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Strolling is a complex activity that requires the synchronization of the brain, anxiety, and muscles, as well as rhythmic movement of the lower limbs. Gait may be abnormal if coordination is disrupted. As a result, exoskeletons should be used to treat it effectively. The connection and other systems contained in the exoskeletons could be used to mimic the behavior of the human lower leg. These mechanisms are created utilizing complex traditional methods. This study proposes a new gait-inspired method based on a genetic algorithm (GA) for synthesizing a four-bar mechanism for exoskeletons. For each phase of the gait, the trajectory is calculated and merged using optimization algorithms. Each phase of the trajectory passes through 10 precision points, for an entirety of 20 precision points in 1 gait cycle. For the problem under consideration, it is discovered that the GA outperforms other literature techniques. Finally, the proposed design for a lower limb exoskeleton is depicted as a solid model. Furthermore, the generated link-age accurately tracks all the transition points, and the simulation of the planned linkage for one gait cycle has been illustrated using a stick diagram.

Background: Indoor air pollution is a major public health concern, contributing to approximately 2.9 million deaths and 81.1 million disability-adjusted life years lost annually. This issue disproportionately affects underprivileged communities that depend on solid fuels for cooking. As a result, these communities suffer from heightened exposure to indoor air pollutants, which increases the risk of morbidity, mortality, and worsening health disparities., Objective: This study investigates the association between socioeconomic status and mortality related to indoor air pollution across multiple countries., Methods: Data from the 2019 Demographic and Health Survey, WHO, and World Bank were utilized to examine the impact of socioeconomic status on indoor air pollution-related mortality. The primary outcome was mortality associated with solid fuel use, with income quintiles as the independent variable. Linear and logistic regression analyses were applied to assess these relationships., Results: Logistic regression analysis revealed a strong negative association where household income increases and indoor air pollution-related mortality significantly decreases. Specifically, Households in the highest income quartile showed a 22% reduction progressively in the odds of mortality risk compared to the lowest income quintile. Additionally, access to clean fuel correlated with a 0.59 times lower odds of mortality, highlighting the clean energy sources' protecting effect., Conclusion: The findings highlight the critical need to prioritize clean fuel access, particularly in low-income communities, to reduce indoor air pollution mortality. Policies should focus on increasing clean energy accessibility and supporting vulnerable populations through targeted subsidies and poverty alleviation programs to reduce indoor air pollution exposure disparities., Competing Interests: The author declares that there is nothing to disclose., (Copyright: © 2025 Muayad Albadrani. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and aim: Being a central organ in homeostasis and maintaining the health of the biological system, kidneys are exposed to variable toxicants. Long-term exposure to nephrotoxic molecules causes chronic renal damage that causes fibrosis and loss of function. Such damage can be initiated by oxidative stress which provokes inflammation. We aim at investigating the potential therapeutic effects of Boswellia serrata (BS) gum resin extract in managing CCl 4 -induced renal toxicity. Methods: Male Wistar albino rats were assigned to groups: healthy control; CCl 4 -treated (CCl 4 , twice/week, for 6 weeks); CCl 4 + BS-treated: CCl 4 for 6 weeks followed by BS (150 mg/kg/day) for 2 weeks; and CCl 4 + Silymarin-treated: CCl 4 for 6 weeks followed by Silymarin (100 mg/kg/day) for 2 weeks. Blood and kidney tissue were utilized to assess oxidative stress status, inflammatory cytokines, and histopathological changes. Results: BS treatment ameliorated signs of renal damage and fibrosis as it improved renal antioxidant status and renal function markers and significantly reduced the levels of inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8 along with the fibrogenic marker TGF-β. Kidney tissues showed improved histological features after BS treatment. Conclusions: BS gum resin extract has significant therapeutic potential against CCl 4 -induced renal damage and fibrosis. These effects could be mediated via its previously reported antioxidant, free radical scavenging, and anti-inflammatory effects.

Background: Congenital heart diseases are among the most common birth defects, significantly impacting infant health. Recent evidence suggests that exposure to endocrine-disrupting chemicals may contribute to the incidence of congenital heart diseases. This study systematically reviews and analyzes the association between maternal endocrine-disrupting chemicals exposure and congenital heart diseases., Methodology: This systematic review and meta-analysis followed the Cochrane Handbook and PRISMA guidelines. We included studies assessing the link between maternal exposure to various endocrine-disrupting chemicals and the incidence of congenital heart diseases without restricting the study design or exposure assessment methods. Data were extracted from four databases, including PubMed, Scopus, Web of Science, and Cochrane Library, up to June 2024. Quality assessment of observational studies was conducted using the Newcastle-Ottawa Scale. Statistical analysis was performed using RevMan software version 5.3, presenting results as odds ratios with 95% confidence intervals., Results: Fifty-nine studies were included in the meta-analysis. The pooled analysis revealed a significant association between maternal endocrine-disrupting chemical exposure and the incidence of congenital heart diseases when measured using human samples (odds ratio = 1.63, 95% confidence interval [1.35-1.97], p < 0.00001). Notably, exposure to heavy metals, polycyclic aromatic hydrocarbons, and perfluoroalkyl compounds was strongly associated with congenital heart diseases. However, non-sample-based methods showed no significant overall correlation (odds ratio = 1.08, 95% confidence interval [0.93-1.26], p = 0.30), except for housing renovation compounds, which were linked to a higher incidence of congenital heart diseases., Conclusions: Maternal exposure to specific endocrine-disrupting chemicals, particularly heavy metals and polycyclic aromatic hydrocarbons, significantly increases the risk of congenital heart diseases. These findings underscore the need for preventive measures to reduce endocrine-disrupting chemicals exposure during pregnancy and further research to elucidate the underlying mechanisms.

Background: HPV represents one of the most common sexually transmitted infections worldwide, with significant adverse clinical consequences such as cervical cancer. However, the knowledge and awareness regarding HPV and its vaccination, particularly among Saudi women, are still under debate. Our study aims to investigate the knowledge, awareness, and attitude toward HPV and its vaccines among women in the Medina region., Methods: A descriptive cross-sectional study was conducted from July 2024 to September 2024 in women aged more than 18 years and residing in Medina. The collected data included information regarding women's demographics, knowledge, awareness, and attitudes toward HPV and its vaccination. All the statistical analyses were executed using SPSS., Results: A total of 721 participants enrolled in our study after adequate completion of the online questionnaire. The majority of the population (45.2%) is aged 18-25 years, with 51.3% of participants being single regarding marital status. A total of 59.4% of the participants have heard about HPV, 37% know that it is sexually transmitted, and 37.4% know about its ability to cause cervical cancer. Social media and the internet were the primary sources of information regarding the HPV vaccine, with 41.6% thinking that the HPV vaccine can be effective against HPV infection. Around 40% of the participants showed an attitude toward receiving the HPV vaccine as they feel they are at risk. The educational status and monthly income were notably associated with the overall knowledge and awareness regarding HPV and its vaccine., Conclusions: Our descriptive cross-sectional study highlights the significant gap in knowledge and awareness regarding HPV and its vaccine, with a lack of awareness identified as the commonest barrier preventing people from receiving the HPV vaccination. Hence, enhancing the knowledge and awareness level is essential to increase vaccination rates.

