Background. Extensive studies have been carried out to investigate the association between obesity and the risk of rheumatoid arthritis (RA); however, the results of the current reported original studies remain inconsistent. This study aimed to clarify the relationship between body mass index and rheumatoid arthritis by conducting an updated overall and dose-response meta-analysis. Methods. The relevant literature was searched using the PubMed and Embase databases (through 20 September 2018) to identify all eligible published studies. Random-effect models and dose-response meta-analyses were used to estimate the pooled risk ratio (RR) with a 95% confidence interval (CI). Subgroup analyses were also conducted based on the characteristics of the participants. Sensitivity analyses and publication bias tests were also performed to explore potential heterogeneity and bias in the meta-analysis. Results. Sixteen studies that included a total of 406,584 participants were included in the meta-analysis. Compared to participants with normal weight, the pooled RRs of rheumatoid arthritis were 1.12 (95% CI, 1.04-1.20) in overweight and 1.23 (95% CI, 1.09-1.39) in obese participants. There was evidence of a nonlinear relationship between body mass index (BMI) and RA (P  for nonlinearity less than 0.001 in the overall meta-analysis, P for nonlinearity=0.025 in the case-control studies, P for nonlinearity=0.0029 in the cohort studies). No significant heterogeneity was found among studies (I2=10.9% for overweight and I2=45.5% for obesity). Conclusion. The overall and dose-response meta-analysis showed that increased BMI was associated with an increased risk for rheumatoid arthritis, which might present a prevention strategy for the prevention or control of rheumatoid arthritis. The nonlinear relationship between BMI and RA might present a personal prevention strategy for RA.

Red blood cell distribution width (RDW) is the coefficient of variation of red blood cell size, considered to be associated with cardiovascular disease (CVD). This study aimed to comprehensively synthesize previous studies on RDW and CVD outcomes through an overall and dose-response meta-analysis. PubMed, Embase and Web of Science were searched systematically for English and Chinese language publications up to November 30, 2015. We extracted data from publications matching our inclusion criteria for calculating pooled hazard ratio (HR), which was used to assess prognostic impact of RDW on CVD. Twenty-seven articles, consisting of 28 studies and 102,689 participants (mean age 63.9 years, 63,703 males/36,846 females, 2,140 gender-unmentioned subjects) were included in the present meta-analysis. The pooled HRs are 1.12 (95% CI = 1.09–1.15) for the association of all-cause mortality (ACM) per 1% increase of RDW, 1.12(95% CI = 1.08–1.17) for major adverse cardiac events (MACEs) per 1% increase of RDW. A dose-response curve relating RDW increase to its effect on CVD outcomes was established (p_curve < 0.001). For every 1-unit increase of RDW, there is an increased risk of occurrence of ACM (pooled HR = 1.03, 95% CI = 1.02–1.04) and MACEs (pooled HR = 1.04, 95% CI = 1.01–1.06). This study indicates RDW may be a prognostic indicator for CVD outcomes.

