Evaluation of expanded 2-aminobenzothiazole library as inhibitors of a model histidine kinase and virulence suppressors in Pseudomonas aeruginosa.

Bacterial resistance to antibiotics is a rapidly increasing threat to human health. New strategies to combat resistant organisms are desperately needed. One potential avenue is targeting two-component systems, which are the main bacterial signal transduction pathways used to regulate development, metabolism, virulence, and antibiotic resistance. These systems consist of a homodimeric membrane-bound sensor histidine kinase, and a cognate effector, the response regulator. Histidine kinases play an essential role in the regulation of multiple virulence mechanisms including toxin production, immune evasion, and antibiotic resistance. Targeting virulence, as opposed to development of bactericidal compounds, could reduce evolutionary pressure for acquired resistance. Additionally, compounds targeting the highly conserved catalytic and adenosine triphosphate-binding (CA) domain have the potential to impair multiple two-component systems that regulate virulence in one or more pathogens. We conducted in vitro structure-activity relationship studies of 2-aminobenzothiazole-based inhibitors designed to target the CA domain. We found that these compounds, which inhibit the model histidine kinase, HK853 from Thermotoga maritima, have anti-virulence activities inPseudomonas aeruginosa, reducing motility phenotypes and toxin production associated with the pathogenic functions of this bacterium.

A Brief Pro-Diversity Social Marketing Intervention Improves Grades and Well-Being of Students From Marginalized Groups.

Despite much research on improving intergroup relations, the evidence for long-term effects in real-world settings is mixed. We used the social marketing approach to create an "Inclusivity Page" that could be added to course syllabi. The page contained three targeted pro-diversity messages based on social norms, personal benefits, and concrete behavioral recommendations. We tested our intervention in a large randomized controlled trial in university classrooms (Nstudents = 1,799). We obtained students' course grades and overall college GPAs several years later. A subset of students also completed an outcome survey three months after the intervention. Students from underrepresented racial groups exposed to the intervention early in college had better course grades and GPAs. We also observed an enhanced sense of belonging and better emotional and physical health among students from all marginalized groups. Our research demonstrates the utility of employing a targeted approach to improve experiences of members of marginalized groups.

Our needs have been ignored for a long time: Factors affecting willingness of Black and Hispanic/Latinx sexual and gender minority communities to donate biospecimens.

The study aimed to document factors affecting willingness to engage in biospecimen donation for substance use research among Black and Hispanic/Latinx sexual and gender minority (SGM) people. From May to July 2022, we interviewed 22 Black and Hispanic/Latinx SGM people from The PRIDE Study, a cohort of SGM people in the United States and its territories, using Zoom videoconferencing software. Fourteen participants were sexual minority people, and eight participants were gender minority people. We took an inductive, collaborative qualitative analytic approach to identify themes. Themes included: (1) community benefits, (2) personal benefits, (3) community exploitation, (4) personal risks, (5) convenience, (6) trustworthiness of the research team, (7) perceived value in donating, and (8) normalization of biospecimen collection. Participants were generally motivated to engage in biospecimen donation for altruistic purposes. The most cited concerns were related to data security, misuse, and privacy. Researchers must be proactive in building trust with Black and Hispanic/Latinx SGM communities to increase engagement, diversify biospecimen repositories and reduce health inequities. Future research involving biospecimens should provide biospecimen education during the consent process and prioritize participant convenience.

Conversion practice recall and mental health symptoms in sexual and gender minority adults in the USA: a cross-sectional study.

BACKGROUND: Conversion practices are associated with psychological morbidity, yet few studies have evaluated differences between efforts to change gender identity, sexual orientation, or both. We aimed to examine the individual and joint association of conversion practice recall targeted at gender identity or sexual orientation, or both, with current mental health symptoms among sexual and gender minority people. METHODS: This cross-sectional study used data from The PRIDE Study, a US-based, online, prospective cohort study of sexual and gender minority adults who were recruited through social media, digital advertisements, and sexual and gender minority community-based events and organisations. For this analysis, we included participants who completed a lifetime questionnaire in 2019-20 and a subsequent annual questionnaire in 2020-21 without missing outcome data. All questionnaires were in English. The exposure was lifetime recall of conversion practice targeting gender identity alone, sexual orientation alone, or both (versus no conversion practice). Mental health outcomes were continuous measures: Generalized Anxiety Disorder 7-item scale, Patient Health Questionnaire 9-item (depression) scale, Post-Traumatic Stress Disorder Checklist 6-item scale, and Suicide Behaviors Questionnaire-Revised scale. We used linear regression to analyse the associations of conversion practice recall and mental health symptoms, controlling for demographic and childhood factors and stratified between cisgender and transgender and gender diverse groups. Sensitivity analyses evaluated the potential impact of unmeasured confounding. Analyses were conducted in R. We included people with related lived experience in the design and implementation of this study. FINDINGS: Of 6601 participants who completed the lifetime questionnaire in 2019-20, 4440 completed the subsequent annual questionnaire in 2020 or 2021, and 4426 did not have missing outcome data. Of the 4426 included participants, 4073 (92·0%) identified as White (either alone or in combination with other ethnoracial options), 460 (10·4%) identified with multiple ethnoracial identities, and 1923 (43·4%) were transgender and gender diverse. Participants' age ranged from 18 years to 84 years (median 31·7 years, IQR 25·5-44·1). 149 (3·4%) participants reported sexual orientation-related conversion practice alone, 43 (1·0%) reported gender identity-related conversion practice alone, and 42 (1·0%) reported both. Recalling both forms of conversion practice was most strongly associated with greater post-traumatic stress disorder (PTSD; ß 2·84, 95% CI 0·94-4·74) and suicidality (2·14, 0·95-3·32) symptoms. Recall of only sexual orientation-related conversion practice was associated with greater symptoms of PTSD (1·10, 0·22-1·98). Recall of gender identity-related conversion practice alone was most strongly associated with greater depressive symptoms (3·24, 1·03-5·46). Only associations for suicidality differed between cisgender and transgender and gender diverse participants, although the latter showed higher mental health symptoms overall. Findings were moderately robust to potential sources of unmeasured confounding in sensitivity analysis. INTERPRETATION: Recall of conversion practice exposure was associated with a range of mental health symptoms among sexual and gender minority people. These findings support calls to ban conversion practices because of their effects as a structural determinant of mental health. FUNDING: Gill Foundation, Dona Rockstad, and Patient-Centered Outcomes Research Institute.

Patient-reported pregnancy loss and maternal complications: Insights from the sickle cell disease implementation consortium.

OBJECTIVE: Sickle cell disease (SCD) is associated with complications during pregnancy and can negatively influence maternal outcomes. Our study aimed to determine the prevalence and predictors of maternal morbidity among participants enrolled in an eight-site SCD Implementation Consortium (SCDIC) registry. METHODS: We conducted a cross-sectional analysis of female registry participants, aged 15-45 years, with a confirmed diagnosis of SCD. Participants completed a survey of self-reported pregnancies and outcomes. RESULTS: Seven hundred and thirty-eight individuals had at least one pregnancy event, with 1076 live births. Twenty percent reported a pregnancy loss or fetal demise. Of the 1076 live births, 75% involved at least one complication. The most prevalent complications were pain crises (61.1%) and pregnancy requiring blood transfusion(s) (33.0%). Multiparous individuals with a prior occurrence of a complication in a previous pregnancy had higher odds of recurrence of the same complication in subsequent pregnancies (i.e., previous acute crisis was associated with subsequent acute pain events odds ratio [OR]: 3.13; 95% confidence interval [CI]: 2.06-4.76) and prior transfusion requiring another transfusion (OR: 3.22; 95% CI: 2.01-5.16). CONCLUSION: Individuals reported a high prevalence of pregnancy loss and maternal complications. Our findings underscore the importance of preconception counseling and early initiation of perinatal care in SCD.

A Tale of 102,726 Messages: Characterizing the Modern Urologist's Portal Message Burden After Common Urologic Surgeries.

