Evidence that extreme rainfall intensity is increasing at the global scale has strengthened considerably in recent years. Research now indicates that the greatest increases are likely to occur in ...short‐duration storms lasting less than a day, potentially leading to an increase in the magnitude and frequency of flash floods. This review examines the evidence for subdaily extreme rainfall intensification due to anthropogenic climate change and describes our current physical understanding of the association between subdaily extreme rainfall intensity and atmospheric temperature. We also examine the nature, quality, and quantity of information needed to allow society to adapt successfully to predicted future changes, and discuss the roles of observational and modeling studies in helping us to better understand the physical processes that can influence subdaily extreme rainfall characteristics. We conclude by describing the types of research required to produce a more thorough understanding of the relationships between local‐scale thermodynamic effects, large‐scale atmospheric circulation, and subdaily extreme rainfall intensity.
Key Points
Significant increases in rainfall intensity are expected at subdaily time scalesDescribes link between subdaily extreme rainfall and atmospheric temperatureDiscusses role of observations and modeling to help understand future change
Mitogen-activated protein kinase (MAPK) cascades are key signaling pathways involved in the regulation of normal cell proliferation, survival and differentiation. Aberrant regulation of MAPK cascades ...contribute to cancer and other human diseases. In particular, the extracellular signal-regulated kinase (ERK) MAPK pathway has been the subject of intense research scrutiny leading to the development of pharmacologic inhibitors for the treatment of cancer. ERK is a downstream component of an evolutionarily conserved signaling module that is activated by the Raf serine/threonine kinases. Raf activates the MAPK/ERK kinase (MEK)1/2 dual-specificity protein kinases, which then activate ERK1/2. The mutational activation of Raf in human cancers supports the important role of this pathway in human oncogenesis. Additionally, the Raf-MEK-ERK pathway is a key downstream effector of the Ras small GTPase, the most frequently mutated oncogene in human cancers. Finally, Ras is a key downstream effector of the epidermal growth factor receptor (EGFR), which is mutationally activated and/or overexpressed in a wide variety of human cancers. ERK activation also promotes upregulated expression of EGFR ligands, promoting an autocrine growth loop critical for tumor growth. Thus, the EGFR-Ras-Raf-MEK-ERK signaling network has been the subject of intense research and pharmaceutical scrutiny to identify novel target-based approaches for cancer treatment. In this review, we summarize the current status of the different approaches and targets that are under evaluation and development for the therapeutic intervention of this key signaling pathway in human disease.
From 5000 to 10 000 kidney patients die prematurely in the United States each year, and about 100 000 more suffer the debilitating effects of dialysis, because of a shortage of transplant kidneys. To ...reduce this shortage, many advocate having the government compensate kidney donors. This paper presents a comprehensive cost‐benefit analysis of such a change. It considers not only the substantial savings to society because kidney recipients would no longer need expensive dialysis treatments—$1.45 million per kidney recipient—but also estimates the monetary value of the longer and healthier lives that kidney recipients enjoy—about $1.3 million per recipient. These numbers dwarf the proposed $45 000‐per‐kidney compensation that might be needed to end the kidney shortage and eliminate the kidney transplant waiting list. From the viewpoint of society, the net benefit from saving thousands of lives each year and reducing the suffering of 100 000 more receiving dialysis would be about $46 billion per year, with the benefits exceeding the costs by a factor of 3. In addition, it would save taxpayers about $12 billion each year.
This analysis of a government program to compensate kidney donors indicates the monetary value of saving thousands of lives each year and reducing the suffering of a hundred thousand more on dialysis would be about $46 billion per year, and would save taxpayers about $12 billion a year.
The most common form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motor neurons, is caused by dominant mutations in the ubiquitously expressed Cu-Zn Superoxide ...dismutase (SOD1). In chimeric mice that are mixtures of normal and SOD1 mutant-expressing cells, toxicity to motor neurons is shown to require damage from mutant SOD1 acting within nonneuronal cells. Normal motor neurons in SOD1 mutant chimeras develop aspects of ALS pathology. Most important, nonneuronal cells that do not express mutant SOD1 delay degeneration and significantly extend survival of mutant-expressing motor neurons.
Emerging evidence supports the use of therapeutic drug monitoring (TDM) of β-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how ...sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for β-lactam TDM in ICUs. A questionnaire survey was developed to describe various aspects relating to the conduct of β-lactam TDM in an ICU setting. Data sought included: β-lactams chosen for TDM, inclusion criteria for selecting patients, blood sampling strategy, analytical methods, pharmacokinetic (PK)/pharmacodynamic (PD) targets and dose adjustment strategies. Nine ICUs were included in this survey. Respondents were either ICU or infectious disease physicians, pharmacists or clinical pharmacologists. Piperacillin (co-formulated with tazobactam) and meropenem (100% of units surveyed) were the β-lactams most commonly subject to TDM, followed by ceftazidime (78%), ceftriaxone (43%) and cefazolin (43%). Different chromatographic and microbiological methods were used for assay of β-lactam concentrations in blood and other biological fluids (e.g. CSF). There was significant variation in the PK/PD targets (100% fT>MIC up to 100% fT>4xIC) and dose adjustment strategies used by each of the sites. Large variations were found in the type of β-lactams tested, the patients selected for TDM and drug assay methods. Significant variation observed in the PK/PD targets and dose adjustment strategies used supports the need for further studies that robustly define PK/PD targets for ICU patients to ensure a greater consistency of practice for dose adjustment strategies for optimizing β-lactam dosing with TDM.
Successive locations of individual large earthquakes (M
> 5.5) over years to centuries can be difficult to explain with simple Coulomb stress transfer (CST) because it is common for seismicity to ...circumvent nearest-neighbour along-strike faults where coseismic CST is greatest. We demonstrate that Coulomb pre-stress (the cumulative CST from multiple earthquakes and interseismic loading on non-planar faults) may explain this, evidenced by study of a 667-year historical record of earthquakes in central Italy. Heterogeneity in Coulomb pre-stresses across the fault system is >±50 bars, whereas coseismic CST is <±2 bars, so the latter will rarely overwhelm the former, explaining why historical earthquakes rarely rupture nearest neighbor faults. However, earthquakes do tend to occur where the cumulative coseismic and interseismic CST is positive, although there are notable examples where earthquake propagate across negatively stressed portions of faults. Hence Coulomb pre-stress calculated for non-planar faults is an ignored yet vital factor for earthquake triggering.
A dominant paradigm for mid-latitude air-sea interaction identifies the synoptic-scale atmospheric “noise” as the main driver for the observed ocean surface variability. While this conceptual model ...successfully holds over most of the mid-latitude ocean surface, its soundness over frontal zones (including western boundary currents; WBC) characterized by intense mesoscale activity, has been questioned in a number of studies suggesting a driving role for the small scale ocean dynamics (mesoscale oceanic eddies) in the modulation of air-sea interaction. In this context, climate models provide a powerful experimental device to inspect the emerging scale-dependent nature of mid-latitude air-sea interaction. This study assesses the impact of model resolution on the representation of air-sea interaction over the Gulf Stream region, in a multi-model ensemble of present-climate simulations performed using a common experimental design. Lead-lag correlation and covariance patterns between sea surface temperature (SST) and turbulent heat flux (THF) are diagnosed to identify the leading regimes of air-sea interaction in a region encompassing both the Gulf Stream system and the North Atlantic subtropical basin. Based on these statistical metrics it is found that coupled models based on “laminar” (eddy-parameterised) and eddy-permitting oceans are able to discriminate between an ocean-driven regime, dominating the region controlled by the Gulf Stream dynamics, and an atmosphere-driven regime, typical of the open ocean regions. However, the increase of model resolution leads to a better representation of SST and THF cross-covariance patterns and functional forms, and the major improvements can be largely ascribed to a refinement of the oceanic model component.
Post-traumatic stress disorder (PTSD) has been linked to hypertension, but most research on PTSD and hypertension is cross-sectional, and potential mediators have not been clearly identified. ...Moreover, PTSD is twice as common in women as in men, but understanding of the PTSD-hypertension relationship in women is limited. We examined trauma exposure and PTSD symptoms in relation to incident hypertension over 22 years in 47 514 civilian women in the Nurses' Health Study II.
We used proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for new-onset hypertension (N = 15 837).
PTSD symptoms assessed with a screen were modestly associated with incident hypertension in a dose-response fashion after adjusting for potential confounders. Compared to women with no trauma exposure, women with 6-7 PTSD symptoms had the highest risk of developing hypertension (HR 1.20, 95% CI 1.12-1.30), followed by women with 4-5 symptoms (HR 1.17, 95% CI 1.10-1.25), women with 1-3 symptoms (HR 1.12, 95% CI 1.06-1.18), and trauma-exposed women with no symptoms (HR 1.04, 95% CI 1.00-1.09). Findings were maintained, although attenuated, adjusting for hypertension-relevant medications, medical risk factors, and health behaviors. Higher body mass index and antidepressant use accounted for 30% and 21% of the PTSD symptom-hypertension association, respectively.
Screening for hypertension and reducing unhealthy lifestyle factors, particularly obesity, in women with PTSD may hold promise for offsetting cardiovascular risk.
Objective
To determine the relationships between systemic sclerosis (SSc)–related autoantibodies, as well as their clinical associations, in a well‐characterized Australian patient cohort.
Methods
...Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP‐A and CENP‐B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90‐kd nucleolar protein NOR‐90, fibrillarin, Th/To, PM/Scl‐75, PM/Scl‐100, Ku, topoisomerase I (topo I), tripartite motif–containing protein 21/Ro 52, and platelet‐derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data.
Results
A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures.
Conclusion
Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.
Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively ...preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.
This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.
A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS 6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).
Trilaciclib demonstrated an improvement in the patient’s tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib’s myelopreservation benefits.
NCT02499770.
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