Combinatorial, additive and dose-dependent drug-microbiome associations.

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease.

Null mutants of a tomato Rho of plants exhibit enhanced water use efficiency without a penalty to yield.

Improving water use efficiency in crops is a significant challenge as it involves balancing water transpiration and CO2 uptake through stomatal pores. This study investigates the role of SlROP9, a tomato Rho of Plants protein, in guard cells and its impact on plant transpiration. The results reveal that SlROP9 null mutants exhibit reduced stomatal conductance while photosynthetic CO2 assimilation remains largely unaffected. Notably, there is a notable decrease in whole-plant transpiration in the rop9 mutants compared to the wild type, especially during noon hours when the water pressure deficit is high. The elevated stomatal closure observed in rop9 mutants is linked to an increase in reactive oxygen species formation. This is very likely dependent on the respiratory burst oxidase homolog (RBOH) NADPH oxidase and is not influenced by abscisic acid (ABA). Consistently, activated ROP9 can interact with RBOHB in both yeast and plants. In diverse tomato accessions, drought stress represses ROP9 expression, and in Arabidopsis stomatal guard cells, ABA suppresses ROP signaling. Therefore, the phenotype of the rop9 mutants may arise from a disruption in ROP9-regulated RBOH activity. Remarkably, large-scale field experiments demonstrate that the rop9 mutants display improved water use efficiency without compromising fruit yield. These findings provide insights into the role of ROPs in guard cells and their potential as targets for enhancing water use efficiency in crops.

Morphological, cellular, and molecular basis of brain infection in COVID-19 patients.

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis.

BACKGROUND & AIMS: Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in alcohol-related liver disease (ALD) is unclear. In this biopsy-controlled, prospective, observational study, we characterized the liver and plasma lipidomes in patients with early ALD. METHODS: We performed mass spectrometry-based lipidomics of paired liver and plasma samples from 315 patients with ALD and of plasma from 51 matched healthy controls. We associated lipid levels with histologic fibrosis, inflammation, and steatosis with correction for multiple testing and adjustment for confounders. We further investigated sphingolipid regulation by means of quantitative real-time polymerase chain reaction sequencing of microRNA, prediction of liver-related events, and tested causality with Mendelian randomization. RESULTS: We detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Most sphingolipids (sphingomyelins and ceramides) and phosphocholines were co-down-regulated in both liver and plasma, where lower abundance correlated with higher fibrosis stage. Sphingomyelins showed the most pronounced negative correlation to fibrosis, mirrored by negative correlations in both liver and plasma with hepatic inflammation. Reduced sphingomyelins predicted future liver-related events. This seemed to be characteristic of "pure ALD," as sphingomyelin levels were higher in patients with concomitant metabolic syndrome and ALD/nonalcoholic fatty liver disease overlap. Mendelian randomization in FinnGen and UK Biobanks indicated ALD as the cause of low sphingomyelins, and alcohol use disorder did not correlate with genetic susceptibility to low sphingomyelin levels. CONCLUSIONS: Alcohol-related liver fibrosis is characterized by selective and progressive lipid depletion in liver and blood, particularly sphingomyelins, which also associates with progression to liver-related events.

Comparative Metabolomics and Microbiome Analysis of Ethanol versus OMNImet/gene•GUT Fecal Stabilization.

Metabolites from feces provide important insights into the functionality of the gut microbiome. As immediate freezing is not always feasible in gut microbiome studies, there is a need for sampling protocols that provide the stability of the fecal metabolome and microbiome at room temperature (RT). Here, we investigated the stability of various metabolites and the microbiome (16S rRNA) in feces collected in 95% ethanol (EtOH) and commercially available sample collection kits with specific preservatives OMNImet•GUT/OMNIgene•GUT. To simulate field-collection scenarios, the samples were stored at different temperatures at varying durations (24 h + 4 °C, 24 h RT, 36 h RT, 48 h RT, and 7 days RT) and compared to aliquots immediately frozen at -80 °C. We applied several targeted and untargeted metabolomics platforms to measure lipids, polar metabolites, endocannabinoids, short-chain fatty acids (SCFAs), and bile acids (BAs). We found that SCFAs in the nonstabilized samples increased over time, while a stable profile was recorded in sample aliquots stored in 95% EtOH and OMNImet•GUT. When comparing the metabolite levels between aliquots stored at room temperature and at +4 °C, we detected several changes in microbial metabolites, including multiple BAs and SCFAs. Taken together, we found that storing samples at RT and stabilizing them in 95% EtOH yielded metabolomic results comparable to those from flash freezing. We also found that the overall composition of the microbiome did not vary significantly between different storage types. However, notable differences were observed in the α diversity. Altogether, the stability of the metabolome and microbiome in 95% EtOH provided results similar to those of the validated commercial collection kits OMNImet•GUT and OMNIgene•GUT, respectively.

Evaluating quantum entanglement generation in two-dimensional graphene systems through lithium ion interactions: A DFT-based study.

In this article, we employed concepts from Density Functional Theory to investigate the interaction energy behavior between the fragments of two-dimensional systems composed of graphene-based materials and lithium ions. Specifically, the proposed system consists of two graphene sheets separated by a controlled distance (face-to-face), with a lithium ion positioned at the center of this separation. Additionally, we examined potential electronic transitions within these systems and assessed the feasibility of quantum entanglement generation and manipulation. Our findings revealed that the interaction energies within the analyzed systems exhibited behavior akin to that described by the Lennard-Jones potential, which characterizes systems with favorable energy for their formation. The results further yielded estimates for the constants ϵ and σ , with values of - 66 . 59  kcal/mol and 1.63  Å , respectively. Specific electronic transitions were identified, suggesting the potential for quantum entanglement generation and manipulation among the two-dimensional graphene system mediated by the lithium ion interactions.

Expansion and diversification of the Glycine max (Gm) ERD15-like subfamily of the PAM2-like superfamily.

MAIN CONCLUSION: Despite modulating senescence and drought responses, the GmERD15-like subfamily members are differentially induced by multiple stresses and diverge partially in stress signaling functions. The PAM2 motif represents a binding site for poly (A)-binding proteins (PABPs), often associated with RNA metabolism regulation. The PAM2-containing protein ERD15 stands out as a critical regulator of diverse stress responses in plants. Despite the relevance of the PAM2 motif, a comprehensive analysis of the PAM2 superfamily and ERD15-like subfamily in the plant kingdom is lacking. Here, we provide an extensive in silico analysis of the PAM2 superfamily and the ERD15-like subfamily in soybean, using Arabidopsis and rice sequences as prototypes. The Glycine max ERD15-like subfamily members were clustered in pairs, likely originating from DNA-based gene duplication, as the paralogs display high sequence conservation, similar exon/intron genome organization, and are undergoing purifying selection. Complementation analyses of an aterd15 mutant demonstrated that the plant ERD15-like subfamily members are functionally redundant in response to drought, osmotic stress, and dark-induced senescence. Nevertheless, the soybean members displayed differential expression profiles, biochemical activity, and subcellular localization, consistent with functional diversification. The expression profiles of Glyma04G138600 under salicylic acid (SA) and abscisic acid (ABA) treatments differed oppositely from those of the other GmERD15-like genes. Abiotic stress-induced coexpression analysis with soybean PABPs showed that Glyma04G138600 was clustered separately from other GmERD15s. In contrast to the AtERD15 stress-induced nuclear redistribution, Glyma04G138600 and Glyma02G260800 localized to the cytoplasm, while Glyma03G131900 fractionated between the cytoplasm and nucleus under normal and stress conditions. These data collectively indicate that despite modulating senescence and drought responses, the GmERD15-like subfamily members are differentially induced by multiple stresses and may diverge partially in stress signaling functions.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

OBJECTIVE: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group. METHODS: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. RESULTS: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (dmax = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .40). Earlier age at seizure onset ( η ρ max 2 = .05) and longer epilepsy duration ( η ρ max 2 = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. SIGNIFICANCE: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy.

