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Paints are widely used in indoor settings yet there are no data for volatile per- and polyfluoroalkyl substances (PFAS) for paints or knowledge if paints are potentially important sources of human exposure to PFAS. Different commercial paints (

At the end of 2020, the National Institute of Neurological Disorders and Stroke, an institute of the National Institutes of Health, completed an 18 month-long strategic planning process that involved and engaged diverse internal and external biomedical and general stakeholders. The Institute published and disseminated its 2021-2026 Strategic Plan online in December 2020. Now, 1 year into its implementation, this progress report presents accomplishments to date, new initiatives and opportunities, and a preview of the metrics and benchmarks we will use to gauge the future progress of the strategic plan's implementation.

We developed a two-stage temperature control system for a long-term stable measurement of AMoRE neutrinoless double beta decay experiment using a dilution refrigerator. The first-stage control was made with a standard PID system using an AC bridge with a ruthenium oxide thermometer as the main thermometer of the mixing chamber plate. The second-stage control was obtained with a magnetic microcalorimeter (MMC) that is configured as a sensitive thermometer for a detector tower, the main experiment. Under single-stage temperature control on the temperature of the mixing chamber plate only with the RuO2 thermometer, the MMC recorded temperature stability of the detector plate of 9 μK rms over 100 min. Under two-stage temperature control, with the first-stage of the mixing chamber plate at 11 mK via the RuO2 thermometer and the second-stage of the detector plate at 12 mK via the MMC, the MMC recorded a temperature stability of 0.5 μK rms over 100 min. Moreover, the heat channels of the AMoRE experiment obtained considerable improvement in energy resolutions when switching from single-stage (RuO2) to two-stage (RuO2 + MMC) control.

Focal lesions within the subchondral bone, termed subchondral bone cysts (SBCs), are clinically accepted radiographic markers of advanced osteoarthritis (OA), but their etiology in the hip is not well understood.This study used micro-computed tomography (μCT), and histological and immunocytological analysis to examine the prevalence, size, location, and morphological and cellular features of SBCs found within 34 femoral heads (14 male, 20 female; age range = 43-80 years) obtained from total hip arthroplasty procedures.SBCs were common-present in 91% of the femoral heads examined-and frequently commuted with the surface of the femoral head, but otherwise showed no preferred anatomical location. Few associations were found between SBC features and patient characteristics such as BMI, age and sex. SBCs were also heterogenous in composition, ranging from fibrous (most common) to predominantly fatty (least common) and often containing vasculature, nerve fibers, cartilage islands, and bony spicules. Despite this heterogeneity, focal abnormalities in bone density and cartilage thickness were consistently observed. Bone adjacent to SBCs was denser than that in the primary compressive group, and cartilage thickness in regions overlying SBCs was lower than in non-overlying regions. In contrast to these local bony changes, μCT-based finite element analyses indicated that the stiffness of the primary compressive group was only mildly affected by SBCs.These findings indicate that SBCs in the femoral head involve extensive perturbations in cellular activity, culminating in myriad skeletal tissue types and spatially heterogenous changes in bone and cartilage morphology that are likely to affect OA progression.

Lysosomotropic agent chloroquine was shown to sensitize non-stem glioblastoma cells to radiation in vitro with p53-dependent apoptosis implicated as one of the underlying mechanisms. The in vivo outcomes of chloroquine or its effects on glioblastoma stem cells have not been previously addressed. This study undertakes a combinatorial approach encompassing in vitro, in vivo and in silico investigations to address the relationship between chloroquine-mediated radiosensitization and p53 status in glioblastoma stem cells. Our findings reveal that chloroquine elicits antagonistic impacts on signaling pathways involved in the regulation of cell fate via both transcription-dependent and transcription-independent mechanisms. Evidence is provided that transcriptional impacts of chloroquine are primarily determined by p53 with chloroquine-mediated activation of pro-survival mevalonate and p21-DREAM pathways being the dominant response in the background of wild type p53. Non-transcriptional effects of chloroquine are conserved and converge on key cell fate regulators ATM, HIPK2 and AKT in glioblastoma stem cells irrespective of their p53 status. Our findings indicate that pro-survival responses elicited by chloroquine predominate in the context of wild type p53 and are diminished in cells with transcriptionally impaired p53. We conclude that p53 is an important determinant of the balance between pro-survival and pro-death impacts of chloroquine and propose that p53 functional status should be taken into consideration when evaluating the efficacy of glioblastoma radiosensitization by chloroquine., Cells, 12 (9), ISSN:2073-4409

