Reckoning With Our Past and Righting Our Future: Report From the Behavior Therapy Task Force on Sexual Orientation and Gender Identity/Expression Change Efforts (SOGIECEs).

Sexual orientation and gender identity/expression change efforts (SOGIECEs) are discredited practices that are associated with serious negative effects and incompatible with modern standards for clinical practice. Despite evidence linking SOGIECEs with serious iatrogenic effects, and despite support for LGBTQ+-affirmative care alternatives, SOGIECE practices persist. In the 1970s and 1980s, Behavior Therapy published articles testing and/or endorsing SOGIECEs, thereby contributing to their overall development, acceptance, and use. The Behavior Therapy Task Force on SOGIECEs was assembled to conduct a rigorous review of the SOGIECE articles published in Behavior Therapy and to decide whether, and what, formal action(s) should be taken on these articles. This report provides a detailed review of the historic SOGIECE literature published in Behavior Therapy and outlines the Task Force's deliberative and democratic processes resulting in actions to: (1) add prominent advisory information to k = 24 SOGIECE papers in the form of digital "black box" disclaimers that caution readers that the SOGIECE practices tested or described in these papers are inconsistent with modern standards, (2) offset organizational financial benefits from the publication of these papers, and (3) promote LGBTQ+-affirmative practices. SOGIECEs are not the only concerning practices across the field's history, and the pages of today's scientific journals include practices that will be at odds with tomorrow's moral standards and ethical guidelines. This report calls for precautionary measures and editorial safeguards to minimize the future likelihood and impact of problematic published scholarship, including the need to fully include those with relevant lived experiences in all aspects of clinical science and peer review.

Incidentally Discovered 99mTc-MDP Uptake on Bone Scan in Otosclerosis.

Otosclerosis is a poorly understood clinical entity causing progressive conductive hearing loss. Here we present the first known evidence of otosclerosis demonstrating 99mTc-MDP uptake on bone scan. This presents an opportunity to explore the role of nuclear medicine imaging in early detection, staging, and even informing treatment and prognosis of this condition. Laryngoscope, 2024.

Cardiometabolic Co-morbidity Burden and Circulating Biomarkers in Patients With Chronic Coronary Disease in the ISCHEMIA Trials.

Cardiometabolic co-morbidities, diabetes (DM), hypertension (HTN), and obesity contribute to cardiovascular disease. Circulating biomarkers facilitate prognostication for patients with cardiovascular disease. We explored the relation between cardiometabolic co-morbidity burden in patients with chronic coronary disease and biomarkers of myocardial stretch, injury, inflammation, and platelet activity. We analyzed participants from the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trials biorepository with plasma biomarkers (N-terminal probrain natriuretic peptide, high-sensitivity cardiac troponin T, high-sensitivity C-reactive protein, interleukin-6, soluble CD40 ligand, and growth differentiation factor-15) and clinical risk factors (hemoglobin A1c [HbA1c], systolic blood pressure [SBP], and body mass index [BMI]) at baseline. We defined cardiometabolic co-morbidities as DM, HTN, and obesity at baseline. Co-morbidity burden is characterized by the number and severity of co-morbidities. Controlled co-morbidities were defined as HbA1c <7% for those with DM, SBP <130 mm Hg for those with HTN, and BMI <30 kg/m2. Severely uncontrolled was defined as HbA1c ≥8%, SBP ≥160 mm Hg, and BMI ≥35 kg/m2. We performed linear regression analyses to examine the association between co-morbidity burden and log-transformed biomarker levels, adjusting for age, gender, estimated glomerular filtration rate controlled for hemodialysis, and left ventricular ejection fraction. A total of 752 participants (mean age 66 years, 19% women, 84% White) were included in this analysis. Self-reported Black race, current smokers, history of myocardial infarction, and heart failure had a greater cardiometabolic co-morbidity burden. The presence of ≥1 severely uncontrolled co-morbidity was associated with significantly higher baseline levels of high-sensitivity cardiac troponin T, high-sensitivity C-reactive protein, interleukin-6, and growth differentiation factor-15 than participants with no co-morbidities. In conclusion, increasing cardiometabolic co-morbidity burden in patients with chronic coronary disease is associated with higher levels of circulating biomarkers of myocardial injury and inflammation.

