Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance.

Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear. Here, we show that Lgr5+ intestinal stem cell (ISC)-specific inducible Cbl-knockout (KO) on a Cblb null mouse background (iDKO) induced rapid loss of the Lgr5 Hi ISCs with transient expansion of the Lgr5 Lo transit-amplifying population. LacZ-based lineage tracing revealed increased ISC commitment toward enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro, Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single-cell RNA sequencing in organoids identified Akt-mTOR (mammalian target of rapamycin) pathway hyperactivation upon iDKO, and pharmacological Akt-mTOR axis inhibition rescued the iDKO defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine-tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.

Exploring the impact of pediatric short bowel syndrome on parent well-being using a disease-specific pilot survey.

BACKGROUND: Children with short bowel syndrome (SBS) have complex care needs, most of which are met in the home by family caregivers who may experience a range of stressors unique to this experience. Prior research suggests that parents of children with SBS have poorer health-related quality of life than peers parenting children without health needs, but the mechanisms shaping parent outcomes are understudied. METHODS: A pilot survey was developed using a community-driven research design to measure the impact of disease-specific items on parent-perceived well-being. The cross-sectional survey, which included both closed-ended and open-ended items, was distributed to a convenience sample of parents of children with SBS. Quantitative and qualitative data were integrated for a mixed-methods analysis of how individual items impacted parent well-being. RESULTS: Twenty parents completed the survey. Sleep interruptions, lack of support and resources, and psychological stressors and their mental health implications were more frequently reported as stressors than logistics related to caregiving (e.g., managing therapies and preparing specialized meals). CONCLUSION: The impact of a child's SBS on parent well-being may stem mainly from three interconnected domains: poor sleep and its consequences, lack of access to support and resources, and a range of psychological stressors that affect parent mental health. Understanding the mechanisms through which SBS shapes parent well-being is a necessary first step for developing targeted interventions to support parents and provide family-centered care.

Small and large bowel anatomy is associated with enteral autonomy in infants with short bowel syndrome: A retrospective cohort study.

BACKGROUND: Achievement of enteral autonomy (EA) is the ultimate treatment goal in pediatric intestinal failure (IF). We aimed to assess predictors of EA in pediatric short bowel syndrome (SBS) and explore the impact of residual small bowel (SB) and large bowel (LB) length on EA. METHODS: A retrospective cohort study was performed on infants aged <12 months (n = 367, six centers) with SBS referred between 2010 and 2015. The cohort was stratified based on the achievement of EA. Statistical testing was completed using t-test, chi-square, Cox proportional hazards regression model, and Kaplan-Meier analysis. RESULTS: EA was achieved in 229 patients. In the multivariable analysis, the percentage of residual LB (hazard ratio [HR] = 1.02; 95% CI = 1.01-1.02) and SB (HR = 1.01; 95% CI = 1.01-1.02) length, presence of the ileocecal valve (HR = 2.02; 95% CI=1.41-2.88), and not coming from a high-volume transplantation center (HR = 2.42; 95% CI = 1.68-3.49) were positively associated with EA, whereas a negative association was seen with the presence of stoma at the time when shortest remnant was documented (HR = 0.72; 95% CI = 0.52-1.00). EA achievement was significantly different between the anatomical subgroups (log-rank test P < 0.001) with an EA rate of 80.4% in infants with ≥50% SB and LB (median time 209 days); 62.5% with ≥50% SB and <50% LB (397 days); 58.3% with <50% SB and ≥50% LB (1192 days), and 25.9% with <50% SB and LB. Necrotizing enterocolitis (NEC) was not associated with a better achievement of EA (NEC vs other etiologies: log-rank test P = 0.33). CONCLUSIONS: Overall, 62% of infants with IF secondary to SBS achieved EA over a mean time of follow-up of 2.3 years. A colon length of >50% can compensate for the loss of small bowel (<50%) and account for similar EA rates as those in children with residual SB > 50%.

Sustained elimination of parenteral support in adult patients with under 60 cm of small intestine: A case series.

Patients with short bowel syndrome (SBS) are often managed by expert multidisciplinary teams. One of the main goals in the management of SBS is the weaning of parenteral support (PS). Weaning of PS removes the risks associated with long-term central line placement and eliminates the need for intestinal transplant. Whereas several papers detail the ongoing care and management of patients with SBS who are dependent on PS, there are few reports discussing the successful weaning of PS in this patient population. We present five case studies examining weaning of PS in adult patients with <60-cm small bowel and partial or full colon who were enrolled in a multidisciplinary adult intestinal rehabilitation program. The case studies demonstrate weaning can occur >2 years after initial assessment and enrollment in an expert program. The ability of the program to focus on individualized care and frequent patient communication is key to PS weaning in patients with SBS.

