Cystatin C and Creatinine Concentrations Are Uninformative Biomarkers of Sarcopenia: A Cross-Sectional NHANES Study.

OBJECTIVES: Differences in creatinine and cystatin C-based estimates of glomerular filtration rate (eGFRDiff = eGFRCr - eGFRCysC) may reflect differences in muscle mass. We sought to determine if eGFRDiff (1) reflects lean mass, (2) identifies sarcopenic individuals beyond estimates based on age, body mass index (BMI), and sex; and (3) demonstrates associations differently in those with and without chronic kidney disease (CKD). DESIGN AND METHODS: This cross-sectional study included 3,754 participants, ages 20-85 years, with creatinine and cystatin C concentration levels, and dual-energy X-ray absorptiometry scans from National Health and Nutrition Examination Survey data (1999-2006). Dual-energy X-ray absorptiometry-derived appendicular lean mass index (ALMI) estimated muscle mass. Non-race-based CKD Epidemiology Collaboration equations estimated glomerular filtration rate using eGFRCr, eGFRCysC, and both biomarkers (eGFRCysC&Cr). CKD was defined as eGFRCysC&Cr <60 mL/minute/1.73 m2. ALMI sex-specific T-scores (compared with young adult) < -2.0 defined sarcopenia. In estimating ALMI, we compared the coefficient of determination (R2) values from: 1) eGFRDiff, 2) clinical characteristics (age, BMI, and sex), and 3) clinical characteristics plus eGFRDiff. Using logistic regression, we evaluated each model's C-statistic to diagnose sarcopenia. RESULTS: eGFRDiff was negatively and weakly associated with ALMI (No CKD: R2 = 0.006, p-value 0.002; CKD: R2 = 0.001, P value .9). Clinical characteristics explained most of the variation in ALMI (No CKD: R2 = 0.851, CKD: R2 = 0.828), and provided strong discrimination of sarcopenia (No CKD C-statistic: 0.950; CKD C-statistic: 0.943). Adding eGFRDiff improved the R2 by 0.025, and the C-statistic by 0.003. Tests for interaction between eGFRDiff and CKD were not significant (all P values > .05). CONCLUSIONS: Although eGFRDiff has statistically significant associations with ALMI and sarcopenia in univariate analyses, multivariate analyses demonstrate that eGFRDiff does not capture more information beyond routine clinical characteristics (age, BMI, and sex).

Correction: Coppock et al. Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial. Life 2022, 12, 453.

The authors wish to make a change to the author names (deleting one author-Constantine Daskalakis) for this paper [...].

Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial.

Despite the widespread availability of effective vaccines, new cases of infection with severe acute respiratory syndrome coronavirus-2, the cause of coronavirus disease 2019 (COVID-19), remain a concern in the settings of vaccine hesitancy and vaccine breakthrough. In this randomized, controlled, phase 2 trial, we hypothesized that high-dose ascorbic acid delivered intravenously to achieve pharmacologic concentrations may target the high viral phase of COVID-19 and thus improve early clinical outcomes. Sixty-six patients admitted with COVID-19 and requiring supplemental oxygen were randomized to receive either escalating doses of intravenous ascorbic acid plus standard of care or standard of care alone. The demographic and clinical characteristics were well-balanced between the two study arms. The primary outcome evaluated in this study was clinical improvement at 72 h after randomization. While the primary outcome was not achieved, point estimates for the composite outcome and its individual components of decreased use of supplemental oxygen, decreased use of bronchodilators, and the time to discharge were all favorable for the treatment arm. Possible favorable effects of ascorbic acid were most apparent during the first 72 h of hospitalization, although these effects disappeared over the course of the entire hospitalization. Future larger trials of intravenous ascorbic acid should be based on our current understanding of COVID-19 with a focus on the potential early benefits of ascorbic in hospitalized patients.

Low variability of plant protein intake in the CKiD cohort does not demonstrate changes in estimated GFR nor electrolyte balance.

BACKGROUND: Vegetable or plant-based sources of protein may confer health benefits in children with progressive kidney disease. Our aims were to understand the effect of the proportion of vegetable protein intake on changes in estimated GFR and to understand the effect of the proportion of vegetable protein intake on serum levels of bicarbonate, phosphorus, and potassium. METHODS: Children with baseline eGFR between 30 and 90 mL/min/1.73 m2 were recruited from 59 centers across North America as part of the chronic kidney disease in children (CKiD) study. The percentage of dietary vegetable protein (VP%) was gathered from annual Food Frequency Questionnaires. We performed longitudinal linear mixed models to determine the effect of VP% on eGFR and longitudinal logistic mixed models to determine the effect of VP% on electrolyte balance (potassium, phosphorus, bicarbonate). RESULTS: Two thousand visits from 631 subjects. Across all dichotomized groups of children (sex, African American race, Hispanic ethnicity, glomerular etiology of CKD, hypertension, anemia, hyperkalemia, hyperphosphatemia, acidosis, BMI < 95th percentile), the median VP% was 32-35%. The longitudinal mixed model analysis did not show any effect of VP% on eGFR electrolyte (bicarbonate, phosphorus, and potassium) abnormalities (p > 0.1). CONCLUSIONS: A diverse cohort of children with CKD has a narrow and homogeneous intake of vegetable protein. Due to the low variability of plant-based protein in the cohort, there were no associations between the percentage of plant protein intake and changes in eGFR nor electrolyte balance. A higher resolution version of the Graphical abstract is available as Supplementary information.

Investigation of long interspersed element-1 retrotransposons as potential risk factors for idiopathic temporal lobe epilepsy.

OBJECTIVE: To determine if long interspersed element-1 (L1) retrotransposons convey risk for idiopathic temporal lobe epilepsy (TLE). METHODS: Surgically resected temporal cortex from individuals with TLE (N = 33) and postmortem temporal cortex from individuals with no known neurological disease (N = 33) were analyzed for L1 content by Restriction Enzyme Based Enriched L1Hs sequencing (REBELseq). Expression of three KCNIP4 splice variants was assessed by droplet digital PCR (ddPCR). Protein ANalysis THrough Evolutionary Relationships (PANTHER) was used to determine ontologies and pathways for lists of genes harboring L1 insertions. RESULTS: We identified novel L1 insertions specific to individuals with TLE, and others specific to controls. Although there were no statistically significant differences between cases and controls in the numbers of known and novel L1 insertions, PANTHER analyses of intragenic L1 insertions showed statistically significant enrichments for epilepsy-relevant gene ontologies in both cases and controls. Gene ontologies "neuron projection development" and "calcium ion transmembrane transport" were among those found only in individuals with TLE. We confirmed novel L1 insertions in several genes associated with seizures/epilepsy, including a de novo somatic L1 retrotransposition in KCNIP4 that occurred after neural crest formation in one patient. However, ddPCR results suggest this de novo L1 did not alter KCNIP4 mRNA expression. SIGNIFICANCE: Given current data from this small cohort, we conclude that L1 elements, either rare heritable germline insertions or de novo somatic retrotranspositions, may contribute only minimally to overall genetic risk for idiopathic TLE. We suggest that further studies in additional patients and additional brain regions are warranted.

LDL-apheresis-induced remission of focal segmental glomerulosclerosis recurrence in pediatric renal transplant recipients.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) in pediatric patients is typically difficult to treat and will progress to end-stage renal disease (ESRD) in about 10% of cases. Following kidney transplantation, FSGS can recur in up to 56% of renal allografts-with a near 100% recurrence in subsequent transplants. METHODS: Four different pediatric centers across the USA and the UK employed a protocol using LDL-apheresis (LDL-A) and pulse solumedrol to treat recurrent FSGS after transplantation in seven patients. All the patients included in this series demonstrated immediate, or early, recurrence of FSGS, which clinically presented as nephrotic-range proteinuria within hours to days after implantation of the kidney. RESULTS: All patients experienced reductions in urinary protein to creatinine ratios resulting in partial or complete remission. All patients demonstrated improvements in their estimated GFRs at their most recent follow-up since LDL-A discontinuation. CONCLUSIONS: This case series describes the successful treatment, across four different pediatric centers, of seven pediatric patients with recurrent post-transplant FSGS using the Liposorber® LA-15 in combination with pulse solumedrol.

Poor adherence to early childhood blood pressure measurement guidelines in a large pediatric healthcare system.

BACKGROUND: Children who were born prematurely, those with a very low birthweight, or who have survived the neonatal intensive care unit (NICU) are at risk for the development of hypertension and chronic kidney disease (CKD), and thus require blood pressure screening less than 3 years of age, per American Academy of Pediatrics (AAP) 2004 and 2017 guidelines. METHODS: We reviewed the practice patterns of a large pediatric health care system and assessed adherence to the AAP clinical practice guidelines on blood pressure measurements in children less than 3 years of age for hypertension and CKD with the following risk factors: prematurity, very low birthweight, and a neonatal intensive care setting encounter. This retrospective chart review included a total of 9965 patients with a median gestational age of 34 weeks. RESULTS: Overall, 38% of patients had at least one blood pressure measured less than 3 years of age. Primary care accounted for 41% of all outpatient encounters and 4% of all blood pressure measurements. Surgical specialties (i.e., ophthalmology, otolaryngology, and orthopedics) accounted for many non-primary care visits and were less likely than medical specialties (i.e., cardiology and nephrology) to obtain a blood pressure measurement (p < 0.0001). CONCLUSIONS: This study of a large healthcare system's practice revealed a lack of basic screening for hypertension in a population known to be at risk for hypertension and CKD.

Use of a Robotic Sampler (PIPER) for Evaluation of Particulate Matter Exposure and Eczema in Preschoolers.

While the association of eczema with asthma is well recognized, little research has focused on the potential role of inhalable exposures and eczema. While indoor air quality is important in the development of respiratory disease as children in the U.S. spend the majority of their time indoors, relatively little research has focused on correlated non-respiratory conditions. This study examined the relationship between particulate matter (PM) exposures in preschool age children and major correlates of asthma, such as wheeze and eczema. Air sampling was carried out using a robotic (PIPER) child-sampling surrogate. This study enrolled 128 participants, 57 male and 71 female children. Ages ranged from 3 to 58 months with the mean age of 29.3 months. A comparison of subjects with and without eczema showed a difference in the natural log (ln) of PM collected from the PIPER air sampling (p = 0.049). PIPER's sampling observed an association between the ln PM concentrations and eczema, but not an association with wheezing history in pre-school children. Our findings are consistent with the hypothesis of the role of the microenvironment in mediating atopic dermatitis, which is one of the predictors of persistent asthma. Our findings also support the use of PIPER in its ability to model and sample the microenvironment of young children.

Drebrin a knockout eliminates the rapid form of homeostatic synaptic plasticity at excitatory synapses of intact adult cerebral cortex.

Homeostatic synaptic plasticity (HSP) is important for maintaining neurons' excitability within the dynamic range and for protecting neurons from unconstrained long-term potentiation that can cause breakdown of synapse specificity (Turrigiano [2008] Cell 135:422-435). Knowledge of the molecular mechanism underlying this phenomenon remains incomplete, especially for the rapid form of HSP. To test whether HSP in adulthood depends on an F-actin binding protein, drebrin A, mice deleted of the adult isoform of drebrin (DAKO) but retaining the embryonic isoform (drebrin E) were generated. HSP was assayed by determining whether the NR2A subunit of N-methyl-D-aspartate receptors (NMDARs) can rise rapidly within spines following the application of an NMDAR antagonist, D-APV, onto the cortical surface. Electron microscopic immunocytochemistry revealed that, as expected, the D-APV treatment of wild-type (WT) mouse cortex increased the proportion of NR2A-immunolabeled spines within 30 minutes relative to basal levels in hemispheres treated with an inactive enantiomer, L-APV. This difference was significant at the postsynaptic membrane and postsynaptic density (i.e., synaptic junction) as well as at nonsynaptic sites within spines and was not accompanied by spine size changes. In contrast, the D-APV treatment of DAKO brains did not augment NR2A labeling within the spine cytoplasm or at the synaptic junction, even though basal levels of NR2A were not significantly different from those of WT cortices. These findings indicate that drebrin A is required for the rapid (<30 minutes) form of HSP at excitatory synapses of adult cortices, whereas drebrin E is sufficient for maintaining basal NR2A levels within spines.