Analysis of muscle synergies and muscle network in sling exercise rehabilitation technique.

The study assessed motor control strategies across the four sling exercises of supine sling exercise (SSE), prone sling exercise (PSE), left side-lying sling exercise (LLSE), and right side-lying sling exercise (RLSE) positions base on the muscle synergies and muscle network analyses. Muscle activities of bilateral transversus abdominis (TA), rectus abdominis, multifidus (MF), and erector spinae (ES) were captured via surface electromyography. Muscle synergies were extracted through principal components analysis (PCA) and non-negative matrix factorization (NNMF). Muscle synergies number, muscle synergies complexity, muscle synergies sparseness, muscle synergies clusters and muscle networks were calculated. PCA results indicated that SSE and PSE decomposed into 2.88 ± 0.20 and 2.82 ± 0.15 synergies respectively, while the LLSE and RLSE positions decomposed into 3.76 ± 0.14 and 3.71 ± 0.11 muscle synergies, respectively, which were more complex (P = 0.00) but less sparse (P = 0.01). Muscle synergies clusters analysis indicated common muscle synergies among different sling exercises. SSE position demonstrated specific muscle synergies with a strong contribution of the bilateral TA. LLSE-specific synergy has a strong contribution of the left erector spinae (ES). The RLSE-specific synergy has significant contributions from the right ES and multifidus. Muscle networks were functionally organized, with clustering coefficient (F(1.5, 24) = 6.041, P = 0.01) and global efficiency of the undirected network (F(1.5, 24) = 6.041, P = 0.01), and betweenness-centrality of the directed network (F(2.7, 44) = 6.453, P = 0.00). Our research highlights the importance of evaluating muscle synergies and network adaptation strategies in individuals with neuromuscular disorders and developing targeted therapeutic interventions accordingly.

Safety and Efficacy Comparison of Tenecteplase and Alteplase for Clinically Suspected Large Vessel Occlusion Strokes without Thrombectomy.

INTRODUCTION: Tenecteplase is a thrombolytic with higher fibrin affinity and is potentially better in clot lysis. A higher spontaneous recanalisation rate for large vessel occlusion (LVO) strokes had been shown in comparison studies with alteplase. Results of the LVO studies reflect the composite effect of the thrombolytic and thrombectomy, as patients would be treated by thrombectomy had they not been recanalised by intravenous thrombolysis alone. Thrombectomy is not readily available in many parts of the world. Our study aimed to compare the outcomes of suspected LVO patients treated with tenecteplase versus alteplase only, without the confounding effect of thrombectomy. METHODS: This is a retrospective review. Data of patients given tenecteplase from May 2020 to August 2023 and those given alteplase 0.9 mg/kg from January 2019 to August 2023 were retrieved. Due to fluctuation in supply of tenecteplase during the COVID pandemic, some LVO patients were given alteplase. Patients with anterior circulation, clinically suspected LVO strokes (defined as National Institutes of Health Stroke Scale (NIHSS) score ≥6, plus cortical signs or hyperdense vessel sign), with thrombolysis given within 4.5 h of stroke onset were analysed. Patients with thrombectomy done were excluded. Safety and efficacy outcomes were compared. RESULTS: There were 245 tenecteplase-treated patients treated between May 1, 2020, and August 31, 2023, and 732 patients were treated with alteplase between January 1, 2019, to August 31, 2023. Out of these, 148 tenecteplase patients and 138 alteplase 0.9 mg/kg patients fulfilled the study criteria. The symptomatic intracerebral haemorrhage rate was non-significantly lower in the tenecteplase group (2.1% vs. 5.8%, p = 0.13). There were no significant differences in the rate of ≥8-point NIHSS improvement (23.6% vs. 23.7%, p = 1) or the ≥4-point improvement (40.5% vs. 40.7%, p = 1) at 24 h. At 3 months, 21.6% of tenecteplase patients had good functional outcome (modified Rankin scale [mRS] 0-2), compared to 26.3% in the alteplase group (p = 0.40). CONCLUSION: In this pragmatic study of clinically suspected anterior circulation LVO patients without thrombectomy, outcome solely reflects the effects of tenecteplase. Tenecteplase showed comparable safety and efficacy to alteplase, but the result should be interpreted with caution in view of its small sample size and non-randomised study design.