Background and Objectives Effective deprescribing requires shared decision making between a patient and their clinician, and should be used when implementing evidence-based deprescribing conversations. As part of the Shed-MEDS clinical trial, this study assessed barriers and enablers that influence patient decision making in deprescribing to inform future implementation efforts and adaptations. Research Design and Methods Shed-MEDS, a randomized controlled deprescribing trial, included hospitalized older adults discharging to post-acute care facilities. A trained clinician reviewed each participant’s medical history and medication list to identify medications with potential for deprescribing. The study clinician then conducted a semistructured patient-centered deprescribing interview to determine patient (or surrogate) concerns about medications and willingness to deprescribe. Reeve et al.’s (2013) framework was used to categorize barriers and enablers to deprescribing from the patient’s perspective, including “appropriateness of cessation,” “fear,” “dislike of a medication,” “influences,” and “process of cessation.” Results Overall, participants/surrogates (N = 177) agreed with 63% (883 total medications) of the study clinician’s deprescribing recommendations. Thematic analysis revealed that “appropriateness” of a medication was the most common barrier (88.2%) and enabler (67.3%) to deprescribing. Other deprescribing enablers were in the following domains: “influences” (22.7%), “process” (22.5%), “pragmatic” (19.4%), and “dislike” (5.3%). Discussion and Implications Use of a semistructured deprescribing interview conversation tool allowed study clinicians to elicit individual barriers and enablers to deprescribing from the patient’s perspective. Participants in this study expressed more agreement than disagreement with study clinicians’ deprescribing recommendations. These results should inform future implementation efforts that incorporate a patient-centered framework during deprescribing conversations. Clinical Trials Registration Number NCT02979353

Background. Myopia is the most common clinical refractive error of the eye. Only in Russia, there are about 15 million myopic people. Currently, in addition to traditional correction (glasses, soft contact lenses), keratorefractive surgery actively develops; however, due to the initial parameters of the cornea or the magnitude of the refractive error, it may be contraindicated to the patient. Nowadays an alternative to these correction methods for young patients with refractive errors of high and ultra-high degrees is the implantation of a phakic intraocular lens.The aim. To evaluate the efficiency of refractive errors correction using phakic IOL implantation.Materials and methods. We carried out a retrospective analysis of outpatient records of 56 patients who received surgical treatment for myopia and complex myopic astigmatism at the Orenburg branch of the S. Fyodorov Eye Microsurgery Federal State Institution in the period from 2019 to 2020 (110 eyes), all patients underwent implantation of a phakic intraocular lens IPCL V2.0, IPCL V2.0 TORIC. Patients were examined before surgery and on the first day after surgery. In addition to standard, special clinical and functional examination methods were used: optical biometry on the IOL-Master 700, determination of the density of endothelial cells using an endothelial microscope, examination of the fundus under cycloplegia; if necessary, peripheral laser coagulation of the retina was performed before calculating phakic IOLs.Results. All operations and the early postoperative period went without complications. The target BCVA (0.75–1.0) was achieved in 90 (81.8 %) eyes. All patients were satisfied with the treatment results.Conclusion. Implantation of IPCL V2.0 and IPCL V2.0 TORIC phakic IOLs is an effective method for correcting refractive errors, regardless of the degree of myopia and the presence of astigmatism.

Counterfeit medicines are a healthcare security problem, posing not only a direct threat to patient safety and public health but also causing heavy economic losses. Current anticounterfeiting methods are limited due to the toxicity of the constituent materials and the focus of secondary packaging level protections. We introduce an edible, imperceptible, and scalable matrix code of information representation and data storage for pharmaceutical products. This matrix code is digestible as it is composed of silk fibroin genetically encoded with fluorescent proteins produced by ecofriendly, sustainable silkworm farming. Three distinct fluorescence emission colors are incorporated into a multidimensional parameter space with a variable encoding capacity in a format of matrix arrays. This code is smartphone-readable to extract a digitized security key augmented by a deep neural network for overcoming fabrication imperfections and a cryptographic hash function for enhanced security. The biocompatibility, photostability, thermal stability, long-term reliability, and low bit error ratio of the code support the immediate feasibility for dosage-level anticounterfeit measures and authentication features. The edible code affixed to each medicine can serve as serialization, track and trace, and authentication at the dosage level, empowering every patient to play a role in combating illicit pharmaceuticals.

