To prove such a mechanism, it is necessary to demonstrate the presence of CagA in the colonized bronchial epithelial cells. Besides lung cancer, H. pylori infection was considered to play a role in other pulmonary diseases. In a longitudinal community-based study, Fullerton et al. [46] found no association between H. pylori seropositivity and chronic obstructive pulmonary diseases, asthma, atopy, and allergic diseases. In addition, they found that the H. pylori serological status had no effect on the decline in lung function over 9 years. Regarding E.N.T. diseases, multiple studies evaluated the presence of H. pylori in nasal

Rapamycin datasheet polyposis and adenotonsillar tissue as well as the involvement of the bacterium in oropharyngeal and laryngeal disorders last year [47–49]. Ozyurt et al. [47] did not find any difference in the prevalence of H. pylori and cagA, evaluated by PCR and RT-PCR, in nasal polyps and larynx tissues in

individuals with normal nasal mucosa. learn more The study by Ozcan et al. [48] on a potential relationship between chronic otitis media with effusion and H. pylori infection was not conclusive either. On the contrary, Kaptan et al. [49] showed that chronic nonspecific pharyngitis was significantly related to H. pylori infection and suggested the use of antibiotics also active against H. pylori in the treatment of chronic pharyngitis. Anemia is an important public health problem in developing countries and very often it is a possible consequence of a common nutritional defect, iron deficiency. The possible role of H. pylori infection in the development of hyposideremic anemia was recently investigated in five Latin America countries, Argentina, Bolivia, Brazil, Cuba, Mexico, and Venezuela [50], but no evidence was found to confirm the responsibility of such an infection. Brazilian

individuals were investigated in greater depth [51] and, although no significant association was observed between anemia and H. pylori infection, 上海皓元 a crude multilevel linear regression showed a reduction of 0.07 g/dL in those who were colonized, after adjusting for sex, skin color, income, age, and smoking. A major problem in those countries, however, is that only approximately 50% of anemia cases can be attributed to iron deficiency; other causes, which include malaria, hookworm infestation, schistosomiasis, inherited conditions such as thalassemia and dietary vitamin deficiency do not always emerge in the clinical history of individuals. Numerous case reports published in minor journals revealed that the eradication of H. pylori infection resolved iron-deficiency anemia [52–58].

The physiological state of crustaceans varies over time and is strongly linked to their moult stage (Chang, 1995; Carvalho & Phan, 1998). For example, levels of ecdysone and vitellogenin fluctuate during the moult cycle and are involved in pairing decision (Dunham, 1978; Ducruet, 1982; Subramoniam, 2000). However, females do not reproduce at each successive moult as noticed for many species (Jormalainen & Merilaita, 1995; Souty-Grosset

Tanespimycin mouse et al., 1998) and even during the breeding period, egg-depositing moults (with reproduction) may alternate with growth moults (without reproduction). The types of moult are expected to affect differentially the pairing outcomes (Sparkes, Keogh & Haskins,

2000), as well as size-assortative mating. This latter point has not specifically been investigated in crustaceans. Predictions can be made about the role of the moulting cycle in size-assortative mating. If size-assortative pairing results from the constraints of carrying a female for males or from the spatial heterogeneity in the local environment, then the stage of moulting cycle should not have an effect. In this case, the variability in size-assortative pairing should be low and independent of where males and females are in their moulting cycle. If sexual selection indeed determines male choice (‘timing and takeover Lorlatinib molecular weight hypotheses’), then the level of size-assortative pairing should vary according to female moult stage and be more pronounced late in the female moult cycle. In the freshwater gammaridean amphipod Gammarus pulex, a pattern of positive size-assortative pairing during PCMG has been well described. The objective of the present work was to study the influence of female moult stage on the variation and intensity of size-assortative pairing in MCE G. pulex. Both paired and unpaired individuals were collected in the field, sized and their position in the moult cycle was characterized by observing the new cuticle formation. The data allowed us to determine whether female moulting status influenced the individual’s

decision and therefore the outcome of pairing. Males and females of G. pulex were collected from the Suzon River at Val Suzon (in the north of Dijon, Burgundy, France) using a hand net and brought back to the laboratory. Individual females were maintained in the laboratory (temperature 15 ± 1°C, light : dark cycle 12:12 h) in dishes (10 cm diameter, 8 cm height) filled with aerated dechlorinated ultraviolet-treated tap water and fed ad libitum with elm leaves. At the end of the assays, gammarids were anesthetized with CO2 gas and then killed in 70% ethanol. Body size was measured by linear dimensions (height of the fourth coxal plate) using a Nikon SMZ 1500 stereoscopic microscope and Lucia G 4.91 software (Nikon, Tokyo, Japan).

One study observed HBeAg positive patients, 233 treated with IFN and 233 untreated for 6.8 years, with cancers detected in 2% of treated patients and 7%

of untreated controls, showing carcinogenesis significantly reduced in the IFN therapy group (P < 0.025).[90] On the other hand, the other study of HBeAg positive patients, 208 treated with IFN and 203 untreated, found no significant difference in the rate MLN2238 in vivo of carcinogenesis (2.9% vs 0%).[260] Although many other studies have evaluated the relationship between IFN therapy and carcinogenesis,[261-266] they have all been cohort studies and their results do not consistently demonstrate a carcinogenesis suppressor effect for IFN. In these cohort studies, the carcinogenesis rate in the control group (untreated patients) varies greatly from 0% to 30.8%, and the rate including patients with cirrhosis also varies from 0% to 100%, with considerable differences in subject clinical backgrounds. These differences

in the clinical background of applicable cases may be related to the variations in the reported carcinogenesis suppression effect of IFN. Dorsomorphin mw A number of meta-analyses have examined the relationship between IFN therapy and carcinogenesis. One analysis of 11 studies comprising 1006 patients treated with IFN and 1076 untreated controls found IFN therapy significantly reduced the carcinogenesis risk ratio to 0.59.[267] Another meta-analysis of 8 studies found that, although carcinogenesis was suppressed in IFN treated patients compared to untreated controls medchemexpress (risk difference 5.0%), the carcinogenesis suppression

effect was found in a subgroup of ethnic Asians, where the carcinogenesis rate in the untreated controls was ≥10%, and ≥70% of subjects were HBeAg positive.[268] A third meta-analysis of 7 studies evaluated the therapeutic effect of IFN in patients with cirrhosis, 122 cases of HCC developed in 1505 patients with liver cirrhosis, and a carcinogenesis risk difference of 6.4% in IFN treated patients compared to untreated controls.[269] The authors discussed that, although all 7 studies indicated a tendency for IFN therapy to suppress carcinogenesis, only 3 studies showed a significant difference, of which 2 studies were results from Asia. Then they concluded that the overall significant difference disappeared with elimination of the last 2 Asian studies, and no firm conclusion was made concerning carcinogenesis suppression by IFN therapy. Another meta-analysis of 12 studies examining 1292 IFN treated patients and 1450 untreated controls, IFN therapy significantly reduced the carcinogenesis risk ratio to 0.66.[270] A sub-analysis indicated that carcinogenesis was suppressed by IFN therapy in liver cirrhosis patients (11.6% vs 21.5%, risk ratio 0.53, 95% CI: 0.36–0.78), whereas for non-cirrhosis patients the cancer rate was low, 0.9% in treated patients and 1.1% in untreated controls, showing no significant difference.

One study observed HBeAg positive patients, 233 treated with IFN and 233 untreated for 6.8 years, with cancers detected in 2% of treated patients and 7%

of untreated controls, showing carcinogenesis significantly reduced in the IFN therapy group (P < 0.025).[90] On the other hand, the other study of HBeAg positive patients, 208 treated with IFN and 203 untreated, found no significant difference in the rate LBH589 research buy of carcinogenesis (2.9% vs 0%).[260] Although many other studies have evaluated the relationship between IFN therapy and carcinogenesis,[261-266] they have all been cohort studies and their results do not consistently demonstrate a carcinogenesis suppressor effect for IFN. In these cohort studies, the carcinogenesis rate in the control group (untreated patients) varies greatly from 0% to 30.8%, and the rate including patients with cirrhosis also varies from 0% to 100%, with considerable differences in subject clinical backgrounds. These differences

in the clinical background of applicable cases may be related to the variations in the reported carcinogenesis suppression effect of IFN. GSI-IX clinical trial A number of meta-analyses have examined the relationship between IFN therapy and carcinogenesis. One analysis of 11 studies comprising 1006 patients treated with IFN and 1076 untreated controls found IFN therapy significantly reduced the carcinogenesis risk ratio to 0.59.[267] Another meta-analysis of 8 studies found that, although carcinogenesis was suppressed in IFN treated patients compared to untreated controls medchemexpress (risk difference 5.0%), the carcinogenesis suppression

