89Zr-ImmunoPET for the Specific Detection of EMP2-Positive Tumors.

Epithelial membrane protein-2 (EMP2) is upregulated in a number of tumors and therefore remains a promising target for mAb-based therapy. In the current study, image-guided therapy for an anti-EMP2 mAb was evaluated by PET in both syngeneic and immunodeficient cancer models expressing different levels of EMP2 to enable a better understanding of its tumor uptake and off target accumulation and clearance. The therapeutic efficacy of the anti-EMP2 mAb was initially evaluated in high- and low-expressing tumors, and the mAb reduced tumor load for the high EMP2-expressing 4T1 and HEC-1-A tumors. To create an imaging agent, the anti-EMP2 mAb was conjugated to p-SCN-Bn-deferoxamine (DFO) and radiolabeled with 89Zr. Tumor targeting and tissue biodistribution were evaluated in syngeneic tumor models (4T1, CT26, and Panc02) and human tumor xenograft models (Ramos, HEC-1-A, and U87MG/EMP2). PET imaging revealed radioactive accumulation in EMP2-positive tumors within 24 hours after injection, and the signal was retained for 5 days. High specific uptake was observed in tumors with high EMP2 expression (4T1, CT26, HEC-1-A, and U87MG/EMP2), with less accumulation in tumors with low EMP2 expression (Panc02 and Ramos). Biodistribution at 5 days after injection revealed that the tumor uptake ranged from 2 to approximately 16%ID/cc. The results show that anti-EMP2 mAbs exhibit EMP2-dependent tumor uptake with low off-target accumulation in preclinical cancer models. The development of improved anti-EMP2 Ab fragments may be useful to track EMP2-positive tumors for subsequent therapeutic interventions.

A Paratope-Enhanced Method to Determine Breadth and Depth TCR Clonal Metrics of the Private Human T-Cell Vaccine Response after SARS-CoV-2 Vaccination.

Quantitative metrics for vaccine-induced T-cell responses are an important need for developing correlates of protection and their use in vaccine-based medical management and population health. Molecular TCR analysis is an appealing strategy but currently requires a targeted methodology involving complex integration of ex vivo data (antigen-specific functional T-cell cytokine responses and TCR molecular responses) that uncover only public antigen-specific metrics. Here, we describe an untargeted private TCR method that measures breadth and depth metrics of the T-cell response to vaccine challenge using a simple pre- and post-vaccine subject sampling, TCR immunoseq analysis, and a bioinformatic approach using self-organizing maps and GLIPH2. Among 515 subjects undergoing SARS-CoV-2 mRNA vaccination, we found that breadth and depth metrics were moderately correlated between the targeted public TCR response and untargeted private TCR response methods. The untargeted private TCR method was sufficiently sensitive to distinguish subgroups of potential clinical significance also observed using public TCR methods (the reduced T-cell vaccine response with age and the paradoxically elevated T-cell vaccine response of patients on anti-TNF immunotherapy). These observations suggest the promise of this untargeted private TCR method to produce T-cell vaccine-response metrics in an antigen-agnostic and individual-autonomous context.

Environmental Interaction of Resolved Human Cytomegalovirus Infection With Crohn's Disease Location.

Active cytomegalovirus (CMV) infection complicates management of inflammatory bowel disease, but the relationship of resolved CMV infection to Crohn's disease (CD) behavior or localization is unknown. This article reports a striking risk (9-fold) of Crohn's disease localization to the colon with prior CMV infection. It also reports imputed mucosal cellular composition, HLA class 1, and KIR gene variants that delimit prior observations regarding HLA and KIR associations with Crohn's disease risk and behavior.

Novel Diagnostic Autoantibodies Against Endothelial Protein C Receptor in Patients With Ulcerative Colitis.

There have been many reports on serologic autoantibodies in inflammatory bowel diseases (IBD),1 consisting of ulcerative colitis (UC) and Crohn's disease (CD), and recently Kuwada et al2 reported a new autoantibody against integrin αvß6 with high sensitivity and specificity for UC. Concurrently, we had discovered autoantibodies against endothelial protein C receptor (EPCR) in Takayasu arteritis (TAK), which is sometimes complicated by UC.3 Interestingly, this autoantibody was found in most patients with TAK associated with UC, and we found that the positivity rate in patients with UC without TAK was also high, suggesting that anti-EPCR antibody is a candidate autoantibody useful for the diagnosis of UC.4 To clarify the diagnostic usefulness of anti-EPCR antibodies in patients with IBD and their relationship to several disease subphenotypes and their disease activities, we analyzed the serum samples from patients with IBD and non-IBD control subjects in Japan and the United States.

