Identification and surgical management of acute severe ulcerative colitis: A guide for general practitioners.

BACKGROUND: Approximately 25% of patients with ulcerative colitis (UC) develop acute severe UC (ASUC), necessitating urgent care. General practitioners (GPs), whether based in rural or urban settings, are instrumental in detecting early warning signs, expediting emergency interventions, coordinating with medical teams, educating patients and overseeing outpatient care. This involvement ensures timely, appropriate surgical responses, especially if complications arise or medical treatments prove ineffective. OBJECTIVE: This review provides GPs with an understanding of ASUC evaluation and risk assessment, emphasising surgical management and complementing existing medical methods. The objective is to equip GPs, whether in rural or urban environments, with the knowledge and confidence to play an integral role in the treatment team. DISCUSSION: Identifying and diagnosing ASUC is crucial for timely emergency care. Moreover, effective ASUC management demands appropriate preoperative work-up. GPs should be adept at monitoring treatment efficacy and guiding patients through surgical aftercare. Thus, GPs should be well versed in diagnostic criteria and surgical approaches for ASUC, as well as their important role within a multidisciplinary team.

Ileal pouch-anal anastomosis provides good functional and quality of life outcomes following proctocolectomy: A 33-year single centre experience.

BACKGROUND: Restorative proctocolectomy (RP) with ileal pouch-anal anastomosis (IPAA) remains the gold standard for the surgical management of patients with medically refractive mucosal ulcerative colitis. We aimed to identify functional and quality of life (QOL) outcomes in RP and IPAA surgery patients at our institution. METHODS: A retrospective observational study was performed including all patients who had undergone RP and IPAA between August 1984 and November 2017 at Royal Prince Alfred Hospital (RPAH). RESULTS: 316 consecutive patients were identified, median age 39 (range 5 to 81) years. The median duration of disease was 60 (range 1 to 528) months. Ulcerative colitis was the main preoperative diagnosis with the main RP indication being failure of medical treatment. The median postoperative stay post-IPAA was 11 (range of 5 to 67) days. Pouchitis was the most common late complication (22.1%), bleeding pouch (3.5%) the earliest, with a 6.8% rate of symptomatic anastomotic leak. Visual analogue scale QOL measure (P-value <0.001), St Marks incontinence score (P-value = 0.001) and Cleveland clinic score (P-value = 0.002) all revealed significant improvement in functional outcomes and QOL. CONCLUSION: QOL and functional outcomes following RP with IPAA in patients at our institution are excellent and comparable to institutions with larger patient numbers.

Economic Evaluation in Kidney Transplantation: A Scoping Review and Novel PESTLE Stakeholder Gaps Analysis.

AIM: The objective of this study was to systematically review the literature related to the economic evaluation of kidney transplantation to determine the extent of current research and identify gaps for future research. SUBJECT AND METHODS: We searched 4 medical and 2 economic electronic databases as well as hand-searching reference lists of review articles and other pertinent articles. Exclusion criteria included articles that did not include original work (ie, reviews), were not in English, and were not journal articles or economic working papers (eg, commentaries, theses, abstracts). Full-text data abstraction included qualitative and quantitative parameters with the intent to perform a gap analysis for future research. RESULTS: A total of 299 articles were included and spanned a 48-year period from 1968 to 2016, with >73% published in 2000 or after. The most common topics included immunosuppression drugs, dialysis vs kidney transplantation, organ allocation, and the potential market for donor organs. Most articles were from the United States and originated from 73 medical journals and 34 economic journals or working paper centers. There were 58 articles dealing with costing, 153 using cost-effectiveness, 69 using economic modeling, 6 performing systematic reviews with meta-analyses, and 13 exploring the qualitative financial environment of individuals and the economy. CONCLUSIONS: Research gaps were identified in every parameter used to evaluate the studies, and a new system of gap analysis for scoping reviews was also proposed.

Inhibition of focal adhesion kinase 2 results in a macrophage polarization shift to M2 which attenuates local and systemic inflammation and reduces heterotopic ossification after polysystem extremity trauma.