effect was found in a subgroup of ethnic Asians, where the carcinogenesis rate in the untreated controls was ≥10%, and ≥70% of subjects were HBeAg positive.[268] A third meta-analysis of 7 studies evaluated the therapeutic effect of IFN in patients with cirrhosis, 122 cases of HCC developed in 1505 patients with liver cirrhosis, and a carcinogenesis risk difference of 6.4% in IFN treated patients compared to untreated controls.[269] The authors discussed that, although all 7 studies indicated a tendency for IFN therapy to suppress carcinogenesis, only 3 studies showed a significant difference, of which 2 studies were results from Asia. Then they concluded that the overall significant difference disappeared with elimination of the last 2 Asian studies, and no firm conclusion was made concerning carcinogenesis suppression by IFN therapy. Another meta-analysis of 12 studies examining 1292 IFN treated patients and 1450 untreated controls, IFN therapy significantly reduced the carcinogenesis risk ratio to 0.66.[270] A sub-analysis indicated that carcinogenesis was suppressed by IFN therapy in liver cirrhosis patients (11.6% vs 21.5%, risk ratio 0.53, 95% CI: 0.36–0.78), whereas for non-cirrhosis patients the cancer rate was low, 0.9% in treated patients and 1.1% in untreated controls, showing no significant difference.

One study observed HBeAg positive patients, 233 treated with IFN and 233 untreated for 6.8 years, with cancers detected in 2% of treated patients and 7%

of untreated controls, showing carcinogenesis significantly reduced in the IFN therapy group (P < 0.025).[90] On the other hand, the other study of HBeAg positive patients, 208 treated with IFN and 203 untreated, found no significant difference in the rate STI571 manufacturer of carcinogenesis (2.9% vs 0%).[260] Although many other studies have evaluated the relationship between IFN therapy and carcinogenesis,[261-266] they have all been cohort studies and their results do not consistently demonstrate a carcinogenesis suppressor effect for IFN. In these cohort studies, the carcinogenesis rate in the control group (untreated patients) varies greatly from 0% to 30.8%, and the rate including patients with cirrhosis also varies from 0% to 100%, with considerable differences in subject clinical backgrounds. These differences

in the clinical background of applicable cases may be related to the variations in the reported carcinogenesis suppression effect of IFN. CH5424802 purchase A number of meta-analyses have examined the relationship between IFN therapy and carcinogenesis. One analysis of 11 studies comprising 1006 patients treated with IFN and 1076 untreated controls found IFN therapy significantly reduced the carcinogenesis risk ratio to 0.59.[267] Another meta-analysis of 8 studies found that, although carcinogenesis was suppressed in IFN treated patients compared to untreated controls 上海皓元医药股份有限公司 (risk difference 5.0%), the carcinogenesis suppression

effect was found in a subgroup of ethnic Asians, where the carcinogenesis rate in the untreated controls was ≥10%, and ≥70% of subjects were HBeAg positive.[268] A third meta-analysis of 7 studies evaluated the therapeutic effect of IFN in patients with cirrhosis, 122 cases of HCC developed in 1505 patients with liver cirrhosis, and a carcinogenesis risk difference of 6.4% in IFN treated patients compared to untreated controls.[269] The authors discussed that, although all 7 studies indicated a tendency for IFN therapy to suppress carcinogenesis, only 3 studies showed a significant difference, of which 2 studies were results from Asia. Then they concluded that the overall significant difference disappeared with elimination of the last 2 Asian studies, and no firm conclusion was made concerning carcinogenesis suppression by IFN therapy. Another meta-analysis of 12 studies examining 1292 IFN treated patients and 1450 untreated controls, IFN therapy significantly reduced the carcinogenesis risk ratio to 0.66.[270] A sub-analysis indicated that carcinogenesis was suppressed by IFN therapy in liver cirrhosis patients (11.6% vs 21.5%, risk ratio 0.53, 95% CI: 0.36–0.78), whereas for non-cirrhosis patients the cancer rate was low, 0.9% in treated patients and 1.1% in untreated controls, showing no significant difference.

