Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial

OBJECTIVE: Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). METHODS: In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). RESULTS: At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. CONCLUSION: In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.     

Toward integrated opisthorchiasis control in northeast Thailand: The Lawa project

Human liver fluke, Opisthorchis viverrini, a food-borne trematode is a significant public health problem in Southeast Asia, particularly in Thailand. Despite a long history of control programmes in Thailand and a nationwide reduction, O. viverrini infection prevalence remains high in the northeastern provinces. Therefore, a new strategy for controlling the liver fluke infection using the EcoHealth/One Health approach was introduced into the Lawa Lake area in Khon Kaen province where the liver fluke is endemic. A programme has been carried using anthelminthic treatment, novel intensive health education methods both in the communities and in schools, ecosystem monitoring and active community participation. As a result, the infection rate in the more than 10 villages surrounding the lake has declined to approximate one third of the average of 50% as estimated by a baseline survey. Strikingly, the Cyprinoid fish species in the lake, which are the intermediate host, now showed less than 1% prevalence compared to a maximum of 70% at baseline. This liver fluke control programme, named “Lawa model,” is now recognised nationally and internationally, and being expanding to other parts of Thailand and neighbouring Mekong countries. Challenges to O. viverrini disease control, and lessons learned in developing an integrative control programme using a community-based, ecosystem approach, and scaling-up regionally based on Lawa as a model are described.     

A Qualitative,Cross-Sectional Study of Positive and Negative Comments of Residency Programs Across 9 Medical and Surgical Specialties

IMPORTANCE

Residency applicants often use social media to discuss the positive and negative features of prospective training programs. An examination of the content discussed by applicants could provide guidance for how a medical education faculty can better engage with prospective trainees and adapt to meet the educational expectations of a new generation of digital-native physicians.

The efficacy of immediate versus delayed antibiotic administration on bacterial growth and biofilm production of selected strains of uropathogenic Escherichia coli and Pseudomonas aeruginosa

Purpose

The treatment of urinary tract infections (UTI) with antibiotics is commonly used, but recurrence and antibiotic resistance have been growing and concerning clinicians. We studied whether the rapid onset of a protective biofilm may be responsible for the lack of effectiveness of antibiotics against selected bacteria.

Materials and Methods

Two established uropathogenic Escherichia coli strains, UTI89 and CFT073, and two Pseudomonas aeruginosa strains, PA01 and Boston-41501, were studied to establish a reliable biofilm formation process. Bacterial growth (BG) was determined by optical density at 600 nm (OD 600) using a spectrophotometer, while biofilm formation (BF) using crystal violet staining was measured at OD 550. Next, these bacterial strains were treated with clinically relevant antibiotics, ciprofloxacin HCl (200 ng/mL and 2 μg/mL), nitrofurantoin (20 μg/mL and 40 μg/mL) and ampicillin (50 μg/mL) at time points of 0 (T0) or after 6 hours of culture (T6). All measurements, including controls (bacteria -1% DMSO), were done in triplicates and repeated three times for consistency.

Results

The tested antibiotics effectively inhibited both BG and BF when administered at T0 for UPEC strains, but not when the antibiotic administration started 6 hours later. For Pseudomonas strains, only Ciprofloxacin was able to significantly inhibit bacterial growth at T0 but only at the higher concentration of 2 μg/mL for T6.

Conclusion

When established UPEC and Pseudomonas bacteria were allowed to culture for 6 hours before initialization of treatment, the therapeutic effect of selected antibiotics was greatly suppressed when compared to immediate treatment, probably as a result of the protective nature of the biofilm.     

Boosting can explain patterns of fluctuations of ratios of inapparent to symptomatic dengue virus infections

Dengue is the most prevalent arboviral disease worldwide, and the four dengue virus (DENV) serotypes circulate endemically in many tropical and subtropical regions. Numerous studies have shown that the majority of DENV infections are inapparent, and that the ratio of inapparent to symptomatic infections (I/S) fluctuates substantially year-to-year. For example, in the ongoing Pediatric Dengue Cohort Study (PDCS) in Nicaragua, which was established in 2004, the I/S ratio has varied from 16.5:1 in 2006–2007 to 1.2:1 in 2009–2010. However, the mechanisms explaining these large fluctuations are not well understood. We hypothesized that in dengue-endemic areas, frequent boosting (i.e., exposures to DENV that do not lead to extensive viremia and result in a less than fourfold rise in antibody titers) of the immune response can be protective against symptomatic disease, and this can explain fluctuating I/S ratios. We formulate mechanistic epidemiologic models to examine the epidemiologic effects of protective homologous and heterologous boosting of the antibody response in preventing subsequent symptomatic DENV infection. We show that models that include frequent boosts that protect against symptomatic disease can recover the fluctuations in the I/S ratio that we observe, whereas a classic model without boosting cannot. Furthermore, we show that a boosting model can recover the inverse relationship between the number of symptomatic cases and the I/S ratio observed in the PDCS. These results highlight the importance of robust dengue control efforts, as intermediate dengue control may have the potential to decrease the protective effects of boosting.

Dengue virus (DENV) is the most prevalent vector-borne viral disease of humans, with recent estimates of around 105 million individuals infected annually (1). It comprises four antigenically distinct serotypes, DENV-1 to -4 (2), and is transmitted to humans by Aedes aegypti and, less frequently, Aedes albopictus mosquitoes (3–5). While most studies have focused on symptomatic infections, epidemiologic studies have shown that for dengue, the majority of infections are inapparent (3, 5), that is, infections that do not cause detected disease but result in a fourfold or greater rise in antibody titers. However, large fluctuations in annual dengue inapparent:symptomatic (I/S) ratios have been documented worldwide (5). For example, cohort studies able to detect inapparent DENV infections in Nicaragua (6–9), Peru (10), and Thailand (11) have shown that the I/S ratio of DENV infections ranges widely year to year. In the Pediatric Dengue Cohort Study (PDCS) in Nicaragua, the longest running dengue cohort study, the I/S ratio has varied widely, from 16.5:1 in 2006–2007 (7) to 1.2:1 in 2009–2010 (9). We currently do not understand the drivers of these fluctuations; however, we do know that potential extrinsic drivers, such as differences in replication rates of the predominating serotype, cannot explain them (5). Gaining a mechanistic understanding of these fluctuations in the I/S ratio is likely to be critical for understanding potential drivers of epidemic potential and severe dengue disease and for enacting effective control policies.Extensive research has been conducted into the causes of DENV infection and disease, and there is now some evidence to suggest that immune interactions among viruses and strains may be responsible for fluctuating patterns (12–14). In particular, this extensive body of work has shown that severe disease occurs due to immunopathology (4, 15, 16). The most important risk factor for severe dengue disease is secondary heterologous infections (4), due in part to a phenomenon called antibody-dependent enhancement (ADE), in which antibodies from a first infection cross-react with virus from a secondary infection, leading to incomplete neutralization. The resulting partially neutralized immune complexes enhance infection into Fc receptor-bearing cells (17). Low to intermediate titers of cross-reactive anti-DENV antibodies have been shown to enhance subsequent dengue disease severity in human populations (15, 18, 19). However, neutralizing antibody titers are thought to be protective against dengue disease, and a recent study showed that higher preinfection neutralizing antibody titers correlated with lower probability of symptomatic infection in children in the PDCS (20). Importantly, individuals with inapparent heterologous secondary infections had significantly higher preinfection titers than individuals with symptomatic heterologous secondary infections (20–22), providing direct evidence that preinfection neutralizing antibody titer is an important determinant of disease outcome. Therefore, it is plausible that the variability in preinfection antibody titer could explain fluctuations in I/S ratios.Recent work has suggested that frequent exposure to DENV may boost the immune response and result in modest increases in neutralizing antibody titer (20), which in turn may protect individuals against symptomatic infection. Evidence for boosting comes from analysis of neutralizing antibodies following primary infection. Here we have defined boosting as exposures to DENV that do not lead to extensive viremia and that result in a less than fourfold rise in antibody titers. Traditionally, the temporary period of cross-protection against heterotypic serotypes following a primary infection is explained by waning cross-reactive antibodies, resulting in a decrease in neutralizing antibody titers (23). However, an analysis of neutralizing antibody titers from the PDCS showed that neutralizing antibody titers did not decrease in the time between primary and secondary DENV infection, but in fact increased marginally (20). A comparable trend was seen in Thailand (24) and in a long-term hospital-based study in Nicaragua (25, 26). The increase in neutralizing antibody titer may be due to immune boosts (20), suggesting that children may be regularly exposed to DENV without experiencing symptoms or meeting the criteria for inapparent infection. There is also evidence of a phenomenon similar to boosting in a human vaccine study (27) and in a study in nonhuman primates (28), where in both cases there was initial exposure that resulted in viremia and seroconversion and a second challenge that did not result in viremia but did result in increased antibody titers. Clearly, in years with a high incidence of dengue, we would expect boosting to occur more frequently, and thus in the years immediately following high dengue incidence, we would expect fewer symptomatic infections, as individuals would be protected against symptomatic infection due to boosts (5).Here we used mathematical models to determine which mechanisms can recover the fluctuations in the I/S ratio in DENV infections. Since our aim was to gain a conceptual qualitative understanding of the role of the impact of a range of mechanisms, we took the classic simplifying approach of not explicitly modeling the mosquito population dynamics. All models are adapted from existing dengue epidemiologic models (12, 29) and include immunity against homologous reinfection, a period of cross-protection following infection, and seasonality. For simplicity, we model the whole population but also present results from a model of the pediatric cohort from which our data are taken. With only these factors, a year-to-year variation in case number is seen, but not a variation in I/S ratio. This model was first modified to include the basic assumption that antibody titer decreases with time since infection and is predictive of infection outcome (20), to evaluate whether I/S fluctuations can be recovered by shorter periods of cross-protection between primary infections and secondary heterotypic infections for inapparent secondary infections than for symptomatic secondary infections, as previously suggested (6, 23).We then explored whether I/S ratio differences can be explained by protection against symptomatic disease due to boosting of the immune response. We define boosts as exposures to homotypic or heterotypic DENV serotypes that “boost” the immune response and result in a modest rise in antibody titers (less than fourfold rise, below the threshold of classification as an inapparent infection), possibly due to limited viremia. It is important to note that with boosting, the antibody titer that we measure might not fall. Although it was previously thought that homologous DENV infection confers lifelong immunity against the infecting serotype (30), recent work has shown that homologous DENV reinfections do occur (31). We hypothesize that a boost in antibody titer can protect an individual during subsequent infections, resulting in the development of inapparent infection instead of symptomatic infection. We show that a boosting model can recover the fluctuations in the I/S ratio, recover the inverse relationship between the number of symptomatic cases and the I/S ratio in the PDCS, and recover a positive relationship between the I/S ratio in a given year and the number of cases in the previous year, as has been previously noted (5, 11). These models suggest that boosts may be occurring frequently in endemic areas and need to be considered when constructing effective dengue control policies.