Introduction: Heterotopic ossification (HO) is a complex pathology often observed in combat injured casualties who have sustained severe, high energy polytraumatic extremity injuries. Once HO has developed, prophylactic therapies are limited outside of surgical excision. Tourniquet-induced ischemia injury (IR) exacerbates trauma-mediated musculoskeletal tissue injury, inflammation, osteogenic progenitor cell development and HO formation. Others have shown that focal adhesion kinase-2 (FAK2) plays a key role in regulating early inflammatory signaling events. Therefore, we hypothesized that targeting FAK2 prophylactically would mitigate extremity trauma induced IR inflammation and HO formation. Methods: We tested whether the continuous infusion of a FAK2 inhibitor (Defactinib, PF-573228; 6.94 µg/kg/min for 14 days) can mitigate ectopic bone formation (HO) using an established blast-related extremity injury model involving femoral fracture, quadriceps crush injury, three hours of tourniquet-induced limb ischemia, and hindlimb amputation through the fracture site. Tissue inflammation, infiltrating cells, osteogenic progenitor cell content were assessed at POD-7. Micro-computed tomography imaging was used to quantify mature HO at POD-56. Results: In comparison to vehicle control-treated rats, FAK2 administration resulted in no marked wound healing complications or weight loss. FAK2 treatment decreased HO by 43%. At POD-7, marked reductions in tissue proinflammatory gene expression and assayable osteogenic progenitor cells were measured, albeit no significant changes in expression patterns of angiogenic, chondrogenic and osteogenic genes. At the same timepoint, injured tissue from FAK-treated rats had fewer infiltrating cells. Additionally, gene expression analyses of tissue infiltrating cells resulted in a more measurable shift from an M1 inflammatory to an M2 anti-inflammatory macrophage phenotype in the FAK2 inhibitor-treated group. Discussion: Our findings suggest that FAK2 inhibition may be a novel strategy to dampen trauma-induced inflammation and attenuate HO in patients at high risk as a consequence of severe musculoskeletal polytrauma.

Neutrophil and NETosis Modulation in Traumatic Heterotopic Ossification.

OBJECTIVE: To characterize the role of neutrophil extracellular traps (NETs) in heterotopic ossification (HO) formation and progression and to use mechanical and pharmacological methods to decrease NETosis and mitigate HO formation. BACKGROUND: Traumatic HO is the aberrant osteochondral differentiation of mesenchymal progenitor cells after traumatic injury, burns, or surgery. While the innate immune response has been shown to be necessary for HO formation, the specific immune cell phenotype and function remain unknown. Neutrophils, one of the earliest immune cells to respond after HO-inducing injuries, can extrude DNA, forming highly inflammatory NETs. We hypothesized that neutrophils and NETs would be diagnostic biomarkers and therapeutic targets for the detection and mitigation of HO. METHODS: C57BL6J mice underwent burn/tenotomy (a well-established mouse model of HO) or a non-HO-forming sham injury. These mice were either (1) ambulated ad libitum, (2) ambulated ad libitum with daily intraperitoneal hydroxychloroquine, ODN-2088 (both known to affect NETosis pathways), or control injections, or (3) had the injured hind limb immobilized. Single-cell analysis was performed to analyze neutrophils, NETosis, and downstream signaling after the HO-forming injury. Immunofluorescence microscopy was used to visualize NETosis at the HO site and neutrophils were identified using flow cytometry. Serum and cell lysates from HO sites were analyzed using enzyme-linked immunosorbent assay for myeloperoxidase-DNA and ELA2-DNA complexes to identify NETosis. Micro-computerized tomography was performed on all groups to analyze the HO volume. RESULTS: Molecular and transcriptional analyses revealed the presence of NETs within the HO injury site, which peaked in the early phases after injury. These NETs were highly restricted to the HO site, with gene signatures derived from both in vitro NET induction and clinical neutrophil characterizations showing a high degree of NET "priming" at the site of injury, but not in neutrophils in the blood or bone marrow. Cell-cell communication analyses revealed that this localized NET formation coincided with high levels of toll-like receptor signaling specific to neutrophils at the injury site. Reducing the overall neutrophil abundance within the injury site, either pharmacologically through treatment with hydroxychloroquine, the toll-like receptor 9 inhibitor OPN-2088, or mechanical treatment with limb offloading, results in the mitigation of HO formation. CONCLUSIONS: These data provide a further understanding of the ability of neutrophils to form NETs at the injury site, clarify the role of neutrophils in HO, and identify potential diagnostic and therapeutic targets for HO mitigation.

Procedure-based assessment implementation in colorectal surgery: a scoping review.

BACKGROUND: Competency-based training (CBT) programs use procedure-based assessments (PBAs) to evaluate trainees' abilities to perform specific procedures in clinical settings, similar to Entrustable Professional Activities (EPAs). PBAs help determine trainees' readiness for advanced training levels. However, there is limited evidence on implementing colorectal-specific PBAs in surgical training schemes. This review aims to identify observed and perceived challenges to implementing PBAs in workplace settings. METHODS: A scoping review following the Joanna Briggs Institute Protocol for Scoping Reviews (JBI-ScR) was conducted. Eligible studies provided evidence on the implementation, feasibility, and challenges of PBAs in colorectal surgery, including various study designs from retrospective to prospective. RESULTS: Of the 80 screened studies, 75 were excluded based on exclusion criteria. Most of the included studies were conducted in national training institutions in the United Kingdom, assessing 778 colorectal procedures with specific PBAs. The main facilitators of implementing PBAs were structured assessments, focused assessors' training, and electronic forms usage. CONCLUSION: This review offers insight into the practicality and feasibility of implementing PBAs in colorectal surgery. Identified challenges include the need for adequate assessor training and the time-consuming nature of the assessment. These findings could improve PBA implementation in colorectal surgery and enhance surgical education quality. However, the limited number of studies and existing literature heterogeneity call for more research to identify other gaps.

Cost-Effectiveness and Budget Impact of a Novel Antithrombotic Drug Removal System to Reduce Bleeding Risk in Patients on Preoperative Ticagrelor Undergoing Cardiac Surgery.

BACKGROUND: Antithrombotic drugs, including the P2Y12 inhibitor ticagrelor, increase the risk of perioperative bleeding in patients requiring urgent cardiac surgery. Perioperative bleeding can lead to increased mortality and prolong intensive care unit and hospital stays. A novel sorbent-filled hemoperfusion cartridge that intraoperatively removes ticagrelor via hemoadsorption can reduce the risk of perioperative bleeding. We estimated the cost-effectiveness and budget impact of using this device versus standard practices to reduce the risk of perioperative bleeding during and after coronary artery bypass grafting from the US healthcare sector perspective. METHODS: We used a Markov model to analyze the cost-effectiveness and budget impact of the hemoadsorption device in three cohorts: (1) surgery within 1 day from last ticagrelor dose; (2) surgery between 1 and 2 days from last ticagrelor dose; and (3) a combined cohort. The model analyzed costs and quality-adjusted life years (QALYs). Results were interpreted as both incremental cost-effectiveness ratios and net monetary benefits (NMBs) at a cost-effectiveness threshold of $100,000/QALY. We analyzed parameter uncertainty using deterministic and probabilistic sensitivity analyses. RESULTS: The hemoadsorption device was dominant for each cohort. Patients with less than 1 day of washout in the device arm gained 0.017 QALYs at a savings of $1748 (USD), for an NMB of $3434. In patients with 1-2 days of washout, the device arm yielded 0.014 QALYs and a cost savings of $151, for an NMB of $1575. In the combined cohort, device gained 0.016 QALYs and a savings of $950 for an NMB of $2505. Per-member-per-month cost savings associated with device was estimated to be $0.02 for a one-million-member health plan. CONCLUSION: This model found the hemoadsorption device to provide better clinical and economic outcomes compared with the standard of care in patients who required surgery within 2 days of ticagrelor discontinuation. Given the increasing use of ticagrelor in patients with acute coronary syndrome, incorporating this novel device may represent an important part of any bundle to save costs and reduce harm.

