Pulmonary symptoms associated with heavy alcohol consumption among people living with HIV: an analysis of the NHANES 1999-2010.

AIM: This matched case-control study aimed to provide epidemiologic evidence of increased burden of respiratory symptoms and pulmonary function decline among people living with human immunodeficiency virus (HIV) and a history of heavy alcohol consumption. METHODS: Cases were participants with HIV (PWH; n = 75, 33%), and controls were participants without HIV (PWoH; n = 150, 67%). PWH were matched to PWoH by age and sex in the ratio of 1:2. Eligible participants responded to the respiratory health National Health and Nutrition Examination Survey questionnaire [prolonged coughs (≥3 months), bringing up of phlegm (≥3 months), and a history of wheezing or whistling in the chest (past year)]. The effects of both alcohol and HIV on participants' pulmonary function were determined using linear regression analysis. RESULTS: History of heavy alcohol consumption was more prevalent among PWH (40%) compared to PWoH (27%). PWH who had a history of heavy alcohol consumption had a higher prevalence of coughing most days (45% vs. 4%, P = .0010), bringing up phlegm most days (31% vs. 0%, P = .0012), and wheezing or whistling in the chest (40% vs. 20%, P = .058) compared to participants who did not heavily consume alcohol. Furthermore, a history of heavy alcohol consumption was associated with decreased forced expiratory volume (ml) in 1 s/forced vital capacity among PWH (ß = - 0.098 95% C.I. -0.16, -0.04, P = .03) after adjusting for having smoked at least 100 cigarettes in life. CONCLUSION: A history of heavy alcohol use increased respiratory symptoms and suppressed pulmonary function among people living with HIV. This study provides epidemiological evidence of the respiratory symptom burden of people living with HIV who have a history of heavy alcohol consumption.

Hepatocyte-Specific Triggering of Hepatic Stellate Cell Profibrotic Activation by Apoptotic Bodies: The Role of Hepatoma-Derived Growth Factor, HIV, and Ethanol.

Liver disease is one of the leading comorbidities in HIV infection. The risk of liver fibrosis development is potentiated by alcohol abuse. In our previous studies, we reported that hepatocytes exposed to HIV and acetaldehyde undergo significant apoptosis, and the engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) potentiates their pro-fibrotic activation. However, in addition to hepatocytes, under the same conditions, ABs can be generated from liver-infiltrating immune cells. The goal of this study is to explore whether lymphocyte-derived ABs trigger HSC profibrotic activation as strongly as hepatocyte-derived ABs. ABs were generated from Huh7.5-CYP2E1 (RLW) cells and Jurkat cells treated with HIV+acetaldehyde and co-culture with HSC to induce their pro-fibrotic activation. ABs cargo was analyzed by proteomics. ABs generated from RLW, but not from Jurkat cells activated fibrogenic genes in HSC. This was driven by the expression of hepatocyte-specific proteins in ABs cargo. One of these proteins is Hepatocyte-Derived Growth Factor, for which suppression attenuates pro-fibrotic activation of HSC. In mice humanized with only immune cells but not human hepatocytes, infected with HIV and fed ethanol, liver fibrosis was not observed. We conclude that HIV+ABs of hepatocyte origin promote HSC activation, which potentially may lead to liver fibrosis progression.

A Pathogenic Role of Non-Parenchymal Liver Cells in Alcohol-Associated Liver Disease of Infectious and Non-Infectious Origin.

Now, much is known regarding the impact of chronic and heavy alcohol consumption on the disruption of physiological liver functions and the induction of structural distortions in the hepatic tissues in alcohol-associated liver disease (ALD). This review deliberates the effects of alcohol on the activity and properties of liver non-parenchymal cells (NPCs), which are either residential or infiltrated into the liver from the general circulation. NPCs play a pivotal role in the regulation of organ inflammation and fibrosis, both in the context of hepatotropic infections and in non-infectious settings. Here, we overview how NPC functions in ALD are regulated by second hits, such as gender and the exposure to bacterial or viral infections. As an example of the virus-mediated trigger of liver injury, we focused on HIV infections potentiated by alcohol exposure, since this combination was only limitedly studied in relation to the role of hepatic stellate cells (HSCs) in the development of liver fibrosis. The review specifically focusses on liver macrophages, HSC, and T-lymphocytes and their regulation of ALD pathogenesis and outcomes. It also illustrates the activation of NPCs by the engulfment of apoptotic bodies, a frequent event observed when hepatocytes are exposed to ethanol metabolites and infections. As an example of such a double-hit-induced apoptotic hepatocyte death, we deliberate on the hepatotoxic accumulation of HIV proteins, which in combination with ethanol metabolites, causes intensive hepatic cell death and pro-fibrotic activation of HSCs engulfing these HIV- and malondialdehyde-expressing apoptotic hepatocytes.

Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation.

Recently, we found that both HIV and acetaldehyde, an alcohol metabolite, induce hepatocyte apoptosis, resulting in the release of large extracellular vesicles called apoptotic bodies (ABs). The engulfment of these hepatocyte ABs by hepatic stellate cells (HSC) leads to their profibrotic activation. This study aims to establish the mechanisms of HSC activation after engulfment of ABs from acetaldehyde and HIV-exposed hepatocytes (ABAGS+HIV). In vitro experiments were performed on Huh7.5-CYP (RLW) cells to generate hepatocyte ABs and LX2 cells were used as HSC. To generate ABs, RLW cells were pretreated for 24 h with acetaldehyde, then exposed overnight to HIV1ADA and to acetaldehyde for 96 h. Thereafter, ABs were isolated from cell suspension by a differential centrifugation method and incubated with LX2 cells (3:1 ratio) for profibrotic genes and protein analyses. We found that HSC internalized ABs via the tyrosine kinase receptor, Axl. While the HIV gag RNA/HIV proteins accumulated in ABs elicited no productive infection in LX2 and immune cells, they triggered ROS and IL6 generation, which, in turn, activated profibrotic genes via the JNK-ERK1/2 and JAK-STAT3 pathways. Similarly, ongoing profibrotic activation was observed in immunodeficient NSG mice fed ethanol and injected with HIV-derived RLW ABs. We conclude that HSC activation by hepatocyte ABAGS+HIV engulfment is mediated by ROS-dependent JNK-ERK1/2 and IL6 triggering of JAK-STAT3 pathways. This can partially explain the mechanisms of liver fibrosis development frequently observed among alcohol abusing PLWH.

Regulation of sedimentation rate shapes the evolution of multicellularity in a close unicellular relative of animals.

Significant increases in sedimentation rate accompany the evolution of multicellularity. These increases should lead to rapid changes in ecological distribution, thereby affecting the costs and benefits of multicellularity and its likelihood to evolve. However, how genetic and cellular traits control this process, their likelihood of emergence over evolutionary timescales, and the variation in these traits as multicellularity evolves are still poorly understood. Here, using isolates of the ichthyosporean genus Sphaeroforma-close unicellular relatives of animals with brief transient multicellular life stages-we demonstrate that sedimentation rate is a highly variable and evolvable trait affected by at least 2 distinct physical mechanisms. First, we find extensive (>300×) variation in sedimentation rates for different Sphaeroforma species, mainly driven by size and density during the unicellular-to-multicellular life cycle transition. Second, using experimental evolution with sedimentation rate as a focal trait, we readily obtained, for the first time, fast settling and multicellular Sphaeroforma arctica isolates. Quantitative microscopy showed that increased sedimentation rates most often arose by incomplete cellular separation after cell division, leading to clonal "clumping" multicellular variants with increased size and density. Strikingly, density increases also arose by an acceleration of the nuclear doubling time relative to cell size. Similar size- and density-affecting phenotypes were observed in 4 additional species from the Sphaeroforma genus, suggesting that variation in these traits might be widespread in the marine habitat. By resequencing evolved isolates to high genomic coverage, we identified mutations in regulators of cytokinesis, plasma membrane remodeling, and chromatin condensation that may contribute to both clump formation and the increase in the nuclear number-to-volume ratio. Taken together, this study illustrates how extensive cellular control of density and size drive sedimentation rate variation, likely shaping the onset and further evolution of multicellularity.

