Workspace and dexterity analysis of the hybrid mechanism master robot in Sinaflex robotic telesurgery system: An in vivo experiment.

Sinaflex robotic telesurgery system has been introduced recently to provide ergonomic postures for the surgeon along with dexterous workspace for robotic telesurgery. The robot is described, and the forward and inverse kinematics are derived and validated by an experiment. The robot and operational workspaces and their dexterity are investigated and compared using the data collected during a dog vasectomy robotic telesurgery by Sinaflex. According to the simulation results, the workspace of the end effector is as large as 914.56 × 105 mm3, which can completely cover the ergonomic human hand workspace. The dexterity of the robot for the total and operational workspace is 0.4557 and 0.6565, respectively. In terms of the workspace size and the amount of dexterity, Sinaflex master robot can be considered a good choice to fulfil the requirements of the surgeon side robot in robotic telesurgery systems.

Arc-to-line frame registration method for ultrasound and photoacoustic image-guided intraoperative robot-assisted laparoscopic prostatectomy.

PURPOSE: To achieve effective robot-assisted laparoscopic prostatectomy, the integration of transrectal ultrasound (TRUS) imaging system which is the most widely used imaging modality in prostate imaging is essential. However, manual manipulation of the ultrasound transducer during the procedure will significantly interfere with the surgery. Therefore, we propose an image co-registration algorithm based on a photoacoustic marker (PM) method, where the ultrasound/photoacoustic (US/PA) images can be registered to the endoscopic camera images to ultimately enable the TRUS transducer to automatically track the surgical instrument. METHODS: An optimization-based algorithm is proposed to co-register the images from the two different imaging modalities. The principle of light propagation and an uncertainty in PM detection were assumed in this algorithm to improve the stability and accuracy of the algorithm. The algorithm is validated using the previously developed US/PA image-guided system with a da Vinci surgical robot. RESULTS: The target-registration-error (TRE) is measured to evaluate the proposed algorithm. In both simulation and experimental demonstration, the proposed algorithm achieved a sub-centimeter accuracy which is acceptable in practical clinics (i.e., 1.15 ± 0.29 mm from the experimental evaluation). The result is also comparable with our previous approach (i.e., 1.05 ± 0.37 mm), and the proposed method can be implemented with a normal white light stereo camera and does not require highly accurate localization of the PM. CONCLUSION: The proposed frame registration algorithm enabled a simple yet efficient integration of commercial US/PA imaging system into laparoscopic surgical setting by leveraging the characteristic properties of acoustic wave propagation and laser excitation, contributing to automated US/PA image-guided surgical intervention applications.

Automatic search for photoacoustic marker using automated transrectal ultrasound.

Real-time transrectal ultrasound (TRUS) image guidance during robot-assisted laparoscopic radical prostatectomy has the potential to enhance surgery outcomes. Whether conventional or photoacoustic TRUS is used, the robotic system and the TRUS must be registered to each other. Accurate registration can be performed using photoacoustic (PA markers). However, this requires a manual search by an assistant [IEEE Robot. Autom. Lett8, 1287 (2023).10.1109/LRA.2022.3191788]. This paper introduces the first automatic search for PA markers using a transrectal ultrasound robot. This effectively reduces the challenges associated with the da Vinci-TRUS registration. This paper investigated the performance of three search algorithms in simulation and experiment: Weighted Average (WA), Golden Section Search (GSS), and Ternary Search (TS). For validation, a surgical prostate scenario was mimicked and various ex vivo tissues were tested. As a result, the WA algorithm can achieve 0.53°±0.30° average error after 9 data acquisitions, while the TS and GSS algorithm can achieve 0.29∘±0.31∘ and 0.48°±0.32° average errors after 28 data acquisitions.

Pathology-based radiation dose in computed tomography: investigation of the effect of lung lesions on water-equivalent diameter, CTDIVol and SSDE in COVID-19 patients.

