The effect of adjusting LDL-cholesterol for Lp(a)-cholesterol on the diagnosis of familial hypercholesterolaemia

BACKGROUND: Familial hypercholesterolaemia (FH) diagnostic tools help prioritise patients for genetic testing and include LDL-C estimates commonly calculated using the Friedewald equation. However, cholesterol contributions from lipoprotein(a) (Lp(a)) can overestimate 'true' LDL-C, leading to potentially inappropriate clinical FH diagnosis. OBJECTIVE: To assess how adjusting LDL-C for Lp(a)-cholesterol affects FH diagnoses using Simon Broome (SB) and Dutch Lipid Clinic Network (DLCN) criteria. METHODS: Adults referred to a tertiary lipid clinic in London, UK were included if they had undergone FH genetic testing based on SB or DLCN criteria. LDL-C was adjusted for Lp(a)-cholesterol using estimated cholesterol contents of 17.3%, 30% and 45%, and the effects of these adjustments on reclassification to 'unlikely' FH and diagnostic accuracy were determined. RESULTS: Depending on the estimated cholesterol content applied, LDL-C adjustment reclassified 8-23% and 6-17% of patients to 'unlikely' FH using SB and DLCN criteria, respectively. The highest reclassification rates were observed following 45% adjustment in mutation-negative patients with higher Lp(a) levels. This led to an improvement in diagnostic accuracy (46% to 57% with SB, and 32% to 44% with DLCN following 45% adjustment) through increased specificity. However all adjustment factors led to erroneous reclassification of mutation-positive patients to 'unlikely' FH. CONCLUSION: LDL-C adjustment for Lp(a)-cholesterol improves the accuracy of clinical FH diagnostic tools. Adopting this approach would reduce unnecessary genetic testing but also incorrectly reclassify mutation-positive patients. Health economic analysis is needed to balance the risks of over- and under-diagnosis before LDL-C adjustments for Lp(a) can be recommended

History of childbirths relates to region-specific brain aging patterns in middle and older-aged women

Pregnancy involves maternal brain adaptations, but little is known about how parity influences women’s brain aging trajectories later in life. In this study, we replicated previous findings showing less apparent brain aging in women with a history of childbirths, and identified regional brain aging patterns linked to parity in 19,787 middle and older-aged women. Using novel applications of brain-age prediction methods, we found that a higher number of previous childbirths was linked to less apparent brain aging in striatal and limbic regions. The strongest effect was found in the accumbens – a key region in the mesolimbic reward system, which plays an important role in maternal behavior. While only prospective longitudinal studies would be conclusive, our findings indicate that subcortical brain modulations during pregnancy and postpartum may be traceable decades after childbirth

The maternal brain: Region‐specific patterns of brain aging are traceable decades after childbirth

Pregnancy involves maternal brain adaptations, but little is known about how parity influences women's brain aging trajectories later in life. In this study, we replicated previous findings showing less apparent brain aging in women with a history of childbirths, and identified regional brain aging patterns linked to parity in 19,787 middle‐ and older‐aged women. Using novel applications of brain‐age prediction methods, we found that a higher number of previous childbirths were linked to less apparent brain aging in striatal and limbic regions. The strongest effect was found in the accumbens—a key region in the mesolimbic reward system, which plays an important role in maternal behavior. While only prospective longitudinal studies would be conclusive, our findings indicate that subcortical brain modulations during pregnancy and postpartum may be traceable decades after childbirth

Decaying lava extrusion rate at El Reventador Volcano, Ecuador measured using high-resolution satellite radar

Lava extrusion at erupting volcanoes causes rapid changes in topography and morphology on the order of tens or even hundreds of metres. Satellite radar provides a method for measuring changes in topographic height over a given time period to an accuracy of metres, either by measuring the width of radar shadow cast by steep sided features, or by measuring the difference in radar phase between two sensors separated in space. We measure height changes, and hence estimate extruded lava volume flux, at El Reventador, Ecuador between 2011 and 2016, using data from the Radarsat-2 and TanDEM-X satellite missions. We find 39 new lava flows were extruded between 9 February 2012 and 24 August 2016, with a cumulative volume of 44.8M m3 dense rock equivalent and a gradually decreasing eruption rate. The average dense rock rate of lava extrusion during this time is 0.31 ± 0.02 m3s−1, which is similar to the long term average from 1972 to 2016. Apart from a volumetrically small dyke opening event between 9 March and 10 June 2012, lava extrusion at El Reventador is not accompanied by any significant magmatic ground deformation. We use a simple physics-based model to estimate that the volume of the magma reservoir under El Reventador is greater than 3 km3. Our lava extrusion data can be equally well fit by models representing a closed reservoir depressurising during the eruption with no magma recharge, or an open reservoir with a time-constant magma recharge rate of up to 0.35 ± 0.01 m3s−

