Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22.

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.

IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction.

BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling.

BACKGROUND & AIMS: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and µMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans. RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis. CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH. IMPACT AND IMPLICATIONS: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis.

Oral health profile and periodontal diseases awareness and knowledge among the jordanian population: a cross-sectional study.

OBJECTIVE: To explore the oral health profile and periodontal diseases awareness and knowledge among the Jordanian population. In addition, we aimed to identify predictors of good knowledge of periodontal diseases. METHOD: This was an online cross-sectional survey study that was conducted in Jordan between January and May 2022. A total of 13 item from the world health organisation (WHO) oral health questionnaire for adults were used to examine the oral health profile of our study participants. In addition, a previously developed questionnaire by Abdulbaqi et al. were adapted and used to examine participants' knowledge about periodontal diseases. Binary logistic regression analysis was used to identify predictors of better knowledge of periodontal diseases. RESULTS: This study involved 1,099 participants in total. More than half of them (61.1%) claimed that throughout the previous 12 months, they had experienced pain or discomfort in their mouths or teeth. Nearly half of the participants said their teeth and gums were in good or very good condition. 70.7% said they brush their teeth once or more per day. The vast majority of them (93.0%) claimed to brush their teeth using toothpaste that contained 61.9% fluoride. The most frequent cited cause for dental visits was pain or difficulty with teeth, gums, or mouth (36.3%), according to almost one-third of study participants who said they had visited a dentist during the previous six months. The most commonly reported problems that occurs frequently due to the state of the participants' teeth or mouth were avoiding smiling because of teeth, feeling embarrassed due to appearance of teeth, and having difficulty in biting foods with 11.0%, 10.2%, and 9.0%, respectively. Tea with sugar (16.5%) was the most frequently reported beverage as being consumed frequently on a daily basis. The most popular tobacco product to be smoked often on a daily basis was cigarettes (21.6%). For periodontitis knowledge questions, the percentage of accurate responses ranged from 32.3 to 55.8%. The majority of participants (55.8%) were able to recognize that poor oral hygiene is one of the most frequent causes of malodor, whereas the least number of participants (32.3%) were able to recognize that improper teeth brushing is a frequent cause of gingival recession. CONCLUSION: The average degree of periodontitis knowledge among Jordanians was moderate. Along with it, there were modest oral hygiene practices. In order to prevent further oral complications that have a detrimental influence on patients' quality of life, educational campaigns are required to increase public awareness of knowledge and practices in terms of proper oral hygiene and periodontitis.

Lactobacillus rhamnosus R0011 Treatment Enhanced Efficacy of Capecitabine against Colon Cancer in Male Balb/c Mice.

The microbiome of the intestinal system is well-known as a modulatory factor. Having a balanced status of microbiota could help to prevent diseases, especially cancers related to the gastrointestinal system. We investigated the effects of Lactobacillus rhamnosus (Lr) and capecitabine on tumor size and physiologic features, such as bodyweight, liver enzymes, and blood profile, in a subcutaneously induced cancer model using CT-26 murine colon carcinoma cells. We divided 48 male Balb/c inbred mice into six groups. Lr had been orally pre-inoculated to the mice for 14 day consecutively. CT-26 cells were implanted subcutaneously into the mice's flank. Following the injection of cancer cells, Lr was inoculated to the mice three times per week for four weeks. Capecitabine was inoculated in the third week after the induction of cancer. The tumor size was significantly decreased in treated groups in comparison to the cancer group (1174.5 ± 63.8, 1119.2 ± 86.3, and 985.6 ± 48 mm3 vs. 1674.2 ± 66 mm3, P < 0.0001). Data showed that Lr and capecitabine enhanced Bax/Bcl-2 ratio and caspase-3 level compared to cancer group (p < 0.0001). White blood cells (WBCs) were significantly decreased in the capecitabine group compared to probiotic group (P < 0.05). Measurement of bodyweight, liver enzymes, and interleukin-6 (IL-6) level showed that Lr, in addition to preventive and therapeutic effects, might have protective effects against chemotherapy side effects. Preventing WBCs' reduction, protecting mice from losing weight, induction of apoptosis, and enhancing the serum level of IL-6 indicated that Lr might be associated with better management of colorectal cancer and chemotherapy side effects.

Complications Associated with Low Position versus Good Position Umbilical Venous Catheters in Neonates of ≤32 Weeks' Gestation.

OBJECTIVE: This study aimed to determine the incidence of umbilical venous catheter associated infection (UVCAI) in very preterm infants based on UVC tip position. STUDY DESIGN: In this retrospective cohort study, infants born at ≤32 weeks were divided into groups with a UVC tip in either a low-lying or good position. The primary outcome was UVCAI. Survival analysis represented time to infection between groups. Subgroup analyses were based on duration of UVC indwelling time. RESULTS: Of 1,983 infants, 1,638 infants were eligible; 33% had low-lying UVC and 67% had good position UVC. Survival analyses suggested a significantly higher probability of infection was associated with low UVC (adjusted hazard ratio [HR]: 1.9, 95% confidence interval [CI]: 1.1-3.2; p = 0.001). The risk of infection was higher for UVC of >7 days duration (adjusted HR: 2.2, 95% CI: 1.1-4.2). Extravasation as a complication was significantly higher in the low UVC versus good position UVC (1.3 vs. 0.1%; odds ratio: 14.4, 95% CI: 1.8-119). CONCLUSION: Low-lying UVC was associated with higher risk of infection and extravasation. KEY POINTS: · Low-lying UVC are at higher risk of UVCAI.. · Presence of UVC in situ for > 7 days carries higher risk of UVCAI.. · There was a higher risk of UVC extravasation with low UVCs..

IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans.

BACKGROUND & AIMS: Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. METHODS: We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf-/-, Lta-/-, and Ltb-/- mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. RESULTS: Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp-/- mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte-derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. CONCLUSIONS: Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.

Probiotic Lactobacillus rhamnosus Supplementation Improved Capecitabine Protective Effect against Gastric Cancer Growth in Male BALB/c Mice.

The gastric cancer (GC) is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Herein, we studied the effects of probiotics (Lactobacillus rhamnosus) on subcutaneous implantation of xenograft GC. Moreover, the effect of probiotics (L. rhamnosus) was compared with the capecitabine drug as known used drug against GC. Human GC tissue was obtained from patients with gastric adenocarcinoma and grafted into mice armpit. Probiotic (L. rhamnosus) was given to animals by gavage 2 weeks prior to GC and 4 weeks after GC induction. Also, capecitabine was orally added through feeding tube at the last week of treatment procedure. All grafted animals received cyclosporine a day before the surgery and during the study period to prevent graft rejection. Capecitabine-probiotic complex reduced the size of the axillary implanted GC when compared with control group. Furthermore, combination of capecitabine and probiotic increased apoptotic and necrotic responses in the grafted tumor, blood cells (red blood cells, white blood cells, and platelet counts) in comparison with capecitabine. Probiotic (L. rhamnosus) administration effectively improved the therapeutic index and outcomes, and also, improved the therapeutic effects of the capecitabine.

A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury.

Acute liver injury can be secondary to a variety of causes, including infections, intoxication, and ischemia. All of these insults induce hepatocyte death and subsequent inflammation, which can make acute liver injury a life-threatening event. IL-22 is a dual natured cytokine which has context-dependent protective and pathogenic properties during tissue damage. Accordingly, IL-22 was shown to promote liver regeneration upon acute liver damage. However, other studies suggest pathogenic properties of IL-22 during chronic liver injury. IL-22 binding protein (IL-22BP, IL-22Ra2) is a soluble inhibitor of IL-22 that regulates IL-22 activity. However, the significance of endogenous IL-22BP in acute liver injury is unknown. We hypothesized that IL-22BP may play a role in acute liver injury. To test this hypothesis, we used Il22bp-deficient mice and murine models of acute liver damage induced by ischemia reperfusion and N-acetyl-p-aminophenol (acetaminophen) administration. We found that Il22bp-deficient mice were more susceptible to acute liver damage in both models. We used Il22 × Il22bp double-deficient mice to show that this effect is indeed due to uncontrolled IL-22 activity. We could demonstrate mechanistically increased expression of Cxcl10 by hepatocytes, and consequently increased infiltration of inflammatory CD11b+Ly6C+ monocytes into the liver in Il22bp-deficient mice upon liver damage. Accordingly, neutralization of CXCL10 reversed the increased disease susceptibility of Il22bp-deficient mice. In conclusion, our data indicate that IL-22BP plays a protective role in acute liver damage, via controlling IL-22-induced Cxcl10 expression.

