Miracle-dz/UniFAR-FTUs huggingface dataset:
Digital therapeutics in pain medicine

In this issue of the Korean Journal of Pain, Joo et al. [1] reports a study on the effects of a virtual reality (VR) program on procedure-related pain in patients undergoing fluoroscopy-guided lumbar sympathetic ganglion block. In this study, the VR program provided an additional analgesic effect in combination with local anesthetic infiltration as well as an anxiolytic effect. This non-pharmacologic intervention is expected to be a useful adjunctive treatment for painful interventions, without serious complications. To the best of my knowledge, the first application of VR technology in pain medicine might be SpiderWorld, a VR program for adjunctive analgesia during burn wound care, employed by Hoffman et al. [2]. Since then, the therapeutic effects of VR have been reported not only in patients with acute pain but also in patients with chronic pain such as fibromyalgia or headache [3]. Currently, several digital healthcare companies are trying to prove the therapeutic effect of VR programs and commercialize them in pain medicine. Firsthand technology Inc., founded by Hoffmann et al., has mainly explored the effects of VR programs, such as SnowWorld, in patients with acute and chronic pain [4]. AppliedVR Inc., another promising company in this field, has explored the efficacy of VR programs in acute postoperative and chronic pain [5]. However, medical applications of digital technologies are not limited to VR alone. The medical application of software programs or digital devices is being accepted as a new therapeutic modality, called digital therapeutics (DTx), with the accumulation of evidence of their effectiveness in medicine. The Digital Therapeutics Alliance defines DTx as “evidence-based therapeutic interventions driven by high-quality software programs to prevent, manage, or treat a medical disorder or disease” [6]. DTx belongs to contemporary digital healthcare and includes medical devices that focus primarily on the prevention, treatment, and management of diseases. It includes a variety of software programs, such as mobile applications, games, and chatbots, as well as VR. The first DTx application approved by the Food and Drug Administration (FDA) was reSET, a cognitive behavioral therapy for substance use disorder using a smartphone application [6]. It was developed by Pear Therapeutics and released in November 2018 in partnership with Sandoz, a division of the Novartis group. Subsequently, reSET-O, a smartphone application for opioid use disorder, was released in the market by Pear Therapeutics in December 2018, after obtaining FDA approval [6]. In a recent retrospective claims-based study, the
Inhibition of miR-29 activity in the myeloid lineage increases response to calcitonin and trabecular bone volume in mice.

The miR-29-3p family (miR-29a, miR-29b, miR-29c) of microRNAs is increased during RANKL-induced osteoclastogenesis. In vivo, activation of a miR-29-3p tough decoy inhibitor (TuD) in LysM-cre expressing cells (myeloid lineage) resulted in mice displaying enhanced trabecular and cortical bone volume, due to decreased bone resorption. Calcitonin receptor (Calcr) is a miR-29 target that negatively regulates bone resorption. CALCR was significantly increased in RANKL-treated miR-29-decoy osteoclasts, and these cells were more responsive to the inhibitory effect of calcitonin on osteoclast formation. Further, cathepsin K (Ctsk), which is critical for resorption, was decreased in miR-29-decoy cells. CALCR is a Gs coupled receptor and its activation raises cAMP levels. In turn, cAMP suppresses cathepsin K, and cAMP levels were increased in miR-29-decoy cells. siRNA-mediated knock down of Calcr in miR-29 decoy osteoclasts allowed recovery of cathepsin K levels in these cells. Overall, using a novel knockin tough decoy mouse model, we identified a new role for miR-29-3p in bone homeostasis. In RANKL-driven osteoclastogenesis, as seen in normal bone remodeling, miR-29-3p promotes resorption. Consequently, inhibition of miR-29-3p activity in the myeloid lineage leads to increased trabecular and cortical bone. Further, this study documents an inter-relationship between CALCR and CTSK in osteoclastic bone resorption, which is modulated by miR-29-3p.
Positive impact of a faecal-based screening programme on colorectal cancer mortality risk

Introduction The effectiveness of colorectal cancer (CRC) screening programs is directly related to participation and the number of interval CRCs. The objective was to analyse specific-mortality in a cohort of individuals invited to a CRC screening program according to type of CRC diagnosis (screen-detected cancers, interval cancers, and cancers among the non-uptake group). Material and methods Retrospective cohort that included invitees aged 50–69 years of a CRC screening program (target population of 85,000 people) in Catalonia (Spain) from 2000–2015 with mortality follow-up until 2020. A screen-detected CRC was a cancer diagnosed after a positive faecal occult blood test (guaiac or immunochemical); an interval cancer was a cancer diagnosed after a negative test result and before the next invitation to the program (≤24 months); a non-uptake cancer was a cancer in subjects who declined screening. Results A total of 624 people were diagnosed with CRC (n = 265 screen-detected, n = 103 interval cancers, n = 256 non-uptake). In the multivariate analysis, we observed a 74% increase in mortality rate in the group with interval CRC compared to screen-detected CRC adjusted for age, sex, location and stage (HR: 1.74%, 95% CI:1.08–2.82, P = 0.02). These differences were found even when we restricted for advanced-cancers participants. In the stratified analysis for type of faecal occult blood test, a lower mortality rate was only observed among FIT screen-detected CRCs. Conclusion CRC screening with the FIT was associated with a significant reduction in CRC mortality.
Toxicity of Refugio Beach Oil to Sand Crabs (Emerita analoga), Blue Mussels (Mytilus sp.), and Inland Silversides (Menidia beryllina)

Monterey formation crude oil spilled from an onshore pipeline and entered the surf zone near Refugio State Beach, Santa Barbara County, California (USA) on 19 May 2015. During this season, early life stages of many marine fish and invertebrates were present. Surf zone water and beach porewater samples were collected during the 4 mo after the spill and 2 yr later for chemical analyses. Elevated polycyclic aromatic hydrocarbon (PAH) and total petroleum hydrocarbon concentrations were observed in surf zone water and porewater near the release point, declining with distance and time. Early life stage toxicity was investigated by conducting 6‐ and 7‐d static renewal bioassays with sand crab (Emerita analoga) post larvae (megalopae) and inland silverside larvae (Menidia beryllina), respectively, and a 48‐h blue mussel (Mytilus sp.) embryo development bioassay. Dilutions of a high‐energy water accommodated fraction of the Refugio Beach oil and a seawater control were prepared to simulate surf zone PAH concentrations (nominal PAH45; 0, 0.5, 1, 5, 10, 50, 100, and 500 µg/L). The PAH45 median lethal concentrations (LC50s), based on measured concentrations, were 381 µg/L for Mytilus sp. , 75.6 µg/L for Menidia, and 40.9 µg/L for Emerita. Our results suggest that PAH concentrations in coastal waters of the spill‐affected area were potentially lethal to early life stages of fish and invertebrates. Environ Toxicol Chem 2021;40:2578–2586. © 2021 SETAC
Chitosan-bovine serum albumin-Carbopol 940 nanogels for mupirocin dermal delivery: ex-vivo permeation and evaluation of cellular binding capacity via radiolabeling

Abstract The goal of this study was to develop and examine the nanogel-based topical delivery system of mupirocin. Nanogels were prepared with chitosan and bovine serum albumin by ionic gelation and Carbopol 940 was added to improve the gelling/adhesive properties. Detailed characterization studies were performed and the cellular binding capacity of radiolabeled nanogels was investigated on CCD-1070Sk cell lines. Results indicate the successful formation of nanogels with particle size and zeta potential ranged between 341.920–603.320 nm and 13.120–24.300 mV, respectively. The mechanical and rheological studies proved pseudoplastic and strong elastic gel behavior (G′ > G′′). Mupirocin was successfully entrapped into nanogels with a ratio of more than 95% and the loaded drug was slowly released up to 93.89 ± 3.07% within 24 h. The ex vivo penetration and permeation percentages of mupirocin were very low (1.172 ± 0.202% and 0.161 ± 0.136%) indicating the suitability of nanogels for dermal use against superficial skin infections. The microbiological studies pointed out the effectiveness of nanogels against Staphylococcus aureus strains. Nanogels did not show toxicity signs and the cell binding capacity of radiolabeled formulations was found to be higher than [99mTc]NaTcO4 to CCD-1070Sk cell line. Overall, mupirocin nanogels might be considered as a potential and safe topical treatment option for bacterial skin infections.
Aflibercept, a VEGF (Vascular Endothelial Growth Factor)-Trap, Reduces Vascular Permeability and Stroke-Induced Brain Swelling in Obese Mice

Supplemental Digital Content is available in the text. Background and Purpose: Brain edema is an important underlying pathology in acute stroke, especially when comorbidities are present. VEGF (Vascular endothelial growth factor) signaling is implicated in edema. This study investigated whether obesity impacts VEGF signaling and brain edema, as well as whether VEGF inhibition alters stroke outcome in obese subjects. Methods: High-fat diet-induced obese mice were subjected to a transient middle cerebral artery occlusion. VEGF-A and VEGFR2 (receptor) expression, infarct volume, and swelling were measured 3 days post-middle cerebral artery occlusion. To validate the effect of an anti-VEGF strategy, we used aflibercept, a fusion protein that has a VEGF-binding domain and acts as a decoy receptor, in human umbilical vein endothelial cells stimulated with rVEGF (recombinant VEGF; 50 ng/mL) for permeability and tube formation. In vivo, aflibercept (10 mg/kg) or IgG control was administered in obese mice 3 hours after transient 30 minutes middle cerebral artery occlusion. Blood-brain barrier integrity was assessed by IgG staining and dextran extravasation in the postischemic brain. A separate cohort of nonobese (lean) mice was subjected to 40 minutes middle cerebral artery occlusion to test the effect of aflibercept on malignant infarction. Results: Compared with lean mice, obese mice had increased mortality, infarct volume, swelling, and blood-brain barrier disruption. These outcomes were also associated with increased VEGF-A and VEGFR2 expression. Aflibercept reduced VEGF-A-stimulated permeability and tube formation in human umbilical vein endothelial cells. Compared with the IgG-treated controls, mice treated with aflibercept had reduced mortality rates (40% versus 17%), hemorrhagic transformation (43% versus 27%), and brain swelling (28% versus 18%), although the infarct size was similar. In nonobese mice with large stroke, aflibercept neither improved nor exacerbated stroke outcomes. Conclusions: The study demonstrates that aflibercept selectively attenuates stroke-induced brain edema and vascular permeability in obese mice. These findings suggest the repurposing of aflibercept to reduce obesity-enhanced brain edema in acute stroke.
Antibacterial activity of Mallotus japonicus (L.F.) Müller Argoviensis on growth of Aeromonas hydrophila, A. salmonicida, Edwardsiella tarda and Vibrio anguillarum

The present study evaluated the antimicrobial activities of the medicinal plant Mallotus japonicus against the fish pathogenic bacteria, Aeromonas hydrophila, Aeromonas salmonicida, Edwardisella tarda and Vibrio anguillarum, and also describes the antimicrobial activities of the major and minor active compounds present within the plant extract. The synergistic effects by way of combination of these compounds were also evaluated and described. Chemical constituents of the plant extracts were analysed using the liquid chromatography‐mass spectrometry (LC‐MS) and described.
Pesticides and risk assessment in Shanghai fruit and raw eaten vegetables

ABSTRACT A database of 392 pesticides established by an Ultrahigh performance liquid chromatography-tandem Q/Orbitrap high-resolution mass spectrometer (UPLC-Q/Orbitrap-HRMS) was used to screen multiple residues of pesticides in fruit and raw eaten vegetables from planting farms in Shanghai. Risk assessment was conducted with the screened results of the determined pesticides as to evaluate food safety. In 95% of the samples, one or more pesticides had a content below the maximum residue limits (MRLs) as set in the national Chinese standard. The co-occurrence of multi-residues of pesticides was more severe in peach and muskmelon, when compared with other food. All hazard index values of different groups were in the range of 0.19% to 12.3%, demonstrating that chronic dietary risk of studied fruits and raw eaten vegetables is low and the studied food samples were safe for human consumption in terms of these detected pesticides.
Racial differences in persistence to secondary prevention medication regimens after ischemic stroke

ABSTRACT Background: Prior stroke is one of the biggest risk factors for future stroke events. Effective secondary prevention medication regimens can dramatically reduce recurrent stroke risk. Guidelines recommend the use of antithrombotic, antihypertensive and lipid-lowering medications after stroke. Medication adherence is known to be better in the presence of a caregiver but long-term adherence after stroke is unknown and disparities may persist. Methods: We examined the effects of race and sex on baseline prescription and maintenance of secondary prevention regimens in the presence of a caregiver using the Caring for Adults Recovering from the Effects of Stroke (CARES) study, an ancillary study of the national REasons for Geographic and Racial Differences in Stroke (REGARDS). Results: Incident ischemic stroke survivors (N = 172; 36% Black) with family caregivers had medications recorded at hospital discharge and on average 9.8 months later during a home visit. At discharge, antithrombotic prescription (95.9%), lipid-lowering medications (78.8%) and antihypertensives (89.9%) were common and there were no race or sex differences in discharge prescription rates. One year later, medication persistence had fallen to 86.6% for antithrombotics (p = 0.002) and 69.8% for lipid lowering (p = 0.008) but increased to 93.0% for antihypertensives (p = 0.30). Blacks were more likely to have discontinued antithrombotics than Whites (18.3% v 7.7%, p = 0.04). No significant differences in persistence were seen with age, sex, income, depression, or cognitive impairment. Conclusions: Medication persistence was high in this sample, likely due to the presence of a caregiver. In our cohort, despite similar prescription rates at the time of hospital discharge, Black stroke survivors were more than twice as likely to stop antithrombotics than Whites. The effect of changes in patterns of medication usage on health outcomes in Black stroke survivors warrants continued investigation.
Plasmodium vivax Latent Liver Stage Infection and Relapse: Biological Insights and New Experimental Tools.

Plasmodium vivax is the most widespread human malaria parasite, in part because it can form latent liver stages known as hypnozoites after transmission by female anopheline mosquitoes to human hosts. These persistent stages can activate weeks, months, or even years after the primary clinical infection; replicate; and initiate relapses of blood stage infection, which causes disease and recurring transmission. Eliminating hypnozoites is a substantial obstacle for malaria treatment and eradication since the hypnozoite reservoir is undetectable and unaffected by most antimalarial drugs. Importantly, in some parts of the globe where P. vivax malaria is endemic, as many as 90% of P. vivax blood stage infections are thought to be relapses rather than primary infections, rendering the hypnozoite a major driver of P. vivax epidemiology. Here, we review the biology of the hypnozoite and recent discoveries concerning this enigmatic parasite stage. We discuss treatment and prevention challenges, novel animal models to study hypnozoites and relapse, and hypotheses related to hypnozoite formation and activation. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
High linear energy transfer carbon-ion irradiation upregulates PD-L1 expression more significantly than X-rays in human osteosarcoma U2OS cells

Abstract Programmed death ligand 1 (PD-L1) expression on the surface of cancer cells affects the efficacy of anti-PD-1/PD-L1 immune checkpoint therapy. However, the mechanism underlying PD-L1 expression in cancer cells is not fully understood, particularly after ionizing radiation (IR). Here, we examined the impact of high linear energy transfer (LET) carbon-ion irradiation on the expression of PD-L1 in human osteosarcoma U2OS cells. We found that the upregulation of PD-L1 expression after high LET carbon-ion irradiation was greater than that induced by X-rays at the same physical and relative biological effectiveness (RBE) dose, and that the upregulation of PD-L1 induced by high LET carbon-ion irradiation was predominantly dependent on ataxia telangiectasia and Rad3-related (ATR) kinase activity. Moreover, we showed that the downstream signaling, e.g. STAT1 phosphorylation and IRF1 expression, was upregulated to a greater extent after high LET carbon-ion irradiation than X-rays, and that IRF1 upregulation was also ATR dependent. Finally, to visualize PD-L1 molecules on the cell surface in 3D, we applied immunofluorescence-based super-resolution imaging. The three-dimensional structured illumination microscopy (3D-SIM) analyses revealed substantial increases in the number of presented PD-L1 molecules on the cell surface after high LET carbon-ion irradiation compared with X-ray irradiation.
The potential role of stress and sex steroids in heritable effects of sevoflurane

Abstract Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane. Summary sentence GABAergic general anesthetics, in particular sevoflurane, induce acute and long-term neuroendocrine abnormalities and epigenomic alterations in germ cells, as well as epigenomic, transcriptomic, and behavioral abnormalities in male offspring.
Trading accuracy for speed over the course of a decision

While making decisions in uncertain and dynamic environments, humans and other animals often need to balance the desire to gather sensory information (to make the best choice) with the urgency to act, facing a speed-accuracy tradeoff (SAT). Given the ubiquity of the SAT across species, extensive research has been devoted to understanding the computational mechanisms allowing its regulation at different timescales, including from one context to another, and from one decision to another. However, in unstable environments, animals frequently need to change their SAT on even shorter timescales – i.e., over the course of an ongoing decision – and very little is known about the mechanisms that allow such rapid adaptations. The present study aimed at addressing this issue. Human subjects performed a decision task with changing evidence, dissociating in time the deliberation process from the moment of commitment. In this task, subjects received rewards for correct answers but incurred penalties for mistakes. An increase or a decrease in penalty occurring halfway through the trial promoted rapid SAT shifts, favoring speeded decisions either in the early or in the late stage of the trial. Importantly, these shifts were associated with stage-specific adjustments in the accuracy criterion exploited for committing to a choice and relatedly, with dynamic, non-linear changes in urgency. Those subjects who decreased the most their accuracy criterion at a given decision stage exhibited the highest gain in speed, but also the highest cost in terms of performance accuracy at that time. Altogether, the current findings offer a unique extension of former work, by suggesting that dynamic changes in urgency allow the regulation of the SAT within the timescale of a single decision.
Interfacial Water Many-Body Effects Drive Structural Dynamics and Allosteric Interactions in SARS-CoV-2 Main Protease Dimerization Interface

Following our previous work (Chem. Sci.2021, 12, 4889−490734168762), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 μs) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network that is stable only at physiological pH. Structural correlations analysis between its residues and the catalytic site confirms the presence of a buried allosteric site. However, noticeable differences in allosteric connectivity are observed between PFFs and non-PFFs. Interfacial polarizable water molecules are shown to appear at the heart of this discrepancy because they are connected to the global interface H-bond network and able to adapt their dipole moment (and dynamics) to their diverse local physicochemical microenvironments. The water–interface many-body interactions appear to drive the interface volume fluctuations and to therefore mediate the allosteric interactions with the catalytic cavity.