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.

Discrepancies in Financial Conflicts of Interest in Robotic Cardiothoracic Surgery Studies.

BACKGROUND: In academic surgery publications, self-reporting of conflicts of interest (COI) has often proved to be inaccurate. Here, we review the accuracy of COI disclosures for studies related to the use of robotic technology in cardiothoracic surgery and evaluate factors associated with increased discrepancies. METHODS: A literature search identified robotic surgery-related studies with at least 1 American author published between January 2015 and December 2020 from 3 major American cardiothoracic surgery journals (The Journal of Thoracic and Cardiovascular Surgery, The Annals of Thoracic Surgery, and Annals of Cardiothoracic Surgery). Industry payments from Intuitive Surgical (Intuitive) were collected with use of the Centers for Medicare and Medicaid Open Payments database. COI discrepancies were identified by comparing author declaration statements with payments found for the year of publication and the year prior (24-month period). RESULTS: A total of 144 studies (764 authors) were identified. At least 1 author of 112 studies (78%) had received payments from Intuitive. At least 1 author of 98 studies (68%) had received an undeclared payment from Intuitive. Authors who accurately disclosed payments received significantly higher median payments compared with authors who did not ($16,511 [interquartile range, $6389-$159,035] vs $1762 [interquartile range, $338-$7500]; P < .0001). Last authors were significantly more likely to have a COI discrepancy compared with middle and first authors (P = .018; P = .0015). CONCLUSIONS: Most studies investigating the use of robotic technology in cardiothoracic surgery did not accurately declare COI with Intuitive. This study highlights the need for improved accuracy of reporting industry sponsorship by publishing authors.

Heart Transplant Waitlist Outcomes and Wait Time by Center Volume in the Pre-2018 Allocation Change Era.

Although the transplant outcomes of centers are heavily monitored and compared, with a particular link between posttransplant outcomes and center volume demonstrated, little data exist comparing waitlist outcomes. Here, we explored waitlist outcomes by transplant center volume. We performed a retrospective analysis of adults listed for primary heart transplantation (HTx) from 2008 to 2018 using the United Network for Organ Sharing database. Transplant centers were split into low (<10 HTx/year), medium (10-30 HTx/year), and high (>30 HTx/year) volume, and waitlist outcomes were compared. Of the 35,190 patients included in our study, 23,726 (67.4%) underwent HTx, 4,915 (14.0%) died or deteriorated before receiving HTx, 1,356 (3.9%) were delisted due to recovery, and 1,336 (3.8%) underwent left ventricular assist device (LVAD) implantation. High-volume centers had higher rates of survival to transplant (71.3% vs. 60.6% for low-volume centers and 64.9% for medium-volume centers), and low rates of death or deterioration (12.6% vs. 14.6% for low-volume centers and 15.1% for medium-volume centers). Listing at a low-volume center was independently associated with death or delisting before HTx (HR 1.18, p = 0.007), whereas listing at a high-volume center (HR 0.86; p < 0.001) and prelisting LVAD (HR 0.67, p < 0.001) were protective. Death or delisting before HTx was lowest for patients listed in higher volume centers.

Closed Incision Negative Pressure Therapy in Oncoplastic Breast Surgery: A Comparison of Outcomes.

We aim to discern the impact of closed incision negative pressure therapy (ciNPT) on wound healing in the oncoplastic breast surgery population. Methods: A retrospective analysis was conducted on patients who underwent oncoplastic breast surgery with and without ciNPT in a single health system over 6 years. Oncoplastic breast surgery was defined as breast conservation surgery involving partial mastectomy with immediate volume displacement or replacement techniques. Primary outcomes were rates of clinically significant complications requiring either medical or operative intervention, including seroma, hematoma, fat necrosis, wound dehiscence, and infection. Secondary outcomes were rates of minor complications. Results: ciNPT was used in 75 patients; standard postsurgical dressing was used in 142 patients. Mean age (P = 0.73) and Charlson Comorbidity Index (P = 0.11) were similar between the groups. The ciNPT cohort had higher baseline BMIs (28.23 ± 4.94 versus 30.55 ± 6.53; P = 0.004), ASA levels (2.35 ± 0.59 versus 2.62 ± 0.52; P = 0.002), and preoperative macromastia symptoms (18.3% versus 45.9%; P ≤ 0.001). The ciNPT cohort had statistically significant lower rates of clinically relevant complications (16.9% versus 5.3%; P = 0.016), the number of complications (14.1% versus 5.3% with one complication, 2.8% versus 0% with >2; P = 0.044), and wound dehiscence (5.6% versus 0%; P = 0.036). Conclusions: The use of ciNPT reduces the overall rate of clinically relevant postoperative complications, including wound dehiscence. The ciNPT cohort had higher rates of macromastia symptoms, BMI, and ASA, all of which put them at increased risk for complications. Therefore, ciNPT should be considered in the oncoplastic population, especially in those patients with increased risk for postoperative complications.

The adoption of oncoplastic surgery: Is there a learning curve?

INTRODUCTION: Oncoplastic surgery (OPS) is a form of breast conservation surgery involving partial mastectomy followed by volume displacement or replacement surgery. As the field of OPS is growing, we sought to determine if there was a learning curve to this surgery. METHODS: A retrospective chart review was conducted of all patients who underwent OPS over a 6-year period with a single surgeon formally trained in both Plastic Surgery and Breast Oncology. Cumulative summation analysis (CUSUM) was performed on mean operative time to generate the learning curve and learning curve phases. Outcomes were compared between phases to determine significance. RESULTS: Mean operative time decreased significantly across the 6-year period, generating three distinct learning curve phases: Learner phase (cases 1-23), Competence phase (24-73), and Mastery phase (74 and greater). The overall positive margin rate was 10.9% and there was no significant difference in rates between phases (p = 0.49). Overall complication rates, reoperation rates, and locoregional recurrence remained the same across all phases (p = 0.16; p = 0.65; p = 0.41). The rate of partial nipple loss decreased between phases (p = 0.02). CONCLUSION: As with many complex operations, there does appear to be a learning curve with OPS, as the operative time and the rates of partial nipple loss decreased over time.

Single Versus Dual Surgeon Approaches to Oncoplastic Surgery: A Comparison of Outcomes.

INTRODUCTION: Oncoplastic surgery (OPS) is traditionally performed using a dual surgeon (DS) approach that involves both a breast surgeon and a plastic surgeon. It is also performed using a single surgeon (SS) approach with a surgeon trained in both breast surgical oncology and plastic surgery. We sought to determine if outcomes differed between SS versus DS OPS approaches. METHODS: A retrospective chart review was conducted of all OPS performed in a single health system over a 6-y period by either an SS or a DS approach. Primary outcomes were rates of positive margins and the overall complication rate; secondary outcomes were loco-regional recurrence, disease-free survival, and overall survival. RESULTS: A total of 217 patients were identified; 117 were SS cases and 100 were DS cases. Baseline preoperative patient characteristics were similar between the two groups as there was no difference in mean Charlson Comorbidity Index scores (P = 0.07). There was no difference in tumor stage (P = 0.09) or nodal status (P = 0.31). Rates of positive margins were not significantly different (10.9% (SS) versus 9% (DS); P = 0.81), nor were rates of complications (11.1% (SS) versus 15% (DS); P = 0.42). Rates of locoregional recurrence were also not significantly different (1.7% (SS) versus 0% (DS); P = 0.5). Disease-free survival and overall survival were not significantly different at 1-y, 3-y, and 5-y time points (P = 0.20 and P = 0.23, respectively) although follow-up time was not sufficient for definitive analysis regarding survival. CONCLUSIONS: Both SS and DS approaches to OPS have similar outcomes with regards to positive margin rates and surgical complication rates and are comparably safe.

Management of Gynecomastia and Male Benign Diseases.

Gynecomastia is a common benign breast disease involving abnormally increased mammary gland tissue that can affect men of all ages. It is usually due to a hormonal imbalance without a definitive underlying cause (idiopathic), or secondary to medications/drugs, systemic disorders, or malignancy. Gynecomastia is often self-limiting, and its management is watchful waiting. Other male benign breast diseases, such as cysts, lipomas, seromas, infections, and pseudoangiomatous stromal hyperplasia, should be worked up in a similar manner and often require surgical drainage or excision.

Spontaneous Progressive Muscle Weakness with Persistent Leukocytosis.

Iliacus compartment syndrome is a rare clinical condition which can result in a severe, unilateral, femoral neuropraxia. Recognition of this syndrome as the cause of a developing neuropathy is often delayed given a lack of familiarity with this clinical diagnosis and the retroperitoneal location of the iliacus muscle. Prompt diagnosis is important to avoid risk of consequent muscle necrosis, rhabdomyolysis, and possibly permanent nerve injury. We describe a case of iliacus compartment syndrome in an elderly, frail woman with end-stage renal disease, anticoagulated for atrial fibrillation, who presented with subacute, progressive lower extremity muscle weakness and pain in the setting of complicated metabolic derangements. She was found to have a spontaneous large hematoma in her left iliacus muscle on computed tomography scan. Despite an initial diagnostic delay, she was successfully managed with an iliacus fasciotomy, which led to complete resolution of her symptoms.

A Rare Occurrence of Isolated Brain Metastases from Gastric Cancer.

BACKGROUND: Gastric cancer is the fourth most common cancer worldwide and the second most common cause of cancer-related death. The majority of newly diagnosed gastric cancer cases present either as locally advanced tumor growth or with distant metastases. CASE REPORT: Here, we describe a case of isolated brain metastases in a male patient with gastric cancer. Initially, our patient presented with dysphagia and was diagnosed with gastric cancer after a thorough evaluation. One year after chemotherapy and surgical resection of his gastric cancer, he presented with headaches, nausea, dizziness, and photophobia. Further evaluation of these symptoms led to the discovery of three metastatic brain lesions without evidence of extracranial metastases. CONCLUSIONS: Our review of the literature has found that such cases are rare. Additionally, our review of the literature demonstrates the poor outcomes associated with metastatic brain lesions from gastric cancer and highlights the importance of surgical resection in increasing overall survival time.

GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.

OBJECTIVE: Early-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband. METHODS: Three modern translational medicine tools were utilized: 1) high-throughput sequencing technology to identify a novel de novo mutation; 2) in vitro expression and electrophysiology assays to confirm the variant protein's dysfunction; and 3) screening of existing drug libraries to identify potential therapeutic compounds. RESULTS: A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by NMDA receptors containing the mutant GluN2A-L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine; while screening of a previously reported GRIN2A mutation (N615K) with these compounds produced contrasting results. Consistent with these data, adjunct memantine therapy reduced our proband's seizure burden. INTERPRETATION: This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease.