Digital mobility sub-study in the Parkinson's Progressive Marker Initiative (PPMI) study

This poster details the gait sub-study project in PPMI. The sub-study aims to test the feasibility and validity of digital mobility data for enrichment of the prodromal screening and to assess the sensitivity of these measures to early phase progression in prodromal and recently diagnosed patients with Parkinson’s disease. The poster details the protocol and the initial preliminary results of the first 21 participants. The post5er was presented in the Movement Disorders Society Conference held in Copenhagen, Denmark in Sept 2023

High-Resolution Transmission Spectroscopy of the Terrestrial Exoplanet GJ 486b

Terrestrial exoplanets orbiting M-dwarf stars are promising targets for transmission spectroscopy with existing or near-future instrumentation. The atmospheric composition of such rocky planets remains an open question, especially given the high X-ray and ultraviolet flux from their host M dwarfs that can drive atmospheric escape. The 1.3 $R_\oplus$ exoplanet GJ 486b ($T_{\rm{eq}} \sim$ 700 K), orbiting an M3.5 star, is expected to have one of the strongest transmission spectroscopy signals among known terrestrial exoplanets. We observed three transits of GJ 486b using three different high-resolution spectrographs: IRD on Subaru, IGRINS on Gemini-South, and SPIRou on the Canada-France-Hawai'i Telescope. We searched for atmospheric absorption from a wide variety of molecular species via the cross-correlation method, but did not detect any robust atmospheric signals. Nevertheless, our observations are sufficiently sensitive to rule out several clear atmospheric scenarios via injection and recovery tests, and extend comparative exoplanetology into the terrestrial regime. Our results suggest that GJ 486b does not possess a clear H$_2$/He-dominated atmosphere, nor a clear 100% water-vapor atmosphere. Other secondary atmospheres with high mean molecular weights or H$_2$/He-dominated atmospheres with clouds remain possible. Our findings provide further evidence suggesting that terrestrial planets orbiting M-dwarf stars may experience significant atmospheric loss.Comment: Accepted for publication in A

Tunable Indistinguishable Photons From Remote Quantum Dots

Single semiconductor quantum dots have been widely studied within devices that can apply an electric field. In the most common system, the low energy offset between the InGaAs quantum dot and the surrounding GaAs material limits the magnitude of field that can be applied to tens of kVcm^-1, before carriers tunnel out of the dot. The Stark shift experienced by the emission line is typically 1 meV. We report that by embedding the quantum dots in a quantum well heterostructure the vertical field that can be applied is increased by over an order of magnitude whilst preserving the narrow linewidths, high internal quantum efficiencies and familiar emission spectra. Individual dots can then be continuously tuned to the same energy allowing for two-photon interference between remote, independent, quantum dots

Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA

HIV-infected individuals are living longer on antiretro-viral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV- individuals. First,we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across \u3e80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA).We find that decreased HLA methylation is predictive of lower CD4/CD8T cell ratio, linking molecular aging, epigenetic regulation, and disease progression

Planets Around Low-Mass Stars (PALMS). V. Age-Dating Low-Mass Companions to Members and Interlopers of Young Moving Groups

Copyright © 2015. The American Astronomical Society. All rights reserved.We present optical and near-infrared adaptive optics (AO) imaging and spectroscopy of 13 ultracool (>M6) companions to late-type stars (K7-M4.5), most of which have recently been identified as candidate members of nearby young moving groups (YMGs; 8-120 Myr) in the literature. The inferred masses of the companions (~10-100 Mjup) are highly sensitive to the ages of the primary stars so we critically examine the kinematic and spectroscopic properties of each system to distinguish bona fide YMG members from old field interlopers. 2MASS J02155892-0929121 C is a new M7 substellar companion (40-60 Mjup) with clear spectroscopic signs of low gravity and hence youth. The primary, possibly a member of the ~40 Myr Tuc-Hor moving group, is visually resolved into three components, making it a young low-mass quadruple system in a compact (1 Gyr) tidally-locked spectroscopic binaries without convincing kinematic associations with any known moving group. The high rate of false positives in the form of old active stars with YMG-like kinematics underscores the importance of radial velocity and parallax measurements to validate candidate young stars identified via proper motion and activity selection alone. Finally, we spectroscopically confirm the cool temperature and substellar nature of HD 23514 B, a recently discovered M8 benchmark brown dwarf orbiting the dustiest-known member of the Pleiades.NASANSFMt. Cuba Astronomical FoundationSamuel OschinAlfred P. Sloan Foundatio

Politics at the Cutting Edge: Intergovernmental Policy Innovation in the Affordable Care Act

In the eight years since the passage of the Patient Protection and Affordable Care Act (ACA), state governments have remained critical sites of contention over the law. Intense partisan conflict over ACA implementation has raised questions about traditional theories of intergovernmental relations, which posit that federal–state cooperation depends largely on policy design. Yet, few studies have examined how partisanship, as well as other important factors, shape state policy innovations under the ACA. This article examines the ACA’s State Innovation Models (SIM) initiative. SIM is specifically geared towards incentivizing states to experiment with new models of payment and delivery that can improve health outcomes and/or reduce health-care costs. Drawing on a combination of quantitative and qualitative evidence, we find that states’ participation in SIM is shaped by partisanship, administrative capacity, and state policy legacies. Our findings have implications for future efforts at intergovernmental health reforms

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients

Civil Partnership in the United Kingdom and a Moderate Proposal for Change in the United States [Note]

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