Tools to Measure the Impact of Structural Racism and Discrimination on Gastrointestinal and Hepatology Disease Outcomes: A Scoping Review.

BACKGROUND & AIMS: Structural racism and discrimination (SRD) are important upstream determinants of health perpetuated by discriminatory laws and policies. Therefore, measuring SRD and its impact on health is critical to developing interventions that address resultant health disparities. We aimed to identify gastrointestinal (GI) or liver studies that report measures of SRD or interventions to achieve health equity in these domains by addressing upstream determinants of health. METHODS: We conducted a scoping review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses scoping reviews guidelines. Studies that used an SRD measure or examined an upstream intervention in GI or liver disease were included. Studies that described health disparities in GI or liver conditions without mentioning SRD were excluded. Study characteristics, findings, and limitations were extracted. RESULTS: Forty-six articles (19 studies using SRD measures and 27 studies of upstream interventions) were identified. Measures of residential racial segregation were reported most frequently. SRD was associated with poorer health outcomes for racial and ethnic minority populations. Although upstream intervention studies focused primarily on policies related to colon cancer screening and organ graft allocation, racial and ethnic disparities often persisted post-intervention. CONCLUSIONS: To achieve health equity in GI and liver conditions, there is an urgent need for research that goes beyond describing health disparities to incorporating measures of SRD and implementing interventions that address this understudied determinant of health.

Epigenetic modifier SMCHD1 maintains a normal pool of long-term hematopoietic stem cells.

SMCHD1 (structural maintenance of chromosomes hinge domain containing 1) is a noncanonical SMC protein that mediates long-range repressive chromatin structures. SMCHD1 is required for X chromosome inactivation in female cells and repression of imprinted and clustered autosomal genes, with SMCHD1 mutations linked to human diseases facioscapulohumeral muscular dystrophy (FSHD) and bosma arhinia and micropthalmia syndrome (BAMS). We used a conditional mouse model to investigate SMCHD1 in hematopoiesis. Smchd1-deleted mice maintained steady-state hematopoiesis despite showing an impaired reconstitution capacity in competitive bone marrow transplantations and age-related hematopoietic stem cell (HSC) loss. This phenotype was more pronounced in Smchd1-deleted females, which showed a loss of quiescent HSCs and fewer B cells. Gene expression profiling of Smchd1-deficient HSCs and B cells revealed known and cell-type-specific SMCHD1-sensitive genes and significant disruption to X-linked gene expression in female cells. These data show SMCHD1 is a regulator of HSCs whose effects are more profound in females.

BAF complex-mediated chromatin relaxation is required for establishment of X chromosome inactivation.

The process of epigenetic silencing, while fundamentally important, is not yet completely understood. Here we report a replenishable female mouse embryonic stem cell (mESC) system, Xmas, that allows rapid assessment of X chromosome inactivation (XCI), the epigenetic silencing mechanism of one of the two X chromosomes that enables dosage compensation in female mammals. Through a targeted genetic screen in differentiating Xmas mESCs, we reveal that the BAF complex is required to create nucleosome-depleted regions at promoters on the inactive X chromosome during the earliest stages of establishment of XCI. Without this action gene silencing fails. Xmas mESCs provide a tractable model for screen-based approaches that enable the discovery of unknown facets of the female-specific process of XCI and epigenetic silencing more broadly.

Opioid-Related Constipation.

Opioid-related constipation encompasses constipation directly caused by opioid use (opioid-induced constipation [OIC]) as well as pre-existing constipation worsened by opioid use (opioid-exacerbated constipation [OEC]). Over-the-counter laxatives should be used as first-line agents for both OIC and OEC, given their efficacy, low cost, and high safety profiles. Symptoms of OIC and responses to therapy can be assessed with the Bowel Function Index. Individuals with OIC refractory to laxatives may be responsive to peripherally acting µ-opioid receptor antagonists. Although data supporting the superiority of one prescription agent over another is lacking, all have proven effective for the treatment of OIC.

Nitrogen legacies in anthropogenic landscapes: a case study in the Mondego Basin in Portugal.

Nitrogen (N) legacies have built up in anthropogenic landscapes over decades of agricultural intensification, and these legacies lead to time lags in water quality change measurable even beyond the moment of application of N. It is important to understand these legacies to quantify the relationship between N inputs and N concentrations in streams and implement best management practices for water quality improvement; however, little is known about the magnitude of legacies in various landscape elements like soils and groundwater. Here, we have used the ELEMeNT (Exploration of Long-tErM Nutrient Trajectories) model to explore the buildup and depletion of N legacies over a 216-year period, across the Mondego River Basin, a 6645-km2 watershed in Portugal, where human interventions have considerably changed the characteristics of the basin to prevent floods and improve farming conditions in recent decades. The results show that the increase in the amount of inorganic fertilizer applied was the main driver for the anthropogenic N loads in the watershed from 1950 until the beginning of the 1990s. The N inputs have been decreasing since then, but N loads in the river did not document any decrease till the 1990s; after which there was a decline. This time lag between the N inputs to the watershed and the N loads in the river (about two decades) is a function of accumulation of N legacy.

