Faculty Bibliography

OBJECTIVE:The PDN-Sensory randomized controlled trial (RCT) evaluated the effects of high-frequency 10-kHz spinal cord stimulation (10-kHz SCS) on pain and sensory function in individuals with painful diabetic neuropathy (PDN). RESEARCH DESIGN AND METHODS/METHODS:Participants were randomized 1:1 to conventional medical management (CMM) alone or 10-kHz SCS plus CMM. The primary and key secondary end points were the proportions of participants with pain response (≥50% lower limb pain relief) and sensory improvement (≥3-point reduction in modified Toronto Clinical Neuropathy Score [mTCNS]). Hierarchical secondary outcomes included intraepidermal nerve fiber density (IENFD), sleep, and health and neuropathy-related quality of life (QoL). IENFD and mTCNS assessments were allocation blinded. RESULTS:A total of 91 participants were randomly assigned to CMM alone (n = 50) or 10-kHz SCS plus CMM (n = 41). In a modified intention-to-treat worst-case analysis, 27 of 34 participants in the 10-kHz SCS group who underwent a temporary trial achieved the primary outcome, versus 2 of 50 CMM-alone participants (P < 0.001). Among those with 6-month data, mTCNS sensory improvement was observed in 16 of 29 (55.2%) 10-kHz SCS participants versus 12 of 48 (25.0%) CMM-alone participants (P = 0.01). The mean change in lower-calf IENFD was 0.58 fibers/mm with 10-kHz SCS versus -0.07 with CMM alone (P = 0.03). Eight of 10 hierarchical secondary end points were met (including sleep and QoL). CONCLUSIONS:The PDN-Sensory RCT replicated previous pain-reduction findings and showed prespecified, objective improvements in sensory function and IENFD. These 6-month findings support clinically meaningful benefit and are consistent with a potential disease-modifying effect that requires longer-term confirmation.

OBJECTIVE:To evaluate cochlear implant (CI) speech perception and usage outcomes in patients after prolonged unilateral deafness. METHODS:Retrospective cohort study at five tertiary academic centers of adult patients with prolonged (> 10 years) unilateral severe to profound hearing loss who underwent cochlear implantation. Main outcome measures included post-operative word recognition scores (WRSs) and average daily usage of CI. RESULTS:A total of 68 patients were analyzed with a median duration of unilateral deafness of 17 years (IQR, 12-35 years). The mean individual average daily CI usage was 8.4 h (SD, 4.5 h) at ≤ 1 year after implantation and 7.1 h (SD, 5.0 h) at > 1 year. The majority of patients (54.5%, 30 patients) had an absolute increase in WRS of ≥ 20% after implantation and 32.7% (18 patients) had an absolute increase of ≥ 50%. Univariate analysis comparing pre- and post-operative speech recognition in patients who completed the same test revealed a clinically and statistically significant improvement, with a mean change of 28.4% (SD 31.6%; p < 0.001) at their latest audiogram. In the analysis excluding those without post-operative data, duration of deafness was not predictive of post-CI WRS on multivariable analysis. CONCLUSIONS:Most patients with prolonged unilateral auditory deprivation in our study benefited from a CI. Although the duration of auditory deprivation was found to be inconsistently associated with poorer CI speech perception performance, our findings support individualized CI candidacy assessment and suggest that prolonged deafness alone should not be used as an absolute exclusion criterion for cochlear implantation.

Somatic mutations accumulate throughout life in every cell, and this process constitutes one of the hallmarks of aging-genomic instability. Caloric restriction (CR) has been shown to extend lifespan across diverse species. Using high-fidelity duplex DNA sequencing of bulk liver, bulk kidney, hepatocytes, and cerebellar neurons, we found that CR in mice reduces genome-wide somatic mutation burdens across multiple tissues and cell types. CR reduced both substitution and insertion/deletion burdens, with the magnitude of these effects varying across sample types. CR also decreased the activity of the enigmatic single-base substitution (SBS) mutational process SBS5 that gives rise to most mutations in mammals. Surprisingly, the mutation burden reduction from CR was greatest in transcriptionally inactive regions. This work illuminates links between diet, aging, and genomic integrity and establishes genomic integrity as a modifiable axis of aging.

Disruption of circadian glucocorticoid (GC) rhythms is associated with chronic stress and obesity, yet its metabolic signature remains poorly defined. Using a physiological mouse model, we show that the liver is largely protected from pathological steatosis despite profound obesity and hyperinsulinemia. We identify a unique redistribution of insulin resistance: rhythm disruption does not globally impair insulin action as occurs in diet-induced obesity. Instead, skeletal muscle develops severe insulin resistance while adipose and hepatic tissues remain functionally insulin responsive. This preserved sensitivity allows the adipose tissue to act as a metabolic reservoir, utilizing sustained hyperinsulinemia to sequester lipids and shield the liver from toxic fatty-acid flux. These findings reveal that GC-rhythm disruption uncouples obesity from hepatic steatosis by redistributing insulin action from skeletal muscle to adipose tissue and liver. Thus, GC-rhythm disruption and high-fat diet are independent and additive drivers of adiposity with divergent hepatic effects.

OBJECTIVES/OBJECTIVE:Chronic hepatitis C can complicate the treatment of coronary artery disease (CAD), especially among racial and ethnic minority patients. This study explores racial and ethnic differences in the prevalence of hepatitis C and inpatient mortality among patients admitted to the hospital primarily for a CAD event in the USA. METHODS:An observational analysis was conducted using data from the 2016 to 2021 National Inpatient Sample, including 1,946,182 CAD patients, of whom 7426 (0.38%) had chronic hepatitis C. We performed weighted logistic regressions to analyze the relationship between race and ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, and other races) regarding the prevalence of hepatitis C and inpatient mortality, adjusting for patient sociodemographic characteristics and comorbidities. RESULTS:Non-Hispanic Black patients had the highest prevalence of hepatitis C (adjusted odds ratio [aOR] = 1.57, 95% confidence interval [CI] 1.48-1.67) and Hispanic patients with underlying hepatitis C had the highest in-hospital mortality (aOR = 1.56, 95% CI 1.11-2.20) compared to non-Hispanic White patients and other racial groups. CONCLUSIONS:We found significant racial and ethnic differences in the prevalence of hepatitis C and mortality among patients with underlying chronic hepatitis C admitted primarily for CAD events in the USA. This disparity may exist due to lower rates of hepatitis C virus (HCV) treatment, higher severity and prevalence of underlying health conditions, poorer healthcare access and insurance coverage, and a higher rate of alcohol use and cirrhosis progression in minority populations.

OBJECTIVE/UNASSIGNED:To examine the effect of DT56a (Femarelle®), a non-hormonal oral treatment for the management of menopause, on symptoms of vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause (GSM) in postmenopausal women. METHODS/UNASSIGNED: = 12) postmenopausal women with severe VVA (100% parabasal cells on cervical cytology) and at least one severe VVA symptom were recruited for a 12-week open-label pilot study. At baseline and week 12, participants underwent physical examination, Pap smear, vaginal ultrasound, vaginal cultures, vaginal pH assessment, and vaginal maturation index evaluation. Subjects also completed questionnaires assessing atrophy symptoms and quality of life using the Utian Quality of Life (UQoL) scale. Follow-up at 24 months was available for several participants. RESULTS/UNASSIGNED:After 12 weeks of treatment, all patients showed a significant reduction in vaginal pH. In addition, 11 of the 12 women demonstrated significant improvement in the vaginal maturation index and UQoL questionnaire scores. CONCLUSIONS/UNASSIGNED:DT56a significantly improved subjective and objective parameters of VVA/GSM, including vaginal pH, vaginal maturation index, and quality of life. These findings support its potential role as a non-hormonal systemic treatment option for women with VVA/GSM.

