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Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Currently, pirfenidone and nintedanib are the only FDA-approved drugs for the treatment of IPF and are now the standard of care. This is a significant step in slowing down the progression of the disease. However, the drugs are unable to stop or reverse established fibrosis. Several retrospective clinical studies indicate that proton pump inhibitors (PPIs; FDA-approved to treat gastroesophageal reflux) are associated with favorable outcomes in patients with IPF, and emerging preclinical studies report that PPIs possess antifibrotic activity. In this study, we evaluated the antifibrotic efficacy of the PPI esomeprazole when combined with pirfenidone in vitro and in vivo. In cell culture studies of IPF lung fibroblasts, we assessed the effect of the combination on several fibrosis-related biological processes including TGFβ-induced cell proliferation, cell migration, cell contraction, and collagen production. In an in vivo study, we used mouse model of TGFβ-induced lung fibrosis to evaluate the antifibrotic efficacy of esomeprazole/pirfenidone combination. We also performed computational studies to understand the molecular mechanisms by which esomeprazole and/or pirfenidone regulate lung fibrosis. We found that esomeprazole significantly enhanced the anti-proliferative effect of pirfenidone and favorably modulated TGFβ-induced cell migration and contraction of collagen gels. We also found that the combination significantly suppressed collagen production in response to TGFβ in comparison to pirfenidone monotherapy. In addition, our animal study demonstrated that the combination therapy effectively inhibited the differentiation of lung fibroblasts into alpha smooth muscle actin (αSMA)-expressing myofibroblasts to attenuate the progression of lung fibrosis. Finally, our bioinformatics study of cells treated with esomeprazole or pirfenidone revealed that the drugs target several extracellular matrix (ECM) related pathways with esomeprazole preferentially targeting collagen family members while pirfenidone targets the keratins. In conclusion, our cell biological, computational, and in vivo studies show that the PPI esomeprazole enhances the antifibrotic efficacy of pirfenidone through complementary molecular mechanisms. This data supports the initiation of prospective clinical studies aimed at repurposing PPIs for the treatment of IPF and other fibrotic lung diseases where pirfenidone is prescribed.

Abstract Background Colorectal cancer (CRC) is the third most common cause of cancer death in both genders worldwide. Aims This study aimed to evaluate the outcomes and prognostic factors of CRC patients at Tikur Anbessa Specialized Hospital in Ethiopia. Methods and Results A prospective cohort study was conducted on 209 patients from January 2020 to September 2022. Kaplan–Meier curves and bivariate and multivariate Cox regression analyses were used to analyze overall and progression‐free survival, with a significance value of P

Historically, the effort by academia and industry to develop new chemical entities into lifesaving drugs has limited success in meeting the demands of today’s healthcare. Repurposing drugs that are originally approved by the United States Food and Drug Administration or by regulatory authorities around the globe is an attractive strategy to rapidly develop much-needed therapeutics for oncologic indications that extend from treating cancer to managing treatment-related complications. This review discusses computational approaches to harness existing drugs for new therapeutic use in oncology.

This review article outlines six molecular pathways that confer resistance of cancer cells to ionizing radiation, and describes how proton pump inhibitors (PPIs) may be used to overcome radioresistance induced by alteration of one or more of these signaling pathways. The inflammatory, adaptive, hypoxia, DNA damage repair, cell adhesion, and developmental pathways have all been linked to the resistance of cancer cells to ionizing radiation. Here we describe the molecular link between alteration of these pathways in cancer cells and development of resistance to ionizing radiation, and discuss emerging data on the use of PPIs to favorably modify one or more components of these pathways to sensitize cancer cells to ionizing radiation. Understanding the relationship between altered signaling pathways, radioresistance, and biological activity of PPIs may serve as a basis to repurpose PPIs to restore key biological processes that are involved in cancer progression and to sensitize cancer cells to radiation therapy.