Associations between brain structures, cognition and dual-task performance in patients with mild cognitive impairment: A study based on voxel-based morphology.

BACKGROUND: This study aimed to explore the associations between brain structures, cognition, and motor control in participants with mild cognitive impairment (MCI), with a focus on dual-task performance. METHODS: Thirty MCI patients and thirty healthy controls were enrolled. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Structural magnetic resonance imaging data were analyzed using voxel-based morphometry (VBM) to calculate brain parenchyma volume and gray matter volume (GMV). Participants performed single- and dual-task Timed Up and Go (TUG) tests, and the correlations between significant GMV differences and task execution time was analyzed. RESULTS: MCI patients showed significantly lower MoCA scores, particularly in visuospatial/executive, attention, and delayed recall domains (p < 0.05). Dual-task TUG execution time was significantly increased in MCI patients (p < 0.05). The GMV in the right anterior lobe of the cerebellum and both insulae was positively correlated with visuospatial/executive scores (FDR-corrected, p < 0.05). The GMV of the right cerebellar anterior lobe and insula were significantly reduced in MCI patients (p < 0.05). The GMV of the right cerebellar anterior lobe was negatively correlated with dual-task execution time (r = -0.32, p = 0.012). CONCLUSION: Smaller GMV in the right anterior lobe of the cerebellum was associated with impaired dual-task performance, which may provide more evidence for the neural mechanisms of cognitive and motor function impairments in MCI.

Causal link between metabolic related factors and osteoarthritis: a Mendelian randomization investigation.

Introduction: Metabolic syndrome (MetS) is significantly associated with osteoarthritis (OA), especially in MetS patients with blood glucose abnormalities, such as elevated fasting blood glucose (FG), which may increase OA risk. Dietary modifications, especially the intake of polyunsaturated fatty acids (PUFAs), are regarded as a potential means of preventing MetS and its complications. However, regarding the effects of FG, Omega-3s, and Omega-6s on OA, the research conclusions are conflicting, which is attributed to the complexity of the pathogenesis of OA. Therefore, it is imperative to thoroughly evaluate multiple factors to fully understand their role in OA, which needs further exploration and clarification. Methods: Two-sample univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were employed to examine the causal effect of metabolic related factors on hip OA (HOA) or knee OA (KOA). The exposure and outcome datasets were obtained from Open GWAS IEU. All cases were independent European ancestry data. Three MR methods were performed to estimate the causal effect: inverse-variance weighting (IVW), weighted median method (WMM), and MR-Egger regression. Additionally, the intercept analysis in MR-Egger regression is used to estimate pleiotropy, and the IVW method and MR-Egger regression are used to test the heterogeneity. Results: The UVMR analysis revealed a causal relationship between FG and HOA. By MVMR analysis, the study discovered a significant link between FG (OR = 0.79, 95%CI: 0.64∼0.99, p = 0.036) and KOA after accounting for body mass index (BMI), age, and sex hormone-binding globulin (SHBG). However, no causal effects of FG on HOA were seen. Omega-3s and Omega-6s did not have a causal influence on HOA or KOA. No significant evidence of pleiotropy was identified. Discussion: The MR investigation showed a protective effect of FG on KOA development but no causal relationship between FG and HOA. No causal effect of Omega-3s and Omega-6s on HOA and KOA was observed. Shared genetic overlaps might also exist between BMI and age, SHBG and PUFAs for OA development. This finding offers a novel insight into the treatment and prevention of KOA from glucose metabolism perspective. The FG cutoff value should be explored in the future, and consideration should be given to demonstrating the study in populations other than Europeans.

e3SIM: epidemiological-ecological-evolutionary simulation framework for genomic epidemiology.

Infectious disease dynamics are driven by the complex interplay of epidemiological, ecological, and evolutionary processes. Accurately modeling these interactions is crucial for understanding pathogen spread and informing public health strategies. However, existing simulators often fail to capture the dynamic interplay between these processes, resulting in oversimplified models that do not fully reflect real-world complexities in which the pathogen's genetic evolution dynamically influences disease transmission. We introduce the epidemiological-ecological-evolutionary simulator (e3SIM), an open-source framework that concurrently models the transmission dynamics and molecular evolution of pathogens within a host population while integrating environmental factors. Using an agent-based, discrete-generation, forward-in-time approach, e3SIM incorporates compartmental models, host-population contact networks, and quantitative-trait models for pathogens. This integration allows for realistic simulations of disease spread and pathogen evolution. Key features include a modular and scalable design, flexibility in modeling various epidemiological and population-genetic complexities, incorporation of time-varying environmental factors, and a user-friendly graphical interface. We demonstrate e3SIM's capabilities through simulations of realistic outbreak scenarios with SARS-CoV-2 and Mycobacterium tuberculosis, illustrating its flexibility for studying the genomic epidemiology of diverse pathogen types.

The Impact of Gastroesophageal Reflux Disease and Proton Pump Inhibitor Use on the Risk of Repeat Catheter Ablation for Atrial Fibrillation.

INTRODUCTION: Gastroesophageal reflux disease (GERD) has been associated with increased incidence/recurrence of atrial fibrillation (AF). However, the impact of GERD and proton pump inhibitor (PPI) therapy on outcomes of AF catheter ablation remains unclear. We aimed to assess the association between the presence of GERD and risk of repeat AF ablation, stratified by PPI therapy. METHODS: A retrospective cohort study was conducted on patients with paroxysmal/persistent AF undergoing initial ablation in January 2011-September 2015. GERD was defined by endoscopic findings, objective reflux testing, or clinical symptoms. The association between GERD/PPI use and time to repeat ablation was evaluated by time-to-event analysis with censoring at the last clinic follow-up within 1 year. RESULTS: Three hundred eighty-one subjects were included. Patients with GERD (n = 80) had a higher 1-year repeat ablation rate compared with those with no GERD (25% vs 11.3%, P = 0.0034). Stratifying by PPI use, patients with untreated GERD (37.5%) more likely needed repeat ablation compared with reflux-free (11.3%, P = 0.0003) and treated GERD (16.7%, P = 0.035) subjects. On multivariable Cox regression analyses, GERD was an independent risk factor of repeat ablation (hazard ratio [HR] 3.30, confidence interval [CI] 1.79-6.08, P = 0.0001). Specifically, untreated GERD was associated with earlier repeat ablation compared with no GERD (HR 4.02, CI 1.62-12.05, P = 0.0013). However, no significant difference in repeat ablation risk was noted between reflux-free and PPI-treated GERD groups. DISCUSSION: GERD was an independent predictor for risk of repeat AF ablation within 1 year, even after controlling for major cardiovascular comorbidities and confounders. PPI therapy modulated this risk, as repeat ablation-free survival for PPI-treated GERD was noninferior to reflux-free patients.

PV Panel Model Parameter Estimation by Using Particle Swarm Optimization and Artificial Neural Network.

