bluuebunny/crossref_metadata_2025 huggingface dataset:
DUSP16 IS A NOVEL IBD GENE IMPLICATED IN THE REGULATION OF DIFFERENTIATION AND HOMEOSTASIS OF INTESTINAL EPITHELIAL CELLS
Authors: Ntunzwenimana Jessy , Alikashani Azadeh , Beauchamp Claudine , Paquette Jean , Boucher Gabrielle , Goyette Philippe , Rioux John
Published: January 2021

Inflammatory bowel disease (IBD) are chronic inflammatory diseases including Crohn’s disease (CD) and ulcerative colitis (UC). More than 200 genomic regions have been identified and validated (association values〈 5x10-8) to be associated with CD, UC or IBD. These regions may contain multiple genes and the current challenge lies in identifying the causal gene in each of these. To address this problem, we performed a functional genomic screen of 145 genes from validated IBD loci, in a relevant intestinal epithelial cell model (HT-29). The results of this transcriptome-based screening revealed that the candidate IBD gene DUSP16 (a dual specificity phosphatase targeting MAP kinases (MAPKs) phosphorylation) as well as the known IBD gene KSR1 (a scaffold protein regulating the spatiotemporal activation of the ERK) regulate the expression of genes involved in intestinal differentiation and homeostasis. They induce, among others, the expression of the PIGR gene that encodes the polymeric immunoglobulin receptor. PIGR plays a role in transporting dimeric IgA molecules from the basolateral membrane of epithelial cells to the intestinal lumen, via transcytosis, where they play an essential role in protecting the epithelium against intestinal pathogens. Our hypothesis is that DUSP16 and KSR1 modulate the activity of MAPKs in intestinal epithelial cells to induce PIGR expression, thus participating in the maintenance of homeostasis of the intestinal barrier.

To better understand how DUSP16 modulates the expression of PIGR, we used an approach of over- expression (cDNA) and knockdown (shRNA) of DUSP16 in HT-29 cells. Our results confirmed that DUSP16 induction increases the expression of PIGR, whereas a knockdown of DUSP16 reduces the basal level of PIGR. Next we confirmed by Western Blot that the induction of DUSP16 was accompanied by a decrease in MAPK phosphorylation. The involvement of MAPKs was also confirmed through the use of chemical inhibitors specific for each MAPK, with inhibition of ERK and p38 showing the strongest induction of PIGR expression. We are currently analyzing known functional mutants of DUSP16 and KSR1 to determine their impact on MAPK activity and on PIGR expression. This work supports a role for PIGR in disease pathogenesis, adding to two recent studies that documented that patients suffering from UC accumulated somatic mutations in a group of genes regulating the expression of PIGR by Interleukin 17. The mutated genes, including PIGR, were positively selected in inflamed tissues, indicating the importance of the biological function occupied by this gene in the maintenance of homeostasis.

In conclusion, our study successfully identified functional links between two genes from independent IBD loci, and suggests that these DUSP16 and KSR1 play a role in the process of epithelial transcytosis and the development of IBD.
GENETIC POLYMOPRHISMS MAY DIFFERENTIATE BETWEEN COMPLICATED PEDIATRIC SMALL BOWEL VERSUS COLONIC CROHN’S DISEASE
Authors: Patel Halee , Harris R Alan , Qian Justin , Britto Savini , Opekun Antone , Kellermayer Richard
Published: January 2021

Objectives

About 9% of pediatric Crohn’s disease (CD) patients experience complications within 3 years from diagnosis in spite of anti-Tumor Necrosis Factor-alpha (anti-TNF) biologic treatment. Within 5 years, such complications may require surgical interventions in up to 20% of cases. Due to the relatively rare nature of these complicated pediatric CD cases within large CD cohorts, traditional genome wide association studies (GWAS) rarely capture this patient population. Our aim was to identify critical genetic associations of anti-TNF refractory complicated pediatric CD subtypes.

Methods

The study was approved by BCM IRB. Included patients had developed CD between the ages of 6 and 18. The Paris classification was used to place patients in the following categories:

1. Anti-TNF refractory small bowel CD (RSB-CD): L4b; L4b/B2; or L4b/B2B3 who had or were imminent to have small bowel resection.

2.. Anti-TNF refractory colonic CD (RC-CD): L2 requiring ileal diversion; or L2/B2; or L2/B2B3 who had or were considered to receive colectomy or partial colonic resection.

Whole-exome sequencing (WES) was performed from peripheral blood derived DNA. PLINK (https://www.cog-genomics.org/plink2/) was used to identify enriched single nucleotide polymorphisms (SNPs). The level of significance for exome wide differentiation was relaxed to p<0.01. The potential deleteriousness of single nucleotide variants was determined by CADD (https://cadd.gs.washington.edu/). Gene Ontology enRIchment anaLysis and visuaLizAtion tool (GORILLA) was used to compare gene lists associated with colonic enriched SNPs versus ileal enriched SNPs (http://geneontology.org/).

Results

In eight RSB-CD and 11 RC-CD cases, age at presentation, gender, ethnicity, and need for surgery (75% and 55%, respectively) did not significantly differ between the groups. There were 269 genes associated with 277 SNPs that had significantly (p<0.01) different allele variation between colonic vs ileal CD. Of these, 170 genes associated with 116 distinct SNPs had a CADD score of >10. Out of the top five SNP candidate associated genes, four (4/5 = 80%: EFNA3, STEAP1B, DSG1, and CYP4F2) have been already linked with Crohn’s disease and/or colitis. GORILLA based investigation indicated that colonic CD associated genes were enriched (p<0.001) in biologic function relevant for lipid metabolic process (GO:0006629), small molecule metabolic process (GO:0044281), and organic substance metabolic process (GO:0071704) compared to ileal CD associated genes.

Conclusions

We have uncovered candidate genetic risk loci, which may differentially influence pediatric CD towards developing primarily small intestinal or colonic complications. The discovered loci hold significant potential as novel genetic modifiers, which may set the basis for risk assessment, prevention and personalized treatment against complicated pediatric CD.
UTILIZATION OF WHOLE EXOME SEQUENCING DATA TO IDENTIFY CLINICALLY RELEVANT PHARMACOGENOMIC VARIANTS IN INFLAMMATORY BOWEL DISEASE
Authors: Mulder Daniel , Khalouei Sam , Warner Neil , Gonzaga-Jauregui Claudia , Church Peter , Walters Tom , Ramani Arun , Griffiths Anne , Cohn Iris , Muise Aleixo
Published: January 2021

Objectives

We hypothesized that variants within clinically relevant pharmacogenes could be identified using a whole exome sequencing (WES) dataset derived from a cohort of over 1000 IBD patients.

Methods

Pediatric patients diagnosed with IBD underwent WES. We selected 18 genes with supporting literature where specific exonic variants would influence clinical care.

Results

We identified actionable pharmacogenes variants in 63% of patients. Importantly, 5% of IBD patients were at risk for serious adverse effects from anaesthesia and 3% were at increased risk for thrombosis.

Conclusions

We identified exonic variants in the majority of our IBD patients that directly impact clinical care.

Flowchart of our pharmacogenomic analysis pipeline. After enrolment (n=2309), each patient underwent whole exome sequencing and sequence alignment. Available family members were also sequenced. Analyzed samples were limited to patients and family members with IBD (n=1097). Pharmacogenes relevant to patients with IBD were identified by literature review and evaluation of pharmGKB (total of 18 genes). Variant filtering was performed using Stargazer and GEMINI frameworks. In our cohort, there were 8 relevant pharmacogenes with variants that would alter clinical care based on current guidelines and standard of care. 63% of the patients had at least one variant that could impact care.
BMC322- A RATIONALLY-DESIGNED LIVE BACTERIAL CONSORTIUM BASED ON MICROBIOME FUNCTIONAL GENOMIC ANALYSIS FOR TREATMENT OF IBD
Authors: Polonsky Omri , Meshner Shiri , Eshar Shiri , Ben-Shabat Sheerli Kruger , Tirosh Osnat , Haber Elran , Ringel Yehuda
Published: January 2021

The mechanisms by which the intestinal microbiome affects intestinal inflammation and disease activity in IBD is not clear. Most of the current data on the association between the intestinal microbiome and IBD is focusing on the intestinal microbial taxa and very little is known about the functionality of the microbiome in this condition.

Aim: To construct a live bacterial consortium for reduction of intestinal inflammation in IBD based on a high-resolution functional microbial analysis, and its association with anti-inflammatory processes.

Methods: Fecal metagenomics samples (n=581) and corresponding fecal calprotectin (FCP) levels from patients with Crohn’s disease and Ulcerative Colitis were downloaded from the NCBI (SRA SRP057027, http://hmpdacc.org, SRA SRP002163 and SRP056641 (BioProject PRJNA275349)).

Computational analysis was performed using PRISM (Biomica Ltd, Rehovot Israel), a proprietary metagenomics analysis platform integrating assembly-based and reference-based analyses for functional genomics profiling and utilizing BioCOGS, Biomica’s internal comprehensive catalogue of microbial gene-orthology groups. We compared microbial functions between subjects based on severity of inflammation (FCP<70 vs FCP >250 and FCP >250 vs FCP <250) and identified microbial functions associated with low inflammation (FDR 0.1).

Validation of the anti-inflammatory activity of BMC322 was performed using a DSS-induced colitis mouse model.

Results: Out of the dozens of identified functions, 32 were related to host anti-inflammatory processes, intestinal barrier integrity and colonocyte function. Our functional microbiome investigation has pointed to novel metabolic mechanisms by which specific strains may attenuate mucosal inflammation. Using functional annotations, we infer the biological processes governing microbe-host interactions contributing to reduced inflammation, and identify 16 bacteria of which 4 strains comprise the full array of the identified microbial functions associated with lower disease severity. These strains comprise BMC322- a novel live-bacterial consortium for inflammation reduction in IBD.

The anti-inflammatory activity of these strains was validated in in-vitro studies and demonstrated efficacy in preliminary a mouse model of DSS-induced colitis; including shortening period of recovery, disease activity index and fecal lipocalin 2.

Conclusion: High-resolution functional genomics profiling of the gut microbiome enables identification of microbial-derived functions relevant to inflammatory disease activity, and microbial strains bearing specific inflammation-reduction activity. These strains have provided the basis for the construction of a 4-strain consortium for intervention in IBD. Preliminary work has validated the anti-inflammatory activity of these strains and their potential as novel therapeutic modality for IBD.
DIETARY FIBER DEPRIVATION QUELLS COLONIC INFLAMMATION BY TARGETING GUT PATHOBIONTS IN A NEW MODEL OF CROHN’S DISEASE
Authors: Caruso Roberta , Kuffa Peter , Inohara Naohiro , Nunez Gabriel
Published: January 2021

Crohn’s disease (CD) is a chronic intestinal inflammatory disorder that results from a dysregulated mucosal immune response to symbiotic bacteria in genetically susceptible individuals. While genetic predispositions to CD have been well documented, the overall contribution of genetic factors to disease development remains unclear. Indeed, abnormal interactions between microbes and the immune system have been identified as the core defect leading to chronic intestinal inflammation. We used a “multi-hit” genetic approach to study the complex interplay between host immunity and microbes in the context of CD. We have found that the combined deficiency of NOD2 and phagocyte NADPH oxidase (i.e. CYBB), two CD susceptibility genes, triggers microbiota-dependent and spontaneous TH1-type colitis in mice that is accompanied by the pathological hallmarks seen in CD patients. Disease was induced by Mucispirillum schaedleri, a gram-negative mucus-dwelling anaerobe. The absence of the two anti-microbial genes (i.e. NOD2 and CYBB) resulted in a marked accumulation of M. schaedleri in the gut lumen, the colonic mucus layer and ultimately a focal penetration of the intestinal wall. Accumulation of M. schaedleri was associated with impaired recruitment of neutrophils in the intestine and subsequently inefficient elimination of the bacterium. Among the environmental factors associated with CD, diet shapes the composition of the gut microbiota and can be used to manage disease symptoms. Our experiments have shown that consumption of a fiber-free diet leads to a depletion of the colonic mucus layer and increased proximity between microbes and the gut epithelium. Interestingly, these experimental conditions are effective at inhibiting intestinal inflammation observed in our model of CD-like colitis when used both as a preventive and as a therapeutic approach. In addition to shaping the overall gut microbiota composition, this dietary intervention specifically alters the abundance and/or localization of the disease-causing M. schaedleri in the double mutant mice. Our results provide direct evidence that a specific intestinal microbe can, in conjunction with impaired bacterial clearance, trigger CD-like disease. Our results also indicate that dietary approaches can be successfully used to target microbial-driven intestinal pathology.
EXPLORING CO-INFECTIONS IN THE GASTROINTESTINAL TRACT: DISSECTING THE INTERACTION BETWEEN FUSOBACTERIUM NUCLEATUM AND CLOSTRIDIODES DIFFICILE
Authors: Engevik Melinda , Danhof Heather , Auchtung Jennifer , Nicholson Maribeth , Wu Qinglong , Savidge Tor , Britton Robert , Versalovic James
Published: January 2021

Background

Clostridioides difficile is a common healthcare associated pathogen in U.S. hospitals, incurring billions of dollars in treatment costs each year. Microbiome analysis of C. difficile infected (CDI) patients have revealed alterations of the gut microbiota. It has been speculated that select members of this altered microbiota may influence C. difficile pathogenesis. C. difficile is known to reside in the intestinal mucus layer, but at present the interactions between C. difficile and other mucus-associated bacteria are poorly defined. To address these gaps in knowledge, we have focused on an entirely human-centered approach, employing human-derived MUC2, fecal bioreactors and patient samples. We hypothesized that select mucus-associated bacteria would promote C. difficile colonization and biofilm formation.

Methods & Results

To create a model of the human intestinal mucus layer and gut microbiota, we developed a bioreactor system with human MUC2-coated coverslips. Bioreactors were inoculated with healthy human feces, treated with clindamycin and infected with C. difficile to mimic CDI. C. difficile was found to colonize and form biofilms on MUC2-coated coverslips and 16S rRNA sequencing revealed a unique biofilm profile with substantial co-colonization with Fusobacterium. Consistent with our bioreactor data, publicly available datasets and patient stool samples revealed that a subset of patients with C. difficile infection harbored high levels of F. nucleatum OTUs. We also isolated microbes from adult patients and pediatric IBD patient stool who were positive for C. difficile and F. nucleatum and identified co-localization between these strains. RNAseq data revealed significant changes in C. difficile chemotaxis and surface adhesion genes following exposure to F. nucleatum metabolites. C. difficile was found to co-aggregate with F. nucleatum; an effect that was inhibited by blocking the Fusobacterial adhesin RadD and C. difficile flagella. Moreover, a ΔradD mutant of F. nucleatum lost the ability to aggregate with C. difficile. Conversely, removal of flagella from C. difficile significantly reduced the interaction between WT F. nucleatum and C. difficile. Addition of F. nucleatum also enhanced C. difficile biofilm formation, increasing the levels extracellular polysaccharide.

