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Introduction The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2−) advanced breast cancer. However, most patients receiving this combination will ultimately progress and require further therapies.Several studies have demonstrated that the onset of a ESR1 gene mutation lead to AIs resistance in the advanced setting. ESR1 mutations can be detected in circulating tumour DNA (ctDNA) using a digital PCR assay. Our study aims to prove the clinical efficacy of periodic monitoring for emerging or rise of ESR1 mutations in ctDNA to trigger an early change from AI plus palbociclib to fulvestrant plus palbociclib treatment while assessing global safety.Methods PADA-1 is a randomised, open-label, multicentric, phase III trial conducted in patients receiving AI and palbociclib as first line therapy for metastatic ER +HER2- breast cancer. 1000 patients will be included and treated with palbociclib in combination with an AI. Patients will be screened for circulating blood ESR1 mutation detection at regular intervals. Patients for whom a rising circulating ESR1 mutation is detected without tumour progression (up to N=200) will be randomised (1:1) between (1) Arm A: no modification of therapy; and (2) Arm B: palbociclib in combination with fulvestrant, a selective ER down-regulator. At tumour progression, an optional crossover will be offered to patients randomised in arm A. The coprimary endpoints are (1) Grade ≥3 haematological toxicities and their associations with baseline characteristics and (2) progression-free survival in randomised patients.Ethics and dissemination The study has been approved by the French medicines agency (ANSM) and by an ethics committee (ref 01/17_1 CPP Ouest-IV Nantes) in January 2017. The trial results will be published in academic conference presentations and international peer-reviewed journals.Trial registration numbers EudraCT: 2016-004360-18; NCT03079011.

Gravitational instabilities can be significant threats to populations and infrastructure. For hazard assessment, it is important to estimate the geometry and volume of potential unstable masses. This characterization can be particularly difficult in volcanic contexts due to the succession of deposition and erosion phases. Indeed, it results in complex layering geometries in which the interfaces between geological layers may be neither parallel nor planar. Geometry characterization is all the more complex when unstable masses are located in steep and hard to access landscapes, which limits data acquisition. In this work, we show how remote observations can be used to estimate the surface envelope of an unstable mass on a volcanic cliff. We use ortho-photographs, aerial views and topographic surveys to (i) describe the different geological units of the cliff, (ii) characterize the stability of geological units, (iii) infer the paleo-morphology of the site and (iv) estimate potential unstable volumes. We investigate the Samperre cliff in Martinique (Lesser Antilles, French West Indies) as a study site, where recurrent destabilizations since at least 1988 have produced debris flows that threaten populations and infrastructure. Our analysis suggests that the destabilizations occurring on the cliff may be associated with the re-opening of a paleo-valley filled by pyroclastic materials. We estimate that between 3.5×106 and 8.3×106 m3 could still be mobilized by future destabilizations in the coming decades.

Growing emissions from Pacific Northwest wildfires have increased atmospheric carbon monoxide in August, raising questions about potential health impacts as the seasonal pattern of air quality changes for large regions of North America.

Abstract Complaints of sleep disturbance are prevalent among breast cancer (BC) patients and are predictors of quality of life. Still, electrophysiological measures of sleep are missing in patients, which prevents from understanding the pathophysiological consequences of cancer and its past treatments. Using polysomnography, sleep can be investigated in terms of macro- (e.g. awakenings, sleep stages) and micro- (i.e. cortical activity) structure. We aimed to characterize sleep complaints, and macro- and microstructure in 33 BC survivors untreated by chemotherapy and that had finished radiotherapy since at least 6 months (i.e. out of the acute effects of radiotherapy) compared to 21 healthy controls (HC). Compared to HC, BC patients had a larger number of awakenings (p = 0.008); and lower Delta power (p

Abstract Aims Heart failure (HF) patients have a high risk of mortality due to sudden cardiac death (SCD) and non‐SCD, including pump failure death (PFD). Anaemia predicts more severe symptomatic burden and higher morbidity, as noted by markedly increased hospitalizations and readmission rates, and mortality, underscoring its importance in HF management. Herein, we aimed to determine whether haemoglobin (Hb) level at discharge affects the mode of death and influences SCD risk prediction. Methods We evaluated the data of 3020 consecutive acute HF patients from a Japanese prospective multicentre registry. Patients were divided into four groups based on discharge Hb levels. SCD was defined as an unexpected and otherwise unexplained death in a previously stable patient or death due to documented or presumed cardiac arrhythmia without a clear non‐cardiovascular cause. The mode of death (SCD, PFD or other cause) was adjudicated by a central committee. Finally, we investigated whether adding Hb level to the Seattle Proportional Risk Model (SPRM; established risk score utilized to estimate ‘proportion’ of SCD among death events) would affect its performance. Results The mean age of studied patients was 74.3 ± 12.9 years, and 59.8% were male. The mean Hb level was 12.0 ± 2.1 g/dL (61.3% of patients had anaemia defined by World Health Organization criteria). During the 2‐year follow‐up, 474 deaths (15.7%) occurred, including 93 SCDs (3.1%), 171 PFDs (5.7%) and 210 other deaths (7.0%; predominantly non‐cardiac death). Absolute risk of PFD (P

Abstract Aims Continuous‐flow left ventricular assist devices (LVADs) as destination therapy (DT) are a recommended treatment by National Institute for Health and Care Excellence England for end‐stage heart failure patients ineligible for cardiac transplantation. Despite the fact that DT is frequently used as an LVAD indication across other major European countries and the United States, with consistent improvements in quality‐of‐life and longevity, National Health Service (NHS) England does not currently fund DT, mainly due to concerns over cost‐effectiveness. On the basis of the recently published ENDURANCE Supplemental Trial studying DT patients, we assessed for the first time the cost‐effectiveness of DT LVADs compared with medical management (MM) in the NHS England. Methods and results We developed a Markov multiple‐state economic model using NHS cost data. LVAD survival and adverse event rates were derived from the ENDURANCE Supplemental Trial. MM survival was based on Seattle Heart Failure Model estimates in the absence of contemporary clinical trials for this population. Incremental cost‐effectiveness ratios (ICERs) were calculated over a lifetime horizon. A discount rate of 3.5% per year was applied to costs and benefits. Deterministic ICER was £46 207 per quality‐adjusted life year (QALY). Costs and utilities were £204 022 and 3.27 QALYs for the LVAD arm vs. £77 790 and 0.54 QALYs for the MM arm. Sensitivity analyses confirmed robustness of the primary analysis. Conclusions The implantation of the HeartWare™ HVAD™ System in patients ineligible for cardiac transplantation as DT is a cost‐effective therapy in the NHS England healthcare system under the end‐of‐life willingness‐to‐pay threshold of £50 000/QALY, which applies for VAD patients.

This study characterizes a massive African dust intrusion into the Caribbean Basin and southern US in June 2020, which is nicknamed the “Godzilla” dust plume, using a comprehensive set of satellite and ground-based observations (including MODIS, CALIOP, SEVIRI, AERONET, and EPA Air Quality network) and the NASA GEOS global aerosol transport model. The MODIS data record registered this massive dust intrusion event as the most intense episode over the past 2 decades. During this event, the aerosol optical depth (AOD) observed by AERONET and MODIS peaked at 3.5 off the coast of West Africa and 1.8 in the Caribbean Basin. CALIOP observations show that the top of the dust plume reached altitudes of 6–8 km in West Africa and descended to about 4 km altitude over the Caribbean Basin and 2 km over the US Gulf of Mexico coast. The dust intrusion event degraded the air quality in Puerto Rico to a hazardous level, with maximum daily PM10 concentration of 453 µg m−3 recorded on 23 June. The dust intrusion into the US raised the PM2.5 concentration on 27 June to a level exceeding the EPA air quality standard in about 40 % of the stations in the southern US. Satellite observations reveal that dust emissions from convection-generated haboobs and other sources in West Africa were large albeit not extreme on a daily basis. However, the anomalous strength and northern shift of the North Atlantic Subtropical High (NASH) together with the Azores low formed a closed circulation pattern that allowed for accumulation of the dust near the African coast for about 4 d. When the NASH was weakened and wandered back to the south, the dust outflow region was dominated by a strong African easterly jet that rapidly transported the accumulated dust from the coastal region toward the Caribbean Basin, resulting in the record-breaking African dust intrusion. In comparison to satellite observations, the GEOS model reproduced the MODIS observed tracks of the meandering dust plume well as it was carried by the wind systems. However, the model substantially underestimated dust emissions from haboobs and did not lift up enough dust to the middle troposphere for ensuing long-range transport. Consequently, the model largely missed the satellite-observed elevated dust plume along the cross-ocean track and underestimated the dust intrusion into the Caribbean Basin by a factor of more than 4. Modeling improvements need to focus on developing more realistic representations of moist convection, haboobs, and the vertical transport of dust.

Abstract Background Early research suggests the COVID-19 pandemic worsened intimate partner violence (IPV) in the US. In particular, stay-at-home orders and social distancing kept survivors in close proximity to their abusers and restricted access to resources and care. We aimed to understand and characterize the impact of the pandemic on delivery of IPV care in Boston. Methods We conducted individual interviews with providers of IPV care and support in the Greater Boston area, including healthcare workers, social workers, lawyers, advocates, and housing specialists, who continued to work during the COVID-19 pandemic. Using thematic analysis, we identified themes describing the challenges and opportunites providers faced in caring for survivors during the pandemic. Results Analysis of 18 interviews yielded four thematic domains, encompassing 18 themes and nine sub-themes. Thematic analysis revealed that the pandemic posed an increased threat to survivors of IPV by exacerbating external stressors and leading to heightened violence. On a system level, the pandemic led to widespread uncertainty, strained resources, amplified inequities, and loss of community. On an individual level, COVID-19 restrictions limited survivors’ abilities to access resources and to be safe, and amplified pre-existing inequities, such as limited technology access. Those who did not speak English or were immigrants experienced even more difficulty accessing resources due to language and/or cultural barriers. To address these challenges, providers utilized video and telephone interactions, and stressed the importance of creativity and cooperation across different sectors of care. Conclusions While virtual care was essential in allowing providers to care for survivors, and also allowed for increased flexibility, it was not a panacea. Many survivors faced additional obstacles to care, such as language barriers, unequal access to technology, lack of childcare, and economic insecurity. Providers addressed these barriers by tailoring services and care modalities to an individual’s needs and circumstances. Going forward, some innovations of the pandemic period, such as virtual interactions and cooperation across care sectors, may be utilized in ways that attend to shifting survivor needs and access, thereby improving safe, equitable, and trauma-informed IPV care.

Background As patients derive variable benefit from generator changes (GCs) of implantable cardioverter‐defibrillators (ICDs) with an original primary prevention (PP) indication, better predictors of outcomes are needed. Methods and Results In the National Cardiovascular Data Registry ICD Registry, patients undergoing GCs of initial non‐cardiac resynchronization therapy PP ICDs in 2012 to 2016, predictors of post‐GC survival and survival benefit versus control heart failure patients without ICDs were assessed. These included predicted annual mortality based on the Seattle Heart Failure Model, left ventricular ejection fraction (LVEF) >35%, and the probability that a patient's death would be arrhythmic (proportional risk of arrhythmic death [PRAD]). In 40 933 patients undergoing GCs of initial noncardiac resynchronization therapy PP ICDs (age 67.7±12.0 years, 24.5% women, 34.1% with LVEF >35%), Seattle Heart Failure Model–predicted annual mortality had the greatest effect size for decreased post‐GC survival (P35% had a lower Seattle Heart Failure Model–adjusted survival versus 23 472 control heart failure patients without ICDs (model interaction hazard ratio, 1.21 [95% CI, 1.11–1.31]). In patients undergoing GCs of initial noncardiac resynchonization therapy PP ICDs with LVEF ≤35%, the model indicated worse survival versus controls in the 21% of patients with a PRAD 65%. The association of the PRAD with survival benefit or harm was similar in patients with or without pre‐GC ICD therapies. Conclusions Patients who received replacement of an ICD originally implanted for primary prevention and had at the time of GC either LVEF >35% alone or both LVEF ≤35% and PRAD

Satellite aerosol products such as the Dark Target (DT) produced from the MODerate resolution Imaging Spectroradiometer (MODIS) are useful for monitoring the progress of air pollution. Unfortunately, the DT often fails to retrieve during the heaviest aerosol events as well as the more moderate events in winter. Some of the literature attributes this lack of retrieval to the cloud mask. However, we found this lack of retrieval is mainly traced to thresholds used for masking of inland water and snow. Modifications to these two masks greatly increase 50 % of the retrievals of aerosol optical depth at 0.55 µm (AOD) greater than 1.0. The “extra”-high-AOD retrievals tend to be biased when compared with a ground-based sun photometer (AErosol RObotic NETwork, AERONET). Reducing bias in new retrievals requires two additional steps. One is an update to the assumed aerosol optical properties (aerosol model); the haze in this region is both less absorbing and lower in altitude than what is assumed in the global algorithm. The second is accounting for the scale height of the aerosol, specifically that the heavy-aerosol events in the region are much closer to the surface than what is assumed by the global DT algorithm. The resulting combination of modified masking thresholds, new aerosol model, and lower aerosol layer scale height was applied to 3 months of MODIS observations (January–March 2013) over eastern China. After these two additional steps are implemented, the significant increase in new retrievals introduces no overall bias at a high-AOD regime but does degrade other overall validation statistics. We also find that the research algorithm is able to identify additional pollution events that AERONET instruments may not due to different spatial sampling. Mean AOD retrieved from the research algorithm increases from 0.11 to 0.18 compared to values calculated from the operational DT algorithm during January to March of 2013 over the study area. But near Beijing, where the severe pollution occurs, the new algorithm increases AOD by as much as 3.0 for each 0.5∘ grid box over the previous operational-algorithm values.

Abstract Aims The objective of this study was to compare functional outcomes through 1 year in patients with core‐lab verified moderate to severe (Grades 2+ to 4+) functional mitral regurgitation (FMR) treated with the Carillon device or control in the blinded sham‐controlled REDUCE‐FMR (Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation) study. Methods and results The main outcomes of this analysis were the change in 6 min walk test (6MWT) distance, incidence of heart failure hospitalization or death, change in New York Heart Association (NYHA) class, and change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score through 1 year of follow‐up. The minimum clinically important difference (MCID) was defined as a ≥30 m increase in 6MWT distance, an NYHA decrease in ≥1 class, and a ≥3 point increase in KCCQ score. The proportion of patients achieving the MCID in each treatment group was compared using Fisher's exact test, and the number needed to treat (NNT) with the Carillon device was calculated. Among 83 patients (62 Carillon and 21 sham), no statistically significant group differences were observed in the baseline characteristics. All outcomes at 1 year numerically favoured the Carillon group, including MCID for the 6MWT distance (59% vs. 23%, P = 0.029; NNT = 2.8), NYHA class (48% vs. 33%, P = 0.38; NNT = 6.9), KCCQ score (69% vs. 47%, P = 0.14; NNT = 4.5), and freedom from heart failure hospitalization or death (60% vs. 48%, P = 0.45; NNT = 8.3). Conclusions REDUCE‐FMR was the first blinded sham‐controlled trial to report outcomes with percutaneous therapy for the treatment of FMR. Trends towards improvement in mean 6MWT distance, KCCQ score, and NYHA class were observed with the Carillon device. A substantially higher number of patients achieved MCID for all patient‐centred outcomes with the Carillon device compared with the sham procedure.

