A distinct transcriptome characterizes neural crest-derived cells at the migratory wavefront during enteric nervous system development.

Enteric nervous system development relies on intestinal colonization by enteric neural crest-derived cells (ENCDCs). This is driven by a population of highly migratory and proliferative ENCDCs at the wavefront, but the molecular characteristics of these cells are unknown. ENCDCs from the wavefront and the trailing region were isolated and subjected to RNA-seq. Wavefront-ENCDCs were transcriptionally distinct from trailing ENCDCs, and temporal modelling confirmed their relative immaturity. This population of ENCDCs exhibited altered expression of ECM and cytoskeletal genes, consistent with a migratory phenotype. Unlike trailing ENCDCs, the wavefront lacked expression of genes related to neuronal or glial maturation. As wavefront ENCDC genes were associated with migration and developmental immaturity, the genes that remain expressed in later progenitor populations may be particularly pertinent to understanding the maintenance of ENCDC progenitor characteristics. Dusp6 expression was specifically upregulated at the wavefront. Inhibiting DUSP6 activity prevented wavefront colonization of the hindgut, and inhibited the migratory ability of post-colonized ENCDCs from midgut and postnatal neurospheres. These effects were reversed by simultaneous inhibition of ERK signaling, indicating that DUSP6-mediated ERK inhibition is required for ENCDC migration in mouse and chick.

Bone Marrow Stem Cells Derived from Nerves Have Neurogenic Properties and Potential Utility for Regenerative Therapy.

Neurons and glia of the peripheral nervous system are derived from progenitor cell populations, originating from embryonic neural crest. The neural crest and vasculature are intimately associated during embryonic development and in the mature central nervous system, in which they form a neurovascular unit comprised of neurons, glia, pericytes, and vascular endothelial cells that play important roles in health and disease. Our group and others have previously reported that postnatal populations of stem cells originating from glia or Schwann cells possess neural stem cell qualities, including rapid proliferation and differentiation into mature glia and neurons. Bone marrow receives sensory and sympathetic innervation from the peripheral nervous system and is known to contain myelinating and unmyelinating Schwann cells. Herein, we describe a population of neural crest-derived Schwann cells residing in a neurovascular niche of bone marrow in association with nerve fibers. These Schwann cells can be isolated and expanded. They demonstrate plasticity in vitro, generating neural stem cells that exhibit neurogenic potential and form neural networks within the enteric nervous system in vivo following transplantation to the intestine. These cells represent a novel source of autologous neural stem cells for the treatment of neurointestinal disorders.

Sharing Lessons From Successes: Long-term Care Facilities That Weathered the Storm of COVID-19 and Staffing Crises.

PURPOSE: To identify leadership styles and staffing strategies in Missouri long-term care (LTC) facilities that stood out among their peers as "positive deviants" with regard to COVID-19 infections and staffing shortages. METHODS: Statewide survey of all LTC facilities to identify exemplar facilities with stable staffing and low rates of COVID-19. Interviews with senior leaders were conducted in 10 facilities in the state to understand the strategies employed that led to these "positive outliers." A result-based educational program was designed to describe their actions and staff reactions. RESULTS: Exemplar leaders used transformational leadership style. Top reasons for their success were as follows: (1) trusting and supportive staff relationships; (2) positive presence and communication; and (3) use of consistent staffing assignments. Strong statewide participation was noted in the educational programs.

A pilot study characterizing longitudinal changes in fecal microbiota of patients with Hirschsprung-associated enterocolitis.

PURPOSE: Hirschsprung disease is a neurointestinal disease that occurs due to failure of enteric neural crest-derived cells to complete their rostrocaudal migration along the gut mesenchyme, resulting in aganglionosis along variable lengths of the distal bowel. Despite the effective surgery that removes the aganglionic segment, children with Hirschsprung disease remain at high risk for developing a potentially life-threatening enterocolitis (Hirschsprung-associated enterocolitis). Although the etiology of this enterocolitis remains poorly understood, several recent studies in both mouse models and in human subjects suggest potential involvement of gastrointestinal microbiota in the underlying pathogenesis of Hirschsprung-associated enterocolitis. METHODS: We present the first study to exploit the Illumina MiSeq next-generation sequencing platform within a longitudinal framework focused on microbiomes of Hirschsprung-associated enterocolitis in five patients. We analyzed bacterial communities from fecal samples collected at different timepoints starting from active enterocolitis and progressing into remission. RESULTS: We observed compositional differences between patients largely attributable to variability in age at the time of sample collection. Remission samples across patients exhibited compositional similarity, including enrichment of Blautia, while active enterocolitis samples showed substantial variability in composition. CONCLUSIONS: Overall, our findings provide continued support for the role of GI microbiota in the pathogenesis of Hirschsprung-associated enterocolitis.

