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JOURNAL/nrgr/04.03/01300535-202412000-00032/figure1/v/2024-04-08T165401Z/r/image-tiff For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered at ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Background: Although ERAS protocols have many benefits, there are some deficiencies in their understanding and implementation by healthcare professionals. The present study was conducted to investigate the compliance of the current perioperative practices of healthcare professional with the ERAS protocols and to assess barriers to the implementation of ERAS protocols in colorectal surgery., Methods: This cross-sectional descriptive study conducted in the surgical clinics and operating rooms of a training and research hospital between January 2020 and September 2020 included 110 physician and nurse members of surgical teams. Data were collected using the Questionnaire for Evaluating the Use of the ERAS Protocol and Identifying Barriers to Implementation in Colorectal Surgery., Results: The compliance of the current perioperative practices by healthcare professionals with the ERAS protocols ranged between 15.5% (routinely leaving nasogastric tubes in situ following colorectal resection) and 61.8% (being aware of the concept of balanced analgesia). Variables such as the healthcare professional's profession, title, years in practice and colorectal surgery experience led to a difference between them in terms of their compliance of the practices with the ERAS protocols ( p  < 0.05). Based on the healthcare professionals' comments about barriers to the implementation of the ERAS protocol, themes such as education, teamwork, communication and lack of resources were created., Conclusion: Healthcare professionals' compliance level of the current perioperative practices with the ERAS protocols was mostly low. Barriers to the implementation of the ERAS protocols had a multi-factor structure that concerns the multidisciplinary team.

Background: Early-onset colon cancer (EOCC) has increasing incidence and disproportionately affects African-Americans. This analysis aims to compare EOCC survival among Black and White patients after matching relevant socio-demographic factors and stage., Methods: The 2004-2017 NCDB database was queried for Black and White patients, age<50, who underwent colectomy for adenocarcinoma. A one-to-one match on race was performed based on sociodemographic factors and disease stage (I-IV). Five-year survival differences were analyzed with Cox proportional hazards models., Results: 5322 Black-White matched pairs were analyzed. Compared to White patients, Black patients averaged more days to surgery (19 ​± ​68 vs 16 days ​± ​32, p ​< ​0.001) and to chemotherapy (63 ​± ​8 vs. 57 ​± ​39, p ​< ​0.001). Black stage III patients were 20% less likely to receive chemotherapy (OR 0.8, 95% CI 0.7-0.9, p ​= ​0.0006), and had a 17% increased rate of death (HR 1.17, 95% CI 1.0-1.3, p ​= ​0.01) after adjusting for sex, comorbidity score, tumor location and chemotherapy., Conclusions: Black patients with stage 3 EOCC are less likely to receive chemotherapy and have worse survival. Further evaluation is warranted to identify potential factors driving these observed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Several management options exist for colonic decompression in the setting of malignant large bowel obstruction, including oncologic resection, surgical diversion, and SEMS as a bridge-to-surgery. Consensus has yet to be reached on optimal treatment pathways. The aim of the present study was to perform a network meta-analysis comparing short-term postoperative morbidity and long-term oncologic outcomes between oncologic resection, surgical diversion, and self-expanding metal stents (SEMS) in left-sided malignant colorectal obstruction with curative intent., Methods: Medline, Embase, and CENTRAL were systematically searched. Articles were included if they compared two or more of the following in patients presenting with curative left-sided malignant colorectal obstruction: (1) emergent oncologic resection; (2) surgical diversion; and/or (3) SEMS. The primary outcome was overall 90-day postoperative morbidity. Pairwise meta-analyses were performed with inverse variance random effects. Random-effect Bayesian network meta-analysis was performed., Results: From 1277 citations, 53 studies with 9493 patients undergoing urgent oncologic resection, 1273 patients undergoing surgical diversion, and 2548 patients undergoing SEMS were included. Network meta-analysis demonstrated a significant improvement in 90-day postoperative morbidity in patients undergoing SEMS compared to urgent oncologic resection (OR0.34, 95%CrI0.01-0.98). Insufficient RCT data pertaining to overall survival (OS) precluded network meta-analysis. Pairwise meta-analysis demonstrated decreased five-year OS for patients undergoing urgent oncologic resection compared to surgical diversion (OR0.44, 95%CI0.28-0.71, p < 0.01)., Conclusions: Bridge-to-surgery interventions may offer short- and long-term benefits compared to urgent oncologic resection for malignant colorectal obstruction and should be increasingly considered in this patient population. Further prospective study comparing surgical diversion and SEMS is needed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sex is a key biological variable in traumatic brain injury (TBI) and plays a significant role in neuroinflammatory responses. However, the molecular mechanisms contributing to this sexually dimorphic neuroinflammatory response remain elusive. Here we describe a significant and previously unreported tissue enrichment and sex-specific alteration of a set of inflammatory microRNAs (miRNAs) in CD11b+ cells of brain and bone marrow isolated from naïve mice as well as mice subjected to TBI. Our data from naïve mice demonstrated that expression levels of miR-146a-5p and miR-150-5p were relatively higher in brain CD11b+ cells, and that miR-155-5p and miR-223-3p were highly enriched in bone marrow CD11b+ cells. Furthermore, while miR-150-5p and miR-155-5p levels were higher in male brain CD11b+ cells, no significant sexual difference was observed for miR-146a-5p and miR-223-3p. However, TBI resulted in sex-specific differential responses of these miRNAs in brain CD11b+ cells. Specifically, miR-223-3p levels in brain CD11b+ cells were markedly elevated in both sexes in response to TBI at 3 and 24 h, with levels in females being significantly higher than males at 24 h. We then focused on analyzing several miR-223-3p targets and inflammation-related marker genes following injury. Corresponding to the greater elevation of miR-223-3p in females, the miR-223-3p targets, TRAF6 and FBXW7 were significantly reduced in females compared to males. Interestingly, anti-inflammatory genes ARG1 and IL4 were higher in females after TBI than in males. These observations suggest miR-223-3p and other inflammatory responsive miRNAs may play a key role in sex-specific neuroinflammatory response following TBI., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Accumulating evidence suggests that gut microbes modulate brain plasticity via the bidirectional gut-brain axis and play a role in stroke rehabilitation. However, the microbial species alterations associated with stroke and their correlation with functional outcome measures following acute stroke remain unknown. Here we measure post-stroke gut dysbiosis and how it correlates with gut permeability and cognitive functions in 12 stroke participants, 18 controls with risk factors for stroke, and 12 controls without risk factors. Stool samples were used to measure the microbiome with whole genome shotgun sequencing and leaky gut markers. We genotyped APOE status and measured diet composition and motor, cognitive, and emotional status using NIH Toolbox. We used linear regression methods to identify gut microbial associations with cognitive and emotional assessments. We did not find significance differences between the two control groups. In contrast, the bacteria populations of the Stroke group were statistically dissimilar from the control groups. Relative abundance analysis revealed notable decreases in butyrate-producing microbial taxa, secondary bile acid-producing taxa, and equol-producing taxa. The Stroke group had higher levels of the leaky gut marker alpha-1-antitrypsin in the stool than either of the groups and several taxa including Roseburia species (a butyrate producer) were negatively correlated with alpha-1-antitrypsin. Stroke participants scored lower on memory testing than those in the two control groups. Stroke participants with more Roseburia performed better on the picture vocabulary task; more Bacteroides uniformis (a butyrate producer) and less Escherichia coli (a pro-inflammatory species) reported higher levels of self-efficacy. Intakes of fiber, fruit and vegetable were lower, but sweetened beverages were higher, in the Stroke group compared with controls. Vegetable consumption was correlated with many bacterial changes among the participants, but only the species Clostridium bolteae, a pro-inflammatory species, was significantly associated with stroke. Our findings indicate that stroke is associated with a higher abundance of proinflammatory species and a lower abundance of butyrate producers and secondary bile acid producers. These altered microbial communities are associated with poorer functional performances. Future studies targeting the gut microbiome should be developed to elucidate whether its manipulation could optimize rehabilitation and boost recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Hammond, Powell, Green, Chlipala, Frank, Yackzan, Yanckello, Chang, Xing, Heil, Springer, Pennypacker, Stromberg, Sawaki and Lin.)

Introduction: Malnutrition and deconditioning impact postoperative morbidity and mortality. Computed tomography (CT) body composition variables are used as markers of nutritional status and sarcopenia. The objective of this study is to evaluate the impact of sarcopenia, using CT variables, on postoperative outcomes following transanal total mesorectal excision (TaTME) for rectal cancer., Methods: This was an institutional retrospective cohort analysis of consecutive rectal cancer patients who underwent TaTME between April 2014 and May 2020. Psoas muscle index (PMI) was calculated from diagnostic CT scans. Based on previous studies, patients in the lowest PMI tertile by gender were considered sarcopenic. Fisher's exact and Mann-Whitney U test were used to compare categorical and continuous variables, respectively. Readmission rates and postoperative complications were compared between groups. Backward stepwise logistic regression was used to determine the association between sarcopenia and 30-day postoperative complications., Results: 85 patients were analyzed, of which 63% were male, with a median age of 59 (IQR: 51-65), and median BMI of 28 (IQR: 24-32). Of the entire cohort, 34% (n = 29) were sarcopenic (median PMI 5.39 IQR: 4.49-6.71). No significant difference in baseline characteristics between sarcopenic and nonsarcopenic patients were observed. 55% of sarcopenic patients experienced a complication within 30 days compared to 24% of nonsarcopenic patients (p = 0.01). 41% of sarcopenic patients required hospital readmission within 30 days compared to 17% of their nonsarcopenic counterparts (p = 0.014). Sarcopenic patients also experienced significantly higher rates of post-operative small bowel obstruction (10% vs. 0%, p = 0.04). Multivariable analyses identified that sarcopenic patients have a fourfold increase in odds of experiencing a 30-day postoperative complication (OR: 4.44, 95%CI: 1.6-12.4, p < 0.05) after adjusting for gender., Conclusion: Preoperative sarcopenia is associated with increased 30-day postoperative complications following TaTME for rectal cancer. Postoperative complications can have serious oncologic implications by delaying adjuvant chemotherapy. Therefore, preoperative recognition of sarcopenia prior to undergoing TaTME for rectal cancer may provide an opportunity for early intervention with prehabilitation programs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Completion proctectomy is traditionally performed using a combination of abdominal and perineal approaches. Access to and exposure of the pelvis through the abdominal cavity can be limited in patients with prior surgery or inflammatory conditions. We describe a novel technique for a total transperineal approach for proctectomy for Crohn's proctitis, avoiding technical challenges, risks, and recovery associated with abdominal surgery., Technique: We utilized the skills and expertise acquired from our experience with transanal total mesorectal excision to perform a total transperineal laparoscopic proctectomy in a male patient with medically refractory proctitis. He previously underwent an anterior resection, drainage of a chronic presacral abscess, omental pedicle flap transposition to the pelvis, and end colostomy for severe Crohn's colitis. The total transperineal laparoscopic proctectomy approach avoids the need for abdominal access, including the risks associated with abdominal entry, adhesiolysis, pelvic access and visualization, and wound-related issues. Following an initial intersphincteric perineal dissection, the GelPOINT Path minimal access platform is utilized to perform a total transperineal proctectomy., Results: The patient recovered uneventfully and was discharged to home 2 days after surgery. At 1-month postoperative follow-up, the patient is recovering well with complete healing of the perineal wound., Conclusion: We demonstrate the feasibility, safety, and technical steps of a minimally invasive completion proctectomy for fistulizing Crohn's proctitis by using a total transperineal approach. This approach allowed us to utilize direct, inline, high-definition visualization to access and safely operate in the distal aspects of a narrow, scarred, and fibrotic pelvis while avoiding the need for any abdominal access. Advanced experience with redo pelvic and minimally invasive transanal surgery is critical. See Video at http://links.lww.com/DCR/B664., (Copyright © The ASCRS 2021.)

Background: Over the last decade, use of laparoscopy for the treatment of colon cancer has been variable despite evidence of benefit, possibly reflecting surgeon expertise rather than other factors., Objective: The purpose of this study was to examine the spatial variation in the use of laparoscopy for colon cancer surgery and to determine what factors may influence use., Design: This was a population-based retrospective analysis from April 2008 to March 2015., Settings: All Canadian provinces (excluding Quebec) were included., Patients: The study included all patients ≥18 years of age undergoing elective colectomy for colon cancer., Main Outcome Measures: The primary outcome was laparoscopy use rates. Predictors of use included patient and disease characteristics, year of surgery, rurality, hospital and surgeon volumes, and distance from a colorectal fellowship training center., Results: A total of 34,725 patients were identified, and 42% underwent laparoscopic surgery. Significant spatial variations in laparoscopy use were identified, with 95% of high-use clusters located ≤100 km and 98% of low-use clusters located >100 km from a colorectal fellowship center. There were no high-use clusters located around large academic centers without colorectal fellowships. At the individual level, patients living within 25 km and 26 to 100 km of a fellowship center were 2.6 and 1.6 times more likely to undergo laparoscopic surgery compared with those >100 km away (95% CI, 2.47-2.79, p < 0.00; 95% CI, 1.53-1.71, p < 0.001). Surgeon and hospital volumes were associated with increased rates of laparoscopy use (p < 0.001)., Limitations: Data were obtained from an administrative database, and despite 85% to 95% published validity, they remain subject to misclassification, response, and measurement bias., Conclusions: Significant spatial variations in the use of laparoscopy for colon cancer surgery exist. After adjusting for patient and system factors, proximity to a colorectal fellowship training center remained a strong predictor of laparoscopy use. There remain regional variations in colon cancer treatment, with discrepancies in the surgical care offered to Canadian patients based solely on location. See Video Abstract at http://links.lww.com/DCR/B595., Variacin Regional En El Uso De Laparoscopia Para El Tratamiento Electivo Del Cncer De Colon En Canad La Importancia De Los Sitios De Capacitacin Para Residentes: ANTECEDENTES:Durante la última década, la utilización de la laparoscopia para el tratamiento del cáncer de colon ha sido variable a pesar de la evidencia de beneficio; posiblemente reflejando la experiencia del cirujano, más que otros factores.OBJETIVO:Examinar la variación espacial en el uso de la laparoscopia para la cirugía del cáncer de colon y determinar qué factores pueden influir en la utilización.DISEÑO:Análisis retrospectivo poblacional de abril de 2008 a marzo de 2015.ENTORNO CLÍNICO:Todas las provincias canadienses (excepto Quebec).PACIENTES:Todos los pacientes> 18 años sometidos a colectomía electiva por cáncer de colon.PRINCIPALES MEDIDAS DE RESULTADO:El principal resultado fueron las tasas de utilización de laparoscopia. Los predictores de uso incluyeron las características del paciente y la enfermedad, el año de la cirugía, la ruralidad, los volúmenes de hospitales y cirujanos, y la distancia a un centro de formación de residentes colorectales.RESULTADOS:Se identificaron 34.725 pacientes, 42% fueron sometidos a cirugía laparoscópica. Se identificaron variaciones espaciales significativas en el uso de laparoscopia, con el 95% de los conglomerados de alto uso ubicados a <100 km y el 98% de los conglomerados de bajo uso ubicados a> 100 km, desde un centro de residencia colorectal. No había grupos de alto uso ubicados alrededor de grandes centros académicos sin residentes colorrectales. A nivel individual, los pacientes que vivían dentro de los 25 km y 26-100 km de un centro de residentes tenían 2,6 y 1,6 veces más probabilidades de someterse a una cirugía laparoscópica, respectivamente, en comparación con aquellos a> 100 km de distancia (95% CI 2,47-2,79, p <0,00; IC del 95% 1,53-1,71, p <0,001). Los volúmenes de cirujanos y hospitales se asociaron con mayores tasas de utilización de laparoscopia (p <0,001).LIMITACIONES:Los datos se obtuvieron de una base de datos administrativa y, a pesar de una validez publicada del 85-95%, siguen sujetos a errores de clasificación, respuesta y sesgo de medición.CONCLUSIONES:Existen variaciones espaciales significativas en el uso de la laparoscopia para la cirugía del cáncer de colon. Después de ajustar por factores del paciente y del sistema, la proximidad a un centro de formación de residentes colorectales siguió siendo un fuerte predictor del uso de laparoscopia. Sigue habiendo variaciones regionales en el tratamiento del cáncer de colon, con discrepancias en la atención quirúrgica ofrecida a los pacientes canadienses basadas únicamente en la ubicación. Consulte Video Resumen en http://links.lww.com/DCR/B595., (Copyright © The ASCRS 2021.)

Aneurysmal subarachnoid hemorrhage (aSAH) is a high mortality hemorrhagic stroke that affects nearly 30,000 patients annually in the United States. Approximately 30% of aSAH patients die during initial hospitalization and those who survive often carry poor prognosis with one in five having permanent physical and/or cognitive disabilities. The poor outcome of aSAH can be the result of the initial catastrophic event or due to the many acute or delayed neurological complications, such as cerebral ischemia, hydrocephalus, and re-bleeding. Unfortunately, no effective biomarker exists to predict or diagnose these complications at a clinically relevant time point when neurologic injury can be effectively treated and managed. Recently, a number of studies have demonstrated that microRNAs (miRNAs) in extracellular biofluids are highly associated with aSAH and complications. Here we provide an overview of the current research on relevant human studies examining the correlation between miRNAs and aSAH complications and discuss the potential application of using miRNAs as biomarkers in aSAH management.

Approximately one-third of aneurysmal subarachnoid hemorrhage (aSAH) patients develop delayed cerebral vasospasm (DCV) 3-10 days after aneurysm rupture resulting in additional, permanent neurologic disability. Currently, no validated biomarker is available to determine the risk of DCV in aSAH patients. MicroRNAs (miRNAs) have been implicated in virtually all human diseases, including aSAH, and are found in extracellular biofluids including plasma and cerebrospinal fluid (CSF). We used a custom designed TaqMan Low Density Array miRNA panel to examine the levels of 47 selected brain and vasculature injury related miRNAs in CSF and plasma specimens collected from 31 patients with or without DCV at 3 and 7 days after aSAH, as well as from eight healthy controls. The analysis of the first 18-patient cohort revealed a striking differential expression pattern of the selected miRNAs in CSF and plasma of aSAH patients with DCV from those without DCV. Importantly, this differential expression was observed at the early time point (3 days after aSAH), before DCV event occurs. Seven miRNAs were identified as reliable DCV risk predictors along with a prediction model constructed based on an array of additional 19 miRNAs on the panel. These chosen miRNAs were then used to predict the risk of DCV in a separate, testing cohort of 15 patients. The accuracy of DCV risk prediction in the testing cohort reached 87%. The study demonstrates that our novel designed miRNA panel is an effective predictor of DCV risk and has strong applications in clinical management of aSAH patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Springer, Xie, Fardo and Hatton.)

Background: The number of Canadian Residency Matching Service (CaRMS) applicants ranking surgical specialties as their first choice has declined over the past 20 years; concurrently, there has been a reduction in the number of hours spent teaching undergraduate medical education (UGME) anatomy, particularly with cadaveric dissection. The aim of this study was to determine the factors that most influence selection of a surgical specialty, with specific focus on the impact of UGME anatomy training., Methods: A 36-item cross-sectional survey was designed by experts in medical education and distributed to all current surgical residents in Canada in October 2018. Responses were recorded on a 5-point Likert scale or by means of list ranking. We analyzed univariable outcomes with a t test for continuous outcomes and the χ2 test for dichotomous outcomes., Results: Of 1493 surgical residents, 228 responded to the survey (response rate 15.3%). Respondents reported experiences on core rotations and elective rotations, and access to a mentor as the most important factors in deciding to pursue a surgical residency. Anatomy training with or without cadaveric dissection was moderately influential in respondents' first-choice CaRMS discipline (mean Likert scale score 2.97 [standard deviation (SD) 1.34] and 2.87 [SD 1.26], respectively). General surgery residents' CaRMS applications were more likely to have been influenced by UGME anatomy training than the applications by residents in other surgical specialties (p < 0.001). The impact of UGME anatomy training did not vary between postgraduate years or between male and female residents., Conclusion: Canadian surgical residents' decision to apply to a surgical specialty did not seem to be strongly influenced by their UGME anatomy training, with or without cadaveric dissection, but, rather, by factors such as clinical experience and surgical mentorship. Further evaluation of groups that were more positively affected by their UGME anatomy training is warranted., Competing Interests: None declared., (© 2021 Joule Inc. or its licensors.)

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function. We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation (i.e., miR-142-3p, miR-142-5p, and miR-146a) are altered in the hippocampus at 3-12 hours following a severe traumatic brain injury. In the present study, we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats. In addition, several inflammatory genes were analyzed in the cytosol fractions. The analysis showed that while elevated levels were observed in cytoplasm, the mitochondria-enriched miRNAs, miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury. Although not statistically significant, miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury, and recovered by 7 days. In contrast, miRNAs that are not enriched in mitochondria, including miR-124a, miR-150, miR-19b, miR-155, and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days. The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury. No major alterations were observed in sham operated animals. This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers. These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling. To test this, we utilized a novel peptide-based nanoparticle strategy for in vitro and in vivo delivery of a miR-146a mimic as a potential therapeutic strategy for targeting nuclear factor-kappaB inflammatory modulators in the injured brain. Nanoparticle delivery of miR-146a to BV-2 or SH-SY5Y cells significantly reduced expression of TNF receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1), two important modulators of the nuclear factor-kappaB (NF-κB) pro-inflammatory pathway. Moreover, injections of miR-146a containing nanoparticles into the brain immediately following controlled cortical impact injury significantly reduced hippocampal TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 levels. Taken together, our studies demonstrate the subcellular alteration of inflammatory miRNAs after traumatic brain injury and establish proof of principle that nanoparticle delivery of miR-146a has therapeutic potential for modulating pro-inflammatory effectors in the injured brain. All of the studies performed were approved by the University of Kentucky Institutional Animal Care and Usage Committee (IACUC protocol # 2014-1300) on August 17, 2017., Competing Interests: None

Background: The incidence of colorectal cancer in North America is rising among patients younger than 50 years. Available data are conflicting regarding presentation and outcomes in this population. This review aimed to synthesize literature regarding young patients with colorectal cancer with respect to patient demographics, disease extent and survival, compared with patients older than 50 years., Methods: We searched Medline, Embase, the Cochrane Central Register of Controlled Trials and PubMed for articles published between 1990 and the time of search. Articles comparing North American patients with colorectal cancer younger and older than 50 years were eligible for inclusion. We used a random-effects model to pool odds ratios., Results: Eight retrospective studies were eligible for inclusion (n = 790 959). Mean age was 42.6 years (standard deviation [SD] 5.07) in the younger group, and 69.1 years (SD 9.25) in the older group. Young patients were more likely to present with regional (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.16-1.40) and distant disease (OR 1.47, 95%CI 1.30-1.67). Considering patients at all stages of disease, differences in 5-year overall survival (OR 1.54, 95%CI 0.96-2.47) and cancer-specific survival (OR 1.01, 95%CI 0.91-1.13) were not statistically significant between groups. However, when controlling for disease extent, 5-year cancer-specific survival was significantly higher among young patients with local (OR 1.69, 95%CI 1.43-1.99), regional (OR 1.37, 95%CI 1.16-1.63) and distant disease (OR 1.79, 95%CI 1.45-2.21)., Conclusion: North American patients presenting with colorectal cancer before the age of 50 years are more likely to have advanced disease. Although overall and cancer-specific survival is not significantly different between these groups, younger patients have improved survival when controlling for cancer stage., Competing Interests: None declared., (© 2021 Joule Inc. or its licensors.)

Background: Immunosuppressed patients with diverticular disease are at higher risk of postoperative complications, however reported rates have varied. The aim of this study is to compare postoperative outcomes in immunosuppressed and immunocompetent patients undergoing surgery for diverticular disease., Methods: Medline, EMBASE, and CENTRAL were searched. Articles were included if they compared immunosuppressed and immunocompetent patients undergoing surgery for diverticular disease., Results: From 204 citations, 11 studies with 2,977 immunosuppressed patients and 780,630 immunocompetent patients were included. Mortality was greater in immunosuppressed patients compared to immunocompetent patients for emergent surgery (RR 1.91, 95%CI 1.24-2.95, p < 0.01), but not elective surgery (RR 1.70, 95%CI 0.14-20.47, p = 0.68). Morbidity was greater in immunosuppressed patients compared to immunocompetent patients for elective surgery (RR 2.18, 95%CI 1.02-4.65, p = 0.04), but not emergent surgery (RR 1.40, 95%CI 0.68-2.90, p = 0.37)., Conclusions: Increased consideration for elective operation may preclude the need for emergent surgery and the associated increase in postoperative mortality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA) is commonly performed for patients with refractory ulcerative colitis (UC). Pouchitis occurs in 20-50% of these patients. Fecal calprotectin is a biomarker that correlates well with the pouchitis disease activity index. However, its role in the diagnosis and management of acute pouchitis has not been thoroughly defined. The aim of this study is to review previously established cut-off values and contextualize the clinical utility of fecal calprotectin., Methods: Search of Medline, EMBASE, CENTRAL, and PubMed was performed. Articles were eligible if they measured fecal calprotectin in the setting of pouchitis in patients who underwent TPC with IPAA for UC. Risk of bias of the included studies was evaluated with the QUADAS-2., Results: From 117 relevant citations, seven studies with 256 patients (44.8% female, 39.88 years) met inclusion criteria. The pooled prevalence of pouchitis was 42%. The derived fecal calprotectin cut-off values ranged from 56 to 494 μg/g. The corresponding sensitivities and specificities ranged from 57 to 100% and 38 to 92%, respectively. The area under the curve was reported in three studies and ranged from 0.832 to 0.840., Conclusion: Fecal calprotectin may be a reliable diagnostic tool for acute pouchitis in patients following TPC with IPAA for UC. The high sensitivity of fecal calprotectin for detection of pouchitis makes it a valuable test for ruling out pouchitis. When used in conjunction with other biomarkers, the high specificity offers value in ruling in pouchitis. However, given the complexity of this disease process, relying solely on biomarkers for diagnosis is currently unreasonable.

Background: Enhanced Recovery After Surgery (ERAS) protocols use evidence-based perioperative practices that reduce morbidity and length of stay and improve patient satisfaction. ERAS is considered standard of care; however, utilization remains low and substantial practice variation exists. The aim of this study was to pragmatically characterize variation in colorectal surgery practice and identify predictors of ERAS utilization., Methods: A survey of general surgeons identified using the Ontario College of Physicians and Surgeons database was conducted. Information on basic demographic characteristics, utilization of ERAS and predictors of ERAS implementation was collected. Nine ERAS behaviours were analyzed. Multivariable analysis was used to determine effects of demographic, hospital and surgeon covariates on ERAS utilization., Results: Seven hundred and ninety-seven general surgeons were invited to participate in the survey, and 235 general surgeons representing 84 Ontario hospitals responded (30% response rate). Surgeons practising in academic settings and in large community hospitals represented 30% and 47% of the respondents, respectively. A total of 20% of the respondents used all 9 ERAS behaviours consistently. Rates of diet advancement on postoperative day 0, intravenous fluid restriction and having catheter and line procedures were significantly higher among respondents who adhered to ERAS protocols than among those who did not (74% v. 54%, p = 0.004; 92% v. 80%, p = 0.01; and 91% v. 41%, p < 0.001, respectively). Respondents from academic settings reported practising nearly 1 more ERAS behaviour than those from small community hospitals (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.42 to 1.31, p < 0.001). Multivariable analysis demonstrated that colorectal fellowship training or exposure to ERAS during training did not significantly affect ERAS behaviour utilization (OR 0.32, 95% CI -0.31 to 0.94, p = 0.16; OR 0.28, 95% CI -0.26 to 0.82, p = 0.16, respectively)., Conclusion: Substantial practice variation in colorectal surgery still exists. Individual ERAS principles are commonly followed; however, ERAS behaviours are not widely formalized into hospital protocols.

Background: Compared to open rectal surgery, laparoscopy is associated with lower perioperative morbidity but unclear oncologic outcomes. Unique technical challenges exist with laparoscopic rectal surgery and access based on geographical location is unknown. The purpose of this study was to determine whether proximity to colorectal fellowship training sites influences laparoscopy utilization for rectal cancer surgery., Methods: Population based retrospective spatial analysis assessing regional rates of laparoscopy use in patients (≥ 18 years of age) undergoing rectal cancer surgery in Canada (excluding Quebec) from April 2008 to March 2014., Results: Overall, 11,261 patients underwent rectal cancer surgery. Four Canadian colorectal fellowship training centers were identified. Rectal surgeries were performed laparoscopically 27% of the time, and this significantly increased from 18.1 to 40.3% between 2008 and 2014. Multivariate analysis adjusting for province, disease, hospital, patient, and surgeon factors demonstrated that patients living within 25 km of a colorectal fellowship training site had 2.5 times higher odds of laparoscopy use and those living within 26-100 km had 1.8 times higher odds of laparoscopy [95% confidence interval (CI) 2.14-2.71, p < 0.001, 95% CI 1.64-2.07, p < 0.001 respectively]. High-volume surgeons and hospitals were associated with increased laparoscopy use (1.25, 95% CI 1.11-1.4 and 1.36, 95% CI 1.21-1.53, p < 0.001 respectively)., Conclusions: Significant geographical variation to laparoscopic rectal cancer surgery access in a publicly funded healthcare system currently exists. The inverse relationship between colorectal fellowship training site distance and undergoing a laparoscopic rectal surgery highlights the current disparities in Canadian health care and the need for surgical mentorship to increase uptake of advanced surgical techniques in rural neighbourhoods.

The mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are specific ER domains that contact the mitochondria and function to facilitate communication between ER and mitochondria. Disruption of contact between the mitochondria and ER is associated with a variety of pathophysiological conditions including neurodegenerative diseases. Considering the many cellular functions of MAMs, we hypothesized that MAMs play an important role in regulating microRNA (miRNA) activity linked to its unique location between mitochondria and ER. Here we present new findings from human and rat brains indicating that the MAMs are subcellular sites enriched for specific miRNAs. We employed subcellular fractionation and TaqMan® RT-qPCR miRNA analysis to quantify miRNA levels in subcellular fractions isolated from male rat brains and six human brain samples. We found that MAMs contain a substantial number of miRNAs and the profile differs significantly from that of cytosolic, mitochondria, or ER. Interestingly, MAMs are particularly enriched in inflammatory-responsive miRNAs, including miR-146a, miR-142-3p, and miR-142-5p in both human and rat brains; miR-223 MAM enrichment was observed only in human brain samples. Further, mitochondrial uncoupling or traumatic brain injury in male rats resulted in the alteration of inflammatory miRNA enrichment in the isolated subcellular fractions. These observations demonstrate that miRNAs are distributed differentially in organelles and may re-distribute between organelles and the cytosol in response to cellular stress and metabolic demands.

Aim: Patients with inflammatory bowel disease (IBD) are at increased risk of postoperative venous thromboembolism (VTE) following major abdominal surgery. The pathogenesis is multifactorial and not fully understood. A combination of pathophysiology, patient and surgical risk factors increase the risk of postoperative VTE in these patients. Despite being at increased risk, IBD patients are not regularly prescribed extended pharmacological thromboprophylaxis following colorectal surgery. Currently, there is a paucity of evidence-based guidelines. Thus, the aim of this review is to evaluate the role of extended pharmacological thromboprophylaxis in IBD patients undergoing colorectal surgery., Method: A search of Ovid Medline, EMBASE and PubMed databases was performed. A qualitative analysis was performed using 10 clinical questions developed by colorectal surgeons and a thrombosis haematologist. The Newcastle-Ottawa Scale was utilized to assess the quality of evidence., Results: A total of 1229 studies were identified, 38 of which met the final inclusion criteria (37 retrospective, one case-control). Rates of postoperative VTE ranged between 0.6% and 8.9%. Patient-specific risk factors for postoperative VTE included ulcerative colitis, increased age and obesity. Surgery-specific risk factors for postoperative VTE included open surgery, emergent surgery and ileostomy creation. Patients with IBD were more frequently at increased risk in the included studies for postoperative VTE than patients with colorectal cancer. The risk of bias assessment demonstrated low risk of bias in patient selection and comparability, with variable risk of bias in reported outcomes., Conclusion: There is a lack of evidence regarding the use of extended pharmacological thromboprophylaxis in patients with IBD following colorectal surgery. As these patients are at heightened risk of postoperative VTE, future study and consideration of the use of extended pharmacological thromboprophylaxis is warranted., (Colorectal Disease © 2019 The Association of Coloproctology of Great Britain and Ireland.)