Improving patient safety culture in Saudi Arabia (2012-2015): trending, improvement and benchmarking.

BACKGROUND: Measuring patient safety culture can provide insight into areas for improvement and help monitor changes over time. This study details the findings of a re-assessment of patient safety culture in a multi-site Medical City in Riyadh, Kingdom of Saudi Arabia (KSA). Results were compared to an earlier assessment conducted in 2012 and benchmarked with regional and international studies. Such assessments can provide hospital leadership with insight on how their hospital is performing on patient safety culture composites as a result of quality improvement plans. This paper also explored the association between patient safety culture predictors and patient safety grade, perception of patient safety, frequency of events reported and number of events reported. METHODS: We utilized a customized version of the patient safety culture survey developed by the Agency for Healthcare Research and Quality. The Medical City is a tertiary care teaching facility composed of two sites (total capacity of 904 beds). Data was analyzed using SPSS 24 at a significance level of 0.05. A t-Test was used to compare results from the 2012 survey to that conducted in 2015. Two adopted Generalized Estimating Equations in addition to two linear models were used to assess the association between composites and patient safety culture outcomes. Results were also benchmarked against similar initiatives in Lebanon, Palestine and USA. RESULTS: Areas of strength in 2015 included Teamwork within units, and Organizational Learning-Continuous Improvement; areas requiring improvement included Non-Punitive Response to Error, and Staffing. Comparing results to the 2012 survey revealed improvement on some areas but non-punitive response to error and Staffing remained the lowest scoring composites in 2015. Regression highlighted significant association between managerial support, organizational learning and feedback and improved survey outcomes. Comparison to international benchmarks revealed that the hospital is performing at or better than benchmark on several composites. CONCLUSION: The Medical City has made significant progress on several of the patient safety culture composites despite still having areas requiring additional improvement. Patient safety culture outcomes are evidently linked to better performance on specific composites. While results are comparable with regional and international benchmarks, findings confirm that regular assessment can allow hospitals to better understand and visualize changes in their performance and identify additional areas for improvement.

Ethnopharmacological survey of home remedies used for treatment of hair and scalp and their methods of preparation in the West Bank-Palestine.

BACKGROUND: Natural products have many uses and purposes, including those linked to pharmaceutics and cosmetics. The aim of this study was to investigate the use of natural remedies for the treatment of hair and scalp disorders in the West Bank, Palestine. METHODS: An ethnopharmacological survey of herbal remedies and other natural products used in cosmetics and cosmeceuticals was carried out in the West Bank, Palestine. A questionnaire was distributed to 267 herbalists, traditional healers, hairdressers and rural dwellers. Collected information included: the names of plants and other natural products, the parts used, hair conditions, diseases and problems for which these products were used and also their methods of preparation. To identify the most important species used, the factor of informant's consensus (Fic), fidelity level (Fl) and the use-value (UV) were calculated. RESULTS: Collected data showed that 41 plants are utilized for the treatment of hair and scalp disorders, belonging to 27 families; among them Lamiaceae and Rosaceae, which were the most commonly used. Plant oils and their fruits are the most commonly used parts. Hair loss, dandruff, split hair endings and lice treatment, are reported as the most treated disorders. The number of plant species used consisted of 19, 14, 13, and again 13 with a factor of informant's consensus (Fic) for these disorders corresponding to 0.93, 0.94, 0.95 and 0.92, respectively. Fl was 100% for many plants; the highest UV value (0.84) was registered for Lawsonia inermis, which belongs to the Lythraceae family. CONCLUSIONS: This study showed that many natural remedies are still used in Palestine for the treatment of scalp and hair disorders as well as for cosmeceutical purposes. This study is of great importance as it allows us to have a greater perspective on our folkloric use of these natural products. A combined scientific effort between informants and the scientific community, working in this field, may help in the discovery of new cosmetics, cosmeceutical and nutraceutical products.

Ethnopharmacological survey of herbal remedies used for treatment of various types of cancer and their methods of preparations in the West Bank-Palestine.

BACKGROUND: Plants have been the primary source of medicines since life on earth; more than 50 % of existing cancer treatments are derived from plants. METHODS: An ethnopharmacological survey of herbal remedies used in cancer treatment was carried out in the West Bank/ Palestine. A questionnaire was distributed to one hundred and fifty herbalists, traditional healers and rural dwellers. Collected information included the names of plants, the used parts, types of cancers for which these plants were used and also their methods of preparation. To identify the most important species used, Factor of informant's consensus (F(ic)), Fidelity level (Fl) and the Use-value (UV) were calculated. RESULTS: Collected data has shown that 72 plants are utilized for treatment of cancer, belonging to 44 families; from them Compositae and Lamiaceae were the most common. Leaves and fruits were the most commonly used parts, while decoctions, infusions and syrups were the main methods of preparation. Lung cancer was the most common type of cancer treated with these plants and Ephedra alata was the most commonly used plant for treatment of cancer in Palestine. The Fic was high for all the plants; Fl was 100% for many plants, the highest UV (0.72) was for Ephedra alata. CONCLUSIONS: This study showed that many herbal remedies are still used by herbalists in Palestine for treatment of cancer; some of them have been approved scientifically while others are not. A combined effort between informants and scientific institutions working in this field can help in the discovery of new anticancer agents. Moreover, scientists must explore the most suitable method of extraction, formulation and dose determination in order to achieve the best benefits from these herbals.

Successful vaginal delivery in a patient with reconstructed bladder exstrophy and vaginoplasty after cesarean section, a case report from Syria.

INTRODUCTION AND IMPORTANCE: Bladder exstrophy (BE) is a rare congenital anomaly in which the anterior wall of the bladder is absent. In females, sexuality and fertility may be negatively affected with the association with pubic diastasis, dysplasia of the pelvic floor muscles, clitoris bifurcated, short vagina or narrow introitus. PRESENTATION OF CASE: We present a case of 26-year-old woman with treated BE, vaginoplasty, and bicornuate uterus that came at week 36 of gestation. An elective cesarean section was made by paramedian section. Five years later, she came back with placental abruption at week 30 of gestation, and a successful vaginal delivery was made. DISCUSSION: Bladder exstrophy is a challenging disease that is accompanied with other morbidities. Impaired fertility is common due to previous surgeries and concomitant diseases, and pregnancy is high risk for both mother and baby. Delivery should be at a tertiary referral obstetric hospital. CONCLUSION: Balancing the pros and cones of medical decision in order to achieve the best outcomes for both the mother and child is crucial, as choosing the right decision depends on the presentation and past history of the patient not only the existence of the bladder exstrophy.

A Geospatial Drug Abuse Risk Assessment and Monitoring Dashboard Tailored for School Students: Development Study With Requirement Analysis and Acceptance Evaluation.

BACKGROUND: The enormous consequences of drugs include suicides, traffic accidents, and violence, affecting the individual, family, society, and country. Therefore, it is necessary to constantly identify and monitor the drug abuse rate among school-going youth. A geospatial dashboard is vital for the monitoring of drug abuse and related crime incidence in a decision support system. OBJECTIVE: This paper mainly focuses on developing MyAsriGeo, a geospatial drug abuse risk assessment and monitoring dashboard tailored for school students. It introduces innovative functionality, seamlessly orchestrating the assessment of drug abuse usage patterns and risks using multivariate student data. METHODS: A geospatial drug abuse dashboard for monitoring and analysis was designed and developed in this study based on agile methodology and prototyping. Using focus group and interviews, we first examined and gathered the requirements, feedback, and user approval of the MyAsriGeo dashboard. Experts and stakeholders such as the National Anti-Drugs Agency, police, the Federal Department of Town and Country Planning, school instructors, students, and researchers were among those who responded. A total of 20 specialists were involved in the requirement analysis and acceptance evaluation of the pilot and final version of the dashboard. The evaluation sought to identify various user acceptance aspects, such as ease of use and usefulness, for both the pilot and final versions, and 2 additional factors based on the Post-Study System Usability Questionnaire and Task-Technology Fit models were enlisted to assess the interface quality and dashboard sufficiency for the final version. RESULTS: The MyAsriGeo geospatial dashboard was designed to meet the needs of all user types, as identified through a requirement gathering process. It includes several key functions, such as a geospatial map that shows the locations of high-risk areas for drug abuse, data on drug abuse among students, tools for assessing the risk of drug abuse in different areas, demographic information, and a self-problem test. It also includes the Alcohol, Smoking, and Substance Involvement Screening Test and its risk assessment to help users understand and interpret the results of student risk. The initial prototype and final version of the dashboard were evaluated by 20 experts, which revealed a significant improvement in the ease of use (P=.047) and usefulness (P=.02) factors and showed a high acceptance mean scores for ease of use (4.2), usefulness (4.46), interface quality (4.29), and sufficiency (4.13). CONCLUSIONS: The MyAsriGeo geospatial dashboard is useful for monitoring and analyzing drug abuse among school-going youth in Malaysia. It was developed based on the needs of various stakeholders and includes a range of functions. The dashboard was evaluated by a group of experts. Overall, the MyAsriGeo geospatial dashboard is a valuable resource for helping stakeholders understand and respond to the issue of drug abuse among youth.

Enhancing medical training in conflict zones and remote areas through innovation: introducing the Canadian Virtual Medical University Initiative.

Background: The WHO projects a global shortage of 4.3 million physicians by 2030, with the largest deficits in developing and conflict-affected regions. Our aim is to train competent physicians rapidly and affordably through remote education programs. Methods: We developed an online medical training curriculum with four levels, focusing on different aspects of human body systems using a competency-based, student-centered approach. This study evaluates the first three levels; level four (internship) is outside this scope. The 105 medical students from eight Afghan universities were randomly assigned to nine groups. The curriculum includes Entrustable Professional Activities (EPA) for the cardiovascular system: level 1 covers basic medical sciences, level 2 pathology and basic clinical skills, and level 3 full clinical competencies. EPAs were delivered asynchronously online via Lecturio, CyberPatient, and Zoom. The 30-day intervention included 4 h of weekly online classes for formative assessment, collaborative learning, and evaluation, supervised by medical faculty members. Virtual pre- and post-intervention evaluations used multiple-choice questions and objective structured clinical examination (OSCE). We also conducted a satisfaction survey and open interview forum. Data triangulation from observations, surveys, and interviews validated curriculum effectiveness. The benchmarking method assessed cost-effectiveness. Findings: Pre- and post-intervention analysis showed a significant increase in clinical competencies and knowledge acquisition (P < 0.0001). The CyberPatient intervention improved clinical competency quality (P < 0.0001) and shortened decision-making time (P < 0.001). Cost analysis revealed that a virtual medical university would be 95% more cost-effective than traditional medical education. Interpretation: Integrating virtual technology with modern curriculum concepts in pre-internship years can effectively address healthcare training gaps and enhance education quality for healthcare workers at a low cost. Funding: Provided by CanHealth International. A UBC spin-off not-for-profit organization.

IL-22 promotes liver regeneration after portal vein ligation.

Background: Insufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL. Methods: Liver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used. Results: The remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes. Conclusion: IL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.

The opioid industry document archive: New directions in research on corporate political strategy.

The opioid crisis in the United States has resulted in more than 500,000 deaths since 1999, and recent estimates suggest that attributable deaths could reach 842,000 by 2032. While heroin and synthetic products such as fentanyl now account for the majority of opioid overdoses, the prescription opioid crisis that emerged in the mid-1990s was the primary antecedent to the current situation. Recent settlements in litigation against opioid producers, suppliers and retailers has resulted in the release of almost 2.5 million previously confidential internal documents that have been made publicly accessible via the online Opioid Industry Documents Archive, a collaboration between the University of California, San Francisco and Johns Hopkins University. These corporate records provide critical insights into the operations and strategies of manufacturers and other actors in the opioid supply chain. This article describes the provenance of the opioid documents and their potential value as a research resource. It then outlines methodological approaches to their analysis, drawing on comparisons in conducting research using the Truth Tobacco Industry Documents. The Opioid Industry Documents Archive is a new and important addition to existing industry document collections that enable scrutiny and analysis of the role of corporate actors in determining health outcomes. Beyond their immediate application to researching the corporate and regulatory foundations of the current opioid crisis, the opioid document collections will contribute to a greater understanding of the commercial determinants of public health by providing means to better locate the causes of public health crises, identify politically acceptable solutions to their resolution, and inform strategies for preventing future corporate-driven epidemics.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

IL-22BP controls the progression of liver metastasis in colorectal cancer.

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC.

A Critical Role of the IL-22-IL-22 Binding Protein Axis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22-IL-22BP axis in HCC.