Dodecyl creatine ester therapy: from promise to reality.

Pathogenic variants in SLC6A8, the gene which encodes creatine transporter SLC6A8, prevent creatine uptake in the brain and result in a variable degree of intellectual disability, behavioral disorders (e.g., autism spectrum disorder), epilepsy, and severe speech and language delay. There are no treatments to improve neurodevelopmental outcomes for creatine transporter deficiency (CTD). In this spotlight, we summarize recent advances in innovative molecules to treat CTD, with a focus on dodecyl creatine ester, the most promising drug candidate.

Creatine supplementation and resistance training to preserve muscle mass and attenuate cancer progression (CREATINE-52): a protocol for a double-blind randomized controlled trial.

BACKGROUND: Muscle mass is important for metastatic prostate cancer survival and quality of life (QoL). The backbone of treatment for men with metastatic castration sensitive prostate cancer (mCSPC) is androgen deprivation therapy (ADT) with an androgen signaling inhibitor. ADT is an effective cancer treatment, but it facilitates significant declines in muscle mass and adverse health outcomes important to mCSPC survivors, such as fatigue, and reductions in physical function, independence, insulin sensitivity, and QoL. In non-metastatic CSPC survivors, resistance training (RT) preserves muscle mass and improves these related health outcomes, but the biggest barrier to RT in CSPC survivors of all stages is fatigue. Creatine monohydrate supplementation coupled with RT (Cr + RT) may address this barrier since creatine plays a critical role in energy metabolism. Cr + RT in cancer-free older adults and other clinical populations improves muscle mass and related health outcomes. Evidence also suggests that creatine supplementation can complement cancer treatment. Thus, Cr + RT is a strategy that addresses gaps in survivorship needs of people with mCSPC. The purpose of this parallel, double-blind randomized controlled trial is to test the effects of 52-weeks of Cr + RT compared with placebo (PLA) and RT (PLA + RT) on muscle mass, other related health outcomes, and markers of cancer progression. METHODS: We will carry out this trial with our team's established, effective, home-based, telehealth RT program in 200 mCSPC survivors receiving ADT, and evaluate outcomes at baseline, 24-, and 52-weeks. RT will occur twice weekly with elastic resistance bands, and an established creatine supplementation protocol will be used for supplementation delivery. Our approach addresses a major facilitator to RT in mCSPC survivors, a home-based RT program, while utilizing a supervised model for safety. DISCUSSION: Findings will improve delivery of comprehensive survivorship care by providing a multicomponent, patient-centered lifestyle strategy to preserve muscle mass, improve health outcomes, and complement cancer treatment (NCT06112990).

Creatine in Cognitive Performance: A Commentary.

Given the importance of cognition in everyday life, medicines that improve cognition safely and affordably are highly wanted. Creatine is an amino acid-derived substance that aids in the restoration of adenosine triphosphate (ATP), which provides energy to muscle and brain tissue. Although the relationship between creatine and cognitive performance is still debatable, here is a brief description of creatine's influence on cognition with probable implications for future research on this intriguing topic.

Creatine supplementation with exercise reduces α-synuclein oligomerization and necroptosis in Parkinson's disease mouse model.

Parkinson's disease (PD) is an incurable neurological disorder that causes typical motor deficits. In this study, we investigated the effects of creatine supplementation and exercise in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We found that 2% creatine supplementation and/or exercise intervention for 4 weeks elicited neurobehavioral recovery and neuroprotective effects regarding dopaminergic cell loss in MPTP-treated mice; this effect implies functional preservation of dopaminergic cells in the substantia nigra, as reflected by tyrosine hydroxylase expression recovery. Creatine and exercise reduced necroptotic activity in dopaminergic cells by lowering mixed lineage kinase domain-like protein (MLKL) modification to active phenotypes (phosphorylation at Ser345 and oligomerization) and phosphorylated receptor-interacting protein kinase 1 (RIPK1) (Ser166-p) and RIPK3 (Ser232-p) levels. In addition, creatine and exercise reduced the MPTP-induced increase in pathogenic α-synuclein forms, such as Ser129 phosphorylation and oligomerization. Furthermore, creatine and exercise had anti-inflammatory and antioxidative effects in MPTP mice, as evidenced by a decrease in microglia activation, NF-κB-dependent pro-inflammatory molecule expression, and increase in antioxidant enzyme expression. These phenotypic changes were associated with the exercise/creatine-induced AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) and sirtuin 3 (SIRT3)/forkhead box O3 (FoxO3a) signaling pathways. In all experiments, combining creatine with exercise resulted in considerable improvement over either treatment alone. Consequently, these findings suggest that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model.

Creatine Supplementation and Resistance Training in Patients With Breast Cancer (CaRTiC Study): Protocol for a Randomized Controlled Trial.

BACKGROUND: Creatine supplementation is an effective ergogenic nutrient for athletes, as well as for people starting a health or fitness program. Resistance training has previously been identified as an important method of increasing muscle mass and strength, especially in people with cancer to avoid sarcopenia. The potential of creatine supplementation for adaptations produced by resistance training in patients with cancer is still unknown. The primary aim of this study is to evaluate the effectiveness of a supervised resistance training program intervention with and without creatine supplementation in patients with breast cancer. METHODS: Is a multicentre, randomized, blind, placebo-controlled study. Patients will be randomly assigned to a control group and 2 experimental groups. The first training resistance group (RG) will perform resistance training, while the second experimental resistance-creatine group will perform the same resistance training as the RG and will also receive a 5 g/d creatine supplementation during the intervention. RG participants will follow the same daily dosing protocol, but in their case, with dextrose/maltodextrin. Resistance training will be a 16-week supervised workout that will consist of a series of resistance exercises (leg press, knee extension, knee bends, chest press, sit-ups, back extensions, pull-ups, and shoulder press) that involve the largest muscle groups, performed 3 times a week on nonconsecutive days. Both the RG and the resistance-creatine group will receive a supplement of soluble protein powder (20 to 30 g) daily. CONCLUSION: This intervention will help to better understand the potential of nonpharmacological treatment for improving strength and well-being values in patients with breast cancer with and without creatine supplementation.

Spectroscopic abnormalities in the pregenual anterior cingulate cortex in obsessive-compulsive disorder using proton magnetic resonance spectroscopy: a controlled study.

BACKGROUND: The main aim of the present study is to determine the role of metabolites observed using proton magnetic resonance spectroscopy (1H-MRS) in obsessive-compulsive disorder (OCD). As the literature describing biochemical changes in OCD yields conflicting results, we focused on accurate metabolite quantification of total N-acetyl aspartate (tNAA), total creatine (tCr), total choline-containing compounds (tCh), and myo-inositol (mI) in the anterior cingulate cortex (ACC) to capture the small metabolic changes between OCD patients and controls and between OCD patients with and without medication. METHODS: In total 46 patients with OCD and 46 healthy controls (HC) matched for age and sex were included in the study. The severity of symptoms in the OCD was evaluated on the day of magnetic resonance imaging (MRI) using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Subjects underwent 1H-MRS from the pregenual ACC (pgACC) region to calculate concentrations of tNAA, tCr, tCho, and mI. Twenty-eight OCD and 28 HC subjects were included in the statistical analysis. We compared differences between groups for all selected metabolites and in OCD patients we analyzed the relationship between metabolite levels and symptom severity, medication status, age, and the duration of illness. RESULTS: Significant decreases in tCr (U = 253.00, p = 0.022) and mI (U = 197.00, p = 0.001) in the pgACC were observed in the OCD group. No statistically significant differences were found in tNAA and tCho levels; however, tCho revealed a trend towards lower concentrations in OCD patients (U = 278.00, p = 0.062). Metabolic concentrations showed no significant correlations with the age and duration of illness. The correlation statistics found a significant negative correlation between tCr levels and YBOCS compulsions subscale (cor = -0.380, p = 0.046). tCho and YBOCS compulsions subscale showed a trend towards a negative correlation (cor = -0.351, p = 0.067). Analysis of subgroups with or without medication showed no differences. CONCLUSIONS: Patients with OCD present metabolic disruption in the pgACC. The decrease in tCr shows an important relationship with OCD symptomatology. tCr as a marker of cerebral bioenergetics may also be considered as a biomarker of the severity of compulsions. The study failed to prove that metabolic changes correlate with the medication status or the duration of illness. It seems that a disruption in the balance between these metabolites and their transmission may play a role in the pathophysiology of OCD.

