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1.  Prognosis of schizophrenia in persons with and without a history of cannabis use 
Psychological Medicine  2014;44(12):2513-2521.
Background
The aim of the study was to determinate whether schizophrenia patients with a history of cannabis use have a different prognosis, with regards to readmission and hospital duration, compared with those without a history of cannabis use.
Method
The present investigation was a cohort study of 50 087 Swedish men with data on cannabis use at the ages of 18–20 years. A total of 357 cases of schizophrenia were identified from in-patient care and followed up from 1973 to 2007.
Results
Schizophrenia patients with a history of cannabis use had a higher median duration of first hospital episode (59 days v. 30 days). Patients with a history of cannabis use had a higher median rate of readmission (10 times v. four times). Also, total number of hospital days was higher in patients with a history of cannabis use compared with those without (547 days v. 184 days). Patients with a history of cannabis use had an increased odds of having more than 20 hospital readmissions compared with non-users [3.1, 95% confidence interval (CI) 1.3–7.3] as well as an increased odds of hospital admission lasting more than 2 years (2.4, 95% CI 1.1–7.4) after controlling for diagnosis of personality disorders, family socio-economic position, IQ score, civil status, place of residence, risky use of alcohol and use of other drugs. Patients with a history of cannabis use were less likely to have paranoid schizophrenia compared with never users (8% v. 17%) in the first admission.
Conclusions
Schizophrenia patients with a history of cannabis use had a significantly higher burden of lifetime in-patient care than non-cannabis users. Not only does cannabis increase the risk of schizophrenia, but also our findings indicate that the course and prognosis of schizophrenia may be more severe than schizophrenia cases in general.
doi:10.1017/S0033291714000191
PMCID: PMC4108251  PMID: 25055170
Cannabis; prognosis; psychosis; schizophrenia
2.  HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease 
Annals of internal medicine  2013;158(9):658-666.
Background
Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown.
Objective
To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.
Design
Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.
Setting
Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.
Participants
1176 current and former injection drug users with antibodies to HCV.
Measurements
Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels.
Results
Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older.
Limitation
The process of liver fibrosis began before the study in most persons.
Conclusion
In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.
doi:10.7326/0003-4819-158-9-201305070-00604
PMCID: PMC3708651  PMID: 23440167
3.  The Effect of Cannabis Use and Cognitive Reserve on Age at Onset and Psychosis Outcomes in First-Episode Schizophrenia 
Schizophrenia Bulletin  2011;38(4):873-880.
Objective: Cannabis use is associated with a younger age at onset of psychosis, an indicator of poor prognosis, but better cognitive function, a positive prognostic indicator. We aimed to clarify the role of age at onset and cognition on outcomes in cannabis users with first-episode schizophrenia as well as the effect of cannabis dose and cessation of use.
Methods: Ninety-nine patients without alcohol or substance abuse other than cannabis were divided into lifetime users and never-users of cannabis and compared on measures of premorbid function, cognition, and clinical outcome.
Results: Cannabis users demonstrated better cognition at psychosis onset, which was explained by higher premorbid IQ. They also showed better social function and neither measure changed over the subsequent 15 months. Cannabis users had an earlier age at onset of psychosis, and there was a strong linear relationship between age at first cannabis use and age at onset of both prodromal and psychotic symptoms. Cannabis use spontaneously declined over time with 3-quarters of users giving up altogether. Later age at first cannabis use predicted earlier cessation of use and this in turn was linked to fewer positive psychotic symptoms and days in hospital during the first 2 years.
Conclusions: Cannabis use brings forward the onset of psychosis in people who otherwise have good prognostic features indicating that an early age at onset can be due to a toxic action of cannabis rather than an intrinsically more severe illness. Many patients abstain over time, but in those who persist, psychosis is more difficult to treat.
doi:10.1093/schbul/sbq153
PMCID: PMC3406524  PMID: 21389110
cognition; prognosis; longitudinal
4.  Factors associated with the progression of fibrosis on liver biopsy in Alaska Native and American Indian persons with chronic hepatitis C 
BACKGROUND:
Various factors influence the development and rate of fibrosis progression in chronic hepatitis C virus (HCV) infection.
OBJECTIVES:
To examine factors associated with fibrosis in a long-term outcomes study of Alaska Native/American Indian persons who underwent liver biopsy, and to examine the rate of fibrosis progression in persons with subsequent biopsies.
METHODS:
A cross-sectional analysis of the demographic, inflammatory and viral characteristics of persons undergoing liver biopsy compared individuals with early (Ishak fibrosis score of lower than 3) with those with advanced (Ishak score of 3 or greater) fibrosis. Persons who underwent two or more biopsies were analyzed for factors associated with fibrosis progression.
RESULTS:
Of 253 HCV RNA-positive persons who underwent at least one liver biopsy, 76 (30%) had advanced fibrosis. On multivariate analysis, a Knodell histological activity index score of 10 to 14 and an alpha-fetoprotein level of 8 ng/mL or higher were found to be independent predictors of advanced liver fibrosis (P<0.0001 for each). When surrogate markers of liver inflammation (alanine aminotransferase, aspartate aminotransferase/alanine aminotransferase ratio and alpha-fetoprotein) were removed from the model, type 2 diabetes mellitus (P=0.001), steatosis (P=0.03) and duration of HCV infection by 10-year intervals (P=0.02) were associated with advanced fibrosis. Among 52 persons who underwent two or more biopsies a mean of 6.2 years apart, the mean Ishak fibrosis score increased between biopsies (P=0.002), with progression associated with older age at initial biopsy and HCV risk factors.
CONCLUSIONS:
The presence of type 2 diabetes mellitus, steatosis and duration of HCV infection were independent predictors of advanced fibrosis in the present cohort, with significant fibrosis progression demonstrated in persons who underwent serial biopsies.
PMCID: PMC2918486  PMID: 20652161
Hepatitis C; Liver fibrosis; Liver steatosis
5.  Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study 
Gut  2004;53(3):451-455.
Background: The natural history of hepatitis C virus (HCV) infection remains uncertain. Previous data concerning rates of progression are from studies using estimated dates of infection and single liver biopsy scores. We prospectively studied the rate of progression of fibrosis in HCV infected patients by repeat liver biopsies without intervening treatment.
Patients: We studied 214 HCV infected patients (126 male; median age 36 years (range 5–8)) with predominantly mild liver disease who were prospectively followed without treatment and assessed for risk factors for progression of liver disease. Interbiopsy interval was a median of 2.5 years. Paired biopsies from the same patient were scored by the same pathologist.
Results: Seventy of 219 (33%) patients showed progression of at least 1 fibrosis point in the Ishak score; 23 progressed at least 2 points. Independent predictors of progression were age at first biopsy and any fibrosis on first biopsy. Factors not associated with progression were: necroinflammation, duration of infection, alcohol consumption, alanine aminotransferase levels, current or past hepatitis B virus infection, ferritin, HCV genotype, and steatosis or iron deposition in the initial biopsy.
Conclusions: One third of patients with predominantly mild hepatitis C showed significant fibrosis progression over a median period of 30 months. Histologically, mild hepatitis C is a progressive disease. The overall rate of fibrosis progression in patients with hepatitis C was low but increased in patients who were older or had fibrosis on their index biopsy. These data suggest that HCV infection will place an increasing burden on health care services in the next 20 years.
doi:10.1136/gut.2003.021691
PMCID: PMC1773967  PMID: 14960533
hepatitis C virus; fibrosis; hepatic fibrosis
6.  Relationship Between Alcohol Use Categories and Noninvasive Markers of Advanced Hepatic Fibrosis in HIV-Infected, Chronic Hepatitis C Virus–Infected, and Uninfected Patients 
Advanced hepatic fibrosis was present with nonhazardous alcohol consumption and increased with higher alcohol use categories across groups stratified by HIV and chronic hepatitis C virus (HCV) status. All alcohol use categories were strongly associated with advanced hepatic fibrosis in HIV/HCV-coinfected patients.
Background. It is unclear if the risk of liver disease associated with different levels of alcohol consumption is higher for patients infected with human immunodeficiency virus (HIV) or chronic hepatitis C virus (HCV). We evaluated associations between alcohol use categories and advanced hepatic fibrosis, by HIV and chronic HCV status.
Methods. We performed a cross-sectional study among participants in the Veterans Aging Cohort Study who reported alcohol consumption at enrollment (701 HIV/HCV-coinfected; 1410 HIV-monoinfected; 296 HCV-monoinfected; 1158 HIV/HCV-uninfected). Alcohol use category was determined by the Alcohol Use Disorders Identification Test–Consumption (AUDIT-C) questionnaire and alcohol-related diagnoses and was classified as nonhazardous drinking, hazardous/binge drinking, or alcohol-related diagnosis. Advanced hepatic fibrosis was defined by FIB-4 index >3.25.
Results. Within each HIV/HCV group, the prevalence of advanced hepatic fibrosis increased as alcohol use category increased. For each alcohol use category, advanced hepatic fibrosis was more common among HIV-infected than uninfected (nonhazardous: 6.7% vs 1.4%; hazardous/binge: 9.5% vs 3.0%; alcohol-related diagnosis: 19.0% vs 8.6%; P < .01) and chronic HCV-infected than uninfected (nonhazardous: 13.6% vs 2.5%; hazardous/binge: 18.2% vs 3.1%; alcohol-related diagnosis: 22.1% vs 6.5%; P < .01) participants. Strong associations with advanced hepatic fibrosis (adjusted odds ratio [95% confidence interval]) were observed among HIV/HCV-coinfected patients with nonhazardous drinking (14.2 [5.91–34.0]), hazardous/binge drinking (18.9 [7.98–44.8]), and alcohol-related diagnoses (25.2 [10.6–59.7]) compared with uninfected nonhazardous drinkers.
Conclusions. Advanced hepatic fibrosis was present at low levels of alcohol consumption, increased with higher alcohol use categories, and was more prevalent among HIV-infected and chronic HCV-infected patients than uninfected individuals. All alcohol use categories were strongly associated with advanced hepatic fibrosis in HIV/HCV-coinfected patients.
doi:10.1093/cid/ciu097
PMCID: PMC4001286  PMID: 24569533
alcohol; liver fibrosis; HIV; hepatitis C; FIB-4
7.  Approach-Bias Predicts Development of Cannabis Problem Severity in Heavy Cannabis Users: Results from a Prospective FMRI Study 
PLoS ONE  2012;7(9):e42394.
A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.
doi:10.1371/journal.pone.0042394
PMCID: PMC3434213  PMID: 22957019
8.  Cannabis Withdrawal Symptoms in Non-Treatment-Seeking Adult Cannabis Smokers 
Drug and alcohol dependence  2010;111(1-2):120-127.
Background
Cannabis withdrawal is not recognized in DSM-IV because of doubts about its clinical significance.
Objectives
Assess the phenomenon of cannabis withdrawal and its relationship to relapse in non-treatment-seeking adults.
Subjects
Convenience sample of 469 adult cannabis smokers who had made a quit attempt while not in a controlled environment.
