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Background: The FOXO3a (forkhead box O3a)-BNIP3 (B-cell lymphoma 2/adenovirus E1B 19kDa interacting protein 3) pathway modulates mitochondrial dynamics and function and contributes to myocardial remodeling in rodent models of heart failure. We sought to investigate the expression of this pathway along with the expression of mitochondrial biogenesis (PGC-1α [peroxisome proliferator-activated receptor-γ coactivator-1α]), dynamics (DRP-1 [dynamin-related protein 1], OPA-1 [optic atrophy 1], and MFN 2 [mitofusin 2]), and oxidative phosphorylation (citrate synthase and electron transport chain complexes) markers and COX IV (cytochrome C oxidase) activity in myocardium from patients with valvular or ischemic heart disease and heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF). Methods and Results: Subepicardial left ventricular biopsies (10×1×1 mm 3 ) were obtained at aortic valve replacement (HFpEF AVR , n=5; and HFrEF AVR , n=4), coronary artery bypass grafting (HFpEF CABG , n=5; and HFrEF CABG , n=5), or left ventricular assist device implantation (HFrEF LVAD , n=4). Subepicardial biopsies from patients with normal left ventricular function (n=2) and from donor hearts (n=3) served as controls (normal). Relative to normal, mitochondrial fragmentation and cristae destruction were evident, and mitochondrial area was decreased in HFpEF; 1.00±0.09 versus 0.71±0.08; P =0.016. These mitochondrial morphological changes were more pronounced in HFrEF (0.54±0.06); P =0.002 HFpEF versus HFrEF. BNIP3 (monomer+dimer) expression was increased in HFpEF (3.99±2.44) and in HFrEF (5.19±1.70) relative to normal; P =0.004 and P <0.001, respectively. However, BNIP3 monomer was increased in HFrEF (4.32±1.43) compared with normal (0.99±0.06) and HFpEF (1.97±0.90); P =0.001 and 0.004, respectively. The HFrEF group uniquely showed increase in DRP-1 expression (1.94±0.38) and decreases in PGC-1α expression (0.61±0.07) and COX IV activity (0.70±0.10) relative to normal; P =0.013, P <0.001, and P <0.001, respectively, with no significant change in electron transport chain complexes expression. Conclusions: These findings in human myocardium confirm studies in rodents where contractile dysfunction is associated with activation of the FOXO3a-BNIP3 pathway and altered mitochondrial dynamics, biogenesis, and function.

ObjectivesConflicting research exists surrounding the utility of aspirin to prevent tumor growth in the medical management of vestibular schwannoma (VS). Recent studies demonstrated no association between aspirin and VS growth using linear tumor measurements. Given the heightened sensitivity of volumetric analyses to monitor tumor growth, the current study was conceived with the chief objective of assessing the association between aspirin or other nonsteroidal anti‐inflammatory drug (NSAID) use and VS growth using volumetric analyses.Study DesignRetrospective review.SettingTertiary referral center.Subjects and MethodsA total of 361 patients totaling 1601 volumetrically analyzed magnetic resonance imaging studies who underwent initial observation since January 1, 2003.ResultsIn total, 123 (35%) patients took 81 mg aspirin daily, 23 (7%) took 325 mg aspirin daily, and 41 (11%) reported other NSAID use. Among those taking aspirin, 112 (72%) exhibited volumetric tumor growth during observation compared to 33 (80%) among other NSAID users and 137 (67%) among nonaspirin users. Patients taking aspirin or other NSAIDs were significantly older at time of diagnosis (median, 66 vs 56 years; P <. 001). Neither aspirin use (hazard ratio [HR], 0.96; P =. 73) nor other NSAID use (HR, 1.39; P =. 081) was significantly associated with a reduced risk of volumetric tumor growth. These results were similar following age adjustment (P =. 81 and. 087, respectively). When separating aspirin users by 81‐mg or 325‐mg dosing, neither group exhibited a reduced risk of growth (P =. 95 and. 73, respectively).ConclusionDespite promising initial results, the preponderance of existing literature suggests that aspirin and other NSAID use does not prevent tumor growth in VS.

Abstract Although recent scientific advances have improved our understanding of basic biological mechanisms underlying chemotherapy-induced peripheral neuropathy (CIPN), few interventions are available to prevent or treat CIPN. Although some biological targets from preclinical studies show promise in nonhuman animal models, few targets have been translated to successful clinical trials. To address this problem, the National Cancer Institute’s Symptom Management and Health-Related Quality of Life Steering Committee convened a meeting of experts in the CIPN and oncology symptom management fields to participate in a Clinical Trials Planning Meeting (CTPM). Investigators presented data from preclinical and translational studies for possible CIPN interventions; these were evaluated for readiness of randomized clinical trial testing by experts, and recommendations were provided. Breakout sessions were convened to discuss and develop future studies. The CTPM experts concluded that there is compelling evidence to move forward with selected pharmacological and nonpharmacological clinical trials for the prevention and treatment of CIPN. Several key feasibility issues need to be addressed, however. These include identification of optimal outcome measures to define the CIPN phenotype, establishment of parameters that guide the evaluation of clinically meaningful effects, and adoption of approaches for inclusion of translational and biomarker and/or genetic measures. The results of the CTPM provide support for conducting clinical trials that include both pharmacological and nonpharmacological approaches, alone or in combination, with biomarkers, genetics, or other measures designed to inform underlying CIPN mechanisms. Several working groups were formed to design rigorous CIPN clinical trials, the results of which are ongoing.

ABSTRACT Despite the strong association between diabetes and dementia, it remains to be fully elucidated how insulin deficiency adversely affects brain functions. We show that insulin deficiency in streptozotocin‐induced diabetic mice decreased mitochondrial ATP production and/or citrate synthase and cytochrome oxidase activities in the cerebrum, hypothalamus, and hippocampus. Concomitant decrease in mitochondrial fusion proteins and increased fission proteins in these brain regions likely contributed to altered mitochondrial function. Although insulin deficiency did not cause any detectable increase in reactive oxygen species (ROS) emission, inhibition of monocarboxylate transporters increased ROS emission and further reduced ATP production, indicating the causative roles of elevated ketones and lactate in counteracting oxidative stress and as a fuel source for ATP production during insulin deficiency. Moreover, in healthy mice, intranasal insulin administration increased mitochondrial ATP production, demonstrating a direct regulatory role of insulin on brain mitochondrial function. Proteomics analysis of the cerebrum showed that although insulin deficiency led to oxidative post‐translational modification of several proteins that cause tau phosphorylation and neurofibrillary degeneration, insulin administration enhanced neuronal development and neurotransmission pathways. Together these results render support for the critical role of insulin to maintain brain mitochondrial homeostasis and provide mechanistic insight into the potential therapeutic benefits of intranasal insulin.—Ruegsegger, G. N., Manjunatha, S., Summer, P., Gopala, S., Zabeilski, P., Dasari, S., Vanderboom, P. M., Lanza, I. R., Klaus, K. A., Nair, K. S. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes. FASEB J. 33, 4458–4472 (2019). www.fasebj.org

Summary Background Pregabalin is a calcium channel α2δ ligand that modifies visceral hypersensitivity in IBS patients. Clinical data for pregabalin in IBS are lacking. Aim To test the efficacy of pregabalin on gastrointestinal symptoms in IBS patients. Methods A double‐blind, placebo‐controlled trial was performed. Adults meeting IBS Rome III criteria with ≥3 pain attacks per month were randomised to pregabalin 225 mg vs placebo twice daily for 12 weeks. Questionnaires were completed weekly. The primary endpoint was average pain Bowel Symptom Scale (BSS) scores weeks 9‐12. An intention‐to‐treat analysis of covariance evaluated treatment effects on quantitative endpoints, adjusting for age and gender. Adequate relief and change in pain score were assessed using a chi‐squared test. Results Eighty‐five patients were recruited and randomised. Sample characteristics include: mean age 39.4 (SD = 14.6); 73 (86%) female; 37 (44%) IBS‐D, 29 (35%) IBS‐M, 18 (21%) IBS‐C. The pregabalin arm had lower average pain‐BSS scores weeks 9‐12 (25 vs 42, P = 0.008). Compared with placebo, the overall IBS BSS severity score was lower in the pregabalin arm (26 vs 42, P = 0.009). Differences were observed for the diarrhoea‐BSS and bloating‐BSS scores ( P = 0.049 and 0.016, respectively). No differences between groups were seen for constipation‐BSS scores. Adequate relief was not different between the two arms (46% vs 36%, P = 0.35). 63% pregabalin vs 45% placebo had a change in pain score ≥30 at week 12 from baseline ( P = 0.10). Post‐treatment IBS‐QoL scores did not differ between groups. Conclusion This trial suggests that pregabalin may be beneficial for IBS abdominal pain, bloating and diarrhoea.

Objective The aim of this study was to compare the perioperative morbidity of minimally invasive sacrocolpopexy (MISC) and nonmesh apical vaginal surgeries for repair of vaginal vault prolapse using data from a contemporary nationwide cohort. Methods The American College of Surgeons' National Surgical Quality Improvement Program database was used to identify women who underwent apical prolapse surgery via vaginal approach or MISC from 2010 to 2016. Those undergoing concomitant hysterectomy or transvaginal mesh placement were excluded. Associations of surgical approach with 30-day complications, prolonged hospitalization, and reoperation were evaluated using logistic regression. Readmission within 30 days was calculated using the person-years method and Cox proportional hazards models. Results Overall, 6390 women underwent surgery, including 3852 (60%) via vaginal approach and 2538 (40%) via MISC. Patients undergoing MISC were younger ( P < 0.0001) and less likely to have hypertension ( P = 0.04) or chronic obstructive pulmonary disease ( P = 0.008), with lower American Society of Anesthesiologists scores ( P < 0.0001) and higher preoperative hematocrit ( P = 0.009). The MISC cohort had a lower unadjusted rates of minor complications (3.9% vs 5.6%; P = 0.004), urinary tract infection (3.3% vs 4.8%; P = 0.004), and prolonged hospitalization (5.2% vs 7.9%; P < 0.0001), with a higher rate of nephrologic ( P = 0.01) complications. On multivariable analysis, there were no significant associations of MISC with the risk of 30-day complications (odds ratio [OR], 1.51; 95% confidence interval [CI], 0.92–2.51; P = 0.11), prolonged hospitalization (OR, 0.96; 95% CI, 0.76–1.21; P = 0.72), readmission (HR 1.03; 95% CI, 0.71–1.49; P = 0.88), or reoperation (OR, 0.95; 95% CI, 0.57–1.60; P = 0.86). Conclusions Minimally invasive sacrocolpopexy is associated with similar rates of 30-day complications, prolonged hospitalization, readmission, and reoperation compared with nonmesh vaginal surgeries for apical prolapse.

AbstractBackground and aimsLittle research has been done on tele‐intensive care unit (ICU) implementation across different types of ICUs, and there exist few studies that have used qualitative research methods to analyze the human and organizational factors influencing optimization of telemedicine for newborn resuscitation. The objective of this study was to understand health care professionals' acceptance, utilization, and integration of video telemedicine for newborn resuscitation (termed teleneonatology) in community hospital settings.MethodsFocus group and individual interviews were conducted with 49 health care professionals at six affiliated health system hospitals. Data were gathered from physicians (n = 18), nurses (n = 30), and a nurse practitioner. Data were inductively analyzed using a thematic approach, and then constructs from normalization process theory (NPT) were deductively applied. NPT rendered a general framework to describe and assess how care teams perceive the implementation of teleneonatology and how they interact with this telemedicine service in their local setting.ResultsLocal health care professionals accepted teleneonatology as an important, helpful service, yet its implementation was perceived as both valuable and a threat to professional traditions. Utilization may depend on perceived benefit, mutual understanding of the guidelines, and expectations of use, and other relational, human, contextual, and system factors. Participants in this study agreed on the need for collective work to successfully integrate teleneonatology into the local practice.DiscussionsNPT uncovered that successful implementation of a teleneonatology program may be facilitated by strong interpersonal relationships among care teams, continuous programmatic training and education, and communicating the clinical value of teleneonatology, including its opportunities and benefits.