Conclusions

Collectively, these data demonstrate the unique role of mucus-associated bacteria such as F. nucleatum in facilitating colonization of the mucus layer by pathogenic C. difficile.
DIAGNOSIS CHANGES IN PEDIATRIC IBD: DATA FROM THE IMPROVECARENOW REGISTRY
Authors: Sandberg Kelly , Duarte Harold , Stolfi Adrienne , Saeed Shehzad
Published: January 2021

Background

The change in subclassification of inflammatory bowel diseases (IBD) among patients with Crohn’s (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-u) has previously been described in subpopulations of adult and pediatric patients. To date, no large, multinational registries have described characteristics of pediatric patients who change diagnosis.

Methods

We used the largest (27,628 individual patients for this study) prospective registry in the world for pediatric patients with IBD, ImproveCareNowR (ICN) to characterize those who change diagnosis. Diagnosis in the ICN registry is based on the Paris classification.

Results

7.52% of pediatric patients had any change in diagnosis; 5.19% of patients experienced a change in diagnosis after the initial 3 visits (Table 1). Those who start with a diagnosis of Crohn’s are more likely to change, as compared with starting diagnoses of ulcerative colitis or IBD-u (p < 0.05). A majority of changes involve a diagnosis of IBD-u (75.8%, Figure 1). Among those who change diagnoses, those with initial diagnoses of Crohn’s or IBD-u are more likely to have a BMI Z-score of less than -2, as compared to those with initial diagnosis of UC (p < 0.05). Patients with initial diagnosis of Crohn’s who changed after 3 visits were less likely to have ileocolonic extent, penetrating or stricturing phenotype, or perianal disease documented (p < 0.05). Signs of initial miscoding occurred in less than 0.3% of patients.

Discussion

This is the first reported use of a large prospective pediatric registry to investigate diagnosis changes within IBD. Registration diagnosis of Crohn’s appears to have more clinically impactful findings than those with UC or IBD-u. A majority of all changes involved a diagnosis of IBD-unclassified. Further investigation of diagnosis changes across time and modeling will supplement our understanding of clinical factors predictive of change.
A NOVEL APPROACH TO THE ENDOSCOPIC REPAIR OF AN ENTEROCUTANEOUS FISTULA IN A PATIENT WITH CROHN’S DISEASE
Authors: McKay Cortney , Brown Patrick , Schairer Jason
Published: January 2021

Introduction

Enterocutaneous fistula (ECF) is an abnormal connection that develops anywhere between the gastrointestinal tract and the skin. Fistulae most commonly occur in the context of inflammatory bowel disease. Standard definitive management involves surgery and biologic therapy. We present a case of an ECF treated with endoscopic and medical management.

Case Presentation

A 34-year-old man with Crohn’s disease with prior colectomy and ileorectal anastomosis presented with abdominal pain. CT enterography demonstrated a fistulous tract from the bowel to the anterior abdominal wall concerning for ECF. He subsequently underwent sigmoidoscopy with confirmation of ECF on the ileal side of his anastomosis. He was started on metronidazole 500 mg three times a day, azathioprine at 175 mg daily, and adalimumab 40 mg every other week in attempts to close the fistulous tract, however the patient reported continued drainage. Surgical correction was offered. However, in attempts to avoid surgical resection, he underwent sigmoidoscopy, where the tract was identified. A cytology brush was introduced into the fistula and used to irritate the epithelial layer to promote scarring. Next, doxycycline was injected through a scleroneedle into the track as a sclerosing agent. Argon plasma coagulation (APC) of the fistula internal os and surrounding tissue was performed, followed by deployment of 2 hemoclips to promote closure of the internal os. Initially there was closure but 2 months later there was recurrence of ECF. Sigmoidoscopy was repeated with administration of doxycycline to sclerose the tract, followed by APC to the tissue adjacent to the internal os, and the placement of a hemoclip to oppose the tissue around the internal os. Following endoscopic treatment, the patient’s ECF has remained healed. Since ECF closure, he has been in endoscopic and clinical remission for over 4 years.

Discussion

This approach was successful in the treatment of ECF. Doxycycline has been used for treatment of recurrent pleural effusions, lymphatic malformations and lymphoceles due to its sclerosing properties. Mechanism of action is unknown, but it is believed to be due to the induction of an inflammatory reaction that results in fibrosis and ablation of endothelial-lined cavities. APC has been used in the treatment of gastrointestinal conditions, including angiodysplasias and colonic polyps post polypectomy. There is limited evidence discussing its effectiveness of endoscopic fistulous repairs.

Our experience reviews that the combination of biologic therapy and endoscopic therapeutic options are a successful option in the treatment of ECF. While surgical resection remains a treatment option, patient’s typically favor less invasive strategies. Further studies should investigate endoscopic closure of fistulous tracts in order to provide more treatment modalities to our patients.
AMERICAN GASTROENTEROLOGICAL ASSOCIATION’S QUALITY LEADERSHIP COUNCIL’S PRACTICE WORK GROUP: A NATIONWIDE INITIATIVE TO REDUCE THE USE OF PRESCRIPTION OPIOID AMONG PATIENTS WITH INFLAMMATORY BOWEL DISEASE AT A LOCAL LEVEL
Authors: Siva Shivi , Tse Chung Sang , Coelho-Prabhu Nayantara , Jain Rajeev
Published: January 2021

Background and aims

The use of opioids among patients with inflammatory bowel disease (IBD) in the United States is increasing and it is associated with higher mortality, re-admissions, healthcare utilization, and disability. The American Gastroenterological Association’s (AGA) Quality Leadership Council’s practice workgroup developed educational materials to educate and modify narcotic prescribing habits of providers treating IBD and change the attitudes and expectations of patients who require analgesics.