Peptide-Based Biomimetic Condensates via Liquid-Liquid Phase Separation as Biomedical Delivery Vehicles.

Biomolecular condensates are dynamic liquid droplets through intracellular liquid-liquid phase separation that function as membraneless organelles, which are highly involved in various complex cellular processes and functions. Artificial analogs formed via similar pathways that can be integrated with biological complexity and advanced functions have received tremendous research interest in the field of synthetic biology. The coacervate droplet-based compartments can partition and concentrate a wide range of solutes, which are regarded as attractive candidates for mimicking phase-separation behaviors and biophysical features of biomolecular condensates. The use of peptide-based materials as phase-separating components has advantages such as the diversity of amino acid residues and customized sequence design, which allows for programming their phase-separation behaviors and the physicochemical properties of the resulting compartments. In this Perspective, we highlight the recent advancements in the design and construction of biomimicry condensates from synthetic peptides relevant to intracellular phase-separating protein, with specific reference to their molecular design, self-assembly via phase separation, and biorelated applications, to envisage the use of peptide-based droplets as emerging biomedical delivery vehicles.

Effect of Bougie Use on First-Attempt Success in Tracheal Intubations: A Systematic Review and Meta-Analysis.

The use of a bougie, a flexible endotracheal tube introducer, has been proposed to optimize first-attempt success in emergency department intubations. We aimed to evaluate the available evidence on the association of bougie use in the first attempt and success in tracheal intubations. This was a systematic review and meta-analysis of studies that evaluated first-attempt success between adults intubated with a bougie versus without a bougie (usually with a stylet) in all settings. Manikin and cadaver studies were excluded. A medical librarian searched Ovid Cochrane Central, Ovid Embase, Ovid Medline, Scopus, and Web of Science for randomized controlled trials and comparative observational studies from inception to June 2023. Study selection and data extraction were done in duplicate by 2 independent reviewers. We conducted a meta-analysis with random-effects models, and we used GRADE to assess the certainty of evidence at the outcome level. We screened a total of 2,699 studies, and 133 were selected for full-text review. A total of 18 studies, including 12 randomized controlled trials, underwent quantitative analysis. In the meta-analysis of 18 studies (9,151 patients), bougie use was associated with increased first-attempt intubation success (pooled risk ratio [RR] 1.11, 95% confidence interval [CI] 1.06 to 1.17, low certainty evidence). Bougie use was associated with increased first-attempt success across all analyzed subgroups with similar effect estimates, including in emergency intubations (9 studies; 8,070 patients; RR 1.11, 95% CI 1.05 to 1.16, low certainty). The highest point estimate favoring the use of a bougie was in the subgroup of patients with Cormack-Lehane III or IV (5 studies, 585 patients, RR 1.60, 95% CI 1.40 to 1.84, moderate certainty). In this meta-analysis, the bougie as an aid in the first intubation attempt was associated with increased success. Despite the certainty of evidence being low, these data suggest that a bougie should probably be used first and not as a rescue device in emergency intubations.

Disruption of Resting-State Functional Connectivity in Acute Ischemic Stroke: Comparisons Between Right and Left Hemispheric Insults.

