Evidence suggests that Epstein-Barr virus (EBV) plays a role in triggering or perpetuating disease activity in multiple sclerosis (MS).
We investigated 100 subjects (50 clinically isolated syndrome ...CIS, 25 relapsing-remitting RR MS, 25 primary progressive PP MS) for 1) evidence of EBV reactivation and 2) disease activity as indicated by serial gadolinium (Gd)-enhanced MRIs over a 5-year period. EBV DNA in blood was quantified by real-time quantitative PCR and EBV serology for anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG), anti-viral capsid antigen (VCA) IgG, and anti-EBV IgM. Data were analyzed using repeated measures analysis, analysis of variance, and logistic regression analysis.
All subjects had serologic evidence of previous EBV infection, but no lytic reactivation was detected. Significant differences in EBNA-1 IgG titers were found between subgroups, highest in the RRMS cohort compared with PPMS (p < 0.001) and CIS (p < 0.001). Gd-enhancing lesions on MRI correlated with EBNA-1 IgG (r = 0.33, p < 0.001) and EBNA-1:VCA IgG ratio (r = 0.36, p < 0.001). EBNA-1 IgG also correlated with change in T2 lesion volume (r = 0.27, p = 0.044) and Expanded Disability Status Scale score (r = 0.3, p = 0.035).
The correlation between elevated Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) and gadolinium-enhancing lesions suggests an association between Epstein-Barr virus (EBV) infection and multiple sclerosis (MS) disease activity. The heightened immune response to EBV in MS is specifically related to EBNA-1 IgG, a marker of the latent phase of the virus. The lack of association between acute viral reactivation in the peripheral blood and Gd(+) lesions suggests a limited role of the former in driving disease activity.
The Antarctic Treaty System, acknowledged as a successful model of cooperative regulation of one of the globe's largest commons (1), is under substantial pressure. Concerns have been raised about ...increased stress on Antarctic systems from global environmental change and growing interest in the region's resources (2, 3). Although policy-makers may recognize these challenges, failure to respond in a timely way can have substantial negative consequences. We provide a horizon scan, a systematic means for identifying emerging trends and assisting decision-makers in identifying policies that address future challenges (2, 3). Previous analyses of conservation threats in the Antarctic have been restricted to matters for which available evidence is compelling (4). We reconsider these concerns because they might escalate quickly, judging from recent rapid environmental change in parts of Antarctica and increasing human interest in the region (see the map). We then focus on a more distant time horizon.
We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell ...transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing <50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing <50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm difference, 6.5%; 95% confidence interval, 0.9%-12%; P = .03). This randomized trial demonstrates the efficacy of an echinocandin for antifungal prophylaxis in neutropenic patients.
Adoptive cellular therapy with chimeric antigen receptor T cells (car-ts) has recently received approval from Health Canada and the U.S. Food and Drug Administration after remarkable and durable ...remissions were seen in children with recurrent or refractory leukemia and adults with non-Hodgkin lymphoma-responses that were so impressive that a shift in the paradigm of care has now occurred for children with acute lymphoblastic leukemia. The concept behind car-t immunotherapy is that modification of a patient's own T cells to facilitate their localization to the cancer cell, with subsequent activation of the T cell effector mechanism and proliferation, will result in targeted killing of cancer cells. The car-ts are a novel drug in that the starting material for the manufacture of the car-t product comes from the patient, whose viable T cells are then genetically modified. Thus, collaboration is needed between the pharmaceutical companies, which must meet good manufacturing standards for each patient's unique product, and the treating sites. For regulators and health authorities, this new class of drugs requires new paradigms for assessment and approval. Treatments with car-ts require that institutions address unique logistics requirements and management of novel toxicities. The Hospital for Sick Children has had early experience with both the licensing of clinical trials and the introduction of the first commercial product. Here, we provide an overview of basic concepts and treatment, with caveats drawn from what we have learned thus far in bringing this new therapy to the clinical front line.
Purpose
Breast cancer is the most common malignancy among young women of reproductive age. Adjuvant treatment with tamoxifen reduces the risk of recurrence in hormone-sensitive breast cancer. ...However, the use of tamoxifen is considered contraindicated during pregnancy, because of a limited number of case reports demonstrating potential adverse effects on the fetus. The objective of this report is to give a more broad overview of the available data on the effect of tamoxifen exposure during pregnancy.
Methods
A literature review was performed using PubMed and the databases of the Netherlands Pharmacovigilance Centre Lareb and of the International Network on Cancer, Infertility, and Pregnancy.
Results
A total of 238 cases of tamoxifen use during pregnancy were found. Of the 167 pregnancies with known outcome, 21 were complicated by an abnormal fetal development. The malformations described were non-specific and the majority of cases concerned healthy infants despite exposure to tamoxifen.
Conclusion
There seems to be an increased risk of fetal abnormalities when taking tamoxifen during pregnancy (12.6% in contrast to 3.9% in the general population), but the evidence is limited and no causal relationship could be established. The possible disadvantage of postponing or discontinuing tamoxifen for the maternal prognosis is unclear. Patients should be counseled about the use of tamoxifen during pregnancy instead of presenting it as being absolutely contraindicated.
Abstract
Background
The BETTER (Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Primary Care) intervention was designed to integrate the approach to chronic disease ...prevention and screening in primary care and demonstrated effective in a previous randomized trial.
Methods
We tested the effectiveness of the BETTER HEALTH intervention, a public health adaptation of BETTER, at improving participation in chronic disease prevention and screening actions for residents of low-income neighbourhoods in a cluster randomized trial, with ten low-income neighbourhoods in Durham Region Ontario randomized to immediate intervention vs. wait-list. The unit of analysis was the individual, and eligible participants were adults age 40–64 years residing in the neighbourhoods. Public health nurses trained as “prevention practitioners” held one prevention-focused visit with each participant. They provided participants with a tailored prevention prescription and supported them to set health-related goals. The primary outcome was a composite index: the number of evidence-based actions achieved at six months as a proportion of those for which participants were eligible at baseline.
Results
Of 126 participants (60 in immediate arm; 66 in wait-list arm), 125 were included in analyses (1 participant withdrew consent). In both arms, participants were eligible for a mean of 8.6 actions at baseline. At follow-up, participants in the immediate intervention arm met 64.5% of actions for which they were eligible versus 42.1% in the wait-list arm (rate ratio 1.53 95% confidence interval 1.22–1.84).
Conclusion
Public health nurses using the BETTER HEALTH intervention led to a higher proportion of identified evidence-based prevention and screening actions achieved at six months for people living with socioeconomic disadvantage.
Trial registration
NCT03052959
, registered February 10, 2017.
The efficacy and safety of dual‐therapy regimens of twice‐daily tacrolimus (BID; Prograf) and once‐daily tacrolimus (QD; Advagraf) administered with steroids, without antibody induction, were ...compared in a multicenter, 1:1‐randomized, two‐arm, parallel‐group study in 475 primary liver transplant recipients. A double‐blind, double‐dummy 24‐week period was followed by an open extension to 12 months posttransplant. The primary endpoint, event rate of biopsy‐proven acute rejection (BPAR) at 24 weeks, was 33.7% for tacrolimus BID versus 36.3% for tacrolimus QD (Per‐protocol set; p = 0.512; treatment difference 2.6%, 95% confidence interval −7.3%, 12.4%), falling within the predefined 15% noninferiority margin. At 12 months, BPAR episodes requiring treatment were similar for tacrolimus BID and QD (28.1% and 24.7%). Twelve‐month patient and graft survival was 90.8% and 85.6% for tacrolimus BID and 89.2% and 85.3% for tacrolimus QD. Adverse event (AE) profiles were similar for both tacrolimus BID and QD with comparable incidences of AEs and serious AEs. Tacrolimus QD was well tolerated with similar efficacy and safety profiles to tacrolimus BID.
Once‐daily, prolonged‐release tacrolimus demonstrates therapeutic equivalence and comparable safety profile to established twice‐daily tacrolimus in liver transplant recipients in this randomized, double‐blind, double‐dummy study.
Biofilm formation by Bacillus subtilis is a communal process that culminates in the formation of architecturally complex multicellular communities. Here we reveal that the transition of the biofilm ...into a nonexpanding phase constitutes a distinct step in the process of biofilm development. Using genetic analysis we show that B. subtilis strains lacking the ability to synthesize pulcherriminic acid form biofilms that sustain the expansion phase, thereby linking pulcherriminic acid to growth arrest. However, production of pulcherriminic acid is not sufficient to block expansion of the biofilm. It needs to be secreted into the extracellular environment where it chelates Fe3+ from the growth medium in a nonenzymatic reaction. Utilizing mathematical modeling and a series of experimental methodologies we show that when the level of freely available iron in the environment drops below a critical threshold, expansion of the biofilm stops. Bioinformatics analysis allows us to identify the genes required for pulcherriminic acid synthesis in other Firmicutes but the patchwork presence both within and across closely related species suggests loss of these genes through multiple independent recombination events. The seemingly counterintuitive self-restriction of growth led us to explore if there were any benefits associated with pulcherriminic acid production. We identified that pulcherriminic acid producers can prevent invasion by neighboring communities through the generation of an “iron-free” zone, thereby addressing the paradox of pulcherriminic acid production by B. subtilis.
PDF
