Catalytic Diastereo- and Enantioselective Vinylogous Mannich Reaction of Alkylidenepyrazolones to Isatin-Derived Ketimines

[EN] A valuable organocatalytic vinylogous Mannich reaction between alkylidenepyrazolones and isatin-derived ketimines has been successfully established. Squaramide organocatalyst, prepared from quinine, catalyzed the diastereo- and enantioselective vinylogous Mannich addition, affording a range of aminooxindole-pyrazolone adducts (24 examples) with excellent outcomes: up to 98% yield with complete diastereoselectivity and excellent enantioselectivity (up to 99% ee). Additionally, different synthetic transformations were performed with the chiral pyrazolone-oxindole adducts.Financial support from the Agencia Estatal de Investigacion (AEI, Spanish Government) and Fondo Europeo de Desarrollo Regional (FEDER, European Union) (PID2020-116944GB) and from Conselleria d'Innovacio, Universitat, Ciencia i Societat Digital (AICO/2020/68) is acknowledged. L.C.-F. thanks the Universitat de Valencia for a predoctoral grant. C.V. thanks the Spanish Government for a RyC contract (RYC2016-20187). Access to the NMR, MS, and X-ray facilities from the Servei Central de Suport a la Investigacio Experimental (SCSIE)-UV is also acknowledged.Carceller-Ferrer, L.; Vila, C.; Blay, G.; Muñoz Roca, MDC.; Pedro, JR. (2021). Catalytic Diastereo- and Enantioselective Vinylogous Mannich Reaction of Alkylidenepyrazolones to Isatin-Derived Ketimines. Organic Letters. 23(19):7391-7395. https://doi.org/10.1021/acs.orglett.1c0257173917395231

The effect of a centenary storm on the long-lived seagrass Posidonia oceanica

We used the disturbance resulting from a once in a 100‐yr storm on the northwest Mediterranean coast to examine the extent of the disturbance, the tolerance thresholds to burial, and the medium‐term response of the long‐lived Posidonia oceanica seagrass. Sediment burial at 12 surveyed areas was particularly strong in shallow meadows, with 23% of their surfaces buried, on average, under more than 10 cm of sediment. In contrast, less than 5% of the meadow was affected at deeper locations. At three sites, we tracked short‐term mortality along a gradient of sediment burial. Survival response to burial was clearly nonlinear, with a significant threshold at 4-5 cm, beyond which shoot mortality was 100%. To track medium‐term potential recovery, we established permanent plots subject to three sediment burial levels (0-5, 5-10, and > 10 cm burial) in four meadows. Where the initial shoot mortality was 100%, we recorded no shoot recovery over the 4‐yr period. In the remaining plots, where some shoots remained alive, we detected either further mortality or shoot recovery of 7% per year on average. Extreme storm events can result in sudden catastrophic losses of seagrass cover in shallow P. oceanica meadows. In the long term and due to the long return time of such storms, the species may still be able to recover despite its low recovery potential. However, added anthropogenic stressors, including climate change, may seriously test the ability of long‐lived shallow seagrass ecosystems to resist high‐intensity natural disturbances and may be critical for its persistence

Treatment of subclinical hyperthyroidism: Effect on body composition

Background: subclinical hyperthyroidism (SHT) is associated with harmful effects on cardiovascular system, bone metabolism and progression to clinical hyperthyroidism. Loss of weight is a common fact in patients with clinical hyperthyroidism and of particular relevance in elderly patients. Objective: to assess changes in body composition after radioiodine therapy for SHT due to toxic nodular goiter. Subjects and methods: prospective controlled cohort study. Patients with persistent SHT due to toxic nodular goiter were purposed to receive treatment with radioiodine (treatment group) or to delay treatment until the study was over (control group). All treated patients received 555 MBq of 131I. Body composition (lean mass, fat mass and bone mineral content) was determined by dual-energy X-ray absorptiometry (DEXA) at baseline and 12 months after. Results: twenty-nine patients were studied (age 69.5 ± 11.5; 75.9% women; BMI 27.1 ± 5.7 kg/m²; serum thyrotropin (TSH) 0.20 ± 0.21 µUI/mL; serum free thyroxine (T4) 1.01 ± 0.19 ng/dL), 17 belonging to the treatment group and 12 to the control group. Study groups were comparable, although there was a trend for the treatment group to have more fat mass. No longitudinal changes in body composition were noted in either group, except for a trend to gain fat mass. However, when individuals with age > 65 years were selected, only patients who received radioiodine therapy showed a significant increase in body weight (from 64.1 ± 10.0 to 66.9 ± 9.2 kg), BMI (from 27.3 ± 4.8 to 28.7 ± 4.5 kg/m²), fat mass (from 26.1 ± 8.5 to 27.8 ± 7.9 kg), lean mass (from 36.3 ± 0.4 to 37.4 ± 0.4 kg) and skeletal muscle mass index (SMI) (from 6.0 ± 0.6 to 6.3 ± 0.6 kg/m²). Conclusions: treatment of SHT has impact on body composition in subjects older than 65 years. Weight gain reflects increases in fat and, more interestingly, in lean mass