Abstract Introduction Idiopathic pulmonary fibrosis (IPF) is an orphan disease characterized by progressive loss of lung function resulting in shortness of breath and often death within 3–4 years of diagnosis. Repetitive lung injury in susceptible individuals is believed to promote chronic oxidative stress, inflammation, and uncontrolled collagen deposition. Several preclinical and retrospective clinical studies in IPF have reported beneficial outcomes associated with the use of proton pump inhibitors (PPIs) such as esomeprazole. Accordingly, we sought to investigate molecular mechanism(s) by which PPIs favorably regulate the disease process. Methods We stimulated oxidative stress, pro-inflammatory and profibrotic phenotypes in primary human lung epithelial cells and fibroblasts upon treatment with bleomycin or transforming growth factor β (TGFβ) and assessed the effect of a prototype PPI, esomeprazole, in regulating these processes. Results Our study shows that esomeprazole controls pro-inflammatory and profibrotic molecules through nuclear translocation of the transcription factor nuclear factor-like 2 (Nrf2) and induction of the cytoprotective molecule heme oxygenase 1 (HO1). Genetic deletion of Nrf2 or pharmacological inhibition of HO1 impaired esomeprazole-mediated regulation of proinflammatory and profibrotic molecules. Additional studies indicate that activation of Mitogen Activated Protein Kinase (MAPK) pathway is involved in the process. Our experimental data was corroborated by bioinformatics studies of an NIH chemical library which hosts gene expression profiles of IPF lung fibroblasts treated with over 20,000 compounds including esomeprazole. Intriguingly, we found 45 genes that are upregulated in IPF but downregulated by esomeprazole. Pathway analysis showed that these genes are enriched for profibrotic processes. Unbiased high throughput RNA-seq study supported antifibrotic effect of esomeprazole and revealed several novel targets. Conclusions Taken together, PPIs may play antifibrotic role in IPF through direct regulation of the MAPK/Nrf2/HO1 pathway to favorably influence the disease process in IPF.

Public–private partnerships (PPPs) in the veterinary domain are joint approaches in which public veterinary services and private actors such as private veterinarians, producers' associations, or private companies work together to address complex animal health challenges. They are implemented worldwide and can help to strengthen the capacities of veterinary services, but few have been evaluated. None of the evaluations developed in the veterinary domain explicitly addressed PPPs, their complex program design, their evolving governance, and coordination system, and their impacts. This work represents the first application of the participatory impact pathway methodology for the evaluation of a PPP in the veterinary domain. The PPP evaluated aimed at developing the poultry sector in Ethiopia and improving poultry health service coverage, particularly in remote areas. The combination of semi-structured interviews (n = 64) and collective reflection during three workshops (n participants = 26, 48, 18), captured the viewpoints of public and private partners, actors who influenced the partnership, and actors impacted by it. The context of the PPP was analyzed, and the causal relationships between the PPP and its impacts were investigated. This work showed that collaboration between the public and private sector occurred at several administrative levels. The actors considered a variety of impacts, on the economy, business, trust, and health, which were then measured through different indicators. The actors also identified the added value of the PPP to enrich those impacts. The participatory impact pathway methodology helped to strengthen the engagement of actors in the PPP and to formulate recommendations at the policy level to favor positive results. This case study represents a milestone in building a participatory evaluation framework of PPP in the veterinary domain.

"Candidatus Berkiella cookevillensis" (strain CC99) and "Candidatus Berkiella aquae" (strain HT99), belonging to the Coxiellaceae family, are gram-negative bacteria isolated from amoebae in biofilms present in human-constructed water systems. Both bacteria are obligately intracellular, requiring host cells for growth and replication. The intracellular bacteria-containing vacuoles of both bacteria closely associate with or enter the nuclei of their host cells. In this study, we analyzed the genome sequences of CC99 and HT99 to better understand their biology and intracellular lifestyles. The CC99 genome has a size of 2.9Mb (37.9% GC) and contains 2,651 protein-encoding genes (PEGs) while the HT99 genome has a size of 3.6Mb (39.4% GC) and contains 3,238 PEGs. Both bacteria encode high proportions of hypothetical proteins (CC99: 46.5%; HT99: 51.3%). The central metabolic pathways of both bacteria appear largely intact. Genes for enzymes involved in the glycolytic pathway, the non-oxidative branch of the phosphate pathway, the tricarboxylic acid pathway, and the respiratory chain were present. Both bacteria, however, are missing genes for the synthesis of several amino acids, suggesting reliance on their host for amino acids and intermediates. Genes for type I and type IV (dot/icm) secretion systems as well as type IV pili were identified in both bacteria. Moreover, both bacteria contain genes encoding large numbers of putative effector proteins, including several with eukaryotic-like domains such as, ankyrin repeats, tetratricopeptide repeats, and leucine-rich repeats, characteristic of other intracellular bacteria.

Abstract Background ‘Candidatus Berkiella cookevillensis’ and ‘Ca. Berkiella aquae’ have previously been described as intranuclear bacteria of amoebae. Both bacteria were isolated from amoebae and were described as appearing within the nuclei of Acanthamoeba polyphaga and ultimately lysing their host cells within 4 days. Both bacteria are Gammaproteobacteria in the order Legionellales with the greatest similarity to Coxiella burnetii. Neither bacterium grows axenically in artificial culture media. In this study, we further characterized ‘Ca. B. cookevillensis’ by demonstrating association with nuclei of human phagocytic and nonphagocytic cell lines. Results Transmission electron microscopy (TEM) and confocal microscopy were used to confirm nuclear co-localization of ‘Ca. B. cookevillensis’ in the amoeba host A. polyphaga with 100% of cells having bacteria co-localized with host nuclei by 48 h. TEM and confocal microscopy demonstrated that the bacterium was also observed to be closely associated with nuclei of human U937 and THP-1 differentiated macrophage cell lines and nonphagocytic HeLa human epithelial-like cells. Immunofluorescent staining revealed that the bacteria-containing vacuole invaginates the nuclear membranes and appears to cross from the cytoplasm into the nucleus as an intact vacuole. Conclusion Results of this study indicate that a novel coccoid bacterium isolated from amoebae can infect human cell lines by associating with the host cell nuclei, either by crossing the nuclear membranes or by deeply invaginating the nuclear membranes. When associated with the nuclei, the bacteria appear to be bound within a vacuole and replicate to high numbers by 48 h. We believe this is the first report of such a process involving bacteria and human cell lines.

Currently, there is a need for more and better poultry health services in Ethiopia. However, nationwide data showing the weaknesses of poultry health services are scanty. Hence, availability of diagnostic, vaccination, and clinical services for poultry was assessed. Focus group discussions and household questionnaire survey were conducted with poultry keepers in 10 districts. Lack of poultry health experts, clinical services, drugs, vaccination, and knowledge and skills were identified as top five key findings. In total, 31.6% of respondents reported availability of poultry diagnosis service. Having flock size of 11-20 chickens had higher probabilities of accessing better diagnosis service (AOR = 2.77; 95% CI: 1.12-3.64). Access to diagnosis was directly linked with the availability of veterinary clinics in their localities (AOR = 2.65; 95% CI: 1.16-6.63). Moreover, low access to treatment services (22.98%) was reported and traditional remedies with priority index of 0.68 were reported to be the most commonly used. Chicken flocks with a history of disease occurrence were more likely to have a decision to go for modern treatment services (AOR = 4.26; 95% CI: 2.28-7.95). Only 35.7% of chicken keepers had their flocks vaccinated, and this was irregularly and randomly given, mainly against Newcastle disease. Only 52.9% of them were vaccinated by trained animal health experts. Chicken flocks with availability of veterinary clinics within 5 km were more likely (AOR = 1.62; 95% CI: 1.03-2.54) to have access to vaccination services. Only 53.0% of the chicken flocks had availability of clinics and chicken flocks in Tigray (AOR = 2.15; 95% CI: 1.03- 4.52) and Oromia (AOR = 5.74; 95%CI: 2.51-13.10) had better availability of clinics. Chicken flocks found in Bako district were less likely (AOR = 0.41; 95% CI: 0.18-0.92). The low availability of diagnostic, vaccination, and clinical services shows that poultry health services in Ethiopia have not received attention despite its top national agenda. Hence, the existing low poultry health services need to be solved through public-private partnership, producing adequate poultry health experts, availing vaccines, diagnostics, and therapeutics in the local markets.