Recent unrest (2002–2015) imaged by space geodesy at the highest risk Chilean volcanoes: Villarrica, Llaima, and Calbuco (Southern Andes)

Villarrica, Llaima, and Calbuco volcanoes are the most active and dangerous volcanoes in the Southern Andes, and we use Interferometric Synthetic Aperture Radar (InSAR) observations from multiple satellites (ERS-2, ENVISAT, ALOS, RADARSAT-2, COSMO-SkyMed, TerraSAR-X, Sentinel-1A and ALOS-2) to constrain ground deformation that spans episodes of unrest and eruption at all three volcanoes between 2002 and 2015. We find episodes of ground deformation at each volcano, which we invert using analytic elastic half space models to make some of the first geophysical inferences about the source depths of potential magma chambers. At Llaima, we interpret that the VEI 2 April 3, 2009 eruption was preceded by 6–15 cm of precursory ground uplift one month before from a source 5 km below the surface on the western side of the edifice. The VEI 2 March 3, 2015 Villarrica eruption was followed by a short lived uplift of 5 cm in the SE part of the volcano from a source depth of 6 km. The VEI 4 April 22–23, 2015 Calbuco eruption produced 12 cm of coeruptive subsidence from a source depth 8–11 km and offset 2 km S from the summit. Importantly, we do not find clear evidence that the January 1, 2008, the March 3, 2015 and April 22, 2015 eruptions at Llaima, Villarrica and Calbuco volcanoes were preceded by either transient or continuous ground uplift. There are several possible explanations for the lack of precursory deformation at each volcano – it is possible that any precursory deformation occurred only hours before the eruption (e.g., at Calbuco), pre-eruptive inflation was canceled by co-eruptive subsidence (as we inferred happened during the April 2009 Llaima eruption), the pre-eruptive deformation was too small to be detectable in areas with persistent topography correlated phase delays, pressurized source are deep, or that open-vent volcanoes like Villarrica and Llaima do not pressurize. At all three volcanoes, X and C band interferograms decorrelate in a few weeks due to vegetation, snow and ice, and have persistent atmospheric phase delays that we find cannot be reliably removed with available global weather models. The low number of SAR acquisitions therefore makes it challenging to reliably measure unaliased deformation. We recommend a multi-satellite observing strategy with short repeat periods, frequently acquired high-resolution digital elevation models, and with acquisitions during every satellite overflight that may improve the temporal resolution of measurements

Associations Between Longitudinal Trajectories of Cognitive and Social Activities and Brain Health in Old Age

Importance: Prior neuroimaging studies have found that late-life participation in cognitive (eg, reading) and social (eg, visiting friends and family) leisure activities are associated with magnetic resonance imaging (MRI) markers of the aging brain, but little is known about the neural and cognitive correlates of changes in leisure activities during the life span. / Objectives: To examine trajectories of cognitive and social activities from midlife to late life and evaluate whether these trajectories are associated with brain structure, functional connectivity, and cognition. / Design, Setting, and Participants: This prospective cohort included participants enrolled in the Whitehall II study and its MRI substudy based in the UK. Participants provided information on their leisure activities at 5 times during calendar years 1997 to 1999, 2002 to 2004, 2006, 2007 to 2009, and 2011 to 2013 and underwent MRI and cognitive battery testing from January 1, 2012, to December 31, 2016. Data analysis was performed from October 7, 2017, to July 15, 2019. / Main Outcome and Measures: Growth curve models and latent class growth analysis were used to identify longitudinal trajectories of cognitive and social activities. Multiple linear regression was used to evaluate associations between activity trajectories and gray matter, white matter microstructure, functional connectivity, and cognition. / Results: A total of 574 individuals (468 [81.5%] men; mean [SD] age, 69.9 [4.9] years; median Montreal Cognitive Assessment score, 28 [interquartile range, 26-28]) were included in the present analysis. During a mean (SD) of 15 (4.2) years, cognitive and social activity levels increased during midlife before reaching a plateau in late life. Both baseline (global cognition: unstandardized β [SE], 0.955 [0.285], uncorrected P = .001; executive function: β [SE], 1.831 [0.499], uncorrected P < .001; memory: β [SE], 1.394 [0.550], uncorrected P = .01; processing speed: β [SE], 1.514 [0.528], uncorrected P = .004) and change (global cognition: β [SE], -1.382 [0.492], uncorrected P = .005, executive function: β [SE], -2.219 [0.865], uncorrected P = .01; memory: β [SE], -2.355 [0.948], uncorrected P = .01) in cognitive activities were associated with multiple domains of cognition as well as global gray matter volume (β [SE], -0.910 [0.388], uncorrected P = .02). Baseline (β [SE], 1.695 [0.525], uncorrected P = .001) and change (β [SE], 2.542 [1.026], uncorrected P = .01) in social activities were associated only with executive function, in addition to voxelwise measures of functional connectivity that involved sensorimotor (quadratic change in social activities: number of voxels, 306; P = 0.01) and temporoparietal (linear change in social activities: number of voxels, 16; P = .02) networks. Otherwise, no voxelwise associations were found with gray matter, white matter, or resting-state functional connectivity. False discovery rate corrections for multiple comparisons suggested that the association between cognitive activity levels and executive function was robust (β [SE], 1.831 [0.499], false discovery rate P < .001). / Conclusions and Relevance: The findings suggest that a life course approach may delineate the association between leisure activities and cognitive and brain health and that interventions aimed at improving and maintaining cognitive engagement may be valuable for the cognitive health of community-dwelling older adults

Recent unrest (2002–2015) imaged by space geodesy at the highest risk Chilean volcanoes: Villarrica, Llaima, and Calbuco (Southern Andes)

Villarrica, Llaima, and Calbuco volcanoes are the most active and dangerous volcanoes in the Southern Andes, and we use Interferometric Synthetic Aperture Radar (InSAR) observations from multiple satellites (ERS-2, ENVISAT, ALOS, RADARSAT-2, COSMO-SkyMed, TerraSAR-X, Sentinel-1A and ALOS-2) to constrain ground deformation that spans episodes of unrest and eruption at all three volcanoes between 2002 and 2015. We find episodes of ground deformation at each volcano, which we invert using analytic elastic half space models to make some of the first geophysical inferences about the source depths of potential magma chambers. At Llaima, we interpret that the VEI 2 April 3, 2009 eruption was preceded by 6–15 cm of precursory ground uplift one month before from a source 5 km below the surface on the western side of the edifice. The VEI 2 March 3, 2015 Villarrica eruption was followed by a short lived uplift of 5 cm in the SE part of the volcano from a source depth of 6 km. The VEI 4 April 22–23, 2015 Calbuco eruption produced 12 cm of coeruptive subsidence from a source depth 8–11 km and offset 2 km S from the summit. Importantly, we do not find clear evidence that the January 1, 2008, the March 3, 2015 and April 22, 2015 eruptions at Llaima, Villarrica and Calbuco volcanoes were preceded by either transient or continuous ground uplift. There are several possible explanations for the lack of precursory deformation at each volcano – it is possible that any precursory deformation occurred only hours before the eruption (e.g., at Calbuco), pre-eruptive inflation was canceled by co-eruptive subsidence (as we inferred happened during the April 2009 Llaima eruption), the pre-eruptive deformation was too small to be detectable in areas with persistent topography correlated phase delays, pressurized source are deep, or that open-vent volcanoes like Villarrica and Llaima do not pressurize. At all three volcanoes, X and C band interferograms decorrelate in a few weeks due to vegetation, snow and ice, and have persistent atmospheric phase delays that we find cannot be reliably removed with available global weather models. The low number of SAR acquisitions therefore makes it challenging to reliably measure unaliased deformation. We recommend a multi-satellite observing strategy with short repeat periods, frequently acquired high-resolution digital elevation models, and with acquisitions during every satellite overflight that may improve the temporal resolution of measurements

Association of midlife stroke risk with structural brain integrity and memory performance at older ages: a longitudinal cohort study

Cardiovascular health in midlife is an established risk factor for cognitive function later in life. Knowing mechanisms of this association may allow preventative steps to be taken to preserve brain health and cognitive performance in older age. In this study, we investigated the association of the Framingham stroke-risk score, a validated multifactorial predictor of 10-year risk of stroke, with brain measures and cognitive performance in stroke-free individuals. We used a large (N = 800) longitudinal cohort of community-dwelling adults of the Whitehall II imaging sub-study with no obvious structural brain abnormalities, who had Framingham stroke risk measured five times between 1991 and 2013 and MRI measures of structural integrity, and cognitive function performed between 2012 and 2016 [baseline mean age 47.9 (5.2) years, range 39.7-62.7 years; MRI mean age 69.81 (5.2) years, range 60.3-84.6 years; 80.6% men]. Unadjusted linear associations were assessed between the Framingham stroke-risk score in each wave and voxelwise grey matter density, fractional anisotropy and mean diffusivity at follow-up. These analyses were repeated including socio-demographic confounders as well as stroke risk in previous waves to examine the effect of residual risk acquired between waves. Finally, we used structural equation modelling to assess whether stroke risk negatively affects cognitive performance via specific brain measures. Higher unadjusted stroke risk measured at each of the five waves over 20 years prior to the MRI scan was associated with lower voxelwise grey and white matter measures. After adjusting for socio-demographic variables, higher stroke risk from 1991 to 2009 was associated with lower grey matter volume in the medial temporal lobe. Higher stroke risk from 1997 to 2013 was associated with lower fractional anisotropy along the corpus callosum. In addition, higher stroke risk from 2012 to 2013, sequentially adjusted for risk measured in 1991-94, 1997-98 and 2002-04 (i.e. 'residual risks' acquired from the time of these examinations onwards), was associated with widespread lower fractional anisotropy, and lower grey matter volume in sub-neocortical structures. Structural equation modelling suggested that such reductions in brain integrity were associated with cognitive impairment. These findings highlight the importance of considering cerebrovascular health in midlife as important for brain integrity and cognitive function later in life (ClinicalTrials.gov Identifier: NCT03335696)

Analyzing Explosive Volcanic Deposits From Satellite‐Based Radar Backscatter, Volcán de Fuego, 2018

Satellite radar backscatter has the potential to provide useful information about the progression of volcanic eruptions when optical, ground-based, or radar phase-based measurements are limited. However, backscatter changes are complex and challenging to interpret: explosive deposits produce different signals depending on pre-existing ground cover, radar parameters and eruption characteristics. We use high temporal- and spatial-resolution backscatter imagery to examine the emplacement and alteration of pyroclastic density currents (PDCs), lahar and ash deposits from the June 2018 eruption of Volcán de Fuego, Guatemala, using observatory reports and rainfall gauge data to ground truth our observations. We use a temporally dense time series of backscatter data to reduce noise and extract deposit areas. We observe backscatter changes in six drainages, the largest deposit was 11.9-km-long that altered an area of 6.3 urn:x-wiley:21699313:media:jgrb55183:jgrb55183-math-0001 and had a thickness of 10.5 urn:x-wiley:21699313:media:jgrb55183:jgrb55183-math-00022 m in the lower sections as estimated from radar shadows. The 3 June eruption also produced backscatter signal over an area of 40 urn:x-wiley:21699313:media:jgrb55183:jgrb55183-math-0003, consistent with reported ashfall. We use transient patterns in backscatter time series to identify nine periods of high lahar activity in a single drainage system between June and October 2018. We find that the characterisation of subtle backscatter signals associated with explosive eruptions are best observed with (1) radiometric terrain calibration, (2) speckle correction, and (3) consideration of pre-existing scattering properties. Our observations demonstrate that SAR backscatter can capture the emplacement and subsequent alteration of a range of explosive deposits, allowing the progression of an explosive eruption to be monitored

Towards InSAR Everywhere, All the Time, With Sentinel-1

Sentinel-1A was launched in April 2014, and has been collecting data routinely over more than one year. Sentinel-1B is set for launch on 22 April 2016. The Sentinel-1 constellation has several advantages over previous radar missions for InSAR applications: (1) Data are being acquired systematically for tectonic and volcanic areas, (2) Images cover a wide footprint, 250 km from near to far range in Interferometric Wide Swath (TOPS) mode, (3) Small perpendicular and temporal baselines greatly improve interferometric coherence at C-band, (4) Data are freely available to all users, (5) The mission is planned to be operational for 20 years, with 1C and 1D planned for future launches. These features enable us to map geological processes occurring in any place at anytime using InSAR.We will review progress within COMET towards our ultimate goal of building a fully-automated processing system that provides deformation results and derived products to the wide InSAR and Geophysics communities. In addition to high-resolution-ECMWF-based atmospheric correction model, we will show results of a systematic analysis of interferometric coherence in tectonic and volcanic areas, and discuss the future goals and timeline for the COMET InSAR automated processing system