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

Qualitative extension of the EC′ Zone Diagram to a molecular catalyst for a multi-electron, multi-substrate electrochemical reaction

Traverse the EC′ Zone Diagram with a molecular H 2 -evolving electrocatalyst through systematic variation of the acid p K a , scan rate, acid concentration and catalyst concentration

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