The effects of adverse and positive experiences on cardiovascular health in Australian children.

BACKGROUND: Limited evidence suggests that positive experiences in childhood may promote cardiovascular health, providing additional opportunities for prevention and early intervention. This study aimed to examine the effects of adverse and positive experiences on cardiovascular health in late childhood. METHODS: Data sources: Longitudinal Study of Australian Children (N = 1874). EXPOSURES: Adverse and positive experiences assessed repeatedly (age 0-11 years). OUTCOMES: Cardiovascular health (high versus low or moderate) quantified by four health behaviors (diet, physical activity, cigarette smoking, and sleep) and four health factors (body mass index, non-high-density lipoprotein, blood pressure, and blood glucose) (age 11-12 years) as per the American Heart Association's Life's Essential 8 metrics. ANALYSES: Separate generalized linear models with log-Poisson links were used to estimate the effects of adverse and positive experiences on cardiovascular health, adjusting for confounders. RESULTS: Children exposed to multiple adverse experiences (≥ 2) were less likely to have high cardiovascular health (RR = 0.82, 95% CI = 0.67 to 1.02) than those not exposed. Children exposed to multiple positive experiences (≥ 2) were more likely to have high cardiovascular health (RR = 1.14, 95% CI = 0.94 to 1.38) than those not exposed. Stratified analyses suggested that exposure to multiple positive experiences might buffer the detrimental effects of multiple adverse experiences on cardiovascular health. CONCLUSIONS: Both adverse and positive experiences were found to be modestly associated with cardiovascular health in Australian children. Future research and practice should not only consider addressing childhood adversity but also use a strengths-based approach to promoting positive experiences to improve cardiovascular health.

Protein absorption in the zebrafish gut is regulated by interactions between lysosome rich enterocytes and the microbiome.

Dietary protein absorption in neonatal mammals and fishes relies on the function of a specialized and conserved population of highly absorptive lysosome rich enterocytes (LREs). The gut microbiome has been shown to enhance absorption of nutrients, such as lipids, by intestinal epithelial cells. However, whether protein absorption is also affected by the gut microbiome is poorly understood. Here, we investigate connections between protein absorption and microbes in the zebrafish gut. Using live microscopy-based quantitative assays, we find that microbes slow the pace of protein uptake and degradation in LREs. While microbes do not affect the number of absorbing LRE cells, microbes lower the expression of endocytic and protein digestion machinery in LREs. Using transgene assisted cell isolation and single cell RNA-sequencing, we characterize all intestinal cells that take up dietary protein. We find that microbes affect expression of bacteria-sensing and metabolic pathways in LREs, and that some secretory cell types also take up protein and share components of protein uptake and digestion machinery with LREs. Using custom-formulated diets, we investigated the influence of diet and LRE activity on the gut microbiome. Impaired protein uptake activity in LREs, along with a protein-deficient diet, alters the microbial community and leads to increased abundance of bacterial genera that have the capacity to reduce protein uptake in LREs. Together, these results reveal that diet-dependent reciprocal interactions between LREs and the gut microbiome regulate protein absorption.

A systematic review and Bayesian meta-analysis of 30 years of stress generation research: Clinical, psychological, and sociodemographic risk and protective factors for prospective negative life events.

