Residents' Perspectives of Pregnancy and Growing a Family During Surgical Training: A Review of the Literature.

As more female surgical residents choose to start families during training, concerns regarding program support and peer perceptions emerge. Delayed parenthood, stress, and even attrition can result from inadequate support systems. Database search (MEDLINE, PubMed, EMBASE) in June 2022 identified 17 relevant studies published between 2012-2022, including systematic reviews and qualitative surveys, focused on surgical residents/fellows and program directors. The thematic analysis explored themes related to supporting residents navigating parenthood. Thematic analysis of 17 studies (systematic reviews and qualitative surveys with residents/fellows and program directors) identified key recurring themes related to challenges experienced by surgical residents navigating parenthood. The themes included modified work schedules, mentorship programs, cross-coverage plans, lactation support, childcare options, and clear leave policies. By understanding these challenges and implementing tailored support strategies, surgical residency programs can foster a more inclusive and supportive environment for residents starting families. This can improve resident well-being, reduce attrition, and create a significantly more enjoyable training experience for all involved. This review aims to provide insight into residents' difficulties while pregnant or considering pregnancy and identify changes programs could implement to promote a more supportive culture for pregnant residents.

Predictors of Progression of Appendiceal Mucinous Neoplasm to Pseudomyxoma Peritonei.

Appendiceal mucinous neoplasm (AMN) can present with a spectrum of disease. Predicting factors in development of pseudomyxoma peritonei (PMP) from AMN could aid in management and treatment. The aim of this study was to determine factors predictive of PMP from AMN. This was a retrospective multicenter study of all patients diagnosed with AMN from 2006-2017. Diagnosis of PMP was compared by (1) patient demographics, (2) tumor characteristics, and (3) surgery. Secondary end points were disease-specific survival (DSS) and overall survival (OS).One-hundred thirty-eight patients with AMN were identified. Thirty-six patients (26.1%) had a ruptured appendix at presentation, and 12 patients (8.7%) were diagnosed with PMP during the study period. Eight patients presented with PMP at the time of surgery. No demographic factors were predictive of PMP. Operative approach and extent of initial resection did not correlate with PMP. Tumor rupture at presentation was the only factor associated with PMP, though only 14% of patients who presented with simple rupture eventually progressed to PMP.OS was not different between those who were diagnosed with PMP and those who were not. DSS was significantly lower for the group diagnosed with PMP (P = .007). Tumor rupture at presentation did not influence OS or DSS. The only factor found to be significantly associated with PMP was tumor rupture at presentation. Diagnosis of PMP did not affect OS but did lead to decreased DSS.In conclusion, though a majority of patients who presented with rupture did not go on to develop PMP, tumor rupture at presentation was the only factor significantly associated with PMP. Diagnosis of PMP did not affect OS at 5 years. In patients with AMN who present with a ruptured appendix on final pathology, we recommended continued surveillance, though overall risk of PMP is relatively low.

Surgical management of appendiceal mucinous neoplasm: Is appendectomy sufficient?

BACKGROUND AND OBJECTIVES: Due to the rarity of appendiceal mucinous neoplasms (AMNs), there are few established treatment guidelines. The clinical course varies from incidental detection to progressive spread with pseudomyxoma peritonei (PMP). This study investigated the extent of resection on the prognosis and outcomes of AMNs. METHODS: This multicenter retrospective study evaluated patients with AMN who underwent surgery between 4/2006 to 9/2017. Primary endpoints included overall survival (OS) and disease-specific survival (DSS). Secondary endpoints included PMP incidence and treatment with cytoreductive surgery (CRS). RESULTS: Of the 138 patients with AMN, 70 patients (54%) underwent appendectomy, 26 (19%) cecectomy, and 37 (27%) right hemicolectomy. The median age was 59.7 years and 57 patients (41%) were male. Males were less likely to undergo cecectomy (P = .03). Rupture rates, tumor characteristics, and incidence of PMP were similar across surgery groups. Median follow-up was 61.3 months. Five-year OS and DSS for the total cohort were 94.9% and 98.6%, respectively, and remained similar across all surgery groups. CRS patients were more likely to undergo right hemicolectomy with no difference in survival by surgery type (P = .03). CONCLUSIONS: Patients with AMN have a good overall prognosis and there may be minimal benefit to performing extended surgical resection in these patients.

Complicated gallstone disease: diagnosis and management of Mirizzi syndrome.

BACKGROUND: Mirizzi syndrome (MS) is characterized by an obstruction of the proximal bile duct due to extrinsic compression by either an impacted stone in the gallbladder neck or local inflammatory changes. Although this is a rare syndrome in developed countries (0.7-1.4 %), preoperative diagnosis and careful surgical management are essential to avoid bilio-vascular injuries and misdiagnosed malignancy. METHODS: The purpose of this study was to review our experience in the diagnosis and management of MS, assess the role of laparoscopy and the risk of concomitant gallbladder carcinoma. This study took place in a large county hospital which serves indigent and undocumented immigrants without easy access to healthcare. Data were collected through a retrospective chart review of 4939 patients that underwent cholecystectomy over 6 years. Patient demographics, preoperative, intraoperative, postoperative data and outcomes were analyzed. RESULTS: MS was identified in 60 of 4939 patients (1.21 %) who underwent cholecystectomy. The mean age at presentation was 47 years, and 35 patients were females. The most common symptom at presentation was abdominal pain (100 %) followed by nausea/vomiting (87 %) and jaundice (43 %). Type I MS was diagnosed in 16 patients and 44 had type II MS. Preoperative diagnosis was achieved in 43 patients (71 %). Magnetic resonance cholangiopancreatography was the best diagnostic modality. Laparoscopic cholecystectomy was successful in 4 out of 16 patients with type I MS. Three patients (5.26 %) had simultaneous gallbladder cancer. Overall morbidity was 27 % and mortality was 0. Clavien grade ≥3 complications were seen in six patients (10 %). The mean length of follow-up was 2.3 months (range 0-5) for type I MS patients and 5.4 months (range 0-46) for type II patients. CONCLUSIONS: MS is rare, but preoperative diagnosis or intraoperative suspicion is important. Laparoscopic cholecystectomy may be possible in selected type I cases. Open cholecystectomy is the standard of care for type II MS.

Tryptophan and Cysteine Mutations in M1 Helices of α1ß3γ2L γ-Aminobutyric Acid Type A Receptors Indicate Distinct Intersubunit Sites for Four Intravenous Anesthetics and One Orphan Site.

BACKGROUND: γ-Aminobutyric acid type A (GABAA) receptors mediate important effects of intravenous general anesthetics. Photolabel derivatives of etomidate, propofol, barbiturates, and a neurosteroid get incorporated in GABAA receptor transmembrane helices M1 and M3 adjacent to intersubunit pockets. However, photolabels have not been consistently targeted at heteromeric αßγ receptors and do not form adducts with all contact residues. Complementary approaches may further define anesthetic sites in typical GABAA receptors. METHODS: Two mutation-based strategies, substituted tryptophan sensitivity and substituted cysteine modification-protection, combined with voltage-clamp electrophysiology in Xenopus oocytes, were used to evaluate interactions between four intravenous anesthetics and six amino acids in M1 helices of α1, ß3, and γ2L GABAA receptor subunits: two photolabeled residues, α1M236 and ß3M227, and their homologs. RESULTS: Tryptophan substitutions at α1M236 and positional homologs ß3L231 and γ2L246 all caused spontaneous channel gating and reduced γ-aminobutyric acid EC50. Substituted cysteine modification experiments indicated etomidate protection at α1L232C and α1M236C, R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirinylphenyl) barbituric acid protection at ß3M227C and ß3L231C, and propofol protection at α1M236C and ß3M227C. No alphaxalone protection was evident at the residues the authors explored, and none of the tested anesthetics protected γ2I242C or γ2L246C. CONCLUSIONS: All five intersubunit transmembrane pockets of GABAA receptors display similar allosteric linkage to ion channel gating. Substituted cysteine modification and protection results were fully concordant with anesthetic photolabeling at α1M236 and ß3M227 and revealed overlapping noncongruent sites for etomidate and propofol in ß-α interfaces and R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirinylphenyl) barbituric acid and propofol in α-ß and γ-ß interfaces. The authors' results identify the α-γ transmembrane interface as a potentially unique orphan modulator site.

Mutations at beta N265 in γ-aminobutyric acid type A receptors alter both binding affinity and efficacy of potent anesthetics.

Etomidate and propofol are potent general anesthetics that act via GABAA receptor allosteric co-agonist sites located at transmembrane ß+/α- inter-subunit interfaces. Early experiments in heteromeric receptors identified ßN265 (M2-15') on ß2 and ß3 subunits as an important determinant of sensitivity to these drugs. Mechanistic analyses suggest that substitution with serine, the ß1 residue at this position, primarily reduces etomidate efficacy, while mutation to methionine eliminates etomidate sensitivity and might prevent drug binding. However, the ßN265 residue has not been photolabeled with analogs of either etomidate or propofol. Furthermore, substituted cysteine modification studies find no propofol protection at this locus, while etomidate protection has not been tested. Thus, evidence of contact between ßN265 and potent anesthetics is lacking and it remains uncertain how mutations alter drug sensitivity. In the current study, we first applied heterologous α1ß2N265Cγ2L receptor expression in Xenopus oocytes, thiol-specific aqueous probe modification, and voltage-clamp electrophysiology to test whether etomidate inhibits probe reactions at the ß-265 sidechain. Using up to 300 µM etomidate, we found both an absence of etomidate effects on α1ß2N265Cγ2L receptor activity and no inhibition of thiol modification. To gain further insight into anesthetic insensitive ßN265M mutants, we applied indirect structure-function strategies, exploiting second mutations in α1ß2/3γ2L GABAA receptors. Using α1M236C as a modifiable and anesthetic-protectable site occupancy reporter in ß+/α- interfaces, we found that ßN265M reduced apparent anesthetic affinity for receptors in both resting and GABA-activated states. ßN265M also impaired the transduction of gating effects associated with α1M236W, a mutation that mimics ß+/α- anesthetic site occupancy. Our results show that ßN265M mutations dramatically reduce the efficacy/transduction of anesthetics bound in ß+/α- sites, and also significantly reduce anesthetic affinity for resting state receptors. These findings are consistent with a role for ßN265 in anesthetic binding within the ß+/α- transmembrane sites.

Cysteine substitutions define etomidate binding and gating linkages in the α-M1 domain of γ-aminobutyric acid type A (GABAA) receptors.

Etomidate is a potent general anesthetic that acts as an allosteric co-agonist at GABAA receptors. Photoreactive etomidate derivatives labeled αMet-236 in transmembrane domain M1, which structural models locate in the ß+/α- subunit interface. Other nearby residues may also contribute to etomidate binding and/or transduction through rearrangement of the site. In human α1ß2γ2L GABAA receptors, we applied the substituted cysteine accessibility method to α1-M1 domain residues extending from α1Gln-229 to α1Gln-242. We used electrophysiology to characterize each mutant's sensitivity to GABA and etomidate. We also measured rates of sulfhydryl modification by p-chloromercuribenzenesulfonate (pCMBS) with and without GABA and tested if etomidate blocks modification of pCMBS-accessible cysteines. Cys substitutions in the outer α1-M1 domain impaired GABA activation and variably affected etomidate sensitivity. In seven of eight residues where pCMBS modification was evident, rates of modification were accelerated by GABA co-application, indicating that channel activation increases water and/or pCMBS access. Etomidate reduced the rate of modification for cysteine substitutions at α1Met-236, α1Leu-232 and α1Thr-237. We infer that these residues, predicted to face ß2-M3 or M2 domains, contribute to etomidate binding. Thus, etomidate interacts with a short segment of the outer α1-M1 helix within a subdomain that undergoes significant structural rearrangement during channel gating. Our results are consistent with in silico docking calculations in a homology model that orient the long axis of etomidate approximately orthogonal to the transmembrane axis.

State-dependent etomidate occupancy of its allosteric agonist sites measured in a cysteine-substituted GABAA receptor.

A central axiom of ligand-receptor theory is that agonists bind more tightly to active than to inactive receptors. However, measuring agonist affinity in inactive receptors is confounded by concomitant activation. We identified a cysteine substituted mutant γ-aminobutyric acid type A (GABAA) receptor with unique characteristics allowing the determination of allosteric agonist site occupancy in both inactive and active receptors. Etomidate, the allosteric agonist, is an anesthetic that activates or modulates α1ß2γ2L GABAA receptors via transmembrane sites near ß2M286 residues in M3 domains. Voltage-clamp electrophysiology studies of α1ß2M286Cγ2L receptors show that GABA is an efficacious agonist and that etomidate modulates GABA-activated activity, but direct etomidate agonism is absent. Quantitative analysis of mutant activity using an established Monod-Wyman-Changeux (MWC) allosteric model indicates that the intrinsic efficacy of etomidate, defined as its relative affinity for active versus inactive receptors, is lower than in wild-type receptors. Para-chloromercuribenzene sulfonate covalently modifies ß2M286C side-chain sulfhydryls, irreversibly altering GABA-induced currents. Etomidate concentration dependently reduces the apparent rate of ß2M286C-pCMBS bond formation, tracked electrophysiologically. High etomidate concentrations completely protect the ß2M286C suflhydryl from covalent modification, suggesting close steric interactions. The 50% protective etomidate concentration (PC50) is 14 µM in inactive receptors and 1.1 to 2.2 µM during GABA-activation, experimentally demonstrating that activated receptors bind etomidate more avidly than do inactive receptors. The experimental PC50 values are remarkably close to, and therefore validate, MWC model predictions for etomidate dissociation constants in both inactive and active receptors. Our results support MWC models as valid frameworks for understanding the agonism, coagonism, and modulation of ligand-gated ion channels.