Associations of Apixaban Dose With Safety and Effectiveness Outcomes in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease.

BACKGROUND: Recommendations for apixaban dosing on the basis of kidney function are inconsistent between the US Food and Drug Administration and European Medicines Agency for patients with atrial fibrillation. Optimal apixaban dosing in chronic kidney disease remains unknown. METHODS: With the use of deidentified electronic health record data from the Optum Labs Data Warehouse, patients with atrial fibrillation and chronic kidney disease stage 4/5 initiating apixaban between 2013 and 2021 were identified. Risks of bleeding and stroke/systemic embolism were compared by apixaban dose (5 versus 2.5 mg), adjusted for baseline characteristics by the inverse probability of treatment weighting. The Fine-Gray subdistribution hazard model was used to account for the competing risk of death. Cox regression was used to examine risk of death by apixaban dose. RESULTS: Among 4313 apixaban new users, 1705 (40%) received 5 mg and 2608 (60%) received 2.5 mg. Patients treated with 5 mg apixaban were younger (mean age, 72 versus 80 years), with greater weight (95 versus 80 kg) and higher serum creatinine (2.7 versus 2.5 mg/dL). Mean estimated glomerular filtration rate was not different between the groups (24 versus 24 mL·min-1·1.73 m-2). In inverse probability of treatment weighting analysis, apixaban 5 mg was associated with a higher risk of bleeding (incidence rate 4.9 versus 2.9 events per 100 person-years; incidence rate difference, 2.0 [95% CI, 0.6-3.4] events per 100 person-years; subdistribution hazard ratio, 1.63 [95% CI, 1.04-2.54]). There was no difference between apixaban 5 mg and 2.5 mg groups in the risk of stroke/systemic embolism (3.3 versus 3.0 events per 100 person-years; incidence rate difference, 0.2 [95% CI, -1.0 to 1.4] events per 100 person-years; subdistribution hazard ratio, 1.01 [95% CI, 0.59-1.73]), or death (9.9 versus 9.4 events per 100 person-years; incidence rate difference, 0.5 [95% CI, -1.6 to 2.6] events per 100 person-years; hazard ratio, 1.03 [95% CI, 0.77-1.38]). CONCLUSIONS: Compared with 2.5 mg, use of 5 mg apixaban was associated with a higher risk of bleeding in patients with atrial fibrillation and severe chronic kidney disease, with no difference in the risk of stroke/systemic embolism or death, supporting the apixaban dosing recommendations on the basis of kidney function by the European Medicines Agency, which differ from those issued by the US Food and Drug Administration.

Glucagon-like peptide-1 receptor agonists and the risk of atrial fibrillation in adults with diabetes: a real-world study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. OBJECTIVE: To examine the real-world risk of AF comparing GLP-1RA with other non-insulin glucose-lowering agents. DESIGN: Cohort study using de-identified electronic health record data from the Optum Labs Data Warehouse. PARTICIPANTS: Adult patients with diabetes who were newly prescribed add-on non-insulin glucose-lowering agents and were on metformin between 2005-2020. EXPOSURES: New users of GLP-1RA were separately compared with new users of dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), using 1:1 propensity score matching to adjust for differences in patient characteristics. MAIN MEASURES: The primary outcome was incident AF, defined and captured by diagnosis code for AF. Incidence rate difference (IRD) and hazard ratio (HR) were estimated in the matched cohorts. KEY RESULTS: In the matched cohort of 14,566 pairs of GLP-1RA and DPP4i followed for a median of 3.8 years, GLP-1RA use was associated with a lower risk of AF (IRD, -1.0; 95% CI, -1.8 to -0.2 per 1000 person-years; HR, 0.82; 95% CI, 0.70 to 0.96). In the matched cohort of 9,424 pairs of patients on GLP-1RA and SGLT2i with a median follow-up of 2.9 years, there was no difference in the risk for AF (IRD, 0.4; 95% CI -0.7 to 1.5 per 1000 person-years; HR, 1.12; 95% CI, 0.89 to 1.42). CONCLUSIONS: In this real-word study, GLP-1RA was associated with a lower risk of AF compared with DPP4i, but no difference compared with SGLT2i, suggesting that cardiovascular benefits of GLP-1RA use may extend to prevention for AF in patients with diabetes. Our findings call for future randomized controlled trials to focus on the effects of GLP-1RA on AF prevention.

Plasma Metabolomics of Dietary Intake of Protein-Rich Foods and Kidney Disease Progression in Children.

OBJECTIVE: Evidence regarding the efficacy of a low-protein diet for patients with CKD is inconsistent and recommending a low-protein diet for pediatric patients is controversial. There is also a lack of objective biomarkers of dietary intake. The purpose of this study was to identify plasma metabolites associated with dietary intake of protein and to assess whether protein-related metabolites are associated with CKD progression. METHODS: Nontargeted metabolomics was conducted in plasma samples from 484 Chronic Kidney Disease in Children (CKiD) participants. Multivariable linear regression estimated the cross-sectional association between 949 known, nondrug metabolites and dietary intake of total protein, animal protein, plant protein, chicken, dairy, nuts and beans, red and processed meat, fish, and eggs, adjusting for demographic, clinical, and dietary covariates. Cox proportional hazards models assessed the prospective association between protein-related metabolites and CKD progression defined as the initiation of kidney replacement therapy or 50% eGFR reduction, adjusting for demographic and clinical covariates. RESULTS: One hundred and twenty-seven (26%) children experienced CKD progression during 5 years of follow-up. Sixty metabolites were significantly associated with dietary protein intake. Among the 60 metabolites, 10 metabolites were significantly associated with CKD progression (animal protein: n = 1, dairy: n = 7, red and processed meat: n = 2, nuts and beans: n = 1), including one amino acid, one cofactor and vitamin, 4 lipids, 2 nucleotides, one peptide, and one xenobiotic. 1-(1-enyl-palmitoyl)-2-oleoyl-glycerophosphoethanolamine (GPE, P-16:0/18:1) was positively associated with dietary intake of red and processed meat, and a doubling of its abundance was associated with 88% higher risk of CKD progression. 3-ureidopropionate was inversely associated with dietary intake of red and processed meat, and a doubling of its abundance was associated with 48% lower risk of CKD progression. CONCLUSIONS: Untargeted plasma metabolomic profiling revealed metabolites associated with dietary intake of protein and CKD progression in a pediatric population.

Hyperkalemia in pediatric chronic kidney disease.

BACKGROUND: While hyperkalemia is well described in adult chronic kidney disease (CKD), large studies evaluating potassium trends and risk factors for hyperkalemia in pediatric CKD are lacking. This study aimed to characterize hyperkalemia prevalence and risk factors in pediatric CKD. METHODS: Cross-sectional analysis of Chronic Kidney Disease in Children (CKiD) study data evaluated median potassium levels and percentage of visits with hyperkalemia (K ≥5.5 mmoL/L) in relation to demographics, CKD stage, etiology, proteinuria, and acid-base status. Multiple logistic regression was used to identify risk factors for hyperkalemia. RESULTS: One thousand and fifty CKiD participants with 5183 visits were included (mean age 13.1 years, 62.7% male, 32.9% self-identifying as African American or Hispanic). A percentage of 76.6% had non-glomerular disease, 18.7% had CKD stage 4/5, 25.8% had low CO2, and 54.2% were receiving ACEi/ARB therapy. Unadjusted analysis identified a median serum potassium level of 4.5 mmol/L (IQR 4.1-5.0, p <0.001) and hyperkalemia in 6.6% of participants with CKD stage 4/5. Hyperkalemia was present in 14.3% of visits with CKD stage 4/5 and glomerular disease. Hyperkalemia was associated with low CO2 (OR 7.72, 95%CI 3.05-19.54), CKD stage 4/5 (OR 9.17, 95%CI 4.02-20.89), and use of ACEi/ARB therapy (OR 2.14, 95%CI 1.36-3.37). Those with non-glomerular disease were less frequently hyperkalemic (OR 0.52, 95%CI 0.34-0.80). Age, sex, and race/ethnicity were not associated with hyperkalemia. CONCLUSIONS: Hyperkalemia was observed more frequently in children with advanced stage CKD, glomerular disease, low CO2, and ACEi/ARB use. These data can help clinicians identify high-risk patients who may benefit from earlier initiation of potassium-lowering therapies. A higher resolution version of the Graphical abstract is available as Supplementary information.

Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology.