Remote sensing technologies provide a unique opportunity to identify ground surfaces that are more susceptible to dust emissions at a large scale. As part of the Salton Sea Air Quality Mitigation Program (SSAQMP) of the Imperial Irrigation District (IID), efforts have been made to improve our understanding of fugitive, wind-blown dust emissions around the Salton Sea region in Southern California, United States. Field campaigns were conducted for multiple years to evaluate surface conditions and measure the dust emissions potential in the area. Data collected during the field work were coupled with remote sensing imagery and data mining techniques to map surface characteristics that are important in identifying dust emissions potential. Around the playa domain, surface crust type, sand presence, and soil moisture were estimated. Geomorphic surface types were mapped in the desert domain. Overall accuracy ranged from 91.7% to 99.4% for the crust type mapping. Sand presence mapping showed consistent and slightly better accuracy, ranging from 96.2% to 99.7%. Soil moisture assessment agreed with precipitation records. Geomorphic mapping in the desert domain achieved accuracy above 93.5%, and the spatial pattern was consistent with previous studies. These land surface condition assessments provide important information to support dust emissions estimates in the region.

Power generation, distribution, transmission, and consumption face ongoing challenges such as smart grid management, control, and operation, resulting from high energy demand, the diversity of energy sources, and environmental or regulatory issues. This paper provides a comprehensive overview of blockchain-based solutions for smart grid management, control, and operations. We systematically summarize existing work on the use and implementation of blockchain technology in various smart grid domains. The paper compares related reviews and highlights the challenges in the management, control, and operation for a blockchain-based smart grid as well as future research directions in the five categories: collaboration among stakeholders; data analysis and data management; control of grid imbalances; decentralization of grid management and operations; and security and privacy. All these aspects have not been covered in previous reviews.

Shiferaw Bekele, Tagesech Yohannes, Abdurehman Eshete Mohammed Department of Medical Laboratory Sciences, College of Health Sciences, Jimma University, Jimma, Ethiopia Background: Diabetes mellitus is a group of metabolic disorders that are caused by deficiency in insulin secretion or the decreased ability of insulin to act effectively on target tissues, particularly muscle, liver, and fat. As a result of insulin resistance in the target tissues, particularly in the adipocytes, free fatty acid flux is increased, leading to increased lipid synthesis in hepatocytes, which is responsible for diabetic dyslipidemia.Objective: The objective of this study was to determine the prevalence and associated factors of dyslipidemia among diabetic patients in Durame General Hospital in Kembata Tembaro zone.Methods: A cross-sectional study was conducted from September 2015 to April 2016. In total, 224 subjects were involved in the study by using convenient sampling techniques. Face-to-face interview–administered questionnaire was used to collect sociodemographic data and other possible clinical data associated with the prevalence of dyslipidemia. Fasting venous blood specimens were collected to assess serum lipid profiles. Blood pressure (BP), weight, height, and waist circumference were measured.Results: The prevalence of dyslipidemia was 65.6%. Individual lipid abnormality of elevated LDL-C, TC, TG, and reduced HDL-C were identified in 43.8%, 23.7%, 40.6%, and 41.9% of study subjects, respectively. The prevalence of dyslipidemia was significantly associated with high BP, high body mass index, aging, and longer duration of diabetes mellitus. Conclusion: High prevalence of dyslipidemia was found among diabetic patients in the study area. Therefore, a compressive mechanism is required to screen, treat, and prevent dyslipidemia. Keywords: diabetes, lipid profile, Jimma, Ethiopia

Efficient nuclear reprogramming of somatic cells to pluripotency requires activation of innate immunity. Because innate immune activation triggers reactive oxygen species (ROS) signaling, we sought to determine whether there was a role of ROS signaling in nuclear reprogramming. We examined ROS production during the reprogramming of doxycycline (dox)-inducible mouse embryonic fibroblasts (MEFs) carrying the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc [OSKM]) into induced pluripotent stem cells (iPSCs). ROS generation was substantially increased with the onset of reprogramming. Depletion of ROS via antioxidants or Nox inhibitors substantially decreased reprogramming efficiency. Similarly, both knockdown and knockout of p22phox—a critical subunit of the Nox (1–4) complex—decreased reprogramming efficiency. However, excessive ROS generation using genetic and pharmacological approaches also impaired reprogramming. Overall, our data indicate that ROS signaling is activated early with nuclear reprogramming, and optimal levels of ROS signaling are essential to induce pluripotency.

The recent FDA approval of two drugs, pirfenidone and nintedanib, for the treatment of idiopathic pulmonary fibrosis (IPF) has fueled interest in the development of additional drugs to treat the disease or its major clinical complications including cough and acute exacerbations. Since 2015, there are at least a dozen active interventional studies that are testing the efficacy of novel pharmacotherapies, exercise or stem cells in modifying the disease process in IPF. Additionally, there are combinatorial studies evaluating the effectiveness of pirfenidone or nintedanib in combination with other agents. However, there remains an urgent need for clinical trials to prospectively evaluate the efficacy of existing drugs with promising retrospective data, such as proton pump inhibitors (PPIs), in IPF. Several retrospective cohorts have provided tantalizing data supporting the beneficial effect of PPIs in patients with well-defined IPF. This review provides the general outlook of pharmacotherapies in IPF, and highlights preclinical and retrospective clinical data to make a case for randomized controlled clinical trials of PPIs in IPF.

Insulin resistance syndrome (IRS) is a configuration of cardiovascular risk factors involved in the development of metabolic disorders including type 2 diabetes mellitus. In addition to diet, age, socioeconomic, and environmental factors, genetic factors that impair insulin signaling are centrally involved in the development and exacerbation of IRS. Genetic and pharmacological studies have demonstrated that the nitric oxide (NO) synthase (NOS) genes are critically involved in the regulation of insulin-mediated glucose disposal. The generation of NO by the NOS enzymes is known to contribute to vascular homeostasis including insulin-mediated skeletal muscle vasodilation and insulin sensitivity. By contrast, excessive inhibition of NOS enzymes by exogenous or endogenous factors is associated with insulin resistance (IR). Asymmetric dimethylarginine (ADMA) is an endogenous molecule that competitively inhibits all the NOS enzymes and contributes to metabolic perturbations including IR. The concentration of ADMA in plasma and tissue is enzymatically regulated by dimethylarginine dimethylaminohydrolase (DDAH), a widely expressed enzyme in the cardiovascular system. In preclinical studies, overexpression of DDAH has been shown to reduce ADMA levels, improve vascular compliance, and increase insulin sensitivity. This review discusses the feasibility of the NOS/DDAH pathway as a novel target to develop vasoprotective insulin sensitizers.

Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.

Genetic and pharmacological studies have shown that impairment of the nitric oxide (NO) synthase (NOS) pathway is associated with hypertension and insulin-resistance (IR). In addition, inhibition of NOS by the endogenous inhibitor, asymmetric dimethylarginine (ADMA), may also result in hypertension and IR. On the other hand, overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes ADMA, in mice is associated with lower ADMA, increased NO and enhanced insulin sensitivity. Since DDAH carries a farnesoid X receptor (FXR)-responsive element, we aimed to upregulate its expression by an FXR-agonist, INT-747, and evaluate its effect on blood pressure and insulin sensitivity.In this study, we evaluated the in vivo effect of INT-747 on tissue DDAH expression and insulin sensitivity in the Dahl rat model of salt-sensitive hypertension and IR (Dahl-SS). Our data indicates that high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls.Our study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.

In the title salt, C15H17N2+·ClO4−, the isoindoline N atom is protonated and an intramolecular N—H...N hydrogen bond occurs. In the crystal, N—H...O and numerous weak C—H...O interactions occur between the cation and anion. The O atoms of the perchlorate anion are disordered over four sets of sites with occupancies of 0.438 (4), 0.270 (9), 0.155 (8) and 0.138 (5).

