The effect of anthropogenic aerosol on the reflectivity of stratocumulus cloud decks through changes in cloud amount is a major uncertainty in climate projections. In frequently occurring ...nonprecipitating stratocumulus, cloud amount can decrease through aerosol-enhanced cloud-top mixing. The climatological relevance of this effect is debated because ship exhaust only marginally reduces stratocumulus amount. By comparing detailed numerical simulations with satellite analyses, we show that ship-track studies cannot be generalized to estimate the climatological forcing of anthropogenic aerosol. The ship track-derived sensitivity of the radiative effect of nonprecipitating stratocumulus to aerosol overestimates their cooling effect by up to 200%. The offsetting warming effect of decreasing stratocumulus amount needs to be taken into account if we are to constrain the cloud-mediated radiative forcing of anthropogenic aerosol.
Data sharing through ClinVar offers a unique opportunity to identify interpretation differences between laboratories. As part of a ClinGen initiative, four clinical laboratories (Ambry, GeneDx, ...Partners Healthcare Laboratory for Molecular Medicine, and University of Chicago Genetic Services Laboratory) collaborated to identify the basis of interpretation differences and to investigate if data sharing and reassessment resolve interpretation differences by analyzing a subset of variants.
ClinVar variants with submissions from at least two of the four participating laboratories were compared. For a subset of identified differences, laboratories documented the basis for discordance, shared internal data, independently reassessed with the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines, and then compared interpretations.
At least two of the participating laboratories interpreted 6,169 variants in ClinVar, of which 88.3% were initially concordant. Laboratories reassessed 242/724 initially discordant variants, of which 87.2% (211) were resolved by reassessment with current criteria and/or internal data sharing; 12.8% (31) of reassessed variants remained discordant owing to differences in the application of the ACMG-AMP guidelines.
Participating laboratories increased their overall concordance from 88.3 to 91.7%, indicating that sharing variant interpretations in ClinVar-thereby allowing identification of differences and motivation to resolve those differences-is critical to moving toward more consistent variant interpretations.Genet Med advance online publication 09 March 2017.
The topic of cloud radiative forcing associated with the atmospheric aerosol has been the focus of intense scrutiny for decades. The enormity of the problem is reflected in the need to understand ...aspects such as aerosol composition, optical properties, cloud condensation, and ice nucleation potential, along with the global distribution of these properties, controlled by emissions, transport, transformation, and sinks. Equally daunting is that clouds themselves are complex, turbulent, microphysical entities and, by their very nature, ephemeral and hard to predict. Atmospheric general circulation models represent aerosol–cloud interactions at ever-increasing levels of detail, but these models lack the resolution to represent clouds and aerosol–cloud interactions adequately. There is a dearth of observational constraints on aerosol–cloud interactions. We develop a conceptual approach to systematically constrain the aerosol–cloud radiative effect in shallow clouds through a combination of routine process modeling and satellite and surface-based shortwave radiation measurements. We heed the call to merge Darwinian and Newtonian strategies by balancing microphysical detail with scaling and emergent properties of the aerosol–cloud radiation system.
Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, ...but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC.
In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865.
Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 72% of 54 patients), hypertriglyceridaemia (21 39% of 54 patients), peripheral neuropathy (21 39% of 54 patients), and peripheral oedema (21 39% of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31–63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23–63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21–79).
In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608).
Pfizer.
Background
Racial disparities in the uptake of cancer genetic services are well documented among African American (AA) women. Understanding the multiple social and psychological factors that can ...influence the uptake of genetic testing among AA women is needed.
Methods
Data came from 270 AA women diagnosed with ovarian cancer and participating in a population‐based, case‐control study of ovarian cancer who were asked about genetic testing. Logistic regression analyses tested the associations of predisposing, enabling, and need factors with reported genetic testing uptake.
Results
One‐third of the sample (35%) reported having had genetic testing. In the multivariable model, AA women with higher incomes had more than double the odds of being tested than those with the lowest income (odds ratio OR for $25,000‐$74,999, 2.04; 95% confidence interval CI, 1.06‐3.99; OR for ≥$75,000, 2.32; 95% CI, 0.92‐5.94). AA women who reported employment discrimination were significantly less likely to report genetic testing than those who did not report job discrimination (OR, 0.39; 95% CI, 0.14‐0.95). Marital status, Medicaid versus other insurance, prayer frequency, and perceived social support were significantly associated with genetic testing uptake in bivariate analyses but were not significant contributors in multivariable analyses.
Conclusions
Consistent with other studies of AA women, a minority of African American Cancer Epidemiology Study participants had undergone genetic testing. Having a lower income and experiencing job discrimination decreased the likelihood of testing. These results provide foundational evidence supporting the need for interventions to improve the uptake of genetic testing among AA women by reducing cost barriers and providing credible assurances that genetic results will be kept private and not affect social factors such as employability.
African American women with lower incomes who have experienced job discrimination are less likely to undergo testing. These results support the need for interventions to reduce cost barriers and provide credible assurances that genetic results will be kept private and not affect social factors such as employability.
Changes in aerosols cause a change in net top-of-the-atmosphere
(ToA) short-wave and long-wave radiative fluxes; rapid adjustments in clouds,
water vapour and temperature; and an effective radiative ...forcing (ERF)
of the planetary energy budget. The diverse sources of model uncertainty and
the computational cost of running climate models make it difficult to isolate
the main causes of aerosol ERF uncertainty and to understand how observations
can be used to constrain it. We explore the aerosol ERF uncertainty by using
fast model emulators to generate a very large set of aerosol–climate model
variants that span the model uncertainty due to 27 parameters
related to atmospheric and aerosol processes. Sensitivity analyses shows that
the uncertainty in the ToA flux is dominated (around 80 %) by uncertainties
in the physical atmosphere model, particularly parameters that affect cloud
reflectivity. However, uncertainty in the change in ToA flux caused by
aerosol emissions over the industrial period (the aerosol ERF) is controlled
by a combination of uncertainties in aerosol (around 60 %) and physical
atmosphere (around 40 %) parameters. Four atmospheric and aerosol parameters
account for around 80 % of the uncertainty in short-wave ToA flux (mostly
parameters that directly scale cloud reflectivity, cloud water content or
cloud droplet concentrations), and these parameters also account for around
60 % of the aerosol ERF uncertainty. The common causes of uncertainty mean
that constraining the modelled planetary brightness to tightly match
satellite observations changes the lower 95 % credible aerosol ERF value from
−2.65 to −2.37 W m−2. This
suggests the strongest forcings (below around −2.4 W m−2)
are inconsistent with observations. These results show that, regardless of
the fact that the ToA flux is 2 orders of magnitude larger than the aerosol
ERF, the observed flux can constrain the uncertainty in ERF because their
values are connected by constrainable process parameters. The key to reducing
the aerosol ERF uncertainty further will be to identify observations that can
additionally constrain individual parameter ranges and/or combined parameter
effects, which can be achieved through sensitivity analysis of perturbed
parameter ensembles.
The climatic relevance of aerosol–cloud interactions depends on the sensitivity of the radiative effect of clouds to cloud droplet number N, and liquid water path LWP.
We derive the dependence of ...cloud fraction CF, cloud albedo AC, and the relative cloud radiative effect rCRE=CF⋅AC on N and LWP from 159 large-eddy simulations of nocturnal stratocumulus.
These simulations vary in their initial conditions for temperature, moisture, boundary-layer height, and aerosol concentration but share boundary conditions for surface fluxes and subsidence.
Our approach is based on Gaussian-process emulation, a statistical technique related to machine learning.
We succeed in building emulators that accurately predict simulated values of CF, AC, and rCRE for given values of N and LWP.
Emulator-derived susceptibilities ∂lnrCRE/∂lnN and ∂lnrCRE/∂lnLWP cover the nondrizzling, fully overcast regime as well as the drizzling regime with broken cloud cover.
Theoretical results, which are limited to the nondrizzling regime, are reproduced.
The susceptibility ∂lnrCRE/∂lnN captures the strong sensitivity of the cloud radiative effect to cloud fraction, while the susceptibility ∂lnrCRE/∂lnLWP describes the influence of cloud amount on cloud albedo irrespective of cloud fraction.
Our emulation-based approach provides a powerful tool for summarizing complex data in a simple framework that captures the sensitivities of cloud-field properties over a wide range of states.
Aerosol measurements over the Southern Ocean are used to constrain
aerosol–cloud interaction radiative forcing (RFaci) uncertainty in a global climate model. Forcing uncertainty is quantified using 1 ...million climate model variants that sample the uncertainty in nearly 30 model parameters. Measurements of cloud condensation nuclei and other aerosol properties from an Antarctic circumnavigation expedition strongly constrain natural aerosol emissions: default sea spray emissions need to be increased by around a factor of 3 to be consistent with measurements. Forcing uncertainty is reduced by around 7 % using this set of several hundred measurements, which is comparable to the 8 % reduction achieved using a diverse and extensive set of over 9000 predominantly Northern Hemisphere measurements. When Southern Ocean and Northern Hemisphere measurements are combined, uncertainty in RFaci is reduced by 21 %, and the strongest 20 % of forcing values are ruled out as implausible. In this combined constraint, observationally plausible RFaci is around 0.17 W m−2 weaker (less negative) with 95 % credible values ranging from −2.51 to
−1.17 W m−2 (standard deviation of −2.18 to −1.46 W m−2). The Southern Ocean and Northern Hemisphere measurement datasets are complementary because they constrain different processes. These results
highlight the value of remote marine aerosol measurements.
Severe hailstorms have the potential to damage buildings and crops. However, important processes for the prediction of hailstorms are insufficiently represented in operational weather forecast ...models. Therefore, our goal is to identify model input parameters describing environmental conditions and cloud microphysics, such as the vertical wind shear and strength of ice multiplication, which lead to large uncertainties in the prediction of deep convective clouds and precipitation. We conduct a comprehensive sensitivity analysis simulating deep convective clouds in an idealized setup of a cloud-resolving model. We use statistical emulation and variance-based sensitivity analysis to enable a Monte Carlo sampling of the model outputs across the multi-dimensional parameter space. The results show that the model dynamical and microphysical properties are sensitive to both the environmental and microphysical uncertainties in the model. The microphysical parameters lead to larger uncertainties in the output of integrated hydrometeor mass contents and precipitation variables. In particular, the uncertainty in the fall velocities of graupel and hail account for more than 65 % of the variance of all considered precipitation variables and for 30 %–90 % of the variance of the integrated hydrometeor mass contents. In contrast, variations in the environmental parameters – the range of which is limited to represent model uncertainty – mainly affect the vertical profiles of the diabatic heating rates.
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