A pooled analysis of fall incidence from placebo‐controlled trials of denosumab

Recent studies suggest that the RANK/RANKL system impacts muscle function and/or mass. In the pivotal placebo‐controlled fracture trial of the RANKL inhibitor denosumab in women with postmenopausal osteoporosis, treatment was associated with a lower incidence of non‐fracture‐related falls (p = 0.02). This ad hoc exploratory analysis pooled data from five placebo‐controlled trials of denosumab to determine consistency across trials, if any, of the reduction of fall incidence. The analysis included trials in women with postmenopausal osteoporosis and low bone mass, men with osteoporosis, women receiving adjuvant aromatase inhibitors for breast cancer, and men receiving androgen deprivation therapy for prostate cancer. The analysis was stratified by trial, and only included data from the placebo‐controlled period of each trial. A time‐to‐event analysis of first fall and exposure‐adjusted subject incidence rates of falls were analyzed. Falls were reported and captured as adverse events. The analysis comprised 10,036 individuals; 5030 received denosumab 60 mg subcutaneously once every 6 months for 12 to 36 months and 5006 received placebo. Kaplan–Meier estimates showed an occurrence of falls in 6.5% of subjects in the placebo group compared with 5.2% of subjects in the denosumab group (hazard ratio = 0.79; 95% confidence interval 0.66–0.93; p = 0.0061). Heterogeneity in study designs did not permit overall assessment of association with fracture outcomes. In conclusion, denosumab may reduce the risk of falls in addition to its established fracture risk reduction by reducing bone resorption and increasing bone mass. These observations require further exploration and confirmation in studies with muscle function or falls as the primary outcome

Temporal changes in access to FRAX® in Thailand between 2010 and 2018

Summary The usage of FRAX® tool in Thailand and other countries was explored using Google Analytics data. Over the period 2010–2018, Thailand ranked 35th in the world for FRAX usage (the US is ranked first). Incorporation of FRAX into a national osteoporosis guideline in Thailand appears to have increased its usage. Purpose To document access to the web-based FRAX® tool and specifically its access in Thailand between 2010 and 2018. Methods A descriptive retrospective study using data from Google Analytics that provides numerical and geographical information on internet access to the FRAX tool website worldwide. Result In Thailand, Bangkok is the highest ranked site for FRAX access with more than 20,000 usage sessions since 2010 (3.6 usage session per 1000 population) followed by Khon Kaen and Chiang Mai. It has been accessed from within 76 out of 77 provinces (98.7%). There was a steady increase in access to FRAX from within Thailand of approximately 1000 usage sessions per year between 2010 and 2016. After the FRAX fracture risk calculation was included in the national guideline for osteoporosis management published in late 2016, the rate of increase in access was four-fold higher compared with the previous period. In world ranking, the USA is the country with the most frequent access to the FRAX tool, whereas Thailand was ranked 35th in the world. There were weak but significant correlations between the absolute number of FRAX sessions and population size (r = 0.165, p = 0.011) and land area (r = 0.375, p < 0.001). Conclusion Access to the FRAX tool website is increasing in Thailand. The incorporation of FRAX into national guidelines, in parallel to the adoption of osteoporosis fracture prevention into national policy, has had a rapid and significant impact on its use

Population screening for fracture risk in postmenopausal women - a logical step in reducing the osteoporotic fracture burden?

peer reviewe

Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8(+) T cell response.

Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8(+) T cell populations specific for variants of the nonstructural protein epitope NS3133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3133-DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2(+) TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2(+) TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs

Identification of Conserved and HLA Promiscuous DENV3 T-Cell Epitopes

Anti-dengue T-cell responses have been implicated in both protection and immunopathology. However, most of the T-cell studies for dengue include few epitopes, with limited knowledge of their inter-serotype variation and the breadth of their human leukocyte antigen (HLA) affinity. In order to expand our knowledge of HLA-restricted dengue epitopes, we screened T-cell responses against 477 overlapping peptides derived from structural and non-structural proteins of the dengue virus serotype 3 (DENV3) by use of HLA class I and II transgenic mice (TgM): A2, A24, B7, DR2, DR3 and DR4. TgM were inoculated with peptides pools and the T-cell immunogenic peptides were identified by ELISPOT. Nine HLA class I and 97 HLA class II novel DENV3 epitopes were identified based on immunogenicity in TgM and their HLA affinity was further confirmed by binding assays analysis. A subset of these epitopes activated memory T-cells from DENV3 immune volunteers and was also capable of priming naïve T-cells, ex vivo, from dengue IgG negative individuals. Analysis of inter- and intra-serotype variation of such an epitope (A02-restricted) allowed us to identify altered peptide ligands not only in DENV3 but also in other DENV serotypes. These studies also characterized the HLA promiscuity of 23 HLA class II epitopes bearing highly conserved sequences, six of which could bind to more than 10 different HLA molecules representing a large percentage of the global population. These epitope data are invaluable to investigate the role of T-cells in dengue immunity/pathogenesis and vaccine design. © 2013 Nascimento et al

Population screening for fracture risk in postmenopausal women — a logical step in reducing the osteoporotic fracture burden? [Editorial]

No abstract available

Humidity control as a strategy for lattice optimization applied to crystals of HLA-A*1101 complexed with variant peptides from dengue virus.

T-cell recognition of the antigenic peptides presented by MHC class I molecules normally triggers protective immune responses, but can result in immune enhancement of disease. Cross-reactive T-cell responses may underlie immunopathology in dengue haemorrhagic fever. To analyze these effects at the molecular level, the functional MHC class I molecule HLA-A*1101 was crystallized bound to six naturally occurring peptide variants from the dengue virus NS3 protein. The crystals contained high levels of solvent and required optimization of the cryoprotectant and dehydration protocols for each complex to yield well ordered diffraction, a process that was facilitated by the use of a free-mounting system

Humidity control as a strategy for lattice optimization applied to crystals of HLA-A*1101 complexed with variant peptides from dengue virus.

Crystals of an MHC class I molecule bound to naturally occurring peptide variants from the dengue virus NS3 protein contained high levels of solvent and required optimization of cryoprotectant and dehydration protocols for each complex to yield well ordered diffraction, a process facilitated by the use of a free-mounting system

T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal?

Dengue virus infection poses a growing public health and economic burden in a number of tropical and subtropical countries. Dengue circulates as a number of quasispecies, which can be divided by serology into four groups or serotypes. An interesting feature of Dengue, recognized over five decades ago, is that most severe cases that show hemorrhagic fever are not suffering from a primary infection. Instead, they are reinfected with a virus of different serotype. This observation poses considerable problems in vaccine design, and it is therefore imperative to gain a full understanding of the mechanisms underlying this immunological enhancement of disease. In this study, we examined a T cell epitope restricted by HLA-A*24, a major MHC class I allele, in Southeast Asia in a cohort of children admitted to a hospital with acute Dengue infection. The cytokine profiles and the degranulation capacity of T cells generated to this epitope are defined and compared across different viral serotypes. Cross-reactive Dengue-specific T cells seem to show suboptimal degranulation but high cytokine production, which may contribute to the development of the vascular leak characteristic of Dengue hemorrhagic fever