Southern Chinese patients with systemic lupus erythematosus in Hong Kong have low vitamin D levels

BACKGROUND: Vitamin D insufficiency has been linked to pathogenesis of autoimmune diseases. This study aimed to measure serum 25(OH)D level in patients with systemic lupus erythematosus (SLE) in Hong Kong and to evaluate association between serum 25(OH)D level and disease activity. METHODS: Serum 25(OH)D level was measured by radioimmunoassay in SLE patients and healthy controls. Lupus disease activity was determined by SLE disease activity index (SLEDAI), serum anti-dsDNA antibody, C3 and C4 levels. RESULTS: Fifty-two SLE patients with mean ± standard deviation disease duration of 15.5±8.6 years were recruited. Five patients had active lupus disease. Five (9.6%) patients had serum 25(OH)D levels <30 nmol/L. Serum 25(OH)D level was significantly lower in SLE patients compared to age- and sex-matched controls (n=52) [45.5±12.3 vs 51.1±12.6 nmol/L, P=0.02]. Serum 25(OH)D levels were not found to be related to SLEDAI, elevated anti-dsDNA antibody, low C3 or C4 levels or medications. One vitamin D insufficient patient had low serum albumin-corrected calcium. Serum 25(OH)D levels were found to correlate negatively with estimated glomerular filtration rate (r= –0.30, P=0.03) but was not different between patients who had normal and impaired renal function (P=0.38). CONCLUSION: SLE patients in Hong Kong were found to have low serum 25(OH)D level despite its subtropical location.published_or_final_versionThe 15th Medical Research Conference (15th MRC), Department of Medicine, University of Hong Kong, Hong Kong, 16 January 2010. In Hong Kong Medical Journal, 2010, v. 16 n. 1, suppl. 1, p. 47, abstract no. 7

Guillain-Barré Syndrome and Preceding Infection with Campylobacter, Influenza and Epstein-Barr Virus in the General Practice Research Database

BACKGROUND: A number of infectious agents have previously been suggested as risk factors for the development of Guillain-Barré syndrome (GBS), but robust epidemiologic evidence for these associations is lacking. METHODS AND FINDINGS: We conducted a nested case-control study using data from the United Kingdom General Practice Research Database between 1991 and 2001. Controls were matched to cases on general practice clinic, sex, year of birth and date of outcome diagnosis in their matched case. We found positive associations between GBS and infection with Campylobacter, Epstein-Barr virus and influenza-like illness in the previous two months, as well as evidence of a protective effect of influenza vaccination. After correction for under-ascertainment of Campylobacter infection, the excess risk of GBS following Campylobacter enteritis was 60-fold and 20% of GBS cases were attributable to this pathogen. CONCLUSIONS: Our findings indicate a far greater excess risk of GBS among Campylobacter enteritis patients than previously reported by retrospective serological studies. In addition, they confirm previously suggested associations between infection due to Epstein-Barr virus infection and influenza-like illness and GBS. Finally, we report evidence of a protective effect of influenza vaccination on GBS risk, which may be mediated through protection against influenza disease, or result from a lower likelihood of vaccination among those with recent infection. Cohort studies of GBS incidence in this population would help to clarify the burden of GBS due to influenza, and any potential protective effect of influenza vaccination

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

The effect of inhaled corticosteroids on the risk of diabetes mellitus, prediabetes and glucose regulation in adults with asthma (ICSD Study)

INTRODUCTION: We investigated the risk of long-term inhaled corticosteroids (ICS) on diabetes mellitus (DM), prediabetes, and glucose tolerance in Chinese adult asthmatics in a population-based matched-controlled study. METHODS: A total of 691 asthmatics, aged ≥35 to 74 years, who used ICS regularly for ≥6 months were recruited from four asthma clinics in Hong Kong, excluding those with exacerbation in recent 4 weeks or had taken systemic steroid (SS) in recent 6 months. Each asthmatic was matched 1:1 on age, gender, and body mass index (BMI) with controls from the Hong Kong Cardiovascular Risk Factors Prevalence Study II based on a random population samp…published_or_final_versio

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE(TM) study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE(TM) study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%), and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs. ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared to patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs. later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations

Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma

Abstract Zanubrutinib, a highly selective Bruton tyrosine kinase inhibitor, was evaluated in a phase 1/2 study in patients with various B-cell malignancies. In the subgroup of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), zanubrutinib was administered as 160 mg twice daily (n = 14), 320 mg once daily (n = 18), or ≤160 mg total dose (n = 5). Herein, we report results for patients receiving a total daily dose of 320 mg (N = 32). Median study follow-up was 18.8 months. Eighteen patients discontinued treatment, 10 because of progressive disease and 8 because of adverse events (AEs); 1 AE (peripheral edema) was considered to be related to zanubrutinib treatment. The most common AEs were diarrhea (43.8%), contusion (37.5%), constipation (31.3%), and upper respiratory tract infection (31.3%). Infection was the most commonly reported AE of interest (18.8% of patients experienced grade ≥3 infection). At least 1 AE of grade ≥3 was reported in 59.4% of patients; grade ≥3 AEs that were reported in &amp;gt;2 patients were anemia (12.5%), pneumonia (9.4%), and myalgia (9.4%). Overall response rate was 84%, with 25% achieving a complete response. Median duration of response was 18.5 months. Median progression-free survival (PFS) was 21.1 months. Zanubrutinib was well tolerated and demonstrated activity in patients with R/R MCL. The trial is registered at www.clinicaltrials.gov as #NCT02343120.</jats:p

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

The Conserved Tarp Actin Binding Domain Is Important for Chlamydial Invasion

The translocated actin recruiting phosphoprotein (Tarp) is conserved among all pathogenic chlamydial species. Previous reports identified single C. trachomatis Tarp actin binding and proline rich domains required for Tarp mediated actin nucleation. A peptide antiserum specific for the Tarp actin binding domain was generated and inhibited actin polymerization in vitro and C. trachomatis entry in vivo, indicating an essential role for Tarp in chlamydial pathogenesis. Sequence analysis of Tarp orthologs from additional chlamydial species and C. trachomatis serovars indicated multiple putative actin binding sites. In order to determine whether the identified actin binding domains are functionally conserved, GST-Tarp fusions from multiple chlamydial species were examined for their ability to bind and nucleate actin. Chlamydial Tarps harbored variable numbers of actin binding sites and promoted actin nucleation as determined by in vitro polymerization assays. Our findings indicate that Tarp mediated actin binding and nucleation is a conserved feature among diverse chlamydial species and this function plays a critical role in bacterial invasion of host cells

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation