Modélisation des rayonnements direct et circumsolaire par ciel clair en environnement désertique

Routine measurements of the broadband direct normal irradiance (DNI), i.e. beam irradiance at normal incidence, by means of pyrheliometers or equivalent pyranometric systems include the irradiance originating from within the extent of the solar disc (DNIS) and that from a larger circumsolar region, called the circumsolar normal irradiance (CSNI). Such instruments have equivalent aperture half-angles between 2.5° and 5° which are one order of magnitude greater than the angular radius of the solar disc. The equivalent aperture half-angles of the concentrated solar powered systems are greater than the angular radius of the solar disc, but smaller than that of the measuring systems. Therefore, information on the CSNI should be provided for an improved assessment of the DNI. The objective of this PhD thesis is to contribute to an improved assessment of the beam and circumsolar radiation under cloud-free conditions in a desert environment. After selecting the aerosol optical properties of significance, the radiative transfer model libRadtran was used to model the CSNI and DNIS. A fast and simple parametric model which mimics the libRadtran values is proposed. This model uses standard measurements of the DNI and the diffuse horizontal irradiance as inputs to estimate the circumsolar ratio (CSR) for any aperture half-angle between 0.4° and 5°. The CSR is the ratio of the CSNI to the sum of the CSNI and the DNIS. Knowing the CSR and having the measured DNI, the CSNI and the DNIS can be computed.Les mesures de l'éclairement solaire direct reçu au sol en incidence normale (DNI) par des pyrhéliomètres ou instruments équivalents incluent l'éclairement provenant de l'angle solide du disque solaire (DNIS) et celui provenant d'une région angulaire circumsolaire plus large, appelé éclairement circumsolaire (CSNI). Les instruments ont des demi-angles d'ouverture équivalents variant entre 2,5° et 5°, soit un ordre de grandeur plus grand que le demi-angle du disque solaire. Quant aux demi-angles des systèmes de production d'énergie concentrant les rayons solaires, ils sont plus grands que le demi-angle du disque solaire, et plus petits que ceux des instruments. Par consequent, le CSNI doit être connu pour une estimation précise du DNI. Cette thèse contribue à la connaissance et à la modélisation des éclairements direct et circumsolaire en milieu désertique par conditions de ciel clair. Après avoir déterminé les propiétés optiques des aérosols les plus influentes, le modèle numérique de transfert radiatif libRadtran a été utilisé pour modéliser le CSNI et le DNIS. Un modèle paramétrique simplifié et très rapide a été développé qui reproduit les résultats de libRadtran. Il estime le ratio circumsolaire (CSR), soit le rapport entre le CSNI et la somme du CSNI et du DNIS, à partir de mesures standards du DNI et de l'éclairement diffus. A partir du DNI mesuré et de CSR modélisé, le CSNI et le DNIS peuvent être estimés pour tout demi-angle entre 0,4° et 5°. Le modèle a été validé pour deux stations de mesure, dans les Emirats Arabes Unis et en Algérie

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Modelling the beam and circumsolar radiation under cloud-free conditions in desert environment

Les mesures de l'éclairement solaire direct reçu au sol en incidence normale (DNI) par des pyrhéliomètres ou instruments équivalents incluent l'éclairement provenant de l'angle solide du disque solaire (DNIS) et celui provenant d'une région angulaire circumsolaire plus large, appelé éclairement circumsolaire (CSNI). Les instruments ont des demi-angles d'ouverture équivalents variant entre 2,5° et 5°, soit un ordre de grandeur plus grand que le demi-angle du disque solaire. Quant aux demi-angles des systèmes de production d'énergie concentrant les rayons solaires, ils sont plus grands que le demi-angle du disque solaire, et plus petits que ceux des instruments. Par consequent, le CSNI doit être connu pour une estimation précise du DNI. Cette thèse contribue à la connaissance et à la modélisation des éclairements direct et circumsolaire en milieu désertique par conditions de ciel clair. Après avoir déterminé les propiétés optiques des aérosols les plus influentes, le modèle numérique de transfert radiatif libRadtran a été utilisé pour modéliser le CSNI et le DNIS. Un modèle paramétrique simplifié et très rapide a été développé qui reproduit les résultats de libRadtran. Il estime le ratio circumsolaire (CSR), soit le rapport entre le CSNI et la somme du CSNI et du DNIS, à partir de mesures standards du DNI et de l'éclairement diffus. A partir du DNI mesuré et de CSR modélisé, le CSNI et le DNIS peuvent être estimés pour tout demi-angle entre 0,4° et 5°. Le modèle a été validé pour deux stations de mesure, dans les Emirats Arabes Unis et en Algérie.Routine measurements of the broadband direct normal irradiance (DNI), i.e. beam irradiance at normal incidence, by means of pyrheliometers or equivalent pyranometric systems include the irradiance originating from within the extent of the solar disc (DNIS) and that from a larger circumsolar region, called the circumsolar normal irradiance (CSNI). Such instruments have equivalent aperture half-angles between 2.5° and 5° which are one order of magnitude greater than the angular radius of the solar disc. The equivalent aperture half-angles of the concentrated solar powered systems are greater than the angular radius of the solar disc, but smaller than that of the measuring systems. Therefore, information on the CSNI should be provided for an improved assessment of the DNI. The objective of this PhD thesis is to contribute to an improved assessment of the beam and circumsolar radiation under cloud-free conditions in a desert environment. After selecting the aerosol optical properties of significance, the radiative transfer model libRadtran was used to model the CSNI and DNIS. A fast and simple parametric model which mimics the libRadtran values is proposed. This model uses standard measurements of the DNI and the diffuse horizontal irradiance as inputs to estimate the circumsolar ratio (CSR) for any aperture half-angle between 0.4° and 5°. The CSR is the ratio of the CSNI to the sum of the CSNI and the DNIS. Knowing the CSR and having the measured DNI, the CSNI and the DNIS can be computed