Stress generation posits that (a) individuals at-risk for psychopathology may inadvertently experience higher rates of prospective dependent stress (i.e., stressors that are in part influenced by their thoughts and behaviors) but not independent stress (i.e., stressors occurring outside their influence), and (b) this elevated dependent stress, in some measure, is what places these individuals at-risk for future psychopathology. In recognition of 30 years of stress generation research, we conducted a systematic review and meta-analysis using frequentist and Bayesian approaches (102 articles with 104 eligible studies, N = 31,541). Generally strong support was found for psychopathology predicting dependent stress (e.g., dsOverall psychopathology = 0.36-0.52, BF10 = 946.00 to 4.65 × 10¹8). Moderator analyses for dependent stress revealed larger effects for briefer assessments periods, shorter follow-ups, and self-report measures than for interviews. Among risk factors, depressogenic cognitive styles (ds = .26-.50, BF10 = 47.50 to 1.00 × 105) and general interpersonal vulnerability (ds = .26-.44, BF10 = 2.72 to 2708.00) received the strongest support as stress generation mechanisms, and current evidence is modest for protective factors predicting dependent stress. Overall, larger effects were generally found for prospective prediction of dependent stress than independent stress. Evaluations of mediation in the research literature were relatively few, limiting the current review to qualitative analysis of the mediation component of stress generation. General support was found, however, for dependent stress as a mediator for psychopathology and associated risk factors in relation to subsequent psychopathology. The current review ends with recommendations for future research and integration of stress generation within minority stress frameworks. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Acidification of α-granules in megakaryocytes by vacuolar-type adenosine triphosphatase is essential for organelle biogenesis.

BACKGROUND: Platelets coordinate blood coagulation at sites of vascular injury and play fundamental roles in a wide variety of (patho)physiological processes. Key to many platelet functions is the transport and secretion of proteins packaged within α-granules, organelles produced by platelet precursor megakaryocytes. Prominent among α-granule cargo are fibrinogen endocytosed from plasma and endogenously synthesized von Willebrand factor. These and other proteins are known to require acidic pH for stable packaging. Luminal acidity has been confirmed for mature α-granules isolated from platelets, but direct measurement of megakaryocyte granule acidity has not been reported. OBJECTIVES: To determine the luminal pH of α-granules and their precursors in megakaryocytes and assess the requirement of vacuolar-type adenosine triphosphatase (V-ATPase) activity to establish and maintain the luminal acidity and integrity of these organelles. METHODS: Cresyl violet staining was used to detect acidic granules in megakaryocytes. Endocytosis of fibrinogen tagged with the pH-sensitive fluorescent dye fluorescein isothiocyanate was used to load a subset of these organelles. Ratiometric fluorescence analysis was used to determine their luminal pH. RESULTS: We show that most of the acidic granules detected in megakaryocytes appear to be α-granules/precursors, for which we established a median luminal pH of 5.2 (IQR, 5.0-5.5). Inhibition of megakaryocyte V-ATPase activity led to enlargement of cargo-containing compartments detected by fluorescence microscopy and electron microscopy. CONCLUSION: These observations reveal that V-ATPase activity is required to establish and maintain a luminal acidic pH in megakaryocyte α-granules/precursors, confirming its importance for stable packaging of cargo proteins such as von Willebrand factor.

Prospective Relations between Life Stress, Emotional Clarity, and Suicidal Ideation in an Adolescent Clinical Sample.

OBJECTIVE: Although life stress has been linked to adolescent suicidal ideation, most past research has been cross-sectional, and potential processes characterizing this relation remain unclear. One possibility may be a lack of emotional clarity. Informed by stress generation, the current study examined prospective relations between episodic life stress, lack of emotional clarity, and suicidal ideation in an adolescent clinical sample. METHODS: The sample consisted of 180 youths (Mage = 14.89; SD = 1.35; 71.7% female; 78.9% White; 43.0% sexual minority) recruited from a psychiatric inpatient facility. Suicidal ideation severity was assessed at baseline and 18-month follow-up. Lack of emotional clarity and life stress were assessed at baseline, as well as 6-, and 12-month follow-ups. Two random-intercepts cross-lagged panel models were created to estimate within-person relations for variables of interest. RESULTS: At the within-person level, lack of emotional clarity at baseline predicted greater 6-month impact of interpersonal dependent stressors (b = 0.29, p = .012, 95% CI [0.07, 0.52]), which subsequently predicted a greater 12-month lack of emotional clarity (b = 0.41, p = .005, 95% CI [0.12, 0.70]). Next, a 12-month lack of emotional clarity but not interpersonal dependent stress, predicted greater 18-month suicidal ideation (b = 0.81, p = .006, 95% CI [0.23, 1.30]; R2 = .24, p < .001). No significant relations were found for the lack of emotional clarity and independent stress. CONCLUSIONS: Results support the stress generation hypothesis and suggest that future research should be conducted evaluating whether bolstering youth's understanding of their emotional experiences may reduce subsequent suicidal ideation.