Photovoltaic (PV) panels are one of the popular green energy resources and PV panel parameter estimations are one of the popular research topics in PV panel technology. The PV panel parameters could be used for PV panel health monitoring and fault diagnosis. Recently, a PV panel parameters estimation method based in neural network and numerical current predictor methods has been developed. However, in order to further improve the estimation accuracies, a new approach of PV panel parameter estimation is proposed in this paper. The output current and voltage dynamic responses of a PV panel are measured, and the time series of the I-V vectors will be used as input to an artificial neural network (ANN)-based PV model parameter range classifier (MPRC). The MPRC is trained using an I-V dataset with large variations in PV model parameters. The results of MPRC are used to preset the initial particles' population for a particle swarm optimization (PSO) algorithm. The PSO algorithm is used to estimate the PV panel parameters and the results could be used for PV panel health monitoring and the derivation of maximum power point tracking (MMPT). Simulations results based on an experimental I-V dataset and an I-V dataset generated by simulation show that the proposed algorithms can achieve up to 3.5% accuracy and the speed of convergence was significantly improved as compared to a purely PSO approach.

Adopt-A-Classroom Program: A Potential Platform to Address the Root of Health Disparities in the US.

The underrepresentation of Black doctors is a significant issue in the US that led to the perpetuation of health disparities in the African American community. Racial and ethnic minorities in the US have been shown to have higher rates of chronic diseases, such as hypertension, diabetes, and cardiovascular disease, as well as higher rates of obesity and premature death compared to White people. While Blacks make up more than 13% of the US population, they comprise only 4% of US doctors and less than 7% of medical students. It is believed that this problem requires more deliberate efforts by policymakers and the educational establishment, not only at the undergraduate and medical school level, but earlier in the educational "pipeline"-the K-12 school system. While the medical field is rooted in Science, Technology, Engineering, and Mathematics (STEM), we have launched a new initiative that will provide year-round STEM development activities for K-12 education in Connecticut in Hartford and Waterbury districts, especially among populations with health disparities.

Facile Peptide Macrocyclization and Multifunctionalization via Cyclen Installation.

Cyclen-peptide bioconjugates are usually prepared in multiple steps that require individual preparation and purification of the cyclic peptide and hydrophilic cyclen derivatives. An efficient strategy is discovered for peptide cyclization and functionalization toward lanthanide probe via three components intermolecular crosslinking on solid-phase peptide synthesis with high conversion yield. Multifunctionality can be conferred by introducing different modular parts or/and metal ions on the cyclen-embedded cyclopeptide. As a proof-of-concept, a luminescent Eu3+ complex and a Gd3+-based contrasting agent for in vitro optical imaging and in vivo magnetic resonance imaging, respectively, are demonstrated through utilizing this preparation of cyclen-embedded cyclic arginylglycylaspartic acid (RGD) peptide.

The associations between lumbar proprioception and postural control during and after calf vibration in people with and without chronic low back pain.

The relationships of lumbar proprioception with postural control have not been clarified in people with chronic low back pain. This study aimed to compare the associations between lumbar proprioception and postural control in response to calf vibration in individuals with and without chronic low back pain. In this study, we recruited twenty patients with chronic low back pain (CLBP group) and twenty healthy control subjects (HC group) aged between 18 and 50 years. This study was a cross-sectional study and completed from May 2022 to October 2022. The passive joint repositioning sense (PJRS) test for two positions (15° and 35°) were used to assess lumbar proprioception and expressed as the mean of reposition error (RE). Postural control was tested by adding and removing calf vibration while standing on a stable force plate with eyes closed. The sway velocity in the anterior-posterior (AP) direction of center of pressure (COP) data with a window of 15s epoch at baseline, during and after calf vibration was used to evaluate postural control. Mann-Whitney U-tests were used to compare the difference of lumbar proprioception between two groups, and the independent t-tests were used to compare the difference of postural control at baseline and during vibration, and a mixed design ANOVA was used to compare the difference of postural control during post-perturbation. In addition, to explore the association between postural control and lumbar proprioception and pain intensity, Spearman's correlations were used for each group. The major results are: (1) significantly higher PJRS on RE of 15° (CLBP: 95% CI [2.03, 3.70]; HC: 95% CI [1.03, 1.93]) and PJRS on RE of 35° (CLBP: 95% CI [2.59, 4.88]; HC: 95% CI [1.07, 3.00]) were found in the CLBP group; (2) AP velocity was not different between the CLBP group and the HC group at baseline and during calf vibration. However, AP velocity was significantly larger in the CLBP group compared with the HC group at epoch 2-14 after calf vibration, and AP velocity for the CLBP group took a longer time (23 epochs) to return to the baseline after calf vibration compared with the HC group (9 epochs); (3) lumbar proprioception represented by PJRS on RE of 15°correlated negatively with AP velocity during and after vibration for the HC group. Within the CLBP group, no significant relationships between PJRS on RE for two positions (15° and 35°) and AP velocity in any postural phases were found. In conclusion, the CLBP group has poorer lumbar proprioception, slower proprioceptive reweighting and impaired postural control after calf vibration compared to the HC group. Lumbar proprioception offers different information on the control strategy of standing control for individuals with and without CLBP in the situations with proprioceptive disturbance. These results highlight the significance of assessing lumbar proprioception and postural control in CLBP patients.