The title compound, C8H14N22+·C12H8N2O8P−·ClO4−, was formed by the reaction of α,α-bis-m-xylenediamine and sodium bis-p-nitrophenylphosphate in the presence of Zn(ClO4)·6H2O in methanol solution. The two amine groups of the m-xylenediammonium ion are each protonated and each hydrogen-bonded to two O atoms of the phosphate anion, which acts as a 1,3-bridge. The ammonium groups are arranged matched face to face and each pair is doubly bridged by two perchlorate ions through hydrogen bonding. In addition, there are also weak C—H...O interactions. Both the N—H...O and C—H...O interactions are contained in a channel down the a axis. The perchlorate oxygen atoms are disordered over two positions with site occupancy factors of ca 0.7 and 0.3.

Each Cu atom in the dinuclear centrosymmetric title complex, [Cu2Br2(C14H17N3)2](ClO4)2, is ligated in a distorted square-pyramidal geometry (τ = 0.31) by a tridentate bis[2-(2-pyridyl)ethyl]amine ligand, and by two bridging Br atoms. In addition, the dinuclear species is stabilized by two hydrogen-bonded perchlorate anions.

In the title compound, [Cu(ClO4)2(C12H13N3)(C2H3N)], the CuII atom is six-coordinate in a Jahn–Teller distorted octahedral geometry, with coordination by the tridentate chelating ligand, an acetonitrile molecule, and two axial perchlorate anions. The tridentate ligand bis(2-pyridylmethyl)amine chelates meridionally and equatorially while an acetonitrile molecule is coordinated at the fourth equatorial site. The two perchlorate anions are disordered with site occupancy factors of 0.72/0.28. The amine H is involved in intramolecular hydrogen bonding to the perchlorate O atoms and there are extensive but weak intermolecular C—H...O interactions.

The title compound, [Cu(C6H8N2)(C13H15N3)](ClO4)2, is a mixed ligand complex with the CuII atom coordinated by (6-methyl-2-pyridylmethyl)(2-pyridylmethyl)amine, acting as a tridentate ligand, and 2-(2-aminomethyl)pyridine, as a bidentate ligand, leading to an N5 square-pyramidal geometry. The amine H atoms are involved in hydrogen bonding to the perchlorate O atoms and there are extensive but weak intermolecular C—H...O interactions in the crystal structure. The perchlorate ions are each disordered over two positions, with site occupancies of 0.601 (8):0.399 (8) and 0.659 (11):0.341 (11).

BackgroundThe beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (IPF) has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated.MethodsHere, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and fibrosis. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and fibrosis. In addition, we cultured lung fibroblasts from IPF patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease (ILD) databases to examine the effect of PPIs on transplant-free survival.ResultsThe cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6). The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1) and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor β (TGFβ), fibronectin and matrix metalloproteinases (MMPs). Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in IPF patients. Intriguingly, this data demonstrated that IPF patients on PPIs had prolonged survival over controls (median survival of 3.4 vs 2 years).ConclusionsOverall, these data indicate the possibility that PPIs may have protective function in IPF by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.

Background and aimsProton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.MethodsUsing a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.ResultsIn multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.ConclusionsConsistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.

The current state of the art in post-marketing drug surveillance utilizes voluntarily submitted reports of suspected adverse drug reactions. We present data mining methods that transform unstructured patient notes taken by doctors, nurses and other clinicians into a de-identified, temporally ordered, patient-feature matrix using standardized medical terminologies. We demonstrate how to use the resulting high-throughput data to monitor for adverse drug events based on the clinical notes in the EHR.

Recent evidence suggests human embryonic stem cell (hESC) and induced pluripotent stem (iPS) cell lines have differences in their epigenetic marks and transcriptomes, yet the impact of these differences on subsequent terminally differentiated cells is less well understood. Comparison of purified, homogeneous populations of somatic cells derived from multiple independent human iPS and ES lines will be required to address this critical question. Here, we report a differentiation protocol based on embryonic development that consistently yields large numbers of endothelial cells (ECs) derived from multiple hESCs or iPS cells. Mesoderm differentiation of embryoid bodies was maximized, and defined growth factors were used to generate KDR(+) EC progenitors. Magnetic purification of a KDR(+) progenitor subpopulation resulted in an expanding, homogeneous pool of ECs that expressed EC markers and had functional properties of ECs. Comparison of the transcriptomes revealed limited gene expression variability between multiple lines of human iPS-derived ECs or between lines of ES- and iPS-derived ECs. These results demonstrate a method to generate large numbers of pure human EC progenitors and differentiated ECs from pluripotent stem cells and suggest individual lineages derived from human iPS cells may have significantly less variance than their pluripotent founders.

