Challenges in IBD Research 2024: Precision Medicine.

Precision medicine is part of 5 focus areas of the Challenges in IBD Research 2024 research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and pragmatic clinical research. Building on Challenges in IBD Research 2019, the current Challenges aims to provide a comprehensive overview of current gaps in inflammatory bowel diseases (IBDs) research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in interception, remission, and restoration for these diseases. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient-centric research prioritization. In particular, the precision medicine section is focused on the main research gaps in elucidating how to bring the best care to the individual patient in IBD. Research gaps were identified in biomarker discovery and validation for predicting disease progression and choosing the most appropriate treatment for each patient. Other gaps were identified in making the best use of existing patient biosamples and clinical data, developing new technologies to analyze large datasets, and overcoming regulatory and payer hurdles to enable clinical use of biomarkers. To address these gaps, the Workgroup suggests focusing on thoroughly validating existing candidate biomarkers, using best-in-class data generation and analysis tools, and establishing cross-disciplinary teams to tackle regulatory hurdles as early as possible. Altogether, the precision medicine group recognizes the importance of bringing basic scientific biomarker discovery and translating it into the clinic to help improve the lives of IBD patients.

Precision medicine is the practice of getting the most suitable drug or treatment option to each individual patient at the right time. In Crohn's disease and ulcerative colitis, we need to learn more about the diversity of patients to deliver precision medicine.

Duodenal quantitative mucosal morphometry in children with environmental enteric dysfunction: a cross-sectional multi-country analysis.

BACKGROUND: Environmental enteric dysfunction (EED), a chronic inflammatory condition of the small intestine, is an important driver of childhood malnutrition globally. Quantifying intestinal morphology in EED allows for exploration of its association with functional and disease outcomes. OBJECTIVE: We sought to define morphometric characteristics of childhood EED and determine whether morphology features were associated with disease pathophysiology. METHODS: Morphometric measurements and histology were assessed on duodenal biopsy slides for this cross-sectional study from children with EED in Bangladesh, Pakistan, and Zambia (n=69), and those with no pathologic abnormality (NPA; n=8) or celiac disease (n=18) in North America. Immunohistochemistry was also conducted on 46, 8, and 18 biopsy slides, respectively. Linear mixed-effects regression models were used to reveal morphometric differences between EED compared to NPA or celiac disease, and identify associations between morphometry and histology or immunohistochemistry amongst children with EED. RESULTS: In duodenal biopsies, median EED villus height (248 µm), crypt depth (299 µm), and villus:crypt (V:C) ratio (0.9) values ranged between those of NPA (396 µm villus height; 246 µm crypt depth; 1.6 V:C ratio) and celiac disease (208 µm villus height; 365 µm crypt depth; 0.5 V:C ratio). Among EED biopsy slides, morphometric assessments were not associated with histologic parameters or immunohistochemical markers, other than pathologist determined subjective semi-quantitative villus architecture. CONCLUSIONS: Morphometric analysis of duodenal biopsy slides across geographies identified morphologic features of EED, specifically short villi, elongated crypts, and a smaller V:C ratio relative to NPA slides; although not as severe as in celiac slides. Morphometry did not explain other EED features, suggesting that EED histopathologic processes may be operating independently of morphology. While acknowledging the challenges with obtaining relevant tissue, these data form the basis for further assessments of the role of morphometry in EED.

Inspiring diverse researchers in Virginia: Cultivating research excellence through a career-building program.

Historically underrepresented groups in biomedical research have continued to experience low representation despite shifting demographics. Diversity fosters inclusive, higher quality, and innovative team science. One avenue for diversifying research teams is integrating diversity-focused initiatives into Clinical and Translational Science Award (CTSA) Programs, such as the integrated Translational Health Research Institute of Virginia (iTHRIV). In 2020, iTHRIV participated in Building Up, developed by the University of Pittsburgh CTSA, and intended to increase representation and improve career support for underrepresented groups in the biomedical workforce. Drawing lessons from this study, iTHRIV implemented the "inspiring Diverse Researchers in Virginia" (iDRIV) program. This yearlong program provided education, coaching, mentoring, and sponsorship for underrepresented early career investigators in the biomedical workforce. To date, 24 participants have participated in the program across three cohorts. Participants have been predominantly female (92%), with 33% identifying as Hispanic/Latinx, 29% as Black, and 13% as Asian. Notably, 38% of scholars have subsequently achieved at least one accomplishment, such as receiving a local research honor or award and an extramural funding award from a foundation or federal agency. The iTHRIV iDRIV program serves as a model for providing career support to developing investigators from underrepresented backgrounds, with the overall goal of improving patient health.

