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Abstract Background The cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer’s disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood. Methods We enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson’s dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores. Results A total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [β std] = -0.25, P = 0.01), female (β std = 0.20, P = 0.04), and diabetes mellitus (β std = -0.22, P

Abstract Greenland ice core records exhibited 100-fold higher dust concentrations during the Last Glacial Maximum (LGM) than during the Holocene, and dust input temporal variability corresponded to different climate states in the LGM. While East Asian deserts, the Sahara, and European loess have been suggested as the potential source areas (PSAs) for Greenland LGM dust, millennial-scale variability in their relative contributions within the LGM remains poorly constrained. Here, we present the morphological, mineralogical, and geochemical characteristics of insoluble microparticles to constrain the provenance of dust in Greenland NEEM ice core samples covering cold Greenland Stadials (GS)-2.1a to GS-3 (~ 14.7 to 27.1 kyr ago) in the LGM. The analysis was conducted on individual particles in microdroplet samples by scanning electron microscopy with energy dispersive X-ray spectroscopy and Raman microspectroscopy. We found that the kaolinite-to-chlorite (K/C) ratios and chemical index of alteration (CIA) values were substantially higher (K/C: 1.4 ± 0.7, CIA: 74.7 ± 2.9) during GS-2.1a to 2.1c than during GS-3 (K/C: 0.5 ± 0.1, CIA: 65.8 ± 2.8). Our records revealed a significant increase in Saharan dust contributions from GS-2.1a to GS-2.1c and that the Gobi Desert and/or European loess were potential source(s) during GS-3. This conclusion is further supported by distinctly different carbon contents in particles corresponding to GS-2.1 and GS-3. These results are consistent with previous estimates of proportional dust source contributions obtained using a mixing model based on Pb and Sr isotopic compositions in NEEM LGM ice and indicate millennial-scale changes in Greenland dust provenance that are probably linked to large-scale atmospheric circulation variabilities during the LGM.

Abstract Normal pressure hydrocephalus (NPH) patients had altered white matter tract integrities on diffusion tensor imaging (DTI). Previous studies suggested disproportionately enlarged subarachnoid space hydrocephalus (DESH) as a prognostic sign of NPH. We examined DTI indices in NPH subgroups by DESH severity and clinical symptoms. This retrospective case–control study included 33 NPH patients and 33 age-, sex-, and education-matched controls. The NPH grading scales (0–12) were used to rate neurological symptoms. Patients with NPH were categorized into two subgroups, high-DESH and low-DESH groups, by the average value of the DESH scale. DTI indices, including fractional anisotropy, were compared across 14 regions of interest (ROIs). The high-DESH group had increased axial diffusivity in the lateral side of corona radiata (1.43 ± 0.25 vs. 1.72 ± 0.25, p = 0.04), and showed decreased fractional anisotropy and increased mean, and radial diffusivity in the anterior and lateral sides of corona radiata and the periventricular white matter surrounding the anterior horn of lateral ventricle. In patients with a high NPH grading scale, fractional anisotropy in the white matter surrounding the anterior horn of the lateral ventricle was significantly reduced (0.36 ± 0.08 vs. 0.26 ± 0.06, p = 0.03). These data show that DESH may be a biomarker for DTI-detected microstructural alterations and clinical symptom severity.

Abstract Background Mesenchymal stem cells (MSCs) have immunomodulatory properties and therapeutic effects on autoimmune diseases through their secreted factors, referred to as the secretome. However, the specific key factors of the MSC secretome and their mechanisms of action in immune cells have not been fully determined. Most in vitro experiments are being performed using immune cells, but experiments using natural killer (NK) cells have been neglected, and a few studies using NK cells have shown discrepancies in results. NK cells are crucial elements of the immune system, and adjustment of their activity is essential for controlling various pathological conditions. The aim of this study was to elucidate the role of the adipose tissue-derived stem cell (ADSC) secretome on NK cell activity. Methods To obtain the ADSC secretome, we cultured ADSCs in medium and concentrated the culture medium using tangential flow filtration (TFF) capsules. We assessed NK cell viability and proliferation using CCK-8 and CFSE assays, respectively. We analyzed the effects of the ADSC secretome on NK cell activity and pathway-related proteins using a combination of flow cytometry, ELISA, cytotoxicity assay, CD107a assay, western blotting, and quantitative real-time PCR. To identify the composition of the ADSC secretome, we performed LC–MS/MS profiling and bioinformatics analysis. To elucidate the molecular mechanisms involved, we used mRNA sequencing to profile the transcriptional expression of human blood NK cells. Results The ADSC secretome was found to restrict IL-2-mediated effector function of NK cells while maintaining proliferative potency. This effect was achieved through the upregulation of the inhibitory receptor CD96, as well as downregulation of activating receptors and IL-2 receptor subunits IL-2Rα and IL-2Rγ. These changes were associated with attenuated JAK-STAT and AKT pathways in NK cells, which were achieved through the upregulation of cytokine-inducible SH2-containing protein (CIS, encoded by Cish) and dual specificity protein phosphatase 4 (DUSP4). Furthermore, proteomic analysis revealed twelve novel candidates associated with the immunomodulatory effects of MSCs. Conclusions Our findings reveal a detailed cellular outcome and regulatory mechanism of NK cell activity by the ADSC secretome and suggest a therapeutic tool for treating NK-mediated inflammatory and autoimmune diseases using the MSC secretome.

Background: Using a U.S. based, nationally representative sample, this study compares stillbirth and preterm birth outcomes between women living with HIV (WWH) who did and did not use antiretroviral therapy (ART) during pregnancy, additionally assessing ART duration and regimen type. Methods: Using 2001 to 2012 Medicaid Analytic eXtract (MAX) data from the 14 states with the highest prevalence of HIV. We estimated two, propensity score matched, multivariate logistic regression models for both outcomes of stillbirth and preterm birth: (1) any ART use and (2) the number of months on ART during pregnancy for ART users, adjusting for patient-level covariates. Results: Only 34.6% of pregnancies among WWH had a history of ART use and among those, the proportions of stillbirth and preterm birth were 0.9% and 7.9%, respectively. Any ART use was not significantly associated with either outcome of stillbirth (marginal effects [MEs]: 0.06%, 95% confidence interval [CI]: ?0.17 to 0.28) or preterm birth (ME: ?0.12%, 95% CI: ?0.79 to 0.55). For ART users, duration of ART was not significantly associated with either outcome. Black race was a strong independent predictor in both models (stillbirth: 0.80% and 0.84%, preterm birth: 4.19% and 3.76%). Neither protease inhibitor (PI) nor boosted PI regimens were more strongly associated with stillbirth or preterm birth than nucleoside reverse transcriptase inhibitor-based regimens. Conclusion: ART use during pregnancy was low during this period. Our findings suggest that ART use and ART regimen are not associated, positively or negatively, with stillbirth or preterm birth for mothers with Medicaid. Additionally, our findings highlight a persisting need to address disparities in these outcomes for Black women.

Abstract The aim of the present study was to predict amyloid-beta positivity using a conventional T1-weighted image, radiomics, and a diffusion-tensor image obtained by magnetic resonance imaging (MRI). We included 186 patients with mild cognitive impairment (MCI) who underwent Florbetaben positron emission tomography (PET), MRI (three-dimensional T1-weighted and diffusion-tensor images), and neuropsychological tests at the Asan Medical Center. We developed a stepwise machine learning algorithm using demographics, T1 MRI features (volume, cortical thickness and radiomics), and diffusion-tensor image to distinguish amyloid-beta positivity on Florbetaben PET. We compared the performance of each algorithm based on the MRI features used. The study population included 72 patients with MCI in the amyloid-beta-negative group and 114 patients with MCI in the amyloid-beta-positive group. The machine learning algorithm using T1 volume performed better than that using only clinical information (mean area under the curve [AUC]: 0.73 vs. 0.69, p

Background Dose reduction of direct oral anticoagulant (DOAC) medications is inconsistently applied to older adults with multiple morbidities, potentially due to perceived harms and unknown benefits of standard dosing. Methods and Results Using 2013 to 2017 US Medicare claims linked to Minimum Data Set records, we conducted a retrospective cohort study. We identified DOAC initiators (apixaban, dabigatran, rivaroxaban) aged ≥65 years with nonvalvular atrial fibrillation residing in a nursing home. We estimated inverse‐probability of treatment weights for DOAC dose using propensity scores. We examined safety (hospitalization for major bleeding) and effectiveness outcomes (all‐cause mortality, thrombosis [myocardial infarction, stroke, systemic embolism, venous thromboembolism]). We estimated hazard ratios (HRs) and 95% CIs using cause‐specific hazard‐regression models. Of 21 878 DOAC initiators, 48% received reduced dosing. The mean age of residents was 82.0 years, 66% were female, and 31% had moderate/severe cognitive impairment. After estimating inverse‐probability of treatment weights, standard dosing was associated with a higher rate of bleeding (HR, 1.18 [95% CI, 1.03–1.37]; 9.4 versus 8.0 events per 100 person‐years). Standard‐dose therapy was associated with the highest rates of bleeding among those aged >80 years (9.1 versus 6.7 events per 100 person‐years) and with a body mass index

Abstract Lipophilic but not hydrophilic statins have been shown to be associated with reduced risk for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. We investigated differential actions of lipophilic and hydrophilic statins and their ability to modulate a clinical prognostic liver signature (PLS) predicting HCC risk in patients with liver disease. Hepatitis C virus (HCV)–infected Huh7.5.1 cells, recently developed as a model to screen HCC chemopreventive agents, were treated with lipophilic statins (atorvastatin and simvastatin) and hydrophilic statins (rosuvastatin and pravastatin), and then analyzed by RNA sequencing and PLS. Lipophilic statins, particularly atorvastatin, more significantly suppressed the HCV‐induced high‐risk pattern of PLS and genes in YAP and AKT pathway implicated in fibrogenesis and carcinogenesis, compared with the hydrophilic statins. While atorvastatin inhibited YAP activation through the mevalonate pathway, the distinctive AKT inhibition of atorvastatin was mediated by stabilizing truncated retinoid X receptor alpha, which has been known to enhance AKT activation, representing a target for HCC chemoprevention. In addition, atorvastatin modulated the high‐risk PLS in an in vitro model of nonalcoholic fatty liver disease (NAFLD). Conclusion: Atorvastatin distinctively inhibits YAP and AKT activation, which are biologically implicated in HCC development, and attenuates a high‐risk PLS in an in vitro model of HCV infection and NAFLD. These findings suggest that atorvastatin is the most potent statin to reduce HCC risk in patients with viral and metabolic liver diseases.

This study examined the impact of university students’ perceptions of food insecurity on psychological well-being, self-efficacy, and life satisfaction and observed that the students’ gender plays a moderating role in this causal relationship, based on a total of 491 university students who participated in this empirical study. This study used SPSS (Version 22.0) and AMOS (Version 20.0) for the analyses. This study examines the structural relationship of this causal model. Our findings suggest that students’ perceived food insecurity negatively affects the status of their psychological well-being and self-efficacy. However, contrary to expectations, perceived food insecurity has no negative effects on students’ life satisfaction. In addition, the level of students’ psychological well-being positively influences their life satisfaction, while self-efficacy does not. The moderating effects of gender differences in this research were also disclosed. Limitations and future research directions are also discussed.

Introduction: Women living with human immunodeficiency virus (WLHIV) may face additional challenges and differential birth outcomes when compared with women without human immunodeficiency virus (HIV). There is limited research to date studying birth outcomes among a nationally representative sample of WLHIV. This study compares stillbirth and prematurity rates between HIV-positive (HIV+) and HIV-negative (HIV?) mothers in the Medicaid program. Methods: We used 12 years (2001?2012) of Medicaid Analytic eXtract data. We included Medicaid claims from the 14 states with the highest prevalence of HIV: California, Florida, Georgia, Illinois, Louisiana, Massachusetts, Maryland, North Carolina, New Jersey, New York, Ohio, Pennsylvania, Texas, and Virginia. Primary outcomes were stillbirth and preterm birth. We used logistic regression models adjusting for age, race, Medicaid coverage, eligibility, substance use, rurality, comorbidities, and state fixed effects to compare differences in rates for women with and without HIV. Results: Our study included a total of 33,078 HIV+ and 7,663,758 HIV? pregnancies from Medicaid enrollees between 2001 and 2012. The proportions of stillbirths and preterm births were higher for HIV+ when compared with HIV? mothers (0.9% vs. 0.7% and 8.0% vs. 6.6%, p?0.0001). After adjusting for covariates, being HIV+ was not significantly associated with both stillbirth (odds ratio [OR]: 1.05) or prematurity (OR: 1.01). Black race was a strong independent predictor of both stillbirth and prematurity (OR: 1.99 and 1.51, p?

Abstract Background Current understanding of hematopoiesis is largely derived from mouse models that are physiologically distant from humans. Humanized mice provide the most physiologically relevant small animal model to study human diseases, most notably preclinical gene therapy studies. However, the clonal repopulation dynamics of human hematopoietic stem and progenitor cells (HSPC) in these animal models is only partially understood. Using a new clonal tracking methodology designed for small sample volumes, we aim to reveal the underlying clonal dynamics of human cell repopulation in a mouse environment. Methods Humanized bone marrow-liver-thymus (hu-BLT) mice were generated by transplanting lentiviral vector-transduced human fetal liver HSPC (FL-HSPC) in NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice implanted with a piece of human fetal thymus. We developed a methodology to track vector integration sites (VIS) in a mere 25 µl of mouse blood for longitudinal and quantitative clonal analysis of human HSPC repopulation in mouse environment. We explored transcriptional and epigenetic features of human HSPC for possible VIS bias. Results A total of 897 HSPC clones were longitudinally tracked in hu-BLT mice—providing a first-ever demonstration of clonal dynamics and coordinated expansion of therapeutic and control vector-modified human cell populations simultaneously repopulating in the same humanized mice. The polyclonal repopulation stabilized at 19 weeks post-transplant and the contribution of the largest clone doubled within 4 weeks. Moreover, 550 (~ 60%) clones persisted over 6 weeks and were highly shared between different organs. The normal clonal profiles confirmed the safety of our gene therapy vectors. Multi-omics analysis of human FL-HSPC revealed that 54% of vector integrations in repopulating clones occurred within ± 1 kb of H3K36me3-enriched regions. Conclusions Human repopulation in mice is polyclonal and stabilizes more rapidly than that previously observed in humans. VIS preference for H3K36me3 has no apparent negative effects on HSPC repopulation. Our study provides a methodology to longitudinally track clonal repopulation in small animal models extensively used for stem cell and gene therapy research and with lentiviral vectors designed for clinical applications. Results of this study provide a framework for understanding the clonal behavior of human HPSC repopulating in a mouse environment, critical for translating results from humanized mice models to the human settings.

Background and Objective Although sleep is a potentially important determinant of performance in esports, there have been no published data on the sleep behavior of professional esports athletes. The aim of this study is to investigate sleep aspects and sleep risk factors in esports athletes. Methods Thirty-four esports athletes were compared with 21 nonathletes from the general population to assess their sleep patterns and mood. Study 1 is a quantitative study with a 2-week observation period of sleep that was performed after evaluating insomnia severity, daytime sleepiness, sleep knowledge, and mood state. During the sleep observation period, participants recorded sleep diaries. In study 2, qualitative research was conducted with in-depth interviews from 6 participants. Results The esports athlete group reported significantly delayed sleep phase compared to the nonathlete group (d = 2.10 hours, p < 0.001). The esports athlete group reported significantly lower sleep quality and scores for feeling refreshed upon awakening, higher depression scores and significantly higher proportion of individuals with clinical symptoms of depression compared to the nonathlete group (ps < 0.01). In study 2, six themes emerged from the interviews: sleep risk factors, sleep protective factors, lifestyle, stressors, organizational management, and demands for sleep/psychological intervention. Conclusions The professional esports athletes showed more depressed mood and more delayed sleep phase compared to the non-athletes. A wide range of interventions tailored to esports athletes should be developed and implemented on both individual and organizational levels.

Natural killer (NK) cells are innate immune lymphocytes that play an important role in anti-viral and anti-tumour immune responses. Several cancer immunotherapy approaches targeting NK cells are currently in clinical or preclinical development. Here, we aimed to find food nutrients that activate NK cells and determine their usefulness as candidates for anti-cancer and anti-metastatic drugs. Resveratrol appeared to activate NK cells most effectively among the substances tested and synergistically increased IFN-γ secretion and NK cell cytotoxicity with interleukin-2 (IL-2). CD107a, NKp30, and NKG2D expression levels were upregulated on the surface of NK cells upon treatment with resveratrol in combination with IL-2 compared with treatment with IL-2 alone. Moreover, NK cell activity in human and mouse whole blood was enhanced upon treatment with resveratrol. Most importantly, administration of resveratrol effectively inhibited tumour growth and metastasis in mice. In conclusion, we suggest that resveratrol may represent a candidate anti-cancer drug that acts by activating NK cells in vivo.

Abstract Background While the traditional Medicare program imposes a deductible for hospital admissions, many Medicare Advantage plans have instituted per-diem copayments for hospital care. Little evidence exists about the effects of changes in cost-sharing for hospital care among the elderly. Changing inpatient benefits from a deductible to a per diem may benefit enrollees with shorter lengths of stay, but adversely affect the out-of-pocket burden for hospitalized enrollees with longer lengths of stay. Methods We used a quasi-experimental difference-in-differences study to compare longitudinal changes in proportion hospitalized, inpatient admissions and days per 100 enrollees, and hospital length of stay between enrollees in MA plans that changed inpatient benefit from deductible at admission to per diem, intervention plans, and enrollees in matched control plans – similar plans that maintained inpatient deductibles. The study population included 423,634 unique beneficiaries enrolled in 23 intervention plans and 36 matched control plans in the 2007–2010 period. Results The imposition of per-diem copayments were associated with adjusted declines of 1.3 admissions/100 enrollees (95% CI − 1.8 to − 0.9), 6.9 inpatient days/100 enrollees (95% CI − 10.1 to − 3.8) and 0.7 percentage points in the probability of hospital admission (95% CI − 1.0 to − 0.4), with no significant change in adjusted length of stay in intervention plans relative to control plans. For persons with 2 or more hospitalizations in the year prior to the cost-sharing change, adjusted declines were 3.5 admissions/100 (95% CI − 8.4 to 1.4), 31.1 days/100 (95% CI − 75.2 to 13.0) and 2.2 percentage points in the probability of hospitalization (95% CI − 3.8 to − 0.6) in intervention plans relative to control plans. Conclusions Instituting per-diem copayments was associated with reductions in number of admissions and hospital stays, but not length of stay once admitted. Effects of inpatient cost-sharing changes were magnified for persons with greater baseline use of hospital care.

The obesity problem has reached a critical level and is threatening not only personal health but also public health systems around the world. Obesity in young adults is especially rapidly growing and many studies have confirmed that the best prevention is developing healthy eating habits with the improvement of food and health promotion literacy competencies. In this context, this study diagnoses the present levels of food literacy and health promotion literacy among young adults and explores the relationships between both literacies and their healthy eating habits. A total of 325 young adults in South Korea participated in this research, and the results are as follows. First, all food literacy components, which are food and nutrition knowledge, food skills, and resilience, are positively associated with healthy eating habits. Second, health promotion literacy is also positively associated with young adults’ healthy eating habits. Lastly, unlike the primary information sources, gender has a moderating effect on the relationships between both literacies and healthy eating habits. This indicates that the government and educational sectors should propose more policy supports and solid education systems in order to help young adults develop their food and health promotion literacies for overall well-being in the future.

Fucoxanthin (FCX) is a xanthophyll carotenoid present in brown seaweed. The goal of this study was to examine whether FCX supplementation could attenuate obesity-associated metabolic abnormalities, fibrosis, and inflammation in two diet-induced obesity (DIO) mouse models. C57BL/6J mice were fed either a high-fat/high-sucrose/high-cholesterol (HFC) diet or a high-fat/high-sucrose (HFS) diet. The former induces more severe liver injury than the latter model. In the first study, male C57BL/6J mice were fed an HFC diet, or an HFC diet containing 0.015% or 0.03% (w/w) FCX powder for 12 weeks to develop obesity-induced nonalcoholic steatohepatitis (NASH). In the second study, mice were fed an HFS diet or an HFS diet containing 0.01% FCX powder for 8 weeks. FCX did not change body weight gain and serum lipid profiles compared to the HFC or HFS controls. No significant differences were present in liver triglyceride and total cholesterol, hepatic fat accumulation, and serum alanine aminotransferase levels between control and FCX-fed mice regardless of whether they were on an HFC or HFS diet. FCX did not mitigate mRNA abundance of genes involved in lipid synthesis, cholesterol metabolism, inflammation, and fibrosis in the liver and white adipose tissue, while hepatic fatty acid β-oxidation genes were significantly elevated by FCX in both HFC and HFS feeding studies. Additionally, in the soleus muscle, FCX supplementation significantly elevated genes that regulate mitochondrial biogenesis and fatty acid β-oxidation, concomitantly increasing mitochondrial DNA copy number, compared with HFC. In summary, FCX supplementation had minor effects on hepatic and white adipose inflammation and fibrosis in two different DIO mouse models.

Accumulation of aggregated amyloid-β (Aβ) in the brain is considered the first pathological event within the pathogenesis of Alzheimer’s disease (AD). It is difficult to accurately identify the initial brain regions of Aβ accumulation due to the time-lag between the start of the pathophysiology and symptom onset. However, focal regional amyloid uptake on amyloid PET scans may provide insights into this. Hence, we aimed to evaluate the topographic distribution of amyloid deposition in patients with cognitive impairment and to identify the starting order of amyloid accumulation in the brain using conditional probability. We enrolled 58 patients composed of 9 normal cognition (NC), 32 mild cognitive impairment (MCI), and 17 dementia showing focal regional amyloid deposition corresponding to a brain amyloid plaque load (BAPL) score of 2 among those who visited the Memory Clinic of Asan Medical Center and underwent an 18F-florbetaben PET scan (March 2013 to April 2019). Regions of interest (ROI) included the frontal, parietal, lateral temporal, and occipital cortices, the posterior cingulate/precuneus, and the striatum. The most frequent occurrence of Aβ deposition was in the posterior cingulate/precuneus (n = 41, 68.3%). The second most frequent site was the lateral temporal cortex (n = 24, 40.0%), followed by the lateral parietal cortex (n = 21, 35.6%) and other lesions, such as the frontal and occipital cortices. The striatum was the least frequently affected. Our study found that the posterior cingulate/precuneus and the lateral temporal and parietal cortices may be the earliest areas to be affected by Aβ accumulation. Longitudinal follow-up of focal brain amyloid deposition may help elucidate the evolutionary pattern of Aβ accumulation in the brain of people with AD continuum.

Objective: Current guidelines for gout recommend a treat-to-target approach with serum uric acid (SUA). However, there is little evidence for the dose-dependent effects of urate-lowering therapy (ULT). Herein, we analyzed the reported SUA-lowering effect and SUA target achievement differences for various doses of xanthine oxidase inhibitors. Methods: Approved ULT drugs were selected from the FDA Drug Database. We included prospective randomized controlled trials of ULT drugs from ClinicalTrials.gov, articles published in the journal “Drugs”, and Embase, a literature database. A meta-analysis was performed to determine the ability of different ULT drugs and doses to lower and maintain a target SUA < 6 mg/dL. Results: We identified 35 trials including 8172 patients with a baseline SUA of 8.92 mg/dL. The allopurinol, febuxostat, and topiroxostat showed dose-proportional SUA-lowering responses. Compared with allopurinol 300 mg daily, febuxostat 80 mg daily and 120 mg daily more effectively maintained SUA < 6 mg/dL. Conclusion: Allopurinol, febuxostat, and topiroxostat showed dose-proportional ability to lower and achieve a target SUA < 6 mg/dL. Significance and Innovations. We showed dose-dependent SUA lowering effects of allopurinol, febuxostat, and topiroxostat. Febuxostat is effective at ULT compared to allopurinol and could be potentially offered as an alternative agent when patients (1) have CKD, (2) have the human leukocyte antigen HLA-B*5801 allele, and (3) become refractory to allopurinol. Gradual allopurinol dose increase with a lower starting dose is needed in CKD.

Background: Traditionally believed to be an integral part of multiple myeloma (MM) treatment, the role of hematopoietic stem-cell transplantation (HSCT) is being challenged. As such, we sought to evaluate the impact of HSCT in the era of novel agents. Methods: A multicenter, retrospective, longitudinal cohort study was carried out between January 2016 and December 2018. A total of 55 patients who received VTD (bortezomib-thalidomide-dexamethasone) as first-line treatment and KRd (carfilzomib-lenalidomide-dexamethasone) as second-line treatment were analyzed for outcomes. Results: The enrolled patients were divided into Group 1, defined as those who continued KRd treatment until progression ( n = 41), versus Group 2, defined as those who underwent HSCT after a certain number of cycles of KRd ( n = 14). Both groups showed a generally favorable response to KRd, with overall response rate (ORR) of 87.9% and clinical benefit rate of 92.8% after a median of seven cycles in Group 1, and ORR 92.8% and clinical benefit rate 100% after median of five cycles in Group 2. However, significantly poorer progression-free survival (PFS) ( p = 0.004) was observed in Group 1 (median 12 months) compared with Group 2 (median not reached). Multivariate analyses identified HSCT after KRd as potential risk factors associated with PFS. Also, in Group 1, bortezomib refractoriness was associated with significantly shorter PFS compared with those who were responsive (median 12 months versus 14 months, respectively, p = 0.039). Conclusions: In conclusion, even with the advent of novel agents, HSCT still remains a valuable treatment modality with additive efficacy.

BackgroundFindings on the association between health literacy and anti-retroviral (ARV) adherence are inconsistent. Health literacy is usually operationalized with simple tests of basic literacy, but more complex conceptions of health literacy include content knowledge. People living with chronic illness also conceptualize and experience illness in ways other than biomedical or mechanistic models of disease.ObjectiveThere are no instruments that comprehensively assess knowledge of people living with HIV concerning HIV disease and treatment; or psychological adjustment to being HIV+. Little is known about the relationship between factual knowledge, or positive identification as HIV+, and anti-retroviral (ARV) adherence.MethodsFormative work with in-depth semi-structured interviews, and cognitive testing, to develop a structured instrument assessing HIV-related knowledge, and personal meanings of living with HIV. Pilot administration of the instrument to a convenience sample of 101 respondents.Key resultsRespondents varied considerably in their expressed need for in-depth knowledge, the accuracy of their understanding of relevant scientific concepts and facts about ARV treatment, and psychological adjustment and acceptance of HIV+ status. Most knowledge domains were not significantly related to self-reported ARV adherence, but accurate knowledge specifically about ARV treatment was (r = 0.25, p = .02), as was an adapted version of the Need for Cognition scale (r = .256, p = .012). Negative feelings about living with HIV (r = .33, p = .0012), and medication taking (r = .276, p = .008) were significantly associated with non-adherence.ConclusionThe instrument may be useful in diagnosing addressable reasons for non-adherence, as a component of psychoeducational interventions, and for evaluation of such interventions.

Tumor metastasis into the central nervous system (CNS) and lymph nodes (LNs) is a major obstacle for effective therapies. Therapeutic monoclonal antibodies (mAb) have revolutionized tumor treatment; however, their efficacy for treating metastatic tumors-particularly, CNS and LN metastases-is poor due to inefficient penetration into the CNS and LNs following intravenous injection. We recently reported an effective delivery of mAb to the CNS by encapsulating the anti-CD20 mAb rituximab (RTX) within a thin shell of polymer that contains the analogs of choline and acetylcholine receptors. This encapsulated RTX, denoted as n-RTX, eliminated lymphoma cells systemically in a xenografted humanized mouse model using an immunodeficient mouse as a recipient of human hematopoietic stem/progenitor cells and fetal thymus more effectively than native RTX; importantly, n-RTX showed notable anti-tumor effect on CNS metastases which is unable to show by native RTX. As an important step toward future clinical translation of this technology, we further analyzed the properties of n-RTX in immunocompetent animals, rats, and non-human primates (NHPs). Our results show that a single intravenous injection of n-RTX resulted in 10-fold greater levels in the CNS and 2-3-fold greater levels in the LNs of RTX, respectively, than the injection of native RTX in both rats and NHPs. In addition, we demonstrate the enhanced delivery and efficient B-cell depletion in lymphoid organs of NHPs with n-RTX. Moreover, detailed hematological analysis and liver enzyme activity tests indicate n-RTX treatment is safe in NHPs. As this nanocapsule platform can be universally applied to other therapeutic mAbs, it holds great promise for extending mAb therapy to poorly accessible body compartments.

Prediction errors (PEs) encode representations of rewarding and aversive experiences and are critical to reinforcement processing. The feedback-related negativity (FRN), a component of the event-related potential (ERP) that is sensitive to valenced feedback, is believed to reflect PE signals. Reinforcement is also studied using frontal midline theta (FMΘ) activity, which peaks around the same time as the FRN and increases in response to unexpected events compared to expected events. We recorded EEG while participants completed a monetary incentive delay (MID) task that included positive reinforcement and negative reinforcement conditions with multiple levels of the outcome, as well as control conditions that had no reinforcement value. Despite the overlap of FRN and FMΘ, these measures indexed dissociable cognitive processing. The FRN was sensitive to errors in both positive and negative reinforcement but not in control conditions, while frontal theta instead was sensitive to outcomes in positive reinforcement and control conditions, but not in negative reinforcement conditions. The FRN was sensitive to the point level of feedback in both positive and negative reinforcement, while FMΘ was not influenced by the feedback point level. Results are consistent with recent results indicating that the FRN is influenced by unsigned PEs (i.e., a salience signal). In contrast, we suggest that our findings for frontal theta are consistent with hypotheses suggesting that the neural generators of FMΘ are sensitive to both negative cues and the need for control.

Lymphomas arising in the central nervous system (CNS) of immunocompromised hosts are most commonly non-Hodgkin’s lymphomas and are highly associated with Epstein-Barr virus (EBV). Here we report an autopsy case of EBV-associated CNS diffuse large B-cell lymphoma (DLBCL) in a host suffering from systemic lupus erythematosus who underwent immunosuppressive therapy. After autopsy, EBV-associated CNS DLBCL as well as pulmonary mixed aspergillosis and Pneumocystis jirovecii pneumonia were added to the cause of clinical manifestations of complicated pneumonia and cerebral hemorrhage in this immunocompromised patient. In conclusion, complex disease processes were revealed by autopsy in this case, indicating that the clinicopathological correlations observed through autopsy can improve our understanding of disease progression and contribute to the management of similar patients in the future.

Abstract Background The initial days of a Medicare-covered skilled nursing facility (SNF) stay may have no cost-sharing or daily copayments depending on beneficiaries’ enrollment in traditional Medicare or Medicare Advantage. Some policymakers have advocated imposing first-dollar cost-sharing to reduce post-acute expenditures. We examined the relationship between first-dollar cost-sharing for a SNF stay and use of inpatient and SNF services. Methods We identified seven Medicare Advantage plans that introduced daily SNF copayments of $25-$150 in 2009 or 2010. Copays began on the first day of a SNF admission. We matched these plans to seven matched control plans that did not introduce first-dollar cost-sharing. In a difference-in-differences analysis, we compared changes in SNF and inpatient utilization for the 172,958 members of intervention and control plans. Results In intervention plans the mean annual number of SNF days per 100 continuously enrolled inpatients decreased from 768.3 to 750.6 days when cost-sharing changes took effect. Control plans experienced a concurrent increase: 721.7 to 808.1 SNF days per 100 inpatients (adjusted difference-in-differences: −87.0 days [95% CI (−112.1,-61.9)]). In intervention plans, we observed no significant changes in the probability of any SNF service use or the number of inpatient days per hospitalized member relative to concurrent trends among control plans. Conclusions Among several strategies Medicare Advantage plans can employ to moderate SNF use, first-dollar SNF cost-sharing may be one influential factor. Trial registration Not applicable.

Improvement of dietary habits is recommended for the management of cerebrovascular and cardiovascular diseases (CCVD). This study aimed to evaluate the dietary habits of CCVD patients and compare them with the general population by using the Diet Quality Index—International (DQI-I). Data from the Korean National Health and Nutrition Examination Surveys (2013–2016) were used. Cardiovascular diseases included myocardial infarction, angina pectoris, and heart failure; and cerebrovascular diseases included stroke, cerebral infarction, and hemorrhage. In total, 12,683 subjects over 20 years old were included, comprising 718 CCVD patients and 11,965 non-CCVD subjects. Survey-weighted multiple linear regression analyses with adjustment for covariates were used to compare DQI-I scores. The mean total DQI-I scores for the CCVD and non-CCVD groups were 66.7 ± 9.2 and 67.8 ± 9.2, respectively. After adjusting for covariates, the CCVD group had DQI-I scores significantly lower than the non-CCVD group (coefficient −1.13, p-value = 0.011). In the analysis of each DQI-I component, the CCVD group had lower scores for variety (coefficient −0.54, p-value = 0.004) and adequacy (coefficient −0.86, p-value = 0.001). In this study, using nationally representative data, dietary habits of CCVD patients were shown to be lower in quality than non-CCVD subjects. Therefore, evaluation and education of adequate dietary habits are needed in the management of CCVD patients.

Among the various types of shape changing materials, liquid crystal elastomers (LCEs) have received significant attention as they can undergo programmed and reversible shape transformations. The molecular engineering of LCEs is the key to manipulating their phase transition, mechanical properties, and actuation performance. In this work, LCEs containing three different types of butyl groups (n-, iso-, and sec-butyl) in the side chain were synthesized, and the effect of isomeric amine chain extenders on the thermal, mechanical, and actuation properties of the resulting LCEs was investigated. Because of the considerably low reactivity of the sec-butyl group toward the diacrylate in the LC monomer, only a densely crosslinked LCE was synthesized. Most interestingly, the mechanical properties, actuation temperature, and blocking stress of the LCEs comprising isobutyl groups were higher than those of the LCEs comprising n-butyl groups. This difference was attributed to the presence of branches in the LCEs with isobutyl groups, which resulted in a tighter molecular packing and reduced the free volume. Our results suggest a facile and effective method for synthesizing LCEs with tailored mechanical and actuation properties by the choice of chain extenders, which may advance the development of soft actuators for a variety of applications in aerospace, medicine, and optics.

While some studies have assessed patient recall of important information from ambulatory care visits, none has done so recently. Furthermore, little is known about features of clinical interactions which are associated with patient understanding and recall, without which shared decision making, a widely shared ideal for patient care, cannot occur. Our objective was to evaluate characteristics of patients and outpatient encounters associated with patient recall of information after one week, along with observation of elements of shared decision making. This was an observational study based on coded transcripts of 189 outpatient encounters, and post-visit interviews with patients 1 week later. Coding used three previously validated systems, adopted for this study. Forty-nine percent of decisions and recommendations were recalled accurately without prompting; 36% recalled with a prompt; 15% recalled erroneously or not at all. Provider behaviors hypothesized to be associated with patient recall, such as open-questioning and "teach back," were rare. Patients with less than high school education recalled 38% of items freely and accurately, while patients with a college degree recalled 65% (p < .0001). In a multivariate model, the total number of items to be recalled per visit, and percentage of utterances in decision-making processes by the provider ("verbal dominance"), were significant predictors of poorer recall. The item count was associated with poorer recall for lower, but not higher, educated patients.

BackgroundOlder patients with aneurysmal subarachnoid hemorrhage (aSAH) are unique, and determinants of post–acute care outcomes are not well elucidated. The primary objective was to identify hospital characteristics associated with 30‐day readmission and mortality rates after hospital discharge among older patients with aSAH. Methods and ResultsThis cohort study used Medicare patients ≥65 years discharged from US hospitals from January 1, 2008, to November 30, 2010, after aSAH. Medicare data were linked to American Hospital Association data to describe characteristics of hospitals treating these patients. Using multivariable logistic regression to adjust for patient characteristics, hospital factors associated with (1) hospital readmission and (2) mortality within 30 days after discharge were identified. A total of 5515 patients ≥65 years underwent surgical repair for aSAH in 431 hospitals. Readmission rate was 17%, and 8.5% of patients died within 30 days of discharge. In multivariable analyses, patients treated in hospitals with lower annualized aSAH volumes were more likely to be readmitted 30 days after discharge (lowest versus highest quintile, 1–2 versus 16–30 cases; adjusted odds ratio, 2.10; 95% confidence interval, 1.56–2.84). Patients treated in hospitals with lower annualized aSAH volumes (lowest versus highest quintile: adjusted odds ratio, 1.52; 95% confidence interval, 1.05–2.19) had a greater likelihood of dying 30 days after discharge. ConclusionsOlder patients with aSAH discharged from hospitals treating lower volumes of such cases are at greater risk of readmission and dying within 30 days. These findings may guide clinician referrals, practice guidelines, and regulatory policies influencing which hospitals should care for older patients with aSAH.

In magnetic resonance imaging, precise measurements of longitudinal relaxation time (T1) is crucial to acquire useful information that is applicable to numerous clinical and neuroscience applications. In this work, we investigated the precision of T1 relaxation time as measured using the variable flip angle method with emphasis on the noise propagated from radiofrequency transmit field (B1+) measurements. The analytical solution for T1 precision was derived by standard error propagation methods incorporating the noise from the three input sources: two spoiled gradient echo (SPGR) images and a B1+ map. Repeated in vivo experiments were performed to estimate the total variance in T1 maps and we compared these experimentally obtained values with the theoretical predictions to validate the established theoretical framework. Both the analytical and experimental results showed that variance in the B1+ map propagated comparable noise levels into the T1 maps as either of the two SPGR images. Improving precision of the B1+ measurements significantly reduced the variance in the estimated T1 map. The variance estimated from the repeatedly measured in vivoT1 maps agreed well with the theoretically-calculated variance in T1 estimates, thus validating the analytical framework for realistic in vivo experiments. We concluded that for T1 mapping experiments, the error propagated from the B1+ map must be considered. Optimizing the SPGR signals while neglecting to improve the precision of the B1+ map may result in grossly overestimating the precision of the estimated T1 values.

Macrophages are polarized into different phenotypes depending on tissue microenvironment where they reside. In obesity-associated inflammation, M1-type macrophages are predominant in the inflamed tissue, exerting pro-inflammatory responses. Our previous studies demonstrate that blackcurrant consumption attenuates hepatic inflammation and lipopolysaccharide-stimulated inflammatory responses of splenocytes in obese mice. In this study, we determined whether blackcurrant modulates macrophage phenotypes to exert its anti-inflammatory action. Mouse bone marrow-derived macrophages (BMDM) and human THP-1 macrophages were polarized into M1 macrophages in the presence or absence of blackcurrant extract (BCE). BCE repressed M1 polarization of both murine and human macrophages. Also, to gain insight into the role of blackcurrant metabolites produced in vivo in the regulation of macrophage phenotypes, BMDM were treated with serum obtained from lean or obese mice fed blackcurrant. While serum from lean mice fed blackcurrant did not exert either anti-inflammatory actions or suppressive effects on M1 polarization, serum from obese mice fed blackcurrant reduced the expression of pro-inflammatory genes in BMDM. Our data demonstrate that BCE suppresses M1 polarization, with reduced pro-inflammatory responses. Moreover, this study suggests that blackcurrant metabolites may not exert their anti-inflammatory effect directly by altering macrophage phenotypes, but possibly by inhibiting the production of obesity-associated inflammatory factors.

OBJECTIVE:To evaluate the seizure characteristics and outcome after immunotherapy in adult patients with autoimmune encephalitis (AE) and new-onset seizure. METHODS:Adult (age ≥18 years) patients with AE and new-onset seizure who underwent immunotherapy and were followed-up for at least 6 months were included. Seizure frequency was evaluated at 2-4 weeks and 6 months after the onset of the initial immunotherapy and was categorized as "seizure remission", "> 50% seizure reduction", or "no change" based on the degree of its decrease. RESULTS:Forty-one AE patients who presented with new-onset seizure were analysed. At 2-4 weeks after the initial immunotherapy, 51.2% of the patients were seizure free, and 24.4% had significant seizure reduction. At 6 months, seizure remission was observed in 73.2% of the patients, although four patients died during hospitalization. Rituximab was used as a second-line immunotherapy in 12 patients who continued to have seizures despite the initial immunotherapy, and additional seizure remission was achieved in 66.6% of them. In particular, those who exhibited partial response to the initial immunotherapy had a better seizure outcome after rituximab, with low adverse events. CONCLUSION:AE frequently presented as seizure, but only 18.9% of the living patients suffered from seizure at 6 months after immunotherapy. Aggressive immunotherapy can improve seizure outcome in patients with AE.

Our current focus on the effects of Photodynamic Therapy (PDT) using silicon phthalocyanine Pc 4 photosensitizer on malignant T lymphocytes arose due to preclinical observations that Jurkat cells, common surrogate for human T cell lymphoma, were more sensitive to Pc 4-PDT-induced killing than epidermoid carcinoma A431 cells. Mycosis fungoides (MF) as well as Sezary syndrome (SS) are variants of cutaneous T-cell lymphoma (CTCL) in which malignant T-cells invade the epidermis. In this study, we investigated the cytotoxicity of Pc 4-PDT in peripheral blood cells obtained from patients with SS and in skin biopsies of patients with MF. Our data suggest that Pc 4-PDT preferentially induces apoptosis of CD4+CD7− malignant T-lymphocytes in the blood relative to CD11b+ monocytes and nonmalignant T-cells. In vivo Pc 4-PDT of MF skin also photodamages the antiapoptotic protein Bcl-2.

Hormone receptor--positive (HR+) disease is the most frequently diagnosed subtype of breast cancer. Among tumor subtypes, natural course of HR+ breast cancer is indolent with favorable prognosis compared to other subtypes such as human epidermal growth factor protein 2--positive disease and triple-negative disease. HR+ tumors are dependent on steroid hormone signaling and endocrine therapy is the main treatment option. Recently, the discovery of cyclin-dependent kinase 4/6 inhibitors and their synergistic effects with endocrine therapy has dramatically improved treatment outcome of advanced HR+ breast cancer. The demonstrated efficacy of additional nonhormonal agents, such as targeted therapy against mammalian target of rapamycin and phosphatidylinositol 3-kinase signaling, poly(ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and immunotherapeutic agents have further expanded the available therapeutic options. This article reviews the latest advancements in the treatment of HR+ breast cancer, and in doing so discusses not only the development of currently available treatment regimens but also emerging therapies that invite future research opportunities in the field. [ABSTRACT FROM AUTHOR]