ABSTRACTThe use of non-toxic and eco-friendly natural dyes on textiles has received much attention due to the increased environmental awareness to avoid some hazardous synthetic dyes. In the present study, an eco-friendly approach was developed to impart colour and antibacterial properties to cotton fabrics dyed with Justicia schimperiana leaf extract as a non-toxic natural colourant. The solvent method of extraction and exhaust dyeing method was used for this study. Copper sulphate, ferrous sulphate, and alum were applied in a simultaneous -mordanting process as a mordanting agent. The effects of shade percentage, dyeing temperature, and dyeing time on the obtained colour strength of the fabrics were investigated. Optimisation of dyeing conditions was carried out using Box Behnken design of expert software. An optimum level of 3. 28 colour strength (K/S) was observed in the sample treated with a shade percentage of 50 (% o.w.f), 72 °C dyeing temperature, and 45 minutes of dyeing time. Antibacterial properties of treated fabrics were evaluated against common pathogenic bacteria, Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). The results indicated the treated fabrics possessed desirable antibacterial properties. The washing and rubbing fastness of the dyed fabrics were also reported.

Abstract Background Undernutrition, manifested as stunting and/or thinness, is a major public health concern in low-income countries, including Ethiopia. Factors such as sociodemographic, economic, and dietary status influence children’s academic achievement. This study aimed to assess the association between dietary diversity, nutritional status, and academic performance of school-age children in pastoral communities in Southeast Ethiopia. Methods A school-based cross-sectional study was conducted among 395 randomly selected school-age children. A multistage sampling followed by systematic random sampling was used to collect the data. Students’ academic performance (AP) was evaluated by computing two-semester average grade scores of the 2016/17 academic year in all disciplines using the school record. A pre-tested, interviewer-administered, structured questionnaire was used to collect the data. To assess nutritional status, the z scores of height for age (HAZ) and BMI for age (BAZ) were employed according to WHO’s new reference values. The WHO Anthroplus software was used to generate nutritional indices. A structural equation model (SEM) was used to examine the direct, indirect, and total effects of the dietary diversity score (DDS), HAZ score, and BAZ score on AP. The beta coefficient (β) along with the confidence interval (CI) were used to estimate the strength of the association. Results The prevalence of stunting and thinness was 26.6% (95% CI: 21.8, 31.4%) and 28.9% (95% CI: 24.3, 33.2%), respectively. The proportion of dietary diversity (DD) among school-age children was 40% (95% CI: 35.7, 45.3%) low DD and 60% (95% CI: 54.7, 64.3%) adequate DD. The SEM revealed that a unit increment in the child’s DDS (unstandardised β = 0.130, 95% CI: 0.049 to 0.211) did have direct and total effects on the HAZ score. However, HAZ score, BAZ score, and DDS did not have direct, indirect, or total effects on AP. Similarly, DDS did not have direct or total effects on the BAZ score. Conclusion The academic performance (AP) was low among these school-age children, and the prevalence of stunting and thinness was high. Thus, nutrition interventions on dietary diversity for school-age children would be crucial interventions for increasing academic achievement.

Abstract Quality teacher–child interaction is considered one of the primary mechanisms through which educational experience fosters the development of children’s competencies. Teachers’ self-efficacy and beliefs about developmentally appropriate practices influence the quality of classroom interaction. However, the findings are mixed, and more research must be done within the preschool teacher population. The present study investigated teacher-related factors influencing teacher–child interaction quality with preschool children. Two rating scales and one observation measure were used to survey and observe 55 preschool teachers in preschool centres of Arba Minch town, Ethiopia. Statistically significant positive correlations were found between teacher factors (i.e., teacher belief, self-efficacy, teaching experience) and teacher–child interaction quality (emotional support, classroom organization, and instructional support). Teacher belief significantly predicted teachers’ emotional support and classroom organization, while teaching experience significantly predicted instructional support. The findings of this study have implications for concerned bodies striving to achieve the 2030 sustainable development goals aimed at increasing the supply of qualified teachers to ensure all girls and boys have access to quality early childhood development and care so that they are ready for primary education, especially in the least developed countries.

Abstract Protein biomarkers are associated with mortality in cardiovascular disease, but their effect on predicting respiratory and all-cause mortality is not clear. We tested whether a protein risk score (protRS) can improve prediction of all-cause mortality over clinical risk factors in smokers. We utilized smoking-enriched (COPDGene, LSC, SPIROMICS) and general population-based (MESA) cohorts with SomaScan proteomic and mortality data. We split COPDGene into training and testing sets (50:50) and developed a protRS based on respiratory mortality effect size and parsimony. We tested multivariable associations of the protRS with all-cause, respiratory, and cardiovascular mortality, and performed meta-analysis, area-under-the-curve (AUC), and network analyses. We included 2232 participants. In COPDGene, a penalized regression-based protRS was most highly associated with respiratory mortality (OR 9.2) and parsimonious (15 proteins). This protRS was associated with all-cause mortality (random effects HR 1.79 [95% CI 1.31–2.43]). Adding the protRS to clinical covariates improved all-cause mortality prediction in COPDGene (AUC 0.87 vs 0.82) and SPIROMICS (0.74 vs 0.6), but not in LSC and MESA. Protein–protein interaction network analyses implicate cytokine signaling, innate immune responses, and extracellular matrix turnover. A blood-based protein risk score predicts all-cause and respiratory mortality, identifies potential drivers of mortality, and demonstrates heterogeneity in effects amongst cohorts.

Abstract Background Human Immune deficiency Virus (HIV) infected children are at higher risk of developing pneumonia. Particularly, in the early phase of HIV infection, the risk of acquiring pneumonia is high, and it remains a major public health problem even after the test and treatment strategy. There is no clear evidence of the overall incidence of pneumonia among HIV-infected children in Amhara region. Aimed to assess the incidence of pneumonia and its predictors among HIV-infected children receiving Antiretroviral therapy in Amhara Region Comprehensive Specialized Hospitals, 2022. Methods A multicenter retrospective follow-up study was conducted from June 10, 2014, to February 28, 2022, among 430 HIV-positive children receiving antiretroviral therapy. A simple random sampling technique was used. The data was taken from the national antiretroviral intake and follow-up forms. The data were collected via the KoBo toolbox and analyzed using Stata version 17. The Kaplan–Meier curve and log-rank test were employed. Bivariable and multivariable Cox regression was carried out to identify predictors of pneumonia and a P-value

Abstract Background Perinatal mortality is a global health problem, especially in Ethiopia, which has the highest perinatal mortality rate. Studies about perinatal mortality were conducted in Ethiopia, but which factors specifically contribute to the change in perinatal mortality across time is unknown. Objectives To assess the trend and multivariate decomposition of perinatal mortality in Ethiopia using EDHS 2005–2016. Methods A community-based, cross-sectional study design was used. EDHS 2005–2016 data was used, and weighting has been applied to adjust the difference in the probability of selection. Logit-based multivariate decomposition analysis was used using STATA version 14.1. The best model was selected using the lowest AIC value, and variables were selected with a p-value less than 0.05 at 95% CI. Result The trend of perinatal mortality in Ethiopia decreased from 37 per 1000 births in 2005 to 33 per 1000 births in 2016. About 83.3% of the decrease in perinatal mortality in the survey was attributed to the difference in the endowment (composition) of the women. Among the differences in the endowment, the difference in the composition of ANC visits, taking the TT vaccine, urban residence, occupation, secondary education, and birth attendant significantly decreased perinatal mortality in the last 10 years. Among the differences in coefficients, skilled birth attendants significantly decreased perinatal mortality. Conclusion and recommendation The perinatal mortality rate in Ethiopia has declined over time. Variables like ANC visits, taking the TT vaccine, urban residence, occupation, secondary education, and skilled birth attendants reduce perinatal mortality. To reduce perinatal mortality more, scaling up maternal and newborn health services has a critical role.