Family dementia caregivers with suicidal ideation improve with mentalizing imagery therapy: Results from a pilot study.

Background: Family caregivers of persons living with dementia often experience increased depression and suicidal ideation (SI). However, the feasibility and impact of therapies on caregiver SI has remained largely unexplored. Mentalizing imagery therapy (MIT) helps reduce psychological symptoms through mindfulness and guided imagery. This pilot study examined the feasibility of participation by caregivers with SI in a randomized controlled trial (RCT) of MIT versus a psychosocial support group (SG), and the respective impact of group on SI, depression, and secondary outcomes. Methods: A secondary analysis of data from an RCT of 4-week MIT or SG for caregivers (n = 46) was performed, identifying SI (n = 23) and non-SI (n = 23) cohorts. Group attendance and home practice were compared between cohorts. In the SI cohort (total n = 23, MIT n = 11, SG n = 12), group differences in SI, depression, and secondary outcomes were evaluated post-group and at 4-month follow-up. Results: Attendance in both groups and home practice in MIT were similar between SI and non-SI cohorts. In the SI cohort, MIT evinced greater improvements relative to SG in SI (p=.02) and depression (p=.02) post-group, and other secondary outcomes at follow-up. Limitations: Limitations include small sample size and single-item assessments of SI from validated depression rating scales. Conclusions: Participation in an RCT was feasible for caregivers with SI. MIT resulted in important benefits for SI and depression, while SG showed no acute SI benefit. The role of MIT in improving SI should be confirmed with adequately powered trials, as effective therapies to address caregiver SI are critical.

Measures of Suicidal Thoughts and Behaviors in Children and Adolescents: A Systematic Review and Recommendations for Use in Clinical and Research Settings.

Empirically supported measures of suicidal thoughts and behaviors (STBs) are needed to serve as reference outcomes for suicide risk screening tools and to monitor severity and treatment progress in children and adolescents with STBs. The present paper systematically reviewed existing measures of STBs in youth and studies evaluating their psychometric properties and clinical utility. Measures were then evaluated on reliability, validity, and clinical utility. Sixteen articles (20 independent samples) were found with psychometric data with youth samples for eight measures. Interview-based measures were found to have the strongest psychometric support and clinical utility. Significant limitations exist for all self-report measures due to inherent characteristics of these measures that cannot be remedied through additional psychometric study. There is an urgent need for the development and validation of new self-report measures of STBs, particularly for preadolescent children, sexual and gender minority youth, and racial/ethnic minority youth.

Rectified Latent Variable Model-Based EMG Factorization of Inhibitory Muscle Synergy Components Related to Aging, Expertise and Force-Tempo Variations.

Muscle synergy has been widely acknowledged as a possible strategy of neuromotor control, but current research has ignored the potential inhibitory components in muscle synergies. Our study aims to identify and characterize the inhibitory components within motor modules derived from electromyography (EMG), investigate the impact of aging and motor expertise on these components, and better understand the nervous system's adaptions to varying task demands. We utilized a rectified latent variable model (RLVM) to factorize motor modules with inhibitory components from EMG signals recorded from ten expert pianists when they played scales and pieces at different tempo-force combinations. We found that older participants showed a higher proportion of inhibitory components compared with the younger group. Senior experts had a higher proportion of inhibitory components on the left hand, and most inhibitory components became less negative with increased tempo or decreased force. Our results demonstrated that the inhibitory components in muscle synergies could be shaped by aging and expertise, and also took part in motor control for adapting to different conditions in complex tasks.

