Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

A totally OSM gift to astrocytes relieves inflammation.

Dectin-1 is known for promoting anti-fungal responses through the signaling molecule Card9. In this issue of Immunity, Deerhake et al. now report that during autoimmune neuroinflammation, Dectin-1 can promote a neuroprotective feed-forward pathway through Card9-independent upregulation of Oncostatin M.

Regulation of neuroinflammation by B cells and plasma cells.

The remarkable success of anti-CD20 B cell depletion therapies in reducing the burden of multiple sclerosis (MS) disease has prompted significant interest in how B cells contribute to neuroinflammation. Most focus has been on identifying pathogenic CD20+ B cells. However, an increasing number of studies have also identified regulatory functions of B lineage cells, particularly the production of IL-10, as being associated with disease remission in anti-CD20-treated MS patients. Moreover, IL-10-producing B cells have been linked to the attenuation of inflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. In addition to IL-10-producing B cells, antibody-producing plasma cells (PCs) have also been implicated in suppressing neuroinflammation. This review will examine regulatory roles for B cells and PCs in MS and EAE. In addition, we speculate on the involvement of regulatory PCs and the cytokine BAFF in the context of anti-CD20 treatment. Lastly, we explore how the microbiota could influence anti-inflammatory B cell behavior. A better understanding of the contributions of different B cell subsets to the regulation of neuroinflammation, and factors that impact the development, maintenance, and migration of such subsets, will be important for rationalizing next-generation B cell-directed therapies for the treatment of MS.

Fantastic IgA plasma cells and where to find them.

IgA is produced in large quantities at mucosal surfaces by IgA+ plasma cells (PC), protecting the host from pathogens, and restricting commensal access to the subepithelium. It is becoming increasingly appreciated that IgA+ PC are not constrained to mucosal barrier sites. Rather, IgA+ PC may leave these sites where they provide both host defense and immunoregulatory function. In this review, we will outline how IgA+ PC are generated within the mucosae and how they subsequently migrate to their "classical" effector site, the gut lamina propria. From there we provide examples of IgA+ PC displacement from the gut to other parts of the body, referencing examples during homeostasis and inflammation. Lastly, we will speculate on mechanisms of IgA+ PC displacement to other tissues. Our aim is to provide a new perspective on how IgA+ PC are truly fantastic beasts of the immune system and identify new places to find them.

Multilevel Proteomic Profiling of Colorectal Adenocarcinoma Caco-2 Cell Differentiation to Characterize an Intestinal Epithelial Model.

Emergent advancements on the role of the intestinal microbiome for human health and disease necessitate well-defined intestinal cellular models to study and rapidly assess host, microbiome, and drug interactions. Differentiated Caco-2 cell line is commonly utilized as an epithelial model for drug permeability studies and has more recently been utilized for investigating host-microbiome interactions. However, its suitability to study such interactions remains to be characterized. Here, we employed multilevel proteomics to demonstrate that both spontaneous and butyrate-induced Caco-2 differentiations displayed similar protein and pathway changes, including the downregulation of proteins related to translation and proliferation and upregulation of functions implicated in host-microbiome interactions, such as cell adhesion, tight junction, extracellular vesicles, and responses to stimuli. Lysine acetylomics revealed that histone protein acetylation levels were decreased along with cell differentiation, while the acetylation in proteins associated with mitochondrial functions was increased. This study also demonstrates that, compared to spontaneous differentiation methods, butyrate-containing medium accelerates Caco-2 differentiation, with earlier upregulation of proteins related to host-microbiome interactions, suggesting its superiority for assay development using this intestinal model. Altogether, this multiomics study emphasizes the controlled progression of Caco-2 differentiation toward a specialized intestinal epithelial-like cell and establishes its suitability for investigating the host-microbiome interactions.

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.

Vitamin Supplement Use in Patients With CKD: Worth the Pill Burden?

All vitamins play essential roles in various aspects of body function and systems. Patients with chronic kidney disease (CKD), including those receiving dialysis, may be at increased risk of developing vitamin deficiencies due to anorexia, poor dietary intake, protein energy wasting, restricted diet, dialysis loss, or inadequate sun exposure for vitamin D. However, clinical manifestations of most vitamin deficiencies are usually subtle or undetected in this population. Testing for circulating levels is not undertaken for most vitamins except folate, B12, and 25-hydroxyvitamin D because assays may not be available or may be costly to perform and do not always correlate with body stores. The last systematic review through 2016 was performed for the Kidney Disease Outcome Quality Initiative (KDOQI) 2020 Nutrition Guideline update, so this article summarizes the more recent evidence. We review the use of vitamins supplementation in the CKD population. To date there have been no randomized trials to support the benefits of any vitamin supplementation for kidney, cardiovascular, or patient-centered outcomes. The decision to supplement water-soluble vitamins should be individualized, taking account the patient's dietary intake, nutritional status, risk of vitamins deficiency/insufficiency, CKD stage, comorbid status, and dialysis loss. Nutritional vitamin D deficiency should be corrected, but the supplementation dose and formulation need to be personalized, taking into consideration the degree of 25-hydroxyvitamin D deficiency, parathyroid hormone levels, CKD stage, and local formulation. Routine supplementation of vitamins A and E is not supported due to potential toxicity. Although more trial data are required to elucidate the roles of vitamin supplementation, all patients with CKD should undergo periodic assessment of dietary intake and aim to receive various vitamins through natural food sources and a healthy eating pattern that includes vitamin-dense foods.

Impact of head and neck radiation on long-term outcomes after carotid revascularization.

OBJECTIVE: Radiation-induced carotid artery stenosis (RICS) is a well-described phenomenon seen after head and neck cancer radiation. Previously published literature suggests that, compared with atherosclerotic disease, RICS may result in worse long-term outcomes and early restenosis. This study aims to evaluate the effect of radiation on long-term outcomes after various carotid revascularization techniques using a multi-center registry database. METHODS: Patients in the Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) registry for carotid artery intervention (carotid endarterectomy [CEA]; transfemoral carotid artery stenting [CAS]; transcarotid artery revascularization [TCAR]), who are 65 years or older were included in the study. VQI Vascular Implant Surveillance and Interventional Outcomes Network (VISION) Medicare-linked database was used to obtain long-term procedure-specific outcomes. Primary endpoints were 3-year death, stroke, and reintervention. We performed propensity matching between patients with prior radiation and those without. Kaplan-Meier analysis and a multivariate logistic regression model were used to analyze the outcome variables. RESULTS: A total of 56,472 patients had undergone carotid revascularization (CEA, n = 48,307; TCAR, n = 4593; CAS, n = 3572), 1244 patients with prior radiation and 54,925 patients without prior radiation. The prior radiation group was more likely to be male (71.9% vs 60.3%; P < .01), to receive a stent (47.5% vs 13.5%; P < .01), and to be on P2Y12 inhibitor (55.2% vs 38.3%; P < .01). Propensity matching was performed on 1223 patients (CEA, n = 655; TCAR, n = 292; CAS, n = 287). There were no significant differences in 30-day outcomes for death, stroke, or major adverse cardiovascular events for all three procedures. The prior radiation group had higher rates of cranial nerve injury (3.7% vs 1.8%; P = .04) and 90-day readmission (23.5% vs 18.3%; P = .01) after CEA. For long-term outcomes, prior radiation significantly increased mortality risk for CEA and CAS (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.38-2.27 and HR, 1.56; 95% CI, 1.02-2.36, respectively). The 3-year risk of stroke for CEA in radiated patients was also significantly higher (HR, 1.47; 95% CI, 1.03-2.09) compared with non-radiated patients. Prior radiation did not significantly affect death and stroke in patients undergoing TCAR. Prior radiation also did not impact the rates of short and long-term reintervention after CEA, CAS, or TCAR. CONCLUSIONS: Prior head and neck radiation significantly increases the risk for mortality and stroke for CEA and the risk for mortality after CAS. Long-term outcomes for TCAR are not significantly affected by prior radiation. TCAR may be the preferred treatment modality for patients with radiation-induced carotid stenosis.

Iatrogenic blood loss from phlebotomy during adult extracorporeal membrane oxygenation: A retrospective cohort study.