Crohn's disease in endoscopic remission, obesity, and cases of high genetic risk demonstrates overlapping shifts in the colonic mucosal-luminal interface microbiome.

BACKGROUND: Crohn's disease (CD) patients demonstrate distinct intestinal microbial compositions and metabolic characteristics compared to unaffected controls. However, the impact of inflammation and underlying genetic risk on these microbial profiles and their relationship to disease phenotype are unclear. We used lavage sampling to characterize the colonic mucosal-luminal interface (MLI) microbiome of CD patients in endoscopic remission and unaffected controls relative to obesity, disease genetics, and phenotype. METHODS: Cecum and sigmoid colon were sampled from 110 non-CD controls undergoing screening colonoscopy who were stratified by body mass index and 88 CD patients in endoscopic remission (396 total samples). CD polygenic risk score (GRS) was calculated using 186 known CD variants. MLI pellets were analyzed by 16S ribosomal RNA gene sequencing, and supernatants by untargeted liquid chromatography-mass spectrometry. RESULTS: CD and obesity were each associated with decreased cecal and sigmoid MLI bacterial diversity and distinct bacterial composition compared to controls, including expansion of Escherichia/Shigella. Cecal and sigmoid dysbiosis indices for CD were significantly greater in obese controls than non-overweight controls. CD, but not obesity, was characterized by altered biogeographic relationship between the sigmoid and cecum. GRS was associated with select taxonomic shifts that overlapped with changes seen in CD compared to controls including Fusobacterium enrichment. Stricturing or penetrating Crohn's disease behavior was characterized by lower MLI bacterial diversity and altered composition, including reduced Faecalibacterium, compared to uncomplicated CD. Taxonomic profiles including reduced Parasutterella were associated with clinical disease progression over a mean follow-up of 3.7 years. Random forest classifiers using MLI bacterial abundances could distinguish disease state (area under the curve (AUC) 0.93), stricturing or penetrating Crohn's disease behavior (AUC 0.82), and future clinical disease progression (AUC 0.74). CD patients showed alterations in the MLI metabolome including increased cholate:deoxycholate ratio compared to controls. CONCLUSIONS: Obesity, CD in endoscopic remission, and high CD genetic risk have overlapping colonic mucosal-luminal interface (MLI) microbiome features, suggesting a shared microbiome contribution to CD and obesity which may be influenced by genetic factors. Microbial profiling during endoscopic remission predicted Crohn's disease behavior and progression, supporting that MLI sampling could offer unique insight into CD pathogenesis and provide novel prognostic biomarkers.

Mission, Organization, and Future Direction of the Serological Sciences Network for COVID-19 (SeroNet) Epidemiologic Cohort Studies.

Background: Global efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies. Methods: In the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders). Results: Several studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes. Conclusions: In this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

The T-Cell Response to SARS-CoV-2 Vaccination in Inflammatory Bowel Disease is Augmented with Anti-TNF Therapy.

T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 vaccination in inflammatory bowel disease patients are poorly correlated. T-cell responses are preserved by most biologic therapies, but augmented by anti-tumor necrosis factor (anti-TNF) treatment. While anti-TNF therapy blunts the antibody response, cellular immunity after vaccination is robust.

Magnetic resonance imaging for characterization of hepatocellular carcinoma metabolism.

With a better understanding of the pathophysiological and metabolic changes in hepatocellular carcinoma (HCC), multiparametric and novel functional magnetic resonance (MR) and positron emission tomography (PET) techniques have received wide interest and are increasingly being applied in preclinical and clinical research. These techniques not only allow for non-invasive detection of structural, functional, and metabolic changes in malignant tumor cells but also characterize the tumor microenvironment (TME) and the interactions of malignant tumor cells with the TME, which has hypoxia and low pH, resulting from the Warburg effect and accumulation of metabolites produced by tumor cells and other cellular components. The heterogeneity and complexity of the TME require a combination of images with various parameters and modalities to characterize tumors and guide therapy. This review focuses on the value of multiparametric magnetic resonance imaging and PET/MR in evaluating the structural and functional changes of HCC and in detecting metabolites formed owing to HCC and the TME.

Longitudinal SARS-CoV-2 mRNA Vaccine-Induced Humoral Immune Responses in Patients with Cancer.

