Clinical prediction models are often not evaluated properly in specific settings or updated, for instance, with information from new markers. These key steps are needed such that models are fit for ...purpose and remain relevant in the long-term. We aimed to present an overview of methodological guidance for the evaluation (i.e., validation and impact assessment) and updating of clinical prediction models.
We systematically searched nine databases from January 2000 to January 2022 for articles in English with methodological recommendations for the post-derivation stages of interest. Qualitative analysis was used to summarize the 70 selected guidance papers.
Key aspects for validation are the assessment of statistical performance using measures for discrimination (e.g., C-statistic) and calibration (e.g., calibration-in-the-large and calibration slope). For assessing impact or usefulness in clinical decision-making, recent papers advise using decision-analytic measures (e.g., the Net Benefit) over simplistic classification measures that ignore clinical consequences (e.g., accuracy, overall Net Reclassification Index). Commonly recommended methods for model updating are recalibration (i.e., adjustment of intercept or baseline hazard and/or slope), revision (i.e., re-estimation of individual predictor effects), and extension (i.e., addition of new markers). Additional methodological guidance is needed for newer types of updating (e.g., meta-model and dynamic updating) and machine learning-based models.
Substantial guidance was found for model evaluation and more conventional updating of regression-based models. An important development in model evaluation is the introduction of a decision-analytic framework for assessing clinical usefulness. Consensus is emerging on methods for model updating.
The Mars Science Laboratory mission reached Bradbury Landing in August 2012. In its first 500 sols, the rover Curiosity was commissioned and began its investigation of the habitability of past and ...present environments within Gale Crater. Curiosity traversed eastward toward Glenelg, investigating a boulder with a highly alkaline basaltic composition, encountering numerous exposures of outcropping pebble conglomerate, and sampling aeolian sediment at Rocknest and lacustrine mudstones at Yellowknife Bay. On sol 324, the mission turned its focus southwest, beginning a year‐long journey to the lower reaches of Mt. Sharp, with brief stops at the Darwin and Cooperstown waypoints. The unprecedented complexity of the rover and payload systems posed challenges to science operations, as did a number of anomalies. Operational processes were revised to include additional opportunities for advance planning by the science and engineering teams.
Key Points
Curiosity has investigated the habitability of Gale Crater, Mars
Curiosity has explored environments with evidence of ancient fluvial activity
The unprecedented complexity of the rover challenged science operations
The first four rocks examined by the Mars Science Laboratory Alpha Particle X‐ray Spectrometer indicate that Curiosity landed in a lithologically diverse region of Mars. These rocks, collectively ...dubbed the Bradbury assemblage, were studied along an eastward traverse (sols 46–102). Compositions range from Na‐ and Al‐rich mugearite Jake_Matijevic to Fe‐, Mg‐, and Zn‐rich alkali‐rich basalt/hawaiite Bathurst_Inlet and span nearly the entire range in FeO* and MnO of the data sets from previous Martian missions and Martian meteorites. The Bradbury assemblage is also enriched in K and moderately volatile metals (Zn and Ge). These elements do not correlate with Cl or S, suggesting that they are associated with the rocks themselves and not with salt‐rich coatings. Three out of the four Bradbury rocks plot along a line in elemental variation diagrams, suggesting mixing between Al‐rich and Fe‐rich components. ChemCam analyses give insight to their degree of chemical heterogeneity and grain size. Variations in trace elements detected by ChemCam suggest chemical weathering (Li) and concentration in mineral phases (e.g., Rb and Sr in feldspars). We interpret the Bradbury assemblage to be broadly volcanic and/or volcaniclastic, derived either from near the Gale crater rim and transported by the Peace Vallis fan network, or from a local volcanic source within Gale Crater. High Fe and Fe/Mn in Et_Then likely reflect secondary precipitation of Fe3+ oxides as a cement or rind. The K‐rich signature of the Bradbury assemblage, if igneous in origin, may have formed by small degrees of partial melting of metasomatized mantle.
Key Points
Rocks at the MSL landing site are diverse and alkali‐ and volatile metal‐rich.
Three of the first four rocks studied by APXS form a mixing line in element plots.
The alkali‐rich nature reflects an igneous source affected by metasomatism.
In 2012, NASA's Curiosity rover landed on Mars to assess its potential as a habitat for past life and investigate the paleoclimate record preserved by sedimentary rocks inside the ...~150-kilometer-diameter Gale impact crater. Geological reconstructions from Curiosity rover data have revealed an ancient, habitable lake environment fed by rivers draining into the crater. We synthesize geochemical and mineralogical data from lake-bed mudstones collected during the first 1300 martian solar days of rover operations in Gale. We present evidence for lake redox stratification, established by depth-dependent variations in atmospheric oxidant and dissolved-solute concentrations. Paleoclimate proxy data indicate that a transition from colder to warmer climate conditions is preserved in the stratigraphy. Finally, a late phase of geochemical modification by saline fluids is recognized.
Detection of Silica-Rich Deposits on Mars Squyres, S.W; Arvidson, R.E; Ruff, S ...
Science (American Association for the Advancement of Science),
05/2008, Letnik:
320, Številka:
5879
Journal Article
Recenzirano
Mineral deposits on the martian surface can elucidate ancient environmental conditions on the planet. Opaline silica deposits (as much as 91 weight percent SiO₂) have been found in association with ...volcanic materials by the Mars rover Spirit. The deposits are present both as light-toned soils and as bedrock. We interpret these materials to have formed under hydrothermal conditions and therefore to be strong indicators of a former aqueous environment. This discovery is important for understanding the past habitability of Mars because hydrothermal environments on Earth support thriving microbial ecosystems.
BACKGROUND AND PURPOSE Oxidative stress i.e. increased levels of reactive oxygen species (ROS) has been suggested as a pathomechanism of different diseases, although the disease‐relevant sources of ...ROS remain to be identified. One of these sources may be NADPH oxidases. However, due to increasing concerns about the specificity of the compounds commonly used as NADPH oxidase inhibitors, data obtained with these compounds may have to be re‐interpreted.
EXPERIMENTAL APPROACH We compared the pharmacological profiles of the commonly used NADPH oxidase inhibitors, diphenylene iodonium (DPI), apocynin and 4‐(2‐amino‐ethyl)‐benzolsulphonyl‐fluoride (AEBSF), as well as the novel triazolo pyrimidine VAS3947. We used several assays for detecting cellular and tissue ROS, as none of them is specific and artefact free.
KEY RESULTS DPI abolished NADPH oxidase‐mediated ROS formation, but also inhibited other flavo‐enzymes such as NO synthase (NOS) and xanthine oxidase (XOD). Apocynin interfered with ROS detection and varied considerably in efficacy and potency, as did AEBSF. Conversely, the novel NADPH oxidase inhibitor, VAS3947, consistently inhibited NADPH oxidase activity in low micromolar concentrations, and interfered neither with ROS detection nor with XOD or eNOS activities. VAS3947 attenuated ROS formation in aortas of spontaneously hypertensive rats (SHRs), where NOS or XOD inhibitors were without effect.
CONCLUSIONS AND IMPLICATIONS Our data suggest that triazolo pyrimidines such as VAS3947 are specific NADPH oxidase inhibitors, while DPI and apocynin can no longer be recommended. Based on the effects of VAS3947, NADPH oxidases appear to be a major source of ROS in aortas of SHRs.
Small-molecule synthesis usually relies on procedures that are highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of ...compounds to enable investigations of their practical potential. Here we report the synthesis of 14 distinct classes of small molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block–based synthesis platform to include even Csp3-rich polycyclic natural product frameworks and discovering a catch-and-release chromatographic purification protocol applicable to all of the corresponding intermediates. With thousands of compatible building blocks already commercially available, many small molecules are now accessible with this platform. More broadly, these findings illuminate an actionable roadmap to a more general and automated approach for small-molecule synthesis.
Exercise has been reported to decrease cancer-related fatigue and to increase quality of life (QoL) in various breast cancer (BC) populations. However, studies investigating exercise during ...radiotherapy or resistance training are scarce. We conducted a randomized, controlled trial (BEST study) to assess the efficacy of 12-week resistance training on fatigue beyond possible psychosocial effects of a group-based intervention.
One hundred sixty patients with BC stage 0–III were randomly assigned to a 12-week progressive resistance training (2 times/week) or a 12-week relaxation control (RC, 2 times/week). Both interventions were group-based. The primary end point fatigue was assessed with a 20-item multidimensional questionnaire, QoL with EORTC questionnaires. Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13.
Adherence to the intervention program as well as the completion rate (97%) for the primary outcome variable fatigue was high. In intention-to-treat analyses for the N = 155 patients, significant between-group mean differences (MD) favoring the exercise group (EX) were observed for general fatigue (P = 0.044), especially for the subscale physical fatigue MD = -0.8; 95% confidence interval -1.5 to -0.2, P = 0.013, but not for affective (P = 0.91) or cognitive fatigue (P = 0.65). For QoL, significantly larger improvements regarding the role function (P = 0.035) and pain (P = 0.040) were noted among exercisers compared with RCs. Future perspective improved significantly stronger in the RC group compared with the EX group (P = 0.047).
The 12-week resistance training program was a safe, feasible and efficacious strategy to improve cancer-related fatigue and components of QoL in BC patients during adjuvant radiotherapy. As exercise was compared with another group-based intervention, results indicate that resistance training effects on fatigue and QoL go beyond psychosocial benefits, and that the clinically relevant overall benefit of resistance exercise compared with usual care can be assumed to be higher.
ClinicalTrials.gov NCT01468766.
Platelet activation is essential for primary hemostasis and acute thrombotic vascular occlusions. On activation, platelets release their prothrombotic granules and expose phosphatidylserine, thus ...fostering thrombin generation and thrombus formation. In other cell types, both degranulation and phosphatidylserine exposure are modified by sphingomyelinase-dependent formation of ceramide. The present study thus explored whether acid sphingomyelinase participates in the regulation of platelet secretion, phosphatidylserine exposure, and thrombus formation.
Collagen-related peptide-induced or thrombin-induced ATP release and P-selectin exposure were significantly blunted in platelets from Asm-deficient mice (Smpd1(-/-)) when compared with platelets from wild-type mice (Smpd1(+/+)). Moreover, phosphatidylserine exposure and thrombin generation were significantly less pronounced in Smpd1(-/-) platelets than in Smpd1(+/+) platelets. In contrast, platelet integrin αIIbβ3 activation and aggregation, as well as activation-dependent Ca(2+) flux, were not significantly different between Smpd1(-/-) and Smpd1(+/+) platelets. In vitro thrombus formation at shear rates of 1700 s(-1) and in vivo thrombus formation after FeCl3 injury were significantly blunted in Smpd1(-/-) mice while bleeding time was unaffected. Asm-deficient platelets showed significantly reduced activation-dependent ceramide formation, whereas exogenous ceramide rescued diminished platelet secretion and thrombus formation caused by Asm deficiency. Treatment of Smpd1(+/+) platelets with bacterial sphingomyelinase (0.01 U/mL) increased, whereas treatment with functional acid sphingomyelinase-inhibitors, amitriptyline or fluoxetine (5 μmol/L), blunted activation-dependent platelet degranulation, phosphatidylserine exposure, and thrombus formation. Impaired degranulation and thrombus formation of Smpd1(-/-) platelets were again overcome by exogenous bacterial sphingomyelinase.
Acid sphingomyelinase is a completely novel element in the regulation of platelet plasma membrane properties, secretion, and thrombus formation.
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