Effect of patient factors, center, and era on Fontan timing: An observational study using the Pediatric Health Information Systems Database.

BACKGROUND: There are no consensus guidelines defining optimal timing for the Fontan operation, the last planned surgery in staged palliation for single-ventricle heart disease. OBJECTIVES: Identify patient-level characteristics, center-level variation, and secular trends driving Fontan timing. METHODS: A retrospective observational study of subjects who underwent Fontan from 2007 to 2021 at centers in the Pediatric Health Information Systems database was performed using linear mixed-effects modeling in which age at Fontan was regressed on patient characteristics and date of operation with center as random effect. RESULTS: We included 10,305 subjects (40.4% female, 44% non-white) at 47 centers. Median age at Fontan was 3.4 years (IQR 2.6-4.4). Hypoplastic left heart syndrome (-4.4 months, 95%CI -5.5 to -3.3) and concomitant conditions (-2.6 months, 95%CI -4.1 to -1.1) were associated with younger age at Fontan. Subjects with technology-dependence (+4.6 months, 95%CI 3.1-6.1) were older at Fontan. Black (+4.1 months, 95%CI 2.5-5.7) and Asian (+8.3 months, 95%CI 5.4-11.2) race were associated with older age at Fontan. There was significant variation in Fontan timing between centers. Center accounted for 10% of variation (ICC 0.10, 95%CI 0.07-0.14). Center surgical volume was not associated with Fontan timing (P = .21). Operation year was associated with age at Fontan, with a 3.1 month increase in age for every 5 years (+0.61 months, 95%CI 0.48-0.75). CONCLUSIONS: After adjusting for patient-level characteristics there remains significant inter-center variation in Fontan timing. Age at Fontan has increased. Future studies addressing optimal Fontan timing are warranted.

Metabolic characterization of human sperm cells using the Seahorse metabolic flux analyzer.

BACKGROUND: The concerning trend on male infertility global prevalence, together with the unexplainable causes in half of those cases, highlights that there are still aspects of this disease to be understood and solved. To address this issue, one should not only be aware of the limitations of the implemented diagnostic tools, but also understand the sperm cell in depth, structurally, biochemically, molecularly in order to develop reliable and ready-to-be new/improved diagnostic tools. In this sense, the sperm cells metabolism, highly related to its functionality, seems to be a promising aspect to explore. Though there is much information on the human sperm metabolism, there is still a lack of a quick integrated and comprehensive analysis that may be introduced with the potential to reveal innovative clinically relevant information. OBJECTIVES: Find metabolic details on human sperm that can be accessed easily, in real time and using few cells, relying on the bivalent potential of the Seahorse flux analyzer (SFA). RESULTS: We have obtained standard records on human sperm cells' oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), that together with the metabolic metrics provided information on sperm cells' oxidative and glycolytic metabolism. Furthermore, a metabolic interindividual variation was observed. DISCUSSION AND CONCLUSION: Although the comparison with other species or cell types is not linear and warrant further studies, the metabolic profile of human sperm cells seems to be similar to that of other species. Altogether our results corroborate the value of SFA for metabolic human sperm cell analysis, warranting new studies, and anticipating several applications in the male infertility field.

Antihypertensive medication nonadherence and target organ damage in children with chronic kidney disease.

