Using practice effects for targeted trials or sub-group analysis in Alzheimer\u27s disease: How practice effects predict change over time

OBJECTIVE: To describe the presence of practice effects in persons with Alzheimer disease (AD) or mild cognitive impairment (MCI) and to evaluate how practice effects affect cognitive progression and the outcome of clinical trials. METHODS: Using data from a meta-database consisting of 18 studies including participants from the Alzheimer disease Cooperative Study (ADCS) and the Alzheimer Disease Neuroimaging Initiative (ADNI) with ADAS-Cog11 as the primary outcome, we defined practice effects based on the improvement in the first two ADAS-Cog11 scores and then estimated the presence of practice effects and compared the cognitive progression between participants with and without practice effects. The robustness of practice effects was investigated using CDR SB, an outcome independent the definition itself. Furthermore, we evaluated how practice effects can affect sample size estimation. RESULTS: The overall percent of practice effects for AD participants was 39.0% and 53.3% for MCI participants. For AD studies, the mean change from baseline to 2 years was 12.8 points for the non-practice effects group vs 7.4 for the practice effects group; whereas for MCI studies, it was 4.1 for non-practice effects group vs 0.2 for the practice effects group. AD participants without practice effects progressed 0.9 points faster than those with practice effects over a period of 2 years in CDR-SB; whereas for MCI participants, the difference is 0.7 points. The sample sizes can be different by over 35% when estimated based on participants with/without practice effects. CONCLUSION: Practice effects were prevalent and robust in persons with AD or MCI and affected the cognitive progression and sample size estimation. Planning of future AD or MCI clinical trials should account for practice effects to avoid underpower or considers target trials or stratification analysis based on practice effects

Using Global Positioning Systems (GPS) and temperature data to generate time-activity classifications for estimating personal exposure in air monitoring studies: an automated method

Background: Personal exposure studies of air pollution generally use self-reported diaries to capture individuals’ time-activity data. Enhancements in the accuracy, size, memory and battery life of personal Global Positioning Systems (GPS) units have allowed for higher resolution tracking of study participants’ locations. Improved time activity classifications combined with personal continuous air pollution sampling can improve assessments of location-related air pollution exposures for health studies. Methods: Data was collected using a GPS and personal temperature from 54 children with asthma living in Montreal, Canada, who participated in a 10-day personal air pollution exposure study. A method was developed that incorporated personal temperature data and then matched a participant’s position against available spatial data (i.e., road networks) to generate time-activity categories. The diary-based and GPS-generated time-activity categories were compared and combined with continuous personal PM2.5 data to assess the impact of exposure misclassification when using diary based methods. Results: There was good agreement between the automated method and the diary method; however, the automated method (means: outdoors = 5.1%, indoors other =9.8%) estimated less time spent in some locations compared to the diary method (outdoors = 6.7%, indoors other = 14.4%). Agreement statistics (AC1 = 0.778) suggest ‘good’ agreement between methods over all location categories. However, location categories (Outdoors and Transit) where less time is spent show greater disagreement: e.g., mean time “Indoors Other” using the time-activity diary was 14.4% compared to 9.8% using the automated method. While mean daily time “In Transit” was relatively consistent between the methods, the mean daily exposure to PM2.5 while “In Transit” was 15.9 μg/m3 using the automated method compared to 6.8 μg/m3 using the daily diary. Conclusions: Mean times spent in different locations as categorized by a GPS-based method were comparable to those from a time-activity diary, but there were differences in estimates of exposure to PM2.5 from the two methods. An automated GPS-based time-activity method will reduce participant burden, potentially providing more accurate and unbiased assessments of location. Combined with continuous air measurements, the higher resolution GPS data could present a different and more accurate picture of personal exposures to air pollution

Video Didactic Preparation Augments Problem-Based Learning for First Year Medical Students.

Problem-based learning (PBL) utilizes a self-directed strategy. This process relies on group participation to succeed. Students without a background in biology or medicine can feel overwhelmed by the complexity of the subject matter and unable to participate in the group learning process. We incorporated curated educational videos in the PBL curriculum to help address this situation. First year medical students participated in this study in the form of a typical PBL session. They were then assessed on basic and clinical science knowledge and their learning experience. Student basic science and clinical knowledge were similar between the student groups. However, the students given a list of suggested videos scored higher in their learning experience, perception of feeling prepared, and participating in the group PBL experience than students who were not given the video list. Results from this study indicate that videos can be utilized to enhance the PBL process

Household determinants of biocontaminant exposures in Canadian homes

Exposure to biocontaminants, such as dust mites, animal dander, bacteria, and mold, is associated with a range of health effects. This study identified household characteristics associated with indoor biocontaminant loadings in four Canadian cities. Floor dust was collected in 290 Canadian homes in Edmonton, Halifax, Montreal, and Windsor. The dust samples were analyzed for house dust mite allergens (Der f 1 and Der p 1), cat allergen (Fel d 1), cockroach allergen (Bla g 1), beta-(1,3)-D-glucan, and endotoxin. Household information was obtained through questionnaires and home inspections. We performed univariate and multivariate analyses to identify household determinants of biocontaminant loadings and mold odor presence. We observed large regional variations for all biocontaminants, except for cockroach allergen. The ranges of the contaminants measured in loadings and concentrations were similar to that of previous Canadian studies. Household characteristics including presence of carpeting, low floor cleaning frequency, older home age, presence of pets, and indoor relative humidity above 45% were positively associated with the presence of multiple indoor biocontaminants. High floor cleaning frequency and use of dehumidifiers were negatively associated with the presence of multiple indoor biocontaminants. Mold odor was positively associated with older home age, past water damage, and visible mold growth

Src activates Abl to augment Robo1 expression in order to promote tumor cell migration

Cell migration is an essential step in cancer invasion and metastasis. A number of orchestrated cellular events involving tyrosine kinases and signaling receptors enable cancer cells to dislodge from primary tumors and colonize elsewhere in the body. For example, activation of the Src and Abl kinases can mediate events that promote tumor cell migration. Also, activation of the Robo1 receptor can induce tumor cell migration. However, while the importance of Src, Abl, and Robo1 in cell migration have been demonstrated, molecular mechanisms by which they collectively influence cell migration have not been clearly elucidated. In addition, little is known about mechanisms that control Robo1 expression. We report here that Src activates Abl to stabilize Robo1 in order to promote cell migration. Inhibition of Abl kinase activity by siRNA or kinase blockers decreased Robo1 protein levels and suppressed the migration of transformed cells. We also provide evidence that Robo1 utilizes Cdc42 and Rac1 GTPases to induce cell migration. In addition, inhibition of Robo1 signaling can suppress transformed cell migration in the face of robust Src and Abl kinase activity. Therefore, inhibitors of Src, Abl, Robo1 and small GTPases may target a coordinated pathway required for tumor cell migration

Influence of Fiber Volume and Alignment on Impact Resistance of Braided Carbon Fiber Epoxy Composites

The effect of axial tow alignment within a laminate ply stack on the impact penetration threshold for a series of composite panels was evaluated; specifically, the effect of a lateral shift in alignment to induce fiber nesting. Panels were fabricated from braided T700S carbon fiber and TenCate Advanced Composites's TC275-1 epoxy resin prepreg. Axial tows in each ply were aligned, offset, or rotated to evaluate the influence of such parameters on impact penetration resistance. Panel-to-panel variation in thickness, resin content, and fiber volume ratio were measured. Ultimately, process-related deviations drove penetration limits on impact. Influence of axial tow alignment was difficult to discern outside of the processing-induced variations between panels

Clinical utility of chromogranin A and octreotide in large cell neuro endocrine carcinoma of the uterine corpus

Primary neuroendocrine tumors of the female genital tract have been described in the cervix, ovaries and uterus. Large cell neuroendocrine carcinoma (LCNC) of the uterine corpus is the least common and appears to behave the most aggressively. We report a rare case of a large cell neuroendocrine tumor of the endometrium. These tumors are not well characterized, unlike neuroendocrine tumors of the uterine cervix. Consequently, the optimal management remains still unclear. The treatment of our case consisted of surgery, radiotherapy, chemotherapy, and octreotide. Despite the aggressive treatment, the patient died of disease progression 12 months after the initial diagnosis. We discuss the diagnosis, prognosis, and treatment options for LCNC of the genital tract, and potential future therapeutics

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

Measurement of the hadronic photon structure function F_{2}^{γ} at LEP2

The hadronic structure function of the photon F_{2}^{γ} (x, Q²) is measured as a function of Bjorken x and of the photon virtuality Q² using deep-inelastic scattering data taken by the OPAL detector at LEP at e⁺e⁻ centre-of-mass energies from 183 to 209 GeV. Previous OPAL measurements of the x dependence of F_{2}^{γ} are extended to an average Q² of 〈Q²〉=780 GeV² using data in the kinematic range 0.15<x<0.98. The Q² evolution of F_{2}^{γ} is studied for 12.1<〈Q²〉<780 GeV² using three ranges of x. As predicted by QCD, the data show positive scaling violations in F_{2}^{γ} with F_{2}^{γ} (Q²)/α = (0.08±0.02⁺⁰·⁰⁵_₀.₀₃) + (0.13±0.01⁺⁰·⁰¹_₀.₀₁) lnQ², where Q² is in GeV², for the central x region 0.10–0.60. Several parameterisations of F_{2}^{γ} are in qualitative agreement with the measurements whereas the quark-parton model prediction fails to describe the data