ObjectivesHeart failure (HF) management has significantly improved over the past two decades, leading to better survival. This study aimed to assess changes in predicted mortality risk after 12 months of management in a multidisciplinary HF clinic.Materials and MethodsOut of 1,032 consecutive HF outpatients admitted from March-2012 to November-2018, 357 completed the 12-months follow-up and had N-terminal pro-B-type natriuretic peptide (NTproBNP), high sensitivity troponin T (hs-TnT), and interleukin-1 receptor-like-1 (known as ST2) measurements available both at baseline and follow-up. Three contemporary risk scores were used: MAGGIC-HF, Seattle HF Model (SHFM), and the Barcelona Bio-HF (BCN Bio-HF) calculator, which incorporates the three above mentioned biomarkers. The predicted risk of all-cause death at 1 and 3 years was calculated at baseline and re-evaluated after 12 months.ResultsA significant decline in predicted 1-and 3-year mortality risk was observed at 12 months: MAGGIC ~16%, SHFM ~22% and BCN Bio-HF ~15%. In the HF with reduced ejection fraction (HFrEF) subgroup guideline-directed medical therapy led to a complete normalization of left ventricular ejection fraction (≥50%) in almost a third of the patients and to a partial normalization (41–49%) in 30% of them. Repeated risk assessment after 12 months with SHFM and BCN Bio-HF provided adequate discrimination for all-cause 3-year mortality (C-Index: MAGGIC-HF 0.762, SHFM 0.781 and BCN Bio-HF 0.791).ConclusionMortality risk declines in patients with HF managed for 12 months in a multidisciplinary HF clinic. Repeating the mortality risk assessment after optimizing the HF treatment is recommended, particularly in the HFrEF subgroup.

Proven by multiple theoretical and practical studies, multi-angular spectral polarimetry is ideal for comprehensive retrieval of properties of aerosols. Furthermore, a large number of advanced space polarimeters have been launched recently or planned to be deployed in the coming few years (Dubovik et al., 2019). Nevertheless, at present, practical utilization of aerosol products from polarimetry is rather limited, due to the relatively small number of polarimetric compared to photometric observations, as well as challenges in making full use of the extensive information content available in these complex observations. Indeed, while in recent years several new algorithms have been developed to provide enhanced aerosol retrievals from satellite polarimetry, the practical value of available aerosol products from polarimeters yet remains to be proven. In this regard, this paper presents the analysis of aerosol products obtained by the Generalized Retrieval of Atmosphere and Surface Properties (GRASP) algorithm from POLDER/PARASOL observations. After about a decade of development, GRASP has been adapted for operational processing of polarimetric satellite observations and several aerosol products from POLDER/PARASOL observations have been released. These updated PARASOL/GRASP products are publicly available (e.g., http://www.icare.univ-lille.fr, last access: 16 October 2018, http://www.grasp-open.com/products/, last access: 28 March 2020); the dataset used in the current study is registered under https://doi.org/10.5281/zenodo.3887265 (Chen et al., 2020). The objective of this study is to comprehensively evaluate the GRASP aerosol products obtained from POLDER/PARASOL observations. First, the validation of the entire 2005–2013 archive was conducted by comparing to ground-based Aerosol Robotic Network (AERONET) data. The subjects of the validation are spectral aerosol optical depth (AOD), aerosol absorption optical depth (AAOD) and single-scattering albedo (SSA) at six wavelengths, as well as Ångström exponent (AE), fine-mode AOD (AODF) and coarse-mode AOD (AODC) interpolated to the reference wavelength 550 nm. Second, an inter-comparison of PARASOL/GRASP products with the PARASOL/Operational, MODIS Dark Target (DT), Deep Blue (DB) and Multi-Angle Implementation of Atmospheric Correction (MAIAC) aerosol products for the year 2008 was performed. Over land both satellite data validations and inter-comparisons were conducted separately for different surface types, discriminated by bins of normalized difference vegetation index (NDVI): < 0.2, 0.2 ≤ and < 0.4, 0.4 ≤ and < 0.6, and ≥ 0.6. Three PARASOL/GRASP products were analyzed: GRASP/HP (“High Precision”), Optimized and Models. These different products are consistent but were obtained using different assumptions in aerosol modeling with different accuracies of atmospheric radiative transfer (RT) calculations. Specifically, when using GRASP/HP or Optimized there is direct retrieval of the aerosol size distribution and spectral complex index of refraction. When using GRASP/Models, the aerosol is approximated by a mixture of several prescribed aerosol components, each with their own fixed size distribution and optical properties, and only the concentrations of those components are retrieved. GRASP/HP employs the most accurate RT calculations, while GRASP/Optimized and GRASP/Models are optimized to achieve the best trade-off between accuracy and speed. In all these three options, the underlying surface reflectance is retrieved simultaneously with the aerosol properties, and the radiative transfer calculations are performed “online” during the retrieval. All validation results obtained for the full archive of PARASOL/GRASP products show solid quality of retrieved aerosol characteristics. The GRASP/Models retrievals, however, provided the most solid AOD products, e.g., AOD (550 nm) is unbiased and has the highest correlation (R ∼ 0.92) and the highest fraction of retrievals (∼ 55.3 %) satisfying the accuracy requirements of the Global Climate Observing System (GCOS) when compared to AERONET observations. GRASP/HP and GRASP/Optimized AOD products show a non-negligible positive bias (∼ 0.07) when AOD is low (< 0.2). On the other hand, the detailed aerosol microphysical characteristics (AE, AODF, AODC, SSA, etc.) provided by GRASP/HP and GRASP/Optimized correlate generally better with AERONET than do the results of GRASP/Models. Overall, GRASP/HP processing demonstrates the high quality of microphysical characteristics retrieval versus AERONET. Evidently, the GRASP/Models approach is more adapted for retrieval of total AOD, while the detailed aerosol microphysical properties are limited when a mixture of aerosol models with fixed optical properties are used. The results of a comparative analysis of PARASOL/GRASP and MODIS products showed that, based on validation against AERONET, the PARASOL/GRASP AOD (550 nm) product is of similar and sometimes of higher quality compared to the MODIS products. All AOD retrievals are more accurate and in good agreement over ocean. Over land, especially over bright surfaces, the retrieval quality degrades and the differences in total AOD products increase. The detailed aerosol characteristics, such as AE, AODF and AODC from PARASOL/GRASP, are generally more reliable, especially over land. The global inter-comparisons of PARASOL/GRASP versus MODIS showed rather robust agreement, though some patterns and tendencies were observed. Over ocean, PARASOL/Models and MODIS/DT AOD agree well with the correlation coefficient of 0.92. Over land, the correlation between PARASOL/Models and the different MODIS products is lower, ranging from 0.76 to 0.85. There is no significant global offset; though over bright surfaces MODIS products tend to show higher values compared to PARASOL/Models when AOD is low and smaller values for moderate and high AODs. Seasonal AOD means suggest that PARASOL/GRASP products show more biomass burning aerosol loading in central Africa and dust over the Taklamakan Desert, but less AOD in the northern Sahara. It is noticeable also that the correlation for the data over AERONET sites are somewhat higher, suggesting that the retrieval assumptions generally work better over AERONET sites than over the rest of the globe. One of the potential reasons may be that MODIS retrievals, in general, rely more on AERONET climatology than GRASP retrievals. Overall, the analysis shows that the quality of AOD retrieval from multi-angular polarimetric observations like POLDER is at least comparable to that of single-viewing MODIS-like imagers. At the same time, the multi-angular polarimetric observations provide more information on other aerosol properties (e.g., spectral AODF, AODC, AE), as well as additional parameters such as AAOD and SSA.