Concurrent abnormal non-acid reflux is associated with additional chronic rejection risk in lung transplant patients with increased acid exposure.

Acid reflux has been associated with allograft injury and rejection in lung transplant patients; however, the pathogenic role of non-acid reflux remains debated. We aimed to evaluate the impact of concurrent abnormal non-acid reflux with acid reflux on chronic rejection in lung transplant patients with acid reflux. This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant combined impedance-pH study off acid suppression. Only subjects with acid exposure >4% were included. Non-acid reflux (pH > 4) episodes >27 was considered abnormal per prior normative studies. Chronic rejection was defined as chronic lung allograft dysfunction (CLAD) per International Society for Heart and Lung Transplantation criteria. Time-to-event analyses were performed using Cox proportional hazards and Kaplan-Maier methods, with censoring at death, anti-reflux surgery, or last follow-up. In total, 68 subjects (28 abnormal/40 normal non-acid reflux) met inclusion criteria for the study. Baseline demographic/clinical characteristics were similar between groups. Among this cohort of patients with increased acid exposure, subjects with concurrent abnormal non-acid reflux had significantly higher risk of CLAD than those without on Kaplan-Meier analysis (log-ranked P = 0.0269). On Cox multivariable regression analysis controlling for body mass index, age at transplantation, and proton pump inhibitor use, concurrent abnormal non-acid reflux remained independently predictive of increased CLAD risk (hazard ratio 2.31, confidence interval: 1.03-5.19, P = 0.04). Presence of concurrent abnormal non-acid reflux in lung transplant subjects with increased acid exposure is associated with additional risk of chronic rejection. Non-acid reflux may also contribute to pathogenicity in lung allograft injury/rejection, supporting a potential role for impedance-based testing in this population.

Investigating the nexus of metabolic syndrome, serum uric acid, and dementia risk: a prospective cohort study.

BACKGROUND: The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk. METHODS: Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors. RESULTS: Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19-1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51-2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 µmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02-1.21; VD: HR = 1.50, 95% CI = 1.28-1.77). CONCLUSIONS: Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies.

Twice-Daily Proton Pump Inhibitor Induces Higher Remission Rate in Eosinophilic Esophagitis Than Once-Daily Regimen Regardless of Total Daily Dose.

INTRODUCTION: The optimal proton pump inhibitor (PPI) regimen for eosinophilic esophagitis (EoE) is unclear. We compared histologic response rates of different dosing combinations. METHODS: A total of 305 patients with newly diagnosed EoE received standard (omeprazole 20 mg daily), once-daily moderate (40 mg daily), twice-daily moderate (20 mg twice daily), or high (40 mg twice daily) dose PPI for ≥8 weeks. RESULTS: Approximately 42.3% achieved histologic response to PPI, with higher rates for twice-daily (moderate 52.8%/high 54.3%) than once-daily (standard 11.8%/moderate 10%) dosing ( P < 0.0001). On multivariable analysis, twice-daily moderate (adjusted odds ratio 6.75, confidence interval 2.53-18.0, P = 0.0008) and high (adjusted odds ratio 12.8, confidence interval 4.69-34.8, P < 0.0001) doses independently predicted histologic response. DISCUSSION: Twice-daily PPI is associated with higher EoE histologic response rates than once-daily regimen.