The Effect of Skeletal Muscle-Specific Creatine Treatment on ALS NMJ Integrity and Function.

Although skeletal muscle (hSKM) has been proven to be actively involved in Amyotrophic Lateral Sclerosis (ALS) neuromuscular junction (NMJ) dysfunction, it is rarely considered as a pharmacological target in preclinical drug discovery. This project investigated how improving ALS hSKM viability and function effects NMJ integrity. Phenotypic ALS NMJ human-on-a-chip models developed from patient-derived induced pluripotent stem cells (iPSCs) were used to study the effect of hSKM-specific creatine treatment on clinically relevant functional ALS NMJ parameters, such as NMJ numbers, fidelity, stability, and fatigue index. Results indicated comparatively enhanced NMJ numbers, fidelity, and stability, as well as reduced fatigue index, across all hSKM-specific creatine-treated systems. Immunocytochemical analysis of the NMJs also revealed improved post-synaptic nicotinic Acetylcholine receptor (AChR) clustering and cluster size in systems supplemented with creatine relative to the un-dosed control. This work strongly suggests hSKM as a therapeutic target in ALS drug discovery. It also demonstrates the need to consider all tissues involved in multi-systemic diseases, such as ALS, in drug discovery efforts. Finally, this work further establishes the BioMEMs NMJ platform as an effective means of performing mutation-specific drug screening, which is a step towards personalized medicine for rare diseases.

Efficacy and safety assessment of mineralocorticoid receptor antagonists in patients with chronic kidney disease.

BACKGROUND: The objective of our study is to evaluate the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) and determine the optimal MRA treatment regimen in patients with chronic kidney disease (CKD). METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library from their inception to June 20, 2022. The composite kidney outcome, cardiovascular events, urinary albumin to creatinine ratio (UACR), estimated glomerular filtration rate (EGFR), serum potassium, systolic blood pressure (SBP), diastolic blood pressure (DBP), creatine and creatine clearance were included for analysis. We conducted pairwise meta-analyses and Bayesian network meta-analyses (NMA) and calculated the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 26 studies with 15,531 participants. By pairwise meta-analyses, we found that MRA treatment could significantly reduce UACR in CKD patients with or without diabetes. Notably, compared to placebo, Finerenone was associated with a lower risk of composite kidney outcome and cardiovascular events. Data from NMA demonstrated an overt UACR reduction without increasing serum potassium by Apararenone, Esaxerenone, and Finerenone in CKD patients. Spironolactone decreased SBP and DBP but elevated CKD patients' serum potassium. CONCLUSIONS: Compared to placebo, Apararenone, Esaxerenone, and Finerenone might ameliorate albuminuria in CKD patients without causing elevated serum potassium levels. Remarkably, Finerenone conferred a cardiovascular benefit, and Spironolactone lowered blood pressure in CKD patients.

The role of resistance training and creatine supplementation on oxidative stress, antioxidant defense, muscle strength, and quality of life in older adults.

Background: The aim of this study was to evaluate the effect of resistance training (RT) with creatine monohydrate supplementation (CS) on serum levels of 8-hydroxydeoxyguanosine (8-OHdG), malondialdehyde (MDA), glutathione peroxidase (GPX), and total antioxidant capacity (TAC) in older adults. Objectives: This study evaluated the effect of resistance training with creatine monohydrate supplementation on oxidative stress and antioxidant defense, muscle strength and quality of life in older adults. Methods: We examined 45 non-athlete volunteer older men and women (mean, 68.1 ± 7.2 years old), were randomly selected and divided into three groups of 15: RT with creatine supplementation (RT + CS), RT with placebo (RT + P) and control group. RT protocol was performed for 10 weeks, three sessions per week. Creatine supplement was taken daily at a dose of 0.1 g/kg of body weight, while the placebo group consumed the same amount of starch. Fasting blood samples were taken before the start of program and at the end of the RT period. Results: In the training groups, after 10 weeks of RT, a significant decrease in MDA and 8 - OHDG as well as a significant increase in serum levels of GPX and TAC were observed (in all cases, p = 0.001). In addition, creatinine levels were enhanced in the RT + CS (p = 0.014). Training intervention also improved quality of life and muscle strength in the experimental groups (p = 0.001), although muscle strength changes were more visible in the RT + CS group than in the RT + P group (p < 0/05). Conclusion: Regular resistance training can be recommended as a very suitable non-pharmacological approach to strengthen the body's antioxidant system, muscle strength and quality of life in older adults. There are no definite findings on the role of creatine on the antioxidant system and quality of life in older adults, but the use of this supplement in addition to RT can double the amount of strength gained from resistance training.

Neuroprotection and Therapeutic Implications of Creatine Supplementation for Brain Injury Complications.

Creatine supplementation has not been researched for Traumatic Brain Injury (TBI) extensively, but studies suggest potential as a neuroprotective agent and potential treatment for brain-injury complications. Patients suffering from TBI experience mitochondrial dysfunction, neuropsychological burden, and deficits in cognitive performance due to malperformance of brain creatine levels, diminished brain Adenosine Triphosphate (ATP) levels, glutamate toxicity, and oxidative stress. In this systemic review, the current available research is reviewed to examine the effects of creatine on common sequalae of TBI within children, adolescents, and mice. Past and present data still lacks the knowledge of creatine supplementation for the adult population and military members during TBI. PubMed was searched for studies which assessed the correlation between creatine supplementation of TBI complications. The search strategy yielded 40 results, of which 15 articles were included in this systemic review. The results of the review supported an apparent understanding creatine does offer an obvious benefit to patients suffering from TBI and post-injury complications under specific guidelines. Time and dose dependent metabolic alterations seem to be only exceptionally prevalent when given as a prophylaxis or if given acutely. Results are only clinically significant after a month of supplementation. Although patients may need many therapeutic treatments to recover from TBI, especially in acute resuscitation, creatine shows superior efficacy as a neuroprotective agent in battling the chronic manifestations which lead to oxidative stress and cognitive function post brain injury.

The Folic Acid and Creatine Trial: Treatment Effects of Supplementation on Arsenic Methylation Indices and Metabolite Concentrations in Blood in a Bangladeshi Population.

BACKGROUND: Chronic arsenic (As) exposure is a global environmental health issue. Inorganic As (InAs) undergoes methylation to monomethyl (MMAs) and dimethyl-arsenical species (DMAs); full methylation to DMAs facilitates urinary excretion and is associated with reduced risk for As-related health outcomes. Nutritional factors, including folate and creatine, influence one-carbon metabolism, the biochemical pathway that provides methyl groups for As methylation. OBJECTIVE: Our aim was to investigate the effects of supplementation with folic acid (FA), creatine, or the two combined on the concentrations of As metabolites and the primary methylation index (PMI: MMAs/InAs) and secondary methylation index (SMI: DMAs/MMAs) in blood in Bangladeshi adults having a wide range of folate status. METHODS: In a randomized, double-blinded, placebo (PBO)-controlled trial, 622 participants were recruited independent of folate status and assigned to one of five treatment arms: a) PBO (n=102), b) 400µg FA/d (400FA; n=153), c) 800µg FA/d (800FA; n=151), d) 3g creatine/d (creatine; n=101), or e) 3g creatine+400µg of FA/d (creatine+400FA; n=103) for 12 wk. For the following 12 wk, half of the FA participants were randomly switched to the PBO while the other half continued FA supplementation. All participants received As-removal water filters at baseline. Blood As (bAs) metabolites were measured at weeks 0, 1, 12, and 24. RESULTS: At baseline, 80.3% (n=489) of participants were folate sufficient (≥9 nmol/L in plasma). In all groups, bAs metabolite concentrations decreased, likely due to filter use; for example, in the PBO group, blood concentrations of MMAs (bMMAs) (geometric mean±geometric standard deviation) decreased from 3.55±1.89µg/L at baseline to 2.73±1.74 at week 1. After 1 wk, the mean within-person increase in SMI for the creatine+400FA group was greater than that of the PBO group (p=0.05). The mean percentage decrease in bMMAs between baseline and week 12 was greater for all treatment groups compared with the PBO group [400FA: -10.4 (95% CI: -11.9, -8.75), 800FA: -9.54 (95% CI: -11.1, -7.97), creatine: -5.85 (95% CI: -8.59, -3.03), creatine+400FA: -8.44 (95% CI: -9.95, -6.90), PBO: -2.02 (95% CI: -4.03, 0.04)], and the percentage increase in blood DMAs (bDMAs) concentrations for the FA-treated groups significantly exceeded that of PBO [400FA: 12.8 (95% CI: 10.5, 15.2), 800FA: 11.3 (95% CI: 8.95, 13.8), creatine+400FA: 7.45 (95% CI: 5.23, 9.71), PBO: -0.15 (95% CI: -2.85, 2.63)]. The mean decrease in PMI and increase in SMI in all FA groups significantly exceeded PBO (p<0.05). Data from week 24 showed evidence of a reversal of treatment effects on As metabolites from week 12 in those who switched from 800FA to PBO, with significant decreases in SMI [-9.0% (95% CI: -3.5, -14.8)] and bDMAs [-5.9% (95% CI: -1.8, -10.2)], whereas PMI and bMMAs concentrations continued to decline [-7.16% (95% CI: -0.48, -14.3) and -3.1% (95% CI: -0.1, -6.2), respectively] for those who remained on 800FA supplementation. CONCLUSIONS: FA supplementation lowered bMMAs and increased bDMAs in a sample of primarily folate-replete adults, whereas creatine supplementation lowered bMMAs. Evidence of the reversal of treatment effects on As metabolites following FA cessation suggests short-term benefits of supplementation and underscores the importance of long-term interventions, such as FA fortification. https://doi.org/10.1289/EHP11270.

Fronto-Cerebellar Neurometabolite Alterations After Methylphenidate in Children and Adolescents With ADHD: A Proton Magnetic Resonance Spectroscopy Study.

OBJECTIVE: The fronto-cerebellar circuit is involved in ADHD pathophysiology. Methylphenidate, as a first-line medication for ADHD, affects different brain regions, however, its effect on the fronto-cerebellar circuit is not investigated sufficiently. We aimed to investigate the effect of 8-week treatment with methylphenidate on neurometabolite ratios in the fronto-cerebellar circuit in ADHD participants using magnetic resonance spectroscopy (MRS). METHODS: Fifteen drug-naïve ADHD children and adolescents were enrolled in the present study. Two single-voxel MR spectra were acquired from the right dorsolateral prefrontal cortex (DLPFC) and left Crus 1, before and after the medication. Also, neuropsychological and behavioral assessments were administered. RESULTS: After medication, the glutamate/creatine in the DLPFC and the choline/creatine in the Crus 1 decreased in the ADHD participants. CONCLUSION: These findings propose that methylphenidate-induced metabolite changes in the fronto-cerebellar circuit could be associated with improvement in cognitive/behavioral characteristics in ADHD. Also, results highlighted cerebellar engagement in ADHD pathophysiology.

Real-world data for the renal safety of abemaciclib combined with bisphosphonate in HR+/HER2- advanced breast cancer.

OBJECTIVE: Our study evaluated the renal safety of abemaciclib plus endocrine therapy (ET) with bisphosphonate as a treatment option for hormone receptor positive, human epidermal growth factor receptor 2 (HER-2) negative (HR+/HER2-) advanced breast cancer (ABC), especially with bone metastasis. METHODS: Data were collected from HR+/HER2- ABC patients who received abemaciclib with ET between March 2021 and May 2022 in a single medical center in China. We performed an analysis of the change in serum creatine (Cr) and creatine clearance (CrCl), time to first abnormal Cr value, and Common Terminology Criteria for Adverse Events grade of increased creatinine. RESULTS: A total of 210 patients were included in the final analysis, with a median age of 56 years and a median weight of 65 kg. Any grade laboratory-assessing increased Cr occurred in 87.1% of patients, while CrCl rarely went down to 30 ml/min. Associations between start dose with grade of increased Cr and menopausal status with alert value, which is defined as creatinine clearance <30 ml/min, were indicated. CONCLUSION: This study shows that abemaciclib combined with bisphosphonate would be safe for renal function in HR+/HER2- ABC patients with bone metastases.

Variation of homocysteine levels in rheumatoid arthritis patients: relationship to inflammation, cardiovascular risk factors, and methotrexate.

BACKGROUND: The aim of this study was to evaluate the variation of homocysteine (Hcy) levels in patients with rheumatoid arthritis (RA) and to analyze the relationship to inflammatory parameters, cardiovascular risk, and methotrexate (MTX). METHODS: This cross-sectional study assessed disease activity and treatment in RA patients. The European League Against Rheumatism (EULAR) 2015 HeartSCORE was performed for cardiovascular (CV) risk estimation and levels of plasma Hcy, serum folate concentrations, vitamin B12, and erythrocyte sedimentation rate (ESR) were measured. RESULTS: A total of 103 participants with mean age 53 ± 10 years and mean disease duration 10.55 ± 7.34 years were included. Patients were treated with MTX in 69.9% of cases and corticosteroid in 80.5% of cases. Of all patients, 13% had a cardiovascular inheritance, 25% were hypertensive, and 18% had diabetes. The EULAR 2015 HeartSCORE was high and very high (≥5%) in 35% of cases. Mean Hcy level was 12.54 ± 4.2 µmol/L [6.89-32.92] and hyperhomocysteinemia was noted in 20.4% of patients. Analytic study demonstrated that hyperhomocysteinemia was associated with male gender (p = 0.01), MTX use (p = 0.01), smoking (p = 0.008), renal failure (p = 0.04), and high disease activity (p = 0.05), but there was no association with the HeartSCORE (p = 0.23). Hcy level was negatively correlated with folate (p = 0.009) and vitamin B12 level (p = 0.02) and positively with age (p = 0.01), C­reactive protein (CRP; p = 0.05), and Simplified Disease Activity Index (SDAI; p = 0.03). In multivariate logistic regression analysis, current MTX use, levels of vitamin B12 and creatine, and Clinical Disease Activity Index (CDAI) appeared to be independent factors associated with hyperhomocysteinemia. CONCLUSION: MTX use, CDAI, and the levels of vitamin B12 and creatine are independent factors associated with hyperhomocysteinemia.

Creatine supplementation to improve the peripheral and central inflammatory profile in cerebral palsy.

This opinion paper presents a brief review on the potential use of Creatine (Cr) to improve the inflammatory profile in individuals with Cerebral Palsy (CP). CP is a condition that causes muscle atrophy followed by reduced strength and altered muscle tone. The prevalence of chronic diseases is higher in people with CP due to this, which are often associated with peripheral inflammation, but there are no studies that have evaluated central inflammation in this condition. Nevertheless, the anti-inflammatory action of Cr has already been observed in different types of studies. Thus, the use of experimental models of CP to evaluate the expression of the inflammatory markers, especially in the brain, as well as approaches to reduce the impairments already observed becomes essential. Results obtained in these preclinical studies may contribute to the quality of therapeutic strategies offered to children suffering from CP, the most common cause of chronic motor disability in childhood.

Association of Finerenone Use With Reduction in Treatment-Emergent Pneumonia and COVID-19 Adverse Events Among Patients With Type 2 Diabetes and Chronic Kidney Disease: A FIDELITY Pooled Secondary Analysis.

Importance: Patients with chronic kidney disease and type 2 diabetes have a higher risk of developing pneumonia as well as an increased risk of severe COVID-19-associated adverse events and mortality. Therefore, the anti-inflammatory effects of mineralocorticoid receptor antagonists via blockade of the mineralocorticoid receptor may alter the risk of pneumonia and COVID-19-associated adverse events in patients with chronic kidney disease and type 2 diabetes. Objective: To evaluate whether the selective, nonsteroidal mineralocorticoid receptor antagonist finerenone is associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Design, Setting, and Participants: This secondary analysis used patient-level data from FIDELITY, a prespecified pooled analysis of 2 multicenter, double-blind, placebo-controlled, event-driven, phase 3 randomized clinical trials: FIDELIO-DKD and FIGARO-DKD, conducted between September 2015 and February 2021. Patients in FIDELIO-DKD or FIGARO-DKD with type 2 diabetes and chronic kidney disease (urine albumin to creatine ratio, 30-5000 mg/g, estimated glomerular filtration rate ≥25 mL/min/1.73 m2) were assessed. Data were analyzed from May 15, 2021, to July 28, 2022. Exposure: Patients were randomized to finerenone (10 or 20 mg once daily) or matching placebo. Main Outcomes and Measures: The main outcomes were investigator-reported incidences of treatment-emergent infective pneumonia adverse events and serious adverse events (during and up to 3 days after treatment) and any COVID-19 adverse events. Results: Of 13 026 randomized patients (mean [SD] age, 64.8 [9.5] years; 9088 [69.8%] men), 12 999 were included in the FIDELITY safety population (6510 patients receiving finerenone; 6489 patients receiving placebo). Over a median (range) treatment duration of 2.6 (0-5.1) years, finerenone was consistently associated with reduced risk of pneumonia and serious pneumonia vs placebo. Overall, 307 patients (4.7%) treated with finerenone and 434 patients (6.7%) treated with placebo experienced pneumonia (hazard ratio [HR], 0.71; 95% CI, 0.64-0.79; P < .001). Serious pneumonia occurred in 171 patients (2.6%) treated with finerenone and 250 patients (3.9%) treated with placebo (HR, 0.69; 95% CI, 0.60-0.79; P < .001). Incidence proportions of COVID-19 adverse events were 86 patients (1.3%) in the finerenone group and 118 patients (1.8%) in the placebo group (HR, 0.73; 95% CI, 0.60-0.89; P = .002). Conclusions and Relevance: These findings suggest that mineralocorticoid receptor blockade with finerenone was associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Further clinical studies may be warranted. Trial Registration: ClinicalTrials.gov identifiers: FIDELIO-DKD: NCT02540993; FIGARO-DKD: NCT02545049.

Overlap syndrome in a 12-year-old girl with systemic lupus erythematosus and anti-oj antibody-positive polymyositis: a case report.

BACKGROUND: The peculiar presentation of overlap syndrome in children makes precise diagnosis difficult. Children with overlap syndrome may or may not have specific antibodies. We present the case of a 12-year-old girl diagnosed with overlap syndrome of systemic lupus erythematosus (SLE) and juvenile polymyositis (JPM) who tested positive for anti-OJ antibodies. CASE PRESENTATION: We describe the case of a 12-year-old girl diagnosed with SLE at the age of 7 and presented with fever with malar rash, periungual erythema, generalized weakness, and multiple joint pain at admission. The patient had persistent joint pain and weakness after intravenous methylprednisolone administration and complained of an inability to walk with a positive test for Gower's sign one week after admission, accompanied by elevated alanine aminotransferase (ALT) and creatine-phospho-kinase (CPK) levels. The results of nerve conduction velocity test were normal. Electromyography revealed abundant spontaneous activity and myopathic motor unit action potentials in the right deltoid, biceps, and iliopsoas, in addition to fibrillation and mild myopathic motor unit action potentials in the right rectus femoris muscle. Magnetic resonance imaging revealed diffusely increased signal intensities in the myofascial planes of the bilateral iliopsoas, gluteus, obturator, pectineus, and hamstring muscles. Anti-nuclear antibody, anti-RNP, and rheumatoid factor IgG tests were positive, and inflammatory myopathy autoantibodies revealed anti-OJ antibody positivity, which strongly indicated autoimmune myositis. High-resolution computed tomography of the lung revealed mild pericardial effusion without any evidence of interstitial lung disease. We initiated intravenous pulses of methylprednisolone treatment, followed by cyclosporine, mycophenolate mofetil, and oral steroids. Clinical improvement with a delayed, slowly reduced CPK level after the above treatment and she was discharged after the 18th day of hospitalization. CONCLUSION: Overlap syndrome with inflammatory myositis can occur years later in pediatric SLE cases. We should be alert when patients with SLE develop a new presentation characterized by decreased SLE-specific autoantibody titers, positive anti-RNP antibodies, and elevated CPK. Treatment of the overlap syndrome of SLE and JPM is individualized, and the course differs between pediatric and adult patients.

Effect of proteins, amino acids, and other nitrogenated supplements on the skeletal muscle mass in people living with HIV (PLWH): A systematic review.

