Validity, Significance, Strengths, Limitations, and Evidentiary Value of Real-World Clinical Data for Combination Therapy in Alzheimer's Disease: Comparison of Efficacy and Effectiveness Studies

Background: Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer's disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness. Objective: To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs). Methods: Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs. Results: RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization. Conclusions: Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed

Inelastic interaction mean free path of negative pions in tungsten

The inelastic interaction mean free paths lambda of 5, 10, and 15 GeV/c pions were measured by determining the distribution of first interaction locations in a modular tungsten-scintillator ionization spectrometer. In addition to commonly used interaction signatures of a few (2-5) particles in two or three consecutive modules, a chi2 distribution is used to calculate the probability that the first interaction occurred at a specific depth in the spectrometer. This latter technique seems to be more reliable than use of the simpler criteria. No significant dependence of lambda on energy was observed. In tungsten, lambda for pions is 206 plus or minus 6 g/sq cm

Muon and Cosmogenic Neutron Detection in Borexino

Borexino, a liquid scintillator detector at LNGS, is designed for the detection of neutrinos and antineutrinos from the Sun, supernovae, nuclear reactors, and the Earth. The feeble nature of these signals requires a strong suppression of backgrounds below a few MeV. Very low intrinsic radiogenic contamination of all detector components needs to be accompanied by the efficient identification of muons and of muon-induced backgrounds. Muons produce unstable nuclei by spallation processes along their trajectory through the detector whose decays can mimic the expected signals; for isotopes with half-lives longer than a few seconds, the dead time induced by a muon-related veto becomes unacceptably long, unless its application can be restricted to a sub-volume along the muon track. Consequently, not only the identification of muons with very high efficiency but also a precise reconstruction of their tracks is of primary importance for the physics program of the experiment. The Borexino inner detector is surrounded by an outer water-Cherenkov detector that plays a fundamental role in accomplishing this task. The detector design principles and their implementation are described. The strategies adopted to identify muons are reviewed and their efficiency is evaluated. The overall muon veto efficiency is found to be 99.992% or better. Ad-hoc track reconstruction algorithms developed are presented. Their performance is tested against muon events of known direction such as those from the CNGS neutrino beam, test tracks available from a dedicated External Muon Tracker and cosmic muons whose angular distribution reflects the local overburden profile. The achieved angular resolution is 3-5 deg and the lateral resolution is 35-50 cm, depending on the impact parameter of the crossing muon. The methods implemented to efficiently tag cosmogenic neutrons are also presented.Comment: 42 pages. 32 figures on 37 files. Uses JINST.cls. 1 auxiliary file (defines.tex) with TEX macros. submitted to Journal of Instrumentatio

A Study of the Residual 39Ar Content in Argon from Underground Sources

The discovery of argon from underground sources with significantly less 39Ar than atmospheric argon was an important step in the development of direct-detection dark matter experiments using argon as the active target. We report on the design and operation of a low background detector with a single phase liquid argon target that was built to study the 39Ar content of the underground argon. Underground argon from the Kinder Morgan CO2 plant in Cortez, Colorado was determined to have less than 0.65% of the 39Ar activity in atmospheric argon.Comment: 21 pages, 10 figure

Borexino calibrations: Hardware, Methods, and Results

Borexino was the first experiment to detect solar neutrinos in real-time in the sub-MeV region. In order to achieve high precision in the determination of neutrino rates, the detector design includes an internal and an external calibration system. This paper describes both calibration systems and the calibration campaigns that were carried out in the period between 2008 and 2011. We discuss some of the results and show that the calibration procedures preserved the radiopurity of the scintillator. The calibrations provided a detailed understanding of the detector response and led to a significant reduction of the systematic uncertainties in the Borexino measurements

New experimental limits on the Pauli forbidden transitions in 12^{12}C nuclei obtained with 485 days Borexino data

The Pauli exclusion principle (PEP) has been tested for nucleons ($n,p$) in $^{12}C$ with the Borexino detector.The approach consists of a search for $\gamma$, $n$, $p$ and $\beta^\pm$ emitted in a non-Paulian transition of 1$P_{3/2}$- shell nucleons to the filled 1$S_{1/2}$ shell in nuclei. Due to the extremely low background and the large mass (278 t) of the Borexino detector, the following most stringent up-to-date experimental bounds on PEP violating transitions of nucleons have been established: $\tau({^{12}\rm{C}}\to{^{12}\widetilde{\rm{C}}}+\gamma) \geq 5.0\cdot10^{31}$ y, $\tau({^{12}\rm{C}}\to{^{11}\widetilde{\rm{B}}}+ p) \geq 8.9\cdot10^{29}$ y, $\tau({^{12}\rm{C}}\to{^{11}\widetilde{\rm{C}}}+ n) \geq 3.4 \cdot 10^{30}$ y, $\tau({^{12}\rm{C}}\to{^{12}\widetilde{\rm{N}}}+ e^- + \widetilde{\nu_e}) \geq 3.1\cdot 10^{30}$ y and $\tau({^{12}\rm{C}}\to{^{12}\widetilde{\rm{B}}}+ e^+ + \nu_e) \geq 2.1 \cdot 10^{30}$ y, all at 90% C.L. The corresponding upper limits on the relative strengths for the searched non-Paulian electromagnetic, strong and weak transitions have been estimated: $\delta^2_{\gamma} \leq 2.2\cdot10^{-57}$, $\delta^2_{N} \leq 4.1\cdot10^{-60}$ and $\delta^2_{\beta} \leq 2.1\cdot10^{-35}$.Comment: 9 pages, 6 figure