REPAIRS Delphi: A UK and Ireland Consensus Statement on the Management of Infected Arterial Pseudoaneurysms Secondary to Groin Injecting Drug Use.

OBJECTIVE: Consensus guidelines on the optimal management of infected arterial pseudoaneurysms secondary to groin injecting drug use are lacking. This pathology is a problem in the UK and globally, and operative management options remain contentious. This study was designed to establish consensus to promote better management of these patients, drawing on the expert experience of those in a location with a high prevalence of illicit drug use. METHODS: A three round modified Delphi was undertaken, systematically surveying consultant vascular surgeons in the UK and Ireland using an online platform. Seventy five vascular surgery units were invited to participate, with one consultant providing the unit consensus practice. Round one responses were thematically analysed to generate statements for round two. These statements were evaluated by participants using a five point Likert scale. Consensus was achieved at a threshold of 70% or more agreement or disagreement. Those statements not reaching consensus were assessed and modified for round three. The results of the Delphi process constituted the consensus statement. RESULTS: Round one received 64 (86%) responses, round two 59 (79%) responses, and round three 62 (83%) responses; 73 out of 75 (97%) units contributed. Round two comprised 150 statements and round three 24 statements. Ninety one statements achieved consensus agreement and 15 consensus disagreement. The Delphi statements covered sequential management of these patients from diagnosis and imaging, antibiotics and microbiology, surgical approach, wound management, follow up, and additional considerations. Pre-operative imaging achieved consensus agreement (97%), with computerised tomography angiogram being the modality of choice (97%). Ligation and debridement without arterial reconstruction was the preferred approach at initial surgical intervention (89%). Multidisciplinary management, ensuring holistic care and access to substance use services, also gained consensus agreement. CONCLUSION: This comprehensive consensus statement provides a strong insight into the standard of care for these patients.

Evaluating temporal trends and the impact of surgical subspecialisation on patient outcomes following adhesional small bowel obstruction: a multicentre cohort study.

PURPOSE: Small bowel obstruction (SBO) is the most common indication for laparotomy in the UK. While general surgeons have become increasingly subspecialised in their elective practice, emergency admissions commonly remain undifferentiated. This study aimed to assess temporal trends in the management of adhesional SBO and explore the influence of subspecialisation on patient outcomes. METHODS: Data was collected for patients admitted acutely with adhesional SBO across acute NHS trusts in Northern England between 01/01/02 and 31/12/16, including demographics, co-morbidities and procedures performed. Patients were excluded if a potentially non-adhesional cause was identified and were grouped by the responsible consultant's subspecialty. The primary outcome of interest was 30-day inpatient mortality. RESULTS: Overall, 2818 patients were admitted with adhesional SBO during a 15-year period. There was a consistent female preponderance, but age and comorbidity increased significantly over time (both p < 0.001). In recent years, more patients were managed operatively with a trend away from delayed surgery also evident (2002-2006: 65.7% vs. 2012-2016: 42.7%, p < 0.001). Delayed surgery was associated with an increased mortality risk on multivariable regression analysis (OR: 2.46 (1.46-4.23, p = 0.001)). CT scanning was not associated with management strategy or timing of surgery (p = 0.369). There was an increased propensity for patients to be managed by gastrointestinal (colorectal and upper gastrointestinal) subspecialists over time. Length of stay (p < 0.001) and 30-day mortality (p < 0.001) both improved in recent years, with the best outcomes seen in colorectal (2.6%) and vascular subspecialists (2.4%). However, following adjustment for confounding variables, consultant subspecialty was not a predictor of mortality. CONCLUSION: Outcomes for patients presenting with adhesional SBO have improved despite the increasing burden of age and co-morbidity. While gastrointestinal subspecialists are increasingly responsible for their care, mortality is not influenced by consultant subspecialty.

The associations of psoas and masseter muscles with sarcopenia and related adverse outcomes in older trauma patients: a retrospective study.

BACKGROUND: There is an emerging role for radiological evaluation of psoas muscle as a marker of sarcopenia in trauma patients. Older trauma patients are more likely to undergo cranial than abdomino-pelvic imaging. Identifying sarcopenia using masseter cross-sectional area (M-CSA) has shown correlation with mortality. We sought to determine the correlation between psoas: lumbar vertebral index (PLVI) and the M-CSA, and their association with health outcomes. METHODS: Patients aged 65 or above, who presented as a trauma call over a 1-year period were included if they underwent cranial or abdominal CT imaging. Images were retrospectively analysed to obtain PLVI and mean M-CSA measurements. Electronic records were abstracted for outcomes. Logistic regression methods, log scale analyses, Cox regression model and Kaplan-Meier plots were used to determine association of sarcopenia with outcomes. RESULTS: There were 155 eligible patients in the M-CSA group and 204 patients in the PLVI group. Sarcopenia was defined as the lowest quartile in each group. Pearson's correlation indicated a weakly positive linear relationship (r = 0.35, p < 0.001) between these. There was no statistical association between M-CSA sarcopenia status and any measured outcomes. Those with PLVI sarcopenia were more likely to die in hospital (adjusted OR 3.38, 95% CI 1.47-9.73, p = 0.006) and at 2 years (adjusted HR 1.90, 95% CI 1.11-3.25, p = 0.02). Only 29% patients with PLVI sarcopenia were discharged home, compared with 58% without sarcopenia (p = 0.001). CONCLUSION: Sarcopenia, defined by PLVI, is predictive of increased in-patient and 2-year mortality. Our study did not support prognostic relevance of M-CSA.

Use of a modified Delphi process to develop research priorities in major trauma.

PURPOSE: The burden of major trauma within the UK is ever increasing. There is a need to establish research priorities within the field. Delphi methodology can be used to develop consensus opinion amongst a group of stakeholders. This can be used to prioritise clinically relevant, patient-centred research questions to guide future funding allocations. The aim of our study was to identify key future research priorities pertaining to the management of major trauma in the UK. METHODS: A three-phased modified Delphi process was undertaken. Phase 1 involved the submission of research questions by members of the trauma community using an online survey (Phase 1). Phases 2 and 3 involved two consecutive rounds of prioritisation after questions were subdivided into 6 subcategories: Brain Injury, Rehabilitation, Trauma in Older People, Pre-hospital, Interventional, and Miscellaneous (Phases 2 and 3). Cut-off points were agreed by consensus amongst the steering subcommittees. This established a final prioritised list of research questions. RESULTS: In phase 1, 201 questions were submitted by 65 stakeholders. After analysis and with consensus achieved, 186 questions were taken forward for prioritisation in phase 2 with 114 included in phase 3. 56 prioritised major trauma research questions across the 6 categories were identified with a clear focus on long-term patient outcomes. Research priorities across the patient pathway from roadside to rehabilitation were deemed of importance. CONCLUSIONS: Consensus within the major trauma community has identified 56 key research questions across 6 categories. Dissemination of these questions to funding bodies to allow for the development of high-quality research is now required. There is a clear indication for targeted multi-centre multi-disciplinary research in major trauma.

Laparoscopic subtotal cholecystectomy; change in practice over a 10-year period.

BACKGROUND: Laparoscopic subtotal cholecystectomy is a recognised safe, alternative strategy when a critical view of safety cannot be obtained. This study audits the change in practice at a District General Hospital following the adoption of subtotal cholecystectomy in 2013. METHODS: Retrospective case series included consecutive cholecystectomies over a ten-year period in a single institution. Cases were divided into subgroups based on operation date. Primary outcome was the proportion of patients undergoing laparoscopic total cholecystectomy, laparoscopic subtotal and laparoscopic converted to open cholecystectomy. Secondary outcomes included incidence of bile leak, complication rate, return to theatre, and length of stay. RESULTS: There were 4217 cases: 1381 in Group A (pre-adoption of subtotal cholecystectomy 2009-2012), and 2836 in Group B (post-adoption of subtotal cholecystectomy 2013-2019). The rate of laparoscopic total cholecystectomy was higher in Group A than Group B (95.4% vs. 92.8%, p < 0.001). In the subtotal group (n = 114, 14 (12.3%) patients had bile leak, 6 (5.3%) underwent re-laparoscopy, and median length of stay was 2 days. CONCLUSION: Laparoscopic subtotal cholecystectomy appears to be an acceptable alternative technique at this centre, reducing the rate of open conversion and length of stay, with a low reintervention rate for bile leak.

Discovery of Acyl-sulfonamide Nav1.7 Inhibitors GDC-0276 and GDC-0310.

Nav1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 (1) and GDC-0310 (2), selective Nav1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.

Psychometric properties of End-of-Life Caregiving Experience Appraisal Scale: Iranian critical care nurses.

BACKGROUND: Health care providers should be able to provide good quality end-of-life care. A tool to evaluate the positive and negative consequences of caring for dying patients is warranted. AIM: The aim of this study was to evaluate the psychometric properties of the Persian version of the End-of-Life Caregiving Experience Appraisal Scale (EOLCAS). METHODS: This research was conducted in two phases. Phase I: The World Health Organization Protocol of forward-backward translation and an expert panel in order to determine face and content validity. Phase II: Survey development with 310 nurses who worked in critical care units, construct validity (construct, convergent and divergent validity), internal consistency (average inter-item correlation, Cronbach's alpha and McDonald's omega) and construct reliability were evaluated. RESULTS: The exploratory factor analysis showed that the present scale (Persian version) has four factors: Negative physical-emotional and social consequences, transcendental communication, information deficits and future rumination, which explained 83.92% of the overall extracted variance. Convergent and divergent validity were confirmed for all factors. The internal consistency and construct reliability were acceptable. CONCLUSION: The scale has a multidimensional concept that is sufficiently reliable and the use of the scale would be helpful in measuring consequences of caring for dying patients. RELEVANCE TO CLINICAL PRACTICE: This scale makes a significant contribution in that it helps in the recognition of positive and negative consequences of critical care nurses' caring for dying patients.

A Modified AUGIS Delphi Process to Establish Future Research Priorities in Benign Upper Gastrointestinal Surgery.

BACKGROUND: The aim of our study was to use a modified Delphi process to determine the research priorities amongst benign upper gastrointestinal (UGI) surgeons in the United Kingdom. METHODS: Delphi methodology may be utilised to develop consensus opinion amongst a group of experts. Members of the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland were invited to submit individual research questions via an online survey (phase I). Two rounds of prioritisation by multidisciplinary expert healthcare professionals (phase II and III) were completed to determine a final list of high-priority research questions. RESULTS: Four hundred and twenty-seven questions were submitted in phase I, and 51 with a benign UGI focus were taken forward for prioritisation in phase II. Twenty-eight questions were ranked in phase III. A final list of 11 high-priority questions had an emphasis on acute pancreatitis, Barrett's oesophagus and benign biliary disease. CONCLUSION: A modified Delphi process has produced a list of 11 high-priority research questions in benign UGI surgery. Future studies and awards from funding bodies should reflect this consensus list of prioritised questions in the interest of improving patient care and encouraging collaborative research.

A modified AUGIS Delphi process to establish research priorities in bariatric and metabolic surgery.

Delphi methodology may be utilized to develop consensus opinion among a group of experts. The aim of our study was to use a modified Delphi process to determine the future research priorities among bariatric and metabolic healthcare professionals in the United Kingdom. Members of the Association of Upper Gastrointestinal Surgeons and the British Obesity and Metabolic Surgery Society were invited to submit individual research questions via an online survey (phase I). Two rounds of prioritization by multidisciplinary expert healthcare professionals (phase II and III) were completed to determine a final list of high-priority research questions. Fifty-one bariatric and metabolic surgery-focused questions were identified in phase I. Thirty-five questions were taken forward for prioritization in phase II. Eleven high-priority questions were identified in phase III. The final list of high-priority questions had an emphasis on the pathophysiology and long-term sequelae of bariatric and metabolic surgery. A modified Delphi process has produced a list of 11 high-priority research questions in bariatric and metabolic surgery. Future studies and awards from funding bodies should reflect this consensus list of prioritized questions in the interest of improving patient care and encouraging collaborative research across multiple centres.

Use of a modified Delphi approach to develop research priorities in HPB surgery across the United Kingdom.

BACKGROUND: Research prioritisation can help identify clinically relevant questions and encourage high-quality, patient-centred research. Delphi methodology aims to develop consensus opinion within a group of experts, with recent Delphi projects helping to define the research agenda and funding within several medical and surgical specialties. METHODS: All members of the Association of Upper Gastrointestinal Surgeons (AUGIS) were asked to submit clinical research questions using an online survey (Phase 1). Two consecutive rounds of Delphi prioritisation by multidisciplinary HPB healthcare professionals (Phase 2) were undertaken to establish a final list of the most highly prioritised research questions. A multidisciplinary steering committee analysed the results of each phase. RESULTS: Ninety-three HPB-focussed questions were identified in Phase 1, with thirty-seven questions of sufficient priority to enter a further prioritisation round. A final group of 11 questions considered highest priority were identified. The most highly ranked research questions related to treatment pathways, operative strategies and the impact of HPB procedures on quality of life, particularly for malignant disease. CONCLUSION: Expert consensus has identified research priorities within the UK HPB surgical community over the coming years. Funding applications, to establish well-designed, high quality collaborative research are now required to address these questions.

Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity.

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious NaV1.7 inhibitors reported to date.

Does time of surgery influence the rate of false-negative appendectomies? A retrospective observational study of 274 patients.

BACKGROUND: Multiple disciplines have described an "after-hours effect" relating to worsened mortality and morbidity outside regular working hours. This retrospective observational study aimed to evaluate whether diagnostic accuracy of a common surgical condition worsened after regular hours. METHODS: Electronic operative records for all non-infant patients (age > 4 years) operated on at a single centre for presumed acute appendicitis were retrospectively reviewed over a 56-month period (06/17/2012-02/01/2017). The primary outcome measure of unknown diagnosis was compared between those performed in regular hours (08:00-17:00) or off hours (17:01-07:59). Pre-clinical biochemistry and pre-morbid status were recorded to determine case heterogeneity between the two groups, along with secondary outcomes of length of stay and complication rate. RESULTS: Out of 289 procedures, 274 cases were deemed eligible for inclusion. Of the 133 performed in regular hours, 79% were appendicitis, compared to 74% of the 141 procedures performed off hours. The percentage of patients with an unknown diagnosis was 6% in regular hours compared to 15% off hours (RR 2.48; 95% CI 1.14-5.39). This was accompanied by increased numbers of registrars (residents in training) leading procedures off hours (37% compared to 24% in regular hours). Pre-morbid status, biochemistry, length of stay and post-operative complication rate showed no significant difference. CONCLUSIONS: This retrospective study suggests that the rate of unknown diagnoses for acute appendicitis increases overnight, potentially reflecting increased numbers of unnecessary procedures being performed off hours due to poorer diagnostic accuracy. Reduced levels of staffing, availability of diagnostic modalities and changes to workforce training may explain this, but further prospective work is required. Potential solutions may include protocolizing the management of common acute surgical conditions and making more use of non-resident on call senior colleagues.

Securing the Appendiceal Stump During Emergency Appendicectomy: Options and Influencing Factors in Current UK Surgical Practice.

INTRODUCTION: The aim of our study was to identify the most commonly employed methods and influencing factors for securing the appendiceal stump in current NHS practice. METHODS: An electronic survey of the Scottish Surgical Research Group network, invitation extended to the UK National Research Collaborative. RESULTS: A total of 111 responses were received from 32 surgical centers; 28 (25.2%) consultants, 66 (59.5%) specialty trainees and 12 (10.8%) core trainees. Endoscopic ligatures were the preferred method in 96 (86.5%) with no difference in those with the greatest operative experience (P=0.79), 12 (10.8%) preferred polymeric clips. Ease of application (70.3%) and severity of stump inflammation (65.8%) had the greatest influence on the method chosen. Cost was a factor in 36.0%. CONCLUSIONS: The preferred method for securing the appendiceal stump in UK practice is endoscopic ligatures regardless of operative experience. Factors with the greatest influence on the method employed include the ease of application and severity of stump inflammation. Our findings are likely to be representative of current NHS practice in Scotland.

A training tool to assess laparoscopic image navigation task performance in novice camera assistants.

BACKGROUND: A number of tools for assessing task performance of the laparoscopic camera assistant have been described, but few focus on the acquisition and assessment of the attainment of proficiency in novice laparoscopic camera assistants. Our aim was to develop a simulated objective assessment tool for a novice camera assistant. MATERIALS AND METHODS: A 10-cycle image navigation task tool was developed. This involved a series of 360° clockwise and anticlockwise rotation maneuvers of a 30° laparoscope along its shaft, focusing on a predefined geometric target on a 45° fixed slope in a laparoscopic box trainer. The tasks were to simultaneously maintain neutral horizon, optimum distance, and centering. Task accuracy and time to completion were assessed objectively at 3-s intervals on an unedited video recording. RESULTS: Twenty-nine novice medical students were assessed. Novices improved mean total error and task completion time (first versus fifth cycle, mean errors 15.4 versus 8.4, P = 0.048; mean task time 158.1 versus 92.9 s, P = 0.04). This improvement continued until the task cycle was completed (sixth versus 10th cycles, 7.9 versus 6.2, P = 0.01; 91.9 versus 76.6 s, P < 0.0001). There was a significant decrease in centering errors (5.2 versus 2.4, P = 0.001) and horizon (4.8 versus 2.3, P = 0.004), when comparing the first versus fifth task cycle. It took six cycles for optimum distance to achieve significance (5.4 versus 3.3, P = 0.023). CONCLUSIONS: Using our assessment tool, novices achieved an objective proficiency-gain curve for laparoscopic camera navigation tasks. There was improvement in errors related to maintaining horizon, optimum distance, and centering. Mean task completion time also decreased. This tool could be used as an additional mean of assessment and training in novice surgical trainees.

Results of a national multicenter audit assessment of gynecologic history in surgical patients.

OBJECTIVE: To determine the adequacy of assessing gynecologic history for females of reproductive age (FRA) admitted to a general surgery department. METHODS: The present prospective multicenter audit included FRA who were admitted for elective or emergency procedures to general surgery departments in Scotland between May 11 and May 25, 2015. Data were compared between patients who were admitted for elective and emergency treatment. RESULTS: There were 530 FRA included from 18 centers, including 169 (31.9%) and 361 (68.1%) elective and emergency admissions, respectively. The date of last menstrual period was document for 203 (38.3%) patients, use of contraception for 149 (28.1%), sexual activity for 83 (15.7%), pregnancy status for 274 (51.7%), and the possibility of pregnancy for 237 (44.7%). A higher incidence of documented date of last menstrual period (P=0.002) and pregnancy status (P<0.001) were identified among emergency admissions, and the possibility of pregnancy was documented more commonly among elective admissions (P<0.001). CONCLUSIONS: Key factors required for gynecologic assessment were often not documented for FRA admitted to general surgery both as elective and emergency admissions. Surgical teams and medical undergraduates require educating regarding the importance of obtaining gynecologic history for all FRA.

National multicentre audit of pregnancy status in general surgery admissions in Scotland.

BACKGROUND: Documentation of pregnancy status (PS) is an integral component of the assessment of women of reproductive age when admitted to hospital. Our aim was to determine how accurately PS was documented in a multicentre audit of female admissions to general surgery. METHODS: A prospective multicentre audit of elective and emergency admissions was performed in 18 Scottish centres between 08:00 on 11 May 2015 and 07:59 on 25 May 2015. The lower age limit was the minimum age for admission to the adult surgical ward and the upper age limit was 55 years. RESULTS: There were 2743 admissions, with 612 (22.3%) women of reproductive age. After 82 exclusions, the final total was 530: 169 (31.9%) elective and 361 (68.1%) emergency. Documentation of PS was achieved in 274 (51.7%) cases: 52 (30.8%) elective and 222 (61.5%) emergency. In 318 (88.1%) of the emergency admissions, the patient had abdominal pain. Of these, 211 (65.1%) had a documented PS. The possibility of pregnancy was established in 237 (44.7%) cases. DISCUSSION: Establishing the possibility of pregnancy before surgery is poor, particularly in the elective setting. Objective documentation of PS in the emergency setting in those with abdominal pain is also poor. Our study highlights an important safety issue in the management of female patients. We advocate electronic storage of pregnancy test results and new guidelines to cover both elective and emergency surgery. PS should form part of the pre-theatre safety brief and checklist.

How shall we manage the incidentally found thyroid nodule?

Thyroid incidentalomas are commonly found on cross-sectional imaging of the neck and they are equally likely to be malignant as palpable thyroid nodules. Guidelines on their management are conflicting. Ultrasonography cannot accurately differentiate benign from malignant thyroid nodules and fine needle aspiration biopsy should be used selectively to avoid over-diagnosis and over-treatment. If the clinician follows current guidelines for the investigation of thyroid incidentalomas a proportion of malignant incidentalomas will inevitably be missed. Whether this is clinically important is controversial as it is generally agreed that the natural history of small incidental thyroid cancers is indolent. However a subset may have a more aggressive behaviour and it is not currently possible to predict whether a malignant incidentaloma will progress to clinical disease or remain latent. In this article we review the evidence-base around the current guidelines for investigating thyroid incidentalomas and suggest a practical approach to their management.

A multivalent approach towards linked dual-pharmacology prostaglandin F receptor agonist/carbonic anhydrase-II inhibitors for the treatment of glaucoma.

Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated. Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain. Application of Theravance's multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described. Compound 29 exhibits weak potency (pEC(50)=5.7, IA>1.0) as an FP agonist with high binding affinity (pK(i)=8.1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide.

Neurons in the human hippocampus and amygdala respond to both low- and high-level image properties.

A large number of studies have demonstrated that structures within the medial temporal lobe, such as the hippocampus, are intimately involved in declarative memory for objects and people. Although these items are abstractions of the visual scene, specific visual details can change the speed and accuracy of their recall. By recording from 415 neurons in the hippocampus and amygdala of human epilepsy patients as they viewed images drawn from 10 image categories, we showed that the firing rates of 8% of these neurons encode image illuminance and contrast, low-level properties not directly pertinent to task performance, whereas in 7% of the neurons, firing rates encode the category of the item depicted in the image, a high-level property pertinent to the task. This simultaneous representation of high- and low-level image properties within the same brain areas may serve to bind separate aspects of visual objects into a coherent percept and allow episodic details of objects to influence mnemonic performance.

A stereoselective approach to the azaspiro[5.5]undecane ring system using a conjugate addition/dipolar cycloaddition cascade: application to the total synthesis of (+/-)-2,7,8-epi-perhydrohistrionicotoxin.

An efficient stereocontrolled route to the spirocyclic perhydrohistrionicotoxin derivative (+/-)-2,7,8-epi-PHTx (4) is described. The reaction of 2-butyl-3-(methoxymethoxy)cyclohexanone oxime with 2,3-bis(phenylsulfonyl)-1,3-butadiene gives rise to a 7-oxa-1-azanorbornane cycloadduct in high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to give a transient nitrone which then undergoes an intramolecular dipolar cycloaddition. Treatment of the cycloadduct with 5% Na/Hg results in reductive nitrogen-oxygen bond cleavage to furnish an azaspiro[5.5]undecane. Elaboration to the dihydropyridin-4(1H)-one 24 was followed by stereoselective conjugate addition using n-pentyl cuprate to give azaspirocycle 25. The stereochemistry of the product was deduced from an X-ray crystal structure of the corresponding N-tosylhydrazone derivative. The dominant factor controlling the stereochemistry of the conjugate addition is the A(1,3)-strain present in the planar vinylogous amide. A stereoelectronically preferred axial attack by the organocuprate at the beta-position leads to the observed diastereoselectivity. Azaspirocycle 25 was transformed into 2,7,8-epi-PHTx (4) in five additional steps. Utilizing this tandem conjugate addition/dipolar cycloaddition cascade, we have also successfully synthesized azaspiro[5.5]undecane 36, which had previously been converted into (+/-)-perhydrohistrionicotoxin (2), thereby completing a formal total synthesis of this alkaloid.