Quantification of pharmacodynamic interactions between dexmedetomidine and midazolam in the rat

ABSTRACT The pharmacodynamic (PD) interaction between the benzodiazepine agonist midazolam and the ␣ 2 -adrenergic agonist dexmedetomidine was characterized for defined measures of anesthetic action and cardiovascular and ventilatory side effects in 33 rats. For various combinations of constant plasma concentrations of midazolam (0.1-20 g/ml) and dexmedetomidine (0.3-19 ng/ml) obtained by target-controlled infusion, the whisker reflex (WR), righting reflex (RR), startle reflex to noise (SR), tail clamp response (TC), and corneal reflex (CR) were assessed. EEG (power in 0.5-3.5-Hz frequency band), mean arterial pressure, and heart rate were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The nature and extent of PD interaction was quantified by the model parameter synergy (SYN Ͻ 0, antagonism; SYN ϭ 0, additivity; and SYN Ͼ 0, synergy). With increasing drug concentrations WR was lost first, followed by RR, SR, TC, and CR. These effects were accompanied by an increase of the EEG measure. The drug interaction was synergistic for all stimulus-response measures and the degree of synergy increased with deeper levels of central nervous system depression (SYN was 7.3, 145, 560, 374, and 1490 for WR, RR, SR, TC, and CR, respectively). The cardiovascular side effects of dexmedetomidine, evaluated at similar PD endpoints, were reduced in the presence of midazolam. Ventilatory side effects were minor for all drug combinations. The nature and extent of the PD interactions were not reflected in the EEG measure. In clinical anesthetic practice adequate general anesthesia requires a minimum of two different classes of anesthetic drugs. A hypnotic (inhalational anesthetic, i.v. anesthetic) and an analgesic (opiate) drug are titrated to achieve adequate CNS depression. A muscle relaxant can be used to facilitate surgical procedures. This anesthetic combination is termed "balanced anesthesia" (Hug, 1990; Many variables influence the complex relationship between dosage, plasma concentration, and drug effect. To optimize the delivery of anesthetic drugs to individual patients, it is important to distinguish between pharmacokinetic (PK) and pharmacodynamic (PD) interactions. For example, Dexmedetomidine, a selective ␣ 2 -adrenergic agonist, is being studied for potential use in anesthetic practice because of its combined analgesic, sedative, hypnotic, and anxiolytic effect

Colorectal cancer surveillance in Hodgkin lymphoma survivors at increased risk of therapy-related colorectal cancer: Study design

Background: Second primary malignancies are a major cause of excess morbidity and mortality in cancer survivors. Hodgkin lymphoma survivors who were treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine have an increased risk to develop colorectal cancer. Colonoscopy surveillance plays an important role in colorectal cancer prevention by removal of the precursor lesions (adenomas) and early detection of cancer, resulting in improved survival rates. Therefore, Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine could benefit from colonoscopy, or other surveillance modalities, which are expected to reduce colorectal cancer incidence and mortality. Current knowledge on clinicopathological and molecular characteristics of therapy-related colorectal cancer is limited. The pathogenesis of such colorectal cancers might be different from the pathogenesis in the general population and therefore these patients might require a different clinical approach. We designed a study with the primary aim to assess the diagnostic yield of a first surveillance colonoscopy among Hodgkin lymphoma survivors at increased risk of colorectal cancer and to compare these results with different screening modalities in the general population. Secondary aims include assessment of the test characteristics of stool tests and evaluation of burden, acceptance and satisfaction of CRC surveillance through two questionnaires. Methods/Design: This prospective multicenter cohort study will include Hodgkin lymphoma survivors who survived =8years after treatment with infradiaphragmatic radiotherapy and/or procarbazine (planned inclusion of 259 participants). Study procedures will consist of a surveillance colonoscopy with removal of precursor lesions (adenomas) and 6-8 normal colonic tissue biopsies, a fecal immunochemical test and a stool DNA test. All neoplastic lesions encountered will be classified using relevant histomorphological, immunohistochemical and molecular analyses in order to obtain more insight into colorectal carcinogenesis in Hodgkin lymphoma survivors. The Miscan-model will be used for cost-effectiveness analyses. Discussion: Evaluation of the diagnostic performance, patient acceptance and burden of colorectal cancer surveillance is necessary for future implementation of an individualized colorectal cancer surveillance program for Hodgkin lymphoma survivors. In addition, more insight into treatment-induced colorectal carcinogenesis will provide the first step towards prevention and personalized treatment. This information may be extrapolated to other groups of cancer survivors. Trial registration: Registered at the Dutch Trial Registry (NTR): NTR4961

Study on cosmogenic activation above ground for the DarkSide-20k project

The activation of materials due to the exposure to cosmic rays may become an important background source for experiments investigating rare event phenomena. DarkSide-20k is a direct detection experiment for galactic dark matter particles, using a two-phase liquid argon time projection chamber filled with 49.7 tonnes (active mass) of Underground Argon (UAr) depleted in 39Ar. Here, the cosmogenic activity of relevant long-lived radioisotopes induced in the argon and other massive components of the set-up has been estimated; production of 120 t of radiopure UAr is foreseen. The expected exposure above ground and production rates, either measured or calculated, have been considered. From the simulated counting rates in the detector due to cosmogenic isotopes, it is concluded that activation in copper and stainless steel is not problematic. Activation of titanium, considered in early designs but not used in the final design, is discussed. The activity of 39Ar induced during extraction, purification and transport on surface, in baseline conditions, is evaluated to be 2.8% of the activity measured in UAr from the same source, and thus considered acceptable. Other products in the UAr such as 37Ar and 3H are shown to not be relevant due to short half-life and assumed purification methods

Measurement of isotopic separation of argon with the prototype of the cryogenic distillation plant Aria for dark matter searches

The Aria cryogenic distillation plant, located in Sardinia, Italy, is a key component of the DarkSide-20k experimental program for WIMP dark matter searches at the INFN Laboratori Nazionali del Gran Sasso, Italy. Aria is designed to purify the argon, extracted from underground wells in Colorado, USA, and used as the DarkSide-20k target material, to detector-grade quality. In this paper, we report the first measurement of argon isotopic separation by distillation with the 26 m tall Aria prototype. We discuss the measurement of the operating parameters of the column and the observation of the simultaneous separation of the three stable argon isotopes: 36Ar , 38Ar , and 40Ar . We also provide a detailed comparison of the experimental results with commercial process simulation software. This measurement of isotopic separation of argon is a significant achievement for the project, building on the success of the initial demonstration of isotopic separation of nitrogen using the same equipment in 2019

Directionality of nuclear recoils in a liquid argon time projection chamber

The direct search for dark matter in the form of weakly interacting massive particles (WIMP) is performed by detecting nuclear recoils (NR) produced in a target material from the WIMP elastic scattering. A promising experimental strategy for direct dark matter search employs argon dual-phase time projection chambers (TPC). One of the advantages of the TPC is the capability to detect both the scintillation and charge signals produced by NRs. Furthermore, the existence of a drift electric field in the TPC breaks the rotational symmetry: the angle between the drift field and the momentum of the recoiling nucleus can potentially affect the charge recombination probability in liquid argon and then the relative balance between the two signal channels. This fact could make the detector sensitive to the directionality of the WIMP-induced signal, enabling unmistakable annual and daily modulation signatures for future searches aiming for discovery. The Recoil Directionality (ReD) experiment was designed to probe for such directional sensitivity. The TPC of ReD was irradiated with neutrons at the INFN Laboratori Nazionali del Sud, and data were taken with 72 keV NRs of known recoil directions. The direction-dependent liquid argon charge recombination model by Cataudella et al. was adopted and a likelihood statistical analysis was performed, which gave no indications of significant dependence of the detector response to the recoil direction. The aspect ratio R of the initial ionization cloud is estimated to be 1.037 +/- 0.027 and the upper limit is R < 1.072 with 90% confidence levelComment: 20 pages, 10 figures, submitted to Eur. Phys. J.

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice

Sensitivity projections for a dual-phase argon TPC optimized for light dark matter searches through the ionization channel

Dark matter lighter than 10 GeV/c$^2$ encompasses a promising range of candidates. A conceptual design for a new detector, DarkSide-LowMass, is presented, based on the DarkSide-50 detector and progress toward DarkSide-20k, optimized for a low-threshold electron-counting measurement. Sensitivity to light dark matter is explored for various potential energy thresholds and background rates. These studies show that DarkSide-LowMass can achieve sensitivity to light dark matter down to the solar neutrino floor for GeV-scale masses and significant sensitivity down to 10 MeV/c$^2$ considering the Migdal effect or interactions with electrons. Requirements for optimizing the detector's sensitivity are explored, as are potential sensitivity gains from modeling and mitigating spurious electron backgrounds that may dominate the signal at the lowest energies