Methods: A total of 56 patients, in whom the initial standard triple therapy had failed to eradicate H. pylori infection, were randomly assigned into two groups. The first group (n = 28) received pantoprazole 40 mg twice daily, moxifloxacine 400 mg once daily and amoxicilline 1000 mg twice daily for 10 days. The second group received pantoprazole 40 mg twice daily, amoxicilline 1000 mg twice daily for 5 days followed by pantoprazole 40 mg twice daily, moxifloxacine 400 mg once daily and metronidazole 400 mg twice daily for the next 5 days. Testing for H. pylori

infection after treatment was done find more using the (13) C-urea breath test six weeks after completing the treatment. Results: 50 patients (89%) completed the study. The eradication rates were 71,4% (20/28) and 73% (19/26) in the first group and 75% (21/28) and 77% (17/22) in the second group by intention-to-treat (p = 0,04) and per-protocol (p = 0,08) analyses respectively. Compliance was higher in the second group. Adverse effects were described in 3 patients in the first group and in 5 patients in the second, but were mild and did not require discontinuation of

therapy. Conclusion: Considering better compliance and higher eradication rates, moxifloxacine BYL719 based sequential therapy represents favorable second line alternative for H. pylori infection. Key Word(s): 1. Helicobacter pylori; 2. second line; 3. sequential therapy; 4. triple therapy; Presenting Author: XUAN HUANG Additional Authors: BIN LV, SHUO ZHANG, QUN DAI, BING-BING CHEN, LI-NA MENG Corresponding Author: BIN LV Affiliations: the First Affiliated Hospital, Zhejiang Chinese Medical University Objective: Radix curcumae (RC)-derived diterpenoid C is recemtly obtained from RC ether extract by us, and its chemical properties and constitution are different

from curcumin and β-elemene. Our previous experiments have shown that RC-derived diterpenoid C has better anti-tumor activity and RC-derived diterpenoid C of high concentration can induce apoptosis. But it inhibit inflammation effect and mechanism is unclear. Methods: We used I-type Hp to infect human gastric epithelial GES-1 cell lines, and then Hp-infected GES-1 cells were medchemexpress treated with RC-derived diterpenoid C of different concentrations (5 ug/ml, 10 ug/ml, 20 ug/ml)and amoxicillin. The expression of P65, IKKα and IKKγ proteins was detected with Western blot, and the expression of interleukin (IL)-8, IL-6 and IL-4 was determined with ELISA method. Results: MTT indicated that the IC5 of RC-derived diterpenoid C and amoxicillin all were 5 ug/ml for gastric GES-1 cells. The expression of IL-8 was significantly increased, especially at 12 hour time point; and the expression of IL-4 was decreased in Hp-infected GES-1 cells. After Hp-infected GES-1 cells were treated with RC-derived diterpenoid C of different concentrations and amoxicillin, the expression of IL-8 was decreased at 12 h, 24 h, 48 h, 72 h points (P < 0.

Methods: A total of 56 patients, in whom the initial standard triple therapy had failed to eradicate H. pylori infection, were randomly assigned into two groups. The first group (n = 28) received pantoprazole 40 mg twice daily, moxifloxacine 400 mg once daily and amoxicilline 1000 mg twice daily for 10 days. The second group received pantoprazole 40 mg twice daily, amoxicilline 1000 mg twice daily for 5 days followed by pantoprazole 40 mg twice daily, moxifloxacine 400 mg once daily and metronidazole 400 mg twice daily for the next 5 days. Testing for H. pylori

infection after treatment was done learn more using the (13) C-urea breath test six weeks after completing the treatment. Results: 50 patients (89%) completed the study. The eradication rates were 71,4% (20/28) and 73% (19/26) in the first group and 75% (21/28) and 77% (17/22) in the second group by intention-to-treat (p = 0,04) and per-protocol (p = 0,08) analyses respectively. Compliance was higher in the second group. Adverse effects were described in 3 patients in the first group and in 5 patients in the second, but were mild and did not require discontinuation of

therapy. Conclusion: Considering better compliance and higher eradication rates, moxifloxacine Ibrutinib mw based sequential therapy represents favorable second line alternative for H. pylori infection. Key Word(s): 1. Helicobacter pylori; 2. second line; 3. sequential therapy; 4. triple therapy; Presenting Author: XUAN HUANG Additional Authors: BIN LV, SHUO ZHANG, QUN DAI, BING-BING CHEN, LI-NA MENG Corresponding Author: BIN LV Affiliations: the First Affiliated Hospital, Zhejiang Chinese Medical University Objective: Radix curcumae (RC)-derived diterpenoid C is recemtly obtained from RC ether extract by us, and its chemical properties and constitution are different