INTRODUCTION/UNASSIGNED:Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of neurotoxic chemotherapy agents. Despite its substantial global burden, the prevalence of chronic CIPN (persisting for ≥3 months after completion of chemotherapy) remains uncertain. We aimed to estimate the global prevalence of chronic CIPN and assess variations based on chemotherapy regimen, cancer type, geographic region, and human development index (HDI). METHODS/UNASSIGNED:A systematic search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus was conducted from database inception to May 2025. A random-effects model with Freeman-Tukey transformation was used for meta-analysis. The primary outcome was the global prevalence of chronic CIPN. Subgroup analysis explored prevalence by time since chemotherapy completion, geographic region, chemotherapy regimen, cancer type, and study design. RESULTS/UNASSIGNED:A total of 197 studies from 36 countries (72,794 patients who received chemotherapy, 26,258 with chronic CIPN) were included. The pooled global prevalence of chronic CIPN was 44.50% (95% CI 40.77-48.25). Subgroup analyses revealed significant variation by geographic region, chemotherapy class, and cancer type. Chronic CIPN prevalence was 54.37% (95% CI 48.24-60.45) at 3-12 months post-chemotherapy, 37.12% (95% CI 30.15-44.26) at 12-24 months post-chemotherapy, and 40.36% (95% CI 34.72-46.08) at ≥24 months post-chemotherapy. CONCLUSION/UNASSIGNED:Chronic CIPN affects a substantial proportion of cancer survivors, with prevalence influenced by time since completion of chemotherapy, geographic region, chemotherapy type, and cancer type. These findings highlight the need for targeted surveillance, prevention, and management, particularly for high-risk populations.

BACKGROUND/UNASSIGNED:In-stent restenosis (ISR) remains an important cause of repeat revascularization despite advances in drug-eluting stent technology. Contemporary adoption patterns and outcomes of adjunctive plaque-modification strategies for ISR are incompletely characterized. We evaluated national trends and in-hospital outcomes of ISR percutaneous coronary intervention treated with adjunctive plaque-modification devices versus conventional plain old balloon angioplasty. METHODS/UNASSIGNED:All ISR percutaneous coronary intervention procedures in the National Cardiovascular Data Registry CathPCI Registry from July 2009 to June 2024 were analyzed. Adjunctive ISR therapy was defined as use of excimer laser atherectomy, intravascular lithotripsy, cutting/scoring balloon angioplasty, or rotational/orbital atherectomy with or without stent implantation. Conventional plain old balloon angioplasty included balloon angioplasty with or without stent placement and no adjunctive devices. Multivariable logistic regression clustered by operator was used to assess adjusted in-hospital outcomes. RESULTS/UNASSIGNED:Among 1 065 354 ISR admissions (1 182 599 lesions), adjunctive devices were used in 26.5% of cases, increasing from 20.8% in 2018 Q1 to 40.7% by 2024 Q2. Intravascular lithotripsy showed the most rapid adoption, reaching 16.1% of ISR cases within 4 years of US introduction. Adjunctive therapy was associated with higher odds of in-hospital mortality (odds ratio, 1.25 [95% CI, 1.19-1.31]), myocardial infarction (odds ratio, 1.30 [95% CI, 1.24-1.35]), bleeding (odds ratio, 1.29 [95% CI, 1.26-1.33]), and stroke (odds ratio, 1.11 [95% CI, 1.02-1.22]). Recurrent ISR (14.3%) was more often managed with adjunctive therapy (34.2% versus 25.0% for initial ISR) yet had lower absolute complication rates. CONCLUSIONS/UNASSIGNED:ISR remains a major contributor to percutaneous coronary intervention volume. Use of adjunctive plaque-modification devices, especially intravascular lithotripsy, has risen sharply. Adjunctive therapy was associated with higher in-hospital event rates, likely reflecting lesion complexity.