Longitudinal studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced immune responses in patients with cancer are needed to optimize clinical care. In a prospective cohort study of 366 (291 vaccinated) patients, we measured antibody levels [anti-spike (IgG-(S-RBD) and anti-nucleocapsid immunoglobulin] at three time points. Antibody level trajectories and frequency of breakthrough infections were evaluated by tumor type and timing of treatment relative to vaccination. IgG-(S-RBD) at peak response (median = 42 days after dose 2) was higher (P = 0.002) and remained higher after 4 to 6 months (P = 0.003) in patients receiving mRNA-1273 compared with BNT162b2. Patients with solid tumors attained higher peak levels (P = 0.001) and sustained levels after 4 to 6 months (P < 0.001) compared with those with hematologic malignancies. B-cell targeted treatment reduced peak (P = 0.001) and sustained antibody responses (P = 0.003). Solid tumor patients receiving immune checkpoint inhibitors before vaccination had lower sustained antibody levels than those who received treatment after vaccination (P = 0.043). Two (0.69%) vaccinated and one (1.9%) unvaccinated patient had severe COVID-19 illness during follow-up. Our study shows variation in sustained antibody responses across cancer populations receiving various therapeutic modalities, with important implications for vaccine booster timing and patient selection. SIGNIFICANCE: Long-term studies of immunogenicity of SARS-CoV-2 vaccines in patients with cancer are needed to inform evidence-based guidelines for booster vaccinations and to tailor sequence and timing of vaccinations to elicit improved humoral responses.

Debaryomyces is enriched in Crohn's disease intestinal tissue and impairs healing in mice.

Alterations of the mycobiota composition associated with Crohn's disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that Debaryomyces hansenii preferentially localized to and was abundant within incompletely healed intestinal wounds of mice and inflamed mucosal tissues of CD human subjects. D. hansenii cultures from injured mice and inflamed CD tissues impaired colonic healing when introduced into injured conventionally raised or gnotobiotic mice. We reisolated D. hansenii from injured areas of these mice, fulfilling Koch's postulates. Mechanistically, D. hansenii impaired mucosal healing through the myeloid cell-specific type 1 interferon-CCL5 axis. Taken together, we have identified a fungus that inhabits inflamed CD tissue and can lead to dysregulated mucosal healing.

Outcomes after Endovascular Stent Placement for Long-Segment Superficial Femoral Artery Lesions.

BACKGROUND: Endovascular intervention is commonly pursued as first-line management of symptomatic, long-segment superficial femoral artery (SFA) disease. The relative effectiveness and comparative long-term outcomes among bare metal stents (BMS), covered stents (CS), and drug-eluting stents (DES) for long-segment SFA lesions remain uncertain. METHODS: A retrospective cohort study identified patients with symptomatic SFA lesions measuring at least 15 cm in length who successfully received an endovascular stent (BMS, CS, or DES). The outcomes were patency, patient presentation upon stent occlusion, amputation-free survival (AFS), and all-cause mortality. Proportional hazards regressions and a multinomial logistic regression model were used to control for significant confounders. RESULTS: A total of 226 procedures were analyzed (BMS: 95 [42%]; CS: 74 [33%]; DES: 57 [25%]). There were no significant differences among the 3 stent types with respect to age, prevalence of either diabetes or end-stage renal disease, or smoking history. The median length of the SFA lesion varied across the cohorts (BMS: 28 cm [interquartile range, IQR 20-30]; CS: 26 cm [IQR 20-30]; DES: 20 cm [IQR 16-25]; P = 0.002). The unadjusted primary patency of BMS at 12, 24, and 48 month following index stent placement was 57%, 47%, and 44%, respectively. This is compared to 62%, 49%, and 42% for CS, and 81%, 66%, and 53% for DES, respectively (log-rank P = 0.044). In adjusted models, however, there were no significant differences in primary patency among the stent types. Compared to CS however, DES was associated with improved primary-assisted patency (hazard ratio [HR] for patency loss: 0.35, P = 0.008) and secondary patency (HR: 0.32, P = 0.011). Across the entire follow-up period, stent occlusions occurred in 38 (40%) BMS cases, 42 (57%) CS, and 11 (19%) DES (P < 0.001). Of these, acute limb ischemia (ALI) occurred in 2 (5%) BMS cases, 14 (33%) CS, and 1 (9%) DES (P = 0.010). After adjustment, the relative risk of presenting with ALI as opposed to claudication was 27 times greater among patients re-presenting with occluded CS compared to BMS (P = 0.020). There were no significant differences in AFS or all-cause mortality across the 3 cohorts. CONCLUSIONS: For long-segment SFA lesions, DES is associated with improved primary-assisted and secondary patency over long-term follow-up. In the event of stent occlusion, CS is associated with an increased risk of ALI.

Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls. METHODS: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti-tumor necrosis factor and anti-interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted. RESULTS: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-tumor necrosis factor rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders. CONCLUSIONS: Reduced SB but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease, but normalized after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines.

Biomarkers of Crohn's Disease to Support the Development of New Therapeutic Interventions.

BACKGROUND: Currently, 2 coprimary end points are used by health authorities to determine the effectiveness of therapeutic interventions in patients with Crohn's disease (CD): symptomatic remission (patient-reported outcome assessment) and endoscopic remission (ileocolonoscopy). However, there is lack of accepted biomarkers to facilitate regulatory decision-making in the development of novel therapeutics for the treatment of CD. METHODS: With support from the Helmsley Charitable Trust, Critical Path Institute formed the Crohn's Disease Biomarkers preconsortium (CDBpC) with members from the pharmaceutical industry, academia, and nonprofit organizations to evaluate the CD biomarker landscape. Biomarkers were evaluated based on biological relevance, availability of biomarker assays, and clinical validation data. RESULTS: The CDBpC identified the most critical need as pharmacodynamic/response biomarkers to monitor disease activity in response to therapeutic intervention. Fecal calprotectin (FC) and serum C-reactive protein (CRP) were identified as biomarkers ready for the regulatory qualification process. A number of exploratory biomarkers and potential panels of these biomarkers was also identified for additional development. Given the different factors involved in CD and disease progression, a combination of biomarkers, including inflammatory, tissue injury, genetic, and microbiome-associated biomarkers, will likely have the most utility. CONCLUSIONS: The primary focus of the Inflammatory Bowel Disease Regulatory Science Consortium will be development of exploratory biomarkers and the qualification of FC and CRP for IBD. The Inflammatory Bowel Disease Regulatory Science Consortium, focused on tools to support IBD drug development, will operate in the precompetitive space to share data, biological samples for biomarker testing, and assay information for novel biomarkers.

EMP2 Is a Novel Regulator of Stemness in Breast Cancer Cells.

Little is known about the role of epithelial membrane protein-2 (EMP2) in breast cancer development or progression. In this study, we tested the hypothesis that EMP2 may regulate the formation or self-renewal of breast cancer stem cells (BCSC) in the tumor microenvironment. In silico analysis of gene expression data demonstrated a correlation of EMP2 expression with known metastasis-related genes and markers of cancer stem cells (CSC) including aldehyde dehydrogenase (ALDH). In breast cancer cell lines, EMP2 overexpression increased and EMP2 knockdown decreased the proportion of stem-like cells as assessed by the expression of the CSC markers CD44+/CD24-, ALDH activity, or by tumor sphere formation. In vivo, upregulation of EMP2 promoted tumor growth, whereas knockdown reduced the ALDHhigh CSC population as well as retarded tumor growth. Mechanistically, EMP2 functionally regulated the response to hypoxia through the upregulation of HIF-1α, a transcription factor previously shown to regulate the self-renewal of ALDHhigh CSCs. Furthermore, in syngeneic mouse models and primary human tumor xenografts, mAbs directed against EMP2 effectively targeted CSCs, reducing the ALDH+ population and blocking their tumor-initiating capacity when implanted into secondary untreated mice. Collectively, our results show that EMP2 increases the proportion of tumor-initiating cells, providing a rationale for the continued development of EMP2-targeting agents.

Long-term outcomes of lower extremity graft preservation using antibiotic beads in patients with early deep wound infections after major arterial reconstructions.

OBJECTIVE: Bypass graft preservation with wound sterilization using serial antibiotic bead exchange has been described in patients presenting with deep wound infections after extremity bypass. The long-term benefits of this approach remain poorly understood. We examined whether graft preservation and wound sterilization with antibiotic beads affect amputation rates and patient survival. METHODS: Patients who underwent operations for aortoiliac or infrainguinal aneurysmal or occlusive arterial disease were retrospectively analyzed. The Infection group included those with patent vascular grafts who developed Szilagyi class II or III deep wound infections within 90 days of index reconstruction and had no evidence of anastomotic or arterial bleeding. All patients in the infection group were managed with graft preservation using serial antibiotic bead exchange every 3 to 5 days until wound cultures became negative. This group was compared with a contemporary group of controls who underwent similar interventions but did not develop wound infections postoperatively. The primary outcome was amputation-free survival, defined as survival without major amputation. Secondary outcomes included major amputations and the occurrence of anastomotic pseudoaneurysms necessitating repair. Inverse propensity score weighting was used for risk adjustment between the groups. RESULTS: Over an 8-year period, we treated 701 patients (infection, 68; controls, 633). Compared with controls, patients in the infection group had a higher body mass index (mean, 28.5 vs 26.3, P = .002) and more prosthetic conduits placed during the index reconstruction. Amputation-free survival for the infection vs the control group was 78 vs 76% at 2 years, 61 vs 66% at 4 years, and 51 vs 57% at 6 years postoperatively (log-rank test, P = .516). Freedom from major amputation for the infection vs the control group was 82 vs 86% at 2 years, 80 vs 82% at 4 years, and 80 vs 76% at 6 years postoperatively (log-rank test, P = .568). In the risk-adjusted model, the presence of treated infection did not affect amputation-free survival (hazard ratio, 0.82; P = .440) or major amputation (hazard ratio, 1.02; P = .949). Anastomotic pseudoaneurysms occurred only in the Infection group (4.4%; P = .001), and were treated with interposition grafts without complications. CONCLUSIONS: Bypass graft preservation with wound sterilization using serial antibiotic bead exchange is associated with excellent limb salvage and survival rates, similar to those of noninfected wounds. With the use of this preservation strategy, close follow-up for timely detection of anastomotic pseudoaneurysms is recommended.

