New Journal, Same Ongoing Challenge: Advancing Policies that Promote the Health and Well-Being of Children and Families

The publication of the inaugural issue of the Journal of Applied Research on Children is a notable milestone for its sponsoring organization, CHILDREN AT RISK (www.childrenatrisk.org). With the release of “Volume 1, Number 1,” we as the Co-Editors in Chief would like to take the opportunity to thank the inaugural contributors whose articles follow and to answer the obvious question of “Why publish a new journal?”

The cellular and molecular involvement of glutathione in cisplatin-induced apoptosis

The goal of this study was to investigate the cellular and molecular mechanisms by which glutathione (GSH) is involved in the process of apoptosis induced by cisplatin [cis-diamminedichloroplatinum(II), cis-DDP] in the HL60 human promyelocytic leukemia cell line. The data show that during the onset or induction of apoptosis, GSH levels in cisplatin-treated cells increased 50% compared to control cells. The increase in intracellular GSH was associated with enhanced expression of γ-glutamylcysteine synthetase (γ-GCS), the enzyme that catalyzes the rate- limiting step in the biosynthesis of glutathione. After depletion of intracellular GSH with D,L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of γ-GCS, biochemical and morphological analysis revealed that the mechanism of cell death had switched from apoptosis to necrosis. In contrast, when intracellular GSH was elevated by exposure of cells to a GSH-ethyl-ester and then treatment with cisplatin, no change in the induction and kinetics of apoptosis were observed. However, when cells were exposed to cisplatin before intracellular GSH levels were increased, apoptosis was observed to occur 6 hours earlier compared to cells without GSH elevation. To further examine the molecular aspects of these effects of GSH on the apoptotic process, changes in the expression of bcl-2 and bax, were investigated in cells with depleted and elevated GSH. Using reverse transcription polymerase chain reaction, no significant change in the expression of bcl-2 gene transcripts was observed in cells in either the GSH depleted or elevated state; however, a 75% reduction in GSH resulted in a 40% decrease in the expression of bax gene transcripts. In contrast, a 6-fold increase in GSH increased the expression of bax by 3-fold relative to controls. Similar results were obtained for bax gene expression and protein synthesis by northern analysis and immunoprecipitation, respectively. These results suggest that GSH serves a dual role in the apoptotic process. The first role which is indirect, involves the protection of the cell from extensive damage following exposure to a specific toxicant so as to prevent death by necrosis, possibly by interacting with the DNA damaging agent and/or its active metabolites. The second role involves a direct involvement of GSH in the apoptotic process that includes upregulation of bax expression. ^

Learning What Works: Demonstrating Practice Effectiveness with Children and Families Through Retrospective Investigation

Intensive family preservation services (IFPS), designed to stabilize at-risk families and avert out-of-home care, have been the focus of many randomized, experimental studies. Employing a retrospective “clinical data-mining” (CDM) methodology (Epstein, 2001), this study makes use of available information extracted from client records in one IFPS agency over the course of two years. The primary goal of this descriptive and associational study was to gain a clearer understanding of IFPS service delivery and effectiveness. Interventions provided to families are delineated and assessed for their impact on improved family functioning, their impact on the reduction of family violence, as well as placement prevention. Findings confirm the use of a wide range of services consistent with IFPS program theory. Because the study employs a quasi-experimental, retrospective use of available information, clinical outcomes described cannot be causally attributed to interventions employed as with randomized controlled trials. With regard to service outcomes, findings suggest that family education, empowerment services and advocacy are most influential in placement prevention and in ameliorating unmanageable behaviors in children as well as the incidence of family violence.

Behavioral cognitions and factors related to hepatitis B vaccine acceptance and compliance in a cohort of drug users in Houston, Texas

Purpose. Drug users are a large group of those at highest risk for contracting Hepatitis B (HBV). This study sought to identify predictors of HBV vaccine acceptance and compliance in a cohort of current drug users in Houston, Texas. Perceived severity of HBV, perceived risk of HBV, perceived peer support of HBV vaccine, and perceived benefits of HBV vaccine were also examined assess their relationship to HBV compliance. ^ Methods. A randomized intervention study was conducted in a cohort of current drug users in Houston, Texas. Participants were recruited by community outreach workers from two urban neighborhoods in Houston known for high drug use. Participants were randomized to a standard vaccine schedule group or an accelerated vaccine schedule group. Participants were also randomized to either a standard behavioral intervention group or an enhanced behavioral intervention group designed to increase HBV vaccine acceptance and compliance. Baseline visits included an interview for demographic factors, drug and sexual behaviors, and HBV beliefs; and participants received the first dose of the HBV vaccine and one of the behavioral interventions. ^ Results. Of 1,643 screening participants, 77% accepted the HBV vaccine. Participants ages ≥50 were twice as likely to accept the vaccine. African Americans and less frequent drug users were also significantly more likely to accept the vaccine. Of the 1,259 participants who enrolled in the study, 75% were compliant to the HBV vaccine. Predictors of compliance were found to be race, housing status, and alcohol use. Speedball users were found to be 74% less likely to be compliant the HBV vaccine. None of the behavioral constructs assessed were found to significantly predict HBV compliance. However, additional analyses found that there were significant changes in mean scores of the behavioral concepts when measured at six month follow-up. ^ Conclusion. Results from this study indicate that when offered a free vaccine in the drug user community, a large percentage will be compliant to the vaccine series. The behavioral cognitions commonly used in HBV compliance research need to be extended to accurately fit this cohort. Also, vaccine intervention focus needs to be on reaching the homeless segment of the drug users and the speedball users. ^

Comparison of compliance and immune response of drug users on the standard and accelerated hepatitis B vaccine schedules - Houston, Texas

Despite the availability of hepatitis B vaccine for over two decades, drug users and other high-risk adult populations have experienced low vaccine coverage. Poor compliance has limited efforts to reduce transmission of hepatitis B infection in this population. Evidence suggests that immunological response in drug users is impaired compared to the general population, both in terms of lower seroprotection rates and antibodies levels.^ The current study investigated the effectiveness of the multi-dose hepatitis B vaccine and compared the effect of the standard and accelerated vaccine schedules in a not-in-treatment, drug-using adult population in the city of Houston, USA.^ A population of drug-users from two communities in Houston, susceptible to hepatitis B, was sampled by outreach workers and referral methodology. Subjects were randomized either to the standard hepatitis vaccine schedule (0, 1-, 6-month) or to an accelerated schedule (0, 1-, 2-month). Antibody levels were detected through laboratory analyses at various time-points. The participants were followed for two years and seroconversion rates were calculated to determine immune response.^ A four percent difference in the overall compliance rate was observed between the standard (73%) and accelerated schedules (77%). Logistic regression analyses showed that drug users living on the streets were twice as likely to not complete all three vaccine doses (p=0.028), and current speedball use was also associated with non-completion (p=0.002). Completion of all three vaccinations in the multivariate analysis was also correlated with older age. Drug users on the accelerated schedule were 26% more likely to achieve completion, although this factor was marginally significant (p=0.085).^ Cumulative adequate protective response was gained by 65% of the HBV susceptible subgroup by 12-months and was identical for both the standard and accelerated schedules. Excess protective response (>=100 mIU/mL) occurred with greater frequency at the later period for the standard schedule (36% at 12-months compared to 14% at six months), while the greater proportion of excess protective response for the accelerated schedule occurred earlier (34% at 6 months compared to 18% at 12-months). Seroconversion at the adequate protective response level of 10 mIU/mL was reached by the accelerated schedule group at a quicker rate (62% vs. 49%), and with a higher mean titer (104.8 vs. 64.3 mIU/mL), when measured at six months. Multivariate analyses indicated a 63% increased risk of non-response for older age and confirmed the existence of an accelerating decline in immune response to vaccination manifesting after 40 years (p=0.001). Injecting more than daily was also highly associated with the risk of non-response (p=0.016).^ The substantial increase in the seroprotection rate at six months may be worth the trade-off against the faster antibody titer decrease and is recommended for enhancing compliance and seroconversion. Utilization of the accelerated schedule with the primary objective of increasing compliance and seroconversion rates during the six months after the first dose may confer early protective immunity and reduce the HBV vulnerability of drug users who continue, or have recently initiated, increased high risk drug use and sexual behaviors.^

Antiretroviral therapy adherence and the use of condoms among African American HIV-positive crack cocaine users