A phase 2, single-arm trial evaluating 131I-PSMA-1095 targeted radioligand therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. 131I-PSMA-1095 (also known as 131I-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment. METHODS: We conducted a single-arm, phase 2 trial to assess efficacy and tolerability of 131I-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent 18F-DCFPyL PET and 18F-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of 131I-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed. RESULTS: Eleven patients were screened for inclusion and nine patients received 131I-PSMA-1095. The median baseline PSA was 162 µg/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia. CONCLUSION: 131I-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of 131I-PSMA-1095 compared to 177Lu-PSMA-617.

The antidepressant effect of whole-body hyperthermia is associated with the classical interleukin-6 signaling pathway.

There is urgent need for novel antidepressant treatments that confer therapeutic benefits via engagement with identified mechanistic targets. The objective of the study was to determine whether activation of the classical anti-inflammatory interleukin-6 signaling pathways is associated with the antidepressant effects of whole-body hyperthermia. A 6-week, randomized, double-blind study compared whole-body hyperthermia with a sham condition in a university-based medical center. Medically healthy participants aged 18-65 years who met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score ≥ 16 were randomized with 1-to-1 allocation in blocks of 6 to receive whole-body hyperthermia or sham. Of 338 individuals screened, 34 were randomized, 30 received interventions and 26 had ≥ 2 blood draws and depressive symptom assessments. Secondary data analysis examined change in the ratio of IL-6:soluble IL-6 receptor pre-intervention, post-intervention, and at weeks 1 and 4. Hierarchical linear modeling tested whether increased IL-6:soluble IL-6 receptor ratio post-intervention was associated with decreased depressive symptom at weeks 1, 2, 4 and 6 for those randomized to whole-body hyperthermia. Twenty-six individuals were randomized to whole-body hyperthermia [n = 12; 75 % female; age = 37.9 years (SD = 15.3) or sham [n = 14; 57.1 % female; age = 41.1 years (SD = 12.5). When compared to the sham condition, active whole-body hyperthermia only increased the IL-6:soluble IL-6 receptor ratio post-treatment [F(3,72) = 11.73,p < .001], but not pre-intervention or at weeks 1 and 4. Using hierarchical linear modeling, increased IL-6:sIL-6R ratio following whole-body hyperthermia moderated depressive symptoms at weeks 1, 2, 4 and 6, such that increases in the IL-6:soluble IL-6 receptor ratio were associated with decreased depressive symptoms at weeks 1, 2, 4 and 6 for those receiving the active whole-body hyperthermia compared to sham treatment (B = -229.44, t = -3.82,p < .001). Acute activation of classical intereukin-6 signaling might emerge as a heretofore unrecognized novel mechanism that could be harnessed to expand the antidepressant armamentarium.

Post-traumatic stress disorder in a national sample of preadolescent children 9 to 10 years old: Prevalence, correlates, clinical sequelae, and treatment utilization.

Although posttraumatic stress disorder (PTSD) has been well characterized in adults, its epidemiology in children is unclear. The current study provides the first population-based examination of the prevalence of PTSD, sociodemographic and psychiatric correlates, clinical sequelae, and associations with psychiatric treatment in preadolescents 9-10 years old in the United States. Data from the Adolescent Brain and Cognitive Development (ABCD) Study (release 5.0) was analyzed. Participants (unweighted n = 11,875) were recruited from 21 sites across the United States. Current and lifetime PTSD prevalence were estimated, as was treatment use among children with PTSD. Sociodemographic, psychiatric correlates and sequelae of PTSD were analyzed using logistic regression, as was the association between PTSD and psychiatric treatment. After the application of propensity weights, lifetime prevalence of PTSD was 2.17%. Sexual minority status, being multiracial, having unmarried parents, and family economic insecurity were associated with greater odds of PTSD. Among psychiatric disorders, separation anxiety was most strongly associated with PTSD, although general comorbid psychopathology was associated with greater odds of PTSD. Prior history of PTSD predicted a new onset of other psychiatric disorders after PTSD remission. Nearly one in three children with lifetime PTSD did not receive psychiatric treatment, despite negative long-term outcomes of PTSD and significant psychiatric comorbidity. Even among preadolescents who experience full remission of PTSD, a significant risk for future psychiatric illness remains. Further, the current findings underscore the need for improved efforts to reduce unmet treatment needs among those with PTSD at this age.

Assessing Adverse Outcomes and Learning Needs in Canadian Psychiatric Independent Medical Examinations.

Despite the importance of independent medical examinations (IMEs), there is virtually no literature on the risks to the IME assessor nor the learning needs of psychiatrists in this area. To address this deficit, a retrospective chart review of nearly 38,000 cases from the Canadian Medical Protective Association (CMPA) identified 108 files involving complaints or legal actions against psychiatrists performing IMEs. Most complaints identified by the CMPA were to regulatory bodies, including biased opinion, inadequate assessment, inappropriately relying on a requester's information without independent evaluation, nonadherence to regulatory body policies, cursory documentation lacking relevant details, and communication breakdowns. A survey by the Canadian Academy of Psychiatry and the Law (CAPL) and the Canadian Psychiatric Association (CPA) had 306 Canadian psychiatrist respondents. About 37 percent of psychiatrists completing IMEs reported medico-legal consequences, including complaints to regulatory authorities. Only 40 percent of those doing IMEs and 20 percent of all psychiatrists had formal training in doing IMEs. The studies confirm that despite a low but important risk of medico-legal consequences, many psychiatrists performing IMEs do not have formalized training. Using the new CAPL Canadian Guidelines for Forensic Psychiatry Assessment and Report Writing is a step to reduce the risk of such evaluations.

An evaluation of emotion recognition, emotion reactivity, and emotion dysregulation as prospective predictors of 12-month trajectories of non-suicidal self-injury in an adolescent psychiatric inpatient sample.

BACKGROUND: Little is known about trajectories of NSSI. We aimed to identify NSSI trajectories in adolescent psychiatric inpatients and emotional processes that differentiate between trajectories. METHODS: Participants were 180 adolescents (71.7 % female; mean age of 14.89 years, SD = 1.35) from a psychiatric inpatient facility. NSSI was assessed at their index hospitalization, as well as 6, and 12 months after discharge. Emotion recognition, emotion reactivity, and emotion dysregulation were assessed at baseline. Latent class mixture modeling was used to identify different NSSI trajectories and ANOVAs were used to evaluate predictors of the trajectories. RESULTS: Analyses yielded three NSSI trajectories. These included a stable low-frequency class (90.53 % of sample), a stable moderate-frequency class, and a class characterized by high-frequency NSSI at baseline but that largely resolves by 6-month follow-up. After adjustments for multiple comparisons were made, only emotion regulation at baseline differentiated between the trajectories, with greater overall emotion dysregulation and greater emotional non-acceptance (a facet of emotion dysregulation) characterizing the initially high-frequency class and the stable moderate-frequency class more than the stable low-frequency class (ps < .05). Difficulties engaging in goal-directed behavior when distressed characterized the stable moderate-frequency NSSI class more than the stable low-frequency class (p < .05). Limitations The study sample consists predominantly of female and White adolescents and thus may not generalize to other demographic groups. CONCLUSIONS: The current findings suggest that interventions involving emotion regulation with adolescents who engage in NSSI would particularly benefit from a focus on increasing acceptance of emotional experiences.