Cell-to-Cell Communications in Alcohol-Associated Liver Disease.

This review covers some important new aspects of the alcohol-induced communications between liver parenchymal and non-parenchymal cells leading to liver injury development. The information exchange between various cell types may promote end-stage liver disease progression and involves multiple mechanisms, such as direct cell-to-cell interactions, extracellular vesicles (EVs) or chemokines, cytokines, and growth factors contained in extracellular fluids/cell culture supernatants. Here, we highlighted the role of EVs derived from alcohol-exposed hepatocytes (HCs) in activation of non-parenchymal cells, liver macrophages (LM), and hepatic stellate cells (HSC). The review also concentrates on EV-mediated crosstalk between liver parenchymal and non-parenchymal cells in the settings of HIV- and alcohol co-exposure. In addition, we overviewed the literature on the crosstalk between cell death pathways and inflammasome activation in alcohol-activated HCs and macrophages. Furthermore, we covered highly clinically relevant studies on the role of non-inflammatory factors, sinusoidal pressure (SP), and hepatic arterialization in alcohol-induced hepatic fibrogenesis. We strongly believe that the review will disclose major mechanisms of cell-to-cell communications pertained to alcohol-induced liver injury progression and will identify therapeutically important targets, which can be used for alcohol-associated liver disease (ALD) prevention.

Alcohol: basic and translational research; 15th annual Charles Lieber &1st Samuel French satellite symposium.

The present review is based on the research presented at the symposium dedicated to the legacy of the two scientists that made important discoveries in the field of alcohol-induced liver damage: Professors C.S. Lieber and S.W. French. The invited speakers described pharmacological, toxicological and patho-physiological effects of alcohol misuse. Moreover, genetic biomarkers determining adverse drug reactions due to interactions between therapeutics used for chronic or infectious diseases and alcohol exposure were discussed. The researchers presented their work in areas of alcohol-induced impairment in lipid protein trafficking and endocytosis, as well as the role of lipids in the development of fatty liver. The researchers showed that alcohol leads to covalent modifications that promote hepatic dysfunction and injury. We concluded that using new advanced techniques and research ideas leads to important discoveries in science.

A review of alcohol-pathogen interactions: New insights into combined disease pathomechanisms.

Progression of chronic infections to end-stage diseases and poor treatment results are frequently associated with alcohol abuse. Alcohol metabolism suppresses innate and adaptive immunity leading to increased viral load and its spread. In case of hepatotropic infections, viruses accelerate alcohol-induced hepatitis and liver fibrosis, thereby promoting end-stage outcomes, including cirrhosis and hepatocellular carcinoma (HCC). In this review, we concentrate on several unexplored aspects of these phenomena, which illustrate the combined effects of viral/bacterial infections and alcohol in disease development. We review alcohol-induced alterations implicated in immunometabolism as a central mechanism impacting metabolic homeostasis and viral pathogenesis in Simian immunodeficiency virus/human immunodeficiency virus infection. Furthermore, in hepatocytes, both HIV infection and alcohol activate oxidative stress to cause lysosomal dysfunction and leakage and apoptotic cell death, thereby increasing hepatotoxicity. In addition, we discuss the mechanisms of hepatocellular carcinoma and tumor signaling in hepatitis C virus infection. Finally, we analyze studies that review and describe the immune derangements in hepatotropic viral infections focusing on the development of novel targets and strategies to restore effective immunocompetency in alcohol-associated liver disease. In conclusion, alcohol exacerbates the pathogenesis of viral infections, contributing to a chronic course and poor outcomes, but the mechanisms behind these events are virus specific and depend on virus-alcohol interactions, which differ among the various infections.

