New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of Pediatric Medulloblastoma.

Pediatric medulloblastoma (MB) is the most common pediatric brain tumor with varying prognoses depending on the distinct molecular subtype. The four consensus subgroups are WNT, Sonic hedgehog (SHH), Group 3, and Group 4, which underpin the current 2021 WHO classification of MB. While the field of knowledge for treating this disease has significantly advanced over the past decade, a deeper understanding is still required to improve the clinical outcomes for pediatric patients, who are often vulnerable in ways that adult patients are not. Here, we discuss how recent insights into the pathogenesis of pediatric medulloblastoma have directed current and future research. This review highlights new developments in understanding the four molecular subtypes' pathophysiology, epigenetics, and therapeutic targeting. In addition, we provide a focused discussion of recent developments in imaging, and in the surgery, chemotherapy, and radiotherapy of pediatric medulloblastoma. The article includes a brief explanation of healthcare costs associated with medulloblastoma treatment.

Discharge Opioid Prescribing Patterns in an Academic Orthopaedic Setting: Level of Training and Subspecialty Patterns.

INTRODUCTION: Despite increased research on opioids in the orthopaedic literature, little is known of the prescribing practices of orthopaedic providers based on their level of training. The purpose of this study was to describe the discharge opioid prescribing patterns of orthopaedic providers, stratifying by level of training and orthopaedic subspecialty, within a single medical system. METHODS: A retrospective review of orthopaedic surgical encounters was performed over a 1-year period for adults who received a discharge opioid prescription. Patient demographics and prescriber characteristics were collected, including the provider's level of training (attending, fellow, resident, physician assistant [PA], and nurse practitioner [NP]) and surgical subspecialty. Junior residents were postgraduate year 1 to 3, whereas senior residents/fellows were postgraduate year 4 to 6. Discharge opioids were converted to milligram morphine equivalents (MMEs). Overprescribing was defined as a prescribing more than a seven-day supply or >45 MMEs per day. Multivariable linear regression analysis determined the factors associated with discharge MMEs, whereas logistic regression determined the factors associated with overprescribing opioids. RESULTS: Of the 3,786 patients reviewed, 1,500 met the criteria for inclusion in the study. The greatest proportion of opioid prescriptions was written by junior residents (33.9%), followed by NPs (30.1%), PAs (24.1%), senior residents/fellows (10.6%), and attendings (1.2%). Compared with junior residents, senior residents prescribed -59.4 MMEs, NPs prescribed +104 MMEs, and attendings prescribed +168 MMEs (P < 0.05), whereas PAs prescribed similar amounts (P > 0.05). Orthopaedic subspecialty was also predictive of discharge MMEs (P < 0.05). Senior residents and attendings were more likely to prescribe more than seven days of opioids (P < 0.05), whereas NPs and PAs were more likely to prescribe >45 MMEs per day (P < 0.05). DISCUSSION: This study demonstrates significant variability in opioid prescribing practices according to provider level of training and subspecialty. National guidelines for opioid prescribing practices and educational programs may help reduce such variability. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival.

Huntington's disease (HD) is caused by an autosomal dominant polyglutamine expansion mutation of Huntingtin (HTT). HD patients suffer from progressive motor, cognitive, and psychiatric impairments, along with significant degeneration of the striatal projection neurons (SPNs) of the striatum. HD is widely accepted to be caused by a toxic gain-of-function of mutant HTT. However, whether loss of HTT function, because of dominant-negative effects of the mutant protein, plays a role in HD and whether HTT is required for SPN health and function are not known. Here, we delete Htt from specific subpopulations of SPNs using the Cre-Lox system and find that SPNs require HTT for motor regulation, synaptic development, cell health, and survival during aging. Our results suggest that loss of HTT function in SPNs could play a critical role in HD pathogenesis.