Forced capillary wetting of viscoelastic fluids.

HYPOTHESIS: Achieving rapid capillary wetting is highly desirable in nature and industries. Previous endeavors have primarily concentrated on passive wetting strategies through surface engineering. However, these approaches are inadequate for high-viscosity fluids due to the significant viscous resistance, especially for non-Newtonian fluids. In contrast, forced wetting emerges as a promising method to address the challenges associated with achieving rapid wetting of non-Newtonian fluids in capillaries. EXPERIMENTS: To investigate the forced wetting behavior of viscoelastic fluids in capillaries, we employ Xanthan Gum (XG) aqueous solutions as target fluids with the storage modulus significantly exceeding the loss modulus. We utilize smooth glass capillaries connected to a syringe pump to achieve high moving speeds of up to 1 m/s. FINDINGS: Our experiments reveal a significant distinction in the power-law exponent that governs the scaling relationship between the dynamic contact angle and velocity for viscoelastic fluids compared to Newtonian fluids. This exponent is considerably smaller and varies based on the concentration of viscoelastic fluids and the diameter of the capillaries. We suggest that the viscosity dominates the wetting dynamics of viscoelastic fluids, manifested by the contact line morphology-dependent behavior. This insight has significant implications for microfluidics and drug injectability.

Heartburn Relief Is the Major Unmet Need for Drug Development in Gastroesophageal Reflux Disease: Threshold Value Analysis.

BACKGROUND AND AIMS: Heartburn symptoms contribute to healthcare-seeking among patients with gastroesophageal reflux disease (GERD). Despite clinical guidance, management is often dictated by insurance restrictions. Several potassium-competitive acid blockers (PCABs) are under development as a new class of therapy. We performed economic analyses to align GERD drug development with the needs of gastroenterologists, insurers and patients in a value-based environment. METHODS: A decision-analytic model was constructed to compare vonoprazan 20 mg daily (an example of a PCAB), common over-the-counter or prescription proton pump inhibitor regimens, and no treatment over a 1-year time horizon. Clinical responses were evaluated based on the proportions of heartburn-free days in a recent phase 3 multicenter trial. Healthcare utilization for persistent reflux symptoms was derived from national observational studies compared with healthy control subjects. Costs and quality-adjusted life years were reported. RESULTS: Without insurance coverage for appropriate therapy, patients spend $4443 and insurers spend $3784 on average per year for inadequately treated GERD symptoms. Our model estimates that PCABs could save at least $3000 in annual costs to patients and insurers, could generate quality-adjusted life year gains (+0.06 per year), and could be cost-saving to insurers as a covered option at a price up to $8.57 per pill, if these drugs are able to demonstrate similar effectiveness to proton pump inhibitors in future trials evaluating heartburn relief and erosive esophagitis healing to regulators. Threshold prices reflect pricing after all pharmacy benefits manager rebates and discounts. DISCUSSION: We demonstrate that aiming GERD-related drug development toward heartburn relief appears critical to align cost-effective incentives for industry and insurers with those of patients and gastroenterologists.

Catalytic Enantioselective Nucleophilic α-Chlorination of Ketones with NaCl.

