Role of Mechanistic Target of Rapamycin and Autophagy in Alcohol-Induced Adipose Atrophy and Liver Injury.

Chronic alcohol consumption induces adipose tissue atrophy. However, the mechanisms for how alcohol induces lipodystrophy and its impact on liver steatosis and injury are not fully elucidated. Autophagy is a highly conserved lysosomal degradation pathway, which regulates cellular homeostasis. Mice with autophagy deficiency in adipose tissue have impaired adipogenesis. However, whether autophagy plays a role in alcohol-induced adipose atrophy and how altered adipocyte autophagy contributes to alcohol-induced liver injury remain unclear. To determine the role of adipose autophagy and mechanistic target of rapamycin (mTOR) in alcohol-induced adipose and liver pathogenesis, we generated adipocyte-specific Atg5 knockout (KO), adipocyte-specific mTOR KO, adipocyte-specific Raptor KO, and adipocyte-specific tuberous sclerosis complex 1 KO mice by crossing floxed mice with Adipoq-Cre. The KO mice and their matched wild-type mice were challenged with chronic-plus-binge alcohol mouse model. Chronic-plus-binge alcohol induced adipose atrophy with increased autophagy and decreased Akt/mTOR signaling in epididymal adipose tissue in wild-type mice. Adipocyte-specific Raptor KO mice experienced exacerbated alcohol-induced steatosis, but neither adipocyte-specific mTOR nor adipocyte-specific tuberous sclerosis complex 1 KO mice exhibited similar detrimental effects. Adipocyte-specific Atg5 KO mice had increased circulating levels of fibroblast growth factor 21 and adiponectin and were resistant to alcohol-induced adipose atrophy and liver injury. In conclusion, autophagy deficiency in adipose tissue leads to reduced sensitivity to alcohol-induced adipose atrophy, which ameliorates alcohol-induced liver injury in mice.

Where Is the Break-even Point for Community Health Workers? Using National Data and Local Programmatic Costs to Find the Break-even Point for a Metropolitan Community Health Worker Program.

BACKGROUND: Community health worker (CHW) programs take many forms and have been shown to be effective in improving health in several contexts. The extent to which they reduce unnecessary care is not firmly established. OBJECTIVES: This study estimates the number of hospitalizations and emergency department (ED) visits that would need to be avoided to recoup program costs for a CHW program that addressed both medical and social needs. RESEARCH DESIGN: A programmatic cost analysis is conducted using 6 different categories: personnel, training, transportation, equipment, facilities, and administrative costs. First, baseline costs are established for the current program and then estimate the number of avoided ED visits or hospitalizations needed to recoup program costs using national average health care estimates for different patient populations. MEASURES: Data on program costs are taken from administrative program records. Estimates of ED visit and hospitalization costs (or charges in some cases) are taken from the literature. RESULTS: To fully offset program costs, each CHW would need to work with their annual caseload of 150 participants to avoid almost 50 ED visits collectively. If CHW participants also avoided 2 hospitalizations, the number of avoided ED visits needed to offset costs reduces to about 34. CONCLUSIONS: Estimates of avoided visits needed to reach the break-even point are consistent with the literature. The analysis does not take other outcomes of the program from the clients' or workers' perspectives into account, so it is likely an upper bound on the number of avoided visits needed to be cost-effective.

An Integrative Total Worker Health Framework for Keeping Workers Safe and Healthy During the COVID-19 Pandemic.

OBJECTIVE: The aim was to recommend an integrated Total Worker Health (TWH) approach which embraces core human factors and ergonomic principles, supporting worker safety, health, and well-being during the COVID-19 pandemic. BACKGROUND: COVID-19 has resulted in unprecedented challenges to workplace safety and health for workers and managers in essential businesses, including healthcare workers, grocery stores, delivery services, warehouses, and distribution centers. Essential workers need protection, accurate information, and a supportive work environment with an unwavering focus on effective infection control. METHOD: The investigators reviewed emerging workplace recommendations for reducing workers' exposures to the novel coronavirus and the challenges to workers in protecting their health. Using a theoretical framework and guidelines for integrating safety and health management systems into an organization for TWH, the investigators adapted the framework's key characteristics to meet the specific worker safety and health issues for effective infection control, providing supports for increasing psychological demands while ensuring a safe work environment. RESULTS: The recommended approach includes six key characteristics: focusing on working conditions for infection control and supportive environments for increased psychological demands; utilizing participatory approaches involving workers in identifying daily challenges and unique solutions; employing comprehensive and collaborative efforts to increase system efficiencies; committing as leaders to supporting workers through action and communications; adhering to ethical and legal standards; and using data to guide actions and evaluate progress. CONCLUSION: Applying an integrative TWH approach for worker safety, health, and well-being provides a framework to help managers systematically organize and protect themselves, essential workers, and the public during the COVID-19 pandemic. APPLICATION: By using the systems approach provided by the six implementation characteristics, employers of essential workers can organize their own efforts to improve system performance and worker well-being during these unprecedented times.

Impaired TFEB-Mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-Induced Liver Injury and Steatosis in Mice.

BACKGROUND & AIMS: Defects in lysosome function and autophagy contribute to the pathogenesis of alcoholic liver disease. We investigated the mechanisms by which alcohol consumption affects these processes by evaluating the functions of transcription factor EB (TFEB), which regulates lysosomal biogenesis. METHODS: We performed studies with GFP-LC3 mice, mice with liver-specific deletion of TFEB, mice with disruption of the transcription factor E3 gene (TFE3-knockout mice), mice with disruption of the Tefb and Tfe3 genes (TFEB and TFE3 double-knockout mice), and Tfebflox/flox albumin cre-negative mice (controls). TFEB was overexpressed from adenoviral vectors or knocked down with small interfering RNAs in mouse livers. Mice were placed on diets of regular ethanol feeding plus an acute binge to induce liver damage (ethanol diet); some mice also were given injections of torin-1, an inhibitor of the kinase activity of the mechanistic target of rapamycin (mTOR). Liver tissues were collected and analyzed by immunohistochemistry, immunoblots, and quantitative real-time polymerase chain reaction to monitor lysosome biogenesis. We analyzed levels of TFEB in liver tissues from patients with alcoholic hepatitis and from healthy donors (controls) by immunohistochemistry. RESULTS: Liver tissues from mice on the ethanol diet had lower levels of total and nuclear TFEB compared with control mice, and hepatocytes had decreased lysosome biogenesis and autophagy. Hepatocytes from mice on the ethanol diet had increased translocation of mTOR into lysosomes, resulting in increased mTOR activation. Administration of torin-1 increased liver levels of TFEB and decreased steatosis and liver injury induced by ethanol. Mice that overexpressed TFEB in the liver developed less severe ethanol-induced liver injury and had increased lysosomal biogenesis and mitochondrial bioenergetics compared with mice carrying a control vector. Mice with knockdown of TFEB and TFEB-TFE3 double-knockout mice developed more severe liver injury in response to the ethanol diet than control mice. Liver tissues from patients with alcohol-induced hepatitis had lower nuclear levels of TFEB than control tissues. CONCLUSIONS: We found that ethanol feeding plus an acute binge decreased hepatic expression of TFEB, which is required for lysosomal biogenesis and autophagy. Strategies to block mTOR activity or increase levels of TFEB might be developed to protect the liver from ethanol-induced damage.

Mechanisms, pathophysiological roles and methods for analyzing mitophagy - recent insights.

In 2012, we briefly summarized the mechanisms, pathophysiological roles and methods for analyzing mitophagy. As then, the mitophagy field has continued to grow rapidly, and many new molecular mechanisms regulating mitophagy and molecular tools for monitoring mitophagy have been discovered and developed. Therefore, the purpose of this review is to update information regarding these advances in mitophagy while focusing on basic molecular mechanisms of mitophagy in different organisms and its pathophysiological roles. We also discuss the advantage and limitations of current methods to monitor and quantify mitophagy in cultured cells and in vivo mouse tissues.

Chronic Deletion and Acute Knockdown of Parkin Have Differential Responses to Acetaminophen-induced Mitophagy and Liver Injury in Mice.

We previously demonstrated that pharmacological induction of autophagy protected against acetaminophen (APAP)-induced liver injury in mice by clearing damaged mitochondria. However, the mechanism for removal of mitochondria by autophagy is unknown. Parkin, an E3 ubiquitin ligase, has been shown to be required for mitophagy induction in cultured mammalian cells following mitochondrial depolarization, but its role in vivo is not clear. The purpose of this study was to investigate the role of Parkin-mediated mitophagy in protection against APAP-induced liver injury. We found that Parkin translocated to mitochondria in mouse livers after APAP treatment followed by mitochondrial protein ubiquitination and mitophagy induction. To our surprise, we found that mitophagy still occurred in Parkin knock-out (KO) mice after APAP treatment based on electron microscopy analysis and Western blot analysis for some mitochondrial proteins, and Parkin KO mice were protected against APAP-induced liver injury compared with wild type mice. Mechanistically, we found that Parkin KO mice had decreased activated c-Jun N-terminal kinase (JNK), increased induction of myeloid leukemia cell differentiation protein (Mcl-1) expression, and increased hepatocyte proliferation after APAP treatment in their livers compared with WT mice. In contrast to chronic deletion of Parkin, acute knockdown of Parkin in mouse livers using adenovirus shRNA reduced mitophagy and Mcl-1 expression but increased JNK activation after APAP administration, which exacerbated APAP-induced liver injury. Therefore, chronic deletion (KO) and acute knockdown of Parkin have differential responses to APAP-induced mitophagy and liver injury in mice.

Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice.

BACKGROUND & AIMS: Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in the US and many other countries. Metabolism of APAP results in formation of APAP protein adducts (APAP-AD) in hepatocytes and triggers mitochondrial dysfunction and necrosis. However, the mechanisms for how APAP-AD are removed from hepatocytes remain unknown. METHODS: Mice or primary hepatocytes were treated with APAP. APAP-AD were determined by immunoblot, immunostaining and high pressure liquid chomatography with electrochemical detection analysis. RESULTS: We found that APAP-AD were detected at 1h, peaked at approximately 2h, declined at 6h and almost full removed at 24h post treatment with APAP in mouse livers and in primary mouse hepatocytes. APAP-AD displayed a punctate pattern and were colocalized with GFP-LC3 positive autophagosomes and Lamp1 positive lysosomes in APAP-treated primary hepatocytes. Moreover, isolated autophagosomes and autolysosomes from APAP-treated mouse livers contained APAP-AD, suggesting autophagy may selectively remove APAP-AD. APAP-AD were detected in both detergent soluble and insoluble pools in APAP-treated mouse livers and hepatocytes. More importantly, pharmacological inhibition of autophagy by leupeptin or chloroquine increased whereas induction of autophagy by Torin 1 decreased serum APAP-AD levels in APAP-treated mice, which correlated with alanine aminotransferase levels and liver necrosis. Furthermore, SQSTM1/p62, an autophagy receptor protein, was recruited to APAP-AD. Adenovirus-mediated shRNA knockdown of SQSTM1/p62 led to increased APAP-AD and necrosis in primary hepatocytes. CONCLUSIONS: Our data indicate that APAP-AD are removed though selective autophagy. Pharmacological induction of autophagy may be a novel promising approach for treating APAP-induced liver injury. LAY SUMMARY: Acetaminophen overdose can form acetaminophen protein adducts and mitochondria damage in hepatocytes resulting in liver injury. Activation of autophagy-lysosomal degradation pathway can help to remove acetaminophen protein adducts. Pharmacological induction of autophagy may be a novel promising approach for treating APAP-induced liver injury.

Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis.

Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily with its endogenous ligands bile acids. Mice with whole body FXR deficiency develop liver tumors spontaneously, but the underlying mechanism is unclear. Moreover, it is unknown whether FXR deficiency in liver alone serves as a tumor initiator or promoter during liver carcinogenesis. This study aims to evaluate the effects of hepatocyte-specific FXR deficiency (FXR(hep-/-)) in liver tumor formation. The results showed that FXR(hep-/-) mice did not show spontaneous liver tumorigenesis with aging (up to 24 mo of age). Therefore FXR(hep-/-) mice were fed a bile acid (cholic acid)-containing diet alone or along with a liver tumor initiator, diethylnitrosamine (DEN). Thirty weeks later, no tumors were found in wild-type or FXR(hep-/-) mice without any treatment or with DEN only. However, with cholic acid, while only some wild-type mice developed tumors, all FXR(hep-/-) mice presented with severe liver injury and tumors. Interestingly, FXR(hep-/-) mouse livers increased basal expression of tumor suppressor p53 protein, apoptosis, and decreased basal cyclin D1 expression, which may prevent tumor development in FXR(hep-/-) mice. However, cholic acid feeding reversed these effects in FXR(hep-/-) mice, which is associated with an increased cyclin D1 and decreased cell cycle inhibitors. More in-depth analysis indicates that the increased in cell growth might result from disturbance of the MAPK and JAK/Stat3 signaling pathways. In conclusion, this study shows that hepatic FXR deficiency may only serve as a tumor initiator, and increased bile acids is required for tumor formation likely by promoting cell proliferation.

Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice.

Alcoholic liver disease claims two million lives per year. We previously reported that autophagy protected against alcohol-induced liver injury and steatosis by removing damaged mitochondria. However, the mechanisms for removal of these mitochondria are unknown. Parkin is an evolutionarily conserved E3 ligase that is recruited to damaged mitochondria to initiate ubiquitination of mitochondrial outer membrane proteins and subsequent mitochondrial degradation by mitophagy. In addition to its role in mitophagy, Parkin has been shown to have other roles in maintaining mitochondrial function. We investigated whether Parkin protected against alcohol-induced liver injury and steatosis using wild-type (WT) and Parkin knockout (KO) mice treated with alcohol by the acute-binge and Gao-binge (chronic plus acute-binge) models. We found that Parkin protected against liver injury in both alcohol models, likely because of Parkin's role in maintaining a population of healthy mitochondria. Alcohol caused greater mitochondrial damage and oxidative stress in Parkin KO livers compared with WT livers. After alcohol treatment, Parkin KO mice had severely swollen and damaged mitochondria that lacked cristae, which were not seen in WT mice. Furthermore, Parkin KO mice had decreased mitophagy, ß-oxidation, mitochondrial respiration, and cytochrome c oxidase activity after acute alcohol treatment compared with WT mice. Interestingly, liver mitochondria seemed able to adapt to alcohol treatment, but Parkin KO mouse liver mitochondria had less capacity to adapt to Gao-binge treatment compared with WT mouse liver mitochondria. Overall, our findings indicate that Parkin is an important mediator of protection against alcohol-induced mitochondrial damage, steatosis, and liver injury.

Targeting Pink1-Parkin-mediated mitophagy for treating liver injury.

Alcoholic liver disease and acetaminophen overdose are common causes of severe liver disease and liver failure in the United States for which there is no cure. Therefore, development of new therapeutic strategies for treatment of liver injury caused by acetaminophen and alcohol is needed. We demonstrated that autophagy protects against alcohol and acetaminophen-induced liver injuries by removing damaged mitochondria via mitophagy, which is a selective form of autophagy specific for degradation of damaged mitochondria. Parkin is well-known to be required for mitophagy induction in in vitro models, and we previously showed that the Parkin-mediated mitophagy pathway likely plays a protective role against alcohol and acetaminophen-induced liver injuries. Therefore, pharmacological upregulation of the Parkin-mediated mitophagy pathway in the liver may provide a novel and effective therapeutic option for treatment of acetaminophen and alcohol-induced liver injuries. In this review, we discuss regulation of Parkin-mediated mitophagy and possible therapeutic targets of intervention in this pathway.

Health-related employer support, recurring pain, and direct insurance costs for a self-insured employer.

BACKGROUND: Poor psychosocial workplace factors have been found to cause or exacerbate a variety of health problems, including pain. However, little work has focused on how psychosocial workplace factors, such as health-related employer support, relate to future medical expenditures after controlling for health. Health-related support has also not been well explored in previous literature as a psychosocial factor. This study estimated the association of health-related employer support and pain with future medical expenditures, after including many additional controls. METHODS: This study used a restricted data set comprised of medical claims and survey data for one company in the U.S. Participants were included in the sample if they had worked for their employer for at least 12 months prior to the survey and if they were continuously eligible for health insurance (N=1,570). Future medical expenditures were measured using administrative claims data covering inpatient, outpatient, mental health and pharmaceutical insurance claims during a year. Health-related employer support was measured using participants' answers about whether the employer would support their efforts to positively change their emotional or physical health. Pain was measured as recurring pain from any condition over the previous year. RESULTS: Having any physical health-related employer support was associated with a 0.06 increase in the probability of having future medical expenditures greater than zero, 95% CI [0.01, 0.11], but not with total expenditures. Having pain was associated with a 0.06 increase, 95% CI [0.04, 0.09], in the probability of having future medical expenditures greater than zero and with $3,027 additional total expenditures, 95% CI [$1,077, $4,987]. CONCLUSIONS: After controlling for health and pain, psychosocial workplace factors were not robustly associated with future medical expenditures. Pain was associated with increased medical expenditures for the self-insured employer in this study, adjusting for a variety of factors.

Can Better Leadership Reduce Nursing Home Staff Turnover?

OBJECTIVES: To assess whether a measure of leadership support for worker safety, health, and well-being predicts staff turnover in nursing homes after controlling for other factors. DESIGN: This paper uses administrative payroll data to measure facility-level turnover and uses a survey measure of nursing home leadership commitment to workers. In addition, we use data from Medicare to measure various nursing home characteristics. SETTING AND PARTICIPANTS: Nursing homes with at least 30 beds serving adults in California, Ohio, and Massachusetts were invited to participate in the survey. The analysis sample included 495 nursing homes. METHODS: We used a multivariable ordinary least squares model with turnover rate as the dependent variable. We used an indicator for nursing homes who scored above the median on the measure of leadership that supports worker safety, health, and well-being. Control variables include bed count (deciles), ownership (corporate/noncorporate × for-profit/not-for-profit), percent of residents on Medicaid, state, being in a nonmetropolitan county, and total nurse staffing per patient day in the 2 quarters before the survey. RESULTS: The unadjusted turnover rate was lower for those nursing homes that scored higher on leadership commitment to worker safety, health, and well-being. After controlling for additional variables, greater leadership commitment was still associated with lower turnover but with some attenuation. CONCLUSIONS AND IMPLICATIONS: We find that nursing homes with leadership that communicated and demonstrated commitment to worker safety, health, and well-being had relatively fewer nurses leave during the study period, with turnover rates approximately 10% lower than homes without. These findings suggest that leadership may be a valuable tool for reducing staff turnover.

Predicting COVID-19 Cases in Nursing Homes of California and Ohio: Does the Work Environment Matter?

OBJECTIVE: The cross-sectional study evaluates if the pre-pandemic work environments in nursing homes predict COVID-19 cases among residents and staff, accounting for other factors. METHOD: Leveraging data from a survey of California and Ohio nursing homes (n = 340), we examined if Workplace Integrated Safety and Health domains - Leadership, Participation, and Comprehensive and Collaborative strategies predicted cumulative COVID-19 cases among nursing home residents and staff. RESULTS: In Ohio, a 1-unit increase in Leadership score was associated with 2 fewer staff cases and 4 fewer resident cases. A 1-unit increase in Comprehensive and Collaborative Strategies score in California showed an average marginal effect of approximately 1 less staff case and 2 fewer resident cases. CONCLUSION: These findings suggest that leadership commitment and inter-department collaboration to prioritize worker safety, may have protected against COVID-19 cases in nursing homes.

Mechanisms of STAT3 activation in the liver of FXR knockout mice.

Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR(-/-) mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR(-/-) mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR(-/-) mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR(-/-) but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR(-/-) mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR(-/-) mice.

Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice.

Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. Induction of SHP serves as a major mechanism of FXR in suppressing gene expression. Both FXR(-/-) and SHP(-/-) mice develop spontaneous hepatocellular carcinoma (HCC). SHP is one of the most strongly induced genes by FXR in the liver and is a tumor suppressor, therefore, we hypothesized that deficiency of SHP contributes to HCC development in the livers of FXR(-/-) mice and therefore, increased SHP expression in FXR(-/-) mice reduces liver tumorigenesis. To test this hypothesis, we generated FXR(-/-) mice with overexpression of SHP in hepatocytes (FXR(-/-)/SHP(Tg)) and determined the contribution of SHP in HCC development in FXR(-/-) mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXR(-/-) mice. However, SHP overexpression led to a lower grade of dysplasia, reduced indicator cell proliferation and increased apoptosis. All tumor-bearing mice had increased serum bile acid levels and IL-6 levels, which was associated with activation of hepatic STAT3. In conclusion, SHP partially protects FXR(-/-) mice from HCC formation by reducing tumor malignancy. However, disrupted bile acid homeostasis by FXR deficiency leads to inflammation and injury, which ultimately results in uncontrolled cell proliferation and tumorigenesis in the liver.

Role of intracellular calcium in proteasome inhibitor-induced endoplasmic reticulum stress, autophagy, and cell death.

PURPOSE: Proteasome inhibition induces endoplasmic reticulum (ER) stress and compensatory autophagy to relieve ER stress. Disturbance of intracellular calcium homeostasis can lead to ER stress and alter the autophagy process. It has been suggested that inhibition of the proteasome disrupts intracellular calcium homeostasis. However, it is unknown if intracellular calcium affects proteasome inhibitor-induced ER stress and autophagy. METHODS: Human colon cancer HCT116 Bax positive and negative cell lines were treated with MG132, a proteasome inhibitor. BAPTA-AM, a cell permeable free calcium chelator, was used to modulate intracellular calcium levels. Autophagy and cell death were determined by fluorescence microscopy and immunoblot analysis. RESULTS: MG132 increased intracellular calcium levels in HCT116 cells, which was suppressed by BAPTA-AM. MG132 suppressed proteasome activity independent of Bax and intracellular calcium levels in HCT116 cells. BAPTA-AM inhibited MG132-induced cellular vacuolization and ER stress, but not apoptosis. MG132 induced autophagy with normal autophagosome-lysosome fusion. BAPTA-AM seemed not to affect autophagosome-lysosome fusion in MG132-treated cells but further enhanced MG132-induced LC3-II levels and GFP-LC3 puncta formation, which was likely via impaired lysosome function. CONCLUSIONS: Blocking intracellular calcium by BAPTA-AM relieved MG132-induced ER stress, but it was unable to rescue MG132-induced apoptosis, which was likely due to impaired autophagic degradation.

Targeting autophagy for the treatment of liver diseases.

Autophagy is a lysosomal degradation pathway that can degrade bulk cytoplasm and superfluous or damaged organelles, such as mitochondria, to maintain cellular homeostasis. It is now known that dysregulation of autophagy can cause pathogenesis of numerous human diseases. Here, we discuss the critical roles that autophagy plays in the pathogenesis of liver diseases such as non-alcoholic and alcoholic fatty liver, drug-induced liver injury, protein aggregate-related liver diseases, viral hepatitis, fibrosis, aging and liver cancer. In particular, we discuss the emerging therapeutic potential by pharmacological modulation of autophagy for these liver diseases.

Presence of unsafe chemical impurities, accelerated evaporation of alcohol, and lack of key labeling requirements are risks and concerns for some alcohol-based hand sanitizers and dispenser practices during the COVID-19 pandemic.

Alcohol-based hand sanitizers (ABHS) have been an important hand hygiene tool during the COVID-19 pandemic. Recently, ABHS from non-traditional drug manufacturers have entered the market, triggered by a lack of ABHS availability. Some of these ABHS contain high levels of chemical impurities that may be harmful with frequent exposure. Additionally, the use of refillable dispensers designed to accept ABHS from bulk containers allows for mixing and evaporation that may compromise ABHS integrity. To understand the risks associated with low quality ABHS and bulk refilling practices, we collected 77 ABHS samples sourced from community settings (restaurants, grocery stores, etc.) and 40 samples from a single school district. All samples were obtained from bulk refillable dispensers that were in use. Samples were analyzed for alcohol content, chemical impurities, aesthetic qualities, and presence of drug labeling information. Additionally, we performed laboratory-based experiments to determine the impact of dispenser design on alcohol evaporation rates. Over 70% of samples for which photos were available showed lack of essential labeling information, including missing "Drug Facts Labels". For ABHS samples acquired from community settings, nearly 14% of samples had visible impurities, and over 30% of samples had concentrations of acetal and acetaldehyde in excess of FDA interim limits. Subpotent ethanol concentrations were observed in 9.09% and 82.05% of samples from community settings and the school district, respectively, with the school district sample results being associated with dispenser misuse. Laboratory-based experiments show dispenser design significantly impacts the rate of ethanol evaporation of ABHS products, especially if stored in open refillable dispensers without an internal reservoir. This study demonstrates risks associated with use of inferior ABHS and bulk refilling practices. Regulatory agencies should issue guidance on best practices in community settings to ensure the integrity of ABHS as an essential public health tool to prevent the spread of COVID-19 and other transmissible diseases.

Chlamydia partner services for females in California family planning clinics.

BACKGROUND: Prompt treatment of exposed partners is critical for preventing further transmission of chlamydia, reinfection, and sequelae among females. Patient-delivered partner therapy (PDPT) has been allowable in California since 2001; however, few data are available regarding PDPT use and treatment outcomes. METHODS: Eight family planning clinics participated in a partner services evaluation from 2005 to 2006. Females aged 16 to 35 years with chlamydia were interviewed to determine the partner service received and partner treatment outcomes; a subset of partners was also interviewed. Determinants of reported partner treatment were assessed using multivariate logistic regression. Selected medical records were reviewed to assess reinfection rates. RESULTS: Overall, 743 female patients disclosed 952 partners; 58% of whom were identified as steady partners. Reported partner services included concurrent patient-partner treatment visits (15% of partners), PDPT (19%), patient referral (55%), health department referral (0.1%), and no partner management (11%). On the basis of patient report, 82% of partners were notified and 54% received treatment. Of the 166 (17%) partners interviewed, 139 (84%) reported that they had received treatment, which correlated well with patient report. Reported partner treatment was higher for concurrent treatment visits and PDPT (79% and 80%, respectively) compared to patient referral (44%, P < 0.0001). Adjusted for clinic and relationship status, partners managed with concurrent treatment visits or PDPT were more likely to receive treatment compared with partners managed with patient referral (adjusted odds ratios, 3.5; 95% confidence interval, 2.1-5.8 and adjusted odds ratios, 4.3; 95% confidence interval, 2.6-7.2, respectively). Among the patients retested within 6 months after treatment, 18% were reinfected; reinfection rates did not differ by type of partner service. CONCLUSIONS: Although overall rates of reported partner treatment were low, concurrent patient-partner treatment visits and PDPT were associated with significantly higher rates of partner treatment. However, these methods may be underutilized in California family planning settings.