Abstract Aims Optimal blood pressure (BP) control is imperative to reduce complications, especially strokes, in continuous flow ventricular assist device (VAD) patients. Doppler BP has been shown to be an accurate and reliable non‐invasive BP measurement method in HeartMate II and HVAD patients. We examined whether Doppler BP is also accurate in patients with the HeartMate 3 VAD. Methods and results In a prospective, longitudinal cohort of HeartMate 3 patients, arterial line BP and simultaneously measured Doppler opening pressure were obtained. Correlation and agreement between Doppler opening pressure and arterial line mean arterial pressure (MAP) versus systolic blood pressure (SBP) were analysed, as well as the effect of pulse pressure on the accuracy of Doppler opening pressure. A total of 589 pairs of simultaneous Doppler opening pressure and arterial line pressure readings were obtained in 43 patients. Doppler opening pressure had good correlation with intra‐arterial MAP (r = 0.754) and more closely approximated MAP than SBP (mean error 2.0 vs. −8.6 mmHg). Pulse pressure did not have a clinically significant impact on the accuracy of the Doppler BP method. These results in HeartMate 3 patients are very similar to previous results in HeartMate II and HVAD patients. Conclusions Doppler BP method should be the default non‐invasive BP measurement method in continuous flow VAD patients including patients implanted with the HeartMate 3.

Abstract LUX-ZEPLIN (LZ) is a second-generation direct dark matter experiment with spin-independent WIMP-nucleon scattering sensitivity above $${1.4 \times 10^{-48}}\, {\hbox {cm}}^{2}$$ 1.4 × 10 - 48 cm 2 for a WIMP mass of $${40}\, \hbox {GeV}/{\hbox {c}}^{2}$$ 40 GeV / c 2 and a $${1000}\, \hbox {days}$$ 1000 days exposure. LZ achieves this sensitivity through a combination of a large $${5.6}\, \hbox {t}$$ 5.6 t fiducial volume, active inner and outer veto systems, and radio-pure construction using materials with inherently low radioactivity content. The LZ collaboration performed an extensive radioassay campaign over a period of six years to inform material selection for construction and provide an input to the experimental background model against which any possible signal excess may be evaluated. The campaign and its results are described in this paper. We present assays of dust and radon daughters depositing on the surface of components as well as cleanliness controls necessary to maintain background expectations through detector construction and assembly. Finally, examples from the campaign to highlight fixed contaminant radioassays for the LZ photomultiplier tubes, quality control and quality assurance procedures through fabrication, radon emanation measurements of major sub-systems, and bespoke detector systems to assay scintillator are presented.

To better understand and characterize current uncertainties in the important observational constraint of climate models of aerosol optical depth (AOD), we evaluate and intercompare 14 satellite products, representing nine different retrieval algorithm families using observations from five different sensors on six different platforms. The satellite products (super-observations consisting of 1∘×1∘ daily aggregated retrievals drawn from the years 2006, 2008 and 2010) are evaluated with AErosol RObotic NETwork (AERONET) and Maritime Aerosol Network (MAN) data. Results show that different products exhibit different regionally varying biases (both under- and overestimates) that may reach ±50 %, although a typical bias would be 15 %–25 % (depending on the product). In addition to these biases, the products exhibit random errors that can be 1.6 to 3 times as large. Most products show similar performance, although there are a few exceptions with either larger biases or larger random errors. The intercomparison of satellite products extends this analysis and provides spatial context to it. In particular, we show that aggregated satellite AOD agrees much better than the spatial coverage (often driven by cloud masks) within the 1∘×1∘ grid cells. Up to ∼50 % of the difference between satellite AOD is attributed to cloud contamination. The diversity in AOD products shows clear spatial patterns and varies from 10 % (parts of the ocean) to 100 % (central Asia and Australia). More importantly, we show that the diversity may be used as an indication of AOD uncertainty, at least for the better performing products. This provides modellers with a global map of expected AOD uncertainty in satellite products, allows assessment of products away from AERONET sites, can provide guidance for future AERONET locations and offers suggestions for product improvements. We account for statistical and sampling noise in our analyses. Sampling noise, variations due to the evaluation of different subsets of the data, causes important changes in error metrics. The consequences of this noise term for product evaluation are discussed.

Background: With increasing diagnoses and available treatment options for transthyretin amyloidosis cardiomyopathy (ATTR-CM), risk stratification of ATTR-CM patients is imperative. Objectives: We hypothesized that diuretic dose and New York Heart Association (NYHA) functional class are independent predictors of mortality in ATTR-CM and would be incrementally additive to existent risk scores. Methods: Consecutive ATTR-CM patients referred to a single center were identified. Adjusted Cox proportional hazards models determined the association between diuretic dose (furosemide equivalent in mg/kg) at time of diagnosis and the primary outcome of all-cause mortality. The incremental value of adding diuretic dose and NYHA functional class to existing ATTR-CM risk scores was assessed for discrimination and calibration. Results: 309 patients were identified, with mean age 73.2 ± 9.8 years, 84.1% male, and 66% wild type. Daily mean diuretic dose was 0.6 ± 1.0 mg/kg and significantly associated with all-cause mortality (unadjusted hazard ratio: 2.12 per 1-mg/kg increase, [95% confidence interval: 1.71 to 2.61] and fully adjusted hazard ratio: 1.43 [95% confidence interval: 1.06 to 1.93]). Testing previously published ATTR risk scores, adding diuretic dose as categories (0 mg/kg, >0 to 0.5 mg/kg, >0.5 to 1 mg/kg, and >1 to 2 mg/kg) improved the area under the curve of the Mayo risk score from 0.693 to 0.767 and the UK risk score from 0.711 to 0.787 while preserving calibration. Adding NYHA functional class further improved the area under the curve to 0.798 and 0.816, respectively. Conclusions: Diuretic dose and NYHA functional class are independent predictors of mortality in ATTR-CM patients and provide incremental value to existing ATTR-CM risk scores.

Background: Concomitant biceps tendon pathology is often present in patients undergoing rotator cuff repair (RCR). Management of biceps pathology has been reported to influence outcomes of RCR; however, the impact on the pace of recovery remains unclear. The purpose of this study was to analyze the effects of simultaneous RCR with biceps tenodesis (RCR-BT) on time to achieve maximum improvement and recovery speed for pain and function. Methods: A retrospective review of 535 patients who underwent primary RCR for full-thickness tears. Patients treated with simultaneous RCR-BT were compared with RCR-only. Outcome measures and motion were recorded at preoperative routine postoperative intervals. Plateau in maximal improvement and recovery speed were analyzed for both pain and functional recovery. Results: Baseline American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) function was significantly lower for the RCR-BT cohort (20.5) compared with RCR-only (23.9; P = .008). For visual analog scale (VAS) pain and measured motion, the plateau in maximal improvement occurred at 6 months for RCR-BT compared with 12 months for the RCR-only group. The remainder of the patient-reported outcome measures took 12 months to achieve a plateau in maximal improvement. At 3 months, 79% of improvement in pain and 42%-49% of functional improvement was achieved in the RCR-BT cohort. Similarly, at 3 months, the RCR-only cohort achieved 73% of pain improvement and 36%-57% of functional improvement at 3 months. Conclusion: Patients requiring RCR with simultaneous biceps tenodesis have lower baseline ASES function and earlier postoperative plateaus in pain relief and motion improvement following surgery. Nonetheless, the speed of recovery was not influenced by the biceps tenodesis.

Purpose: The Time to First Metastatic Recurrence (TFMR) could be considered as an indirect reflection of the tumour growth kinetics which plays an important role in cancer. Molecular subtypes such as expression of estrogen receptor are known predictive factors of TFMR. The CinéBreast study aimed to identify predictive factors of the time to TFMR. Methods: The French Epidemiological Strategy and Medical Economics (ESME) Metastatic Breast Cancer (MBC) Database (NCT03275311) was used, which contains data from a cohort of metastatic breast cancer patients from 2008 to 2016 using retrospective data collection. It is a national multi-centre database. The impact of TFMR on overall survival (OS) since first metastasis was also evaluated. Results: Among 16 702 patients recorded in the ESME MBC database, 10 595 had an initially localised breast cancer with hormone receptor (HR) and HER2 status available, with a metastatic recurrence. Median follow up was 56 months. Median TFMR was 59 months (120: 24%). HER2+ and TNBC were respectively 4 times and 12 times (p

Satellite instruments provide a vantage point for studying aerosol loading consistently over different regions of the world. However, the typical lifetime of a single satellite platform is on the order of 5–15 years; thus, for climate studies, the use of multiple satellite sensors should be considered. Discrepancies exist between aerosol optical depth (AOD) products due to differences in their information content, spatial and temporal sampling, calibration, cloud masking, and algorithmic assumptions. Users of satellite-based AOD time-series are confronted with the challenge of choosing an appropriate dataset for the intended application. In this study, 16 monthly AOD products obtained from different satellite sensors and with different algorithms were inter-compared and evaluated against Aerosol Robotic Network (AERONET) monthly AOD. Global and regional analyses indicate that products tend to agree qualitatively on the annual, seasonal and monthly timescales but may be offset in magnitude. Several approaches were then investigated to merge the AOD records from different satellites and create an optimised AOD dataset. With few exceptions, all merging approaches lead to similar results, indicating the robustness and stability of the merged AOD products. We introduce a gridded monthly AOD merged product for the period 1995–2017. We show that the quality of the merged product is as least as good as that of individual products. Optimal agreement of the AOD merged product with AERONET further demonstrates the advantage of merging multiple products. This merged dataset provides a long-term perspective on AOD changes over different regions of the world, and users are encouraged to use this dataset.

Emissions and long-range transport of mineral dust and combustion-related aerosol from burning fossil fuels and biomass vary from year to year, driven by the evolution of the economy and changes in meteorological conditions and environmental regulations. This study offers both satellite and model perspectives on the interannual variability and possible trends of combustion aerosol and dust in major continental outflow regions over the past 15 years (2003–2017). The decade-long record of aerosol optical depth (AOD, denoted as τ), separately for combustion aerosol (τc) and dust (τd), over global oceans is derived from the Collection 6 aerosol products of the Moderate Resolution Imaging Spectroradiometer (MODIS) onboard both Terra and Aqua. These MODIS Aqua datasets, complemented by aerosol source-tagged simulations using the Community Atmospheric Model version 5 (CAM5), are then analyzed to understand the interannual variability and potential trends of τc and τd in the major continental outflows. Both MODIS and CAM5 consistently yield a similar decreasing trend of −0.017 to −0.020 per decade for τc over the North Atlantic Ocean and the Mediterranean Sea that is attributable to reduced emissions from North America and Europe, respectively. On the contrary, both MODIS and CAM5 display an increasing trend of +0.017 to +0.036 per decade for τc over the tropical Indian Ocean, the Bay of Bengal, and the Arabian Sea, which reflects the influence of increased anthropogenic emissions from South Asia and the Middle East in the last 2 decades. Over the northwestern Pacific Ocean, which is often affected by East Asian emissions of pollution and dust, the MODIS retrievals show a decreasing trend of −0.021 per decade for τc and −0.012 per decade for τd, which is, however, not reproduced by the CAM5 model. In other outflow regions strongly influenced by biomass burning smoke or dust, both MODIS retrievals and CAM5 simulations show no statistically significant trends; the MODIS-observed interannual variability is usually larger than that of the CAM5 simulation.

Objective: While open adrenalectomy was performed for many years, minimally invasive adrenalectomy has become the gold-standard for surgical resection of adrenal masses owing to superior perioperative outcomes. The objective of this video is to describe our technique of performing robot-assisted total and partial adrenalectomy. Patients and surgical procedure: In this video, we use the case of a left-sided aldosteronoma to demonstrate our technique of a left robot-assisted total adrenalectomy and a large right-sided tumor with solid enhancing component and mass effect compressing the IVC to demonstrate a right robot-assisted total adrenalectomy. Additionally, we briefly highlight nuances of performing a partial adrenalectomy and the utility of ultrasound in this setting. Results: There were no intraoperative or postoperative complications. All patients were discharged per our routine pathway on post-operative day one. Through our step-by-step video, we demonstrate our technical approach and tips to successfully perform a robotic total and partial adrenalectomy. Conclusion: Robot-assisted adrenalectomy is an effective and well-established option for the management of adrenal masses. The added dexterity and improved visualization provided by the robotic approach allows surgeons to provide patients with an effective, efficient, and oncologically appropriate operation with rapid convalescence.

Background Despite the belief that heart failure therapies are not effective in transthyretin cardiac amyloidosis, data are limited. We tested the association of neurohormonal blockade use with survival. Methods and Results A total of 309 consecutive patients with transthyretin cardiac amyloidosis were identified. Medication inventory was obtained at baseline and subsequent visits. Exposure included a neurohormonal blockade class (β‐blocker [βB], angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, and mineralocorticoid antagonist) at baseline and subsequent visits. βB was modeled as baseline use, time‐varying use, and in an inverse probability treatment weighted model. Primary outcome was all‐cause mortality analyzed with adjusted Cox proportional hazards models. Continuing compared with stopping βB during follow‐up was tested. Mean age was 73.2 years, 84.1% were men, and 17.2% had atrial fibrillation/flutter at baseline. At the time of study entry, 49.8% were on βBs, 35.0% were on angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, and 23.9% were on mineralocorticoid antagonists. For the total cohort, there was a trend toward harm in the unadjusted model for baseline βB use, but this was neutral after adjustment. When βB use was analyzed as a time‐varying exposure, there was no association with mortality. βB discontinuation was associated with decreased mortality for the total cohort. Findings were consistent in inverse probability treatment weighted models. For angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker or mineralocorticoid antagonist use, there was no association with mortality after adjustment for the total cohort. Conclusions There was no association of neurohormonal blockade use with survival in transthyretin cardiac amyloidosis. For the total cohort, deprescribing βB may be associated with improved survival. Additional studies are needed to confirm these findings.

For nearly 2 decades we have been quantitatively observing the Earth's aerosol system from space at one or two times of the day by applying the Dark Target family of algorithms to polar-orbiting satellite sensors, particularly MODIS and VIIRS. With the launch of the Advanced Himawari Imager (AHI) and the Advanced Baseline Imagers (ABIs) into geosynchronous orbits, we have the new ability to expand temporal coverage of the traditional aerosol optical depth (AOD) to resolve the diurnal signature of aerosol loading during daylight hours. The Korean–United States Air Quality (KORUS-AQ) campaign taking place in and around the Korean peninsula during May–June 2016 initiated a special processing of full-disk AHI observations that allowed us to make a preliminary adoption of Dark Target aerosol algorithms to the wavelengths and resolutions of AHI. Here, we describe the adaptation and show retrieval results from AHI for this 2-month period. The AHI-retrieved AOD is collocated in time and space with existing AErosol RObotic NETwork stations across Asia and with collocated Terra and Aqua MODIS retrievals. The new AHI AOD product matches AERONET, and the standard MODIS product does as well, and the agreement between AHI and MODIS retrieved AOD is excellent, as can be expected by maintaining consistency in algorithm architecture and most algorithm assumptions. Furthermore, we show that the new product approximates the AERONET-observed diurnal signature. Examining the diurnal patterns of the new AHI AOD product we find specific areas over land where the diurnal signal is spatially cohesive. For example, in Bangladesh the AOD increases by 0.50 from morning to evening, and in northeast China the AOD decreases by 0.25. However, over open ocean the observed diurnal cycle is driven by two artifacts, one associated with solar zenith angles greater than 70∘ that may be caused by a radiative transfer model that does not properly represent the spherical Earth and the other artifact associated with the fringes of the 40∘ glint angle mask. This opportunity during KORUS-AQ provides encouragement to move towards an operational Dark Target algorithm for AHI. Future work will need to re-examine masking including snow mask, re-evaluate assumed aerosol models for geosynchronous geometry, address the artifacts over the ocean, and investigate size parameter retrieval from the over-ocean algorithm.

Abstract Background Investigator-initiated clinical studies (IITs) are crucial to generate reliable evidence that answers questions of day-to-day clinical practice. Many challenges make IITs a complex endeavour, for example, IITs often need to be multinational in order to recruit a sufficient number of patients. Recent studies highlighted that well-trained study personnel are a major factor to conduct such complex IITs successfully. As of today, however, no overview of the European training activities, requirements and career options for clinical study personnel exists. Methods To fill this knowledge gap, a survey was performed in all 11 member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardised questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the landscape of academic training opportunities, to facilitate the exchange of expertise and experience among countries and to identify new fields of action. Results The survey found that training for Good Clinical Practice (GCP) and investigator training is offered in all but one country. A specific training for study nurses or study coordinators is also either provided or planned in ten out of eleven countries. A majority of countries train in monitoring and clinical pharmacovigilance and offer specific training for principal investigators but only few countries also train operators of clinical research organisations (CRO) or provide training for methodology and quality management systems (QMS). Minimal requirements for study-specific functions cover GCP in ten countries. Only three countries issued no requirements or recommendations regarding the continuous training of study personnel. Yet, only four countries developed a national strategy for training in clinical research and the career options for clinical researchers are still limited in the majority of countries. Conclusions There is a substantial and impressive investment in training and education of clinical research in the individual ECRIN countries. But so far, a systematic approach for (top-down) strategic and overarching considerations and cross-network exchange is missing. Exchange of available curricula and sets of core competencies between countries could be a starting point for improving the situation.

Abstract Aims Accurate blood pressure (BP) measurement in continuous‐flow ventricular assist device (CF‐VAD) patients is imperative to reduce stroke risk. This study assesses the accuracy of the Doppler opening pressure method compared with the gold standard arterial line method in CF‐VAD patients. Methods and results In a longitudinal cohort of HeartMate II and HVAD patients, arterial line BP and simultaneously measured Doppler opening pressure were obtained. Overall correlation, agreement between Doppler opening pressure and arterial line mean vs. systolic pressure, and the effect of arterial pulsatility on the accuracy of Doppler opening pressure were analysed. A total of 1933 pairs of Doppler opening pressure and arterial line pressure readings within 1 min of each other were identified in 154 patients (20% women, mean age 55 ± 15, 50% HeartMate II and 50% HVAD). Doppler opening pressure had good correlation with invasive mean arterial pressure (r = 0.742, P

The Indonesian fire and smoke event of 2015 was an extreme episode that affected public health and caused severe economic and environmental damage. The MODIS Dark Target (DT) aerosol algorithm, developed for global applications, significantly underestimated regional aerosol optical depth (AOD) during this episode. The larger-than-global-averaged uncertainties in the DT product over this event were due to both an overly zealous set of masks that mistook heavy smoke plumes for clouds and/or inland water, and also an aerosol model developed for generic global aerosol conditions. Using Aerosol Robotic Network (AERONET) Version 3 sky inversions of local AERONET stations, we created a specific aerosol model for the extreme event. Thus, using this new less-absorbing aerosol model, cloud masking based on results of the MODIS cloud optical properties algorithm, and relaxed thresholds on both inland water tests and upper limits of the AOD retrieval, we created a research algorithm and applied it to 80 appropriate MODIS granules during the event. Collocating and comparing with AERONET AOD shows that the research algorithm doubles the number of MODIS retrievals greater than 1.0, while also significantly improving agreement with AERONET. The final results show that the operational DT algorithm had missed approximately 0.22 of the regional mean AOD, but as much as AOD = 3.0 for individual 0.5∘ grid boxes. This amount of missing AOD can skew the perception of the severity of the event, affect estimates of regional aerosol forcing, and alter aerosol modeling and forecasting that assimilate MODIS aerosol data products. These results will influence the future development of the global DT aerosol algorithm.