Are You "Tilting at Windmills" or Undertaking a Valid Clinical Trial?

In this review, several aspects surrounding the choice of a therapeutic intervention and the conduct of clinical trials are discussed. Some of the background for why human studies have evolved to their current state is also included. Specifically, the following questions have been addressed: 1) What criteria should be used to determine whether a scientific discovery or invention is worthy of translation to human application? 2) What recent scientific advance warrants a deeper understanding of clinical trials by everyone? 3) What are the different types and phases of a clinical trial? 4) What characteristics of a human disorder should be noted, tracked, or stratified for a clinical trial and what inclusion /exclusion criteria are important to enrolling appropriate trial subjects? 5) What are the different study designs that can be used in a clinical trial program? 6) What confounding factors can alter the accurate interpretation of clinical trial outcomes? 7) What are the success rates of clinical trials and what can we learn from previous clinical trials? 8) What are the essential principles for the conduct of valid clinical trials

Fabrication Methods for Adaptive Deformable Mirrors

Previously, it was difficult to fabricate deformable mirrors made by piezoelectric actuators. This is because numerous actuators need to be precisely assembled to control the surface shape of the mirror. Two approaches have been developed. Both approaches begin by depositing a stack of piezoelectric films and electrodes over a silicon wafer substrate. In the first approach, the silicon wafer is removed initially by plasmabased reactive ion etching (RIE), and non-plasma dry etching with xenon difluoride (XeF2). In the second approach, the actuator film stack is immersed in a liquid such as deionized water. The adhesion between the actuator film stack and the substrate is relatively weak. Simply by seeping liquid between the film and the substrate, the actuator film stack is gently released from the substrate. The deformable mirror contains multiple piezoelectric membrane layers as well as multiple electrode layers (some are patterned and some are unpatterned). At the piezolectric layer, polyvinylidene fluoride (PVDF), or its co-polymer, poly(vinylidene fluoride trifluoroethylene P(VDF-TrFE) is used. The surface of the mirror is coated with a reflective coating. The actuator film stack is fabricated on silicon, or silicon on insulator (SOI) substrate, by repeatedly spin-coating the PVDF or P(VDFTrFE) solution and patterned metal (electrode) deposition. In the first approach, the actuator film stack is prepared on SOI substrate. Then, the thick silicon (typically 500-micron thick and called handle silicon) of the SOI wafer is etched by a deep reactive ion etching process tool (SF6-based plasma etching). This deep RIE stops at the middle SiO2 layer. The middle SiO2 layer is etched by either HF-based wet etching or dry plasma etch. The thin silicon layer (generally called a device layer) of SOI is removed by XeF2 dry etch. This XeF2 etch is very gentle and extremely selective, so the released mirror membrane is not damaged. It is possible to replace SOI with silicon substrate, but this will require tighter DRIE process control as well as generally longer and less efficient XeF2 etch. In the second approach, the actuator film stack is first constructed on a silicon wafer. It helps to use a polyimide intermediate layer such as Kapton because the adhesion between the polyimide and silicon is generally weak. A mirror mount ring is attached by using adhesive. Then, the assembly is partially submerged in liquid water. The water tends to seep between the actuator film stack and silicon substrate. As a result, the actuator membrane can be gently released from the silicon substrate. The actuator membrane is very flat because it is fixed to the mirror mount prior to the release. Deformable mirrors require extremely good surface optical quality. In the technology described here, the deformable mirror is fabricated on pristine substrates such as prime-grade silicon wafers. The deformable mirror is released by selectively removing the substrate. Therefore, the released deformable mirror surface replicates the optical quality of the underlying pristine substrate

Small Satellites: A Revolution in Space Science

This report describes the results of a study program sponsored by the Keck Institute for Space Studies (KISS) at the California Institute of Technology to explore how small satellite systems can uniquely enable new discoveries in space science. The disciplines studied span astrophysics, heliophysics, and planetary science (including NEOs, and other small bodies) based on remote and in-situ observations. The two workshops and study period that comprised this program brought together space scientists, engineers, technologists, mission designers, and program managers over 9 months. This invitation-only study program included plenary and subject matter working groups, as well as short courses and lectures for the public. Our goal was to conceive novel scientific observations, while identifying technical roadblocks, with the vision of advancing a new era of unique explorations in space science achievable using small satellite platforms from 200 kg down to the sub-kg level. The study program participants focused on the role of small satellites to advance space science at all levels from observational techniques through mission concept design. Although the primary goal was to conceive mission concepts that may require significant technology advances, a number of concepts realizable in the near-term were also identified. In this way, one unexpected outcome of the study program established the groundwork for the next revolution in space science, driven by small satellites platforms, with a near-term and far-term focus. There were a total of 35 KISS study participants across both workshops (July 16-20, 2012 and October 29-31, 2012) from 15 institutions including JPL, Caltech, JA / PocketSpacecraft.com, MIT, UCLA, U. Texas at Austin, U. Michigan, USC, The Planetary Society, Space Telescope Science Institute, Cornell, Cal Poly SLO, Johns Hopkins University, NRL, and Tyvak LLC. The first workshop focused on identifying new mission concepts while the second workshop explored the technology and engineering challenges identified via a facilitated mission concept concurrent design exercise. The Keck Institute limits the number of participants per workshop to at most 30 to encourage close interaction where roughly 20% involved in this study were students. This report is organized to communicate the outcome of the study program. It is also meant to serve as a public document to inform the larger community of the role small satellites can have to initiate a new program of exploration and discovery in space science. As such, it includes recommendations that could inform programmatic 1-5 decision making within space exploration agencies, both in the USA and internationally, on the promise of low-cost, focused, and high impact science should a strategic plan for small satellite space science be pursued. As such, the study program organizers and all participants are available to respond to any aspect of this report

Experimental Treatments for Spinal Cord Injury: What you Should Know

Experiencing a spinal cord injury (SCI) is extremely distressing, both physically and psychologically, and throws people into a complex, unfamiliar world of medical procedures, terminology, and decision making. You may have already had surgery to stabilize the spinal column and reduce the possibility of further damage. You are understandably distressed about the functions you may have lost below the level of spinal injury. You wish to recover any lost abilities as soon as possible. You, your family, or friends may have searched the Internet for treatments and cures

End-to-end numerical modeling of the Roman Space Telescope coronagraph

The Roman Space Telescope will have the first advanced coronagraph in space, with deformable mirrors for wavefront control, low-order wavefront sensing and maintenance, and a photon-counting detector. It is expected to be able to detect and characterize mature, giant exoplanets in reflected visible light. Over the past decade the performance of the coronagraph in its flight environment has been simulated with increasingly detailed diffraction and structural/thermal finite element modeling. With the instrument now being integrated in preparation for launch within the next few years, the present state of the end-to-end modeling is described, including the measured flight components such as deformable mirrors. The coronagraphic modes are thoroughly described, including characteristics most readily derived from modeling. The methods for diffraction propagation, wavefront control, and structural and thermal finite-element modeling are detailed. The techniques and procedures developed for the instrument will serve as a foundation for future coronagraphic missions such as the Habitable Worlds Observatory.Comment: 113 pages, 85 figures, to be published in SPIE Journal of Astronomical Telescopes, Instruments, and System

Walking Outcome After Traumatic Paraplegic Spinal Cord Injury: The Function of Which Myotomes Makes a Difference?

BACKGROUND: Accurate prediction of walking function after a traumatic spinal cord injury (SCI) is crucial for an appropriate tailoring and application of therapeutical interventions. Long-term outcome of ambulation is strongly related to residual muscle function acutely after injury and its recovery potential. The identification of the underlying determinants of ambulation, however, remains a challenging task in SCI, a neurological disorder presented with heterogeneous clinical manifestations and recovery trajectories. OBJECTIVES: Stratification of walking function and determination of its most relevant underlying muscle functions based on stratified homogeneous patient subgroups. METHODS: Data from individuals with paraplegic SCI were used to develop a prediction-based stratification model, applying unbiased recursive partitioning conditional inference tree (URP-CTREE). The primary outcome was the 6-minute walk test at 6 months after injury. Standardized neurological assessments ≤15 days after injury were chosen as predictors. Resulting subgroups were incorporated into a subsequent node-specific analysis to attribute the role of individual lower extremity myotomes for the prognosis of walking function. RESULTS: Using URP-CTREE, the study group of 361 SCI patients was divided into 8 homogeneous subgroups. The node specific analysis uncovered that proximal myotomes L2 and L3 were driving factors for the differentiation between walkers and non-walkers. Distal myotomes L4-S1 were revealed to be responsible for the prognostic distinction of indoor and outdoor walkers (with and without aids). CONCLUSION: Stratification of a heterogeneous population with paraplegic SCI into more homogeneous subgroups, combined with the identification of underlying muscle functions prospectively determining the walking outcome, enable potential benefit for application in clinical trials and practice

Targeted copy number variant identification across the neurodegenerative disease spectrum

Background: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. Methods: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). Results: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer\u27s disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of \u3e3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. Conclusion: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration

Origins Space Telescope: Baseline mission concept

The Origins Space Telescope will trace the history of our origins from the time dust and heavy elements permanently altered the cosmic landscape to present-day life. How did galaxies evolve from the earliest galactic systems to those found in the Universe today? How do habitable planets form? How common are life-bearing worlds? To answer these alluring questions, Origins will operate at mid-and far-infrared (IR) wavelengths and offer powerful spectroscopic instruments and sensitivity three orders of magnitude better than that of the Herschel Space Observatory, the largest telescope flown in space to date. We describe the baseline concept for Origins recommended to the 2020 US Decadal Survey in Astronomy and Astrophysics. The baseline design includes a 5.9-m diameter telescope cryocooled to 4.5 K and equipped with three scientific instruments. A mid-infrared instrument (Mid-Infrared Spectrometer and Camera Transit spectrometer) will measure the spectra of transiting exoplanets in the 2.8 to 20 μm wavelength range and offer unprecedented spectrophotometric precision, enabling definitive exoplanet biosignature detections. The far-IR imager polarimeter will be able to survey thousands of square degrees with broadband imaging at 50 and 250 μm. The Origins Survey Spectrometer will cover wavelengths from 25 to 588 μm, making wide-area and deep spectroscopic surveys with spectral resolving power R ∼ 300, and pointed observations at R ∼ 40,000 and 300,000 with selectable instrument modes. Origins was designed to minimize complexity. The architecture is similar to that of the Spitzer Space Telescope and requires very few deployments after launch, while the cryothermal system design leverages James Webb Space Telescope technology and experience. A combination of current-state-of-the-art cryocoolers and next-generation detector technology will enable Origins\u27 natural background-limited sensitivity

Galaxy evolution probe

The Galaxy Evolution Probe (GEP) is a concept for a mid- and far-infrared space observatory to measure key properties of large samples of galaxies with large and unbiased surveys. GEP will attempt to achieve zodiacal light and Galactic dust emission photon background-limited observations by utilizing a 6-K, 2.0-m primary mirror and sensitive arrays of kinetic inductance detectors (KIDs). It will have two instrument modules: a 10 to 400  μm hyperspectral imager with spectral resolution R  =  λ  /  Δλ  ≥  8 (GEP-I) and a 24 to 193  μm, R  =  200 grating spectrometer (GEP-S). GEP-I surveys will identify star-forming galaxies via their thermal dust emission and simultaneously measure redshifts using polycyclic aromatic hydrocarbon emission lines. Galaxy luminosities derived from star formation and nuclear supermassive black hole accretion will be measured for each source, enabling the cosmic star formation history to be measured to much greater precision than previously possible. Using optically thin far-infrared fine-structure lines, surveys with GEP-S will measure the growth of metallicity in the hearts of galaxies over cosmic time and extraplanar gas will be mapped in spiral galaxies in the local universe to investigate feedback processes. The science case and mission architecture designed to meet the science requirements is described, and the KID and readout electronics state of the art and needed developments are described. This paper supersedes the GEP concept study report cited in it by providing new content, including: a summary of recent mid-infrared KID development, a discussion of microlens array fabrication for mid-infrared KIDs, and additional context for galaxy surveys. The reader interested in more technical details may want to consult the concept study report