Decreased Glucose Metabolism and Declined Chaperones Are Unique Features Required for the Survival of Senescent Fibroblasts and Pyruvate Dehydrogenase Is a Potent Senolytic Target

ABSTRACT Cellular senescence contributes to aging and age‐related diseases. Deep identifications of the senescence‐specific cellular features are crucial to the better understanding of the survival and maintenance of senescence and the development of novel senolytics against senescent cells. By a global proteomic profiling of senescent human BJ fibroblasts induced by ionizing radiation, 178 cellular proteins with at least 4‐fold or greater changes in abundance were identified, representing the cellular landscape of the senescent fibroblasts. Functional enrichments and biological experiments demonstrated that the decreased glucose metabolism, reduced ATP and alpha‐KG production, and declined chaperones are the most striking features associated with senescent fibroblasts. Moreover, these proteomic features are closely correlated with their transcription alterations confirmed by RT‐PCR. Respectively, inhibiting pyruvate dehydrogenase (critical enzyme to supply acetyl‐CoA to TCA cycle) or glutaminase GLS1 (crucial enzyme to supplement TCA cycle intermediate alpha‐KG) or inhibiting Hsp90 (important member of chaperones) led to the selective killing of senescent fibroblasts, indicating the essential roles of the TCA cycle or chaperones in the survival and maintenance of cellular senescence. Most importantly, co‐inhibiting the TCA cycle and Hsp90 gave rise to the enhanced selective killing of senescent fibroblasts as well as the therapy‐induced senescent cancer cells and the alleviation of physical dysfunctions in aged mice, suggesting the synergistic regulation of cellular senescence by the TCA cycle and chaperones. Thus, our profiling revealed key cellular features for the survival and maintenance in senescent normal cells, demonstrating that pyruvate dehydrogenase is a novel and potent senolytic target for the selective elimination of senescence.

Comparing Outcomes of a Rapid High‐Sensitivity Troponin Protocol Between Hospital‐Based and Freestanding Emergency Departments

ABSTRACT Study Objectives Significant variability exists in patient populations and diagnostic capabilities among hospital‐based emergency departments (HBEDs) and freestanding emergency departments (FSEDs). While high sensitivity cardiac troponin (hs‐cTn) research has focused on HBEDs, its application in FSEDs remains unexplored. This study assesses the comparative, real‐world effectiveness of a 0/1‐h accelerated protocol (AP) using hs‐cTn between HBEDs and FSEDs. Methods We conducted a pre‐planned, secondary analysis of a stepped‐wedge cluster randomized trial involving nine EDs within an integrated health system, from July 2020 to March 2021, comprised of five HBEDs and four FSEDs. The trial implemented a 0/1‐h AP utilizing hs‐cTnI to evaluate acute myocardial infarction (AMI). Adult ED patients with an ECG and cardiac troponin ordered were eligible, excluding those with STEMI, hs‐cTnI > 18 ng/L, or trauma‐related symptoms. The primary outcome was safe ED discharge, defined as discharge without death or AMI within 30 days. Results The trial included 32,609 patients, 26,957 in HBEDs and 5652 in FSEDs. Safe discharge from HBED occurred 53.7% (5935/11,062) of the time in the standard care arm and 50.3% (7991/15895) under the AP (aOR 1.04, 95% CI 0.94–1.15, p  = 0.50). Safe discharge from a FSED occurred 86.0% (2102/2443) of the time in the standard care arm and increased to 95.0% (3049/3209) under the AP (aOR 1.48, 95% CI 1.03–2.13, p  = 0.033). Overall, the observed association between the AP and safe discharge was stronger in FSEDs than in HBEDs ( Δ $$ \Delta $$ log(aOdds) 1.05, 95% CI (0.82, 1.29), p  < 0.001). Conclusion Implementing a 0/1‐h AP using hs‐cTnI to evaluate for AMI was associated with higher rates of safe discharge in FSEDs compared to HBEDs.

Navigating CEO Characteristics, Strategic Choices and Firm Success

ABSTRACT This study explores the relationship between the CEOs' demographic characteristics (age, tenure and professional qualification) and business strategy (prospector vs. defender) development. Using evidence from a sample of 4826 Australian firm‐year observations, the findings suggest that CEO age and tenure are negatively associated with the prospector business strategy, while CEO education is positively associated with the prospector business strategy. Further analysis suggests that CEO age negatively impacts firm performance. The results are robust based on firm‐fixed effects, propensity score matching and lagged CEO demographic characteristics. Policymakers in Australia could consider introducing CEO Mandatory Retirement Policies (MRPs).

Negative Urgency Mediates the Effect of Family Conflict on Cannabis Positive Expectancy: The Moderating Role of Anterior Cingulate Cortex

ABSTRACT Cannabis positive expectancies, favourable beliefs about cannabis effects, are a key risk factor for cannabis initiation and problematic use during adolescence. Prior research demonstrated a robust association between cannabis positive expectancies and increased use among adolescents, yet less is known about the developmental aetiology, biobehavioural mechanisms and cognitive context that contribute to these expectancies. The present study examines the intermediary role of negative urgency, a facet of impulsivity characterized by rash action under distress. Additionally, the study investigates whether anterior cingulate cortex (ACC) activation during emotional reward processing moderates this indirect effect. We conducted a longitudinal moderated mediation model with three waves of data from the Adolescent Brain and Cognitive Development (ABCD) study, analysing 6638 youths (baseline M age  = 10.1 years; 47.8% female). Family conflict at baseline predicted increased cannabis positive expectancies ΔT5T7 through increases in negative urgency at T5 ( β  = 0.017, p  < 0.001, 95% CI [0.045, 0.069]). Heightened ACC activity at T5 (anticipatory large loss), including bilateral caudal and rostral regions, intensified negative urgency's impact on cannabis positive expectancy ΔT5T7: Left caudal ( β  = 0.081, p  < 0.001, 95% CI [0.041, 0.122]), right caudal ( β  = 0.062, p  = 0.004, 95% CI [0.020, 0.105]), right rostral ( β  = 0.041, p  = 0.026, 95% CI [0.001, 0.081]) and left rostral ( β  = 0.052, p  = 0.01, 95% CI [0.012, 0.092]). This study highlights how neural activity amplifies stress‐related effects on adolescent substance use expectations, suggesting emotional decision‐making as a target for prevention.

Associations between county‐level e‐cigarette‐inclusive Tobacco 21 law population coverage and e‐cigarette use behaviors among United States adolescents in Monitoring the Future

Abstract Background and aims In the United States (US), Tobacco 21 (T21) laws set the minimum legal sale age for all tobacco products to 21 years. This study aimed to examine whether e‐cigarette‐inclusive T21 laws were associated with e‐cigarette use behaviors and related disparities among US adolescents. Design We used nationally representative, repeated cross‐sectional Monitoring the Future data to compare self‐reported current e‐cigarette use (2014–2022) and first e‐cigarette initiation (2015–2022) among adolescents in counties with 100% ('full') versus <100% ('partial or no') e‐cigarette‐inclusive T21 law population coverage using modified Poisson regression, examining differences by sex, race and ethnicity, parental educational attainment and college educational expectations through interactions. Setting United States. Participants 8th, 10th and 12th graders. Measurements County‐level e‐cigarette‐inclusive T21 law population coverage was determined using Tobacco 21 Population Coverage Database and US Census Bureau population data. Current e‐cigarette use was defined as any past 30‐day use among the entire sample. First e‐cigarette initiation was defined as first use in the current grade among adolescents who had not initiated use prior to the current grade. Findings Compared with 8th, 10th and 12th graders in counties with partial or no e‐cigarette‐inclusive T21 law coverage, 8th [marginal effect (ME) = −1.8%, 95% confidence interval (CI) = −3.1% to −0.6%], 10th (ME = −2.6%, 95% CI = −4.6% to −0.6%) and 12th graders (ME = −2.7%, 95% CI = −5.2% to −0.1%) in counties with full coverage had a lower current e‐cigarette use prevalence. For current e‐cigarette use, we also observed statistically significant interactions by sociodemographic factors. Across all grades, full [8th: predicted prevalence (PP) = 5.9%, 95% CI = 4.7%–7.1%; 10th: PP = 11.8%, 95% CI = 10.2%–13.4%; 12th: 18.1%, 95% CI = 15.6%–20.6%] versus partial or no coverage (8th: PP = 7.5%, 95% CI = 6.2%–8.8%; 10th: PP = 16.3%, 95% CI = 15.0%–17.6%; 12th: 23.4%, 95% CI = 21.9%–24.8%) was associated with lower current e‐cigarette use among males but not females. By race and ethnicity, associations were statistically significant across all grades, but the magnitude and direction of these associations varied by subgroup and grade. Among 12th graders, full (PP = 16.1%, 95% CI = 13.9%–18.3%) versus partial or no coverage (PP = 20.5%, 95% CI = 19.0%–22.1%) was associated with lower current e‐cigarette use among those who said they ‘probably will’ graduate from a four‐year college but not among those with other educational expectations. We did not find sufficient evidence to support an association between e‐cigarette‐inclusive T21 law coverage and first e‐cigarette initiation overall or across sociodemographic subgroups. Conclusions E‐cigarette‐inclusive Tobacco 21 laws appear to be associated with lower current e‐cigarette use among US adolescents. However, we lacked sufficient evidence to support an association with first e‐cigarette use initiation. We also observed sociodemographic differences in these associations for current e‐cigarette use.

Unpacking the Effects of Conflict on Fertilizer Use and Maize Yields: Empirical Evidence From Nigeria

ABSTRACT Conventional recommendations emphasize increasing the use of inorganic fertilizer to enhance maize yields in African countries south of the Sahara, but it is not clear how smallholders’ exposure to violent conflicts affect demand, yield responses, and the profitability of fertilizers. Our study tackles this question. We analyze how maize yield responds to fertilizer use and assess the profitability of fertilizer use in conflict‐affected settings. We then investigate how conflict impacts the profitability of fertilizer, given that armed conflicts are likely to increase input costs, logistical difficulties, and market uncertainties. Our study reveals that yield responses to nitrogen are very low in Nigeria. We also show that exposure to conflict reduces input use rates and decreases the marginal physical productivity of nitrogen in maize production, making investment in fertilizer less profitable. Recognizing this effect of conflict on input use and maize yield response is crucial for targeting and resource allocation decisions among smallholders in similar conflict‐affected regions. Moreover, the effect of conflict highlights how external factors, beyond the scope of agronomic practices, influence the economic incentives for fertilizer application and the resulting yield outcomes.

Resecting Beyond the Central Pelvic Compartment in Pelvic Exenterations for Gynaecological Malignancies: Outcomes From a Tertiary Unit

ABSTRACT Background Pelvic exenterations (PE) in solid organ gynaecological malignancies have historically been confined to the central pelvic compartment but an expansion of resection extent to include the lateral compartment is now technically feasible. There remains uncertainty about its influence on outcomes. Methods Retrospective study of consecutive patients undergoing PE for non‐ovarian gynaecological malignancies in a tertiary referral unit. Two groups were assessed and compared: standard resections including but not beyond the pelvic sidewall (SR); and extended resections beyond the pelvic side wall (lateral compartment excisions; internal iliac vessels and/or obturator internus/piriformis resection and/or bone resection) (ER). Results Thirty‐one patients underwent 32 PE: of these, 21 patients underwent SR (65.6%) with 11 who underwent ER (34.4%). Clear microscopic resection margins (R0) were achieved in 72.7% for ER versus 90.5% for SR. The overall 30‐day major complication rate (≥Clavien‐Dindo III) was 45.5% for the ER group versus 19.9% for SR. Median length‐of‐stay for ER was longer than for SR (38 vs. 18.5 days). The 1‐year DFS for ER was 66.7% versus 77.8% for SR. The 2‐year DFS for ER group was 60% versus 57.1% for SR. Conclusions In this study of contemporary patients, the short‐term patient outcomes of ER were consistent with other similar cohorts in the literature and comparable to SR in this cohort. There is an urgent need for larger multicentre studies to clarify the influence of PE resectional extent on resection margin status, patient outcomes and survival.

Extracellular Vesicle miRNAs as Biomarkers of Asthma Severity

The Challenge of Recurrent Presumed Adhesional Small Bowel Obstruction: How Magnetic Resonance Enterography Might Help

The Dual‐Surgeon Approach for Penile Prosthesis Surgery: A Case Series Highlighting Benefits of This Novel Approach

ABSTRACT Objective To assess the outcomes of a dual‐surgeon approach to inflatable penile prosthesis (IPP) surgery, where two non‐fellowship‐trained urologists partnered to perform these procedures following intensive proctoring by an international expert. Patients and Methods A retrospective analysis of patients who underwent ‘dual‐surgeon’ IPP surgery over a 10‐year period between August 2008 and July 2018 was performed. Data on patient demographics, peri‐operative parameters, complications (Clavien‐Dindo system), rate of prosthesis failure, and the necessity of revision surgery were extracted, analysed and compared to published outcomes from high volume institutions. Results A total of 175 patients underwent IPP surgery over a 10‐year period. The mean age was 64 years (IQR 59–70), the mean operative time was 65.7 min (range 32–157 min), and the mean length of stay in hospital was 1.6 nights (range 1–6 nights). The majority of patients (90.9%) received a Coloplast Titan Implant. The overall complication rate was 22.2% (38/175). Notably, there were no complications > Clavein‐dindo grade III. Six patients (3.4%) required revision surgery for mechanical failure. Conclusions Dual surgeons performing IPP after intensive training from visiting international experts can achieve comparable outcomes to high volume local and international centres. This strategy of dual‐surgeon collaboration should be considered in low volume implanters with no prior fellowship training in prosthetic urology.