Challenges recruiting to a proof-of-concept pharmaceutical trial for a rare disease: The trigeminal neuralgia experience

Background: This study aimed to describe recruitment challenges encountered during a phase IIa study of vixotrigine, a state and use-dependent Nav1.7 channel blocker, in individuals with trigeminal neuralgia. Methods: This was an international, multicenter, placebo-controlled, randomized withdrawal study that included a 7-day run-in period, a 21-day open-label phase, and a 28-day double-blind phase in which patients (planned n = 30) were randomized to vixotrigine or placebo. Before recruitment, all antiepileptic drugs had to be stopped, except for gabapentin or pregabalin. After the trial, patients returned to their original medications. Patient recruitment was expanded beyond the original five planned (core) centers in order to meet target enrollment (total recruiting sites N = 25). Core sites contributed data related to patient identification for study participation (prescreening data). Data related to screening failures and study withdrawal were also analyzed using descriptive statistics. Results: Approximately half (322/636; 50.6%) of the patients who were prescreened at core sites were considered eligible for the study and 56/322 (17.4%) were screened. Of those considered eligible, 26/322 (8.1%) enrolled in the study and 6/322 (1.9%) completed the study. In total, 125 patients were screened across all study sites and 67/125 (53.6%) were enrolled. At prescreening, reasons for noneligibility varied by site and were most commonly diagnosis change (78/314; 24.8%), age > 80 years (75/314; 23.9%), language/distance/mobility (61/314; 19.4%), and noncardiac medical problems (53/314; 16.9%). At screening, frequently cited reasons for noneligibility included failure based on electrocardiogram, insufficient pain, and diagnosis change. Conclusions: Factors contributing to recruitment challenges encountered in this study included diagnosis changes, anxiety over treatment changes, and issues relating to distance, language, and mobility. Wherever possible, future studies should be designed to address these challenges. Trial registration: ClinicalTrials.gov, NCT01540630. EudraCT, 2010-023963-16. 07 Aug 2015

Diagnose und Graduierung zervikaler intraepithelialer Neoplasien

Zusammenfassung: Diagnose und Graduierung von zervikalen intraepithelialen Neoplasien (CIN) gehören zu den häufigen Fragestellungen in der histopathologischen Diagnostik. Trotzdem kann die Unterscheidung zwischen reaktiven Veränderungen und CIN1 bzw. die Graduierung einer CIN Schwierigkeiten bereiten. In dieser Studie wurde untersucht, ob die Bestimmung der Proliferationsmarker Ki-67 und Mcm2 sowie von p16 zur Beantwortung dieser Fragestellungen beitragen. Untersucht wurden die immunhistochemischen Expressionsprofile dieser Marker an 297Proben aus dysplasiefreiem Portioepithel, CIN1, CIN2 und CIN3 mittels Gewebemikroarrays. Die mittels Ki-67 bzw. Mcm2 ermittelte Proliferationsrate zeigte eine Zunahme von dysplasiefreiem Epithel über CIN1, CIN2 zu CIN3 (p<0.001 bei beiden Markern). Mittels Ki-67 ließ sich am besten zwischen dysplasiefreiem Epithel und CIN1 unterscheiden. Zur Abgrenzung von CIN1 zu CIN2 bot sich eine Kombination von Ki-67 und p16 an. Bei einer Ki-67-Expression von<25% handelte es sich um eine CIN1 mit einer Sensitivität von 91,7% und einer Spezifität von 54,3%. Die zusätzliche Untersuchung der Expression von p16 konnte einen weiteren Teil der Fälle mit einer Ki-67-Expression von<25% stratifizieren. Die Anzahl p16-positiver Fälle betrug bei normalen Epithelien 0%, bei CIN1 7%, bei CIN2 46% und bei CIN3 86%. Somit war mittels p16 eine Abgrenzung der CIN2 zur CIN3 nur zum Teil möglich. Die histopathologische Evaluation am HE-Schnitt bleibt Grundlage der Beurteilung von zervikalen intraepithelialen Neoplasien, jedoch kann die Analyse von Ki-67 und p16 zur Diagnose und Graduierung beitrage

Klonale Verwandtschaft von Hodgkin-Lymphomen und deren Rezidiven

Zusammenfassung: In dieser Studie untersuchten wir, ob es sich bei Rezidiven von klassischen Hodgkin-Lymphomen (HL) um Rezidive im engeren Sinn oder aber um klonal unverwandte Sekundärtumoren handelt. Die Untersuchungen erfolgten an formalinfixierten, paraffineingebetteten Gewebeproben von 11Patienten. Hodgkin- bzw. Sternberg-Reed-Riesenzellen wurden nach immunhistochemischer Markierung mit CD30 mittels Laser mikrodisseziert und die Fragmentlängen des Schwerkettenimmunglobulin-Gens (IgH) unter Verwendung von FR3- und J-Konsensusprimern analysiert. Zwei Frührezidive nach einer HL-Erstdiagnose zeigten klonale Verwandschaft zu den Primärtumoren, während 3 von 4Frührezidiven nach einem Erst- oder Zweitrezidiv nicht mit dem vorangegangenen HL verwandt waren. Drei Spätrezidive waren mit dem ursprünglichen HL klonal unverwandt. Wir schließen daraus, dass es sich bei so genannten "Rezidiven" von HL z.T. um klonal unverwandte Zweitneoplasien handeln kann, was möglicherweise von therapeutischer Relevanz sein könnt

HV/HR-CMOS sensors for the ATLAS upgrade—concepts and test chip results

In order to extend its discovery potential, the Large Hadron Collider (LHC) will have a major upgrade (Phase II Upgrade) scheduled for 2022. The LHC after the upgrade, called High-Luminosity LHC (HL-LHC), will operate at a nominal leveled instantaneous luminosity of 5× 1034 cm−2 s−1, more than twice the expected Phase I . The new Inner Tracker needs to cope with this extremely high luminosity. Therefore it requires higher granularity, reduced material budget and increased radiation hardness of all components. A new pixel detector based on High Voltage CMOS (HVCMOS) technology targeting the upgraded ATLAS pixel detector is under study. The main advantages of the HVCMOS technology are its potential for low material budget, use of possible cheaper interconnection technologies, reduced pixel size and lower cost with respect to traditional hybrid pixel detector. Several first prototypes were produced and characterized within ATLAS upgrade R&#38;D effort, to explore the performance and radiation hardness of this technology. In this paper, an overview of the HVCMOS sensor concepts is given. Laboratory tests and irradiation tests of two technologies, HVCMOS AMS and HVCMOS GF, are also given

The healing pattern of osteoid osteomas on computed tomography and magnetic resonance imaging after thermocoagulation

Objective To compare the healing pattern of osteoid osteomas on computed tomography (CT) and magnetic resonance imaging (MRI) after successful and unsuccessful thermocoagulation. Materials and methods Eighty-six patients were examined by CT and 18 patients by dynamic gadolinium-enhanced MRI before and after thermocoagulation for osteoid osteoma. Thermocoagulation was successful in 73% (63/86) and unsuccessful in 27% (23/86) of patients followed by CT. Thermocoagulation was successful in 72% (13/18) of patients followed by MRI. After treatment, the healing of the nidus on CT was evaluated using different healing patterns (complete ossification, minimal nidus rest, decreased size, unchanged size or thermonecrosis). On MRI the presence of reactive changes (joint effusion, "oedema-like" changes of bone marrow and soft tissue oedema) and the delay time (between arterial and nidus enhancement) were assessed and compared before and after thermocoagulation. Results Complete ossification or a minimal nidus rest was observed on CT in 58% (16/28) of treatment successes (with > 12 months follow-up), but not in treatment failures. "Oedema-like" changes of bone marrow and/or soft tissue oedema were seen on MR in all patients before thermocoagulation and in all treatment failures. However, residual "oedema-like" changes of bone marrow were also found in 69% (9/13) of treatment successes. An increased delay time was observed in 62% (8/13) of treatment successes and in 1/5 of treatment failures. Conclusion Complete, or almost complete, ossification of the treated nidus on CT correlated with successful treatment. Absence of this ossification pattern, however, did not correlate with treatment failure. CT could not be used to identify the activity of the nidus following treatment. The value of MR parameters to assess residual activity of the nidus was limited in this study

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate &lt;0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P &lt; 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood

Radiation-hard active pixel sensors for HL-LHC detector upgrades based on HV-CMOS technology

Luminosity upgrades are discussed for the LHC (HL-LHC) which would make updates to the detectors necessary, requiring in particular new, even more radiation-hard and granular, sensors for the inner detector region. A proposal for the next generation of inner detectors is based on HV-CMOS: a new family of silicon sensors based on commercial high-voltage CMOS technology, which enables the fabrication of part of the pixel electronics inside the silicon substrate itself. The main advantages of this technology with respect to the standard silicon sensor technology are: low material budget, fast charge collection time, high radiation tolerance, low cost and operation at room temperature. A traditional readout chip is still needed to receive and organize the data from the active sensor and to handle high-level functionality such as trigger management. HV-CMOS has been designed to be compatible with both pixel and strip readout. In this paper an overview of HV2FEI4, a HV-CMOS prototype in 180 nm AMS technology, will be given. Preliminary results after neutron and X-ray irradiation are shown

Search for squarks and gluinos with the ATLAS detector in final states with jets and missing transverse momentum using √s=8 TeV proton-proton collision data

A search for squarks and gluinos in final states containing high-p T jets, missing transverse momentum and no electrons or muons is presented. The data were recorded in 2012 by the ATLAS experiment in s√=8 TeV proton-proton collisions at the Large Hadron Collider, with a total integrated luminosity of 20.3 fb−1. Results are interpreted in a variety of simplified and specific supersymmetry-breaking models assuming that R-parity is conserved and that the lightest neutralino is the lightest supersymmetric particle. An exclusion limit at the 95% confidence level on the mass of the gluino is set at 1330 GeV for a simplified model incorporating only a gluino and the lightest neutralino. For a simplified model involving the strong production of first- and second-generation squarks, squark masses below 850 GeV (440 GeV) are excluded for a massless lightest neutralino, assuming mass degenerate (single light-flavour) squarks. In mSUGRA/CMSSM models with tan β = 30, A 0 = −2m 0 and μ > 0, squarks and gluinos of equal mass are excluded for masses below 1700 GeV. Additional limits are set for non-universal Higgs mass models with gaugino mediation and for simplified models involving the pair production of gluinos, each decaying to a top squark and a top quark, with the top squark decaying to a charm quark and a neutralino. These limits extend the region of supersymmetric parameter space excluded by previous searches with the ATLAS detector