Center for Clinical Research (United States)

Fast-acting subperception therapy in spinal cord stimulation (FAST-SCS) uses low-frequency, subthreshold stimulation to engage the dorsal column-mediated surround inhibition mechanism and thereby relieve pain. Our study was performed to better characterize the multidimensional long-term clinical outcomes of FAST-SCS therapy in patients with chronic low back and/or leg pain. Our prospective, multicenter, single-arm, open-label trial, conducted at 12 pain management centers across the USA, included male and female patients with chronic low back pain with/without leg pain refractory to conservative therapy. All eligible patients received an SCS implant. Outcomes evaluated included pain relief, disability, mobility, health-related quality of life, sleep quality, depression, pain catastrophizing, and global impression of change. Fifty-six patients received a permanent SCS implant and 55 were activated with FAST-SCS therapy. At 12months, 89% and 59% of patients achieved ≥ 50% and ≥ 80% pain relief, respectively (p < 0.0001), and pain intensity (verbal numerical rating scale) decreased by 4.9 ± 2.2 points (p < 0.0001). Significant improvements were observed in disability (Oswestry Disability Index - 24 ± 16 points, p < 0.0001) and endurance (6-Minute Walk Test + 73 ± 96m, p < 0.0001), while mobility and balance improved without reaching statistical significance (Timed Up-and-Go test - 7.5 ± 37.5s, p = 0.17). All psychosocial measures improved significantly at 12months compared to baseline, with an increase in the EQ5D-5L index (+ 0.200 ± 0.182, p < 0.0001) and decreases in the Pittsburgh Sleep Quality index (- 3.96 ± 4.31, p < 0.0001), Pain Catastrophizing Score (- 13.3 ± 11.4, p < 0.0001), and Beck Depression Index (- 7.9 ± 10.0, p < 0.0001). At 12months, 87% of patients reported being "much" or "very much" improved. Responses to FAST-SCS were at or above the minimal clinically important differences across all measured clinical dimensions. This prospective study demonstrated that FAST-SCS provided statistically significant, multidimensional benefits across pain, disability, mobility, and psychosocial outcomes over 12months in patients with chronic low back and/or leg pain. These findings support the use of FAST-SCS in this patient population. ClinicalTrials.gov (NCT04618471). https://www. gov/study/NCT04618471 .

Background:Away rotations are considered integral to the plastic surgery application process; however, they can be financially burdensome. Programs have instituted awards to offset rotation costs for individuals with socioeconomic barriers in part to increase diversity in plastic surgery. However, the effectiveness of these awards is unknown. The study investigated the rank order of applicants who received awards to fund away rotations.Methods:A survey was administered to 40 plastic surgery programs that reportedly offer awards for diverse applicants. The survey confirmed whether the program offered awards for away rotators in the 2023–2024 match cycle. Those programs were asked about their institution demographics, away rotations, interview process, and rank process. Each program was asked to categorize their top 10 ranked applicants as home students, award recipients, nonaward rotators, or nonrotators. Programs were also asked to categorize any applicants they did not rank.Results:Seventeen programs responded, and only 10 reported having award programs. The programs had similar processes for applicant selection, rotation structure, and student evaluation. Most programs did not interview all rotators, and it was common to rank fewer candidates than were interviewed. Two award recipients were ranked in the top 10, whereas 3 were not ranked. No award recipients were ranked to match.Conclusions:Our preliminary study demonstrated a need for a central repository of information about away rotation scholarships. The data indicate that there was no significant difference in rank order between applicant categories; however, awardees were not ranked to match at any institution.

ABSTRACT Cardiac hypertrophy, a response to pathological stimuli, eventually progresses to heart failure (HF). AJUBA is a multifunctional protein expressed in various human tissues, serving as a critical modulator of cellular processes and signalling pathways involved in cardiac hypertrophy and remodelling. It plays significant roles in cellular signalling, gene transcription, and cytoskeletal organisation, modulating cardiac growth, inflammation, and cell survival. However, the precise function of AJUBA in cardiac hypertrophy remains unclear. In the present study, we examined its function as a novel regulator of HF and pathological cardiac hypertrophy. AJUBA expression was significantly decreased in patients with HF and in mouse models subjected to pressure overload. Using AJUBA knockout mice, we found that compromised echocardiographic function and increased heart weight‐to‐body weight ratios are signs of worsened cardiac hypertrophy and dysfunction due to AJUBA deficiency. Mechanistic studies revealed that AJUBA acts as a co‐activator of C/EBPβ, enhancing the transcription of NEDD4, which promotes the ubiquitin‐mediated degradation of DVL2. This prevents the activation of the Ca 2+ /calmodulin‐dependent protein kinase II/histone deacetylase 4 signalling pathway, which is essential for heart hypertrophy. Furthermore, during in vitro experiments, AJUBA overexpression reduced hypertrophic responses in cardiomyocytes, whereas AJUBA silencing intensified these changes. Therefore, these findings underscore the protective role of AJUBA in maintaining cardiac homeostasis. Targeting AJUBA or its associated pathways may offer viable therapeutic strategies for regulating HF and cardiac hypertrophy.

We performed an individual patient data analysis of COMBINE AF to assess differences in 14 clinically relevant outcomes between patients with paroxysmal (PAF) vs. non-PAF. Cox-proportional-hazards models stratified by trial and adjusted for CHA2DS2-VASc elements were constructed. Sensitivity analyses were performed across subgroups. Among 71,466 patients with AF, 16,609 (23 %) had PAF. The overall follow-up period was 157,225 patient-years (median 2.2 years). Compared with non-PAF patients, PAF patients were more likely to be women (43 % vs 35 %), have prior coronary artery disease (35 % vs 31 %), and use aspirin (41 % vs 32 %), but were less likely to be Asian (12 % vs 15 %) or have CHA₂DS₂-VASc ≥4 (59 % vs 60 %) (all p<0.01). In adjusted analyses, PAF was associated with a lower risk of stroke/systemic embolic event (HR, 0.81; 95 % CI, 0.73-0.90; p<0.001) and all-cause death (HR, 0.81; 95 % CI, 0.75-0.86; p<0.001), but higher risk of major or clinically relevant non-major bleeding (HR, 1.07; 95 % CI, 1.02-1.13; p=0.005). Risk of myocardial infarction was numerically higher in PAF (HR, 1.15; 95 % CI, 1.00-1.32; p=0.057). Major bleeding risk was similar between groups (HR, 1.04; 95 % CI, 0.96-1.12; p=0.36). Findings were consistent across subgroups, trials, anticoagulant types, and sensitivity analyses. Compared to non-PAF, adjusted risks in PAF patients were lower for stroke/systemic embolic event and all-cause death, and higher for major or clinically relevant non-major bleeding and myocardial infarction.These findings highlight clinically important differences in outcomes by AF type that may have clinical applications for AF patients.

Limited bone support in suprabony defects hinders predictable regeneration, but adjunctive biologics can improve results. This systematic review and meta-analysis aimed to evaluate the clinical efficacy of adjunctive biologics combined with open flap debridement (OFD) compared with OFD alone when treating suprabony defects. A systematic literature search was performed to identify controlled trials evaluating adult patients presenting horizontal periodontal defects. The primary outcome included residual probing depth (PD). Random-effects meta-analyses were performed; heterogeneity was assessed using I 2 statistics; risk of bias was evaluated using Cochrane RoB-2; and evidence of quality was appraised via the GRADE framework. Nine studies comprising 303 patients were included. Adjunctive use of biologics-including enamel matrix derivative (EMD), platelet-rich fibrin (PRF) and hyaluronic acid (HA)-significantly enhanced clinical outcomes compared to OFD alone, with pooled mean differences favouring EMD and PRF for both residual PD (-0.89 and -0.42 mm) and clinical attachment level (CAL) (-1.32 and -0.69 mm). While subgroup differences were observed, notably with EMD, high heterogeneity was present for CAL and PD, and evidence of certainty ranged from low to very low. Adjunctive biologics improve clinical outcomes in suprabony periodontal defects; however, rigorous standardised trials are needed for reaching firm conclusions.

Plastics are used broadly for various applications, and their degradation and fragmentation have led to widespread accumulation of nanoplastics in the environment. Although nanoplastics are ubiquitous and intractable in the environment and in organisms, their potential health impacts remain unclear. Emerging evidence showed that nanoplastics can cross the blood-brain barrier and accumulate in the brain. However, the effects of nanoplastics on neuronal health and functions in the brain are poorly understood. Here, we examined the effects of nanoplastic exposure on neurotransmitter release by measuring FM 4-64 (a lipophilic styryl dye) release from synaptic vesicles during electrical stimulation after exposing rat hippocampal neurons to 1-10 μg/mL of fluorescent polystyrene nanoplastics with an average diameter of 42 nm. We found that nanoplastics accumulated in the presynaptic terminal of hippocampal neurons and reduced stimulation-induced FM 4-64 release in a dose-dependent manner. Furthermore, nanoplastics decreased Ca2+ elevation in the presynaptic terminal of hippocampal neurons during electrical stimulation. Our results suggest that accumulated nanoplastics in the brain can impair neuronal functions by disrupting neurotransmitter release and Ca2+ dynamics in the presynaptic terminal of neurons, which could eventually lead to neurodegeneration.

Both diabetes mellitus (DM) and chronic kidney disease (CKD) predispose to cardiac remodeling and coronary microvascular dysfunction, which is proposed to be mediated through increased oxidative stress. To link oxidative stress and cardiac remodeling in DM and CKD, CKD was induced in genetically modified DM swine (INSC94Y transgenic) at 10–12 weeks of age via renal microembolization, while non-embolized DM and wild-type (WT) swine served as controls. Compared to WT, 1) DM animals displayed modest LV dilation and a slight decline in ejection fraction, with increased end-systolic pressures and coronary blood flow. Addition of CKD did not further aggravate these alterations, but increased the pressure and diastolic wall stress compared to WT. 2) Proteomic analysis revealed enrichment in metabolic pathways involving fatty acids and glutamate, thus highlighting substantial metabolic reprogramming in both DM and DM_CKD groups. Re-analysis of proteomic data from human HFpEF patients showed differential regulation of similar pathways as well as anti-oxidant enzymes. 3) Isolated mitochondrial respiration was reduced in DM and DM_CKD hearts across multiple substrates (fatty acids, pyruvate-malate, glutamate-malate, and succinate), implicating broad mitochondrial dysfunction. 4) DM_CKD animals showed heightened oxidative stress in both coronary vasculature and myocardium as compared to both WT and DM [13 ± 3 (WT), 14 ± 3 (DM) and 39 ± 10% positive nuclei (DM_CKD)]. 5) LV-interstitial fibrosis was increased in DM_CKD (3.72 ± 0.50%) vs WT (1.70 ± 0.29%), with DM having an intermediate phenotype (2.82 ± 0.37%). Thus, even mild CKD in the presence of DM is accompanied by oxidative stress and ECM deposition. Our findings highlight the critical role of CKD in accelerating cardiac pathology and underscore the importance of targeting the cardiorenal axis in future therapeutic strategies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00395-025-01153-6.