Few resting-state functional magnetic resonance imaging (RS-fMRI) studies evaluated the impact of acute ischemic changes on cerebral functional connectivity (FC) and its relationship with functional outcomes after acute ischemic stroke (AIS), considering the side of lesions. To characterize alterations of FC of patients with AIS by analyzing 12 large-scale brain networks (NWs) with RS-fMRI. Additionally, we evaluated the impact of the side (right (RH) or left (LH) hemisphere) of insult on the disruption of brain NWs. 38 patients diagnosed with AIS (17 RH and 21 LH) who performed 3T MRI scans up to 72 h after stroke were compared to 44 healthy controls. Images were processed and analyzed with the software toolbox UF2C with SPM12. For the first level, we generated individual matrices based on the time series extraction from 70 regions of interest (ROIs) from 12 functional NWs, constructing Pearson's cross-correlation; the second-level analysis included an analysis of covariance (ANCOVA) to investigate differences between groups. The statistical significance was determined with p < 0.05, after correction for multiple comparisons with false discovery rate (FDR) correction. Overall, individuals with LH insults developed poorer clinical outcomes after six months. A widespread pattern of lower FC was observed in the presence of LH insults, while a contralateral pattern of increased FC was identified in the group with RH insults. Our findings suggest that LH stroke causes a severe and widespread pattern of reduction of brain networks' FC, presumably related to the impairment in their long-term recovery.

Effect of nuts on lipid profile and inflammatory biomarkers in atherosclerotic cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Nut-enriched diets are related to improve lipid and inflammatory biomarkers in meta-analyses in the context of primary cardiovascular prevention. However, primary studies on secondary cardiovascular prevention are scarce and controversial. This systematic review and meta-analysis aimed to evaluate the effect of nut supplementation on lipid and inflammatory profiles in individuals with atherosclerotic cardiovascular disease, and the frequency of adverse events. METHODS: Six databases were used for research: PubMed, EMBASE, BVS, Cochrane Library, Web of Science, and ClinicalTrials.gov, until February 2023, with no language restrictions. We performed random-effects meta-analyses to compare nut-enriched diets vs. control diets for pre-post intervention changes. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system assessed the evidence's certainty. RESULTS: From the 5187 records identified, eight publications containing data referring to five randomized clinical trials involving 439 participants were included in the final analyses. The nuts evaluated were almonds, pecans, Brazil nuts, and mixed nuts, with doses ranging between 5 g and 85 g (median: 30 g/day). The intervention time varied between 6 and 12 weeks. Compared to nut-free diets, nut intake did not have a statistically significant effect on lipid profile biomarkers, except on the atherogenic index (MD: -0.32 [95% CI -0.58 to -0.06], I2 = 0% - moderate certainty of the evidence). Similarly, there was no effect of nuts on inflammatory profile biomarkers. It was not possible to aggregate data on adverse events. CONCLUSIONS: Nut supplementation did not change lipid and inflammatory profiles in the secondary cardiovascular prevention setting.

Innovative sustainable bioreactor-in-a-granule formulation of Trichoderma asperelloides.

The advancement of fungal biocontrol agents depends on replacing cereal grains with low-cost agro-industrial byproducts for their economical mass production and development of stable formulations. We propose an innovative approach to develop a rice flour-based formulation of the beneficial biocontrol agent Trichoderma asperelloides CMAA1584 designed to simulate a micro-bioreactor within the concept of full biorefinery process, affording in situ conidiation, extended shelf-life, and effective control of Sclerotinia sclerotiorum, a devastating pathogen of several dicot agricultural crops worldwide. Rice flour is an inexpensive and underexplored byproduct derived from broken rice after milling, capable of sustaining high yields of conidial production through our optimized fermentation-formulation route. Conidial yield was mainly influenced by nitrogen content (0.1% w/w) added to the rice meal coupled with the fermentor type. Hydrolyzed yeast was the best nitrogen source yielding 2.6 × 109 colony-forming units (CFU)/g within 14 days. Subsequently, GControl, GLecithin, GBreak-Thru, GBentonite, and GOrganic compost+Break-Thru formulations were obtained by extrusion followed by air-drying and further assessed for their potential to induce secondary sporulation in situ, storage stability, and efficacy against Sclerotinia. GControl, GBreak-Thru, GBentonite, and GOrganic compost+Break-Thru stood out with the highest number of CFU after sporulation upon re-hydration on water-agar medium. Shelf-life of formulations GControl and GBentonite remained consistent for > 3 months at ambient temperature, while in GBentonite and GOrganic compost+Break-Thru formulations remained viable for 24 months during refrigerated storage. Formulations exhibited similar efficacy in suppressing the myceliogenic germination of Sclerotinia irrespective of their concentration tested (5 × 104 to 5 × 106 CFU/g of soil), resulting in 79.2 to 93.7% relative inhibition. Noteworthily, all 24-month-old formulations kept under cold storage successfully suppressed sclerotia. This work provides an environmentally friendly bioprocess method using rice flour as the main feedstock to develop waste-free granular formulations of Trichoderma conidia that are effective in suppressing Sclerotinia while also improving biopesticide shelf-life. KEY POINTS: • Innovative "bioreactor-in-a-granule" system for T. asperelloides is devised. • Dry granules of aerial conidia remain highly viable for 24 months at 4 °C. • Effective control of white-mold sclerotia via soil application of Trichoderma-based granules.

Effects of mixed nuts as part of a Brazilian Cardioprotective diet on LDL-cholesterol in adult patients after myocardial infarction: a multicenter randomized controlled clinical trial.

BACKGROUND: Nuts consumption is related to cardioprotective effects on primary cardiovascular prevention, but studies conducted in secondary prevention are small, scarce and controversial. The objective of this trial was to evaluate the effects of a regional and sustainable cardioprotective diet added or not with an affordable mixed nuts on cardiometabolic features in patients with previous myocardial infarction. METHODS: DICA-NUTS study is a national, multi-center, and superiority-parallel randomized clinical trial. Males and females over 40 years old diagnosed with previous myocardial infarction in the last 2 to 6 months were included. Patients were allocated into two groups: the Brazilian Cardioprotective diet (DICA Br) supplemented with 30 g/day of mixed nuts (10 g of peanuts; 10 g of cashew; 10 g of Brazil nuts) (intervention group, n = 193); or only DICA Br prescription (control group, n = 195). The primary outcome was low-density lipoprotein cholesterol means (in mg/dL) after 16 weeks. Secondary outcomes were other lipid biomarkers, glycemic and anthropometric data and diet quality. RESULTS: After adjustment for baseline values, participating study site, time since myocardial infarction and statin treatment regimen (high potency, moderate and low potency/no statins), no significant difference was found between the groups in low-density lipoprotein cholesterol concentrations (intervention-control difference: 3.48 mg/dL [-3.45 to 10.41], P = 0.32). Both groups improved their overall diet quality at the end of the study without differences between them after 16 weeks (intervention-control difference: 1.05 (-0.9 to 2.99); P = 0.29). Other lipids, glycemic profile and anthropometrics were also not different between study groups at the end of the study. CONCLUSION: Adding 30 g/day of mixed nuts to the DICA Br for 16 weeks did not change lipid, glycemic and anthropometric features in the post-myocardial infarction setting. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov website under number NCT03728127 and its World Health Organization Universal Trial Number (WHO-UTN) is U1111-1259-8105.

Progestogens in women with threatened miscarriage or recurrent miscarriage: A meta-analysis.

INTRODUCTION: Clinical practice guidelines provide inconsistent recommendations regarding progestogen supplementation for threatened and recurrent miscarriage. We conducted a systematic review and meta-analysis to assess the effectiveness and safety of progestogens for these patients. MATERIAL AND METHODS: We searched Medline, Embase, and Cochrane Central Registry of Controlled Trials up to October 6, 2023 for randomized control trials (RCTs) comparing progestogen supplementation to placebo or no treatment for pregnant women with threatened or recurrent miscarriage. We assessed the risk of bias using a modified version of the Cochrane risk-of-bias tool and the certainty of evidence using the GRADE approach. RESULTS: Of 15 RCTs (6616 pregnancies) reporting on threatened or recurrent miscarriage, 12 (5610 pregnancies) reported on threatened miscarriage with or without a prior history of miscarriage. Results indicated that progesterone probably increases live births (relative risk (RR) 1.04, 95% confidence interval (CI) 0.99-1.10, absolute increase 3.1%, moderate certainty). Of these RCTs, three (1973 pregnancies) reporting on threatened miscarriage with a prior history of miscarriage indicated that progesterone possibly increases live births (RR 1.06, 95% CI: 0.97-1.16, absolute increase 4.4%; low certainty), while four (2540 pregnancies) reporting on threatened miscarriage and no prior miscarriage left the effect very uncertain (RR 1.02, 95% CI: 0.96-1.10, absolute increase 1.7%; very low certainty). Three trials reporting on 1006 patients with a history of two or more prior miscarriages indicated progesterone probably increases live births (RR 1.08, 95% CI: 0.98-1.19, absolute increase 5.7%, moderate certainty). Six RCTs that reported on 2979 patients with at least one prior miscarriage indicated that progesterone probably increases live births (RR 1.07, 95% CI: 1.01-1.13, absolute increase 5.0%; moderate certainty). Progesterone probably has little or no effect on congenital anomalies (RR 1.06, 95% CI: 0.76-1.48, absolute increase 0.1%; moderate certainty), and other serious adverse pregnancy events (RR 1.07, 95% CI: 0.83-1.40, absolute increase 0.2%, moderate certainty). CONCLUSIONS: In women at increased risk of pregnancy loss, progestogens probably increase live births without increasing adverse maternal and neonatal events. It remains possible that the benefit is restricted to those with prior miscarriages.

Synergism Between Essential Oils and Evaluation of Their Activities with a Focus on Malassezia furfur Control.

Seborrheic dermatitis is a chronic inflammatory disease caused by Malassezia yeast species that affects the regions of the body where the sebaceous glands are present. The combined use of different essential oils (EOs) can increase their spectrum of action. Thus, the present study aimed to evaluate the action of EOs alone and in combination with each other on M. furfur, in planktonic and biofilm form, and their anti-inflammatory and mutagenic potential, in addition to the effects on the viability of cells lines. Of the 40 evaluated EOs, 22 showed activity against M. furfur at 0.5 - 2.0 mg/mL concentrations. Among the most active species, a blend of essential oils (BEOs) composed of Cymbopogon martini (Roxb.) Will. Watson (MIC = 0.5 mg/mL) and Mentha × piperita L. (MIC = 1.0 mg/mL) was selected, which showed a synergistic effect against yeast when evaluated through the checkerboard assay. The fungicidal activity was maintained by the addition of anti-inflammatory oil from Varronia curassavica Jacq. to BEOs. The BEOs also showed activity in the inhibition of biofilm formation and in the eradication of the biofilm formed by M. furfur, being superior to the action of fluconazole. Furthermore, it did not show mutagenic potential and did not interfere with the cell viability of both evaluated cell lines (HaCaT and BMDMs). TNF-α levels were reduced only by C. martini; however, this property was maintained when evaluating BEOs. BEOs had no effect on IL-8 levels. Thus, the BEOs may be indicated for alternative treatments against seborrheic dermatitis.

Risk of falls is associated with 30-day mortality among older adults in the emergency department.

OBJECTIVE: Falls in older adults correlate with heightened morbidity and mortality. Assessing fall risk in the emergency department (ED) not only aids in identifying candidates for prevention interventions but may also offer insights into overall mortality risk. We sought to examine the link between fall risk and 30-day mortality in older ED adults. METHODS: Observational cohort study of adults aged ≥ 75years who presented to an academic ED and who were assessed for fall risk using the Memorial Emergency Department Fall Risk Assessment Tool (MEDFRAT), a validated, ED-specific screening tool. The fall risk was classified as low (0-2 points), moderate (3-4 points), or high (≥5) risk. The primary outcome was 30-day mortality. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 941 patients whose fall risk was assessed in the ED were included in the study. Median age was 83.7 years; 45.6% were male, 75.6% lived in private residences, and 62.7% were admitted. Mortality at 30 days among the high fall risk group was four times that of the low fall risk group (11.8% vs 3.1%; HR 4.00, 95% CI 2.18 to 7.34, p < 0.001). Moderate fall risk individuals had nearly double the mortality rate of the low-risk group (6.0% vs 3.1%), but the difference was not statistically significant (HR 1.98, 95% CI 0.91 to 4.32, p = 0.087). CONCLUSION: ED fall risk assessments are linked to 30-day mortality. Screening may facilitate the stratification of older adults at risk for health deterioration.

Internal dose rate due to intake of uranium and thorium by fish from a dam reservoir associated with a uranium mine in Brazil.

Uranium mining can cause environmental impacts on non-human biota around mine sites. Because of this, the reduction in non-human biota exposure becomes an important issue. Environmental radioprotection results from the evolution of human radioprotection; it is based on dose rate to non-human biota and uses, as a biological target, and has harmful effects on populations. In the present study, a flooded impoundment created following dam construction in a uranium mine plant undergoing decommissioning was investigated. Internal dose rates due to activity concentration of natural uranium (Unat) and 232Th in omnivorous, phytophagous, and carnivorous fish species were estimated. Radionuclide activity concentrations were obtained by spectrophotometry with arsenazo III in the visible range. The dose rate contribution of 232Th was lower than that of Unat. There were no differences between the internal dose rates to studied fish species due to 232Th, but there were differences for Unat. A dose rate of 2.30·10-2 µGy∙d-1 was found due to the two studied radionuclides. Although this value falls below the benchmark for harmful effects, it is important to acknowledge that the assessment did not account for other critical radionuclides from uranium mining, which also contribute to the internal dose. Moreover, the study did not assess external doses. As a result, the possibility cannot be excluded that dose rates at the study area overcome the established benchmarks for harmful effects.

BRET-based effector membrane translocation assay monitors GPCR-promoted and endocytosis-mediated Gq activation at early endosomes.

G protein-coupled receptors (GPCRs) are gatekeepers of cellular homeostasis and the targets of a large proportion of drugs. In addition to their signaling activity at the plasma membrane, it has been proposed that their actions may result from translocation and activation of G proteins at endomembranes-namely endosomes. This could have a significant impact on our understanding of how signals from GPCR-targeting drugs are propagated within the cell. However, little is known about the mechanisms that drive G protein movement and activation in subcellular compartments. Using bioluminescence resonance energy transfer (BRET)-based effector membrane translocation assays, we dissected the mechanisms underlying endosomal Gq trafficking and activity following activation of Gq-coupled receptors, including the angiotensin II type 1, bradykinin B2, oxytocin, thromboxane A2 alpha isoform, and muscarinic acetylcholine M3 receptors. Our data reveal that GPCR-promoted activation of Gq at the plasma membrane induces its translocation to endosomes independently of ß-arrestin engagement and receptor endocytosis. In contrast, Gq activity at endosomes was found to rely on both receptor endocytosis-dependent and -independent mechanisms. In addition to shedding light on the molecular processes controlling subcellular Gq signaling, our study provides a set of tools that will be generally applicable to the study of G protein translocation and activation at endosomes and other subcellular organelles, as well as the contribution of signal propagation to drug action.

Musculoskeletal manifestations of COVID-19.

During the COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected millions of people worldwide, with acute respiratory distress syndrome (ARDS) being the most common severe condition of pulmonary involvement. Despite its involvement in the lungs, SARS-CoV-2 causes multiple extrapulmonary manifestations, including manifestations in the musculoskeletal system. Several cases involving bone, joint, muscle, neurovascular and soft tissues were reported shortly after pandemic onset. Even after the acute infection has resolved, many patients experience persistent symptoms and a decrease in quality of life, a condition known as post-COVID syndrome or long COVID. COVID-19 vaccines have been widely available since December 2020, preventing millions of deaths during the pandemic. However, adverse reactions, including those involving the musculoskeletal system, have been reported in the literature. Therefore, the primary goal of this article is to review the main imaging findings of SARS-CoV-2 involvement in the musculoskeletal system, including acute, subacute, chronic and postvaccination manifestations.