The gut microbiota plays crucial roles in the development and functions of the central nervous system (CNS) as well as in modulation of neurobehavior in heath and disease. The gut brush border enzyme intestinal alkaline phosphatase (IAP) is an important positive regulator of gut microbial homeostasis. In mice, IAP is encoded by Akp3 gene, which is specifically expressed in the duodenum of the small intestine. IAP deficiency alters gut bacterial composition and gut barrier function. Decreased IAP activity has been observed in aging, gut inflammatory diseases, and metabolic disorders. We hypothesized that this enzyme could also play an important role in modulating neurobehavior. We performed deep sequencing of gut bacterial 16S rRNA and found that IAP deficiency changed gut microbiota composition at various taxonomic levels. Using targeted metabolomic analysis, we also found that IAP deficiency resulted in changes of gut bacteria-derived metabolites in serum and brain metabolism. Neurobehavioral analyses revealed that Akp3-/- (IAP knockout) mice had decreased basal nociception thresholds, increased anxiety-like behavior, and reduced locomotor activity. Furthermore, Akp3-/- mice had more pronounced brain microglial phagocytic activity, together with an increase in the activated microglia population. Fecal microbiota transplantation from wildtype to Akp3-/- mice partially improved neurobehavior and reduced brain microglial phagocytic activity in Akp3-/- mice. This study demonstrates that deficiency of the endogenous gut-derived host factor IAP induces behavioral phenotype changes (nociception; motor activity, and anxiety) and affects brain microglia activity. Changes in the gut microbiota induced by knocking down Akp3 contribute to behavioral changes, which is probably mediated by microglia activity modulated by the gut bacteria-derived metabolites.

Surgeons have been under great pressure during the COVID pandemic. Their careers are filled with fast paced decisions, life and death situations, and long hours at work. The COVID pandemic created more tasks and even new responsibilities at times, but when the operating rooms were closed down, there was less work. The COVID experience invited the opportunity to rethink mentoring in the surgery department at the Massachusetts General Hospital. The leadership experimented with a new style of mentoring which involved a team approach. In addition, they tried something else that was new: adding a lifestyle medicine expert and wellness coach to the mentoring team. The program was tested on 13 early stage surgeons who found the experience to be beneficial, and they commented that they wished they had it even earlier in their careers. Including a non-surgeon who was a lifestyle medicine physician and wellness coach added an element of whole person health that was acceptable to the surgeons and even embraced as the majority of them elected to follow up with one on one coaching after the mentoring meeting. This team mentoring program with senior surgeons and a lifestyle medicine expert is one that can be explored by other departments and other hospitals given its success at the department of surgery at Massachusetts General Hospital.

Primary hyperaldosteronism refers to the autonomous secretion of the hormone aldosterone from the adrenal gland, resulting in low renin levels. This usually occurs in individuals between the ages of 30 to 50 years old. The majority of these cases are caused either by a solitary, functioning adrenal adenoma or aldosteronoma (70%) or by idiopathic bilateral hyperplasia (30%). Other uncommon causes include adrenal carcinoma and familial hyperaldosteronism. Patients typically present with hypokalemia and long-standing hypertension that is difficult to control despite multi-drug therapy; nevertheless, further tests are required for diagnosis. An elevated plasma aldosterone level with a suppressed plasma renin level is strongly suggestive of the diagnosis. Once confirmed, further evaluation should be directed toward determining if the cause is a unilateral aldosteronoma or bilateral adrenal hyperplasia. This is done through imaging studies and adrenal vein sampling. Unilateral aldosteronoma is best managed by adrenalectomy, with the laparoscopic approach being the preferred method. Bilateral adrenal hyperplasia is often best treated medically, because only 20%–30% benefit from surgery. Here, we present the case of a 48-year-old woman who had long-standing hypertension and hypokalemia and was found to have hyperaldosteronism and low renin levels. A CT scan showed a small mass in the left adrenal gland, and adrenal vein sampling showed higher levels of aldosterone on the left side than on the right, confirming a unilateral aldosteronoma. Laparoscopic access was gained, the adrenal gland was exposed, dissected by controlling the periadrenal tissues with the harmonic scalpel, the adrenal vein was then ligated, and the adrenal gland was removed.

BACKGROUND & AIMS: Fibrosis and tissue stiffening are hallmarks of inflammatory bowel disease (IBD). We have hy-pothesized that the increased stiffness directly contributes to the dysregulation of the epithelial cell homeostasis in IBD. Here, we aim to determine the impact of tissue stiffening on the fate and function of the intestinal stem cells (ISCs). METHODS: We developed a long-term culture system consisting of 2.5-dimensional intestinal organoids grown on a hydrogel matrix with tunable stiffness. Single-cell RNA sequencing provided stiffness-regulated transcriptional signatures of the ISCs and their differentiated progeny. YAP-knockout and YAP-overexpression mice were used to manipulate YAP expres-sion. In addition, we analyzed colon samples from murine Exception & Big items.xlsx models and patients with IBD demonstrated cellular and molec-ular remodeling reminiscent of those observed in vitro. CON-CLUSIONS: Collectively, our findings highlight that matrix stiffness potently regulates the stemness of ISCs and their differentiation trajectory, supporting the hypothesis that fibrosis-induced gut stiffening plays a direct role in epithelial remodeling in IBD.

BACKGROUND:Intestinal homeostasis is a crucial factor for complication-free short- and long-term postoperative recovery. The brush border enzyme intestinal alkaline phosphatase (IAP) is an important regulator of gut barrier function and intestinal homeostasis and prevents endotoxemia by detoxifying lipopolysaccharides (LPSs). As IAP is predominantly secreted by enterocytes in the duodenum, we hypothesized that pancreaticoduodenectomy (PD) leads to a significantly stronger decrease in IAP than other major abdominal surgery. STUDY DESIGN:Pre- and postoperative blood, stool, and intestinal samples were collected from patients undergoing PD, as well as other major surgical procedures without duodenectomy. The samples were analyzed using enzyme histochemistry, the para -nitrophenyl phosphate method for IAP, and the limulus amebocyte lysate assay for LPS. RESULTS:Overall, 88 patients were prospectively enrolled in the study. Fecal IAP activity negatively correlated with serum LPS (r = -0.3603, p = 0.0006). PD led to a significant decline in IAP compared to preoperative baseline levels (p < 0.0001). The decline in IAP correlated with the length of proximal small intestinal resection (r = 0.4271, p = 0.0034). Compared to controls, PD was associated with a much more pronounced reduction in IAP-also after adjusting for surgical trauma (operative time, blood loss; r = 0.4598, p = 0.0086). Simultaneously, PD triggered a clearly more prominent increase in serum LPS compared to controls (p = 0.0001). Increased postoperative LPS was associated with an elongated hospitalization (r = 0.7534, p = 0.0062) and more prominent in pancreatic cancer (p = 0.0009). CONCLUSIONS:Based upon the functional roles for IAP, supplementation with exogenous IAP might be a new treatment option to improve short- and long-term outcome after PD.

: While outpatient minimally invasive adrenalectomy (OMIA) has been shown to be feasible since the early 2000s, widespread adoption from surgeons, professional societies and insurers is lacking. Amidst a global pandemic, the feasibility of outpatient procedures, including adrenalectomy, are reappraised. We aimed to systematically evaluate the published literature on OMIA, focusing on its feasibility, safety, advantages, and limitations. In this systematic literature review we summarize studies describing characteristics and outcomes of laparoscopic transabdominal, posterior retroperitoneoscopic, and robotic adrenalectomies in which patients were discharged the same calendar day as surgery. Of the 13 mostly retrospective single-center studies included, outpatient adrenalectomy was reported to be feasible across a wide spectrum of patients including all ages >18 years old, obese patients, those with physical status American Society of Anesthesiologists (ASA) class III and above, as well as for a variety of surgical indications. Better pre-operative functional status, lower BMI, and primary aldosteronism as the surgical indication have been associated with same-day discharge. While comparison data with matched inpatient cases is sparse, available data suggests that outpatient adrenalectomy is associated with similar complication, readmission and mortality rates as inpatient adrenalectomy, while providing high satisfaction to patients and decreased hospitalization costs. While further larger studies are needed to investigate the feasibility and safety of outpatient adrenalectomy in more inclusive cohorts, recognition of minimally invasive adrenalectomy as a potential outpatient procedure by professional organizations and insurers is also needed for wider adoption.

Background. Adrenal metastasectomy is associated with increased survival in non-small cell lung cancer (NSCLC) with isolated adrenal metastases. Although clinical use of adrenal metastasectomy has expanded, indications remain poorly defined. The aim of this study was to evaluate the clinical benefit of adrenal metastasectomy for all lung cancer subtypes. Patients and Methods. We performed a retrospective cohort study of patients who underwent adrenal metastasectomy for metastatic lung cancer at six institutions between 2001 and 2015. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Cox proportional hazards regressions and Kaplan-Meier survival analysis were performed. Results. For 122 patients, the mean age was 60.5 years and 49.2% were female. Median time to detection of the metastasis was 11 months, and 41.8% were ipsilateral to the primary lung cancer. Median DFS was 40 months (1 year: 64.8%; 5 year: 42.9%). Factors associated with longer DFS included primary tumor resection [hazard ratio (HR): 0.001; p = 0.005], longer time to adrenal metastasis (HR: 0.94; p = 0.005), and ipsilateral metastases (HR: 0.13; p = 0.004). Shorter DFS corresponded with older age (HR: 1.11; p = 0.01), R1 resection (HR: 8.94; p = 0.01), adjuvant radiation (HR: 9.45; p = 0.02), and open adrenal metastasectomy (HR: 10.0; p = 0.03). Median OS was 47 months (1 year: 80.2%; 5 year: 35.2%). Longer OS was associated with ipsilateral metastasis (HR: 0.55; p = 0.02) and adjuvant chemotherapy (HR: 0.35; p = 0.02). Shorter OS was associated with extra-adrenal metastases at adrenalectomy (HR: 3.52; p = 0.007), small cell histology (HR: 15.0; p = 0.04), and lung radiation (HR: 3.37; p = 0.002). Discussion. Durable survival was observed in patients undergoing adrenal metastasectomy and should be considered for isolated adrenal metastases of NSCLC. Small cell histology and extra-adrenal metastases are relative contraindications to adrenal metastasectomy.

IMPORTANCE The COVID-19 pandemic is associated with decreased surgical procedure volumes, but existing studies have not investigated this association beyond the end of 2020, analyzed changes during the post-vaccine release period, or quantified these changes by patient acuity. OBJECTIVE To quantify changes in the volume of surgical procedures at a 1017-bed academic quaternary care center from January 6, 2019, to December 31, 2021. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, 129 596 surgical procedure volumes were retrospectively analyzed during 4 periods: pre-COVID-19 (January 6, 2019, to January 4, 2020), COVID-19 peak (March 15.2020, to May 2, 2020), post-COVID-19 peak (May 3, 2020, to January 2, 2021), and post-vaccine release (January 3, 2021, to December 31, 2021). Surgery volumes were analyzed by subspecialty and case class (elective, emergent, nonurgent, urgent). Statistical analysis was by autoregressive integrated moving average modeling. MAIN OUTCOMES AND MEASURES The primary outcome of this study was the change in weekly surgical procedure volume across the 4 COVID-19 periods. RESULTS A total of 129 596 records of surgical procedures were reviewed. During the COVID-19 peak, overall weekly surgical procedure volumes (mean [SD] procedures per week, 40 6.0 0 [171.45]; 95% CI, 234.56-577.46) declined 44.6% from pre-COVID-19 levels (mean [SD] procedures per week, 732.37 [12.70]; 95% CI, 719.67-745.08; P < .001). This weekly volume decrease occurred across all surgical subspecialties. During the post-COVID peak period, overall weekly surgical volumes (mean [SD] procedures per week, 624.31 [142.45]; 95% CI, 481.85-766.76) recovered to only 85.8% of pre-COVID peak volumes (P < .001). This insufficient recovery was inconsistent across subspecialties and case classes. During the post-vaccine release period, although some subspecialties experienced recovery to pre-COVID-19 volumes, others continued to experience declines. CONCLUSIONS AND RELEVANCE This quaternary care institution effectively responded to the pressures of the COVID-19 pandemic by substantially decreasing surgical procedure volumes during the peak of the pandemic. However, overall surgical procedure volumes did not fully recover to pre-COVID-19 levels well into 2021, with inconsistent recovery rates across subspecialties and case classes. These declines suggest that delays in surgical procedures may result in potentially higher morbidity rates in the future. The differential recovery rates across subspecialties may inform institutional focus for future operational recovery.

Fazendin, Jessica M. MD; Gartland, Rajshri M. MD, MPH; Stephen, Antonia MD; Porterfield, John R. Jr MD; Hodin, Richard MD; Lindeman, Brenessa MD, MEHP Author Information

Background: Almost half of practicing surgeons in the United States are currently older than 55, but guidelines on how to prepare for retirement are limited. We sought to identify possible facilitators for, and obstacles to, surgeons' preparations for retirement. Methods: A qualitative study was conducted using semi-structured interviews with clinically inactive academic surgeons. Emergent themes were identified via a grounded theory approach. Results: We interviewed 12 surgeons (83% male; median age 75 years). Major barriers to retirement from surgery included uncertainty about when to retire, limited identity outside of surgery, and perception of retirement as strictly individual/private. Facilitators of a successful retirement identified by the participants included early career financial planning, awareness of career trajectory, development of post-surgery goals, and utilization of collective knowledge. Conclusion: There are numerous barriers encountered by surgeons seeking to transition from clinical practice to retirement that could be overcome by dedicated departmental and institutional efforts.

Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses and bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn’s disease colon resection viromes provoked inflammation, which was successfully dampened by non-IBD viromes. The IBD colon tissue virome was perturbed, including an increase in the enterovirus B species of eukaryotic picornaviruses, not previously detected in fecal virome studies. Mice humanized with non-IBD colon tissue viromes were protected from intestinal inflammation, whereas IBD virome mice exhibited exacerbated inflammation in a nucleic acid sensing–dependent fashion. Furthermore, there were detrimental consequences for IBD patient–derived intestinal epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed to viromes. Our results demonstrate that innate recognition of IBD or non-IBD human viromes autonomously influences intestinal homeostasis and disease phenotypes. Thus, perturbations in the intestinal virome, or an altered ability to sense the virome due to genetic variation, contribute to the induction of IBD. Harnessing the virome may offer therapeutic and biomarker potential.

The clinical significance of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) RNA in stool remains uncertain. We found that extrapulmonary dissemination of infection to the gastrointestinal tract, assessed by the presence of SARS-CoV-2 RNA in stool, is associated with decreased coronavirus disease 2019 (COVID-19) survival. Measurement of SARS-CoV-2 RNA in stool may have utility for clinical risk assessment.

Summary Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found virus like particles (VLPs) enriched from normal human colon resections, containing eukaryotic viruses and bacteriophages (collectively, the virome), actively elicited atypical anti-inflammatory innate immune programs. Conversely, IBD patient VLPs provoked inflammation, which was successfully dampened by healthy VLPs. The IBD colon tissue virome was perturbed, including enriched Picornovirus Enterovirus B, not previously observed in fecal virome studies. Mice with humanized healthy colon tissue viromes had attenuated intestinal inflammation while those with IBD-derived viromes exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD-associated MDA5 loss-of-function on patient intestinal epithelial cells exposed to healthy or IBD viromes. Our results demonstrate that innate recognition of either healthy or IBD human viromes autonomously influences disease phenotypes in IBD. Harnessing the virome may offer therapeutic and biomarker potential. One Sentence Summary Human viromes divergently shape host immunity and disease

SummaryDoes fibrotic gut stiffening caused by inflammatory bowel diseases (IBD) direct the fate of intestinal stem cells (ISCs)? To address this question we first developed a novel long-term culture of quasi-3D gut organoids plated on hydrogel matrix of varying stiffness. Stiffening from 0.6kPa to 9.6kPa significantly reduces Lgr5highISCs and Ki67+progenitor cells while promoting their differentiation towards goblet cells. These stiffness-driven events are attributable to YAP nuclear translocation. Matrix stiffening also extends the expression of the stemness marker Olfactomedin 4 (Olfm4) into villus-like regions, mediated by cytoplasmic YAP. We next used single-cell RNA sequencing to generate for the first time the stiffness-regulated transcriptional signatures of ISCs and their differentiated counterparts. These signatures confirm the impact of stiffening on ISC fate and additionally suggest a stiffening-induced switch in metabolic phenotype, from oxidative phosphorylation to glycolysis. Finally, we used colon samples from IBD patients as well as chronic colitis murine models to confirm thein vivostiffening-induced epithelial deterioration similar to that observedin vitro. Together, these results demonstrate stiffness-dependent ISC reprograming wherein YAP nuclear translocation diminishes ISCs and Ki67+progenitors and drives their differentiation towards goblet cells, suggesting stiffening as potential target to mitigate gut epithelial deterioration during IBD.

Myocardial metastasis from a cutaneous squamous cell carcinoma (SCC) is rare. Herein we have presented a case of metastasis from cutaneous SCC to the myocardium in a renal transplant recipient, which was confirmed by a cardiac fine-needle biopsy. Postmortem examination revealed disseminated metastatic disease involving myocardium, lungs, thyroid, skin, and peritoneum secondary to cutaneous SCC likely related to immunosuppression. At 46 years of age, he received a renal transplant for chronic renal failure caused by chronic glomerulonephritis. He started to develop multiple nonmelanoma skin cancers 4 years later. At least 23 invasive SCCs and 14 basal cell carcinomas were excised. His immunosuppressive regimen consisted of cyclosporine (150 mg), azathioprine (75 mg), and prednisone (10 mg daily), which was not modified despite multiple nonmelanoma skin cancers. Our case report further illustrates the potentially aggressive and fatal nature of cutaneous SCCs that can develop in organ transplant recipients. It argues for modification of the immunosuppressive regimen in such patients. The management of renal transplant patients with nonmelanoma skin cancers remains difficult and complex.

Rationale: Liver fibrosis is frequently associated with gut barrier dysfunction, and the lipopolysaccharides (LPS) -TLR4 pathway is common to the development of both. Intestinal alkaline phosphatase (IAP) has the ability to detoxify LPS, as well as maintain intestinal tight junction proteins and gut barrier integrity. Therefore, we hypothesized that IAP may function as a novel therapy to prevent liver fibrosis. Methods: Stool IAP activity from cirrhotic patients were determined. Common bile duct ligation (CBDL) and Carbon Tetrachloride-4 (CCl4)-induced liver fibrosis models were used in WT, IAP knockout (KO), and TLR4 KO mice supplemented with or without exogenous IAP in their drinking water. The gut barrier function and liver fibrosis markers were tested. Results: Human stool IAP activity was decreased in the setting of liver cirrhosis. In mice, IAP activity and genes expression decreased after CBDL and CCl4 exposure. Intestinal tight junction related genes and gut barrier function were impaired in both models of liver fibrosis. Oral IAP supplementation attenuated the decrease in small intestine tight junction protein gene expression and gut barrier function. Liver fibrosis markers were significantly higher in IAP KO compared to WT mice in both models, while oral IAP rescued liver fibrosis in both WT and IAP KO mice. In contrast, IAP supplementation did not attenuate fibrosis in TLR4 KO mice in either model. Conclusions: Endogenous IAP is decreased during liver fibrosis, perhaps contributing to the gut barrier dysfunction and worsening fibrosis. Oral IAP protects the gut barrier and further prevents the development of liver fibrosis via a TLR4-mediated mechanism.

Patients with diverticular disease complicated by abscess and/or perforation represent the most severely afflicted with the highest mortality and poorest outcomes. This study investigated patient and operative factors associated with poor outcomes from diverticulitis complicated by abscess or perforation. We analyzed the National Inpatient Sample to identify inpatient discharges for colonic diverticulitis in the United States from 1/1988 to 9/2015. We identified patients with perforation and/or intestinal abscess based on ICD-9 codes. The primary outcome was inpatient mortality. During the study period, a total of 993,220 patients were discharged with diverticulitis from sampled U.S. hospitals. From this group, 10.7% had an abscess and 1.0% had a perforation associated with diverticular disease. Inpatient mortality of diverticulitis patients with a perforation was 5.4% compared to 1.5% in those without a perforation (p<0.001). Patients with a perforation who underwent surgery had an inpatient mortality of 6.3% vs. 3.0% mortality amongst patients with a perforation who did not undergo an operation (p<0.001). Patients with a perforation that underwent surgery had a 31% increased mortality risk for each day after admission that a procedure was delayed (OR 1.31, CI 1.05–1.78; p=0.03). Mortality risk was increased for patients with either abscess or perforation who underwent surgery if they were female, age ≥65, higher comorbidity, were admitted urgently, underwent peritoneal lavage, or had a post-procedural complication. Patients with perforated diverticular disease had substantial associated inpatient mortality compared to those with uncomplicated diverticulitis. This increased risk may be associated with performance of peritoneal lavage or because of a delay to procedural intervention.