SAGES peritoneal dialysis access guideline update 2023.

BACKGROUND: Minimally invasive surgery has been used for both de novo insertion and salvage of peritoneal dialysis (PD) catheters. Advanced laparoscopic, basic laparoscopic, open, and image-guided techniques have evolved as the most popular techniques. The aim of this guideline was to develop evidence-based guidelines that support surgeons, patients, and other physicians in decisions on minimally invasive peritoneal dialysis access and the salvage of malfunctioning catheters in both adults and children. METHODS: A guidelines committee panel of the Society of American Gastrointestinal and Endoscopic Surgeons reviewed the literature since the prior guideline was published in 2014 and developed seven key questions in adults and four in children. After a systematic review of the literature, by the panel, evidence-based recommendations were formulated using the Grading of Recommendations Assessment, Development and Evaluation approach. Recommendations for future research were also proposed. RESULTS: After systematic review, data extraction, and evidence to decision meetings, the panel agreed on twelve recommendations for the peri-operative performance of laparoscopic peritoneal dialysis access surgery and management of catheter dysfunction. CONCLUSIONS: In the adult population, conditional recommendations were made in favor of: staged hernia repair followed by PD catheter insertion over simultaneous and traditional start over urgent start of PD when medically possible. Furthermore, the panel suggested advanced laparoscopic insertion techniques rather than basic laparoscopic techniques or open insertion. Conditional recommendations were made for either advanced laparoscopic or image-guided percutaneous insertion and for either nonoperative or operative salvage. A recommendation could not be made regarding concomitant clean-contaminated surgery in adults. In the pediatric population, conditional recommendations were made for either traditional or urgent start of PD, concomitant clean or clean-contaminated surgery and PD catheter placement rather than staged, and advanced laparoscopic placement rather than basic or open insertion.

Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: outcomes of a dedicated anesthesia and surgery protocol.

BACKGROUND: Patients requiring percutaneous endoscopic gastrostomy (PEG) for amyotrophic lateral sclerosis (ALS) related dysphagia represent a clinical challenge. Diminished pulmonary function and aspiration risks can lead to anesthesia-related complications, and gastric displacement from hemidiaphragm elevation may preclude safe gastric access. This study reports the efficacy and outcomes of a dedicated anesthesia/surgery management protocol for ALS patients undergoing PEG. METHODS: In 2013, a PEG placement protocol for ALS patients was developed emphasizing efficient pre-operative evaluation, rapidly metabolized anesthetic agents, and minimization of opioid use. Outcomes were analyzed retrospectively. Preoperative weight loss, pulmonary function tests, total analgesia, procedural time, and 90-day morbidity and mortality were recorded. RESULTS: From 2013-2019, 67 ALS patients (mean age 65.3 years, 52.2% female) received a PEG under the protocol. Mean percentage weight loss 6 months before PEG was 9.3 ± 5.1% with 38.8% of patients meeting criteria for severe malnutrition. Mean anesthesia time (propofol induction to anesthesia emergence) was 34.5 ± 10.8 min and mean operative time (endoscope insertion to dressing placement) was 16.4 ± 8.2 min. Regional anesthesia with liposomal bupivacaine was performed in 76.1%. All attempts at PEG placement were successful. With a mean follow-up of 6.1 ± 6.8 months, all PEGs were functional and there were no surgical site complications. Thirty-day readmission rate was 7.0% and 90-day mortality was 22.4% (46.7% occurring within 30 days). Mean time from surgery to death was 8.8 ± 7.8 months. CONCLUSIONS: Protocols for optimizing PEG may help overcome challenges present in the ALS patient population. Despite patient comorbidities, protocol implementation and dedicated team members resulted in a high procedural success rate and low complication rate. Further study is warranted to optimize the timing of PEG placement in relation to ALS disease progression and determine the utility of regional anesthesia during PEG placement.

SAGES/AHPBA guidelines for the use of minimally invasive surgery for the surgical treatment of colorectal liver metastases (CRLM).

BACKGROUND: Colorectal liver metastases (CRLM) occur in roughly half of patients with colorectal cancer. Minimally invasive surgery (MIS) has become an increasingly acceptable and utilized technique for resection in these patients, but there is a lack of specific guidelines on the use of MIS hepatectomy in this setting. A multidisciplinary expert panel was convened to develop evidence-based recommendations regarding the decision between MIS and open techniques for the resection of CRLM. METHODS: Systematic review was conducted for two key questions (KQ) regarding the use of MIS versus open surgery for the resection of isolated liver metastases from colon and rectal cancer. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Additionally, the panel developed recommendations for future research. RESULTS: The panel addressed two KQs, which pertained to staged or simultaneous resection of resectable colon or rectal metastases. The panel made conditional recommendations for the use of MIS hepatectomy for both staged and simultaneous resection when deemed safe, feasible, and oncologically effective by the surgeon based on the individual patient characteristics. These recommendations were based on low and very low certainty of evidence. CONCLUSIONS: These evidence-based recommendations should provide guidance regarding surgical decision-making in the treatment of CRLM and highlight the importance of individual considerations of each case. Pursuing the identified research needs may help further refine the evidence and improve future versions of guidelines for the use of MIS techniques in the treatment of CRLM.

Impact on Anesthetic Agent Consumption After Autonomic Neural Blockade as Part of a Combined Anesthesia Protocol: A Randomized Clinical Trial.

BACKGROUND: The intraoperative autonomic neural blockade (ANB) was found safe and effective in controlling pain and associated symptoms and reducing analgesic consumption after laparoscopic sleeve gastrectomy (LSG). This study evaluated whether ANB performed at the outset of LSG reduces anesthetic consumption and promotes hemodynamic stability. METHODS: This prospective, double-blinded, randomized trial involved patients undergoing LSG in 2 high-volume institutions. Patients were randomized to receive ANB either at the onset or the end of the procedure. The primary outcome measure was the consumption of remifentanil and sevoflurane. Secondary outcomes included Aldrete scale score differences in the recovery room and hemodynamic stability during the surgery. RESULTS: In total, 80 patients (40 in the ANB at the onset group and 40 in the control group) were included for analysis. The consumption of remifentanil was significantly lower in the onset group compared to the control group (mean difference -0.04 mcg/kg/min, 95% confidence interval [CI], -0.06 to -0.02; P < .0001). There were no differences in the Aldrete scale scores between the 2 groups. Mean heart rate (HR) and mean arterial pressure (MAP) were also significantly less during surgery in the ANB at the onset group. No complications related to the ANB occurred. CONCLUSIONS: Performing ANB at the onset of LSG is a safe and effective approach that reduces remifentanil consumption and promotes hemodynamic stability during the procedure. This technique holds promise for optimizing anesthesia management in LSG and other minimally invasive surgeries.

Endoscopic management of colovesical and colovaginal fistulas with over-the-scope clips: A single-institution case series.

AIM: Conventional surgical management of colovesical and colovaginal fistulas can be morbid and is contraindicated in many patients. Our aim in this work is to evaluate our experience in the management of colovesical and colovaginal fistulas with endoscopic over-the-scope (OTS) clips. METHOD: A retrospective review of all patients who underwent attempted endoscopic OTS clip management of colovesical and colovaginal fistulas between 2013 and 2020 was performed. Preoperative risk factors, operative details and postoperative outcomes are reported. RESULTS: Ten patients were identified. Fistula types were: colovesical (five), rectovesical (two), colovaginal (two) and rectovaginal (one). The aetiology of the fistula was diverticular disease in seven (70%) cases and surgical complication of pelvic surgery in three (30%). The mean defect age was 157 ± 98 days, the mean defect diameter was 4.5 mm (range 2-10 mm) and the mean fistula length was 15 mm (range 2-25 mm). In nine (90%) cases, fistula identification and cannulation were performed through the nonenteric lumen of the fistula. Initial management with an OTS clip was technically successful in eight (80%) patients. Of the eight patients who underwent OTS clip placement, long-term success (mean follow-up 218 days, range 25-673 days) was achieved after initial intervention in four (50%) patients. One patient underwent serial OTS clip procedures and achieved long-term success after four interventions; three patients have not undergone a repeat procedure after initial failure. CONCLUSION: Endoscopic management of colovesical and colovaginal fistulas with OTS clips offers a promising therapeutic option for patients with contraindications to conventional surgical management. Immediate technical success and long-term success rates are similar to other gastrointestinal tract applications of OTS clips.

Is preparation of a sterile operative field before percutaneous endoscopic gastrostomy necessary? A cost-effectiveness analysis.

BACKGROUND: Despite the non-sterile nature of the alimentary tract, percutaneous endoscopic gastrostomy (PEG) procedures are often performed after creating a sterile surgical field to reduce infection risk. Our group has previously demonstrated no statistically significant difference in the rate of surgical site infection (SSI) following PEG performed with or without sterile operative fields. The purpose of this study is to evaluate the cost-effectiveness of working with or without sterile operative fields during PEG. METHODS: A decision tree model of PEG with and without sterile operative fields was created to evaluate the cost-effectiveness of these two methods. The primary outcome was incremental cost-effectiveness ratio with a ceiling willingness to pay threshold assumed of $100,000 per quality-adjusted life year (QALY). Costs were from the perspective of the healthcare system with a time horizon for the model of 90 days. Sensitivity analyses were performed on all model parameters. RESULTS: In the base case analysis, sterile operative field PEG was cost-effective resulting in 0.2225 QALYs at an expected cost of $2,099. PEG procedures without a sterile operative field yielded less QALYs (0.2224) at a higher cost ($2,199) and were dominated. These procedures became cost-effective when the expected cost was < $1618 (e.g., $140 less than sterile operative field PEG) or when the SSI rate was < 1.6% (e.g., 0.2% higher than sterile operative field PEG) while holding all other variables constant. CONCLUSION: PEG procedures performed without a sterile operative field can be cost-effective compared to procedures performed with a sterile operative field if the rates of SSI remain similar. Cost savings from foregoing a sterile operative field appear to be offset if the SSI rate increases > 0.2% above that of sterile operative field PEG procedures.

Minimally invasive versus open hepatectomy for the resection of colorectal liver metastases: a systematic review and meta-analysis.

BACKGROUND: While surgical resection has a demonstrated utility for patients with colorectal liver metastases (CRLM), it is unclear whether minimally invasive surgery (MIS) or an open approach should be used. This review sought to assess the efficacy and safety of MIS versus open hepatectomy for isolated, resectable CRLM when performed separately from (Key Question (KQ) 1) or simultaneously with (KQ2) the resection of the primary tumor. METHODS: PubMed, Embase, Google Scholar, Cochrane CENTRAL, International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov databases were searched to identify both randomized controlled trials (RCTs) and non-randomized comparative studies published during January 2000-September 2020. Two independent reviewers screened literature for eligibility, extracted data from included studies, and assessed internal validity using the Cochrane Risk of Bias 2.0 Tool and the Newcastle-Ottawa Scale. A random-effects meta-analysis was performed using risk ratios (RR) and mean differences (MD). RESULTS: From 2304 publications, 35 studies were included for meta-analysis. For staged resections, three RCTs and 20 observational studies were included. Data from RCTs indicated MIS having similar disease-free survival (DFS) at 1-year (RR 1.03, 95%CI 0.70-1.50), overall survival (OS) at 5-years (RR 1.04, 95%CI 0.84-1.28), fewer complications of Clavien-Dindo Grade III (RR 0.62, 95%CI 0.38-1.00), and shorter hospital length of stay (LOS) (MD -6.6 days, 95%CI -10.2, -3.0). For simultaneous resections, 12 observational studies were included. There was no evidence of a difference between MIS and the open group for DFS-1-year, OS-5-year, complications, R0 resections, blood transfusions, along with lower blood loss (MD -177.35 mL, 95%CI -273.17, -81.53) and shorter LOS (MD -3.0 days, 95%CI -3.82, -2.17). CONCLUSIONS: Current evidence regarding the optimal approach for CRLM resection demonstrates similar oncologic outcomes between MIS and open techniques, however MIS hepatectomy had a shorter LOS, lower blood loss and complication rate, for both staged and simultaneous resections.

Laparoscopic sleeve gastrectomy in patients with complex abdominal wall hernias.

BACKGROUND: Patients with severe obesity and complex abdominal wall hernias (CAWH) present a challenging clinical dilemma. Their body mass index (BMI) is often prohibitive of successful ventral hernia repair (VHR) and the CAWH presents technical challenges when pursuing bariatric surgery. Our hernia center policy is to refer patients with severe obesity for evaluation with the surgical weight loss program. This study describes outcomes of laparoscopic sleeve gastrectomy (LSG) in patients with both severe obesity and CAWH. METHODS: A retrospective analysis was performed on data prospectively collected between 2014 and 2020. CAWH patients referred for and undergoing LSG were included. Revisional bariatric surgery patients were excluded. The dataset was augmented with operative time, BMI changes, length of stay (LOS), hernia characteristics, postoperative complications, time from referral to weight loss surgery, and time from LSG to VHR. RESULTS: Twenty patients (10 males, mean age 54.3 years) met inclusion criteria. Mean BMI at LSG was 45.6 ± 6.1 kg/m2. Mean hernia area was 494.9 ± 221.2 cm2 and 90% had hernia extension into the subxiphoid and/or epigastric regions. Mean time from bariatric referral to LSG was 10.5 ± 5.4 months. Mean LSG operative time was 121.2 ± 50.3 min, and mean LOS was 1.6 ± 0.8 days. One patient had postoperative bleeding necessitating laparoscopic re-exploration. There were no readmissions. Sixteen patients subsequently underwent VHR on average13.5 ± 11.7 months later and on average 22.6 ± 12.5 months after initial hernia consultation. Two patients had a hernia-related complication between the period of initial hernia consultation and ultimate repair. Mean BMI was 37.5 ± 7.5 kg/m2 (mean 20.7 ± 12.3% decrease, p < 0.0001) at mean follow-up of 27.2 ± 17.2 months. CONCLUSIONS: LSG can be performed successfully even in patients with CAWH. Outcomes do not appear to differ significantly from typical patients undergoing LSG. Further study with larger cohorts is warranted to better delineate complication rates in this population as well as to determine long-term outcomes.

Over-the-scope clip management of non-acute, full-thickness gastrointestinal defects.

BACKGROUND: Endoscopic management of full-thickness gastrointestinal tract defects (FTGID) has become an attractive management strategy, as it avoids the morbidity of surgery. We have previously described the short-term outcomes of over-the-scope clip management of 22 patients with non-acute FTGID. This study updates our prior findings with a larger sample size and longer follow-up period. METHODS: A retrospective analysis of prospectively collected data was conducted. All patients undergoing over-the-scope clip management of FTGID between 2013 and 2019 were identified. Acute perforations immediately managed and FTGID requiring endoscopic suturing were excluded. Patient demographics, endoscopic adjunct therapies, number of endoscopic interventions, and need for operative management were evaluated. Success was strictly defined as complete FTGID closure. RESULTS: We identified 92 patients with 117 FTGID (65 fistulae and 52 leaks); 27.2% had more than one FTGID managed simultaneously. The OTSC device (Ovesco Endoscopy, Tubingen, Germany) was utilized in all cases. Additional closure attempts were required in 22.2% of defects. With a median follow-up period of 5.5 months, overall defect closure success rate was 66.1% (55.0% fistulae vs. 79.6% leaks, p = 0.007). There were four mortalities from causes unrelated to the FTGID. Only 14.9% of patients with FTGID underwent operative management. There were no complications related to endoscopic intervention and no patients required urgent surgical intervention. CONCLUSIONS: Over-the-scope clip management of FTGID represents a safe alternative to potentially morbid operative intervention. When strictly defining success as complete closure of all FTGID, endoscopy was successful in 64.4% of patients with only a small minority of patients ultimately requiring surgery.

Cellular contractility changes are sufficient to drive epithelial scattering.

Epithelial scattering occurs when cells disassemble cell-cell junctions, allowing individual epithelial cells to act in a solitary manner. Epithelial scattering occurs frequently in development, where it accompanies epithelial-mesenchymal transitions and is required for individual cells to migrate and invade. While migration and invasion have received extensive research focus, how cell-cell junctions are detached remains poorly understood. An open debate has been whether disruption of cell-cell interactions occurs by remodeling of cell-cell adhesions, increased traction forces through cell substrate adhesions, or some combination of both processes. Here we seek to examine how changes in adhesion and contractility are coupled to drive detachment of individual epithelial cells during hepatocyte growth factor (HGF)/scatter factor-induced EMT. We find that HGF signaling does not alter the strength of cell-cell adhesion between cells in suspension, suggesting that changes in cell-cell adhesion strength might not accompany epithelial scattering. Instead, cell-substrate adhesion seems to play a bigger role, as cell-substrate adhesions are stronger in cells treated with HGF and since rapid scattering in cells treated with HGF and TGFß is associated with a dramatic increase in focal adhesions. Increases in the pliability of the substratum, reducing cells ability to generate traction on the substrate, alter cells׳ ability to scatter. Further consistent with changes in substrate adhesion being required for cell-cell detachment during EMT, scattering is impaired in cells expressing both active and inactive RhoA mutants, though in different ways. In addition to its roles in driving assembly of both stress fibers and focal adhesions, RhoA also generates myosin-based contractility in cells. We therefore sought to examine how RhoA-dependent contractility contributes to cell-cell detachment. Inhibition of Rho kinase or myosin II induces the same effect on cells, namely an inhibition of cell scattering following HGF treatment. Interestingly, restoration of myosin-based contractility in blebbistatin-treated cells results in cell scattering, including global actin rearrangements. Scattering is reminiscent of HGF-induced epithelial scattering without a concomitant increase in cell migration or decrease in adhesion strength. This scattering is dependent on RhoA, as blebbistatin-induced scattering is reduced in cells expressing dominant-negative RhoA mutants. This suggests that induction of myosin-based cellular contractility may be sufficient for cell-cell detachment during epithelial scattering.

Inpatient Choledocholithiasis Management: a Cost-Effectiveness Analysis of Management Algorithms.

BACKGROUND: Choledocholithiasis is commonly encountered. It is frequently managed with laparoscopic common bile duct exploration or endoscopic retrograde cholangiopancreatography (either preoperative, intraoperative, or postoperative relative to laparoscopic cholecystectomy). The purpose of this study is to determine the most cost-effective method to manage inpatient choledocholithiasis. METHODS: A decision tree model was created to evaluate the cost-effectiveness of laparoscopic common bile duct exploration and preoperative, intraoperative, and postoperative endoscopic retrograde cholangiopancreatography. The primary outcome was incremental cost-effectiveness ratio with a ceiling willingness to pay threshold assumed of $100,000 per quality-adjusted life year. Model parameters were determined through review of published literature and institutional data. Costs were from the perspective of the healthcare system with a time horizon of 1 year. Sensitivity analyses were performed on model parameters. RESULTS: In the base case analysis, laparoscopic common bile duct exploration was cost-effective, resulting in 0.9909 quality-adjusted life years at an expected cost of $18,357. Intraoperative endoscopic retrograde cholangiopancreatography yielded more quality-adjusted life years (0.9912) at a higher cost ($19,717) with an incremental cost-effectiveness ratio of $4,789,025, exceeding the willingness to pay threshold. Both preoperative and postoperative endoscopic retrograde cholangiopancreatographies were eliminated for being both more costly and less effective. Laparoscopic common bile duct exploration remained cost-effective if the probability of successful biliary clearance was above 0.79, holding all other variables constant. If its base cost remained below $18,400 and intraoperative endoscopic retrograde cholangiopancreatography base cost rose above $18,200, then laparoscopic common bile duct exploration remained cost-effective. CONCLUSION: Laparoscopic common bile duct exploration is the most cost-effective method to manage choledocholithiasis. Efforts to ensure availability of local expertise and resources for this procedure are warranted.

Radiographic identification of thoracoabdominal hernias.

PURPOSE: Hernias spanning both chest and abdominal walls are uncommon and associated with chest wall trauma, coughing and obesity. This study describes the radiographic appearance of these hernias to guide proper identification and operative planning. Proposed standardized reporting patterns are also presented. METHODS: The cross sectional imaging of patients presenting with thoracoabdominal hernias was reviewed. Radiographic reports were supplemented by surgeon imaging review and operative findings during repair. Defect dimensions, hernia content, level of herniation, presence of osseous or cartilaginous disruption of the chest wall and degree of rib displacement were collected. Disruption of myofascial planes was also noted. RESULTS: Six patients were identified. All hernias occurred below the 9th rib and were associated with complete intercostal muscle disruption. The transversus abdominis was disrupted in all hernias and the internal oblique was disrupted in five of the hernias. The majority (83%) had caudal rib displacement (median 6.8 cm compared to contralateral side). Median hernia width was 10.35 cm (1.6-19.1 cm) and median length was 10.2 cm (1.8-14.3 cm). Five patients had associated bone/cartilage injuries: two with 11th rib fractures, two with combined bone and cartilaginous fractures and one with a surgical rib resection. CONCLUSION: The typical injury pattern of thoracoabdominal hernias includes disruption of the intercostal muscles, transversus abdominis, and commonly the internal oblique with an intact external oblique. Inferior rib displacement by hernia contents and unopposed pull of the abdominal musculature is common. Osseous or cartilaginous disruption always occurs unless the defect is bounded on at least one side by a floating rib.

Paragastric Autonomic Neural Blockade to Prevent Early Visceral Pain and Associated Symptoms After Laparoscopic Sleeve Gastrectomy: a Randomized Clinical Trial.

BACKGROUND: Visceral pain (VP) following laparoscopic sleeve gastrectomy remains a substantial problem. VP is associated with autonomic symptoms, especially nausea and vomiting, and is unresponsive to traditional pain management algorithms aimed at alleviating somatic (incisional) pain. The present study was performed to evaluate the safety and effectiveness of laparoscopic paragastric autonomic neural blockade (PG-ANB) in managing the symptoms associated with VP following sleeve gastrectomy. STUDY DESIGN: This prospective, double-blinded, randomized clinical trial involved patients undergoing laparoscopic sleeve gastrectomy at two high-volume institutions. The patients were randomized to laparoscopic transversus abdominis plane block with or without PG-ANB. The primary outcome was patient-reported pain scores assessed at 1, 8, and 24 h postoperatively. The secondary outcome measures were analgesic requirements, nausea, vomiting, hiccups, and hemodynamic changes immediately after PG-ANB and postoperatively. RESULTS: In total, 145 patients (block group, n = 72; control group, n = 73) were included in the study. The heart rate and mean arterial pressure significantly decreased 10 min after PG-ANB. The visual analog scale score for pain was significantly lower in the PG-ANB than in the control group at 1 h postoperatively (p < 0.001) and 8 h postoperatively (p < 0.001). Vomiting, nausea, sialorrhea, and hiccups were significantly less prevalent in the PG-ANB group. Patients in the PG-ANB group received fewer cumulative doses of analgesics at 1 h postoperatively (p = 0.003) and 8 h postoperatively (p < 0.001). No differences between the groups were detected at 24 h (p = 0.298). No complications related to PG-ANB occurred. CONCLUSION: PG-ANB safely and effectively reduces early VP, associated autonomic symptoms, and analgesic requirements after laparoscopic sleeve gastrectomy.

A zyxin-nectin interaction facilitates zyxin localization to cell-cell adhesions.

Cell-cell junction remodeling is associated with dramatic actin reorganizations. Several actin regulatory systems have been implicated in actin remodeling events as cell-cell contacts are assembled and disassembled, including zyxin/LPP-VASP complexes. These complexes facilitate strong cell-cell adhesion by maintaining actin-membrane connections. It has been proposed that zyxin and LPP localize to cell-cell junctions via a well-defined interaction with alpha-actinin. This was recently confirmed for LPP, but zyxin localization at cell-cell contacts occurs independently of alpha-actinin binding. Here we seek to map the zyxin sequence responsible for localization to cell-cell contacts and identify the protein that docks zyxin at this cellular location. Previous results have shown that a zyxin fragment excluding the alpha-actin binding site and the LIM domains (amino acids 51-392) can independently localize to cell-cell contacts. Here, expression of smaller zyxin fragments show that zyxin localization requires amino acids 230-280. A yeast-two-hybrid screen, using the central region of zyxin as bait, resulted in the identification of the cell-cell adhesion receptor nectin-4 as a zyxin binding partner. Further demonstrating zyxin-nectin interactions, zyxin binds the intracellular domain of nectin-2 in vitro. Depletion of nectin-2 from L cells expressing E-cadherin results in a loss of zyxin localization to cell-cell contacts, demonstrating that the zyxin-nectin interaction plays a critical role in zyxin targeting to these sites.

Epidemiology and Perioperative Mortality of Exploratory Laparotomy in Rural Ghana.

Background: Perioperative mortality rate (POMR) has been identified as an important measure of access to safe surgical and anesthesia care in global surgery. There has been limited study on this measure in rural Ghana. In order to identify areas for future quality improvement efforts, we aimed to assess the epidemiology of exploratory laparotomy and to investigate POMR as a benchmark quality measure. Methods: Surgical records were reviewed at a regional referral hospital in Eastern Region, Ghana to identify cases of exploratory laparotomy from July 2017 through June 2018. Patient demographics, health information, and outcomes data were collected. Logistic regression was used to identify predictors of perioperative mortality. Findings: The study included operations for 286 adult and 60 pediatric patients. Only 60% of patients were covered by National Health Insurance (NHI). The overall POMR was 11.5% (12.6% adults; 6.7% pediatric). Sixty percent of mortalities were referrals from outside hospitals and the mortality rate for referrals was 13.5%. Odds of mortality was 13 times greater with perforated peptic ulcer disease (OR = 13.1, p = 0.025) and 12 times greater with trauma (OR = 11.7, p = 0.042) when compared to the most common operation. Female sex (OR = 0.3, p = 0.016) and NHI (OR = 0.4, p = 0.031) were protective variables. Individuals 60 years and older (OR = 3.3, p = 0.016) had higher mortality. Conclusion: POMR can be an important outcome and quality indicator for rural populations. Interventions aimed at decreasing emergent hernia repair, preventing perforation of peptic ulcer disease, improving rural infrastructure for response to major trauma, and increasing NHI coverage may improve POMR in rural Ghana.

MEK inhibitor GSK1120212-mediated radiosensitization of pancreatic cancer cells involves inhibition of DNA double-strand break repair pathways.

PURPOSE: Over 90% of pancreatic adenocarcinoma PC express oncogenic mutant KRAS that constitutively activates the Raf-MEK-MAPK pathway conferring resistance to both radiation and chemotherapy. MEK inhibitors have shown promising anti-tumor responses in recent preclinical and clinical studies, and are currently being tested in combination with radiation in clinical trials. Here, we have evaluated the radiosensitizing potential of a novel MEK1/2 inhibitor GSK1120212 (GSK212,or trametinib) and evaluated whether MEK1/2 inhibition alters DNA repair mechanisms in multiple PC cell lines. METHODS: Radiosensitization and DNA double-strand break (DSB) repair were evaluated by clonogenic assays, comet assay, nuclear foci formation (γH2AX, DNA-PK, 53BP1, BRCA1, and RAD51), and by functional GFP-reporter assays for homologous recombination (HR) and non-homologous end-joining (NHEJ). Expression and activation of DNA repair proteins were measured by immunoblotting. RESULTS: GSK212 blocked ERK1/2 activity and radiosensitized multiple KRAS mutant PC cell lines. Prolonged pre-treatment with GSK212 for 24-48 hours was required to observe significant radiosensitization. GSK212 treatment resulted in delayed resolution of DNA damage by comet assays and persistent γH2AX nuclear foci. GSK212 treatment also resulted in altered BRCA1, RAD51, DNA-PK, and 53BP1 nuclear foci appearance and resolution after radiation. Using functional reporters, GSK212 caused repression of both HR and NHEJ repair activity. Moreover, GSK212 suppressed the expression and activation of a number of DSB repair pathway intermediates including BRCA1, DNA-PK, RAD51, RRM2, and Chk-1. CONCLUSION: GSK212 confers radiosensitization to KRAS-driven PC cells by suppressing major DNA-DSB repair pathways. These data provide support for the combination of MEK1/2 inhibition and radiation in the treatment of PC.

Progressive bone and joint abnormalities of the spine and lower extremities in cerebral palsy.

Bone and joint changes in cerebral palsy result from muscle spasticity and contracture. The spine and the joints of the lower extremity are most commonly affected. Scoliosis may progress rapidly and may continue after skeletal maturity. Increased thoracic kyphosis and lumbar lordosis, spondylolisthesis, spondylolysis, and pelvic obliquity may accompany the scoliosis. Progressive hip flexion and adduction lead to windswept deformity, increased femoral anteversion, apparent coxa valga, subluxation, deformity of the femoral head, hip dislocation, and formation of a pseudoacetabulum. In the knee, flexion contracture, patella alta, and patellar fragmentation are the most commonly seen abnormalities. Recurvatum deformity can also develop in the knee secondary to contracture of the rectus femoris muscle. Progressive equinovalgus and equinovarus of the foot and ankle are associated with rocker-bottom deformity and subluxation of the talonavicular joint. Early recognition of progressive deformity in patients with cerebral palsy allows timely treatment and prevention of irreversible change.