Open Payments Data Analysis of General and Fellowship-trained Surgeons Receiving Industry General Payments From 2016 to 2020: Payment Disparities and COVID-19 Pandemic Impact.

OBJECTIVE: To characterize industry nonresearch payments made to general and fellowship-trained surgeons between 2016 and 2020. BACKGROUND: The Centers for Medicare & Medicaid Services Open Payments Data (OPD) reports industry payments made to physicians related to drugs and medical devices. General payments are those not associated with research. METHODS: OPD data were queried for general and fellowship-trained surgeons who received general payments from 2016 to 2020. Payments' nature, amount, company, covered product, and location were collected. Surgeons' demographics, subspecialty, and leadership roles in hospitals, societies, and editorial boards were evaluated. RESULTS: From 2016 to 2020, 44,700 general and fellowship-trained surgeons were paid $535,425,543 in 1,440,850 general payments. The median payment was $29.18. The most frequent payments were for food and beverage (76.6%) and travel and lodging (15.6%); however, the highest dollar payments were for consulting fees ($93,128,401; 17.4%), education ($88,404,531; 16.5%), royalty or license ($87,471,238; 16.3%), and travel and lodging ($66,333,149; 12.4%). Five companies made half of all payments ($265,654,522; 49.6%): Intuitive Surgical ($128,517,411; 24%), Boston Scientific ($48,094,570; 9%), Edwards Lifesciences ($41,835,544, 7.8%), Medtronic Vascular ($33,607,136; 6.3%), and W. L. Gore & Associates ($16,626,371; 3.1%). Medical devices comprised 74.7% of payments ($399,897,217), followed by drugs and biologicals ($33,945,300; 6.3%). Texas, California, Florida, New York, and Pennsylvania received the most payments; however, the top dollar payments were in California ($65,702,579; 12.3%), Michigan ($52,990,904, 9.9%), Texas ($39,362,131; 7.4%), Maryland ($37,611,959; 7%), and Florida ($33,417,093, 6.2%). General surgery received the highest total payments ($245,031,174; 45.8%), followed by thoracic surgery ($167,806,514; 31.3%) and vascular surgery ($60,781,266; 11.4%). A total of 10,361 surgeons were paid >$5000, of which 1614 were women (15.6%); in this group, men received higher payments than women (means, $53,446 vs $22,571; P <0.001) and thoracic surgeons received highest payments (mean, $76,381; NS, P =0.14). A total of 120 surgeons were paid >$500,000 ($203,011,672; 38%)-5 non-Hispanic White (NHW) women (4.2%) and 82 NHW (68.3%), 24 Asian (20%), 7 Hispanic (5.8%), and 2 Black (1.7%) men; in this group, men received higher payments than women (means, $1,735,570 vs $684,224), and NHW men received payments double those of other men (means, $2,049,554 vs $955,368; NS, P =0.087). Among these 120 highly paid surgeons (>$500,000), 55 held hospital and departmental leadership roles, 30 were leaders in surgical societies, 27 authored clinical guidelines, and 16 served on journal editorial boards. During COVID-19, 2020 experienced half the number of payments than the preceding 3 years. CONCLUSIONS: General and fellowship-trained surgeons received substantial industry nonresearch payments. The highest-paid recipients were men. Further work is warranted in assessing how race, gender, and leadership roles influence the nature of industry payments and surgical practice. A significant decline in payments was observed early during the COVID-19 pandemic.

Real-World Management of High Stool Output in Patients with Short Bowel Syndrome: An International Multicenter Survey.

BACKGROUND: International practice guidelines for high-stool-output (HSO) management in short bowel syndrome (SBS) are available, but data on implementation are lacking. This study describes the approach used to manage HSO in SBS patients across different global regions. METHODS: This is an international multicenter study evaluating medical management of HSO in SBS patients using a questionnaire survey. Thirty-three intestinal-failure centers were invited to complete the survey as one multidisciplinary team. RESULTS: Survey response rate was 91%. Dietary recommendations varied based on anatomy and geographic region. For patients without colon-in-continuity (CiC), clinical practices were generally consistent with ESPEN guidelines, including separation of fluid from solid food (90%), a high-sodium diet (90%), and a low-simple-sugar diet (75%). For CiC patients, practices less closely followed guidelines, such as a low-fat diet (35%) or a high-sodium diet (50%). First-line antimotility and antisecretory medications were loperamide and proton-pump inhibitors. Other therapeutic agents (e.g., pancreatic enzymes and bile acid binders) were utilized in real-world practices, and usage varied based on intestinal anatomy. CONCLUSION: Expert centers largely followed published HSO-management guidelines for SBS patients without CiC, but clinical practices deviated substantially for CiC patients. Determining the reasons for this discrepancy might inform future development of practice guidelines.

Cbl and Cbl-b Ubiquitin Ligases are Essential for Intestinal Epithelial Stem Cell Maintenance.

Among the signaling pathways that control the stem cell self-renewal and maintenance vs. acquisition of differentiated cell fates, those mediated by receptor tyrosine kinase (RTK) activation are well established as key players. CBL family ubiquitin ligases are negative regulators of RTKs but their physiological roles in regulating stem cell behaviors are unclear. While hematopoietic Cbl/Cblb knockout (KO) leads to a myeloproliferative disease due to expansion and reduced quiescence of hematopoietic stem cells, mammary epithelial KO led to stunted mammary gland development due to mammary stem cell depletion. Here, we examined the impact of inducible Cbl/Cblb double-KO (iDKO) selectively in the Lgr5-defined intestinal stem cell (ISC) compartment. Cbl/Cblb iDKO led to rapid loss of the Lgr5 Hi ISC pool with a concomitant transient expansion of the Lgr5 Lo transit amplifying population. LacZ reporter-based lineage tracing showed increased ISC commitment to differentiation, with propensity towards enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro , Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single cell RNAseq analysis of organoids revealed Akt-mTOR pathway hyperactivation in iDKO ISCs and progeny cells, and pharmacological inhibition of the Akt-mTOR axis rescued the organoid maintenance and propagation defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.

Surgical considerations in the management of short bowel syndrome.

Patients with short bowel syndrome (SBS) are optimally managed in centers of expertise with dedicated multidisciplinary intestinal failure (IF) teams. Over the life of a patient with SBS, many different surgical concerns may arise requiring intervention. These can range from reasonably simple procedures, such as the creation or maintenance of gastrostomy tube and enterostomies, to complex reconstructions of multiple enterocutaneous fistulas or the performance of intestine-containing transplants. This review will cover the development of a surgeon's role on the IF team; common surgical issues arising in patients with SBS, with a focus on decision-making rather than technique; and, finally, a brief overview of transplantation and some related decision-making issues.

Optimizing transition from pediatric to adult care in short bowel syndrome and intestinal failure.

As the majority of children with short bowel syndrome (SBS) and intestinal failure (IF) are now surviving into adulthood, there is a paradigm shift from short-term management to long-term outcomes and a growing need to focus on healthcare transition (HCT). It is imperative that adolescents and young adults with SBS and IF receive disease education, empowerment, and support as they navigate the transition from pediatric to adult care. Furthermore, both pediatric and adult healthcare providers who manage these patients should be aware of the challenges faced by this population, barriers to their HCT, and strategies to overcome them. This article reviews the literature on HCT in children with chronic illnesses, discusses barriers to HCT in SBS/IF, identifies the important constituents of the transition process in SBS/IF, and provides recommendations for the successful and smooth transition of the pediatric patient to the adult healthcare environment. Structured and multicomponent HCT programs should become the standard of care to ensure uninterrupted high-quality care across the life span for patients with SBS/IF.

A multidisciplinary team evaluation of management guidelines for adult short bowel syndrome.

BACKGROUND & AIMS: An international, multidisciplinary management working group (MWG) convened to review clinically useful short bowel syndrome (SBS) literature and identify gaps and inconsistencies in the management of adults with SBS. METHODS: Using nominal group technique for literature review, key publications were identified, discussed, and ranked by importance related to management of SBS. Gaps in management recommendations for SBS were identified upon critical review of the selected publications. RESULTS: Five guidelines, seven review articles, one series of six articles, and one single center series were selected and prioritized for their importance to SBS management. Evaluation of the articles by the MWG identified ten gaps and opportunities to standardize and improve SBS management. CONCLUSION: The main practice areas in need of more definitive guidelines are the management of high stool output and strategies to improve absorption of medications, nutrients, and fluids. An understanding of current real-world clinical practices related to these gaps could allow for development of best practice standards and improve patient-focused care.

Case presentation and panel discussion: Transitions in care.

There is evidence that significant quality problems arise as patients transitions in care from one setting to another. Attention to nutrition during transitions of care is important to avoid complication. During the American Society for Parenteral and Enteral Nutrition 2022 preconference course, nutrition during transition of care from pediatric to adult care, from the intensive care unit to the hospital floors and from the hospital to home was addressed.

Characteristics of adult intestinal failure centers: An international multicenter survey.

BACKGROUND: Current guidelines recommend that patients with chronic intestinal failure (CIF) should be managed by a multidisciplinary team (MDT). However, the characteristics of real-world IF centers and the patients they care for are lacking. The study aims to describe IF center characteristics as well as characteristics of patients with CIF across different global regions. METHODS: This is an international multicenter study of adult IF centers using a survey. The questionnaire survey included questions regarding program and patient characteristics. Thirty-three investigational centers were invited to participate. Each center was asked to answer the survey questions as one MDT. RESULTS: The survey center response rate was 91%. The median number of patients with CIF per center was 128 (range, 30-380). The most common disciplines reported were gastroenterologist (93%), dietitian (90%), nurse (83%), and advanced practitioner (nurse practitioner and physician assistant, 77%). There were centers that did not have a pharmacist, surgeon, psychologist, and social worker (30%, 37%, 60%, and 70%, respectively). The median full-time equivalents (FTEs) per 100 patients were 1.1 for nurses, 1 for dietitians, 1 for advanced practitioners, and 0.9 for gastroenterologists. Short bowel syndrome was the most common cause of CIF (50%) followed by intestinal dysmotility (20%). CONCLUSION: The majority of centers were managing around 100 patients with CIF. Despite the widespread use of the MDT, there are some variances in team characteristics. Gastroenterologists were the most common physicians supporting MDTs. In IF centers, one FTE of each core discipline was supported to manage 100 patients with CIF.

Cholecystectomy prior to short bowel syndrome does not alter nutritional prognosis.

BACKGROUND: Previous cholecystectomy is common in patients with short bowel syndrome (SBS). An intact gallbladder is beneficial in preventing cirrhosis in SBS patients, but the nutritional consequences of cholecystectomy are largely unknown. Our aim was to evaluate the effect of pre-SBS cholecystectomy on need for chronic parenteral nutrition (PN). METHODS: We reviewed 485 adults with SBS: 267 underwent cholecystectomy prior to SBS and 218 patients had an intact gallbladder. Demographic data, intestinal anatomy, and nutritional outcome were compared. RESULTS: Pre-SBS cholecystectomy patients were more likely to have had postoperative SBS and BMI >35. Intestinal remnant length and anatomy type and performance of surgical rehabilitation procedures within the first year were similar. Overall, there was no significant difference in the need for PN > 1year between the two groups. There was also no significant difference in the need for PN > 1year in any specific subgroup of intestinal remnant length or intestinal anatomy. CONCLUSIONS: Cholecystectomy performed prior to the development of SBS does not influence the nutritional prognosis of SBS, regardless of the intestinal remnant length and anatomy type.

An international multicenter validation study of the Toronto listing criteria for pediatric intestinal transplantation.

Deciding which patients would benefit from intestinal transplantation (IT) remains an ethical/clinical dilemma. New criteria* were proposed in 2015: ≥2 intensive care unit (ICU) admissions, loss of ≥3 central venous catheter (CVC) sites, and persistently elevated conjugated bilirubin (CB ≥ 75 µmol/L) despite 6 weeks of lipid modification strategies. We performed a retrospective, international, multicenter validation study of 443 children (61% male, median gestational age 34 weeks [IQR 29-37]), diagnosed with IF between 2010 and 2015. Primary outcome measure was death or IT. Sensitivity, specificity, NPV, PPV, and probability of death/transplant (OR, 95% confidence intervals) were calculated for each criterion. Median age at IF diagnosis was 0.1 years (IQR 0.03-0.14) with median follow-up of 3.8 years (IQR 2.3-5.3). Forty of 443 (9%) patients died, 53 of 443 (12%) were transplanted; 11 died posttransplant. The validated criteria had a high predictive value of death/IT; ≥2 ICU admissions (p < .0001, OR 10.2, 95% CI 4.0-25.6), persistent CB ≥ 75 µmol/L (p < .0001, OR 8.2, 95% CI 4.8-13.9). and loss of ≥3 CVC sites (p = .0003, OR 5.7, 95% CI 2.2-14.7). This large, multicenter, international study in a contemporary cohort confirms the validity of the Toronto criteria. These validated criteria should guide listing decisions in pediatric IT.

Characteristics of chronic intestinal failure in the USA based on analysis of claims data.

BACKGROUND: This study investigated the prevalence, characteristics, and management of patients with chronic intestinal failure (CIF) in the United States in 2012-2020, based on parenteral support (PS) prescription claims and healthcare utilization. METHODS: Patients with CIF were identified from the Integrated DataVerse® claims database if they had at least two PS prescriptions within 6 months and a relevant diagnosis. Analysis included prevalence and characteristics of patients with CIF, their travel distance to receive PS prescriptions, and the distribution of PS providers and their prescribing history. RESULTS: Up to 24,048 patients with CIF were identified, equivalent to 75 patients per million. CIF affected people of all ages, being more prevalent in women than in men. Many providers signed PS orders for small patient groups over short time periods, whereas few providers signed PS orders for large patient groups long term, indicating a lack of centralization. The distribution of PS providers suggested a disparity in healthcare coverage in rural vs urban areas, leading to patients traveling considerable distances to receive PS prescriptions. This may be exacerbated by a decline of providers with expertise in CIF and nutrition. CONCLUSIONS: Healthcare disparities for patients with CIF have likely been obscured by the lack of CIF-specific diagnostic and procedure codes, obliging providers to code for their patients under other codes. Effective policy changes, including centralized care, revision of reimbursement models, and expansion of nutrition-focused education in addition to the newly introduced International Classification of Diseases codes, are needed to provide the best care for patients.

Management of short-bowel syndrome: A survey of unmet educational needs among healthcare providers.

BACKGROUND: Management of short-bowel syndrome with intestinal failure (SBS-IF) is complex and requires a multidisciplinary approach. Because of the rarity of SBS-IF, healthcare professionals (HCPs) often lack clinical experience with the disease and may benefit from education regarding SBS-IF and its management. This study identified unmet educational needs related to the management of patients with SBS-IF. METHODS: This was a prospective, web-based survey (December 2019-January 2020) in which a series of clinical questions were posed to US HCPs after presenting three standardized SBS-IF cases to assess current practice patterns. HCPs were then asked a series of questions to identify potential knowledge gaps and unmet educational needs relating to SBS-IF management. RESULTS: Overall, 558 HCPs completed the survey, with 12%-38% having a formal SBS-IF multidisciplinary team currently available to make treatment decisions within their institution. Clinicians involved in care included gastroenterologists (93%), registered dietitians (79%), gastroenterology nurse practitioners and physician assistants (37%), registered nurses (43%), social workers (45%), and psychologists/psychiatrists (27%). There was underuse of published guidelines and limited understanding of the course of intestinal adaptation. Responses to the clinical scenarios highlighted disparities in SBS-IF care delivery, including diagnosis, management goals, medications prescribed, and nutrition practices. CONCLUSIONS: Future SBS-IF educational interventions for HCPs should aim to improve awareness and understanding of the disease, facilitate timely diagnosis, and standardize management practices to ensure patients receive optimal interdisciplinary care as widely as possible.

A beautiful struggle: Parent-perceived impact of short bowel syndrome on child and family wellbeing.

BACKGROUND: Despite considerable improvements in outcomes for children with short bowel syndrome (SBS), many clinicians remain pessimistic about long-term quality of life (QoL) for this population. METHODS: The validated FaMM tool was used to measure parent-perceived impact of the child's condition on child and family life. Partnered disease-specific survey questions relevant to child's overall wellbeing and family function were additionally completed and reported. The cross-sectional surveys were distributed to a convenience sample of parents of children with SBS. Child and family wellbeing were described and compared across child age group and involvement of an intestinal rehabilitation program (IRP). Multivariate regression analyses investigated associations between outcomes and IRP management. Open-ended responses were analyzed to investigate perceived impact of the child's SBS on the parent. RESULTS: Seventeen parents completed both surveys; 71% perceived child QoL as higher today than what they had originally been told to expect. Child daily life and family difficulty scores suggest parents perceived both to be fairly "normal". While acknowledging effort invested in condition management, parents perceived high competence in managing their child's condition; 56% perceived personal growth resulting from their child's SBS journey. IRP management was associated with better child daily life (4.11, p = 0.015), family difficulty (-4.85, p = 0.048), and family management ability (4.28, p = 0.014) scores. CONCLUSIONS: Many parents perceive child and family life with SBS to be fairly "normal", manage their child's care with great competence, and report personal growth because of their child's SBS journey. Additional research inclusive of diverse patient and parent backgrounds is warranted. LEVEL OF EVIDENCE: prognosis study; Level IV.

Gamma and Decay Energy Spectroscopy Measurements of Trinitite.

We report gamma ray spectroscopy measurements of trinitite samples and analogous samples obtained from detonation sites in Nevada and Semipalatinsk, as well as in situ measurements of topsoil at the Trinity site. We also report the first isotopic composition measurements of trinitite using the novel forensics technique of decay energy spectroscopy (DES) as a complement to traditional forensics techniques. Our gamma spectroscopy and DES measurements are compared to other published results.