One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic ß-Lactone-Oxindoles and Double Ring-Opening.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic ß-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the ß-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

α-Functionalisation of Cyclic Sulfides Enabled by Lithiation Trapping.

A general and straightforward procedure for the lithiation trapping of cyclic sulfides such as tetrahydrothiophene, tetrahydrothiopyran and a thiomorpholine is described. Trapping with a wide range of electrophiles is demonstrated, leading to more than 50 diverse α-substituted saturated sulfur heterocycles. The methodology provides access to a range of α-substituted cyclic sulfides that are not easily synthesised by the currently available methods.

Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution of Tetra-substituted Morpholinone and Benzoxazinone Lactols.

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89 %, 99 : 1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5) and C(6), as well as benzannulation (>35 examples in total). The DKR process is amenable to scale-up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=O⋅⋅⋅isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.

Synthesis of Tetra-Substituted 3-Hydroxyphthalide Esters by Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution.

A general and highly enantioselective method for the preparation of tetra-substituted 3-hydroxyphthalide esters via isothiourea-catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)-HyperBTM (5 mol %) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99 %, 99 : 1 er). Substitution of the aromatic core within the 3-hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3), is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computationally, with a key substrate heteroatom donor O⋅⋅⋅acyl-isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.

Complicated Diverticular Disease.

The modern management of colonic diverticular disease involves grouping patients into uncomplicated or complicated diverticulitis, after which the correct treatment paradigm is instituted. Recent controversies suggest overlap in management strategies between these two groups. While most reports still support surgical intervention for the treatment of complicated diverticular disease, more data are forthcoming suggesting complicated diverticulitis does not merit surgical resection in all scenarios. Given the significant risk for complication in surgery for diverticulitis, careful attention should be paid to patient and procedure selection. Here, we define complicated diverticulitis, discuss options for surgical intervention, and explain strategies for avoiding operative pitfalls that result in early and late postoperative complications.

Diagnosis and Management of Parastomal Hernias.

CASE SUMMARY: A 63-year-old woman with history of stage II rectal adenocarcinoma status postneoadjuvant chemoradiation and subsequent abdominoperineal resection presented with worsening bulge and inability to pouch stoma. CT scan revealed a 4-cm parastomal hernia. After discussion with the patient regarding management options, she elected to undergo repair of hernia defect. A robot-assisted laparoscopic parastomal hernia repair with synthetic mesh via the Sugarbaker technique was performed. After a short stay in the hospital, the patient recovered well and reported no recurrent symptoms.

Trauma Recidivism and Mortality Following Violent Injuries in Young Adults.

BACKGROUND: Trauma recidivism accounts for approximately 44% of emergency department admissions and remains a significant health burden with this patient cohort carrying higher rates of morbidity and mortality. METHODS: A level 1 trauma center registry was queried for patients aged 18-25 y presented between 2009 and 2015. Patients with nonaccidental gunshot wounds, stab wounds, or blunt assault-related injuries were categorized as violent injuries. Primary outcomes included mortality and recidivism, which were defined as patients with two unrelated traumas during the study period. Hospital records and the Social Security Death Index were used to aid in outcomes. RESULTS: A total of 6484 patients presented with 1215 (18.7%) sustaining violent injuries (87.4% male, median age 22.2 y). Mechanism of violent injuries included 64.4% gunshot wound, 21.1% stab, and 14.8% blunt assault. Compared with nonviolent injuries, violent injury patients had increased risk of mortality (9.3% versus 2.1%, P < 0.0001). Out-of-hospital mortality was 2.6% (versus 0.5% nonviolent, P < 0.0005), with an average time to death being 6.4 mo from initial injury. Recidivism was 24.9% with mean time to second violent injury at 31.9 ± 21.0 mo; 14.9% had two trauma readmissions, and 8.0% had ≥3. Ninety percent of subsequent injuries occurred within 5 y, with 19.1% in the first year. CONCLUSIONS: The burden of injury after violent trauma extends past discharge as patients have significantly higher mortality rates following hospital release. Over one-quarter present with a second unrelated trauma or death. Improved medical, psychological, and social collaborative treatment of these high-risk patients is needed to interrupt the cycle of violent injury.

Prophylactic Ureteral Catheters for Colectomy: A National Surgical Quality Improvement Program-Based Analysis.

BACKGROUND: Despite improvement in technique and technology, using prophylactic ureteral catheters to avoid iatrogenic ureteral injury during colectomy remains controversial. OBJECTIVE: The aim of this study was to evaluate outcomes and costs attributable to prophylactic ureteral catheters with colectomy. DESIGN: This was a retrospective study. SETTINGS: The study was conducted at a single tertiary care center. PATIENTS: The colectomy-targeted American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2014 was queried. MAIN OUTCOME MEASURES: The primary end point was the rate of 30-day ureteral injury after colectomy. Univariate and multivariate analyses determined factors associated with ureteral injury and urinary tract infection in patients undergoing colectomy. RESULTS: A total of 51,125 patients were identified with a mean age of 60.9 ± 14.9 years and a BMI of 28.4 ± 6.7 k/m; 4.90% (n = 2486) of colectomies were performed with prophylactic catheters, and 333 ureteral injuries (0.65%) were identified. Prophylactic ureteral catheters were most commonly used for diverticular disease (42.2%; n = 1048), with injury occurring most often during colectomy for diverticular disease (36.0%; n = 120). Univariate analysis of outcomes demonstrated higher rates of ileus, wound infection, urinary tract infection, urinary tract infection as reason for readmission, superficial site infection, and 30-day readmission in patients with prophylactic ureteral catheter placement. On multivariate analysis, prophylactic ureteral catheter placement was associated with a lower rate of ureteral injury (OR = 0.45 (95% CI, 0.25-0.81)). LIMITATIONS: This was a retrospective study using a clinical data set. CONCLUSIONS: Here, prophylactic ureteral catheters were used in 4.9% of colectomies and most commonly for diverticulitis. On multivariate analysis, prophylactic catheter placement was associated with a lower rate of ureteral injury. Additional research is needed to delineate patient populations most likely to benefit from prophylactic ureteral stent placement. See Video Abstract at http://links.lww.com/DCR/A482.

Trainee-associated outcomes in laparoscopic colectomy for cancer: propensity score analysis accounting for operative time, procedure complexity and patient comorbidity.

BACKGROUND: Surgical trainee association with operative outcomes is controversial. Studies are conflicting, possibly due to insufficient control of confounding variables such as operative time, case complexity, and heterogeneous patient populations. As operative complications worsen long-term outcomes in oncologic patients, understanding effect of trainee involvement during laparoscopic colectomy for cancer is of utmost importance. Here, we hypothesized that resident involvement was associated with worsened 30-day mortality and 30-day overall morbidity in this patient population. METHODS: Patients undergoing laparoscopic colectomy for oncologic diagnosis from 2005 to 2012 were assessed using the American College of Surgeons National Surgical Quality Improvement Program dataset. Propensity score matching accounted for demographics, comorbidities, case complexity, and operative time. Attending only cases were compared to junior, middle, chief resident, and fellow level cohorts to assess primary outcomes of 30-day mortality and 30-day overall morbidity. RESULTS: A total of 13,211 patients met inclusion criteria, with 4075 (30.8%) cases lacking trainee involvement and 9136 (69.2%) involving a trainee. Following propensity matching, junior (PGY 1-2) and middle level (PGY 3-4) resident involvement was not associated with worsened outcomes. Chief (PGY 5) resident involvement was associated with worsened 30-day overall morbidity (15.5 vs. 18.6%, p = 0.01). Fellow (PGY > 5) involvement was associated with worsened 30-day overall morbidity (16.0 vs. 21.0%, p < 0.001), serious morbidity (9.3 vs. 13.5%, p < 0.001), minor morbidity (9.8 vs. 13.1%, p = 0.002), and surgical site infection (7.9 vs. 10.5%, p = 0.006). No differences were seen in 30-day mortality for any resident level. CONCLUSION: Following propensity-matched analysis of cancer patients undergoing laparoscopic colectomy, chief residents, and fellows were associated with worsened operative outcomes compared to attending along cases, while junior and mid-level resident outcomes were no different. Further study is necessary to determine what effect the PGY surgical trainee level has on post-operative morbidity in cancer patients undergoing laparoscopic colectomy in the context of multiple collinear factors.

Post-operative morbidity, but not mortality, is worsened by operative delay in septic diverticulitis.

PURPOSE: Optimal timing of surgery for acute diverticulitis remains unclear. A non-operative approach followed by elective surgery 6-week post-resolution is favored. However, a subset of patients fail on the non-operative management during index admission. Here, we examine patients requiring emergent operation to evaluate the effect of surgical delay on patient outcomes. METHODS: Patients undergoing emergent operative intervention for acute diverticulitis were queried using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2005 to 2012. Primary endpoints of 30-day overall morbidity and mortality were evaluated via univariate and multivariate analysis. RESULTS: Of the 2,119 patients identified for study inclusion, 57.2 % (n = 1212) underwent emergent operative intervention within 24 h, 26.3 % (n = 558) between days 1-3, 12.9 % (n = 273) between days 3-7, and 3.6 % (n = 76) greater than 7 days from admission. End colostomy was performed in 77.4 % (n = 1,640) of cases. Unadjusted age and presence of major comorbidities increased with operative delay. Further, unadjusted 30-day overall morbidity, mortality, septic complications, and post-operative length of stay increased significantly with operative delay. On multivariate analysis, operative delay was not associated with increased 30-day mortality but was associated with increased 30-day overall morbidity. CONCLUSIONS: Hartmann's procedure has remained the standard operation in emergent surgical management of acute diverticulitis. Delay in definitive surgical therapy greater than 24 h from admission is associated with higher rates of morbidity and protracted post-operative length of stay, but there is no increase in 30-day mortality. Prospective study is necessary to further answer the question of surgical timing in acute diverticulitis.

Surgeon case volume and readmissions after laparoscopic Roux-en-Y gastric bypass: more is less.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is a commonly performed bariatric procedure. Readmissions are used as a quality indicator with a nationwide emphasis on reduction. In LRYGB surgery, surgeon volume studies have focused on correlation with technical outcomes, offering limited data on readmissions. Our aim was to evaluate nationwide data to explore the relationship between surgeon case volume and hospital readmissions following LRYGB. METHODS: The Bariatric Outcomes Longitudinal Database from 2011 was used for this study. Analysis was restricted to patients who underwent non-revisional LRYGB. Surgeons performing more than 50 LRYGB during the study period were defined as high-volume surgeons (HVS). Multivariable logistic regression modeling was used to control for patient demographics and comorbidities. RESULTS: We identified 32,521 patients who underwent LRYGB with an overall 30-day readmission rate of 5.5 %, mean age 45.7 (12.0) years, and mean BMI 47.2 (8.0) kg/m2. There were no major differences in BMI (47.3 ± 8.1 vs 47.1 ± 7.9, p = 0.282) or age (45.5 ± 12.0 vs 45.8 ± 12.0, p = 0.030) between low-volume surgeon (LVS) and HVS patients. After controlling for baseline characteristics, HVS patients were less likely to be readmitted compared to those with a LVS (OR = 0.85, 95 % CI 0.77-0.94), with a readmission rate of 5.2 vs 6.1 % (p = 0.001). Additionally, HVS patients had lower rates of 30-day mortality (OR = 0.50, 95 % CI 0.27-0.91), complication (OR = 0.81, 95 % CI 0.75-0.87), reoperation (OR = 0.82, 95 % CI 0.72-0.93), and anastomotic leak (OR = 0.64, 95 % CI 0.46-0.87). CONCLUSIONS: Readmission following LRYGB is significantly associated with surgeon operative volume; surgeons that perform fewer than 50 LRYGB per year are more likely to have 30-day readmissions and complications. Our findings support other more generalized studies suggesting surgeon case volume is inversely associated with increased risk of adverse outcomes and complications. As such, performance of LRYGB by HVS may decrease patient morbidity, hospital readmission, and overall healthcare utilization.

Comparative effectiveness of Roux-en-Y gastric bypass and sleeve gastrectomy in super obese patients.

BACKGROUND: The disproportionate increase in the super obese (SO) is a hidden component of the current obesity pandemic. Data on the safety and efficacy of bariatric procedures in this specific patient population are limited. Our aim is to assess the comparative effectiveness of the two most common bariatric procedures in the SO. METHODS: Using the Bariatric Outcomes Longitudinal Database from 2007 to 2012, we compared SO patients (BMI ≥ 50) undergoing laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Stepwise logistic regression modeling was used to calculate a propensity score to adjust for patient demographics and comorbidities. RESULTS: We identified 50,987 SO patients who underwent RYGB (N = 42,119) or SG (N = 8868). There was no difference in adjusted overall 30-day complication rate comparing RYGB and SG patients (11.5 vs. 11.1 %, p = 0.250). RYGB patients had higher adjusted rates of 30-day mortality (0.3 vs. 0.2 %, p = 0.042), reoperation (4.0 vs. 2.4 %, p < 0.001), and readmission (6.9 vs. 5.5 %, p < 0.001) compared to SG patients. The percent of total weight loss (%TWL) was significantly higher for RYGB patients compared to SG at 3 months (14.1 vs. 13.1 %, p < 0.001), 6 months (25.2 vs. 22.4 %, p < 0.001), and 12 months (34.5 vs. 29.7 %, p < 0.001). RYGB patients had increased resolution of all measured comorbidities: diabetes mellitus (61.6 vs. 50.8 %, p < 0.001), hypertension (43.1 vs. 34.5 %, p < 0.001), gastroesophageal reflux disease (53.9 vs. 32.5 %, p < 0.001), hyperlipidemia (39.7 vs. 32.5 %, p < 0.001), and obstructive sleep apnea (42.8 vs. 40.6 %, p = 0.058) at 12 months compared to SG patients. CONCLUSIONS: There are significant differences in comorbidity improvement and resolution as well as weight loss between RYGB and SG in the SO population. There was no difference in overall 30-day complications, but more RYGB patients required readmission and reoperation. However, RYGB was considerably more effective in controlling obesity-related comorbidities. Our results favor performance of RYGB in SO patients of appropriate risk.

What are the results of colonic volvulus surgery?

BACKGROUND: Operative results of volvulus are largely unknown because of infrequent diagnosis. OBJECTIVE: We examined the results of operative intervention for colonic volvulus. DESIGN: We merged trackable data from the California Inpatient Database with Supplemental Files for Revisit Analyses between January 1, 2005, and December 31, 2007. SETTINGS: Trackable data from California discharge records. PATIENTS: We identified all of the patients with colonic volvulus who underwent 1 of 4 surgical procedures, including manipulation/fixation of the colon, right colectomy, left colectomy, or total colectomy. MAIN OUTCOME MEASURES: During the 36-month study period, we identified recurrence risk, recurrence requiring reoperation, time to reoperation, stoma formation, disposition on discharge, and in-hospital mortality. Fisher exact, χ(2), and ANOVA tests were used when appropriate. RESULTS: We identified 2141 patients with colonic volvulus who were undergoing intraoperative manipulation/fixation of the colon (n = 209 (12%)), right (n = 728 (41%)), left (n = 781 (44%)), or total colectomy (n = 56 (3%)). Patients treated with intraoperative manipulation/fixation were younger, more likely to be women, and more likely to have private insurance. Patients who underwent total colectomy had the highest risk of mortality (21%), highest risk of stoma creation (64%), and longest length of stay (18 days); were more likely to be readmitted (9%); and were the most likely to be discharged to a skilled nursing facility (48%). Patients treated with intraoperative manipulation/fixation had the lowest mortality, risk of stoma formation, length of stay, and likelihood of discharge to skilled nursing facility but the highest risk of subsequent procedures for volvulus (26%) over a follow-up ranging from 0 to 687 days. LIMITATIONS: This study was limited by retrospective study design, heterogeneous patient factors, and inability to identify the time of last follow-up. CONCLUSIONS: The majority of patients with volvulus underwent a resectional procedure. A subset without resection had favorable initial outcomes but remained at high risk for subsequent procedures. There may be a potential role for evaluating intraoperative manipulation/fixation in a small subset of patients with colonic volvulus.

All things not being equal: readmission associated with procedure type.

BACKGROUND: There is an accelerated effort to reduce hospital readmissions despite minimal data detailing risk factors associated with this outcome. MATERIALS AND METHODS: We analyzed National Surgical Quality Improvement Project data from January 1, 2011-December 31, 2011, evaluating all patients undergoing one of 34 targeted operative procedures across all surgical specialties. Multivariate regression models of risk for readmission were developed including targeted procedure codes, demographic variables, preoperative variables, intraoperative variables, and postoperative adverse events. Our main outcome measure was hospital readmission. RESULTS: A total of 217, 389 patients met study inclusion criteria. Minimal associations existed between patient factors and risk of readmission. Adverse events including unplanned operating room return (odds ratio [OR] 8.5; confidence interval [CI] 8.0-9.0), pulmonary embolism (OR 8.2; CI 7.1-9.6), deep incisional infection (OR 7.5; CI 6.7-8.5), and organ space infection (OR 5.8; CI 5.3-6.3) were associated with increased risk of readmission. Our data suggest the type of procedure performed is significantly associated with risk of readmission. Furthermore, multivariate analysis revealed procedures, involving the pancreas, rectum, bladder, and lower extremity vascular bypass, were associated with the highest risk of readmission. CONCLUSIONS: Postoperative complications demonstrated stronger association with readmission than patient factors. Focused analysis of higher risk procedures may provide insight into strategies for risk reduction.

Acute cholecystitis: risk factors for conversion to an open procedure.

BACKGROUND: Laparoscopic cholecystectomy is one of the most common general surgical procedures performed. Conversion to an open procedure (CTO) is associated with increased morbidity and length of stay. Patients presenting with acute cholecystitis are at higher risk for CTO. Studies have attempted to examine risk factors for CTO in patients who undergo laparoscopic cholecystectomy for acute cholecystitis but are limited by small sample size. The aim of this study was to identify preoperative variables that predict higher risk for CTO in patients presenting with acute cholecystitis. MATERIALS AND METHODS: Patients undergoing laparoscopic cholecystectomy for acute cholecystitis from 2005-2011 were identified from the American College of Surgeons' National Surgical Quality Improvement Program Participant Use File. Patients who underwent successful laparoscopic surgery were compared with those who required CTO. Demographics, comorbidities, and 30-d outcomes were analyzed. Multivariable logistic regression was used for variables with P value <0.1, with CTO used as the dependent variable. RESULTS: A total of 7242 patients underwent laparoscopic cholecystectomy for acute cholecystitis. CTO was reported in 436 patients (6.0%). Those who required conversion were older (60.7 ± 16.2 versus 51.6 ± 18.0, P = 0.0001) and mean body mass index was greater (30.8 ± 7.6 versus 30.0 ± 7.3, P = 0.033) compared with those whose procedure was completed laparoscopically. Vascular, cardiac, renal, pulmonary, neurologic, hepatic disease, diabetes, and bleeding disorders were more prevalent in CTO patients. Mortality (2.3% versus 0.7%, P < 0.0001), overall morbidity (21.8% versus 6.0%, P < 0.0001), serious morbidity (14.9% versus 3.8%, P < 0.0001), reoperation (3.4% versus 1.4%, P = 0.001), and surgical site infection (9.2% versus 1.8%, P < 0.0001) rates, as well as length of stay (8.6 ± 13.0 versus 3.4 ± 6.7, P < 0.0001) were greater in those requiring CTO. The following factors were independently associated with CTO: age (odds ratio [OR], 1.01, P = 0.015), male gender (OR, 1.77, P = 0.005), body mass index (OR, 1.04, P < 0.0001), preoperative alkaline phosphatase (OR, 1.01, P = 0.0005), white blood cell count (OR, 1.06, P = 0.0001), and albumin (OR, 0.52, P = 0.0001). CONCLUSIONS: CTO for acute cholecystitis remains low but not clinically negligible. The identified risk factors can potentially guide management and patient selection for delayed intervention for acute cholecystitis.

Obstructing ventral hernias are not independently associated with surgical site infections.

BACKGROUND: Delayed operative intervention in the setting of adhesive bowel obstruction has been recently shown to increase the rate of surgical site infection (SSI), raising the concern for bacterial translocation. The effect of obstruction on SSI rate in patients with ventral hernia is unknown. The aim of this study was to assess the association between bowel obstruction and SSI in patients undergoing ventral hernia repair (VHR). MATERIALS AND METHODS: This study is a retrospective database review. Patients undergoing isolated VHR from 2005-2011 were identified from the American College of Surgeons' National Surgical Quality Improvement Program database. Demographics, comorbidities, and 30-d outcomes were analyzed. Multivariate logistic regression was used for variables with a P value of <0.1. RESULTS: A total of 68,811 patients underwent isolated VHR; 53.1% were male with mean age of 53 ± 15 y and body mass index of 32 ± 8. Hernia-related obstruction was found in 17,058 (24.8%). In patients with obstruction, SSI was more frequent (3.2% versus 2.6%, P < 0.001). Obesity, advanced age, vascular, pulmonary, hepatic, renal disease, and diabetes were more prevalent. After controlling for confounding baseline variables, bowel obstruction was not independently associated with SSI (odds ratio, 0.983, 95% confidence interval, 0.872-1.107). Subgroup analysis of clean classified cases also demonstrated the lack of independent association between obstruction and SSI. CONCLUSIONS: Obstruction in patients undergoing VHR is not independently associated with SSI. Our results suggest that mesh implantation remains a viable option in this setting. Other confounding comorbid conditions should be assessed at the time of surgical intervention to identify patients appropriate for mesh repair.

Blowhole colostomy for the urgent management of distal large bowel obstruction.

BACKGROUND: Complete obstruction of the distal colon or rectum often presents as a surgical emergency. This study evaluated the efficacy of blowhole colostomy versus transverse loop colostomy for the emergent management of distal large intestinal obstruction. METHODS: Retrospective chart review of all colostomy procedures (CPT 44320) performed for complete distal large bowel obstruction during the past 6 y in a university hospital practice was undertaken. Blowhole was compared with loop colostomy with a primary endpoint of successful colonic decompression. RESULTS: One hundred forty-one patients underwent colostomy creation during the study period. Of these, 61 were completed for acute obstruction of the distal colon or rectum (19 blowhole versus 42 loop colostomy). No differences between study groups were seen in age, gender, body mass index, malnutrition, American Society of Anesthesiology class, time to liquid or regular diet, 30-d or inhospital mortality, or rates of complications. Patients undergoing blowhole colostomy had significantly higher cecal diameters at diagnosis (9.14 versus 7.31 cm, P = 0.0035). Operative time was shorter in blowhole procedures (43 versus 51 min, P = 0.017). Postoperative length of stay was significantly shorter for blowhole colostomy (6 versus 8 d, P = 0.014). The primary endpoint of successful colonic decompression was met in all colostomy patients. CONCLUSIONS: Diverting blowhole colostomy is a safe, quick, and effective procedure for the urgent management of distal colonic obstruction associated with obstipation and massive distention.

Thymic stromal lymphopoietin mediates the host response and increases mortality during sepsis.

BACKGROUND: Sepsis and subsequent multiorgan system failure is associated with high rates of mortality and morbidity. Thymic stromal lymphopoietin (TSLP) is a cytokine that can be produced by keratinocytes and epithelial cells. Primarily, TSLP has been shown to promote counter-inflammatory processes. However, its potential expression or role in the pathogenesis of sepsis is largely unexplored. We hypothesized that TSLP is expressed during sepsis and TSLP blockade would alter the immune response and mortality. MATERIALS AND METHODS: Mice underwent cecal ligation and puncture (CLP) to produce a physiologically relevant murine model for sepsis. Cohorts were either treated with neutralizing TSLP antibodies or isotype controls before the CLP to determine changes in survival, bacterial loads, cytokine levels, and neutrophil function. RESULTS: It was observed that TSLP levels peaked at 6 h and remained detectable up to 48 h after CLP. Mice pretreated with neutralizing TSLP showed decreased mortality and bacterial load after CLP. Additionally, we determined that septic mice pretreated with the anti-TSLP antibody had increased tumor necrosis factor alpha and oxidative burst as well as increased interleukin 17 and neutrophil numbers compared with mice pretreated with isotype controls. CONCLUSIONS: TSLP levels peak early but are sustained during the first 48 h of sepsis. We speculate that TSLP blunts the neutrophil response resulting in increased bacterial load and mortality.

Enantioselective Synthesis in Continuous Flow: Polymer-Supported Isothiourea-Catalyzed Enantioselective Michael Addition-Cyclization with α-Azol-2-ylacetophenones.

A packed reactor bed incorporating a polymer-supported isothiourea HyperBTM catalyst derivative has been used to promote the enantioselective synthesis of a range of heterocyclic products derived from α-azol-2-ylacetophenones and -acetamides combined with alkyl, aryl, and heterocyclic α,ß-unsaturated homoanhydrides in continuous flow via an α,ß-unsaturated acyl-ammonium intermediate. The products are generated in good to excellent yields and generally in excellent enantiopurity (up to 97:3 er). Scale-up is demonstrated on a 15 mmol scale, giving the heterocyclic product in 68% overall yield with 98:2 er after recrystallization.

De-epimerizing DyKAT of ß-lactones generated by isothiourea-catalysed enantioselective [2 + 2] cycloaddition.

An enantioselective isothiourea-catalysed [2 + 2] cycloaddition of C(1)-ammonium enolates with pyrazol-4,5-diones is used to construct spirocyclic ß-lactones in good yields, excellent enantioselectivity (99 : 1 er) but with modest diastereocontrol (typically 70 : 30 dr). Upon ring-opening with morpholine or alternative nucleophilic amines and alcohols ß-hydroxyamide and ß-hydroxyester products are generated with enhanced diastereocontrol (up to >95 : 5 dr). Control experiments show that stereoconvergence is observed in the ring-opening of diastereoisomeric ß-lactones, leading to a single product (>95 : 5 dr, >99 : 1 er). Mechanistic studies and DFT analysis indicate a substrate controlled Dynamic Kinetic Asymmetric Transformation (DyKAT) involving epimerisation at C(3) of the ß-lactone under the reaction conditions, coupled with a hydrogen bond-assisted nucleophilic addition to the Si-face of the ß-lactone and stereodetermining ring-opening. The scope and limitations of a one-pot protocol consisting of isothiourea-catalysed enantio-determining [2 + 2] cycloaddition followed by diastereo-determining ring-opening are subsequently developed. Variation within the anhydride ammonium enolate precursor, as well as N(1) and C(3) within the pyrazol-4,5-dione scaffold is demonstrated, giving a range of functionalised ß-hydroxyamides with high diastereo- and enantiocontrol (>20 examples, up to >95 : 5 dr and >99 : 1 er) via this DyKAT.