Substantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies

Alzheimer's disease (AD) is a prevalent, progressive, and ultimately fatal neurodegenerative disorder that is defined pathologically by the accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. There remains an unmet need for therapies that can halt or slow the course of AD. To address this need, the FDA has provided a mechanism, under its Accelerated Approval pathway, for potential therapeutics to be approved based in part on their ability to reduce brain amyloid. Through this pathway, two monoclonal anti-amyloid antibodies, aducanumab and lecanemab, have been approved for clinical use. More recently, another amyloid-lowering antibody, donanemab, generated a statistically significant outcome in a phase 3 clinical trial and will shortly come under FDA review. While these monoclonal antibodies are not yet routinely used in clinical practice, the series of recent positive clinical trials has fostered enthusiasm amongst some AD experts. Here, we discuss three key limitations regarding recent anti-amyloid clinical trials: (1) there is little to no evidence that amyloid reduction correlates with clinical outcome, (2) the reported efficacy of anti-amyloid therapies may be partly, or wholly, explained by functional unblinding, and (3) donanemab in its phase 3 trial had no effect on tau burden, the pathological hallmark more closely related to cognition. Taken together, these observations call into question the efficacy of anti-amyloid therapies.Comment: 11 pages, 2 figures; Update 11/18/2023: Added subheadings to manuscript to improve readability, added a new data point to Figure 1A and Figure 2 for the recently published A4 clinical tria

Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study

Immunoterapia; Pembrolizumab; neoplàsies mamàries triple-negativesInmunoterapia; Pembrolizumab; neoplasias mamarias triple-negativasImmunotherapy; Pembrolizumab; triple-negative breast neoplasmsBackground: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, ?1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ?24 weeks), progression-free survival, and overall survival. Results: All enrolled patients (N¼170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ?3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2þ–21.5þ) and in the PD-L1–positive (range, 6.3–21.5þ) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

High-resolution observations of tungsten liner collapse and early jet formation

High-resolution photography of collapsing tungsten-lined shaped charges has revealed surface texturing both similar to and strikingly different from that previously observed during copper liner collapse. The behavior of three types of tungsten-lined shaped charges, with different liner designs and high explosives but with similar tungsten processing, were characterized by image-converter camera and fast- framing camera photography, and flash x-ray radiography. 120-mm- diameter, trumpet-shaped Octol charges produced surface blistering near the base of the tungsten liner, probably due to inhomogeneities near the liner-explosive interface resulting from cast loading. 148- mm-diameter, quasi-conical LX-14 charges produced smooth shocked- surface texture similar to that observed in conical, copper-lined LX- 14 (Viper) charges. 81-mm-diameter, conical LX-20 charges produced severe radial texturing throughout the collapsing tungsten liner, which transitioned to azimuthal banding on the jet surface. For each type of charge, obscuring debris from the tungsten jet tip prevented clear imaging of the jet surface at late time. 8 refs., 6 figs., 2 tabs

Reference Distorted Prices

I show that when consumers (mis)perceive prices relative to reference prices, budgets turn out to be soft, prices tend to be lower and the average quality of goods sold decreases. These observations provide explanations for decentralized purchase decisions, for people being happy with a purchase even when they have paid their evaluation, and for why trade might affect high quality local firms 'unfairly'

Professional Expectations of Provider LGBTQ Competence: Where We Are and Where We Need to Go

Introduction: Mental and behavioral health professional organizations use their governing documents to set expectations of provider competence in working with LGBTQ+ clients. Method: The codes of ethics and training program accreditation guidelines of nine mental and behavioral health disciplines (n=16) were analyzed using template analysis. Results: Coding resulted in fives themes: mission and values, direct practice, clinician education, culturally competent professional development, and advocacy. Expectations for provider competency vary greatly across disciplines. Conclusion: Having a mental and behavioral health workforce that is uniformly competent in meeting the unique needs of LGBTQ populations is key for supporting the mental and behavioral health of LGBTQ persons.This work was supported by the University of Maryland Prevention Research Center cooperative agreement from the Centers for Disease Control and Prevention (grant U48DP006382). N.D.W. also acknowledges support from the Southern Regional Education Board and the Robert Wood Johnson Foundation Health Policy Research Scholars Program. J.N.F. also acknowledges support from the Maryland Population Research Center, by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant P2CHD041041). This work does not expressly represent the views of the Centers for Disease Control and Prevention, National Institutes of Health, or the Robert Wood Johnson Foundation

Development of intuitive rules: Evaluating the application of the dual-system framework to understanding children's intuitive reasoning

This is an author-created version of this article. The original source of publication is Psychon Bull Rev. 2006 Dec;13(6):935-53 The final publication is available at www.springerlink.com Published version: http://dx.doi.org/10.3758/BF0321390

Frequency decoding of periodically timed action potentials through distinct activity patterns in a random neural network

Frequency discrimination is a fundamental task of the auditory system. The mammalian inner ear, or cochlea, provides a place code in which different frequencies are detected at different spatial locations. However, a temporal code based on spike timing is also available: action potentials evoked in an auditory-nerve fiber by a low-frequency tone occur at a preferred phase of the stimulus-they exhibit phase locking-and thus provide temporal information about the tone's frequency. In an accompanying psychoacoustic study, and in agreement with previous experiments, we show that humans employ this temporal information for discrimination of low frequencies. How might such temporal information be read out in the brain? Here we demonstrate that recurrent random neural networks in which connections between neurons introduce characteristic time delays, and in which neurons require temporally coinciding inputs for spike initiation, can perform sharp frequency discrimination when stimulated with phase-locked inputs. Although the frequency resolution achieved by such networks is limited by the noise in phase locking, the resolution for realistic values reaches the tiny frequency difference of 0.2% that has been measured in humans.Comment: 16 pages, 5 figures, and supplementary informatio

The Eliza effect and its dangers: from demystification to gender critique

This essay provides a gender critique of the Eliza effect. It delineates the way in which the Eliza effect is operationalised in AI research even as it is ostensibly demystified, for example in the writings of Douglas Hofstadter and Joseph Weizenbaum. It then exposes the gendered assumptions embedded in the nomenclature used to name this misperception of the computer as having capabilities equivalent to the human. It traces the genealogy of that nomenclature back through Weizenbaum’s ELIZA, to George Bernard Shaw’s Pygmalion. A close reading of the play is deployed in order to reveal the structural inequities of gender, class, and who or what gets to be human, that are both explored in the play and encoded in the operation and operationalisations of the Eliza effect. It concludes by attending to that operation and operationalisation in relation to today’s Virtual Personal Assistant’s, and makes a case for the importance of critique in order to expose the inequitable structures of power obscured and compounded by the Eliza effect – both its name, and that which it names

Discovery of very high energy gamma rays from PKS 1424+240 and multiwavelength constraints on its redshift

We report the first detection of very-high-energy (VHE) gamma-ray emission above 140 GeV from PKS 1424+240, a BL Lac object with an unknown redshift. The photon spectrum above 140 GeV measured by VERITAS is well described by a power law with a photon index of 3.8 +- 0.5_stat +- 0.3_syst and a flux normalization at 200 GeV of (5.1 +- 0.9_stat +- 0.5_syst) x 10^{-11} TeV^-1 cm^-2 s^-1, where stat and syst denote the statistical and systematical uncertainty, respectively. The VHE flux is steady over the observation period between MJD 54881 and 55003 (2009 February 19 to June 21). Flux variability is also not observed in contemporaneous high energy observations with the Fermi Large Area Telescope (LAT). Contemporaneous X-ray and optical data were also obtained from the Swift XRT and MDM observatory, respectively. The broadband spectral energy distribution (SED) is well described by a one-zone synchrotron self-Compton (SSC) model favoring a redshift of less than 0.1. Using the photon index measured with Fermi in combination with recent extragalactic background light (EBL) absorption models it can be concluded from the VERITAS data that the redshift of PKS 1424+240 is less than 0.66.Comment: accepted for publication, Ap

Fabry-Perot measurements and analysis of TOW-2A liner collapse and jet formation

A TOW-2A 146 mm shaped charge was fired and observed with five beam Fabry-Perot laser velocimetry. The liner collapse velocities were measured at five lines of sight covering the outer half of the liner. A record of 8-10 {mu}s in length was obtained for each sight line The velocity records at late time differ for each location, reflecting the varying charge-to-mass ratio as the end of the liner is approached. The results were analyzed with the CALE-2D hydrodynamic simulation code. The calculations reproduce the jump-off times, the shapes of the velocity jumps and the late time velocity asymptotes, but they underestimate the jump-off velocities by 6-7%. The calculations show that there exist no features in the velocity records that require spallation to account for them. Rather, the standard Steinberg-Guinan material model adequately accounts for the response of this copper liner to LX-14