Background: The optimum model of perinatal care for low-risk pregnancies has been a topic of debate. Obstetrician-led care tends to perform unnecessary interventions, whereas the quality of midwife-led care has been subject to debate. This review aimed to assess whether midwife-led care reduces childbirth intervention and whether this comes at the expense of maternal and neonatal wellbeing. Methods: PubMed, Scopus, Cochrane Library, and Web of Science were systematically searched for relevant studies. Studies were checked for eligibility by screening the titles, abstracts, and full texts. We performed meta-analyses using the inverse variance method using RevMan software version 5.3. We pooled data using the risk ratio and mean difference with the 95% confidence interval. Results: This review included 44 studies with 1,397,320 women enrolled. Midwife-led care carried a lower risk of unplanned cesarean and instrumental vaginal deliveries, augmentation of labor, epidural/spinal analgesia, episiotomy, and active management of labor third stage. Women who received midwife-led care had shorter hospital stays and lower risks of infection, manual removal of the placenta, blood transfusion, and intensive care unit (ICU) admission. Furthermore, neonates delivered under midwife-led care had lower risks of acidosis, asphyxia, transfer to specialist care, and ICU admission. Postpartum hemorrhage, perineal tears, APGAR score < 7, and other outcomes were comparable between the two models of management. Conclusions: Midwife-led care reduced childbirth interventions with favorable maternal and neonatal outcomes in most cases. We recommend assigning low-risk pregnancies to midwife-led perinatal care in health systems with infrastructure allowing for smooth transfer when complications arise. Further research is needed to reflect the situation in low-resource countries.

Cancer is a critical health problem, and chemotherapy administration is mandatory for its eradication. However, chemotherapy like doxorubicin (Dox) has serious side-effects including cognitive impairment or chemo brain. Melatonin is a neuroprotective agent that has antioxidant, and anti-inflammatory effects. We aimed to explore melatonin's effect on Dox-induced chemo brain to discover new mechanisms associated with Dox-induced neurotoxicity and try to prevent its occurrence. Thirty-two male albino rats had been equally divided into four groups; control, melatonin-administrated, Dox-induced chemo brain, and melatonin + Dox treated. On the 9th day, brain had been excised after scarification and had been assessed for reactive oxygen species measurement, histopathological analysis, immunohistochemical, gene and protein expressions for the nuclear factor erythroid 2-related factor 2 (Nrf2), p53 and Silent information regulator 2 homolog 1 (SIRT1). Our results show that melatonin coadministration diminished Dox induced hippocampal and prefrontal cortex (PFC) cellular degeneration. It alleviated Nitric Oxide (NO) level and reversed the decline of antioxidant enzyme activities. It also upregulated Nrf2, SIRT1 and downregulated p53 gene expression in rats receiving Dox. Moreover, melatonin elevated the protein expression level of Nrf2, SIRT1 and reduced p53 corresponding to immunohistochemical results. The data suggested that melatonin can mitigate Dox-induced neurotoxicity by aggravating the endogenous antioxidants and inducing neurogenesis through activation of Nrf2/p53-SIRT1signaling pathway in adult rats' PFC. These effects were associated with Nrf2, SIRT1 activation and p53 inhibition. This could be guidance to add melatonin as an adjuvant supplement to Dox regimens to limit its adverse effect on the brain function., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background and Aim: Candida infection is a significant cause of morbidity and mortality in neonatal intensive care units (NICU) globally. We aimed to conduct a systematic review to investigate the prevalence of candida among causative organisms of neonatal sepsis and identify the distribution of candida species infecting Saudi neonates., Methods: We comprehensively searched Web of Science, Scopus, PubMed, and Cochrane Library from their inception till November 2023. After screening titles, abstracts, and full texts, we ultimately included 21 eligible studies. The designs of the included studies were randomized clinical trials, cohorts, case-control, and case reports; the methodological quality was appraised using the Cochrane risk of bias assessment tool, NIH tool for observational studies, and Murad tool for assessing case reports., Results: Our systematic review and meta-analysis pooled data reported in 21 studies in the Saudi populations, which provided data on different types of candidal infections in 2346 neonates. The pooled data of ten retrospective studies enrolling 1823 neonates revealed that candida species resembled 4.2% of the causative organisms of neonatal sepsis among Saudi neonates (95%CI [2.5%; 5.9%], p = 0.000). Additionally, out of a total of 402 candida species that were identified among the included studies, C. albicans prevailed mostly among Saudi neonates, followed by C. parapsilosis , NS candida, and C. tropicalis (50.25%, 21.40%, 12.44%, and 9.45%, respectively)., Conclusions: We found that candida species prevailed in 4.2% of 1823 cases of neonatal sepsis; the most common candida species was C. albicans . We could not pool data regarding risk factors or susceptibility of candida species to different treatment modalities due to insufficient data, requiring future large-scale, high-quality studies to be conducted.

Introduction: Warts, benign skin growths caused by various human papillomavirus strains, are categorized as genital and non-genital. Non-genital warts often lack noticeable symptoms but can lead to psychological distress due to factors like embarrassment. Traditional treatments, including physical and chemical methods, show limitations, prompting the exploration of novel approaches like intralesional immunotherapy. The clinical challenge lies in selecting the most effective modality., Objective: In our study, we used the network meta-analysis (NMA) as a statistical tool to explore the most effective intralesional immunotherapy interventions., Methods: Comprehensive searches of Web of Science, PubMed, Cochrane, and Scopus databases were conducted until December 2023. Eligible studies were analyzed for outcomes presented as risk ratios (RRs) with 95% confidence intervals (CI). Treatments were ranked using the P-score in an NMA performed with R software., Results: We included 68 RCTs in our study. For complete response, needling showed a significant difference compared to Candida albicans antigen (RR= 0.13, 95% CI [0.02; 0.99]) and Mw (RR= 0.12, 95% CI [0.02; 0.94]). In overall response, both bleomycin and furosemide with digoxin were significant compared to autoimplantation (RR= 0.46, 95% CI [0.24; 0.88]) and (RR= 0.40, 95% CI [0.18; 0.91]) respectively. Similarly, both were significant compared to cryotherapy (RR= 0.45, 95% CI [0.27; 0.76]) and (RR= 0.40, 95% CI [0.19; 0.82]) respectively., Conclusion: This NMA indicates needling, furosemide with digoxin, and PBP antigen stimulants as effective for non-genital warts, surpassing traditional treatments in complete and overall response. Direct comparisons in future research are warranted to confirm their superiority.

