Multicenter Assessment of Cryoanalgesia Use in Minimally Invasive Repair of Pectus Excavatum: A 20-center Retrospective Cohort Study.

OBJECTIVE: To assess the clinical implications of cryoanalgesia for pain management in children undergoing minimally invasive repair of pectus excavatum (MIRPE). BACKGROUND: MIRPE entails significant pain management challenges, often requiring high postoperative opioid use. Cryoanalgesia, which blocks pain signals by temporarily ablating intercostal nerves, has been recently utilized as an analgesic adjunct. We hypothesized that the use of cryoanalgesia during MIRPE would decrease postoperative opioid use and length of stay (LOS). MATERIALS AND METHODS: A multicenter retrospective cohort study of 20 US children's hospitals was conducted of children (age below 18 years) undergoing MIRPE from January 1, 2014, to August 1, 2019. Differences in total postoperative, inpatient, oral morphine equivalents per kilogram, and 30-day LOS between patients who received cryoanalgesia versus those who did not were assessed using bivariate and multivariable analysis. P value <0.05 is considered significant. RESULTS: Of 898 patients, 136 (15%) received cryoanalgesia. Groups were similar by age, sex, body mass index, comorbidities, and Haller index. Receipt of cryoanalgesia was associated with lower oral morphine equivalents per kilogram (risk ratio=0.43, 95% confidence interval: 0.33-0.57) and a shorter LOS (risk ratio=0.66, 95% confidence interval: 0.50-0.87). Complications were similar between groups (29.8% vs 22.1, P =0.07), including a similar rate of emergency department visit, readmission, and/or reoperation. CONCLUSIONS: Use of cryoanalgesia during MIRPE appears to be effective in lowering postoperative opioid requirements and LOS without increasing complication rates. With the exception of preoperative gabapentin, other adjuncts appear to increase and/or be ineffective at reducing opioid utilization. Cryoanalgesia should be considered for patients undergoing this surgery.

Indications for a "Surgery-First" Approach for the Treatment of Lower Extremity Arterial Disease.

BACKGROUND: In recent years, there has been a tendency toward an "endovascular-first" approach for the treatment for femoropopliteal arterial disease. The purpose of this study is to determine if there are patients that are better served with an initial femoropopliteal bypass (FPB) rather than an endovascular attempt at revascularization. METHODS: A retrospective analysis of all patients undergoing FPB between June 2006 - December 2014 was performed. Our primary endpoint was primary graft patency, defined as patent using ultrasound or angiography without secondary intervention. Patients with <1-year follow-up were excluded. Univariate analysis of factors significant for 5-year patency was performed using χ2 tests for binary variables. A binary logistic regression analysis incorporating all factors identified as significant by univariate analysis was used to identify independent risk factors for 5-year patency. Event-free graft survival was evaluated using Kaplan-Meier models. RESULTS: We identified 241 patients undergoing FPB on 272 limbs. FPB indication was disabling claudication in 95 limbs, chronic limb-threatening ischemia (CLTI) in 148, and popliteal aneurysm in 29. In total, 134 FPB were saphenous vein grafts (SVG), 126 were prosthetic grafts, 8 were arm vein grafts, and 4 were cadaveric/xenografts. There were 97 bypasses with primary patency at 5 or more years of follow-up. Grafts patent at 5 years by Kaplan-Meier analysis were more likely to have been performed for claudication or popliteal aneurysm (63% 5-year patency) as compared with CLTI (38%, P < 0.001). Statistically significant predictors (using log rank test) of patency over time were use of SVG (P = 0.015), surgical indication of claudication or popliteal aneurysm (P < 0.001), Caucasian race (P = 0.019) and no history of COPD (P = 0.026). Multivariable regression analysis confirmed these 4 factors as significant independent predictors of 5-year patency. Of note, there was no statistical correlation between FPB configuration (above or below knee anastomosis, in-situ versus reversed saphenous vein) and 5-year patency. There were 40 FPBs in Caucasian patients without a history of COPD receiving SVG for claudication or popliteal aneurysm that had a 92% estimated 5-year patency by Kaplan-Meier survival analysis. CONCLUSIONS: Long-term primary patency that was substantial enough to consider open surgery as a first intervention was demonstrated in Caucasian patients without COPD, having good quality saphenous vein, and who underwent FPB for claudication or popliteal artery aneurysm.

Predictors of mortality in nonagenarians undergoing abdominal aortic aneurysm repair: Analysis of the National Surgical Quality Improvement Program dataset.

BACKGROUND: The present study used the American College of Surgeons National Surgical Quality Improvement Program dataset to identify the predictors of 30-day mortality for nonagenarians undergoing endovascular aortic aneurysm repair (EVAR) or open surgical repair (OSR). METHODS: Patients aged >90 years who had undergone abdominal aortic aneurysm repair from 2005 to 2017 were identified using procedure codes. Those with operative times <15 minutes were excluded. The demographics, preoperative comorbidities, and postoperative complications of those who had died by 30 days were compared with those of the patients alive at 30 days. RESULTS: A total of 1356 nonagenarians met the criteria: 1229 (90.6%) had undergone EVAR and 127 (9.4%) had undergone OSR. The overall 30-day mortality was 10.4%. The patients who had died within 30 days were significantly more likely to have undergone OSR than EVAR (40.9% vs 7.2%; P < .001). They also had a greater incidence of dependent functional status (22.0% for those who had died vs 8.1% for those alive at 30 days; P < .001), American Society of Anesthesiology (ASA) classification of ≥4 (81.2% vs 18.8%; P < .001), perioperative blood transfusion (59.6% vs 20.3%; P < .001), postoperative pneumonia (12.1% vs 2.9%; P = .001), mechanical ventilation >48 hours (22.7% vs 2.6%; P < .001), and acute renal failure (12.1% vs 0.5%; P < .001). The EVAR group had a 30-day mortality rate of 2.6% in 1008 elective cases and 28.6% in 221 emergent cases. The OSR group had a 30-day mortality rate of 19.1% in 47 elective cases and 53.7% in 80 emergent cases. In the EVAR cohort, the 30-day mortality group had had a significantly greater incidence of dependent functional status (17% for those who had died vs 8% for those alive at 30 days; P = .004), ASA classification of ≥4 (76.4% vs 40.3%; P < .001), perioperative blood transfusion (57% vs 19%; P < .001), emergency surgery (71% vs 14%; P < .001), and longer operative times (150 vs 128 minutes; P = .001). CONCLUSIONS: Nonagenarians had an incrementally increased, but acceptable, risk of 30-day mortality with EVAR in elective and emergent cases compared with that reported for octogenarians and cohorts of patients not selected for age. We found greater mortality for patients with dependent status, a higher ASA classification, emergent repair, and OSR. These preoperative risk factors could help identify the best surgical candidates. Given these results, consideration for EVAR or OSR might be reasonable for highly selected patients, especially for elective patients with a larger abdominal aortic aneurysm diameter for whom the risk of rupture is higher.

Estimating sympathetic tone by recording subcutaneous nerve activity in ambulatory dogs.

INTRODUCTION: We tested the hypothesis that subcutaneous nerve activity (SCNA) of the thorax correlates with the stellate ganglion nerve activity (SGNA) and can be used to estimate the sympathetic tone. METHODS AND RESULTS: We implanted radio transmitters in 11 ambulatory dogs to record left SGNA, left thoracic vagal nerve activity (VNA), and left thoracic SCNA, including 3 with simultaneous video monitoring and nerve recording. Two additional dogs were studied under general anesthesia with apamin injected into the right stellate ganglion while the right SGNA and the right SCNA were recorded. There was a significant positive correlation between integrated SGNA (iSGNA) and integrated SCNA (iSCNA) in the first 7 ambulatory dogs, with correlation coefficient of 0.70 (95% confidence interval [CI] 0.61-0.84, P < 0.05 for each dog). Tachycardia episodes (heart rate exceeding 150 bpm for ≥3 seconds) were invariably preceded by SGNA and SCNA. There was circadian variation of both SCNA and SGNA. Crosstalk was ruled out because SGNA, VNA, and SCNA bursts had different timing and activation patterns. In an eighth dog, closely spaced bipolar subcutaneous electrodes also recorded SCNA, but with reduced signal to noise ratio. Video monitoring in additional 3 dogs showed that movement was not a cause of high frequency SCNA. The right SGNA correlated strongly with right SCNA and heart rate in 2 anesthetized dogs after apamin injection into the right stellate ganglion. CONCLUSIONS: SCNA recorded by bipolar subcutaneous electrodes correlates with the SGNA and can be used to estimate the sympathetic tone.

The Evolving Effectiveness of Biologics in Avoiding Surgery in Children With Ulcerative Colitis: At what Nutritional Cost?

BACKGROUND: Pediatric ulcerative colitis (UC) treatment has changed dramatically with the introduction of multiple biologics. The goal of this study was to determine the effectiveness of these new biologics on achieving remission, nutritional impact, and eventual need for surgery in children. METHODS: We retrospectively analyzed hospital records of UC patients (ages 1-19) seen at a pediatric gastroenterology clinic between January 2012 andAugust 2020. Patients were divided into groups: 1) medically without biologics or surgery; 2) patients treated with one biologic; and 3) patients treated with multiple biologics 4)patients that underwent colectomy. RESULTS: There were 115 UC patients with a mean follow-up of 5.9 ± 3.7 years (1 month-15.3 years). PUCAI score at diagnosis was mild in 52 patients (45%), moderate in 25 (21%), and severe in 5 (4.3%). PUCAI score for 33 patients (29%) could not be calculated. There were 48 (41.3%) in group 1 with 58% remission, 34 (29.6%) in group 2 with 71% remission, 24 (20.8%) in group 3 with 29% remission, and only 9 (7.8%) in group 4 with 100% remission. The majority (55%) of surgical patients had colectomy within the first year of diagnosis. BMI improved after surgery (P = 0.001). The change from one biologic to others did not improve nutrition over time. DISCUSSION: New biologics are changing the landscape in maintaining remission from UC. The current need for surgery is much lower than previously published studies. In medically refractive UC, nutritional status only improved after surgery. Addition of another biologic for medically refractory ulcerative colitis in order to avoid surgery must take into account the positive impact surgery has on nutrition and disease remission.

Clostridioides difficile infection after appendectomy: An analysis of short-term outcomes from the NSQIP database.

BACKGROUND: Clostridioides difficile infection can be a significant complication in surgical patients. The purpose of this study was to describe the incidence and impact on outcomes of Clostridioides difficile infection in adult patients after appendectomy. METHODS: The American College of Surgeons National Surgical Quality Improvement Program data set was used to identify all patients with the primary procedure code of appendectomy between 2016 and 2018. Patient demographics and clinical characteristics were extracted from the database, and descriptive statistics were performed. A multivariate logistic regression was created to identify predictors of Clostridioides difficile infection following appendectomy. RESULTS: A total of 135,272 patients who underwent appendectomy were identified, and of those, 469(0.35%) developed Clostridioides difficile infection. Patients with Clostridioides difficile infection were more likely to be older (51.23 vs 40.47 years; P < .0001), female (P = .004), American Society of Anesthesiology score >2 (P < .0001), present with septic shock (P < .0001), or lack functional independence (P < .0001). Patients with Clostridioides difficile infection were more likely to have increased operative time (62.9 vs 50.4 minutes; P < .0001), have perforated appendicitis (48.9% vs 23.5%; P < .0001), and underwent open surgery (7.0% vs 4.0%; P = .0006). Postoperatively, patients with Clostridioides difficile infection required a longer length of stay (4.8 vs 1.8 days; P < .0001), had increased mortality (2.1% vs 0.1%; P < .0001), higher incidences of postoperative abscess (14.9% vs 2.9%; P < .0001), postoperative sepsis (15.1% vs 4.0%; P < .0001), and readmission (30.7% vs 3.4%; all P < .0001). On multivariate analysis, older age (P < .0001), female sex (P = .0043), septic shock (P = .0002), open surgery (P = .037), and dirty wound class (P = .0147) were all independently predictive factors of Clostridioides difficile infection after appendectomy. CONCLUSION: Clostridioides difficile infection is an uncommon postoperative complication of appendectomy and is associated with worse outcomes and higher mortality. Older patients, female sex, those with sepsis, and those undergoing open surgery are at higher risk for developing Clostridioides difficile infection.

Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: targeting the pyrophosphate binding sub-domain.

Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (K(i)=5 nM), and one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC(50)=0.45 µM). Compound 4 was as potent as Gleevec (IC(50)=0.56 µM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with K(i)'s lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N- and A-sub-site of IMPDH.

Small-Conductance Calcium-Activated Potassium Current in Normal Rabbit Cardiac Purkinje Cells.

BACKGROUND: Purkinje cells (PCs) are important in cardiac arrhythmogenesis. Whether small-conductance calcium-activated potassium (SK) channels are present in PCs remains unclear. We tested the hypotheses that subtype 2 SK (SK2) channel proteins and apamin-sensitive SK currents are abundantly present in PCs. METHODS AND RESULTS: We studied 25 normal rabbit ventricles, including 13 patch-clamp studies, 4 for Western blotting, and 8 for immunohistochemical staining. Transmembrane action potentials were recorded in current-clamp mode using the perforated-patch technique. For PCs, the apamin (100 nmol/L) significantly prolonged action potential duration measured to 80% repolarization by an average of 10.4 ms (95% CI, 0.11-20.72) (n=9, P=0.047). Voltage-clamp study showed that apamin-sensitive SK current density was significantly larger in PCs compared with ventricular myocytes at potentials ≥0 mV. Western blotting of SK2 expression showed that the SK2 protein expression in the midmyocardium was 58% (P=0.028) and the epicardium was 50% (P=0.018) of that in the pseudotendons. Immunostaining of SK2 protein showed that PCs stained stronger than ventricular myocytes. Confocal microscope study showed SK2 protein was distributed to the periphery of the PCs. CONCLUSIONS: SK2 proteins are more abundantly present in the PCs than in the ventricular myocytes of normal rabbit ventricles. Apamin-sensitive SK current is important in ventricular repolarization of normal PCs.

Right Ventricular Outflow Tract Reconstruction With a Polytetrafluoroethylene Monocusp Valve: A 20-Year Experience.

In patients with tetralogy of Fallot (TOF), pulmonary atresia (PA), and other congenital right ventricular outflow tract (RVOT) malformations, polytetrafluoroethylene (PTFE) monocusp outflow tract patches (MOTP) relieve obstruction and provide pulmonary valve competence. The purpose of this study was to determine whether our PTFE-MOTP was an acceptable short- and mid-term remedy for patients with TOF or PA as assessed by freedom from severe pulmonary regurgitation and freedom from reoperation. From 1994-2014, 171 patients (mean age 1.5 ± 1.5 years; median 1.1 years) with TOF or PA underwent initial right ventricular outflow tract (RVOT) reconstruction with a PTFE-MOTP. Patients were studied intraoperatively and serially postoperatively using echocardiography and cardiac magnetic resonance imaging (CMR) to determine pulmonary valve dysfunction defined as a peak gradient >40mmHg or valve regurgitation>moderate. The mean follow-up duration was 10.9 ± 5.8 years (range: 1 month-20 years). There were 5 late deaths and 1 early death. There was a significant difference between the preoperative and postoperative peak RVOT gradients (74.0 vs 25.2mmHg). Of the 171 patients, 25 were lost to follow-up, and 42 have required replacement of their monocusp valves 10.1 ± 5.0 years (range: 5 months-19 years) after original monocusp insertion. At 10-year follow-up, severe pulmonary regurgitation was seen in less than 25% of patients, and severe pulmonary stenosis was seen in less than 10% of patients. Since 2007, CMR was used in 44 patients to characterize cardiac function in patients under consideration for PTFE-MOTP replacement. The average right ventricular-to-left ventricular (RV/LV) ratio on CMR was 1.7 ± 0.5 in these patients. CMR also showed that RV ejection fraction (52 ± 9%) and left ventricular ejection fraction (58 ± 7%) were both preserved in most patients. The PTFE-MOTP is an excellent short-term and mid-term option for initial RVOT reconstruction, particularly in children with TOF with nonsalvageable pulmonary valve or PA-ventricular septal defect.

Synthesis and biological activity of novel N6-substituted and 2,N6-disubstituted adenine ribo- and 3'-C-methyl-ribonucleosides as antitumor agents.

A series of N6-aminopurine-9-ß-D-ribonucleosides and ribose-modified 3'-C-methyl analogues substituted at N6-position with a small group like hydroxy, methoxy or amino group or at C2(N6) position have been synthesized and tested against a panel of human leukemia and carcinoma cell lines. N6-Hydrazino-9-ß-D-ribofuranosyl-purine (5) displayed the best antiproliferative activity in the low micromolar or submicromolar range against all tested tumor cell lines. The activity of this nucleoside is related in part to ribonucleotide reductase inhibition. C2-modification or 3'-C-methylation in N6-substituted adenosine analogues leads to a decrease or loss in activity.