Ethanol attenuates presentation of cytotoxic T-lymphocyte epitopes on hepatocytes of HBV-infected humanized mice.

BACKGROUND AND AIMS: Approximately 3.5% of the global population is chronically infected with Hepatitis B Virus (HBV), which puts them at high risk of end-stage liver disease, with the risk of persistent infection potentiated by alcohol consumption. However, the mechanisms underlying the effects of alcohol on HBV persistence remain unclear. Here, we aimed to establish in vivo/ex vivo evidence that alcohol suppresses HBV peptides-major histocompatibility complex (MHC) class I antigen display on primary human hepatocytes (PHH), which diminishes the recognition and clearance of HBV-infected hepatocytes by cytotoxic T-lymphocytes (CTLs). METHODS: We used fumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chain knock-out (FRG-KO) humanized mice transplanted with human leukocyte antigen-A2 (HLA-A2)-positive hepatocytes. The mice were HBV-infected and fed control and alcohol diets. Isolated hepatocytes were exposed ex vivo to HBV 18-27-HLA-A2-restricted CTLs to quantify cytotoxicity. For mechanistic studies, we measured proteasome activities, unfolded protein response (UPR), and endoplasmic reticulum (ER) stress in hepatocytes from HBV-infected humanized mouse livers. RESULTS AND CONCLUSIONS: We found that alcohol feeding attenuated HBV core 18-27-HLA-A2 complex presentation on infected hepatocytes due to the suppression of proteasome function and ER stress induction, which diminished both the processing of HBV peptides and trafficking of HBV-MHC class I complexes to the hepatocyte surface. This alcohol-mediated decrease in MHC class I-restricted antigen presentation of the CTL epitope on target hepatocytes reduced the CTL-specific elimination of infected cells, potentially leading to HBV-infection persistence, which promotes end-stage liver disease outcomes.

Low-Level Groundwater Atrazine in High Atrazine Usage Nebraska Counties: Likely Effects of Excessive Groundwater Abstraction.

Recent studies observed a correlation between estrogen-related cancers and groundwater atrazine in eastern Nebraska counties. However, the mechanisms of human exposure to atrazine are unclear because low groundwater atrazine concentration was observed in counties with high cancer incidence despite having the highest atrazine usage. We studied groundwater atrazine fate in high atrazine usage Nebraska counties. Data were collected from Quality Assessed Agrichemical Contaminant Nebraska Groundwater, Parameter-Elevation Regressions on Independent Slopes Model (PRISM), and water use databases. Descriptive statistics and cluster analysis were performed. Domestic wells (59%) were the predominant well type. Groundwater atrazine was affected by well depth. Clusters consisting of wells with low atrazine were characterized by excessive groundwater abstraction, reduced precipitation, high population, discharge areas, and metropolitan counties. Hence, low groundwater atrazine may be due to excessive groundwater abstraction accompanied by atrazine. Human exposure to atrazine in abstracted groundwater may be higher than the estimated amount in groundwater.

Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells.

Although the causes of hepatotoxicity among alcohol-abusing HIV patients are multifactorial, alcohol remains the least explored "second hit" for HIV-related hepatotoxicity. Here, we investigated whether metabolically derived acetaldehyde impairs lysosomes to enhance HIV-induced hepatotoxicity. We exposed Cytochrome P450 2E1 (CYP2E1)-expressing Huh 7.5 (also known as RLW) cells to an acetaldehyde-generating system (AGS) for 24 h. We then infected (or not) the cells with HIV-1ADA then exposed them again to AGS for another 48 h. Lysosome damage was assessed by galectin 3/LAMP1 co-localization and cathepsin leakage. Expression of lysosome biogenesis-transcription factor, TFEB, was measured by its protein levels and by in situ immunofluorescence. Exposure of cells to both AGS + HIV caused the greatest amount of lysosome leakage and its impaired lysosomal biogenesis, leading to intrinsic apoptosis. Furthermore, the movement of TFEB from cytosol to the nucleus via microtubules was impaired by AGS exposure. The latter impairment appeared to occur by acetylation of α-tubulin. Moreover, ZKSCAN3, a repressor of lysosome gene activation by TFEB, was amplified by AGS. Both these changes contributed to AGS-elicited disruption of lysosome biogenesis. Our findings indicate that metabolically generated acetaldehyde damages lysosomes and likely prevents their repair and restoration, thereby exacerbating HIV-induced hepatotoxicity.

Duration on ART, Alcohol Use and HIV Stage May Predict Risky Sexual Behavior in a Resource-limited Environment: A Cross-sectional Study.

BACKGROUND: The intention of antiretroviral therapy (ART) and regular clinic visits are to engender safe sex attitudes among HIV-infected individuals. However, this may not be the case due to the perceived therapeutic benefits of ART and may result in exposure to drug-resistant HIV strains. OBJECTIVES: We aimed to determine the prevalence and predict the factors associated with risky sexual behaviors among ART users in a resource-limited environment. METHODS: Two hundred and ninety-one sexually active ART-users aged 18-50 years and seeking care at the HIV clinic in Dodoma, Tanzania, participated in this study. The outcome variables modeled in a logistic regression were condom use, multiple sex partners, casual sex partners, and payment for sex. The predictors included in the models were the patients' socio-demographic characteristics. In addition, a new variable, sexual risk scores, was generated by culminating all the outcome variables. Finally, a multiple Poisson regression with the socio-demographic variables of the participants was used to model the sexual risk scores. RESULTS: Patients reported inconsistent/no condom use (44%), payment for sex (4%), casual sex encounters (13%), multiple sex partners (21%), and STD symptoms (15%). While having a casual sexual partner was significantly associated with age group in a Pearson Chi-square (p=0.0147), participants ≤35 years old were less likely to have single-sex partners than older participants (AOR: 0.188, 95 C.I: 0.042-0.849). Meanwhile, the likelihood of condom use was higher among participants with no HIV-infected family members (AOR= 2.409, 95% C.I:1.236,4.697) and among participants who had single-sex partners (AOR= 2.721, 95% C.I.: 1.115,6.640); these participants were less likely to report STD symptoms (AOR=0.265, 95% C.I.: 0.081-0.865). Adjusted analysis showed that estimated mean sexual risk scores significantly increased (mean, λ=1.61, 95% C.I:1.0817-2.4063) for recent ART recipients (within 1-3 years vs. ≥8 years). However, sexual risk scores of participants with HIV stage 3 were 38.8% lower than participants at stage 4 (95% C.I.: 0.3910-0.9558), and non-alcohol drinkers had an adjusted mean sexual risk score of 29% lower than participants who were alcohol drinkers (95% C.I.: 0.5102-0.9879). CONCLUSION: Researchers should prioritize patients at HIV CTC for education concerning safe sexual practices for those characterized by alcohol consumption, younger age (less than 35 years old), HIV stage 4, or commencement of ART within three years.

Pancreatogenic Diabetes: Triggering Effects of Alcohol and HIV.

Multiorgan failure may not be completely resolved among people living with HIV despite HAART use. Although the chances of organ dysfunction may be relatively low, alcohol may potentiate HIV-induced toxic effects in the organs of alcohol-abusing, HIV-infected individuals. The pancreas is one of the most implicated organs, which is manifested as diabetes mellitus or pancreatic cancer. Both alcohol and HIV may trigger pancreatitis, but the combined effects have not been explored. The aim of this review is to explore the literature for understanding the mechanisms of HIV and alcohol-induced pancreatotoxicity. We found that while premature alcohol-inducing zymogen activation is a known trigger of alcoholic pancreatitis, HIV entry through C-C chemokine receptor type 5(CCR5)into pancreatic acinar cells may also contribute to pancreatitis in people living with HIV (PLWH). HIV proteins induce oxidative and ER stresses, causing necrosis. Furthermore, infiltrative immune cells induce necrosis on HIV-containing acinar cells. When necrotic products interact with pancreatic stellate cells, they become activated, leading to the release of both inflammatory and profibrotic cytokines and resulting in pancreatitis. Effective therapeutic strategies should block CCR5 and ameliorate alcohol's effects on acinar cells.

Alcohol-and-HIV-Induced Lysosomal Dysfunction Regulates Extracellular Vesicles Secretion in Vitro and in Liver-Humanized Mice.

BACKGROUND: Alcohol abuse is common in people living with HIV-1 and dramaticallyenhances the severity of HIV-induced liver damage by inducing oxidative stress and lysosomaldysfunction in the liver cells. We hypothesize that the increased release of extracellular vesicles(EVs) in hepatocytes and liver humanized mouse model is linked to lysosome dysfunction. METHODS: The study was performed on primary human hepatocytes and human hepatoma RLWXP-GFP (Huh7.5 cells stably transfected with CYP2E1 and XPack-GFP) cells and validated on ethanol-fed liverhumanizedfumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chainknockout (FRG-KO) mice. Cells and mice were infected with HIV-1ADA virus. RESULTS: We observedan increase in the secretion of EVs associated with a decrease in lysosomal activity and expressionof lysosomal-associated membrane protein 1. Next-generation RNA sequencing of primary humanhepatocytes revealed 63 differentially expressed genes, with 13 downregulated and 50 upregulatedgenes in the alcohol-HIV-treated group. Upstream regulator analysis of differentially expressedgenes through Ingenuity Pathway Analysis identified transcriptional regulators affecting downstreamgenes associated with increased oxidative stress, lysosomal associated disease, and function andEVs biogenesis. Our in vitro findings were corroborated by in vivo studies on human hepatocytetransplantedhumanized mice, indicating that intensive EVs' generation by human hepatocytes andtheir secretion to serum was associated with increased oxidative stress and reduction in lysosomalactivities triggered by HIV infection and ethanol diet. CONCLUSION: HIV-and-ethanol-metabolisminducedEVs release is tightly controlled by lysosome status in hepatocytes and participates in thedevelopment of double-insult-induced liver injury.

Intimate Partner Violence and Brain Injury Screening.

The study examined rates of possible brain injury among survivors of intimate partner violence. Of the 171 women screened, 91% indicated they had been hit in the head or strangled, and 31% reported it happened more than six times in their life. Only 35% of women who were hit in the head or strangled received medical treatment, and 64% reported losing consciousness or experienced a period of being dazed and confused. Organizations serving intimate partner violence survivors should routinely screen survivors for brain injury so they can obtain timely referrals for neurorehabilitation services to improve their quality of life.

Obeticholic acid attenuates human immunodeficiency virus/alcohol metabolism-induced pro-fibrotic activation in liver cells.

BACKGROUND: The morbidity and mortality of human immunodeficiency virus (HIV)-infection is often associated with liver disease, which progresses slowly into severe liver dysfunction. There are multiple insults which exacerbate HIV-related liver injury, including HIV-associated dysregulation of lipid metabolism and fat turnover, co-infections with hepatotropic viruses and alcohol abuse. As we reported before, exposure of hepatocytes to HIV and alcohol metabolites causes high oxidative stress, impairs proteasomal and lysosomal functions leading to accumulation of HIV in these cells, which end-ups with apoptotic cell death and finally promotes development of liver fibrosis. AIM: To study whether obeticholic acid (OCA) prevents HIV/ethanol metabolism-induced hepatotoxicity and subsequent activation of hepatic stellate cells (HSC) by HIV+ apoptotic hepatocyte engulfment. METHODS: Huh7.5-CYP (RLW) cells were exposed to HIV and acetaldehyde-generating system (AGS) in the presence or absence of OCA. In the cells, we measured the expression of HIV-related markers: HIVgagRNA-by real-time polymerase chain reaction (PCR), p24- by western blot, HIV DNA-by semi-nested PCR, integrated HIV DNA-by ddPCR. Lysosomal and proteasomal activities were measured using fluorometrically-labeled substrates. For hepatocyte apoptosis, cleaved caspase 3 and cleaved PARP were visualized by western blot and cytokeratin 18- by M30 ELISA-in supernatants. Apoptotic bodies were generated from untreated and HIV-treated RLW cells exposed to UV light. Pro-fibrotic activation of HSC was characterized by Col1A1 and transforming growth factor-ß mRNAs, while inflammasome activation- by NLRP3, caspase 1, interleukin (IL)-6, IL-1ß mRNA levels. RESULTS: In RLW cells, OCA treatment attenuated HIV-AGS-induced accumulation of HIVgagRNA, HIV DNA and p24. OCA suppressed reactive oxygen species production and restored chymotrypsin-like proteasome activity as well as cathepsin B lysosome activity. OCA also decreased HIV-AGS-triggered apoptosis in RLW cells. Exposure of HIV-containing apoptotic hepatocytes to HSC prevented activation of inflammasome and induced pro-fibrotic activation in these cells. CONCLUSION: We conclude that by suppressing oxidative stress and restoring proteasomal and lysosomal functions impaired by HIV and ethanol metabolism, OCA decreases accumulation of HIV in hepatocytes, leading to down-regulation of apoptosis in these cells. In addition, OCA reverses pro-fibrotic and inflammasome-related activation of HSC triggered by engulfment of HIV-containing apoptotic hepatocytes, potentially contributing to suppression of liver fibrosis development.

Cervical Cancer Screening among Women Receiving Antiretroviral Therapy in a Resource-Limited Environment.

BACKGROUND: Cervical cancer is among the most prevalent cancer among women worldwide and women living with HIV are at increased risk, especially in a resource-limited environment. OBJECTIVE: This study aimed to determine levels of awareness, knowledge, uptake, and willingness to screen for cervical cancer among women receiving care in an HIV clinic at Dodoma Regional Referral Hospital (DRRH), Tanzania. METHODS: Data were collected for a period of three weeks from July 21 to August 11, 2017 using a mobile phone data collection App. A total of 421 Women aged 18-50 years old were included in the study. RESULTS: Majority of the women interviewed (n=306, 73%) were aware of cervical cancer. Among those who were aware, 84% (n=257) did not recall ever being screened for cervical cancer, and majority had a poor knowledge of cervical cancer. Educational level completed (p=0.01), income per month (p=0.02), age group (p<0.0001), and area of residence (p<0.0001) were all significantly associated to awareness of cervical cancer. Most of the women who have never screened (n=231, 91%) expressed willingness to be screened. Prior uptake of cervical cancer screening was associated with number of live births (p=0.001) and area of residence (p=0.04). And Willingness to screen was significantly associated with age groups (p=0.03) and the number of live births (p=0.03). Moreover, we found that younger age and urban residence was positively associated with awareness and uptake of cervical cancer screening. Willingness was found to decrease as age increased. CONCLUSION: The study found that despite older women's higher risk of cervical cancer, those who indicated willingness to screen were younger. Additional education, health promotion, and integration of cervical cancer screening services is needed to improve cervical cancer awareness and screening uptake at the HIV clinic.
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Alcohol Metabolism Potentiates HIV-Induced Hepatotoxicity: Contribution to End-Stage Liver Disease.

In an era of improved survival due to modern antiretroviral therapy, liver disease has become a major cause of morbidity and mortality, resulting in death in 15-17% of human immunodeficiency virus (HIV)-infected patients. Alcohol enhances HIV-mediated liver damage and promotes the progression to advanced fibrosis and cirrhosis. However, the mechanisms behind these events are uncertain. Here, we hypothesize that ethanol metabolism potentiates accumulation of HIV in hepatocytes, causing oxidative stress and intensive apoptotic cell death. Engulfment of HIV-containing apoptotic hepatocytes by non-parenchymal cells (NPCs) triggers their activation and liver injury progression. This study was performed on primary human hepatocytes and Huh7.5-CYP cells infected with HIV-1ADA, and major findings were confirmed by pilot data obtained on ethanol-fed HIV-injected chimeric mice with humanized livers. We demonstrated that ethanol exposure potentiates HIV accumulation in hepatocytes by suppressing HIV degradation by lysosomes and proteasomes. This leads to increased oxidative stress and hepatocyte apoptosis. Exposure of HIV-infected apoptotic hepatocytes to NPCs activates the inflammasome in macrophages and pro-fibrotic genes in hepatic stellate cells. We conclude that while HIV and ethanol metabolism-triggered apoptosis clears up HIV-infected hepatocytes, continued generation of HIV-expressing apoptotic bodies may be detrimental for progression of liver inflammation and fibrosis due to constant activation of NPCs.

Harmonious genetic combinations rewire regulatory networks and flip gene essentiality.

We lack an understanding of how the full range of genetic variants that occur in individuals can interact. To address this shortcoming, here we combine diverse mutations between genes in a model regulatory network, the galactose (GAL) switch of budding yeast. The effects of thousands of pairs of mutations fall into a limited number of phenotypic classes. While these effects are mostly predictable using simple rules that capture the 'stereotypical' genetic interactions of the network, some double mutants have unexpected outcomes including constituting alternative functional switches. Each of these 'harmonious' genetic combinations exhibits altered dependency on other regulatory genes. These cases illustrate how both pairwise and higher epistasis determines gene essentiality and how combinations of mutations rewire regulatory networks. Together, our results provide an overview of how broad spectra of mutations interact, how these interactions can be predicted, and how diverse genetic solutions can achieve 'wild-type' phenotypic behavior.

Comparison of agricultural injuries reported in the media and census of fatal occupational injuries.

The Bureau of Labor Statistics (BLS) publishes annual statistics on occupational injuries and fatalities in the United States. The BLS fatality data include all agricultural workers while the non-fatal injury data only cover hired employees on large farms. In 2012, the Central States Center for Agricultural Safety and Health (CS-CASH) began collecting regional media monitoring data of agricultural injury incidents to augment national statistics. The aims of this report were: a) to compare CS-CASH injury and fatality data collected via print and online sources to data reported in previous studies, and b) to compare fatality data from media monitoring to BLS Census of Fatal Occupational Injuries (CFOI) data. CS-CASH media monitoring data were collected from a news clipping service and an internet detection and notification system. These data covered years 2012-2017 in seven Midwestern states (Iowa, Kansas, Minnesota, Missouri, Nebraska, North Dakota, and South Dakota). CS-CASH occupational fatality data were compared with aggregate CFOI data for the region during 2012-2015. Media monitoring captured 1048 injury cases; 586 (56%) were non-fatal and 462 (44%) were fatal. The numbers of occupational fatality cases from media monitoring and CFOI were nearly identical (280 vs. 282, respectively), and the distributions by type of injury were similar. Findings suggest that media monitoring can capture equal numbers of fatalities compared to CFOI. Non-fatal injuries, not captured by national surveillance systems, can be collected and tracked using print and electronic media. Risk factors, identified in media sources, such as gender, age, time, and source of the incident are consistent with previously reported data. Media monitoring can provide timely access to detailed information on individual cases, which is important for detecting unique and emerging hazards, designing interventions and for setting policy and guiding national strategies.