Biohybrid systems have been developed to better understand the design principles and coordination mechanisms of biological systems. We consider whether two functional regulatory features of the heart—mechanoelectrical signaling and automaticity—could be transferred to a synthetic analog of another fluid transport system: a swimming fish. By leveraging cardiac mechanoelectrical signaling, we recreated reciprocal contraction and relaxation in a muscular bilayer construct where each contraction occurs automatically as a response to the stretching of an antagonistic muscle pair. Further, to entrain this closed-loop actuation cycle, we engineered an electrically autonomous pacing node, which enhanced spontaneous contraction. The biohybrid fish equipped with intrinsic control strategies demonstrated self-sustained body–caudal fin swimming, highlighting the role of feedback mechanisms in muscular pumps such as the heart and muscles.

Background Considering the prolongation of the COVID-19 pandemic, the lack of studies on burnout, particularly in healthcare workers, needs to be addressed. This report aimed to identify the risk factors of burnout by comparing the level of burnout between nurses in general wards and those in COVID-19-dedicated wards in a national university hospital. Methods A survey based on the Korean version of Burnout Assessment Tool (BAT-K) was conducted on nurses between 10 January and 31 January 2022. The BAT-K consists of exhaustion, mental distance, cognitive impairment, emotional impairment and secondary symptoms. Results A total of 165 nurses, including 81 nurses from the COVID-19-dedicated ward, completed the questionnaire. The percentage of general-ward nurses with an emotional impairment score above the clinical cutoff was higher than that of COVID-19 ward nurses. General ward compared to the COVID-19 ward increased the risk of presenting with total-core symptoms. Two factors increased the risk regarding mental distance: short career length and underlying disease. Conclusions In contrast to previous studies, the risk of burnout in the COVID-19-ward nurses was lower than that of the general ward nurses. The risk regarding mental distance was correlated with short career length and presence of an underlying disease.

Supplementary Figure S1. Potency against FGFR family and kinome selectivity. Supplementary Figure S2. Kinases with a cysteine at the equivalent position to Cys552 in FGFR4. Supplementary Figure S3. MALDI Mass Spectrometry of FGFR4. Supplementary Figure S4. Induction of Caspase 3/7 activity in Hep 3B cells. Supplementary Figure S5. FGFR4 turnover rates in Hep 3B cells. Supplementary Figure S6. Analysis of TCGA HCC samples. Supplementary Table S1. Kinetic parameters of FGFR4 inhibition by BLU9931. Supplementary Table S2. Pharmacokinetic parameters for BLU9931.

Supplementary Methods and Figure Legends

Internal exposure of the human body to potentially harmful chemical substances can be assessed by Human Biomonitoring (HBM). HBM can be used to generate conclusive data that may provide an overview of exposure levels in entire or specific population groups. This knowledge can promote the understanding of potential risks of the substances of interest or help monitoring the success of regulatory measures taken on the political level. Study planning and design are key elements of any epidemiologic study to generate reliable data. In the field of HBM, this has been done using differing approaches on various levels of population coverage so far. Comparison and combined usage of the resulting data would contribute to understanding exposure and its factors on a larger scale, however, the differences between studies make this a challenging and somewhat limited endeavour. This article presents templates for documents that are required to set up an HBM study, thus facilitating the generation of harmonised HBM data as a step towards standardisation of HBM in Europe. They are designed to be modular and adaptable to the specific needs of a single study while emphasising minimum requirements to ensure comparability. It further elaborates on the challenges encountered during the process of creating these documents during the runtime of the European Joint Programme HBM4EU in a multi-national expert team and draws up lessons learnt in the context of knowledge management. This report was developed under the Horizon 2020 project HBM4EU (WP7 “Survey design and fieldwork preparation”) (www.hbm4eu.eu). HBM4EU has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 733032. This article reflects only the authors’ view and the European Commission is not responsible for any use that may be made of the information it contains. The authors would like to express their gratitude towards all partners participating in WP7, to wards the HBM4EU Chemical Group Leaders who have contributed with their valuable experiences and expertise to the creation of the described documents as well as towards the cofunding national authorities. Sí

Suppl. Table 2. CSF and Matching Tissues Available for the Study Suppl. Table 3. Metabolite concentrations in the three cohorts (t-test Statistics) Suppl. Table 4. Site-specific thresholds for D-/L-2HG Suppl. Table 5. Information about site-specific accuracy for D-2HG Suppl. Table 6. Tumor tissue sample demographics tested in parallel by MS and NMR

Raf inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent activating mutations in B-Raf. Here, we show that cell lines and tumors harboring mutant B-Raf were sensitive to a novel series of Raf inhibitors (e.g., V600EB-Raf A375, IC50 on cells = 2 nmol/L; ED50 on tumor xenografts = 1.3 mg/kg). However, in cells and tumors with wild-type B-Raf, exposure to Raf inhibitors resulted in a dose-dependent and sustained activation of mitogen-activated protein kinase signaling. In some of these cell lines, Raf inhibition led to entry into the cell cycle, enhanced proliferation, and significantly stimulated tumor growth in vivo. Inhibition with structurally distinct Raf inhibitors or isoform-specific small interfering RNA knockdown of Raf showed that these effects were mediated directly through Raf. Either A-Raf or C-Raf mediated the Raf inhibitor–induced mitogen-activated protein kinase pathway activation in an inhibitor-specific manner. These paradoxical effects of Raf inhibition were seen in malignant and normal cells in vitro and in vivo. Hyperplasia of normal epithelial cells in the esophagus and the stomach was evident in mice with all efficacious Raf inhibitors (n = 8) tested. An implication of these results is that Raf inhibitors may induce unexpected normal cell and tumor tissue proliferation in patients. Mol Cancer Ther; 9(8); 2399–410. ©2010 AACR.

Supplementary Data from Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of ABT-199 observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199–induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL.Significance:These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.

Purpose:There is a need for strategies to prevent prostate cancer. Cholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease and has been proposed for chemoprevention. Using preclinical models and a window-of-opportunity clinical trial, we describe an adaptive antitumor immunity resulting from cholesterol lowering.Experimental Design:Statins do not reliably lower serum cholesterol in mice. Therefore, oral ezetimibe was administered to mice to lower serum cholesterol to clinically relevant levels and evaluated the final adaptive immune response. T-lymphocytes-specific mTORC2 knockout mice were used to evaluate mTOR signaling and antitumor immunity. Pretreatment and posttreatment prostate tumors and lymphocytes were examined from a window-of-opportunity clinical trial where men with prostate cancer were treated with 2 to 6 weeks of aggressive cholesterol-lowering intervention prior to radical prostatectomy.Results:Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and had enhanced central CD8+ T-cell memory. In mice and in patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. T-lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In patients, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas.Conclusions:Lowering serum cholesterol decreased signaling through mTORC2 and enhanced antitumor CD8+ T-cell memory. We provide a rationale for large-scale clinical testing of cholesterol lowering strategies for prostate cancer chemoprevention.

Suppl. Table 1. Histology, age, gender, diagnosis, site of CSF draws, longitudinal # and IDH1/2 mutation status of 84 tumor samples analyzed. Highlighted in 'yellow' are CSF samples that tested positive for IDH1 mutant staining, while their DNA indicated WT IDH.

Legends for each supplementary figure

Supplemental Figure 1. Protein and gene expression profiling of hypodiploid ALL. Supplemental Figure 2. Pairing biochemical characterization with viability/survival assays in hypodiploid B-ALL. Supplemental Figure 3. Primagraft samples used for ex vivo and in vivo experiments. Supplemental Figure 4. In vivo engraftment of hypodiploid ALL xenografts and response to ABT-199 during trial. Supplemental Figure 5. Clonal characterization of hypodiploid tumors at the beginning and end of trial. Supplemental Figure 6. Genome editing assays. Supplemental Figure 7. Genomic, karyotypic characterization and mechanistic experiments on Beck-1732 cells. Supplementary Tables of samples used in the in vivo studies.