Review article: current and future treatment approaches for IBS with constipation.

BACKGROUND: Multiple efficacious therapies are currently available for treating irritable bowel syndrome with constipation (IBS-C). IBS-C specific survey tools that assess symptom relief, treatment satisfaction, and quality of life are important for gauging real-world effectiveness. AIMS/METHODS: This article reviews clinical trial efficacy data as well as survey data on adequate relief and quality of life from pivotal trials for lubiprostone, linaclotide, plecanatide, tenapanor, and tegaserod. A brief discussion of agents in development with novel mechanisms of action is also provided. RESULTS/CONCLUSIONS: Quality of life and symptom metrics should be standardized and continue to be represented in future IBS-C trials. The choice of agent should be tailored to probability of improving symptoms, safety, tolerability, and cost.

Efficacy and Safety of Neostigmine and Decompressive Colonoscopy for Acute Colonic Pseudo-Obstruction: A Single-Center Analysis.

BACKGROUND: Acute colonic pseudo-obstruction (ACPO) is characterized by acute colonic dilation in the absence of anatomical obstruction. Neostigmine is an acetylcholinesterase inhibitor recommended as first-line salvage therapy for uncomplicated ACPO. Decompressive colonoscopy is recommended if neostigmine is contraindicated or unsuccessful. There is a need to better characterize relative efficacy and factors impacting treatment choice. The aim of the study was to examine the use, efficacy, and safety of neostigmine and decompressive colonoscopy in the management of ACPO at a single academic center. METHODS: Patients ≥ 18 years of age meeting established criteria for uncomplicated ACPO and with cecal diameter ≥ 10 cm on imaging between 1999 and 2019 were identified. Individuals were categorized as having received supportive care alone or subsequent trials of neostigmine or decompressive colonoscopy. Demographics and pre- and post-intervention data were collected, including indication and contraindication to intervention used, time to intervention, initial response, and adverse events. RESULTS: In 46 cases of ACPO (N = 42 patients), all but one individual received initial supportive care. Seven responded to conservative measures alone. Of the patients failing supportive care, 15 cases were initially treated with neostigmine (response rate 86.7%) and 24 initially underwent decompressive colonoscopy (response rate 95.8%) (P = 0.390). One episode of transient bradycardia, resolved with atropine, occurred in the neostigmine group. One patient experienced respiratory instability during colonoscopy. CONCLUSIONS: Both neostigmine and decompressive colonoscopy appear effective for treating uncomplicated ACPO in individuals failing conservative therapy. Adverse events were infrequent in both cohorts. Future prospective studies examining treatment for ACPO should focus on whether either intervention is superior to the other.

Focus on Pharmacotherapy for Irritable Bowel Syndrome with Constipation.

Irritable bowel syndrome with constipation is a common disorder that significantly impairs quality of life. There are now multiple classes of therapeutics that have been shown via rigorous clinical testing to improve the abdominal and bowel symptoms attributed to irritable bowel syndrome with constipation. These include the secretagogues (lubiprostone, linaclotide, plecanatide, tenapenor) and the prokinetic agent tegaserod. This article highlights the pivotal evidence for these agents and most recent treatment guidance from the major North American gastroenterological societies. When pharmaceuticals are used, a patient-specific approach based on efficacy, safety, tolerability, access, and affordability is recommended.

A functional genetic screen identifies aurora kinase b as an essential regulator of Sox9-positive mouse embryonic lung progenitor cells.

Development of a branching tree in the embryonic lung is crucial for the formation of a fully mature functional lung at birth. Sox9+ cells present at the tip of the primary embryonic lung endoderm are multipotent cells responsible for branch formation and elongation. We performed a genetic screen in murine primary cells and identified aurora kinase b (Aurkb) as an essential regulator of Sox9+ cells ex vivo. In vivo conditional knockout studies confirmed that Aurkb was required for lung development but was not necessary for postnatal growth and the repair of the adult lung after injury. Deletion of Aurkb in embryonic Sox9+ cells led to the formation of a stunted lung that retained the expression of Sox2 in the proximal airways, as well as Sox9 in the distal tips. Although we found no change in cell polarity, we showed that loss of Aurkb or chemical inhibition of Aurkb caused Sox9+ cells to arrest at G2/M, likely responsible for the lack of branch bifurcation. This work demonstrates the power of genetic screens in identifying novel regulators of Sox9+ progenitor cells and lung branching morphogenesis.

Naldemedine for the treatment of opioid-induced constipation in adults with chronic noncancer pain.

This review aims to summarize the efficacy data for naldemedine, a member of the novel peripherally acting µ-opioid receptor antagonists (PAMORAs), which gained US FDA approval for the treatment of opioid-induced constipation in adults with chronic noncancer pain-related syndromes in 2017. In Phase III trials, patients receiving naldemedine were significantly more likely to meet the primary end point ≥3 spontaneous bowel movements/week and an increase of ≥1 spontaneous bowel movement/week from baseline for at least 9/12 weeks compared to placebo (p < 0.0001). The most frequent adverse events were abdominal pain (8%) and diarrhea (7%). Based on available data, naldemedine appears to be an effective and safe first-line therapy for the treatment of opioid-induced constipation in adults with chronic noncancer pain.