Background: Laparoscopic rectal surgery is technically challenging and often low volume. Alternatively, colon resections utilize similar advanced laparoscopic skills and are more common but it is unknown whether this experience affects laparoscopic rectal surgery outcomes. The purpose of this paper is to determine the volume-outcome relationship between several colorectal procedures and laparoscopic rectal surgery outcomes., Methods: This was a population-based retrospective cohort of all colorectal surgeries with primary anastomoses performed across Canada (excluding Quebec) between April 2008 and March 2015. Patient characteristics, comorbidities, procedures, and discharge details were collected from the Canadian Institute for Health Information. Volumes for common colorectal procedures were calculated for individual surgeons. All-cause morbidity, defined as complications arising during the index admission and contributing to an increased length of stay by more than 24 h, was the primary outcome examined., Results: A total of 5323 laparoscopic rectal surgery cases and 108,034 colorectal cases, between 180 hospitals and 620 surgeons, were identified. Data analysis demonstrated that high-volume laparoscopic rectal surgeons (OR 0.77, CI 0.61-0.96, p = 0.020) and high-volume open rectal surgeons (OR 0.76, CI 0.61-0.93, p = 0.009) significantly reduced all-cause morbidity. Conversely, surgeon volumes for laparoscopic and open colon cases had no effect on laparoscopic rectal outcomes., Conclusion: High-volume surgeon status in laparoscopic and open rectal surgery are important predictors of all-cause morbidity after laparoscopic rectal surgery, while laparoscopic colon surgery volumes did not impact outcomes. This may reflect more dissimilarity between colon and rectal cases and less transferability of advanced laparoscopic skills than previously thought.

Purpose: Surgical consultation is recommended for all patients with fulminant Clostridioides difficile infection (CDI). If surgery is required, total abdominal colectomy (TAC) is most commonly performed. However, diverting loop ileostomy and colonic lavage have been recently developed as a potential colon-sparing approach to fulminant CDI. The aim of this review is to compare TAC and diverting loop ileostomy with colonic lavage for fulminant CDI., Methods: Search of MEDLINE, EMBASE, CENTRAL, and PubMed was performed. Articles were eligible for inclusion if they compared TAC and diverting loop ileostomy with colonic lavage. The primary outcome was postoperative mortality, and the secondary outcome was postoperative complications. Quality of included studies was assessed using Newcastle-Ottawa Scale., Results: From 64 relevant citations, 5 studies (4 retrospective cohorts, 1 case series) with 3683 patients were included. Compared to TAC, diverting loop ileostomy with colonic lavage did not significantly reduce overall mortality (RR 1.10, 95% CI 0.60 to 1.99, P = 0.77), rate of reoperation (RR 1.02, 95% CI, 0.63 to 1.63, P = 0.94), or overall postoperative complications (RR 0.51, 95% CI, 0.22 to 1.17, P = 0.11). Rates of colonic preservation with the use of diverting loop ileostomy with colonic lavage ranged from 76% to 100%., Conclusion: There does not appear to be a survival advantage with the use of diverting loop ileostomy with colonic lavage compared to TAC for fulminant CDI. However, diverting loop ileostomy with colonic lavage results in increased rates of colonic preservation, restoration of intestinal continuity, and laparoscopic surgery. This review is limited by the small number of included studies.

Eukaryotic cell organelles exert unique functions individually but also interact with each other for essential cellular functions. This physical interface between the organelles serves as an important platform for biomolecule trafficking and signaling. Mitochondria are membrane-bound organelles and form a dynamic contact with other organelles. The interactions and communication between mitochondria and endoplasmic reticulum (ER) are facilitated by an ER specific domain, named mitochondria associated ER membrane (MAM). Due to its unique location, the MAM is a "hotspot" for important cell signaling and biochemical processes including calcium homeostasis, lipid synthesis/exchange, inflammasome and autophagosome formation, and mitochondria fission/fusion. Although techniques are available for isolation of organelle fractions including MAM, most utilize animal tissues and cell lines. Here we describe a protocol that is tailored to the isolation of highly purified MAM, mitochondria, ER, and cytosol from human brain. In addition, we include a protocol for the isolation of total RNA and subsequent analysis of microRNAs from these highly purified organelle fractions. Finally, we include a panel of protein markers that are useful for validating the enrichment and purity of each subcellular fraction.

Purpose: Acute urinary retention (AUR) is a common postoperative complication in colorectal surgery. In pelvic colorectal operations, the optimal duration for postoperative urinary catheter use is controversial. This systematic review and meta-analysis aims to compare early (POD 1), intermediate (POD 3), and late (POD 5) urinary catheter removal., Methods: Medline, EMBASE, CENTRAL, and PubMed databases were searched. Articles were eligible for inclusion if they compared patients with urinary catheter removal on POD 1 or earlier to patients with urinary catheter removal on POD 2 or later in major pelvic colorectal surgeries. The primary outcome was rate of postoperative AUR. The secondary outcome was rates of postoperative urinary tract infection (UTI)., Results: From 691 relevant citations, five studies with 928 patients were included. Comparison of urinary catheter removal on POD 1 versus POD 3 demonstrated no significant difference in rate of urinary retention (RR 1.36, 95%CI 0.83-2.21, P = 0.22); however, compared to POD 5, rates of AUR were significantly higher (RR 2.58, 95%CI 1.51-4.40, P = 0.0005). Rates of UTI were not significantly different between POD 1 and POD 3 urinary catheter removal (RR 0.40, 95%CI 0.05-3.71, P = 0.45), but removal on POD 5 significantly increased risk of UTI compared to POD 1 (RR 0.50, 95%CI 0.31-0.81, P = 0.005)., Conclusion: Risk of AUR can be minimized with late postoperative urinary catheter removal compared to early removal, but at the cost of increased risk of UTI. Patient-specific factors should be taken into consideration when deciding upon optimal duration of postoperative urinary catheterization.

Background: Abdominoperineal resection (APR) is the primary surgical approach to low rectal cancers. Both prone and lithotomy patient positioning during the perineal dissection are currently acceptable approaches. There is no consensus on whether patient positioning has an impact on operative and oncologic outcomes. The aim of this review was to compare the perioperative and long-term oncologic outcomes between prone and lithotomy patient positioning., Materials and Methods: Search of Medline, Embase, Web of Science, CENTRAL, PubMed, and ClinicalTrials.gov databases was performed. Articles were eligible for inclusion if they compared prone and lithotomy positioning for the perineal portion of APR for rectal cancer in one of the primary outcomes. Quality of included studies was assessed using Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool., Results: Nine studies with 888 patients in the prone group and 897 in the lithotomy group were included. Compared with lithotomy position, prone position had a significantly lower perforation rate (risk ratio: 0.50, 95% confidence interval [CI]: 0.32 to 0.79, P = 0.003) and rates of positive circumferential resection margin involvement (risk ratio: 0.66, 95% CI: 0.44 to 1.00, P = 0.05). Prone position also had a significantly shorter operative time than lithotomy position (mean difference: -45.20 min, 95% CI: -63.03 to -27.36, P < 0.00001). Positioning did not affect 5-y overall survival or local and distal recurrence., Conclusions: Prone positioning may lead to lower rates of perforation and circumferential resection margin involvement in APR. In addition, it may lead to shorter operative time. Larger randomized studies are required to confirm the results of this review and examine the difference in long-term outcomes., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Antibiotics are the front-line treatment against many bacterial infectious diseases in human. The excessive and long-term use of antibiotics in human cause several side effects. It is important to understand the underlying molecular mechanisms of action of antibiotics in the host cell to avoid the side effects due to the prevalent uses. In the current study, we investigated the crosstalk between mitochondria and lysosomes in the presence of widely used antibiotics: erythromycin (ERM) and clindamycin (CLDM), which target the 50S subunit of bacterial ribosomes. We report here that both ERM and CLDM induced caspase activation and cell death in several different human cell lines. The activity of the mitochondrial respiratory chain was compromised in the presence of ERM and CLDM leading to bioenergetic crisis and generation of reactive oxygen species. Antibiotics treatment impaired autophagy flux and lysosome numbers, resulting in decreased removal of damaged mitochondria through mitophagy, hence accumulation of defective mitochondria. We further show that over-expression of transcription factor EB (TFEB) increased the lysosome number, restored mitochondrial function and rescued ERM- and CLDM-induced cell death. These studies indicate that antibiotics alter mitochondria and lysosome interactions leading to apoptotsis and may develop a novel approach for targeting inter-organelle crosstalk to limit deleterious antibiotic-induced side effects.

While mitochondria maintain essential cellular functions, such as energy production, calcium homeostasis, and regulating programmed cellular death, they also play a major role in pathophysiology of many neurological disorders. Furthermore, several neurodegenerative diseases are closely linked with synaptic damage and synaptic mitochondrial dysfunction. Unfortunately, the ability to assess mitochondrial dysfunction and the efficacy of mitochondrial-targeted therapies in experimental models of neurodegenerative disease and CNS injury is limited by current mitochondrial isolation techniques. Density gradient ultracentrifugation (UC) is currently the only technique that can separate synaptic and non-synaptic mitochondrial sub-populations, though small brain regions cannot be assayed due to low mitochondrial yield. To address this limitation, we used fractionated mitochondrial magnetic separation (FMMS), employing magnetic anti-Tom22 antibodies, to develop a novel strategy for isolation of functional synaptic and non-synaptic mitochondria from mouse cortex and hippocampus without the usage of UC. We compared the yield and functionality of mitochondria derived using FMMS to those derived by UC. FMMS produced 3x more synaptic mitochondrial protein yield compared to UC from the same amount of tissue, a mouse hippocampus. FMMS also has increased sensitivity, compared to UC separation, to measure decreased mitochondrial respiration, demonstrated in a paradigm of mild closed head injury. Taken together, FMMS enables improved brain-derived mitochondrial yield for mitochondrial assessments and better detection of mitochondrial impairment in CNS injury and neurodegenerative disease.

Background: The morbidity and mortality associated with colorectal resections are responsible for significant healthcare use. Identification of efficiencies is vital for decreasing healthcare cost in a resource-limited system., Objective: The purpose of this study was to characterize the short-term cost associated with all colon and rectal resections., Design: This was a population-based, retrospective administrative analysis., Settings: This analysis was composed of all colon and rectal resections with anastomosis in Canada (excluding Quebec) between 2008 and 2015., Patients: A total of 108,304 patients ≥18 years of age who underwent colon and/or rectal resections with anastomosis were included., Main Outcome Measures: Total short-term inpatient cost for the index admission and the incremental cost of each comorbidity and complication (in 2014 Canadian dollars) were measured. Cost predictors were modeled using hierarchical linear regression and Monte Carlo Markov Chain estimation., Results: Multivariable regression demonstrated that the adjusted average cost of a 50-year-old man undergoing open colon resection for benign disease with no comorbidities or complications was $9270 ((95% CI, $7146-$11,624; p = <0.001). With adjustment for complications, laparoscopic colon resections carried a cost savings of $1390 (95% CI, $1682-$1099; p = <0.001) compared with open resections. Surgical complications were the main driver for increased cost, because anastomotic leaks added $9129 (95% CI, $8583-$9670; p = <0.001). Medical complications such as renal failure requiring dialysis ($16,939 (95% CI, $15,548-$18,314); p = <0.001) carried significant cost. Complications requiring reoperation cost $16,313 (95% CI, $15,739-$16,886; p = <0.001). The costliest complication cumulatively was reoperation, which exceeded $95 million dollars over the course of the study., Limitations: Inherent biases associated with administrative databases limited this study., Conclusions: Medical and surgical complications (especially those requiring reoperation) are major drivers of increased resource use. Laparoscopic colorectal resection with or without adjustment for complications carries a clear cost advantage. There is opportunity for considerable cost savings by reducing specific complications or by preoperatively optimizing select patients susceptible to costly complication. See Video Abstract at http://links.lww.com/DCR/A839.

Background: Enhanced recovery after surgery (ERAS) protocols after colorectal surgery use several perioperative, intraoperative and postoperative interventions that decrease morbidity, length of stay, and improve patient satisfaction. ERAS is increasingly being considered standard of care; however, uptake of formalized protocols remains low. The objective is to characterize the provincial rates of ERAS utilization after colorectal surgery and identify barriers and limitations to ERAS implementation., Methods: A total of 797 general surgeons were identified through the College of Physicians and Surgeons of Ontario. A survey identifying demographics, rates of ERAS utilization, and barriers to implementation was distributed. Logistic regression determined the effects of demographic and hospital covariates on ERAS utilization., Results: A total of 235 general surgeons representing 84 Ontario hospitals participated (response rate 29.5%). Surgeons working in academic or large community hospitals represented the majority of the cohort (30.5% and 47.2%, respectively). Multivariable analysis showed no significant effect of surgeon demographics, years in practice, or training details on ERAS protocol utilization; however, practicing in small community hospitals (compared with large and academic hospitals) was significantly associated with not using ERAS protocols (odds ratio, 0.02; 95% confidence interval, 0-0.3; P = 0.005). Over 50% of respondents used ERAS principles but did not have a formal protocol. Barriers to implementing ERAS protocols included patient variability, lack of institutional and nursing support, and poor communication with the care team., Conclusions: Small community hospitals are less likely to use formal ERAS protocols; however, most Ontario surgeons are using ERAS principles after colorectal surgery. Barriers to ERAS implementation are broad and the present study has provided a pragmatic solution to change., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Intra-abdominal abscesses account for a large proportion of surgical complications and carry high mortality if not promptly controlled. Image-guided percutaneous drainage is standard of care. The objective of the study was to identify factors that predict abscess recurrence after percutaneous drain (PD) removal and determine if imaging before drain removal effects recurrence., Methods: A consecutive multicenter retrospective cohort analysis of all patients who underwent PD insertion for abscesses between January 1, 2015, and December 31, 2015, was performed. Patient characteristics, PD details, and abscess recurrence were assessed., Results: One hundred eighty-eight patients underwent PD insertion for spontaneous or postoperative abscesses, and overall abscess recurrence was 21%. Drains remained in situ for a median of 21.5 d (interquartile range: 9-42 d) with antibiotics used in 91% of cases. Forty-seven patients (25%) had a sinogram before PD removal, while 22% had computed tomography (CT) scans and 11% had ultrasounds. Hierarchical multivariable regression analysis showed that imaging before PD removal was associated with a 66% reduction in the odds of abscess recurrence (OR 0.34; 95% confidence interval [CI] 0.13-0.70; P = 0.006). Sinogram use was associated with an 86% reduction in the odds of recurrence (OR 0.14; 95% CI 0.02-0.39; P = 0.002) and ultrasound use was associated with a 78% reduction in the odds of recurrence (OR 0.22; 95% CI 0.02-0.76; P = 0.044) while CT use was not associated with a significant reduction in recurrence., Conclusions: Imaging before PD removal is associated with a reduction in the rates of abscess recurrence and requirement for additional drainage procedures or surgery. In addition, CT is not superior to ultrasound or sinograms as an imaging modality., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The mitochondrion serves many functions in the central nervous system (CNS) and other organs beyond the well-recognized role of adenosine triphosphate (ATP) production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition (mPT) state due to formation of the cyclosporine A sensitive permeability transition pore (mPTP). In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex-perimental strategies targeting the mPTP., Competing Interests: None declared

Background: Postoperative ileus is a poorly understood multifactorial outcome following colorectal surgery that presents significant clinical challenges and contributes to increased morbidity, length of stay, and healthcare cost. To date, there are few pharmacological interventions that shorten the duration of postoperative ileus., Objective: This study is the first to evaluate the efficacy of simethicone in treating postoperative ileus symptoms in patients undergoing colorectal surgery., Design: A multicenter, double-blinded, placebo controlled randomized controlled trial., Settings: This trial was conducted at two academic tertiary care centres in Ontario, Canada., Participants: 118 patients undergoing colorectal surgery., Interventions: Patients were randomized to receive either a five-day course of oral simethicone (n = 58) or a placebo (n = 60)., Main Outcome Measures: The primary outcome was time to first passage of flatus. Secondary outcomes included time to first bowel movement, postoperative length of stay, and postoperative pain. Statistical analyses were performed on an intention-to-treat basis. Statistical significance set at p = 0.05., Results: The median time to first passage of flatus in simethicone arm was 25.2 h and 26.7 h in controls (P = 0.98). There were no significant differences in the median time to first bowel movement (simethicone = 41.1 h vs. control = 42.9 h, P = 0.91) or median length of hospital stay (simethicone = 4.5 days vs. control = 4.0 days, P = 0.63)., Conclusions: This study failed to show a difference in return of gastrointestinal motility in patients receiving simethicone following colorectal surgery. Postoperative ileus remains a significant clinical and economic burden to the healthcare system and further research is needed to identify a reliable and effective method of treatment., (Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of the study was to compare functional outcomes of acute inpatient rehabilitation for spinal epidural abscess patients with and without history of intravenous substance abuse., Design: This is a retrospective case series study in freestanding rehabilitation hospital., Methods: Charts of 28 spinal epidural abscess patients admitted from January 2012 to September 2015: 13 with intravenous substance abuse and 15 without intravenous substance abuse were reviewed. Both groups received standard-of-care rehabilitation. Statistical analyses of Functional Independence Measure scores were conducted using individual 2 (substance use) × 2 (rehabilitation status) repeated measures analysis of variance. Functional outcomes were defined by total Functional Independence Measure scores as well as motor and cognitive subsets. Length of stay and morphine equivalents were also compared., Results: There were no significant differences between the two groups. There was a significant main effect of treatment on total Functional Independence Measure scores (P < 0.001), Functional Independence Measure motor scores (P < 0.001), and Functional Independence Measure cognitive scores (P < 0.01) from admission to discharge. Subsequent Student's t tests revealed that the scores of both groups significantly improved on all Functional Independence Measure components. There were no group differences on length of stay and morphine equivalents at discharge., Conclusions: Acute inpatient rehabilitation can effectively improve functional outcomes in spinal epidural abscess patients with or without intravenous substance abuse, even though these two patient groups can vary in clinical factors.

Mitochondrial homeostasis is essential for maintaining cellular function and survival in the central nervous system (CNS). Mitochondrial function is significantly compromised after spinal cord injury (SCI) and is associated with accumulation of high levels of calcium, increased production of free radicals, oxidative damage, and eventually mitochondrial permeability transition (mPT). The formation of the mPT pore (mPTP) and subsequent mPT state are considered to be end stage events in the decline of mitochondrial integrity, and strategies that inhibit mPT can limit mitochondrial demise. Cyclosporine A (CsA) is thought to inhibit mPT by binding to cyclophilin D and has been shown to be effective in models of CNS injury. CsA, however, also inhibits calcineurin, which is responsible for its immunosuppressive properties. In the present study, we conducted a dose-response examination of NIM811, a nonimmunosuppressive CsA analog, on recovery of function and tissue sparing in a rat model of moderate to severe SCI. The results of our experiments revealed that NIM811 (10 mg/kg) significantly improved open field locomotor performance, while the two higher doses tested (20 and 40 mg/kg) significantly improved return of reflexive bladder control and significantly decreased the rostral-caudal extent of the lesion. Taken together, these results demonstrate the ability of NIM811 to improve recovery of function in SCI and support the role of protecting mitochondrial function as a potential therapeutic target.

Traumatic brain injury (TBI) is a leading cause of long-term impairments in higher cognitive functioning, including deficits in attention and memory. It is well known that some of these persistent deficits are related, in part, to ongoing secondary injury events characterized by pervasive biochemical and pathophysiological stressors, including a rapid and sustained phase of mitochondrial dysfunction. A loss of mitochondrial function impacts a number of important cellular events and we have begun to investigate the novel hypothesis that mitochondria play a critical role in regulating the cellular activity of specific microRNAs in response to cellular demands and stressors. In this special issue report, we summarize briefly the rationale for investigating the crosstalk between mitochondria and microRNA, and provide recent preliminary data suggesting that mitochondria-microRNA interactions are modified in response to TBI-related cellular stressors. We postulate that this interaction is critical for regulating appropriate cellular microRNA responses, which opens up opportunities for therapeutic interventions targeting both mitochondrial function and microRNA activity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cerebellar function is critical for coordinating movement and motor learning. However, events occurring in the cerebellum following spinal cord injury (SCI) have not been investigated in detail. We provide evidence of SCI-induced cerebellar synaptic changes involving a loss of granule cell parallel fiber input to distal regions of the Purkinje cell dendritic tree. This is accompanied by an apparent increase in synaptic contacts to Purkinje cell proximal dendrites, presumably from climbing fibers originating in the inferior olive. We also observed an early stage injury-induced decrease in the levels of cerebellin-1, a synaptic organizing molecule that is critical for establishing and maintaining parallel fiber-Purkinje cell synaptic integrity. Interestingly, this transsynaptic reorganizational pattern is consistent with that reported during development and in certain transgenic mouse models. To our knowledge, such a reorganizational event has not been described in response to SCI in adult rats. Regardless, the novel results of this study are important for understanding SCI-induced synaptic changes in the cerebellum, which may prove critical for strategies focusing on promoting functional recovery.

Objectives: To investigate the incidence of spinal abscess and substance abuse in a tertiary care hospital after state legislation titled "House Bill 1" (HB1) mandated stricter regulation of prescription drugs of abuse in Kentucky in 2012., Design: A retrospective case series study design was used to review the incidence of spinal abscess and drug abuse diagnoses admissions from 2010 to 2014. Variances in the incidence of spinal abscess and substance abuse were plotted across this time frame., Results: The incidence of intraspinal abscess increased 1.56-fold in 2011 (n = 26) and 2012 (n = 25) relative to 2010 (n = 16). However, in 2013, the year following implementation of HB1 legislation, the incidence of intraspinal abscess increased 2.38-fold (n = 38) and then 4.19-fold (n = 67) in 2014. The incidence of intraspinal abscess in subjects with drug abuse diagnosis remained constant between 2010 (n = 3) and 2012 (n = 3). However, it increased twofold (n = 7) in 2013 and then ninefold (n = 27) in 2014. A correlation coefficient (rSAD ) of 0.775 revealed a strong association between the increase incidence of intraspinal abscess and diagnosis of drug abuse., Conclusions: The results of this retrospective study demonstrate an increased incidence of intraspinal abscess associated with drug abuse after passage of HB1 legislation regulating prescriptions of controlled medications in Kentucky. This increased incidence may be related to individuals relying on nonprescription drugs of abuse due to more highly regulated access to controlled prescription medications. However, additional factors unrelated to HB1 legislation must be taken into account., (Wiley Periodicals, Inc.)

Traumatic brain injury (TBI) is a major cause of death and disability. However, the molecular events contributing to the pathogenesis are not well understood. Mitochondria serve as the powerhouse of cells, respond to cellular demands and stressors, and play an essential role in cell signaling, differentiation, and survival. There is clear evidence of compromised mitochondrial function following TBI; however, the underlying mechanisms and consequences are not clear. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally, and function as important mediators of neuronal development, synaptic plasticity, and neurodegeneration. Several miRNAs show altered expression following TBI; however, the relevance of mitochondria in these pathways is unknown. Here, we present evidence supporting the association of miRNA with hippocampal mitochondria, as well as changes in mitochondria-associated miRNA expression following a controlled cortical impact (CCI) injury in rats. Specifically, we found that the miRNA processing proteins Argonaute (AGO) and Dicer are present in mitochondria fractions from uninjured rat hippocampus, and immunoprecipitation of AGO associated miRNA from mitochondria suggests the presence of functional RNA-induced silencing complexes. Interestingly, RT-qPCR miRNA array studies revealed that a subset of miRNA is enriched in mitochondria relative to cytoplasm. At 12h following CCI, several miRNAs are significantly altered in hippocampal mitochondria and cytoplasm. In addition, levels of miR-155 and miR-223, both of which play a role in inflammatory processes, are significantly elevated in both cytoplasm and mitochondria. We propose that mitochondria-associated miRNAs may play an important role in regulating the response to TBI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The purpose of this research was to examine the morbidity, mortality and rate of recurrent bowel obstruction associated with the treatment of small bowel obstruction (SBO) in older adults., Methods: We prospectively enrolled all patients 70 years or older with an SBO who were admitted to a tertiary care teaching centre between Jul. 1, 2011, and Sept. 30, 2012. Data regarding presentation, investigations, treatment and outcomes were collected., Results: Of the 104 patients admitted with an SBO, 49% were managed nonoperatively and 51% underwent surgery. Patients who underwent surgery experienced more complications (64% v. 27%, p = 0.002) and stayed in hospital longer (10 v. 3 d, p < 0.001) than patients managed nonoperatively. Nonoperative management was associated with a high rate of recurrent SBO: 31% after a median follow-up of 17 months. Of the patients managed operatively, 60% underwent immediate surgery and 40% underwent surgery after attempted nonoperative management. Patients in whom nonoperative management failed underwent surgery after a median of 2 days, and 89% underwent surgery within 5 days. The rate of bowel resection was high (29%) among those who underwent delayed surgery. Surgery after failed nonoperative management was associated with a mortality of 14% versus 3% for those who underwent immediate surgery; however, this difference was not significant., Conclusion: These data suggest that some elderly patients with SBO may be waiting too long for surgery.