Investigating the Structural Dynamics of Therapeutic Proteins using Time resolved Hydrogen deuterium Exchange Mass Spectrometry

Biopharmaceutical products have drastically grown as essential treatments in clinical settings. Hence, the drug industry is moving towards protein-based therapeutics with increasing demands for parallel advancement in bioanalytical technologies. This thesis centers around displaying the versatility of coupling front-end analytical methods to mass spectrometers. We implement time-resolved electrospray ionization hydrogen-deuterium exchange (TRESI-HDX) and ion mobility spectroscopy (IMS) MS for uncovering new and exciting insights into therapeutic protein dynamics and protein-substrate interactions on millisecond timescale. Using automated continuous flow injection (CFI) has enhanced the analytical throughput of our results. Collectively, the implications for these results widen the fundamental understanding of the studied proteins. Understanding the crosstalk between dynamics and function may help scientists to design new and improved therapeutics

UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer

Abstract Background Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH). Methods Immunohistochemistry was used to characterize UGDH expression in histological and molecular subtypes of EOC. EOC cell lines were subtyped according to the molecular subtypes and the functional effects of modulating UGDH expression in vitro and in vivo in C1/Mesenchymal and C4/Differentiated subtype cell lines was examined. Results High UGDH expression was observed in high-grade serous ovarian cancers and a distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype. High UGDH was associated with a poor prognosis in the C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Knockdown of UGDH in the C1/mesenchymal molecular subtype reduced spheroid formation and viability and reduced the CD133 + /ALDH high TIC population. Conversely, overexpression of UGDH in the C4/Differentiated subtype reduced the TIC population. In co-culture models, UGDH expression in spheroids affected the gene expression of mesothelial cells causing changes to matrix remodeling proteins, and fibroblast collagen production. Inflammatory cytokine expression of spheroids was altered by UGDH expression. The effect of UGDH knockdown or overexpression in the C1/ Mesenchymal and C4/Differentiated subtypes respectively was tested on mouse intrabursal xenografts and showed dynamic changes to the tumor stroma. Knockdown of UGDH improved survival and reduced tumor burden in C1/Mesenchymal compared to controls. Conclusions These data show that modulation of UGDH expression in ovarian cancer reveals distinct roles for UGDH in the C1/Mesenchymal and C4/Differentiated molecular subtypes of EOC, influencing the tumor microenvironmental composition. UGDH is a strong potential therapeutic target in TICs, for the treatment of EOC, particularly in patients with the mesenchymal molecular subtype

KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma

Abstract Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers

SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck

Summary: Cancers often display immune escape, but the mechanisms are incompletely understood. Herein, we identify SMYD3 as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab. SMYD3 depletion induces upregulation of multiple type I interferon (IFN) response and antigen presentation machinery genes in HNSCC cells. Mechanistically, SMYD3 binds to and regulates the transcription of UHRF1, encoding for a reader of H3K9me3, which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1, and silences their expression. SMYD3 further maintains the repression of immune-related genes through intragenic deposition of H4K20me3. In vivo, Smyd3 depletion induces influx of CD8+ T cells and increases sensitivity to anti-programmed death 1 (PD-1) therapy. SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC