Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner.

Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2-/-Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2-/-Fancd2-/- HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001). CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.

Pathologist Computer-Aided Diagnostic Scoring of Tumor Cell Fraction: A Swiss National Study.

Tumor cell fraction (TCF) estimation is a common clinical task with well-established large interobserver variability. It thus provides an ideal test bed to evaluate potential impacts of employing a tumor cell fraction computer-aided diagnostic (TCFCAD) tool to support pathologists' evaluation. During a National Slide Seminar event, pathologists (n = 69) were asked to visually estimate TCF in 10 regions of interest (ROIs) from hematoxylin and eosin colorectal cancer images intentionally curated for diverse tissue compositions, cellularity, and stain intensities. Next, they re-evaluated the same ROIs while being provided a TCFCAD-created overlay highlighting predicted tumor vs nontumor cells, together with the corresponding TCF percentage. Participants also reported confidence levels in their assessments using a 5-tier scale, indicating no confidence to high confidence, respectively. The TCF ground truth (GT) was defined by manual cell-counting by experts. When assisted, interobserver variability significantly decreased, showing estimates converging to the GT. This improvement remained even when TCFCAD predictions deviated slightly from the GT. The standard deviation (SD) of the estimated TCF to the GT across ROIs was 9.9% vs 5.8% with TCFCAD (P < .0001). The intraclass correlation coefficient increased from 0.8 to 0.93 (95% CI, 0.65-0.93 vs 0.86-0.98), and pathologists stated feeling more confident when aided (3.67 ± 0.81 vs 4.17 ± 0.82 with the computer-aided diagnostic [CAD] tool). TCFCAD estimation support demonstrated improved scoring accuracy, interpathologist agreement, and scoring confidence. Interestingly, pathologists also expressed more willingness to use such a CAD tool at the end of the survey, highlighting the importance of training/education to increase adoption of CAD systems.

Implementing quality management strategies improves clinical quality as a voluntary medical male circumcision program in Namibia matures: a process analysis.

BACKGROUND: Surgical voluntary medical male circumcision (VMMC) is a safe procedure; however, maintaining quality standards at scale, particularly during scale-up, is a challenge making ongoing quality management (QM) efforts essential. This study describes program quality measured by rates of adverse events (AEs) over four years of VMMC implementation in Namibia, compares AE rates over time, and discusses QM processes that contextualize AE trends and illustrate improvements in quality as the program matured. The International Training and Education Center for Health (I-TECH) assisted the Namibian Ministry of Health and Social Services (MoHSS) in expanding VMMC in three regions among boys and men over 10 years of age between January 2015 and September 2019. METHODS: A comprehensive package of QM strategies was implemented by multi-disciplinary onsite teams with support from national and international technical advisors. Retrospective routine MoHSS data from the VMMC register, client forms, and monthly AE reports were collected during implementation in the three regions to assess the impact of QM interventions on AEs and to calculate the proportion of clients who experienced AEs over time. The proportion of clients who experienced an AE over time was compared using a Cochran-Armitage test for trend. RESULTS: Between January 2015 and September 2019, 40,336 clients underwent VMMC and 593 (1.5%) clients experienced a post-operative AE in the three supported regions. The AE rate was highest in the first quarter of clinical service delivery in each region (January-March 2015 in Oshana and Zambezi, October-December 2017 in //Kharas) but declined over the implementation period as the program matured. This observed trend between program maturity and declining AE rates over time was significant (p < 0.001) when compared using a Cochran-Armitage test for trend. CONCLUSIONS: As the I-TECH-supported VMMC program matured, QM measures were introduced and routinized, and clinical quality improved over time with the rate of AEs decreasing significantly over the implementation period. Applying systematic and continuous QM processes and approaches across the continuum of VMMC services and considering local context can contribute to increased clinical safety. QM measures that are established in more mature program sites can be quickly adopted to respond to quality issues in program expansion sites.

Liver Stiffness by Transient Elastography to Detect Porto-Sinusoidal Vascular Liver Disease With Portal Hypertension.

BACKGROUND AND AIMS: Porto-sinusoidal vascular liver disease (PSVD) is a rare cause of portal hypertension. PSVD is still often misdiagnosed as cirrhosis, emphasizing the need to improve PSVD diagnosis strategies. Data on liver stiffness measurement using transient elastography (TE-LSM) in PSVD are limited. The aim of this study was to evaluate the accuracy of TE-LSM to discriminate PSVD from cirrhosis in patients with signs of portal hypertension. APPROACH AND RESULTS: Retrospective multicenter study comparing TE-LSM in patients with PSVD, according to Vascular Liver Disease Interest Group criteria, with patients with compensated biopsy-proven cirrhosis associated with alcohol (n = 117), HCV infection (n = 110), or NAFLD (n = 46). All patients had at least one sign of portal hypertension among gastroesophageal varices, splenomegaly, portosystemic collaterals, history of ascites, or platelet count < 150 × 109 /L. The 77 patients with PSVD included in the test cohort had lower median TE-LSM (7.9 kPa) than the patients with alcohol-associated, HCV-related, and NAFLD-related cirrhosis (33.8, 18.2, and 33.6 kPa, respectively; P < 0.001). When compared with cirrhosis, a cutoff value of 10 kPa had a specificity of 97% for the diagnosis of PSVD with a 85% positive predictive value. A cutoff value of 20 kPa had a sensitivity of 94% for ruling out PSVD with a 97% negative predictive value. Of the patients, 94% were well-classified. Even better results were obtained in a validation cohort including 78 patients with PSVD. CONCLUSIONS: This study including a total of 155 patients with PSVD and 273 patients with cirrhosis demonstrates that TE-LSM < 10 kPa strongly suggests PSVD in patients with signs of portal hypertension. Conversely, when TE-LSM is >20 kPa, PSVD is highly unlikely.

Emotional reactions of trained overdose responders who use opioids following intervention in an overdose event.

Background: Our aim was to explore emotional reactions to intervening in an overdose event from the perspective of individuals who use opioids (peer responders). In addition, we were interested in the impact this experience may have on peer responders' feelings about helping in an overdose situation in the future. Methods: For this qualitative sub-study of a randomized controlled trial (RCT), data from 61 interviews were analyzed thematically using an inductive approach. Results: Peer responders had diverse emotional reactions to the overdose event. These ranged from a sense of pride and other positive feelings associated with their ability to help to ambivalence about being involved in situations perceived as challenging and burdensome. There were few reports of the overdose event as an exclusively negative experience. Many peer responders perceived it as their duty to use naloxone again if required. However, some had ambivalent feelings toward this responsibility, which may be related to negative experiences with previous intervention efforts. Conclusions: The capacity of people who use opioids to help reduce the harms associated with opioid overdose is experienced as empowering by some. Nonetheless, engaging peer responders in strategies to reduce opioid-related mortality should be coupled with appropriate resources to process their experiences and emotional responses.

The diagnostic performance of a simulated "short" gadoxetic acid-enhanced MRI protocol is similar to that of a conventional protocol for the detection of colorectal liver metastases.

OBJECTIVES: To compare the performance of standard and simulated short gadoxetic acid-enhanced MRI protocols for the detection of colorectal liver metastases (CRLM). METHODS: From 2008 to 2017, 67 patients (44 men (66%); mean age 65 ± 11 years old) who underwent gadoxetic acid-enhanced MRI during the initial work-up for colorectal cancer were included. Exams were independently reviewed by two readers blinded to clinical data in two reading sessions: (1) all acquired sequences (standard "long" protocol) and (2) only T2-weighted, diffusion-weighted, and hepatobiliary phase images (simulated "short" protocol). Readers characterized detected lesions using a 5-point scale (1-certainly benign to 5-certainly malignant). A lesion was considered a CRLM when the score was ≥ 3. The reference standard was histopathology or 12-month imaging follow-up. Chi-square, Student's t, and McNemar tests were used for comparisons. RESULTS: A total of 486 lesions including 331 metastases (68%) were analyzed. The metastasis detection rate was 86.1% (95% CI 82-89.4)-86.7% (82.6-90) and 85.8% (81.6-89.2)-87% (82.9-90.2) with the short and long protocols, respectively (p > 0.99). Among detected lesions, 92.1% (89.1-94.4)-94.8% (92.2-96.6) and 84.6% (80.8-87.7)-88.8% (85.4-91.5) were correctly classified with the short and long protocols, respectively (p = 0.13 and p = 0.10). The results remained unchanged when lesions scored ≥ 4 were considered as CRLM. CONCLUSION: The diagnostic performance of a simulated short gadoxetic enhanced-MR protocol including T2-weighted, diffusion-weighted, and hepatobiliary phase appears similar to that of a standard long protocol including dynamic phase images. Since this protocol shortens the duration of MR examination, it could facilitate the evaluation of patients with colorectal liver metastases. KEY POINTS: • The detection rate of colorectal metastases with a simulated, short, MRI protocol was similar to that of a standard protocol. • The performance of both protocols for the differentiation of metastases and benign lesions appears to be similar. • A short MR imaging protocol could facilitate the evaluation of patients with colorectal liver metastases.