Methods

Council members participated in two 1-hour virtual planning meetings to develop a key driver diagram to illustrate the aims, theories to achieve the aims, and specific action items to change ideas of opioid prescribing practices. Four working groups were created to perform a literature search and create educational resources for providers and patients regarding the risks of opioid use and non-opioid alternatives for pain management. The educational resources were reviewed by the Crohn’s and Colitis Foundation prior to online publication electronic and dissemination to the AGA membership.

Results

We developed a key driver diagram (Figure 1) to illustrate the components of promoting non-opioid pain management in patients with IBD. Educational materials were developed to 1) Delineate the risk factors for opioid abuse among patients with IBD to prescribers of a controlled substance including; Crohn’s disease, functional gastrointestinal disorders, anxiety, depression, female sex, a history of narcotic abuse, ≥2 previous surgeries, moderate to severe pain, clinical disease activity, sexual, emotional and physical abuse, 2) Recommend alternative therapies for opioids including medications and non-pharmacological treatment alternatives (Table 1), 3) Address salient key points that patients should discuss with their provider if an opioid is prescribed including complications associated with prolonged use of narcotic medications, and 4) Illustrate alternate medical therapy and other techniques for patients including yoga and mindfulness-based techniques, cognitive behavioral therapy, and medical hypnosis.

Conclusions

Using quality improvement methods, we developed educational materials for patients with IBD and providers treating IBD on opioid avoidance and non-opioid alternative therapy utilizing an evidence-based approach.
GUT-DIRECTED SELF-HYPNOSIS FOR INFLAMMATORY BOWEL DISEASE PROTOCOL: COMPLIMENTARY PSYCHOTHERAPY FOR REMISSION AUGMENTATION, IBS-LIKE SYMPTOMS, AND SURGERY RECOVERY
Authors: Paulton Joshua , Gill Amanjot , Prevost Joelle
Published: January 2021

Background

Gut-directed hypnosis (GDH) is a complimentary therapy for Inflammatory Bowel Disease (IBD), that can be learnt by patients to practice self-hypnosis. GDH in IBD has augmented remission and improved inflammation. GDH has a history of successful use for Irritable Bowel Syndrome (IBS). In IBD it may also improve IBS-like symptoms in remission and recovery from surgery. GDH is suitable for youth and adult IBD patients. In hypnosis, a relaxed state is inducted then suggestions to subconscious mind processes are made. In IBD, the mechanism of action of GDH is unknown but may influence the disease stress response.

Aims

Aims are the development of a GDH self-hypnosis protocol for IBD, with appropriate target symptoms. Patients first learn to practice with a clinician, then as complimentary psychotherapy for remission augmentation, IBS-like symptoms, and surgery recovery.

Methods

GDH is practiced first with a clinician, and then by patients as self-hypnosis (table 1). Patients receive psycho-education on GDH for IBD. Next, appropriate treatment goals are made, based on target symptoms. Relaxation techniques induce patient to a deeply relaxed state. Therapeutic suggestions specific to patient goals are given: verbal suggestions, visualizations, and post-hypnotic suggestions. Suggestions can focus on having a healthy digestive system, inflammation and symptoms reduction, and achievement and sustainment of remission. Patients emerge from hypnosis, are debriefed, and encouraged to practice ongoing self-hypnosis.

Results

In IBD, GDH self-hypnosis can be learnt from clinicians and practiced by patients as a complimentary therapy. Patients’ achievement and sustainment of remission, with clinical markers of inflammation can be monitored. Patients can monitor subjective improvement of IBS-like symptoms and post surgery, recovery progress can be monitored.

Conclusions

GDH has a history of use for IBS. In IBD, it has been shown to modulate remission, and may improve IBS-like symptoms, and in surgery recovery. The mechanism of action of GDH in IBD may influence the disease stress response. Clinicians trained in GDH are limited currently. Patients may learn GDH self- hypnosis to as a complimentary psychotherapy.
SELF-COMPASSION IN ADOLESCENTS AND YOUNG ADULTS WITH INFLAMMATORY BOWEL DISEASE: RELATIONSHIP OF SELF-COMPASSION TO PSYCHOLOGICAL AND PHYSICAL OUTCOMES
Authors: Neiman Nicole , Yeh Ann Ming , Bensen Rachel , Sanjines Elvi , Wren Anava
Published: January 2021

Background

Adolescents and young adults (AYA) with Inflammatory Bowel Disease (IBD) are at increased risk for poor psychological and physical well-being. Self-compassion (i.e., understanding and acceptance towards oneself) has been associated with better psychological and physical outcomes in AYA with chronic health conditions. There is limited research exploring self-compassion in AYA with IBD.

