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Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis

Abstract: View references (80) Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. Findings: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (–0·20, –0·23 to –0·16), levofloxacin (–0·06, –0·09 to –0·04), moxifloxacin (–0·07, –0·10 to –0·04), or bedaquiline (–0·14, –0·19 to –0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. Interpretation: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America. © 2018 Elsevier Ltd

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Pathogenicity locus determinants and toxinotyping of Clostridioides difficile isolates recovered from Iranian patients

Abstract:Little is known about the toxin profiles, toxinotypes and variations of toxin Clostridioides difficile C (tcdC) in Iranian C. difficile isolates. A total of 818 stool specimens were obtained from outpatients (n = 45) and hospitalized patients (n = 773) in Tehran, Iran, from 2011 to 2017. The 44 C. difficile isolates were subjected to PCR of toxin C. difficile A (tcdA), toxin C. difficile B (tcdB), tcdA 3′-end deletion, toxinotyping and sequencing of the tcdC gene. Thirty-eight isolates (86.36%) were identified as tcdA and tcdB positive, and the remaining six isolates (13.63%) were nontoxigenic. All tcdA- and tcdB-positive isolates yielded an amplicon of 2535 bp by PCR for the tcdA 3′ end. Fourteen (36.84%), seventeen (44.73%) and seven (18.43%) isolates belonged to wild-type, toxin C. difficile C subclone3 (tcdC-sc3) and tcdC-A genotype of tcdC, respectively. Thirty-one isolates (81.57%) belonged to toxinotype 0, and seven isolates (18.42%) were classified as toxinotype V. This study provides evidence for the circulation of historical and hypervirulent isolates in the healthcare and community settings. Furthermore, it was also demonstrated that the tcdC-A genotype and toxinotype V are not uncommon among Iranian C. difficile isolates. © 2018

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A potentially fatal error in diagnosis of a pulmonary hydatid cyst

Abstract:Introduction: Echinococcosis is still an important public health challenge in endemic areas that is associated with considerable morbidity. A complicated pulmonary hydatid cyst can be a daunting situation if not diagnosed and managed properly. Case Presentation: Our case was a young female with a huge pulmonary hydatid cyst who developed a sudden rupture of cyst. She was operated by an erroneous diagnosis of a complicated diaphragmatic hernia which resulted in a life-threatening event. Conclusions: Based on a broad range of clinical presentations and diverse radiographic appearances, the diagnosis of a complicated pulmonary hydatid cyst is not always straightforward. A pulmonary hydatid cyst, which obscures the diaphragmatic shadow, might be misdiagnosed as a diaphragmatic hernia on plain radiography. Accurate diagnosis depends on a precise clinical judgment particularly in endemic regions, otherwise serious morbidity is anticipated. © 2017, Archives of Clinical Infectious Diseases.

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Genetic Diversity and Antifungal Susceptibility of Candida parapsilosis Sensu Stricto Isolated from Bloodstream Infections in Turkish Patients

Abstract:Background: Candida parapsilosis sensu stricto is an emerging cause of hospital-acquired Candida infections, predominantly in southern Europe, South America, and Asia. We investigated the genetic diversity and antifungal susceptibility profile of 170 independent C. parapsilosis sensu stricto strains obtained from patients with candidemia who were treated at the Ege University Hospital in Izmir, Turkey, between 2006 and 2014. The identity of each strain was confirmed via PCR amplification and digestion of the secondary alcohol dehydrogenase-encoding gene. The 24-h geometric mean minimum inhibitory concentrations of the antifungal agents, in increasing order, were as follows: posaconazole, 0.10 µg/mL; voriconazole, 0.21 µg/mL; caspofungin, 0.38 µg/mL; amphotericin B, 0.61 µg/mL; anidulafungin, 0.68 µg/mL; and fluconazole, 2.95 µg/mL. Microsatellite genotyping of the isolates (using fluorescently labeled primers and a panel of four different short-nucleotide repeat fragments) identified 25, 17, 17, and 8 different allelic genotypes at the CP6, B5, CP4, and CP1 locus, respectively. Posaconazole, caspofungin, and amphotericin B showed the greatest in vitro activity of the tested systemic azole, echinocandin, and polyene agents, respectively, and the observed antifungal susceptibility of the isolates was shown to be independent of their isolation source. We obtained a combined discriminatory power of 0.99 with a total of 130 genotypes for 170 isolates tested. Finally, microsatellite profiling analysis confirmed the presence of identical genotype between separate isolates, supporting that effective surveillance and infection-prevention programs are essential to limit the impact of C. parapsilosis sensu stricto on hospitalized patients’ health. © 2018, Springer Science+Business Media B.V., part of Springer Nature.

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Risk factors associated with survival of pulmonary tuberculosis

Abstract:Objective/Background: We conducted this study among adults with pulmonary tuberculosis (TB) who received treatment, in order to determine the risk factors associated with survival of during treatments. Methods: A retrospective cohort study was conducted from 2005-2015 with newly registered TB patients in the Hospital of Masih Daneshvari Doctor, Tehran, Iran. Overall, 5313 patients met our studys cohort definition, but the analysis was performed on 2299 patients (43.2%) who had a correct address and they could be traced-out by the Medical – registry. Time in days was used in survival model and patients who were still alive (until last follow-up date) considered as censored. To study the effect of risk factors on patients’ survival, the generalized gamma regression model was used. Results: Based on the results of univariate analysis, gender (RR=2 (95% CI: 1.1−3.7), high school education (Relative Risk: RR=0.3 (95% CI: 0.2−0.7), higher education (RR=0.3 (95% CI: 0.1−0.9), smoker (RR=2.5 (95% CI: 1.4−4.2), drug user (RR=2.4 (95% CI: 1.4−4), TB contact (RR=0.5 (95% CI: 0.3−0.8) and HIV positive (RR=4 (95% CI: 1.7−9.2) affected patients’ survival. Moreover, the results of multivariate analysis showed that, gender (RR=5.5 (95% CI: 2.2−13.5), age (RR=1.1 (95% CI: 1−1.1), adverse drug effect (RR=2.5 (95% CI: 1.2−5.4), smoker (RR=3.3 (95% CI: 1.2−9.4), TB contact (RR=0.2 (95% CI: 0.1−0.5), diabetic mellitus (RR=3 (95% CI: 1−8.3), HIV positive (RR=26 (95% CI: 4.6−145.9) and comorbidities (RR=4.9 (95% CI: 2−11.6) were identified as factors affecting patients’ survival. Conclusion: Our data indicated associated risk factors in TB mortality and could suggest way to progressing national tuberculosis program (NTP) for predicating and plan for effective interventional strategies. © 2018, Iranian Journal of Public Health. All rights reserved.

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MiR-1224 Expression is increased in human macrophages after infection with Bacillus Calmette-Guérin (BCG)

Abstract:Tuberculosis (TB) remains a major threat to human health. Understanding the strategies mycobacteria take to overcome immune defense is important in order to control the infection. Micro (mi)RNAs are master regulators of most pathways in the human body. Infection with mycobacterium impacts upon the host metabolic pathways as they are subverted to obtain the nutrition for intracellular TB survival. In this study, we aimed to investigate the effect of Bacillus Calmette-Guerin (BCG) infection on the expression of three miRNAs (miR-1224,-484 and-425), which are important in infection and in the regulation of metabolic pathways. Peripheral blood monocyte-derived macrophage (MDM) cultures were prepared and infected with BCG at a multiplicity of infection (MOI)=10 or left uninfected as a control. 72h post-infection, RNA was extracted from the cultured cells and cDNA synthesis and real-time PCR performed. Expression levels miRNAs were normalized to the levels of U6 snRNA (Rnu6) using the 2-ΔΔCt method. Infection with BCG resulted in a highly significant increase in miR-1224 expression (24.4}3.8-fold induction) in human MDMs. The induction of miR-484 (1.8}0.3-fold increase) and of miR-425 (1.2±0.2-fold increase) was less increased compared to miR-1224. Mycobacterium tolerates a hostile microenvironment by escaping from lysosomal degradation and providing a lipid-rich niche by trigger with and re-pattering host metabolism. This study highlighted the potential roles of miRNAs in host responses upon mycobacterium infection. © June 2018, Iran J Allergy Asthma Immunol. All rights reserved.

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Implementing tuberculosis close-contact investigation in a Tertiary Hospital in Iran

Abstract:Background: Close contact investigation is the essential key in tuberculosis (TB) case finding and an effective strategy for TB control program within any society. Methods: In this prospective study, 1186 close family contacts of hospitalized TB patients (index) in a referral TB hospital in Tehran-Iran were passively studied. These people were studied to rollout TB infection and disease. Demographic characteristics, clinical and laboratory data of these individuals were reviewed and summarized for analysis. Results: A total of 886 (74.4%) close-family contacts completed their investigation. The index TB patients of these individuals were sputum smear negative for acid-fast bacilli in 137 cases (11.6%) and the rest were smear positive. A total of 610 (68.8%) close-family contact ruled out for TB infection or disease (Group I). A total of 244 cases (27.5%) had latent TB infection (Group II) and active TB (Group III) was confirmed in 32 cases (3.6%). A significant difference was shown for female gender, signs and symptoms, family size, and positive radiological finding between Group I and Group II. The study of index parameter including positive sputum smear/culture did not reveal any significant difference, but positive cavitary lesion significantly more has seen in active TB group (P = 0.004). Conclusions: This study emphasizes on sign and symptoms and radiological finding in TB contact investigation, where index parameters including positive smear/culture, does not implicate any priority. Although cavitary lesions in index patient have more accompanied by active TB, close contact study should include all of TB indexes. This investigation should include chest radiography for these individuals. © 2018 International Journal of Preventive Medicine.

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Effect of methamphetamine exposure on the plasma levels of endothelial-derived microparticles

Abstract:Background: Methamphetamine (Meth), a neurotoxin, induces inflammation, oxidative stress, and triggers endothelial dysfunction and cardiovascular disease which is the second cause of death among individuals with Meth-use disorder. Oxidative stress and inflammation trigger the microparticle (MP) release. These are extracellular vesicles extracted from cell surface and identified in biological fluids. MP levels alter during pathological conditions, suggesting its potential biomarker role. In this respect, we designed the present experiment to investigate the effects of Meth on the plasma level of the endothelial-derived microparticle (EMP). Methods: Animals received Meth (4 mg/kg i.p.) for 1, 7 and 14 days and then, the plasma level of EMPs was evaluated, using cell surface markers, including AnnexinV, CD144, CD31, CD41a antigens with the flow cytometry method. The biochemical indices and locomotor activity were also assessed in a rat model. Results: Meth increased locomotor activity (Meth-1, 277.12 ± 20.17; Meth-7, 262.25 ± 11.95; Meth-14, 265.75 ± 14.75), inflammatory and oxidative indices as evidenced by rising of the C-reactive protein (Meth-7, 39.4 ± 1.24; Meth-14, 38.58 ± 2.19, vs 8.65 ± 0.45, mg/L) and malondialdehyde (Meth-7, 9.74 ± 1.38; Meth-14, 14.6 ± 1.45, vs 4.43 ± 0.32 nmol/L) plasma levels. We also found that Meth triggered endothelial injury, as demonstrated by elevated levels of EMP (Meth-7, 4.77 ± 0.22; Meth-14, 5.91 ± 0.34, % total events/mL) compared with control group. Conclusion: Our data showed that Meth exposure stimulates inflammatory and oxidative pathways and facilitates the EMPs shedding. Measuring the level of EMPs might be applied as a potential diagnostic index to monitor the endothelial dysfunction in substance-use disorders. © 2018 Elsevier B.V.

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Budesonide facilitates weaning from mechanical ventilation in difficult-to-wean very severe COPD patients: Association with inflammatory mediators and cells

Abstract:Introduction: Mechanical ventilatory support is life-saving therapy for patients with respiratory failure in intensive care units (ICU) but is linked to ventilator-associated pneumonia and other nosocomial infections. Interventions that improve the efficiency of weaning from mechanical ventilation may improve patient outcomes. Objective: To determine whether inhaled budesonide decreases time-to-weaning in COPD stage 4 difficult-to-wean patients and reduces the release of pro-inflammatory cytokines in ICU patients. Materials and methods: We recruited 55 difficult-to-wean COPD patients (Stage 4) within the ICU of the Masih Daneshvari Hospital. Subjects were randomly assigned to receive inhaled budesonide (0.5 mg/day) or placebo (normal saline). Dynamic compliance and BAL cytokines were measured. Results: Budesonide significantly reduced the number of days on MV (days-to-weaning = 4.6 ± 1.6 days) compared to that seen in the control group (7.2 ± 2.7 days, p = 0.014). Dynamic compliance was significantly improved in the budesonide group on days 3 (p = 0.018) and 5 (p = 0.011) The levels of CXCL-8 and IL-6 diminished on days 3–5 after start of budesonide (p < 0.05). Conclusion: In COPD patients on MV, nebulized budesonide was associated with reduced BAL CXCL8 and IL-6 levels and neutrophil numbers as well as an improvement in ventilatory mechanics and facilitated weaning. © 2017 Elsevier Inc.

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A preliminary study of microrna-208b after acute myocardial infarction: Impact on 6-month survival

Abstract:Introduction. miRNAs contribute to a variety of essential biological processes including development, proliferation, differentiation, and apoptosis. Circulating microRNAs are very stable and have shown potential as biomarkers of cardiovascular disease. microRNA-208b expression was increased in the blood of patients with acute myocardial infarction (AMI) and has been proposed as a biomarker for early diagnosis. In this pilot study, we investigate the potential of circulating miR-208b as a prognostic biomarker of 6-month survival in AMI patients. Methods. Plasma samples from 21 patients and 8 age- and gender-matched healthy adults were collected, and circulating levels of miR-208b were detected using quantitative real-time PCR. Results. miR-208b levels were higher in healthy control subjects (9.6-fold; P ≤ 0 05). Within the AMI patients, the levels of miR-208b were significantly lower in the survivor versus nonsurvivor group (fold change = 6.51 and 14.1, resp.; P ≤ 0 05). The Kaplan-Meier curve revealed that the 6-month survival time was significantly higher among AMI patients with a relative expression of miR-208b lower than 12.38. The hazard ratio (HR) for the relative expression of miR-208b (<12.38 was the reference) was 5.08 (95% CI: 1.13–22.82; P = 0 03). Conclusion. Our results showed that elevated miR-208b expression was associated with reduced long-term survival in AMI patients. These pilot data indicate the need for a large follow-up study to confirm whether miR-208b can be used as a predictor of 6-month survival time after AMI. Copyright © 2018 Mostafa Alavi-Moghaddam et al.

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Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis

Abstract:Background: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. Methods: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1–3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. Findings: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8–9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1–7·3), but no significant effect on mortality (aOR 0·7, 0·4–1·1) or acquired rifampicin resistance (aOR 0·1, 0·0–1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2–0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. Interpretation: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. Funding: World Health Organization and Canadian Institutes of Health Research. © 2018 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved.

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Effects of the polyunsaturated fatty acids, EPA and DHA, on hematological malignancies: A systematic review

Abstract:Omega-3 polyunsaturated fatty acids (PUFAs) have well established anti-cancer properties. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are among this biologically active family of macromolecules for which various anti-cancer effects have been explained. These PUFAs have a high safety profile and can induce apoptosis and inhibit growth of cancer cells both in vitro and in vivo, following a partially selective manner. They also increase the efficacy of chemotherapeutic agents by increasing the sensitivity of different cell lines to specific anti-neoplastic drugs. Various mechanisms have been proposed for the anti-cancer effects of these omega-3 PUFAs; however, the exact mechanisms still remain unknown. While numerous studies have investigated the effects of DHA and EPA on solid tumors and the responsible mechanisms, there is no consensus regarding the effects and mechanisms of action of these two FAs in hematological malignancies. Here, we performed a systematic review of the beneficial effects of EPA and DHA on hematological cell lines as well as the findings of related in vivo studies and clinical trials. We summarize the key underlying mechanisms and the therapeutic potential of these PUFAs in the treatment of hematological cancers. Differential expression of apoptosis-regulating genes and Glutathione peroxidase 4 (Gp-x4), varying abilities of different cancerous and healthy cells to metabolize EPA into its more active metabolites and to uptake PUFAS are among the major factors that determine the sensitivity of cells to DHA and EPA. Considering the abundance of data on the safety of these FAs and their proven anti-cancer effects in hematological cell lines and the lack of related human studies, further research is warranted to find ways of exploiting the anticancer effects of DHA and EPA in clinical settings both in isolation and in combination with other therapeutic regimens. © Moloudizargari et al.

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Revision and implementation of “Clinical guideline for tuberculosis and HIV in prisons”, Great Tehran Prison, Iran

Abstract:Aim: To evaluate the feasibility of the revised “Clinical Guideline for HIV and TB” in the Great Tehran Prison during October 2013 to June 2014. Methods: The guideline includes all aspects of HIV/TB diagnosis based on active case finding (ACF), treatment and care services. Before the implementation, a focus group discussion was conducted, and attended by experts on prison health. The objective was to identify defects and limitations of the guideline. After the discussion, the guideline was revised. The Great Tehran Prison contains three separate units; all prisoners are taken first to “reception and identification unit (quarantine)” and then send to two housing units according to their legal status. An HIV ACF strategy was employed in the quarantine, and two units through a voluntary provider-initiated HIV testing. Three staff of the triangular clinic trained the prisoners about common routes of HIV transmission and the symptoms of TB in the units. In the quarantine, all prisoners were examined for all HIV-risk factors, HIV testing and symptoms of TB. In unit one, healthcare staff continued the ACF process, while in unit two, the peers of prisoners were assigned as the healthcare communicators to proceed with the strategy. At this caring process, when the test result was positive, then the process of care, treatment and follow ups was initiated. Moreover, the use of directly observed therapy (DOT) for antiretroviral therapy (ART) and TB was applied to the sick prisoners. There was also a follow-up caring for released prisoner to refer them to care and treatment services outside the prison. Results: The guideline was implemented in the prison successfully. Conclusion: Regarding feasibility of the guideline, the investigators of this study suggest that the guideline should be implemented in other prisons across the country. © 2018 Bentham Science Publishers.

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