Hand, foot, and mouth disease (HFMD) is a global health concern. Family Picornaviridae members, particularly enterovirus A71 (EVA71) and coxsackievirus A16 (CVA16), are the primary etiological agents of HFMD; however, a third enterovirus A species, CVA6, has been recently associated with epidemic outbreaks. Study of the pathogenesis of CVA6 infection and development of antivirals and vaccines are hindered by a lack of appropriate animal models. We have developed and characterized a murine model of CVA6 infection that was employed to evaluate the antiviral activities of different drugs and the protective efficacies of CVA6-inactivated vaccines. Neonatal mice were susceptible to CVA6 infection via intramuscular inoculation, and the susceptibility of mice to CVA6 infection was age and dose dependent. Five-day-old mice infected with 10 ^5.5 50% tissue culture infective doses of the CVA6 WF057R strain consistently exhibited clinical signs, including reduced mobility, lower weight gain, and quadriplegia with significant pathology in the brain, hind limb skeletal muscles, and lungs of the infected mice in the moribund state. Immunohistochemical analysis and quantitative reverse transcription-PCR (qRT-PCR) analyses showed high viral loads (11 log ₁₀ /mg) in skeletal muscle, and elevated levels of interleukin-6 (IL-6; >2,000 pg/ml) were associated with severe viral pneumonia and encephalitis. Ribavirin and gamma interferon administered prophylactically diminished CVA6-associated pathology in vivo , and treatment with IL-6 accelerated the death of neonatal mice. Both specific anti-CVA6 serum and maternal antibody play important roles in controlling CVA6 infection and viral replication. Collectively, these findings indicate that this neonatal murine model will be invaluable in future studies to develop CVA6-specific antivirals and vaccines. IMPORTANCE Although coxsackievirus A6 (CVA6) infections are commonly mild and self-limiting, a small proportion of children may have serious complications, such as encephalitis, acute flaccid paralysis, and neurorespiratory syndrome, leading to fatalities. We have established a mouse model of CVA6 infection by inoculation of neonatal mice with a CVA6 clinical isolate that produced consistent pathological outcomes. Here, using this model of CVA6 infection, we found that high levels of IL-6 were associated with severe viral pneumonia and encephalitis, as in an evaluation of antiviral efficacy in vivo , IL-6 had no protective effect and instead accelerated death in neonatal mice. We demonstrated that, as antiviral drugs, both gamma interferon and ribavirin played important protective roles in the early stages of infection, with increased survival in treated neonatal mice challenged with CVA6. Moreover, active and passive immunization with the inactivated vaccines and anti-CVA6 serum also protected mice against homologous challenge infections.

Coxsackievirus A10 (CVA10) is one of the major pathogens associated with hand, foot, and mouth disease (HFMD). CVA10 infection can cause herpangina and viral pneumonia, which can be complicated by severe neurological sequelae. The morbidity and mortality of CVA10-associated HFMD have been increasing in recent years, particularly in the pan-Pacific region. There are limited studies, however, on the pathogenesis and immunology of CVA10-associated HFMD infections, and few antiviral drugs or vaccines have been reported. In the present study, a cell-adapted CVA10 strain was employed to inoculate intramuscularly 5-day-old ICR mice, which developed significant clinical signs, including reduced mobility, lower weight gain, and quadriplegia, with significant pathology in the brain, hind limb skeletal muscles, and lungs of infected mice in the moribund state. The severity of illness was associated with abnormally high expression of the proinflammatory cytokine interleukin 6 (IL-6). Antiviral assays demonstrated that ribavirin and gamma interferon administration could significantly inhibit CVA10 replication bothin vitroandin vivo. In addition, formaldehyde-inactivated CVA10 whole-virus vaccines induced immune responses in adult mice, and maternal neutralizing antibodies could be transmitted to neonatal mice, providing protection against CVA10 clinical strains. Furthermore, high-titer antisera were effective against CVA10 and could relieve early clinical symptoms and improve the survival rates of CVA10-challenged neonatal mice. In summary, we present a novel murine model to study CVA10 pathology that will be extremely useful in developing effective antivirals and vaccines to diminish the burden of HFMD-associated disease.IMPORTANCEHand, foot, and mouth disease cases in infancy, arising from coxsackievirus A10 (CVA10) infections, are typically benign, resolving without any significant adverse events. Severe disease and fatalities, however, can occur in some children, necessitating the development of vaccines and antiviral therapies. The present study has established a newborn-mouse model of CVA10 that, importantly, recapitulates many aspects of human disease with respect to the neuropathology and skeletal muscle pathology. We found that high levels of the proinflammatory cytokine interleukin 6 correlated with disease severity and that ribavirin and gamma interferon could decrease viral titersin vitroandin vivo. Whole-virus vaccines produced immune responses in adult mice, and immunized mothers conferred protection on neonates against challenge from CVA10 clinical strains. Passive immunization with high-titer antisera could also improve survival rates in newborn animals.