Neutrophils: Novel Contributors to Estrogen-Dependent Intracranial Aneurysm Rupture Via Neutrophil Extracellular Traps.

Background Intracranial aneurysms (IAs) are more prevalent in women than men, and aneurysmal subarachnoid hemorrhage disproportionately affects postmenopausal women. These sex differences suggest estrogen protects against IA progression that can lead to rupture, but the underlying mechanisms are not fully understood. Although studies have demonstrated estrogen regulates inflammatory processes that contribute to IA pathogenesis, the role of neutrophils remains to be characterized. Using a murine model, we tested our hypothesis that neutrophils contribute to IA pathophysiology in an estrogen-dependent manner. Methods and Results We compared neutrophil infiltration in C57BL/6 female mice that develop IAs to those with a normal circle of Willis. Next, we investigated the estrogen-dependent role of neutrophils in IA formation, rupture, and symptom-free survival using a neutrophil depletion antibody. Finally, we studied the role of neutrophil extracellular trap formation (NETosis) as an underlying mechanism of aneurysm progression. Mice that developed aneurysms had increased neutrophil infiltration compared with those with a normal circle of Willis. In estrogen-deficient female mice, both neutrophil depletion and NETosis inhibition decreased aneurysm rupture. In estrogen-deficient female mice treated with estrogen rescue and estrogen-intact female mice, neither neutrophil depletion nor NETosis inhibition affected IA formation, rupture, or symptom-free survival. Conclusions Neutrophils contribute to aneurysm rupture in an estrogen-dependent manner. NETosis appears to be an underlying mechanism for neutrophil-mediated IA rupture in estrogen deficiency. Targeting NETosis may lead to the development of novel therapeutics to protect against IA rupture in the setting of estrogen deficiency.

EUS-Guided Vascular Interventions.

Endoscopic ultrasound (EUS) has numerous advanced applications as a diagnostic and therapeutic modality in contemporary medicine. Through intraluminal placement, EUS offers a real-time Doppler-guided endoscopic visualization and access to intra-abdominal vasculature, which were previously inaccessible using historical methods. We aim to provide a comprehensive review of key studies on both current and future EUS-guided vascular applications. This review details EUS-based vascular diagnostic techniques of portal pressure measurements in the prognostication of liver disease and portal venous sampling for obtaining circulating tumor cells in the diagnosis of cancer. From an interventional perspective, we describe effective EUS-guided treatments via coiling and cyanoacrylate injections of gastric varices and visceral artery pseudoaneurysms. Specific attention is given to clinical studies on efficacy and procedural techniques described by investigators for each EUS-based application. We explore novel and future emerging EUS-based interventions, such as liver tumor ablation and intrahepatic portosystemic shunt placement.

Chronic opioid users with dysphagia are indistinguishable from symptomatic nonusers on functional lumen imaging probe evaluation.

BACKGROUND: Opioid-induced esophageal dysmotility (OIED) includes spastic esophageal motility disorders, increasingly recognized in the contemporary opioid epidemic. We assessed functional lumen imaging probe (FLIP) findings in diagnosing OIED. METHODS: Symptomatic patients undergoing FLIP with no prior foregut surgery who completed validated questionnaires were identified and segregated into chronic opioid users and nonusers in this cohort study. Esophagogastric junction (EGJ) distensibility index (DI), EGJ diameter, and esophageal body contraction patterns were extracted. Symptom profiles were compared to FLIP findings between chronic opioid users and nonusers. Outcome was evaluated in a subset using the same validated questionnaires. RESULTS: Over the 18-months study period, of 116 patients (median age 62 years, 70.7% female), 33 (28.4%) were chronic opioid users, with median morphine milligram equivalent of 30 mg. While presenting symptoms were similar, chronic opioid users reported higher perceptive symptoms (p = 0.008) and worse quality of life (p = 0.01) compared to nonusers. Median DI trended lower in chronic opioid users (p = 0.08), with more retrograde repetitive contractions (p < 0.001) and less absent contractility (p = 0.007), but final FLIP diagnoses were similar compared to nonusers. There was no correlation between opioid dose and FLIP metrics. In the subset with follow-up, perceptive symptoms trended higher in chronic opioid users (p = 0.08), but symptom improvement following therapy was similar in both groups. CONCLUSIONS & INFERENCES: Symptomatic chronic opioid users have FLIP diagnoses that are similar to nonusers, despite higher perceptive symptoms and worse quality of life. Dominant symptoms improve both in chronic opioid users and nonusers following treatment directed by FLIP.

Pentobarbital Coma Use in a Pregnant Patient With Refractory Intracranial Hypertension: A Case Report.

OBJECTIVE: Intracranial hypertension is a life-threatening condition that requires emergent diagnosis and management. Although pentobarbital coma for refractory intracranial hypertension has been studied in the general population, this study is the first reported case of pentobarbital coma use in a pregnant patient. METHODS: We performed a retrospective chart review of a pregnant patient with refractory intracranial hypertension and reviewed the current literature on the role of pentobarbital coma. RESULTS: We present the case of a 35-year-old woman at 26 weeks of gestation who developed refractory intracranial hypertension secondary to rupture of a dural arteriovenous fistula. The patient was taken to surgery for decompressive hemicraniectomy, clot evacuation, and dural arteriovenous fistula resection. Subsequently, the patient was treated with pentobarbital coma for 5 days and achieved adequate control of her intracranial pressures. The patient and fetus were closely monitored by the obstetrics team with no apparent harm to fetal well-being during her hospital stay. The patient underwent planned cesarean delivery at term, and both the mother and newborn were discharged in stable condition with no known pentobarbital-related complications. CONCLUSIONS: Thus, we present the first case report demonstrating that pentobarbital coma may be a safe and efficacious option for treating pregnant patients with life-threatening refractory intracranial hypertension. We also provide dosing information for pentobarbital administration. Additional studies and reports involving pregnant patients are needed to better understand the impact of pentobarbital on both the mother and fetus. Furthermore, long-term follow-up of both the mother and newborn is critical to identifying any delayed sequelae of neonatal exposure to pentobarbital.

Cost Drivers in Carpal Tunnel Release Surgery: An Analysis of 8,717 Patients in New York State.

PURPOSE: The annual high volume of carpal tunnel releases (CTRs) has a large financial impact on the health care system. Validating the cost drivers related to CTR in a large, diverse patient population may aid in developing cost reduction strategies to benefit health care systems. METHODS: Adult patients with carpal tunnel syndrome who underwent CTR were identified in the New York Statewide Planning and Research Cooperative System database from 2016 to 2017. The Statewide Planning and Research Cooperative System is a comprehensive all-payer database that collects all inpatient and outpatient preadjudicated claims in New York. A multivariable mixed model regression with random effects was performed for the facility to assess the variables that contributed significantly to the total charge. The variables included were patient age, sex, anesthesia method, whether the surgery took place in an ambulatory surgery center or a hospital outpatient department, operation time in minutes, primary insurance type, race, ethnicity, Charlson Comorbidity Index, and categories for billed procedure codes. RESULTS: During the period of 2016 to 2017, 8,717 claims were included, with a mean charge per claim of $4,865. General anesthesia was associated with higher charges than local anesthesia. A procedure at a hospital outpatient department was associated with an approximately 48.2% increase in the total charge compared with that at an ambulatory surgery center. A 1-minute increase in the operation time was associated with a 0.3% increase in the total charge. Claims with antiemetics, antihistamines, benzodiazepines, intravenous fluids, narcotic agents, or preoperative antibiotics were associated with higher total charges than claims that did not bill for these. Compared with endoscopic procedures, open procedures had a 44.3% decrease in the total charges. CONCLUSIONS: This comprehensive multivariable model has validated that general anesthesia, hospital-based surgery, the use of antibiotics and opioids, longer operative times, and endoscopic CTR significantly increased the cost of surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and decision analyses II.

Demographic Disparities amongst Patients Receiving Carpal Tunnel Release: A Retrospective Review of 92,921 Patients.

Despite strong evidence supporting the efficacy of surgical release for carpal tunnel syndrome (CTS), previous studies have suggested that surgery is not performed equally amongst races and sex. The purpose of this study was to investigate potential socioeconomic disparities in the surgical treatment for CTS. METHODS: Adult patients (≥18) were identified in the New York Statewide Planning and Research Cooperative System database from 2011 to 2018 by diagnosis code for CTS. All carpal tunnel surgery procedures in the outpatient setting were identified using Current Procedural Terminology codes. Using a unique identifier for each patient, the diagnosis data were linked to procedure data. A multivariable logistic regression was performed to assess the impact of patient factors on the likelihood of receiving surgery. RESULTS: In total, 92,921 patients with CTS were included in the analysis and 30,043 (32.3%) went on to have surgery. Older age and workers compensation insurance had increased the odds of surgery. Feminine gender had lower odds of surgery. Asian, African American, and other races had decreased odds of surgery relative to the White race. Patients of Hispanic ethnicity had decreased odds of surgery compared with non-Hispanic ethnicity. Patients with Medicare, Medicaid, or self-pay insurance were all less likely to undergo surgery relative to private insurance. Higher social deprivation was also associated with decreased odds of surgery. CONCLUSIONS: Surgical treatment of CTS is unequally distributed amongst gender, race, and socioeconomic status. Additional research is necessary to identify the cause of these disparities to improve equity in patient care.

Adropin decreases endothelial monolayer permeability after cell-free hemoglobin exposure and reduces MCP-1-induced macrophage transmigration.

BACKGROUND: Cell-free heme-containing proteins mediate endothelial injury in a variety of disease states including subarachnoid hemorrhage and sepsis by increasing endothelial permeability. Inflammatory cells are also attracted to sites of vascular injury by monocyte chemotactic protein 1 (MCP-1) and other chemokines. We have identified a novel peptide hormone, adropin, that protects against hemoglobin-induced endothelial permeability and MCP-1-induced macrophage migration. METHODS: Human microvascular endothelial cells were exposed to cell-free hemoglobin (CFH) with and without adropin treatment before measuring monolayer permeability using a FITC-dextran tracer assay. mRNA and culture media were collected for molecular studies. We also assessed the effect of adropin on macrophage movement across the endothelial monolayer using an MCP-1-induced migration assay. RESULTS: CFH exposure decreases adropin expression and increases paracellular permeability of human endothelial cells. Treating cells with synthetic adropin protects against the increased permeability observed during the natural injury progression. Cell viability was similar in all groups and Hmox1 expression was not affected by adropin treatment. MCP-1 potently induced macrophage migration across the endothelial monolayer and adropin treatment effectively reduced this phenomenon. CONCLUSIONS: Endothelial injury is a hallmark of many disease states. Our results suggest that adropin treatment could be a valuable strategy in preventing heme-mediated endothelial injury and macrophage infiltration. Further investigation of adropin therapy in animal models and human tissue specimens is needed.

Performance After Anterior Cruciate Ligament Reconstruction in National Basketball Association Players.

BACKGROUND: Anterior cruciate ligament (ACL) injury in National Basketball Association (NBA) players can have a significant impact on player longevity and performance. Current literature reports a high rate of return to play, but there are limited data on performance after ACL reconstruction (ACLR). PURPOSE/HYPOTHESIS: To determine return to play and player performance in the first and second seasons after ACLR in NBA players. We hypothesized that players would return at a high rate. However, we also hypothesized that performance in the first season after ACLR would be worse as compared with the preinjury performance, with a return to baseline by postoperative year 2. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: An online database of NBA athlete injuries between 2010 and 2019 was queried using the term ACL reconstruction. For the included players, the following data were recorded: name; age at injury; position; height, weight, and body mass index; handedness; NBA experience; dates of injury, surgery, and return; knee affected; and postoperative seasons played. Regular season statistics for 1 preinjury season and 2 postoperative seasons were compiled and included games started and played, minutes played, and player efficiency rating. Kaplan-Meier survivorship plots were computed for athlete return-to-play and retirement endpoints. RESULTS: A total of 26 athletes underwent ACLR; of these, 84% (95% CI, 63.9%-95.5%) returned to play at a mean 372.5 days (95% CI, 323.5-421.5 days) after surgery. Career length after injury was a mean of 3.36 seasons (95% CI, 2.27-4.45 seasons). Factors that contributed to an increased probability of return to play included younger age at injury (odds ratio, 0.71 [95% CI, 0.47-0.92]; P = .0337) and fewer years of experience in the NBA before injury (odds ratio, 0.70 [95% CI, 0.45-0.93]; P = .0335). Postoperatively, athletes played a significantly lower percentage of total games in the first season (48.4%; P = .0004) and second season (62.1%; P = .0067) as compared with the preinjury season (78.5%). Player efficiency rating in the first season was 19.3% less than that in the preinjury season (P = .0056). Performance in the second postoperative season was not significantly different versus preinjury. CONCLUSION: NBA players have a high rate of RTP after ACLR. However, it may take longer than a single season for elite NBA athletes to return to their full preinjury performance. Younger players and those with less NBA experience returned at higher rates.

Spinal cord detethering without laminectomy or laminotomy.

BACKGROUND: Tethered cord syndrome occurs when there is abnormal tension on the distal spinal cord, which limits its elevation as patients grow. This results in stretching of the neural elements and microvasculature, resulting in both direct and ischemic injury.[7] Animal studies suggest that impairment of oxidative metabolic pathways may contribute to neuronal injury.[7] Associated conditions include myelomeningocele, lipomyelomeningocele, intraspinal lipomas, diastematomyelia, thickened/fatty filum terminale, and trauma.[2] Tethering may be asymptomatic or result in a variety of symptoms including lower extremity weakness/sensory deficits, bowel/bladder dysfunction, scoliosis, pes cavus, and back/leg pain.[6] Early surgical intervention has been shown to improve outcomes and may be performed prophylactically or to prevent symptom progression.[1,3] More specifically, retrospective studies demonstrate that surgical intervention in patients under the age of 2 years is associated with improved outcomes.[5] In some cases, detethering may result in clinical improvement.[3]. CASE DESCRIPTION: We present a case of a 6-month-old male with a low-lying conus medullaris, lumbar syrinx, mildly abnormal urodynamic studies, and asymmetric utilization of his lower extremities observed during the evaluation of a Y-shaped gluteal cleft. He underwent elective spinal cord detethering via the safe and effective, minimally invasive technique described in the video.The patient's parents gave informed consent for treatment and video recording. Institutional review board approval was deemed unnecessary. CONCLUSION: Given the variety of surgical techniques used for cord detethering, this video may assist other surgeons in developing techniques that require little to no compromise of the developing bony spinal column while achieving sufficient release of the spinal cord.[4].

Interleukin-6 Promotes Murine Estrogen Deficiency-Associated Cerebral Aneurysm Rupture.

BACKGROUND: Estrogen deficiency is associated with cerebral aneurysm rupture, but the precise mechanism is unknown. OBJECTIVE: To test the hypothesis that IL-6 is required for the increase in aneurysm rupture rate observed in estrogen-deficient mice. METHODS: We analyzed IL-6 expression in human cerebral aneurysms. We induced cerebral aneurysms in estrogen-deficient female C57BL/6 mice that had undergone 4-vinylcyclohexene diepoxide (VCD) treatment or bilateral ovariectomy (OVE). Mice were blindly randomized to selective IL-6 inhibition (IL-6 receptor [IL-6R] neutralizing antibody, n = 25) or control (isotype-matched IgG, n = 28). Murine cerebral arteries at the circle of Willis were assessed for aneurysm rupture and macrophage infiltration. RESULTS: IL-6 is expressed in human cerebral aneurysms, but not in control arteries. Serum IL-6 is elevated in ovariectomized female mice compared to sham control (14.3 ± 1.7 pg/mL vs 7.4 ± 1.5 pg/mL, P = .008). Selective IL-6R inhibition suppressed cerebral aneurysm rupture in estrogen-deficient mice compared with control (VCD: 31.6% vs 70.0%, P = .026; OVE: 28.6% vs 65.2%, P = .019). IL-6R inhibition had no effect on formation or rupture rate in wild-type mice. IL-6R neutralizing antibody significantly reduced macrophage infiltration at the circle of Willis (1.9 ± 0.2 vs 5.7 ± 0.6 cells/2500 µm2; n = 8 vs n = 15; P < .001). CONCLUSION: IL-6 is increased in the serum of estrogen-deficient mice and appears to play a role in promoting murine estrogen deficiency-associated cerebral aneurysm rupture via enhanced macrophage infiltration at the circle of Willis. Inhibition of IL-6 signaling via IL-6 receptor neutralizing antibody inhibits aneurysm rupture in estrogen-deficient mice. IL-6 receptor inhibition had no effect on aneurysm formation or rupture in wild-type animals.

Geriatric distal femur fracture: Are we underestimating the rate of local and systemic complications?

BACKGROUND: Low energy distal femur fractures often occur in a fragile elderly population that is prone to local and systemic complications following operative treatment of extremity fractures. The nonunion rate and early complication rate following laterally based locked plating in this specific fracture are not well described. METHODS: We conducted a retrospective cohort study conducted at three affiliated tertiary care hospitals to evaluate nonunion, early post operative complications, discharge disposition, length of stay, and mortality in patients over 60 years old undergoing laterally based locked plating of a low energy distal femur fracture. RESULTS: Forty-four out of 176 patients were deceased at one year (25%). Predictors of one year mortality included older age, higher Charlson Comorbidity Index (CCI), and delay to surgery greater than 2days (p<0.001). Of 99 patients alive and with follow up at one year, 24 (24%) developed a nonunion and 21 of 24 required nonunion surgery. Development of a surgical site infection was statistically significantly correlated with development of nonunion. Age and CCI did not predict development of nonunion. Average length of stay was 10days and 82% of patients were discharged to a skilled nursing facility. Thirty eight percent of patients experienced at least one postoperative systemic complication. CONCLUSIONS: Laterally based locked plating of the low energy geriatric distal femur fracture is most often followed by a tumultuous post-operative course with a high rate of local and systemic complications including death, nonunion, and extended hospital stays. LEVEL OF EVIDENCE: Level III prognostic.