2016 ACR-EULAR adult dermatomyositis and polymyositis and juvenile dermatomyositis response criteria-methodological aspects

Objective. The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM. Methods. Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a survey regarding clinically meaningful improvement in the core set measures (CSM) and a conjoint-analysis survey (using 1000Minds software) to derive relative weights of CSM and candidate definitions. Six types of candidate definitions for response criteria were derived using survey results, logistic regression, conjoint analysis, application of conjoint-analysis weights to CSM and published definitions. Sensitivity, specificity and area under the curve were defined for candidate criteria using consensus patient profile data, and selected definitions were validated using clinical trial data. Results. Myositis specialists defined the degree of clinically meaningful improvement in CSM for minimal, moderate and major improvement. The conjoint-analysis survey established the relative weights of CSM, with muscle strength and Physician Global Activity as most important. Many candidate definitions showed excellent sensitivity, specificity and area under the curve in the consensus profiles. Trial validation showed that a number of candidate criteria differentiated between treatment groups. Top candidate criteria definitions were presented at the consensus conference. Conclusion. Consensus methodology, with definitions tested on patient profiles and validated using clinical trials, led to 18 definitions for adult PM/DM and 14 for JDM as excellent candidates for consideration in the final consensus on new response criteria for myositis

The impact of inflammation on bone mass in children

Bone is a dynamic tissue. Skeletal bone integrity is maintained through bone modeling and remodeling. The mechanisms underlying this bone mass regulation are complex and interrelated. An imbalance in the regulation of bone remodeling through bone resorption and bone formation results in bone loss. Chronic inflammation influences bone mass regulation. Inflammation-related bone disorders share many common mechanisms of bone loss. These mechanisms are ultimately mediated through the uncoupling of bone remodeling. Cachexia, physical inactivity, pro-inflammatory cytokines, as well as iatrogenic factors related to effects of immunosuppression are some of the common mechanisms. Recently, cytokine signaling through the central nervous system has been investigated for its potential role in bone mass dysregulation in inflammatory conditions. Growing research on the molecular mechanisms involved in inflammation-induced bone loss may lead to more selective therapeutic targeting of these pathological signaling pathways

Are low-value care measures up to the task? A systematic review of the literature

Background Reducing low-value care is a core component of healthcare reforms in many Western countries. A comprehensive and sound set of low-value care measures is needed in order to monitor low-value care use in general and in provider-payer contracts. Our objective was to review the scientific literature on low-value care measurement, aiming to assess the scope and quality of current measures. Methods A systematic review was performed for the period 2010–2015. We assessed the scope of low-value care recommendations and measures by categorizing them according to the Classification of Health Care Functions. Additionally, we assessed the quality of the measures by 1) analysing their development process and the level of evidence underlying the measures, and 2) analysing the evidence regarding the validity of a selected subset of the measures. Results Our search yielded 292 potentially relevant articles. After screening, we selected 23 articles eligible for review. We obtained 115 low-value care measures, of which 87 were concentrated in the cure sector, 25 in prevention and 3 in long-term care. No measures were found in rehabilitative care and health promotion. We found 62 measures from articles that translated low-value care recommendations into measures, while 53 measures were previously developed by institutions as the National Quality Forum. Three measures were assigned the highest level of evidence, as they were underpinned by both guidelines and literature evidence. Our search yielded no information on coding/criterion validity and construct validity for the included measures. Despite this, most measures were already used in practice. Conclusion This systematic review provides insight into the current state of low-value care measures. It shows that more attention is needed for the evidential underpinning and quality of these measures. Clear information about the level of evidence and validity helps to identify measures that truly represent low-value care and are sufficiently qualified to fulfil their aims through quality monitoring and in innovative payer-provider contracts. This will contribute to creating and maintaining the support of providers, payers, policy makers and citizens, who are all aiming to improve value in health care

CCR5 receptor antagonism inhibits hepatitis C virus (HCV) replication in vitro.

Background and aimThe hepatitis C virus (HCV) is a single-strand RNA virus that infects millions of people worldwide. Recent advances in therapy have led to viral cure using two- and three- drug combinations of direct acting inhibitors of viral replication. CCR5 is a chemokine receptor that is expressed on hepatocytes and represents a key co-receptor for HIV. We evaluated the effect of CCR5 blockade or knockdown on HCV replication in Huh7.5JFH1 cells.MethodsCells were exposed to varying concentrations of maraviroc (CCR5 inhibitor), cenicriviroc (CCR2/CCR5 inhibitor), sofosbuvir (nucleotide polymerase inhibitor), or raltegravir (HIV integrase inhibitor).ResultsHCV RNA was detected utilizing two qualitative strand-specific RT-PCR assays. HCV core antigen and NS3 protein was quantified in the supernatant and cell lysate, respectively. siRNA was utilized to knockdown CCR5 gene expression in hepatocytes. Alternatively, anti-CCR5 antibodies were employed to block the receptor. Supernatant levels of HCV RNA (expressed as fold change) were not reduced in the presence of raltegravir but were reduced 8.55-fold and 12.42-fold with cenicriviroc and maraviroc, respectively. Sofosbuvir resulted in a 16.20-fold change in HCV RNA levels. HCV core and NS3 protein production was also reduced in a dose-dependent manner. Two distinct anti-CCR5 antibodies also resulted in a significant reduction in HCV protein expression, as did siRNA knockdown of CCR5 gene expression.ConclusionsThese data provide evidence that CCR5 modulation could have a significant effect on HCV replication in an in vitro system. Further evaluation of the role of CCR5 inhibition in clinical settings may be warranted

Cloning of Vgt3, a major QTL for flowering time in maize

Flowering time is a complex trait important for crop adaptation to local environments and an essential breeding target to face the challenge of global climate change. A major quantitative trait locus (QTL) for flowering time and number of nodes (ND), qVgt3.05 (Vgt3), was previously identified on chromosome 3, bin 3.05, in a maize introgression library (IL) derived from the cross B73 x Gasp\ue9 Flint (recipient and donor genotypes, respectively. Salvi et al. 2011). In order to clone Vgt3, B73 was crossed with its early isogenic line 39-1-2-33 which carries a 17-cM Gasp\ue9 Flint introgression on bin 3.05. Using this cross, Vgt3 showed an addictive effect of 1.4 nodes, explained 56.6% of the phenotypic variance and was mapped within 0.3 cM. For positional cloning, a total of 7,500 F2 plants were phenotyped and genotyped with SNPs and SSR markers flanking the QTL interval. One-hundred recombinants lines were derived and the QTL was further narrowed the target genomic region to a 380-kb interval. A MADS-box gene with no coding sequence variation between the two alleles was found in the physical interval. However, the MADS-box gene RNA expression profile and transgenics testing confirmed its effect on flowering time. We are currently searching for the Vgt3 causative regulatory region by studying chromosome structural variation between the B73 and Gasp\ue9 Flint alleles