Citations

Abstract Immune checkpoint inhibitors (ICI) have transformed cancer therapy but can induce a spectrum of endocrine complications. Acquired generalized lipodystrophy (AGL) is a rare adverse effect, leading to severe metabolic derangements including insulin-resistant diabetes, dyslipidemia, and hepatic steatosis. Marked hypoleptinemia is noted in these patients, and leptin-replacement therapy is known to be beneficial in patients with other forms of AGL. Though rare, T-cell lymphoma has been reported in patients with AGL on leptin therapy, and there has been much debate on the association between hyperleptinemia and cancer. The safety and efficacy of leptin therapy in patients with ICI-induced AGL and cancer are therefore not clear. We report a 66-year-old woman with metastatic lung adenocarcinoma who developed multiple endocrine disorders including AGL with metabolic abnormalities following pembrolizumab therapy. Initiation of daily metreleptin led to marked improvement in dyslipidemia, glycemic control, and hepatic steatosis, with no evidence of cancer recurrence after 2 years of leptin-replacement therapy. While further studies are warranted to establish the long-term efficacy and safety of leptin in ICI-induced AGL patients with a history of malignancy, this case report provides useful information for the management of these rare, challenging patients.

Miller et al. maintain that thalamic SEEG can now be considered a cornerstone of standard clinical practice in individualized epilepsy care, helping to define seizure onset and spread, assess therapeutic stimulation, map connectivity, and identify target-specific biomarkers for responsive neurostimulation.

Abstract Background To date, no scoring system has adequately defined clinical efficacy of erectile dysfunction (ED) therapies when evaluating differences between cohorts or in meta-analytic studies. Aim To outline the minimal criteria required for any therapy to be considered clinically effective in the treatment of ED. Methods An analytic review was performed of standardized ED questionnaires, with a particular emphasis placed on the International Index of Erectile Function, Erectile Function Domain (IIEF-EFD), and the minimally clinically important difference (MCID) concept. The data were used to create a societal position statement and recommendations on best practices within clinical trials to determine treatment efficacy. Outcomes The SMSNA provided 6 key statements and recommendations to suggest best practices and define minimal thresholds for improvements required for an ED therapy to be considered clinically effective. Results The IIEF-EFD currently represents the preferred standardized questionnaire to evaluate for changes in erectile function post-treatment and is the only questionnaire adequate to assess primary outcomes. To claim efficacy, investigational treatments must demonstrate MCID between cohorts (eg, 2-, 5-, or 7-point median improvements between groups among mild, moderate, or severe ED cohorts) in prospective, randomized, placebo-controlled, and adequately powered studies. In studies employing mixed-severity ED populations, a method of calculating an adjusted MCID was proposed based on statistical weighting principles. Similarly, a novel method for analyzing differences between cohorts in meta-analytic studies was presented to incorporate the concept of MCID. Based on these principles, the SMSNA would not support efficacy of a therapy based on statistical significance in a meta-analytic study alone. Similarly, studies claiming efficacy utilizing responder approaches (ie, statistically higher percentage of men achieving MCID between cohorts) would not be acceptable unless the median difference between groups on the IIEF-EFD achieved MCID. Clinical Implications The current position statement provides important, evidence-based data and scientific principles to help define what may be considered as an effective therapy in the treatment of ED. This framework provides a basis that decision-makers, clinicians, and patients may use to help differentiate clinically effective therapies. Strengths & Limitations The published literature is limited by a lack of validated instruments and data defining MCID for ED therapies between cohorts and with meta-analytic studies. The current position statement provides important guidance on these areas of ambiguity pending further, definitive data. Conclusion The current position statement provides detailed guidance on key criteria required to conclude efficacy of therapies used to treat ED.

Abstract Background Although novel treatments targeting amyloid‐beta (Aβ) have been recently approved by the FDA, there remains a critical need for alternative therapeutic strategies to delay the onset and progression of Alzheimer's disease (AD). Mitochondrial dysfunction and disrupted brain energy homeostasis are key hallmarks of early‐stage AD. Developing treatments that address these deficits could offer substantial benefits. We identified mitochondrial complex I (mtCI) as a druggable target and demonstrated that its mild inhibition using the small molecule CP2 improves brain energy homeostasis, restores synaptic and cognitive function, and activates neuroprotective signaling in AD mouse models. However, the mechanistic link between mtCI inhibition, glucose metabolism, and energy homeostasis remains unclear. Methods Cellular energy metabolism was assessed in neuroblastoma SH‐SY5Y cells expressing mutant human APP protein (APPswe) and in control cells. Glycolytic function, mitochondrial energetics, and fatty acid β‐oxidation (FAO) were measured using a Seahorse Analyzer. Glucose transporter (GLUT) translocation to the cell surface was evaluated using flow cytometry and immunofluorescence staining. Protein expression changes were analyzed via Western blot, and glucose uptake was quantified with the Glucose Uptake‐Glo™ assay. Additionally, metabolic flux analysis using 13C‐labeled glucose and targeted metabolomics by mass spectrometry were performed to measure specific metabolites. Results APPswe cells displayed significant reductions in glycolysis and spare respiratory capacity, indicative of impaired mitochondrial energy production under stress. These deficits were accompanied by reduced glucose uptake, which was partially compensated by an increase in FAO. At concentrations relevant to in vivo treatments, CP2 acutely enhanced GLUT translocation to the cell surface, increasing glucose uptake within one hour. Enhanced glucose utilization in OXPHOS machinery was confirmed by inhibition of PDH phosphorylation and increased conversion of pyruvate to acetyl‐CoA, fueling the TCA cycle and generating critical signaling metabolites essential for gene regulation. These mechanisms were mediated by AMPK. Conclusion Our findings suggest that mild inhibition of mtCI activates multiple neuroprotective mechanisms, including improved glucose metabolism and energy homeostasis. These consistent results in human cells and AD mouse models highlight the translational potential of this therapeutic approach for AD.

Abstract Background Some data suggest that neuroinflammation may be associated with pro‐inflammatory states in the body. Systemic, proinflammatory cytokines (TNFα, IL‐1, IL‐6, etc.) are produced by a variety of comorbidities. Neuroinflammation has been shown to be associated with the accumulation of amyloid in the brain (Becher, Heneka). We hypothesized that systemic cytokine production could be associated with neuroinflammation and thereby be related to brain amyloid accumulation. This study aims to evaluate the relationship between neuroinflammation, amyloid accumulation and systemic cytokines. Method 90 participants from the Mayo Clinic Study of Aging (MCSA) received a fasting cytokine panel over a 5‐year span where IL‐1, IL‐6, IL‐10, TNFa levels were measured. Participants were divided into four groups: cognitively unimpaired with normal levels of amyloid (CU A‐, n = 25), cognitively unimpaired with elevated amyloid (CU A+, n = 25), and mild cognitively impaired (MCI) with amyloid positive (MCI A+, n = 25), and Alzheimer's disease (AD) with elevated amyloid (AD A+, n = 15). To compare regional standardized uptake value ratio (SUVr) from neuroinflammation PET based on amyloid status (A+ vs A‐) and the four cytokines, Spearman's rank correlation and Fishers r‐to‐z transformations were used to assess pairwise group differences. Result Using Spearman's rank correlation and Fishers r‐to‐z transformations, no strong relationship was found between systemic inflammation and neuroinflammation. While comparing CUA‐ vs CUA+ in Figure 1, three regions (supplementary motor area, frontal superior medial lobe, and middle cingulate cortex) showed a significant difference ( p < 0.05). However, Figure 2 showed an overarching trend bias towards significance across most regions in IL10, IL6, and TNFa. Conclusion Although significant relationships between systemic inflammation, brain amyloid and neuroinflammation were limited, the data show an overarching trend bias in broad brain regions, suggesting that further analyses are needed, possibly with larger sample sizes, to assess the relationship of regional neuroinflammation and amyloid to systemic inflammation. Future analyses could also regress out factors like sex, age, and genotype to further proinflammatory cytokine research.

Background/Objectives: The purpose of this study is to assess whether the addition of an oxymetazoline (OXY) hemostatic solution, which can be used to manage pulpal bleeding, maintains higher MTA survivability than pulpotomies treated with FS. Methods: In this retrospective cross-sectional study, patient data (n = 75) were used to assess radiographic and clinical signs and symptoms of pathosis in primary molars treated with a pulpotomy and a stainless-steel crown. Pulpotomies treated with FS (Group 1) were compared to those treated with MTA with OXY-induced hemostasis (Group 2). Restricted mean survival times (RMSTs) were calculated for the two groups, and Cox proportional hazards regression was used to analyze the effects of patient and practice level covariates on radiographic and clinical pathosis. Results: Cox proportional-hazard regression identified three potential covariates (age, pulpotomy groups, and procedure location) that predicted radiographic pathosis. The adjusted hazard ratio for Group 2 was 0.30 (95% CI: 0.11–0.82), indicating improved radiographic outcomes compared with Group 1 (p = 0.02). The 36-month RMST for Group 2 was 30.1 months (95% CI: 26.5–33.7) compared to 24.7 months (21.6–27.8) for Group 1 (p = 0.025). Conclusions: A pulpotomy utilizing OXY hemostasis prior to MTA placement led to a higher chance of pulpotomy survival than FS.