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.

External Validation of the Breast Cancer Surgery Risk Calculator (BCSRc): A Predictive Model for Postoperative Complications.

BACKGROUND: The breast cancer surgical risk calculator (BCSRc) is a prognostic tool that determines a breast cancer patient's unique risk of acute complications following each possible surgical intervention. When used in the preoperative setting, it can help to stratify patients with an increased complication risk and enhance the patient-physician informed decision-making process. The objective of this study was to externally validate the four models used in the BCSRc on a large cohort of patients who underwent breast cancer surgery. METHODS: The BCSRc was developed by using a retrospective cohort from the National Surgical Quality Improvement Program database from 2005 to 2018. Four models were built by using logistic regression methods to predict the following composite outcomes: overall, infectious, hematologic, and internal organ complications. This study obtained a new cohort of patients from the National Surgical Quality Improvement Program by utilizing participant user files from 2019 to 2020. The area under the curve, brier score, and Hosmer-Lemeshow goodness of fit test measured model performance, accuracy, and calibration, respectively. RESULTS: A total of 192,095 patients met inclusion criteria in the development of the BCSRc, and the validation cohort included 60,144 women. The area under the curve during external validation for each model was approximately 0.70. Accuracy, or Brier scores, were all between 0.04 and 0.003. Model calibration using the Hosmer-Lemeshow statistic found all p-values > 0.05. All of these model coefficients will be updated on the web-based BCSRc platform: www.breastcalc.org . CONCLUSIONS: The BCSRc continues to show excellent external-validation measures. Collectively, this prognostic tool can enhance the decision-making process, help stratify patients with an increased complication risk, and improve expectant management.

Perceptions of General Surgery Program Leadership and Residents on Research Sabbatical.

INTRODUCTION: The incorporation of a 1-y- or 2-y research period during general surgery residency is increasingly common in many academic programs, yet often, it is heterogeneously structured and ill-defined. This survey-based observational study aimed to characterize the perceptions of general surgery program directors (PDs) and residents regarding an in-training, dedicated research sabbatical. METHODS: Two surveys were conducted using Qualtrics software. One survey was sent to general surgery residency PDs, and the other was sent to general surgery residents currently on a research sabbatical. The primary aim of the survey was to assess the PDs' and research residents' perceptions of the research sabbatical. RESULTS: Seven hundred and fifty-two surveys were analyzed, of which 120 were from PDs and 632 from research residents. Among the residents, 44.1% felt that the research time delayed their surgical training. Regarding research funding, 46.7% of the responding residents said that their residency program funded their research, 30.9% said they acquired funding independently, and 19.1% said that it came from a combination of residency program and independent funding. Finally, regarding how residents found their research opportunity, 42.7% said they found it independently and 53.3% said their program provided it. CONCLUSIONS: Research sabbaticals during residency may be considered essential to academic development. However, in this survey-based study, perceptions of research time and its structure varied greatly between PDs and residents. An intentional push toward developing guidelines for research sabbaticals may benefit residency program leadership and residents.

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.

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.

Time for Brain Medicine.

Unprecedented knowledge of the brain is inevitably contributing to the convergence of neurology and psychiatry. However, clinical training continues to follow a divergent approach established in the 19th century. An etiological approach will continue to shift more psychiatric patients to the care of neurologists who are untrained in psychiatric management. At the same time, this new era of diagnostic biomarkers and neuroscience-based precision treatments requires skills not readily available to those trained in psychiatry. The challenges in training the next generation of doctors include establishing competence involving aspects of the whole brain, fostering the subspecialized expertise needed to remain current, and developing programs that are feasible in duration and practical in implementation. A new 4-year residency training program proposed in this article could replace existing residency programs. The program includes 2 years of common and urgent training in various aspects of neurology and psychiatry followed by 2 years of elective subspecialty tracks. The concept is similar to internal medicine residencies and fellowships. No changes to existing departmental structures are necessary. In concert with the emerging biological approach to the brain, "brain medicine" is proposed as a new name to denote this practice in the simplest terms: a focus on all aspects of the brain.