BACKGROUND: Nonadherence is common in children with chronic kidney disease (CKD). This may contribute to inadequate blood pressure control and adverse outcomes. This study examined associations between antihypertensive medication nonadherence, ambulatory blood pressure monitoring (ABPM) parameters, kidney function, and cardiac structure among children with CKD. METHODS: We performed secondary analyses of data from the CKD in Children (CKiD) study, including participants with treated hypertension who underwent ABPM, laboratory testing, and echocardiography biannually. Nonadherence was defined by self-report of any missed antihypertensive medication 7 days prior to the study visit. Linear regression and mixed-effects models were used to assess the association of nonadherence with baseline and time-updated ABPM profiles, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and left ventricular mass index (LVMI). RESULTS: Five-hundred and eight participants met inclusion criteria, followed for a median of 2.9 years; 212 (42%) were female, with median age 13 years (IQR 10-16), median baseline eGFR 49 (33-64) ml/min/1.73 m2 and median UPCR 0.4 (0.1-1.0) g/g. Nonadherence occurred in 71 (14%) participants. Baseline nonadherence was not significantly associated with baseline 24-h ABPM parameters (for example, mean 24-h SBP [ß - 0.1, 95% CI - 2.7, 2.5]), eGFR (ß 1.0, 95% CI - 0.9, 1.2), UCPR (ß 1.1, 95% CI - 0.8, 1.5), or LVMI (ß 0.6, 95% CI - 1.6, 2.9). Similarly, there were no associations between baseline nonadherence and time-updated outcome measures. CONCLUSIONS: Self-reported antihypertensive medication nonadherence occurred in 1 in 7 children with CKD. We found no associations between nonadherence and kidney function or cardiac structure over time. A higher resolution version of the Graphical abstract is available as Supplementary information.

Trends in Ductus Arteriosus Stent Versus Blalock-Taussig-Thomas Shunt Use and Comparison of Cost, Length of Stay, and Short-Term Outcomes in Neonates With Ductal-Dependent Pulmonary Blood Flow: An Observational Study Using the Pediatric Health Information Systems Database.

BACKGROUND: The modified Blalock-Taussig-Thomas shunt is the gold standard palliation for securing pulmonary blood flow in infants with ductal-dependent pulmonary blood flow. Recently, the ductus arteriosus stent (DAS) has become a viable alternative. METHODS AND RESULTS: This was a retrospective multicenter study of neonates ≤30 days undergoing DAS or Blalock-Taussig-Thomas shunt placement between January 1, 2017 and December 31, 2020 at hospitals reporting to the Pediatric Health Information Systems database. We performed generalized linear mixed-effects modeling to evaluate trends in intervention and intercenter variation, propensity score adjustment and inverse probability weighting with linear mixed-effects modeling to analyze length of stay and cost of hospitalization, and generalized linear mixed modeling to analyze differences in 30-day outcomes. There were 1874 subjects (58% male, 61% White) from 45 centers (29% DAS). Odds of DAS increased with time (odds ratio [OR] 1.23, annually, P<0.01 [95% CI, 1.10-1.38]) with significant intercenter variation (median OR, 3.81 [95% CI, 2.74-5.91]). DAS was associated with shorter hospital length of stay (ratio of geometric means, 0.76 [95% CI, 0.63-0.91]), shorter intensive care unit length of stay (ratio of geometric means, 0.77 [95% CI, 0.61-0.97]), and less expensive hospitalization (ratio of geometric means, 0.70 [95% CI, 0.56-0.87]). Intervention was not significantly associated with odds of 30-day transplant-free survival (OR,1.18 [95% CI, 0.70-1.99]) or freedom from catheter reintervention (OR, 1.02 [95% CI, 0.65-1.58]), but DAS was associated with 30-day freedom from composite adverse outcome (OR, 1.51 [95% CI, 1.11-2.05]). CONCLUSIONS: Use of DAS is increasing, but there is variability across centers. Though odds of transplant-free survival and reintervention were not significantly different after DAS, and DAS was associated with shorter length of stay and lower in-hospital costs.

Blockade of Inflammatory Markers Attenuates Cardiac Remodeling and Fibrosis in Rats with Supravalvular Aortic Stenosis.

Since cardiac inflammation has been considered an important mechanism involved in heart failure, an anti-inflammatory treatment could control cardiac inflammation and mitigate the worsening of cardiac remodeling. This study evaluated the effects of dexamethasone (DEX) and ramipril treatment on inflammation and cardiac fibrosis in an experimental model of heart failure induced by supravalvular aortic stenosis. Wistar rats (21d) were submitted to an aortic stenosis (AS) protocol. After 21 weeks, an echocardiogram and a maximal exercise test were performed, and after 24 weeks, rats were treated with DEX, ramipril or saline for 14d. The left ventricle (LV) was removed for histological and inflammatory marker analyses. The AS group showed exercise intolerance (-32% vs. Sham), higher relative wall thickness (+63%), collagen deposition and capillary rarefaction, followed by cardiac disfunction. Both treatments were effective in reducing cardiac inflammation, but only DEX attenuated the increased relative wall thickness (-17%) and only ramipril reduced LV fibrosis. In conclusion, both DEX and ramipril decreased cardiac inflammatory markers, which probably contributed to the reduced cardiac fibrosis and relative wall thickness; however, treated AS rats did not show any improvement in cardiac function. Despite the complex pharmacological treatment of heart failure, treatment with an anti-inflammatory could delay the patient's poor prognosis.

Strategies to Guide Preemptive Waitlisting and Equity in Waittime Accrual by Race/Ethnicity.

BACKGROUND: Use of eGFR to determine preemptive waitlisting eligibility may contribute to racial/ethnic disparities in access to waitlisting, which can only occur when the eGFR falls to ≤20 ml/min per 1.73 m 2 . Use of an alternative risk-based strategy for waitlisting may reduce these inequities ( e.g. , a kidney failure risk equation [KFRE] estimated 2-year risk of kidney failure) rather than the standard eGFR threshold for determining waitlist eligibility. Our objective was to model the amount of preemptive waittime that could be accrued by race and ethnicity, applying two different strategies to determine waitlist eligibility. METHODS: Using electronic health record data, linear mixed models were used to compare racial/ethnic differences in preemptive waittime that could be accrued using two strategies: estimating the time between an eGFR ≤20 and 5 ml/min per 1.73 m 2 versus time between a 25% 2-year predicted risk of kidney failure (using the KFRE, which incorporates age, sex, albuminuria, and eGFR to provide kidney failure risk estimation) and eGFR of 5 ml/min per 1.73 m 2 . RESULTS: Among 1290 adults with CKD stages 4-5, using the Chronic Kidney Disease Epidemiology Collaboration equation yielded shorter preemptive waittime between an eGFR of 20 and 5 ml/min per 1.73 m 2 in Black (-6.8 months; 95% confidence interval [CI], -11.7 to -1.9), Hispanic (-10.2 months; -15.3 to -5.1), and Asian/Pacific Islander (-10.3 months; 95% CI, -15.3 to -5.4) patients compared with non-Hispanic White patients. Use of a KFRE threshold to determine waittime yielded smaller differences by race and ethnicity than observed when using a single eGFR threshold, with shorter time still noted for Black (-2.5 months; 95% CI, -7.8 to 2.7), Hispanic (-4.8 months; 95% CI, -10.3 to 0.6), and Asian/Pacific Islander (-5.4 months; -10.7 to -0.1) individuals compared with non-Hispanic White individuals, but findings only met statistical significance criteria in Asian/Pacific Islander individuals. When we compared potential waittime availability using a KFRE versus eGFR threshold, use of the KFRE yielded more equity in waittime for Black ( P = 0.02), Hispanic ( P = 0.002), and Asian/Pacific Islander ( P = 0.002) patients. CONCLUSIONS: Use of a risk-based strategy was associated with greater racial equity in waittime accrual compared with use of a standard single eGFR threshold to determine eligibility for preemptive waitlisting.

PEERNaija-a mobile health platform incentivizing medication adherence among youth living with HIV in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: Poor medication adherence is a major barrier to HIV control among youth living with HIV (Y-PLWH). The PEERNaija application (app) is an adapted smartphone app grounded in social cognitive and contigency management theories and designed to harness peer-based social incentives and conditional financial incentives to promote medication adherence. The app delivers a multifaceted medication adherence intervention including (1) peer-based social incentives, (2) financial incentives, (3) virtual peer social support, and (4) early clinic-based outreach for non-adherent Y-PLWH. A pilot trial of the app will be conducted in Nigeria, Africa's most populous country with the 4th largest HIV epidemic, and home to 10% of the world's four million Y-PLWH. METHODS: In this randomized controlled trial, we will compare implementation outcomes (feasibility, acceptability, appropriateness measured via validated scales, enrollment and application installation rates, feedback surveys and focus group discussions with participants, and back-end application data), and preliminary efficacy (in improving medication adherence and viral suppression) of the PEERNaija app at 6 months. Participants in Arm 1 (PEERNaija) will receive daily medication reminders, peer-based social incentives, and virtual peer social support. Participants in Arm 2 (PEERNaija +) will additionally receive a conditional financial incentive based on their adherence performance. Eligibility for Y-PLWH includes (1) being aged 14-29 years, (2) being on ART, (3) owning a smartphone, (4) being willing to download an app, and (5) being able to read simple text in English. DISCUSSION: This study will serve as the basis for a larger intervention trial evaluating the PEERNaija app (and the integration of mHealth, incentive, and peer-support-based strategies) to improve HIV outcomes in a critically important region of the world for Y-PLWH. TRIAL REGISTRATION: ClinicalTrials.gov. NCT04930198. First submitted date: May 25, 2021. Study start: August 1, 2021, https://clinicaltrials.gov/ . PROTOCOL VERSION: January 21, 2022.

New Insights on Sperm Function in Male Infertility of Unknown Origin: A Multimodal Approach.

The global trend of rising (male) infertility is concerning, and the unidentifiable causes in half of the cases, the so-called unknown origin male infertility (UOMI), demands a better understanding and assessment of both external/internal factors and mechanisms potentially involved. In this work, it was our aim to obtain new insight on UOMI, specifically on idiopathic (ID) and Unexplained male infertility (UMI), relying on a detailed evaluation of the male gamete, including functional, metabolic and proteomic aspects. For this purpose, 1114 semen samples, from males in couples seeking infertility treatment, were collected at the Reproductive Medicine Unit from the Centro Hospitalar e Universitário de Coimbra (CHUC), from July 2018-July 2022. Based on the couples' clinical data, seminal/hormonal analysis, and strict eligibility criteria, samples were categorized in 3 groups, control (CTRL), ID and UMI. Lifestyle factors and anxiety/depression symptoms were assessed via survey. Sperm samples were evaluated functionally, mitochondrially and using proteomics. The results of Assisted Reproduction Techniques were assessed whenever available. According to our results, ID patients presented the worst sperm functional profile, while UMI patients were similar to controls. The proteomic analysis revealed 145 differentially expressed proteins, 8 of which were specifically altered in ID and UMI samples. Acrosin (ACRO) and sperm acrosome membrane-associated protein 4 (SACA4) were downregulated in ID patients while laminin subunit beta-2 (LAMB2), mannose 6-phosphate isomerase (MPI), ATP-dependent 6-phosphofructokinase liver type (PFKAL), STAR domain-containing protein 10 (STA10), serotransferrin (TRFE) and exportin-2 (XPO2) were downregulated in UMI patients. Using random forest analysis, SACA4 and LAMB2 were identified as the sperm proteins with a higher chance of distinguishing ID and UMI patients, and their function and expression variation were in accordance with the functional results. No alterations were observed in terms of lifestyle and psychological factors among the 3 groups. These findings obtained in an experimental setting based on 3 well-defined groups of subjects, might help to validate new biomarkers for unknown origin male infertility (ID and UMI) that, in the future, can be used to improve diagnostics and treatments.

Defining and Promoting Pediatric Pulmonary Health: Leveraging Patient Reported Outcomes.

Patient-reported outcomes are based on patient (or caregiver) descriptions without direct measurement by a health care provider. To capture patient-reported outcomes, various patient-reported outcome measures (PROMs) have been created. Using PROMs has been linked to improved patient satisfaction, patient-provider communication, and clinical outcomes in many pediatric fields. Despite a long-standing history of utilizing PROMs for the evaluation and management of childhood asthma, pediatric pulmonologists lag behind other pediatric subspecialists in the use of PROMs. During the National Heart, Lung, and Blood Institute's "Defining and Promoting Pediatric Pulmonary Health" workshop, critical knowledge gaps and research opportunities in the use of PROMs for childhood respiratory health were reviewed. In particular, PROMs can be employed as screening tools in the general population for the primary or secondary prevention of pediatric lung diseases. Incorporating these PROMs into the pediatric primary care setting would be especially impactful. In addition, the use of PROMs for the evaluation and management of asthma suggests that they can be applied to other childhood respiratory diseases. Ongoing multicenter studies or national consortia that study pediatric lung diseases could be leveraged to conduct research designed to develop, validate, and assess the utility of PROMs to assess childhood respiratory health. Harnessing the electronic health record will be critical for the successful adoption of PROMs in children with lung diseases. Ultimately, an integrative approach to systematically address numerous barriers at the level of the provider, patient, and health care system will be needed to attain this goal and achieve sustainability.

A randomized controlled trial of preemptive rituximab to prevent recurrent focal segmental glomerulosclerosis post-kidney transplant (PRI-VENT FSGS): protocol and study design.

Background: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease requiring kidney transplantation and can recur in the allograft in 30-80% of recipients resulting in reduced graft survival. Plasmapheresis has shown efficacy in treating some cases of recurrent FSGS but isolated plasmapheresis has not demonstrated efficacy in preventing recurrent FSGS. Rituximab has had anecdotal success in preventing recurrence in a single center study but has not been studied in combination with plasmapheresis for preventing FSGS recurrence. Methods: We are conducting a randomized, controlled, multicenter clinical trial of adult and pediatric kidney transplant recipients with primary FSGS to assess whether plasmapheresis in combination with rituximab prevents recurrent disease post-transplantation. Discussion: Rituximab combined with plasmapheresis is a promising, novel therapy to prevent recurrent FSGS, a disease with limited therapeutic options and no consensus guidelines for prevention or treatment. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03763643, identifier NCT03763643.

Association Between Dialysis Facility Ownership and Mortality Risk in Children With Kidney Failure.

Importance: In adults, treatment at profit dialysis facilities has been associated with a higher risk of death. Objective: To determine whether profit status of dialysis facilities is associated with the risk of death in children with kidney failure treated with dialysis and whether any such association is mediated by differences in access to transplant. Design, Setting, and Participants: This retrospective cohort study reviewed US Renal Data System records of 15 359 children who began receiving dialysis for kidney failure between January 1, 2000, and December 31, 2019, in US dialysis facilities. The data analysis was performed between May 2, 2022, and June 15, 2023. Exposure: Time-updated profit status of dialysis facilities. Main Outcomes and Measures: Adjusted Fine-Gray models were used to determine the association of time-updated profit status of dialysis facilities with risk of death, treating kidney transplant as a competing risk. Cox proportional hazards regression models were also used to determine time-updated profit status with risk of death regardless of transplant status. Results: The final cohort included 8465 boys (55.3%) and 6832 girls (44.7%) (median [IQR] age, 12 [3-15] years). During a median follow-up of 1.4 (IQR, 0.6-2.7) years, with censoring at transplant, the incidence of death was higher at profit vs nonprofit facilities (7.03 vs 4.06 per 100 person-years, respectively). Children treated at profit facilities had a 2.07-fold (95% CI, 1.83-2.35) higher risk of death compared with children at nonprofit facilities in adjusted analyses accounting for the competing risk of transplant. When follow-up was extended regardless of transplant status, the risk of death remained higher for children treated in profit facilities (hazard ratio, 1.47; 95% CI, 1.35-1.61). Lower access to transplant in profit facilities mediated 67% of the association between facility profit status and risk of death (95% CI, 45%-100%). Conclusions and Relevance: Given the higher risk of death associated with profit dialysis facilities that is partially mediated by lower access to transplant, the study's findings indicate a need to identify root causes and targeted interventions that can improve mortality outcomes for children treated in these facilities.

End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine.

Heparin is the most common anticoagulant used in clinical practice but shows some downsides such as short half-life (for the high molecular weight heparin) and secondary effects. On the other hand, its low molecular weight analogue cannot be neutralized with protamine, and therefore cannot be used in some treatments. To address these issues, we conjugated polyethylene glycol (PEG) to heparin reducing end (end-on) via oxime ligation and studied the interactions of the conjugate (Hep-b-PEG) with antithrombin III (AT) and protamine. Isothermal titration calorimetry showed that Hep-b-PEG maintains the affinity to AT. Dynamic light scattering demonstrated that the Hep-b-PEG formed colloidal stable nanocomplexes with protamine instead of large multi-molecular aggregates, associated with heparin side effects. The in vitro (human plasma) and in vivo experiments (Sprague Dawley rats) evidenced an extended half-life and higher anticoagulant activity of the conjugate when compared to unmodified heparin.

Exercise-induced angiogenesis is attenuated by captopril but maintained under perindopril treatment in hypertensive rats.

Angiogenesis is an important exercise-induced response to improve blood flow and decrease vascular resistance in spontaneously hypertensive rats (SHR), but some antihypertensive drugs attenuate this effect. This study compared the effects of captopril and perindopril on exercise-induced cardiac and skeletal muscle angiogenesis. Forty-eight Wistar rats and 48 SHR underwent 60 days of aerobic training or were kept sedentary. During the last 45 days, rats were treated with captopril, perindopril or water (Control). Blood pressure (BP) measurements were taken and histological samples from the tibialis anterior (TA) and left ventricle (LV) muscles were analyzed for capillary density (CD) and vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and endothelial nitric oxide synthase (eNOS) protein level. Exercise increased vessel density in Wistar rats due to higher VEGFR-2 (+17%) and eNOS (+31%) protein level. Captopril and perindopril attenuated exercise-induced angiogenesis in Wistar rats, but the attenuation was small in the perindopril group, and this response was mediated by higher eNOS levels in the Per group compared to the Cap group. Exercise increased myocardial CD in Wistar rats in all groups and treatment did not attenuate it. Both exercise and pharmacological treatment reduced BP of SHR similarly. Rarefaction was found in TA of SHR compared to Wistar, due to lower levels of VEGF (-26%) and eNOS (-27%) and treatment did not avoid this response. Exercise prevented these reductions in control SHR. While rats treated with perindopril showed angiogenesis in the TA muscle after training, those rats treated with captopril showed attenuated angiogenesis (-18%). This response was also mediated by lower eNOS levels in Cap group compared with Per and control group. Myocardial CD was reduced in all sedentary hypertensive compared with Wistar and training restored the number of vessels compared with sedentary SHR. In conclusion, taken into account only the aspect of vessel growth, since both pharmacological treatments reduced BP in SHR, the result of the present study suggests that perindopril could be a drug of choice over captopril for hypertensive practitioners of aerobic physical exercises, especially considering that it does not attenuate angiogenesis induced by aerobic physical training in skeletal and cardiac muscles.

Imaging fibrosis in pediatric kidney transplantation: A pilot study.

BACKGROUND: Noninvasive alternatives to biopsy for assessment of interstitial fibrosis and tubular atrophy (IFTA), the major determinant of kidney transplant failure, remain profoundly limited. Elastography is a noninvasive technique that propagates shear waves across tissues to measure their stiffness. We aimed to test utility of elastography for early detection of IFTA in pediatric kidney allografts. METHODS: We compared ultrasound (USE) and MR elastography (MRE) stiffness measurements, performed on pediatric transplant recipients referred for clinically indicated biopsies, and healthy controls. RESULTS: Ten transplant recipients (median age 16 years) and eight controls (median age 16.5 years) were enrolled. Three transplant recipients had "stable" allografts and seven had Banff Grade 1 IFTA. Median time from transplantation to biopsy was 12 months. Mean estimated glomerular filtration rate was 61.5 mL/min/1.73m2 by creatinine-cystatin-C CKiD equation at time of biopsy. Mean stiffness, calculated through one-way ANOVA, was higher for IFTA allografts (23.4 kPa USE/5.6 kPa MRE) than stable allografts (13.7 kPa USE/4.4 kPa MRE) and controls (9.1 kPa USE/3.6 kPa MRE). Pearson's coefficient between USE and MRE stiffness values was strong (r = .97). AUC for fibrosis prediction in transplanted kidneys was high for both modalities (0.91 USE and 0.89 MRE), although statistically nonsignificant (p > .05). Stiffness cut-off values for USE and MRE were 13.8 kPa and 4.6 kPa, respectively. Both values yielded a sensitivity of 100% but USE specificity (72%) was slightly higher than MRE (67%). CONCLUSION: Elastography shows potential for detection of low-grade IFTA in allografts although a larger sample is imperative for clinical validation.

Physical Training vs. Perindopril Treatment on Arterial Stiffening of Spontaneously Hypertensive Rats: A Proteomic Analysis and Possible Mechanisms.

(1) Background: Arterial stiffness is an important predictor of cardiovascular events. Perindopril and physical exercise are important in controlling hypertension and arterial stiffness, but the mechanisms are unclear. (2) Methods: Thirty-two spontaneously hypertensive rats (SHR) were evaluated for eight weeks: SHRC (sedentary); SHRP (sedentary treated with perindopril-3 mg/kg) and SHRT (trained). Pulse wave velocity (PWV) analysis was performed, and the aorta was collected for proteomic analysis. (3) Results: Both treatments determined a similar reduction in PWV (-33% for SHRP and -23% for SHRT) vs. SHRC, as well as in BP. Among the altered proteins, the proteomic analysis identified an upregulation of the EH domain-containing 2 (EHD2) protein in the SHRP group, required for nitric oxide-dependent vessel relaxation. The SHRT group showed downregulation of collagen-1 (COL1). Accordingly, SHRP showed an increase (+69%) in the e-NOS protein level and SHRT showed a lower COL1 protein level (-46%) compared with SHRC. (4) Conclusions: Both perindopril and aerobic training reduced arterial stiffness in SHR; however, the results suggest that the mechanisms can be distinct. While treatment with perindopril increased EHD2, a protein involved in vessel relaxation, aerobic training decreased COL1 protein level, an important protein of the extracellular matrix (ECM) that normally enhances vessel rigidity.

Patient-Reported Outcomes Over 24 Months in Pediatric CKD: Findings From the MyKidneyHealth Cohort Study.

RATIONALE & OBJECTIVE: The lived experience of children with chronic kidney disease (CKD) is poorly characterized. We examined the associations between patient-reported outcome (PRO) scores measuring their fatigue, sleep health, psychological distress, family relationships, and global health with clinical outcomes over time in children, adolescents, and younger adults with CKD and investigated how the PRO scores of this group compare with those of other children, adolescents, and younger adults. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 212 children, adolescentss, and adults aged 8 to 21 years with CKD and their parents recruited from 16 nephrology programs across North America. PREDICTORS: CKD stage, disease etiology, and sociodemographic and clinical variables. OUTCOME: PRO scores over 2 years. ANALYTICAL APPROACH: We compared PRO scores in the CKD sample with a nationally representative general pediatric population (ages 8 to 17 years). Change of PROs over time and association of sociodemographic and clinical variables with PROs were assessed using multivariable regression models. RESULTS: For all time points, 84% of the parents and 77% of the children, adolescents, and younger adults completed PRO surveys . The baseline PRO scores for the participants with CKD revealed a higher burden of fatigue, sleep-related impairment, psychological distress, impaired global health, and poorer family relationships compared with the general pediatric population, with median score differences≥1 SD for fatigue and global health. The baseline PRO scores did not differ by CKD stage or glomerular versus nonglomerular etiology. Over 2 years, PROs were stable with a<1-point annual change on average on each measure and intraclass correlation coefficients ranging from 0.53 to 0.79, indicating high stability. Hospitalization and parent-reported sleep problems were associated with worse fatigue, psychological health, and global health scores (all P<0.04). LIMITATIONS: We were unable to assess responsiveness to change with dialysis or transplant. CONCLUSIONS: Children with CKD experience a high yet stable burden of impairment across numerous PRO measures, especially fatigue and global health, independent of disease severity. These findings underscore the importance of assessing PROs, including fatigue and sleep measures, in this vulnerable population. PLAIN-LANGUAGE SUMMARY: Children with chronic kidney disease (CKD) have many treatment demands and experience many systemic effects. How CKD impacts the daily life of a child is poorly understood. We surveyed 212 children, adolescents, and younger adults with CKD and their parents over 24 months to assess the participants' well-being over time. Among children, adolescents, and younger adults with CKD we found a very high and persistent burden of psychological distress that did not differ by degree of CKD or type of kidney disease. The participants with CKD endorsed greater impairment in fatigue and global health compared with healthy children, adolescents, and younger adults, and parent-reported sleep problems were associated with poorer patient-reported outcome (PRO) scores across all domains. These findings emphasize the importance of including PRO measures, including fatigue and sleep measures, into routine clinical care to optimize the lived experience of children with CKD.

Dexamethasone-Induced Arterial Stiffening Is Attenuated by Training due to a Better Balance Between Aortic Collagen and Elastin Levels.

PURPOSE: Although the cardioprotective benefits of exercise training are well known, the effects of training on dexamethasone (DEX)-induced arterial stiffness are still unclear. This study was aimed at investigating the mechanisms induced by training to prevent DEX-induced arterial stiffness. METHODS: Wistar rats were allocated into 4 groups and submitted to combined training (aerobic and resistance exercises, on alternate days, 60% of maximal capacity, for 74 d) or were kept sedentary: sedentary control rats (SC), DEX-treated sedentary rats (DS), combined training control (CT), and DEX-treated trained rats (DT). During the last 14 d, rats were treated with DEX (50 µg/kg per body weight, per day, s.c.) or saline. RESULTS: DEX increased PWV (+44% vs +5% m/s, for DS vs SC, p<0.001) and increased aortic COL 3 protein level (+75%) in DS. In addition, PWV was correlated with COL3 levels (r=0.682, p<0.0001). Aortic elastin and COL1 protein levels remained unchanged. On the other hand, the trained and treated groups showed lower PWV values (-27% m/s, p<0.001) vs DS and lower values of aortic and femoral COL3 compared with DS. CONCLUSION: As DEX is widely used in several situations, the clinical relevance of this study is that the maintenance of good physical capacity throughout life can be crucial to alleviate some of its side effects, such as arterial stiffness.

Predicting psychosocial risk in pediatric kidney transplantation: An exploratory cluster analysis of a revised Pediatric Transplant Rating Instrument.

BACKGROUND: The Pediatric Transplant Rating Instrument (P-TRI) is a 17-item scale developed to assess psychosocial risk factors for poor outcomes after solid organ transplantation. Research has identified the limitations of the original instrument and proposed revisions to improve clinical utility. This project examined patterns of risk in children being evaluated for kidney transplant using a revised P-TRI. METHODS: A multidisciplinary kidney transplant team revised the P-TRI. A social worker and a psychologist collaboratively completed the modified instrument for 37 children after the psychosocial pretransplant evaluation. Electronic medical records were reviewed for transplant status (transplanted, active waitlist, inactive) 1 year later. Exploratory cluster analyses and chi-square tests examined patterns of risk and correlates with cluster membership. RESULTS: Three clusters were identified. The high-risk group (29.7%) had difficulties with medication and appointment adherence, strained relationships with the medical team, and the presence of parent psychiatric history. The medium-risk group (35.1%) had difficulties with parent knowledge, financial strain, and risk factors for medication nonadherence. The low-risk group (35.1%) demonstrated no difficulties with adherence or financial strain. Clusters were prospectively associated with transplant status, such that those in the high-risk group were less likely to be transplanted within 1 year post-evaluation. CONCLUSIONS: The revised P-TRI demonstrated good construct validity as risk level appeared to be associated with transplant listing status 1 year post-evaluation. These results suggest that standardized pretransplant psychosocial risk assessment tools may have value in optimizing transplant access if they can be paired with targeted, multidisciplinary interventions to address concerns early in the transplant process.