New considerations for PM, black carbon and particle number concentration for air quality monitoring across different European cities

In many large cities of Europe standard air quality limit values of particulate matter (PM) are exceeded. Emissions from road traffic and biomass burning are frequently reported to be the major causes. As a consequence of these exceedances a large number of air quality plans, most of them focusing on traffic emissions reductions, have been implemented in the last decade. In spite of this implementation, a number of cities did not record a decrease of PM levels. Thus, is the efficiency of air quality plans overestimated? Do the road traffic emissions contribute less than expected to ambient air PM levels in urban areas? Or do we need a more specific metric to evaluate the impact of the above emissions on the levels of urban aerosols? This study shows the results of the interpretation of the variability of levels of PM, Black Carbon (BC), aerosol number concentration (N) and a number of gaseous pollutants in seven selected urban areas covering road traffic, urban background, urban-industrial, and urban-shipping environments from southern, central and northern Europe. The results showed that variations of PM and N levels do not always reflect the variation of the impact of road traffic emissions on urban aerosols. However, BC levels vary proportionally with those of traffic related gaseous pollutants, such as CO, NO₂ and NO. Due to this high correlation, one may suppose that monitoring the levels of these gaseous pollutants would be enough to extrapolate exposure to traffic-derived BC levels. However, the BC/CO, BC/NO₂ and BC/NO ratios vary widely among the cities studied, as a function of distance to traffic emissions, vehicle fleet composition and the influence of other emission sources such as biomass burning. Thus, levels of BC should be measured at air quality monitoring sites. During morning traffic rush hours, a narrow variation in the N/BC ratio was evidenced, but a wide variation of this ratio was determined for the noon period. Although in central and northern Europe N and BC levels tend to vary simultaneously, not only during the traffic rush hours but also during the whole day, in urban background stations in southern Europe maximum N levels coinciding with minimum BC levels are recorded at midday in all seasons. These N maxima recorded in southern European urban background environments are attributed to midday nucleation episodes occurring when gaseous pollutants are diluted and maximum insolation and O₃ levels occur. The occurrence of SO₂ peaks may also contribute to the occurrence of midday nucleation bursts in specific industrial or shipping-influenced areas, although at several central European sites similar levels of SO₂ are recorded without yielding nucleation episodes. Accordingly, it is clearly evidenced that N variability in different European urban environments is not equally influenced by the same emission sources and atmospheric processes. We conclude that N variability does not always reflect the impact of road traffic on air quality, whereas BC is a more consistent tracer of such an influence. However, N should be measured since ultrafine particles (<100 nm) may have large impacts on human health. The combination of PM₁₀ and BC monitoring in urban areas potentially constitutes a useful approach for air quality monitoring. BC is mostly governed by vehicle exhaust emissions, while PM₁₀ concentrations at these sites are also governed by non-exhaust particulate emissions resuspended by traffic, by midday atmospheric dilution and by other nontraffic emissions

New considerations for PM, Black Carbon and particle number concentration for air quality monitoring across different European cities