Methods
Subjects completed a 176-item Marijuana Quit Questionnaire collecting information on sociodemographic characteristics, cannabis use history, and their “most difficult” cannabis quit attempt.
Results
42.4% of subjects had experienced a lifetime withdrawal syndrome, of whom 70.4% reported using cannabis in response to withdrawal. During the index quit attempt, 95.5% of subjects reported ≥1 individual withdrawal symptom (mean [SD] 9.5 [6.1], median 9.0); 43.1% reported ≥10. Number of withdrawal symptoms was significantly associated with greater frequency and amount of cannabis use, but symptoms occurred even in those using less than weekly. Symptoms were usually of ≥ moderate intensity and often prompted actions to relieve them. Alcohol (41.5 %) and tobacco (48.2%) were used more often than cannabis (33.3%) for this purpose. There was little change during withdrawal in use of other legal or illegal substances.
Conclusions
Cannabis withdrawal is a common syndrome among adults not seeking treatment. The intention to relieve withdrawal symptoms can drive relapse during quit attempts, giving cannabis withdrawal clinical significance as a target of treatment.
doi:10.1016/j.drugalcdep.2010.04.010
PMCID: PMC2930056  PMID: 20510550
cannabis; marijuana; withdrawal; tolerance; relapse
9.  Association of Cannabis Use with Opioid Outcomes among Opioid-Dependent Youth 
Drug and alcohol dependence  2013;132(0):342-345.
Objective
Cannabis use is common among opioid-dependent patients, but studies of its association with treatment outcome are mixed. In this secondary analysis, the association of cannabis use with opioid treatment outcome is assessed.
Methods
In the main study, participants (N=152) aged 15-21 years were randomized to receive psychosocial treatments and either a 12-week course of buprenorphine-naloxone with a dose taper to zero in weeks 9-12, or a 2-week detoxification with buprenorphine-naloxone. Drug use was assessed by self-report and urine drug screen at baseline and during study weeks 1-12. The association between cannabis and opioid use at weeks 4, 8, and 12 was examined using logistic regression models.
Results
Participants reported a median of 3.0 days (range=0-30) cannabis use in the past month; half (50.3%; n=77) reported occasional use, one-third reported no use (33.1%; n=50), and one-sixth reported daily cannabis use (16.6%; n=25). Median lifetime cannabis use was 4.0 years (range=0-11) and median age of initiation of use was 15.0 years (range 9-21). Neither past cannabis use (age of initiation and use in the month prior to baseline) nor concurrent use was associated with level of opioid use.
Conclusions
Overall, cannabis use had no association with opioid use over 12 weeks in this sample of opioid-dependent youth. While cannabis use remains potentially harmful, it was not a predictor of poor opioid treatment outcome.
doi:10.1016/j.drugalcdep.2013.02.030
PMCID: PMC3724203  PMID: 23528523
cannabis use; opioid dependence; buprenorphine; adolescent substance abuse
10.  Hepatitis C Disease Severity in Living Versus Deceased Donor Liver Transplant Recipients: An Extended Observation Study 
Hepatology (Baltimore, Md.)  2014;59(4):1311-1319.
Donor factors influence hepatitis C virus (HCV) disease severity in liver transplant (LT) recipients. Living donors, because they are typically young and have short cold ischemic times, may be advantageous for HCV-infected patients. Among HCV-infected patients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) surviving >90 days and followed for a median 4.7 years, advanced fibrosis (Ishak stage ≥3) and graft loss were determined. The 5-year cumulative risk of advanced fibrosis was 44% and 37% in living donor LT (LDLT) and deceased donor LT (DDLT) patients (P = 0.16), respectively. Aspartate aminotransferase (AST) activity at LT (hazard ratio [HR] = 1.38 for doubling of AST, P = 0.005) and biliary strictures (HR = 2.68, P = 0.0001) were associated with advanced fibrosis, but LDLT was not (HR = 1.11, 95% confidence interval [CI] 0.73-1.69, P = 0.63). The 5-year unadjusted patient and graft survival probabilities were 79% and 78% in LDLT, and 77% and 75% in DDLT (P = 0.43 and 0.32), with 27% and 20% of LDLT and DDLT graft losses due to HCV (P = 0.45). Biliary strictures (HR = 2.25, P = 0.0006), creatinine at LT (HR = 1.74 for doubling of creatinine, P = 0.0004), and AST at LT (HR = 1.36 for doubling of AST, P = 0.004) were associated with graft loss, but LDLT was not (HR = 0.76, 95% CI: 0.49-1.18, P = 0.23).
Conclusion
Donor type does not affect the probability of advanced fibrosis or patient and graft survival in HCV-infected recipients. Thus, while LDLT offers the advantage of shorter wait times, there is no apparent benefit for HCV disease progression. Biliary strictures have a negative effect on HCV fibrosis severity and graft survival, and a high AST at LT may be an important predictor of fibrosis risk post-LT.
doi:10.1002/hep.26920
PMCID: PMC4118586  PMID: 24677192
11.  Association between age at onset of psychosis and age at onset of cannabis use in non-affective psychosis 
Schizophrenia research  2012;139(1-3):157-160.
Introduction
Several studies have associated cannabis use with the development of schizophrenia. However, it has been difficult to disentangle the effects of cannabis from that of other illicit drugs, as previous studies have not evaluated pure cannabis users. To test whether the onset of cannabis use had an effect on the initiation of psychosis, we examined the time relationship between onset of use and onset of psychosis, restricting our analysis to a cohort of individuals who only used cannabis and no other street drugs.