Arteriovenous fistula maturation rate is not affected by ipsilateral tunneled dialysis catheter.

OBJECTIVE: The effect that ipsilateral tunneled dialysis catheters (TDC) have on arteriovenous fistula (AVF) maturation is unclear. We sought to define this association by comparing AVF maturation rates in patients with contralateral TDC with those with ipsilateral TDC. METHODS: A review of a prospectively maintained database including all AVF creation procedures between 2009 and 2016 was performed. All patients with a TDC in place at the time of AVF creation were included in this study. Clinical and functional maturation rates were compared in patients with contralateral vs ipsilateral dialysis catheters. Categorical variables were analyzed by a two-tailed Fisher's exact test. A P value of less than .05 was considered statistically significant. RESULTS: There were 187 patients who underwent fistula creation with a TDC in place during the study period. Of those, 137 patients had a contralateral TDC and 50 had an ipsilateral TDC. A greater proportion of contralateral patients were first-time dialysis access patients at the time of index AVF creation (67% vs 48%; P = .03). There was no difference in clinical (contralateral 73% vs ipsilateral 78%; P = .57) and functional (contralateral 64% vs ipsilateral 74%) maturation rates between the two groups. The rate of TDC removal after AVF maturation was also not different (contralateral 64% vs ipsilateral 72%; P = .30). There was also no statistical difference in the rates of thrombosis at less than 30 days, outflow stenosis, central stenosis, and steal syndrome. CONCLUSIONS: There was no association between TDC sidedness and AVF maturation or early failure in our cohort. Planning for AVF creation should not be influenced by attempts to avoid an ipsilateral TDC.

The promising future of drones in prehospital medical care and its application to battlefield medicine.

Unmanned aerial vehicles, commonly referred to as drones, have been made widely available in recent years leading to an exponential growth in their roles and applications. The rapidly developing field of medical drones is on the verge of revolutionizing prehospital medicine enabling advanced health care delivery to once-inaccessible patients. The aim of this review is to clarify the basic technical properties of currently available medical drones and review recent advances and their usefulness in military and civilian health care missions. A thorough search was conducted using conventional medical literature databases and nonmedical popular search engines. The results indicate increasingly rapid incorporation of unmanned aerial vehicles into search and rescue missions, telemedicine assignments, medical supply routes, public health surveillance, and disaster management. Medical drones appear to be of great benefit for improving survivability of deployed forces on and off the battlefield. The emerging aerial medical delivery systems appear to provide particularly promising solutions for bridging some of the many serious gaps between third world health care systems and their western counterparts and between major metropolitan centers and distant rural communities. The global nature of drone-based health care delivery needs points to a need for an international effort between collaborating civilian and military medical forces to harness the currently available resources and novel emerging technologies for broader lifesaving capabilities. LEVEL OF EVIDENCE: Level V.

Challenges in IBD Research: Novel Technologies.

Novel technologies is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the novel technologies section is focused on prioritizing unmet clinical needs in IBD that will benefit from novel technologies applied to: 1) non-invasive detection and monitoring of active inflammation and assessment of treatment response; 2) mucosal targeted drug delivery systems; and 3) prevention of post-operative septic complications and treatment of fistulizing complications. Proposed approaches include development of multiparametric imaging modalities and biosensors, to enable non invasive or minimally invasive detection of pro-inflammatory signals to monitor disease activity and treatment responses. Additionally, technologies for local drug delivery to control unremitting disease and increase treatment efficacy while decreasing systemic exposure are also proposed. Finally, research on biopolymers and other sealant technologies to promote post-surgical healing; and devices to control anastomotic leakage and prevent post-surgical complications and recurrences are also needed.

Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.

Malassezia Is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Models.

Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn's disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn's disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD.