The quality of the retrieved temperature-versus-pressure (or T(p)) profiles is described for the middle atmosphere for the publicly available Sounding of the Atmosphere using Broadband Emission ...Radiometry (SABER) Version 1.07 (V1.07) data set. The primary sources of systematic error for the SABER results below about 70 km are (1) errors in the measured radiances, (2) biases in the forward model, and (3) uncertainties in the corrections for ozone and in the determination of the reference pressure for the retrieved profiles. Comparisons with other correlative data sets indicate that SABER T(p) is too high by 1-3 K in the lower stratosphere but then too low by 1 K near the stratopause and by 2 K in the middle mesosphere. There is little difference between the local thermodynamic equilibrium (LTE) algorithm results below about 70 km from V1.07 and V1.06, but there are substantial improvements/differences for the non-LTE results of V1.07 for the upper mesosphere and lower thermosphere (UMLT) region. In particular, the V1.07 algorithm uses monthly, diurnally averaged CO2 profiles versus latitude from the Whole Atmosphere Community Climate Model. This change has improved the consistency of the character of the tides in its kinetic temperature (T(sub k)). The T(sub k) profiles agree with UMLT values obtained from ground-based measurements of column-averaged OH and O2 emissions and of the Na lidar returns, at least within their mutual uncertainties. SABER T(sub k) values obtained near the mesopause with its daytime algorithm also agree well with the falling sphere climatology at high northern latitudes in summer. It is concluded that the SABER data set can be the basis for improved, diurnal-to-interannual-scale temperatures for the middle atmosphere and especially for its UMLT region.
The complexity and heterogeneity of patients with multimorbidity and polypharmacy renders traditional disease‐oriented guidelines often inadequate and complicates clinical decision making. To address ...this challenge, guidelines have been developed on multimorbidity or polypharmacy. To systematically analyse their recommendations, we conducted a systematic guideline review using the Ariadne principles for managing multimorbidity as analytical framework. The information synthesis included a multistep consensus process involving 18 multidisciplinary experts from seven countries. We included eight guidelines (four each on multimorbidity and polypharmacy) and extracted about 250 recommendations. The guideline addressed (i) the identification of the target population (risk factors); (ii) the assessment of interacting conditions and treatments: medical history, clinical and psychosocial assessment including physiological status and frailty, reviews of medication and encounters with healthcare providers highlighting informational continuity; (iii) the need to incorporate patient preferences and goal setting: eliciting preferences and expectations, the process of shared decision making in relation to treatment options and the level of involvement of patients and carers; (iv) individualized management: guiding principles on optimization of treatment benefits over possible harms, treatment communication and the information content of medication/care plans; (v) monitoring and follow‐up: strategies in care planning, self‐management and medication‐related aspects, communication with patients including safety instructions and adherence, coordination of care regarding referral and discharge management, medication appropriateness and safety concerns. The spectrum of clinical and self‐management issues varied from guiding principles to specific recommendations and tools providing actionable support. The limited availability of reliable risk prediction models, feasible interventions of proven effectiveness and decision aids, and limited consensus on appropriate outcomes of care highlight major research deficits. An integrated approach to both multimorbidity and polypharmacy should be considered in future guidelines.
Content List – Read more articles from the symposium: “Multimorbidity research at the cross‐roads: developing the evidence for clinical practice and health policy”.
New biological models are incorporating the realistic processes underlying biological responses to climate change and other human-caused disturbances. However, these more realistic models require ...detailed information, which is lacking for most species on Earth. Current monitoring efforts mainly document changes in biodiversity, rather than collecting the mechanistic data needed to predict future changes. We describe and prioritize the biological information needed to inform more realistic projections of species' responses to climate change. We also highlight how trait-based approaches and adaptive modeling can leverage sparse data to make broader predictions. We outline a global effort to collect the data necessary to better understand, anticipate, and reduce the damaging effects of climate change on biodiversity.
Introduction
Molecular testing of Inherited bleeding coagulation disorders (IBCDs) not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and in certain ...cases genotype–phenotype correlations are important for predicting the clinical course of the disease and to allow tailor‐made follow‐up of individuals. Until recently, genotyping has been mainly performed by Sanger sequencing, a technique known to be time consuming and expensive. Currently, next‐generation sequencing (NGS) offers a new potential approach that enables the simultaneous investigation of multiple genes at manageable cost.
Aim
The aim of this study was to design and to analyse the applicability of a 23‐gene NGS panel in the molecular diagnosis of patients with IBCDs.
Methods
A custom target enrichment library was designed to capture 31 genes known to be associated with IBCDs. Probes were generated for 296 targets to cover 86.3 kb regions (all exons and flanking regions) of these genes. Twenty patients with an IBCDs phenotype were studied using NGS technology.
Results
In all patients, our NGS approach detected causative mutations. Twenty‐one pathogenic variants were found; while most of them were missense (18), three deletions were also identified. Six novel mutations affecting F8, FGA, F11, F10 and VWF genes, and 15 previously reported variants were detected. NGS and Sanger sequencing were 100% concordant.
Conclusion
Our results demonstrate that this approach could be an accurate, reproducible and reliable tool in the rapid genetic diagnosis of IBCDs.
The microscopic environment inside a metazoan organism is highly crowded. Whether individual cells can tailor their behavior to the limited space remains unclear. In this study, we found that cells ...measure the degree of spatial confinement by using their largest and stiffest organelle, the nucleus. Cell confinement below a resting nucleus size deforms the nucleus, which expands and stretches its envelope. This activates signaling to the actomyosin cortex via nuclear envelope stretch-sensitive proteins, up-regulating cell contractility. We established that the tailored contractile response constitutes a nuclear ruler-based signaling pathway involved in migratory cell behaviors. Cells rely on the nuclear ruler to modulate the motive force that enables their passage through restrictive pores in complex three-dimensional environments, a process relevant to cancer cell invasion, immune responses, and embryonic development.
Growth regimes of gold thin films deposited by magnetron sputtering at oblique angles and low temperatures are studied from both theoretical and experimental points of view. Thin films were deposited ...in a broad range of experimental conditions by varying the substrate tilt angle and background pressure, and were analyzed by field emission scanning electron microscopy and grazing-incidence small-angle x-ray scattering techniques. Results indicate that the morphological features of the films strongly depend on the experimental conditions, but can be categorized within four generic microstructures, each of them defined by a different bulk geometrical pattern, pore percolation depth and connectivity. With the help of a growth model, a microstructure phase diagram has been constructed where the main features of the films are depicted as a function of experimentally controllable quantities, finding a good agreement with the experimental results in all the studied cases.
Essentials
Diagnosis of sitosterolemia, a rare recessive or syndromic disorder, is usually delayed.
Peripheral blood smear is extremely useful for establishing the suspicion of sitosterolemia.
...High‐throughput sequencing technology enables the molecular diagnosis of inherited thrombocytopenias.
Accurate characterization of sitosterolemia helps us determine appropriate management.
Summary
Background
Sitosterolemia (STSL) is a recessive inherited disorder caused by pathogenic variants in the ABCG5 and ABCG8 genes. Increased levels of plasma plant sterols (PSs) usually result in xanthomas and premature coronary atherosclerosis, although hematologic abnormalities may occasionally be present. This clinical picture is unfamiliar to many physicians, and patients may be at high risk of misdiagnosis.
Objectives
To report two novel ABCG5 variants causing STSL in a Spanish patient, and review the clinical and mutational landscape of STSL.
Patient/Methods
A 46‐year‐old female was referred to us with lifelong macrothrombocytopenia. She showed familial hypercholesterolemia‐related xanthomas. Molecular analysis was performed with high‐throughput sequencing. Plasma PS levels were evaluated with gas–liquid chromatography. The STSL landscape was reviewed with respect to specific online databases and all reports published since 1974.
Results
A blood smear revealed giant platelets and stomatocytes. Novel compound heterozygous variants were detected in exons 7 (c.914C>G) and 13 (c.1890delT) of ABCG5. The patient showed an increased plasma level of sitosterol. These findings support the diagnosis of STSL. In our review, we identified only 25 unrelated STLS patients who presented with hematologic abnormalities including macrothrombocytopenia. It remains unknown why only some patients develop hematologic abnormalities.
Conclusions
This is the first Spanish STSL patient to be reported and molecularly characterized. The early diagnosis of STLS is strongly supported by the presence of stomatocytes in blood smears. The definitive diagnosis of STSL by measurement of serum PS levels and molecular analyses prompted the use of ezetimibe therapy.
Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are ...mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.
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