Lung lesions can increase the CT number and affect the water-equivalent diameter (Dw), Dw-based conversion factor (CFw), and Dw-based size-specific dose estimate (SSDEw). We evaluated the effect of COVID-19 lesions and total severity score (TSS) on radiation dose considering the effect of automatic tube current modulation (ATCM) and fixed tube current (FTC). A total of 186 chest CT scans were categorised into five TSS groups, including healthy, minimal, mild, moderate and severe. The effective diameter (Deff), Dw, CFw, Deff-based conversion factor (CFeff), volume computed tomography dose index (CTDIVol), pathological dose impact factor (PDIF) 1 and SSDEw were calculated. TSS was correlated with Dw (r = 0.29, p-value = 0.001), CTDIVol (ATCM) (r = 0.23, p = 0.001) and PDIF (r = - 0.51, p-value = 0.001). $\overline{{\mathrm{SSDE}}_{\mathrm{w}}}$ (FTC) was significantly different among all groups. $\overline{{\mathrm{SSDE}}_{\mathrm{w}}}$ (ATCM) was greater for moderate (13%) and mild (14%) groups. Increasing TSS increase the Dw and causes a decrease in CFw and $\overline{{\mathrm{SSDE}}_{\mathrm{w}}}$ (FTC), and can increase $\overline{{\mathrm{SSDE}}_{\mathrm{w}}}$ (ATCM) in some Dw ranges.

Multi-Frequency 3D Shear Wave Absolute Vibro-Elastography (S-WAVE) System for the Prostate.

This article describes a novel system for quantitative and volumetric measurement of tissue elasticity in the prostate using simultaneous multi-frequency tissue excitation. Elasticity is computed by using a local frequency estimator to measure the three-dimensional local wavelengths of steady-state shear waves within the prostate gland. The shear wave is created using a mechanical voice coil shaker which transmits simultaneous multi-frequency vibrations transperineally. Radio frequency data is streamed directly from a BK Medical 8848 transrectal ultrasound transducer to an external computer where tissue displacement due to the excitation is measured using a speckle tracking algorithm. Bandpass sampling is used that eliminates the need for an ultra-fast frame rate to track the tissue motion and allows for accurate reconstruction at a sampling frequency that is below the Nyquist rate. A roll motor with computer control is used to rotate the transducer and obtain 3D data. Two commercially available phantoms were used to validate both the accuracy of the elasticity measurements as well as the functional feasibility of using the system for in vivo prostate imaging. The phantom measurements were compared with 3D Magnetic Resonance Elastography (MRE), where a high correlation of 96% was achieved. In addition, the system has been used in two separate clinical studies as a method for cancer identification. Qualitative and quantitative results of 11 patients from these clinical studies are presented here. Furthermore, an AUC of 0.87±0.12 was achieved for malignant vs. benign classification using a binary support vector machine classifier trained with data from the latest clinical study with leave one patient out cross-validation.

3-D Transducer Mounted Shear Wave Absolute Vibro-Elastography: Proof of Concept.

Quantitative tissue stiffness characterization using ultrasound (US) has been shown to improve prostate cancer (PCa) detection in multiple studies. Shear wave absolute vibro-elastography (SWAVE) allows quantitative and volumetric assessment of tissue stiffness using external multifrequency excitation. This article presents a proof of concept of a first-of-a-kind 3-D hand-operated endorectal SWAVE system designed to be used during systematic prostate biopsy. The system is developed with a clinical US machine, requiring only an external exciter that can be mounted directly to the transducer. Subsector acquisition of radio frequency (RF) data allows imaging of shear waves with a high effective frame rate (up to 250 Hz). The system was characterized using eight different quality assurance phantoms. Due to the invasive nature of prostate imaging, at this early stage of development, validation of in vivo human tissue was instead carried out by intercostally scanning the livers of n = 7 healthy volunteers. The results are compared with 3-D magnetic resonance elastography (MRE) and an existing 3-D SWAVE system with a matrix array transducer (M-SWAVE). High correlations were found with MRE (99% in phantoms, 94% in liver data) and with M-SWAVE (99% in phantoms, 98% in liver data).

Kinematic and Workspace Analysis of the Master Robot in the Sinaflex Robotic Telesurgery System.