In many large cities of Europe standard air quality limit values of particulate matter (PM) are exceeded. Emissions from road traffic and biomass burning are frequently reported to be the major causes. As a consequence of these exceedances a large number of air quality plans, most of them focusing on traffic emissions reductions, have been implemented in the last decade. In spite of this implementation, a number of cities did not record a decrease of PM levels. Thus, is the efficiency of air quality plans overestimated? Do the road traffic emissions contribute less than expected to ambient air PM levels in urban areas? Or do we need a more specific metric to evaluate the impact of the above emissions on the levels of urban aerosols? This study shows the results of the interpretation of the 2009 variability of levels of PM, Black Carbon (BC), aerosol number concentration (N) and a number of gaseous pollutants in seven selected urban areas covering road traffic, urban background, urban-industrial, and urban-shipping environments from southern, central and northern Europe. The results showed that variations of PM and N levels do not always reflect the variation of the impact of road traffic emissions on urban aerosols. However, BC levels vary proportionally with those of traffic related gaseous pollutants, such as CO, NO2 and NO. Due to this high correlation, one may suppose that monitoring the levels of these gaseous pollutants would be enough to extrapolate exposure to traffic-derived BC levels. However, the BC/CO, BC/NO2 and BC/NO ratios vary widely among the cities studied, as a function of distance to traffic emissions, vehicle fleet composition and the influence of other emission sources such as biomass burning. Thus, levels of BC should be measured at air quality monitoring sites. During morning traffic rush hours, a narrow variation in the N/BC ratio was evidenced, but a wide variation of this ratio was determined for the noon period. Although in central and northern Europe N and BC levels tend to vary simultaneously, not only during the traffic rush hours but also during the whole day, in urban background stations in southern Europe maximum N levels coinciding with minimum BC levels are recorded at midday in all seasons. These N maxima recorded in southern European urban background environments are attributed to midday nucleation episodes occurring when gaseous pollutants are diluted and maximum insolation and O3 levels occur. The occurrence of SO2 peaks may also contribute to the occurrence of midday nucleation bursts in specific industrial or shipping-influenced areas, although at several central European sites similar levels of SO2 are recorded without yielding nucleation episodes. Accordingly, it is clearly evidenced that N variability in different European urban environments is not equally influenced by the same emission sources and atmospheric processes. We conclude that N variability does not always reflect the impact of road traffic on air quality, whereas BC is a more consistent tracer of such an influence. However, N should be measured since ultrafine particles (<100 nm) may have large impacts on human health. The combination of PM10 and BC monitoring in urban areas potentially constitutes a useful approach for air quality monitoring. BC is mostly governed by vehicle exhaust emissions, while PM10 concentrations at these sites are also governed by non-exhaust particulate emissions resuspended by traffic, by midday atmospheric dilution and by other non-traffic emissions

Organocatalytic Enantioselective Aminoalkylation of Pyrazol-3-ones with Aldimines Generated in Situ from α‐Amido Sulfones

Herein, an efficient asymmetric aminoalkylation of pyrazolones with α-amido sulfones catalyzed by a quinine-derived squaramide in dichloromethane/aqueous media has been established. A variety of chiral amines were obtained with high yields (up to 98%) and excellent enantioselectivities (up to 99% ee). The corresponding products are transformed into optically active acetylated pyrazoles after treatment with Ac2O/Et3N, because of the instability of some adducts. The reaction tolerates a wide range of α-amido sulfones and different pyrazolones

Hughes Abdominal Repair Trial (HART) – Abdominal wall closure techniques to reduce the incidence of incisional hernias: study protocol for a randomised controlled trial

Background Incisional hernias are common complications of midline closure following abdominal surgery and cause significant morbidity, impaired quality of life and increased health care costs. The ‘Hughes Repair’ combines a standard mass closure with a series of horizontal and two vertical mattress sutures within a single suture. This theoretically distributes the load along the incision length as well as across it. There is evidence to suggest that this technique is as effective as mesh repair for the operative management of incisional hernias; however, no trials have compared the Hughes Repair with standard mass closure for the prevention of incisional hernia formation following a midline incision. Methods/design This is a 1:1 randomised controlled trial comparing two suture techniques for the closure of the midline abdominal wound following surgery for colorectal cancer. Full ethical approval has been gained (Wales REC 3, MREC 12/WA/0374). Eight hundred patients will be randomised from approximately 20 general surgical units within the United Kingdom. Patients undergoing open or laparoscopic (more than a 5-cm midline incision) surgery for colorectal cancer, elective or emergency, are eligible. Patients under the age of 18 years, those having mesh inserted or undergoing musculofascial flap closure of the perineal defect in abdominoperineal wound closure, and those unable to give informed consent will be excluded. Patients will be randomised intraoperatively to either the Hughes Repair or standard mass closure. The primary outcome measure is the incidence of incisional hernias at 1 year as assessed by standardised clinical examination. The secondary outcomes include quality of life patient-reported outcome measures, cost-utility analysis, incidence of complete abdominal wound dehiscence and C-POSSUM scores. The incidence of incisional hernia at 1 year, assessed by computerised tomography, will form a tertiary outcome. Discussion A feasibility phase has been completed. The results of the study will be used to inform current and future practice and potentially reduce the risk of incisional hernia formation following midline incisions

Phenomenology of high-ozone episodes in NE Spain

Ground-level and vertical measurements (performed using tethered and non-tethered balloons), coupled with modelling, of ozone (O3), other gaseous pollutants (NO, NO2, CO, SO2) and aerosols were carried out in the plains (Vic Plain) and valleys of the northern region of the Barcelona metropolitan area (BMA) in July 2015, an area typically recording the highest O3 episodes in Spain. Our results suggest that these very high O3 episodes were originated by three main contributions: (i) the surface fumigation from high O3 reservoir layers located at 1500-3000 m a.g.l. (according to modelling and non-tethered balloon measurements), and originated during the previous day(s) injections of polluted air masses at high altitude; (ii) local/regional photochemical production and transport (at lower heights) from the BMA and the surrounding coastal settlements, into the inland valleys; and (iii) external (to the study area) contributions of both O3 and precursors. These processes gave rise to maximal O3 levels in the inland plains and valleys northwards from the BMA when compared to the higher mountain sites. Thus, a maximum O3 concentration was observed within the lower tropospheric layer, characterised by an upward increase of O3 and black carbon (BC) up to around 100-200 m a.g.l. (reaching up to 300 µg m−3 of O3 as a 10 s average), followed by a decrease of both pollutants at higher altitudes, where BC and O3 concentrations alternate in layers with parallel variations, probably as a consequence of the atmospheric transport from the BMA and the return flows (to the sea) of strata injected at certain heights the previous day(s). At the highest altitudes reached in this study with the tethered balloons (900-1000 m a.g.l.) during the campaign, BC and O3 were often anti-correlated or unrelated, possibly due to a prevailing regional or even hemispheric contribution of O3 at those altitudes. In the central hours of the days a homogeneous O3 distribution was evidenced for the lowest 1 km of the atmosphere, although probably important variations could be expected at higher levels, where the high O3 return strata are injected according to the modelling results and non-tethered balloon data. Relatively low concentrations of ultrafine particles (UFPs) were found during the study, and nucleation episodes were only detected in the boundary layer. Two types of O3 episodes were identified: type A with major exceedances of the O3 information threshold (180 µg m−3 on an hourly basis) caused by a clear daily concatenation of local/regional production with accumulation (at upper levels), fumigation and direct transport from the BMA (closed circulation); and type B with regional O3 production without major recirculation (or fumigation) of the polluted BMA/regional air masses (open circulation), and relatively lower O3 levels, but still exceeding the 8 h averaged health target. To implement potential O3 control and abatement strategies two major key tasks are proposed: (i) meteorological forecasting, from June to August, to predict recirculation episodes so that NOx and VOC abatement measures can be applied before these episodes start; (ii) sensitivity analysis with high-resolution modelling to evaluate the effectiveness of these potential abatement measures of precursors for O3 reduction

Outcome of children and adolescents with central nervous system tumors in phase I trials

Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged < 18 years at enrollment in their first dose-finding trial between 2000 and 2014 at eight ITCC centers were included retrospectively. Survival was evaluated using univariate/multivariate analyses. Overall, 114 patients were included (109 evaluable for efficacy). Median age was 10.2 years (range 1.0-17.9). Main diagnoses included: medulloblastoma/primitive neuroectodermal tumors (32.5%) and high-grade gliomas (23.7%). Complete/partial responses (CR/PR) were reported in 7.3% patients and stable disease (SD) in 23.9%. Performance status of 90-100%, school/work attendance, normal ALT/AST and CR/PR/SD correlated with better overall survival (OS) in the univariate analysis. No variables assessable at screening/enrollment were associated with OS in the multivariate analysis. Five patients (4.5%) were discontinued from study due to toxicity. No toxic deaths occurred. Median OS was 11.9 months with CR/PR, 14.5 months with SD and 3.7 months with progressive disease (p < 0.001). The enrollment of children and adolescents with CNS tumors in phase I trials is feasible, safe and offers potential benefit for the patients. Sustained disease stabilization has a promising role as a marker of anti-tumor activity in children with CNS tumors participating in phase I trials