Effects of Sacubitril/Valsartan Versus Irbesartan in Patients With Chronic Kidney Disease.

BACKGROUND: Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, but its effects on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease are unknown. METHODS: The UK HARP-III trial (United Kingdom Heart and Renal Protection-III), a randomized double-blind trial, included 414 participants with an estimated glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. The primary outcome was measured GFR at 12 months using ANCOVA with adjustment for each individual's baseline measured GFR. All analyses were by intention to treat. RESULTS: In total, 207 participants were assigned to sacubitril/valsartan and 207 to irbesartan. Baseline measured GFR was 34.0 (SE, 0.8) and 34.7 (SE, 0.8) mL/min/1.73 m2, respectively. At 12 months, there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, -0.1 (0.7) mL/min/1.73 m2. Effects were similar in all prespecified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9, or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference, -9%; 95% CI, -18 to 1). However, compared with irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI, 3.4-7.4) and 2.1 (95% CI, 1.0-3.3) mm Hg and levels of troponin I and N terminal of prohormone brain natriuretic peptide (tertiary end points) by 16% (95% CI, 8-23) and 18% (95% CI, 11-25), respectively. The incidence of serious adverse events (29.5% versus 28.5%; rate ratio, 1.07; 95% CI, 0.75-1.53), nonserious adverse reactions (36.7% versus 28.0%; rate ratio, 1.35; 95% CI, 0.96-1.90), and potassium ≥5.5 mmol/L (32% versus 24%, P=0.10) was not significantly different between randomized groups. CONCLUSIONS: Over 12 months, sacubitril/valsartan has similar effects on kidney function and albuminuria to irbesartan, but it has the additional effect of lowering blood pressure and cardiac biomarkers in people with chronic kidney disease. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com . Unique identifier: ISRCTN11958993.

Declining comorbidity-adjusted mortality rates in English patients receiving maintenance renal replacement therapy.

We aimed to compare long-term mortality trends in end-stage renal disease versus general population controls after accounting for differences in age, sex and comorbidity. Cohorts of 45,000 patients starting maintenance renal replacement therapy (RRT) and 5.3 million hospital controls were identified from two large electronic hospital inpatient data sets: the Oxford Record Linkage Study (1965-1999) and all-England Hospital Episode Statistics (2000-2011). All-cause and cause-specific three-year mortality rates for both populations were calculated using Poisson regression and standardized to the age, sex, and comorbidity structure of an average 1970-2008 RRT population. The median age at initiation of RRT in 1970-1990 was 49 years, increasing to 61 years by 2006-2008. Over that period, there were increases in the prevalence of vascular disease (from 10.0 to 25.2%) and diabetes (from 6.7 to 33.9%). After accounting for age, sex and comorbidity differences, standardized three-year all-cause mortality rates in treated patients with end-stage renal disease between 1970 and 2011 fell by about one-half (relative decline 51%, 95% confidence interval 41-60%) steeper than the one-third decline (34%, 31-36%) observed in the general population. Declines in three-year mortality rates were evident among those who received a kidney transplant and those who remained on dialysis, and among those with and without diabetes. These data suggest that the full extent of mortality rate declines among RRT patients since 1970 is only apparent when changes in comorbidity over time are taken into account, and that mortality rates in RRT patients appear to have declined faster than in the general population.

Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation.

Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.

Biliary Tract and Liver Complications in Polycystic Kidney Disease.

Polycystic liver disease is a well described manifestation of autosomal dominant polycystic kidney disease (ADPKD). Biliary tract complications are less well recognized. We report a 50-year single-center experience of 1007 patients, which raised a hypothesis that ADPKD is associated with biliary tract disease. We tested this hypothesis using all England Hospital Episode Statistics data (1998-2012), within which we identified 23,454 people with ADPKD and 6,412,754 hospital controls. Hospitalization rates for biliary tract disease, serious liver complications, and a range of other known ADPKD manifestations were adjusted for potential confounders. Compared with non-ADPKD hospital controls, those with ADPKD had higher rates of admission for biliary tract disease (rate ratio [RR], 2.24; 95% confidence interval [95% CI], 2.16 to 2.33) and serious liver complications (RR, 4.67; 95% CI, 4.35 to 5.02). In analyses restricted to those on maintenance dialysis or with a kidney transplant, RRs attenuated substantially, but ADPKD remained associated with biliary tract disease (RR, 1.19; 95% CI, 1.08 to 1.31) and perhaps with serious liver complications (RR, 1.15; 95% CI, 0.98 to 1.33). The ADPKD versus non-ADPKD RRs for biliary tract disease were larger for men than women (heterogeneity P<0.001), but RRs for serious liver complications appeared higher in women (heterogeneity P<0.001). Absolute excess risk of biliary tract disease associated with ADPKD was larger than that for serious liver disease, cerebral aneurysms, and inguinal hernias but less than that for urinary tract infections. Overall, biliary tract disease seems to be a distinct and important extrarenal complication of ADPKD.

Developing Advanced AI Ecosystems to Enhance Diagnosis and Care for Patients with Depression.

Major Depressive Disorder (MDD) has a significant impact on the daily lives of those affected. This concept paper presents a project that aims at addressing MDD challenges through innovative therapy systems. The project consists of two use cases: a multimodal neurofeedback (NFB) therapy and an AI-based virtual therapy assistant (VTA). The multimodal NFB integrates EEG and fNIRS to comprehensively assess brain function. The goal is to develop an open-source NFB toolbox for EEG-fNIRS integration, augmented by the VTA for optimized efficacy. The VTA will be able to collect behavioral data, provide personalized feedback and support MDD patients in their daily lives. This project aims to improve depression treatment by bringing together digital therapy, AI and mobile apps to potentially improve outcomes and accessibility for people living with depression.

Outcomes and timing for intervention of partial adrenalectomy in patients with a solitary adrenal remnant and history of bilateral phaeochromocytomas.

OBJECTIVE: To evaluate the outcomes and timing of intervention for adrenal-sparing surgery in patients left with a solitary adrenal remnant after bilateral adrenal surgeries. PATIENTS AND METHODS: Patients were included in the study if they had undergone bilateral adrenal surgery as a treatment for phaeochromocytoma and were left with a solitary adrenal remnant. Perioperative, functional and oncological outcomes were evaluated in 21 patients who met the inclusion criteria. RESULTS: There was minimal perioperative morbidity and no perioperative mortality. After a median (range) follow-up of 21 (3-143) months, there were two cases of persistent disease. Ten patients (48%) required steroid supplementation upon discharge, with four subsequently discontinuing this treatment. Patients were more likely to require steroid supplementation after surgery if they underwent simultaneous adrenalectomy and contralateral partial adrenalectomy, rather than staged procedures (86 vs 40%, P = 0.02). Patients who underwent surgery for tumours > 4 cm were more likely to require long-term steroids than patients who underwent surgery for lesions < 4 cm (75 vs 18%, P = 0.05). CONCLUSIONS: Patients left with a solitary adrenal remnant after bilateral adrenal surgery have low surgical morbidity, reasonable functional outcomes and low rates of recurrence at an intermediate follow-up period. A staged approach could decrease the immediate postoperative need for steroids, and intervention before the largest tumour reaches 4 cm could decrease the rate of long-term steroid dependence.

Lumbar stenosis rates in symptomatic patients using weight-bearing and recumbent magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to determine the rate of lumbar stenosis detected via magnetic resonance imaging (MRI) in patients with symptomatic foraminal stenosis, lateral recess stenosis, or central stenosis. METHODS: A retrospective review was performed on 1983 MRI scans from a 2-year period on 1486 symptomatic patients. Of these patients, 761 were scanned in the recumbent position using low-field (0.3 T, Airis II; Hitachi, Twinsburg, Ohio) MRI, and 725 were scanned in an upright sitting position using midfield (0.6 T) open Upright MRI (Fonar Corp, Melville, NY). In total, 986 serial scans (recumbent) and 997 serial scans (weight-bearing) were performed. RESULTS: Of scans performed in the recumbent position, stenoses were identified in 382 scans (38.8%), central stenosis in 119 scans (12%), lateral recess stenosis in 91 scans (9.2%), and foraminal stenosis in 327 scans (33.2%). Of scans performed in a weight-bearing position, stenoses were identified in 565 scans (56.7%), central stenosis in 136 scans (13.6%), lateral recess stenosis in 206 scans (20.7%), and foraminal stenosis in 524 scans (52.6%). CONCLUSIONS: The stenosis rates as indicated by MRI interpretation ranged between 38.5% (recumbent) and 56.7% (weight-bearing). These rates are higher than those reported in the medical literature for asymptomatic patients. Further study is needed to determine whether weight-bearing, compared with recumbent, MRI better informs the clinician in the diagnosis of spinal stenosis.

Single-dermatome single-incision laparoscopic right hemicolectomy.

We describe a novel single-incision laparoscopy right hemicolectomy technique using a single-dermatomal, muscle-splitting approach through a 4-cm incision located between the right anterior superior iliac spine and pubic tubercle. This new technique may be superior to traditional single-incision laparoscopy colectomy with the potential benefits of less post-operative pain, lower opioid requirements, lower risk of incisional hernia and better cosmesis but requires further validation.

Accelerometer-measured physical activity and functional behaviours among people on dialysis.

BACKGROUND: The feasibility of wrist-worn accelerometers, and the patterns and determinants of physical activity, among people on dialysis are uncertain. METHODS: People on maintenance dialysis were fitted with a wrist-worn AxivityAX3 accelerometer. Subsets also wore a 14-day electrocardiograph patch (Zio®PatchXT) and wearable cameras. Age-, sex- and season-matched UK Biobank control groups were derived for comparison. RESULTS: Median (interquartile range) accelerometer wear time for the 101 recruits was 12.5 (10.4-13.5) days, of which 73 participants (mean age 66.5 years) had excellent wear on both dialysis and non-dialysis days. Mean (standard error) overall physical activity levels were 15.5 (0.7) milligravity units (mg), 14.8 (0.7) mg on dialysis days versus 16.2 (0.8) mg on non-dialysis days. This compared with 28.1 (0.5) mg for apparently healthy controls, 23.4 (0.4) mg for controls with prior cardiovascular disease (CVD) and/or diabetes mellitus and 22.9 (0.6) mg for heart failure controls. Each day, we estimated that those on dialysis spent an average of about 1 hour (h/day) walking, 0.6 h/day engaging in moderate-intensity activity, 0.7 h/day on light tasks, 13.2 h/day sedentary and 8.6 h/day asleep. Older age and self-reported leg weakness were associated with decreased levels of physical activity, but the presence of prior CVD, arrhythmias and listing for transplantation were not. CONCLUSIONS: Wrist-worn accelerometers are an acceptable and reliable method to measure physical activity in people on dialysis and may also be used to estimate functional behaviours. Among people on dialysis, who are broadly half as active as general population controls, age and leg weakness appear to be more important determinants of low activity levels than CVD.

Partial adrenalectomy: underused first line therapy for small adrenal tumors.

PURPOSE: Many patients with small adrenal masses undergo total adrenalectomy. We evaluated partial adrenalectomy outcomes by performing a comprehensive literature review. MATERIALS AND METHODS: We performed a PubMed search of the English language literature using the queries partial adrenalectomy and adrenal sparing surgery, and identified 317 and 155 articles, respectively. We excluded case reports or series with fewer than 5 patients, articles not focused on surgical management and those that did not indicate perioperative outcomes. The remaining articles were cross-referenced by author and institution to eliminate studies with redundant cases. Demographics, diagnosis, tumor characteristics, perioperative and functional outcomes, and recurrence data were collected when available. RESULTS: A total of 22 articles from a total of 22 first authors met our inclusion criteria, describing outcomes in a total of 417 patients. There has been an increasing trend toward partial adrenalectomy worldwide in the last 20 years. Partial adrenalectomy is most commonly done for Conn's syndrome, followed by pheochromocytoma. Most procedures are laparoscopic with minimal morbidity. The recurrence rate is only 3% and more than 90% of patients remain steroid independent. CONCLUSIONS: Partial adrenalectomy surgical outcomes and perioperative complications are similar to those reported for total adrenalectomy. When partial adrenalectomy is done for small adrenal lesions, the malignancy rate is negligible, the recurrence rate is low and most patients remain steroid-free at long-term followup. These data strongly support the acceptance of partial adrenalectomy as first line treatment for small adrenal masses.

Lumbar disk protrusion rates of symptomatic patients using magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to determine the rate of disk protrusions detected via magnetic resonance imaging (MRI) in patients symptomatic for spine pain, radiculopathy, or other spine-related pain. METHODS: A retrospective review of 1983 MRI scans was performed over a 2-year period on 1486 patients, each of whom was symptomatic for spine pain, radiculopathy, or other noncancer, spine-related pain. Of these patients, 761 were scanned in the recumbent position using low-field (0.3 T, Airis II, Hitachi, Twinsburg, Ohio) MRI, and 725 were scanned in an upright, sitting position using mid-field (0.6 T) open Upright MRI (Fonar, Melville, NY). In total, 986 serial scans were performed on patients in the recumbent position and 997 serial scans on patients in the weight-bearing position. RESULTS: One or more disk protrusions were identified in 73.3% of scans performed in the sitting position and in 50.1% of scans performed in the recumbent position. Most disk protrusions occurred at L5-S1 (52.3% and 29.8%), L4-L5 (42.6% and 26.7%), and L3-L4 (26.7% and 13.1%) in upright and recumbent positions, respectively. CONCLUSIONS: The disk protrusion rate in this group of patients ranged between 50.1% (recumbent) and 73.3% (weight-bearing). These rates are higher than rates reported in the medical literature for asymptomatic patients, a finding that supports the decision to further evaluate patients with persistent spine-related pain.

Calcitonin gene-related peptide inhibits early B cell development in vivo.

Recent in vitro studies suggest that calcitonin gene-related peptide (CGRP) inhibits early B cell differentiation; however, there is no evidence in the intact animal for a role for CGRP in B cell development. Here, we show that in vivo treatment of mice with CGRP reduces the number of IL-7 responsive B cell progenitors in bone marrow. A single CGRP treatment reduces IL-7-responsive B cell progenitors by up to 40% for up to 72 h. The reduction is dose-dependent and can be blocked by a CGRP receptor antagonist, CGRP(8-37). CGRP in serum following injection is highly elevated at 30 min but returns to basal levels by 4 h, suggesting that a single injection of CGRP has long-lasting effects on B cell development. This report provides the first direct in vivo evidence that CGRP, a neuropeptide with multiple effects on mature lymphocytes, also plays a regulatory role in early B cell development in the bone marrow.

Repeat upright positional magnetic resonance imaging for diagnosis of disorders underlying chronic noncancer lumbar pain.

OBJECTIVE: Cases of chronic noncancer pain are both the most frequent and the most difficult that the spine care professional is called upon to treat. We use this case to illustrate the potential effectiveness of repeat positional upright, weight-bearing magnetic resonance (MR) imaging to diagnose disorders and to detect changes in disorders. CLINICAL FEATURES: We present the case of a 35-year-old man referred to our neurosurgical clinic with complaints of chronic, noncancer lower back pain and right-greater-than-left sciatica. Traditional recumbent MR imaging had revealed degenerative disk disease at L5-S1 and a 2.2-mm (grade 1) degenerative spondylolisthesis. The patient had not improved after more than a year of conservative treatments and, moreover, had been prescribed opiates for pain management that were potentially masking changes in his condition. INTERVENTION AND OUTCOMES: After referral to our clinic, we ordered repeat lumbar MR imaging in an upright weight-bearing position (sitting) 14 months after the patient's recumbent MR imaging. The weight-bearing MR imaging revealed a 9.13-mm (grade 1) degenerative spondylolisthesis at L5-S1. The patient underwent arthrodesis. His leg pain and back were significantly and clinically improved. CONCLUSION: When patients with noncancer, lower back pain worsen, fail to improve, or require opiates to manage their pain, updated clinical diagnosis including repeat positional imaging may be an effective diagnostic strategy.

Vestibular dysfunction in patients with chronic pain or underlying neurologic disorders.

CONTEXT: Individuals with vestibular dysfunction are at increased risk for falling. In addition, vestibular dysfunction is associated with chronic pain, which could present a serious public health concern as approximately 43% of US adults have chronic pain. OBJECTIVE: To assess the incidence of vestibular dysfunction in patients receiving medication for chronic, noncancer pain or other underlying neurologic disorders and to determine associated follow-up therapeutic and diagnostic recommendations. METHODS: The authors conducted a retrospective medical record review of consecutive patients who were treated in their private neuroscience practice with medications for chronic pain or underlying neurologic disorders in 2011. All patients underwent a series of tests using videonystagmography for the assessment of vestibular function. Test results and recommendations for therapy and additional testing were obtained. RESULTS: Medical records of 124 patients (78 women, 46 men) were reviewed. Vestibular deficits were detected in 83 patients (66.9%). Patient ages ranged from 29 through 72 years, with a mean age of 50.7 years for women and 52.5 years for men. Physician-recommended therapy and follow-up testing were as follows: 32 patients (38.6%), neurologic examination and possible magnetic resonance (MR) imaging or computed tomography (CT) of the brain; 26 patients (31.3%), vestibular rehabilitation therapy only; 22 patients (26.5%), vestibular and related balance-function rehabilitation therapy, further neurologic examination, and possible MR imaging or CT; 2 patients (2.4%), balance-function rehabilitation therapy and specialized internal auditory canal high-magnification MR imaging or CT to assess for acoustic neuroma; and 1 patient (1.2%), specialized internal auditory canal high-magnification MR imaging or CT to evaluate for possible intracanalicular acoustic neuroma. CONCLUSION: Patients being treated with medications for chronic, noncancer pain or other underlying neurologic disorders may have a higher-than-average incidence of vestibular dysfunction. Baseline assessment and monitoring of the vestibular apparatus may be indicated for these patients.

Scoliosis rates in symptomatic patients as demonstrated with weight-bearing or supine MR imaging.

CONTEXT: In the United States an estimated 6 million persons are affected by scoliosis, which is characterized by a 3-dimensional deformity of the spine that involves a curvature in the sagittal, frontal, and transverse planes. OBJECTIVE: To determine the rates of scoliosis in patients with spine-related pain unassociated with cancer, as demonstrated by magnetic resonance (MR) images obtained with patients in either a weight-bearing or a supine position. METHODS: The authors conducted a retrospective review of MR images obtained during a 2-year period in patients referred because of symptoms of radiculopathy or other spine-related pain unassociated with cancer and unresolved after conservative treatment. Images were obtained either with the patient supine or with the patient in a weight-bearing, seated position, and all images were reviewed by a neuroimaging physician. Scoliosis was assessed according to the Cobb angle method. RESULTS: A total of 1982 MR images from 1486 patients were reviewed. Of those, 986 images in 761 patients were obtained with a low-field-strength (0.3-T) MR imager with the patient supine, and 996 images in 725 patients were obtained with a mid-field-strength (0.6-T) MR imager with the patient in a weight-bearing, seated position. Scoliosis (dextroscoliosis, levoscoliosis, or both) was identified in 958 MR images (48.3%), of which 779 (78.2%) were obtained with patients in a weight-bearing position and 179 (18.2%) were obtained with patients in a supine position. CONCLUSION: The scoliosis rate was lower in the supine MR imaging group than in the weight-bearing MR imaging group. Scoliosis rates may be affected by the position in which the patient is examined, with the possibility that the weight-bearing position differentially exposes scoliosis, compared with the supine position.