Uncertainty in surface wind speed projections over the Iberian Peninsula: CMIP6 GCMs versus a WRF-RCM.

This study assessed the projected near-surface wind speed (SWS) changes and variability over the Iberian Peninsula for the 21st century. Here, we compared Coupled Model Intercomparison Project Phase 6 global climate models (GCMs) with a higher spatial resolution regional climate model (RCM; ∼20 km), known as WRF-CESM2, which was created by a dynamic downscaling of the Community Earth System Model version 2 (CESM2) using the Weather Research and Forecasting (WRF) model. Our analysis found that the GCMs tended to overestimate observed SWS for 1985-2014, while the higher spatial resolution of the WRF-CESM2 did not improve the accuracy and underestimated the SWS magnitude. GCMs project a decline of SWS under high shared socioeconomic pathways (SSPs) greenhouse concentrations, such as SSP370 and SSP585, while an interdecadal oscillation appears in SSP126 and SSP245 for the end of the century. The WRF-CESM2 under SSP585 predicts the opposite increasing SWS. Our results suggest that 21st-century projections of SWS are uncertain even for regionalized products and should be taken with caution.

Risk Factor Interactions, Non-High-Density Lipoprotein Cholesterol to Apolipoprotein B Ratio, and Severity of Coronary Arteriosclerosis in South Asian Individuals: An Observational Cohort Study.

Background South Asian individuals are at higher risk for arteriosclerotic cardiovascular disease and diabetes. The factors associated with arteriosclerotic cardiovascular disease severity and their interactions are unknown. Methods and Results This is a retrospective cohort study of the first 1162 South Asian participants enrolled in the South Asian Heart Center's AIM to Prevent Program who completed noncontrast coronary computed tomography scans. Using machine-learning algorithms, we identified and modeled the interaction of predictor variables with coronary artery calcification (CAC) severity in South Asian individuals. Anthropometric, laboratory, demographic, and lifestyle predictor variables were analyzed using continuous boosted regression trees to model the relationship with and in between predictor variables and CAC. Participants with CAC were older, predominately men, had smoking history, had personal histories of diabetes, hypertension, and hypercholesterolemia, and had family histories of coronary artery disease. Insulin, body mass index, blood pressure, fasting blood sugar, hemoglobin A1c, and waist-to-height ratio were associated with CAC but not low-density lipoprotein cholesterol or lipoprotein (a). The arteriosclerotic cardiovascular disease score failed to classify individuals. Only age, body mass index, non-high-density lipoprotein cholesterol/apolipoprotein B ratio, smoking risk, fasting blood sugar, and diastolic blood pressure were predictive, explaining 30.3% of CAC severity. A non-high-density lipoprotein cholesterol/apolipoprotein B ratio of 1.4 or less markedly increased coronary calcification. Conclusions Our findings highlight factors associated with dysmetabolism and cholesterol-depleted non-high-density lipoprotein cholesterol particles with coronary arteriosclerosis, possibly explaining the dual epidemics of diabetes and arteriosclerotic cardiovascular disease in this population. Markers of glucose dysmetabolism and the non-high-density lipoprotein cholesterol to apolipoprotein B ratio should become the focus of assessment for cardiovascular risk in South Asian individuals, with prevention strategies directed at improving glucose metabolic health.

Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432.

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.

Evaluation of global terrestrial near-surface wind speed simulated by CMIP6 models and their future projections.

We evaluate the performance of Coupled Model Intercomparison Project Phase 6 (CMIP6) models in simulating the observed global terrestrial near-surface wind speed (NSWS) and project its future changes under three different Shared Socioeconomic Pathways (SSPs). Results show that the CESM2 has the best ability in reproducing the observed NSWS trends, although all models examined are generally not doing well. Based on projections of CESM2, the global NSWS will decrease from 2021 to 2100 under all three SSPs. The projected NSWS declines significantly over the north of 20°N, especially across North America, Europe, and the mid-to-high latitudes of Asia; meanwhile, it increases over the south of 20°N. Under SSP585, there would be more light-windy days and fewer strong-windy days than those under SSP245, which leads to a significant global NSWS decline. Robust hemispheric-asymmetric changes in the NSWS could be due to the temperature gradient in the two hemispheres under global warming, with -1.2%, -3.5%, and -4.1% in the Northern Hemisphere, and 0.8%, 1.0%, and 1.5% in the Southern Hemisphere, for the near-term (2021-2040), mid-term (2041-2060), and long-term (2081-2100), respectively.

Teleconnections between large-scale oceanic-atmospheric patterns and interannual surface wind speed variability across China: Regional and seasonal patterns.

Great attention has been paid to the long-term decline in terrestrial near-surface wind speed (SWS) in China. However, how the SWS varies with regions and seasons and what modulates these changes remain unclear. Based on quality-controlled and homogenized terrestrial SWS data from 596 stations, the covarying SWS patterns during the Asian Summer Monsoon (ASM) and the Asian Winter Monsoon (AWM) seasons are defined for China using empirical orthogonal function (EOF) analysis for 1961-2016. The dominant SWS features represented by EOF1 patterns in both seasons show a clear decline over most regions of China. The interannual variability of the EOF1 patterns is closely related to the Northeast Asia Low Pressure (NEALP) and the Arctic Oscillation (AO), respectively. The EOF2 and EOF3 patterns during ASM (AWM) season describe a dipole mode of SWS between East Tibetan Plateau and East China Plain (between East Tibetan Plateau and Northeast China), and between Southeast and Northeast China (between Northeast China and the coastal areas of Southeast China), respectively. These dipole structures of SWS changes are closely linked with the oceanic-atmospheric oscillations on interannual scale.

Resultados de los concentrados plaquetarios en la regeneración ósea guiada / Results of platelet concentrates in guided bone regeneration

Los defectos óseos alrededor de los implantes dentales son considerados enfermedades que afectan el soporte y estabilidad del implante dental lo que limita la oseointegración. El tratamiento de estos defectos involucra procedimientos de regeneración ósea guiada que se define como la reproducción o reconstitución de una parte perdida o dañada del tejido óseo periimplantario con el fin de restaurar su arquitectura y función. El plasma rico en plaquetas y el plasma rico en fibrina son concentrados de plaquetas autólogos ampliamente usados en la regeneración periodontal y regeneración ósea guiada; sin embargo, sus resultados clínicos, histológicos y radiográficos son discutidos cuando se tratan defectos óseos alrededor de implantes dentales. En la presente revisión se realizó una búsqueda de la información mediante las bases de datos de diferentes buscadores (PubMed, SciELO, Redalyc y ScienceDirect) para encontrar artículos que traten sobre el uso de los concentrados plaquetarios (plasma rico en plaquetas y plasma rico en fibrina) en la terapia de la regeneración ósea guiada. Clínicamente, los concentrados plaquetarios otorgan resultados favorables en la reducción de la profundidad de sondaje y ganancia de nivel de inserción clínica en el tratamiento de defectos infraóseos periodontales. Histológicamente, los concentrados plaquetarios favorecen la neoformación ósea aumentando la velocidad de regeneración. Radiográficamente, los concentrados plaquetarios favorecen el aumento de densidad ósea, relleno óseo y tejido mineralizado. Con ello, se logra una reducción significativa del tamaño del defecto óseo(AU)

Bone defects around dental implants are considered to be diseases affecting the support and stability of the implant, thus limiting osseointegration. Treatment of these defects involves guided bone regeneration procedures, defined as the reproduction or reconstitution of a part lost or damaged of the peri-implant bone tissue with the purpose of restoring its architecture and function. Platelet-rich plasma and fibrin-rich plasma are autologous platelet concentrates widely used in guided bone regeneration and periodontal regeneration. However, their clinical, histological and radiographic results are debated when bone defects around dental implants are dealt with. The present review included a search for information in the databases of various search engines (PubMed, SciELO, Redalyc and ScienceDirect) to find papers about the use of platelet concentrates (platelet-rich plasma and fibrin-rich plasma) in guided bone regeneration therapy. Clinically, platelet concentrates yield favorable results in reducing probing depth and raising the level of clinical insertion in the treatment of periodontal intraosseous defects. Histologically, platelet concentrates enhance bone neoformation, speeding up regeneration. Radiographically, platelet concentrates lead to an increase in bone density, bone filler and mineralized tissue. A significant reduction is thus achieved in the size of the bone defect(AU)

Detection of high-risk pregnancies in low-resource settings: a case study in Guatemala.

BACKGROUND: Maternal and neonatal mortality is still very high at a global level, even though its reduction is a goal established among the Sustainable Development Goals by the United Nations. In order to improve prenatal care to address this challenge, this article proposes a strategy to detect and refer high risk pregnancies in rural setting through a portable ultrasound system combined with blood and urine strip tests. METHODS: The Healthy Pregnancy project was conceived as a single, explanatory and positivist case study, with a sample of ten thousand pregnant women attended by itinerant nurses of the Departments of Alta Verapaz and San Marcos. These nurses were trained and equipped with 31 portable ultrasound, and blood and urine tests to detect common obstetric pathology. Moreover, two obstetricians were responsible for remotely supervising the quality of prenatal care. Target communities were selected by the Health Directorates of the public health system from those that had the highest maternal mortality in previous years. RESULTS: The project attended to 10,108 women in 2 years and 3 months. 55 twin gestations (0.54%) were diagnosed. Non-cephalic presentation was found in 14.87% of the pregnant women attended from week 32 onwards. 20 patients were referred for non-evolutive gestation. An 11.08% prevalence of anemia was detected. Urine infections were diagnosed in 16.43% of the cases. Proteinuria was detected in 2.6% of patients, but only 17 of them presented high blood pressure and were therefore referred with a suspected pre-eclampsia. DISCUSSION: The results obtained indicate that an intervention of these characteristics makes it possible to improve the quality of care of rural pregnant women in low and middle-income countries. CONCLUSION: The results show that with suitable equipment, training, and supervision, the nursing staff in charge of care in rural areas can identify and refer most of the obstetric risks in time, which may contribute to the reduction of maternal mortality. TRIAL REGISTRATION: This research was not registered because it is a case study in which the assignment of the medical intervention was not at the discretion of the investigators.

GSK2646264, a spleen tyrosine kinase inhibitor, attenuates the release of histamine in ex vivo human skin.

BACKGROUND AND PURPOSE: Chronic spontaneous urticaria presents as a heterogeneous syndrome characterised by wheals, angioedema, or both for greater than 6 weeks. Spleen tyrosine kinase mediates allergen-induced mast cell degranulation via the IgE signalling pathway, a central component of wheal formation and inflammation. In this study, we investigated the effects of perfused or topically administered GSK2646264 on IgE-mediated histamine release from mast cells in an ex vivo human skin model. EXPERIMENTAL APPROACH: Using a novel SkiP device, ex vivo human skin from mastectomy surgeries was challenged with anti-IgE, complement 5a (C5a), and buffer to induce histamine release from skin mast cells. Histamine was collected via microdialysis fibres and measured fluorometrically. GSK2646264 was delivered via perfusion either using microdialysis fibres or topically in a cream. Drug concentrations in the skin were measured by LC-MS, and a pharmacokinetic/ pharmacodynamic (PK/PD) relationship developed. KEY RESULTS: Perfused GSK2646264 significantly inhibited anti-IgE (but not C5a)-induced histamine release in a concentration-dependent manner. The 0.5, 1, and 3% cream delivered GSK2646264 to the dermis above the IC90 and dose-dependently attenuated anti-IgE-induced histamine release. CONCLUSIONS AND IMPLICATIONS: GSK2646264 administered topically or direct to the dermis blocked histamine release from in situ skin mast cells. A PK/PD relationship curve suggests that dermal concentrations above 6.8 µM should lead to approximately 90% inhibition of histamine release from skin mast cells following activation of the Fc fragment of IgE receptor 1a, implicating a potential use for the compound in skin mast cell diseases such as urticaria.

Association Between 6-Week Postdischarge Risk Classification and 12-Month Outcomes After Orthopedic Trauma.

Importance: Numerous studies have demonstrated that long-term outcomes after orthopedic trauma are associated with psychosocial and behavioral health factors evident early in the patient's recovery. Little is known about how to identify clinically actionable subgroups within this population. Objectives: To examine whether risk and protective factors measured at 6 weeks after injury could classify individuals into risk clusters and evaluate whether these clusters explain variations in 12-month outcomes. Design, Setting, and Participants: A prospective observational study was conducted between July 16, 2013, and January 15, 2016, among 352 patients with severe orthopedic injuries at 6 US level I trauma centers. Statistical analysis was conducted from October 9, 2017, to July 13, 2018. Main Outcomes and Measures: At 6 weeks after discharge, patients completed standardized measures for 5 risk factors (pain intensity, depression, posttraumatic stress disorder, alcohol abuse, and tobacco use) and 4 protective factors (resilience, social support, self-efficacy for return to usual activity, and self-efficacy for managing the financial demands of recovery). Latent class analysis was used to classify participants into clusters, which were evaluated against measures of function, depression, posttraumatic stress disorder, and self-rated health collected at 12 months. Results: Among the 352 patients (121 women and 231 men; mean [SD] age, 37.6 [12.5] years), latent class analysis identified 6 distinct patient clusters as the optimal solution. For clinical use, these clusters can be collapsed into 4 groups, sorted from low risk and high protection (best) to high risk and low protection (worst). All outcomes worsened across the 4 clinical groupings. Bayesian analysis shows that the mean Short Musculoskeletal Function Assessment dysfunction scores at 12 months differed by 7.8 points (95% CI, 3.0-12.6) between the best and second groups, by 10.3 points (95% CI, 1.6-20.2) between the second and third groups, and by 18.4 points (95% CI, 7.7-28.0) between the third and worst groups. Conclusions and Relevance: This study demonstrates that during early recovery, patients with orthopedic trauma can be classified into risk and protective clusters that account for a substantial amount of the variance in 12-month functional and health outcomes. Early screening and classification may allow a personalized approach to postsurgical care that conserves resources and targets appropriate levels of care to more patients.

Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease.

The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.

South Asian Cardiovascular Disease & Cancer Risk: Genetics & Pathophysiology.

South Asians (SAs) are at heightened risk for cardiovascular disease as compared to other ethnic groups, facing premature and more severe coronary artery disease, and decreased insulin sensitivity. This disease burden can only be partially explained by conventional risk factors, suggesting the need for a specific cardiovascular risk profile for SAs. Current research, as explored through a comprehensive literature review, suggests the existence of population specific genetic risk factors such as lipoprotein(a), as well as population specific gene modulating factors. This review catalogues the available research on cardiovascular disease and genetics, anthropometry, and pathophysiology, and cancer genetics among SAs, with a geographical focus on the U.S. A tailored risk profile will hinge upon population customized classification and treatment guidelines, informed by continued research.

Unexpected timely fracture union in matrix metalloproteinase 9 deficient mice.

Immediately following a fracture, a fibrin laden hematoma is formed to prevent bleeding and infection. Subsequently, the organized removal of fibrin, via the protease plasmin, is essential to permit fracture repair through angiogenesis and ossification. Yet, when plasmin activity is lost, the depletion of fibrin alone is insufficient to fully restore fracture repair, suggesting the existence of additional plasmin targets important for fracture repair. Previously, activated matrix metalloproteinase 9 (MMP-9) was demonstrated to function in fracture repair by promoting angiogenesis. Given that MMP-9 is a defined plasmin target, it was hypothesized that pro-MMP-9, following plasmin activation, promotes fracture repair. This hypothesis was tested in a fixed murine femur fracture model with serial assessment of fracture healing. Contrary to previous findings, a complete loss of MMP-9 failed to affect fracture healing and union through 28 days post injury. Therefore, these results demonstrated that MMP-9 is dispensable for timely fracture union and cartilage transition to bone in fixed femur fractures. Pro-MMP-9 is therefore not a significant target of plasmin in fracture repair and future studies assessing additional plasmin targets associated with angiogenesis are warranted.

Frecuencia de patologías pulpares atendidas en una clínica docente de Ecuador / Frequency of pulpal pathologies attended in a teaching clinic

Objetivos: Determinar la frecuencia de patologías pulpares en pacientes de 18 a 45 años de edad que acudieron a la clínica de odontología de la Unidad Académica de Ciencia Odontológica de la Universidad Católica de Cuenca en el año lectivo 2013 ­ 2014. Material y métodos: Se realizó un estudio descriptivo transversal en 320 pacientes con un rango de edad entre 18 y 45 años mediante un formulario en el que se recogió nombre, edad, sexo, historia clínica, diente afectado y la patología pulpar presentada por el paciente. Resultados: La patología pulpar más frecuente fue pulpitis irreversible (62 %), seguido de necrosis (38%). Los pacientes de entre 26 a 30 y 40 a 45 años presentaron una frecuencia de pulpitis irreversible de 70 y 75 % respectivamente. Mientras que la frecuencia de necrosis no superó el 50 % de los casos en ningún grupo etario, siendo mayor en los grupos de 36 a 40 años y 18 a 25 años. Conclusiones: No existe diferencia significativa entre ambos sexos. (AU)

Objectives: To determinate pulpal pathologies frequency in patients from 18 to 45 years who were attended in dental clinic of Unidad Académica de Ciencia Odontológica de la Universidad Católica de Cuenca among 2013 ­ 2014 academic year. Material and methods: A cross-sectional descriptive study was performed in 320 patients between 18 and 45 years through a form in which name, age, sex, medical history, affected tooth and the pulp pathology presented by the patient were collected. RESULTS: irreversible pulpitis was the most frequent pulp pathology (62%), followed by necrosis (38%). Patients between 26-30 and 40-45 years had an irreversible pulpitis frequency of 70 and 75%, respectively. While the frequency of necrosis did not exceed 50% of the cases in any age group, being greater in the groups from 36 to 40 years and 18 to 25 years. Conclusions: There is no significant difference between the sex. (AU)

Click chemistry enables preclinical evaluation of targeted epigenetic therapies.

The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments. We also demonstrate the differential distribution and effects of BET inhibitors in normal and malignant cells in vivo. This study provides a potential framework for the preclinical assessment of a wide range of drugs.

Does Physician Reimbursement Correlate to Risk in Orthopaedic Trauma?

This study investigated whether current Medicare reimbursements for orthopaedic trauma procedures correlate with complications. A total of 18,510 patients representing 33 orthopaedic trauma procedures from 2005 to 2011 were studied. Adverse events and Medicare payments for each orthopaedic trauma procedure were collected. Linear regressions determined correlations between complications and Medicare payments for orthopaedic trauma procedures. A weak correlation between Medicare payments and complications was found for all procedures (r = .399, p = .021). A 1.0% increase in complications was associated with a payment increase of only $100. There were no correlations between complications and reimbursements for upper extremity (p = .878) and lower extremity (p = .713) procedures. A strong correlation (r = .808, p = .015) existed for hip and pelvic fractures, but a 1.1% increase in hip and pelvic complications correlated with only an increase of $100 in reimbursements. This study is the first to show that Medicare payments are not strongly correlated with complications, therefore demonstrating the potential risks of a bundled payment system for orthopaedic trauma surgeons.

Use of a portable system with ultrasound and blood tests to improve prenatal controls in rural Guatemala.

BACKGROUND: Maternal and neonatal mortality figures remain unacceptably high worldwide and new approaches are required to address this problem. This paper evaluates the impact on maternal and neonatal mortality of a pregnancy care package for rural areas of developing countries with portable ultrasound and blood/urine tests. METHODS: An observational study was conducted, with intervention and control groups not randomly assigned. SETTING: Rural areas of the districts of Senahu, Campur and Carcha, in Alta Verapaz Department (Guatemala). The control group is composed by 747 pregnant women attended by the community facilitator, which is the common practice in rural Guatemala. The intervention group is composed by 762 pregnant women attended under the innovative Healthy Pregnancy project. That project strengthens the local prenatal care program, providing local nurses training, portable ultrasound equipment and blood and urine tests. The information of each pregnancy is registered in a medical exchange tool, and is later reviewed by a gynecology specialist to ensure a correct diagnosis and improve nurses training. RESULTS: No maternal deaths were reported within the intervention group, versus five cases in the control group. Regarding neonatal deaths, official data revealed a 64 % reduction for neonatal mortality. A 37 % prevalence of anemia was detected. Non-urgent referral was recommended to 70 pregnancies, being fetal malpresentation the main reported cause. CONCLUSION: Impact data on maternal mortality (reduction to zero) and neonatal mortality (NMR was reduced to 36 %) are encouraging, although we are aware of the limitations of the study related to possible biasing and the small sample size. The major reduction of maternal and neonatal mortality provides promising prospects for these low-cost diagnostic procedures, which allow to provide high quality prenatal care in isolated rural communities of developing countries. TRIAL REGISTRATION: This research was not registered because it is an observational study where the assignment of the medical intervention was not at the discretion of the investigators.

Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors.

The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.