Aminative Suzuki-Miyaura coupling.

The Suzuki-Miyaura and Buchwald-Hartwig coupling reactions are widely used to form carbon-carbon (C-C) and carbon-nitrogen (C-N) bonds, respectively. We report the incorporation of a formal nitrene insertion process into the Suzuki-Miyaura reaction, altering the products from C-C-linked biaryls to C-N-C-linked diaryl amines and thereby joining the Suzuki-Miyaura and Buchwald-Hartwig coupling pathways to the same starting-material classes. A combination of a bulky ancillary phosphine ligand on palladium and a commercially available amination reagent enables efficient reactivity across aryl halides and pseudohalides, boronic acids and esters, and many functional groups and heterocycles. Mechanistic insights reveal flexibility on the order of bond-forming events, suggesting potential for expansion of the aminative cross-coupling concept to encompass diverse nucleophiles and electrophiles as well as four-component variants.

Use of Tobacco Products and Suicide Attempts Among Elementary School-Aged Children.

Importance: The use of tobacco products, including e-cigarettes and vaping, has rapidly increased among children. However, despite consistent associations found between smoking cigarettes and suicidal behaviors among adolescents and adults, there are limited data on associations between emerging tobacco products and suicidal behaviors, especially among preadolescent children. Objective: To examine whether the use of tobacco products is associated with nonsuicidal self-injury (NSSI), suicidal ideation (SI), and suicide attempts (SAs) among preadolescent children. Design, Setting, and Participants: This cohort study, conducted from September 1, 2022, to September 5, 2023, included participants in the Adolescent Brain Cognitive Development study, a population-based cohort of 11 868 US children enrolled at 9 and 10 years of age. The cross-sectional investigation focused on 3-year periods starting from the baseline to year 2 of follow-up. Statistical analysis was performed from October 1, 2022, to June 30, 2023. Main Outcomes and Measures: Children's use of tobacco products was assessed based on youth reports, including lifetime experiences of various nicotine-related products, supplemented with hair toxicologic tests. Main outcomes were children's lifetime experiences of NSSI, SI, and SAs, assessed using the K-SADS-5 (Kiddie Schedule for Affective Disorders and Schizophrenia for the DSM-5). Multivariate logistic regression was conducted to examine the associations of the use of tobacco products with NSSI, SI, and SAs among the study participants. Sociodemographic, familial, and children's behavioral, temperamental, and clinical outcomes were adjusted in the analyses. Results: Of 8988 unrelated study participants (median age, 9.8 years [range, 8.9-11.0 years]; 4301 girls [47.9%]), 101 children (1.1%) and 151 children (1.7%) acknowledged lifetime use of tobacco products at baseline and at 18-month follow-up, respectively. After accounting for various suicide risk factors and potential confounders, children reporting use of tobacco products were at a 3 to 5 times increased risk of SAs (baseline: n = 153 [adjusted odds ratio (OR), 4.67; 95% CI, 2.35-9.28; false discovery rate (FDR)-corrected P < .001]; year 1: n = 227 [adjusted OR, 4.25; 95% CI, 2.33-7.74; FDR-corrected P < .001]; and year 2: n = 321 [adjusted OR, 2.85; 95% CI, 1.58-5.13; FDR-corrected P = .001]). Of all facets of impulsivity measures that were significant correlates of use of tobacco products, negative urgency was the only independent risk factor for SAs (adjusted OR, 1.52 [95% CI, 1.31-1.78]; FDR-corrected P < .001). In contrast, children's alcohol, cannabis, and prescription drug use were not associated with SAs. Conclusions and Relevance: This study of US children suggests that the increased risk of SAs, consistently reported for adolescents and adults who smoke cigarettes, extends to a range of emerging tobacco products and manifests among elementary school-aged children. Further investigations are imperative to clarify the underlying mechanisms and to implement effective preventive policies for children.

An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance.

We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.