Survival and cancer recurrence after short-course perioperative probiotics in a randomized trial.

BACKGROUND & AIMS: The long-term impact of perioperative probiotics remains understudied while mounting evidence links microbiome and oncogenesis. Therefore, we analyzed overall survival and cancer recurrence among patients enrolled in a randomized trial of perioperative probiotics. METHODS: 6-year follow-up of surgical patients participating in a randomized trial evaluating short-course perioperative oral probiotic VSL#3 (n = 57) or placebo (n = 63). RESULTS: Study groups did not differ in age, preoperative hemoglobin, ASA status, and Charlson comorbidity index. There was a significant difference in preoperative serum albumin (placebo group 4.0 ± 0.1 vs. 3.7 ± 0.1 g/dL in the probiotic group, p = 0.030). Thirty-seven deaths (30.8 %) have occurred during a median follow-up of 6.2 years. Overall survival stratified on preoperative serum albumin and surgical specialty was similar between groups (p = 0.691). Age (aHR = 1.081, p = 0.001), serum albumin (aHR = 0.162, p = 0.001), and surgical specialty (aHR = 0.304, p < 0.001) were the only predictors of overall survival in the multivariate model, while the placebo/probiotic group (aHR = 0.808, p = 0.726) was not predictive. The progression rate among cancer patients was similar in the probiotic group (30.3 %, 10/33) compared to the placebo group (21.2 %, 7/33; p = 0.398). The progression-free survival was not significantly different (unstratified p = 0.270, stratified p = 0.317). CONCLUSIONS: Perioperative short-course use of VSL#3 probiotics does not influence overall or progression-free survival after complex surgery for visceral malignancy.

Differences in Resident Self-Evaluation and Clinical Competency Committee Evaluation Using ACGME Milestone Versions 1.0 and 2.0.

OBJECTIVE: Intentionally self-driven professional development of surgical resident physicians is a hallmark of surgical training and is expected to gain further traction as Entrustable Professional Activities (EPAs) become the new paradigm for surgical education. We aimed to analyze how surgical residents rate themselves as compared to the evaluation of the Clinical Competency Committee using ACGME Milestones Version 1 (M1.0) and Version 2 (M2.0). DESIGN: We asked 22 general surgical trainees for self-evaluation of Milestones (both M1.0 and M2.0) from 2017 semiannually to 2022. ACGME-required Milestone evaluations by the Clinical Competency Committee (CCC) were independently performed after the time window for resident self-evaluation. Neither trainees nor CCC were aware of the other party's evaluations. There were 1552 paired data available for evaluating individual competencies by both trainees and CCC. Paired Wilcoxon signed-rank tests were then performed among the corresponding pairs. SETTING: MercyOne Des Moines Medical Center, Des Moines, IA; Teaching tertiary referral center. PARTICIPANTS: Twenty-two general surgical trainees at this hospital and 28 faculty surgeons participated in this study. RESULTS: The average self-evaluation of surgical residents was lower in the M1.0 cohort compared to the corresponding CCC evaluation (1.96 ± 0.72 vs. 2.11 ± 0.67; p < 0.001). M1.0 self-assessments and CCC-assessments were statistically similar for ICS (p = 0.548) and PROF (p = 0.554) competencies and differed for MK (p < 0.001), PBLI (p < 0.001), PC (p < 0.001), SBP (p = 0.008). On the contrary, the M2.0 cohort demonstrated higher average self-evaluation of surgical residents compared to the corresponding CCC evaluation (2.75 ± 0.87 vs. 2.12 ± 0.97; p < 0.001). Significant differences were observed for all 6 ACGME competencies using M2.0 self-assessments and CCC-assessments (all p < 0.001). Multivariate regression modeling (p < 0.001, R2 = 0.255) predicted the degree of discordance between self-assessment and CCC-assessed achievement of competencies with a significant effect of gender (baseline male: coef = -0.232, p < 0.001), PGY level (-0.083 per year, p < 0.001) and Milestone version (0.831, p < 0.001). A significant interaction exists for all gender/Milestone combinations except for the female trainees with M1.0. CONCLUSIONS: The difference between self-evaluated Milestone achievement and faculty-driven CCC evaluation of surgical resident physician performance is more evident in Milestones 2.0 than in Milestones 1.0. Residents self-evaluate higher compared to faculty using Milestones 2.0. This discrepancy is seen among both genders and is more pronounced among male residents overestimating core competencies with M2.0 self-evaluation than formal CCC assessment.

Rising Incidence of Peri-Operative Bactibilia among Patients Undergoing Complex Biliopancreatic Surgery.

Background: Biliary instrumentation is associated with bactibilia and post-operative infection. Bactibilia incidence over time remains unknown. Patients and Methods: Consecutive patients with bilioenteric anastomosis surgery and available surveillance intra-operative bile duct cultures were evaluated for post-operative infection. The study period (2008-2019) was divided into quartiles to examine time-based trends. Results: Among 101 cases, 60 intra-operative bile duct cultures had no growth and 41 patients had documented at least one culture-positive isolate in their bile. Frequency of patients with culture-positive intra-operative bile increased over the study period (period 1, 1/28, 3.6% vs. period 2, 7/21, 33.3% vs. period 3, 15/26, 57.7% vs. period 4, 18/26, 69.2%; p < 0.001). Culture-positive post-operative infection (17/101; 16.8%) was not associated with intra-operative bile duct culture (p = 0.552), however, the same micro-organism isolate was identified on post-operative infection and intra-operative culture of bile duct bile among six of 17 patients (35.3%). Conclusions: We found an increasing incidence of bactibilia and post-operative culture-positive infections over the last decade. One-third of patients with a positive intra-operative bile duct culture experienced post-operative infection with the same organism, yet a clear link between bile colonization and post-operative infection was not established.

Signet ring cell carcinoma of the gastrointestinal tract: National trends on treatment effects and prognostic outcomes.

BACKGROUND: Signet ring cell carcinoma (SRCC) is a distinct malignancy occurring across the tubular gastrointestinal tract (tGIT). We comprehensively examined the outcomes of patients diagnosed with SRCC across tGIT. METHODS: SRCC and not-otherwise-specified adenocarcinoma (NOS) patients reported to the National Cancer Database from 2004 to 2015 were included. Baseline characteristics, outcomes and site-specific adjusted hazard ratios (aHR) derived from Cox models of SRCC patients were compared to those of NOS patients. Overall survival (OS) was primary endpoint. RESULTS: A total of 41,686 SRCC (4.6%) and 871,373 NOS patients (95.4%) were included. SRCC patients were younger (63.1 ± 14.7 vs. 67.0 ± 13.4 y, p < 0.001) and more likely to present with Stage IV disease than NOS patients (42.5% vs. 24.5%, p < 0.001). Stomach (n = 24,433) and colon (n = 9,914) contributed highest frequency of SRCC. SRCC histology was associated with shorter OS (aHR = 1.377, p < 0.001) in multivariate model. There was an interaction between SRCC and chemotherapy effects on risk of death (interaction aHR = 1.072, pinteraction< 0.001) and between SRCC histology and disease site, suggesting that the effect of SRCC on OS is site-dependent, with a higher increased risk of death in patients with rectal SRCC (aHR = 2.378, pinteraction< 0.001). CONCLUSION: Significant negative prognostic effect associated with SRCC is site-dependent across the GIT. Surgical and or systemic therapy was associated with improved OS among SRCC patients, but remained lower than NOS patients. Further understanding of gastrointestinal SRCC molecular profile is needed to better inform future treatment strategies.

The Use of Rivaroxaban for Unprovoked Pulmonary Embolism in the Setting of Antithrombin Deficiency.

A 24-year-old woman with antithrombin (AT) deficiency presented with right-sided pleuritic chest pain of five days duration with diagnosis of pulmonary embolism (PE) made at an outside hospital. After discussion of treatment options with the patient, her treatment was changed to rivaroxaban protocol. The case illustrates an appropriate treatment plan for patients with AT deficiency presenting with unprovoked PE, especially when prioritizing ease of use.

Effect of Surgical Oncologist Turnover on Hospital Volume and Treatment Outcomes Among Patients With Upper GI Malignancies.

PURPOSE: Lack of surgical expertise may affect cancer care delivery. Here, we examined the impact of surgical oncologist vacancy and turnover in a community cancer center serving a mixed urban and rural population. METHODS: Survival outcomes of patients with potentially resectable esophageal, gastric, and pancreatic carcinomas treated in the index hospital (n = 519) were compared with those of a then-contemporary control group derived from the state-specific SEER registry (n = 3,340). The onboarding period (ie, the period without a surgical oncologist) and early and late periods with a surgical oncologist were defined. RESULTS: At the state level, there was a steady trend of patients who were annually referred (290.4 ± 34.3 patients per year; P < .001) and underwent operation (158.7 ± 18.7 patients per year; P < .001). We observed the absence of an analogous trend in the index hospital (P = .141). The index hospital diagnosed 12.2% of state cancers of interest during the years with surgical oncologists but only 6.7% of cancers when surgical oncologists were absent (P = .031). The survival model adjusted for age, stage, and primary disease site comparing the early and late periods demonstrated that being treated in the index hospital did not result in inferior survival (hazard ratio, 1.067; P = .265). CONCLUSION: Loss of surgical oncologists was associated with referral decline and likely out-migration of patients, whereas prompt restoration of surgical oncology services reinstated volumes and preserved survival outcomes.

Influence of prior appendectomy and cholecystectomy on Clostridioides difficile infection recurrence and mortality.

BACKGROUND: Remote appendectomy was linked to increased incidence of Clostridioides difficile infection (CDI). We evaluated the effect of absence of vermiform appendix and/or gallbladder on recurrence rate and severity of CDI. METHODS: We assessed a systemwide patient cohort diagnosed with initial CDI in 2014 (n = 250). The primary outcome was recurrence. RESULTS: Appendix and gallbladder were absent among 47 and 64 patients, respectively. CDI recurrence rate was similar among patients without and with appendix (24/47, 51.1% versus 90/203 patients, 44.3%; p = 0.404) and similar among patients without and with gallbladder (29/64 patients, 45.3% versus 85/186 patients, 45.7%; p = 0.957). Mortality was similar between appendectomy versus appendix in situ patients (3/47, 6.4% versus 9/203, 4.4%; p = 0.573), but higher mortality rate was seen among those without gallbladder (7/64 patients with prior cholecystectomy, 10.9% versus 5/186 patients with intact gallbladder, 2.7%; p = 0.008). CONCLUSION: Clostridioides difficile recurrence rate is not affected by remote appendectomy or cholecystectomy. Patients with prior cholecystectomy experience higher mortality rates associated with their CDI.

Randomized Trial of Perioperative Probiotics Among Patients Undergoing Major Abdominal Operation.

BACKGROUND: We investigated the utility and safety of short-course oral probiotics among patients undergoing major abdominal operations. Perioperative probiotics can decrease length of stay and lower rates of infectious complications. We assessed whether perioperative probiotics decrease major complications among patients undergoing high-risk gastrointestinal operations in a pragmatic randomized trial. STUDY DESIGN: This double-blind trial randomized 135 patients undergoing elective major gastrointestinal operations to perioperative oral probiotic VSL#3 taken just before operation and twice daily up to 15 total doses (n = 67) or placebo (n = 68). The primary outcomes measure was 30-day composite end point of death, unplanned readmission, or any infection. RESULTS: Primary end point occurred among 17 patients in the placebo group (25.0%) vs 22 patients in the probiotic group (32.8%; p = 0.315). Thirty-day mortality was 2 (2.9%) in the placebo group compared with 1 (1.5%) in the probiotic group (p = 1.000). The placebo group patients experienced lower 30-day readmission rate (3 of 68 [4.4%]) compared with the probiotic group (11 of 67 [16.4%]; p = 0.022). None of the placebo patients were readmitted for dehydration, but 5 of 11 probiotic group patients (45%; p = 0.049) were readmitted for dehydration as a consequence of diet intolerance and/or diarrhea. There was no difference in 30-day infection rate between the groups (15 or 68 [22%] in the placebo group vs 15 of 67 [22.4%] in the probiotic group; p = 0.963). CONCLUSIONS: Perioperative use of VSL#3 probiotic did not affect 30-day composite end point of mortality, readmission, and infection rate. A significantly higher readmission rate was observed among those exposed to probiotics. Additional studies remain warranted.

The effect of intravenous insulin, apheresis and oral lipid-lowering agents on non-fasting hypertriglyceridemia and associated pancreatitis.

OBJECTIVES: There is evidence that increasing severity of hypertriglyceridemia increases the risk of acute pancreatitis. There is a debate about superiority of treatment methods and previous works have specifically called for direct comparison between IV insulin and apheresis techniques. Identify patient characteristics predictive of lipid-lowering therapy selection in a large community hospital for treatment of hypertriglyceridemia; evaluate for a concentration-dependent relationship between hypertriglyceridemia severity and risk of acute pancreatitis; assess for differences in clinical outcomes between patients treated with IV insulin versus apheresis. METHODS: Single center, retrospective cohort study including patients with hypertriglyceridemia between January 2007 and December 2016. Main measures included frequency of pancreatitis, choice of lipid-lowering therapy, and clinical comparisons of diet, oral lipid-lowering agents, IV insulin, and apheresis. RESULTS: Initial serum triglyceride level and disease acuity was higher among patients in insulin and apheresis groups. Neither triglyceride level, Charlson comorbidity index, age, BISAP score, nor initial CRP predicted use of IV insulin versus apheresis. Prevalence of pancreatitis increased with higher triglyceride level, reaching 48% with triglycerides >2000 md/dL (p < 0.001). There was a significant decrease in serum triglycerides at each time interval (p < 0.05) in patients treated with IV insulin and apheresis, but no difference in clearance rate between the two. Length of stay did not differ between IV insulin and apheresis. CONCLUSION: The presence of pancreatitis, hyperglycemia, and hypertriglyceridemia severity influenced selection of therapies like IV insulin and apheresis. We found no superiority of either IV insulin or apheresis in the treatment of severe hypertriglyceridemia among patients hospitalized for pancreatitis.

Metabotropic glutamate receptor 1 splice variants mGluR1a and mGluR1b combine in mGluR1a/b dimers in vivo.

The assembly of two covalently linked monomers into dimeric complexes is a prerequisite for metabotropic glutamate receptor 1 (mGluR1) function. The former concept of a strictly homodimeric subunit contribution in metabotropic glutamate receptor complexes has recently been brought into question. Alternative splicing of the GRM1 gene results in expression of variants that vary within their intracellular C-termini. Here we bring evidence that the short mGluR1b variant is found preferentially in a complex with the long mGluR1a variant in the rodent brain. The mGluR1a and mGluR1b variants distribution overlaps in Purkinje cells and the two variants colocalize in their spines. However mGluR1a and mGluR1b show distinct sub-cellular localization when expressed alone in neurons. We discovered that trafficking of mGluR1b to distal dendrites is reliant on its association with mGluR1a and that the long C-terminus of mGluR1a within the mGluR1a/b dimer is necessary for trafficking of the complex.

Sequential inter- and intrasubunit rearrangements during activation of dimeric metabotropic glutamate receptor 1.

The metabotropic glutamate receptor 1 (mGluR1), a class C member of the heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor family, is a constitutive dimer that regulates excitatory neurotransmission. We investigated the role of homodimer formation in mGluR1 activation by examining activation-dependent inter- and intrasubunit conformational changes by fluorescence resonance energy transfer (FRET). We inserted yellow and cyan fluorescent proteins in the second intracellular loop and at the carboxyl terminus of mGluR1 to act as FRET sensors and expressed these proteins in human embryonic kidney 293 cells. Agonist-dependent activation of these mGluR1 chimeras rapidly increased the intersubunit FRET, suggesting rapid movement of the subunits relative to each other. After intersubunit movement, the intrasubunit FRET decreased, reflecting conformational changes within a subunit. Cotransfection of chimeric receptor subunits that were capable or incapable of G protein coupling revealed that only a single subunit assumes an active state in an mGluR1 receptor dimer.

Surface expression of metabotropic glutamate receptor variants mGluR1a and mGluR1b in transfected HEK293 cells.

Class C G-protein coupled receptors form obligatory dimers. Metabotropic glutamate receptors (mGluRs) are found commonly as homodimers. Alternative splicing of mGluR1 gene results in vivo in the expression of a long variant mGluR1a and at least two short variants mGluR1b and d. The amino acid sequences diverge within their carboxyl-termini six amino acid residues following RRKK motif. This four basic residue sequence was shown to have pronounced impact on function and trafficking of the short variants, while for mGluR1a the long C-terminus reduces the effects caused by presence of the RRKK motif. Here we investigated consequences of interactions between long mGluR1a and short mGluR1b variants. Our results show that mGluR1a interferes with mGluR1b trafficking to the cell surface in HEK293 transfected cells. Expression of a mGlu1a mutant incapable of activating G-proteins with mGluR1b mutated in the glutamate binding site led to the formation of a functional heterodimer. Moreover, we show that swapping long mGluR1a and/or short mGluR1b C-termini with corresponding regions in chimerical GB1 and GB2 gamma-amino butyric acid b (GABAb) receptor subunits do not exclude heterodimerization. These data reveal that the C-terminal ends of mGluR1 do not control subunit association, such that mGluR1 dimers with two distinct C-termini can form and function properly.

Reelin, very-low-density lipoprotein receptor, and apolipoprotein E receptor 2 control somatic NMDA receptor composition during hippocampal maturation in vitro.

Reelin is a secreted protein that regulates brain layer formation during embryonic development. Reelin binds several receptors, including two members of the low-density lipoprotein (LDL) receptor family, the apolipoprotein E receptor 2 (ApoER2) and the very-low-density lipoprotein receptor (VLDLR). Despite the high level of expression of Reelin and ApoER2 in the postnatal brain, their functions in the adult CNS remain elusive. Here, using electrophysiological, immunocytochemical, and biochemical approaches in cultured postnatal hippocampal neurons, we show that Reelin controls the change in subunit composition of somatic NMDA glutamate receptors (NMDARs) during maturation. We found that maturation is characterized by the gradual decrease of the participation of NR1/2B receptors to whole-cell NMDAR-mediated currents. This maturational change was mirrored by a timely correlated increase of both Reelin immunoreactivity in neuronal somata and the amount of secreted Reelin. Chronic blockade of the function of Reelin with antisense oligonucleotides or the function-blocking antibody CR-50 prevented the decrease of NR1/2B-mediated whole-cell currents. Conversely, exogenously added recombinant Reelin accelerated the maturational changes in NMDA-evoked currents. The maturation-induced change in NMDAR subunits also was blocked by chronic treatment with an inhibitor of the Src kinase signaling pathway or an antagonist of the LDL receptors, but not by inhibitors of another class of Reelin receptor belonging to the integrin family. Consistent with these results, immunocytochemistry revealed that NR1-expressing neurons also expressed ApoER2 and VLDLR. These data reveal a new role for Reelin and LDL receptors and reinforce the idea of a prominent role of extracellular matrix proteins in postnatal maturation.