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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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..

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.

Expression of virulence genes in Group B Streptococcus isolated from symptomatic pregnant women with term and preterm delivery

Aims@#Maternal vaginal Group B Streptococcus (GBS) colonization is considered a risk factor for preterm delivery and, consequently, neonatal infections. Previous studies have portrayed the important roles of these virulence factors, including hemolytic pigment, hyaluronidase (HylB), serine-rich protein (Srr) and bacterial surface adhesion of GBS (BsaB) in mediating GBS colonization and intrauterine ascending infection, causing preterm delivery. This study aimed to investigate the association between mRNA expression of virulence genes in GBS isolates obtained from symptomatic pregnant women and preterm delivery.@*Methodology and results@#GBS isolates were obtained from high vaginal swabs of 40 symptomatic pregnant women of gestational age of less than 37 weeks. RNA was extracted from these GBS isolates and RT-qPCR was performed to determine the relative mRNA expression of GBS virulence genes, including CylE (encode enzyme required for the biosynthesis of the hemolytic pigment), HylB, Srr-1 and BsaB. Socio-demographic details and obstetric history were not found to be associated with the delivery outcomes of these women. The GBS isolates from symptomatic pregnant women who delivered prematurely showed a higher expression of CylE gene and a trend towards an elevated expression of HylB gene compared to women with term delivery. Meanwhile the expression of both Srr-1 and BsaB genes was similar between symptomatic pregnant women who had term or preterm delivery.@*Conclusion, significance and impact of study@#The results suggest that following vaginal colonization, both CylE and HylB genes are likely to contribute to intrauterine ascending infection and inflammation, leading to preterm delivery in humans. These virulence factors may be targeted for the pre-clinical stages of vaccine development or therapeutic intervention.

Efferocytosis fuels malignant pleural effusion through TIMP1.

Malignant pleural effusion (MPE) results from the capacity of several human cancers to metastasize to the pleural cavity. No effective treatments are currently available, reflecting our insufficient understanding of the basic mechanisms leading to MPE progression. Here, we found that efferocytosis through the receptor tyrosine kinases AXL and MERTK led to the production of interleukin-10 (IL-10) by four distinct pleural cavity macrophage (Mφ) subpopulations characterized by different metabolic states and cell chemotaxis properties. In turn, IL-10 acts on dendritic cells (DCs) inducing the production of tissue inhibitor of metalloproteinases 1 (TIMP1). Genetic ablation of Axl and Mertk in Mφs or IL-10 receptor in DCs or Timp1 substantially reduced MPE progression. Our results delineate an inflammatory cascade-from the clearance of apoptotic cells by Mφs, to production of IL-10, to induction of TIMP1 in DCs-that facilitates MPE progression. This inflammatory cascade offers a series of therapeutic targets for MPE.

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.

The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies.

The human liver fulfills several vital tasks daily and possesses an impressive ability to self-regenerate. However, the capacity of this self-healing process can be exhausted by a variety of different liver diseases, such as alcoholic liver damage, viral hepatitis, or hepatocellular carcinoma. Over time, all these diseases generally lead to progressive liver failure that can become fatal if left untreated. Thus, a great effort has been directed towards the development of innovative therapies. The most recently discovered therapies often involve modifying the patient's immune system to enhance a beneficial immune response. Current data suggest that, among others, the cytokine IL-22 might be a promising therapeutical candidate. IL-22 and its endogenous antagonist, IL-22BP, have been under thorough scientific investigation for nearly 20 years. While IL-22 is mainly produced by TH22 cells, ILC3s, NKT cells, or γδ T cells, sources of IL-22BP include dendritic cells, eosinophils, and CD4+ cells. In many settings, IL-22 was shown to promote regenerative potential and, thus, could protect tissues from pathogens and damage. However, the effects of IL-22 during carcinogenesis are more ambiguous and depend on the tumor entity and microenvironment. In line with its capabilities of neutralizing IL-22 in vivo, IL-22BP possesses often, but not always, an inverse expression pattern compared to its ligand. In this comprehensive review, we will summarize past and current findings regarding the roles of IL-22 and IL-22BP in liver diseases with a particular focus on the leading causes of advanced liver failure, namely, liver infections, liver damage, and liver malignancies.

SspABCD-SspFGH Constitutes a New Type of DNA Phosphorothioate-Based Bacterial Defense System.

Unlike nucleobase modifications in canonical restriction-modification systems, DNA phosphorothioate (PT) epigenetic modification occurs in the DNA sugar-phosphate backbone when the nonbridging oxygen is replaced by sulfur in a double-stranded (ds) or single-stranded (ss) manner governed by DndABCDE or SspABCD, respectively. SspABCD coupled with SspE constitutes a defense barrier in which SspE depends on sequence-specific PT modifications to exert its antiphage activity. Here, we identified a new type of ssDNA PT-based SspABCD-SspFGH defense system capable of providing protection against phages through a mode of action different from that of SspABCD-SspE. We provide further evidence that SspFGH damages non-PT-modified DNA and exerts antiphage activity by suppressing phage DNA replication. Despite their different defense mechanisms, SspFGH and SspE are compatible and pair simultaneously with one SspABCD module, greatly enhancing the protection against phages. Together with the observation that the sspBCD-sspFGH cassette is widely distributed in bacterial genomes, this study highlights the diversity of PT-based defense barriers and expands our knowledge of the arsenal of phage defense mechanisms.IMPORTANCE We recently found that SspABCD, catalyzing single-stranded (ss) DNA phosphorothioate (PT) modification, coupled with SspE provides protection against phage infection. SspE performs both PT-simulated NTPase and DNA-nicking nuclease activities to damage phage DNA, rendering SspA-E a PT-sensing defense system. To our surprise, ssDNA PT modification can also pair with a newly identified 3-gene sspFGH cassette to fend off phage infection with a different mode of action from that of SspE. Interestingly, both SspFGH and SspE can pair with the same SspABCD module for antiphage defense, and their combination provides Escherichia coli JM109 with additive phage resistance up to 105-fold compared to that for either barrier alone. This agrees with our observation that SspFGH and SspE coexist in 36 bacterial genomes, highlighting the diversity of the gene contents and molecular mechanisms of PT-based defense systems.

Staying ahead of the curve: avigating changes and maintaining gains in patient safety culture - a mixed-methods study.

OBJECTIVES: This study examines how the results of the Hospital Survey on Patient Safety Culture changed between 2012 and 2019 and identifies organisational factors affecting these changes. DESIGN: The study combined the use of quantitative surveys of staff and qualitative interviews with hospital leadership. Secondary data analysis was performed for previous surveys. SETTING: This study was conducted in a tertiary care teaching multisite hospital in Riyadh, Saudi Arabia. PARTICIPANTS: One thousand hospital staff participated in the survey. Thirty-one executive board members and directors and four focus groups of frontliners were qualitatively interviewed. PRIMARY AND SECONDARY OUTCOME MEASURES: Twelve safety culture dimensions were assessed to study the patient safety culture as perceived by the healthcare professionals. An additional semi-structured interview was conducted to identify organisational factors, changes, and barriers affecting the patient safety culture. Furthermore, suggestions to improve patient safety were proposed. RESULTS: Comparing the results revealed a general positive trend in scores from 2012 to 2019. The areas of strength included teamwork within and across units, organisational learning, managerial support, overall perception of safety and feedback and communication about error. Non-punitive response to error, staffing and communication and openness consistently remain the lowest-scoring composites. Interview results revealed that organisational changes may have influenced the answers of the participants on some survey composites. CONCLUSIONS: Patient safety is a moving target with areas for improvement that are continuously identified. Effective quality improvement initiatives can lead to visible changes in the patient safety culture in a hospital, and consistent leadership commitment and support can maintain these improvements.

Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease

ObjectiveTo evaluate the efficacy of ivermectin (IVM) as an addition to the standard of care (SOC) treatment in COVID-19 patients with mild and moderate disease Materials and MethodsA randomized clinical trial (Trial registration # NCT04392713) was carried out at Combined Military Hospital Lahore from March 15, 2020, to June 15, 2020. Eighty-six patients with reverse transcriptase-polymerase chain reaction (RT-PCR) proven SARS-CoV-2 infection completed the trial protocol. Patients were stratified via the lottery method into two groups. Group A was administered standard of care (SOC) treatment as per existing hospital guidelines whereas group B was given ivermectin (single dose of 12 milligrams) along with SOC treatment. PCR was repeated at 72 hours, 7th day, and at 14th day of admission for both the groups and the point at which the PCR became negative was noted. Complete blood counts, liver function tests and renal function tests were done at recruitment, 7th day, and 14th day. The primary outcome was the viral clearance, measured as days to achieve PCR negativity. The secondary outcome was the development of any adverse side effects pertinent to ivermectin or derangement in baseline laboratory parameters. ResultsIn group A, 36 (80%) participants were males, and 9 (20%) were females, whereas in group B, 37 (90.2%) were males and 4 (9.8%) were females. Mean age was 39.0{+/-} 12.6 and 42.2 {+/-} 12.0 years for groups A and B, respectively (p= 0.394). There was early viral clearance in group B as compared to group A (p=0.001). No adverse reaction or derangements in laboratory parameters was noted in the intervention arm during the trial period. ConclusionIn the intervention arm, early viral clearance was observed and no side effects were documented. Therefore ivermectin is a potential addition to the standard care of treatment in COVID-19 patients.

Rationalizing heptadecaphobia: TH 17 cells and associated cytokines in cancer and metastasis.

Cancer is one of the leading causes of death worldwide. When cancer patients are diagnosed with metastasis, meaning that the primary tumor has spread to at least one different site, their life expectancy decreases dramatically. In the past decade, the immune system´s role in fighting cancer and metastasis has been studied extensively. Importantly, immune cells and inflammatory reactions generate potent antitumor responses but also contribute to tumor development. However, the molecular and cellular mechanisms underlying this dichotomic interaction between the immune system and cancer are still poorly understood. Recently, a spotlight has been cast on the distinct subsets of immune cells and their derived cytokines since evidence has implicated their crucial impact on cancer development. T helper 17 cell (TH 17) cells, which express the master transcriptional factor Retinoic acid-receptor-related orphan receptor gamma t, are among these critical cell subsets and are defined by their production of type 3 cytokines, such as IL-17A, IL-17F, and IL-22. Depending on the tumor microenvironment, these cytokines can also be produced by other immune cell sources, such as T cytotoxic 17 cell, innate lymphoid cells, NKT cells, or γδ T cells. To date, a lot of data have been collected describing the divergent functions of IL-17A, IL-17F, and IL-22 in malignancies. In this comprehensive review, we discuss the role of these TH 17- and non-TH 17-derived type 3 cytokines in different tumor entities. Furthermore, we will provide a structured insight into the strict regulation and subsequent downstream mechanisms of these cytokines in cancer and metastasis.