Association Between Alcohol Use Disorder and Hospital Readmission Rates and Outcomes in Cancer Survivors: A Population Cohort Study.

BACKGROUND: Alcohol use disorder (AUD) is the most common substance use disorder and is characterized by heavy alcohol use and the inability to control drinking. This study sought to compare the rate, timing, length, and total costs of hospital readmissions among cancer survivors with and without AUD. METHODS: We used the Nationwide Readmissions Database in 2017 and 2018 in this cohort study. Cancer survivors with an AUD diagnosis during their index hospitalization were included in the exposure group. Propensity score matching was used to identify cancer survivors without AUD for the control group. The primary outcome was all-cause readmission, and secondary outcomes included days to, length of, and total cost of readmission. Outcomes were measured after 90 and 180 days of follow-up. Logistic regression was used to measure the likelihood of readmission, and negative binomial regression and gamma regression were used for the other outcomes. RESULTS: Of 485,962 cancer survivors, 13,953 (2.9%) had co-occurring AUD. Cancer survivors with AUD had slightly higher odds of 90-day (odds ratio, 1.14; 95% CI, 1.06-1.22) and 180-day (odds ratio, 1.11; 95% CI, 1.05-1.18) readmission compared with those without AUD. Cancer survivors with AUD who were readmitted after 90 days also had higher readmission costs ($3,785 vs $3,376; P=.03). No differences in time to and length of readmission were observed between groups. The odds of readmission were higher among cancer survivors with AUD irrespective of age and type of cancer. Male, but not female, cancer survivors with AUD were more likely than those without AUD to be readmitted in both follow-up periods. CONCLUSIONS: This population-based cohort study of cancer survivors in the United States found that AUD is associated with higher 90- and 180-day readmission rates and higher related health care costs after 90 days of follow-up. Hospitalized cancer survivors with AUD may benefit from addiction treatment and discharge planning that addresses their co-occurring AUD.

Vestibular and visual brain areas in the medial cortex of the human brain.

Self-motion perception involves an interaction between vestibular and visual brain regions. In the lateral brain, it includes the parietoinsular vestibular cortex and the posterior insular cortex. In the medial cortex, the cingulate sulcus visual (CSv) area is known to process visual-vestibular cues. Here, we show that the vestibular-visual network of the medial cortex extends beyond area CSv. We examined brain activations of 36 healthy right-handed participants by functional magnetic resonance imaging (fMRI) during stimulation with caloric vestibular, thermal, or visual motion cues. Consistent with previous research, we found that area CSv responded to both vestibular and visual cues but not to thermal cues. Moreover, the V6 complex and the precuneus motion (PcM) area responded primarily to (laminar-translational) visual motion cues. However, we also observed a region inferior to CSv within the pericallosal sulcus (vicinity of anterior retrosplenial) that primarily responded to vestibular cues. This vestibular pericallosal sulcus (vPCS) region did not respond to either visual or thermal cues. It was also distinct from a more posterior motion-sensitive region in the retrosplenial complex (mRSC) that responded to (radial) visual motion but not to vestibular and thermal cues. Together, our results suggest that the vestibular-visual network in the medial cortex not only includes areas CSv, PcM, and the V6 complex but also two additional brain regions adjacent to the callosum. These two brain regions exhibit similarities in terms of their locations and responses to vestibular and visual cues with self-motion-related brain regions recently described in nonhuman primates.NEW & NOTEWORTHY Self-motion perception involves several vestibular and visual cortical regions. Within the medial cortex, the cingulate sulcus visual (CSv) area, the precuneus motion (PcM) area, and the V6 complex respond selectively to self-motion cues. Here, we show that vestibular information is also processed in the pericallosal sulcus (vPCS), whereas (radial) visual motion information is associated with activation in the retrosplenial cortex (mRSC).

Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction.

A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT6 receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of Alzheimer's disease (AD). The novel compounds featured a tricyclic scaffold, namely thieno[3,2-h]cinnolinone, thienocyclopentapyridazinone and thienocycloheptapyridazinone, connected through alkyl chains of variable length to proper amine moieties, most often represented by N-benzylpiperazine or 1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-1H-indole as structural elements addressing AChE and 5-HT6 interaction, respectively. Our study highlighted the versatility of thienocycloalkylpyridazinones as useful architectures for AChE interaction, with several N-benzylpiperazine-based analogues emerging as potent and selective hAChE inhibitors with IC50 in the 0.17-1.23 µM range, exhibiting low to poor activity for hBChE (IC50 = 4.13-9.70 µM). The introduction of 5-HT6 structural moiety phenylsulfonylindole in place of N-benzylpiperazine, in tandem with a pentamethylene linker, gave potent 5-HT6 thieno[3,2-h]cinnolinone and thienocyclopentapyridazinone-based ligands both displaying hAChE inhibition in the low micromolar range and unappreciable activity towards hBChE. While docking studies provided a rational structural explanation for AChE/BChE enzyme and 5-HT6 receptor interaction, in silico prediction of ADME properties of tested compounds suggested further optimization for development of such compounds in the field of MTDL for AD.

Mitogen-like Cerium-Based Nanoparticles Protect Schmidtea mediterranea against Severe Doses of X-rays.

Novel radioprotectors are strongly demanded due to their numerous applications in radiobiology and biomedicine, e.g., for facilitating the remedy after cancer radiotherapy. Currently, cerium-containing nanomaterials are regarded as promising inorganic radioprotectors due to their unrivaled antioxidant activity based on their ability to mimic the action of natural redox enzymes like catalase and superoxide dismutase and to neutralize reactive oxygen species (ROS), which are by far the main damaging factors of ionizing radiation. The freshwater planarian flatworms are considered a promising system for testing new radioprotectors, due to the high regenerative potential of these species and an excessive amount of proliferating stem cells (neoblasts) in their bodies. Using planarian Schmidtea mediterranea, we tested CeO2 nanoparticles, well known for their antioxidant activity, along with much less studied CeF3 nanoparticles, for their radioprotective potential. In addition, both CeO2 and CeF3 nanoparticles improve planarian head blastema regeneration after ionizing irradiation by enhancing blastema growth, increasing the number of mitoses and neoblasts' survival, and modulating the expression of genes responsible for the proliferation and differentiation of neoblasts. The CeO2 nanoparticles' action stems directly from their redox activity as ROS scavengers, while the CeF3 nanoparticles' action is mediated by overexpression of "wound-induced genes" and neoblast- and stem cell-regulating genes.

Influence of the Synthesis Scheme of Nanocrystalline Cerium Oxide and Its Concentration on the Biological Activity of Cells Providing Wound Regeneration.

In the ongoing search for practical uses of rare-earth metal nanoparticles, cerium dioxide nanoparticles (nanoceria) have received special attention. The purpose of this research was to study the biomedical effects of nanocrystalline forms of cerium oxide obtained by different synthesis schemes and to evaluate the effect of different concentrations of nanoceria (from 10-2 to 10-6 M) on cells involved in the regeneration of skin cell structures such as fibroblasts, mesenchymal stem cells, and keratinocytes. Two different methods of nanoceria preparation were investigated: (1) CeO-NPs-1 by precipitation from aqueous solutions of cerium (III) nitrate hexahydrate and citric acid and (2) CeO-NPs-2 by hydrolysis of ammonium hexanitratocerate (IV) under conditions of thermal autoclaving. According to the X-ray diffraction, transmission electron microscopy, and dynamic light scattering data, CeO2-1 consists of individual particles of cerium dioxide (3-5 nm) and their aggregates with diameters of 60-130 nm. CeO2-2 comprises small aggregates of 8-20 nm in diameter, which consist of particles of 2-3 nm in size. Cell cultures of human fibroblasts, human mesenchymal stem cells, and human keratinocytes were cocultured with different concentrations of nanoceria sols (10-2, 10-3, 10-4, 10-5, and 10-6 mol/L). The metabolic activity of all cell types was investigated by MTT test after 48 and 72 h, whereas proliferative activity and cytotoxicity were determined by quantitative cell culture counting and live/dead test. A dependence of biological effects on the method of nanoceria preparation and concentration was revealed. Data were obtained with respect to the optimal concentration of sol to achieve the highest metabolic effect in the used cell cultures. Hypotheses about the mechanisms of the obtained effects and the structure of a fundamentally new medical device for accelerated healing of skin wounds were formulated. The method of nanoceria synthesis and concentration fundamentally and significantly change the biological activity of cell cultures of different types-from suppression to pronounced stimulation. The best biological activity of cell cultures was determined through cocultivation with sols of citrate nanoceria (CeO-NPs-1) at a concentration of 10-3-10-4 M.

Heavily Gd-Doped Non-Toxic Cerium Oxide Nanoparticles for MRI Labelling of Stem Cells.

Recently, human mesenchymal stem cells (hMSc) have attracted a great deal of attention as potential therapeutic agents in the treatment of socially significant diseases. Despite substantial advances in stem-cell therapy, the biological mechanisms of hMSc action after transplantation remain unclear. The use of magnetic resonance imaging (MRI) as a non-invasive method for tracking stem cells in the body is very important for analysing their distribution in tissues and organs, as well as for ensuring control of their lifetime after injection. Herein, detailed experimental data are reported on the biocompatibility towards hMSc of heavily gadolinium-doped cerium oxide nanoparticles (Ce0.8Gd0.2O2-x) synthesised using two synthetic protocols. The relaxivity of the nanoparticles was measured in a magnetic field range from 1 mT to 16.4 T. The relaxivity values (r1 = 11 ± 1.2 mM-1 s-1 and r1 = 7 ± 1.2 mM-1 s-1 in magnetic fields typical of 1.5 and 3 T MRI scanners, respectively) are considerably higher than those of the commercial Omniscan MRI contrast agent. The low toxicity of gadolinium-doped ceria nanoparticles to hMSc enables their use as an effective theranostic tool with improved MRI-contrasting properties.

Regulation of fiber-specific actin expression by the Drosophila SRF ortholog Blistered.

Serum response factor (SRF) has an established role in controlling actin homeostasis in mammalian cells, yet its role in non-vertebrate muscle development has remained enigmatic. Here, we demonstrate that the single Drosophila SRF ortholog, termed Blistered (Bs), is expressed in all adult muscles, but Bs is required for muscle organization only in the adult indirect flight muscles. Bs is a direct activator of the flight muscle actin gene Act88F, via a conserved promoter-proximal binding site. However, Bs only activates Act88F expression in the context of the flight muscle regulatory program provided by the Pbx and Meis orthologs Extradenticle and Homothorax, and appears to function in a similar manner to mammalian SRF in muscle maturation. These studies place Bs in a regulatory framework where it functions to sustain the flight muscle phenotype in Drosophila Our studies uncover an evolutionarily ancient role for SRF in regulating muscle actin expression, and provide a model for how SRF might function to sustain muscle fate downstream of pioneer factors.

Quantum Nondemolition Measurements of Moving Target States.

We present a protocol for probing the state of a quantum system by its resonant coupling and entanglement with a meter system. By continuous measurement of a time evolving meter observable, we infer the evolution of the entangled systems and, ultimately, the state and dynamics of the system of interest. The photon number in a cavity field is thus resolved by simulated monitoring of the Rabi oscillations of a resonantly coupled two-level system, and we propose to regard this as a practical extension of quantum nondemolition measurements with applications in quantum metrology and quantum computing.

Predicting the naturalistic course in anxiety disorders using clinical and biological markers: a machine learning approach.

BACKGROUND: Disease trajectories of patients with anxiety disorders are highly diverse and approximately 60% remain chronically ill. The ability to predict disease course in individual patients would enable personalized management of these patients. This study aimed to predict recovery from anxiety disorders within 2 years applying a machine learning approach. METHODS: In total, 887 patients with anxiety disorders (panic disorder, generalized anxiety disorder, agoraphobia, or social phobia) were selected from a naturalistic cohort study. A wide array of baseline predictors (N = 569) from five domains (clinical, psychological, sociodemographic, biological, lifestyle) were used to predict recovery from anxiety disorders and recovery from all common mental disorders (CMDs: anxiety disorders, major depressive disorder, dysthymia, or alcohol dependency) at 2-year follow-up using random forest classifiers (RFCs). RESULTS: At follow-up, 484 patients (54.6%) had recovered from anxiety disorders. RFCs achieved a cross-validated area-under-the-receiving-operator-characteristic-curve (AUC) of 0.67 when using the combination of all predictor domains (sensitivity: 62.0%, specificity 62.8%) for predicting recovery from anxiety disorders. Classification of recovery from CMDs yielded an AUC of 0.70 (sensitivity: 64.6%, specificity: 62.3%) when using all domains. In both cases, the clinical domain alone provided comparable performances. Feature analysis showed that prediction of recovery from anxiety disorders was primarily driven by anxiety features, whereas recovery from CMDs was primarily driven by depression features. CONCLUSIONS: The current study showed moderate performance in predicting recovery from anxiety disorders over a 2-year follow-up for individual patients and indicates that anxiety features are most indicative for anxiety improvement and depression features for improvement in general.

Achieving malaria testing and treatment targets for children under five in Mozambique: a cost-effectiveness analysis.

BACKGROUND: The entire population of Mozambique is at risk for malaria, which remains one of the leading causes of death. The 2017-2022 National Malaria Strategic Plan focuses on reducing malaria morbidity and mortality in high- and low-transmission areas. This study aimed to estimate the costs and health benefits of six variations of the World Health Organization's "test-and-treat" strategy among children under five. METHODS: A decision tree model was developed that estimates the costs and health outcomes for children under five. Data on probabilities, costs, weights for disability-adjusted life years (DALYs), and quality-adjusted life years (QALYs) were based on peer-reviewed, grey literature, and primary data analysis of the 2018 Malaria Indicator Survey. Six scenarios were compared to the status quo and calculated the incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained, DALY averted, and life saved. Deterministic and probabilistic sensitivity analyses were conducted to understand the effect of parameter uncertainty on the findings. RESULTS: In the base case, reaching the target of 100% testing with rapid diagnostic tests (RDTs; Scenario 1) is more cost-effective than improving the testing rate alone by 10% (Scenario 2). Achieving a 100% (Scenario 3) or a 10% increase in treatment rate (Scenario 4) have ICERs that are lower than Scenarios 1 and 2. Both Scenarios 5 and 6, which represent combinations of Scenarios 1-4, have lower ICERs than their constituent strategies on their own, which suggests that improvements in treatment are more cost-effective than improvements in testing alone. These results held when DALYs averted or lives saved were used as health outcomes. Deterministic and probabilistic sensitivity analyses revealed that the cost-effectiveness of Scenarios 1-6 are subject sensitive to parameter uncertainty, though Scenarios 4 and 5 are the optimal choice when DALYs averted or QALYs gained were used as the measure of health outcomes across all cost-effectiveness thresholds. CONCLUSIONS: Improving testing rates alone among children at risk for malaria has the potential to improve health but may not be the most efficient use of limited resources. Instead, small or large improvements in treatment, whether alone or in conjunction with improvements in testing, are the most cost-effective strategies for children under five in Mozambique.

Photochemical Synthesis and Electrochemical and Photophysical Properties of 2,7-Diarylbenzo[1,2-d:4,3-d']bis(thiazoles).

This article focuses on the development of practical approaches to the preparation of benzo[1,2-d:4,3-d']bis(thiazoles) using blue light-induced photochemical cyclization of N,N'-(1,4-aryl)dithioamides in the presence of p-chloranil as a mild oxidant. The proposed method allows to obtain benzo[1,2-d:4,3-d']bis(thiazoles) containing donor substituents in the conjugated chain. Photophysical and (spectro)electrochemical properties of 2,6-di([2,2'-bithiophen]-5-yl)benzo[1,2-d:4,3-d']bis(thiazole) and -benzo[1,2-d:4,5-d']bis(thiazole) are studied in detail. The properties of the synthesized compounds suggest their potential applications for organic electronics.

Electronic and mechanical anharmonicities in the vibrational spectra of the H-bonded, cryogenically cooled X- · HOCl (X=Cl, Br, I) complexes: Characterization of the strong anionic H-bond to an acidic OH group.

We report vibrational spectra of the H2-tagged, cryogenically cooled X- · HOCl (X = Cl, Br, and I) ion-molecule complexes and analyze the resulting band patterns with electronic structure calculations and an anharmonic theoretical treatment of nuclear motions on extended potential energy surfaces. The complexes are formed by "ligand exchange" reactions of X- · (H2O)n clusters with HOCl molecules at low pressure (∼10-2 mbar) in a radio frequency ion guide. The spectra generally feature many bands in addition to the fundamentals expected at the double harmonic level. These "extra bands" appear in patterns that are similar to those displayed by the X- · HOD analogs, where they are assigned to excitations of nominally IR forbidden overtones and combination bands. The interactions driving these features include mechanical and electronic anharmonicities. Particularly intense bands are observed for the v = 0 → 2 transitions of the out-of-plane bending soft modes of the HOCl molecule relative to the ions. These involve displacements that act to break the strong H-bond to the ion, which give rise to large quadratic dependences of the electric dipoles (electronic anharmonicities) that drive the transition moments for the overtone bands. On the other hand, overtone bands arising from the intramolecular OH bending modes of HOCl are traced to mechanical anharmonic coupling with the v = 1 level of the OH stretch (Fermi resonances). These interactions are similar in strength to those reported earlier for the X- · HOD complexes.

Cost-effectiveness of alcohol use treatments in patients with alcohol-related cirrhosis.

BACKGROUND & AIMS: Alcohol use treatment such as medication-assisted therapies (MATs) and counseling are available and effective in promoting alcohol abstinence. We sought to explore the cost-effectiveness of different alcohol use treatments among patients with compensated alcohol-related cirrhosis (AC). METHODS: We simulated a cohort of patients with compensated AC receiving care from a hepatology clinic over their lifetimes. We estimated costs (in 2017 US$) and benefits in terms of quality-adjusted life years (QALYs) gained from healthcare and societal perspectives. Transition probabilities, costs, and health utility weights were taken from the literature. Treatment effects of FDA-approved MATs (acamprosate and naltrexone) and non-FDA approved MATs (baclofen, gabapentin, and topiramate) and counseling were based on a study of employer-insured patients with AC. We calculated incremental cost-effectiveness ratios (ICERs) and performed one-way and probabilistic sensitivity analyses to understand the impact of parameter uncertainty. RESULTS: Compared to a do-nothing scenario, MATs and counseling were found to be cost-saving from a healthcare perspective, which means that they provide more benefits with less costs than no intervention. Compared to other interventions, acamprosate and naltrexone cost the least and provide the most QALYs. If the effectiveness of MATs and counseling decreased, these interventions would still be cost-effective based on the commonly used $100,000 per QALY gained threshold. Several sensitivity and scenario analyses showed that our main findings are robust. CONCLUSIONS: Among patients with compensated AC, MATs and counseling are extremely cost-effective, and in some cases cost-saving, interventions to prevent decompensation and improve health. Health policies (e.g. payer reimbursement) should emphasize and appropriately compensate for these interventions. LAY SUMMARY: Alcohol use treatments, including physician counseling and medication-assisted therapies (MATs), improve the outcomes of patients with compensated alcohol-related cirrhosis, though use and access have remained suboptimal. In this study, we found that counseling and MATs are extremely cost-effective, and in some cases cost-saving, interventions to help patients with alcohol-related cirrhosis abstain from alcohol and improve their health. Wider use of these interventions should be encouraged.

The Impact of Choosing Wisely Interventions on Low-Value Medical Services: A Systematic Review.

Policy Points Dissemination of Choosing Wisely guidelines alone is unlikely to reduce the use of low-value health services. Interventions by health systems to implement Choosing Wisely guidelines can reduce the use of low-value services. Multicomponent interventions targeting clinicians are currently the most effective types of interventions. CONTEXT: Choosing Wisely aims to reduce the use of unnecessary, low-value medical services through development of recommendations related to service utilization. Despite the creation and dissemination of these recommendations, evidence shows low-value services are still prevalent. This paper synthesizes literature on interventions designed to reduce medical care identified as low value by Choosing Wisely and evaluates which intervention characteristics are most effective. METHODS: We searched peer-reviewed and gray literature from the inception of Choosing Wisely in 2012 through June 2019 to identify interventions in the United States motivated by or using Choosing Wisely recommendations. We also included studies measuring the impact of Choosing Wisely on its own, without interventions. We developed a coding guide and established coding agreement. We coded all included articles for types of services targeted, components of each intervention, results of the intervention, study type, and, where applicable, study quality. We measured the success rate of interventions, using chi-squared tests or Wald tests to compare across interventions. FINDINGS: We reviewed 131 articles. Eighty-eight percent of interventions focused on clinicians only; 48% included multiple components. Compared with dissemination of Choosing Wisely recommendations only, active interventions were more likely to generate intended results (65% vs 13%, p < 0.001) and, among those, interventions with multiple components were more successful than those with one component (77% vs 47%, p = 0.002). The type of services targeted did not matter for success. Clinician-based interventions were more effective than consumer-based, though there is a dearth of studies on consumer-based interventions. Only 17% of studies included a control arm. CONCLUSIONS: Interventions built on the Choosing Wisely recommendations can be effective at changing practice patterns to reduce the use of low-value care. Interventions are more effective when targeting clinicians and using more than one component. There is a need for high-quality studies that include active controls.

Examining Equity Effects of Health Interventions in Cost-Effectiveness Analysis: A Systematic Review.

OBJECTIVE: This systematic review aims to catalogue and describe published applications of equity-informative cost-effectiveness analysis (CEAs). METHODS: Following PRISMA guidelines, we searched Medline for English-language, peer-reviewed CEAs published on or before August 2019. We included CEAs that evaluated 2 or more alternatives; explicitly mentioned equity as a consideration or decision-making principle; and applied an equity-informative CEA method to analyze or examine at least 1 equity criterion in an applied CEA. We extracted data on selected characteristics and analyzed reporting quality using the CHEERS checklist. RESULTS: Fifty-four articles identified through a search and bibliography reviews met the inclusion criteria. All articles were published on or after 2010, with 80% published after 2015. Most studies evaluated primary prevention interventions in disease areas such as cancer, infectious diseases, and cardiovascular disease. Equity impact analysis alone was the most common equity-informative CEA (56%), followed by equity impact analysis with financial protection effects (30%). At least 11 different equity criteria have been used in equity-informative CEAs; socioeconomic status and race/ethnicity were used most frequently. Seventy-eight percent of studies reported finding "greater value" in an intervention after examining its distributional effects. CONCLUSION: The number of equity-informative CEAs is increasing, and the wide range of equity criteria, diseases, interventions, settings, and populations represented suggests that broad application of these methods is feasible but will require further refinement. Inclusion of equity into CEAs may shift the value of evaluated interventions and can provide crucial additional information for decision makers.

Cost-effectiveness of implantable ventricular assist devices in older children with stable, inotrope-dependent dilated cardiomyopathy.

BACKGROUND: In a stable, inotrope-dependent pediatric patient with dilated cardiomyopathy, we evaluated the cost-effectiveness of continuous-flow VAD implantation compared to a watchful waiting approach using chronic inotropic therapy. METHODS: We used a state-transition model to estimate the costs and outcomes of 14-year-old (INTERMACS profile 3) patients receiving either VAD or watchful waiting. We measured benefits in terms of lifetime QALYs gained. Model inputs were taken from the literature. We calculated the ICER, or the cost per additional QALY gained, of VADs and performed multiple sensitivity analyses to test how our assumptions influenced the results. RESULTS: Compared to watchful waiting, VADs produce 0.97 more QALYs for an additional $156 639, leading to an ICER of $162 123 per QALY gained from a healthcare perspective. VADs have 17% chance of being cost-effective given a cost-effectiveness threshold of $100 000 per QALY gained. Sensitivity analyses suggest that VADs can be cost-effective if the costs of implantation decrease or if hospitalization costs or mortality among watchful waiting patients is higher. CONCLUSIONS: As a bridge to transplant, VADs provide a health benefit to children who develop stable, inotrope-dependent heart failure, but immediate implantation is not yet a cost-effective strategy compared to watchful waiting based on commonly used cost-effectiveness thresholds. Early VAD support can be cost-effective in sicker patients and if device implantation is cheaper. In complex conditions such as pediatric heart failure, cost-effectiveness should be just one of many factors that inform clinical decision-making.

Dose-Dependent Effects of Cold Atmospheric Argon Plasma on the Mesenchymal Stem and Osteosarcoma Cells In Vitro.

The antimicrobial, anti-inflammatory and tissue-stimulating effects of cold argon atmospheric plasma (CAAP) accelerate its use in various fields of medicine. Here, we investigated the effects of CAAP at different radiation doses on mesenchymal stem cells (MSCs) and human osteosarcoma (MNNG/HOS) cells. We observed an increase in the growth rate of MSCs at sufficiently low irradiation doses (10-15 min) of CAAP, while the growth of MNNG/HOS cells was slowed down to 41% at the same irradiation doses. Using flow cytometry, we found that these effects are associated with cell cycle arrest and extended death of cancer cells by necrosis. Reactive oxygen species (ROS) formation was detected in both types of cells after 15 min of CAAP treatment. Evaluation of the genes' transcriptional activity showed that exposure to low doses of CAAP activates the expression of genes responsible for proliferation, DNA replication, and transition between phases of the cell cycle in MSCs. There was a decrease in the transcriptional activity of most of the studied genes in MNNG/HOS osteosarcoma cancer cells. However, increased transcription of osteogenic differentiation genes was observed in normal and cancer cells. The selective effects of low and high doses of CAAP treatment on cancer and normal cells that we found can be considered in terms of hormesis. The low dose of cold argon plasma irradiation stimulated the vital processes in stem cells due to the slight generation of reactive oxygen species. In cancer cells, the same doses evidently lead to the formation of oxidative stress, which was accompanied by a proliferation inhibition and cell death. The differences in the cancer and normal cells' responses are probably due to different sensitivity to exogenous oxidative stress. Such a selective effect of CAAP action can be used in the combined therapy of oncological diseases such as skin neoplasms, or for the removal of remaining cancer cells after surgical removal of a tumor.

Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments.

Schizophrenia is a major mental illness characterized by positive and negative symptoms, and by cognitive deficit. Although cognitive impairment is disabling for patients, it has been largely neglected in the treatment of schizophrenia. There are several reasons for this lack of treatments for cognitive deficit, but the complexity of its etiology-in which neuroanatomic, biochemical and genetic factors concur-has contributed to the lack of effective treatments. In the last few years, there have been several attempts to develop novel drugs for the treatment of cognitive impairment in schizophrenia. Despite these efforts, little progress has been made. The latest findings point to the importance of developing personalized treatments for schizophrenia which enhance neuroplasticity, and of combining pharmacological treatments with non-pharmacological measures.

Analysis of Pharmacovigilance Databases for Dolutegravir Safety in Pregnancy.

BACKGROUND: The Botswana Tsepamo study reported neural tube defects (NTDs) in 4 of 426 (0.94%) infants of women receiving preconception dolutegravir (DTG) antiretroviral therapy (ART) vs 14 of 11 300 (0.12%) receiving preconception non-DTG ART. Data are needed to investigate this potential safety signal. Clinicians, patients, and pharmaceutical companies can report adverse drug reactions (ADRs) to pharmacovigilance databases. Data from ADRs reported to various pharmacovigilance databases were searched for NTDs. METHODS: Four pharmacovigilance databases (World Health Organization [WHO] VigiAccess; United Kingdom Medicines Health Regulatory Authority [UK MHRA]; European Medicines Agency [EMA] EudraVigilance; US Food and Drug Administration Adverse Event Reporting System [FAERS]) with online data availability were analyzed for NTD reports for 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), 2 protease inhibitors (darunavir, atazanavir), and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine, efavirenz). Reports in the system organ class "congenital or familial disorders" were searched for NTDs. RESULTS: NTDs have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases (WHO VigiAccess, 116 reactions; UK MHRA, 8 cases; EMA EudraVigilance, 20 cases; FAERS, 44 cases). Six NTDs were identified for DTG across the pharmacovigilance databases. Cases were very hard to interpret, given the lack of clear denominators. CONCLUSIONS: Pharmacovigilance databases have many limitations, most importantly lack of a clear denominator for patients exposed to the drug of interest and duplicate cases that are difficult to identify. Given widespread use of new antiretroviral drugs worldwide and anticipated use of new drugs, prospective follow-up of pregnant women and birth surveillance studies such as Tsepamo are critically needed.

Aging and central vision loss: Relationship between the cortical macro-structure and micro-structure.

Aging and central vision loss are associated with cortical atrophies, but little is known about the relationship between cortical thinning and the underlying cellular structure. We compared the macro- and micro-structure of the cortical gray and superficial white matter of 38 patients with juvenile (JMD) or age-related (AMD) macular degeneration and 38 healthy humans (19-84 years) by multimodal MRI including diffusion-tensor imaging (DTI). A factor analysis showed that cortical thickness, tissue-dependent measures, and DTI-based measures were sensitive to distinct components of brain structure. Age-related cortical thinning and increased diffusion were observed across most of the cortex, but increased T1-weighted intensities (frontal), reduced T2-weighted intensities (occipital), and reduced anisotropy (medial) were limited to confined cortical regions. Vision loss was associated with cortical thinning and enhanced diffusion in the gray matter (less in the white matter) of the occipital central visual field representation. Moreover, AMD (but not JMD) patients showed enhanced diffusion in lateral occipito-temporal cortex and cortical thinning in the posterior cingulum. These findings demonstrate that changes in brain structure are best quantified by multimodal imaging. They further suggest that age-related brain atrophies (cortical thinning) reflect diverse micro-structural etiologies. Moreover, juvenile and age-related macular degeneration are associated with distinct patterns of micro-structural alterations.