Reveromycin A-Induced Apoptosis in Osteoclasts Is Not Accompanied by Necrosis.

Reveromycin A (RM-A), a small natural product isolated from Streptomyces bacteria, is a potential osteoporosis therapeutic in that it specifically induces apoptosis in osteoclasts but not osteoblasts. The purpose of the study presented here was to further elucidate the intracellular mechanisms of RM-A death effects in mature osteoclasts. A specific clone of RAW264.7 murine macrophages that was previously characterized for its ability to acquire an osteoclast nature on differentiation was differentiated in the presence of receptor activator of nuclear factor kappa B ligand (RANKL). Subsequent staining was performed for tartrate-resistant acid phosphatase to confirm their osteoclast character. These osteoclasts were treated with ten micromolar RM-A for 2, 4, 6, 24, and 48 h at a pH of 5.5. Peak apoptosis induction occurred at 4-6 h as measured by caspase 3 activity. Lactate dehydrogenase release assay revealed no significant RM-A-induced necrosis. Western blot analysis of cytoplasmic extracts demonstrated activation of caspase 9 (2.3-fold at 2 h and 2.6-fold at 4 h, each P < 0.05) and no significant changes in Bcl-XL . In nuclear extracts, NFκB levels significantly increased on differentiation with RANKL but then remained constant through RM-A treatment. Over the extended time course studied, RM-A-induced apoptosis in osteoclasts was not accompanied by necrosis, suggesting that RM-A would likely have limited effects on immediate, neighboring bone cell types. This specific cell death profile is promising for potential clinical investigations of RM-A as a bone antiresorptive.

Racial and Socioeconomic Disparities in Complex Abdominal Wall Reconstruction Referrals.

Background: Health disparities are pervasive in surgical care. Particularly racial and socioeconomic inequalities have been demonstrated in emergency general surgery outcomes, but less so in elective abdominal wall reconstruction (AWR). The goal of this study was to evaluate the disparities in referrals to a tertiary hernia center. Methods: A prospectively maintained hernia database was queried for patients who underwent open ventral hernia (OVHR) or minimally invasive surgical (MISR) repair from 2011 to 2022 with complete insurance and address information. Patients were divided by home address into in-state (IS) and out-of-state (OOS) referrals as well as by operative technique. Demographic data and outcomes were compared. Standard and inferential statistical analyses were performed. Results: Of 554 patients, most were IS (59.0%); 334 underwent OVHR, and 220 underwent MISR. IS patients were more likely to undergo MISR (OVHR: 45.6% vs. 81.5%, laparoscopic: 38.2% vs. 14.1%, robotic: 16.2% vs. 4.4%; p < 0.001) when compared to OOS referrals. Of OVHR patients, 44.6% were IS and 55.4% were OOS. Patients' average age and BMI, sex, ASA score, and insurance payer were similar between IS and OOS groups. IS patients were more often Black (White: 77.9% vs. 93.5%, Black: 16.8% vs. 4.3%; p < 0.001). IS patients had more smokers (12.1% vs. 3.2%; p = 0.001), fewer recurrent hernias (45.0% vs. 69.7%; p < 0.001), and smaller defects (155.7 ± 142.2 vs. 256.4 ± 202.9 cm2; p < 0.001). Wound class, mesh type, and rate of fascial closure were similar, but IS patients underwent fewer panniculectomies (13.4% vs. 34.1%; p < 0.001), component separations (26.2% vs. 51.4%; p < 0.001), received smaller mesh (744.2 ± 495.6 vs. 975.7 ± 442.3 cm2; p < 0.001), and had shorter length-of-stay (4.8 ± 2.0 vs. 7.0 ± 5.5 days; p < 0.001). There was no difference in wound breakdown, seroma requiring intervention, hematoma, mesh infection, or recurrence; however, IS patients had decreased wound infections (2.0% vs. 8.6%; p = 0.009), overall wound complications (11.4% vs. 21.1%; p = 0.016), readmissions (2.7% vs. 13.0%; p = 0.001), and reoperations (3.4% vs. 11.4%; p = 0.007). Of MISR patients, 80.9% were IS and 19.1% were OOS. In contrast to OVHR, MISR IS and OOS patients had similar demographics, preoperative characteristics, intraoperative details, and postoperative outcomes. Conclusion: Although there were no differences in referred patients for MISR, this study demonstrates the racial disparities that exist among our IS and OOS complex, open AWR patients. Awareness of these disparities can help clinicians work towards equitable access to care and equal referrals to tertiary hernia centers.

Factors Associated With Respiratory Failure After Open Ventral Hernia Repair: An Evaluation of the NSQIP Database.

An analysis of ACS-NSQIP open ventral hernia repair (OVHR) data (2017-2019) was performed. Respiratory failure (RF) occurred in 643 patients (1%) and not in 63,213 (99%) (nRF). Respiratory failure patients were older (63.7 vs 57 years, P < .001) and more comorbid: insulin-dependent diabetes (14.7% vs 5.8%, P < .001), COPD (19.4% vs 5.2%, P < .001), BMI (36.0 vs 32.8, P < .001), and current tobacco use (24.9% vs 17.6%, P < .001). Respiratory failure patients had greater ASA scores (ASA 3: 63.3% vs 47.8%, P < .001), bowel resection (8.2% vs 1.3%, P < .001), component separation (20.1% vs 9.0%, P < .001), operative times (178.4 vs 98.8 minutes, P < .001), complications (deep wound infections 3.6% vs 1.0%, organ space infections 13.2% vs 1.0%, wound dehiscence 3.1% vs 0.6%, acute renal failure 11.7% vs 0.1%), and hospital stay (13.7 vs 2.3 days), with fewer home discharges (44.3% vs 96.4%) (all P < .001). Respiratory failure patients had higher mortality compared to nRF (20.2% vs 0.1%, P < .001). Respiratory failure after OVHR is rare but correlates closely with significant wound, systemic, and social complications. Preoperative management of risk factors would be appropriate in high-risk patients.

The benefits of preoperative smoking cessation on abdominal wall reconstruction outcomes: An examination of abstinent versus never smokers.

INTRODUCTION: Active smoking is related to wound and respiratory complications following abdominal wall reconstruction (AWR), but no AWR studies directly compare outcomes of abstinent-smokers (AS), fulfilling four-weeks of smoking cessation, to non-smokers (NS). METHODS: Prospectively maintained institutional database was queried for all AWR between 2012 and 2019. AS and NS were included. Primary outcomes were wound and respiratory complications; secondary outcome was recurrence. Standard statistical analyses were performed. RESULTS: Evaluation included 1088 patients, 305 AS and 783 NS. AS had a lower BMI (31.3 vs 32.7 â€‹kg/m2; P â€‹= â€‹0.004) but increased ASA Class III (51.5% vs 34.5 â€‹%, P â€‹= â€‹0.009), COPD (8.9% vs 4.0 â€‹%, P â€‹= â€‹0.001), comorbidities (6.3 vs 4.7, P < 0.001), and wound class (Class III/IV: 25.3% vs 15.8 â€‹%, P â€‹= â€‹0.003). AS had increased defect size (229 vs 209.1 â€‹cm2; P â€‹= â€‹0.023), use of component separation (CST) (52.5% vs 43.8 â€‹%; P â€‹= â€‹0.010) and hospital stay (6.6 vs 6.2 days, P â€‹= â€‹0.015). Postoperative wound, mesh, and pulmonary infection, respiratory failure, and recurrence were similar. On multivariable regression, wound class and complications predicted recurrence. BMI, panniculectomy and CST predicted wound complications. BMI, CST, and wound class predicted respiratory complications. CONCLUSION: Despite greater patient and hernia complexity, smoking cessation appears to result in similar outcomes to never-smokers in this AWR population.

Cricopharyngomyotomy: Outcomes of flexible endoscopic management of small and medium sized Zenker's diverticulum.

BACKGROUND: Zenker's diverticulum (ZD) was historically treated with an open transcervical myotomy with diverticulectomy, but endoscopic approaches have gained popularity, though with little recent data. This study aimed to report flexible endoscopic cricopharyngomyotomy (FEC) outcomes, particularly in smaller diverticula. METHODS: Patients with ZD treated with FEC at a tertiary center were reviewed. Patients were grouped by diverticulum size: small (sZD)≤1.5 â€‹cm; medium (mZD) â€‹> â€‹1.5 â€‹cm. RESULTS: Of 30 patients, median age, BMI, sex, and comorbidities were similar between sZD (n â€‹= â€‹18) and mZD (n â€‹= â€‹12). Overall, 80.0 â€‹% had the procedure performed with a needle knife. Median number of clips for mucosotomy closure (5.0[5.0,6.0]vs.7.0[5.0,7.0]clips;p â€‹= â€‹0.051), operative time (59.5[51.0,75.0]vs.74.5[51.0,93.5]minutes;p â€‹= â€‹0.498), length-of-stay (1.0[1.0,1.0]vs.1.0[1.0,1.0]days;p â€‹= â€‹0.397), and follow-up (20.8[1.1,33.4]vs.15.6[5.4,50.4]months;p â€‹= â€‹0.641) were comparable. There were no postoperative leaks; incomplete myotomy occurred in one sZD, yielding a clinical success rate of 96.7 â€‹%. CONCLUSIONS: FEC has a high success rate for ZD and an advantage in small diverticula, difficult to treat with stapling or open technique.

The Utilization of Laparoscopic Ventral Hernia Repair (LVHR) in Incarcerated and Strangulated Cases: A National Trend in Outcomes.

INTRODUCTION: Early after its adoption, minimally invasive surgery had limited usefulness in emergent cases. However, with improvements in equipment, techniques, and skills, laparoscopy in complex and emergency operations expanded substantially. This study aimed to examine the trend of laparoscopy in incarcerated or strangulated ventral hernia repair (VHR) over time. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for laparoscopic repair of incarcerated and strangulated hernias (LIS-VHR) and compared over 2 time periods, 2014-2016 and 2017-2019. RESULTS: The utilization of laparoscopy in all incarcerated or strangulated VHR increased over time (2014-2016: 39.9% (n = 14 075) vs 2017-2019: 46.3% (n = 18 369), P < .001). Though likely not clinically significant, demographics and comorbidities statistically differed between groups (female: 51.7% vs 50.0%, P = .003; age 54.5 ± 13.7 vs 55.4 ± 13.8 years, P < .001; BMI 34.9 ± 8.0 vs 34.6 ± 7.8 kg/m2, P < .001). Patients from 2017 to 2019 were less comorbid (18.9% vs 16.8% smokers, P < .001; 18.2% vs 17.3% diabetic, P = .036; 4.6% vs 4.1% COPD, P = .021) but had higher ASA classification (III: 43.3% vs 45.7%; IV: 2.5% vs 2.7%, P < .001). Hernia types (primary, incisional, recurrent) were similar in each group. Operative time (89.7 ± 59.3 vs 97.4 ± 63.4 min, P < .001) became longer but length-of-stay (1.4 ± 3.3 vs 1.1 ± 2.6 days, P < .001) decreased. There was no statistical difference in surgical complications, medical complications, reoperation, or readmission rates between periods. CONCLUSION: Laparoscopic VHR has become a routine method for treating incarcerated and strangulated hernias, and its utilization continues to increase over time. Clinical outcomes have remained the same while hospital stays have decreased.

Implementation of a penicillin allergy protocol in open abdominal wall reconstruction: Preoperative optimization program.

INTRODUCTION: Beta-lactam prophylaxis is the first-line preoperative antibiotic in open abdominal wall reconstruction. However, of the 11% patients reporting a penicillin allergy (PA), most receive second-line, non-ß-lactam prophylaxis. Previously, abdominal wall reconstruction research from our institution demonstrated increased wound complications, readmissions, and reoperations with non-ß-lactam prophylaxis. Therefore, a collaborative quality improvement initiative was developed with the infectious disease service, and a penicillin allergy protocol was instituted that stratified patients' risk of allergic reaction with a goal to increase ß-lactam prophylaxis use. The effect of the penicillin allergy protocol on open abdominal wall reconstruction outcomes was prospectively evaluated. METHODS: Patients with penicillin allergy undergoing open abdominal wall reconstruction were identified and grouped according to penicillin allergy protocol implementation. Pre-penicillin allergy protocol underwent open abdominal wall reconstruction before January 1, 2020, predominantly receiving non-ß-lactam prophylaxis; post-penicillin allergy protocol underwent open abdominal wall reconstruction between January 1, 2020-November 1, 2023, predominantly receiving ß-lactam prophylaxis. Incidence of surgical site infection was the primary outcome. Standard and inferential statistical analyses were performed. RESULTS: Of 315 patients with penicillin allergy, 250 underwent open abdominal wall reconstruction pre-penicillin allergy protocol and 65 post-penicillin allergy protocol. Pre- and post-penicillin allergy protocol were similar in allergic reaction severity history, sex, race, age, diabetes, American Society of Anesthesiologists score, hernia defect size, and mesh type (P > .05). Post-penicillin allergy protocol had lower body mass index (33.4 ± 7.9 vs 29.8 ± 5.3 kg/m2; P = .002) and fewer active smokers (12.4% vs 1.5%; P = .019). Expectedly, post-penicillin allergy protocol received more ß-lactam prophylaxis (22.8% vs 83.1%; P < .001) and no antibiotic-induced allergic reactions. Post-penicillin allergy protocol had significantly fewer surgical site infections (24.4% vs 3.1%; P < .001), wound breakdown (16.0% vs 3.1%; P = .004), reoperations (19.2% vs 0.0%; P < .001), and readmissions (25.3% vs 9.2%; P = .006) but no statistically significant reduction in recurrence (8.4% vs 1.5%; P = .057). CONCLUSIONS: The penicillin allergy protocol safely increased the number of patients with penicillin allergy undergoing open abdominal wall reconstruction receiving ß-lactam prophylaxis and decreased the rate of surgical site infections, wound complications, reoperations, and readmissions. These data supported the systemwide implementation of the penicillin allergy protocol for both general and orthopedic surgery, which has been incorporated into the electronic medical record of 13 hospitals within the system.

Cortical spreading depression occurs during elective neurosurgical procedures.

OBJECTIVE Cortical spreading depression (CSD) has been observed with relatively high frequency in the period following human brain injury, including traumatic brain injury and ischemic/hemorrhagic stroke. These events are characterized by loss of ionic gradients through massive cellular depolarization, neuronal dysfunction (depression of electrocorticographic [ECoG] activity) and slow spread (2-5 mm/min) across the cortical surface. Previous data obtained in animals have suggested that even in the absence of underlying injury, neurosurgical manipulation can induce CSD and could potentially be a modifiable factor in neurosurgical injury. The authors report their initial experience with direct intraoperative ECoG monitoring for CSD. METHODS The authors prospectively enrolled patients undergoing elective craniotomy for supratentorial lesions in cases in which the surgical procedure was expected to last > 2 hours. These patients were monitored for CSD from the time of dural opening through the time of dural closure, using a standard 1 × 6 platinum electrode coupled with an AC or full-spectrum DC amplifier. The data were processed using standard techniques to evaluate for slow potential changes coupled with suppression of high-frequency ECoG propagating across the electrodes. Data were compared with CSD validated in previous intensive care unit (ICU) studies, to evaluate recording conditions most likely to permit CSD detection, and identify likely events during the course of neurosurgical procedures using standard criteria. RESULTS Eleven patients underwent ECoG monitoring during elective neurosurgical procedures. During the periods of monitoring, 2 definite CSDs were observed to occur in 1 patient and 8 suspicious events were detected in 4 patients. In other patients, either no events were observed or artifact limited interpretation of the data. The DC-coupled amplifier system represented an improvement in stability of data compared with AC-coupled systems. Compared with more widely used postoperative ICU monitoring, there were additional challenges with artifact from saturation during bipolar cautery as well as additional noise peaks detected. CONCLUSIONS CSD can occur during elective neurosurgical procedures even in brain regions distant from the immediate operative site. ECoG monitoring with a DC-coupled full-spectrum amplifier seemed to provide the most stable signal despite significant challenges to the operating room environment. CSD may be responsible for some cases of secondary surgical injury. Though further studies on outcome related to the occurrence of these events is needed, efforts to decrease the occurrence of CSD by modification of anesthetic regimen may represent a novel target for study to increase the safety of neurosurgical procedures.

The structure of creative cognition in the human brain.

Creativity is a vast construct, seemingly intractable to scientific inquiry-perhaps due to the vague concepts applied to the field of research. One attempt to limit the purview of creative cognition formulates the construct in terms of evolutionary constraints, namely that of blind variation and selective retention (BVSR). Behaviorally, one can limit the "blind variation" component to idea generation tests as manifested by measures of divergent thinking. The "selective retention" component can be represented by measures of convergent thinking, as represented by measures of remote associates. We summarize results from measures of creative cognition, correlated with structural neuroimaging measures including structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (1H-MRS). We also review lesion studies, considered to be the "gold standard" of brain-behavioral studies. What emerges is a picture consistent with theories of disinhibitory brain features subserving creative cognition, as described previously (Martindale, 1981). We provide a perspective, involving aspects of the default mode network (DMN), which might provide a "first approximation" regarding how creative cognition might map on to the human brain.