitate the Mtb persistence. Understanding the role of these proteins in host cellular pathways and the intricate mechanisms paves the way for the development of novel therapeutic strategies to combat TB infections.

Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats.

Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [18F]FE-PE2I ([18F]-(E)-N-(3-iodoprop-2-enyl)-2ß-carbofluoroethoxy-3ß-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S-ketamine alters DAT availability. We also performed [3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [18F]FE-PE2I PET or [3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted.

Intravenous tranexamic acid reduces complications following surgical treatment of pathologic fractures of the lower extremity.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate the postoperative complications associated with administering intravenous (IV) tranexamic acid (TXA) in patients undergoing surgical fixation for neoplastic pathologic fractures of the lower extremities. METHODS: Patients ≥18 years old who underwent surgical intervention for neoplastic pathologic lower extremity fractures from 2015 to 2021 were identified using the Premier Healthcare Database. This cohort was divided by TXA receipt on the index surgery day. Patient demographics, hospital factors, patient comorbidities, and 90-day complications were assessed and compared between the cohorts. RESULTS: From 2015 to 2021, 4497 patients met inclusion criteria (769 TXA[+] and 3728 TXA[-]). Following propensity score matching, patients who received TXA had a significantly shorter length of stay than those who did not (7.6 ± 7.3 days vs. 9.0 ± 15.2, p = 0.036). Between the two cohorts, there were no significant differences in comorbidities. Regarding differences in postoperative complications, TXA(+) patients had significantly decreased odds of deep vein thrombosis (DVT) (1.87% vs. 5.46%; odds ratio [OR]:0.33; 95% confidence interval: 0.17-0.62; p = 0.001). CONCLUSION: Administration of IV TXA may be associated with a decreased risk of postoperative DVT without an increased risk of other complications. Orthopedic surgeons should consider the utilization of IV TXA in patients treated surgically for neoplastic pathologic fractures of the lower extremity.

Inferior vena cava filter thromboprophylaxis in surgical cancer patients.

BACKGROUND AND OBJECTIVES: This study evaluated the utilization and outcomes of inferior vena cava (IVC) filters as thromboprophylaxis in cancer patients undergoing surgery. METHODS: This single-center retrospective study analyzed baseline patient characteristics and clinical outcomes of surgical cancer patients who received perioperative prophylactic IVC filters. Primary clinical endpoints included venous thromboembolism (VTE) incidence and filter complications. A statistical correlative analysis was conducted to identify risk factors related to pulmonary embolism (PE), deep vein thrombosis (DVT), and filter thrombi, as well as advanced technique filter removal and mortality at 6 months. RESULTS: A total of 252 surgical oncology patients (median age, 59; female 51%) received IVC filters for the perioperative prevention of PE. Primary surgical sites included spine (n = 91, 36%), orthopedic extremity/joint (n = 49, 19%), genitourinary (n = 47, 19%), brain/cranial (n = 40, 16%), abdominal (n = 18, 7%), multisite (n = 4, 2%), and chest (n = 3, 1%). Moreover, 15% of patients experienced DVTs in the postplacement preretrieval period, while 2% (n = 6) of patients experienced definitive PEs. A total of 36% of IVC filters were ultimately retrieved, with an average filter dwell time of 7.4 months. Complications occurred in one retrieval. CONCLUSION: Prophylactic perioperative IVC filters in surgical cancer patients resulted in minimal complications while ultimately resulting in a low incidence of PE.

No association between error-related ERPs and trait anxiety in a nonclinical sample: Convergence across analytical methods including mass-univariate statistics.

Enhanced error monitoring, as indexed by increased amplitude of the error-related negativity (ERN) event-related potential (ERP) component, has been suggested to reflect a vulnerability neuro-marker of anxiety disorders. Another error-related ERP component is the error positivity (Pe), which reflects late-stage error processing. The associations between heightened ERN and Pe amplitudes and anxiety levels in the nonclinical population have been inconsistent. In this preregistered study, we examined the association between anxiety, ERN, and Pe, using different analytical methods (mass-univariate analyses, MUAs and conventional analyses), self-reported anxiety scales (STAI and STICSA), and trial numbers (all correct trials and equal numbers of correct and error trials). In a sample of 82 healthy adults, both conventional and MUAs demonstrated a robust enhancement of the ERN and Pe to errors relative to the correct-response ERPs. However, the mass-univariate approach additionally unveiled a wider array of electrodes and a longer effect duration for this error enhancement. Across the analytic methods, the results showed a lack of consistent correlation between trait anxiety and error-related ERPs. Findings were not modulated by trial numbers, analyses, or anxiety scales. The present results suggest a lack of enhancement of error monitoring by anxious traits in individuals with subclinical anxiety and those with clinical anxiety but without a clinical diagnosis. Importantly, the absence of such correlation questions the validity of the ERN as a neural marker for anxiety disorders. Future studies that investigate neuro-markers of anxiety may explore alternative task designs and employ robust statistics to provide a more comprehensive understanding of anxiety vulnerability.

Domain specificity of error monitoring: An ERP study in young and older adults.

Metacognition refers to the ability to monitor and control one's cognitive processes, which plays an important role in decision-making throughout the lifespan. It is still debated whether metacognitive abilities decline with age. Neuroimaging evidence suggests that metacognition is served by domain-specific mechanisms. These domains may differentially decline with increasing age. The current investigates whether the error-related negativity (ERN) and the error positivity (Pe) which reflect error detection and error awareness, respectively, differ across perceptual and memory domains in young and older adults. In total, 38 young adults and 37 older adults completed a classic Flanker Task (perceptual) and an adapted memory-based version. No difference in ERN amplitude was found between young and older adults and across domains. Perceptual ERN peaked earlier than Memory ERN. Memory ΔERN was larger than Perceptual ΔERN. Pe was smaller in older adults and ΔPe was larger for perceptual than memory flanker. Memory Pe peaked earlier in young as compared to older adults. Multivariate analyses of whole scalp data supported cross-domain differences. During the task, ERN decreased in young but not in older adults. Memory Pe decreased in young adults but increased in older adults while no significant change in perceptual Pe was found. The study's findings suggest that neural correlates of error monitoring differ across cognitive domains. Moreover, it was shown that error awareness declines in old age but its within-task dynamics vary across cognitive domains. Possible mechanisms underlying metacognition impairments in aging are discussed.

Circulating perturbation of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is associated to cardiac remodeling and NLRP3 inflammasome in cardiovascular patients with insulin resistance risk.

Lipidome perturbation occurring during meta-inflammation is associated to left ventricle (LV) remodeling though the activation of the NLRP3 inflammasome, a key regulator of chronic inflammation in obesity-related disorders. Little is known about phosphatidylcholine (PC) and phosphatidylethanolamine (PE) as DAMP-induced NLRP3 inflammasome. Our study is aimed to evaluate if a systemic reduction of PC/PE molar ratio can affect NLRP3 plasma levels in cardiovascular disease (CVD) patients with insulin resistance (IR) risk. Forty patients from IRCCS Policlinico San Donato were enrolled, and their blood samples were drawn before heart surgery. LV geometry measurements were evaluated by echocardiography and clinical data associated to IR risk were collected. PC and PE were quantified by ESI-MS/MS. Circulating NLRP3 was quantified by an ELISA assay. Our results have shown that CVD patients with IR risk presented systemic lipid impairment of PC and PE species and their ratio in plasma was inversely associated to NLRP3 levels. Interestingly, CVD patients with IR risk presented LV changes directly associated to increased levels of NLRP3 and a decrease in PC/PE ratio in plasma, highlighting the systemic effect of meta-inflammation in cardiac response. In summary, PC and PE can be considered bioactive mediators associated to both the NLRP3 and LV changes in CVD patients with IR risk.

Microplastics Biodegradation by Estuarine and Landfill Microbiomes.

Plastic pollution poses a worldwide environmental challenge, affecting wildlife and human health. Assessing the biodegradation capabilities of natural microbiomes in environments contaminated with microplastics is crucial for mitigating the effects of plastic pollution. In this work, we evaluated the potential of landfill leachate (LL) and estuarine sediments (ES) to biodegrade polyethylene (PE), polyethylene terephthalate (PET), and polycaprolactone (PCL), under aerobic, anaerobic, thermophilic, and mesophilic conditions. PCL underwent extensive aerobic biodegradation with LL (99 ± 7%) and ES (78 ± 3%) within 50-60 days. Under anaerobic conditions, LL degraded 87 ± 19% of PCL in 60 days, whereas ES showed minimal biodegradation (3 ± 0.3%). PE and PET showed no notable degradation. Metataxonomics results (16S rRNA sequencing) revealed the presence of highly abundant thermophilic microorganisms assigned to Coprothermobacter sp. (6.8% and 28% relative abundance in anaerobic and aerobic incubations, respectively). Coprothermobacter spp. contain genes encoding two enzymes, an esterase and a thermostable monoacylglycerol lipase, that can potentially catalyze PCL hydrolysis. These results suggest that Coprothermobacter sp. may be pivotal in landfill leachate microbiomes for thermophilic PCL biodegradation across varying conditions. The anaerobic microbial community was dominated by hydrogenotrophic methanogens assigned to Methanothermobacter sp. (21%), pointing at possible syntrophic interactions with Coprothermobacter sp. (a H2-producer) during PCL biodegradation. In the aerobic experiments, fungi dominated the eukaryotic microbial community (e.g., Exophiala (41%), Penicillium (17%), and Mucor (18%)), suggesting that aerobic PCL biodegradation by LL involves collaboration between fungi and bacteria. Our findings bring insights on the microbial communities and microbial interactions mediating plastic biodegradation, offering valuable perspectives for plastic pollution mitigation.

Damage of polyethylene microplastics on the intestine multilayer barrier, blood cell immune function and the repair effect of Leuconostoc mesenteroides DH in the large-scale loach (Paramisgurnus dabryanus).

Polyethylene microplastics (PE-MPs) has become a global concern due to their widespread distribution and hazardous properties in aquatic habitats. In this study, the accumulation effect of PE-MPs in the intestine of large-scale loach (Paramisgurnus dabryanus) was explored by adding different concentrations of PE-MPs to the water, the destination of PE-MPs after breaking the intestinal barrier and the effects caused. The collected data showed that PE-MPs accumulation for 21d altered the histomorphology and antioxidant enzyme activity of the intestine, induced dysbiosis of the intestinal flora. 10 mg/L of PE-MPs induced a significant increase in the transcript levels of intestinal immunity factors in loach after 21d of exposure. Moreover, the levels of diamine oxidase (DAO) and d-lactic acid (D-Lac) in the gut and serum of loach were significantly increased after exposure to PE-MPs at all concentrations (1, 5, 10 mg/L). Subsequently, the presence of PE-MPs was detected in the blood, suggesting that the disruption of the intestinal multilayer barrier allowed PE-MPs to spill into the circulation. The accumulation of PE-MPs (1,5,10 mg/L) in the blood led to massive apoptosis and necrosis of blood cells and activated phagocytosis in response to PE-MPs invasion. To alleviate the damage, this study further exposure the effect of probiotics on PE-MPs treated loach by adding Leuconostoc mesenteroides DH (109 CFU/g) to the feed. The results showed that DH significantly increased the intestinal index and reduced the levels of DAO and D-Lac. To investigate the reason, we followed the PE-MPs in the intestine and blood of the loach and found that the number of PE-MPs particles was significantly reduced in the probiotic group, while the PE-MPs content in the feces was elevated. Thus, we concluded that DH reducing the accumulation of PE-MPs in the intestinal by increases fecal PE-MPs, which in turn mitigates the damage to the intestinal barrier caused by PE-MPs, and reduces the amount of PE-MPs in the blood. This work offers a robust analysis to understand the mechanisms of damage to the intestinal barrier by MPs and the fate of MPs after escaping the intestinal barrier and provide a new perspective on the application of probiotics in mitigating PE-MPs toxicity.

Pulmonary hypertension-related deaths in patients with acute pulmonary embolism in the United States, 2003 to 2020.

BACKGROUND: Data regarding the mortality trends in pulmonary embolism (PE)-related mortality in patients with concomitant pulmonary hypertension (PH) are lacking. We assessed the trends in PE-related mortality in patients with concomitant PH in the United States (US) over the past 2 decades and during the first year of the COVID-19 pandemic using data from the Centers for Disease Control and Prevention's (CDC) Wide-ranging ONline Data for Epidemiologic Research (WONDER) dataset. METHODS: Mortality data were retrieved from the publicly available CDC WONDER mortality dataset from 2003 to 2020. Age-adjusted mortality rates (AAMRs), per 100,000 population, were assessed using Joinpoint regression modelling and expressed as estimated average annual percentage change (AAPC) with relative 95% CIs and stratified by urbanicity, sex, age, and race/ethnicity. RESULTS: Over the study period, the AAMR for PE/PH-related mortality linearly increased (AAPC: +4.3% [95% CI: 3.7 to 4.9], p < 0.001) without sex differences. The AAMR increase was more pronounced in White individuals (AAPC: +4.8% [95% CI: 4.1 to 5.5], p < 0.001) and in subjects living in rural areas (AAPC: +5.1% [95% CI: 3.8 to 6.4], p < 0.001) compared to those living in urban areas. During the first year of the COVID-19 pandemic there was a significant excess in PE/PH-related mortality among women, older than 65 years and living in rural areas. CONCLUSIONS: The rate of PE/PH-related mortality in the US is increasing. Although the early diagnosis of PH in patients with acute PE has become easier with improved diagnostic modalities, the mortality rate of these patients remains high.

Comparing DOAC and warfarin outcomes in an obese population using the 'real-world' Michigan Anticoagulation Quality Improvement Initiative (MAQI2) registry.

INTRODUCTION: Direct oral anticoagulants (DOACs) have overtaken warfarin in the treatment of nonvalvular atrial fibrillation (AF) and venous thromboembolism (VTE). Limited data explore the safety of DOACs in obesity. METHODS: This multicenter retrospective study between June 2015 and September 2019 uses the Michigan Anticoagulation Quality Improvement Initiative (MAQI2) registry to compare DOACs and warfarin across weight classes (not obese: body mass index (BMI) ⩾ 18.5 and < 30; obese: BMI ⩾ 30 and < 40; severely obese: BMI ⩾ 40). Primary outcomes include major, clinically relevant nonmajor (CRNM), and minor bleeding events per 100 patient-years. Secondary outcomes include stroke, recurrent VTE, and all-cause mortality. RESULTS: DOACs were prescribed to 49% of the 4089 patients with AF and 46% of the 3162 patients with VTE. Compared to patients treated with warfarin, those treated with DOACs had a higher estimated glomerular filtration rate across BMI categories regardless of indication. In the AF population, severely obese patients treated with DOACs had more major (3.4 vs 1.8, p = 0.004), CRNM (8.6 vs 5.9, p = 0.019), and minor bleeding (11.4 vs 9.9, p = 0.001). There was no difference in stroke or all-cause mortality. In the VTE population, both CRNM (7.5 vs 6.7, p = 0.042) and minor bleeding (19.3 vs 10.5, p < 0.001) events occurred at higher rates in patients treated with DOACs. There was no difference in recurrent pulmonary embolism, stroke, or all-cause mortality. CONCLUSION: There is a higher rate of bleeding in severely obese patients with VTE and AF treated with DOACs compared to warfarin, without a difference in secondary outcomes. Further studies to compare the anticoagulant classes and understand bleeding drivers in this population are needed.

Validation of a pulmonary embolism risk assessment model in gynecological inpatients : Clinical trial: A single-center, retrospective study.

OBJECTIVE: To compare the predictive efficacy of the PADUA and Caprini models for pulmonary embolism (PE) in gynecological inpatients, analyze the risk factors for PE, and validate whether both models can effectively predict mortality rates. METHODS: A total of 355 gynecological inpatients who underwent computed tomography pulmonary angiography (CTPA) were included in the retrospective analysis. The comparative assessment of the predictive capabilities for PE between the PADUA and Caprini was carried out using receiver operating characteristic (ROC) curves. Logistic regression analysis was used to identify risk factors associated with PE. Additionally, Kaplan-Meier survival analysis plots were generated to validate the predictive efficacy for mortality rates. RESULTS: Among 355 patients, the PADUA and Caprini demonstrated the area under the curve (AUC) values of 0.757 and 0.756, respectively. There was no statistically significant difference in the AUC between the two models (P = 0.9542). Multivariate logistic analysis revealed immobility (P < 0.001), history of venous thromboembolism (VTE) (P = 0.002), thrombophilia (P < 0.001), hormonal treatment (P = 0.022), and obesity (P = 0.019) as independent risk factors for PE. Kaplan-Meier survival analysis demonstrated the reliable predictive efficacy of both the Caprini (P = 0.00051) and PADUA (P = 0.00031) for mortality. ROC for the three- and six-month follow-ups suggested that the Caprini model exhibited superior predictive efficacy for mortality. CONCLUSIONS: The PADUA model can serve as a simple and effective tool for stratifying high-risk gynecological inpatients before undergoing CTPA. The Caprini model demonstrated superior predictive efficacy for mortality rates.

