Airborne 2-Micron Double-Pulsed Integrated Path Differential Absorption Lidar for Column CO2 Measurement

Double-pulse 2-micron lasers have been demonstrated with energy as high as 600 millijouls and up to 10 Hz repetition rate. The two laser pulses are separated by 200 microseconds and can be tuned and locked separately. Applying double-pulse laser in DIAL system enhances the CO2 measurement capability by increasing the overlap of the sampled volume between the on-line and off-line. To avoid detection complicity, integrated path differential absorption (IPDA) lidar provides higher signal-to-noise ratio measurement compared to conventional range-resolved DIAL. Rather than weak atmospheric scattering returns, IPDA rely on the much stronger hard target returns that is best suited for airborne platforms. In addition, the IPDA technique measures the total integrated column content from the instrument to the hard target but with weighting that can be tuned by the transmitter. Therefore, the transmitter could be tuned to weight the column measurement to the surface for optimum CO2 interaction studies or up to the free troposphere for optimum transport studies. Currently, NASA LaRC is developing and integrating a double-Pulsed 2-micron direct detection IPDA lidar for CO2 column measurement from an airborne platform. The presentation will describe the development of the 2-micron IPDA lidar system and present the airborne measurement of column CO2 and will compare to in-situ measurement for various ground target of different reflectivity

Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease

Tuberculosis (TB) is the leading cause of death worldwide due to an infectious agent. Data have accumulated over decades suggesting that variability in human susceptibility to TB disease has a genetic component. Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to many pathogens in mouse models, but little is known about their role in human infections. Human TLRs have been reported to recognize mycobacterial antigens and initiate an immune response. We tested the hypothesis that amino acid-altering polymorphisms in five TLRs were associated with susceptibility to TB disease using a population-based case-control study with 1,312 adult TB patients and controls. Full-coding region sequencing of the five TLR genes in all 1,312 subjects yielded a data set in excess of 16 Mb. Rare nonsynonymous polymorphisms in TLR6-TLR1-TLR10 were significantly overrepresented among African-American TB cases compared with ethnically-matched control subjects. Common nonsynonymous polymorphisms in TLR6-TLR1-TLR10 also were significantly associated with TB disease in certain ethnic groups. Among African Americans, homozygotes for the common-variant haplotype TLR1-248S, TLR1-602I, and TLR6-249S had a significantly increased TB disease risk. A transmission/disequilibrium test on an independent sample found that the TLR1-248S variant was preferentially transmitted to diseased children, thereby confirming disease association. These results are consistent with recent reports implicating TLR1 variants, including TLR1-602, in significantly altered innate immune responses. Also consistent with disease association, rare TLR6 variants were defective in their ability to mediate NF-κB signal transduction in transfected human cells. Taken together, the data suggest that variant TLRs contribute to human susceptibility to TB disease. Extensive full-exon resequencing was critical for revealing new information about the role of TLRs in human-pathogen interactions and the genetic basis of innate immune function

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Exploring the views of being a proxy from the perspective of unpaid carers and paid carers: developing a proxy version of the Adult Social Care Outcomes Toolkit (ASCOT)

Background: Outcomes-based policy and administration of public services present a compelling argument for the value of outcomes data. However, there are a number of challenges inherent in collecting these data from people who are unable to complete a paper-based survey or interview due to cognitive or communication impairments. In this paper, we explore the views of being a proxy from the perspective of unpaid carers and paid carers who may be asked to act as a proxy on behalf of the person(s) they care for. We consider the key issues that need to be addressed when adapting an instrument designed to measure social care outcomes, the Adult Social Care Outcomes Tool (ASCOT), into a proxy-report tool. Methods: Participants took part in either a focus group (35 paid carers in eight focus groups), or a one-to-one interview (eight unpaid carers). All participants were recruited via carer organisations and care providers. Transcripts, field notes and audio data collected during focus groups and interviews were analysed using a thematic framework approach. Results: Participants agreed that any person acting as a proxy would need to be very familiar with the care recipient, as well as their needs and care provision. A number of provisions for proxy respondents were proposed to improve face validity and acceptability of completing a questionnaire by proxy, and to ensure that any potential bias is reduced in the design of the questionnaire. These included: providing two sets of response options for each proxy perspective (the proxy themselves and the proxy view of how they think the care recipient would respond); a comments box to help people explain why they have selected a given response option (especially where these indicate unmet need); and providing clear guidance for the proxy respondent on how they should complete the questionnaire. Conclusions: This study has shown some of the challenges involved in assessing outcomes by proxy and explored some potential ways these can be mitigated. The findings highlight the benefits of developing and testing proxy measures in a robust way to widen participation in social care research

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Twenty actions for a “good Anthropocene”—perspectives from early-career conservation professionals

Humans are now recognized as the main drivers of environmental change, leaving the future of our planet dependent on human action or inaction. Although the outlook of our planet is often depicted in a “doom and gloom” manner due to recent troubling environmental trends, we suggest that a “good Anthropocene” (in which human quality of life may be maintained or improved without cost to the environment) is attainable if we engage in adaptive, multi-disciplinary actions capable of addressing the socio-ecological issues of today and tomorrow. Early-career conservation scientists and practitioners have an unmatched understanding of novel technologies and social connectivity and, as those left with the ever-growing responsibility to be the problem solvers of the attributed increasing environmental consequences of living in the Anthropocene, their perspectives on steps towards a good Anthropocene are valuable. Here we present a list of 20 actions derived by early-career conservation scientists and practitioners for conservationists to help achieve a good Anthropocene that utilize the social connectivity and technology of today. Central to these actions are the notions that multi-, inter-, and trans-disciplinary collaboratives that embrace diverse world views need to be integrated into decision-making processes; training and outreach platforms need to communicate both environmental challenges and solutions broadly; and conservation successes need to be acknowledged and disseminated in a forward-looking, adaptive capacity. Together the 20 actions identified here reinforce the underlying paradigm shift that must accompany living in the Anthropocene, given that biodiversity and healthy ecosystems are requisite for sustained human life. By sharing this list of actions, we look to promote positive socio-environmental changes towards the collective goal of achieving a good Anthropocene.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Twenty actions for a “good anthropocene”—perspectives from early-career conservation professionals

Humans are now recognized as the main drivers of environmental change, leaving the future of our planet dependent on human action or inaction. Although the outlook of our planet is often depicted in a “doom and gloom” manner due to recent troubling environmental trends, we suggest that a “good Anthropocene” (in which human quality of life may be maintained or improved without cost to the environment) is attainable if we engage in adaptive, multi-disciplinary actions capable of addressing the socio-ecological issues of today and tomorrow. Early-career conservation scientists and practitioners have an unmatched understanding of novel technologies and social connectivity and, as those left with the ever-growing responsibility to be the problem solvers of the attributed increasing environmental consequences of living in the Anthropocene, their perspectives on steps towards a good Anthropocene are valuable. Here we present a list of 20 actions derived by early-career conservation scientists and practitioners for conservationists to help achieve a good Anthropocene that utilize the social connectivity and technology of today. Central to these actions are the notions that multi-, inter-, and trans-disciplinary collaboratives that embrace diverse world views need to be integrated into decision-making processes; training and outreach platforms need to communicate both environmental challenges and solutions broadly; and conservation successes need to be acknowledged and disseminated in a forward-looking, adaptive capacity. Together the 20 actions identified here reinforce the underlying paradigm shift that must accompany living in the Anthropocene, given that biodiversity and healthy ecosystems are requisite for sustained human life. By sharing this list of actions, we look to promote positive socio-environmental changes towards the collective goal of achieving a good Anthropocene

Long-term follow-up of the RESONATE™ phase 3 trial of ibrutinib versus ofatumumab.

Ibrutinib, a once-daily oral inhibitor of Bruton\u27s tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE™, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the US and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR] 0.133; 95% CI, 0.099-0.178) was observed. Overall survival benefit continues (HR 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those withtherapies, and presence o