Transcatheter Aortic Valve-in-Valve-in-Valve Replacement in a Young Woman With Transcatheter Structural Valve Deterioration Within a Degenerated Aortic Root Homograft.

Transcatheter aortic valve replacement is a well-established procedure for older patients with symptomatic, severe aortic stenosis. However, data are lacking on its durability and long-term complications, particularly in young patients and patients treated for aortic valve regurgitation. This article describes the case of a 27-year-old woman with complex congenital cardiovascular disease who, after 4 previous aortic valve replacement procedures, presented with structural deterioration of her most recent replacement valve, which had been placed by transcatheter aortic valve replacement inside a failed aortic root homograft 6 years earlier. After the patient had undergone this transcatheter aortic valve replacement procedure to treat aortic valve regurgitation related to her degenerated aortic root homograft, she became pregnant and successfully carried her high-risk pregnancy to term. However, the replacement valve deteriorated during the late stages of pregnancy, resulting in substantial hemodynamic changes between the first trimester and the postpartum period. To avoid repeat sternotomy, a redo transcatheter valve-in-valve replacement procedure procedure was performed through the right carotid artery. Because the patient wanted to have more children and therefore avoid anticoagulation, a SAPIEN 3 transcatheter valve (Edwards Lifesciences) was placed as a bridge to a future, more-durable aortic root replacement. The result in this case suggests that in patients with complex adult congenital pathology, transcatheter aortic valve replacement can be used as a temporizing bridge to subsequent, definitive aortic valve repair.

Discoidin domain receptor 2 regulates aberrant mesenchymal lineage cell fate and matrix organization.

Extracellular matrix (ECM) interactions regulate both the cell transcriptome and proteome, thereby determining cell fate. Traumatic heterotopic ossification (HO) is a disorder characterized by aberrant mesenchymal lineage (MLin) cell differentiation, forming bone within soft tissues of the musculoskeletal system following traumatic injury. Recent work has shown that HO is influenced by ECM-MLin cell receptor signaling, but how ECM binding affects cellular outcomes remains unclear. Using time course transcriptomic and proteomic analyses, we identified discoidin domain receptor 2 (DDR2), a cell surface receptor for fibrillar collagen, as a key MLin cell regulator in HO formation. Inhibition of DDR2 signaling, through either constitutive or conditional Ddr2 deletion or pharmaceutical inhibition, reduced HO formation in mice. Mechanistically, DDR2 perturbation alters focal adhesion orientation and subsequent matrix organization, modulating Focal Adhesion Kinase (FAK) and Yes1 Associated Transcriptional Regulator and WW Domain Containing Transcription Regulator 1 (YAP/TAZ)-mediated MLin cell signaling. Hence, ECM-DDR2 interactions are critical in driving HO and could serve as a previously unknown therapeutic target for treating this disease process.

The Impact of the Affordable Care Act on Disparities in Utilization of Cardiovascular Preventive Services by Socioeconomic Status.

Disparities in cardiovascular outcomes are persistent in our society. The objective was to track the trends before and after the passage of the Affordable Care Act in socioeconomic status (SES) disparities in utilization of cardiovascular disease (CVD) preventive services among nonelderly adults aged 18-64 years. This study used the National Health Interview Survey (2011-2017) to compare utilization of blood pressure, cholesterol, glycemic screening, and diet and smoking cessation advice over time between groups stratified by SES and race using difference-in-difference analysis. This study also measured the differences over time in specific vulnerable population subgroups (Hispanic, low-income and uninsured vs. White, middle-high-income, and insured). The study population included 176,961 surveyed individuals (mean age 40 [±13] years; 51% female; 67.7% non-Hispanic White) between 2011 and 2017, translating to 194.8 million nonelderly US adults per year. Most individuals were from high-income SES (40.0%), followed by middle-income (28.1%), low-income (13.6%), and lowest income SES (18.3%). The proportion of CVD preventive services increased over all SES categories through the study period. The biggest relative changes were seen among low-income individuals. The difference in blood pressure checks, cholesterol checks, and smoking cessation advise between high- and lowest income groups showed a statistically significant decrease at 5.2%, 4.8%, and 11.2%, respectively, between 2011 and 2017. The findings demonstrate a trend in reduction of CVD preventive care disparities between SES groups. However, a gap still exists, and this study highlights the need for continuous improvement to eliminate SES disparities.

