Getting physicians to open the survey: little evidence that an envelope teaser increases response rates

BACKGROUND: Physician surveys are an important tool to assess attitudes, beliefs and self-reported behaviors of this policy relevant group. In order for a physician to respond to a mailed survey, they must first open the envelope. While there is some evidence that package elements can impact physician response rates, the impact of an envelope teaser is unknown. Here we assess this by testing the impact of adding a brightly colored "$25 incentive" sticker to the outside of an envelope on response rates and nonresponse bias in a survey of physicians. METHODS: In the second mailing of a survey assessing physicians' moral beliefs and views on controversial health care topics, initial nonrespondents were randomly assigned to receive a survey in an envelope with a colored "$25 incentive" sticker (teaser group) or an envelope without a sticker (control group). Response rates were compared between the teaser and control groups overall and by age, gender, region of the United States, specialty and years in practice. Nonresponse bias was assessed by comparing the demographic composition of the respondents to the nonrespondents in the experimental and control condition. RESULTS: No significant differences in response rates were observed between the experimental and control conditions overall (p = 0.38) or after stratifying by age, gender, region, or practice type. Within the teaser condition, there was some variation in response rate by years since graduation. There was no independent effect of the teaser on response when simultaneously controlling for demographic characteristics (OR = 0.875, p = 0.4112). CONCLUSIONS: Neither response rates nor nonresponse bias were impacted by the use of an envelope teaser in a survey of physicians in the United States

Mayaro Virus in Wild Mammals, French Guiana

A serologic survey for Mayaro virus (Alphavirus, Togaviridae) in 28 wild nonflying forest mammal species in French Guiana showed a prevalence ranging from 0% to 52% and increasing with age. Species active during the day and those who spent time in trees were significantly more infected, results consistent with transmission implicating diurnal mosquitoes and continuous infectious pressure

A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis

Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase 1 (sTK1) activity. At data-cutoff, fifty-four patients received a median of 13 cycles (range 2.6-43.5). The rate of G3 + ANC was 21.3% (95% CI: 11.2-36.1%) without G4 in C1, and 40.7% (95% CI: 27.9-54.9%), including 38.9% G3 and 1.8% G4, in all cycles. The clinical benefit rate was 80.4% (95% CI: 66.5-89.7%). The median progression-free survival (mPFS) (95% CI) was 19.75 (12.11-34.89), 33.5 (17.25-not reached [NR]), and 11.96 (10.43-NR) months, in the overall, endocrine sensitive or resistant population, respectively. High sTK1 at baseline, C1 day 15 (C1D15), and C2D1 were independently prognostic for shorter PFS (p = 9.91 × 1

Reproducibility of the NanoString 22-gene molecular subgroup assay for improved prognostic prediction of medulloblastoma

Medulloblastoma is the most frequent malignant brain tumor in children. Four medulloblastoma molecular subgroups, MBSHH , MBWNT , MBGRP3 and MBGRP4 , have been identified by integrated high-throughput platforms. Recently, a 22-gene panel NanoString-based assay was developed for medulloblastoma molecular subgrouping, but the robustness of this assay has not been widely evaluated. Mutations in the gene for human telomerase reverse transcriptase (hTERT) have been found in medulloblastomas and are associated with distinct molecular subtypes. This study aimed to implement the 22-gene panel in a Brazilian context, and to associate the molecular profile with patients' clinical-pathological features. Formalin-fixed, paraffin-embedded (FFPE) medulloblastoma samples (n = 104) from three Brazilian centers were evaluated. Expression profiling of the 22-gene panel was performed by NanoString and a Canadian series (n = 240) was applied for training phase. hTERT mutations were analyzed by PCR followed by direct Sanger sequencing and the molecular profile was associated with patients' clinicopathological features. Overall, 65% of the patients were male, average age at diagnosis was 18 years and 7% of the patients presented metastasis at diagnosis. The molecular classification was attained in 100% of the cases, with the following frequencies: MBSHH (n = 51), MBWNT (n = 19), MBGRP4 (n = 19) and MBGRP3 (n = 15). The MBSHH and MBGRP3 subgroups were associated with older and younger patients, respectively. The MBGRP4 subgroup exhibited the lowest 5-year cancer-specific overall survival (OS), yet in the multivariate analysis, only metastasis at diagnosis and surgical resection were associated with OS. hTERT mutations were detected in 29% of the cases and were associated with older patients, increased hTERT expression and MBSHH subgroup. The 22-gene panel provides a reproducible assay for molecular subgrouping of medulloblastoma FFPE samples in a routine setting and is well-suited for future clinical trials.We thank Barretos Cancer Hospital and FINEP (MCTI/ FINEP/MS/SCTIE/DECIT - BioPlat 1302/13) for partially funding the present study. LFL is supported by Public Ministry of Labor Campinas (Research, Prevention and Education of Occupational Cancer) in Campinas, Brazil. RMR is sponsored by National Council for Scientific and Technological Development (CNPq, Brazil).info:eu-repo/semantics/publishedVersio

Helicobacter pylori versus the Host: Remodeling of the Bacterial Outer Membrane Is Required for Survival in the Gastric Mucosa

Modification of bacterial surface structures, such as the lipid A portion of lipopolysaccharide (LPS), is used by many pathogenic bacteria to help evade the host innate immune response. Helicobacter pylori, a gram-negative bacterium capable of chronic colonization of the human stomach, modifies its lipid A by removal of phosphate groups from the 1- and 4′-positions of the lipid A backbone. In this study, we identify the enzyme responsible for dephosphorylation of the lipid A 4′-phosphate group in H. pylori, Jhp1487 (LpxF). To ascertain the role these modifications play in the pathogenesis of H. pylori, we created mutants in lpxE (1-phosphatase), lpxF (4′-phosphatase) and a double lpxE/F mutant. Analysis of lipid A isolated from lpxE and lpxF mutants revealed lipid A species with a 1 or 4′-phosphate group, respectively while the double lpxE/F mutant revealed a bis-phosphorylated lipid A. Mutants lacking lpxE, lpxF, or lpxE/F show a 16, 360 and 1020 fold increase in sensitivity to the cationic antimicrobial peptide polymyxin B, respectively. Moreover, a similar loss of resistance is seen against a variety of CAMPs found in the human body including LL37, β-defensin 2, and P-113. Using a fluorescent derivative of polymyxin we demonstrate that, unlike wild type bacteria, polymyxin readily associates with the lpxE/F mutant. Presumably, the increase in the negative charge of H. pylori LPS allows for binding of the peptide to the bacterial surface. Interestingly, the action of LpxE and LpxF was shown to decrease recognition of Helicobacter LPS by the innate immune receptor, Toll-like Receptor 4. Furthermore, lpxE/F mutants were unable to colonize the gastric mucosa of C57BL/6J and C57BL/6J tlr4 -/- mice when compared to wild type H. pylori. Our results demonstrate that dephosphorylation of the lipid A domain of H. pylori LPS by LpxE and LpxF is key to its ability to colonize a mammalian host

Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets for diagnosis and therapy of the ischemic heart?

Despite advances in myocardial reperfusion therapies, acute myocardial ischemia/reperfusion injury and consequent ischemic heart failure represent the number one cause of morbidity and mortality in industrialized societies. Although different therapeutic interventions have been shown beneficial in preclinical settings, an effective cardioprotective or regenerative therapy has yet to be successfully introduced in the clinical arena. Given the complex pathophysiology of the ischemic heart, large scale, unbiased, global approaches capable of identifying multiple branches of the signaling networks activated in the ischemic/reperfused heart might be more successful in the search for novel diagnostic or therapeutic targets. High-throughput techniques allow high-resolution, genome-wide investigation of genetic variants, epigenetic modifications and associated gene expression profiles. Platforms such as proteomics and metabolomics (not described here in detail) also offer simultaneous readouts of hundreds of proteins and metabolites. Isolated omics analyses usually provide Big Data requiring large data storage, advanced computational resources and complex bioinformatics tools. The possibility of integrating different omics approaches gives new hope to better understand the molecular circuitry activated by myocardial ischemia, putting it in the context of the human "diseasome".Since modifications of cardiac gene expression have been consistently linked to pathophysiology of the ischemic heart, the integration of epigenomic and transcriptomic data seems a promising approach to identify crucial disease networks. Thus, the scope of this Position Paper will be to highlight potentials and limitations of these approaches, and to provide recommendations to optimize the search for novel diagnostic or therapeutic targets for acute ischemia/reperfusion injury and ischemic heart failure in the post-genomic era

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio