De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.

N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure-function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.

The Benefit of Cost-Transparency Calculators Does Not Extend to Vascular Surgery Patients.

BACKGROUND: In 2021, the Centers for Medicare & Medicaid Services (CMS) mandated that every hospital create a publicly available webtool for pricing various medical services in an effort to give patients transparency in regard to their health care expenses and allow patients to "shop around" to receive the care most fitting their budget. Our objective is to investigate the utility this mandate provides for vascular surgery patients. METHODS: Standardized searches were performed to find patient cost calculators for Newsweek's Top 50 Hospitals in the United States. If the webtool was found, a list of standardized searches were performed to investigate whether the tool listed prices for the following vascular procedures: Arteriovenous fistula (AVF), varicose vein procedures, and Endovascular Aneurysm Repair (EVAR). RESULTS: Of the 50 hospitals included, all had an easily accessible web-based cost estimator tool. The average time to find the cost estimator was 33.27 sec. Of these 50 hospitals, 10% provided cost information on AVF surgery, 12% provided cost information on varicose vein procedures, and 0% provided information on EVAR. There was no difference in the hospital's likelihood to report a price based on region of the United States. Average preinsurance price for AVF surgery was $11,933.61 and $22,191 for vein procedures. CONCLUSIONS: In conclusion, despite good adherence to the CMS mandate requiring a publicly available pricing tool, these tools provide little to no information for vascular surgery patients. Overall, this discrepancy places vascular surgery patients at a significant disadvantage. As such, vascular patients do not have access to the knowledge necessary to financially prepare for surgery, and furthermore, they are not afforded the luxury to choose where to have procedures performed based on price variability. Hopefully this research will encourage hospitals to broaden the scope of their cost calculators to allow it to benefit all patients.

Oncoplastic Surgery Outcomes in the Older Breast Cancer Population: A Matched-Cohort Comparison Study.

BACKGROUND: Oncoplastic breast surgery (OBS) is a form of breast conservation surgery (BCS) that involves a partial mastectomy followed by immediate volume displacement or volume replacement surgical techniques. To date, there are few studies evaluating OBS in older patients. Therefore, we sought to determine if outcomes differed between patients 65 years and older versus younger patients who underwent oncoplastic surgical procedures. METHODS: A retrospective chart review was performed for all oncoplastic breast operations within a single health system from 2015 to 2021. Patients were stratified by age, with patients 65 years and older (OBS65+) identified and then matched with younger patients (OBS <65) based on BMI. Primary outcomes were positive margin rates and overall complication rates; secondary outcomes were locoregional recurrence (LR), distant recurrence (DR), disease-free survival (DFS), overall survival (OS), and long-term breast asymmetry. RESULTS: A total of 217 patients underwent OBS over the 6-year period, with 22% being OBS65+. Preoperatively, older patients experienced higher American Anesthesia (ASA) scores, Charlson Co-morbidity index (CCI) scores, and higher rates of diabetes mellitus, hypertension, and grade 3 breast ptosis. Despite this, no significant differences were found between primary or secondary outcomes compared to younger patients undergoing the same procedures. CONCLUSIONS: Oncoplastic breast reconstruction is a safe option in patients 65 years and older, with overall similar recurrence rates, positive margin rates, and survival when compared to younger patients. Although the older cohort of patients had greater preoperative risk, there was no difference in overall surgical complication rates or outcomes. Supporting the argument that all oncoplastic breast reconstruction techniques should be offered to eligible patients, irrespective of age.