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emerging infectious diseases - Top 30 Publications

Design, Synthesis and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC.

Over the past several decades the frequency of antibacterial resistance in hospitals, including multi-drug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding (PPB) was improved while retaining potent anti-pseudomonal activity in vitro and in vivo.

Incidental mosquitocidal effect of an ivermectin mass drug administration on Anopheles farauti conducted for scabies control in the Solomon Islands.

The Solomon Islands is targeting elimination of malaria by 2030. The dominant vector is the predominantly exophagic, exophilic Anopheles farauti sensu strictu. This biting behaviour limits the efficacy of conventional vector control tools and highlights the need for new strategies. When administered to humans ivermectin has been shown to have a mosquitocidal effect. Mass drug administration (MDA) with ivermectin is an emerging strategy in the control of scabies. In this study we explored any incidental effect of ivermectin MDA conducted for scabies control on mosquitoes.

Gut microbiota and host defense in critical illness.

The review aims to discuss emerging evidence in the field of microbiome-dependent roles in host defense during critical illness with a focus on lung, kidney, and brain inflammation.

Outbreaks of nontuberculous mycobacteria.

The purpose of this review is to summarize the emerging literature on nontuberculous mycobacteria outbreaks in healthcare settings. As our ability to identify mycobacterial species develops, we are better able to recognize epidemiologic connections and better understand the prevalence and importance of these outbreaks and pseudo-outbreaks in healthcare settings.

High Infection Rates for Adult Macaques after Intravaginal or Intrarectal Inoculation with Zika Virus.

Unprotected sexual intercourse between persons residing in or traveling from regions with Zika virus transmission is a risk factor for infection. To model risk for infection after sexual intercourse, we inoculated rhesus and cynomolgus macaques with Zika virus by intravaginal or intrarectal routes. In macaques inoculated intravaginally, we detected viremia in 75% of macaques and virus RNA in 100%, followed by seroconversion. In macaques inoculated intrarectally, we detected viremia, virus RNA, or both, in 100% of both species, followed by seroconversion. The magnitude and duration of infectious virus in blood of macaques suggest humans infected with Zika virus through sexual transmission will likely generate viremias sufficient to infect competent mosquito vectors. Our results indicate that transmission of Zika virus by sexual intercourse might serve as a virus maintenance mechanism in the absence of mosquito-to-human transmission and could increase the probability of establishment and spread of Zika virus in regions where this virus is not present.

Long-lasting tuberculous pleurisy.

Emerging Infectious Diseases and Blood Safety: Modeling the Transfusion-Transmission Risk.

While the transfusion-transmission (TT) risk associated with the major transfusion-relevant viruses such as HIV is now very low, during the last 20 years there has been a growing awareness of the threat to blood safety from emerging infectious diseases, a number of which are known to be, or are potentially, transfusion transmissible. Two published models for estimating the transfusion-transmission risk from EIDs, referred to as the Biggerstaff-Petersen model and the European Upfront Risk Assessment Tool (EUFRAT), respectively, have been applied to several EIDs in outbreak situations. We describe and compare the methodological principles of both models, highlighting their similarities and differences. We also discuss the appropriateness of comparing results from the two models. Quantitating the TT risk of EIDs can inform decisions about risk mitigation strategies and their cost-effectiveness. Finally, we present a qualitative risk assessment for Zika virus (ZIKV), an EID agent that has caused several outbreaks since 2007. In the latest and largest ever outbreak, several probable cases of transfusion-transmission ZIKV have been reported, indicating that it is transfusion-transmissible and therefore a risk to blood safety. We discuss why quantitative modeling the TT risk of ZIKV is currently problematic.

Sources of variability in the measurement of Ascaris lumbricoides infection intensity by Kato-Katz and qPCR.

Understanding and quantifying the sources and implications of error in the measurement of helminth egg intensity using Kato-Katz (KK) and the newly emerging "gold standard" quantitative polymerase chain reaction (qPCR) technique is necessary for the appropriate design of epidemiological studies, including impact assessments for deworming programs.

Advantages and limitations for users of double pit pour-flush latrines: a qualitative study in rural Bangladesh.

In rural Bangladesh, India and elsewhere, pour-flush pit latrines are the most common sanitation system. When a single pit latrine becomes full, users must empty it themselves and risk exposure to fresh feces, pay an emptying service to remove pit contents or build a new latrine. Double pit pour-flush latrines may serve as a long-term sanitation option including high water table areas because the pits do not need to be emptied immediately and the excreta decomposes into reusable soil.

Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase LdtMt2 by biapenem and tebipenem.

The carbapenem subclass of β-lactams is among the most potent antibiotics available today. Emerging evidence shows that, unlike other subclasses of β-lactams, carbapenems bind to and inhibit non-classical transpeptidases (L,D-transpeptidases) that generate 3 → 3 linkages in bacterial peptidoglycan. The carbapenems biapenem and tebipenem exhibit therapeutically valuable potencies against Mycobacterium tuberculosis (Mtb).

Prevalence and extent of heteroresistance by next generation sequencing of multidrug-resistant tuberculosis.

Amplicon-based Next Generation Sequencing (NGS) is an emerging method for Mycobacterium tuberculosis drug susceptibility testing (DST) but has not been well described. We examined 158 clinical multidrug-resistant M. tuberculosis isolates via NGS of 11 resistance-associated gene regions covering 3519 nucleotides. Across these gene regions, complete resistance or heteroresistance (defined as 1%-99% mutation) was present in at least one isolate in 6.3% of loci. The number of isolates with heteroresistance was highest for gyrA codon 94, rpoB codons 526 and 531, and embB codons 306, 372 and 406 (range 11-26% of isolates exhibited heteroresistance). 57% of MDR strains had heteroresistance of one or more recognized resistance-associated mutation. Heteroresistant loci generally exhibited high or low degrees of mutation (>90% or <10%). The deep sensitivity of NGS for detecting low level pncA heteroresistance appeared to improve genotypic-phenotypic PZA susceptibility correlations over that of Sanger. NGS demonstrates that heteroresistance in TB in the regions of key genes is common and will need to be bioinformatically managed. The clinical significance of such heteroresistance is unclear, and further study of pncA should be pursued.

Illness experiences of diabetes in the context of malaria in settings experiencing double burden of disease in southeastern Tanzania.

Tanzania is doubly burdened with both non-communicable and infectious diseases, but information on how Tanzanians experience the co-existence of these conditions is limited. Using Kleinman's eight prompting questions the study synthesizes explanatory models from patients to describe common illness experiences of diabetes in a rural setting where malaria is the predominant health threat.

Elevation as a proxy for mosquito-borne Zika virus transmission in the Americas.

When Zika virus (ZIKV) first began its spread from Brazil to other parts of the Americas, national-level travel notices were issued, carrying with them significant economic consequences to affected countries. Although regions of some affected countries were likely unsuitable for mosquito-borne transmission of ZIKV, the absence of high quality, timely surveillance data made it difficult to confidently demarcate infection risk at a sub-national level. In the absence of reliable data on ZIKV activity, a pragmatic approach was needed to identify subnational geographic areas where the risk of ZIKV infection via mosquitoes was expected to be negligible. To address this urgent need, we evaluated elevation as a proxy for mosquito-borne ZIKV transmission.

Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally.

Feasibility and applicability of antimicrobial stewardship in immunocompromised patients.

Antimicrobial stewardship is the primary intervention in the battle against antimicrobial resistance, but clinicians do not always apply many key antimicrobial stewardship principles to patients with significant immune defects due to lack of data and fear of bad outcomes. We review evidence regarding the application of stewardship principles to immunocompromised patients, with a focus on solid organ and hematopoietic stem cell transplant recipients.

Bumped kinase inhibitor gastrointestinal exposure is necessary to treat Cryptosporidium infection.

There is a substantial need for novel therapeutics to combat the widespread impact caused by Crytosporidium infection. However, there is a lack of knowledge on which drug pharmacokinetic characteristics are key to generate an in vivo response specifically if systemic drug exposure is crucial for in vivo efficacy. To identify which pharmacokinetic properties are correlated with in vivo efficacy, we generated physiologically based pharmacokinetic (PBPK) models to simulate systemic and gastrointestinal (GI) drug concentrations for a series of bumped kinase inhibitors (BKI) that have nearly identical in vitro potency against Cryptosporidium but display divergent pharmacokinetic properties. When BKI concentrations were used to predict in vivo efficacy with a neonatal model of Cryptosporidium infection, BKI concentrations in the large intestine were the sole predictors of the observed in vivo efficacy. The significance of large intestinal BKI exposure for predicting in vivo efficacy was further supported with an adult mouse model of Cryptosporidium infection. This study suggests that drug exposure in the large intestine is essential for generating a superior in vivo response, and that PBPK models can assist in the prioritization of lead pre-clinical drug candidates for in vivo testing.

Delayed Diagnosis of Tuberculous Meningitis Misdiagnosed as Herpes Simplex Virus-1 Encephalitis With the FilmArray Syndromic Polymerase Chain Reaction Panel.

The FilmArray meningitis/encephalitis (ME) panel is a novel syndromic, nucleic acid amplification test for diagnosis of acute meningitis and encephalitis. Emerging data on its performance are concerning for false-positive results. We present a case of tuberculous meningitis misdiagnosed as herpes simplex virus-1 encephalitis with the FilmArray ME panel. Strategies to mitigate erroneous results are discussed.

Faecal microbiota transplantation: Where did it start? What have studies taught us? Where is it going?

The composition and activity of microorganisms in the gut, the microbiome, is emerging as an important factor to consider with regard to the treatment of many diseases. Dysbiosis of the normal community has been implicated in inflammatory bowel disease, Crohn's disease, diabetes and, most notoriously, Clostridium difficile infection. In Canada, the leading treatment strategy for recalcitrant C. difficile infection is to receive faecal material which by nature is filled with microorganisms and their metabolites, from a healthy individual, known as a faecal microbiota transplantation. This influx of bacteria into the gut helps to restore the microbiota to a healthy state, preventing C. difficile from causing further disease. Much of what is known with respect to the microbiota and faecal microbiota transplantation comes from animal studies simulating the human disease. Although these models allow researchers to perform studies that would be difficult in humans, they do not always recapitulate the human microbiome. This makes the translation of these results to humans somewhat questionable. The purpose of this review is to analyse these animal models and discuss the advantages and the disadvantages of them in relation to human translation. By understanding some of the limitation of animal models, we will be better able to design and perform experiments of most relevance to human applications.

Contribution of human lung parenchyma and leukocyte influx to oxidative stress and immune-mediated pathology following Nipah infection.

Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause a fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD scid gamma mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the Bone marrow, Liver, and Thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections.Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune system reconstituted mice in order to identify the overall effect of immune cells in NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects, irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in the lung grafts. In addition, the presence of human leukocytes increased expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI, and informs efforts to identify therapeutic targets.IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis of the human lung, and the relative contribution of the innate immune response and NiV in acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system reconstituted mouse model we showed that NiV Bangladesh strain induced similar cytopathic lesions in lung grafts, as described in patients, irrespective of the donor origin or the presence of leukocytes. However, the human immune system interfered with virus spread, responded to infection by leukocyte infiltrations in the small airways and alveolar area, induced oxidative stress, and triggered production of cytokines and chemokines that regulate inflammatory influx by leukocytes in response to infection. Understanding how leukocytes interact with NiV and cause ALI in human lung xenografts is crucial for identifying therapeutic targets.

Spontaneous mutation at amino acid 544 of the Ebola glycoprotein potentiates virus entry and selection in tissue culture.

Ebolaviruses have a surface glycoprotein (GP1,2) required for virus attachment and entry into cells. Mutations affecting GP1,2 functions can alter virus growth properties. We generated a recombinant vesicular stomatitis virus encoding Ebola Virus Makona variant GP1,2 (rVSV-MAK-GP) and observed emergence of a T544I mutation in the Makona GP1,2 gene during tissue culture passage in certain cell lines. The T544I mutation emerged within two passages when VSV-MAK-GP was grown on Vero E6, Vero, and BS-C-1 cells but not when it was passaged on Huh7 and HepG2 cells. The mutation led to a marked increase in virus growth kinetics and conferred a robust growth advantage over wildtype rVSV-MAK-GP on Vero E6 cells. Analysis of complete viral genomes collected from patients in Western Africa indicated that this mutation was not found in Ebola Virus clinical samples. However, we observed the emergence of T544I during serial passage of various Ebola Makona isolates on Vero E6 cells. Three independent isolates showed emergence of T544I from undetectable levels in non-passaged virus or virus passaged once, to frequencies greater than 60% within a single passage, consistent with it being a tissue culture adaptation. Intriguingly, T544I is not found in any Sudan, Bundibugyo, or Tai Forest ebolavirus sequences. Furthermore, T544I did not emerge when we serial passaged recombinant VSV encoding GP1,2 from these ebolaviruses. This report provides experimental evidence that the spontaneous mutation T544I is a tissue culture adaptation in certain cell lines and that it may be unique for the species Zaire ebolavirusIMPORTANCE Ebola virus (Zaire) species is the most lethal species of all ebolaviruses in terms of mortality rate and number of deaths. Understanding how the Ebola virus surface glycoprotein functions to facilitate entry in cells is an area of intense research. Recently, three groups independently identified a polymorphism in the Ebola glycoprotein (I544) that enhanced virus entry, but they did not agree in their conclusions regarding its impact on pathogenesis. Our findings here address the origins of this polymorphism and provide experimental evidence showing that it is the result of spontaneous mutation (T544I) specific to tissue culture conditions, suggesting it has no role in pathogenesis. We further show that this mutation may be unique to the species Zaire ebolavirus as it does not occur in Sudan, Bundibugyo, and Tai Forest ebolaviruses. Understanding the mechanism behind this mutation can provide insight into functional differences that exist in culture conditions and among ebolavirus glycoproteins.

Point of Care Testing for Infectious Diseases -- Past, Present and Future.

Point-of-care (POC) diagnostics provide rapid actionable information for patient care at the time and site of encounter with the health care system. The usual platform has been the lateral flow immunoassay. Recently, emerging molecular diagnostics have met requirements for speed, low cost and ease of use for POC applications. A major driver for POC development is the ability to diagnose infectious diseases at sites with limited infrastructure. Potential use in both wealthy and resource-limited settings has fueled an intense effort to build on existing technologies and to generate new technologies for diagnosis of a broad spectrum of infectious diseases.

Advances Afoot in Microbiology.

In 2016, the American Academy of Microbiology convened a colloquium to examine point-of-care (POC) microbiology testing and to evaluate its effects on clinical microbiology. Colloquium participants included representatives from clinical microbiology laboratories, industry, and the government, who together made recommendations regarding the implementation, oversight and evaluation of POC microbiology testing. The colloquium report is timely and well-written. (V. Dolen et al., Changing Diagnostic Paradigms for Microbiology, 2017, Emerging POC microbiology tests, especially nucleic acid amplification tests, have the potential to advance medical care.

Multiplex PCR method for MinION and Illumina sequencing of Zika and other virus genomes directly from clinical samples.

Genome sequencing has become a powerful tool for studying emerging infectious diseases; however, genome sequencing directly from clinical samples (i.e., without isolation and culture) remains challenging for viruses such as Zika, for which metagenomic sequencing methods may generate insufficient numbers of viral reads. Here we present a protocol for generating coding-sequence-complete genomes, comprising an online primer design tool, a novel multiplex PCR enrichment protocol, optimized library preparation methods for the portable MinION sequencer (Oxford Nanopore Technologies) and the Illumina range of instruments, and a bioinformatics pipeline for generating consensus sequences. The MinION protocol does not require an Internet connection for analysis, making it suitable for field applications with limited connectivity. Our method relies on multiplex PCR for targeted enrichment of viral genomes from samples containing as few as 50 genome copies per reaction. Viral consensus sequences can be achieved in 1-2 d by starting with clinical samples and following a simple laboratory workflow. This method has been successfully used by several groups studying Zika virus evolution and is facilitating an understanding of the spread of the virus in the Americas. The protocol can be used to sequence other viral genomes using the online Primal Scheme primer designer software. It is suitable for sequencing either RNA or DNA viruses in the field during outbreaks or as an inexpensive, convenient method for use in the lab.

Genomic epidemiology reveals multiple introductions of Zika virus into the United States.

Zika virus (ZIKV) is causing an unprecedented epidemic linked to severe congenital abnormalities. In July 2016, mosquito-borne ZIKV transmission was reported in the continental United States; since then, hundreds of locally acquired infections have been reported in Florida. To gain insights into the timing, source, and likely route(s) of ZIKV introduction, we tracked the virus from its first detection in Florida by sequencing ZIKV genomes from infected patients and Aedes aegypti mosquitoes. We show that at least 4 introductions, but potentially as many as 40, contributed to the outbreak in Florida and that local transmission is likely to have started in the spring of 2016-several months before its initial detection. By analysing surveillance and genetic data, we show that ZIKV moved among transmission zones in Miami. Our analyses show that most introductions were linked to the Caribbean, a finding corroborated by the high incidence rates and traffic volumes from the region into the Miami area. Our study provides an understanding of how ZIKV initiates transmission in new regions.

High prevalence of four novel astrovirus genotype species identified from rodents in China.

Astroviruses cause gastrointestinal and neurological infections in humans and animals. Since astrovirus is genetically diverse and different astrovirus genotypes can be found in the same animal species, astrovirus is a potential zoonotic threat to humans. In this study, we screened for astroviruses in rodents from Hong Kong, Hunan and Guangxi. Astrovirus was detected in 11.9 % (67/562) of rectal swab specimens. Phylogenetic analysis of the ORF1b region, which encodes the RdRp, showed that there were four distinct clusters (clusters A, B, C and D). Whole genome sequencing was performed for 11 representative strains from each of these four clusters. The mean amino acid genetic distances (p-dist) of full-length ORF2 were >0.634 between clusters A, B, C and other known astroviruses. The p-dist between clusters A and B, A and C, and B and C were 0.371-0.375, 0.517-0.549 and 0.524-0.555, respectively. Within cluster C, the p-dist between HN-014 and GX-006 was 0.372. Since strains with p-dist of ≥0.368 in ORF2 are now considered to be of separate genotypes species, cluster A, cluster B, cluster C-HN-014 and cluster C-GX-006 can be classified as novel genotype species. Cluster D was most closely related to the rodent astrovirus previously identified in Hong Kong. Since rodents live in close proximity to humans, interspecies jumping of these novel astroviruses may represent a threat to human health.

Native valve endocarditis caused by Lactococcus garvieae: an emerging human pathogen.

A 57-year-old man presented with native mitral valve endocarditis caused by Lactococcus garvieae, a known animal pathogen that is increasingly being reported as a cause of human infections. The organism was cultured in four sets of blood cultures and identification was initially made by matrix-assisted laser desorption/ionisation-time of flight mass spectrometry and confirmed by 16S rDNA PCR of the blood culture isolate. He was successfully treated with 6 weeks of both amoxicillin and gentamicin and underwent valve replacement surgery after 4 weeks of antimicrobial treatment. The removed valve was sterile but L. garvieae DNA was detected on the valve using 16S rDNA PCR. The cause of the L. garvieae infection could not be ascertained but flexible sigmoidoscopy demonstrated colonic polyps, which have been linked to infection with this organism.

Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial.

- Macrolides can ameliorate inflammation in respiratory diseases, providing clinical benefits. Data in influenza is lacking.

Helicobacter Infection Significantly Alters Pregnancy Success in Laboratory Mice.

Helicobacter spp. are gram-negative, helically shaped bacteria that cause gastric and enterohepatic infections in mammalian species. Although Helicobacter infection frequently is implicated to interfere with reproductive success, few experimental data support these claims. We therefore retrospectively investigated the effect of Helicobacter infection on murine pregnancy outcome after the identification of endemic Helicobacter infection in an animal research facility. Multiplex conventional PCR analysis was used to characterize Helicobacter infection status in one inbred and 2 transgenic strains of mice in 2 self-contained rooms assigned to the same investigator. Outcomes of timed-mating experiments were compared among Helicobacter spp.-infected and uninfected mice of the same strain; Helicobacter infection was eradicated from the colony through fostering with uninfected dams. Although Helicobacter infection affected fecundity in only one strain of transgenic mouse, the total number of embryos per gravid uterus was significantly reduced in C57BL/6J mice that were infected with a single Helicobacter species, H. typhlonius. Helicobacter infection was also associated with a significant increase in the number of resorbing embryos per uterus and significant decreases in pregnancy-associated weight gain relative to uninfected mice in C57BL6/J mice and one transgenic strain. Helicobacter spp.-infected mice of all tested strains exhibited higher frequency of intrauterine hemorrhaging relative to uninfected mice. These results indicate that naturally-acquired Helicobacter infection not only reduces the productivity of a research animal breeding colony, but also negatively impacts embryo health. Despite these deleterious effects, these data suggest that colonies can be rederived to be Helicobacter-free by Cesarean section and fostering with uninfected dams. This paper provides the first evidence that H. typhlonius infection is sufficient to interfere with reproductive success and embryo health of C57BL/6J mice. Animal research facilities should therefore implement Helicobacter spp. surveillance and control practices to avoid confounding experimental results and to improve breeding colony efficiency.

DRodVir: A resource for exploring the virome diversity in rodents.

Emerging zoonotic diseases have received tremendous interests in recent years, as they pose a significant threat to human health, animal welfare, and economic stability. A high proportion of zoonoses originate from wildlife reservoirs. Rodents are the most numerous, widespread, and diverse group of mammals on the earth and are reservoirs for many zoonotic viruses responsible for significant morbidity and mortality. A better understanding of virome diversity in rodents would be of importance for researchers and professionals in the field. Therefore, we developed the DRodVir database (, a comprehensive, up-to-date, and well-curated repository of rodent-associated animal viruses. The database currently covers 7690 sequences from 5491 rodent-associated mammal viruses of 26 viral families detected from 194 rodent species in 93 countries worldwide. In addition to virus sequences, the database provides detailed information on related samples and host rodents, as well as a set of online analytical tools for text query, BLAST search and phylogenetic reconstruction. The DRodVir database will help virologists better understand the virome diversity of rodents. Moreover, it will be a valuable tool for epidemiologists and zoologists for easy monitoring and tracking of the current and future zoonotic diseases. As a data application example, we further compared the current status of rodent-associated viruses with bat-associated viruses to highlight the necessity for including additional host species and geographic regions in future investigations, which will help us achieve a better understanding of the virome diversities in the two major reservoirs of emerging zoonotic infectious diseases.

Prevalence and correlates of hepatitis C virus-associated inflammatory arthritis in a population-based cohort.

The objectives of this study were to determine the prevalence of hepatitis C virus-associated inflammatory arthritis, to describe its clinical and immunologic correlates, and to identify features that are characteristic of arthritis in chronic hepatitis C.