Background: Acute pancreatitis (AP) is an inflammatory condition that resolves spontaneously, but occasionally, develops into systemic inflammation, organ failure and mortality. Oxidative stress and activation of inflammatory pathways represent major players in AP pathogenesis. Current management of AP relies on attenuating injuries to the pancreas and putting the inflammatory process under control. In this study, we investigated the role of sitagliptin in modulating L-arginine-induced AP in rats., Methods: Swiss rats were subdivided into a healthy control group, AP group (a single dose of L-arginine 250 mg/100 g, intraperitoneal), and sitagliptin + L-arginine-treated group (10 mg sitagliptin/kg body weight/day, orally). Sitagliptin treatment started 1 hour after L-arginine injection and continued for 3days. Biochemical and histopathological investigations were performed on serum and tissue samples collected from test animals., Results: L-arginine increased pancreatic meyloperoxidase and serum amylase- and lipase activities and serum levels of TNF-α, LT-α, IFN-γ, IL-1α/β, IL-6, IL-10, IL-12, and IL-15. AP animals showed elevated MDA and NO and decreased GSH and serum calcium levels. Histopathological changes were observed by H&E staining. Sitagliptin treatment significantly ameliorated these biochemical and histological changes diminishing the signs of AP., Conclusion: Sitagliptin treatment was effective in ameliorating L-arginine-induced AP which can be regarded to its anti-inflammatory and antioxidant effect., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Eltahir, Elbadawy, Almikhlafi, Alalawi, Aldhafiri, Alahmadi, Al thagfan, Albadrani, M Eweda and Abouzied.)

Introduction: Sustainable Development Goal (SDG) Target 3.8.2 entails financial protection against catastrophic health expenditure (CHE) by reducing out-of-pocket expenditure (OOPE) on healthcare. India is characterized by one of the highest OOPE on healthcare, in conjunction with the pervasive socio-economic disparities entrenched in the population. As a corollary, India has embarked on the trajectory of ensuring financial risk protection, particularly for the poor, with the launch of various flagship initiatives. Overall, the evidence on wealth-related inequities in the incidence of CHE in low- and middle-Income countries has been heterogenous. Thus, this study was conducted to estimate the income-related inequalities in the incidence of CHE on hospitalization and glean the individual contributions of wider socio-economic determinants in influencing these inequalities in India., Methods: The study employed cross-sectional data from the nationally represented survey on morbidity and healthcare (75th round of National Sample Survey Organization) conducted during 2017-2018, which circumscribed a sample size of 1,13,823 households and 5,57,887 individuals. The inequalities and need-adjusted inequities in the incidence of CHE on hospitalization care were assessed via the Erreygers corrected concentration index. Need-standardized concentration indices were further used to unravel the inter- and intra-regional income-related inequities in the outcome of interest. The factors associated with the incidence of CHE were explored using multivariate logistic regression within the framework of Andersen's model of behavioral health. Additionally, regression-based decomposition was performed to delineate the individual contributions of legitimate and illegitimate factors in the measured inequalities of CHE., Results: Our findings revealed pervasive wealth-related inequalities in the CHE for hospitalization care in India, with a profound gap between the poorest and richest income quintiles. The negative value of the concentration index (EI: -0.19) indicated that the inequalities were significantly concentrated among the poor. Furthermore, the need-adjusted inequalities also demonstrated the pro-poor concentration (EI: -0.26), denoting the unfair systemic inequalities in the CHE, which are disadvantageous to the poor. Multivariate logistic results indicated that households with older adult, smaller size, vulnerable caste affiliation, poorest income quintile, no insurance cover, hospitalization in a private facility, longer stay duration in the hospital, and residence in the region at a lower level of epidemiological transition level were associated with increased likelihood of incurring CHE on hospitalization. The decomposition analysis unraveled that the contribution of non-need/illegitimate factors (127.1%) in driving the inequality was positive and relatively high vis-à-vis negative low contribution of need/legitimate factors (35.3%). However, most of the unfair inequalities were accounted for by socio-structural factors such as the size of the household and enabling factors such as income group and utilization pattern., Conclusion: The study underscored the skewed distribution of CHE as the poor were found to incur more CHE on hospitalization care despite the targeted programs by the government. Concomitantly, most of the inequality was driven by illegitimate factors amenable to policy change. Thus, policy interventions such as increasing the awareness, enrollment, and utilization of Publicly Financed Health Insurance schemes, strengthening the public hospitals to provide improved quality of specialized care and referral mechanisms, and increasing the overall budgetary share of healthcare to improve the institutional capacities are suggested., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sriram, Verma, Gollapalli and Albadrani.)

