The identification of molecular targets and the growing knowledge of their cellular functions have led to the development of small molecule inhibitors as a major therapeutic class for cancer ...treatment. Both multitargeted and highly selective kinase inhibitors are used for the treatment of advanced treatment-resistant cancers, and many have also achieved regulatory approval for early clinical settings as adjuvant therapies or as first-line options for recurrent or metastatic disease. Lessons learned from the development of these agents can accelerate the development of next-generation inhibitors to optimise the therapeutic index, overcome drug resistance, and establish combination therapies. The future of small molecule inhibitors is promising as there is the potential to investigate novel difficult-to-drug targets, to apply predictive non-clinical models to select promising drug candidates for human evaluation, and to use dynamic clinical trial interventions with liquid biopsies to deliver precision medicine.
Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Ocean Engineering, 1994, and Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 1994.
Includes ...bibliographical references (leaves 120-123).
Abstract
We report on the discovery of a new fast radio burst (FRB), FRB 150215, with the Parkes radio telescope on 2015 February 15. The burst was detected in real time with a dispersion measure ...(DM) of 1105.6 ± 0.8 pc cm−3, a pulse duration of 2.8
$^{+1.2}_{-0.5}$
ms, and a measured peak flux density assuming that the burst was at beam centre of 0.7
$^{+0.2}_{-0.1}$
Jy. The FRB originated at a Galactic longitude and latitude of 24.66°, 5.28° and 25° away from the Galactic Center. The burst was found to be 43 ± 5 per cent linearly polarized with a rotation measure (RM) in the range −9 < RM < 12 rad m−2 (95 per cent confidence level), consistent with zero. The burst was followed up with 11 telescopes to search for radio, optical, X-ray, γ-ray and neutrino emission. Neither transient nor variable emission was found to be associated with the burst and no repeat pulses have been observed in 17.25 h of observing. The sightline to the burst is close to the Galactic plane and the observed physical properties of FRB 150215 demonstrate the existence of sight lines of anomalously low RM for a given electron column density. The Galactic RM foreground may approach a null value due to magnetic field reversals along the line of sight, a decreased total electron column density from the Milky Way, or some combination of these effects. A lower Galactic DM contribution might explain why this burst was detectable whereas previous searches at low latitude have had lower detection rates than those out of the plane.
Summary
Identification of high‐risk patients admitted to intensive care with COVID‐19 may inform management strategies. The objective of this meta‐analysis was to determine factors associated with ...mortality among adults with COVID‐19 admitted to intensive care by searching databases for studies published between 1 January 2020 and 6 December 2020. Observational studies of COVID‐19 adults admitted to critical care were included. Studies of mixed cohorts and intensive care cohorts restricted to a specific patient sub‐group were excluded. Dichotomous variables were reported with pooled OR and 95%CI, and continuous variables with pooled standardised mean difference (SMD) and 95%CI. Fifty‐eight studies (44,305 patients) were included in the review. Increasing age (SMD 0.65, 95%CI 0.53–0.77); smoking (OR 1.40, 95%CI 1.03–1.90); hypertension (OR 1.54, 95%CI 1.29–1.85); diabetes (OR 1.41, 95%CI 1.22–1.63); cardiovascular disease (OR 1.91, 95%CI 1.52–2.38); respiratory disease (OR 1.75, 95%CI 1.33–2.31); renal disease (OR 2.39, 95%CI 1.68–3.40); and malignancy (OR 1.81, 95%CI 1.30–2.52) were associated with mortality. A higher sequential organ failure assessment score (SMD 0.86, 95%CI 0.63–1.10) and acute physiology and chronic health evaluation‐2 score (SMD 0.89, 95%CI 0.65–1.13); a lower PaO2:FIO2 (SMD −0.44, 95%CI −0.62 to −0.26) and the need for mechanical ventilation at admission (OR 2.53, 95%CI 1.90–3.37) were associated with mortality. Higher white cell counts (SMD 0.37, 95%CI 0.22–0.51); neutrophils (SMD 0.42, 95%CI 0.19–0.64); D‐dimers (SMD 0.56, 95%CI 0.43–0.69); ferritin (SMD 0.32, 95%CI 0.19–0.45); lower platelet (SMD −0.22, 95%CI −0.35 to −0.10); and lymphocyte counts (SMD −0.37, 95%CI −0.54 to −0.19) were all associated with mortality. In conclusion, increasing age, pre‐existing comorbidities, severity of illness based on validated scoring systems, and the host response to the disease were associated with mortality; while male sex and increasing BMI were not. These factors have prognostic relevance for patients admitted to intensive care with COVID‐19.
Desmopressin is frequently used perioperatively in persons with nonsevere hemophilia A. However, increase in factor (F)VIII:C after desmopressin use is interindividually highly variable. ...Tachyphylaxis has only been reported in test setting for persons with hemophilia A, with a remaining response of approximately 70% after a second dose compared with that after a first dose.
To study tachyphylaxis of FVIII:C response after multiple administration(s) of desmopressin in perioperative persons with nonsevere hemophilia A.
We studied FVIII:C levels after desmopressin before (day 0 D0) and on days 1 (D1) and 2 (D2) after surgery in 26 patients of the DAVID and Little DAVID studies. We studied tachyphylaxis by comparing the responses at D1 and D2 with that at D0. We also assessed the reproducibility of the D0 response in comparison to an earlier performed desmopressin test.
The median absolute FVIII:C increase was 0.50 IU/mL (0.35-0.74; n = 23) at D0, 0.21 IU/mL (0.14-0.28; n = 17) at D1, and 0.23 IU/mL (0.16-0.30; n = 11) at D2. The median percentage of FVIII increase after the second administration (D1) compared with the first (D0) was 42.9% (29.2%-52.5%; n = 17) and that of the third (D2) compared with the first (D0) was 36.4% (23.7%-46.9%; n = 11). The FVIII:C desmopressin response at D0 was comparable with the desmopressin test response in 74% of the patients.
Tachyphylaxis in the surgical setting was considerably more pronounced than previously reported, with FVIII:C at D1 and D2 of 36% to 43% of the initial response. Our results may have important implications for monitoring repeated desmopressin treatment when used perioperatively.
•The factor (F)VIII:C increase after desmopressin in nonsevere hemophilia A is highly variable.•We studied 26 patients who received multiple desmopressin doses perioperatively.•Tachyphylaxis was higher than reported earlier: FVIII:C increase was ∼40% of the first response.•It is advised to monitor FVIII:C after repeated dosing of desmopressin perioperatively.
Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can ...promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio HR = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions del(17p) and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.
•Duvelisib significantly improved progression-free survival and overall response rates compared with ofatumumab in RR CLL/SLL patients.•Duvelisib's efficacy and manageable safety profile support its consideration as a novel, oral monotherapy for RR CLL/SLL patients.
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Population ageing is rapidly becoming a global issue and will have a major impact on health policies and programmes. The World Health Organization's Study on global AGEing and adult health (SAGE) ...aims to address the gap in reliable data and scientific knowledge on ageing and health in low- and middle-income countries. SAGE is a longitudinal study with nationally representative samples of persons aged 50+ years in China, Ghana, India, Mexico, Russia and South Africa, with a smaller sample of adults aged 18-49 years in each country for comparisons. Instruments are compatible with other large high-income country longitudinal ageing studies. Wave 1 was conducted during 2007-2010 and included a total of 34 124 respondents aged 50+ and 8340 aged 18-49. In four countries, a subsample consisting of 8160 respondents participated in Wave 1 and the 2002/04 World Health Survey (referred to as SAGE Wave 0). Wave 2 data collection will start in 2012/13, following up all Wave 1 respondents. Wave 3 is planned for 2014/15. SAGE is committed to the public release of study instruments, protocols and meta- and micro-data: access is provided upon completion of a Users Agreement available through WHO's SAGE website (www.who.int/healthinfo/systems/sage) and WHO's archive using the National Data Archive application (http://apps.who.int/healthinfo/systems/surveydata).
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