In this experimental study, differential labeling with isobaric tags for relative and absolute quantitation (iTRAQ) reagents followed by liquid chromatography (LC) and tandem mass spectrometry (MS/MS) proteomic approach was used to investigate differences in the proteome of rat spinal cord at 24 h following a moderate contusion injury. Spinal cord protein samples from the injury epicenter (or from sham controls) were trypsinized and differentially labeled with iTRAQ isotopic reagents. The differentially labeled samples were then combined into one sample mixture, separated by LC, and analyzed using MS/MS. Proteins were quantified by comparing the peak areas of iTRAQ reporter fragment ions in MS/MS spectra. The outcome of this analysis revealed that proteins involved in ubiquitination, endocytosis and exocytosis, energy metabolism, inflammatory response, oxidative stress, cytoskeletal disruption, and vascular damage were significantly altered at 24 h following spinal cord injury (SCI). This study demonstrates the utility of the iTRAQ method in proteomic studies and provides further insights into secondary events that occur during acute times following SCI.

Neu2000 [2-hydroxy-5-(2,3,5,6-tetrafluoro-4 trifluoromethylbenzylamino) benzoic acid] is a dual-acting neuroprotective agent that functions both as a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist and a free radical scavenger. In the present study, we investigated the scavenging activity of Neu2000 on various classes of reactive oxygen species and reactive nitrogen species (ROS/RNS) as well as its efficacy for reducing free radicals and oxidative stress/damage induced in spinal cord mitochondrial preparations. Neu2000 exerted scavenging activity against superoxide, nitric oxide, and hydroxyl radicals, and efficiently scavenged peroxynitrite. In the mitochondrial studies, Neu2000 markedly inhibited ROS/RNS and hydrogen peroxide levels following antimycin treatment. In addition, Neu2000 effectively scavenged hydroxyl radicals generated by iron(III)-ascorbate, reduced protein carbonyl formation mediated by hydroxyl radicals and peroxynitrite, and prevented glutathione oxidation caused by tert-butyl hydroperoxide in isolated mitochondria. Interestingly, incubation of isolated mitochondria with Neu2000 followed by centrifugation and removal of the supernatant also resulted in a concentration-dependent decrease in lipid peroxidation. This observation suggests that Neu2000 enters mitochondria to target free radicals or indirectly affects mitochondrial function in a manner that promotes antioxidant activity. The results of the present study demonstrate that Neu2000 possesses potent in vitro antioxidant activity due, most likely, to its active phenoxy group., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

While free radicals and inflammation constitute major routes of neuronal injury occurring in amyotrophic lateral sclerosis (ALS), neither antioxidants nor non-steroidal anti-inflammatory drugs have shown significant efficacy in human clinical trials. We examined the possibility that concurrent blockade of free radicals and prostaglandin E(2) (PGE(2))-mediated inflammation might constitute a safe and effective therapeutic approach to ALS. We have developed 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] (AAD-2004) as a derivative of aspirin. AAD-2004 completely removed free radicals at 50 nM as a potent spin-trapping molecule and inhibited microsomal PGE(2) synthase-1 (mPGES-1) activity in response to both lipopolysaccharide-treated BV2 cell with IC(50) of 230 nM and recombinant human mPGES-1 protein with IC(50) of 249 nM in vitro. In superoxide dismutase 1(G93A) transgenic mouse model of ALS, AAD-2004 blocked free radical production, PGE(2) formation, and microglial activation in the spinal cords. As a consequence, AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span. In these assays, AAD-2004 was superior to riluzole or ibuprofen. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in superoxide dismutase 1(G93A). Targeting both mPGES-1-mediated PGE(2) and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

Despite numerous studies reporting some measures of efficacy in the animal literature, there are currently no effective therapies for the treatment of traumatic spinal cord injuries (SCI) in humans. The purpose of this review is to delineate key pathophysiological processes that contribute to neurological deficits after SCI, as well as to describe examples of pharmacological approaches that are currently being tested in clinical trials, or nearing clinical translation, for the therapeutic management of SCI. In particular, we will describe the mechanistic rationale to promote neuroprotection and/or functional recovery based on theoretical, yet targeted pathological events. Finally, we will consider the clinical relevancy for emerging evidence that pharmacologically targeting mitochondrial dysfunction following injury may hold the greatest potential for increasing tissue sparing and, consequently, the extent of functional recovery following traumatic SCI., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction is known to play a pivotal role in cell death mechanisms following traumatic brain injury (TBI). N-methyl-4-isoleucine-cyclosporin (NIM811), a non-immunosuppressive cyclosporin A (CsA) analog, inhibits the mitochondrial permeability transition pore (mPTP) and has been shown to be neuroprotective following TBI in mice. However, the translation of the neuroprotective effects of mPTP inhibitors, including CsA and NIM811, into improved cognitive end points has yet to be fully investigated. Therefore, to build upon these results, a severe unilateral controlled cortical impact model of TBI was used in the present study to establish a dose-response curve for NIM811 in rats. The findings demonstrate that the neuroprotection afforded by NIM811 is dose dependent, with the 10 mg/kg dose being the most effective dose. Once the dose response was established, we evaluated the effect of the optimal dose of NIM811 on behavior, mitochondrial bioenergetics, and mitochondrial oxidative damage following TBI. For behavioral studies, rats were administered NIM811 at 15 min and 24 h post-injury, with cognitive testing beginning 10 days post-injury. Mitochondrial studies involved a single injection of NIM811 at 15 min post-injury followed by mitochondrial isolation at 6 h post-injury. The results revealed that the optimal dose of NIM811 improves cognition, improves mitochondrial functioning, and reduces oxidative damage following TBI.

Traumatic injury to the mammalian spinal cord is a highly dynamic process characterized by a complex pattern of pervasive and destructive biochemical and pathophysiological events that limit the potential for functional recovery. Currently, there are no effective therapies for the treatment of spinal cord injury (SCI) and this is due, in part, to the widespread impact of the secondary injury cascades, including edema, ischemia, excitotoxicity, inflammation, oxidative damage, and activation of necrotic and apoptotic cell death signaling events. In addition, many of the signaling pathways associated with these cascades intersect and initiate other secondary injury events. Therefore, it can be argued that therapeutic strategies targeting a specific biochemical cascade may not provide the best approach for promoting functional recovery. A "systems approach" at the subcellular level may provide a better strategy for promoting cell survival and function and, as a consequence, improve functional outcomes following SCI. One such approach is to study the impact of SCI on the biology and function of mitochondria, which serve a major role in cellular bioenergetics, function, and survival. In this review, we will briefly describe the importance and unique properties of mitochondria in the spinal cord, and what is known about the response of mitochondria to SCI. We will also discuss a number of strategies with the potential to promote mitochondrial function following SCI.

Abnormal brain iron homeostasis has been proposed as a pathological event leading to oxidative stress and neuronal injury under pathological conditions. We examined the possibility that neuronal iron overload would mediate free radical production and delayed neuronal death (DND) in hippocampal CA1 area after transient forebrain ischemia (TFI). Mitochondrial free radicals (MFR) were biphasically generated in CA1 neurons 0.5-8 and 48-60 h after TFI. Treatment with Neu2000, a potent spin trapping molecule, as well as trolox, a vitamin E analogue, blocked the biphasic MFR production and attenuated DND in the CA1, regardless of whether it was administered immediately or even 24 h after reperfusion. The late increase in MFR was accompanied by iron accumulation and blocked by the administration of deferoxamine-an iron chelator. Iron accumulation was attributable to prolonged upregulation of the transferrin receptor and to increased uptake of peripheral iron through a leaky blood-brain barrier. Infiltration of iron-containing cells and iron accumulation were attenuated by depletion of circulating blood cells through X-ray irradiation of the whole body except the head. The present findings suggest that excessive iron transported from blood mediates slowly evolving oxidative stress and neuronal death in CA1 after TFI, and that targeting iron-mediated oxidative stress holds extended therapeutic time window against an ischemic event.