BACKGROUND: Adult extracorporeal membrane oxygenation (ECMO) patients are at high risk for allogeneic blood transfusion. Few studies have characterized iatrogenic blood loss from phlebotomy in adult ECMO patients. We hypothesized that iatrogenic phlebotomy would be a significant source of blood loss during ECMO. METHODS: Adults who had their entire ECMO run at our medical center between 2020 and 2022 were included. Average daily phlebotomy volume and total phlebotomy volume during ECMO were estimated based on the total number of laboratory tests that were processed. In addition, the crude and adjusted association between total phlebotomy volume during ECMO and RBC transfusion during ECMO was evaluated using linear regression and Loess curve analysis. RESULTS: A total of 161 patients who underwent 162 ECMO runs were included. Of the 162 ECMO runs, 88 (54.3%) were veno-arterial and 74 (45.7%) were veno-venous ECMO. Median duration of ECMO was 5 days [25th, 75th percentile = 2, 11]. Median daily phlebotomy volume was 130 mLs [25th, 75th percentile = 94, 170] and median total phlebotomy volume during ECMO was 579 mLs [25th, 75th percentile = 238, 1314]. There was a significant crude and adjusted association between total phlebotomy volume and RBC transfusion during ECMO (beta coefficient = 0.0023 and 0.0024 respectively, both p < .001) based on linear regression analysis. DISCUSSION: Phlebotomy for laboratory testing is a significant source of blood loss during ECMO in adults. Comprehensive patient blood management for adult ECMO patients should include strategies to reduce laboratory testing and/or phlebotomy volume during ECMO.

Acute Kidney Injury in Acute Heart Failure - When to worry and when not to worry?

Acute kidney injury is common in patients with acute decompensated heart failure. It is more common in patients with acute heart failure who suffer from chronic kidney disease. Worsening renal function is often defined as a rise in serum creatinine of more than 0.3 milligrams per deciliter (26.5 µmol/L), which by definition, is acute kidney injury stage one. Perhaps the term acute kidney injury is more appropriate than worsening renal function as it is used universally by nephrologists, internists, and other medical practitioners. In health, the heart and the kidney support each other to maintain body's homeostasis. In disease, the heart and the kidney can adversely affect each other's function causing further clinical deterioration. In patients presenting with acute heart failure and fluid overload, therapy with diuretics for decongestion often causes a rise in serum creatinine and acute kidney injury. However, in the longer term the decongestion improves survival and prevents hospital admissions despite rising serum creatinine and acute kidney injury. It is important to realize that renal venous congestion due to increased right sided heart pressures in acute heart failure is a major cause of kidney dysfunction and hence decongestion therapy improves kidney function in the longer term. This review provides a perspective on the acceptable acute kidney injury with decongestion therapy which is associated with improved survival; as opposed to acute kidney injury due to tubular injury related to sepsis or nephrotoxic drugs, which is associated with poor survival.

The Kidney Failure Risk Equation: Evaluation of Novel Input Variables including eGFR Estimated Using the CKD-EPI 2021 Equation in 59 Cohorts.

SIGNIFICANCE STATEMENT: The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict 2- and 5-year risk of kidney failure in populations with eGFR <60 ml/min per 1.73 m 2 . However, the CKD-EPI 2021 creatinine equation for eGFR is now recommended for use but has not been fully tested in the context of KFRE. In 59 cohorts comprising 312,424 patients with CKD, the authors assessed the predictive performance and calibration associated with the use of the CKD-EPI 2021 equation and whether additional variables and accounting for the competing risk of death improves the KFRE's performance. The KFRE generally performed well using the CKD-EPI 2021 eGFR in populations with eGFR <45 ml/min per 1.73 m 2 and was not improved by adding the 2-year prior eGFR slope and cardiovascular comorbidities. BACKGROUND: The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict kidney failure risk in people with GFR <60 ml/min per 1.73 m 2 . METHODS: Using 59 cohorts with 312,424 patients with CKD, we tested several modifications to the KFRE for their potential to improve the KFRE: using the CKD-EPI 2021 creatinine equation for eGFR, substituting 1-year average ACR for single-measure ACR and 1-year average eGFR in participants with high eGFR variability, and adding 2-year prior eGFR slope and cardiovascular comorbidities. We also assessed calibration of the KFRE in subgroups of eGFR and age before and after accounting for the competing risk of death. RESULTS: The KFRE remained accurate and well calibrated overall using the CKD-EPI 2021 eGFR equation. The other modifications did not improve KFRE performance. In subgroups of eGFR 45-59 ml/min per 1.73 m 2 and in older adults using the 5-year time horizon, the KFRE demonstrated systematic underprediction and overprediction, respectively. We developed and tested a new model with a spline term in eGFR and incorporating the competing risk of mortality, resulting in more accurate calibration in those specific subgroups but not overall. CONCLUSIONS: The original KFRE is generally accurate for eGFR <45 ml/min per 1.73 m 2 when using the CKD-EPI 2021 equation. Incorporating competing risk methodology and splines for eGFR may improve calibration in low-risk settings with longer time horizons. Including historical averages, eGFR slopes, or a competing risk design did not meaningfully alter KFRE performance in most circumstances.

Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study.

AIMS: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). METHODS AND RESULTS: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. CONCLUSION: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.

Patient and Caregiver Impressions of the Impact of Madelung Deformity: A CoULD Registry Analysis.

PURPOSE: This study seeks to investigate demographics of patients with Madelung deformity in a large, geographically diverse sample and understand patient and caregiver perceptions of the impact of this condition. We hypothesized that patients with untreated Madelung deformity have greater pain and lower function compared to the normal population but are less affected than the chosen control group, namely, patients with proximal radioulnar synostosis (PRUS). METHODS: This retrospective study queried the Congenital Upper Limb Differences (CoULD) Registry, a multicenter registry of patients treated in tertiary care pediatric hospitals. We searched patients enrolled as of July 2022 and identified 3,980 total patients and 66 (1.7%) with a diagnosis of Madelung deformity. We reviewed demographics and Patient-Reported Outcomes Measurement Information System (PROMIS; peer relations, depressive symptoms, pain interference, and upper extremity function domains) scores at time of enrollment. We used a matched cohort comparison with propensity scoring for 50 patients with Madelung deformity and 50 patients with PRUS (control cohort). RESULTS: Patients with Madelung deformity presented at an average age of 13.1 years (± 2.1 years). Ninety-eight percent were female, and 82% were White. Seventy-four percent had distal radius-only deformity. Upper extremity PROMIS scores in both the Madelung deformity and the PRUS groups were significantly "worse" than normal, confirming our hypothesis. The Madelung deformity and PRUS cohort scores were not consistently different from one another. PROMIS scores from all other domains, including pain interference, were similar to, or better than normal for both groups, disproving the second part of our hypothesis. CONCLUSIONS: Patients with Madelung deformity averaged 13 years of age and were nearly all female, and the majority had only distal involvement of the radius. Patients with Madelung deformity had lower function based on PROMIS scores, similar to the control cohort, whereas all other PROMIS measures were similar to or better when compared to normal values. Pain interference scores in both cohorts were lower than normal values. Patients with Madelung deformity have decreased function, similar to the comparative cohort of patients with PRUS, but do not present with increased pain. TYPE OF STUDY/LEVEL OF EVIDENCE: Symptom prevalence III.

The Impact on Families of Children With Congenital Upper Extremity Differences.

PURPOSE: To investigate the impact on caregivers of caring for a child with congenital upper extremity differences. METHODS: In this cross-sectional study, caregivers of patients enrolled in the multi-institutional Congenital Upper Limb Difference (CoULD) registry were contacted. Demographic information and the Impact on Family Scale (IOFS), a validated measure of perceived caregiver strain, were collected. Patient-reported outcome measures from the CoULD registry, the Pediatric Outcomes Data Collection Instrument (PODCI), and Patient-Reported Outcomes Measurement Information System (PROMIS) were also analyzed for correlation with IOFS. RESULTS: Two hundred ninety-nine caregivers participated. Factors with significantly stronger impact on family included public insurance; bilateral upper extremity involvement; household income of $20,000-40,000; additional musculoskeletal diagnosis; and a single adult caregiver household. There was a significantly increased subcategory of IOFS-Finance score for distant travel to see the surgeon. Additionally, all categories of the PODCI (upper extremity, mobility, sports, pain, happiness, and global) demonstrated a negative correlation with IOFS. PROMIS upper extremity and peer relations also demonstrated an inverse relationship with IOFS, whereas PROMIS pain interference had a positive correlation with IOFS. The overall IOFS for children with CoULDs was greater than previously reported for children with brachial plexus birth injury, and less than cerebral palsy and congenital heart disease. CONCLUSIONS: Caregivers of children with congenital upper extremity differences report a significant impact on family life. Socioeconomic factors, such as economically disadvantaged or single-caregiver households, and clinical factors, such as bilateral upper extremity involvement, correlate with greater family impact. These findings represent opportunities to identify at-risk families and underscore the importance of caring for the whole family through a multidisciplinary approach. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Cardiovascular Effects of Home Dialysis Therapies: A Scientific Statement From the American Heart Association.

Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage kidney disease. Currently, thrice-weekly in-center hemodialysis for 3 to 5 hours per session is the most common therapy worldwide for patients with treated kidney failure. Outcomes with thrice-weekly in-center hemodialysis are poor. Emerging evidence supports the overarching hypothesis that a more physiological approach to administering dialysis therapy, including in the home through home hemodialysis or peritoneal dialysis, may lead to improvement in several cardiovascular risk factors and cardiovascular outcomes compared with thrice-weekly in-center hemodialysis. The Advancing American Kidney Health Initiative, which has a goal of increasing the use of home dialysis, is aligned with the American Heart Association's 2024 mission to champion a full and healthy life and health equity. We conclude that incorporation of interdisciplinary care models to increase the use of home dialysis therapies in an equitable manner will contribute to the ultimate goal of improving outcomes for patients with kidney failure and cardiovascular disease.

Defining myocardial infarction in trials of people receiving hemodialysis: consensus report from the SONG-HD MI Expert Working group.

Cardiovascular disease is the leading cause of death in patients receiving hemodialysis. Currently, there is no standardized definition of myocardial infarction (MI) for patients receiving hemodialysis. Through an international consensus process MI was established as the core CVD measure for this population in clinical trials. The Standardised Outcomes in Nephrology Group-Hemodialysis (SONG-HD) initiative convened a multidisciplinary, international working group to address the definition of MI in this population. On the basis of current evidence, the working group recommends using the Fourth Universal Definition of Myocardial Infarction with specific caveats with regard to the interpretation of "ischemic symptoms" and performing a baseline 12-lead electrocardiogram to facilitate interpretation of acute changes on subsequent tracings. The working group does not recommend obtaining baseline cardiac troponin values, though does recommend obtaining serial cardiac biomarkers in settings where ischemia is suspected. The application of an evidence-based uniform definition should increase the reliability and accuracy of trial results.

Physical activity and nutrition in chronic kidney disease.

PURPOSE OF REVIEW: Lifestyle intervention is considered a cornerstone in chronic kidney disease management and has been recommended in different international or regional clinical practice guidelines in chronic kidney disease. However, evidence was largely based on the general population. Here we summarized the latest evidence supporting lifestyle intervention in chronic kidney disease. RECENT FINDINGS: Both observational cohort studies as well as randomized controlled trials have demonstrated health benefits with more physical activity in chronic kidney disease. There are compelling observational data supporting different health and kidney benefits with a healthy dietary pattern rich in fruits and vegetables, whole grains, plant-based foods and low in salt, low in sugar, saturated fat, red meat and ultraprocessed foods, a plant-based diet or Mediterranean diet in chronic kidney disease population. Clinical and epidemiologic studies also showed that higher 24 h urine potassium excretion (as proxy of higher dietary potassium intake) may be associated with lower blood pressure, better kidney outcomes and lower mortality in chronic kidney disease population. Randomized controlled trials also suggested that salt substitutes improved blood pressure control, reduced all-cause death and cardiovascular event risk in the general population compared with regular salt. SUMMARY: Accumulating evidence supports the current recommendation of encouraging physical activity and promoting a healthy dietary pattern in chronic kidney disease patients. Whether potassium needs restriction in chronic kidney disease diet requires further review. The safety versus benefits of salt substitutes in patients with moderate and advanced chronic kidney disease warrants further investigation.

Parathyroidectomy versus oral cinacalcet on cardiovascular parameters in peritoneal dialysis patients with advanced secondary hyperparathyroidism (PROCEED): a randomized trial.

BACKGROUND: This trial aimed to evaluate oral cinacalcet versus total parathyroidectomy (PTx) with forearm autografting on cardiovascular surrogate outcomes and health-related quality of life (HRQOL) measures in dialysis patients with advanced secondary hyperparathyroidism (SHPT). DESIGN: In this pilot prospective randomized trial conducted in two university-affiliated hospitals, 65 adult peritoneal dialysis patients with advanced SHPT were randomized to receive either oral cinacalcet or PTx. Primary endpoints were changes in left ventricular (LV) mass index by cardiac magnetic resonance imaging and coronary artery calcium scores (CACS) over 12 months. Secondary endpoints included changes in heart valves calcium scores, aortic stiffness, biochemical parameters of chronic kidney disease-mineral bone disease (CKD-MBD) and HRQOL measures over 12 months. RESULTS: Changes in LV mass index, CACS, heart valves calcium score, aortic pulse wave velocity and HRQOL did not differ between groups or within groups, despite significant reductions in plasma calcium, phosphorus and intact parathyroid hormone in both groups. Cinacalcet-treated patients experienced more cardiovascular-related hospitalizations than those who underwent PTx (P = .008) but the difference became insignificant after adjusting for baseline difference in heart failure (P = .43). With the same monitoring frequency, cinacalcet-treated patients had fewer hospitalizations due to hypercalcemia (1.8%) than patients who underwent PTx (16.7%) (P = .005). No significant changes were observed in HRQOL measures in either group. CONCLUSIONS: Both cinacalcet and PTx effectively improved various biochemical abnormalities of CKD-MBD and stabilized but did not reduce LV mass, coronary artery and heart valves calcification, or arterial stiffness, or improve patient-centered HRQOL measures in PD patients with advanced SHPT. Cinacalcet may be used in place of PTx for treating advanced SHPT. Long-term and powered studies are required to evaluate PTx versus cinacalcet on hard cardiovascular outcomes in dialysis patients. Trial registration: ClinicalTrials.gov identifier: NCT01447368.

Learning to pause: Fidelity of and biases in the developmental acquisition of gaps in the communicative signals of a songbird.

The temporal organization of sounds used in social contexts can provide information about signal function and evoke varying responses in listeners (receivers). For example, music is a universal and learned human behavior that is characterized by different rhythms and tempos that can evoke disparate responses in listeners. Similarly, birdsong is a social behavior in songbirds that is learned during critical periods in development and used to evoke physiological and behavioral responses in receivers. Recent investigations have begun to reveal the breadth of universal patterns in birdsong and their similarities to common patterns in speech and music, but relatively little is known about the degree to which biological predispositions and developmental experiences interact to shape the temporal patterning of birdsong. Here, we investigated how biological predispositions modulate the acquisition and production of an important temporal feature of birdsong, namely the duration of silent pauses ("gaps") between vocal elements ("syllables"). Through analyses of semi-naturally raised and experimentally tutored zebra finches, we observed that juvenile zebra finches imitate the durations of the silent gaps in their tutor's song. Further, when juveniles were experimentally tutored with stimuli containing a wide range of gap durations, we observed biases in the prevalence and stereotypy of gap durations. Together, these studies demonstrate how biological predispositions and developmental experiences differently affect distinct temporal features of birdsong and highlight similarities in developmental plasticity across birdsong, speech, and music. RESEARCH HIGHLIGHTS: The temporal organization of learned acoustic patterns can be similar across human cultures and across species, suggesting biological predispositions in acquisition. We studied how biological predispositions and developmental experiences affect an important temporal feature of birdsong, namely the duration of silent intervals between vocal elements ("gaps"). Semi-naturally and experimentally tutored zebra finches imitated the durations of gaps in their tutor's song and displayed some biases in the learning and production of gap durations and in gap variability. These findings in the zebra finch provide parallels with the acquisition of temporal features of speech and music in humans.