Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor ...the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: Predisposition to adverse drug events with advancing age has led to the development of lists of potentially inappropriate medications (PIMs) to be avoided in the elderly, such as the ...Beers Criteria. The prevalence of Beers medications has been studied widely, but it is still unclear whether PIM use is predictive of adverse events in older people. Objectives: To examine potential associations between exposure to PIMs from the general Beers list and unplanned hospitalizations in elderly Western Australians. Methods: Using an enhanced case-time-control design and conditional logistic regression applied to the pharmaceutical claims and other linked health data of 251 305 Western Australians aged ≥65 years (1993-2005), odds ratios for unplanned hospitalization were obtained, from which attributable fractions, number and proportion of hospitalizations associated with drug exposure were derived. Results: Based on the health profiles of 383 150 hospitalized index subjects, overall PIM exposure was associated with an elevated risk of unplanned hospitalization (adjusted odds ratio = 1.18; 95% confidence interval = 1.15-1.21), this estimated risk increasing with the number of different PIMs and PIM quantity taken. Fifteen percent of unplanned hospitalizations in exposed index subjects (1980 per year) were attributed to PIM exposure. Patients taking meperidine (pethidine), nitrofurantoin, promethazine, indomethacin, and thioridazine appeared to be at particularly high risk of unplanned hospitalization, whereas temazepam, oxazepam, diazepam, digoxin, amiodarone, ferrous sulfate, and naproxen were attributed the greatest numbers of unplanned hospitalizations. Conclusions: Due caution prescribing Beers medications in the elderly seems justified, paying particular attention to PIMs listed above and to the concurrent use of multiple PIMs. Our results also support the retention of specific medications on PIM lists in future developments.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues ...to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up.
The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A class of direct search methods for locally minimizing a Lipschitz continuous black-box function f subject to locally Lipschitz constraints is presented. A sequence of smoothed
penalty functions is ...used. Each smoothed penalty function is approximately minimized in turn. The smoothing is reduced after each minimization, exposing the
exact penalty function in the limit. Convergence to a constrained Clarke stationary point is shown under appropriate regularity conditions. Convergence to one or more KKT points is shown under similar conditions when f and all active constraints are strictly differentiable at each limit point. An implementation of one method in this class is numerically tested and shown to be effective in practice. The implementation uses a discrete quasi-Newton step when possible. Otherwise a global direction search is used to locate a descent direction. Theoretical convergence properties are independent of the quasi-Newton step.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Observations of magnetic reconnection at Earth's magnetopause often display asymmetric structures that are accompanied by strong magnetic field (B) fluctuations and large‐amplitude parallel electric ...fields (E||). The B turbulence is most intense at frequencies above the ion cyclotron frequency and below the lower hybrid frequency. The B fluctuations are consistent with a thin, oscillating current sheet that is corrugated along the electron flow direction (along the X line), which is a type of electromagnetic drift wave. Near the X line, electron flow is primarily due to a Hall electric field, which diverts ion flow in asymmetric reconnection and accompanies the instability. Importantly, the drift waves appear to drive strong parallel currents which, in turn, generate large‐amplitude (~100 mV/m) E|| in the form of nonlinear waves and structures. These observations suggest that turbulence may be common in asymmetric reconnection, penetrate into the electron diffusion region, and possibly influence the magnetic reconnection process.
Key Points
Asymmetric magnetic reconnection at the magnetopause often has strong magnetic field fluctuations and intense parallel electric fields
The magnetic field fluctuations are consistent with a thin, oscillating current sheet that is corrugated along the X line (drift wave)
The drift waves appear to drive strong parallel currents which, in turn, generate large‐amplitude parallel electric fields
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In situ measurements of aerosol microphysical, chemical, and optical properties were made during global-scale flights from 2016-2018 as part of the Atmospheric Tomography Mission (ATom). The NASA ...DC-8 aircraft flew from â¼ 84.sup." N to â¼ 86.sup." S latitude over the Pacific, Atlantic, Arctic, and Southern oceans while profiling nearly continuously between altitudes of â¼ 160 m and â¼ 12 km. These global circuits were made once each season. Particle size distributions measured in the aircraft cabin at dry conditions and with an underwing probe at ambient conditions were combined with bulk and single-particle composition observations and measurements of water vapor, pressure, and temperature to estimate aerosol hygroscopicity and hygroscopic growth factors and calculate size distributions at ambient relative humidity. These reconstructed, composition-resolved ambient size distributions were used to estimate intensive and extensive aerosol properties, including single-scatter albedo, the asymmetry parameter, extinction, absorption, Ãngström exponents, and aerosol optical depth (AOD) at several wavelengths, as well as cloud condensation nuclei (CCN) concentrations at fixed supersaturations and lognormal fits to four modes. Dry extinction and absorption were compared with direct in situ measurements, and AOD derived from the extinction profiles was compared with remotely sensed AOD measurements from the ground-based Aerosol Robotic Network (AERONET); this comparison showed no substantial bias.
The meaning of a sentence differs from the sum of the meanings of its constituents. Left anterior temporal cortex responds to sentences more strongly than to unconnected words. We hypothesized that ...the anterior temporal response to sentences is due to this difference in meaning (compositional semantics). Using positron emission tomography (PET), we studied four experimental conditions (2 × 2 factorial design): In one condition, subjects read normal sentences. In a second condition, they read grammatically correct sentences containing numerous semantic violations (semantically random sentences). In a third condition, we scrambled the word order within the normal sentences, and, in a fourth condition, the word order was scrambled within the semantically random sentences. The left anterior temporal pole responded strongly to sentences compared to scrambled versions of sentences. A similar although weaker response occurred in the left anterior superior temporal sulcus and the left posterior middle temporal gyrus. A subset of voxels within the left anterior temporal pole responded more to semantically random sentences and their scrambled versions than to normal sentences and the corresponding scrambled versions (main effect of semantic randomness). Finally, the grammatical and the semantic factor interacted in a subset of voxels within the anterior temporal pole: Activity was higher when subjects read normal sentences compared to their scrambled versions but not for semantically random sentences compared to their corresponding scrambled versions. The effects of grammar and meaning and, most importantly, the interaction between grammatical and semantic factors are compatible with the hypothesis that the left anterior temporal pole contributes to the composition of sentence meaning.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Study evaluating postoperative course after TORS oropharyngeal resection.•Clinical trial patients receiving deescalated adjuvant therapy for HPV(+)OPSCC.•Patients had acceptable post-operative ...bleeding rates requiring intervention (4.6%)•There were very low rates of postoperative complication.
Dose de-escalation of adjuvant therapy (DART) in patients with HPV(+)OPSCC was investigated in two prospective Phase II and III clinical trials (MC1273 and MC1675). We report the 30-day morbidity and mortality associated with primary TORS resection in patients enrolled in these trials.
Patients with HPV(+)OPSCC, who underwent TORS resection between 2013 and 2020 were considered in this analysis. The severity of postoperative transoral bleeding was graded using both the Hinni Grade (HG) transoral surgery bleeding scale and the Common Terminology for Adverse Events (CTCAE) v5.0. Post-surgical complications within 30 days of surgery, as well as rates of tracheostomy, PEG and nasogastric tube placement.
219 patients were included. A total of 7 (3.2 %) patients had a tracheostomy placed at the time of surgery, and all were decannulated within 26 days (median: 5, range: 2–26). There were 33 (15.1 %) returns to the emergency department (ED) with 10 (4.6 %) patients requiring readmission. Using the HG scale, 10 (4.6 %) patients experienced ≥ Grade 3 bleeding with no Grade 5 or 6 bleeds. In contrast, using the CTCAE scale, 15 patients (6.8 %) experienced ≥ Grade 3 bleeding with no Grade 5 bleeds. There was one post-operative death in a patient withdrawn from the trial, and no deaths related to hemorrhage.
TORS for HPV(+)OPSCC in carefully selected patients at a high volume center was associated with low morbidity and mortality.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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