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.

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 Rockstand, and Patient-Centered Outcomes Research Institute.

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.

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.

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.

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.

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.

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 to 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 to the veterans without SCD, whereby SCD patients were aging approximately 0.7 months more per year than those without SCD (p=4.49x10-8). 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 PTSD from the non-SCD group (p=2.18x10-9), and stronger still when we restricted the SCD patients to those with hemoglobin SS and Sß0 thalassemia genotypes (p=1.61x10-10). 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.

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.

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.

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.

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.

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.

Fully Automated Deep Learning Model to Detect Clinically Significant Prostate Cancer at MRI.

Background Multiparametric MRI can help identify clinically significant prostate cancer (csPCa) (Gleason score ≥7) but is limited by reader experience and interobserver variability. In contrast, deep learning (DL) produces deterministic outputs. Purpose To develop a DL model to predict the presence of csPCa by using patient-level labels without information about tumor location and to compare its performance with that of radiologists. Materials and Methods Data from patients without known csPCa who underwent MRI from January 2017 to December 2019 at one of multiple sites of a single academic institution were retrospectively reviewed. A convolutional neural network was trained to predict csPCa from T2-weighted images, diffusion-weighted images, apparent diffusion coefficient maps, and T1-weighted contrast-enhanced images. The reference standard was pathologic diagnosis. Radiologist performance was evaluated as follows: Radiology reports were used for the internal test set, and four radiologists' PI-RADS ratings were used for the external (ProstateX) test set. The performance was compared using areas under the receiver operating characteristic curves (AUCs) and the DeLong test. Gradient-weighted class activation maps (Grad-CAMs) were used to show tumor localization. Results Among 5735 examinations in 5215 patients (mean age, 66 years ± 8 [SD]; all male), 1514 examinations (1454 patients) showed csPCa. In the internal test set (400 examinations), the AUC was 0.89 and 0.89 for the DL classifier and radiologists, respectively (P = .88). In the external test set (204 examinations), the AUC was 0.86 and 0.84 for the DL classifier and radiologists, respectively (P = .68). DL classifier plus radiologists had an AUC of 0.89 (P < .001). Grad-CAMs demonstrated activation over the csPCa lesion in 35 of 38 and 56 of 58 true-positive examinations in internal and external test sets, respectively. Conclusion The performance of a DL model was not different from that of radiologists in the detection of csPCa at MRI, and Grad-CAMs localized the tumor. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Johnson and Chandarana in this issue.

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.

Integrating multi-modal remote sensing, deep learning, and attention mechanisms for yield prediction in plant breeding experiments.

In both plant breeding and crop management, interpretability plays a crucial role in instilling trust in AI-driven approaches and enabling the provision of actionable insights. The primary objective of this research is to explore and evaluate the potential contributions of deep learning network architectures that employ stacked LSTM for end-of-season maize grain yield prediction. A secondary aim is to expand the capabilities of these networks by adapting them to better accommodate and leverage the multi-modality properties of remote sensing data. In this study, a multi-modal deep learning architecture that assimilates inputs from heterogeneous data streams, including high-resolution hyperspectral imagery, LiDAR point clouds, and environmental data, is proposed to forecast maize crop yields. The architecture includes attention mechanisms that assign varying levels of importance to different modalities and temporal features that, reflect the dynamics of plant growth and environmental interactions. The interpretability of the attention weights is investigated in multi-modal networks that seek to both improve predictions and attribute crop yield outcomes to genetic and environmental variables. This approach also contributes to increased interpretability of the model's predictions. The temporal attention weight distributions highlighted relevant factors and critical growth stages that contribute to the predictions. The results of this study affirm that the attention weights are consistent with recognized biological growth stages, thereby substantiating the network's capability to learn biologically interpretable features. Accuracies of the model's predictions of yield ranged from 0.82-0.93 R2 ref in this genetics-focused study, further highlighting the potential of attention-based models. Further, this research facilitates understanding of how multi-modality remote sensing aligns with the physiological stages of maize. The proposed architecture shows promise in improving predictions and offering interpretable insights into the factors affecting maize crop yields, while demonstrating the impact of data collection by different modalities through the growing season. By identifying relevant factors and critical growth stages, the model's attention weights provide valuable information that can be used in both plant breeding and crop management. The consistency of attention weights with biological growth stages reinforces the potential of deep learning networks in agricultural applications, particularly in leveraging remote sensing data for yield prediction. To the best of our knowledge, this is the first study that investigates the use of hyperspectral and LiDAR UAV time series data for explaining/interpreting plant growth stages within deep learning networks and forecasting plot-level maize grain yield using late fusion modalities with attention mechanisms.

Incidence of liver complications with hemochromatosis associated HFE p.C282Y homozygosity: The role of central adiposity.

BACKGROUND AIMS: The HFE p.C282Y+/+ (homozygous) genotype and central adiposity both increase liver disease and diabetes risks, but combined effects are unclear. We estimated waist-to-hip ratio (WHR) associations with incident clinical outcomes in routine care in p.C282Y+/+ participants in the UK Biobank community cohort. APPROACH RESULTS: Baseline WHR in 1,297 male and 1,602 female p.C282Y+/+ with 13.3-year mean follow-up for diagnoses. Spline regressions and Cox proportional hazard models were adjusted for age and genetic principal components. Cumulative incidence was from age 40 to 80 years. In p.C282Y+/+ males, there were positive linear WHR relationships for hospital inpatient diagnosed liver fibrosis/cirrhosis (p=2.4*10-5), liver cancer (p=0.007), non-alcoholic fatty liver disease (NAFLD) (p=7.7*10-11), and type 2 diabetes (T2D) (p=5.1*10-16). The Hazard Ratio (HR) for high WHR in p.C282Y+/+ males (≥0.96; 33.9%) was HR=4.13 for liver fibrosis/cirrhosis (95%CI: 2.04-8.39, p=8.4*10-5 vs. normal WHR); cumulative age 80 incidence 15.0% (95%CI: 9.8%-22.6%) versus 3.9% (95%CI: 1.9%-7.6%); for liver cancer, cumulative incidence was 9.2% (95%CI: 5.7%-14.6%) versus 3.6% (95%CI: 1.9%-6.6%). Hemochromatosis was diagnosed in 23 (96%) of the 24 high WHR p.C282Y+/+ males with incident fibrosis/cirrhosis. High WHR (≥0.85; 30.0%) p.C282Y+/+ females had raised hazards for liver fibrosis/cirrhosis (HR=9.17, 95%CI: 2.51-33.50, p=3.8*10-7) and NAFLD (HR=5.17, 95%CI: 2.48-10.78, p=1.2*10-5). Fibrosis/cirrhosis associations were similar in the subset with additional primary care diagnoses. CONCLUSION: In p.C282Y+/+ males and females, increasing WHR is associated with substantially higher risks of liver complications. Interventions to reduce central adiposity to improve these outcomes should be tested.

Comparison of Measures of Pain Intensity During Sickle Cell Disease Vaso-Occlusive Episodes.

We aimed to determine the minimal clinically important difference (MCID) in pain severity and agreement between the visual analog scale (VAS) and the verbal numeric rating scale (NRS) in people with sickle cell disease (SCD) experiencing an acute vaso-occlusive episode in the emergency department. In the COMPARE-VOE trial (NCT03933397), participants were administered the VAS (0-100), NRS (0-100), and descriptor scale (a lot better, a little better, same, a little worse, much worse) every 30 minutes while in the emergency department. We analyzed data from 100 participants (mean age 30.2 years; 61% female). We calculated the mean differences and 95% confidence intervals (CIs) between current and preceding scores when the participant reported a little worse or a little better pain for each scale (255 VAS and 150 NRS observations) to assess the MCID for the VAS and NRS. Pearson correlation and the Bland-Altman method were used to assess the agreement among 411 paired VAS and NRS observations. Our results indicated that the MCID for the VAS was 8.77 mm (95% CI: 7.43 mm, 10.83 mm) and the NRS was 8.29 (95% CI: 6.47, 11.60). The VAS and NRS scales had a correlation of .88 (P < .001). The Bland-Altman method indicated a mean difference of -4.6 ± 1.96 and the 95% limits of agreement ranged from 20 to -29. Despite high correlation, there was considerable variability of agreement between the VAS and NRS scales, indicating that these scales are not interchangeable to assess pain during a vaso-occlusive event. PERSPECTIVE: The MCID in pain severity for individuals with a SCD vaso-occlusive episode using the VAS (8.77 mm) is lower than previously reported, and the MCID for NRS was 8.29. The agreement between the VAS and NRS was determined and the scales cannot be used interchangeably to measure SCD pain intensity.

Engaging Sexual and Gender Minority (SGM) Communities for Health Research: Building and Sustaining PRIDEnet.

Lesbian, gay, bisexual, transgender, queer, intersex, asexual, aromantic, and other sexual and/or gender minority (LGBTQIA+) communities are underrepresented in health research and subject to documented health disparities. In addition, LGBTQIA+ communities have experienced mistreatment, discrimination, and stigma in health care and health research settings. Effectively engaging LGBTQIA+ communities and individuals in health research is critical to developing representative data sets, improving health care provision and policy, and reducing disparities. However, little is known about what engagement approaches work well with LGBTQIA+ people. This paper describes the development of PRIDEnet (pridenet.org), a national network dedicated to catalyzing LGBTQIA+ community involvement in health research and built upon well-established community-engaged research (CEnR) principles. PRIDEnet's relationship building and digital communications activities engage thousands of LGBTQIA+-identified people across the country and offer multiple low-threshold ways to participate in specific studies and shape research. These activities comprise a CEnR infrastructure that engages LGBTQIA+ people on behalf of other projects, primarily The PRIDE Study (pridestudy.org) and the National Institutes of Health's All of Us Research Program (joinallofus.org/lgbtqia). Our impact, results, and lessons learned apply to those engaging communities underserved in biomedical research and include: the importance of building adaptable infrastructure that sustains transformational relationships long-term; implementing high-touch activities to establish trust and broad-reach activities to build large data sets; nurturing a team of diverse professionals with lived experiences that reflect those of the communities to be engaged; and maintaining CEnR mechanisms that exceed advice-giving and result in substantive research contributions from beginning to end.

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.