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This is a retrospective analysis of Fabry Outcome Survey data from children/adults (n = 677) receiving agalsidase alfa enzyme replacement therapy for a median of 3 years, examining cerebrovascular, cardiac, and renal morbidity endpoints separately. Cardiac events occurred at younger ages than cerebrovascular or renal events, cerebrovascular events were more frequent in females than males, and males were more likely to experience cardiac and renal events at a younger age than females.

Metastases to the skeletal system are commonly observed in cancer patients, highly affecting the patients' quality of life. Imaging plays a major role in detection, follow-up, and molecular characterisation of metastatic disease. Thus, imaging techniques have been optimised and combined in a multimodal and multiparametric manner for assessment of complementary aspects in osseous metastases. This review summarises both application of the most relevant imaging techniques for bone metastasis in preclinical models and the clinical setting.

Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR

We here present a database of evidence on the impact of agricultural management practices on biodiversity and yield. This database is the result of a systematic literature review, that aimed to identify meta-analyses that use as their response variables any measure of biodiversity and yield. After screening more than 1,086 titles and abstracts, we identified 33 relevant meta-analyses, from which we extracted the overall estimates, the subgroup estimates as well as all information related to them (effect size metric, taxonomic group, crop type etc.). We also extracted information relative to the empirical studies used for each meta-analysis and recorded the countries in which they took place and assessed the quality of each meta-analysis. Our dataset is publicly accessible and can be used for conducting second-order meta-analyses on the effect of management measures on species richness, taxon abundance, biomass and yields. It can also be used to create evidence maps on agriculture-related questions.

Acute myelogenous leukemia (AML) is a heterogeneous disease and often relapses after standard chemotherapy. Recently, the neddylation (NEDD8) and the mammalian target of rapamycin (mTOR) signaling pathways have emerged as promising pharmaceutical targets for AML therapy. However, the interaction of these two pathways remains unclear. Here we evaluated the effects of pevonedistat, an inhibitor of the NEDD8 activating enzyme (NAE), and sapanisertib (TAK-228), an inhibitor of mTORC1 and mTORC2 as single agents or in combination on AML cell lines. We found that inhibition of neddylation with pevonedistat partially inhibited mTOR signaling transduction and vice versa, inhibition of mTOR signaling with sapanisertib partially inhibited neddylation in AML cell lines. Pevonedistat alone was able to induce cytotoxicity in most AML cell lines as well as in primary AML, whereas sapanisertib alone decreased cell metabolic activity, reduced cell size and arrested cells in G0 phase with only minimal induction of cell death. In addition, pevonedistat was able to induce cell differentiation, arrest cells in G2/M cell cycle phases, and induce DNA re-replication and damage. However, co-treatment with sapanisertib suppressed pevonedistat induced apoptosis, differentiation, S/G2/M arrest, and DNA damage. Taken together, our data demonstrate that pevonedistat and sapanisertib exhibit distinct anti-tumor effects on AML cells, i.e. cytotoxic and cytostatic effects, respectively; however, sapanisertib can attenuate pevonedistat-induced cellular responses in AML cells. Understanding mTOR and neddylation pathway interaction could provide therapeutic strategies for treatment of AML and other malignancies.

Nitrogen Dioxide (NO2) is a major atmospheric pollutant which is produced from a variety of anthropogenic sources, notably vehicular emissions. High NO2 concentrations are found in and around the urban environment and as such pose a significant threat to human health. Diffusion tube surveys of NO2 concentrations were carried out at a variety of intersections and road layouts over a 3-month period in 2017. This study identified that ‘hotspots’ in NO2 concentrations frequently occurred in sections of road where vehicles are accelerating or queueing. Under these conditions, concentrations were elevated by 58.6% and 52.6% respectively compared to when vehicles were cruising. Analysis of environmental factors which influence NO2 concentrations show that meteorology, topography, traffic volume and driver behaviour all contribute. The results highlight the complexity of monitoring hotspot locations and show the need for traffic and driver behaviour to be included in vehicle emission models. Additionally, the investigation suggests need for caution when relying on in-situ monitors to determine pollutant exceedances as there is shown to be substantial variation along a street and the location of the monitor is critical. Keywords: Nitrogen dioxide, Urban air pollution, Driver behaviour, Vehicle emissions, Street canyon

Study Objective: To assess the efficacy of a superior hypogastric plexus nerve block in reducing opioid requirements in the first 24 hours after minimally invasive gynecologic surgery., Design: Patient-blinded randomized controlled trial., Setting: Single-center academic institution (Sydney Women's Endosurgery Centre). Two surgeons administering the blocks in their own surgeries., Patients: Patients undergoing either laparoscopic or robot-assisted laparoscopic hysterectomy or myomectomy for benign indications., Interventions: Ropivacaine 10 mL (0.75%) infiltrated into the retroperitoneal space overlying the superior hypogastric plexus vs control of no block given at the completion of surgery., Measurements and Main Results: The primary outcome was the total opioid use in the first 24 hours after surgery, measured in morphine milligram equivalents (MME). Standardized fentanyl patient-controlled analgesia was given to all patients in the trial. The secondary outcome was pain measured on a visual analog scale (1 to 10) at 1, 2, 6, 12, and 24 hours after surgery. Fifty patients out of 56 approached for the study participated in, and completed, the study (89.2%). The patients were randomized over a 5-month period, March 2020 to July 2020. A total of 27 patients were randomized to receive a nerve block, and 23 were randomized to the control. There was a difference of -21.8 MME in the block group compared with the no-block group (95% confidence interval [CI], -38.2 to -5.5; p = .008). This correlated to a 38% reduction in opioid use in the block group. The mean opioid use in the patients in the block group was 33.1 MME (95% CI, 24.2-41.9) and in those in the no-block group 54.9 MME (95% CI, 40.7-69.1). For the block group, opioid use ranged from 1.0 to 76.5 MME, with an interquartile range of 37 (14-51). For the control group, the range was 7.5 to 113.5 MME, with a higher interquartile range of 60 (28-88). Pairwise comparisons of the mean pain scores over the 24 hours showed a lower pain score with a nerve block of 1.8 (95% CI, 1.5-2.1) compared with a no-block score of 2.6 (95% CI, 2.3-2.9) No adverse effects of local anesthetic toxicity, nerve injury, or bowel/vascular injury were noted in any patient., Conclusion: A superior hypogastric plexus nerve block is a simple technique for reducing postoperative opioid requirements and pain in the first 24 hours after minimally invasive gynecologic surgery., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)