Aims

To examine: 1) the reliability of a Self-Compassion Scale (SCS-SF), and 2) how self-compassion relates to physical (i.e., pain interference, fatigue) and psychological (i.e., stress, anxiety, depression) outcomes in a sample of AYA with IBD.

Methods

This study was a collaboration with ImproveCareNow, and all procedures were approved by Stanford’s Institutional Review Board. Study participants included 85 AYA (mean=18 yrs) with IBD (52% Crohn’s; 55% female; 61% White). Participants completed a one-time online survey. The internal reliability of SCS-SF was a = 0.88, indicating high internal consistency. Hierarchical linear regression (HLR) analyses examined the unique contribution of self-compassion to pain interference, fatigue, physical stress, psychological stress, anxiety, and depression after controlling for significant demographic and medical variables (sex, IBD diagnosis, mental health diagnosis).

Results

The overall HLR models were significant for all dependent variables. For physical outcomes, the overall model examining pain interference was significant (F(3, 72) = 4.517; P = 0.003), with sex, IBD diagnosis, and mental health diagnosis accounting for 13% of the variance in pain interference. Self-compassion accounted for an additional 20% of the variance in pain interference over and above demographic/medical variables. For psychological outcomes, the overall model examining anxiety was significant (F(3, 73) = 15.54; P < 0.001), with sex, IBD diagnosis, and mental health diagnosis accounting for 33% of the variance in anxiety. Self-compassion accounted for an additional 46% of the variance in anxiety over and above demographic/medical variables. HLR also demonstrated that self-compassion was a significant independent predictor of pain interference (b = -0.30, P = 0.015), fatigue (b = -0.38, P = 0.001), psychological stress (b = -0.51, P = < 0.001), anxiety (b = -0.41, P = < 0.001), and depression (b = -0.59, P = < 0.001). Participants reporting higher levels of self-compassion had less pain interference, fatigue, stress, anxiety, and depression.

Conclusion

Preliminary results suggest self-compassion may be an important factor in explaining the variability of key physical and psychological outcomes among AYA with IBD. Research should investigate self-compassion in diverse IBD populations, and explore if feelings of kindness and acceptance towards oneself can be a protective factor for AYA by supporting positive coping and adjustment to IBD.
BLOOD-BASED PROGNOSTIC BIOMARKERS IN CROHN’S PATIENTS TREATED WITH BIOLOGICS: A NEW PROMISING TOOL TO PREDICT ENDOSCOPIC OUTCOMES
Authors: Grova Mauro , Crispino Federica , Maida Marcello , Renna Sara , Mocciaro Filippo , Casa Angelo , Giulia Rizzuto , Scimeca Daniela , Di Mitri Roberto , Macaluso Fabio Salvatore , Orlando Ambrogio
Published: January 2021

Background and aims

There is a growing need for biomarkers of inflammation to monitor and predict therapeutic outcome in Crohn’s disease (CD) patients. We aimed to evaluate whether the level of circulating blood cells, expressed as ratios (NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; ELR, eosinophil-to-lymphocyte ratio and ENLR, eosinophil*neutrophil-to-lymphocyte ratio), could be used as early prognostic biomarker of endoscopic response (ER) in patients starting biological therapy with infliximab, adalimumab, vedolizumab and ustekinumab. Association with steroid-free clinical remission at week 54 and endoscopic disease activity at baseline, as well as other variables related with ER were also evaluated as secondary outcomes.

Methods

Consecutive patients with CD who started biological therapy between June 2016 and July 2019 in two Italian tertiary centers were enrolled. We used multivariate analysis to evaluate whether NLR, PLR, ELR and ENLR at baseline and after 12 weeks of treatment could predict ER (SES-CD ≤ 2 or SES-CD ≤ 2 and Rutgeerts score i0-i1) after 54 weeks of treatment. Receiver operating characteristic (ROC) curves were generated to identify the area under the curve (AUC) and find the best cut-off values of NLR, PLR, ELR and ENLR for the prediction of ER. To enhance the diagnostic performance, these ratios were combined with baseline Harvey Bradshaw Index (HBI) in a prognostic model.

Results

107 patients were included. Patients who achieved ER had significantly lower baseline NLR (p = 0.025), ELR (p = 0.013) and ENLR (p = 0.021) compared with those without ER; similar results were confirmed after 12 weeks of treatment for ELR (p = 0.006) and ENLR (p = 0.026). AUC was 0.64 (p = 0.003), 0.67 (p = 0.006) and 0.65 (p=0.014) for NLR, ELR and ENLR, respectively. The best cut-offs values were included in the HBI-based prognostic model: 81.8% of patients with HBI ≥ 5 and higher ratios did not achieve ER, while all patients with HBI < 5 and lower ratios reached ER. Interestingly, ENLR was found to be linearly associated with SES-CD at baseline (p= 0.035).

Conclusions

To the best of our knowledge, this is the first study assessing NLR, ELR and ENLR as predictive markers of therapeutic response in CD patients. Low levels of these ratios can predict endoscopic response and could be used in clinical practice for a better management of CD patients needing biological therapy. Further prospective studies are needed to confirm these results in larger cohorts.
EFFICACY OF INFLIXIMAB DOSE ESCALATION IN PATIENTS WITH REFRACTORY IMMUNOTHERAPY-RELATED COLITIS: A CASE SERIES
Authors: Harris Jessica , Faleck David
Published: January 2021

Introduction

Immune checkpoint inhibitor (ICI)-related colitis (irColitis) is a frequent complication of ICI use in cancer. Treatment algorithms have been adapted from the treatment of inflammatory bowel disease (IBD), including the use of infliximab (IFX) for patients with irColitis refractory to corticosteroids. The efficacy of IFX dose-escalation in patients not responding to standard dose IFX, a common practice in patients with severe IBD, has not been reported in irColitis.

Methods

We describe a retrospective study of patients treated with IFX dose escalation (i.e. 10mg/kg dose) after failure of standard dose IFX (5mg/kg) for irColitis at a tertiary care center in New York City between 2016–2020. Clinical response was defined as improvement in diarrhea to CTCAE Grade ≤1.

Results

Ten patients were treated with high dose IFX for refractory irColitis. High dose IFX was started after a median of 2 (IQR 2-2) doses of standard dose IFX for non-response (n=2) or incomplete response (n=8). Five (50%) patients had a clinical response to high dose IFX after a median of 4 (IQR 3–6) days. Five (50%) patients were refractory to high dose IFX and were treated with Vedolizumab (n= 5) and/or fecal microbiota transplantation (n=2). Patients were followed for a median 457 (IQR 325–567) days from initiation of ICI therapy. No adverse events attributed to IFX were observed in any of the patients.

Discussion

In this series of patients with irColitis refractory to standard dose IFX, high dose IFX was successful in inducing response in 50% of patients. Prospective studies are needed to further elucidate the role and optimal dosing of IFX in irColitis.
Operationalizing ensemble models for scientific advice to fisheries management
Authors: Jardim Ernesto , Azevedo Manuela , Brodziak Jon , Brooks Elizabeth N , Johnson Kelli F , Klibansky Nikolai , Millar Colin P , Minto Cóilín , Mosqueira Iago , Nash Richard D M , Vasilakopoulos Paraskevas , Wells Brian K
Published: January 2021

This paper explores the possibility of using the ensemble modelling paradigm to fully capture assessment uncertainty and improve the robustness of advice provision. We identify and discuss advantages and challenges of ensemble modelling approaches in the context of scientific advice. There are uncertainties associated with every phase in the stock assessment process: data collection, assessment model choice, model assumptions, interpretation of risk, up to the implementation of management advice. Additionally, the dynamics of fish populations are complex, and our incomplete understanding of those dynamics and limited observations of important mechanisms, necessitate that models are simpler than nature. The aim is for the model to capture enough of the dynamics to accurately estimate trends and abundance, and provide the basis for robust advice about sustainable harvests. The status quo approach to assessment modelling has been to identify the “best” model and generate advice from that model, mostly ignoring advice from other model configurations regardless of how closely they performed relative to the chosen model. We discuss and make suggestions about the utility of ensemble models, including revisions to the formal process of providing advice to management bodies, and recommend further research to evaluate potential gains in modelling and advice performance.
Interaction frequency of seabirds with longline fisheries: risk factors and implications for management
Authors: Zhou Can , Brothers Nigel
Published: January 2021

Fishery bycatch poses a serious threat to seabird populations globally. Traditional haul-only post-capture observations are inadequate and inefficient to document seabird bycatch due to the substantial bycatch loss known to occur. Pre-capture observations offer an alternative by documenting seabird interactions leading up to captures. Based on the long-term large-scale dedicated field observations, this study revealed significant risk factors for the pre-capture stages of the seabird bycatch process in pelagic longline fisheries using Bayesian methods. Rough sea conditions were found to correlate with more seabirds following fishing vessels. Species identity, density effect, inter-species effect, and sea condition were found to significantly affect how frequently seabirds aggregated around a fishing vessel engage in bait-taking interactions. Intra-species competition was found to be the dominant type of density effect. Moreover, a web of inter-species interactions was identified to facilitate the bait-taking of superior competitors at the expense of inferior ones. The findings of this study are relevant to fishery managers in updating current data collection protocols to alleviate data issues caused by bycatch loss, to conservation biologists in quantifying bycatch risks for susceptible seabird populations, and in aiding the design and evaluation of bycatch mitigation measures.
Superior Efficacy of a Bedaquiline, Delamanid, and Linezolid Combination Regimen in a Mouse Tuberculosis Model
Authors: Pieterman Elise D , Keutzer Lina , van der Meijden Aart , van den Berg Sanne , Wang Han , Zimmerman Matthew D , Simonsson Ulrika S H , Bax Hannelore I , de Steenwinkel Jurriaan E M
Published: January 2021

Background

The treatment success rate of drug-resistant (DR) tuberculosis is alarmingly low. Therefore, more effective and less complex regimens are urgently required.

Methods

We compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg), and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks. This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Relapse was assessed 12 weeks after treatment. Two logistic regression models were developed to compare the efficacy of both regimens.

Results

Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only 1 mouse had relapse in the BDL group, while in the HRZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively.

Conclusion

The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR tuberculosis.
Digital phenotyping and sensitive health data: Implications for data governance
Authors: Perez-Pozuelo Ignacio , Spathis Dimitris , Gifford-Moore Jordan , Morley Jessica , Cowls Josh
Published: January 2021

In this perspective we want to highlight the rise of what we call “digital phenotyping” or inferring insights about peopleãs health and behavior from their digital devices and data, and the challenges this introduces. Indeed, the collection, processing, and storage of data comes with significant ethical, security and data governance considerations. The COVID-19 pandemic has laid bare the importance of scientific data and modeling, both to understand the nature and spread of the disease, and to develop treatment. But digital devices have also played a (controversial) role, with track and trace systems and increasingly “vaccine passports” being rolled out to help societies open back up. These systems epitomize a wider and longer-standing trend towards seeing almost any form of personal data as potentially health data, especially with the rise of consumer health trackers and other gadgets. Here, we offer an overview of the risks this introduces, drawing on the earlier revolution in genomic sequencing, and propose guidelines to help protect privacy whilst utilizing personal data to help get society back up to speed.
Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study
Authors: Van Dyk Kathleen , Zhou Xingtao , Small Brent J , Ahn Jaeil , Zhai Wanting , Ahles Tim , Graham Deena , Jacobsen Paul B , Jim Heather , McDonald Brenna C , Nudelman Holohan Kelly , Patel Sunita K , Rebeck G William , Root James C , Saykin Andrew J , Cohen Harvey Jay , Mandelblatt Jeanne S , Carroll Judith E
Published: January 2021

Background

Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated.

Methods

We evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity.

Results

There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores.

Conclusions

APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.
s.Two Implementation and Accountability, 7 Monitoring and Review to Assess Human Rights Implementation
Authors: Benjamin Mason Meier , Hanna Huffstetler , Judith Bueno de Mesquita
Published: January 2021

This chapter analyzes the fundamental importance of monitoring and review procedures to assess the implementation of human rights to advance public health. Recognizing monitoring and review as central to human rights accountability, the evolving functions of human rights monitoring highlight the range of national, regional, and international review mechanisms that provide oversight to support the realization of health-related human rights. While these mechanisms often do not have judicial powers—their recommendations are advisory rather than legally binding—the interpretive role entrusted to these review procedures has endowed their health-related recommendations with legitimacy in clarifying human rights treaty provisions and reviewing state efforts to meet treaty obligations. Assessing the implementation of international human rights law through national practice, monitoring institutions can facilitate human rights accountability for public health promotion and operationalize public health data to press governments to implement rights.
s.Two Implementation and Accountability, 9 Advancing Human Rights through Global Health Governance
Authors: Benjamin Mason Meier , Margherita Marianna Cinà , Lawrence O Gostin
Published: January 2021

This chapter addresses the international organizations that have accepted human rights obligations as a way of framing their global health policies, programs, and practices. International organizations within the United Nations (UN) system are engaged in implementing human rights—in both the mission they carry out and the way in which they carry out that mission. The UN has called on all programs, funds, and specialized agencies to mainstream human rights across their efforts, and various agencies have taken up this call to advance human rights for public health – beginning with the evolving role of the World Health Organization and expanding to encompass a sweeping set of international organizations that address health determinants. While there remain obstacles to the systematic operationalization of human rights across the global health governance landscape, international organizations are seeking to integrate their efforts to mainstream human rights in global health.
s.Four New Challenges, 18 Human Subjects in Globalized Health Research
Authors: Andrés Constantin , Roberto Andorno
Published: January 2021

The clinical trials enterprise has expanded globally, involving research developed and owned by research institutions in wealthy countries but conducted with participants in low- and middle-income countries (LMICs). These LMICs commonly provide ready access to large pools of subjects who have never received a particular drug and have—at least historically—a more permissive regulatory environment, raising important questions about the rights of vulnerable participants. The unequal power dynamic and imbalances between researchers and human subjects require specific norms and procedures to respect and protect the human rights of trial participants. Complementing bioethics norms, human rights law offers a lens for understanding participant and public health interests, recognizing the unequal dynamic between the researcher and the individual subject, and furthering the participants’ autonomy and decision-making power. Framing these issues in human rights obligations additionally offers new forms of governance and accountability mechanisms, raising new opportunities for legally enforceable claims.
s.Four New Challenges, 19 The Environment, a Changing Climate, and Planetary Health
Authors: Alexandra L Phelan
Published: January 2021

This chapter addresses the dynamic balance between human health and the environment, with a focus on the global health and human rights threat of climate change. International legal efforts to mitigate environmental damage and climate change—from the 1992 United Nations Framework Convention on Climate Change and its 1997 Kyoto Protocol to the 2015 Paris Agreement—have been limited in addressing the threats posed to global health. Human rights will be necessary to examine efforts to mitigate and respond to these cataclysmic threats, including rising temperatures and extreme weather events, air pollution, infectious diseases, food, water and sanitation, and mental health. Facing this unprecedented threat, advocates can draw from past advances, including the use of litigation to protect human rights affected by the environment, the realization of the right to enjoy the benefits of scientific progress, and the implementation of human rights as a foundation of planetary health.