Methods
Fifty seven subjects with non-affective psychoses who used cannabis prior to developing a psychosis were interviewed using the Diagnostic Interview for Genetic Studies (DIGS). The Family Interview for Genetic Studies (FIGS) was also used to interview a family informant about psychiatric illness in the patient and the entire family. Multiple linear regression techniques were used to estimate the association between variables.
Results
After adjusting for potential confounding factors such as sex, age, lifetime diagnosis of alcohol abuse or dependence, and family history of schizophrenia, the age at onset of cannabis was significantly associated with age at onset of psychosis (β=0.4, 95% CI=0.1–0.7, p=0.004) and age at first hospitalization (β=0.4, 95% CI=0.1–0.8, p=0.008). The mean time between beginning to use cannabis and onset of psychosis was 7.0±4.3. Age at onset of alcohol use was not associated with age at onset of psychosis or age at first hospitalization.
Conclusion
Age at onset of cannabis is directly associated with age at onset of psychosis and age at first hospitalization. These associations remain significant after adjusting for potential confounding factors and are consistent with the hypothesis that cannabis could cause or precipitate the onset of psychosis after a prolonged period of time.
doi:10.1016/j.schres.2012.06.007
PMCID: PMC3415971  PMID: 22727454
cannabis; psychosis; age; sex; schizophrenia
12.  Adolescent cannabis and tobacco use and educational outcomes at age 16: birth cohort study 
Addiction (Abingdon, England)  2015;110(4):658-668.
Aims
To investigate the relationship between cannabis and tobacco use by age 15 and subsequent educational outcomes.
Design
Birth cohort study.
Setting
England.
Participants
The sample was drawn from the Avon Longitudinal Study of Parents and Children; a core sample of 1155 individuals had complete information on all the variables.
Measurements
The main exposures were cannabis and tobacco use at age 15 assessed in clinic by computer-assisted questionnaire and serum cotinine. The main outcomes were performance in standardized assessments at 16 [Key Stage 4, General Certificate of Secondary Education (GCSE)] in English and mathematics (mean scores), completion of five or more assessments at grade C level or higher and leaving school having achieved no qualifications. Analyses were sequentially adjusted for multiple covariates using a hierarchical approach. Covariates considered were: maternal substance use (ever tobacco or cannabis use, alcohol use above recommended limits); life course socio-economic position (family occupational class, maternal education, family income); child sex; month and year of birth; child educational attainment prior to age 11 (Key Stage 2); child substance use (tobacco, alcohol and cannabis) prior to age 15 and child conduct disorder.
Findings
In fully adjusted models both cannabis and tobacco use at age 15 were associated with subsequent adverse educational outcomes. In general, the dose–response effect seen was consistent across all educational outcomes assessed. Weekly cannabis use was associated negatively with English GCSE results [grade point difference (GPD), –5.93, 95% confidence interval (CI) = –8.34, –3.53] and with mathematics GCSE results (GPD, –6.91, 95% CI = –9.92, –3.89). Daily tobacco smoking was associated negatively with English GCSE (GPD, –11.90, 95% CI = –13.47, –10.33) and with mathematics GCSE (GPD, –16.72, 95% CI = –18.57, –14.86). The greatest attenuation of these effects was seen on adjustment for other substance use and conduct disorder. Following adjustment, tobacco appeared to have a consistently stronger effect than cannabis.
Conclusions
Both cannabis and tobacco use in adolescence are associated strongly with subsequent adverse educational outcomes. Given the non-specific patterns of association seen and the attenuation of estimates on adjustment, it is possible that these effects arise through non-causal mechanisms, although a causal explanation cannot be discounted. © 2015 Society for the Study of Addiction
doi:10.1111/add.12827
PMCID: PMC4405050  PMID: 25488831
ALSPAC; cannabis use; cotinine; education; English; GCSE; mathematics; school dropout; smoking
13.  Laser Captured Hepatocytes Show Association of BCHE Loss and Fibrosis Progression in Hepatitis C Infected Drug Users 
Hepatology (Baltimore, Md.)  2012;56(2):544-554.
Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with pre-cirrhotic liver fibrosis (Ishak fibrosis 3–5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in pre-cirrhotic fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity were already decreased at study inception in 19 fibrosis progressors compared to 20 fibrosis non-progressors (p<0.05). Non-progressors also had decreased BCHE activity over time compared to initial values, but these evolved a median (range) 8.6 (7.8–11.4) years after the study period inception(p<0.05). Laser captured portal tracts were enriched for immune related genes when compared to hepatocytes but pre-cirrhotic livers lost this enrichment.
Conclusion
Overall, we found that chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users.
doi:10.1002/hep.25655
PMCID: PMC3388175  PMID: 22331678
butyrylcholinesterase; Hepacivirus; chronic HCV infection; laser capture microdissection; portal tract
14.  Relations of Pre-Onset Cannabis, Alcohol, and Tobacco Use with the Age at Onset of Prodrome and Age at Onset of Psychosis in First-Episode Patients 
The American journal of psychiatry  2009;166(11):1251-1257.
Objective
Several reports suggest that cannabis use is associated with an earlier age at onset of psychosis, though not all studies have operationalized cannabis use as occurring prior to onset of symptoms. This study addressed whether pre-onset cannabis use (and alcohol and tobacco use) is associated with an earlier age at onset of prodromal and psychotic symptoms. Additionally, effects of the progression of frequency of use were examined through time-dependent covariates in survival analyses.
Method
First-episode patients (n=109) hospitalized in two public-sector inpatient psychiatric units underwent in-depth cross-sectional/retrospective assessments. Prior substance use and ages at onset of prodromal and psychotic symptoms were determined using standardized methods. Cox regression modeling was conducted.
Results
Whereas classifying participants according to maximum frequency of use prior to onset (none, ever, weekly, or daily) revealed no significant effects of cannabis or tobacco use on risk of onset, analysis of change in frequency of use prior to onset indicated that progression to daily cannabis and tobacco use was associated with increased risk of onset of psychotic symptoms. Similar or even stronger effects were observed when onset of illness/prodromal symptoms was the outcome. A gender by daily cannabis use interaction was observed—progression to daily use resulted in a much larger increased relative risk of onset of psychosis in females than males.
Conclusions
Pre-onset cannabis use may hasten the onset of psychotic as well as prodromal symptoms. Age at onset is a key prognostic factor in schizophrenia, and discovering modifiable predictors of age at onset is crucial.
doi:10.1176/appi.ajp.2009.09030311
PMCID: PMC3662470  PMID: 19797432
Alcohol; Cannabis; First-episode psychosis; Marijuana; Nicotine; Prodrome; Schizophrenia; Substance abuse; Tobacco
15.  Hepatitis C Virus Infection in San Francisco's HIV-infected Urban Poor 
OBJECTIVE
To measure Hepatitis C Virus (HCV) prevalence, incidence, and initiation of HCV therapy in a representative HIV-infected cohort of the urban poor.
DESIGN
Cohort analysis.
SETTING
The Research and Access to Care for the Homeless (REACH) Cohort is a systematic sample of HIV-infected marginally housed individuals identified from single-room occupancy hotels, homeless shelters, and free lunch programs in San Francisco.
PARTICIPANTS
Two hundred forty-nine participants with 28.9 months (median) of follow-up were studied. Mean age was 44 (range 24 to 75, standard deviation 8.4) years. Eighty-two percent were male, 43% were African-American, 64% were lifetime injection drug users, and 24% had been on the street or in a shelter in the prior month.
INTERVENTIONS
We measured HCV testing and treatment history with structured interviews; additionally, participants were tested for HCV antibodies (EIA-2) with RNA viral load confirmation.
MAIN RESULTS
At baseline, 172 (69.1%) were HCV-positive and 182 (73.1%) were HCV-positive at follow-up, including 155 (62.2%) with viremia. HCV-positive status was associated with having injected drugs, elevated serum alanine aminotransferase, homelessness in the last 1 year, and more severe depressive symptoms. The incidence of new HCV infection was 4.63% per person-year (ppy; 95% confidence interval, 2.31 to 8.13) in the entire cohort and 16.77% ppy among injection drug users. The prevalence of HCV antibody-negative HCV-viremia was 13.2% (10/76). Nonwhites were less likely to receive HCV testing and subspecialty referral, controlled for drug use and other confounders. Sixty-eight percent (123/182) were aware treatment was available; however, only 3.8% (7/182) or 1.16% ppy received HCV treatment.
CONCLUSIONS
While HCV infection is common, HCV treatment is rare in the HIV-HCV coinfected urban poor. Urban poor, nonwhite individuals are less likely to receive HCV testing and subspecialty referral than their white counterparts. Antibody-negative infection may complicate screening and diagnosis in HIV-infected persons.
doi:10.1111/j.1525-1497.2004.30613.x
PMCID: PMC1492202  PMID: 15061745
hepatitis C; HIV infection; HIV/HCV coinfection; HCV treatment; homelessness
16.  Depression Symptoms Associated with Cannabis Dependence in an Adolescent American Indian Community Sample 
Background
Depression and substance use disorders, including cannabis dependence, arise during adolescence, are frequently co-morbid, and represent major health burdens in the general U.S. population. Yet little is known about the association of depression symptoms with cannabis and other substance use and use disorders in Native American adolescents.
Objective
To investigate the comorbidity of cannabis use and depression symptoms in Native American adolescents.
Methods
This study used the Children’s Semi-Structured Assessment for the Genetics of Alcoholism (Adolescent Version) to obtain lifetime DSM-III-R diagnoses from a community sample of 202 (98 boys, 104 girls) American Indian adolescents living on contiguous reservations.
Results
Thirteen percent of boys and 38% of girls had a lifetime DSM-III-R major depression disorder (MDD) independent of substance use. Fifteen percent of boys and 41% of girls had a major depression episode (MDE) either coincident with or independent of cannabis use. MDE and several individual depression symptoms were significantly associated with cannabis dependence in boys but not in girls. The median ages of onset of MDE were the same in the boys and girls who had experienced both depression and cannabis use.
Conclusions
These findings suggest that the association of depression with cannabis dependence is more significant in boys than girls in this population of adolescents.
Scientific Significance
Understanding co-morbidity between depression and cannabis use is important in order to disentangle the etiological relationship between the two and also for designing more effective treatment and prevention strategies, particularly in Native Americans who are at high risk for both disorders.
doi:10.1111/j.1521-0391.2012.00281.x
PMCID: PMC3498983  PMID: 23082832
17.  HIV Mono-infection Is Associated With FIB-4 – A Noninvasive Index of Liver Fibrosis – in Women 
Predictors of liver fibrosis were evaluated in women using a noninvasive index (FIB-4). HIV RNA levels were associated with increased FIB-4 in the absence of viral hepatitis, alcohol use, or antiretroviral therapy. These data complement evidence suggesting a potential relationship between HIV infection and hepatic fibrosis.
Background. FIB-4 represents a noninvasive, composite index that is a validated measure of hepatic fibrosis, which is an important indicator of liver disease. To date, there are limited data regarding hepatic fibrosis in women.
Methods. FIB-4 was evaluated in a cohort of 1227 women, and associations were evaluated in univariate and multivariate regression models among 4 groups of subjects classified by their human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection status.
Results. The median FIB-4 scores were 0.60 in HIV-/HCV- women, 0.83 in HIV-/HCV+ women, 0.86 in HIV+/HCV- women, and 1.30 in HIV+/HCV+ women. In the HIV/HCV co-infected group, multivariate analysis showed that CD4+ cell count and albumin level were negatively associated with FIB-4 (P <.0001), whereas antiretroviral therapy (ART) was positively associated with FIB-4 score (P =.0008). For the HIV mono-infected group, multivariate analysis showed that CD4+ cell count (P <.0001) and albumin level (P =.0019) were negatively correlated with FIB-4 score, ART was positively associated with FIB-4 score (P =.0008), and plasma HIV RNA level was marginally associated with FIB-4 score (P =.080). In 72 HIV mono-infected women who were also hepatitis B surface antigen negative, ART naive, and reported no recent alcohol intake, plasma HIV RNA level was associated with increased FIB-4 score (P =.030).
Conclusions. HIV RNA level was associated with increased FIB-4 score in the absence of hepatitis B, hepatitis C, ART, or alcohol use, suggesting a potential relationship between HIV infection and hepatic fibrosis in vivo. A better understanding of the various demographic and virologic variables that contribute to hepatic fibrosis may lead to more effective treatment of HIV infection and its co-morbid conditions.
doi:10.1093/cid/ciq199
PMCID: PMC3106241  PMID: 21248367
18.  Probability and Predictors of Transition from Abuse to Dependence on Alcohol, Cannabis, and Cocaine: Results from the National Epidemiologic Survey on Alcohol and Related Conditions 
Background:
Little is known about the transition from substance abuse to substance dependence. Objectives: This study aims to estimate the cumulative probability of developing dependence and to identify predictors of transition to dependence among individuals with lifetime alcohol, cannabis, or cocaine abuse.
Methods:
Analyses were done for the subsample of individuals with lifetime alcohol abuse (n = 7802), cannabis abuse (n = 2832), or cocaine abuse (n = 815) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Estimated projections of the cumulative probability of transitioning from abuse to dependence were obtained by the standard actuarial method. Discrete-time survival analyses with time-varying covariates were implemented to identify predictors of transition to dependence.
Results:
Lifetime cumulative probability estimates indicated that 26.6% of individuals with alcohol abuse, 9.4% of individuals with cannabis abuse, and 15.6% of individuals with cocaine abuse transition from abuse to dependence at some point in their lives. Half of the transitions of alcohol, cannabis, and cocaine dependence occurred approximately 3.16, 1.83, and 1.42 years after abuse onset, respectively. Several sociodemographic, psychopathological, and substance use-related variables predicted transition from abuse to dependence for all of the substances assessed.
Conclusion:
The majority of individuals with abuse do not transition to dependence. Lifetime cumulative probability of transition from abuse to dependence was highest for alcohol, followed by cocaine and lastly cannabis. Time from onset of abuse to dependence was shorter for cocaine, followed by cannabis and alcohol. Although some predictors of transition were common across substances, other predictors were specific for certain substances.
doi:10.3109/00952990.2013.772618
PMCID: PMC3755735  PMID: 23721532
transition; abuse; dependence; cannabis; alcohol; cocaine
19.  Impact of lifetime alcohol use on liver fibrosis in a population of HIV-infected patients with and without hepatitis C coinfection 
Background
The effect of alcohol on liver disease in HIV infection has not been well characterized.
Methods
We performed a cross-sectional multivariable analysis of the association between lifetime alcohol use and liver fibrosis in a longitudinal cohort of HIV-infected patients with alcohol problems. Liver fibrosis was estimated with two non-invasive indices, “FIB-4”, which includes platelets, liver enzymes, and age; and “APRI”, which includes platelets and liver enzymes. FIB-4<1.45 and APRI<0.5 defined absence of liver fibrosis. FIB-4>3.25 and APRI>1.5 defined advanced liver fibrosis. The main independent variable was lifetime alcohol consumption (<150 kg, 150–600kg, >600 kg).
Results
Subjects (n=308) were 73% male, mean age 43 years, 49% with hepatitis C virus (HCV) infection, 60% on antiretroviral therapy, 49% with an HIV RNA load<1000 copies/mL, and 18.7% with a CD4 count<200 cells/mm3. Forty-five percent had lifetime alcohol consumption >600 kg, 32.7% 150–600 kg, and 22.3% <150 kg; 33% had current heavy alcohol use, and 69% had >9 years of heavy episodic drinking. Sixty-one percent had absence of liver fibrosis and 10% had advanced liver fibrosis based on FIB-4. In logistic regression analyses controlling for age, gender, HCV infection, and CD4 count, no association was detected between lifetime alcohol consumption and absence of liver fibrosis (FIB-4<1.45) [adjusted odds ratio (AOR)=1.12 (95%CI:0.25–2.52) for 150–600 kg versus <150 kg; AOR=1.11 (95%CI:0.52–2.36) for >600 kg vs. <150 kg; global p=0.95]. Additionally, no association was detected between lifetime alcohol use and advanced liver fibrosis (FIB-4>3.25). Results were similar using APRI, and among those with and without HCV infection.
Conclusions
In this cohort of HIV-infected patients with alcohol problems, we found no significant association between lifetime alcohol consumption and absence of liver fibrosis or the presence of advanced liver fibrosis, suggesting that alcohol may be less important than other known factors that promote liver fibrosis in this population.
doi:10.1111/acer.12129
PMCID: PMC3758457  PMID: 23647488
alcohol; HIV; Hepatitis C virus; liver fibrosis
20.  Steatohepatitis: Risk Factors and Impact on Disease Severity in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection 
Hepatology (Baltimore, Md.)  2008;47(4):1118-1127.
Hepatic steatosis has been reported in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. However, the features of steatohepatitis, including cytologic ballooning and pericellular fibrosis, its risk factors, and the impact on disease severity in such patients are unknown. To assess this, we prospectively reviewed liver histology in consecutive coinfected patients to define the prevalence and severity of the features of steatohepatitis, its risk factors, and its impact on the severity of liver disease. A total of 222 subjects (74% male, mean age 45, 78% African American, 90% genotype 1) were studied. The mean body mass index (BMI) was 26, and 18% had a BMI >30. The prevalence of risk factors for steatosis were: diabetes (31%), hypertension (15%), dyslipidemia (8%), metabolic syndrome (9%), and alcohol abuse (21%). Steatosis was present in 23% and steatohepatitis was present in 17%. The steatosis was mild (5%–33%) in 19%, and moderate to severe (>33%) in 4%. Cytologic ballooning and pericellular fibrosis were present in 30% and 13%, respectively. The mean Ishak score was 6.9, and 33% had bridging fibrosis or cirrhosis. Both steatosis and cytologic ballooning were associated with BMI, metabolic syndrome, and insulin resistance, and presence of either was strongly associated with advanced fibrosis (P < 0.0001). By multiple logistic regressions, the following associations were identified: increased BMI, diabetes, and genotype 3 with steatosis; diabetes with cytologic ballooning; and longer duration of infection with steatohepatitis.
Conclusion
Steatosis and steatohepatitis are present in 23% and 30%, respectively, of patients with HIV/HCV coinfection, and both are associated with an increased risk of having advanced fibrosis. Although we did identify genotype 3, increased BMI, and diabetes as risk factors, we found no independent association with antiretroviral therapy.
doi:10.1002/hep.22134
PMCID: PMC2394857  PMID: 18366118
21.  Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)* 
Drug and alcohol dependence  2010;115(1-2):120-130.
Background
This study aims to estimate general and racial-ethnic specific cumulative probability of developing dependence among nicotine, alcohol, cannabis or cocaine users, and to identify predictors of transition to substance dependence.
Methods
Analyses were done for the subsample of lifetime nicotine (n=15,918), alcohol (n=28,907), cannabis (n=7,389) or cocaine (n=2,259) users who participated in the first and second wave of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Discrete-time survival analyses were implemented to estimate the cumulative probability of transitioning from use to dependence and to identify predictors of transition to dependence.
Results
The cumulative probability estimate of transition to dependence was 67.5% for nicotine users, 22.7% for alcohol users, 20.9% for cocaine users, and 8.9% for cannabis users. Half of the cases of dependence on nicotine, alcohol, cannabis and cocaine were observed approximately 27, 13, 5 and 4 years after use onset, respectively. Significant racial-ethnic differences were observed in the probability of transition to dependence across the four substances. Several predictors of dependence were common across the four substances assessed.
Conclusions
Transition from use to dependence was highest for nicotine users, followed by cocaine, alcohol and cannabis users. Transition to cannabis or cocaine dependence occurred faster than transition to nicotine or alcohol dependence. The existence of common predictors of transition dependence across substances suggests that shared mechanisms are involved. The increased risk of transition to dependence among individuals from minorities or those with psychiatric or dependence comorbidity highlights the importance of promoting outreach and treatment of these populations.
doi:10.1016/j.drugalcdep.2010.11.004
PMCID: PMC3069146  PMID: 21145178
nicotine; alcohol; cannabis; cocaine; dependence; racial-ethnic groups; discrete-time time survival analyses
22.  Assessing mortality in women with hepatitis C virus and HIV using indirect markers of fibrosis 
AIDS (London, England)  2012;26(5):599-607.
Objective
Co-infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality in HIV-infected individuals. However, predictors of mortality are poorly defined and most studies have focused predominantly on co-infection in men. We evaluated whether two indirect markers of hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 scores, were predictive of mortality in a well defined longitudinal cohort of HCV/HIV-co-infected women on HAART.
Methods
HCV/HIV-co-infected women on antiretroviral therapy enrolled in Women’s Interagency HIV Study (WIHS), a National Institutes of Health-funded prospective, multicenter, cohort study of women with and at risk for HIV infection were included. Using Cox regression analysis, associations between APRI and FIB-4 with all-cause mortality were assessed.
Results
Four hundred and fifty HCV/HIV-co-infected women, of whom 191 women died, had a median follow-up of 6.6 years and 5739 WIHS visits. Compared with women with low APRI or FIB-4 levels, severe fibrosis was significantly associated with an increased risk of all-cause mortality {APRI: hazard ratio 2.78 [95% confidence interval (CI) 1.87, 4.12]; FIB-4: hazard ratio 2.58 (95% CI 1.68, 3.95)}. Crude death rates per 1000 patient-years increased with increasing liver fibrosis: 34.8 for mild, 51.3 for moderate and 167.9 for severe fibrosis as measured by FIB-4. Importantly, both APRI and FIB-4 increased during the 5 years prior to death for all women: the slope of increase was greater for women dying a liver-related death compared with nonliver-related death.
Conclusion
Both APRI and FIB-4 are independently associated with all-cause mortality in HCV/HIV-co-infected women and may have clinical prognostic utility among women with HIV and HCV.
doi:10.1097/QAD.0b013e32834fa121
PMCID: PMC3698040  PMID: 22156972
fibrosis markers; hepatitis C virus; HIV; longitudinal study; mortality
23.  Age at Initiation of Cannabis Use Predicts Age at Onset of Psychosis: The 7- to 8-Year Trend 
Schizophrenia Bulletin  2013;39(2):251-254.
We investigated the existence of a temporal association between age at initiation of cannabis use and age at onset of psychotic illness in 997 participants from the 2010 Survey of High Impact Psychosis (SHIP) in Australia. We tested for group differences in age at onset of psychotic illness and in the duration of premorbid exposure to cannabis (DPEC). Analyses were repeated in subgroups of participants with a schizophrenia-spectrum disorder (SSD), a diagnosis of lifetime cannabis dependence (LCD), and a comorbid SSD/LCD diagnosis. The association between age at initiation of cannabis use and age at onset of psychotic illness was linear and significant, F(11, 984) = 13.77, P < .001, even after adjusting for confounders. The effect of age at initiation of cannabis use on DPEC was not significant (mean duration of 7.8 years), and this effect was similar in participants with a SSD, LCD, and comorbid SSD/ LCD diagnosis although a shift toward shorter premorbid exposure to cannabis was noted in the SSD/LCD subgroup (mean duration of 7.19 years for SSD/LCD). A temporal direct relationship between age at initiation of cannabis use and age at onset of psychotic illness was detected with a premorbid exposure to cannabis trend of 7–8 years, modifiable by higher severity of premorbid cannabis use and a diagnosis of SSD. Cannabis may exert a cumulative toxic effect on individuals on the pathway to developing psychosis, the manifestation of which is delayed for approximately 7–8 years, regardless of age at which cannabis use was initiated.
doi:10.1093/schbul/sbs188
PMCID: PMC3576149  PMID: 23314189
cannabis; psychosis; schizophrenia; age at onset; causality; DIP; SHIP
24.  A genetic perspective on the proposed inclusion of cannabis withdrawal in the DSM-5 
Psychological medicine  2012;43(8):1713-1722.
Background
Various studies support the inclusion of cannabis withdrawal to the diagnosis of cannabis use disorders in the upcoming DSM-5. The aims of the current study were to (1) estimate the prevalence of DSM-5 cannabis withdrawal (Criterion B), (2) estimate the role of genetic and environmental influences on individual differences in cannabis withdrawal, and (3) determine the extent to which genetic and environmental influences on cannabis withdrawal overlap with those on DSM-IV defined abuse/dependence.
Methods
The sample included 2276 lifetime cannabis-using adult Australian twins. Cannabis withdrawal was defined in accordance with Criterion B of the proposed DSM-5 revisions. Cannabis abuse/dependence was defined as endorsing one or more DSM-IV criteria of abuse or three or more dependence criteria. The classical twin model was used to estimate the genetic and environmental influences on variation in cannabis withdrawal, as well as its covariation with abuse/dependence.
Results
Of all cannabis users 11.9% met criteria for cannabis withdrawal. Around 50% of between-individual variation in withdrawal could be attributed to additive genetic variation, and the rest of the variation was mostly due to non-shared environmental influences. Importantly, the genetic influences on cannabis withdrawal almost completely (99%) overlapped with those on abuse/dependence.
Conclusions
We showed that cannabis withdrawal symptoms exist among cannabis users, and that cannabis withdrawal is moderately heritable. Genetic influences on cannabis withdrawal are the same as those influencing abuse/dependence. These results add to the wealth of literature that recommends the addition of cannabis withdrawal to the diagnosis of DSM-5 cannabis use disorders.
doi:10.1017/S0033291712002735
PMCID: PMC3733446  PMID: 23194657
Cannabis; dependence; abuse; DSM-5; genetics; twins; withdrawal
25.  Simultaneous cannabis and tobacco use and cannabis-related outcomes in young women 
Drug and alcohol dependence  2008;101(1-2):8-12.
Compared to those who reported a lifetime co-occurrence of cannabis and tobacco use, individuals who report simultaneous use of cannabis and tobacco are more likely to also report higher rates of substance-related problems and psychopathology. In a sample of young women, we examine (a) co-occurring use, or whether regular cigarette smoking is associated with increased cannabis involvement and (b) simultaneous use, a special form of co-occurring use where cannabis and cigarettes are typically used on the same occasion to test whether those who use cannabis and tobacco simultaneously are also more likely to report greater cannabis involvement and (c) the extent to which latent genetic and environmental factors contribute to simultaneous use in those with a history of co-occurring cannabis use and regular cigarette smoking. Women (N=3,427) who report regular cigarette smoking are 4.5–9.5 times more likely to report co-occurring cannabis use and other stages of cannabis involvement, including DSM-IV cannabis abuse and dependence. In those women who report co-occurring regular cigarette smoking and lifetime cannabis use (N=1,073), simultaneous use of cannabis and tobacco was associated with increased likelihood of negative cannabis-related outcomes. Simultaneous users were 1.6 times more likely to meet criteria for DSM-IV cannabis abuse, even after controlling for early covariates and for prior stages of cannabis involvement. Simultaneous use was not heritable, and twin similarity was attributable to shared environmental factors (31%). While our study does not determine causality between simultaneous tobacco-cannabis use and cannabis involvement, results indicate that simultaneous use is potentially a marker for more severe psychosocial consequences associated with cannabis use.
doi:10.1016/j.drugalcdep.2008.10.019
PMCID: PMC3021959  PMID: 19081202
Simultaneous use; cannabis; tobacco; abuse; dependence; twin

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