INTRODUCTION: We aimed to characterize patient portal messaging use after urologic surgery to identify administrative burden and evaluate postoperative clinical associations. METHODS: Epic was queried for all urologic surgeries performed at the Mayo Clinic enterprise between 2019 and 2022. Data from the highest volume procedures were extracted including patient-generated portal messages to their provider and emergency department (ED) visits within 6 months of surgery. Factors associated with portal users and message volume, as well as the impact of portal use on risk of subsequent ED visit, were evaluated. RESULTS: We analyzed data from 23,621 urologic procedures, which generated 102,726 patient portal messages within 6 months of surgery. We found that 55% of our cohort sent at least 1 message. Stratifying by subspecialty, endourologic surgeries generated the fewest number of messages per surgery (3.83; SD, 8.76), whereas female pelvic medicine and reconstructive surgeries yielded the most (6.05; SD, 10.92). Younger age, female sex, and White race were associated with increased portal utilization. Multivariable time-to-event analysis revealed a 33% reduction in the risk of ED presentation within 90 days after surgery for patients using the patient portal compared with those who did not. CONCLUSIONS: While only half of patients sent portal messages after surgery, active users showed a 33% reduction in ED visits, suggesting its potential to reduce health care utilization. Encouraging broader portal adoption can improve outcomes. However, the message burden for urologists necessitates solutions. Resource allocation should prioritize strategies to help urologists manage messages while preserving the established clinical benefits.

Factor structure and psychometric properties of the Muscle Dysmorphic Disorder Inventory (MDDI) among transgender women.

Muscle dysmorphia (MD) is characterized by extreme preoccupation with insufficient muscularity that prompts pathological behaviors and distress/impairment. The Muscle Dysmorphic Disorder Inventory (MDDI) - a widely used measure of MD symptoms - has yet to be validated among transgender women, despite emerging evidence suggesting risk for muscularity-oriented concerns in this population. We examined the MDDI factor structure as well as the reliability and validity of its subscales in a sample of 181 transgender women ages 19-73 years who participated in a national longitudinal cohort study of U.S. sexual and gender minority adults. Confirmatory factor analysis was used to examine model fit for the original three-factor structure of the MDDI (drive for size, appearance intolerance, functional impairment). A re-specified three-factor model allowing covariance of residuals for two conceptually related items demonstrated good overall fit (χ2/df = 1.33, CFI =.94, TLI =.93, RMSEA =.06 [95 % CI =.01,.09], SRMR =.07). Moreover, results supported the internal consistency and convergent and discriminant validity of the MDDI subscales in transgender women. Findings inform the use of the MDDI among transgender women and provide a foundation to support future research on the MDDI and MD symptoms among gender minority populations.

The effect of down-titration and discontinuation of heart failure pharmacotherapy in older people: A systematic review and meta-analysis.

The aim of this study was to investigate whether interventions to discontinue or down-titrate heart failure (HF) pharmacotherapy are feasible and associated with risks in older people. A systematic review and meta-analysis were conducted according to PRISMA 2020 guidelines. Electronic databases were searched from inception to 8 March 2023. Randomized controlled trials (RCTs) and observational studies included people with HF, aged ≥50 years and who discontinued or down-titrated HF pharmacotherapy. Outcomes were feasibility (whether discontinuation or down-titration of HF pharmacotherapy was sustained at follow-up) and associated risks (mortality, hospitalization, adverse drug withdrawal effects [ADWE]). Random-effects meta-analysis was performed when heterogeneity was not substantial (Higgins I2 < 70%). Sub-analysis by frailty status was conducted. Six RCTs (536 participants) and 27 observational studies (810 499 participants) across six therapeutic classes were included, for 3-260 weeks follow-up. RCTs were conducted in patients presenting with stable chronic HF. Down-titrating a renin-angiotensin system inhibitor (RASI) in patients with chronic kidney disease was 76% more likely than continuation (risk ratio [RR] 1.76, 95% confidence interval [CI] 1.14-2.73), with no difference in mortality (RR 0.64, 95% CI 0.30-1.64). Discontinuation of beta-blockers were feasible compared to continuation in preserved ejection fraction (RR 1.00, 95% CI 0.68-1.47). Participants were 25% more likely to re-initiate discontinued diuretics (RR 0.75, 95% CI 0.66-0.86). Digoxin discontinuation was associated with 5.5-fold risk of hospitalization compared to continuation. Worsening HF was the most common ADWE. One observational study measured frailty but did not report outcomes by frailty status. The appropriateness and associated risks of down-titrating or discontinuing HF pharmacotherapy in people aged ≥75 years is uncertain. Evaluation of outcomes by frailty status necessitates investigation.

Protein is expressed in all major organs after intravenous infusion of mRNA-lipid nanoparticles in swine.

In vivo delivery of mRNA is promising for the study of gene expression and the treatment of diseases. Lipid nanoparticles (LNPs) enable efficient delivery of mRNA constructs, but protein expression has been assumed to be limited to the liver. With specialized LNPs, delivery to extrahepatic tissue occurs in small animal models; however, it is unclear if global delivery of mRNA to all major organs is possible in humans because delivery may be affected by differences in innate immune response and relative organ size. Furthermore, limited studies with LNPs have been performed in large animal models, such as swine, due to their sensitivity to complement activation-related pseudoallergy (CARPA). In this study, we found that exogenous protein expression occurred in all major organs when swine were injected intravenously with a relatively low dose of mRNA encapsulated in a clinically relevant LNP formulation. Exogenous protein was detected in the liver, spleen, lung, heart, uterus, colon, stomach, kidney, small intestine, and brain of the swine without inducing CARPA. Furthermore, protein expression was detected in the bone marrow, including megakaryocytes, hematopoietic stem cells, and granulocytes, and in circulating white blood cells and platelets. These results show that nearly all major organs contain exogenous protein expression and are viable targets for mRNA therapies.

Black Americans With Sickle Cell Disease (SCD) Demonstrate Accelerated Epigenetic Pace of Aging Compared to Black Americans Without SCD.

BACKGROUND: Sickle cell disease (SCD) is a chronic medical condition characterized by red blood cell sickling, vaso-occlusion, hemolytic anemia, and subsequently, end-organ damage and reduced survival. Because of this significant pathophysiology and early mortality, we hypothesized that patients with SCD are experiencing accelerated biological aging compared with individuals without SCD. METHODS: We utilized the DunedinPACE measure to compare the epigenetic pace of aging in 131 Black Americans with SCD to 1391 Black American veterans without SCD. RESULTS: SCD patients displayed a significantly accelerated pace of aging (DunedinPACE mean difference of 0.057 points) compared with the veterans without SCD, whereby SCD patients were aging ≈0.7 months more per year than those without SCD (p = 4.49 × 10-8). This was true, even though the SCD patients were significantly younger according to chronological age than the individuals without SCD, making the epigenetic aging discrepancy even more apparent. This association became stronger when we removed individuals with posttraumatic stress disorder from the non-SCD group (p = 2.18 × 10-9), and stronger still when we restricted the SCD patients to those with hemoglobin SS and Sß0 thalassemia genotypes (p = 1.61 × 10-10). CONCLUSIONS: These data support our hypothesis that individuals with SCD experience accelerated biological aging as measured by global epigenetic variation. The assessment of epigenetic measures of biological aging may prove useful to identify which SCD patients would most benefit from clinical interventions to reduce mortality.

Levels and outcomes of 12-step participation among sexual and gender minority subgroups.

INTRODUCTION: Sexual minority (e.g., bisexual, gay, lesbian, queer) and gender minority (e.g., transgender, non-binary, gender expansive) individuals (SGMI) experience higher rates of alcohol and other substance use disorders than their heterosexual and cisgender (i.e., non-transgender) counterparts. 12-Step programs are currently the most common source of support for alcohol and other substance use-related problems in the United States. Little is known about rates and levels of participation and outcomes of SGMI in 12-Step programs. Examining SGMI with a lifetime alcohol or other substance use disorder, this study aims to: 1) describe lifetime attendance rates (any vs. none) and levels of participation (number of program activities) in 12-Step groups among SGMI overall and compare rates of attendance and levels of participation across sexual and gender minority identities and 2) determine how lifetime level of participation in 12-Step programs relates to past-year alcohol and other substance use outcomes. METHODS: We used data collected through The PRIDE Study, a national, large-scale, longitudinal health study of adult SGMI, administering supplemental questions to assess alcohol and other substance use disorders and 12-step participation. Zero-Inflated Negative Binomial models (N = 1353) run with sexual and gender identities as predictors of lifetime 12-step attendance (yes/no) and level of 12-Step participation determine if greater levels of 12-Step participation were associated with lower levels of past-year Alcohol and Substance Use Disorder (AUD & SUD) symptoms. The study ran models for those with lifetime AUD (n = 1074) and SUD (n = 659) separately. RESULTS: Participants who engaged in greater levels of 12-Step participation had lower levels of past-year AUD and SUD symptoms. Gay and queer respondents with AUD were more likely and lesbian respondents with SUD were less likely than other participants to have ever participated in 12-Step programs. All other associations between sexual/gender identities and 12-Step participation disappeared when age was added to the model. CONCLUSIONS: This study provides preliminary evidence that 12-Step participation may be an effective resource for reducing AUD and SUD symptoms among SGMI. Younger SGMI and SGMI holding sexual/gender identities other than gay and queer may require additional support to initiate participation in 12-Step programs.

Suppressing upregulation of fibrinogen after polytrauma mitigates thrombosis in mice.

BACKGROUND: Polytrauma results in systemic inflammation and increased circulating fibrinogen, which increases the risk of microvascular and macrovascular thrombosis that contributes to secondary organ damage and venous thromboembolism (VTE). There are no clinically approved agents to prevent hyperfibrinogenemia after polytrauma. We hypothesized that preventing the increase in fibrinogen levels after polytrauma would suppress thrombosis. METHODS: Small-interfering ribonucleic acid (siRNA) against fibrinogen was encapsulated in lipid nanoparticles (siFibrinogen). Mice underwent a model of polytrauma and were then given varying doses of siFibrinogen, control siRNA, or no treatment. Fibrinogen was measured for 1 week via enxyme-linked immunosorbent assay (ELISA). To model postinjury VTE, the inferior vena cava was ligated 2 days after polytrauma in a portion of the mice. Thrombus weight was measured 48 hours after the inferior vena cava was ligated. RESULTS: Treatment with siFibrinogen prevented hyperfibrinogenemia after trauma without exacerbating the hypofibrinogenemic state that occurs in the acute injury period (1 hour). In treated groups, fibrinogen was significantly lower from 6 hours postinjury through the 7-day monitoring period. Maximal fibrinogen reduction was observed at 72 hours. Here, mice that received 2.0 mg/kg of siFibrinogen had 1% of normal values relative to untreated mice, and mice that received 1.0 or 0.5 mg/kg had 4%. Mice treated with siFibrinogen that underwent the postinjury VTE model had significantly reduced thrombus weight compared with control siRNA-treated animals. More notably, among all siFibrinogen treated mice, 12 of 18 were completely protected from thrombosis, compared with 0 of 9 displaying protection in the control group. CONCLUSION: The rise of fibrinogen and the size of thrombi after polytrauma can be mitigated via the administration of siRNA against fibrinogen. siFibrinogen represents a promising novel target for VTE prophylaxis posttrauma.

Tissue engineering and regenerative medicine approaches in colorectal surgery.

Tissue engineering and regenerative medicine (TERM) is an emerging field that has provided new therapeutic opportunities by delivering innovative solutions. The development of nontraditional therapies for previously unsolvable diseases and conditions has brought hope and excitement to countless individuals globally. Many regenerative medicine therapies have been developed and delivered to patients clinically. The technology platforms developed in regenerative medicine have been expanded to various medical areas; however, their applications in colorectal surgery remain limited. Applying TERM technologies to engineer biological tissue and organ substitutes may address the current therapeutic challenges and overcome some complications in colorectal surgery, such as inflammatory bowel diseases, short bowel syndrome, and diseases of motility and neuromuscular function. This review provides a comprehensive overview of TERM applications in colorectal surgery, highlighting the current state of the art, including preclinical and clinical studies, current challenges, and future perspectives. This article synthesizes the latest findings, providing a valuable resource for clinicians and researchers aiming to integrate TERM into colorectal surgical practice.

Pathways to parenthood among transgender men and gender diverse people assigned female or intersex at birth in the United States: analysis of a Cross-Sectional 2019 Survey.

Objective: To assess pathways to parenthood, pregnancy outcomes, future pregnancy desire, and fertility counseling experiences among a cross-sectional sample of transgender men and gender diverse individuals assigned female or intersex at birth in the United States. Methods: Participants were recruited from The Population Research in Identity and Disparities for Equality (PRIDE) Study and the general public. Eligible participants for this analysis were able to read and understand English, assigned female or intersex at birth, US residents, 18+ years old, and identified as transgender, nonbinary, or gender diverse. We analyzed responses to close-ended survey questions, overall and stratified by gender identity, race/ethnicity, and testosterone use. We also qualitatively assessed open-text responses on fertility counseling. Results: Among the 1694 participants, median age was 27 years (range: 18-72), 12% had ever been pregnant, and 12% were parents. Carrying a pregnancy where the individual was the egg source (36%) was the most common pathway to parenthood. Individuals with an exclusively binary gender identity (ie, transgender man or man) more often reported becoming parents through adoption than individuals with gender diverse identities (19% vs 12%). A third of individuals did not receive fertility counseling prior to initiating testosterone; individuals who exclusively reported nonbinary identities were recommended to investigate fertility preservation options less often (36%) compared to transgender men (50%). Conclusion: Transgender men and gender diverse individuals who were assigned female or intersex at birth build their families through a variety of pathways, including pregnancy, stepparenting, and adoption. Clinicians should avoid making assumptions about reproductive desires in these populations based on gender identities or testosterone use and should provide consistent fertility counseling prior to and after hormone initiation.

Contraceptive use among transgender men and gender diverse individuals in the United States: reasons for use, non-use, and methods used for pregnancy prevention.

OBJECTIVES: To describe contraceptive use for pregnancy prevention among transgender men and gender diverse (TGD) individuals assigned female or intersex at birth (AFIAB) and explore whether contraceptive use differs by testosterone use. STUDY DESIGN: We analyzed data from a cross-sectional, online survey of N=1,694 TGD individuals AFIAB recruited in 2019 through a community-facing website and a national community-engaged cohort study of sexual and/or gender minority (SGM) adults in the US. Descriptive and regression analyses characterized the current and ever use of contraceptive methods for pregnancy prevention, stratified by testosterone use, and described reasons for contraceptive use/non-use. RESULTS: Most respondents (71.0%) had used contraception before with 49.4% using it for pregnancy prevention. The methods for pregnancy prevention that were most frequently ever used for pregnancy prevention included: external condoms (91.8%), combined hormonal contraceptive pills (63.0%), and withdrawal (45.9%). The methods most frequently currently used for pregnancy prevention included: external condoms (35.4%), hormonal IUD (24.8%), and abstinence (19.2%). Some reported formerly (n=55, 6.6%) or currently (n=30, 3.6%) relying on testosterone for pregnancy prevention. Only 4 of the 33 reasons for contraceptive use and non-use differed by testosterone use group. The most reported reasons for never using contraception were not engaging in penis-in-vagina sex (5.7%) or no sex with individuals who produce sperm (4.8%). CONCLUSIONS: Most TGD individuals AFIAB have used contraception, and almost half for pregnancy prevention. The most used methods require minimal and/or non-invasive healthcare system interaction. Some respondents relied on testosterone as birth control, despite a lack of efficacy evidence.

Low Risk of Clinically Important Traumatic Brain Injury in Children Who Tumble Down Stairs.

BACKGROUND: Pediatric trauma management seeks to minimize head computed tomography (HCT) while capturing clinically important traumatic brain injuries (ciTBI). The Pediatric Emergency Care Applied Research Network (PECARN) system stratifies patients as high-, intermediate-, or low-risk for ciTBI. Although designed for free falls, we noted that PECARN criteria often are applied to tumbling down stairs (TDS), with steps estimated at 12", though TDS rarely appeared to result in ciTBI. METHODS: In a retrospective chart review of pediatric TDS patients, data was collected on mechanism of injury, clinical presentation, imaging, and incidence of ciTBI. PECARN scores were developed under three models: TDS-12 (12″ steps), TDS-8 (more accurate 8" steps), and TDS-0 (TDS not a severe mechanism). RESULTS: 344 patients met criteria for study inclusion. Mean age was 6.3 years and 89 (26%) were <2 years. No patients had ciTBI. This included 88 patients who tumbled down 12 steps or more. Across all models, the same 7 patients (2.0%) were at high-risk for ciTBI. Intermediate- and low-risk cohorts were 287 (83%) and 50 (15%) for TDS-12, 171 (50%) and 166 (48%) for TDS-8, and 16 (4.7%) and 321 (93%) for TDS-0, respectively for each model. Under TDS-8, 116 (34%) patients shifted to the low-risk category. Under TDS-0, 271 (79%) patients shifted to the low-risk category, leaving only 23 patients (6.7%) at high- or intermediate-risk (n = 7, 16, respectively). CONCLUSIONS: In pediatric patients, the risk of ciTBI after TDS is low. TDS should not be treated as a free fall in risk assessment. TYPE OF STUDY: Retrospective Modeling Study. LEVEL OF EVIDENCE: Level III.

Perioperative Management and Outcomes after Endovascular Mechanical Thrombectomy in Patients with Submassive (Intermediate-Risk) Pulmonary Embolism: A Retrospective Observational Cohort Study.

Pulmonary embolism (PE) embodies a large healthcare burden globally and is the third leading cause of morbidity and mortality worldwide. Submassive (intermediate-risk) PE accounts for 40% of this burden. However, the optimal treatment pathway for this population remains complex and ill-defined. Catheter-directed interventions (CDIs) have shown promise in directly impacting morbidity and mortality while demonstrating a favorable success rate, safety profile, and decreased length of stay (LOS) in the intensive care unit and hospital. This retrospective review included 22 patients (50% female) with submassive PE who underwent mechanical thrombectomy (MT). A total of 45% had a contraindication to thrombolytics, the mean pulmonary embolism severity index was 127, 36% had saddle PE, the average decrease in mean pulmonary artery pressure (PAP) was 7.2 mmHg following MT, the average LOS was 6.9 days, the 30-day mortality rate was 9%, the major adverse event (MAE) rate was 9%, and the readmission rate was 13.6%. A total of 82% had successful removal of thrombus during MT with no major bleeding complications, intracranial hemorrhage events, or device-related deaths. Acknowledging the limitation of our small sample size, our data indicate that MT in the intermediate-high-risk submassive pulmonary embolism (PE) cohort resulted in a decreased hospital length of stay (LOS) and in-hospital mortality compared to standard anticoagulation therapy alone.

Barriers and Facilitators to Integrating Acupuncture into the U.S. Health Care System: A Scoping Review.

Background: Acupuncture is a widely practiced complementary and integrative health modality that has multiple clinical applications. The use of acupuncture in the United States is rapidly increasing. Although studies have shown the efficacy and effectiveness of acupuncture for various ailments, the integration of acupuncture into the U.S. health care system remains a challenge. Little is known about the factors affecting this integration. Objective: To provide a systematic review of the barriers and facilitators affecting the integration of acupuncture into the U.S. health care system. Methods: Four electronic databases were searched. Three independent reviewers were involved in the screening and data charting processes. Findings were synthesized and categorized into four levels based on the Social Ecological Model. Results: A total of 22 studies were included in the final review. The barriers and facilitators affecting the integration of acupuncture were mapped into four levels (individual, interpersonal, organizational, and policy). The most frequently reported barriers and facilitators were mapped into the Social Ecological Model constructs within the "Individual" level (i.e., beliefs and attitudes of acupuncture, and practical issues) and the "Organizational" level (i.e., credentialing, space and facility, referral system). Conclusion: This review has identified and synthesized the breadth of evidence on the barriers and facilitators to the integration of acupuncture into the U.S. health care system. Results of this review will guide future implementation studies to develop and test implementation strategies to integrate acupuncture into the U.S. health care system.

Transfer RNA acetylation regulates in vivo mammalian stress signaling.

Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here we investigate the impact of N4-acetylcytidine (ac4C), a highly conserved tRNA modification, using a Thumpd1 knockout mouse model. We find that loss of Thumpd1-dependent tRNA acetylation leads to reduced levels of tRNALeu, increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Remarkably, concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translation control as well as therapeutic interventions.

Commensal-derived short-chain fatty acids disrupt lipid membrane homeostasis in Staphylococcus aureus.

The role of commensal anaerobic bacteria in chronic respiratory infections is unclear, yet they can exist in abundances comparable to canonical pathogens in vivo. Their contributions to the metabolic landscape of the host environment may influence pathogen behavior by competing for nutrients and creating inhospitable conditions via toxic metabolites. Here, we reveal a mechanism by which the anaerobe-derived short chain fatty acids (SCFAs) propionate and butyrate negatively affect Staphylococcus aureus physiology by disrupting branched chain fatty acid (BCFA) metabolism. In turn, BCFA impairment results in impaired growth, diminished expression of the agr quorum sensing system, as well as increased sensitivity to membrane-targeting antimicrobials. Altered BCFA metabolism also reduces S. aureus fitness in competition with Pseudomonas aeruginosa, suggesting that airway microbiome composition and the metabolites they produce and exchange directly impact pathogen succession over time. The pleiotropic effects of these SCFAs on S. aureus fitness and their ubiquity as metabolites in animals also suggests that they may be effective as sensitizers to traditional antimicrobial agents when used in combination.