What\u27s in a Kiss

Title with red borderhttps://scholarsjunction.msstate.edu/cht-sheet-music/2440/thumbnail.jp

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Evaluation and application of dye tracing in a karst terrain

The purpose of this investigation was to select and evaluate in the laboratory a tracing method appropriate for use in karstic areas, and to perform field tracing studies in the south central Missouri area bounded by the cities of Rolla, St. James, and Salem in an attempt to establish existing direct flow connections between surface and subsurface waters. Fluorescein (sodium salt), Rhodamine WT, and Rhodamine B were evaluated as tracers in the laboratory and the first two dyes were employed in the field. After careful evaluation of a number of adsorbents, extracting solvents, and detection techniques, a method consisting of concentration of the dye on packets of activated carbon, extraction with a 5 per cent alkali-ethanol solvent, and detection by means of a fluorometer was selected for use in field tracing studies. Ammonium and potassium hydroxide were most appropriate for the extraction of Rhodamine WT and fluorescein, respectively. Fluorescent background material present in the streams and springs of the south central Missouri study area did not interfere with the fluorometric detection of the dyes. A direct or partially direct subsurface connection 6 to 10 miles long was established between the segment of the Dry Fork Creek located in sections 14 and 23, T.36N., R.7W., of Phelps County and the section of the creek contained between Route F and Highway 68. The rate of subsurface flow in this channel was estimated to be in the range of 1.2 to 4.1 feet per minute at a slope of 6.7 to 12.0 feet per mile --Abstract, page ii

Evaluation and application of dye tracing in a karst terrain

The purpose of this investigation was to select and evaluate in the laboratory a tracing method appropriate for use in karstic areas, and to perform field tracing studies in the south central Missouri area bounded by the cities of Rolla, St. James, and Salem in an attempt to establish existing direct flow connections between surface and subsurface waters. Fluorescein (sodium salt), Rhodamine WT, and Rhodamine B were evaluated as tracers in the laboratory and the first two dyes were employed in the field. After careful evaluation of a number of adsorbents, extracting solvents, and detection techniques, a method consisting of concentration of the dye on packets of activated carbon, extraction with a 5 per cent alkali-ethanol solvent, and detection by means of a fluorometer was selected for use in field tracing studies. Ammonium and potassium hydroxide were most appropriate for the extraction of Rhodamine WT and fluorescein, respectively. Fluorescent background material present in the streams and springs of the south central Missouri study area did not interfere with the fluorometric detection of the dyes. A direct or partially direct subsurface connection 6 to 10 miles long was established between the segment of the Dry Fork Creek located in sections 14 and 23, T.36N., R.7W., of Phelps County and the section of the creek contained between Route F and Highway 68. The rate of subsurface flow in this channel was estimated to be in the range of 1.2 to 4.1 feet per minute at a slope of 6.7 to 12.0 feet per mile --Abstract, page ii

Ansätze zur Entwicklung und Charakterisierung von Inhibitoren gegen die Serinprotease Thrombin, die Dengue-Virus-Protease und die bakterielle RNase P

Im Rahmen dieser Arbeit wurden drei Projekte auf Grundlage unterschiedlicher Vorarbeiten realisiert. Dabei kamen in allen drei Projekten die Methoden des rationalen Wirkstoffdesigns zur Anwendung. Im ersten Teilprojekt wurde eine Fragmentbibliothek aus 96 verschiedenen Kleinmolekülen gegen die Serinprotease Thrombin gescreent. Sieben verschiedene Fragmentmoleküle konnten anschließend ihrer komplementären Elektronendichte in den Röntgenstrukturen zugeordnet und ihre Bindungsmodi evaluiert werden. Das entspricht einer Trefferquote von 7.3%. Im Zuge der Evaluation wurde festgestellt, dass die Fragmente die Spezifitätstaschen (S1-S4) der Protease adressieren. Außerdem wurden zielgerichtete Interaktionen mit den katalytisch akti-ven Aminosäuren im Falle der Fragmente J77, J80 und J89 identifiziert. Des Weiteren konn-ten Beiträge zum Verständnis der selektivitätsbestimmenden Charakteristika zwischen den Serinproteasen Trypsin und Thrombin abgeleitet werden. Die Serinprotease Thrombin nimmt eine Schlüsselfunktion in der Blutgerinnungskaskade ein und die Inhibition wird vor allem zur Behandlung des Vorhofkammerflimmerns oder der Prävention von Schlaganfällen ange-strebt. So können die identifizierten Fragmentmoleküle als Startpunkt für die Entwicklung neuer Inhibitoren mit verbesserter Bioverfügbarkeit, Selektivität und Wirksamkeit dienen. Außerdem lassen sich die gewonnenen Erkenntnisse auf die Entwicklung von Inhibitoren gegen Serinproteasen mit ähnlichem Faltungsmuster übertragen. Da bis heute keine spezifische therapeutische Behandlung des Denguefiebers, eine durch Arthropoden übertragene Krankheit, zur Verfügung steht beschäftigt sich diese Arbeit im zweiten Teilprojekt mit der Entwicklung und Evaluation von allosterischen Inhibitoren gegen die Dengue-Virus-Protease (Serotyp 3). Aufbauend auf einem in silico docking wurden 15 verschiedenen Verbindungen erworben und mittels fluoreszenzbasiertem Enzym-Assay getes-tet. Die wirksamste dieser Verbindungen (KMH14, IC50=136±16 μM) zeigte einen nicht-kompetitiven Bindungsmodus und die Kernstruktur wurde als Ausgangspunkt für anschlie-ßende Designzyklen verwendet. Im zweiten Zyklus wurden 17 weitere Verbindungen, die auf dem Kernmotiv von KMH14 aufbauen, in vitro getestet. Die potenteste Verbindung (KMD027, IC50=28±7.9 μM) zeigte eine signifikant erhöhte Aktivität gegen die Dengue-Virus-Protease (Serotyp 3) und ein allgemeines Strukturmotiv für die allosterische Inhibition konnte daraus abgeleitet werden. Im letzten Designzyklus wurde so die Aktivität mittels ge-zielter SAR-Studie auf IC50=12.3±3.5 μM gesteigert. Begleitend wurde versucht, die identifi-zierten Verbindungen kristallographisch zu untersuchen. Dabei gelang es, die Kristallisation in unserem Kristalllabor zu etablieren und stabile soaking-Bedingungen zu identifizieren. Zusätzlich wurde ein binäres Zika-Virus-Konstrukt mutiert, um die Bindetasche zu vergrö-ßern und eine kristallographische Untersuchung der entwickelten Dengue-Virus-Inhibitoren zu ermöglichen. Außerdem konnte eine geringe Zytotoxizität der Liganden ermittelt werden. Alles in allem stellen die Untersuchungen des zweiten Teils dieser Arbeit einen sehr guten Ausgangspunkt für die Entwicklung weiterer potenter Inhibitoren gegen die Dengue-Virus-Protease dar. Der dritte und letzte Teil dieser Arbeit diente der Identifizierung neuer Ansatzpunkte für die Entwicklung von antibiotisch wirksamen Substanzen. Dafür wurde als neues target das P-Protein der RNase P ausgewählt. Da durch Resistenzentwicklungen der Bakterien und fehlen-de Entwicklung neuer Antibiotika eine Zunahme von Infektionskrankheiten mit Todesfolge droht, ist auch hier die Entwicklung von neuartigen Wirkstoffen ein Ziel der Arzneimittelfor-schung. Zunächst wurde das P-Protein der RNase P des pathogenen Organismus Mycobac-terium ulcerans erfolgreich isoliert und mit hoher Ausbeute aufgereinigt. Außerdem wurden Versuche unternommen dieses Protein zu kristallisieren und erste Bedingungen konnten identifiziert werden. Ein bereits literaturbekannter Inhibitor der RNase P konnte in weiteren Experimenten als PAIN (Pan-Assay Interference Compound) identifiziert und dessen postu-lierte Reaktion als Aggregation aufgeklärt werden. Somit ist eine auf falschen Messdaten beru-hende Wirkstoffentwicklung nicht mehr möglich. Zusätzlich können neue Inhibitoren auf-bauend auf den Vorarbeiten entwickelt werden

On a cold winter\u27s ev\u27ning, when bus\u27ness is done, [first line]

Performance Medium: Piano and Voice (with lyrics

Peek-a-boo! Peek-a-boo! Come from behind the chair; [first line of chorus]

Performers: Wm. J. ScanlanPiano and Voice (with lyrics