The renal function trajectory in clinical trial design: challenges and opportunities.

The changes in renal function over time as surrogate endpoints for new drug trials are complicated by many factors, including the often-expected initial decrease in estimated glomerular filtration rate when a new drug is started. Two articles in the journal address this challenge, but multiple other challenges are explored in this commentary. To maximize the benefits of expensive new drugs that may slow decline in renal function, these drugs should be reserved for those patients who have a high probability of rapid loss of kidney function.

Expansion of tumor-infiltrating and marrow-infiltrating lymphocytes from pediatric malignant solid tumors.

Introduction: The expansion of tumor-infiltrating lymphocytes (TIL) for adoptive cellular therapy is under investigation in many solid tumors of adulthood. Marrow-infiltrating lymphocytes (MIL) have demonstrated antitumor reactivity preclinically. Successful expansion of TIL/MIL has not been reported across pediatric solid tumor histologies.

Cardiogenic Shock: Focus on Non-Cardiac Biomarkers.

Purpose Of Review: To examine the evolving multifaceted nature of cardiogenic shock (CS) in the context of non-cardiac biomarkers that may improve CS management and risk stratification.

Recent Findings: There are increasing data highlighting the role of lactate, glucose, and other markers of inflammation and end-organ dysfunction in CS. These biomarkers provide a more comprehensive understanding of the concurrent hemo-metabolic and cellular disturbances observed in CS and offer insights beyond standard structural and functional cardiac assessments.

Interaction between a smartphone and intrathecal baclofen pump case report.

Introduction: Intrathecal Baclofen (ITB) is used for the treatment of spasticity. Pump complications are most commonly related to surgical implantation or catheter dysfunction. Less common complications include catheter access port dysfunction, motor failure from excessive wear on motor gear shafts, or a complete stall of the motor.

Addressing unmet basic needs for children with sickle cell disease in the United States: clinic and staff perspectives.

Background: The purpose of this study was to assess pediatric hematology clinic staff's perspectives regarding barriers and facilitators in addressing unmet basic needs for children with sickle cell disease (SCD).

Methodology: Six focus groups were held at four urban pediatric hematology clinics in the Northeastern region of the United States from November to December 2019. Discussion questions were developed to align with the integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) implementation science framework, focusing on the domains of context and recipient and how clinics address adverse social determinants of health (SDoH) in their patient populations.

Combinatorial Pharmacogenomic Testing Improves Outcomes for Older Adults With Depression.

Objective: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD).

Design: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms.

Setting: Psychiatry specialty and primary care clinics across 60 U.

Combinatorial Pharmacogenomic Algorithm is Predictive of Citalopram and Escitalopram Metabolism in Patients with Major Depressive Disorder.

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism.

β-Arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates.

Multiple G protein-coupled receptors (GPCRs) are targets in the treatment of dementia, and the arrestins are common to their signaling. β-Arrestin2 was significantly increased in brains of patients with frontotemporal lobar degeneration (FTLD-tau), a disease second to Alzheimer's as a cause of dementia. Genetic loss and overexpression experiments using genetically encoded reporters and defined mutant constructs in vitro, and in cell lines, primary neurons, and tau P301S mice crossed with β-arrestin2 mice, show that β-arrestin2 stabilizes pathogenic tau and promotes tau aggregation.

Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial.

Background: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown.

Methods: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial.

Impact of Pharmacogenomics on Clinical Outcomes for Patients Taking Medications With Gene-Drug Interactions in a Randomized Controlled Trial.

Objective: The objective of the Genomics Used to Improve DEpression Decisions (GUIDED) trial was to evaluate the utility of pharmacogenomic testing to improve outcomes among patients with major depressive disorder (MDD) who had not responded to at least 1 prior medication trial. The objective of the present analysis was to assess outcomes for the subset of patients expected to benefit from combinatorial pharmacogenomic testing because they were taking medications with predicted gene-drug interactions.

Methods: Participants (enrolled from April 14, 2014, to February 10, 2017) had an inadequate response to at least 1 psychotropic medication in the current episode of MDD.

Activated cofilin exacerbates tau pathology by impairing tau-mediated microtubule dynamics.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. While the accumulation of Aβ is pivotal to the etiology of AD, both the microtubule-associated protein tau (MAPT) and the F-actin severing protein cofilin are necessary for the deleterious effects of Aβ. However, the molecular link between tau and cofilin remains unclear.

Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study.

Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial - a rater- and patient-blind randomized controlled trial.

Gray Optic Disc Crescent: Evaluation of Anatomic Correlate by Spectral-Domain OCT.

Purpose: To test the hypothesis that the anatomic correlate of the gray optic disc crescent is pigmentation of externally oblique border tissue of Elschnig.

Design: Retrospective study.

Participants: African-American adult men with or without clinically apparent gray optic disc crescents.

Serum biomarkers of inflammation and adiposity in the LABS cohort: associations with metabolic disease and surgical outcomes.

Background: The utility of serum biomarkers related to inflammation and adiposity as predictors of metabolic disease prevalence and outcomes after bariatric surgery are not well-defined.

Methods: Associations between pre- and post-operative serum levels of four biomarkers (C-reactive protein (CRP), cystatin C (CC), leptin, and ghrelin) with baseline measures of adiposity and metabolic disease prevalence (asthma, diabetes, sleep apnea), and weight loss and metabolic disease remission after bariatric surgery were studied in the Longitudinal Assessment of Bariatric Surgery (LABS) cohort.

Results: Baseline CRP levels were positively associated with the odds of asthma but not diabetes or sleep apnea; baseline CC levels were positively associated with asthma, diabetes, and sleep apnea; baseline leptin levels were positively associated with asthma and negatively associated with diabetes and sleep apnea; baseline ghrelin levels were negatively associated with diabetes and sleep apnea.

The Effect of Single Pyramidal Neuron Firing Within Layer 2/3 and Layer 4 in Mouse V1.

Unlabelled: The influence of cortical cell spiking activity on nearby cells has been studied extensively . Less is known, however, about the impact of single cell firing on local cortical networks . In a pioneering study, Kwan and Dan (Kwan and Dan, 2012) reported that in mouse layer 2/3 (L2/3), , stimulating a single pyramidal cell recruits ~2.

The microRNA miR-21 conditions the brain to protect against ischemic and traumatic injuries.

Ischemic and traumatic injuries to CNS remain leading causes of death and disability worldwide, despite decades of research into risk factors, therapies, and preventative measures. Recent studies showed that CNS injuries significantly alter the cerebral microRNAome that impact the secondary brain damage as well as plasticity and recovery. Many microRNA based therapies are currently in various clinical trials for different pathologic conditions indicating their therapeutic potential.

Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes.

Accumulation of amyloid β (Aβ) and tau represent the two major pathological hallmarks of Alzheimer's disease (AD). Despite the critical importance of Aβ accumulation as an early event in AD pathogenesis, multiple lines of evidence indicate that tau is required to mediate Aβ-induced neurotoxic signals in neurons. We have previously shown that the scaffolding protein Ran-binding protein 9 (RanBP9), which is highly elevated in brains of AD and AD mouse models, both enhances Aβ production and mediates Aβ-induced neurotoxicity.

Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation.

Amyloid β (Aβ) accumulation is an early event in the pathogenesis of Alzheimer's disease (AD), leading to mitochondrial and synaptic dysfunction, tau accumulation, and eventual neuronal death. While the p53 apoptotic pathway has clearly been associated with Aβ deposits and neuronal apoptosis, the critical upstream factors contributing to p53 activation in AD are not well understood. We have previously shown that cofilin activation plays a pivotal role in Aβ-induced mitochondrial and synaptic dysfunction.

Staying in service with posttraumatic headache: A retrospective cohort study of patient outcome.

Objective: To predict the probability of a military outcome (medical discharge/retirement) in patients with mild traumatic brain injury from a clinical analysis of predetermined patient and headache characteristics.

Methods: This retrospective cohort study sampled all new patients referred for headache evaluation at the Brain Injury Clinic of the Womack Army Medical Center, Ft. Bragg, NC (August 2008-January 2010).