Safer sex practices, such as consistent condom use, are essential to reduce HIV transmission. Determining causes and/or co-variants related to the likelihood of participating in high-risk sexual behaviors may allow the content of interventions and treatments to minimize HIV transmission to be tailored more effectively. The goal of this study was to examine whether a relationship exists between consistent condom use among African American HIV-positive crack cocaine users and both (1) the use of antiretroviral therapy, and (2) adherence to antiretroviral therapy regimens. The study population consisted of 390 participants. They were at least 18 years old, African American, HIV-positive, and had used crack cocaine within a month prior to an interview conducted sometime between April, 2004, and September, 2007. Bivariate associations were examined using contingency tables and χ2-statistics. The Mantel-Haenszel method was used to control for confounding. This study found neither a significant relationship between use of antiretroviral therapy and consistent condom use (Odds ratio (OR) = 1.38; 95% Confidence interval (95%CI) = 0.86–2.22), nor an association between antiretroviral therapy adherence and consistent condom use (OR = 1.02, 95%CI = 0.60–1.75). The exception was more consistent condom use when sex was traded for money or drugs in those on antiretroviral therapy, compared to those not on such therapy (OR = 2.28, 95%CI = 1.08–4.85). Further studies examining condom use and HIV treatment adherence are recommended. ^

Promising Practices to Engage Families and Support Family Preservation

The Adoption and Safe Families Act of 1997 (ASFA) is the latest legislation in two decades of important child welfare policy in the United States. The Adoption and Safe Families Act has served to shorten the period of time that caseworkers and families have to show that families are making progress toward family preservation, with permanency decisions being made after 12 months, rather than 18. The importance of engaging and motivating families in services has therefore increased. The practice directive of ASFA can be summarized as 'Act Smart, Fast, and Accountable. " Using findings from largely correlational research, concrete recommendations are made to ensure that practices to preserve families are smart, fast, and accountable, particularly critical given these new timeframes.

Translating Rhetoric to Reality: The Future of Family and Children's Services

These remarks were first prepared by the author for the inauguration of the Marion Elizabeth Blue Endowed Professorship in Children and Families at the University of Michigan School of Social Work. They were delivered on October 5, 1999, and originally appeared as a monograph published by the University of Michigan School of Social Work in December 1999. They are reprinted here by permission.

Involvement of a region of 23S ribosomal RNA of {\it E. coli\/} in decoding of termination codons

Involvement of E. coli 23S ribosomal RNA (rRNA) in decoding of termination codons was first indicated by the characterization of a 23S rRNA mutant that causes UGA-specific nonsense suppression. The work described here was begun to test the hypothesis that more 23S rRNA suppressors of specific nonsense mutations can be isolated and that they would occur non-randomly in the rRNA genes and be clustered in specific, functionally significant regions of rRNA.^ Approximately 2 kilobases of the gene for 23S rRNA were subjected to PCR random mutagenesis and the amplified products screened for suppression of nonsense mutations in trpA. All of the suppressor mutations obtained were located in a thirty-nucleotide part of the GTPase center, a conserved rRNA sequence and structure, and they and others made in that region by site-directed mutagenesis were shown to be UGA-specific in their suppression of termination codon mutations. These results proved the initial hypothesis and demonstrated that a group of nucleotides in this region are involved in decoding of the UGA termination codon. Further, it was shown that limitation of cellular availability or synthesis of L11, a ribosomal protein that binds to the GTPase center rRNA, resulted in suppression of termination codon mutations, suggesting the direct involvement of L11 in termination in vivo.^ Finally, in vivo analysis of certain site-specific mutations made in the GTPase center RNA demonstrated that (a) the G$\cdot$A base pair closing the hexanucleotide hairpin loop was not essential for normal termination, (b) the "U-turn" structure in the 1093 to 1098 hexaloop is critical for normal termination, (c) nucleotides A1095 and A1067, necessary for the binding to ribosomes of thiostrepton, an antibiotic that inhibits polypeptide release factor binding to ribosomes in vitro, are also necessary for normal peptide chain termination in vivo, and (d) involvement of this region of rRNA in termination is determined by some unique subset structure that includes particular nucleotides rather than merely by a general structural feature of the GTPase center.^ This work advances the understanding of peptide chain termination by demonstrating that the GTPase region of 23S rRNA participates in recognition of termination codons, through an associated ribosomal protein and specific conserved nucleotides and structural motifs in its RNA. ^

A novel form of CYP3A from rat brain: cDNA cloning, protein characterization and gene regulation of cytochrome P450 3A9

One full length cDNA clone, designated 3aH15, was isolated from a rat brain cDNA library using a fragment of CYP3A2 cDNA as a probe. 3aH15 encoded a protein composed of 503 amino acid residues. The deduced amino acid sequence of 3aH15 was 92% identical to mouse Cyp3a-13 and had a 68.4% to 76.5% homology with the other reported rat CYP3A sequences. Clone 3aH15 was thus named CYP3A9 by Cytochrome P450 Nomenclature Committee. CYP3A9 seems to the major CYP3A isozyme expressed in rat brain. Sexual dimorphism of the expression of CYP3A9 was shown for the first time in rat brain as well as in rat liver. CYP3A9 appears to be female specific in rat liver based on the standards proposed by Kato and Yamazoe who defined sex specific expression of P450s as being a 10-fold or higher expression level in one sex compared with the other. CYP3A9 gene expression was inducible by estrogen treatment both in male and in female rats. Male rats treated with estrogen had a similar expression level of CYP3A9 mRNA both in the liver and brain. Ovariectomy of adult female rats drastically reduced the mRNA level of CYP3A9 which could be fully restored by estrogen replacement. On the other hand, only a two-fold induction of CYP3A9 expression by dexamethasone was observed in male liver and no significant induction of CYP3A9 mRNA was observed in female liver or in the brains. These results suggest that estrogen may play an important role in the female specific expression of the CYP3A9 gene and that CYP3A9 gene expression is regulated differently from other CYP3A isozymes. ^ P450 3A9 recombinant protein was expressed in E. coli using the pCWOri+ expression vector and the MALLLAVF amino terminal sequence modification. This construct gave a high level of expression (130 nmol P450 3A9/liter culture) and the recombinant protein of the modified P450 3A9 was purified to electrophoretic homogeneity (10.1 nmol P450/mg protein) from solubilized fractions using two chromatographic steps. The purified P450 3A9 protein was active towards the metabolism of many clinically important drugs such as imipramine, erythromycin, benzphetamine, ethylmorphine, chlorzoxazone, cyclosporine, rapamycin, etc. in a reconstituted system containing lipid and rat NADPH-P450 reductase. Although P450 3A9 was active towards the catabolism of testosterone, androstenedione, dehydroepiandrosterone (DHEA) and 17β-estradiol, P450 3A9 preferentially catalyzes the metabolism of progesterone to form four different hydroxylated products. Optimal reconstitution conditions for P450 3A9 activities required a lipid mixture and GSH. The possible mechanisms of the stimulatory effects of GSH on P450 3A9 activities are discussed. Sexually dimorphic expression of P450 3A9 in the brain and its involvement in many neuroactive drugs as well as neurosteroids suggest the possible role of P450 3A9 in some mental disorders and brain functions. ^

Cytochrome P450 2D18 in the mammalian brain: Recombinant expression, purification, and characterization of xenobiotic and endobiotic metabolism

The cytochromes P450 (P450) comprise a superfamily of hemoproteins that function in concert with NADPH-cytochrome P450 reductase (P450-reductase) to metabolize both endogenous and exogenous compounds. Many pharmacological agents undergo phase I metabolism by this P450 and P450-reductase monooxygenase system. Phase I metabolism ensures that these highly hydrophobic xenobiotics are made more hydrophilic, and hence easier to extrude from the body. While the majority of phase I metabolism occurs in the liver, metabolism in extrahepatic organ-systems like the intestine, kidney, and brain can have important roles in drug metabolism and/or efficacy. ^ While P450-mediated phase I metabolism has been well studied, investigators have only recently begun to elucidate what physiological roles P450 may have. One way to approach this question is to study P450s that are highly or specifically expressed in extrahepatic tissues. In this project I have studied the role of a recently cloned P450 family member, P450 2D18, that was previously shown to be expressed in the rat brain and kidney, but not in the liver. To this end, I have used the baculovirus expression system to over-express recombinant P450 2D18 and purified the functional enzyme using nickel and hydroxylapatite chromatography. SDS-PAGE analysis indicated that the enzyme was purified to electrophoretic homogeneity and Western analysis showed cross-reactivity with rabbit anti-human P450 2D6. Carbon monoxide difference spectra indicated that the purified protein contained no denatured P450 enzyme; this allowed for further characterization of the substrates and metabolites formed by P450 2D18-mediated metabolism. ^ Because P450 2D18 is expressed in brain, we characterized the activity toward several psychoactive drugs including the antidepressants imipramine and desipramine, and the anti-psychotic drugs chlorpromazine and haloperidol. P450 2D18 preferentially catalyzed the N-demethylation of imipramine, desipramine, and chlorpromazine. This is interesting given the fact that other P450 isoforms form multiple metabolites from such compounds. This limited metabolic profile might suggest that P450 2D18 has some unique function, or perhaps a role in endobiotic metabolism. ^ Further analysis of possible endogenous substrates for P450 2D18 led to the identification of dopamine and arachidonic acid as substrates. It was shown that P450 2D18 catalyzes the oxidation of dopamine to aminochrome, and that the enzyme binds dopamine with an apparent KS value of 678 μM, a value well within reported dopamine concentration in brain dopaminergic systems. Further, it was shown that P450 2D18 binds arachidonic acid with an apparent KS value of 148 μM, and catalyzes both the ω-hydroxylation and epoxygenation of arachidonic acid to metabolites that have been shown to have vasoactive properties in brain, kidney, and heart tissues. These data provide clues for endogenous roles of P450 within the brain, and possible involvement in the pathogenesis of Parkinson's disease. ^

Impact of oral contraceptives on weight, body composition, and cardiovascular disease risk factors in women age 18--30 years participating in a 15-week exercise program

Objective. To assess differences in body weight, body composition, total cholesterol, blood pressure, and blood glucose between OC users and non-users age 18-30 y before and after a 15-week cardiovascular exercise program in Houston, TX from 2003 to 2007.^ Study Design. Secondary analysis of prospective data. ^ Study Subjects. 453 Non-Hispanic white (NHW), Hispanic, and African American (AA) women age 18-30 y with no previous live birth, a history of menstruating, no use of other hormonal contraceptives or medications, no menopause or hysterectomy, and no current pregnancies.^ Measurements. Demographic data, medication use, and menstrual history were assessed via self-administered questionnaires at baseline. Anthropometric and laboratory measures were taken at baseline and 15-weeks. ^ Data Analysis. Linear regression assessed the association between OC use and study variables at baseline, and the change in study variables from baseline to 15-weeks. Logistic regression assessed the association between OC use and CVD risk. Each analysis was also stratified by race/ethnicity. ^ Results. At baseline, OC users had higher total cholesterol (p<.0005) and were above cholesterol risk cut points for CVD (OR=4.3, 95% CI=2.4-7.7) compared to non-users. At baseline, OC use was also associated with higher diastolic blood pressure (p=.018) compared to non-users, primarily in non-Hispanic whites (p=.007). OC use was associated with lower blood glucose compared to non-users in Hispanics only (p=.008). OC use was associated with absolute change in diastolic blood pressure (p=.044) and total cholesterol (p=.003). There was evidence that OC use may affect individuals differently based on race/ethnicity for certain obesity and CVD risk factors.^ Conclusions. OC users and non-users responded similarly to a 15-week cardiovascular exercise program. Exceptions included a greater change in diastolic blood pressure and total cholesterol among NHW and Hispanic OC users compared to non-users after exercise intervention. At baseline, OC use was associated with diastolic blood pressure and was most strongly associated with increased levels of total cholesterol. OC users were at greater risk of having total cholesterol above CVD risk cut points than non-users.^

Examining seasonal variations in physical activity among low-income Hispanic walk-trail users living in the Cameron Park Colonia

This study examines variations in physical activity by season, and within seasons by age and gender among park users living in the Cameron Park Colonia, a low-income Hispanic community along the Texas-Mexico border. This is the first study of its kind to evaluate seasonal variations by physical activity among a Hispanic population. We hypothesized that (1) there are no differences in overall physical activity by season; (2) youth engage in more sport-related physical activity compared to adults, (3) males engage in more physical activity than females, and (4) there are differences in physical activity between walk-trail users compared to non walk-trail users in the park.^ Physical activity behavioral data was collected (males n=2,093; females n=1,014) at two time periods (winter 2007; summer 2007) via direct observations and assessed park use, walking trail use, and physical activity (moderate-to-vigorous physical activity (MVPA) by seasons. Frequencies for physical activities were calculated for gender, age groups, and season. Separate Pearson's chi-square analyses were used to address variations in physical activity, age, gender, intensity level of physical activity by season, between walk-trails users and non walk-trail users.^ People visiting the park engaged in more sedentary behavior in winter than summer and a higher percentage engaged in MVPA in the summer than winter (p<.05). More females engaged in light activity compared to males (p<.05). Walk-trail users consisted mostly of females and engaged in more light activity than non walk-trail users (p<.05) who participated in more MVPA.^ Increasing access to parks and walk-trails may be an intervention strategy to increase physical activity among Hispanics. More research is needed to assess promoting trail use and determining long-term effects on physical activity among minority/ethnic groups at greater risk of a sedentary lifestyle and reasons for trail use and non-use. Future studies should focus on the types of activities Hispanics engage in at different parks particularly between men and women. As a result of this study city officials and planners may use this information to build and design parks that cater to the types of activities that Hispanics engage in and may use to meet physical activity guidelines.^

Pediatric obesity: Managed care collaborating with providers to improve diagnosis and treatment

Child overweight and obesity reaches across ethnic, cultural, socioeconomic and regional barriers. It must be assessed, diagnosed and treated to help families make sustainable behavior changes. Treatment recommendations have been made to address pediatric overweight and obesity. They include screening for risk factors, monitoring BMI trends and educating patients and families to make small sustainable changes. Health insurance companies can play a meaningful role in supporting and facilitating provider education and behavior change to diagnose, treat and prevent pediatric overweight and obesity.^ The aims of this thesis were: (1) Describe a disease management program that uses evidence-based practices to create provider behavior change related to pediatric obesity screening, diagnosis and treatment. (2) Identify ways to improve the implementation of the program based on the perceptions of participating clinicians.^ A literature review was completed to evaluate current recommendations for screening and treating pediatric obesity using the Ovid data base. The evidenced-based recommendations were compared against the practices of the Healthy Lifestyles Program (HeLP). The literature confirmed that HeLP is following evidence-based recommendations for assessment, diagnosis and treatment of pediatric obesity.^ A Children’s Mercy Family Health Partners focus group was convened to create a provider survey. The goals of the survey were to assess providers’ perception of the Healthy Lifestyles Program (HeLP). The survey was sent out through email using Survey Monkey. All survey responses were anonymous. The survey was sent to a total of 80 providers who had completed HeLP. Twenty-five percent responded. The survey results were evaluated to make recommendations for HeLP.^ Results of the survey included motivating factors for participation in HeLP. Concern about the increasing prevalence of pediatric obesity was a frequent motivator for participation. Provider barriers to obesity diagnosis were evaluated. Lack of time during clinic visits a frequent barrier to obesity diagnosis. ^ In conclusion several recommendations for the HeLP were made based on survey results. It is recommended that the program evaluate methods and tools for facilitating effective weight management follow up visits. Promotional materials should highlight the increasing prevalence of pediatric obesity when advertising HeLP. These recommendations will be used to refine the current Healthy Lifestyles Program.^

Immune response to hepatitis B vaccination in drug using populations: A systematic review and meta-regression analysis

Hepatitis B virus (HBV) is a significant cause of liver diseases and related complications worldwide. Both injecting and non-injecting drug users are at increased risk of contracting HBV infection. Scientific evidence suggests that drug users have subnormal response to HBV vaccination and the seroprotection rates are lower than that in the general population; potentially due to vaccine factors, host factors, or both. The purpose of this systematic review is to examine the rates of seroprotection following HBV vaccination in drug using populations and to conduct a meta-analysis to identify the factors associated with varying seroprotection rates. Seroprotection is defined as developing an anti-HBs antibody level of ≥ 10 mIU/ml after receiving the HBV vaccine. Original research articles were searched using online databases and reference lists of shortlisted articles. HBV vaccine intervention studies reporting seroprotection rates in drug users and published in English language during or after 1989 were eligible. Out of 235 citations reviewed, 11 studies were included in this review. The reported seroprotection rates ranged from 54.5 – 97.1%. Combination vaccine (HAV and HBV) (Risk ratio 12.91, 95% CI 2.98-55.86, p = 0.003), measurement of anti-HBs with microparticle immunoassay (Risk ratio 3.46, 95% CI 1.11-10.81, p = 0.035) and anti-HBs antibody measurement at 2 months after the last HBV vaccine dose (RR 4.11, 95% CI 1.55-10.89, p = 0.009) were significantly associated with higher seroprotection rates. Although statistically nonsignificant, the variables mean age>30 years, higher prevalence of anti-HBc antibody and anti-HIV antibody in the sample population, and current drug use (not in drug rehabilitation treatment) were strongly associated with decreased seroprotection rates. Proportion of injecting drug users, vaccine dose and accelerated vaccine schedule were not predictors of heterogeneity across studies. Studies examined in this review were significantly heterogeneous (Q = 180.850, p = 0.000) and factors identified should be considered when comparing immune response across studies. The combination vaccine showed promising results; however, its effectiveness compared to standard HBV vaccine needs to be examined systematically. Immune response in DUs can possibly be improved by the use of bivalent vaccines, booster doses, and improving vaccine completion rates through integrated public programs and incentives.^