Vaginal fungi are associated with treatment-induced shifts in the vaginal microbiota and with a distinct genital immune profile.

Vaginal colonization by fungi may elicit genital inflammation and enhance the risk of adverse reproductive health outcomes, such as HIV acquisition. Cross-sectional studies have linked fungi with an absence of bacterial vaginosis (BV), but it is unclear whether shifts in vaginal bacteria alter the abundance of vaginal fungi. Vaginal swabs collected following topical metronidazole treatment for BV during the phase 2b, placebo-controlled trial of LACTIN-V, a Lactobacillus crispatus-based live biotherapeutic, were assayed with semi-quantitative PCR for the relative quantitation of fungi and key bacterial species and multiplex immunoassay for immune factors. Vaginal fungi increased immediately following metronidazole treatment for BV (adjusted P = 0.0006), with most of this increase attributable to Candida albicans. Vaginal fungi were independently linked to elevated levels of the proinflammatory cytokine interleukin (IL) 17A, although this association did not remain significant after correcting for multiple comparisons. Fungal relative abundance by semi-quantitative PCR returned to baseline levels within 1 month of metronidazole treatment and was not affected by LACTIN-V or placebo administration. Fungal abundance was positively associated with Lactobacillus species, negatively associated with BV-associated bacteria, and positively associated with a variety of proinflammatory cytokines and chemokines, including IL-17A, during and after study product administration. Antibiotic treatment for BV resulted in a transient expanded abundance of vaginal fungi in a subset of women which was unaffected by subsequent administration of LACTIN-V. Vaginal fungi were positively associated with Lactobacillus species and IL-17A and negatively associated with BV-associated bacteria; these associations were most pronounced in the longer-term outcomes.IMPORTANCEVaginal colonization by fungi can enhance the risk of adverse reproductive health outcomes and HIV acquisition, potentially by eliciting genital mucosal inflammation. We show that standard antibiotic treatment for bacterial vaginosis (BV) results in a transient increase in the absolute abundance of vaginal fungi, most of which was identified as Candida albicans. Vaginal fungi were positively associated with proinflammatory immune factors and negatively associated with BV-associated bacteria. These findings improve our understanding of how shifts in the bacterial composition of the vaginal microbiota may enhance proliferation by proinflammatory vaginal fungi, which may have important implications for risk of adverse reproductive health outcomes among women.

Mycobacterium dormancy and antibiotic tolerance within the retinal pigment epithelium of ocular tuberculosis.

Tuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic cycle. In this stage, Mycobacterium tuberculosis resides inside the host in a dormant and antibiotic-tolerant state. Latent TB infection can also lead to multisystemic diseases because M. tuberculosis invades virtually all organs, including ocular tissues. Ocular tuberculosis (OTB) occurs when the dormant bacilli within the ocular tissues reactivate, originally seeded by hematogenous spread from pulmonary TB. Histological evidence suggests that retinal pigment epithelium (RPE) cells play a central role in immune privilege and in protection from antibiotic effects, making them an anatomical niche for invading M. tuberculosis. RPE cells exhibit high tolerance to environmental redox stresses, allowing phagocytosed M. tuberculosis bacilli to maintain viability in a dormant state. However, the microbiological and metabolic mechanisms determining the interaction between the RPE intracellular environment and phagocytosed M. tuberculosis are largely unknown. Here, liquid chromatography-mass spectrometry metabolomics were used to illuminate the metabolic state within RPE cells reprogrammed to harbor dormant M. tuberculosis bacilli and enhance antibiotic tolerance. Timely and accurate diagnosis as well as efficient chemotherapies are crucial in preventing the poor visual outcomes of OTB patients. Unfortunately, the efficacy of current methods is highly limited. Thus, the results will lead to propose a novel therapeutic option to synthetically kill the dormant M. tuberculosis inside the RPE cells by modulating the phenotypic state of M. tuberculosis and laying the foundation for a new, innovative regimen for treating OTB. IMPORTANCE: Understanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection with Mycobacterium tuberculosis and mycobacterial dormancy is crucial to identify new therapeutic methods to cure ocular tuberculosis. The present study showed that RPE cellular metabolism is altered to foster intracellular M. tuberculosis to enter into the dormant and drug-tolerant state, thereby blunting the efficacy of anti-tuberculosis chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with H2O2 and M. tuberculosis infection showed that the intracellular environment within RPE cells is enriched with a greater level of oxidative stress. The antibiotic tolerance of intracellular M. tuberculosis within RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate.

Mycobacterium dormancy and antibiotic tolerance within the retinal pigment epithelium of ocular tuberculosis.

Tuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic cycle. In this stage, Mycobacterium tuberculosis resides inside the host in a dormant and antibiotic-tolerant state. Latent TB infection can lead to a multisystemic diseases because M. tuberculosis invades virtually all organs, including ocular tissues. Ocular tuberculosis (OTB) occurs when the dormant bacilli within ocular tissues reactivate, originally seeded by hematogenous spread from pulmonary TB. Timely and accurate diagnosis as well as efficient chemotherapies are crucial in preventing poor visual outcomes of OTB patients. Histological evidence suggests that retinal pigment epithelium (RPE) cells play a central role in immune privilege and in the protection from the antibiotic effects, making them an anatomical niche for invading M. tuberculosis . RPE cells exhibit high tolerance to environmental redox stresses, allowing phagocytosed M. tuberculosis bacilli to maintain viability in a dormant state. However, the microbiological and metabolic mechanisms determining the interaction between the RPE intracellular environment and phagocytosed M. tuberculosis are largely unknown. Here, liquid chromatography mass spectrometry (LC-MS) metabolomics was used to illuminate the metabolic state within RPE cells reprogrammed to harbor dormant M. tuberculosis bacilli and enhance the antibiotic tolerance. The results have led to propose a novel therapeutic option to synthetically kill the dormant M. tuberculosis inside the RPE cells by modulating the phenotypic state of M. tuberculosis , thus laying the foundation for a new, innovative regimen for treating OTB. Importance: Understanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection with M. tuberculosis and mycobacterial dormancy is crucial to identify new therapeutic methods to cure OTB. The present study showed that RPE cellular metabolism is altered to foster intracellular M. tuberculosis to enter into the dormant and drug tolerant state, thereby blunting the efficacy of anti-TB chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with H2O2 and M. tuberculosis infection showed that intracellular environment within RPE cells is enriched with greater level of oxidative stress. The antibiotic tolerance of intracellular M. tuberculosis within RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate.

Targeting Mycobacterium tuberculosis Persistence through Inhibition of the Trehalose Catalytic Shift.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple antibiotics, an extremely challenging regimen necessitated by Mtb's ability to form drug-tolerant persister cells. Mtb persister formation is dependent on the trehalose catalytic shift, a stress-responsive metabolic remodeling mechanism in which the disaccharide trehalose is liberated from cell surface glycolipids and repurposed as an internal carbon source to meet energy and redox demands. Here, using a biofilm-persister model, metabolomics, and cryo-electron microscopy (EM), we found that azidodeoxy- and aminodeoxy-d-trehalose analogues block the Mtb trehalose catalytic shift through inhibition of trehalose synthase TreS (Rv0126), which catalyzes the isomerization of trehalose to maltose. Out of a focused eight-member compound panel constructed by chemoenzymatic synthesis, the natural product 2-trehalosamine exhibited the highest potency and significantly potentiated first- and second-line TB drugs in broth culture and macrophage infection assays. We also report the first structure of TreS bound to a substrate analogue inhibitor, obtained via cryo-EM, which revealed conformational changes likely essential for catalysis and inhibitor binding that can potentially be exploited for future therapeutic development. Our results demonstrate that inhibition of the trehalose catalytic shift is a viable strategy to target Mtb persisters and advance trehalose analogues as tools and potential adjunctive therapeutics for investigating and targeting mycobacterial persistence.

Survival benefit of neoadjuvant FOLFIRINOX for patients with borderline resectable pancreatic cancer.

Backgrounds/Aims: While patients with borderline resectable pancreatic cancer (BRPC) are a target population for neoadjuvant chemotherapy (NAC), formal guidelines for neoadjuvant therapy are lacking. We assessed the perioperative and oncological outcomes in patients with BRPC undergoing NAC with FOLFIRINOX for patients undergoing upfront surgery (US). Methods: The AHPBA criteria for borderline resectability and/or a CA19-9 level > 100 µ/mL defined borderline resectable tumors retrieved from a prospectively populated institutional registry from 2007 to 2020. The primary outcome was overall survival (OS) at 1 and 3 years. A Cox Proportional Hazard model based on intention to treat was used. A receiver-operator characteristics (ROC) curve was constructed to assess the discriminatory capability of the use of CA19-9 > 100 µ/mL to predict resectability and mortality. Results: Forty BRPC patients underwent NAC, while 46 underwent US. The median OS with NAC was 19.8 months (interquartile range [IQR], 10.3-44.24) vs. 10.6 months (IQR, 6.37-17.6) with US. At 1 year, 70% of the NAC group and 41.3% of the US group survived (p = 0.008). At 3 years, 42.5 % of the NAC group and 10.9% of the US group survived (p = 0.001). NAC significantly reduced the hazard of death (adjusted hazard ratio, 0.20; 95% confidence interval, 0.07-0.54; p = 0.001). CA19-9 > 100 µ/mL showed poor discrimination in predicting mortality, but was a moderate predictor of resectability. Conclusions: We found a survival benefit of NAC with FOLFIRINOX for BRPC. Greater pre-treatment of CA19-9 and multivessel involvement on initial imaging were associated with progression of the disease following NAC.

Point of Care Abdominal Ultrasound.

Abdominal pain is a common emergency department complaint, and point-of-care ultrasound (POCUS) of the abdomen is increasingly being utilized to evaluate clinical manifestations. It aids in accurate diagnoses and assists in procedures, particularly in emergency and critical care settings. Imaging is often required to confirm the etiology of abdominal pain. POCUS provides the benefit of avoiding radiation exposure and enables quicker diagnosis compared to computed tomography scans. There is growing evidence of the diagnostic accuracy for numerous abdominal POCUS applications, including appendicitis, intussusception, diverticulitis, gastric ultrasound and contrast-enhanced ultrasound.

Community level youth-led interventions to improve maternal-neonatal outcomes in low- and middle-income countries: A systematic review of randomised trials.

Background: Evidence on the effectiveness of youth-led interventions for improving maternal-neonatal health and well-being of women and gender diverse childbearing people in low-income and middle-income countries (LMICs) is incomplete. We aimed to summarise the evidence on whether community level youth-led interventions can improve maternal and neonatal outcomes in LMICs. Methods: We included experimental studies of youth-led interventions versus no intervention, standard care, or another intervention. Participants were women and gender diverse childbearing people during antepartum, intrapartum, and postpartum periods. MEDLINE, Embase, CINAHL, Global Health, Web of Science, and Cochrane Library, and grey literature were searched to January 2023. All interventions addressing and targeting maternal-neonatal health and well-being that were youth-led and community level were included. Primary outcomes of interest were maternal death and neonatal death. We excluded based on population, intervention, comparison, and outcome (PICO) and design. Two reviewers independently extracted key information from each included study and assessed risk of bias. Random-effects meta-analysis was performed where there were sufficient data. The certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE). A narrative synthesis was done for results that could not be pooled. Results: Of the 8054 records retrieved, four trials (21 813 enrolled participants) met the inclusion criteria. The Cooperative for Assistance and Relieve Everywhere, Inc. (CARE) Community Score Card intervention compared to standard reproductive health services control did not significantly improve Antenatal Care coverage (difference-in-differences estimate ß = 0.04; 95% confidence interval (CI) = -0.11, 0.18, P = 0.610; one study, low certainty of evidence). The multi-component social mobilisation interventions compared to standard of care had no effect on adolescent/youth pregnancy (adjusted odds ratio estimate = 1.08; 95% CI = 0.87, 1.33; three studies; low certainty of evidence). Conclusions: Youth-led interventions in LMICs did not show a significant improvement in maternal outcomes. More studies are required to make more precise conclusions. Registration: PROSPERO: CRD42021288798.

Methylated cycloalkanes fuel a novel genus in the Porticoccaceae family (Ca. Reddybacter gen. nov).

Cycloalkanes are abundant and toxic compounds in subsurface petroleum reservoirs and their fate is important to ecosystems impacted by natural oil seeps and spills. This study focuses on the microbial metabolism of methylcyclohexane (MCH) and methylcyclopentane (MCP) in the deep Gulf of Mexico. MCH and MCP are often abundant cycloalkanes observed in petroleum and will dissolve into the water column when introduced at the seafloor via a spill or natural seep. We conducted incubations with deep Gulf of Mexico (GOM) seawater amended with MCH and MCP at four stations. Within incubations with active respiration of MCH and MCP, we found that a novel genus of bacteria belonging to the Porticoccaceae family (Candidatus Reddybacter) dominated the microbial community. Using metagenome-assembled genomes, we reconstructed the central metabolism of Candidatus Reddybacter, identifying a novel clade of the particulate hydrocarbon monooxygenase (pmo) that may play a central role in MCH and MCP metabolism. Through comparative analysis of 174 genomes, we parsed the taxonomy of the Porticoccaceae family and found evidence suggesting the acquisition of pmo and other genes related to the degradation of cyclic and branched hydrophobic compounds were likely key events in the ecology and evolution of this group of organisms.

The 2023 Core Content of advanced emergency medicine ultrasonography.

In February 2023, the American Board of Emergency Medicine (ABEM) approved modifications to the Advanced Emergency Medicine Ultrasonography (AEMUS) Core Content, which defines the areas of knowledge considered essential for the practice of AEMUS. This manuscript serves as a revision of the AEMUS Core Content originally published in 2014. The revision of the Core Content for AEMUS training aims to establish standardized education and qualifications necessary for AEMUS fellowship program leadership, clinical application, administration, quality improvement, and research. The Core Content provides the organizational framework and serves as the basis for the development of content for the Focused Practice Examination (FPE) administered by ABEM. AEMUS fellowship directors may reference the Core Content when designing AEMUS fellowship curricula to help prepare graduates for the autonomous practice of AEMUS and the FPE. In this article, an updated revision of the previously published AEMUS Core Content is detailed, and the entire development of the Core Content is presented.

A Tool to Assess Competence in Critical Care Ultrasound Based on Entrustable Professional Activities.

Background: Existing assessment tools for competence in critical care ultrasound (CCUS) have limited scope and interrupt clinical workflow. The framework of entrustable professional activities (EPAs) is well suited to developing an assessment tool that is comprehensive and readily integrated into the intensive care unit (ICU) training environment. Objective: This study sought to design an EPA-based tool to assess competence in CCUS for pulmonary and critical care fellows and to assess the validity and reliability of the tool. Methods: Eight experts in CCUS met to define the core EPAs for CCUS. A nominal group technique was used to reach consensus. An assessment tool was created based on the EPAs with a modified Ottawa entrustability scale. Trained faculty evaluated pulmonary and critical care fellows using this tool in the ICU over a 6-month study period at a single institution. An assessment of validity of the EPA-based tool is made with four sources of validity evidence: content, response process, reliability, and relation to other variables. Reliability and response process data were generated using generalizability theory analysis to estimate sources of variance in entrustment scores. Analysis of response process validity and validity by relation to other variables was performed using regression models. Results: Fifty-four assessments were recorded during the study period, conducted on 23 trainees by 13 faculty. Content validity of the tool was demonstrated using expert consensus and published guidelines from critical care societies to define the EPAs. Response process validity was demonstrated by the low variance in entrustment scores due to evaluators (0.086 or 6%) and high agreement between score and trainee self-assessment (regression coefficient, 0.82; P < 0.0001). Reliability was demonstrated by the high "true" variance in entrustment score attributable to the trainee: 0.674 or 45%. Validity by relation to other variables was demonstrated using regression analysis to show correlation between entrustment score and the number of times a fellow has performed an EPA (regression coefficient, 0.023; P < 0.0001). Conclusion: An EPA-based assessment tool for competence in CCUS was created. We obtained sufficient validity evidence on three of the diagnostic EPAs. Procedural EPAs were infrequently assessed, limiting generalizability in this subgroup.

Going local: Evaluating guideline adherence and appropriateness of antibiotic prescribing in patients with febrile neutropenia at an academic teaching hospital.

Background: Febrile neutropenia (FN) is a medical emergency with significant morbidity and mortality for oncology patients, requiring comprehensive workup and timely antibiotic administration. We evaluated concordance with locally developed FN guidelines and outcomes of cancer patients admitted to general internal medicine at an academic teaching hospital. Methods: We conducted a retrospective observational cohort study of patients admitted between July 1, 2016, and June 30, 2017, for FN. Patients were classified as having low-risk or high-risk FN according to their malignancy and chemotherapy. Primary outcome was the proportion of patients receiving guideline-concordant antibiotics within 48 hours of admission to general internal medicine. Secondary outcomes were the proportion of patients in whom empirical antibiotics were active against pathogens isolated, rate of antibiotic-associated adverse events, and in-hospital mortality. We used logistic regression to model relationship between FN risk and guideline-concordant antibiotics. Results: Among 100 patients included, 34 (34%) were low-risk FN and 66 (66%) were high-risk. Proportion of guideline-concordant empirical antibiotics was significantly lower among low-risk FN patients than high-risk patients: 12 (35%) of 34 versus 47 (71%) of 66 (P = .001). Empirical antibiotics were active against 17 (94%) of 18 isolated pathogens. The mortality rate was 3%, and 16% of patients experienced antibiotic-associated adverse events. Hematological malignancy and infectious diseases-trained physician involvement were associated with guideline-concordant prescribing, with adjusted odds ratios of 3.76 (95% CI, 1.46-9.70; P = .006) and 3.71 (95% CI, 1.49-9.23; P = .005), respectively. Conclusions: Guideline concordance was low compared to published reports. Factors influencing appropriate antimicrobial prescribing in patients with FN warrant further exploration.

Soluble E-cadherin: A marker of genital epithelial disruption.

PROBLEM: The genital epithelial barrier is a crucial first line of defence against HIV, and epithelial disruption may enhance HIV susceptibility. Assessment of genital epithelial integrity requires biopsies, but their collection is not practical in many research settings. A validated biomarker of genital epithelial barrier integrity would therefore be useful. The purpose of this study was to evaluate soluble E-cadherin (sE-cad) as a marker of genital epithelial disruption. METHOD OF STUDY: Using in vitro models of endocervical and foreskin epithelial cells, we assessed changes in sE-cad, IL-6, IL-1ß, and IL-1α levels following mechanical disruption. We also assessed changes in sE-cad levels in vivo in cervicovaginal secretions after epithelial disruption by endocervical cytobrush sampling in Canadian women, and assessed the relationship between levels of sE-cad in coronal sulcus swabs to membrane-bound E-cadherin in the overlying foreskin tissue in Ugandan men. RESULTS: sE-cad levels immediately increased after in vitro epithelial physical disruption with the degree of elevation dependent on the extent of disruption, as did levels of IL-1ß and IL-1α; this was followed by a delayed increase in IL-6 levels. In vivo results confirmed that sE-cad levels in cervicovaginal secretions were elevated 6 h after cytobrush sampling when compared to baseline. Furthermore, levels of sE-cad in the prepuce were inversely correlated with the amount of membrane-bound E-cadherin of overlying tissue. CONCLUSION: Our results validate the use of sE-cad as a marker of epithelial disruption and demonstrate that the processes of physical disruption and inflammation in the genital tract are strongly intertwined.

A consensus list of ultrasound competencies for graduating emergency medicine residents.

Objectives: Emergency ultrasound (EUS) is a critical component of emergency medicine (EM) resident education. Currently, there is no consensus list of competencies for EUS training, and graduating residents have varying levels of skill and comfort. The objective of this study was to define a widely accepted comprehensive list of EUS competencies for graduating EM residents through a modified Delphi method. Methods: We developed a list of EUS applications through a comprehensive literature search, the American College of Emergency Physicians list of core EUS benchmarks, and the Council of Emergency Medicine Residency-Academy of Emergency Ultrasound consensus document. We assembled a multi-institutional expert panel including 15 faculty members from diverse practice environments and geographical regions. The panel voted on the list of competencies through two rounds of a modified Delphi process using a modified Likert scale (1 = not at all important, 5 = very important) to determine levels of agreement for each application-with revisions occurring between the two rounds. High agreement for consensus was set at >80%. Results: Fifteen of 15 panelists completed the first-round survey (100%) that included 359 topics related to EUS. After the first round, 195 applications achieved high agreement, four applications achieved medium agreement, and 164 applications achieved low agreement. After the discussion, we removed three questions and added 13 questions. Fifteen of 15 panelists completed the second round of the survey (100%) with 209 of the 369 applications achieving consensus. Conclusion: Our final list represents expert opinion on EUS competencies for graduating EM residents. We hope to use this consensus list to implement a more consistent EUS curriculum for graduating EM residents and to standardize EUS training across EM residency programs.

Effects of structured Ramadan Nutrition Plan on glycemic control and variability using continuous glucose monitoring in individuals with type 2 diabetes: A pilot study.

BACKGROUND AND AIMS: Continuous glucose monitoring (CGM) has been increasingly used in recent years to evaluate glycemic control and variability in individuals with diabetes observing Ramadan fasting. However, the effectiveness of the Ramadan Nutrition Plan (RNP) in individuals with type 2 diabetes (T2D) using CGM-derived measures has not been investigated. The study aimed to evaluate the effects of structured RNP versus standard care using CGM in individuals with T2D. METHODS: This parallel non-randomized interventional study with patients' preference design involved 21 individuals with T2D (mean age: 49 ± 10 years, BMI: 30.0 ± 6.2 kg/m2). Participants chose to receive either structured RNP (sRNT; structured Ramadan Nutrition Therapy group; n = 14) or standard care (SC; n = 7). Participants wore CGM 5 days before Ramadan and during Ramadan. CGM-derived measures of glycemic variability were calculated using Glyculator version 2.0. RESULTS: Compared to the SC group, the sRNT group significantly reduced their fasting blood glucose levels, HbA1c, total cholesterol, diastolic blood pressure, and increased dietary fiber intake. CGM data showed the sRNT group had significantly lower average sensor glucose, peak sensor value, estimated A1c, percentage and duration of time-above-range, J-index, mean amplitude of glycemic excursion (MAGE), and continuous overall net glycemic action (CONGA); and a significantly higher percentage of time-in-range (TIR). CONCLUSIONS: The structured RNP significantly improved clinical outcomes, glycemic control and variability in individuals with T2D. The study highlights the importance of utilizing CGM sensor data to monitor glycemic excursions during Ramadan fasting. Adequately powered randomized controlled trials are needed to confirm the findings.

Central carbon metabolism remodeling as a mechanism to develop drug tolerance and drug resistance in Mycobacterium tuberculosis.

Suboptimal efficacy of the current antibiotic regimens and frequent emergence of antibiotic-resistant Mycobacterium tuberculosis (Mtb), an etiological agent of tuberculosis (TB), render TB the world's deadliest infectious disease before the COVID-19 outbreak. Our outdated TB treatment method is designed to eradicate actively replicating populations of Mtb. Unfortunately, accumulating evidence suggests that a small population of Mtb can survive antimycobacterial pressure of antibiotics by entering a "persister" state (slowly replicating or non-replicating and lacking a stably heritable antibiotic resistance, termed drug tolerance). The formation of drug-tolerant Mtb persisters is associated with TB treatment failure and is thought to be an adaptive strategy for eventual development of permanent genetic mutation-mediated drug resistance. Thus, the molecular mechanisms behind persister formation and drug tolerance acquisition are a source of new antibiotic targets to eradicate both Mtb persisters and drug-resistant Mtb. As Mtb persisters are genetically identical to antibiotic susceptible populations, metabolomics has emerged as a vital biochemical tool to differentiate these populations by determining phenotypic shifts and metabolic reprogramming. Metabolomics, which provides detailed insights into the molecular basis of drug tolerance and resistance in Mtb, has unique advantages over other techniques by its ability to identify specific metabolic differences between the two genetically identical populations. This review summarizes the recent advances in our understanding of the metabolic adaptations used by Mtb persisters to achieve intrinsic drug tolerance and facilitate the emergence of drug resistance. These findings present metabolomics as a powerful tool to identify previously unexplored antibiotic targets and improved combinations of drug regimens against drug-resistant TB infection.

Emergency department initiated resuscitative endovascular balloon occlusion of the aorta (REBOA) for out-of-hospital cardiac arrest is feasible and associated with improvements in end-tidal carbon dioxide.

Objectives: Out-of-hospital cardiac arrest (OHCA) claims the lives of approximately 350,000 people in the United States each year. Resuscitative endovascular balloon occlusion of the aorta (REBOA) when used as an adjunct to advanced cardiac life support may improve cardio-cerebral perfusion. Our primary research objective was to determine the feasibility of emergency department (ED)-initiated REBOA for OHCA patients in an academic urban ED. Methods: This was a single-center, single-arm, early feasibility trial that used REBOA as an adjunct to advanced cardiac life support (ACLS) in OHCA. Subjects under 80 years with witnessed OHCA and who received cardiopulmonary rescuitation (CPR) within 6 minutes were eligible. Results: Five patients were enrolled between February 2020 and April 2021. The procedure was successful in all patients and 4 of 5 (80%) patients had transient return of spontaneous circulation (ROSC) after aortic occlusion. Unfortunately, all patients re-arrested soon after intra-aortic balloon deflation and none survived to hospital admission. At 30 seconds post-aortic occlusion, investigators noted a statistically significant increase in end tidal carbon dioxide of 26% (95% confidence interval, 10%, 44%). Conclusion: Initiating REBOA for OHCA patients in an academic urban ED setting is feasible. Aortic occlusion during chest compressions is temporally associated with improvements in end tidal carbon dioxide 30 seconds after aortic occlusion. Four of 5 patients achieved ROSC after aortic occlusion; however, deflation of the intra-aortic balloon quickly led to re-arrest and death in all patients. Future research should focus on the utilization of partial-REBOA to prevent re-arrest after ROSC, as well as the optimal way to incorporate this technique with other endovascular reperfusion strategies.

International consensus conference recommendations on ultrasound education for undergraduate medical students.

OBJECTIVES: The purpose of this study is to provide expert consensus recommendations to establish a global ultrasound curriculum for undergraduate medical students. METHODS: 64 multi-disciplinary ultrasound experts from 16 countries, 50 multi-disciplinary ultrasound consultants, and 21 medical students and residents contributed to these recommendations. A modified Delphi consensus method was used that included a systematic literature search, evaluation of the quality of literature by the GRADE system, and the RAND appropriateness method for panel judgment and consensus decisions. The process included four in-person international discussion sessions and two rounds of online voting. RESULTS: A total of 332 consensus conference statements in four curricular domains were considered: (1) curricular scope (4 statements), (2) curricular rationale (10 statements), (3) curricular characteristics (14 statements), and (4) curricular content (304 statements). Of these 332 statements, 145 were recommended, 126 were strongly recommended, and 61 were not recommended. Important aspects of an undergraduate ultrasound curriculum identified include curricular integration across the basic and clinical sciences and a competency and entrustable professional activity-based model. The curriculum should form the foundation of a life-long continuum of ultrasound education that prepares students for advanced training and patient care. In addition, the curriculum should complement and support the medical school curriculum as a whole with enhanced understanding of anatomy, physiology, pathophysiological processes and clinical practice without displacing other important undergraduate learning. The content of the curriculum should be appropriate for the medical student level of training, evidence and expert opinion based, and include ongoing collaborative research and development to ensure optimum educational value and patient care. CONCLUSIONS: The international consensus conference has provided the first comprehensive document of recommendations for a basic ultrasound curriculum. The document reflects the opinion of a diverse and representative group of international expert ultrasound practitioners, educators, and learners. These recommendations can standardize undergraduate medical student ultrasound education while serving as a basis for additional research in medical education and the application of ultrasound in clinical practice.

Effect of Point-of-Care Ultrasound on Clinical Outcomes in Low-Resource Settings: A Systematic Review.

Despite the potential for improved patient care, little is known of the true effect of point-of-care ultrasound (POCUS) on patient outcomes in resource-limited settings. Electronic databases were searched using medical subject heading and free text terms related to POCUS and resource-limited settings through August 2020. Two authors independently selected studies, assessed methodological quality using the Downs and Black scale and extracted data. Twenty observational studies were included in the final review. All studies had moderate to high risk of bias. No studies exhibited an effect on the pre-specified primary outcome of mortality. Varying degrees of change in differential diagnosis and management were reported, but definitions varied widely among studies. Estimates for change in diagnosis as a result of POCUS ranged from 15% to 52%, and those for change in management, from 17% to 87%. Articles on POCUS clinical utility represent a small part (4.6%) of the scholastic literature dedicated to POCUS in low-resource settings. POCUS is a valuable intervention to consider in resource-limited settings, with the potential to change diagnosis and patient management. The exact magnitude of effect remains unknown. There is a continued need for large-scale experimental studies to investigate the effect of POCUS on patient diagnosis, management and mortality.

Community Level Youth-Led Interventions to Improve Maternal-Neonatal Outcomes in Low- and Middle-Income Countries: Protocol for a Systematic Review.

Introduction: On a global scale, women and childbearing people and neonates continue to die from preventable causes related to pregnancy or childbirth. Sustained and accelerated efforts are critical to improve maternal and neonatal health and well-being. Globally, youth are a growing population and have strength in their numbers. Youth are critical, key drivers of change in their communities. Young people hold the potential to affect positive change, and their meaningful engagement is important to improving maternal health and well-being in low- and middle-income countries. Objectives: To assess the effects of community level youth-led interventions for improving maternal-neonatal health and well-being compared with no interventions or another intervention. Methods: We will undertake a literature search that is comprehensive, complete, and exhaustive. This will include databases such as MEDLINE, EMBASE, and the Cochrane Library, as well as a grey literature search. In our systematic review, we will include experimental studies evaluating maternal-neonatal health and well-being associated with or because of the implementation of community level youth-led interventions. Participants will include women and childbearing people (of any age) during antepartum, intrapartum, and postpartum periods (up to 42 days postpartum). We will examine all interventions addressing and targeting maternal-neonatal health and well-being that are youth-led and community-based and aimed at the members of the community. Our comparators will be no intervention or another intervention. Our primary outcomes are maternal deaths and neonatal deaths. Our review will include only studies in low- and middle-income countries conducted in urban or rural areas. Ethics and Dissemination. Ethics approval is not required as we will use secondary data that is publicly available. There are no active participants in our study. We will involve key stakeholders and experts in maternal-neonatal health regarding dissemination and knowledge mobilization strategies. Our findings will be disseminated as an open access publication, be presented publicly, and defended as part of a doctoral thesis. This trial is registered with CRD42021288798.