Extending the viability of human precision-cut intestinal slice model for drug metabolism studies.

Human Precision-cut intestinal slices (hPCIS) are used to study intestinal physiology, pathophysiology, drug efficacy, toxicology, kinetics, and metabolism. However, the use of this ex vivo model is restricted to approximately a 24 h timeframe because of declining viability of the hPCIS during traditional culture. We hypothesized that we could extend the hPCIS viability by using organoid medium. Therefore, we cultured hPCIS for up to 72 h in organoid media [expansion medium (Emed) and differentiation medium (Dmed)]. After incubation, we assessed culture-induced changes on viability markers, specific cell type markers and we assessed the metabolic activity of enterocytes by measuring midazolam metabolite formation. We show that the adenosine triphosphate (ATP)/protein ratio of Emed-cultured hPCIS and morphology of both Emed- and Dmed-cultured hPCIS was improved compared to WME-cultured hPCIS. Emed-cultured hPCIS showed an increased expression of proliferation and stem cell markers, whereas Dmed-cultured hPCIS showed an increased expression of proliferation and enterocyte markers, along with increased midazolam metabolism. Using the Emed, the viability of hPCIS could be extended for up to 72 h, and proliferating stem cells remained preserved. Using Dmed, hPCS also remained viable for up to 72 h, and specifically rescued the metabolizing enterocytes during culture. In conclusion, by using two different organoid culture media, we could extend the hPCIS viability for up to 72 h of incubation and specifically steer stem cells or enterocytes towards their original function, metabolism, and proliferation, potentially allowing pharmacokinetic and toxicology studies beyond the 24 h timeframe.

Pharmacokinetics of 2,000 Milligram Ertapenem in Tuberculosis Patients.

Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC0-∞) was 2,032 (1,751 to 2,346) mg · h/liter, the intercompartmental clearance (CL12) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment (V1) was 1.514 (1.064 to 2.210) liters. A more than dose-proportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time (f40% T>MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f40% T>MIC for most of the patients, and exploration in a phase 2 study can be advocated.

Susceptibility Testing of Antibiotics That Degrade Faster than the Doubling Time of Slow-Growing Mycobacteria: Ertapenem Sterilizing Effect versus Mycobacterium tuberculosis.

Drug susceptibility tests (DSTs) for Mycobacterium tuberculosis require at least 7 days of incubation. Drugs that are unstable at 37°C, such as ertapenem, are likely to be degraded before killing or inhibiting slow-growing bacteria. This would alter the MICs of these drugs, including ertapenem, leading to falsely high MICs. Here, we describe a new strategy we developed to perform DSTs and measure MICs for such unstable compounds.

Quantification and validation of ertapenem using a liquid chromatography-tandem mass spectrometry method.

Ertapenem, a carbapenem, relies on time-dependent killing. Therapeutic drug monitoring (TDM) should be considered, when ertapenem is used in specific populations, to achieve optimal bactericidal activity and optimize drug-dosing regimens. No validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported using deuterated ertapenem as the internal standard. A new simple and robust LC-MS/MS method using a quadrupole mass spectrometer was developed for analysis of ertapenem in human plasma, using deuterated ertapenem as the internal standard. The calibration curve was linear over a range of 0.1 (lower limit of quantification [LLOQ]) to 125 mg/liter. The calculated accuracy ranged from -2.4% to 10.3%. Within-run coefficients of variation (CV) ranged from 2.7% to 11.8%, and between-run CV ranged from 0% to 8.4%. Freeze-thaw stability had a bias of -3.3% and 0.1%. Storage of QC samples for 96 h at 4°C had a bias of -4.3 to 5.6%, storage at room temperature for 24 h had a bias of -10.7% to -14.8%, and storage in the autosampler had a bias between -2.9% and -10.0%. A simple LC-MS/MS method to quantify ertapenem in human plasma using deuterated ertapenem as the internal standard has been validated. This method can be used in pharmacokinetic studies and in clinical studies by performing TDM.

Clinical Meaningfulness in Alzheimer's Disease Clinical Trials. A Report from the EU-US CTAD Task Force.