Does Breast-Conserving Surgery with Radiotherapy have a Better Survival than Mastectomy? A Meta-Analysis of More than 1,500,000 Patients.

BACKGROUND: There have been conflicting studies reporting on survival advantages between breast-conserving surgery with radiotherapy (BCS) in comparison with mastectomy. Our aim was to compare the efficacy of BCS and mastectomy in terms of overall survival (OS) comparing all past published studies. METHODS: We performed a comprehensive review of literature through October 2021 in PubMed, Scopus, and EMBASE. The studies included were randomized controlled trials (RCTs) and cohorts that compare BCS versus mastectomy. We excluded studies that included male sex, stage 0, distant metastasis at diagnosis, bilateral synchronous cancer, neoadjuvant radiation/chemotherapy, and articles with incomplete data. We performed a meta-analysis following the random-effect model with the inverse variance method. RESULTS: From 18,997 publications, a total of 30 studies were included in the final analysis: 6 studies were randomized trials, and 24 were retrospective cohorts. A total of 1,802,128 patients with a follow-up ranging from 4 to 20 years were included, and 1,075,563 and 744,565 underwent BCS and mastectomy, respectively. Among the population, BCS is associated with improved OS compared with mastectomy [relative risk (RR) 0.64, 95% confidence interval (CI) 0.55-0.74]. This effect was similar when analysis was performed in cohorts and multi-institutional databases (RR 0.57, 95% CI 0.49-0.67). Furthermore, the benefit of BCS was stronger in patients who had less than 10 years of follow-up (RR 0.54, 95% CI 0.46-0.64). CONCLUSIONS: Patients who underwent BCS had better OS compared with mastectomy. Such results depicting survival advantage, especially using such a large sample of patients, may need to be included in the shared surgical decision making when discussing breast cancer treatment with patients.

Comparing oncoplastic breast reduction with immediate symmetry surgery to standard breast reduction surgery: Are postoperative complications worse?

INTRODUCTION: Oncoplastic breast reduction mammoplasty (ORM) is an excellent treatment option for women with breast cancer and macromastia undergoing breast conservation therapy. Here, we aim to better understand the risks associated with ORM compared to standard reduction mammoplasty (SRM). METHODS: A retrospective chart review was performed of patients undergoing ORM or SRM from 2015 to 2021. Primary outcomes included the occurrence of major or minor postoperative complications in the two groups and delays to adjuvant therapy (>90 days) among the women undergoing ORM. RESULTS: Women in the ORM group (n = 198) were significantly older (p < 0.001) with a higher prevalence of smoking (p < 0.001), diabetes mellitus (p < 0.01), and a Charlson comorbidity index ≥ 3 (p < 0.001) compared to women undergoing SRM (n = 177). After controlling for potential confounders, there were no significant between-group differences in the odds of developing postoperative complications (odds ratio = 0.80, 95% confidence interval: 0.36-1.69). Only 3% (n = 4) of the 150 women undergoing adjuvant radiation or chemotherapy experienced delays related to postoperative complications. CONCLUSION: ORM has a similar safety profile as SRM, despite the older age and higher number of comorbidities often seen in patients undergoing ORM, and is a safe option for achieving contralateral symmetry at the time of partial mastectomy without delays to adjuvant therapy.

Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure.

High blood pressure is a common cause of chronic kidney disease. Because CD40, a member of the tumor necrosis factor receptor family, has been linked to the progression of kidney disease in ischemic nephropathy, we studied the role of Cd40 in the development of hypertensive renal disease. The Cd40 gene was mutated in the Dahl S genetically hypertensive rat with renal disease by targeted-gene disruption using zinc-finger nuclease technology. These rats were then given low (0.3%) and high (2%) salt diets and compared. The resultant Cd40 mutants had significantly reduced levels of both urinary protein excretion (41.8 ± 3.1 mg/24 h vs. 103.7 ± 4.3 mg/24 h) and plasma creatinine (0.36 ± 0.05 mg/dl vs. 1.15 ± 0.19 mg/dl), with significantly higher creatinine clearance compared with the control S rats (3.04 ± 0.48 ml/min vs. 0.93 ± 0.15 ml/min), indicating renoprotection was conferred by mutation of the Cd40 locus. Furthermore, the Cd40 mutants had a significant attenuation in renal fibrosis, which persisted on the high salt diet. However, there was no difference in systolic blood pressure between the control and Cd40 mutant rats. Thus, these data serve as the first evidence for a direct link between Cd40 and hypertensive nephropathy. Hence, renal fibrosis is one of the underlying mechanisms by which Cd40 plays a crucial role in the development of hypertensive renal disease.