BACKGROUND & AIMS: Skeletal muscle losses (both quantitative and qualitative) and the consequent risk of sarcopenia are important issues in people living with HIV (PLWH), even when treated with antiretroviral therapies (ART). We aimed to conduct a systematic review (SR) investigating the effects of dietary interventions with proteins, amino acids, and other nitrogenated compounds on the skeletal muscle of PLWH. METHODS: We searched the published literature until August 24th, 2020, including clinical trials predominantly with AIDS-free PLWH treated with ART. RESULTS: From the 82 studies initially selected, 75 were excluded for the following reasons: nutritional interventions different from nitrogenated compounds; non-nutritional interventions; lack of information on body composition; and studies with most participants with AIDS. From the publications included (n = 7), the majority were performed with small and heterogeneous samples. None of the studies included any new-generation ART or pre- or post-exposition drugs. Two studies found benefits of supplementation on muscle mass; one was performed in a very unfavorable socioeconomic setting, and the supplementation was based on food-derived substances. The other study supplemented creatine, and its benefits were found only when combined with physical exercise training and only by one of the methods of body composition analysis (DXA). CONCLUSIONS: Our results showed that nutritional interventions with proteins, amino acids, or other nitrogenated compounds could not improve the skeletal muscle mass in PLWH. Further studies are needed, with bigger sample sizes and more precise control of ART schemes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42019139981.

Adjunct Thrombolysis Enhances Brain Reperfusion following Successful Thrombectomy.

OBJECTIVE: This study was undertaken to investigate whether adjunct alteplase improves brain reperfusion following successful thrombectomy. METHODS: This single-center, randomized, double-blind, placebo-controlled study included 36 patients (mean [standard deviation] = 70.8 [13.5] years old, 18 [50%] women) with large vessel occlusion undergoing thrombectomy resulting in near-normal (expanded Thrombolysis in Cerebral Infarction [eTICI] b50/67/2c, n = 23, 64%) or normal angiographic reperfusion (eTICI 3, n = 13, 36%). Seventeen patients were randomized to intra-arterial alteplase (0.225mg/kg), and 19 received placebo. At 48 hours, patients had brain perfusion/diffusion-weighted magnetic resonance imaging (MRI) and MRI-spectroscopy. The primary outcome was the difference in the proportion of patients with areas of hypoperfusion on MRI. Secondary outcomes were the infarct expansion ratio (final to initial infarction volume), and the N-acetylaspartate (NAA) peak relative to total creatine as a marker of neuronal integrity. RESULTS: The prevalence of hypoperfusion was 24% with intra-arterial alteplase, and 58% with placebo (adjusted odds ratio = 0.20, 95% confidence interval [CI] = 0.04-0.91, p = 0.03). Among 14 patients with final eTICI 3 scores, hypoperfusion was found in 1 of 7 (14%) in the alteplase group and 3 of 7 (43%) in the placebo group. Abnormal brain perfusion was associated with worse functional outcome at day 90. Alteplase significantly reduced the infarct expansion ratio compared with placebo (median [interquartile range (IQR)] = 0.7 [0.5-1.2] vs 3.2 [1.8-5.7], p = 0.01) and resulted in higher NAA peaks (median [IQR] = 1.13 [0.91-1.36] vs 1.00 [0.74-1.22], p < 0.0001). INTERPRETATION: There is a high prevalence of areas of hypoperfusion following thrombectomy despite successful reperfusion on angiography. Adjunct alteplase enhances brain reperfusion, which results in reduced expansion of the infarction and improved neuronal integrity. ANN NEUROL 2022;92:860-870.

Insights into the development of pentylenetetrazole-induced epileptic seizures from dynamic metabolomic changes.

Epilepsy is often considered to be a progressive neurological disease, and the nature of this progression remains unclear. Understanding the overall and common metabolic changes of epileptic seizures can provide novel clues for their control and prevention. Herein, a chronic kindling animal model was established to obtain generalized tonic-clonic seizures via the repeated injections of pentylenetetrazole (PTZ) at subconvulsive dose. Dynamic metabolomic changes in plasma and urine from PTZ-kindled rats at the different kindling phases were explored using NMR-based metabolomics, in combination with behavioral assessment, brain neurotransmitter measurement, electroencephalography and histopathology. The increased levels of glucose, lactate, glutamate, creatine and creatinine, together with the decreased levels of pyruvate, citrate and succinate, ketone bodies, asparagine, alanine, leucine, valine and isoleucine in plasma and/or urine were involved in the development and progression of seizures. These altered metabolites reflected the pathophysiological processes including the compromised energy metabolism, the disturbed amino acid metabolism, the peripheral inflammation and changes in gut microbiota functions. NMR-based metabolomics could provide brain disease information by the dynamic plasma and urinary metabolic changes during chronic epileptic seizures, yielding classification of seizure stages and profound insights into controlling epilepsy via targeting deficient energy metabolism.