Introduction: Physician communication is vital for an effective physician-patient relationship. Physician empathy is crucial to patient communication. The relationship between physician empathy, physician communication, and patient satisfaction is not very clear. This study aims to study the mediating role of physician's empathy between physician's communication, physician's empathy, and patient's satisfaction., Methods: A cross-sectional study was conducted at the National Institute of Psychology, Quaid-i-Azam University, during the time period of December 2018 to February 2019. Employing the technique of purposive convenience sampling, data were collected ( N = 238) from psychiatric, cardiology, and dermatology wards of public and private sector hospitals of Islamabad and Rawalpindi. The Communication Assessment Tool, specifically the Patient's Perception of Physician's Empathy and Patient Satisfaction Scale, was used to assess study variables. The measures used in the research assess the patient's perception of the physician's communication, empathy, and patient's satisfaction. Formal permission for the research was taken from the hospital administration with approval from the institutional review boards. Participants were briefed about the purpose of the research. Both verbal and written informed consent was taken from them., Results: The result shows that a physician's empathy plays a mediating role between the physician's communication skills and patient satisfaction. Moreover, Pearson product-moment correlation indicated a significant positive relationship between doctors' communication skills, doctors' empathy, and patients' satisfaction., Conclusion: Building a positive doctor-patient relationship would not only lead to improved patient satisfaction but also reduce the likelihood of medical malpractice. Therefore, steps should be taken to enforce trust, interaction, and empathy in doctor-patient relationships, with patient-centered services. Physician's empathy plays a mediating role between physician's communication skills and patient's satisfaction., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Parkinson's disease (PD) is one of the most common neurodegenerative conditions. Alpha-synuclein deposition, Lewy bodies (LBs) formation, disruption of the autophagic machinery, apoptosis of substantia nigra dopaminergic neurons, oxidative stress, and neuroinflammation are all pathologic hallmarks of PD. The leaves of the stinging Nettle (Urtica dioica L.) have a long history as an herbal cure with antioxidant, anti-inflammatory, anti-cancer, immunomodulatory, and neuroprotective properties. The current study aims for the first time to investigate the role of Nettle supplementation on Rotenone-induced PD. Rats were divided into five groups; a Saline control, Nettle control (100 mg/kg/day), Rotenone control (2 mg/kg/day), Rotenone + Nettle (50 mg /kg/day), and Rotenone + Nettle (100 mg/kg). After four weeks, the rats were examined for behavioral tests. The midbrains were investigated for histopathological alteration and immunohistochemical reaction for Tyrosine hydroxylase in the dopaminergic neurons, α-synuclein for Lewy bodies, caspase 3 for apoptotic neurons, LC3 and P62 for autophagic activity. Midbrain homogenates were examined for oxidative stress markers. mRNA expression of TNFα and Il6; inflammatory markers, Bcl-2, BAX and Caspase 3; apoptosis markers, were detected in midbrains. The results showed that Nettle caused recovery of midbrain dopaminergic neurons, by inhibiting apoptosis, inflammation, and oxidative stress and by restoring the autophagic machinery with clearance of α-synuclein deposits. We can conclude that Nettle is a potentially effective adjuvant in the treatment of Parkinson's disease., Competing Interests: Conflict of Interest None declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The prevalent use of pesticides, including pirimiphos-methyl (PPM) and bifenthrin (BF), poses a serious health risk, particularly to workers who encounter these chemicals daily. Despite the recognized hepatotoxic effects, the specific molecular mechanisms, especially those involving miRNAs in liver damage caused by PPM and BF, are not fully elucidated. Prior studies have not exhaustively analyzed the hepatic miRNA-target gene dynamics following exposure to these pesticides; thus, this research aims to fill that gap through an extensive miRNA analysis to discern their regulation in PPM or BF-induced hepatic toxicity. In this study, male Sprague-Dawley rats were exposed to BF or PPM for 28 days through oral gavage, simulating the chronic exposure faced by humans. We conducted a thorough assessment of the hepatotoxicity induced by PPM and BF, employing multiple evaluation levels, including histological analysis, liver enzyme measurements, and real-time PCR to detect changes in hepatic miRNA-target gene expressions. Additionally, we utilized DIANA-miRPath prediction tools to delineate the functional implications of these hepatic miRNA target genes. Our findings reveal a significant modulation in the expression of rno-miR-155-5p and rno-miR-122-5p, along with their target genes, following PPM and BF treatment. In contrast, rno-miR-21-5p levels remained unaltered. These observations suggest potential utility of these specific hepatic miRNAs as biomarkers for liver injury resulting from pesticide exposure. Subsequent GO enrichment analysis linked target genes to functions like molecular activity, protein binding, and cellular processes. Additionally, KEGG pathway analysis showed these genes, influenced by varied miRNA expressions, play significant roles in metabolic and signaling pathways In conclusion, this study enhances our comprehension of the biological roles of miRNAs in hepatic toxicity induced by PPM and BF. The insights gained here not only shed light on molecular mechanisms but also open avenues for considering these miRNAs as potential diagnostic biomarkers in conditions of pesticide-induced hepatotoxicity, thereby guiding future therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: High percentage of OOP (Out-of-Pocket) costs can lead to poverty and exacerbate existing poverty, with 21.9% of India's 1.324 billion people living below the poverty line. Factors such as increased patient cost-sharing, high-deductible health plans, and expensive medications contribute to high OOP costs. Understanding the poverty-inducing impact of healthcare payments is essential for formulating effective measures to alleviate it., Methods: The study used data from the 75th round of the National Sample Survey Organization (Household Social Consumption in India: Health) from July 2017-June 2018, focusing on demographic-socio-economic characteristics, morbidity status, healthcare utilization, and expenditure. The analysis included 66,237 hospitalized individuals in the last 365 days. Logistic regression model was used to examine the impact of OOP expenditures on impoverishment., Results: Logistic regression analysis shows that there is 0.2868 lower odds of experiencing poverty due to OOP expenditures in households where there is the presence of at least one child aged 5 years and less present in the household compared to households who do not have any children. There is 0.601 higher odds of experiencing poverty due to OOP expenditures in urban areas compared to households in rural areas. With an increasing duration of stay in the hospital, there is a higher odds of experiencing poverty due to OOP health expenditures. There is 1.9013 higher odds of experiencing poverty due to OOP expenditures if at least one member in the household used private healthcare facility compared to households who never used private healthcare facilities., Conclusion: In order to transfer demand from private to public hospitals and reduce OOPHE, policymakers should restructure the current inefficient public hospitals. More crucially, there needs to be significant investment in rural areas, where more than 70% of the poorest people reside and who are more vulnerable to OOP expenditures because they lack coping skills., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Sriram S and Albadrani M.)

Background: Chronic kidney disease (CKD) is defined as abnormalities of kidney structure and/or function persisting for a minimum of three months., Methods:  An online cross-sectional study was conducted in the Kingdom of Saudi Arabia (KSA) between June and August 2022 to assess the knowledge, attitudes, practices, and barriers among family, internal medicine, and general physicians related to CKD screening, diagnosis, and management., Results:  A total of 427 physicians were included in the study. The majority exhibited a strong grasp of the accurate definition of CKD (83%) and recognized common risk factors, such as diabetes (99%), drugs (95%), and hypertension (98%). Two-thirds of physicians were aware of the five stages of CKD and identified estimated glomerular filtration rate (eGFR) and creatinine clearance as the most suitable markers for kidney function. Physicians also displayed knowledge of CKD-related complications. However, a noticeable gap between knowledge and practice was evident. Only one-third of participants reported screening their patients every year, primarily using serum creatinine (92.5%) and eGFR (97%) for diagnosis, while only 16% recognized that stage 4 CKD is the appropriate time to refer patients to nephrologists. In terms of barriers, the majority of physicians reported encountering low barriers to CKD management, but general practitioners working in primary healthcare centers experienced significantly higher levels of barriers., Conclusion: Most participants in our study possess a good level of knowledge and positive attitudes towards CKD diagnosis and management. Nevertheless, a discrepancy between knowledge and practical application, particularly in terms of over-screening and early referral, highlights the need for educational efforts to improve physician practice in KSA. These findings underscore the importance of addressing this gap to promote effective CKD management., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Al-Zaman et al.)

Eight wheat cultivars, Sakha-94, Giza-171, Sids-1, Sids-12, Sids-13, Shandweel-1, Misr-1, and Misr-2, were evaluated for leaf rust at the seedling and adult stages in the 2021 and 2022 seasons. Biochemical, histological, and genetic analyses were performed to determine the link between cultivars that were either sensitive or resistant to the disease. Misr-2 and Giza-171 cultivars had the highest levels of resistance to leaf rust races in 2021 (LTCGT, STSJT, and TTTST) and 2022 (MBGJT, TTTKS, and TTTTT) at the seedling stage. However, at the adult stage, Sakha-94, Giza-171, Misr-1, and Misr-2 cultivars had the highest levels of resistance; consequently, they had the lowest final disease severity and the lowest values of AUDPC. The correlation between the seedling reaction and adult reaction was non-significant, with values of 0.4401 and 0.4793 in the 2021 and 2022 seasons, respectively. Throughout the biochemical, histological, and genetic analyses, it was observed that catalase, peroxidase, and polyphenol oxidase activities significantly increased in the resistant cultivars. The discoloration of superoxide (O 2 -) and hydrogen peroxide (H 2 O 2 ) significantly decreased in resistant and moderately resistant wheat cultivars (Sakha-94, Giza-171, Misr-1, and Misr-2); higher hydrogen peroxide (H 2 O 2 ) and superoxide (O 2 -) levels were recorded for the susceptible cultivars compared to the resistant cultivars. Molecular markers proved that the Lr50 gene was detected in the resistant cultivars. Puccinia triticina infections negatively affected most histological characteristics of flag leaves, especially in susceptible cultivars. The thickness of the blade (µ), the thickness of the upper and lower epidermis (UE and LE), the thickness of mesophyll tissue (MT), and bundle length and width in the midrib were decreased in susceptible cultivars such as Sids-1, Sids-13, and Shandwel-1 compared with resistant cultivars.

Introduction: There are several risk factors attributed to tuberculosis (TB) mortality and morbidity. There are few studies and systematic reviews showing the association of silicosis and tuberculosis at a country level. Very limited studies have been conducted using multi-country data in studying the association of incidence of silicosis with TB mortality and morbidity. Hence, the aim of this research was to explore the association of incidence of silicosis and other important risk factors with TB mortality and morbidity using multi-country data., Methods: Data from 217 WHO region countries were utilized, sourcing TB-related statistics from the Institute of Health Metrics and Evaluation and additional risk factors from the Demographic and Health Survey, Global Burden of Disease, and World Bank for 2019. Regression analysis was conducted to examine the association between silicosis incidence and TB outcomes., Results: The study found an average silicosis incidence of 121.92 per 100,000 population. Additionally, 62.69% of the sample population are exposed to air pollution from solid fuel cooking. Sanitation access stands at an average of 59.67%. Regression outcomes indicate that while alcohol consumption's influence on TB is not statistically significant, a unit increase in silicosis incidence significantly elevates TB deaths (235.9, p = 0.005), YLL (9399.3, p = 0.011), and YLD (910.8, p = 0.002)., Conclusion: The burden of silicosis is found to be one of the important determinants of deaths, YLL, and YLD due to tuberculosis. Country-specific strategies to prevent and control silicosis is a need of the hour.

Background: Hypertensive disorders of pregnancy (HDP) can significantly impact maternal, neonatal, and fetal health. For controlling these disorders, frequent blood pressure measurements are required. Home blood pressure monitoring (HBPM) is a suggested alternative to conventional office monitoring that requires frequent visits. This systematic review was conducted to evaluate the efficacy and safety of HBPM in the control of HDP., Methods: We systematically conducted databases search for relevant studies in June 2022. The relevant studies were identified, and qualitative synthesis was performed. An inverse variance quantitative synthesis was conducted using RevMan software. Continuous outcome data were pooled as means differences, whereas dichotomous ones were summarized as risk ratios. The 95% confidence interval was the measure of variance., Results: Fifteen studies were included in our review (n = 5335). Our analysis revealed a superiority of HBPM in reducing the risk of induction of labor, and postpartum readmission (P = 0.02, and 0.01 respectively). Moreover, the comparison of birth weights showed a significant variation in favor of HBPM (P = 0.02). In the analysis of other outcomes, HBPM was equally effective as office monitoring. Furthermore, HBPM did not result in an elevated risk of maternal, neonatal, and fetal adverse outcomes., Conclusion: Home monitoring of blood pressure showed superiority over office monitoring in some outcomes and equal efficacy in other outcomes., (© 2023. The Author(s).)

Alpha mangostin (AM), isolated from G. mangostana, showed beneficial effects in several disorders due to its antioxidant and anti-inflammatory properties. Acute kidney injury (AKI) due to different etiologies can develop into severe complications, resulting in high mortality rates. In this work, AM is tested for its ability to alleviate AKI in glycerol-induced AKI rat model, where 30 Male Sprague-Dawley rats were assigned to a healthy group, glycerol-treated group and AM-treated group. Glycerol- and AM groups received a single dose of glycerol (per IM, 50% glycerol in saline, 8 ml/kg), whereas control group was injected with saline. AM treatment (a single daily dose, per IP, 175mg/kg) was accomplished for three days. Animals were executed to collect blood samples and kidney tissue for biochemical and histological examination. It was found that glycerol induced increase in serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, serum magnesium, TNF-α and IL-6. It also induced renal edema and hypocalcemia along with histopathological renal damage. AM treatment improved renal histological features and alleviated increase in serum creatinine, BUN, serum magnesium, TNF-α and IL-6 levels, as well as renal edema and lipid peroxidation but did not affect serum calcium levels. This suggests AM as a potential therapeutic agent for treating AKI mainly via its antioxidant and anti-inflammatory properties.

Background: Out of the 1.324 billion people in India (2016), around 12.4% of the population is below the poverty line. In India, out-of-pocket health expenditure (OOP) expenses account for about 62.6% of total health expenditure - one of the highest in the world. High OOP health expenditures push many households into poverty. This study aims to identify the impoverishing effects of OOP health expenditures in India., Methods: Data from the recent national survey by the National Sample Survey Organization - Social Consumption in Health 2014 are used to investigate the effect of OOP health expenditure on household poverty. Poverty headcounts and poverty gaps were estimated at the household level before and after making OOP healthcare payments. A logistic regression model is for predicting the effect of various factors on the incidence of impoverishment due to OOP health expenditures., Results: There were 65,932 households in the sample. The total poverty headcount in the population before making OOP payments was 16.44% and it increased to 19.05% after making OOP payments. This 2.61% increase in the poverty headcount corresponds to 6.47 million households. Logistic regression results showed that medium and large households, household members with increased duration of stay in the hospital, utilization of private health facility and the presence of chronic illness increased odds of impoverishment due to OOP health expenditures., Conclusions: Health insurance programmes must be expanded to cover outpatient and preventive health services, include people above the poverty line, cover the whole household irrespective of the number of members living in the household and the coverage threshold limits must be increased. Urban poor must be enrolled in health insurance programmes without any delay., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

Background: Surgical procedures in the heart requires protection of the heart from ischemia-reperfusion injury. Cardioplegia is the primary myocardial protective method in use. Histidine-tryptophan-ketoglutarate (HTK) solution is an intracellular cardioplegic solution that was initially used to preserve organs for transplantation., Methods: A systematic electronic search was conducted in July 2021, in four databases; PubMed, Scopus, Web of Science, and Cochrane Library for eligible randomized controlled trials. The results were screened and the eligible trials were identified. Thereafter, the relevant data were extracted and pooled as mean difference or risk ratio, and 95% confidence interval in an inverse variance method using RevMan software., Results: This review included 12 trials (n = 1327). HTK solution has resulted significantly in shorter intensive care unit stay (MD = - 0.09; 95% CI [- 0.15, - 0.03], p = 0.006), and shorter hospital stay (MD = - 0.51; 95% CI [- 0.71, - 0.31], p < 0.00001). Moreover, the patients who received the HTK solution had significantly lower levels of creatine kinase (after 4-7 h (MD = - 157.52; 95% CI [- 272.31, - 42.19], p = 0.007), and 24 h (MD = - 136.62; 95% CI [- 267.20, - 6.05], p = 0.04)), as well as creatine kinase muscle brain band (after 44-48 h (MD = - 3.35; 95% CI [- 5.69, - 1.02], p = 0.005))., Conclusion: HTK solution had the same efficacy and safety as other cardioplegic solutions in most of the clinical parameters. Furthermore, the solution showed superiority in fastening the recovery and protecting the myocardium at the biochemical level. HTK solution provides longer myocardial protection; therefore, it limits surgical interruption. HTK solution can be used as an alternative to the currently used cardioplegic solutions., (© 2022. The Author(s).)

Over the past few years, the popularity of graphene as a potential 2D material has increased since graphene-based materials have applications in a variety of fields, including medicine, engineering, energy, and the environment. A large number of graphene sheets as well as an understanding of graphene's structural hierarchy are critical to the development of graphene-based materials. For a variety of purposes, it is essential to understand the fundamental structural properties of graphene. Molecular descriptors were used in this study to investigate graphene sheets' structural behaviour. Based on our findings, reverse degree-based molecular descriptors can significantly affect the exchange-correlation energy prediction. For the exchange-correlation energy of graphene sheets, a linear regression analysis was conducted using the reverse general inverse sum indeg descriptor, RGISI(p,q). From RGISI(p,q), a set of reverse topological descriptors can be obtained all at once as a special case, resulting in a model with a high correlation coefficient ( R between 0.896 and 0.998). Used together, these reverse descriptors are graphed in relation to their response to graphene. Based on this study's findings, it is possible to predict the exchange correlation energy as well as the geometric structures of graphene sheets with very little computational cost.

Background: India is taking steps to provide Universal Health Coverage (UHC). Out-of-pocket (OOP) health care payment is the most important mechanism for health care payment in India. This study aims to investigate the effect of OOP health care payments on catastrophic health expenditures (CHE). Methods: Data from the National Sample Survey Organization, Social Consumption in Health 2014 and 2018 are used to investigate the effect of OOP health expenditure on household welfare in India. Three aspects of catastrophic expenditure were analyzed in this paper: (i) incidence and intensity of 'catastrophic' health expenditure, (ii) socioeconomic inequality in catastrophic health expenditures, and (iii) factors affecting catastrophic health expenditures. Results: The odds of incidence and intensity of CHE were higher for the poorer households. Using the logistic regression model, it was observed that the odds of incidence of CHE was higher among the households with at least one child aged less than 5 years, one elderly person, one secondary educated female member, and if at least one member in the household used a private healthcare facility for treatment. The multiple regression model showed that the intensity of CHE was higher among households with members having chronic illness, and if members had higher duration of stay in the hospital. Subsidizing healthcare to the households having elderly members and children is necessary to reduce CHE. Conclusion: Expanding health insurance coverage, increasing coverage limits, and inclusion of coverage for outpatient and preventive services are vital to protect households. Strengthening public primary health infrastructure and setting up a regulatory organization to establish policies and conduct regular audits to ensure that private hospitals do not increase hospitalizations and the duration of stay is necessary., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Sriram S and Albadrani M.)

Background : Tuberculosis affects around 30% of the population of the world. Tuberculosis causes an increase in early mortality and thus has the potential to increase the number of years of life lost. Globalization directly or indirectly by affecting the factors that increase the susceptibility for tuberculosis infection has the potential to increase the spread and mortality due to tuberculosis. This study assessed the causal link between globalization and the years of life lost due to tuberculosis. Methods : Data from the Demographic and Health Survey (DHS) and World Bank for 2004 and 2005 were used for a number of covariates and possible mediators. Data from the Institute of Health Metrics and Evaluation (IHME) were used for the outcome variable and important globalization indicators. The primary health outcome that was studied is tuberculosis and the measure that was used to quantify tuberculosis mortality is the years of life lost (YLL). Path analysis was used. Results : The main independent variables of economic and social integration were not statistically significant. For every unit increase in the proportion of people that were using treated drinking water, there was a -0.0002 decrease in the YLL due to tuberculosis. For every unit increase in the proportion of people with earth floor, there was a 0.0002 units increase in YLL due to tuberculosis. For every unit increase in the proportion of people living using clean fuel, there was a 0.0004 decrease in the YLL due to tuberculosis. Conclusions: Social and economic globalization have no effect on the years of life lost due to tuberculosis, highlighting that globalization actually does not contribute to tuberculosis mortality. However, improving other important determinants such as sanitation, providing safe drinking water and clean households will reduce the mortality due to tuberculosis, highlighting the need to invest in them., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Sriram S and Albadrani M.)

Cryptosporidiosis is caused by an opportunistic protozoan parasite ( Cryptosporidium parvum and C. hominis ) known as a parasite of humans, especially children and immunocompromised patients. The current study was designed to evaluate the therapeutic efficacy of a mixture of fig and olive leaf extracts as an alternative medicinal plant. Parasitological examination for oocysts in the stool and histopathological alterations in the small intestines were examined. Additionally, biochemical analyses of liver and kidney functions in addition to antioxidant parameters such as superoxide dismutase (SOD), glutathione peroxidase (GSH) and catalase (CAT) in the plasma were evaluated. Our results showed that marked reduction in oocysts shedding and amelioration in intestinal histopathological changes and hepatic or renal functions were detected in all treated groups compared to the control infected group. Additionally, the treated groups with tested extracts at ratios 1:3 and 1:5 showed a significant decrease in the number of oocysts compared to the other treated groups. Results exhibited a significant increase in the plasma SOD, CAT and GSH levels in treated groups compared to the infected control one. This study suggested that a mixture of fig and olive leaf extracts is a convenient promising therapeutic agent for Cryptosporidiosis.

Clinical studies implicated an increased risk of intestinal fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Our previous studies have shown that microcystin-LR (MC-LR) exposure led to altered gut microbiome and increased abundance of lactate producing bacteria and intestinal inflammation in underlying NAFLD. This led us to further investigate the effects of the MC-LR, a PP2A inhibitor in activating the TGF-β fibrotic pathway in the intestines that might be mediated by increased lactate induced redox enzyme NOX2. Exposure to MC-LR led to higher lactate levels in circulation and in the intestinal content. The higher lactate levels were associated with NOX2 activation in vivo that led to increased Smad2/3-Smad4 co-localization and high alpha-smooth muscle actin (α-SMA) immunoreactivity in the intestines. Mechanistically, primary mouse intestinal epithelial cells treated with lactate and MC-LR separately led to higher NOX2 activation, phosphorylation of TGFβR1 receptor and subsequent Smad 2/3-Smad4 co-localization inhibitable by apocynin (NOX2 inhibitor), FBA (a peroxynitrite scavenger) and DMPO (a nitrone spin trap), catalase and superoxide dismutase. Inhibition of NOX2-induced redox signaling also showed a significant decrease in collagen protein thus suggesting a strong redox signaling induced activation of an ectopic fibrotic manifestation in the intestines. In conclusion, the present study provides mechanistic insight into the role of microcystin in dysbiosis-linked lactate production and subsequently advances our knowledge in lactate-induced NOX2 exacerbation of the cell differentiation and fibrosis in the NAFLD intestines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction Beta thalassemia major (BTM) is a chronic hereditary blood disorder. Patients are dependent on blood transfusion and are prone to multiple comorbidities. Depression, anxiety, and stress (DAS) can complicate their condition. No reports from Saudi Arabia to measure DAS in BTM patients. We report the prevalence of DAS symptoms in our BTM patients using the DASS-21 (Depression, Anxiety, and Stress Scale - 21 Items) test. Methods A cross-sectional study including adolescents and adults aged 14 years and above with BTM treated in Almadinah Almunawwarah and excluding patients who had bone marrow transplant or with central nervous system insults were performed. Results A total of 31 male and 31 female patients were enrolled, with a mean age of 24.32 ± 7.05 years. Depression symptoms were detected in 60 % of patients, anxiety symptoms were detected in half of the studied group, and stress symptoms were detected in 38.7% of patients. We found a significant positive correlation between DAS and DASS total score. Age below or above 18, parent's employment, patient's educational level, and status of satisfaction about medical care were statistically significant in having positive effects on scores of DAS symptoms.  Conclusions BTM patients are prone to develop psychological disorders, which can affect the course of the disease. Our results are comparable to international and Arab population studies, which have the highest reported prevalence. It is important to not ignore the psychological evaluation of patients with BTM and to refer them for proper evaluation and management., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Zolaly et al.)

Background: Recent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology., Methods: Using murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis., Results: Results showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box 1 (HMGB1) preferably from brain cells. Released HMGB1 acted as a preferential ligand to toll-like receptor 4 (TLR4) and induced oxidative stress by activation of NOX-2 signaling involving activated p65 protein of the NF-κB complex. Further, the HMGB1-derived downstream signaling cascade activated NLRP3 inflammasome and release of proinflammatory cytokines IL-6 and IL-1β from brain cells. In addition, to advance our present understanding, in vitro studies were performed in primary brain endothelial cells where results showed high circulatory Lcn2 influenced HMGB1 secretion. Mechanistically, we also showed that elevated Lcn2 level in underlying NASH might be a likely cause for induction of blood-brain barrier dysfunction since the adipokine decreased the expression of tight junction protein Claudin 5 and caused subsequent elevation of pro-inflammatory cytokines IL-6 and IL-1β., Conclusion: In conclusion, the NASH-induced brain pathology might be because of increased Lcn2-induced release of HMGB1 and accompanying neuroinflammation.

NAFLD often results in cardiovascular, intestinal and renal complications. Previous reports from our laboratory highlighted NAFLD induced ectopic inflammatory manifestations in the kidney that gave rise to glomerular inflammation. Extending our studies, we hypothesized that existing inflammatory conditions in NAFLD could make the kidneys more susceptible to environmental toxicity. Our results showed that exposure of Microcystin-LR (MC) in NAFLD mice caused a marked increase in cellular scarring with a concomitant increase in mesangial cell activation as observed by increased α-SMA in the extracellular matrix surrounding the glomeruli. Renal tissue surrounding the glomeruli also showed increased NOX2 activation as shown by greater co-localization of p47 Phox and its membrane component gp91Phox both in the mesangial cell and surrounding tissue. Mechanistically, mesangial cells incubated with apocynin, nitrone spin trap DMPO and miR21 inhibitor showed significantly decreased α-SMA, miR21 levels and proinflammatory cytokine release in the supernatant. In parallel, mice lacking miR21, known to be activated by NOX2, when exposed to MC in NAFLD showed decreased mesangial cell activation. Strikingly, phenyl boronic acid incubated cells that were exposed to MC showed significantly decreased mesangial cell activation showing that peroxynitrite might be the major reactive species involved in mediation of the activation process, release of proinflammatory micro RNAs and cytokines that are crucial for renal toxicity. Thus, in conclusion, MC exposure causes NOX2 activation that leads to mesangial cell activation and toxicity via release of peroxynitrite that also represses PTEN by the upregulation of miR21 thus amplifying the toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

About 14% of veterans who suffer from Gulf war illness (GWI) complain of some form of gastrointestinal disorder but with no significant markers of clinical pathology. Our previous studies have shown that exposure to GW chemicals resulted in altered microbiome which was associated with damage associated molecular pattern (DAMP) release followed by neuro and gastrointestinal inflammation with loss of gut barrier integrity. Enteric glial cells (EGC) are emerging as important regulators of the gastrointestinal tract and have been observed to change to a reactive phenotype in several functional gastrointestinal disorders such as IBS and IBD. This study is aimed at investigating the role of dysbiosis associated EGC immune-activation and redox instability in contributing to observed gastrointestinal barrier integrity loss in GWI via altered tight junction protein expression. Using a mouse model of GWI and in vitro studies with cultured EGC and use of antibiotics to ensure gut decontamination we show that exposure to GW chemicals caused dysbiosis associated change in EGCs. EGCs changed to a reactive phenotype characterized by activation of TLR4-S100β/RAGE-iNOS pathway causing release of nitric oxide and activation of NOX2 since gut sterility with antibiotics prevented this change. The resulting peroxynitrite generation led to increased oxidative stress that triggered inflammation as shown by increased NLRP-3 inflammasome activation and increased cell death. Activated EGCs in vivo and in vitro were associated with decrease in tight junction protein occludin and selective water channel aquaporin-3 with a concomitant increase in Claudin-2. The tight junction protein levels were restored following a parallel treatment of GWI mice with a TLR4 inhibitor SsnB and butyric acid that are known to decrease the immunoactivation of EGCs. Our study demonstrates that immune-redox mechanisms in EGC are important players in the pathology in GWI and may be possible therapeutic targets for improving outcomes in GWI symptom persistence., (Copyright © 2019 Kimono, Sarkar, Albadrani, Seth, Bose, Mondal, Li, Kar, Nagarkatti, Nagarkatti, Sullivan, Janulewicz, Lasley, Horner, Klimas and Chatterjee.)

Nonalcoholic fatty liver disease (NAFLD) is an emerging global pandemic. Though significant progress has been made in unraveling the pathophysiology of the disease, the role of protein phosphatase 2A (PP2A) and its subsequent inhibition by environmental and genetic factors in NAFLD pathophysiology remains unclear. The present report tests the hypothesis that an exogenous PP2A inhibitor leads to hepatic inflammation and fibrogenesis via an NADPH oxidase 2 (NOX2)-dependent pathway in NAFLD. Results showed that microcystin (MC) administration, a potent PP2A inhibitor found in environmental exposure, led to an exacerbation of NAFLD pathology with increased CD68 immunoreactivity, the release of proinflammatory cytokines, and stellate cell activation, a process that was attenuated in mice that lacked the p47phox gene and miR21 knockout mice. Mechanistically, leptin-primed immortalized Kupffer cells (a mimicked model for an NAFLD condition) treated with apocynin or nitrone spin trap 5,5 dimethyl-1- pyrroline N -oxide (DMPO) had significantly decreased CD68 and decreased miR21 and α-smooth muscle actin levels, suggesting the role of NOX2-dependent reactive oxygen species in miR21-induced Kupffer cell activation and stellate cell pathology. Furthermore, NOX2-dependent peroxynitrite generation was primarily responsible for cellular events observed following MC exposure since incubation with phenylboronic acid attenuated miR21 levels, Kupffer cell activation, and inflammatory cytokine release. Furthermore, blocking of the AKT pathway attenuated PP2A inhibitor-induced NOX2 activation and miR21 upregulation. Taken together, we show that PP2A may have protective roles, and its inhibition exacerbates NAFLD pathology via activating NOX2-dependent peroxynitrite generation, thus increasing miR21-induced pathology. NEW & NOTEWORTHY Protein phosphatase 2A inhibition causes nonalcoholic steatohepatitis (NASH) progression via NADPH oxidase 2. In addition to a novel emchanism of action, we describe a new tool to describe NASH histopathology.

With increased climate change pressures likely to influence harmful algal blooms, exposure to microcystin, a known hepatotoxin and a byproduct of cyanobacterial blooms can be a risk factor for NAFLD associated comorbidities. Using both in vivo and in vitro experiments we show that microcystin exposure in NAFLD mice cause rapid alteration of gut microbiome, rise in bacterial genus known for mediating gut inflammation and lactate production. Changes in the microbiome were strongly associated with inflammatory pathology in the intestine, gut leaching, tight junction protein alterations and increased oxidative tyrosyl radicals. Increased lactate producing bacteria from the altered microbiome was associated with increased NOX-2, an NADPH oxidase isoform. Activationof NOX2 caused inflammasome activation as shown by NLRP3/ASCII and NLRP3/Casp-1 colocalizations in these cells while use of mice lacking a crucial NOX2 component attenuated inflammatory pathology and redox changes. Mechanistically, NOX2 mediated peroxynitrite species were primary to inflammasome activation and release of inflammatory mediators. Thus, in conclusion, microcystin exposure in NAFLD could significantly alter intestinal pathology especially by the effects on microbiome and resultant redox status thus advancing our understanding of the co-existence of NAFLD-linked inflammatory bowel disease phenotypes in the clinic.

SsnB previously showed a promising role to lessen liver inflammation observed in a mouse model of NAFLD. Since NAFLD can progress to fibrosis, studies were designed to unravel its role in attenuating NAFLD associated fibrosis. Using both in vivo and in vitro approaches, the study probed the possible mechanisms that underlined the role of SsnB in mitigating fibrosis. Mechanistically, SsnB, a TLR4 antagonist, decreased TLR4-PI3k akt signaling by upregulating PTEN protein expression. It also decreased MDM2 protein activation and increased p53 and p21 gene and protein expression. SsnB also downregulated pro-fibrogenic hedgehog signaling pathway, inhibited hepatic stellate cell proliferation and induced apoptosis in hepatic stellate cells, a mechanism that was LPS dependent. Further, SsnB decreased fibrosis by antagonizing TLR4 induced TGFβ signaling pathway. Alternatively, SsnB augmented BAMBI (a TGFβ pseudo-receptor) expression in mice liver by inhibiting TLR4 signaling pathway and thus reduced TGFβ signaling, resulting in decreased hepatic stellate cell activation and extracellular matrix deposition. In vitro experiments on human hepatic stellate cell line showed that SsnB increased gene and protein expression of BAMBI. It also decreased nuclear co-localization of phospho SMAD2/3 and SMAD4 protein and thus attenuated TGFβ signaling in vitro. We also observed a significant decrease in phosphorylation of SMAD2/3 protein, decreased STAT3 activation, alteration of focal adhesion protein and stress fiber disassembly upon SsnB administration in hepatic stellate cells which further confirmed the antagonistic effect of SsnB on TLR4-induced fibrogenesis., (Copyright © 2018. Published by Elsevier B.V.)

Most of the associated pathologies in Gulf War Illness (GWI) have been ascribed to chemical and pharmaceutical exposures during the war. Since an increased number of veterans complain of gastrointestinal (GI), neuroinflammatory and metabolic complications as they age and there are limited options for a cure, the present study was focused to assess the role of butyrate, a short chain fatty acid for attenuating GWI-associated GI and metabolic complications. Results in a GWI-mouse model of permethrin and pyridostigmine bromide (PB) exposure showed that oral butyrate restored gut homeostasis and increased GPR109A receptor copies in the small intestine (SI). Claudin-2, a protein shown to be upregulated in conditions of leaky gut was significantly decreased following butyrate administration. Butyrate decreased TLR4 and TLR5 expressions in the liver concomitant to a decrease in TLR4 activation. GW-chemical exposure showed no clinical signs of liver disease but a significant alteration of metabolic markers such as SREBP1c, PPAR-α, and PFK was evident. Liver markers for lipogenesis and carbohydrate metabolism that were significantly upregulated following GW chemical exposure were attenuated by butyrate priming in vivo and in human primary hepatocytes. Further, Glucose transporter Glut-4 that was shown to be elevated following liver complications were significantly decreased in these mice after butyrate administration. Finally, use of TLR4 KO mice completely attenuated the liver metabolic changes suggesting the central role of these receptors in the GWI pathology. In conclusion, we report a butyrate specific mechanistic approach to identify and treat increased metabolic abnormalities in GWI veterans with systemic inflammation, chronic fatigue, GI disturbances, metabolic complications and weight gain., (Copyright © 2018 Elsevier Inc. All rights reserved.)