Review: Universal mental health interventions for young students in adverse environments - a systematic review of evaluated interventions.

BACKGROUND: Universal classroom-based interventions are a useful method to increase the mental health and resilience in children. Resilience describes the process that leads to a positive development despite adversities. It comprises the seven resources access to material resources, relationships, identity, power and control, cultural adherence, social justice and cohesion. Yet there is a paucity of studies evaluating interventions that enhance resilience in children exposed to adverse childhood experiences. METHOD: This systematic review investigates whether universal classroom-based interventions can increase the seven resilience-related resources in children that live in adverse environments. Search strings were formulated based on an adapted version of the PICO criteria. The risk of bias of the individual studies was assessed using the ROBINS-I tool. RESULTS: Seventeen studies were included in the review, of which 15 found an increase in resilience. The resource power and control was targeted in every intervention. Not one intervention included all seven resources. Intervention outcomes related mostly to just two of the resources (power and control and identity) and were rarely linked to what was being trained in the intervention. CONCLUSION: The results of this review show that classroom-based interventions are suitable for promoting resilience in children living in adverse environments. Yet more high-quality studies are needed that evaluate the effectiveness of universal interventions on children living in adverse environments and specifically the effectiveness of training each of the seven resources. Future developments of school-based interventions should be careful to target and assess all resilience-related resources.

Randomized controlled trial of the Circle of Security-Intensive intervention for mothers with postpartum depression: maternal unresolved attachment moderates changes in sensitivity.

Postpartum depression is related to inadequately sensitive caregiving, putting infants at risk for insecure attachment. Therefore, promoting sensitive maternal caregiving and secure child attachment is particularly important in postpartum depressed mothers and their infants. In this randomized-controlled-trial, we evaluated the efficacy of the Circle of Security-Intensive (COS-I)-intervention in supporting maternal sensitivity and mother-infant-attachment compared to treatment-as-usual (TAU) with unresolved-maternal attachment as a moderator of treatment effect. Eligible mothers with infants (N=72) 4-9 months-old were randomly assigned to treatment (n=36 dyads). Infant attachment was rated at follow-up (child age 16-18 months) (Strange-Situation-procedure). Maternal sensitivity was measured at baseline and follow-up (Mini-Maternal-Behavior-Q-sort). Maternal-unresolved-attachment was assessed at baseline (Adult-Attachment-Interview). We found no significant differences between treatments in infant attachment nor changes in mothers' sensitivity. However, in COS-I, unresolved-mothers exhibited significantly more change in sensitivity than non-unresolved-mothers, whereas in TAU, the opposite was true. These findings may help to optimize clinical use of COS-I.

Is the Power Threshold of 0.8 Applicable to Surgical Science?-Empowering the Underpowered Study.

BACKGROUND: Many articles in the surgical literature were faulted for committing type 2 error, or concluding no difference when the study was "underpowered". However, it is unknown if the current power standard of 0.8 is reasonable in surgical science. METHODS: PubMed was searched for abstracts published in Surgery, JAMA Surgery, and Annals of Surgery and from January 1, 2012 to December 31, 2016, with Medical Subject Heading terms of randomized controlled trial (RCT) or observational study (OBS) and limited to humans were included (n = 403). Articles were excluded if all reported findings were statistically significant (n = 193), or if presented data were insufficient to calculate power (n = 141). RESULTS: A total of 69 manuscripts (59 RCTs and 10 OBSs) were assessed. Overall, the median power was 0.16 (interquartile range [IQR] 0.08-0.32). The median power was 0.16 for RCTs (IQR 0.08-0.32) and 0.14 for OBSs (IQR 0.09-0.22). Only 4 studies (5.8%) reached or exceeded the current 0.8 standard. Two-thirds of our study sample had an a priori power calculation (n = 41). CONCLUSIONS: High-impact surgical science was routinely unable to reach the arbitrary power standard of 0.8. The academic surgical community should reconsider the power threshold as it applies to surgical investigations. We contend that the blueprint for the redesign should include benchmarking the power of articles on a gradient scale, instead of aiming for an unreasonable threshold.

Nature versus nurture: the impact of nativity and site of treatment on survival for gastric cancer.

BACKGROUND: The prognosis of gastric cancer patients is better in Asia than in the West. Genetic, environmental, and treatment factors have all been implicated. We sought to explore the extent to which the place of birth and the place of treatment influences survival outcomes in Korean and US patients with localized gastric cancer. METHODS: Patients with localized gastric adenocarcinoma undergoing potentially curative gastrectomy from 1989 to 2010 were identified from the SEER registry and two single institution databases from the US and Korea. Patients were categorized into three groups: Koreans born/treated in Korea (KK), Koreans born in Korea/treated in the US (KUS), and White Americans born/treated in the US (W), and disease-specific survival rates compared. RESULTS: We identified 16,622 patients: 3,984 (24.0%) KK, 1,046 (6.3%) KUS, and 11,592 (69.7%) W patients. KK patients had longer unadjusted median (not reached) and 5-year disease-specific survival (81.6%) rates than KUS (87 months, 55.9%) and W (35 months, 39.2%; p < 0.001 for all comparisons) patients. This finding persisted on subset analyses of patients with stage IA tumors, without cardia/GEJ tumors, with > 15 examined lymph nodes, and treated at a US center of excellence. On multivariable analysis, KUS (HR 2.80, p < 0.001) and W (HR 5.79, p < 0.001) patients had an increased risk of mortality compared to KK patients. CONCLUSIONS: Both the place of birth and the place of treatment significantly contribute to the improved prognosis of patients with gastric cancer in Korea relative to those in the US, implicating both nature and nurture in this phenomenon.

Prevention of preK-12 School Employee Sexual Misconduct and Abuse.

The abuse of preK-12 students by school personnel is a pervasive, understudied topic that has behavioral, psychological and monetary consequences for victims, their families, and their communities. This special issue is the second of a two-part series and focuses on studies of school employee sexual misconduct prevention training programs and prevention issues and frameworks. This compilation of articles presents evidence that effective training can lead to improved awareness and behavior changes, concerns about policy implementation that may contribute to continued prevalence, and presents strategies and guidelines for prevention. These articles provide considerations for prevention including training, loopholes, and frameworks.

Sexual Abuse and Exploitation of PreK-12 Students by School Personnel.

The abuse of students by PreK-12 school personnel continues to be a multifaceted issue that affects students, staff, parents, and communities at an alarming rate. This two-part special issue builds on the dated and limited literature in this topic area and includes qualitative and quantitative research on prevalence, victim and offender characteristics, barriers to prevention, and frameworks and standards for prevention. Together these articles highlight the need for systematic data collection, policy implementation, accountability, and training and awareness. The findings from these articles provide specific practices that schools can adopt and follow to prevent school employee sexual misconduct.

Preventing School Employee Sexual Misconduct: An Outcome Survey Analysis of Making Right Choices.

This treatment-only study examines the impact of Making Right Choices, an online course prevention program designed to promote the knowledge, awareness, and prevention of school employee sexual misconduct. The sample included 13,007 school employee participants who took the Making Right Choices course between May 6, 2011, and March 12, 2017, in California and New York. The 20-item measure, Preventing Misconduct Assessment, was administered to participants at the end of the online course; completion of the measure was voluntary. Descriptive statistics revealed that a large majority of participants reported increasing their knowledge and awareness of school employee sexual misconduct because of their participation in the Making Right Choices online course. This study yields important findings regarding the impact of a sexual misconduct prevention program and, specifically, the difference it may make for non-licensed school employees. These findings indicate that school employees are accepting of sexual misconduct training programs and rate them as having value.

Lower phosphate levels following pancreatectomy is associated with postoperative pancreatic fistula formation.

BACKGROUND: Whereas hypophosphatemia following hepatectomy is associated with decreased morbidity, hypophosphatemia following pancreatectomy may be associated with increased morbidity, including the development of postoperative pancreatic fistula (POPF). This study aimed to evaluate the relationship between postoperative hypophosphatemia and POPF formation. METHODS: Patients from our institutional Research Patient Data Registry who underwent pancreatectomy from 2001 to 2017 were included. POPF was defined according to the International Study Group for Pancreatic Fistulas (ISGPF) criteria and according to internal criteria for drain removal. Postoperative serum phosphate levels, demographics, and comorbidities were evaluated. Unadjusted and adjusted analyses were performed. RESULTS: 2342 patients underwent pancreatic resection. Mean age was 63.0 years (SD 14.3), 51.2% were male, and 58.7% had pancreatic cancer. Of all resections, 67.7% were pancreaticoduodenectomies. In unadjusted analysis, phosphate levels were significantly and persistently lower on POD 0 and POD 2-5 in patients who developed POPF's. In adjusted analysis, POD 2 phosphate <1.75 predicted an additional 46% increased odds of POPF (OR 1.46 95% CI 1.06-2.01; p = 0.02). Distal pancreatectomy was independently associated with POPF formation when compared to pancreaticoduodenectomy (OR 1.72 95% CI 1.18-2.51; p = 0.005). CONCLUSION: Lower phosphate levels in the early post-operative period following both proximal and distal pancreatectomies is associated with increased risk of POPF.

Most ApoL1 Is Secreted by the Liver.

Two coding sequence variants in the APOL1 gene (G1 and G2) explain much of the increased risk for FSGS, HIV-associated nephropathy, and hypertension-attributed ESRD among people of recent African ancestry. The ApoL1 protein is expressed in a wide variety of cell tissues. It has been assumed that the majority of circulating ApoL1 is produced by the liver, but this has not been shown. Using mass spectrometry, we genotyped and quantified the circulating ApoL1 in two liver transplant recipients whose native APOL1 genotype differed from the genotype of the deceased donors, allowing us to differentiate liver- from nonliver-produced ApoL1. Our findings confirm that the liver is indeed the main source of circulating ApoL1. However, the liver is not the sole source of circulating ApoL1, because we found that residual amounts of native ApoL1 continued to circulate in the blood, even after the liver transplant.

An Online Tool for Global Benchmarking of Risk-Adjusted Surgical Outcomes.

BACKGROUND: Increasing evidence demonstrates significant variation in adverse outcomes following surgery between countries. In order to better quantify these variations, we hypothesize that freely available online risk calculators can be used as a tool to generate global benchmarking of risk-adjusted surgical outcomes. METHODS: This is a prospective cohort study conducted at an academic teaching hospital in South Africa (GSH). Consecutive adult patients undergoing major general or vascular surgery who met the ACS-NSQIP inclusion criteria for a 3-month period were included. Data variables required by the ACS risk calculator were prospectively collected, and patients were followed for 30 days post-surgery for the occurrence of endpoints. Calculating observed-to-expected ratios for ten outcome measures of interest generated risk-adjusted outcomes benchmarked against the ACS-NSQIP consortium. RESULTS: A total of 373 major general and vascular surgery procedures met the inclusion criteria. The GSH operative cohort varied significantly compared to the 2012 ACS-NSQIP database. The risk-adjusted O/E ratios were significant for any complication O/E 1.91 (95 % CI 1.57-2.31), surgical site infections O/E 4.76 (95 % CI 3.71-6.01), renal failure O/E 3.29 (95 % CI 1.50-6.24), death O/E 3.43 (95 % CI 2.19-5.11), and total length of stay (LOS) O/E 3.43 (95 % CI 2.19-5.11). CONCLUSION: Freely available online risk calculators can be utilized as tools for global benchmarking of risk-adjusted surgical outcomes.

Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study.

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.

Parenting stress and postpartum depression/anxiety in mothers with personality disorders: indications for differential intervention priorities.

To date, parenting stress has rarely been examined in clinical samples of mothers with postpartum comorbid Axis-I disorders and Axis-II personality disorders (PD). Previous research has shown important links between maternal psychopathology and the development of child psychopathology. For these reasons, a clinical sample (N = 54) of mothers with various PD and comorbid depression/anxiety disorders were compared in this study. The clinical sample was divided into three groups based on PD: without PD, other PD, and borderline PD (BPD), and then matched according to depression/anxiety diagnoses and age. Parenting stress index (PSI, Abidin, 1995) scores were compared between these subsamples and to a nonclinical control group. No significant differences were found between mothers with various PD on global PSI scores. However, further examination of the PSI subscale scores revealed that PD were linked to an impaired sense of competence and positive reinforcement in relation to parenting. Compared to mothers with other PD, mothers with BPD had significantly more interpersonal issues. Compared to the nonclinical controls, clinically referred mothers had significantly higher PSI global and subscale scores, with notable PD-specific exceptions. These results illustrate the need for more differentiated treatment options for mothers with postpartum depression and/or anxiety disorders with PD to prevent later development of psychopathology in children of these mothers.

Reduced Albumin Dosing During Large-Volume Paracentesis Is Not Associated with Adverse Clinical Outcomes.

BACKGROUND: LVP is used to manage diuretic-resistant ascites in cirrhotic patients. Albumin administration prevents complications including acute kidney injury and paracentesis-induced circulatory dysfunction, but the optimal dose is unclear. AIM: We sought to assess adherence to guidelines enacted in July 2011 at our center for reducing the albumin dose administered at large-volume paracentesis (LVP) and evaluate the cost and rate of complications of LVPs before and after guideline enactment. METHODS: All LVPs performed on cirrhotic patients in our center's Department of Radiology between July 2009 and January 2014 were studied. Outcomes included adherence to guidelines, LVP complications, and administered albumin cost. Groups were compared using Student's t tests for continuous data and Chi-square or Fisher's exact tests for categorical data. A repeated measurements model accounted for patients with multiple LVPs. RESULTS: Of the 935 LVPs, 288 occurred before guideline implementation (group 1) and 647 occurred after (group 2). The mean dose of albumin administered was 13.7 g/L of ascites removed in group 1 versus 10.3 g/L in group 2 (p < 0.0001). Of the group 2 LVPs, 235 (36.3 %) adhered to guidelines. There were no significant differences in LVP complications. CONCLUSIONS: Guidelines were followed in one-third of LVPs. Despite this limited adherence, a reduction in albumin administration and associated cost savings was still observed. There was no increase in LVP-related complications after guideline implementation or in the adherent group, suggesting that albumin dose can be safely reduced. Future efforts should be directed at enhancing guideline adherence and potentially further reducing albumin dosing.

Agrin Inhibition in Enteric Neural Stem Cells Enhances Their Migration Following Colonic Transplantation.

Regenerative cell therapy to replenish the missing neurons and glia in the aganglionic segment of Hirschsprung disease represents a promising treatment option. However, the success of cell therapies for this condition are hindered by poor migration of the transplanted cells. This limitation is in part due to a markedly less permissive extracellular environment in the postnatal gut than that of the embryo. Coordinated interactions between enteric neural crest-derived cells (ENCDCs) and their local environment drive migration along the embryonic gut during development of the enteric nervous system. Modifying transplanted cells, or the postnatal extracellular environment, to better recapitulate embryonic ENCDC migration could be leveraged to improve the engraftment and coverage of stem cell transplants. We compared the transcriptomes of ENCDCs from the embryonic intestine to that of postnatal-derived neurospheres and identified 89 extracellular matrix (ECM)-associated genes that are differentially expressed. Agrin, a heparin sulfate proteoglycan with a known inhibitory effect on ENCDC migration, was highly over-expressed by postnatal-derived neurospheres. Using a function-blocking antibody and a shRNA-expressing lentivirus, we show that inhibiting agrin promotes ENCDC migration in vitro and following cell transplantation ex vivo and in vivo. This enhanced migration is associated with an increased proportion of GFAP + cells, whose migration is especially enhanced.

Longitudinal Evaluation of a Statewide Quality Improvement Program for Nursing Homes.

OBJECTIVES: The National Academies of Sciences, Engineering, and Medicine (NASEM) Nursing Home Quality report recommends that states "develop and operate state-based…technical assistance programs…to help nursing homes…improve care and…operations." The Quality Improvement Program for Missouri (QIPMO) is one such program. This longitudinal evaluation examined and compared differences in quality measures (QMs) and nursing home (NH) characteristics based on intensity of QIPMO services used. DESIGN: A descriptive study compared key QMs of clinical care, facility-level characteristics, and differing QIPMO service intensity use. QIPMO services include on-site clinical consultation by expert nurses; evidence-based practice information; teaching NHs use of quality improvement (QI) methods; and guiding their use of Centers for Medicare and Medicaid Services (CMS)-prepared QM comparative feedback reports to improve care. SETTING AND PARTICIPANTS: All Missouri NHs (n = 510) have access to QIPMO services at no charge. All used some level of service during the study, 2020-2022. METHODS: QM data were drawn from CMS's publicly available website (Refresh April 2023) and NH characteristics data from other public websites. Service intensity was calculated using data from facility contacts (on-site visits, phone calls, texts, emails, webinars). NHs were divided into quartiles based on service intensity. RESULTS: All groups had different beginning QM scores and improved ending scores. Group 2, moderate resource intensity use, started with "worse" overall score and improved to best performing by the end. Group 4, most resource intensity use, improved least but required highest service intensity. CONCLUSIONS AND IMPLICATIONS: This longitudinal evaluation of QIPMO, a statewide QI technical assistance and support program, provides evidence of programmatic stimulation of statewide NH quality improvements. It provides insight into intensity of services needed to help facilities improve. Other states should consider QIPMO success and develop their own programs, as recommended by the NASEM report so their NHs can embrace QI and "initiate fundamental change" for better care for our nation's older adults.