HBO1 is required for the maintenance of leukaemia stem cells.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.

A Mixed-Methods Exploration of Pediatric Intensivists' Attitudes toward End-of-Life Care in Vietnam.

Background: Although the need for palliative care is gaining recognition in Southeast Asia, knowledge about how decisions are made for children near the end of life remains sparse. Objective: To explore pediatric intensivists' attitudes and practices surrounding end-of-life care in Vietnam. Methods: This is a mixed-methods study conducted at a tertiary pediatric and neonatal intensive care unit in Hanoi. Physicians and nurses completed a quantitative survey about their views on end-of-life care. A subset of these providers participated in semistructured interviews on related topics. Analysis of surveys and interviews were conducted. Results were triangulated. Results: Sixty-eight providers (33 physicians and 35 nurses) completed the quantitative survey, and 18 participated in interviews. Qualitative data revealed three overarching themes with numerous subthemes and supporting quotations. The first theme was factors influencing providers' decision-making process to escalate or withdraw treatment. Quantitative data showed that 40% of providers valued the family's ability to pay to continue life-sustaining treatment. Second, communication dynamics in decision making were highlighted; 72% of providers would be willing to override a family's wishes to withdraw life-sustaining treatment. Third, provider perceptions of death varied, with 68% regarding their patients' deaths as a personal failure. Conclusions: We elicited and documented how pediatric intensivists in Vietnam currently think about and provide end-of-life care. These findings indicate a need to strengthen palliative care training, increase family involvement in decision making, implement standardized and official do-not-resuscitate documentation, and expand pediatric hospice services at the individual, hospital, and national levels in Vietnam.

Further Defining the 2012 Multi-Society Task Force Guidelines for Surveillance of High-risk Adenomas: Is a 3-Year Interval Needed for All Patients?

GOALS: We set out to determine whether variation from this 3-year follow-up interval was associated with the finding of subsequent high-risk adenoma (HRA). BACKGROUND: HRAs include the following: (1) an adenoma measuring ≥10 mm, (2) ≥3 adenomas found during a single procedure, and (3) an adenoma with high-grade dysplasia or villous architecture. The current Multi-Society Task Force guideline for timing of surveillance colonoscopy after removal of a HRA is 3 years. STUDY: In 2016, we analyzed 495 patients who had a HRA removed during a 2008 colonoscopy. We compared the frequency of finding another HRA at follow-up intervals. We used the current guidelines as our referent group and performed logistical regression to identify whether any patient characteristics, procedural factors, or type of HRA predicted the development of HRAs on follow-up colonoscopy. RESULTS: Individuals who followed-up at a median of 4.5 years did not have more HRA on follow-up compared with those who followed-up at 3 years (25.2% vs. 21.0%, P=0.062). These groups had similar baseline characteristics. Older individuals, male gender, having a history of polyps, and piecemeal resection of an HRA predicted future HRAs. The removal of ≥3 adenomas in 2008 as well as a combination of multiple, large, and advanced polyps showed a higher risk of future HRAs. CONCLUSIONS: The 2012 Multi-Society Task Force recommendation of 3-year follow-up after removal of HRAs may not apply to all patients. We showed that a combination of patient demographics, procedural factors, and pathology best determines the surveillance colonoscopy interval.

Rete Testis Invasion Is Consistent With Pathologic Stage T1 in Germ Cell Tumors.

OBJECTIVES: Rete testis invasion by germ cell tumors is frequently concomitant with lymphovascular or spermatic cord invasion (LVI/SCI); independent implications for staging are uncertain. METHODS: In total, 171 seminomas and 178 nonseminomatous germ cell tumors (NSGCTs; 46 had 1%-60% seminoma component) came from five institutions. Metastatic status at presentation, as a proxy for severity, was available for all; relapse data were unavailable for 152. Rete direct invasion (ReteD) and rete pagetoid spread (ReteP) were assessed. RESULTS: ReteP and ReteD were more frequent in seminoma than NSGCT. In seminoma, tumor size bifurcated at 3 cm or more or less than 3 cm predicted metastatic status. Tumors with ReteP or ReteD did not differ in size from those without invasions but were less than with LVI/SCI; metastatic status or relapse did not show differences. In NSGCT, ReteP/ReteD did not correlate with size, metastatic status, or relapse. CONCLUSIONS: Findings support retaining American Joint Committee for Cancer pathologic T1 stage designation for rete testis invasion and pT1a/pT1b substaging of seminoma.

Posttransplant Lymphoproliferative Disorder Isolated to the Adrenal Gland in a Liver Transplant Patient.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication that accounts for up to 20% of malignancies after solid organ transplantation. We describe a rare case of isolated PTLD in the adrenal gland occurring 7 months after liver transplant in a patient who developed a primary Epstein-Barr virus infection. He was treated with rituximab and his immunosuppression regimen was minimized. We review the incidence, pathogenesis, presentation, and management of PTLD in the liver-transplant population. Our case highlights the variation in the presentation of PTLD and the importance of a high index of suspicion among the at-risk group.