Catalytic enantioselective α-chlorination of ketones is a highly desirable process. Different from the conventional approaches that employ corrosive electrophilic chlorination reagents, the process disclosed here employs nucleophilic chloride, aqueous NaCl solution, and even seawater, as green inexpensive chlorine sources. This mechanistically distinct and electronically opposite approach provides facile access to diverse highly enantioenriched acyclic α-chloro ketones that are less straightforward by conventional approaches. With a chiral thiourea catalyst, a range of racemic α-keto sulfonium salts underwent enantioconvergent carbon-chlorine bond formation with high efficiency and excellent enantioselectivity under mild conditions. The sulfonium motif plays a crucial triple role by permitting smooth dynamic kinetic resolution to take place via a chiral anion binding mechanism in a well-designed phase-transfer system. This protocol represents a new general platform for the asymmetric nucleophilic α-functionalization of carbonyl compounds.

Impact of Parathyroidectomy Versus Oral Cinacalcet on Bone Mineral Density in Patients on Peritoneal Dialysis With Advanced Secondary Hyperparathyroidism: The PROCEED Pilot Randomized Trial.

RATIONALE & OBJECTIVE: Parathyroidectomy and calcimimetics have been used to reduce fracture risk in patients with kidney failure and advanced secondary hyperparathyroidism (SHPT), but direct comparisons of these treatment approaches have not been implemented. This pilot study compared their effects on bone mineral density (BMD) in this patient population. STUDY DESIGN: A prospective pilot open-label randomized trial. SETTING & PARTICIPANTS: 65 patients receiving maintenance peritoneal dialysis with advanced SHPT recruited from 2 university-affiliated hospitals in Hong Kong. INTERVENTIONS: Total parathyroidectomy with forearm autografting versus oral cinacalcet treatment for 12 months. OUTCOME: Prespecified secondary end points including changes in BMD z and T scores of femoral neck, lumbar spine, and distal radius 12 months after treatment initiation and also categorized as osteopenia or osteoporosis according to the World Health Organization. RESULTS: Both total parathyroidectomy and cinacalcet significantly improved BMD of the lumbar spine and femoral neck over 12 months, but the total parathyroidectomy group had a greater increase than the cinacalcet-treated group (P<0.001). The proportion of study participants classified as having osteopenia/osteoporosis by femoral neck T-score fell from 78.2% to 51.7% in the total parathyroidectomy group (P<0.001) and from 65.7% to 52.0% in cinacalcet-treated group after 12 months (P=0.7). The proportion of participants with a T-score at the lumbar spine classified as osteopenia/osteoporosis fell from 53.1% to 31.0% in the total parathyroidectomy group (P=0.01) and from 59.4% to 53.8% with cinacalcet (P=0.3). No significant change was observed in BMD T or z score of the distal radius over 12 months with either intervention. LIMITATIONS: Bone histology was not assessed, and the study duration was 12 months. CONCLUSIONS: A large proportion of peritoneal dialysis patients with advanced SHPT had low bone densities and osteopenia/osteoporosis. Total parathyroidectomy increased the BMD of the lumbar spine and femoral neck and reduced osteopenia/osteoporosis more than oral cinacalcet. FUNDING: Grants from academic (The University of Hong Kong Research) and not-for-profit (Hong Kong Society of Nephrology) entities. REGISTRATION: Registered at Clinicaltrials.gov with study number NCT01447368. PLAIN-LANGUAGE SUMMARY: It is not known whether oral cinacalcet and surgical parathyroidectomy differ in their effects on bone parameters in patients with advanced secondary hyperparathyroidism (SHPT) receiving peritoneal dialysis. This pilot randomized trial evaluated the effect of medical versus surgical therapy on bone mineral densities (BMD) as prespecified secondary study end points. The findings showed that a large proportion of peritoneal dialysis patients with advanced SHPT had low bone densities and osteopenia/osteoporosis. Parathyroidectomy increased the BMD of the lumbar spine and femoral neck more than cinacalcet over 12 months. Parathyroidectomy reduced the proportion of patients with osteopenia/osteoporosis at the lumbar spine and femoral neck more than cinacalcet after 12 months. Neither intervention led to an increase in the BMD of the distal radius over 12 months.

Baseline Peripheral Eosinophil Count Independently Predicts Proton Pump Inhibitor Response in Eosinophilic Esophagitis.

GOALS: To assess the predictive value of baseline peripheral absolute eosinophil counts (AECs) for proton pump inhibitor (PPI) response in eosinophilic esophagitis (EoE). BACKGROUND: PPI leads to histologic remission in ~50% of EoE patients, although there are few distinguishing clinical features between PPI-responsive (PPI-r-EoE) and nonresponsive (PPI-nr-EoE) diseases. Peripheral eosinophilia is present in ~50% of EoE cases and is associated with eosinophil density on esophageal biopsy and worse clinical outcomes. The association between peripheral eosinophilia and PPI-responsiveness in EoE remains unclear. STUDY: This is a retrospective cohort study of adult EoE patients at a tertiary center between 2012 and 2016. All patients underwent twice daily PPI trials for ≥8 weeks followed by repeat esophageal biopsies and were classified as PPI-r-EoE or PPI-nr-EoE based on histologic response (<15 eosinophils/high power field). Baseline peripheral AEC was obtained within 1 month before index endoscopy. Analyses were performed using Fisher exact/Student t test (univariate) and logistic regression (multivariable). RESULTS: One hundred eighty-three patients (91 PPI-nr-EoE and 92 PPI-r-EoE) were included. Mean peripheral AEC was higher among PPI-nr-EoE patients (0.41 vs 0.24 K/µL, P = 0.013). Baseline peripheral eosinophilia (>0.5 K/µL) was more prevalent among patients with PPI-nr-EoE (70.4% vs 45.5%, P = 0.023) and a history of food impaction (51.9% vs 23.7%, P = 0.0082). On multivariable analyses, peripheral eosinophilia remained an independent predictor for PPI response (adjacent odds ratio = 2.86, CI: 1.07-7.62, P = 0.036) and food impaction (adjacent odds ratio = 2.80, CI: 1.07-7.35, P = 0.037). CONCLUSIONS: Baseline peripheral eosinophilia independently predicts PPI nonresponse and food impaction in EoE patients. Peripheral AEC may help therapy selection in EoE and prevent delays in achieving histologic remission.

Detection of Granzyme B-associated Binding Targets in Peripheral Blood Samples of Hosts in Sickness and in Health Using a Granzyme B-like Peptide Fluorescent Conjugate (GP1R).

Granzyme B, mostly expressed by cytotoxic T lymphocytes in the fight against cancer and infection, is known to induce cell death based on its active enzymatic activity as a serine protease. Recent studies showed cytotoxicity of a non-enzymatic granzyme B-like peptide (also referred to as granzyme B-associated peptide or GP1 in this report) in tumor cells and presence of binding targets for GP1R (i.e., GP1 conjugated with rhodamine fluorochrome) in tumor cells, bacteria, and circulating platelets/neutrophils of healthy hosts. But there were no data on "sick" hosts to help substantiate any potential GP1 based medical applications. Thus, we adopted similar GP1R binding protocols to further study binding of GP1 in different biological samples (including different blood samples of hosts in sickness and in health, cancer cell lines, and trigeminal ganglia culture of infected hosts treated with and without GP1) and determine if any binding patterns might have any associations with different health conditions. The overall preliminary results appear to show certain GP1R + binding patterns in certain blood components (especially neutrophils) have potential correlations with certain health conditions of hosts at sampling times, indicating potential GP1R applications for diagnostic purposes. Findings of different GP1R binding patterns in different cancer cell lines, whole blood samples and trigeminal ganglia culture of experimental mice infected with HSV-1 virus (might cause neuropathy) within a week post-infection, and blood samples of GP1-treated mouse survivors on day 21 post-infection provided preliminary evidence of potential GP1-led tumor cell-specific cell death and treatment efficacy for greater survival.