Comparison of Tenecteplase Versus Alteplase for the Treatment of Pulmonary Embolism and Cardiac Arrest with Suspected Pulmonary Embolism.

High-risk pulmonary embolism (PE) is a life-threatening disease state with current guidelines recommending reperfusion therapy with systemic thrombolytics in addition to anticoagulation. This was a prospective observational cohort study with a historical control group comparing tenecteplase to alteplase for the treatment of PE or cardiac arrest with suspected PE. The primary outcome was the incidence of institutional protocol deviations defined as incorrect thrombolytic dose administered or the incorrect product compounded. Secondary outcomes included any bleeding event, major bleeding event, all-cause mortality, and for patients with a cardiac arrest, successful return of spontaneous circulation (ROSC). Fifty-four patients were included in the study. Protocol deviations occurred in one patient receiving tenecteplase and one patient receiving alteplase (4.0% vs 3.4%; P = 1.0). There was no difference in all-cause mortality (80% vs 86.2%; P = .72), any bleed (12% vs 13.8%; P = 1.0), major bleed (8.0% vs 6.9%; P = 1.0), or ROSC achievement (22.2% vs 28.6%; P = .73) when comparing tenecteplase to alteplase. Our study demonstrates that tenecteplase may be an alternative thrombolytic to alteplase for treatment of PE or cardiac arrest with suspected PE. Further studies comparing the different systemic thrombolytic agents for PE or cardiac arrest with suspected PE are needed.

The color of biodegradable mulch films is associated with differences in peanut yield and bacterial communities.

Biodegradable mulch films (BDMs) are increasingly used in agricultural production as desirable alternatives to the current widespread use of polyethylene (PE) mulch films in China. However, potential effects of different colors of BDMs on field crop production and microbiomes remain unexplored. Here, the differences in bacterial communities of peanut rhizosphere soil (RS) and bulk soil (BS) under non-mulching (CK), PE, and three different colors of BDMs were studied. The results indicated that all treatments could increase the soil temperature, which positively affected the growth of the peanut plants. Moreover, mulching affected the bacterial community structure in RS and BS compared to CK. Furthermore, certain BDM treatments significantly enriched N-fixing bacteria (Bradyrhizobium and Mesorhizobium) and functional groups, increased the closeness of bacterial networks, and harbored more beneficial bacteria as keystone taxa in the RS. This in turn facilitated the growth and development of the peanut plants under field conditions. Our study provides new insights into the micro-ecological effects of mulch films, which can be affected by both the mulch type and color. The observed effects are likely caused by temperature and prevalence of specific microbial functions under the employed films and could guide the development of optimized mulching materials.

External validation of the SHA2PE score and its comparison to the Oakland score for the prediction of safe discharge in patients with lower gastrointestinal bleeding.

BACKGROUND: The growing incidence of lower gastrointestinal bleeding (LGIB) is leading to a rise in-hospital admissions even though most LGIB episodes are self-limiting. The Oakland and SHA2PE scores were designed to identify patients best suited to outpatient care. Our aim is explore the validity of the SHA2PE score and compare both of these scores in terms of predictiveness of safe discharge. METHODS: Retrospective observational study of LGIB patients admitted to a tertiary hospital between June 2014 and June 2019. Safe discharge was defined as the absence of all the following: blood transfusion, haemostatic intervention, re-bleeding, in-hospital death, and re-admission due to LGIB within 28 days after discharge. RESULTS: From 595 hospital admissions for LGIB, 398 episodes were included. Fifty-four per cent met safe discharge criteria, with these cases being younger, with a lower score in the Charlson's index and significantly higher haemoglobin concentration upon arrival. The performance of both scores was good, with an AUC for the Oakland score of 0.85 (95% CI 0.82-0.89) and of 0.797 (95% CI 0.75-0.84) for the SHA2PE score. The Oakland score performed better in terms of prediction of safe discharge, with a positive predictive value and specificity of 100% when a cut-off value of ≤ 8 points was used; however, only a minority of patients might benefit from its implementation given its low sensitivity. CONCLUSIONS: Almost half of the patients admitted for LGIB met criteria for safe discharge. However, the available indexes only allow for the identification of a small proportion of those patients candidates for outpatient care.