Robotic telesurgery systems, including master and slave robots, have emerged in recent years to provide benefits for both surgeons and patients. Surgeons use the master manipulator to navigate the slave robot. The Sinaflex telesurgery system introduced recently by Sina Robotics and Medical Innovators Co., Ltd. consists of two main subsystems: master robotic surgery console and slave surgery robots. As the surgeon use the master robot's handles to control the slave surgery robots, it is important for the master robot to provide the ergonomic postures for the surgeon and also providing a large enough workspace and good manipulability for the surgeon to control it. So in this paper, workspace, manipulability and isotropy of each handle at the master robot of the Sinaflex telesurgery system are analyzed. To this end, the kinematic of the master manipulator is derived, and its Jacobian is calculated. Using the simulation environment, the workspace of the master handle is obtained and drawn. The manipulability of the robot for each points of the workspace is computed. According to the results attained from the simulation study, the most manipulability values lie between 0.1 and 0.9 where it is greater than 0.44 for more than 50% of the whole workspace points of the end effector, which is as large as 574×484×560 mm.

Histone deacetylase inhibitors regulate vitamin C transporter functional expression in intestinal epithelial cells.

Intestinal absorption of vitamin C in humans is mediated via the sodium-dependent vitamin C transporters (hSVCT1 and hSVCT2). hSVCT1 and hSVCT2 are localized at the apical and basolateral membranes, respectively, of polarized intestinal epithelia. Studies have identified low plasma levels of vitamin C and decreased expression of hSVCT1 in patients with several inflammatory conditions including inflammatory bowel disease (IBD). Investigating the underlying mechanisms responsible for regulating hSVCT1 expression are critical for understanding vitamin C homeostasis, particularly in conditions where suboptimal vitamin C levels detrimentally affect human health. Previous research has shown that hSVCT1 expression is regulated at the transcriptional level, however, little is known about epigenetic regulatory pathways that modulate hSVCT1 expression in the intestine. In this study, we found that hSVCT1 expression and function were significantly decreased in intestinal epithelial cells by the histone deacetylase inhibitors (HDACi), valproic acid (VPA), and sodium butyrate (NaB). Further, expression of transcription factor HNF1α, which is critical for SLC23A1 promoter activity, was significantly down regulated in VPA-treated cells. Chromatin immunoprecipitation (ChIP) assays showed significantly increased enrichment of tetra-acetylated histone H3 and H4 within the SLC23A1 promoter following VPA treatment. In addition, knockdown of HDAC isoforms two, and three significantly decreased hSVCT1 functional expression. Following VPA administration to mice, functional expression of SVCT1 in the jejunum was significantly decreased. Collectively, these in vitro and in vivo studies demonstrate epigenetic regulation of SVCT1 expression in intestinal epithelia partly mediated through HDAC isoforms two and three.

Impact of Circulating N-Acylethanolamine Levels with Clinical and Laboratory End Points in Hemodialysis Patients.

BACKGROUND: Patients with ESRD on maintenance hemodialysis (MHD) are particularly susceptible to dysregulation of energy metabolism, which may manifest as protein energy wasting and cachexia. In recent years, the endocannabinoid system has been shown to play an important role in energy metabolism with potential relevance in ESRD. N-acylethanolamines are a class of fatty acid amides which include the major endocannabinoid ligand, anandamide, and the endogenous peroxisome proliferator-activated receptor-α agonists, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). METHODS: Serum concentrations of OEA and PEA were measured in MHD patients and their correlations with various clinical/laboratory indices were examined. Secondarily, we evaluated the association of circulating PEA and OEA levels with 12-month all-cause mortality. RESULTS: Both serum OEA and PEA levels positively correlated with high-density lipoprotein-cholesterol levels and negatively correlated with body fat and body anthropometric measures. Serum OEA levels correlated positively with serum interleukin-6 (IL-6) (rho = 0.19; p = 0.004). Serum PEA and IL-6 showed a similar but nonsignificant trend (rho = 0.12; p = 0.07). Restricted cubic spline analyses showed that increasing serum OEA and PEA both trended toward higher mortality risk, and these associations were statistically significant for PEA (PEA ≥4.7 pmol/mL; reference: PEA <4.7 pmol/mL) after adjustments in a Cox model (hazard ratio 2.99; 95% confidence interval 1.04, 8.64). CONCLUSIONS: In MHD patients, OEA and PEA are significantly correlated with variables related to lipid metabolism and body mass. Additionally, higher serum levels of PEA are associated with mortality risk. Future studies are needed to examine the potential mechanisms responsible for these findings and their clinical implications.

Association of lactate dehydrogenase with mortality in incident hemodialysis patients.

BACKGROUND: Lactate dehydrogenase (LDH) plays a role in the glucose metabolism of the human body. Higher LDH levels have been linked to mortality in various cancer types; however, the relationship between LDH and survival in incident hemodialysis (HD) patients has not yet been examined. We hypothesized that higher LDH level is associated with higher death risk in these patients. METHODS: We examined the association of baseline and time-varying serum LDH with all-cause, cardiovascular and infection-related mortality among 109 632 adult incident HD patients receiving care from a large dialysis organization in the USA during January 2007 to December 2011. Baseline and time-varying survival models were adjusted for demographic variables and available clinical and laboratory surrogates of malnutrition-inflammation complex syndrome. RESULTS: There was a linear association between baseline serum LDH levels and all-cause, cardiovascular and infection-related mortality in both baseline and time-varying models, except for time-varying infection-related mortality. Adjustment for markers of inflammation and malnutrition attenuated the association in all models. In fully adjusted models, baseline LDH levels ≥360 U/L were associated with the highest risk of all-cause mortality (hazard ratios = 1.19, 95% confidence interval 1.14-1.25). In time-varying models, LDH >280 U/L was associated with higher death risk in all three hierarchical models for all-cause and cardiovascular mortality. CONCLUSIONS: Higher LDH level >280 U/L was incrementally associated with higher all-cause and cardiovascular mortality in incident dialysis patients, whereas LDH <240 U/L was associated with better survival. These findings suggest that the assessment of metabolic functions and monitoring for comorbidities may confer survival benefit to dialysis patients.

Modulation of serotonin signaling/metabolism by Akkermansia muciniphila and its extracellular vesicles through the gut-brain axis in mice.

Several studies have reported that the host-microbe interactions in the gut modulate the host serotonin or 5-hydroxytryptamine (5-HT) system. Here, we evaluated the effects of Akkermansia muciniphila and its extracellular vesicles (EVs) on genes pertaining to the serotonergic system in the colon and hippocampus of mice. Male C57BL/6J mice were administered viable A. muciniphila and its EVs for 4 weeks. The serotonin levels in the colon, hippocampus, and serum of mice, as well as the human colon carcinoma cells (Caco-2), were measured by ELISA assays. Also, the effects of A. muciniphila and its EVs on the expression of serotonin system genes in the colon and hippocampus were examined. A. muciniphila and its EVs may have a biological effect on the induction of serotonin levels in the colon and hippocampus of mice. Also, EVs increased the serotonin level in the Caco-2 cell line. In contrast, both treatments decreased the serotonin level in the serum. Both the bacterium and its EVs had significant effects on the mRNA expression of genes, involved in serotonin signaling/metabolism in the colon and hippocampus of mice. Moreover, A. muciniphila and its EVs affected the mRNA expression of inflammatory cytokines (Il-10 and Tnf-α) in the colon, however, there is no significant difference in inflammatory cell infiltrate in the histopathology of the colon. The presence of A. muciniphila and its EVs in the gut promotes serotonin concentration, they also affect serotonin signaling/metabolism through the gut-brain axis and may be considered in new therapeutic strategies to ameliorate serotonin-related disorders.

Associations of Systolic Blood Pressure With Incident CKD G3-G5: A Cohort Study of South Korean Adults.

RATIONALE & OBJECTIVE: Clinical practice guidelines recommend a target blood pressure (BP)<130/80 mm Hg to reduce cardiovascular risk. However, the optimal BP to prevent chronic kidney disease (CKD) is unknown. STUDY DESIGN: Population-based retrospective cohort study. SETTING & PARTICIPANTS: 10.5 million adults who participated in the National Health Insurance Service National Health Checkup Program in South Korea between 2009 and 2015 and had an estimated glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 at the beginning of follow-up. PREDICTORS: Baseline and time-updated systolic BP (SBP) as a continuous variable and categorized as<110, 110 to 119, 120 to 129, 130 to 139, or≥140 mm Hg. OUTCOME: Incident CKD GFR categories 3 to 5 (CKD G3-G5), defined as de novo development of estimated GFR<60 mL/min/1.73 m2 for at least 2 consecutive assessments confirmed at least 90 days apart. ANALYTICAL APPROACH: Cox proportional hazards regression for baseline BP and marginal structural analysis for time-updated BP. RESULTS: During 49,169,311 person-years of follow-up, incident CKD G3-G5 developed in 172,423 (1.64%) individuals with a crude event rate of 3.51 (95% CI, 3.49-3.52) per 1,000 person-years. Compared to a baseline SBP of 120 to 129 mm Hg, HRs for incident CKD G3-G5 for the<110, 110 to 119, 130 to 139, and≥140 mm Hg categories were 0.84 (95% CI, 0.82-0.85), 0.92 (95% CI, 0.91-0.94), 1.11 (95% CI, 1.09-1.12), and 1.30 (95% CI, 1.28-1.31), respectively. For time-updated SBPs, corresponding HRs were 0.57 (95% CI, 0.56-0.59), 0.79 (95% CI, 0.78-0.80), 1.58 (95% CI, 1.55-1.60), and 2.49 (95% CI, 2.45-2.53), respectively. Treated as a continuous exposure, each 10-mm Hg higher SBP was associated with 35% higher risk for incident CKD G3-G5 (95% CI, 1.35-1.36). LIMITATIONS: Use of International Classification of Diseases codes to assess comorbid condition burden; residual confounding, and potential selection bias cannot be excluded. CONCLUSIONS: In this large national cohort study, higher SBPs were associated with higher risk for incident CKD G3-G5. These findings support evaluation of SBP-lowering strategies to reduce the development of CKD.

Circulating Endocannabinoids and Mortality in Hemodialysis Patients.

BACKGROUND: Mortality in patients with end-stage renal disease (ESRD) on maintenance hemodialysis (MHD) remains exceptionally high. While traditional risk factors such as obesity are paradoxically associated with better survival, nontraditional risk factors including cachexia increase the likelihood of poor outcomes. There is accumulating evidence that the endocannabinoid (ECB) system plays a major role in energy preservation and storage, factors which can prevent the deleterious effects of cachexia. Hence, in this study, we evaluated the association of circulating ECB levels with mortality in MHD patients. METHODS: Serum concentrations of anandamide (AEA) and 2-arachidonoyl-sn-glycerol (2-AG), major ECB ligands, were measured in MHD patients. Their correlation with various clinical/laboratory indices and association with 12-month all-cause mortality were examined. RESULTS: Serum 2-AG levels positively correlated with body mass index, serum triglycerides and body anthropometric measures. Meanwhile, serum AEA levels correlated positively with serum interleukin-6, and negatively with serum very low-density lipoprotein levels. While increased serum 2-AG levels were associated with reduced risk of all-cause mortality (hazard ratio [HR] 0.52, 95% CI 0.28-0.98), there was no clear association between serum AEA levels and mortality (HR 0.91, 95% CI 0.48-1.72). CONCLUSIONS: In MHD patients, the circulating levels of ECB ligand, 2-AG, may play an important role in determining body mass and risk of mortality. These observations were unique to 2-AG as similar findings were not obtained with serum AEA. Future studies need to investigate the mechanisms responsible for these associations and examine the modulation of the ECB system as a potential target for therapy in ESRD.

The Impact of Estradiol on Neurogenesis and Cognitive Functions in Alzheimer's Disease.

Alzheimer's disease (AD) is described as cognitive and memory impairments with a sex-related epidemiological profile, affecting two times more women than men. There is emerging evidence that alternations in the hippocampal neurogenesis occur at the early stage of AD. Therapies that may effectively slow, stop, or regenerate the dying neurons in AD are being extensively investigated in the last few decades, but none has yet been found to be effective. The regulation of endogenous neurogenesis is one of the main therapeutic targets for AD. Mounting evidence indicates that the neurosteroid estradiol (17ß-estradiol) plays a supporting role in neurogenesis, neuronal activity, and synaptic plasticity of AD. This effect may provide preventive and/or therapeutic approaches for AD. In this article, we discuss the molecular mechanism of potential estradiol modulatory action on endogenous neurogenesis, synaptic plasticity, and cognitive function in AD.

Serum Endocannabinoid Levels in Patients With End-Stage Renal Disease.

CONTEXT: Previous studies have shown that the endocannabinoid system plays a major role in energy metabolism through the actions of its main mediators, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide (AEA). OBJECTIVE: We examined serum levels of major endocannabinoid mediators and their association with clinical parameters in patients with end-stage renal disease (ESRD). DESIGN AND SETTING: Serum concentrations of 2-AG and AEA were measured in patients on maintenance hemodialysis (MHD) and controls, and correlations with various clinical and laboratory indices were examined. 2-AG was also measured in age and sex-matched healthy subjects for comparison of levels in patients undergoing MHD. MAIN OUTCOME MEASURE: Serum 2-AG. RESULTS: Serum 2-AG levels were significantly elevated in patients with ESRD compared with healthy controls. Higher levels of 2-AG were found in patients on MHD compared to healthy subjects, and similar findings were seen in a second set of subjects in independent analyses. Among 96 patients on MHD, 2-AG levels correlated significantly and positively with serum triglycerides (ρ = 0.43; P < 0.0001), body mass index (ρ = 0.40; P < 0.0001), and body anthropometric measures and negatively with serum high-density lipoprotein cholesterol (ρ = -0.33; P = 0.001) following adjustment for demographic and clinical variables. CONCLUSIONS: In patients on MHD, levels of serum 2-AG, a major endocannabinoid mediator, were increased. In addition, increasing serum 2-AG levels correlated with increased serum triglycerides and markers of body mass. Future studies will need to evaluate the potential mechanisms responsible for these findings.

Toward Intra-Operative Prostate Photoacoustic Imaging: Configuration Evaluation and Implementation Using the da Vinci Research Kit.

We compare different possible scanning geometries for prostate photoacoustic tomography (PAT) while considering a realistic reconstruction scenario in which the limited view of the prostate and the directivity effect of the transducer are considered. Simulations and experiments confirm that an intra-operative configuration in which the photoacoustic signal is received by a pickup transducer from the anterior surface of the prostate provides the best approach. We propose a PAT acquisition system that includes a da Vinci system controlled by the da Vinci Research Kit, an illumination laser, and an ultrasound machine with parallel data acquisition. The robot maneuvers the pickup transducer to form a cylindrical detection surface around the prostate. The robot is programmed to acquire trajectories in which the transducer face is parallel to and oriented toward a rotational tomography axis, while the laser is fired and PAT data are collected at regular intervals. We present our initial images acquired with this novel system.

Validation of a Novel Modified Aptamer-Based Array Proteomic Platform in Patients with End-Stage Renal Disease.

End stage renal disease (ESRD) is characterized by complex metabolic abnormalities, yet the clinical relevance of specific biomarkers remains unclear. The development of multiplex diagnostic platforms is creating opportunities to develop novel diagnostic and therapeutic approaches. SOMAscan is an innovative multiplex proteomic platform which can measure >1300 proteins. In the present study, we performed SOMAscan analysis of plasma samples and validated the measurements by comparison with selected biomarkers. We compared concentrations of SOMAscan-measured prostate specific antigen (PSA) between males and females, and validated SOMAscan concentrations of fibroblast growth factor 23 (FGF23), FGF receptor 1 (FGFR1), and FGFR4 using Enzyme-Linked immunosorbent assay (ELISA). The median (25th and 75th percentile) SOMAscan PSA level in males and females was 4304.7 (1815.4 to 7259.5) and 547.8 (521.8 to 993.4) relative fluorescence units (p = 0.002), respectively, suggesting biological plausibility. Pearson correlation between SOMAscan and ELISA was high for FGF23 (R = 0.95, p < 0.001) and FGFR4 (R = 0.69, p < 0.001), indicating significant positive correlation, while a weak correlation was found for FGFR1 (R = 0.13, p = 0.16). In conclusion, there is a good to near-perfect correlation between SOMAscan and standard immunoassays for FGF23 and FGFR4, but not for FGFR1. This technology may be useful to simultaneously measure a large number of plasma proteins in ESRD, and identify clinically important prognostic markers to predict outcomes.

Obesity Paradox in Advanced Kidney Disease: From Bedside to the Bench.

While obesity is associated with a variety of complications including diabetes, hypertension, cardiovascular disease and premature death, observational studies have also found that obesity and increasing body mass index (BMI) can be linked with improved survival in certain patient populations, including those with conditions marked by protein-energy wasting and dysmetabolism that ultimately lead to cachexia. The latter observations have been reported in various clinical settings including end-stage renal disease (ESRD) and have been described as the "obesity paradox" or "reverse epidemiology", engendering controversy. While some have attributed the obesity paradox to residual confounding in an effort to "debunk" these observations, recent experimental discoveries provide biologically plausible mechanisms in which higher BMI can be linked to longevity in certain groups of patients. In addition, sophisticated epidemiologic methods that extensively adjusted for confounding have found that the obesity paradox remains robust in ESRD. Furthermore, novel hypotheses suggest that weight loss and cachexia can be linked to adverse outcomes including cardiomyopathy, arrhythmias, sudden death and poor outcomes. Therefore, the survival benefit observed in obese ESRD patients can at least partly be derived from mechanisms that protect against inefficient energy utilization, cachexia and protein-energy wasting. Given that in ESRD patients, treatment of traditional risk factors has failed to alter outcomes, detailed translational studies of the obesity paradox may help identify innovative pathways that can be targeted to improve survival. We have reviewed recent clinical evidence detailing the association of BMI with outcomes in patients with chronic kidney disease, including ESRD, and discuss potential mechanisms underlying the obesity paradox with potential for clinical applicability.

LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with cardiac hypertrophy, fibrosis, and increased risk of cardiovascular mortality. LCZ696 (sacubitril/valsartan) is a promising agent that has shown significant potential in treatment of heart failure. We hypothesized that LCZ696 is more effective than valsartan alone in the treatment of cardiovascular abnormalities associated with experimental CKD. METHODS AND RESULTS: Male Sprague-Dawley rats underwent 5/6 nephrectomy and were subsequently randomized to no treatment (CKD), 30 mg/kg valsartan (VAL), or 60 mg/kg LCZ696 (LCZ). After 8 weeks, cardiovascular parameters, including markers of inflammation, oxidative stress, mitochondrial abundance/function, hypertrophy, and fibrosis, were measured. Treatment with LCZ resulted in significant improvements in the heart-body weight ratio and serum concentrations of N-terminal pro-B-type natriuretic peptide and fibroblast growth factor 23 along with improvement of kidney function. In addition, LCZ ameliorated aortic fibrosis and cardiac hypertrophy and fibrosis, reduced markers of cardiac oxidative stress and inflammation, and improved indicators of mitochondrial mass/function. Although VAL also improved some of these indices, treatment with LCZ was more effective than VAL alone. CONCLUSIONS: CKD-associated cardiovascular abnormalities, including myocardial hypertrophy, fibrosis, inflammation, oxidative stress, and mitochondrial depletion/dysfunction, were more effectively attenuated by LCZ treatment than by VAL alone.

Focal application of low-dose-rate brachytherapy for prostate cancer: a pilot study.

PURPOSE: To evaluate the feasibility and to report the early outcomes of focal treatment of prostate cancer using low-dose-rate brachytherapy (LDR-PB). MATERIAL AND METHODS: Seventeen patients were screened with multi-parametric magnetic resonance imaging (mpMRI), 14 of whom proceeded to receive trans-perineal template mapping biopsy (TTMB). Focal LDR-PB was performed on five eligible patients using dual air kerma strength treatment plans based on planning target volumes derived from cancer locations and determined by TTMB. Patient follow-up includes prostate specific antigen (PSA) measurements, urinary and sexual function questionnaires, repeated imaging and TTMB at specific intervals post-treatment. RESULTS: Feasibility of focal LDR-PB was shown and short-term outcomes are promising. While the detection rate of tumors, a majority of which were low grade GS 3 + 3, was found to be low on mpMRI (sensitivity of 37.5%), our results suggest the potential of mpMRI in detecting the presence of higher grade (GS ≥ 3 + 4), and bilateral disease indicating its usefulness as a screening tool for focal LDR-PB. CONCLUSIONS: Low-dose-rate brachytherapy is a favorable ablation option for focal treatment of prostate cancer, requiring minimal modification to the standard (whole gland) LDR-PB treatment, and appears to have a more favorable side effect profile. Further investigation, in the form of a larger study, is needed to assess the methods used and the long-term outcomes of focal LDR-PB.