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.

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.

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.

Assessment of Financial Conflicts of Interest Related to the Use of Dermal Substitutes in Burn Management.

This study aims to systematically review the accuracy of the self-reporting of conflicts of interest (COIs) among studies related to the use of dermal substitute products in burn management and evaluate factors associated with increased discrepancies. To do so, a literature search was done to identify studies investigating the use of dermal substitutes in burn management published between 2015 and 2019. Industry payments were collected using the Centers for Medicare and Medicaid Services Open Payments database. Declared COIs were then compared with the listed payments. Studies and authors were considered to have a COI if they received payments totaling more than $100 for each company. A total of 51 studies (322 authors) were included for analysis. Forty studies and 104 authors received at least one payment from the industry. Of these studies, 38 (95%) studies and 91 (88%) authors were found to have a COI discrepancy. From 2015 to 2019, 1391 general payments (totaling $1,696,848) and 108 research payments (totaling $1,849,537) were made by 82 companies. When increasing the threshold on what would be considered an undisclosed payment, the proportion of authors with discrepancies gradually decreased, from 88% of authors with undisclosed payments more than $100 to 27% of authors with undisclosed payments more than $10,000. Author order, journal impact factor, and study type were not significantly associated with increased risk of discrepancy. We found that the majority of studies investigating the use of dermal substitute products for burn management did not accurately declare COI, highlighting the need for a uniform declaration process and greater transparency of industry sponsorship by authors when publishing peer-reviewed burn surgery research papers.

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.

Nationwide utilization of cardiopulmonary bypass in cardiothoracic trauma: A retrospective analysis of the National Trauma Data Bank.

BACKGROUND: The American College of Surgeons Committee on Trauma requires that all level I trauma centers have cardiopulmonary bypass (CPB) capabilities immediately available. Despite this mandate, there are limited data on the utilization and clinical outcomes among trauma patients requiring CPB in the management of injuries. The aim of this study was to evaluate the current use of CPB in the care of trauma patients. METHODS: This is a retrospective analysis of the National Trauma Data Bank from 2010 to 2015. Adult patients sustaining cardiothoracic injuries who underwent surgical repair within the first 24 hours of admission were included. Propensity score matching was used to compare outcomes (in-hospital mortality, hospital length of stay (LOS), intensive care unit LOS, and complications) between patients who underwent CPB within the first 24 hours of admission and those with similar injuries who did not receive CPB. RESULTS: A total of 28,481 patients who met the inclusion criteria were identified, of whom 319 underwent CPB. Three-hundred three CPB patients were matched to 895 comparison patients who did not undergo CPB. Overall in-hospital mortality was 35%. Patients who were not treated with CPB had a significantly higher in-hospital mortality compared with those treated with CBP (odds ratio, 1.57; 95% confidence interval, 1.16-2.12; p = 0.003); however, complications were significantly lower in those who did not receive CPB (odds ratio, 0.63; 95% confidence interval, 0.47-0.86; p = 0.003). Hospital LOS (non-CPB: mean, 13.4 ± 16.3 days; CPB: mean, 14.7 ± 15.1 days; p = 0.23) and intensive care unit LOS (non-CPB: mean, 9.9 ± 10.7 days; CPB: mean, 10.1 ± 9.7 days; p = 0.08) did not differ significantly between groups. CONCLUSION: The use of CPB in the initial management of select cardiothoracic injuries is associated with a survival benefit. Further investigation is required to delineate which specific injuries would benefit the most from the use of CPB. LEVEL OF EVIDENCE: Therapeutic, level IV.

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.