Recent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer's disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generated a debate on whether the change scores observed on clinical outcome assessments represent a clinically meaningful benefit to patients. An evidence-based conclusion is urgently required to inform decision-making related to the approval, reimbursement, and ultimately, the management of emerging therapies in clinical practice. The EU-US CTAD Task Force met in Boston to address this important question. The current state-of-the-art knowledge for interpreting clinical meaningfulness of AD clinical trial results, including the point of view of patients and study partners on what is clinically meaningful, was discussed and is summarized here. A combination of methodologies to address the challenges emerged. There remain gaps in the understanding of clinical meaningfulness that only long-term longitudinal studies will be able to address.

Simultaneous quantification of anidulafungin and caspofungin in plasma by an accurate and simple liquid chromatography tandem mass-spectrometric method.

INTRODUCTION: Echinocandins are a valuable addition for the treatment of invasive fungal infections, as they are efficacious, demonstrate low toxicity, and have limited drug-drug interactions. In specific clinical situations when altered pharmacokinetics can be expected or dosing guidelines are conflicting, it may be useful to measure concentrations. For this purpose, a liquid chromatography tandem mass-spectrometric method to measure anidulafungin and caspofungin in ethylenediaminetetraacetic acid plasma was developed. METHODS: The method was developed on a Thermo Fisher TSQ Quantum LC-MS/MS. For separation, a BetaBasic C4 (100 mm × 3.0 mm; 5 µm) analytical column was used. Sample preparation consisted of protein precipitation directly in the autosampler vial. The internal standard aculeacin A is structurally related, not used in humans, and commercially available. The method was validated according to the guidelines for bioanalytical method validation of the Food and Drug Administration. RESULTS: The method was accurate (bias ranging from -3.0% to 1.9%) and precise (within-run and between-run coefficients of variation of 2.2% to 7.7% and 1.6% to 9.0%, respectively). All calibration curves were linear over a range of 0.5-10.0 mg/L for anidulafungin and 0.1-20.0 mg/L for caspofungin, and if necessary, samples can be diluted 10-fold. The samples were stable for 3 freeze-thaw cycles, with a bias ranging from 0.6% to 11%. The maximum bias from the worst storage condition, 72 hours at room temperature, was -14.7%. In patient samples, anidulafungin peak concentrations ranged from 2.8 to 8.6 mg/L (n = 20) and trough concentrations ranged from 1.0 to 4.7 mg/L (n = 79). The measured caspofungin concentrations ranged from 1.9 to 7.3 mg/L (n = 20). CONCLUSIONS: The method developed has a straightforward sample preparation and uses a structural analog as the internal standard. This method has been applied successfully for the measurement of anidulafungin and caspofungin concentrations in patient samples, both for clinical practice and for research.

'Time Saved' As a Demonstration of Clinical Meaningfulness and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings.

In Alzheimer's disease (AD) clinical trials, disease-modifying therapies are expected to slow the rate of disease progression. Treatment effects are evaluated using a validated clinical scale as the difference between treatment and placebo in mean change from baseline to endpoint. Understanding the clinical relevance of this metric is not necessarily intuitive. Expressing active treatment-placebo difference as a time metric (i.e., months saved with treatment) has potential to provide a metric that is more easily and consistently interpreted. Using data from the TRAILBLAZER-ALZ study, time component tests (TCTs) were employed to determine the time saved with donanemab (an amyloid lowering drug) treatment. At study endpoint (Week 76), disease progression was delayed by 5.3 months and 5.2 months as measured by the Integrated Alzheimer's Disease Rating Scale (iADRS) and the Clinical Dementia Rating Sum of Boxes (CDR-SB), respectively.

Dietary fiber and its role in performance, welfare, and health of pigs.

Dietary fiber (DF) is receiving increasing attention, and its importance in pig nutrition is now acknowledged. Although DF for pigs was frowned upon for a long time because of reductions in energy intake and digestibility of other nutrients, it has become clear that feeding DF to pigs can affect their well-being and health. This review aims to summarize the state of knowledge of studies on DF in pigs, with an emphasis on the underlying mode of action, by considering research using DF in sows as well as suckling and weaned piglets, and fattening pigs. These studies indicate that DF can benefit the digestive tracts and the health of pigs, if certain conditions or restrictions are considered, such as concentration in the feed and fermentability. Besides the chemical composition and the impact on energy and nutrient digestibility, it is also necessary to evaluate the possible physical and physiologic effects on intestinal function and intestinal microbiota, to better understand the relation of DF to animal health and welfare. Future research should be designed to provide a better mechanistic understanding of the physiologic effects of DF in pigs.

Digital spacer data driven COPD inhaler adherence education: The OUTERSPACE proof-of-concept study.

Pressurized metered dose inhalers are recommended to be used in combination with spacers, yet inhaler technique and adherence are poor. A novel digital "smart" spacer can record spacer use and technique errors and could facilitate personalized education. In this proof-of-concept study, we assessed the usability of the digital spacer and explored its effects on inhaler technique, adherence, long-term systemic drug exposure and clinical outcomes in COPD. Usability was deemed high. One month after personalized digital spacer inhaler education, the mean number of errors per patient per day decreased with 36%, from 6.40 errors/day to 4.07 errors/day (p = 0.038). Drug exposure was confirmed by bioanalytical scalp hair analysis of formoterol. No significant change in clinical outcomes was observed. This study demonstrates the digital spacer's potential value in inhaler education, but larger, longer-term studies are required.

Expression of the familial cardiac valvular dystrophy gene, filamin-A, during heart morphogenesis.

Myxoid degeneration of the cardiac valves is a common feature in a heterogeneous group of disorders that includes Marfan syndrome and isolated valvular diseases. Mitral valve prolapse is the most common outcome of these and remains one of the most common indications for valvular surgery. While the etiology of the disease is unknown, recent genetic studies have demonstrated that an X-linked form of familial cardiac valvular dystrophy can be attributed to mutations in the Filamin-A gene. Since these inheritable mutations are present from conception, we hypothesize that filamin-A mutations present at the time of valve morphogenesis lead to dysfunction that progresses postnatally to clinically relevant disease. Therefore, by carefully evaluating genetic factors (such as filamin-A) that play a substantial role in MVP, we can elucidate relevant developmental pathways that contribute to its pathogenesis. In order to understand how developmental expression of a mutant protein can lead to valve disease, the spatio-temporal distribution of filamin-A during cardiac morphogenesis must first be characterized. Although previously thought of as a ubiquitously expressed gene, we demonstrate that filamin-A is robustly expressed in non-myocyte cells throughout cardiac morphogenesis including epicardial and endocardial cells, and mesenchymal cells derived by EMT from these two epithelia, as well as mesenchyme of neural crest origin. In postnatal hearts, expression of filamin-A is significantly decreased in the atrioventricular and outflow tract valve leaflets and their suspensory apparatus. Characterization of the temporal and spatial expression pattern of filamin-A during cardiac morphogenesis is a crucial first step in our understanding of how mutations in filamin-A result in clinically relevant valve disease.

A fast and simple method for the simultaneous analysis of midazolam, 1-hydroxymidazolam, 4-hydroxymidazolam and 1-hydroxymidazolam glucuronide in human serum, plasma and urine.

For the quantification of the sedative and anesthetic drug midazolam and its main (active) metabolites 1-hydroxymidazolam, 4-hydroxymidazolam and 1-hydroxymidazolam glucuronide in human serum, human EDTA plasma, human heparin plasma and human urine a single accurate method by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) has been developed. Protein precipitation as sample preparation, without the need of a time-consuming deglucuronidation step for the quantification of 1-hydroxymidazolam glucuronide, resulted in a simple and rapid assay suitable for clinical practice with a total runtime of only 1.1  min. The four components and the isotope-labeled internal standards were separated on a C18 column and detection was performed with a triple-stage quadrupole mass spectrometer operating in positive ionization mode. The method was validated based on the "Guidance for Industry Bioanalytical Method Validation" (Food and Drug Administration, FDA) and the "Guideline on bioanalytical method validation" of the European Medicines Agency (EMA). Linearity was proven over the ranges of 5-1500 µg/L for midazolam, 1-hydroxymidazolam and 4-hydroxymidazolam and 25-5000 µg/L for 1-hydroxymidazolam glucuronide, using a sample volume of 100 µL. Matrix comparison indicated that the assay is also applicable to other human matrices like EDTA and heparin plasma and urine. Stability experiments showed good results for the stability of midazolam, 1-hydroxymidazolam and 1-hydroxymidazolam glucuronide in serum, EDTA and heparin plasma and urine stored for 7 days under different conditions. At room temperature, 4-hydroxymidazo-lam is stable for 7 days in EDTA plasma, but stable for only 3 days in serum and heparin plasma and less than 24 h in urine. All four compounds were found to be stable in serum, EDTA plasma, heparin plasma and urine for 7 days after sample preparation and for 3 freeze-thaw cycles. The assay has been applied in therapeutic drug monitoring of midazolam for (pediatric) intensive care patients.

The Computerized Cognitive Composite (C3) in an Alzheimer's Disease Secondary Prevention Trial.

BACKGROUND: Computerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers. OBJECTIVE: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3). DESIGN: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD). SETTING: Multi-center international study. PARTICIPANTS: Clinically normal (CN) older adults (65-85; n=4486). MEASUREMENTS: Participants underwent florbetapir-Positron Emission Tomography for Aß+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer's Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aß+/- groups (n=1323/3163) and PACC. RESULTS: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aß+ performed worse on C3 compared with Aß- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants. CONCLUSIONS: These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.

Pharmacokinetics of rifampin and clarithromycin in patients treated for Mycobacterium ulcerans infection.

In a randomized controlled trial in Ghana, treatment of Mycobacterium ulcerans infection with streptomycin (SM)-rifampin (RIF) for 8 weeks was compared with treatment with SM-RIF for 4 weeks followed by treatment with RIF-clarithromycin (CLA) for 4 weeks. The extent of the interaction of RIF and CLA combined on the pharmacokinetics of the two compounds is unknown in this population and was therefore studied in a subset of patients. Patients received CLA at a dose of 7.5 mg/kg of body weight once daily, rounded to the nearest 125 mg. RIF was administered at a dose of 10 mg/kg, rounded to the nearest 150 mg. SM was given at a dose of 15 mg/kg once daily as an intramuscular injection. Plasma samples were drawn at steady state and analyzed by liquid chromatography-tandem mass spectroscopy. Pharmacokinetic parameters were calculated with the MW/Pharm (version 3.60) program. Comedication with CLA resulted in a 60% statistically nonsignificant increase in the area under the plasma concentration-time curve (AUC) for RIF of 25.8 mg x h/liter (interquartile ratio [IQR], 21.7 to 31.5 mg x h/liter), whereas the AUC of RIF was 15.2 mg x h/liter (IQR, 15.0 to 17.5 mg x h/liter) in patients comedicated with SM (P = 0.09). The median AUCs of CLA and 14-hydroxyclarithromycin (14OH-CLA) were 2.9 mg x h/liter (IQR, 1.5 to 3.8 mg x h/liter) and 8.0 mg x h/liter (IQR, 6.7 to 8.6 mg x h/liter), respectively. The median concentration of CLA was above the MIC of M. ulcerans, but that of 14OH-CLA was not. In further clinical studies, a dose of CLA of 7.5 mg/kg twice daily should be used (or with an extended-release formulation, 15 mg/kg should be used) to ensure higher levels of exposure to CLA and an increase in the time above the MIC compared to those achieved with the currently used dose of 7.5 mg/kg once daily.

Effects of Mental Health Paraprofessional Training for Filipina Foreign Domestic Workers in Singapore.

Research has found that 24% of foreign domestic workers (FDWs) in Singapore have poor mental health (24%), with depressive symptoms being identified as the second most severe psychological symptoms [1]. The study assessed the acceptability and effectiveness of a 4-week cognitive behavioral therapy (CBT)-based paraprofessional training program for FDWs in Singapore on depression literacy and CBT knowledge (primary outcomes), depression-related stigma, as well as attitudes towards seeking professional help (secondary outcomes) immediately and 2 months following the training. Forty female Filipino FDWs were recruited and randomized into either a CBT-based paraprofessional training program or wait-list (WL) group. Participants completed outcome measures before, after, and 2 months following their training. No significant difference was found on changes on any of the outcome variables in the intervention group as compared to the WL group. Following training, both groups showed significantly improved depression literacy, CBT knowledge, and attitudes towards seeking professional help. These changes were sustained at 2-month follow-up. All participants indicated a high level of satisfaction with the training program. While findings from between-group analyses do not support the efficacy of the CBT-based paraprofessional training program in improving depression literacy and related outcomes, participation in the program was associated with improvements in several outcomes within the training group. Future research should explore adaptations to the program (e.g., in terms of training duration and modes of delivery) that would increase its efficacy in improving depression literacy and CBT knowledge among FDWs.

Simple, fast and robust LC-MS/MS method for the simultaneous quantification of canagliflozin, dapagliflozin and empagliflozin in human plasma and urine.

Sodium-glucose cotransporter 2 -inhibitors (SGLT2i) are oral glucose-lowering drugs that have also demonstrated cardioprotective and renoprotective effects. SGLT2i play an increasingly important role in the treatment of type 2 diabetes. Here we report a simple and robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of three SGLT2i (canagliflozin, dapagliflozin and empagliflozin) in human plasma, serum and urine with a runtime of 1 min. Methanol was used as protein precipitating agent. Chromatographic separation was accomplished using a Waters ACQUITY UPLC HSS T3 1.8 µm; 2.1 × 50 mm column with a Waters ACQUITY UPLC HSS T3 1.8 µm VanGuard Pre-column; 2.1 × 5 mm, using gradient elution with ammonium acetate 20 mM (pH 5) and acetonitrile as mobile phase at a flow rate of 0.8 ml/min. Mass spectrometric analysis of the acetate adduct ions was carried out using electrospray with negative ionization and SRM mode. The assay was validated according to FDA and EMA guidelines, including selectivity, linearity, accuracy and precision, dilution integrity, stability and recovery. With a sample volume of 200 µl, linear ranges of 10-5000 µg/L, 1-500 µg/L and 2-1000 µg/L for canagliflozin, dapagliflozin and empagliflozin respectively, were achieved. The assay was successfully applied in two pharmacokinetic studies with dapagliflozin and empagliflozin. In conclusion, we developed and validated a simple, fast and robust LC-MS/MS method for the simultaneous quantification of canagliflozin, dapagliflozin and empagliflozin, that allows rapid analysis of large numbers of samples and can be used for both pharmacokinetic studies and biomedical analysis of canagliflozin, dapagliflozin and empagliflozin.

Increasing metformin concentrations and its excretion in both rat and porcine ex vivo normothermic kidney perfusion model.

INTRODUCTION: Metformin can accumulate and cause lactic acidosis in patients with renal insufficiency. Metformin is known to inhibit mitochondria, while renal secretion of the drug by proximal tubules indirectly requires energy. We investigated whether addition of metformin before or during ex vivo isolated normothermic machine perfusion (NMP) of porcine and rat kidneys affects its elimination. RESEARCH DESIGN AND METHODS: First, Lewis rats were pretreated with metformin or saline the day before nephrectomy. Subsequently, NMP of the kidney was performed for 90 min. Metformin was added to the perfusion fluid in one of three different concentrations (none, 30 mg/L or 300 mg/L). Second, metformin was added in increasing doses to the perfusion fluid during 4 hours of NMP of porcine kidneys. Metformin concentration was determined in the perfusion fluid and urine by liquid chromatography-tandem mass spectrometry. RESULTS: Metformin clearance was approximately 4-5 times higher than creatinine clearance in both models, underscoring secretion of the drug. Metformin clearance at the end of NMP in rat kidneys perfused with 30 mg/L was lower than in metformin pretreated rats without the addition of metformin during perfusion (both p≤0.05), but kidneys perfused with 300 mg/L trended toward lower metformin clearance (p=0.06). Creatinine clearance was not different between treatment groups. During NMP of porcine kidneys, metformin clearance peaked at 90 min of NMP (18.2±13.7 mL/min/100 g). Thereafter, metformin clearance declined, while creatinine clearance remained stable. This observation can be explained by saturation of metformin transporters with a Michaelis-Menten constant (95% CI) of 23.0 (10.0 to 52.3) mg/L. CONCLUSIONS: Metformin was secreted during NMP of both rat and porcine kidneys. Excretion of metformin decreased under increasing concentrations of metformin, which might be explained by saturation of metformin transporters rather than a self-inhibitory effect. It remains unknown whether a self-inhibitory effect contributes to metformin accumulation in humans with longer exposure times.

Expanding the Capability of Microwave Multiplexed Readout for Fast Signals in Microcalorimeters.

Microwave SQUID multiplexing has become a key technology for reading out large arrays of X-ray and gamma-ray microcalorimeters with mux factors of 100 or more. The desire for fast X-ray pulses that accommodate photon counting rates of hundreds or thousands of counts per second per sensor drives system design toward high sensor current slew rate. Typically, readout of high current slew rate events is accomplished by increasing the sampling rate, such that rates of order 1MHz may be necessary for some experiments. In our microwave multiplexed readout scheme, the effective sampling rate is set by the frequency of the flux-ramp modulation (f r) used to linearize the SQUID response. The maximum current slew rate between samples is then nominally Φ 0 f r/2M in (where M in is the input coupling) because it is generally not possible to distinguish phase shifts of > π from negative phase shifts of < -π. However, during a pulse, we know which direction the current ought to be slewing, and this makes it possible to reconstruct a pulse where the magnitude of the phase shift between samples is > π. We describe a practical algorithm to identify and reconstruct pulses that exceed this nominal slew rate limit on the rising edge. Using pulses produced by X-ray transition-edge sensors, we find that the pulse reconstruction has a negligible impact on energy resolution compared to arrival time effects induced by under-sampling the rising edge. This technique can increase the effective slew rate limit by more than a factor of two, thereby either reducing the resonator bandwidth required or extending the energy range of measurable photons. The extra margin could also be used to improve crosstalk or to decrease readout noise.

Detecting Treatment Group Differences in Alzheimer's Disease Clinical Trials: A Comparison of Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) and the Clinical Dementia Rating - Sum of Boxes (CDR-SB).

The Alzheimer's Disease Assessment Scale's cognitive subscale (ADAS-Cog) has been widely used as an outcome measure in Alzheimer's Disease (AD) clinical trials. In its original form (ADAS-Cog11), the scale has been used successfully in mild-to-moderate AD dementia populations, but its use is more limited in the study of earlier disease (mild cognitive impairment [MCI] or mild dementia due to AD) owing to lack of appropriate sensitivity of some items. With recent focus on earlier treatment, efforts have focused on the development of more sensitive tools, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a global assessment tool to evaluate both cognition and function. The ability of the ADAS-Cog and CDR-SB to detect treatment group differences in the clinical trial environment has not been systematically studied. The aim of this analysis was to compare the utility of these tools in detecting treatment group differences, by reviewing study findings identified through advanced searches of clinicaltrials.gov and Ovid, and press releases and scientific presentations. Findings from placebo-controlled studies of ≥ 6m duration and enrolling >100 participants were included; reporting of both the ADAS-Cog and CDR-SB at endpoint was also a requirement. Of the >300 records identified, 34 studies fulfilled the criteria. There were significant placebo versus active drug group differences based on findings from at least one measure for 14 studies. The ADAS-Cog detected treatment differences more frequently than the CDR-SB. Based on these and previously published findings, the ADAS-Cog appears more useful than the CDR-SB in detecting treatment group differences.

The Integrated Alzheimer's Disease Rating Scale (iADRS) Findings from the EXPEDITION3 Trial.

The Integrated Alzheimer's Disease (AD) Rating Scale (iADRS) is a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). It demonstrates acceptable psychometric properties, and is effective in capturing both disease progression and separation of placebo and active drug effect. We assessed the performance of iADRS in the solanezumab EXPEDITION3 study, an 80-week, placebo-controlled study of individuals with mild AD dementia. A statistically significant difference between placebo and active drug was observed for iADRS score change from baseline at Week 28 (p=0.028) through Week 80 (p=0.015). Across the Phase 3 solanezumab trials, iADRS was the only tool that consistently differentiated between solanezumab and placebo groups. These findings suggest that the iADRS is a useful integrated measurement tool for treatment trials of individuals with mild AD dementia.

A 300-mK Test Bed for Rapid Characterization of Microwave SQUID Multiplexing Circuits.

Microwave SQUID multiplexing is a promising technique for multiplexing large arrays of transition edge sensors. A major bottleneck in the development and distribution of microwave SQUID multiplexer chips occurs in the time-intensive design testing and quality assurance stages. To obtain useful RF measurements, these devices must be cooled to temperatures below 500 mK. The need for a more efficient system to screen microwave multiplexer chips has grown as the number of chips requested by collaborators per year reaches into the hundreds. We have therefore assembled a test bed for microwave SQUID circuits, which decreases screening time for four 32-channel chips from 24 h in an adiabatic demagnetization refrigerator to approximately 5 h in a helium dip probe containing a closed cycle 3He sorption refrigerator. We discuss defining characteristics of these microwave circuits and the challenges of establishing an efficient testing setup for them.