Distal Aortic Malperfusion Exacerbated by Antegrade Stent-Graft Placement During Hybrid Repair of Acute DeBakey Type I Aortic Dissection.

We present the case of an acute DeBakey type I aortic dissection with malperfusion. The patient underwent valve resuspension, ascending aortic and partial arch replacement, debranching of the innominate artery, and placement of a small-diameter stent within the left common carotid artery, after which antegrade deployment of a stent-graft into the proximal descending thoracic aorta was performed to expand the true lumen. Distal malperfusion was exacerbated by the stent-graft's traversal into the false lumen, necessitating further endovascular repair to reestablish flow to the distal aorta. Mitigation before stent-graft placement (for example, inserting a wire within the true lumen under fluoroscopic guidance to ensure stent-graft placement in the true lumen) and prompt corrective procedures are paramount, given the grim consequences of prolonged distal ischemia.

Use of intraoperative haemostatic checklists on blood management in patients undergoing cardiac surgery: a scoping review protocol.

INTRODUCTION: A major complication of cardiac surgery is bleeding which can require surgical re-exploration and the transfusion of allogeneic blood products. Re-operative procedures for bleeding have been associated with higher rates of mortality and morbidity, therefore an intervention to reduce this complication would be important. Previous investigation has demonstrated that low-cost solutions, such as the use of an intraoperative haemostatic checklist may result in the reduction of bleeding and subsequent transfusion. The goals of this scoping review aim to assess the efficacy of the use of intraoperative haemostatic checklists on blood management in patients undergoing cardiac surgery. Specifically, the objective is to understand if the use of intraoperative haemostatic checklists has been associated with a reduction in bleeding and blood product utilisation in patients undergoing non-emergent cardiac surgery. METHODS AND ANALYSIS: A scoping review of literature identifying randomised control and observational trials, reporting on haemostatic checklists in cardiac surgery, will be undertaken. The proposed review will be guided by the methodological framework proposed by Arksey and O'Malley. A search will be conducted for published and unpublished (grey) literature. Published literature will be searched in the following electronic databases: Scopus, MEDLINE, EMBASE and the Cochrane Library. Relevant grey literature will be identified through conference abstracts. Outcomes chosen are patient centred to ensure reduced bleeding and overall positive experience that reduces complications intraoperatively. ETHICS AND DISSEMINATION: This study does not require ethical approval as the data used are from available publications. Our dissemination strategy includes peer-review publication, presentation at conferences and relevant stakeholders.

Introducing a New Bond-Forming Activity in an Archaeal DNA Polymerase by Structure-Guided Enzyme Redesign.

DNA polymerases have evolved to feature a highly conserved activity across the tree of life: formation of, without exception, internucleotidyl O-P linkages. Can this linkage selectivity be overcome by design to produce xenonucleic acids? Here, we report that the structure-guided redesign of an archaeal DNA polymerase, 9°N, exhibits a new activity undetectable in the wild-type enzyme: catalyzing the formation of internucleotidyl N-P linkages using 3'-NH2-ddNTPs. Replacing a metal-binding aspartate in the 9°N active site with asparagine was key to the emergence of this unnatural enzyme activity. MD simulations provided insights into how a single substitution enhances the productive positioning of a 3'-amino nucleophile in the active site. Further remodeling of the protein-nucleic acid interface in the finger subdomain yielded a quadruple-mutant variant (9°N-NRQS) displaying DNA-dependent NP-DNA polymerase activity. In addition, the engineered promiscuity of 9°N-NRQS was leveraged for one-pot synthesis of DNA─NP-DNA copolymers. This work sheds light on the molecular basis of substrate fidelity and latent promiscuity in enzymes.

MicroRNA detection in biologically relevant media using a split aptamer platform.

MicroRNA (miRNA)-based intercellular communication has been implicated in many functional and dysfunctional biological processes. This has raised interest in the potential use of miRNAs as biomarkers for diagnosis and prognosis. Though the list of clinically significant miRNA biomarkers is expanding, it remains challenging to adapt current chemical tools to investigate miRNAs in complex environments native to cells and tissues. We describe here a methodology for rapidly developing aptamer-based fluorescent biosensors that can specifically detect miRNAs in biologically relevant media (10-30% v/v), including medium collected from cultured HeLa cells, human serum, and human plasma. This methodology involves the semi-rational design of the hybridization between DNA oligonucleotides and the miRNA target to build a pool of potential aptamers, and the screening of this pool for high signal-to-background ratio and target specificity. The DNA oligonucleotides are readily available and require no chemical modification, rendering these chemical tools highly adaptable to any novel and niche miRNA target. Following this approach, we developed sensors that detect distinct oncogenic miRNA targets (miR-19b, miR-21, and miR-92a) at concentrations as low as 5 nM without amplification and are selective against single-nucleotide mutants. This work provides a systematic approach toward the development of miRNA biosensors that are easily accessible and can perform in biological environments with minimal sample handling.

Cost-Effectiveness of Using the Coronary Artery Calcium Score in Guiding Therapeutic Decisions in Primary Prevention in the Brazilian Population. / Custo-Efetividade do Emprego do Escore de Cálcio Coronariano na Orientação para a Decisão Terapêutica na Prevenção Primária, na População Brasileira.

BACKGROUND: The use of the coronary artery calcium score to aid cardiovascular risk stratification may be a more cost-effective tool than the conventional strategy. OBJECTIVES: Evaluation of the cost-effectiveness of the use of the calcium score in therapeutic guidance for primary cardiovascular prevention. METHODS: A microsimulation model to assess the clinical and economic consequences of atherosclerotic cardiovascular disease, comparing the prevention strategy using the calcium score and the conventional strategy. RESULTS: The results obtained demonstrated a better cost-effectiveness of the therapeutic strategy guided by the calcium score, by reducing incremental costs and increasing quality-adjusted life years (QALY), which corresponds, in number, to improving the quality of life of the individual. CONCLUSIONS: The use of the coronary artery calcium score proved to be more cost-effective than the conventional strategy, both in terms of cost and QALY, in most of the scenarios studied.

FUNDAMENTO: O emprego do escore de cálcio no auxílio da estratificação de risco cardiovascular pode ser ferramenta com melhor custo-efetividade em comparação à estratégia convencional. OBJETIVOS: Avaliação da custo-efetividade do emprego do escore de cálcio na orientação terapêutica para a prevenção primária cardiovascular. MÉTODOS: Modelo de microssimulação para avaliar as consequências clínicas e econômicas da doença cardiovascular aterosclerótica, comparando-se a estratégia de prevenção pelo uso do escore de cálcio e a estratégia convencional. RESULTADOS: Resultados obtidos demonstram melhor custo-efetividade da estratégia terapêutica guiada pelo escore de cálcio, por meio da redução do custo incremental, e aumento nos anos de vida ajustados por qualidade (QALY), que corresponde, em número, ao benefício incorporado à qualidade de vida do indivíduo. CONCLUSÕES: O emprego do escore de cálcio mostrou-se mais custo-efetivo que a estratégia convencional tanto em custo como em QALY, na maioria dos cenários estudados.

Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases.

BACKGROUND: The interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. Using N-ethyl-N-nitrosourea mutagenesis, we found a mouse with an activating mutation in oligoadenylate synthetase 2 (Oas2), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice. METHODS: To determine if sole activation of Oas2 could alter the course of mammary cancer, we combined the Oas2 mutation with the MMTV-PyMT oncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan-Meier survival analysis with immunohistochemistry and flow cytometry. RESULTS: Oas2 mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 was more effective when the Oas2 mutation was present. CONCLUSIONS: These data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy.