Polar Heterobenzylic C(sp3)-H Chlorination Pathway Enabling Efficient Diversification of Aromatic Nitrogen Heterocycles.

Site-selective radical reactions of benzylic C-H bonds are now highly effective methods for C(sp3-H) functionalization and cross-coupling. The existing methods, however, are often ineffective with heterobenzylic C-H bonds in alkyl-substituted pyridines and related aromatic heterocycles that are prominently featured in pharmaceuticals and agrochemicals. Here, we report new synthetic methods that leverage polar, rather than radical, reaction pathways to enable the selective heterobenzylic C-H chlorination of 2- and 4-alkyl-substituted pyridines and other heterocycles. Catalytic activation of the substrate with trifluoromethanesulfonyl chloride promotes the formation of enamine tautomers that react readily with electrophilic chlorination reagents. The resulting heterobenzyl chlorides can be used without isolation or purification in nucleophilic coupling reactions. This chlorination-diversification sequence provides an efficient strategy to achieve heterobenzylic C-H cross-coupling with aliphatic amines and a diverse collection of azoles, among other coupling partners.

Consistent centennial-scale change in European sub-Arctic peatland vegetation toward Sphagnum dominance-Implications for carbon sink capacity.

Climate warming is leading to permafrost thaw in northern peatlands, and current predictions suggest that thawing will drive greater surface wetness and an increase in methane emissions. Hydrology largely drives peatland vegetation composition, which is a key element in peatland functioning and thus in carbon dynamics. These processes are expected to change. Peatland carbon accumulation is determined by the balance between plant production and peat decomposition. But both processes are expected to accelerate in northern peatlands due to warming, leading to uncertainty in future peatland carbon budgets. Here, we compile a dataset of vegetation changes and apparent carbon accumulation data reconstructed from 33 peat cores collected from 16 sub-arctic peatlands in Fennoscandia and European Russia. The data cover the past two millennia that has undergone prominent changes in climate and a notable increase in annual temperatures toward present times. We show a pattern where European sub-Arctic peatland microhabitats have undergone a habitat change where currently drier habitats dominated by Sphagnum mosses replaced wetter sedge-dominated vegetation and these new habitats have remained relatively stable over the recent decades. Our results suggest an alternative future pathway where sub-arctic peatlands may at least partly sustain dry vegetation and enhance the carbon sink capacity of northern peatlands.

Effect of COVID-19 on outpatient services in patients with aortovascular disease: a UK multicentre study.

INTRODUCTION: The SARS-CoV-2 coronavirus disease 2019 (COVID-19) pandemic has disrupted healthcare services worldwide. Outpatient services have necessarily been restructured to accommodate COVID-19 patients and to maintain social distancing measures. The aim of our study was to investigate how the COVID-19 pandemic has affected outpatient healthcare provision for patients with aortovascular disease. METHODS: In this prospective study, a standardised proforma was circulated to seven aortic centres in the UK. Data on outpatient encounters were collected from March to July 2020. Captured data included demographic details, disease pattern, type of encounter (face-to-face, video or telephone), clinic outcome and availability of imaging. RESULTS: A total of 632 patients were included in the study, including 164 (25.9%) new referrals. In this cohort, clinic settings have shifted towards remote consultations, with 424 (67.1%) patients undergoing telephone appointments. Over a third of new patients (34.8%) had a delay in diagnostic tests, which might be attributable to the indirect effects of COVID-19. A total of 102 (16.1%) patients were added to a surgical waiting list following clinic. CONCLUSIONS: To the best of our knowledge, this is the largest study of outpatient activity during the COVID-19 pandemic in patients with aortovascular disease. We demonstrate how the speciality has adapted to accommodate government-endorsed changes in healthcare provision, and question how COVID-19 may have affected access to diagnostics. Finally, we discuss how COVID-19 will affect patients added to surgical waiting lists.

Ivermectin compared with placebo in the clinical course in Mexican patients with asymptomatic and mild COVID-19: a randomized clinical trial.

BACKGROUND: Despite the development and application of vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) around the world, the scientific community is still trying to find some therapies to avoid or ameliorate the fatal evolution of the Coronavirus disease 2019 (COVID-19). Since the publication of the potential use of ivermectin as a treatment against the disease, a pleiad of information about it has been published. However, the evidence is not strong or weak enough to conclude its usefulness in the clinical evolution of patients infected with SARS-CoV-2. We evaluate the efficacy and safety of ivermectin in the treatment of Mexican patients with asymptomatic and mild COVID-19 in a three-day administration in comparison to placebo. METHODS: A randomized, double-blind, placebo-controlled trial was carried out in 66 adults with asymptomatic and mild COVID-19. Patients were randomly assigned 1:1 ratio to ivermectin plus acetaminophen or placebo plus acetaminophen. The primary endpoint was the proportion of subjects without a disease progression to severity according to COVID-19 guidelines by the National Institutes of Health (NIH) since randomization to 14 days. RESULTS: None of the participants presented progression to a severe state in either group. Viral load was measured on Days 1, 5, and 14. No significant differences were observed in baseline or 14-day between groups (p = 0.720 and 0.362, respectively). However, on Day 5, a significant difference in viral load was observed between groups (p = 0.039). The frequency of symptoms was similar between groups, and no significant differences were observed. The most frequent symptom was cough. One severe adverse event associated with SARS-CoV-2 infection was observed in the ivermectin group. CONCLUSIONS: At standard doses, ivermectin is not effective to prevent progression to a severe state or reducing symptoms in adults with asymptomatic and mild COVID-19. Trial registration The study was registered with ClinicalTrial.gov (NCT04407507) on May 29, 2020.

Recent climate change has driven divergent hydrological shifts in high-latitude peatlands.

High-latitude peatlands are changing rapidly in response to climate change, including permafrost thaw. Here, we reconstruct hydrological conditions since the seventeenth century using testate amoeba data from 103 high-latitude peat archives. We show that 54% of the peatlands have been drying and 32% have been wetting over this period, illustrating the complex ecohydrological dynamics of high latitude peatlands and their highly uncertain responses to a warming climate.

Concussion severity and functional outcome using biomarkers in children and youth involved in organized sports, recreational activities and non-sport related incidents.

This prospective multicenter study evaluated differences in concussion severity and functional outcome using glial and neuronal biomarkers glial Fibrillary Acidic (GFAP) and Ubiquitin C-terminal Hydrolase (UCH-L1) in children and youth involved in non-sport related trauma, organized sports, and recreational activities. Children and youth presenting to three Level 1 trauma centersfollowing blunt head trauma with a GCS 15 with a verified diagnosis of a concussion were enrolled within 6 hours of injury. Traumatic intracranial lesions on CT scan and functional outcome within 3 months of injury were evaluated. 131 children and youth with concussion were enrolled, 81 in the no sports group, 22 in the organized sports group and 28 in the recreational activities group. Median GFAP levels were 0.18, 0.07, and 0.39 ng/mL in the respective groups (p = 0.014). Median UCH-L1 levels were 0.18, 0.27, and 0.32 ng/mL respectively (p = 0.025). A CT scan of the head was performed in 110 (84%) patients. CT was positive in 5 (7%), 4 (27%), and 5 (20%) patients, respectively. The AUC for GFAP for detecting +CT was 0.84 (95%CI 0.75-0.93) and for UCH-L1 was 0.82 (95%CI 0.71-0.94). In those without CT lesions, elevations in UCH-L1 were significantly associated with unfavorable 3-month outcome. Concussions in the 3 groups were of similar severity and functional outcome. GFAP and UCH-L1 were both associated with severity of concussion and intracranial lesions, with the most elevated concentrations in recreational activities .

GLUT1, LDHA, and MCT4 Expression Is Deregulated in Cervical Cancer and Precursor Lesions.

Metabolic reprogramming is typical in cancerous cells and is required for proliferation and cellular survival. In addition, oncoproteins of high-risk human papillomavirus (HR-HPV) are involved in this process. This study evaluated the relationship between glucose transporter I (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter type 4 (MCT4) expression and cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC) with HR-HPV infection. The protein expression was evaluated in women with CIN I (n=20), CIN II/III (n=16), or ICC (n=24) by immunohistochemistry. The protein expression was analyzed qualitatively by van Zummeren score and quantitatively by Image ProPlus 6 software. LDHA expression increases in HPV-16 infection. In the CIN I group, GLUT1 immunostaining has a 35% protein expression at the membrane level at more than two thirds of the epithelium, which increased by 21.25% more in CIN II/III in more than two thirds of the epithelium. While LDHA and MCT4 in CIN I mostly do not present immunostaining, or this was only limited to the basal stratum, this expression is increased in CIN II/III and ICC cases. The GLUT1, LDHA, and MCT4 expression increased in ICC. The overexpression in high-grade CIN with HR-HPV infection shows a higher risk for cervical carcinoma progression.

Combined Subcutaneous-Intranasal Immunization With Epitope-Based Antigens Elicits Binding and Neutralizing Antibody Responses in Serum and Mucosae Against PRRSV-2 and SARS-CoV-2.

New vaccine design approaches, platforms, and immunization strategies might foster antiviral mucosal effector and memory responses to reduce asymptomatic infection and transmission in vaccinated individuals. Here, we investigated a combined parenteral and mucosal immunization scheme to induce local and serum antibody responses, employing the epitope-based antigens 3BT and NG19m. These antigens target the important emerging and re-emerging viruses PRRSV-2 and SARS-CoV-2, respectively. We assessed two versions of the 3BT protein, which contains conserved epitopes from the GP5 envelope protein of PRRSV-2: soluble and expressed by the recombinant baculovirus BacDual-3BT. On the other hand, NG19m, comprising the receptor-binding motif of the S protein of SARS-CoV-2, was evaluated as a soluble recombinant protein only. Vietnamese mini-pigs were immunized employing different inoculation routes: subcutaneous, intranasal, or a combination of both (s.c.-i.n.). Animals produced antigen-binding and neut1ralizing antibodies in serum and mucosal fluids, with varying patterns of concentration and activity, depending on the antigen and the immunization schedule. Soluble 3BT was a potent immunogen to elicit binding and neutralizing antibodies in serum, nasal mucus, and vaginal swabs. The vectored immunogen BacDual-3BT induced binding antibodies in serum and mucosae, but PRRSV-2 neutralizing activity was found in nasal mucus exclusively when administered intranasally. NG19m promoted serum and mucosal binding antibodies, which showed differing neutralizing activity. Only serum samples from subcutaneously immunized animals inhibited RBD-ACE2 interaction, while mini-pigs inoculated intranasally or via the combined s.c.-i.n. scheme produced subtle neutralizing humoral responses in the upper and lower respiratory mucosae. Our results show that intranasal immunization, alone or combined with subcutaneous delivery of epitope-based antigens, generates local and systemic binding and neutralizing antibodies. Further investigation is needed to evaluate the capability of the induced responses to prevent infection and reduce transmission.

Failure to EGFR-TKI-based therapy and tumoural progression are promoted by MEOX2/GLI1-mediated epigenetic regulation of EGFR in the human lung cancer.

BACKGROUND: Mesenchyme homeobox-2 (MEOX2)-mediated regulation of glioma-associated oncogene-1 (GLI1) has been associated with poor overall survival, conferring chemoresistance in lung cancer. However, the role of MEOX2/GLI1 in resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs)-based therapy remains unexplored in human lung cancer. METHODS: Functional assays using genetic silencing strategy by short hairpin RNAs, as well as cytotoxic (tetrazolium dye MTT) and clonogenic assays, were performed to evaluate MEOX2/GLI1-induced malignancy capacity in lung cancer cells. Further analysis performed includes western blot, qPCR and ChIP-qPCR assays to identify whether MEOX2/GLI1 promote EGFR/AKT/ERK activation, as well as EGFR overexpression through epigenetic mechanisms. Finally, preclinical tumour progression in vivo and progression-free disease interval analyses in patients treated with EGFR-TKI were included. RESULTS: Overexpressed MEOX2/GLI1 in both EGFR wild-type and EGFR/KRAS-mutated lung cancer cells were detected and involved in the activation/expression of EGFR/AKT/ERK biomarkers. In addition, MEOX2/GLI1 was shown to be involved in the increased proliferation of tumour cells and resistance capacity to cisplatin, EGFR-TKIs (erlotinib and AZD9291 'osimertinib'), AZD8542-SMO, and AZD6244-MEKK1/2. In addition, we identified that MEOX2/GLI1 promote lung tumour cells progression in vivo and are clinically associated with poorer progression-free disease intervals. Finally, both MEOX2 and GLI1 were detected to be epigenetically involved in EGFR expression by reducing both repressive markers polycomb-EZH2 and histone H3K27me3, but, particularly, increasing an activated histone profile H3K27Ac/H3K4me3 at EGFR-gene enhancer-promoter sequences that probably representing a novel EGFR-TKI-based therapy resistance mechanism. CONCLUSION: MEOX2/GLI1 promote resistance to cisplatin and EGFR-TKI-based therapy in lung cancer cells, modulating EGFR/AKT/ERK signalling pathway activation, as well as inducing an aberrant epigenetic modulation of the EGFR-gene expression in human lung cancer.

Cu-Catalyzed Site-Selective Benzylic Chlorination Enabling Net C-H Coupling with Oxidatively Sensitive Nucleophiles.

Site-selective chlorination of benzylic C-H bonds is achieved using a CuICl/bis(oxazoline) catalyst with N-fluorobenzenesulfonimide as the oxidant and KCl as a chloride source. This method exhibits higher benzylic selectivity, relative to established chlorination protocols, and is compatible with diverse alkyl arenes. Sequential benzylic C-H chlorination/nucleophilic substitution affords C-O, C-S, and C-N coupling products with oxidatively sensitive coupling partners.

Daños a la salud asociados a riesgos laborales en el tránsito aéreo mexicano, 2020-2021 / Adverse health effects associated with occupational risk factors among Mexican air traffic workers, 2020-2021

En el sector aéreo los trabajadores laboran en ambientes atípicos, debido a que están expuestos continuamente a diversos riesgos. En aviación, la mayoría de los sistemas de gestión están enfocados en controlar riesgos operativos, es decir, factores que podrían perjudicar el correcto desempeño de las aeronaves. El objetivo del presente estudio consistió en determinar la asociación entre riesgos laborales y daños a la salud, a los que se expone el personal de Servicios a la Navegación en el Espacio Aéreo Mexicano. Para ello, se utilizaron la Encuesta Individual para la Evaluación de la Salud de los Trabajadores, la Prueba de Síntomas Subjetivos de Fatiga y, la Escala de Depresión, Ansiedad y Estrés. Participaron 199 trabajadores y se realizó un análisis multivariable de los resultados, considerando una significancia estadística de p≤0.05 y un intervalo de confianza al 95%. Se encontró que el personal femenino tiene una mayor prevalencia de fatiga (2.31), trastornos del sueño (1.80) y lumbalgia (1.58). El personal de control de tránsito aéreo tiene mayor prevalencia de estrés (2.71) y ansiedad (1.75). Aquellos expuestos a cambios bruscos de temperatura, presentan mayor ansiedad (99%) y estrés (90%). Para mejorar las condiciones laborales en el sector aeronáutico mexicano, se requiere de una adecuada comprensión de la relación que guardan los riesgos con el perfil de daño de los trabajadores. Esta acción permitirá tomar acciones preventivas y correctivas, asertivas y eficientes(AU)

In the aerospace industry people work in atypical environments, because workers are continuously exposed to various risks. In aviation, management systems are focused mainly on controlling operational risks, i.e., factors that could harm the correct performance of an aircraft. The objective of this study was to determine the association between occupational risk factors and adverse health effects among staff belonging to the Mexican Air Space Navigation Services [Servicios a la Navegación en el Espacio Aéreo Mexicano]. We administered the Individual Survey for the Evaluation of Workers' Health, the Subjective Symptoms of Fatigue Test, and the Depression, Anxiety and Stress Scale. A total of 199 workers participated and a multivariate analysis of the results was performed, considering 95% confidence intervals and a statistical significance level of p≤0.05. We found that female staff hada higher prevalence of fatigue (2.31), sleep disorders (1.80) and low back pain (1.58). Air traffic control personnel have a higher prevalence of stress (2.71) and anxiety (1.75). Those exposed to sudden changes in temperature reported more anxiety (99%) and stress (90%). To improve working conditions in the Mexican aeronautical sector, an adequate understanding of the relationship between risks and the injury profile of the workers is required. This action will facilitate the implementation of preventive and corrective, assertive and efficient measures(AU)

IC50 Evaluation of Platinum Nanocatalysts for Cancer Treatment in Fibroblast, HeLa, and DU-145 Cell Lines.

Cancer is a major public health problem being one of the main causes of morbidity and mortality today. Recent advances in catalytic nanomedicine have offered new cancer therapies based on the administration of nanoparticles (NPs) of platinum (Pt) dispersed in catalytic mesoporous nanomaterials (titania, TiO2) with highly selective cytotoxic properties and no adverse effects. A half maximal inhibitory concentration (IC50) study was carried out in cancerous cell lines (HeLa, DU-145, and fibroblasts) to evaluate the cytotoxic effect of different nanomaterials [Pt/TiO2, TiO2, and Pt(acac)2] synthesized by the sol-gel method at concentrations 0-1000 µg/mL. The assays showed that IC50 values for Pt in functionalized TiO2 (NPt) in HeLa (53.74 ± 2.95 µg/mL) and DU-145 (75.07 ± 5.48 µg/mL) were lower than those of pure TiO2 (74.29 ± 8.95 and 82.02 ± 6.03 µg/mL, respectively). Pt(acac)2 exhibited no cytotoxicity. Normal cells (fibroblasts) treated with NPt exhibited no significant growth inhibition, suggesting the high selectivity of the compound for cancerous cells only. TiO2 and NPt were identified as antineoplastic compounds in vitro. Pt(acac)2 is not recommendable because of the low cytotoxicity observed.

Assessing environmental contamination from metal emission and relevant regulations in major areas of coal mining and electricity generation in Australia.

The Hunter and Latrobe Valleys have two of the richest coal deposits in Australia. They also host the largest coal-fired power stations in the country. We reconstructed metal deposition records in lake sediments in the Hunter and Latrobe Valleys to determine if metal deposition in freshwater lakes have increased in the region. The current regulatory arrangement applied to metal emissions from coal-fired power stations in Australia are presented, discussing their capacity to address future increases in metal deposition from these sources. Sediment records of spheroidal carbonaceous particles (SCPs), a component of fly-ash, were also used as an additional line of evidence to identify the contribution of industrial activities related to electricity generation to metal deposition in regions surrounding open-cut coal mines and coal-fired power stations. Sediment metal concentrations and SCP counts in the sedimentary records, from the Hunter and Latrobe Valleys, both indicated that open-cut coal mining and the subsequent combustion of coal in power stations has most likely resulted in an increase in atmospheric deposition of metals in the local region. In particular, the metalloids As and Se showed the greatest enrichment compared to before coal mining commenced. Although the introduction of bag filters at Liddell Power Station and the decommissioning of Hazelwood Power Station appear to have resulted in a decrease of metal deposition in nearby lakes, overall metal deposition in the environment is still increasing. The challenge for the years to come will be to develop better regulation policies and tools that will contribute to reduce metal emissions in these major electricity production centres in Australia.

Induction of mucosal immunity against pathogens by using recombinant baculoviral vectors: Mechanisms, advantages, and limitations.

Over 90% of pathogens of medical importance invade the organism through mucosal surfaces, which makes it urgent to develop safe and effective mucosal vaccines and mucosal immunization protocols. Besides, parenteral immunization does not provide adequate protective immunity in mucosal surfaces. Effective mucosal vaccination could protect local and systemic compartments and favor herd immunity. Although various mucosal adjuvants and Ag-delivery systems have been developed, none has filled the gap to control diseases caused by complex mucosal pathogens. Among the strategies to counteract them, recombinant virions from the baculovirus Autographa californica multiple nucleopolyhedrovirus (rAcMNPV) are useful vectors, given their safety and efficacy to produce mucosal and systemic immunity in animal infection models. Here, we review the immunogenic properties of rAcMNPV virions from the perspectives of mucosal immunology and vaccinology. Some features, which are analyzed and extrapolated from studies with different particulate antigens, include size, shape, surface molecule organization, and danger signals, all needed to break the tolerogenic responses of the mucosal immune tissues. Also, we present a condensed discussion on the immunity provided by rAcMNPV virions against influenza virus and human papillomavirus in animal models. Through the text, we highlight the advantages and limitations of this experimental immunization platform.

Decreased carbon accumulation feedback driven by climate-induced drying of two southern boreal bogs over recent centuries.

Northern boreal peatlands are important ecosystems in modulating global biogeochemical cycles, yet their biological communities and related carbon dynamics are highly sensitive to changes in climate. Despite this, the strength and recent direction of these feedbacks are still unclear. The response of boreal peatlands to climate warming has received relatively little attention compared with other northern peatland types, despite forming a large northern hemisphere-wide ecosystem. Here, we studied the response of two ombrotrophic boreal peatlands to climate variability over the last c. 200 years for which local meteorological data are available. We used remains from plants and testate amoebae to study historical changes in peatland biological communities. These data were supplemented by peat property (bulk density, carbon and nitrogen content), 14 C, 210 Pb and 137 Cs analyses and were used to infer changes in peatland hydrology and carbon dynamics. In total, six peat cores, three per study site, were studied that represent different microhabitats: low hummock (LH), high lawn and low lawn. The data show a consistent drying trend over recent centuries, represented mainly as a change from wet habitat Sphagnum spp. to dry habitat S. fuscum. Summer temperature and precipitation appeared to be important drivers shaping peatland community and surface moisture conditions. Data from the driest microhabitat studied, LH, revealed a clear and strong negative linear correlation (R2  = .5031; p < .001) between carbon accumulation rate and peat surface moisture conditions: under dry conditions, less carbon was accumulated. This suggests that at the dry end of the moisture gradient, availability of water regulates carbon accumulation. It can be further linked to the decreased abundance of mixotrophic testate amoebae under drier conditions (R2  = .4207; p < .001). Our study implies that if effective precipitation decreases in the future, the carbon uptake capacity of boreal bogs may be threatened.

Latexin expression correlated with mineralization of articular cartilage during progression of post-traumatic osteoarthritis in a rat model.

As latexin has been linked with chondrocyte hypertrophic differentiation it is possible that this protein may also be involved in the mineralization of cartilage in OA. Therefore, we correlated latexin expression with the mineralization marker, alkaline phosphatase and determined the mineral deposition in the articular cartilage by analyzing the Ca/P ratio and the collagen fibrils pattern, during the progression of post-traumatic OA in a rat model. OA was induced by medial meniscectomy and post-surgery exercise for 5, 10, 20 and 45 days. Protein expression in articular cartilage was evaluated by immunofluorescence, histochemistry and Western blot. Minerals and structure of collagen fibrils in the superficial zone of cartilage were analyzed by energy dispersive X-ray spectroscopy (EDX) and atomic force microscopy (AFM) respectively. Protein expression analysis showed time-dependent up-regulation of latexin during OA progression. In the cartilage, latexin expression correlated with the expression and activity of alkaline phosphatase. EDX of the superficial zone of cartilage showed a Ca/P ratio closer to theoretical values for basic calcium phosphate minerals. The presence of minerals was also analyzed indirectly with AFM, as the collagen fibril pattern was less evident in the mineralized tissue. Latexin is expressed in articular cartilage from the early stages of post-traumatic OA; however, minerals were detected after latexin expression was up-regulated, indicating that its activity precedes and remains during the pathological mineralization of cartilage. Thus, our results contribute to the identification of molecules involved in the mineralization of articular chondrocytes.

Evaluating glial and neuronal blood biomarkers GFAP and UCH-L1 as gradients of brain injury in concussive, subconcussive and non-concussive trauma: a prospective cohort study.

OBJECTIVES: To evaluate the ability of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1) to detect concussion in children and adult trauma patients with a normal mental status and assess biomarker concentrations over time as gradients of injury in concussive and non-concussive head and body trauma. DESIGN: Large prospective cohort study. SETTING: Three level I trauma centres in the USA. PARTICIPANTS: Paediatric and adult trauma patients of all ages, with and without head trauma, presenting with a normal mental status (Glasgow Coma Scale score of 15) within 4 hours of injury. Rigorous screening for concussive symptoms was conducted. Of 3462 trauma patients screened, 751 were enrolled and 712 had biomarker data. Repeated blood sampling was conducted at 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 hours postinjury in adults. MAIN OUTCOMES: Detection of concussion and gradients of injury in children versus adults by comparing three groups of patients: (1) those with concussion; (2) those with head trauma without overt signs of concussion (non-concussive head trauma controls) and (3) those with peripheral (body) trauma without head trauma or concussion (non-concussive body trauma controls). RESULTS: A total of 1904 samples from 712 trauma patients were analysed. Within 4 hours of injury, there were incremental increases in levels of both GFAP and UCH-L1 from non-concussive body trauma (lowest), to mild elevations in non-concussive head trauma, to highest levels in patients with concussion. In concussion patients, GFAP concentrations were significantly higher compared with body trauma controls (p<0.001) and with head trauma controls (p<0.001) in both children and adults, after controlling for multiple comparisons. However, for UCH-L1, there were no significant differences between concussion patients and head trauma controls (p=0.894) and between body trauma and head trauma controls in children. The AUC for initial GFAP levels to detect concussion was 0.80 (0.73-0.87) in children and 0.76 (0.71-0.80) in adults. This differed significantly from UCH-L1 with AUCs of 0.62 (0.53-0.72) in children and 0.69 (0.64-0.74) in adults. CONCLUSIONS: In a cohort of trauma patients with normal mental status, GFAP outperformed UCH-L1 in detecting concussion in both children and adults. Blood levels of GFAP and UCH-L1 showed incremental elevations across three injury groups: from non-concussive body trauma, to non-concussive head trauma, to concussion. However, UCH-L1 was expressed at much higher levels than GFAP in those with non-concussive trauma, particularly in children. Elevations in both biomarkers in patients with non-concussive head trauma may be reflective of a subconcussive brain injury. This will require further study.

Oxidative Coupling with Zr(IV) Supported by a Noninnocent Anthracene-Based Ligand: Application to the Catalytic Cotrimerization of Alkynes and Nitriles to Pyrimidines.

We report the synthesis and reactivity of Zr complexes supported by a 9,10-anthracenediyl-linked bisphenoxide ligand, L. ZrIVLBn2 (1) undergoes facile photolytic reduction with concomitant formation of bibenzyl and ZrIVL(THF)3 (2), which displays a two-electron reduced anthracene moiety. Leveraging ligand-stored reducing equivalents, 2 promotes the oxidative coupling of internal and terminal alkynes to isolable zirconacyclopentadiene complexes, demonstrating the reversible utilization of anthracene as a redox reservoir. With diphenylacetylene under CO, cyclopentadienone is formed stoichiometrically. 2 is competent for the catalytic formation of pyrimidines from alkynes and nitriles. Mechanistic studies suggest that selectivity for pyrimidine originates from preferred formation of an azazirconacyclopentadiene intermediate, which reacts preferentially with nitriles over alkynes.

Ezrin and E-cadherin expression profile in cervical cytology: a prognostic marker for tumor progression in cervical cancer.

BACKGROUND: Cervical cancer (CC) is the fourth cause of mortality by neoplasia in women worldwide. The use of immunomarkers is an alternative tool to complement currently used algorithms for detection of cancer, and to improve selection of therapeutic schemes. Aberrant expression of Ezrin and E-cadherin play an important role in tumor invasion. In this study we analyzed Ezrin and E-cadherin expression in liquid-based cervical cytology samples, and evaluated their potential use as prognostic immunomarkers. METHODS: Immunocytochemical staining of Ezrin and E-cadherin was performed in cervical samples of 125 patients. The cytological or histological diagnostic was performed by Papanicolaou staining or H&E staining, respectively. HPV genotyping was determined using INNO-LIPA Genotyping Extra kit and the HPV physical status by in situ hybridization. Ezrin expression in HaCaT, HeLa and SiHa cell lines was determined by immunocytochemistry, immunofluorescence and Western blot. RESULTS: High Ezrin expression was observed in cervical cancer samples (70%), samples with multiple infection by HR-HPV (43%), and samples with integrated viral genome (47%). High Ezrin expression was associated with degree of SIL, viral genotype and physical status. In contrast, low E-cadherin expression was found in cervical cancer samples (95%), samples with multiple infection by HR-HPV/LR-HPV (87%) and integrated viral genome (72%). Low E-cadherin expression was associated with degree of SIL and viral genotype. Interestingly, Ezrin nuclear staining was associated with degree of SIL and viral genotype. High Ezrin expression, high percent of nuclear Ezrin and low E-cadherin expression behaved as risk factors for progression to HSIL and cervical cancer. CONCLUSIONS: Ezrin and E-cadherin expression profile in cervical cytology samples could be a potential prognostic marker, useful for identifying cervical lesions with a high-risk of progression to cervical cancer.

Neuronal Biomarker Ubiquitin C-Terminal Hydrolase Detects Traumatic Intracranial Lesions on Computed Tomography in Children and Youth with Mild Traumatic Brain Injury.

This study examined the performance of serum ubiquitin C-terminal hydrolase (UCH-L1) in detecting traumatic intracranial lesions on computed tomography (CT) scan (+CT) in children and youth with mild and moderate TBI (mmTBI) and assessed its performance in trauma control patients without head trauma. This prospective cohort study enrolled children and youth presenting to three level 1 trauma centers after blunt head trauma and a Glasgow Coma Scale (GCS) score of 9-15 as well as trauma control patients with GCS 15 that did not have blunt head trauma. The primary outcome measure was the presence of intracranial lesions on initial CT scan. Blood samples were obtained in all patients within 6 h of injury and measured by enzyme-linked immunosorbent assay ELISA for UCH-L1 (ng/mL). A total of 256 children and youth were enrolled in the study and had serum samples drawn within 6 h of injury for analysis; 196 had blunt head trauma and 60 were trauma controls. CT scan of the head was performed in 151 patients and traumatic intracranial lesions on CT scan were evident in 17 (11%), all of whom had a GCS of 13-15. The area under the receiver operating characteristic curve (AUC) for UCH-L1 in detecting children and youth with traumatic intracranial lesions on CT was 0.83 (95% confidence interval [CI], 0.73-0.93). In those presenting with a GCS of 15, the AUC for detecting lesions was 0.83 (95% CI, 0.72-0.94). Similarly, in children under 5 years of age, the AUC was 0.79 (95% CI, 0.59-1.00). Performance for detecting intracranial lesions at a UCH-L1 cut-off level of 0.18 ng/mL yielded a sensitivity of 100%, a specificity of 47%, and a negative predictive value of 100%. UCH-L1 showed good performance in infants and toddlers younger than 5 years and performed well in children and youth with a GCS score of 15. Before clinical application, further study in larger cohort of children and youth with mild TBI is warranted.