Inspiring Diverse Researchers in Virginia: Cultivating Research Excellence Through a Career Building Program.

Historically underrepresented groups in biomedical research have continued to experience low representation despite shifting demographics. Diversity fosters inclusive, higher quality, and innovative team science. One avenue for diversifying research teams is integrating diversity-focused initiatives into Clinical and Translational Science Award (CTSA) Programs, such as the integrated Translational Health Research Institute of Virginia (iTHRIV). In 2020, iTHRIV participated in Building Up, developed by the University of Pittsburgh CTSA, intended to increase representation and improve career support for underrepresented groups in the biomedical workforce. Drawing lessons from this study, iTHRIV implemented the "inspiring Diverse Researchers in Virginia" (iDRIV) program. This year-long program provided education, coaching, mentoring, and sponsorship for underrepresented early-career investigators in the biomedical workforce. To date, 24 participants have participated in the program across three cohorts. Participants have been predominantly female (92%), with 33% identifying as Hispanic/Latinx, 29% as Black, and 13% Asian. Notably, 38% of scholars have subsequently achieved at least one accomplishment, such as receiving a local research honor or award and an extramural funding award from a foundation or federal agency. The iTHRIV iDRIV program serves as a model for providing career support to developing investigators from underrepresented backgrounds, with the overall goal of improving patient health.

A comparative analysis of current out-of-hospital transfusion protocols to expert recommendations.

Aim: This study aimed to compare current out-of-hospital transfusion (OHT) protocols in Canadian civilian critical care transport organizations (CCTO) to expert recommendations and explore the variability and potential benefits of standardizing OHT practices across Canada. Methods: A comprehensive cross-sectional study was conducted, encompassing all seven Canadian CCTOs that provide OHT. The study assessed adherence to expert recommendations and examined specific aspects of the transfusion process, such as indications for transfusion and cessation criteria. Results: The study found an 89% adherence to expert recommendations for OHT among Canadian CCTOs. It highlighted a strong alignment between current practices and recommendations, possibly attributed to collaborative frameworks like the CAN-PATT network. However, notable variability and ambiguity were observed in transfusion indications and cessation criteria. The study also emphasized the potential benefits of standardizing OHT practices, such as improved policy formulation, better interpretation of emerging literature, and evaluation of OHT efficacy. Conclusion: This cross-sectional study assessed how Canadian CCTOs implement OHT practices compared to expert-recommended practices. The findings underscore the importance of structured protocols in trauma management. Given the consistency in OHT protocol adoption and the comprehensive approach across CCTOs, there's a solid foundation for managing trauma patients in prehospital and transport settings across Canada. As OHT practices continue to evolve, sustained efforts are vital to refine, adapt, and elevate patient care standards in trauma management.

Current state of technical transfusion medicine practice for out-of-hospital blood transfusion in Canada.

BACKGROUND AND OBJECTIVES: Canadian out-of-hospital blood transfusion programmes (OHBTPs) are emerging, to improve outcomes of trauma patients by providing pre-hospital transfusion from the scene of injury, given prolonged transport times. Literature is lacking to guide its implementation. Thus, we sought to gather technical transfusion medicine (TM)-specific practices across Canadian OHBTPs. MATERIALS AND METHODS: A survey was sent to TM representatives of Canadian OHBTPs from November 2021 to March 2022. Data regarding transport, packaging, blood components and inventory management were included and reported descriptively. Only practices involving Blood on Board programme components for emergency use were included. RESULTS: OHBTPs focus on helicopter emergency medical service programmes, with some supplying fixed-wing aircraft and ground ambulances. All provide 1-3 coolers with 2 units of O RhD/Kell-negative red blood cells (RBCs) per cooler, with British Columbia trialling coolers with 2 units of pre-thawed group A plasma. Inventory exchanges are scheduled and blood components are returned to TM inventory using visual inspection and internal temperature data logger readings. Coolers are validated to storage durations ranging from 72 to 124 h. All programmes audit to manage wastage, though there is no consensus on appropriate benchmarks. All programmes have a process for documenting units issued, reconciliation after transfusion and for transfusion reaction reporting; however, training programmes vary. Common considerations included storage during extreme temperature environments, O-negative RBC stewardship, recipient notification, traceability, clinical practice guidelines co-reviewed by TM and a common audit framework. CONCLUSION: OHBTPs have many similarities throughout Canada, where harmonization may assist in further developing standards, leveraging best practice and national coordination.

Overcoming distance: an exploration of current practices of government and charity-funded critical care transport and retrieval organizations.

BACKGROUND: For critically ill and injured patients, timely access to definitive care is associated with a reduction in avoidable mortality. Access to definitive care is significantly affected by geographic remoteness. To overcome this disparity, a robust critical care transport (CCT) or retrieval system is essential to support the equity of care and overcome the tyranny of distance. While critical care transport or retrieval systems have evolved over the years, there is no universally accepted system or standard, which has led to considerable variation in practices. The objective of this mixed-methods study was to identify and explore the current clinical, operational, and educational practices of government and charity-funded critical care transport and retrieval organizations operating across access- and weather- challenged geography. METHODS: This study utilized a mixed-methods approach comprising a rapid review of the literature and semi-structured interviews with identified subject matter experts (SME). RESULTS: A total of 44 articles and 14 interviews with SMEs from six different countries, 12 different services/systems, and seven operational roles, including clinicians (physician, paramedic, and nurse), educator, quality improvement, clinical governance, clinical informatics and research, operations manager, and medical director were included in the narrative analysis. The study identified several themes including deployment, crew composition, selection and education, clinical governance, quality assurance and quality improvement and research. CONCLUSION: This mixed-methods study underscores the paucity of literature describing current clinical, operational, and educational practices of government or charity-funded CCT or retrieval programs operating across access- and weather- challenged geography. While many common themes were identified including clearly defined mission profiles, use of dedicated or specialized transport teams, central coordination, rigorous selection processes, service-sponsored graduate education, and strong clinical governance, there is little consensus and considerable variation in current practices. Further research is needed to identify and harmonize best practices within the CCT and retrieval environments.

Standard RUTF vs. locally-made RUSF for acutely malnourished children: A quasi-experimental comparison of the impact on growth and compliance in a rural community of Pakistan.

BACKGROUND: The reduction in severe and moderate acute malnutrition (SAM and MAM) rates in Pakistan has been sub-optimal compared to other low-and middle-income countries (LMICs). Specially-formulated products have been designed globally to manage SAM and MAM, such as ready-to-use therapeutic food (RUTF) and ready-to-use supplementary food (RUSF), with variable efficacies. RUTF is primarily produced and patented in industrialized countries, raising supply challenges in resource-constrained regions with a high burden of acute malnutrition. RUSF minimizes costs by using locally-available ingredients while providing similar nutritional value. In this study, we compared the efficacy, side effects, and compliance of two months of supplementation with either RUTF or RUSF. METHODS: Children aged nine months in the rural district of Matiari, Pakistan, with a weight-for-height z-score (WHZ) <-2 received either RUTF (500 kcal sachet) for two months in 2015 or RUSF (520 kcal sachet) for two months in 2018. RESULTS: The RUSF group had a higher height gain and mid-upper arm circumferences (MUAC) score. Higher compliance was noted with lower side effects in the RUSF group. A higher compliance rate did correlate with the growth parameters in respective groups. CONCLUSION: Our study found that both RUTF and RUSF partially improve the anthropometric status of acutely malnourished children, with neither being superior to the other.

Development of a national out-of-hospital transfusion protocol: a modified RAND Delphi study.

BACKGROUND: Early resuscitation with blood components or products is emerging as best practice in selected patients with trauma and medical patients; as a result, out-of-hospital transfusion (OHT) programs are being developed based on limited and often conflicting evidence. This study aimed to provide guidance to Canadian critical care transport organizations on the development of OHT protocols. METHODS: The study period was July 2021 to June 2022. We used a modified RAND Delphi process to achieve consensus on statements created by the study team guiding various aspects of OHT in the context of critical care transport. Purposive sampling ensured representative distribution of participants in regard to geography and relevant clinical specialties. We conducted 2 written survey Delphi rounds, followed by a virtual panel discussion (round 3). Consensus was defined as a median score of at least 6 on a Likert scale ranging from 1 ("Definitely should not include") to 7 ("Definitely should include"). Statements that did not achieve consensus in the first 2 rounds were discussed and voted on during the panel discussion. RESULTS: Seventeen subject experts participated in the study, all of whom completed the 3 Delphi rounds. After the study process was completed, a total of 39 statements were agreed on, covering the following domains: general oversight and clinical governance, storage and transport of blood components and products, initiation of OHT, types of blood components and products, delivery and monitoring of OHT, indications for and use of hemostatic adjuncts, and resuscitation targets of OHT. INTERPRETATION: This expert consensus document provides guidance on OHT best practices. The consensus statements should support efficient and safe OHT in national and international critical care transport programs.

A descriptive analysis of the Canadian prehospital and transport transfusion (CAN-PATT) network.

Objective: Out-of-hospital blood transfusion (OHBT) is becoming increasingly common across the prehospital environment, yet there is significant variability in OHBT practices. The Canadian Prehospital and Transport Transfusion (CAN-PATT) network was established to collaborate, standardize, and evaluate the effectiveness of out-of-hospital blood transfusion (OHBT) across Canada. The objectives of this study are to describe the setting and organizational characteristics of CAN-PATT member organizations and to provide a cross-sectional examination of the current OHBT practices of CAN-PATT organizations. Methods: This was a cross-sectional examination of all six critical care transport organizations that are involved in CAN-PATT network. Surveys were sent to identified leads from each organization. The survey focused on three main areas of interest: 1) critical care transport organizational service and coverage, 2) provider, and crew configurations, and 3) OHBT transfusion practices. Results: All six surveys were completed and returned. There are a total of 30 critical care transport bases (19 rotor-wing, 20 fixed-wing and 6 land) across Canada and 11 bases have a blood-on-board program. Crew configurations very between organizations as either dual paramedic or paramedic/nurse teams. Median transport times range from 30 to 46 minutes for rotor-wing assets and 64 to 90 minutes for fixed-wing assets. Half of the CAN-PATT organizations started their out-of-hospital blood transfusion programs within the last three years. Most organizations carry at least two units of O-negative, K-negative red blood cells and some organizations also carry group A thawed plasma, fibrinogen concentrate and/or prothrombin complex concentrate. All organizations advocate for early administration of tranexamic acid for injured patients suspected of bleeding. All organizations return un-transfused blood components to their local transfusion medicine laboratory within a predefined timeframe to reduce wastage. Conclusions: Variations in OHBT practices were identified and we have suggested considerations for standardization of transfusion practices and patient care as it relates to OHBT. This standardization will also enable a robust means of data collection to study and optimize outcomes of patients receiving OHBT. A fulsome description of the participating organizations within CAN-PATT should enhance interpretation of future OHBT studies that will be conducted by this network.

Prediction of massive transfusion with the Revised Assessment of Bleeding and Transfusion (RABT) score at Canadian level I trauma centers.

BACKGROUND: Early damage control resuscitation and massive transfusion (MT) protocol activations improve outcomes in trauma patients with hemorrhagic shock, where scores to guide MT prediction are used including: the Assessment of Blood Consumption (ABC), Shock Index (SI), and Revised Assessment of Bleeding and Transfusion (RABT) scores. Our aim was to validate the RABT score in patients from two level I trauma centers in Canada. METHODS: A retrospective review of adult patients meeting trauma team activation criteria receiving >1 unit of red blood cells (RBCs) within 24 h of admission, from 2015 to 2020, was conducted. A RABT score ≥ 2, ABC score ≥ 2, and Shock Index (SI) ≥ 1 was used to predict MT using both research (≥10 RBCs in 24 h) and clinical (≥3 RBCs in 3 h) definitions. Scores were assessed and compared using sensitivity, specificity, and the area under the receiver operating characteristic (AUROC). RESULTS: We analyzed 514 patients with a mean age of 44.4 (19.2) years and a median injury severity score of 29 [18-38]. For both MT definitions, the RABT score trended towards higher sensitivity and lower specificity compared to ABC score and SI. For both research and clinical definitions of MT, the AUROC for the RABT score was not significantly higher (Research - RABT: 0.673 [0.610-0.735], ABC: 0.642 [0.551-0.734], SI 0.691 [0.625-0.757]; Clinical - RABT: 0.653 [0.608-0.698], ABC: 0.646 [0.600-0.691], SI 0.610 [0.559-0.660]). CONCLUSION: The RABT score is a valid tool for predicting the need for MTPs, performing similarly with a trend towards higher sensitivity when compared to the ABC score and SI.

A Service Evaluation of Prehospital Blood Transfusion by Critical Care Paramedics in British Columbia, Canada.

Early administration of blood products is emerging as best practice in selected trauma and medical patients. Blood products carried by critical care transport (CCT) teams are sometimes the first available to critically ill and injured patients. The purpose of this research was to evaluate the introduction of prehospital transfusion into a paramedic-led CCT program in Canada. A retrospective review of electronic patient care records for all patients who received a prehospital transfusion of uncrossmatched group O packed red blood cells between February 10, 2019, and September 30, 2020, was conducted. Forty-eight patients received a prehospital transfusion. The median age of the patients was 44 years, 81.3% were male, and most patients were victims of blunt trauma. Packed red blood cells were associated with a significant increase in systolic blood pressure (P < .001) and mean arterial pressure (P < .001), a decrease in shock index (P < .001), and a reduction in the time to first transfusion, with minimal waste, no patient-related adverse events, and complete traceability. The results of this service evaluation demonstrate the successful introduction of prehospital transfusion into a paramedic-led CCT program. Further prospective research is needed to assess the impact of such a protocol in this patient population.

Salmonella Typhimurium manipulates macrophage cholesterol homeostasis through the SseJ-mediated suppression of the host cholesterol transport protein ABCA1.

Upon infection of host cells, Salmonella enterica serovar Typhimurium resides in a modified-endosomal compartment referred to as the Salmonella-containing vacuole (SCV). SCV biogenesis is driven by multiple effector proteins translocated through two type III secretion systems (T3SS-1 and T3SS-2). While many host proteins targeted by these effector proteins have been characterised, the role of host lipids in SCV dynamics remains poorly understood. Previous studies have shown that S. Typhimurium infection in macrophages leads to accumulation of intracellular cholesterol, some of which concentrates in and around SCVs; however, the underlying mechanisms remain unknown. Here, we show that S. Typhimurium utilises the T3SS-2 effector SseJ to downregulate expression of the host cholesterol transporter ABCA1 in macrophages, leading to a ~45% increase in cellular cholesterol. Mechanistically, SseJ activates a signalling cascade involving the host kinases FAK and Akt to suppress Abca1 expression. Mutational inactivation of SseJ acyltransferase activity, silencing FAK, or inhibiting Akt prevents Abca1 downregulation and the corresponding accumulation of cholesterol during infection. Importantly, RNAi-mediated silencing of ABCA1 rescued bacterial survival in FAK-deficient macrophages, suggesting that Abca1 downregulation and cholesterol accumulation are important for intracellular survival.

Large-Scale Air Medical Operations in the Age of Coronavirus Disease 2019: Early Leadership Lessons From the Front Lines of British Columbia.

In late 2019, a novel coronavirus was identified as the cause of a cluster of atypical pneumonia cases in Wuhan, China. It subsequently spread throughout China and around the world, quickly becoming a public health emergency. In March 2020, the World Health Organization declared coronavirus disease 2019 a pandemic. This article explores the preparation and early experiences of a large Canadian critical care transport program during the coronavirus disease 2019 pandemic focused on 6 broad strategic objectives centered around staff welfare, regular and transparent communication, networking, evidenced-based approach to personal protective equipment, agile mission planning, and an expedited approach to clinical practice and policy updates and future state modeling.

Systematic reviews of scores and predictors to trigger activation of massive transfusion protocols.

BACKGROUND: The use of massive transfusion protocols (MTPs) in the resuscitation of hemorrhaging trauma patients ensures rapid delivery of blood products to improve outcomes, where the decision to trigger MTPs early is important. Scores and tools to predict the need for MTP activation have been developed for use to aid with clinical judgment. We performed a systematic review to assess (1) the scores and tools available to predict MTP in trauma patients, (2) their clinical value and diagnostic accuracies, and (3) additional predictors of MTP. METHODS: MEDLINE, EMBASE, and CENTRAL were searched from inception to June 2017. All studies that utilized scores or predictors of MTP activation in adult (age, ≥18 years) trauma patients were included. Data collection for scores and tools included reported sensitivities and specificities and accuracy as defined by the area under the curve of the receiver operating characteristic. RESULTS: Forty-five articles were eligible for analysis, with 11 validated and four unvalidated scores and tools assessed. Of four scores using clinical assessment, laboratory values, and ultrasound assessment the modified Traumatic Bleeding Severity Score had the best performance. Of those scores, the Trauma Associated Severe Hemorrhage score is most well validated and has higher area under the curve of the receiver operating characteristic than the Assessment of Blood Consumption and Prince of Wales scores. Without laboratory results, the Assessment of Blood Consumption score balances accuracy with ease of use. Without ultrasound use, the Vandromme and Schreiber scores have the highest accuracy and sensitivity respectively. The Shock Index uses clinical assessment only with fair performance. Other clinical variables, laboratory values, and use of point-of-care testing results were identified predictors of MTP activation. CONCLUSION: The use of scores or tools to predict MTP need to be individualized to hospital resources and skill set to aid clinical judgment. Future studies for triggering nontrauma MTP activations are needed. LEVEL OF EVIDENCE: Systematic review, level III.