The Increasing Prevalence of Fentanyl: A Urinalysis-Based Study Among Individuals With Opioid Use Disorder in New York City.

BACKGROUND AND OBJECTIVES: Opioid-related overdose deaths in North America have increased drastically, partially due to the increased prevalence of illicitly manufactured fentanyl. The current study sought to assess the prevalence and intentionality of fentanyl use among individuals with opioid use disorder (OUD). METHODS: For this secondary analysis (study 1) we screened a total of 1118 urine samples from 316 participants with OUD from 2016 to 2019. Fentanyl knowledge and intentionality of use were assessed in a separate OUD sample (study 2; N = 33). RESULTS: In study 1, 34.6% of all urine samples tested positive for fentanyl. Overall, 149 (47.2%) participants provided more than or equal to one urine sample that tested fentanyl-positive, and 93 (29.4%) provided more than or equal to two fentanyl-positive samples. The number of fentanyl-positive samples, relative to the number of samples tested each year, increased by 330% from year 1 to 3. Study 2 found all participants had pre-existing knowledge that drugs may be adulterated with fentanyl, yet 67% were surprised by their own fentanyl-positive test result. DISCUSSION AND CONCLUSIONS: Like previous studies, our data indicate the high prevalence of fentanyl exposure and low perception of fentanyl-related risk among individuals with OUD, respectively, suggesting that opioid overdose harm reduction efforts may need to focus more on drug users' understanding of risks related to fentanyl use and adulteration of drugs. SCIENTIFIC SIGNIFICANCE: The current studies provide longitudinal data on fentanyl exposure prevalence and risk perception that is uniquely granular by assessing OUD treatment status, and by identifying potential associations between fentanyl exposure with the presence of other drug use and nonfatal overdose. (Am J Addict 2021;30:65-71).

Intervention in an opioid overdose event increases interest in treatment among individuals with opioid use disorder.

Background: This study sought to explore whether intervening in suspected cases of opioid overdose alters interest in treatment for opioid use disorder (OUD). Data were collected as a part of a trial comparing the effects of different overdose education and naloxone distribution (OEND) training curricula on overdose outcomes. Methods: Following OEND training, participants completed four in-person follow-up visits at 1-, 3-, 6- and 12-months. Participants were also regularly contacted to inquire about overdose events they responded to, witnessed, or experienced themselves. Other assessments included the Addiction Severity Index that queries participants' perceived importance of drug treatment on a scale of: 0 (Not at All) to 4 (Extremely). For the current secondary data analysis, treatment importance was assessed at the time points most immediately preceding and following participant intervention in an overdose event using naloxone. Results: The sample reported a mean duration of opioid use of 14.9 (± 11.5) years, with 67% having witnessed an overdose event prior to the study. Of the 321 enrolled, 92 participants used naloxone in response to 166 suspected cases of an opioid overdose. For the entire sample, mean treatment importance did not significantly change throughout the study. Among participants who utilized naloxone, treatment importance increased following the event (Before: 3.03, After: 3.39, p = 0.02). Due to the amount of time between the overdose event and assessment of post-event treatment importance (40.5 days, ±40.2), the current study most likely underestimates this effect. Conclusions: The current study suggests that responding to an overdose event increases interest in OUD treatment. Currently only considered an acute intervention to reduce overdose morbidity and mortality, OEND may have the potential to increase enrollment in medications to treat OUD. However, a prospective investigation needs to determine if the impact of an overdose event could be utilized to increase treatment engagement.

Impulsive Personality Traits Mediate the Relationship Between Attention-Deficit/Hyperactivity Disorder Symptoms and Psychiatric Comorbidity among Patients with Severe Alcohol Use Disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is an established risk factor for developing alcohol use disorder (AUD), and AUD-ADHD comorbidity is associated with additional psychiatric diagnoses. Several lines of evidence support the role of impulsivity as a pathway of these relationships; however, impulsivity is not a unitary construct. Thus, we sought to explore whether separate aspects of impulsivity may explain the relationship between ADHD symptoms and psychiatric comorbidity among inpatients (N = 136) with AUD. Methods: We assessed ADHD symptoms (childhood ADHD [Wender Utah Rating Scale], adult ADHD [Adult ADHD self-report scale]), health-related quality of life (HRQL; EQ-5D-5L), psychiatric comorbidity (Mini International Neuropsychiatric Interview), and impulsive personality traits (Urgency, Premeditation, Perseverance, Sensation seeking [UPPS] scale). Results: 19% of patients screened positive in the retrospective assessment of childhood ADHD, and 17% for adult ADHD. Participants reported moderate levels of problem severity in the HRQL dimensions, and 65% had ≥1 current psychiatric disorders other than AUD and ADHD. Multiple mediation indicated that there was a significant direct effect of childhood ADHD symptoms on psychiatric comorbidity (ß = 0.224, 95% CI [0.080, 1.114]), and indirect effects of both reacting impetuously when experiencing negative emotions (negative urgency; ß = 0.999, 95% CI [0.043, 0.461]) and the tendency to not finish tasks (lack of perseverance; ß = 0.075, 95% CI [0.002, 0.297]). Conclusions: The subcomponents of impulsivity to react rashly when experiencing negative emotions and the tendency to not persist in activities seem to contribute to the relationship between ADHD symptoms (particularly those in childhood) and psychiatric comorbidity among patients with severe AUD.

Deficient Natural Killer Cell NKp30-Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma.

The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor-3 (NCR3) gene is transcribed into several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7-H6) in patients with hepatocellular carcinoma (HCC). Peripheral blood NK cell phenotype was skewed toward a defective/exhausted immune profile with decreased frequencies of cells expressing NKp30 and natural killer group 2, member D and an increased proportion of cells expressing T-cell immunoglobulin and mucin-domain containing-3. Moreover, NKp30-positive NK cells had a reduced expression of NCR3 immunostimulatory splice variants and an increased expression of the inhibitory variant in patients with advanced tumor, resulting in deficient NKp30-mediated functionality. Tumor-infiltrating lymphocytes showed a prevalent inhibitory NKp30 isoform profile, consistent with decreased NKp30-mediated function. Of note, there were significant differences in the cytokine milieu between the neoplastic and the surrounding non-neoplastic tissue, which may have further influenced NKp30 function. Exposure of NK cells to B7-H6-expressing HCC cells significantly down-modulated NKp30, that was prevented by small interfering RNA-mediated knockdown, suggesting a role for this ligand in inhibiting NKp30-mediated responses. Interestingly, B7-H6 expression was reduced in HCC tissue and simultaneously augmented as a soluble form in HCC patients, particularly those with advanced staging or larger nodule size. Conclusion: These findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution.

Abdominal Surgery in Patients With Idiopathic Noncirrhotic Portal Hypertension: A Multicenter Retrospective Study.

In patients with idiopathic noncirrhotic portal hypertension (INCPH), data on morbidity and mortality of abdominal surgery are scarce. We retrospectively analyzed the charts of patients with INCPH undergoing abdominal surgery within the Vascular Liver Disease Interest Group network. Forty-four patients with biopsy-proven INCPH were included. Twenty-five (57%) patients had one or more extrahepatic conditions related to INCPH, and 16 (36%) had a history of ascites. Forty-five procedures were performed, including 30 that were minor and 15 major. Nine (20%) patients had one or more Dindo-Clavien grade ≥ 3 complication within 1 month after surgery. Sixteen (33%) patients had one or more portal hypertension-related complication within 3 months after surgery. Extrahepatic conditions related to INCPH (P = 0.03) and history of ascites (P = 0.02) were associated with portal hypertension-related complications within 3 months after surgery. Splenectomy was associated with development of portal vein thrombosis after surgery (P = 0.01). Four (9%) patients died within 6 months after surgery. Six-month cumulative risk of death was higher in patients with serum creatinine ≥ 100 µmol/L at surgery (33% versus 0%, P < 0.001). An unfavorable outcome (i.e., either liver or surgical complication or death) occurred in 22 (50%) patients and was associated with the presence of extrahepatic conditions related to INCPH, history of ascites, and serum creatinine ≥ 100 µmol/L: 5% of the patients with none of these features had an unfavorable outcome versus 32% and 64% when one or two or more features were present, respectively. Portal decompression procedures prior to surgery (n = 10) were not associated with postoperative outcome. Conclusion: Patients with INCPH are at high risk of major surgical and portal hypertension-related complications when they harbor extrahepatic conditions related to INCPH, history of ascites, or increased serum creatinine.

Tolerogenic properties of liver macrophages in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Our understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis is improving, but there is still limited data on the function of resident liver macrophages in this context, especially when considering their contribution in dampening liver inflammation. METHODS: Liver macrophages were studied in mouse models of prolonged diet-induced liver steatohepatitis and carbon tetrachloride-induced liver injury. We assessed liver macrophages phenotype and costimulatory/inhibitory properties upon exposure to lipopolysaccharide or interleukin 4. We did phagocytosis and antigen presentation assays to investigate liver macrophages function as scavengers and immune response initiators. Using immunofluorescence staining, we further determined, in human liver tissue of patients with simple steatosis, non-alcoholic steatohepatitis and chronic hepatitis B infection, the expression of the co-inhibitory protein CD274 (Programmed-death ligand 1) and major histocompatibility complex (MHC) class II. RESULTS: Both in humans and mice, within chronically inflamed fatty livers, liver macrophages acquired immunomodulatory properties by reducing the expression of MHC class II, and by enhancing co-inhibitory signalling. Liver macrophages circumscribed endotoxin-mediated inflammatory response by upregulating anti-inflammatory genes arginase 1 and interleukin-10. While hepatic macrophages isolated from mice with normal livers were capable of achieving endotoxin tolerance, our results indicated an impairment of this protective mechanism in the presence NASH-like parenchymal abnormalities. CONCLUSIONS: Liver macrophages can achieve endotoxin tolerance, but in the chronically inflamed fatty liver, while they acquire an immunomodulatory phenotype, liver macrophages fail to dampen immune-mediated damage. Therefore, loss of tolerogenicity induced by ongoing liver insult may be a mechanism contributing to the worsening of NAFLD.

Dose-dependent naloxone-induced morphine withdrawal symptoms in opioid-dependent males-a double-blinded, randomized study.

AIMS: Oral opioid preparations combined with naloxone are intended to induce a transient acute withdrawal syndrome to avoid intravenous misuse. This trial aimed to establish an appropriate morphine-naloxone dose ratio for an abuse-deterrent oral opioid formulation. METHODS: In a randomized, double-blinded, 2 × 2 cross-over trial, 43 patients with opioid use disorder were challenged with intravenous morphine HCl Ph.Eur. (75 mg; [morphine mono]) or morphine HCl Ph.Eur. and naloxone HCl Ph.Eur. at ratios of 100:1 (75 mg: 0.75 mg; [morphine-naloxone 100:1]) or 200:1 (75 mg: 0.375 mg; [morphine-naloxone 200:1]). Acute naloxone-induced opioid withdrawal was evaluated using subjective (Short Opiate Withdrawal Scale-German [SOWS-G]) and observer-rated (Objective Opiate Withdrawal Scale [OOWS], Wang scale) questionnaires, and physiological parameters. For statistical analysis, the area under the curve between baseline and 20 minutes after drug administration of the outcome variables was calculated. RESULTS: Intravenous morphine-naloxone caused rapid withdrawal symptoms. Coadministration of naloxone dose-dependently (morphine-naloxone 100:1 > morphine-naloxone 200:1) increased SOWS-G, OOWS and Wang Scale area under the curve when compared to morphine mono, respectively (all P < .0001). A similar response was detectable for changes of pupil diameter. Blood pressure and respiratory rate changed heterogeneously, and heart rate was unaltered by morphine without or with naloxone. CONCLUSION: Morphine-naloxone 100:1 effectively suppresses the pleasurable effects of intravenous morphine and results in an aversive withdrawal reaction. A lower naloxone concentration as used in morphine-naloxone 200:1 does not appear to be appropriate to prevent intravenous morphine misuse.

Implementation and evaluation of a Project ECHO telementoring program for the Namibian HIV workforce.

BACKGROUND: The Namibian Ministry of Health and Social Services (MoHSS) piloted the first HIV Project ECHO (Extension for Community Health Outcomes) in Africa at 10 clinical sites between 2015 and 2016. Goals of Project ECHO implementation included strengthening clinical capacity, improving professional satisfaction, and reducing isolation while addressing HIV service challenges during decentralization of antiretroviral therapy. METHODS: MoHSS conducted a mixed-methods evaluation to assess the pilot. Methods included pre/post program assessments of healthcare worker knowledge, self-efficacy, and professional satisfaction; assessment of continuing professional development (CPD) credit acquisition; and focus group discussions and in-depth interviews. Analysis compared the differences between pre/post scores descriptively. Qualitative transcripts were analyzed to extract themes and representative quotes. RESULTS: Knowledge of clinical HIV improved 17.8% overall (95% confidence interval 12.2-23.5%) and 22.3% (95% confidence interval 13.2-31.5%) for nurses. Professional satisfaction increased 30 percentage points. Most participants experienced reduced professional isolation (66%) and improved CPD credit access (57%). Qualitative findings reinforced quantitative results. Following the pilot, the Namibia MoHSS Project ECHO expanded to over 40 clinical sites by May 2019 serving more than 140 000 people living with HIV. CONCLUSIONS: Similar to other Project ECHO evaluation results in the United States of America, Namibia's Project ECHO led to the development of ongoing virtual communities of practice. The evaluation demonstrated the ability of the Namibia HIV Project ECHO to improve healthcare worker knowledge and satisfaction and decrease professional isolation.

Shifts in hatching date of American crocodile (Crocodylus acutus) in southern Florida.

Globally temperature of marine environments is on the rise and temperature plays an important role in the life-history of reptiles. In this study, we examined the relationship between sea surface temperature and average date of hatching for American crocodiles (Crocodylus acutus) over a 37-year period at two nesting sites, Everglades National Park and Florida Power and Light Turkey Point Power Plant site in southern Florida. Our results indicate that hatch dates are shifting 1.5 days earlier every two years and at half that rate for the Turkey Point site, and with every 1 °C degree increase in temperature, hatching occurs about 10 days earlier in the Everglades and 6 days earlier at Turkey Point. Our results on shifting hatch dates for American crocodiles provide further details about the impacts of temperature change on crocodile life history and suggest that increased temperature may affect their phenology.

Combination of Gene Expression Signature and Model for End-Stage Liver Disease Score Predicts Survival of Patients With Severe Alcoholic Hepatitis.

BACKGROUND & AIMS: Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables. METHODS: We obtained fixed liver biopsy samples from 71 consecutive patients diagnosed with severe AH and treated with corticosteroids from July 2006 through December 2013 in Brussels, Belgium (derivation cohort). Gene expression patterns were analyzed by microarrays and clinical data were collected for 180 days. We identified gene expression signatures and clinical data that are associated with survival without liver transplantation at 90 and 180 days after initiation of corticosteroid therapy. Findings were validated using liver biopsies from 48 consecutive patients with severe AH treated with corticosteroids, collected from March 2010 through February 2015 at hospitals in Belgium and Switzerland (validation cohort 1) and in liver biopsies from 20 patients (9 received corticosteroid treatment), collected from January 2012 through May 2015 in the United States (validation cohort 2). RESULTS: We integrated data on expression patterns of 123 genes and the model for end-stage liver disease (MELD) scores to assign patients to groups with poor survival (29% survived 90 days and 26% survived 180 days) and good survival (76% survived 90 days and 65% survived 180 days) (P < .001) in the derivation cohort. We named this assignment system the gene signature-MELD (gs-MELD) score. In validation cohort 1, the gs-MELD score discriminated patients with poor survival (43% survived 90 days) from those with good survival (96% survived 90 days) (P < .001). The gs-MELD score also discriminated between patients with a poor survival at 180 days (34% survived) and a good survival at 180 days (84% survived) (P < .001). The time-dependent area under the receiver operator characteristic curve for the score was 0.86 (95% confidence interval 0.73-0.99) for survival at 90 days, and 0.83 (95% confidence interval 0.71-0.96) for survival at 180 days. This score outperformed other clinical models to predict survival of patients with severe AH in validation cohort 1. In validation cohort 2, the gs-MELD discriminated patients with a poor survival at 90 days (12% survived) from those with a good survival at 90 days (100%) (P < .001). CONCLUSIONS: We integrated data on baseline liver gene expression pattern and the MELD score to create the gs-MELD scoring system, which identifies patients with severe AH, treated or not with corticosteroids, most and least likely to survive for 90 and 180 days.

Late hepatitis B reactivation following direct-acting antiviral-based treatment of recurrent hepatitis C in an anti-HBc-positive liver transplant recipient.

Direct-acting antivirals (DAAs) have changed the landscape of hepatitis C virus (HCV) treatment, but chronic hepatitis C (CHC) remains a leading indication for liver transplantation (LT). Hepatitis B virus (HBV) reactivation has been reported in HBV-HCV-coinfected patients treated with DAAs. We report on a case of late HBV reactivation after DAA-based treatment of recurrent hepatitis C in an antibody against hepatitis B core antigen (anti-HBc)-positive LT recipient. (Hepatology 2018;67:791-793).

Comorbidity Patterns Among Patients With Opioid Use Disorder and Problem Gambling: ADHD Status Predicts Class Membership.

Objective: Psychiatric comorbidities are highly prevalent among individuals affected by substance use disorders and those with non-substance-related addictive disorders such as gambling disorder. More recently, the frequent co-occurrence of substance use disorders and attention-deficit hyperactivity disorder (ADHD) has received particular attention. The aim of our study was to identify patterns of psychiatric comorbidity and to examine associations between patient group and ADHD status with class membership. Methods: Participants were patients with opioid use disorder enrolled in opioid maintenance treatment (OMT), either recruited from the community (n = 142; M age = 35.8 years; 38.7% female) or prison (n = 133; M age = 35.7 years; 21.8% female), and patients undergoing treatment for problem gambling (PrG; n = 80; M age = 43.1 years; 20% female). To enable direct comparisons, the following instruments were applied: Mini International Neuropsychiatric Interview, Adult ADHD self-report scale, Wender Utah Rating Scale, and European Addiction Severity Index. We used a latent class analysis (LCA) to identify psychiatric comorbidity patterns and a multinomial logistic regression to examine associations between patient group, ADHD status, age, and gender with class membership. Results: The LCA resulted in a three-class solution: (1) a class of individuals with a relatively low probability of current psychiatric comorbidities, except for a high probability of substance use disorders; (2) a class with markedly increased probabilities of current and recurrent psychiatric comorbidities, especially for major depression; and (3) a class with very low probabilities of psychiatric comorbidities, except for moderate probabilities of substance use disorders and antisocial personality disorder. Both OMT patients recruited from the community and those in prison were less likely than PrG patients to be assigned to the most burdened class with respect to psychiatric comorbidity (class 2). Further, both individuals with ADHD in childhood and those with adult ADHD were more likely members of class 2. Conclusions: PrG patients seem to be at an even higher risk for psychiatric comorbidities compared to OMT patients. Raising awareness among practitioners for the high prevalence of psychiatric comorbidities among patients with gambling disorder and individuals with ADHD is crucial to initiate adequate treatment and to improve response.

[Abdominal surgery in patients with portal hypertension†: clinical implication and management]. / Chirurgie abdominale chez les malades avec hypertension portale†: implications et prise en charge.

Abdominal surgery is sometimes needed in patients with portal hypertension. The indication may be related to the underlying liver disease, including liver resection for liver cancer and parietal surgery. Surgery may also be performed for another indication, unrelated to the liver disease. Portal hypertension increases both morbidity and mortality after abdominal surgery, and it should be taken into account when planning surgery timing and surgical strategy. This article provides an overview of the main etiologies of portal hypertension, and the post-operative outcomes after liver resection and non-hepatic abdominal surgery, underlining the importance of a multidisciplinary approach.

Une chirurgie abdominale est parfois nécessaire chez les patients atteints d'hypertension portale. Son indication peut être en lien avec une complication de la maladie du foie, comme une résection de tumeur hépatique ou une chirurgie pariétale, ou avec une affection non liée à la pathologie hépatique. L'hypertension portale augmente la morbidité et la mortalité de cette chirurgie, et l'indication ainsi que la stratégie doivent être définies avec soin. Cet article décrit les causes d'hypertension portale, les risques associés à sa présence lors d'une résection hépatique ou d'une chirurgie abdominale non hépatique. Enfin, il propose une approche multidisciplinaire, associant les chirurgiens, les hépatologues, les anatomopathologistes et les anesthésistes-réanimateurs.