BACKGROUND: Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN). METHODS: Untargeted metabolomic quantification (GC-MS/LC-MS, Metabolon) was performed on plasma from 702 Chronic Kidney Disease in Children study participants (n: FSGS=63, OU=122, A/D/H=109, and RN=86). Lasso regression was used for feature selection, adjusting for clinical covariates. Four methods were then applied to stratify significance: logistic regression, support vector machine, random forest, and extreme gradient boosting. ML training was performed on 80% total cohort subsets and validated on 20% holdout subsets. Important features were selected based on being significant in at least two of the four modeling approaches. We additionally performed pathway enrichment analysis to identify metabolic subpathways associated with CKD cause. RESULTS: ML models were evaluated on holdout subsets with receiver-operator and precision-recall area-under-the-curve, F1 score, and Matthews correlation coefficient. ML models outperformed no-skill prediction. Metabolomic profiles were identified based on cause. FSGS was associated with the sphingomyelin-ceramide axis. FSGS was also associated with individual plasmalogen metabolites and the subpathway. OU was associated with gut microbiome-derived histidine metabolites. CONCLUSION: ML models identified metabolomic signatures based on CKD cause. Using ML techniques in conjunction with traditional biostatistics, we demonstrated that sphingomyelin-ceramide and plasmalogen dysmetabolism are associated with FSGS and that gut microbiome-derived histidine metabolites are associated with OU.

Association of GSTM1 Deletion With Progression of CKD in Children: Findings From the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Loss of function of the product of the GSTM1 gene has been implicated in rapid progression of adult chronic kidney disease (CKD). Its role in pediatric CKD has not been previously described. STUDY DESIGN: Secondary analysis of a prospective observational cohort examining the association between deletions in GSTM1 and progression of CKD. SETTING & PARTICIPANTS: We used data and samples from the prospective Chronic Kidney Disease in Children (CKiD) cohort aged 1-16 years at enrollment with CKD. EXPOSURE: We defined the exposure as fewer than 2 GSTM1 alleles on real-time polymerase chain reaction amplification. OUTCOME: The primary outcome was a composite of 50% decrease in estimated glomerular filtration rate (eGFR) or start of kidney replacement therapy. Secondary outcomes included remission of proteinuria in children with glomerular disease and cardiovascular complications. ANALYTICAL APPROACH: The primary analysis was by Cox proportional hazards model. Analysis was adjusted for age, sex, race, ethnicity, body mass index category, diagnosis category, and eGFR. RESULTS: The analysis included 674 children. Their mean age at most recent visit was 11.9 years; 61% were male, and 20% were Black. There were 241 occurrences of the primary outcome at the time of analysis. After adjustment for baseline characteristics, the risk of progression of CKD for exposed children was 1.94 (95% CI, 1.27-2.97). The effect size was similar with either 1 or 2 deletions (autosomal dominant inheritance). The relationships between number of functional GSTM1 alleles and prespecified secondary outcomes were not statistically significant after adjustment. LIMITATIONS: Missing data, especially for secondary outcomes, and relatively small sample size compared to genetic studies in adults. CONCLUSIONS: GSTM1 deletion is associated with more rapid progression of pediatric CKD after adjustment in this large prospective cohort. No statistically significant associations were seen with secondary outcomes. If replicated, these findings may inform development of interventions for CKD in children.

Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children.

BACKGROUND: Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression. METHODS: We investigated the relationship between urine biomarkers of kidney tubular health (EGF and α-1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m2. Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period. RESULTS: Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and α-1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression. CONCLUSIONS: After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and α-1 microglobulin concentrations were each associated with CKD progression in children.

Factors associated with the absence of pharmacological treatment for common modifiable complications in children with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with many comorbidities requiring complex management. We described treatment patterns for common modifiable CKD complications (high blood pressure, anemia, hyperphosphatemia, and acidosis) according to severity of CKD and examined factors associated with the absence of drug therapy, among participants with a persistent comorbidity, for 1 year in children enrolled in the CKiD study. METHODS: A total of 703 CKiD participants contributed 2849 person-visits over a median 3.5 years of follow-up. Using pairs of annual visits, we examined whether participants with abnormal biomarker levels at the first (index) visit persisted in the abnormal levels 1 year later according to CKD risk stage. Multivariate analyses identified demographic and clinical factors associated with the absence of drug therapy among those with persistent comorbid conditions for 1 year. RESULTS: The overall proportions of person-visits prescribing therapy at 1-year follow-up for treating anemia, acidosis, hyperphosphatemia, and high blood pressure were 54%, 45%, 29%, and 81%, respectively. The frequency of therapy increased with advanced CKD risk stage for all comorbidities; however, 19-23% of participants with acidosis, 24-27% with anemia, and 30-39% with hyperphosphatemia at high-risk stages (E and F) were not prescribed appropriate therapy despite the persistence of abnormal levels of these biomarkers for at least 1 year. The resolution of comorbidities at advanced CKD stages without treatment was unlikely. CONCLUSIONS: Many children with CKD in the CKiD cohort did not receive pharmacological treatment for common and persistent modifiable comorbidities, even in severe CKD risk stages.

Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children.

BACKGROUND: After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline. METHODS: We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30-90 ml/min per 1.73 m2 and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD. RESULTS: Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m2), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly. CONCLUSIONS: Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.

Timing of patient-reported renal replacement therapy planning discussions by disease severity among children and young adults with chronic kidney disease.

BACKGROUND: Preparing children with chronic kidney disease (CKD) for renal replacement therapy (RRT) begins with a discussion about transplant and dialysis, but its typical timing in the course of CKD management is unclear. We aimed to describe participant-reported RRT planning discussions by CKD stage, clinical and sociodemographic characteristics, in the Chronic Kidney Disease in Children (CKiD) cohort. METHODS: Participants responded to the question "In the past year, have you discussed renal replacement therapy with your doctor or healthcare provider?" at annual study visits. Responses were linked to the previous year CKD risk stage based on GFR and proteinuria. Repeated measure logistic models estimated the proportion discussing RRT by stage, with modification by sex, age, race, socioeconomic status, and CKD diagnosis (glomerular vs. non-glomerular). RESULTS: A total of 721 CKiD participants (median age = 12, 62% boys) contributed 2856 person-visits. Proportions of person-visits reporting RRT discussions increased as CKD severity increased (10% at the lowest disease stage and 87% at the highest disease stage). After controlling for CKD risk stage, rates of RRT discussions did not differ by sex, age, race, and socioeconomic status. CONCLUSIONS: Despite participant-reported RRT discussions being strongly associated with CKD severity, a substantial proportion with advanced CKD reported no discussion. While recall bias may lead to underreporting, it is still meaningful that some participants with severe CKD did not report or remember discussing RRT. Initiating RRT discussions early in the CKD course should be encouraged to foster comprehensive preparation and to align RRT selection for optimal health and patient preferences.

Effectiveness and safety of surgical interventions for treating adolescent idiopathic scoliosis: a Bayesian meta-analysis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity in children and adolescents which presents as complex three-dimensional (3D) deformity of the spine and rib cage. This study aimed to estimate the effectiveness and safety of surgical interventions for AIS using Bayesian meta-analysis. METHODS: The PubMed, EMBASE, and Cochrane Controlled Register of Trials were searched through Oct 1, 2019, without language restrictions. Relevant studies evaluating combined effectiveness and safety of surgical interventions for AIS were included according to eligibility criteria. The primary outcome measures included pulmonary function (change of absolute forced vital capacity and forced expiratory volume in 1 second from pre-operation to post-operation) and incidence of complications. The secondary outcome measure was change of Cobb angle from pre-operation to post-operation. Data was pooled using a random effects model in pairwise meta-analysis. Bayesian meta-analysis combined direct and indirect evidence using a Bayesian framework. RESULTS: Twenty-eight case-controlled studies with totally 1970 participants were included. This Bayesian meta-analysis combining direct and indirect evidences indicated that posterior fusion with instrumentation without thoracoplasty (PSF) had the highest probability to achieve better pulmonary function and lower complication rate; video assisted anterior fusion with instrumentation without thoracoplasty (VAT) had the highest probability to obtain better Cobb angle correction based on analysis of rank probability. CONCLUSION: This Bayesian meta-analysis demonstrated that PSF had the highest probability to achieve better post-surgical pulmonary function and lower complication rate, which gives a practical recommendation of PSF as a primary surgical treatment for AIS. The results also support statistics that current surgeries adopted more PSF but less open anterior approach surgery and thoracoplasty. More research work is required to address the effectiveness and safety of VAT for treating AIS more convincingly.

Current and Novel Biomarkers of Progression Risk in Children with Chronic Kidney Disease.

BACKGROUND: Due to the complexity of chronic kidney disease (CKD) pathophysiology, biomarkers representing different mechanistic pathways have been targeted for the study and development of novel biomarkers. The discovery of clinically useful CKD biomarkers would allow for the identification of those children at the highest risk of kidney function decline for timely interventions and enrollment in clinical trials. SUMMARY: Glomerular filtration rate and proteinuria are traditional biomarkers to classify and prognosticate CKD progression in clinical practice but have several limitations. Over the recent decades, novel biomarkers have been identified from blood or urine with metabolomic screening studies, proteomic screening studies, and an improved knowledge of CKD pathophysiology. This review highlights promising biomarkers associated with the progression of CKD that could potentially serve as future prognostic markers in children with CKD. KEY MESSAGES: Further studies are needed in children with CKD to validate putative biomarkers, particularly candidate proteins and metabolites, for improving clinical management.

HPV genotype-specific distribution and attributable risk in cervical intraepithelial neoplasia in a referral population with a history of LSIL.

BACKGROUND AND OBJECTIVE: CINtec PLUS and cobas HPV tests (Roche) were previously ascertained for triaging an LSIL referral population [1]. As part of this study, genotype-specific distribution and attributable risk of high-risk (HR)-HPV in cervical intraepithelial neoplasia (CIN) were determined. METHODS: Archived cervical specimens in ThinPrep PreservCyt (Hologic Inc) from the LSIL referral population (n= 533) were genotyped using the Anyplex II HPV HR test (Anyplex, Seegene Inc). Since the study specimens had been in storage in ambient temperature for 31-47 months since collection, Anyplex results were compared with that of the initial cobas testing of fresh specimens to validate the suitability and stability of specimens for the present study. RESULTS: Overall, Anyplex test was positive in 63% (336/533) vs. 55.7% (297/533) for cobas test. Anyplex test performed identical to cobas test identifying 93.2% (82/88) of ⩾CIN2/adenocarcinoma in situ (AIS). Anyplex test detected genotypes 16/18 in 15.7% (36/230) ⩽CIN1 vs. 45.5% (40/88) ⩾CIN2/AIS; the corresponding figures were 13.5% (31/230) and 45.5% (40/48) for the cobas test. Genotype 16 showed increasing attribution, 13.2% in CIN1, 27.1% in CIN2 and 40% in CIN3/AIS. Of the 12 other high-risk (OHR) types collectively identified by cobas, Anyplex test specifically detected, in decreasing order, genotypes 51, 31, 35, 56, 39, and 45 as the most frequent types, often in multiple-type infections, in 64.8% ⩾CIN2. Regardless, estimated attribution was evident for each of the 12 OHR types in ⩾CIN2. Multiple-type infections were more frequent than single-type infections in all CIN grades. CONCLUSIONS: Attributable risk of all HR-HPV genotypes targeted by both Anyplex and cobas tests was evident in ⩾CIN2/AIS Testing for these genotypes in HPV primary cervical screening and cytology triage could identify those at increased risk of cervical cancer and also be beneficial in the management of LSIL referral populations.

Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD.

BACKGROUND: Children with CKD are at risk for impaired neurocognitive functioning. We investigated metabolomic associations with neurocognition in children with CKD. METHODS: We leveraged data from the Chronic Kidney Disease in Children (CKiD) study and the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease (NiCK) study. CKiD is a multi-institutional cohort that enrolled children aged 6 months to 16 years with eGFR 30-90 ml/min per 1.73 m 2 ( n =569). NiCK is a single-center cross-sectional study of participants aged 8-25 years with eGFR<90 ml/min per 1.73 m 2 ( n =60) and matched healthy controls ( n =67). Untargeted metabolomic quantification was performed on plasma (CKiD, 622 metabolites) and serum (NiCK, 825 metabolites) samples. Four neurocognitive domains were assessed: intelligence, attention regulation, working memory, and parent ratings of executive function. Repeat assessments were performed in CKiD at 2-year intervals. Linear regression and linear mixed-effects regression analyses adjusting for age, sex, delivery history, hypertension, proteinuria, CKD duration, and glomerular versus nonglomerular diagnosis were used to identify metabolites associated with neurocognitive z-scores. Analyses were performed with and without adjustment for eGFR. RESULTS: There were multiple metabolite associations with neurocognition observed in at least two of the analytic samples (CKiD baseline, CKiD follow-up, and NiCK CKD). Most of these metabolites were significantly elevated in children with CKD compared with healthy controls in NiCK. Notable signals included associations with parental ratings of executive function: phenylacetylglutamine, indoleacetylglutamine, and trimethylamine N-oxide-and with intelligence: γ -glutamyl amino acids and aconitate. CONCLUSIONS: Several metabolites were associated with neurocognitive dysfunction in pediatric CKD, implicating gut microbiome-derived substances, mitochondrial dysfunction, and altered energy metabolism, circulating toxins, and redox homeostasis.

The Role of DNA Repair in Immunological Diversity: From Molecular Mechanisms to Clinical Ramifications.

An effective humoral immune response necessitates the generation of diverse and high-affinity antibodies to neutralize pathogens and their products. To generate this assorted immune repertoire, DNA damage is introduced at specific regions of the genome. Purposeful genotoxic insults are needed for the successful completion of multiple immunological diversity processes: V(D)J recombination, class-switch recombination, and somatic hypermutation. These three processes, in concert, yield a broad but highly specific immune response. This review highlights the importance of DNA repair mechanisms involved in each of these processes and the catastrophic diseases that arise from DNA repair deficiencies impacting immune system function. These DNA repair disorders underline not only the importance of maintaining genomic integrity for preventing disease but also for robust adaptive immunity.

Iterative Learning Control With Data-Driven-Based Compensation.

The robust iterative learning control (RILC) can deal with the systems with unknown time-varying uncertainty to track a repeated reference signal. However, the existing robust designs consider all the possibilities of uncertainty, which makes the design conservative and causes the controlled process converging to the reference trajectory slowly. To eliminate this weakness, a data-driven method is proposed. The new design intends to employ more information from the past input-output data to compensate for the robust control law and then to improve performance. The proposed control law is proved to guarantee convergence and accelerate the convergence rate. Ultimately, the experiments on a robot manipulator have been conducted to verify the good convergence of the trajectory errors under the control of the proposed method.

Concomitant Use of Diltiazem With Direct Oral Anticoagulants and Bleeding Risk in Atrial Fibrillation.

Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P-glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m2. At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow-up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding-related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted hazard ratio, 1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted hazard ratio, 1.84 [95% CI, 1.18-2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m2) (P for interaction=0.524 and 0.629, respectively). Among 13 179 warfarin users (the negative control), concomitant diltiazem use was not associated with bleeding. Conclusions Concomitant use of diltiazem with DOACs was associated with a higher bleeding risk in patients with atrial fibrillation, consistently in both subgroups of chronic kidney disease and non-chronic kidney disease. For DOAC users, concomitant diltiazem should be prescribed only when the benefit outweighs the risk, with close monitoring for signs of bleeding.

Use of nephrotoxic medications in adults with chronic kidney disease in Swedish and US routine care.

Background: To characterize the use of nephrotoxic medications in patients with chronic kidney disease (CKD) Stages G3-5 in routine care. Methods: We studied cohorts of adults with confirmed CKD G3-5 undergoing routine care from 1 January 2016 through 31 December 2018 in two health systems [Stockholm CREAtinine Measurements (SCREAM), Stockholm, Sweden (N = 57 880) and Geisinger, PA, USA (N = 16 255)]. We evaluated the proportion of patients receiving nephrotoxic medications within 1 year overall and by baseline kidney function, ranked main contributors and examined the association between receipt of nephrotoxic medication and age, sex, CKD G-stages comorbidities and provider awareness of the patient's CKD using multivariable logistic regression. Results: During a 1-year period, 20% (SCREAM) and 17% (Geisinger) of patients with CKD received at least one nephrotoxic medication. Among the top nephrotoxic medications identified in both cohorts were non-steroidal anti-inflammatory drugs (given to 11% and 9% of patients in SCREAM and Geisinger, respectively), antivirals (2.5% and 2.0%) and immunosuppressants (2.7% and 1.5%). Bisphosphonate use was common in SCREAM (3.3%) and fenofibrates in Geisinger (3.6%). Patients <65 years of age, women and those with CKD G3 were at higher risk of receiving nephrotoxic medications in both cohorts. Notably, provider awareness of a patient's CKD was associated with lower odds of nephrotoxic medication use {odds ratios [OR] 0.85[95% confidence interval (CI) 0.80-0.90] in SCREAM and OR 0.80 [95% CI 0.72-0.89] in Geisinger}. Conclusions: One in five patients with CKD received nephrotoxic medications in two distinct health systems. Strategies to increase physician's awareness of patients' CKD and knowledge of drug nephrotoxicity may reduce prescribing nephrotoxic medications and prevent iatrogenic kidney injury.

Diastolic Function and Ambulatory Hypertension in Children With Chronic Kidney Disease.

[Figure: see text].