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Accuracy of glomerular filtration rate estimates among patients with cancer
Get PDFBackground:
Glomerular filtration rate (GFR) estimation is a key issue in determining cancer treatment eligibility and dosing of treatments with narrow therapeutic index. Yet, little is known about the accuracy of GFR estimation among people with cancer in routine care.
Methods:
In a cross-sectional study including 1611 adults with cancer referred for 1837 determinations of measured GFR (mGFR), we assessed the accuracy of estimated GFR based on creatinine (eGFRcr), cystatin C (eGFRcys) and their combination (eGFRcr-cys). Accuracy was reported as percentage of patients with estimated values within 30% of mGFR; bias and precision as the median and interquartile range of eGFR-mGFR, respectively. Dosing accuracy was assessed by calculating expected dose of carboplatin for area under the curve of 5 mg/mL/min using the Calvert formula.
Results:
Median age was 68 (IQI 61 to 74) years, 38.5% were female with mean mGFR 75 (SD 30) mL/min; 17% had metastatic disease. Accuracy, bias and precision were best for eGFRcr-cys. Using eGFRcr would recommend an “overdose” of carboplatin in 10–20% of participants: this was 3–4 times less common using eGFRcr-cys.
Conclusion:
eGFRcr-cys equations provide the most accurate estimates of mGFR in patients with cancer, with potential to improve dosing accuracy substantially compared to eGFRcr
Structural basis of DNA recombination catalysis and regulation by ϕC31 integrase
Get PDFLarge serine integrases catalyse the insertion (integration) and excision of bacteriophage genomes into and from the genomes of their bacterial hosts via site-specific recombination. The recombination reaction is notable for its striking directionality: integrase recognises and efficiently recombines a ∼50-bp attachment site in the phage DNA (attP), and a ∼40-bp site in the bacterial genome (attB), but is inactive on the product sites attL and attR unless another phage-encoded protein, the Recombination Directionality Factor (RDF) is present, when the reaction is reversed. Serine integrases are versatile tools for applications in experimental biology, biotechnology, synthetic biology and gene therapy. Here we report structures of ϕC31 integrase, the most-studied and most widely used member of the serine integrase family, in complexes with its DNA recombination sites. Our structures, shed light on how the C-terminal coiled-coil motif facilitates recombination and directionality control
Adapt-A-Maze: an open source adaptable and automated rodent behavior maze system
Get PDFMazes are a fundamental and widespread tool in behavior and systems neuroscience research in rodents, especially in spatial navigation and spatial memory investigations in ad libitum behaving animals. However, their form and inflexibility often restrict potential experimental paradigms that involve multiple or adaptive maze designs. Unique layouts often lead to elevated costs, whether financially or in terms of time investment from scientists. To alleviate these issues, we have developed an automated, modular maze system that is flexible and scalable. This open-source Adapt-A-Maze (AAM) system will allow for experiments with multiple track configurations in rapid succession. Additionally, the flexibility can expedite prototyping of behavioral paradigms. Automation ensures less variability in experimental parameters and higher throughput. Finally, the standardized componentry enhances experimental repeatability within labs and replicability across labs. Our maze was successfully used across labs, in multiple experimental designs, with and without extracellular or optical recordings, in rats. The AAM system presents multiple advantages over current maze options and can facilitate novel behavior and systems neuroscience research
Low-frequency ultrasound triggers drug release from perfluorocarbon droplets at low intensities
Get PDFPerfluorocarbon droplets represent a promising platform for ultrasound-triggered drug delivery. Their liquid core can vaporize upon the application of a pressure wave such as ultrasound, resulting in the controlled and targeted release of their drug cargo. These carriers are highly tunable, exhibit a sharp on–off behavior and have longer lifetimes compared to ultrasound-responsive microbubbles. However, despite increasing efforts in the field, achieving an acceptable balance between stability and a safe activation threshold remains challenging. Indeed, stable droplet formulations are usually activated at very high ultrasound pressures, exceeding 1 MPa, raising safety concerns. In this study, we investigated the response of stable surfactant-shelled perfluoropentane droplets to low-intensity pulsed ultrasound. We demonstrated that a significant drug release can be triggered at a pressure as low as 100 kPa using a very low frequency (i.e., 38 kHz). Therefore, we focused on characterizing the behavior of this droplet formulation under 38 kHz ultrasound stimulation, optimizing a protocol able to achieve efficient drug release while adhering to safety guidelines, thus facilitating a future in vivo translation. We systematically examined how drug delivery efficiency varies with different stimulation parameters, including pressure, pulse repetition frequency and duty cycle. Additionally, high-speed camera imaging and ultrasound imaging were performed to further elucidate the response mechanisms of perfluorocarbon droplets to low-frequency ultrasound
NuSTAR as an axion helioscope
Get PDFWe present a novel approach to investigating axions and axionlike particles by studying their potential
conversion into x-rays within the Sun’s atmospheric magnetic field. Utilizing high-sensitivity data from the
nuclear spectroscopic telescope array (NuSTAR) collected during the 2020 solar minimum, along with
advanced solar atmospheric magnetic field models, we establish a new limit on the axion-photon coupling
strength gaγ ≲ 7.3 × 10−12 GeV−1 at 95% CL for axion masses ma ≲ 4 × 10−7 eV. This constraint
surpasses current ground-based experimental limits, studying previously unexplored regions of the
axion-photon coupling parameter space up to masses of ma ≲ 3.4 × 10−4 eV. These findings mark a
significant advancement in our ability to probe axion properties and strengthen indirect searches for dark
matter candidates
Herpes simplex virus type 2 implicated in a case of acute disseminated encephalomyelitis
Get PDFIntroduction. Acute disseminated encephalomyelitis (ADEM) is a well-described neurological disorder that follows acute infection, vaccination and organ transplantation. It is characterized by sudden and widespread areas of inflammation in the central nervous system. Previous case reports have described ADEM with evidence of either recent or current herpes simplex virus type 1 infection. However, here, we report a rare, to our knowledge never before documented, case of ADEM associated with herpes simplex virus type 2 (HSV-2).
Case report. A 20-year-old man presented with weakness and sensory disturbance to the lower limbs, which had gradually progressed over the preceding 7 days, with associated fever, urinary retention and bowel incontinence. Magnetic resonance imaging was in keeping with a diagnosis of ADEM with mainly spinal involvement. Lumbar puncture revealed lymphocytic pleocytosis with elevated protein, and PCR was strongly positive for HSV-2. He was treated with aciclovir and dexamethasone, along with broad-spectrum antibiotics until negative bacterial and mycobacterial culture results were obtained. His functional status improved over the following months, but, despite prolonged rehabilitation, neurological sequelae remain.
Conclusion. HSV-2 may be considered a possible aetiological agent in cases of ADEM
An acoustic isolator-type metamaterial for ultrasound attenuation at MHz frequencies
No full textAcoustic metamaterials (AMMs) offer significant promise for ultrasound probe backing layers due to their capacity to enhance acoustic energy dissipation through tailored sub-wavelength structures. However, practical implementation remains challenging due to difficulties in reliably reproducing the micron-scale features required for MHz-frequency operation, and the lack of quality assurance processes linking design intent to fabricated performance. This work presents the evaluation of a 3D-printed acoustic isolator-type metamaterial (AI-MM) backing designed for MHz operation using a custom aluminum oxide resin. Directional transmission intensity measurements revealed frequency-dependent asymmetry in forward and backward wave propagation (in both experiments and simulations), consistent with passive acoustic isolator behavior. X-ray micro-CT imaging of AI-MM samples revealed dimensional deviations, apex rounding, and local density variation. Attenuation spectra showed that AI-MM backings consistently outperformed homogeneous controls in both simulation and experiment, with frequency-dependent trends indicating enhanced scattering and viscous losses. A local attenuation peak near 2.6 MHz was within the operational range estimated from the measured geometry (2.22–2.94 MHz), underscoring the importance of linking performance to real-world fabrication. These findings support the potential of AI-MMs as tunable passive components in ultrasound systems and highlight the need for integrated design, fabrication, and validation workflows
A new heart for ATLAS: Status of the new Phase-2 ATLAS ITk pixel detector
No full textThe upgrade of the LHC to the High Luminosity LHC (HL-LHC) by the end of this decade will impose significant challenges on the detectors of the LHC experiments. Increased luminosity of up to 7.5 ⋅ 1034 cm−2 s −1 with up to 200 simultaneous p-p interactions per bunch crossing and foreseen run-times equivalent to up to 4000 f b−1 make it necessary to develop new detectors that can cope with the corresponding radiation damage, occupancy, and bandwidth needs. Among other detector upgrades, ATLAS will replace its entire inner tracking system with a new, all-silicon inner tracker (ITk) with a 5-layer hybrid pixel detector at its heart. This new pixel detector will feature a sensitive surface of about 13 m2 and employ several silicon sensor technologies as well as innovative concepts like serial detector powering and evaporative CO2 cooling to unprecedented scales. The ITk pixel project has finished its design and prototyping period and the different detector components are either in the pre-production or production phase. This contribution will give a comprehensive overview of the detector design, the overall project status and the biggest challenges towards production. It will include lessons learned from module pre-production, experience with the RD53B front-end chip, as well as first results on module loading on mechanical support structures. Recent results of system-level tests as well as the remaining project timelines will also be discussed
Measurements of charmed meson and antimeson production asymmetries at √s = 13.6 TeV
Get PDFThis article presents doubly differential measurements of the asymmetries in production rates between mesons containing a charm quark and those containing an anti-charm quark in proton-proton collisions at a centre-of-mass energy of √s = 13.6 TeV using data recorded by the LHCb experiment. The asymmetries of D0, D+ and Ds+ mesons are measured for two-dimensional intervals in transverse momentum and pseudorapidity, within the range 2 . 5 < p T < 25 . 0 GeV/ c and 2 . 0 < η < 4 . 5. No significant production asymmetries are observed. Comparisons to the Pythia 8 and Herwig 7 event generators are also presented, and their agreement with the data is evaluated. These measurements constitute the first measurements of production asymmetries at this centre-of-mass energy of colliding beams, and the first measurements with the LHCb Run 3 detector
Open-textured moral concepts
Get PDFIn this article, I apply the notion of open texture to the moral domain. I argue that moral concepts can exhibit open texture, and that recognising this can yield several explanatory advantages. To begin, I describe the notion of open texture, a type of indeterminacy some of our concepts seem to exhibit. I mention Friedrich Waismann’s original discussion of the notion, but particularly draw upon a recent exposition by Fenner Tanswell. Second, I provide some examples of ways certain moral concepts could be open-textured and suggest that some of our concepts that seem to have undergone change may have exhibited open texture in the past. These include the concepts of “murder”, “racism” and “stealing”. Next, I examine the implications for moral theory more generally, suggesting that the approach is very ecumenical; a wide range of normative theories and meta-ethical views are compatible with open-textured moral concepts. Finally, I consider the theoretical advantages of understanding some of our moral concepts as open-textured. Specifically, I argue that this view provides a new way of understanding faultless disagreements, a more plausible moral epistemology, and can be helpful for accommodating intuitions about moral verdicts from different cultures
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