from curcumin and β-elemene. Our previous experiments have shown that RC-derived diterpenoid C has better anti-tumor activity and RC-derived diterpenoid C of high concentration can induce apoptosis. But it inhibit inflammation effect and mechanism is unclear. Methods: We used I-type Hp to infect human gastric epithelial GES-1 cell lines, and then Hp-infected GES-1 cells were medchemexpress treated with RC-derived diterpenoid C of different concentrations (5 ug/ml, 10 ug/ml, 20 ug/ml)and amoxicillin. The expression of P65, IKKα and IKKγ proteins was detected with Western blot, and the expression of interleukin (IL)-8, IL-6 and IL-4 was determined with ELISA method. Results: MTT indicated that the IC5 of RC-derived diterpenoid C and amoxicillin all were 5 ug/ml for gastric GES-1 cells. The expression of IL-8 was significantly increased, especially at 12 hour time point; and the expression of IL-4 was decreased in Hp-infected GES-1 cells. After Hp-infected GES-1 cells were treated with RC-derived diterpenoid C of different concentrations and amoxicillin, the expression of IL-8 was decreased at 12 h, 24 h, 48 h, 72 h points (P < 0.

The acute and chronic exposure protocols had equivalent effects with respect to the induction of UPR target gene expression (Fig. 8B). Steatosis occurred in 81% of the fish treated with the chronic protocol, but it did not occur after a short exposure (protocols B and Cabozantinib C). However, when the TN was washed out (protocol D), 35% of the fish developed steatosis (Fig. 8C). We then tested whether depleting Atf6 affected steatosis caused by acute

TN treatment (protocol D). The percentage of fish with steatosis was significantly reduced among mbtps11487 mutants (45%) versus WT larvae (65%) chronically challenged with TN, but the percentage increased in response to acute TN treatment (85%) in comparison with their WT siblings (42%; Fig. 8D). Similar results were obtained for atf6 morphants: 76% developed steatosis after acute TN treatment, whereas 46% and 52% of the uninjected and control-injected larvae did (Fig. 8D). Thus, Atf6 depletion potentiates steatosis

this website caused by acute ER stress in both zebrafish and mice.12, 13 We have used zebrafish as a novel tool for understanding the complex relationship between UPR activation and steatosis. Our data demonstrate that both acute and chronic ER stress can lead to steatosis, and they illustrate the opposing roles that Atf6 plays in these different scenarios. We found that Atf6 depletion protects fish from steatosis due to chronic ER stress induced by either foigr mutation or prolonged exposure MCE公司 to TN, but it can accentuate steatosis caused by acute TN treatment. This is an important distinction because most FLD etiologies are likely associated with chronic UPR activation if not frank ER stress. In these cases, attempts to improve

protein folding and reduce UPR signaling are predicted to be therapeutic. Exciting data from mouse models suggest the efficacy of this approach.10, 11, 14, 18 How does chronic UPR activation affect lipid metabolism in the liver? One possibility is that components of the UPR may directly modulate lipid metabolism. Although some studies have implicated lipid synthesis directed by Xbp135 or Srebps17, 18, 36, 37 as a factor in steatosis associated with ER stress, we do not believe that lipid synthesis is a major contributing factor to steatosis in our models. We hypothesize that the foigr mutation and TN treatment induce Atf6, and this in turn may suppress Srebp2 activity; this is consistent with data from mammalian cells.20 Although Atf6 depletion caused a slight up-regulation of Srebp2 target genes, this was insufficient to cause steatosis (see Figs. 7A and 8A,C,D). On the contrary, atf6 morphants were protected from steatosis induced by the foigr mutation. Together, our data suggest that triglyceride and cholesterol synthesis is unlikely to significantly contribute to steatosis caused by chronic ER stress. It is likely that disruption of the secretory pathway prevents lipoprotein secretion.

The acute and chronic exposure protocols had equivalent effects with respect to the induction of UPR target gene expression (Fig. 8B). Steatosis occurred in 81% of the fish treated with the chronic protocol, but it did not occur after a short exposure (protocols B and LY294002 supplier C). However, when the TN was washed out (protocol D), 35% of the fish developed steatosis (Fig. 8C). We then tested whether depleting Atf6 affected steatosis caused by acute

TN treatment (protocol D). The percentage of fish with steatosis was significantly reduced among mbtps11487 mutants (45%) versus WT larvae (65%) chronically challenged with TN, but the percentage increased in response to acute TN treatment (85%) in comparison with their WT siblings (42%; Fig. 8D). Similar results were obtained for atf6 morphants: 76% developed steatosis after acute TN treatment, whereas 46% and 52% of the uninjected and control-injected larvae did (Fig. 8D). Thus, Atf6 depletion potentiates steatosis

www.selleckchem.com/products/emd-1214063.html caused by acute ER stress in both zebrafish and mice.12, 13 We have used zebrafish as a novel tool for understanding the complex relationship between UPR activation and steatosis. Our data demonstrate that both acute and chronic ER stress can lead to steatosis, and they illustrate the opposing roles that Atf6 plays in these different scenarios. We found that Atf6 depletion protects fish from steatosis due to chronic ER stress induced by either foigr mutation or prolonged exposure 上海皓元医药股份有限公司 to TN, but it can accentuate steatosis caused by acute TN treatment. This is an important distinction because most FLD etiologies are likely associated with chronic UPR activation if not frank ER stress. In these cases, attempts to improve

protein folding and reduce UPR signaling are predicted to be therapeutic. Exciting data from mouse models suggest the efficacy of this approach.10, 11, 14, 18 How does chronic UPR activation affect lipid metabolism in the liver? One possibility is that components of the UPR may directly modulate lipid metabolism. Although some studies have implicated lipid synthesis directed by Xbp135 or Srebps17, 18, 36, 37 as a factor in steatosis associated with ER stress, we do not believe that lipid synthesis is a major contributing factor to steatosis in our models. We hypothesize that the foigr mutation and TN treatment induce Atf6, and this in turn may suppress Srebp2 activity; this is consistent with data from mammalian cells.20 Although Atf6 depletion caused a slight up-regulation of Srebp2 target genes, this was insufficient to cause steatosis (see Figs. 7A and 8A,C,D). On the contrary, atf6 morphants were protected from steatosis induced by the foigr mutation. Together, our data suggest that triglyceride and cholesterol synthesis is unlikely to significantly contribute to steatosis caused by chronic ER stress. It is likely that disruption of the secretory pathway prevents lipoprotein secretion.

A history of IDU is common among detainees[7] and injecting may continue while detained,[8-10] with attendant disease find more transmission risks. Tattooing

in closed settings may also be a risk factor for HCV transmission.[11, 12] Finally, there is increasing evidence of a significant risk of HCV transmission among human immunodeficiency virus (HIV)-infected men who have sex with men[13]; given the often high background prevalence of both infections and the lack of condom access in closed settings, this is potentially a serious concern. Despite the evidence of risk, there have been limited efforts to examine the global extent of this problem. A clearer understanding of the epidemiology of HCV in closed settings is essential for determining the scale of the problem, providing a basis for public advocacy efforts, and the development of prevention and treatment interventions. This is particularly so in light of recent advances in HCV therapies and the promise of all-oral, interferon-free treatment in the near future.[14, 15] We

undertook a systematic review and meta-analysis with the aim of determining the Selleck ITF2357 rate of incident HCV infection and the prevalence of anti-HCV among detainees in closed settings. This study is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist.[16] Throughout this article we use the term “”detainees”" to refer to the population of people detained in closed settings. This term was selected as it is inclusive of people who are incarcerated in prisons and jails, as well as those held in less common and less well-known types of closed settings. We used multiple search strategies to identify relevant literature.

Four databases of peer-reviewed literature (Medline, Embase, Criminal Justice Abstracts, and the National Criminal Justice Reference Service) were searched in July 2012. Search strings were developed in consultation with a librarian at the National Drug and Alcohol Research Centre, University of New South Wales. Search strings for Medline and Embase were adapted from Nelson et al.[5] (see Supporting Materials for additional details). Additionally, reference lists of prior reviews on this topic[17-19] were examined and the literature database of the HCV Synthesis Project[20] medchemexpress was searched for citations potentially relevant to closed settings. Gray literature, defined as publications and communications that are not formally published by commercial publishers or peer-reviewed journals, was identified through searches of websites of relevant organizations (e.g., European Monitoring Centre for Drugs and Drug Addiction), regional literature databases (e.g., Latin American and Caribbean Health Sciences), online conference archives (e.g., International AIDS Society conferences), and country-specific government departments.