Global future land use (LU) is an important input for Earth system models for projecting Earth system dynamics and is critical for many modeling studies on future global change. Here we generated a new global gridded LU dataset using the Global Change Analysis Model (GCAM) and a land use spatial downscaling model, named Demeter, under the five Shared Socioeconomic Pathways (SSPs) and four Representative Concentration Pathways (RCPs) scenarios. Compared to existing similar datasets, the presented dataset has a higher spatial resolution (0.05° × 0.05°) and spreads under a more comprehensive set of SSP-RCP scenarios (in total 15 scenarios), and considers uncertainties from the forcing climates. We compared our dataset with the Land Use Harmonization version 2 (LUH2) dataset and found our results are in general spatially consistent with LUH2. The presented dataset will be useful for global Earth system modeling studies, especially for the analysis of the impacts of land use and land cover change and socioeconomics, as well as the characterizing the uncertainties associated with these impacts.Automatic summarization of natural language is a widely studied area in computer science, one that is broadly applicable to anyone who needs to understand large quantities of information. In the medical domain, automatic summarization has the potential to make health information more accessible to people without medical expertise. However, to evaluate the quality of summaries generated by summarization algorithms, researchers first require gold standard, human generated summaries. Unfortunately there is no available data for the purpose of assessing summaries that help consumers of health information answer their questions. To address this issue, we present the MEDIQA-Answer Summarization dataset, the first dataset designed for question-driven, consumer-focused summarization. It contains 156 health questions asked by consumers, answers to these questions, and manually generated summaries of these answers. The dataset's unique structure allows it to be used for at least eight different types of summarization evaluations. We also benchmark the performance of baseline and state-of-the-art deep learning approaches on the dataset, demonstrating how it can be used to evaluate automatically generated summaries.Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.Zika virus (ZIKV) is an emerging mosquito borne flavivirus and a major public health concern causing severe disease. Due to the presence of a lipid membrane and structural heterogeneity, attaining an atomic resolution structure is challenging, but important to understand virus assembly and life cycle mechanisms that offer distinct targets for therapeutic intervention. We here use subvolume refinement to achieve a 3.4 Å resolution structure and identify two distinct lipid moieties. The first arises from the inner leaflet and is coordinated by hydrophobic residues of the M and E transmembrane helices that form a binding pocket not previously characterized. The second lipid arises from the outer leaflet coordinate between two E protein helices. Structure-based mutagenesis identifies critical hydrophobic interactions and their effect on the virus life cycle. Results show that lipids play an essential role in the ZIKV assembly pathway revealing a potential target of lipid based antiviral drug development.The structure and dynamics of liquids on curved surfaces are often studied through the lens of frustration-based approaches to the glass transition. Competing glass transition theories, however, remain largely untested on such surfaces and moreover, studies hitherto have been entirely theoretical/numerical. Here we carry out single particle-resolved imaging of dynamics of bi-disperse colloidal liquids confined to the surface of a sphere. We find that mode-coupling theory well captures the slowing down of dynamics in the moderate to deeply supercooled regime. Strikingly, the morphology of cooperatively rearranging regions changed from string-like to compact near the mode-coupling crossover-a prediction unique to the random first-order theory of glasses. Further, we find that in the limit of strong curvature, Mermin-Wagner long-wavelength fluctuations are irrelevant and liquids on a sphere behave like three-dimensional liquids. A comparative evaluation of competing mechanisms is thus an essential step towards uncovering the true nature of the glass transition.Achieving current electricity sector targets in Central Europe (Austria, Denmark, France, Germany, Poland and Switzerland) will redistribute regional benefits and burdens at sub-national level. Limiting emerging regional inequalities would foster the implementation success. We model one hundred scenarios of electricity generation, storage and transmission for 2035 in these countries for 650 regions and quantify associated regional impacts on system costs, employment, greenhouse gas and particulate matter emissions, and land use. We highlight tradeoffs among the scenarios that minimize system costs, maximize regional equality, and maximize renewable electricity generation. Here, we show that these three aims have vastly different implementation pathways as well as associated regional impacts and cannot be optimized simultaneously. Minimizing system costs leads to spatially-concentrated impacts. Maximizing regional equality of system costs has higher, but more evenly distributed impacts. Maximizing renewable electricity generation contributes to minimizing regional inequalities, although comes at higher costs and land use impacts.Numerous ecosystem manipulative experiments have been conducted since 1970/80 s to elucidate responses of terrestrial carbon cycling to the changing atmospheric composition (CO2 enrichment and nitrogen deposition) and climate (warming and changing precipitation regimes), which is crucial for model projection and mitigation of future global change effects. Here, we extract data from 2,242 publications that report global change manipulative experiments and build a comprehensive global database with 5,213 pairs of samples for plant production (productivity, biomass, and litter mass) and ecosystem carbon exchange (gross and net ecosystem productivity as well as ecosystem and soil respiration). Information on climate characteristics and vegetation types of experimental sites as well as experimental facilities and manipulation magnitudes subjected to manipulative experiments are also included in this database. This global database can facilitate the estimation of response and sensitivity of key terrestrial carbon-cycling variables under future global change scenarios, and improve the robust projection of global change‒terrestrial carbon feedbacks imposed by Earth System Models.Genetic variation is of crucial importance for crop improvement. Landraces are valuable sources of diversity, but for quantitative traits efficient strategies for their targeted utilization are lacking. Here, we map haplotype-trait associations at high resolution in ~1000 doubled-haploid lines derived from three maize landraces to make their native diversity for early development traits accessible for elite germplasm improvement. A comparative genomic analysis of the discovered haplotypes in the landrace-derived lines and a panel of 65 breeding lines, both genotyped with 600k SNPs, points to untapped beneficial variation for target traits in the landraces. The superior phenotypic performance of lines carrying favorable landrace haplotypes as compared to breeding lines with alternative haplotypes confirms these findings. Stability of haplotype effects across populations and environments as well as their limited effects on undesired traits indicate that our strategy has high potential for harnessing beneficial haplotype variation for quantitative traits from genetic resources.Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. https://www.selleckchem.com/products/LY2784544.html These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.Thrombosis leads to platelet activation and subsequent degradation; therefore, replenishment of platelets from hematopoietic stem/progenitor cells (HSPCs) is needed to maintain the physiological level of circulating platelets. Platelet-derived microparticles (PMPs) are protein- and RNA-containing vesicles released from activated platelets. We hypothesized that factors carried by PMPs might influence the production of platelets from HSPCs, in a positive feedback fashion. Here we show that, during mouse acute liver injury, the density of megakaryocyte in the bone marrow increases following an increase in circulating PMPs, but without thrombopoietin (TPO) upregulation. In vitro, PMPs are internalized by HSPCs and drive them toward a megakaryocytic fate. Mechanistically, miR-1915-3p, a miRNA highly enriched in PMPs, is transported to target cells and suppresses the expression levels of Rho GTPase family member B, thereby inducing megakaryopoiesis. In addition, direct injection of PMPs into irradiated mice increases the number of megakaryocytes and platelets without affecting TPO levels. In conclusion, our data reveal that PMPs have a role in promoting megakaryocytic differentiation and platelet production.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

7%) patients died in hospital and 213 011 (84.2%) were discharged home, 18 010 (7.1%) were transferred to another hospital and 17 601 (7%) experienced NHD. In Australia, 14 457 (6.4%) of patients progressed to NHD, compared with 3144 (11.7%) in New Zealand. The rate of NHD increased significantly over time (adjusted OR per year=1.06, 95% CI, 1.06 to 1.07, p<0.001). Increasing age, female sex, non-elective surgery, surgery type and Acute Physiology and Chronic Health Evaluation III Score were all associated with significant increase in NHD.

There was significant increase in NHD after cardiac surgery over time in ANZ. This has significant clinical relevance for informed consent discussions between healthcare providers and patients, and for healthcare services planning.
There was significant increase in NHD after cardiac surgery over time in ANZ. This has significant clinical relevance for informed consent discussions between healthcare providers and patients, and for healthcare services planning.
To report on (a) overall myopia and high myopia prevalence, and (b) the impact of education on the spherical equivalent refractive error in children across Shanghai.

Cross-sectional study.

Across all 17 districts of Shanghai.

910 245 children aged 4-14 years from a school-based survey conducted between 2012 and 2013.

Data of children with non-cycloplegic autorefraction, visual acuity assessment and questionnaire were analysed (67%, n=6 06 476). Prevalence of myopia (≤-1.0 D) and high myopia (≤-5.0 D) was determined. We used a regression discontinuity design to determine the impact of school entry cut-off date (1 September) by comparing refractive errors at each age, for children born pre-September to post-1 September, and performed a multivariate analysis to explore risk factors associated with myopia. Data analysis was performed in 2017-2018.

Prevalence rates of myopia and high myopia were 32.9% (95% CI 32.8% to 33.1%) and 4.2% (95% CI 4.1% to 4.2%), respectively. From 6 years of age onwards, children born pre-September were more myopic compared with those born post-1 September (ahead in school by 1 year, discontinuity at 6 years -0.19 D (95% CI -0.09 to -0.30 D); 14 years -0.67 D (95% CI -0.21 to -1.14 D)).

Our findings suggest that myopia is associated with education, that is primarily focused on near-based activities. Efforts to reduce the burden should be directed to public awareness, reform of education and health systems.
Our findings suggest that myopia is associated with education, that is primarily focused on near-based activities. Efforts to reduce the burden should be directed to public awareness, reform of education and health systems.
Return to sport (RTS) following anterior cruciate ligament reconstruction (ACLR) is the primary goal for most patients. However, the decision of when to RTS is difficult for patients and clinicians as it is based on limited available evidence. Over the past decade, a number of predictor variables have been associated with RTS after ACLR. We present a Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols compliant protocol for a systematic review and meta-analysis of preoperative predictors for RTS/preinjury levels of physical activity following ACLR.

A literature search will be performed in six electronic databases (CINAHL, AMED, MEDLINE, SPORTDiscus and PsycINFO via EBSCOhost and Web of Science) from inception to December 2020. Prospective, retrospective and cross-sectional study designs will be included. To be included, studies will need to identify at least one preoperative predictor and identify the relationship between the predictor(s) and RTS/preinjury levels of physical activity following ACLR. Blinded assessment with consensus agreement will be applied for inclusion of studies, data extraction, risk of bias assessment using the Quality in Prognostic Studies tool and the Grading of Recommendations Assessment, Development and Evaluation framework. If data allows and studies are considered homogeneous, data will be pooled through a meta-analysis. If heterogenous, a narrative synthesis will be completed. Subgroup and sensitivity analyses will be completed, where appropriate.

Ethical permission is not required for this study. The results will be published in a peer-reviewed journal and presented at national and international conferences.

CRD42020222567.
CRD42020222567.
To the best of our knowledge, no case-control study on child and adolescent psychiatric outpatients has investigated the clinical characteristics of patients with child-to-parent violence (CPV). The current study aimed to evaluate the clinical characteristics of child and adolescent psychiatric patients with CPV.

This research included child and adolescent psychiatric patients who were aged 10-15 years during their initial consultation. The participants were allocated to one of two groups children with CPV (CPV group, n=109) and without CPV (non-CPV group, n=713).

This study analysed data including age, sex, diagnostic classification of the primary diagnosis, antisocial behaviour, suicidal attempt or self-harm and refusal to attend school. Moreover, a history of abuse by parents was investigated. Psychological rating scales such as the Spence Children's Anxiety Scale, Depression Self-Rating Scale for Children, Tokyo Autistic Behavior Scale, Attention-deficit/Hyperactivity Disorder-Rating Scale and Oppossought consultation, the findings of the current study should be considered to understand invisible side and to facilitate the use of appropriate treatment approaches. However, a prospective study should be performed to investigate the causality between CPV and clinical characteristics.
Care transitions following stroke should be bridged with collaboration between hospital staff and home rehabilitation teams since well-coordinated transitions can reduce death and disability following a stroke. However, health services are delivered within organisational structures, rather than being based on patients' needs. The aim of this study protocol is to assess the feasibility, operationalised here as fidelity and acceptability, of a codesigned care transition support for people with stroke.

This study protocol describes the evaluation of a feasibility study using a non-randomised controlled design. The codesigned care transition support includes patient information using videos, leaflets and teach back; what-matters-to me dialogue; a coordinated rehabilitation plan; bridged e-meeting; and a message system for cross-organisational collaboration. Patients with stroke, first time or recurrent, who are to be discharged home from hospital and referred to a rehabilitation team in primary healthcare fornt healthcare. The development of this codesigned care transition support has involved people with stroke, significant other, and healthcare professionals. Such involvement has the potential to better identify and reconceptualise problems, and incorporate user experiences.

http//www.clinicaltrials.gov id NCT02925871. https://www.selleckchem.com/products/8-cyclopentyl-1-3-dimethylxanthine.html Date of registration 6 October 2016.

1.
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In the management of type 2 diabetes, autonomy-supporting interventions may be a prerequisite to achieving more long-term improvement. Preliminary evidence has shown that the guided self-determination (GSD) method might have an effect on haemoglobin A1c and diabetes distress in people with type 1 diabetes. Previous trials were at risk of uncertainty. Thus, the objective is to investigate the benefits and harms of a GSD intervention versus an attention control group intervention in adults with type 2 diabetes.

This trial protocol is guided by the The Standard Protocol Items Recommendations for International Trials Statement. We describe the protocol for a pragmatic randomised, dual-centre, parallel-group, superiority clinical trial testing a GSD intervention versus an attention control for people with type 2 diabetes in outpatient clinics. The participants (n=224) will be recruited from two diverse regions of Denmark. The experimental stepped-care intervention will consist of three to five GSD sessions lase regulatory requirement(s). The trial has been approved by the Danish Data Protection Agency (P-2020-864). The Ethics Committee of the Capital Region of Denmark reviewed the trial protocol, but exempted the trial protocol from full review (H-20003638). The results of the trial will be presented at the outpatient clinics treating people with type 2 diabetes, at national and international conferences as well as to associations for people with diabetes and their relatives.

ClinicalTrials.gov identifier NCT04601311.
ClinicalTrials.gov identifier NCT04601311.
Both physical diseases such as infection and chronic pain and psychological disorders such as depression have been associated with herpes zoster (HZ) reactivation. However, the relationship between de Quervain syndrome (DQS), a painful tenosynovitis and HZ remains unclear. We investigated whether DQS increases the risk of HZ reactivation.

A retrospective population-based cohort study.

Taiwan.

We used a subset of Taiwan's National Health Insurance Research Database, the Longitudinal Health Insurance Database which contains the registration files and original claims data of 1 million randomly selected individuals from the National Health Insurance programme. The case group in this study comprised patients newly diagnosed with DQS between 2000 and 2012. Individuals without DQS comprised the control group. Cases and controls were 11 matched by age, sex and index year (defined as the year of DQS diagnosis).

Approximately 55% of the participants were ≤49 years. Most participants were women (77%). The incidence rate of HZ in the DQS group was 8.39 per 1000 person years. After adjustments for age, sex and comorbidities, patients with DQS had a 1.30 times higher risk of HZ reactivation than the control group. Stratification analysis revealed taht DQS increases the HZ risk in individuals ≤64 years, women, and patients without comorbidities.

DQS is associated with an increased risk of HZ. Clinicians should be aware of this risk when dealing with patients with DQS, particularly in young adults.
DQS is associated with an increased risk of HZ. Clinicians should be aware of this risk when dealing with patients with DQS, particularly in young adults.
Muscle strength decline is reported to predict mortality in many cancers. However, there is little knowledge of the relation between muscle strength decline and clinical outcomes of allogeneic haematopoietic stem cell transplantation (allo-HSCT). This study aimed to determine the impact of pre-transplant lower extremity muscle strength (LEMS) on post-transplant overall survival (OS) and non-relapse mortality (NRM).

In this retrospective cohort study, 97 adult patients underwent allo-HSCT during 2012-2020. LEMS was defined as knee extension force divided by patient's body weight. The patients were divided into low and high LEMS groups based on pre-transplant LEMS. OS was measured using the Kaplan-Meier method and the Cox proportional hazards model. The cumulative incidence of NRM was evaluated using the Fine and Gray method, with relapse considered as a competing risk event.

Probability of OS was significantly lower in the low LEMS groups (HR 2.48, 95% CI 1.20 to 5.12, p=0.014) than in the high LEMS group on multivariate analysis.

for more investigations on potential racial/ethnic differences in breast cancer biology. See related commentary by Wang et al., p. 704.
Metabolite profiles provide insight into biologic mechanisms contributing to breast cancer development. We explored the association between prediagnostic plasma metabolites (N = 307) and invasive breast cancer among postmenopausal women in a nested case-control study within the Nurses' Health Study (N = 1,531 matched pairs).

Plasma metabolites were profiled via LC/MS-MS using samples taken ≥10 years (distant, N = 939 cases) and <10 years (proximate, N = 592 cases) before diagnosis. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) comparing the 90th to 10th percentile of individual metabolite level, using the number of effective tests (NEF) to account for testing multiple correlated hypotheses. Associations of metabolite groups with breast cancer were evaluated using metabolite set enrichment analysis (MSEA) and weighted gene coexpression network analysis (WGCNA), with adjustment for the FDR.

No individual metabolites were significantly associated with breast cancer risk. MSEA showed negative enrichment of cholesteryl esters at the distant timepoint [normalized enrichment score (NES) = -2.26; Padj = 0.02]. Positive enrichment of triacylglycerols (TAG) with <3 double bonds was observed at both timepoints. TAGs with ≥3 double bonds were inversely associated with breast cancer at the proximate timepoint (NES = -2.91, Padj = 0.03).

Cholesteryl esters measured earlier in disease etiology were inversely associated with breast cancer. TAGs with many double bonds measured closer to diagnosis were inversely associated with breast cancer risk.

The discovered associations between metabolite subclasses and breast cancer risk can expand our understanding of biochemical processes involved in cancer etiology.
The discovered associations between metabolite subclasses and breast cancer risk can expand our understanding of biochemical processes involved in cancer etiology.
Screening reduces lung cancer mortality, but specificities of eligibility criteria are low. We tested if leukocyte AHRR(cg05575921) methylation improves specificity of lung cancer screening eligibility criteria.

A total of 9,206 and 5,370 individuals of the 1991 to 1994 and 2001 to 2003 examinations of the Copenhagen City Heart Study, Denmark, were followed for lung cancer within 5 years after examination and mortality. Screening eligibility criteria (DANTE, DLCST, ITALUNG, LUSI, NELSON, NLST, and PLCOM2012) were evaluated, and AHRR (cg05575921) methylation extent at different methylation cut points was added. The model with the lowest number of eligible individuals per 5-year lung cancer was validated within the 2001 to 2003 examination.

Eligibility criteria identified risk-groups ranging from 3,182 (DANTE) to 1,641 (ITALUNG) individuals. The positive predictive value was highest for PLCOM2012 (3.2%), while DANTE showed the highest negative predictive value (99.7%). Adding AHRR (cg05575921) methylationnal predictive risk information to identify eligible smokers for lung cancer screening. See related commentary by Hung, p. 698.
A social media campaign for mothers aimed at reducing indoor tanning (IT) by adolescent daughters reduced mothers' permissiveness toward IT in an immediate posttest. Whether the effects persisted at 6 months after the campaign remains to be determined.

Mothers (N = 869) of daughters ages 14-17 in 34 states without bans on IT by minors were enrolled in a randomized trial. All mothers received an adolescent health campaign over 12 months with posts on preventing IT (intervention) or prescription drug misuse (control). Mothers completed a follow-up at 18 months post-randomization measuring IT permissiveness, attitudes, intentions, communication, and behavior, and support for state bans. Daughters (n = 469; 54.0%) just completed baseline and follow-up surveys.

Structural equation modeling showed that intervention-group mothers were less permissive of IT by daughters [unstandardized coefficient, -0.17; 95% confidence interval (CI), -0.31 to -0.03], had greater self-efficacy to refuse daughter's IT requests (0.17; 95% CI, 0.06-0.29) and lower IT intentions themselves (-0.18; 95% CI, -0.35 to -0.01), and were more supportive of bans on IT by minors (0.23; 95% CI, 0.02-0.43) than control-group mothers. Intervention-group daughters expressed less positive IT attitudes than controls (-0.16; 95% CI, 0.31 to -0.01).

The social media campaign may have had a persisting effect of convincing mothers to withhold permission for daughters to indoor tan for 6 months after its conclusion. Reduced IT intentions and increased support for bans on IT by minors also persisted among mothers.

Social media may increase support among mothers to place more restrictions on IT by minors.
Social media may increase support among mothers to place more restrictions on IT by minors.
Epigenetic changes associated with human papillomavirus (HPV)-driven tumors have been described; however, HPV type-specific alterations are less well understood. We sought to compare HPV16-specific methylation changes with those in virus-unassociated head and neck squamous cell carcinomas (HNSCC).

Within The Cancer Genome Atlas, 59 HPV16+ HNSCC, 238 nonviral HNSCC (no detectable HPV or other viruses), and 50 normal head and neck tissues were evaluated. Significant differentially methylated regions (DMR) were selected, and key associated genes were identified. Partial least squares models were generated to predict HPV16 status in additional independent samples.

HPV infection in HNSCC is associated with type-specific methylomic profiles. Multiple significant DMRs were identified between HPV16+, nonviral, and normal samples. https://www.selleckchem.com/products/gant61.html The most significant differentially methylated genes, SYCP2, MSX2, HLTF, PITX2, and GRAMD4, demonstrated HPV16-associated methylation patterns with corresponding alterations in gene expression. Phylogenetically related HPV types (alpha-9 species; HPV31, HPV33, and HPV35) demonstrated a similar methylation profile to that of HPV16 but differed from those seen in other types, such as HPV18 and 45 (alpha-7).

HNSCC linked to HPV16 and types from the same alpha species are associated with a distinct methylation profile. This HPV16-associated methylation pattern is also detected in cervical cancer and testicular germ cell tumors. We present insights into both shared and unique methylation alterations associated with HPV16+ tumors and may have implications for understanding the clinical behavior of HPV-associated HNSCC.

HPV type-specific methylomic changes may contribute to understanding biologic mechanisms underlying differences in clinical behavior among different HPV+ and HPV- HNSCC.
HPV type-specific methylomic changes may contribute to understanding biologic mechanisms underlying differences in clinical behavior among different HPV+ and HPV- HNSCC.
Adherence and persistence studies face several methodologic difficulties, including short-term mortality. We compared approaches to quantify adherence and persistence to first line (1L) oral targeted therapy (TT) in patients diagnosed with metastatic renal cell carcinoma (mRCC).

Patients with mRCC ages 66 years or more who initiated TTs within 4 months of diagnosis were identified in the Surveillance, Epidemiology, and End Results Medicare-linked database (2007-2015). Adherence [proportion of days covered (PDC) >80%] was calculated using (i) PDC with a fixed 6-month denominator including then excluding patients who died within the 6 months and (ii) PDC with a denominator measuring time on treatment. Risk of nonpersistence was obtained by censoring death or treating death as a competing risk using cumulative incidence functions.

Among 485 patients with mRCC initiating a 1L oral TT (sunitinib, 64%; pazopanib, 25%; other, 11%), 40% died within 6 months. Adherence was higher after restricting to patients who survived (60%) compared with including those patients and assigning zero days covered after death (47%). Risk of nonpersistence was higher when censoring patients at death, 0.91 [95% confidence interval (CI), 0.88-0.94], compared with treating death as a competing risk, 0.75 (95% CI, 0.71-0.79).

Different approaches to handling death resulted in different adherence and persistence estimates in the metastatic setting. Future studies should explicitly report the proportion of patient deaths over time and explore appropriate methods to account for death as competing risk.

Use of several approaches can provide a more comprehensive picture of medication-taking behavior in the metastatic setting where death is a major competing risk.
Use of several approaches can provide a more comprehensive picture of medication-taking behavior in the metastatic setting where death is a major competing risk.
Financial hardship is most common among cancer survivors with the fewest financial resources at diagnosis; however, little is known about the financial outcomes of young adult (YA) survivors (ages 20-39 at diagnosis), despite their having fewer financial reserves than older adults.

We utilized data from 3,888 participants in the population-based Detroit Research on Cancer Survivors cohort. Participants self-reported several forms of material and behavioral financial hardship (MFH and BFH, respectively). Psychological financial hardship (PFH) was measured using the Comprehensive Score for financial Toxicity (COST) score. Modified Poisson models estimated prevalence ratios (PR) and 95% confidence intervals (CI) for financial hardship by age at diagnosis controlling for demographic, socioeconomic, and cancer-related factors.

MFH prevalence was inversely associated with age such that 72% of YA survivors reported MFH, 62% ages 40 to 54, 49% ages 55 to 64, and 33% ages 65 to 79 (PRadjusted YA vs. 65+ 1.75; 95% CI, 1.49-2.04; Ptrend < 0.001). BFH was also more common among YA survivors (26%) than those ages 65 to 79 (20%; PRadjusted 1.50; 95% CI, 1.08-2.08; Ptrend = 0.019). Age was positively associated with financial wellbeing. COST scores ranged from 20.7 (95% CI, 19.0-22.4) among YA survivors to 27.2 (95% CI, 26.1-28.2) among adults 65 to 79 years old (Ptrend < 0.001).

In this population of African American cancer survivors, MFH and BFH were more common, and PFH was more severe, in YA survivors compared with those diagnosed as older adults.

Young adulthood at diagnosis should be considered a risk factor for cancer-related financial hardship and addressed in work designed to reduce the adverse financial impacts of cancer.
Young adulthood at diagnosis should be considered a risk factor for cancer-related financial hardship and addressed in work designed to reduce the adverse financial impacts of cancer.
Previous studies on the association between reproductive factors and ovarian cancer survival are equivocal, possibly due to small sample sizes.

Using data on 11,175 people diagnosed with primary invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer (ovarian cancer) from 16 studies in the Ovarian Cancer Association Consortium (OCAC), we examined the associations between survival and age at menarche, combined oral contraceptive use, parity, breastfeeding, age at last pregnancy, and menopausal status using Cox proportional hazard models. The models were adjusted for age at diagnosis, race/ethnicity, education level, and OCAC study and stratified on stage and histotype.

During the mean follow-up of 6.34 years (SD = 4.80), 6,418 patients passed away (57.4%). There was no evidence of associations between the reproductive factors and survival among patients with ovarian cancer overall or by histotype.

This study found no association between reproductive factors and survival after an ovarian cancer diagnosis.

IGD was also associated with increased connectivity between the ventral attention network and somatomotor regions. Furthermore, the IGD groups showed hyperconnectivity between the limbic network and regions of the frontoparietal network. The results suggest that individuals with IGD show large-scale functional network alteration which underpins their core symptoms including poor emotional competence, cue-reactivity and craving, habitual addictive behaviors and impaired executive control. Whether the compensation mechanism exists in IGD is discussed, and further research is needed. The findings provide a neurocognitive network model of IGD, which may serve as functional biomarkers for IGD and have potentials for development of effective diagnosis and therapeutic interventions.Primary tumors of the heart are uncommon; even rarer are primary cardiac neuroendocrine tumors. To our knowledge, only two cases have been described to date, both being high-grade tumors. We report a solitary low-grade neuroendocrine tumor of the heart, unexpectedly discovered during aortic valve repair for infectious bacterial endocarditis on the wall of the right ventricle in a 44-year-old man with a history of balloon valvulotomy as a child. Frozen section was sent intraoperatively and demonstrated a plasmacytoid neoplasm. Final pathology of the biopsies showed a tumor composed of both cohesive and discohesive plasmacytoid cells separated by a vascular network and strands of fibrosis. The tumor showed strong reactivity for AE1/3, synaptophysin, and CDX2 with focal reactivity for chromogranin-A and CD56. Neither necrosis nor a mitotic rate of greater than 2 mitoses per 2 mm2 was seen. A colonoscopy was performed and demonstrated only a tubular adenoma. An esophagogastroduodenoscopy was unremarkable. PET-CT DOTATATE, performed after complete resection of the tumor, demonstrated no abnormal radiotracer uptake. The patient continues to do well at present, 1 year later, and reports no symptoms attributable to carcinoid syndrome or disease progression. The patient was assigned by medical oncology to yearly follow-up and imaging, and is considered to have no evidence of disease.
Emerging epidemiological evidence suggests that compared to engaging in 1 activity mode alone, a combination of moderate-to-vigorous physical activity (MVPA brisk walking/jogging, cycling) and muscle-strengthening exercise (MSE push-ups/sit-ups, using weight machines) has more favorable associations with optimal weight status. However, few studies have examined the dose-dependent and joint associations of MVPA and MSE with obesity.

Based on cross-sectional analyses of the European Health Interview Survey Wave 2 (2013-2014), we examined prevalence ratios (PRs) of joint and stratified associations between MVPA (4 categories (i) 0 min/week, (ii) 1-149 min/week, (iii) 150-299 min/week, and (iv) ≥300 min/week) and MSE (3 categories (i) 0 day/week, (ii) 1 day/week, and (iii) ≥2 days/week) with body mass index-defined obesity (body mass index of ≥30.0 kg/m
) using Poisson regression with robust error variance. PRs were examined unadjusted and adjusted for sociodemographic and lifestyle characteristics (e.g., ses for the prevention and management of obesity should recommend both MVPA and MSE.
This study investigated the effects of a new strontium-doped bioactive glass and fluoride on hydroxyapatite crystallization.

We designed an in vitro experiment with calcium phosphate (CaCl
·2H
O + K
HPO
in buffer solution) with different concentrations of strontium-doped bioactive glass (1 mg/mL or 5 mg/mL), and different concentrations of fluoride (0 ppm, 1 ppm or 5 ppm). Tris-buffered saline served as negative control. After incubation at 37 ℃ for 48 h, the shape and organization of crystals were examined by transmission electron microscopy (TEM) and electron diffraction. Structure of the crystals was assessed by powder X-ray diffraction (P-XRD) and unit cell parameters were calculated. Characterization of the crystals were performed by Raman spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR).

TEM and selected-area electron diffraction revealed that the precipitates in all experimental groups were crystalline apatite. There was an interaction between strontium and fluoride with diffeyapatite crystallization by producing strontium-substituted-hydroxyapatite and strontium-substituted-fluorohydroxyapatite with enhanced bioactivity and reduced solubility which could be beneficial for caries management.
Cytosolic 5'-nucleotidase II (cN-II) and ecto-5'-nucleotidase (CD73) are enzymes involved in the nucleotide metabolism by dephosphorylating nucleoside monophosphates. Both enzymes are involved in cancer by modifying anticancer drug activity, cancer cell biology and immune modulation.

We have modified lung cancer cells (NCI-H292) to become deficient for either or both enzymes using the CRISPR/Cas9 technique, and studied the implication of the two enzymes in the cellular response to different stress condition i.e. https://www.selleckchem.com/products/fenebrutinib-gdc-0853.html chemotherapeutic agents, hypoxia and nucleotide stress.

Our results show that there is no significant role of these enzymes in cell proliferation under hypoxic stress. Similarly, cN-II and CD73 are not involved in wound healing ability under CoCl
-mediated HIF-1α stabilization. Furthermore, our results show that CD73-deficiency is associated with increased apoptosis in response to 1600 μM adenosine, decreased sensitivity to mitomycin and enhanced sensitivity to vincristine. cN-II deficiency increased in vivo tumor growth and sensitivity to vincristine and mitomycin C.

Our study gives new insights into the biological roles of cN-II and CD73 under stress conditions in this particular cancer cell line. Further experiments will help deciphering the molecular mechanisms underlying the observed differences.
Our study gives new insights into the biological roles of cN-II and CD73 under stress conditions in this particular cancer cell line. Further experiments will help deciphering the molecular mechanisms underlying the observed differences.Tyrosinase is the key enzyme in the production of melanin. Tyrosinase inhibitors have gained interest in the cosmetics industry to prevent hyperpigmentation and skin-related disorders by inhibiting melanin production. It has been reported that several Aloe species exhibit anti-tyrosinase efficacy in vitro. In this study, the exudates of thirty-nine South African Aloe species were screened to identify species and compounds with anti-tyrosinase activity. Qualitative screening revealed that twenty-nine Aloe species exhibited tyrosinase inhibition activity with one to three active bands. Quantitative screening was performed for 29 species and expressed as IC50 values. Three species were further analysed and subsequently, aloesin and aloeresin A was isolated from A. ferox and plicataloside from A. plicatilis and A. chabaudii. Aloeresin A was determined to be a substrate of mushroom tyrosinase. Dose-response assays showed that aloesin (IC50 = 31.5 μM) and plicataloside (IC50 = 84.1 μM) exhibited moderate to weak activity. Molecular docking scores for plicataloside were considerably lower than for aloesin (P less then 0.01), confirming its lower IC50. Several Aloe species may have potential for the management of hyperpigmentation or as a skin lightening agent. This is the first report showing that plicataloside, present in A. plicatilis and A. chabaudii, exhibits anti-tyrosinase activity.
Little is known about how a prior knee injury affects the clinical profile of individuals with knee osteoarthritis (KOA) although this is potentially important to personalize care.

To compare individual and clinical characteristics of individuals with KOA with and without a self-reported prior knee injury.

Secondary data analysis of baseline data from the Good Life with osteoArthritis in Denmark (GLAD®) registry.

Individuals with symptomatic KOA, self-reporting a prior knee injury requiring a doctor's assessment, were compared to individuals without prior knee injury on a range of individual and clinical characteristics using multivariable logistic regression.

The analysis included 10,973 individuals with KOA of which 54% self-reported a prior knee injury. The average age was 64 years and 73% were female. We found that being male (Odds Ratio (OR) 0.99), having longer symptom duration of knee pain (OR 1.07), having more painful body sites (OR 1.03), being able to do more chair rises (OR 1.02) and being more physically active in a week (2-4 days; OR1.33) (>4 days; OR 1.24) were associated with self-reporting a prior knee injury whereas being older (OR 0.99), having higher BMI (OR 0.99) and higher quality of life (OR 0.98) were not associated with reporting a prior knee injury.

The overall pattern of our findings rather than specific characteristics indicates that individuals with KOA and a history of a self-reported knee injury have a somewhat different clinical profile than their non-injured peers.
The overall pattern of our findings rather than specific characteristics indicates that individuals with KOA and a history of a self-reported knee injury have a somewhat different clinical profile than their non-injured peers.
To elucidate the role of LRRK2 in intervertebral disc degeneration (IDD) as well as its mitophagy regulation mechanism.

The expression of LRRK2 in human degenerative nucleus pulposus tissues as well as in oxidative stress-induced rat nucleus pulposus cells (NPCs) was detected by western blot. LRRK2 was knocked down in NPCs by lentivirus (LV)-shLRRK2 transfection; apoptosis and mitophagy were assessed by western blot, TUNEL assay, immunofluorescence staining and mitophagy detection assay in LRRK2-deficient NPCs under oxidative stress. After knockdown of Parkin in NPCs with siRNA transfection, apoptosis and mitophagy were further assessed. In puncture-induced rat IDD model, X-ray, MRI, hematoxylin-eosin (HE) and Safranin O-Fast green (SO) staining were performed to evaluate the therapeutic effects of LV-shLRRK2 on IDD.

We found that the expression of LRRK2 was increased in degenerative NPCs both in vivo and in vitro. LRRK2 deficiency significantly suppressed oxidative stress-induced mitochondria-dependent apoptosis in NPCs; meanwhile, mitophagy was promoted. However, these effects were abolished by the mitophagy inhibitor, suggesting the effect of LRRK2 on apoptosis in NPCs is mitophagy-dependent. Furthermore, Parkin knockdown study showed that LRRK2 deficiency activated mitophagy by recruiting Parkin. In vivo study demonstrated that LRRK2 inhibition ameliorated IDD in rats.

The results revealed that LRRK2 is involved in the pathogenesis of IDD, while knockdown of LRRK2 inhibits oxidative stress-induced apoptosis through mitophagy. Thus, inhibition of LRRK2 may be a promising therapeutic strategy for IDD.
The results revealed that LRRK2 is involved in the pathogenesis of IDD, while knockdown of LRRK2 inhibits oxidative stress-induced apoptosis through mitophagy. Thus, inhibition of LRRK2 may be a promising therapeutic strategy for IDD.
Explore patient and dietitian experiences with a multi-component dietary weight loss program for knee osteoarthritis to understand enablers and challenges to success at 6-months.

Qualitative study embedded within a randomised controlled trial. Semi-structured individual interviews with 24 patients with knee osteoarthritis who undertook, and five dietitians who supervised, a weight management program (involving a ketogenic very low calorie diet (VLCD), video consultations, educational resources) over 6months. Data were thematically analysed.

Five themes were developed (1) ease and convenience of program facilitated adherence (structure and simplicity of the meal replacements; not feeling hungry on diet; convenience of consulting via video) (2) social and professional support crucial for success (encouragement from partner, family, and friends; guidance from, and accountability to, dietitian; anxiety around going at it alone) (3) program was engaging and motivating (determination to stick to program; rapid weight loss helped motivation) (4) holistic nature of program was important (suite of high-quality educational resources; exercise important to compliment weight loss) (5) rewarding experience and lifelong impact (improved knee pain and function; positive lifestyle change).

Generation of reactive oxygen species and related oxidants is an inevitable consequence of life. Proteins are major targets for oxidation reactions, because of their rapid reaction rates with oxidants and their high abundance in cells, extracellular tissues, and body fluids. Additionally, oxidative stress is able to degrade lipids and carbohydrates to highly reactive intermediates, which eventually attack proteins at various functional sites. Consequently, a wide variety of distinct posttranslational protein modifications is formed by protein oxidation, glycoxidation, and lipoxidation. Reversible modifications are relevant in physiological processes and constitute signaling mechanisms ("redox signaling"), while non-reversible modifications may contribute to pathological situations and several diseases. A rising number of publications provide evidence for their involvement in the onset and progression of diseases as well as aging processes. Certain protein oxidation products are chemically stable and formed in large quantity, which makes them promising candidates to become biomarkers of oxidative damage. Moreover, progress in the development of detection and quantification methods facilitates analysis time and effort and contributes to their future applicability in clinical routine. The present review outlines the most important classes and selected examples of oxidative protein modifications, elucidates the chemistry beyond their formation and discusses available methods for detection and analysis. Furthermore, the relevance and potential of protein modifications as biomarkers in the context of disease and aging is summarized.Lipid peroxidation and its products have been investigated extensively and their biological importance, particularly in relation to physiological and pathophysiological conditions, has received considerable attention. Lipids are oxidized by three distinct mechanisms, i.e., enzymatic oxidation, nonenzymatic, free radical-mediated oxidation, and nonenzymatic, nonradical-mediated oxidation, which respectively yield specific products. Lipid hydroperoxides are the major primary products formed and are reduced to the corresponding hydroxides by antioxidative enzymes such as selenoproteins, and/or undergo secondary oxidation, generating various products with electrophilic properties, such as 4-hydroxy-2-nonenal. Lipid peroxidation induces a loss of fine structure and natural function of lipids, and can produce cytotoxicity and/or novel biological activity. This review broadly discusses the mechanisms of lipid peroxidation and its products, its utility as a biomarker for oxidative stress, the biological effects of lipid peroxidation products, including their action as a mediator of the adaptive response, and the role of the antioxidant system, particularly selenoproteins and vitamin E, in preventing lipid peroxidation and ferroptosis.CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that is involved in adipocytic and monocytic differentiation. However, the physiological role of C/EBPβ in megakaryocytes (MKs) is not clear. In this study, we investigated the effects of C/EBPβ on the early-stage differentiation of MKs, and explored the potential mechanisms of action. We established a cytosine arabinoside-induced thrombocytopenia mouse model using C57BL/6 mice. In the thrombocytopenia mice, the platelet count was found to be decreased, and the mRNA and protein expression levels of C/EBPβ in MKs were also reduced. Furthermore, the maturation of Dami (MKs cell line) cells was induced by phorbol 12-myristate 13-acetate. When C/EBPβ was silenced in Dami cells by transfection using C/EBPβ-small interfering RNA, the expression of MKs-specific markers CD41 and CD62P, was dramatically decreased, resulting in morphological changes and differentiation retardation in low ploidy, which were evaluated using flow cytometry, real-time polymerase chain reaction, western blot, and confocal microscopy. The mitogen activated protein kinase-extracellular signal-regulated kinase signaling pathway was found to be required for the differentiation of MKs; knockdown of C/EBPβ in MEK/ERK1/2 pathway attenuated MKs differentiation. Overexpression of C/EBPβ in MEK/ERK1/2 pathway inhibited by U0126 did not promote MKs differentiation. To the best of our knowledge, C/EBPβ plays an important role in MKs differentiation and polyploidy cell cycle control. Taken together, C/EBPβ may have thrombopoietic effects in the differentiation of MKs, and may assist in the development of treatments for various disorders.
Intrapatient blood level variability (IPV) of calcineurin inhibitors has been associated with poor outcomes in solid-organ transplant, but data for heart transplant are scarce. Our purpose was to ascertain the clinical impact of IPV in a multi-institutional cohort of heart transplant recipients.

We retrospectively studied patients aged ≥18 years, with a first heart transplant performed between 2000 and 2014 and surviving≥1 year. IPV was assessed by the coefficient of variation of trough levels from posttransplant months 4 to 12. A composite of rejection or mortality/graft loss or rejection and all-cause mortality/graft loss between years 1 to 5 posttransplant were analyzed by Cox regression analysis.

The study group consisted of 1581 recipients (median age, 56 years; women, 21%). Cyclosporine immediate-release tacrolimus and prolonged-release tacrolimus were used in 790, 527 and 264 patients, respectively. On multivariable analysis, coefficient of variation>27.8% showed a nonsignificant trend to association with 5-year rejection-free survival (HR, 1.298; 95%CI, 0.993-1.695; P=.056) and with 5-year mortality (HR, 1.387; 95%CI, 0.979-1.963; P=.065). Association with rejection became significant on analysis of only those patients without rejection episodes during the first year posttransplant (HR, 1.609; 95%CI, 1.129-2.295; P=.011). The tacrolimus-based formulation had less IPV than cyclosporine and better results with less influence of IPV.

IPV of calcineurin inhibitors is only marginally associated with mid-term outcomes after heart transplant, particularly with the tacrolimus-based immunosuppression, although it could play a role in the most stable recipients.
IPV of calcineurin inhibitors is only marginally associated with mid-term outcomes after heart transplant, particularly with the tacrolimus-based immunosuppression, although it could play a role in the most stable recipients.The frozen elephant trunk technique for various thoracic aortic diseases is widely accepted to facilitate future downstream aortic surgery. However, in some cases, the descending aorta is unsuitable for cross-clamping due to progressive aneurysmal changes or dense adhesions to surrounding structures, and frozen elephant trunk retrieval becomes challenging. https://www.selleckchem.com/products/pf-07321332.html This paper presents a case of successful frozen elephant trunk retrieval by partial clamping of the descending aortic aneurysm without dissection of peri-aneurysmal adhesions, and subsequent encircling.
Dialysis-dependent patients have a high risk of cardiovascular death but also a high risk for perioperative mortality in cardiac surgery. Our study examined surgical complications and mortality in Indigenous and non-Indigenous dialysis-dependent patients undergoing cardiac surgery at a single centre.

The retrospective study reviewed 72 consecutive dialysis-dependent patients who underwent cardiac surgery between 2008 and 2018. Data was prospectively collected, and follow-up was obtained from physicians and general practitioners. Multivariable analysis was performed to determine predictors of mortality.

The median age of Indigenous Australian patients was 60 years, compared with 65 years for non-Indigenous patients. Indigenous Australian patients had a significantly higher rate of return to theatre (43% versus 17%). The predominant reason for return to theatre for the whole cohort was postoperative bleeding (n=16, 22%). The overall early mortality rate was 10%. There were 35 late deaths (49%) and overallality between Indigenous and non-Indigenous patients. However, there was a higher rate of return to theatre amongst the Indigenous Australian cohort.
Cardiac magnetic resonance imaging (CMR) image quality can be degraded by artifact in patients with cardiac implantable electronic devices (CIED). We aimed to establish a clinical risk score, so patient selection for diagnostic CMR could be optimised.

In this retrospective cohort study, CMRs performed for clinical use in subjects with CIED from January 2016 to May 2019 were reviewed. Subject anthropometry, CIED generator/lead specifications and pre-scan chest X-ray (CXR) measurements were collected. link2 Generator-related artifact size was measured on axial steady state free precession images. link3 Interpretability of late gadolinium enhancement (LGE) imaging was performed based on a three-grade visual score attributed to each of 17 myocardial segments.

Fifty-seven (57) patients (59±16 years, 74% male) fitted the inclusion criteria. Artifact precluded left ventricle (LV) evaluation (≥5 segments) in 17 (30%). Artifact was more common with implantable cardioverter-defibrillators, related to generator volume, mass, r diagnostic CMR.
Heart failure (HF), as a serious health condition, is characterised by the decreasing ability of the heart to pump enough blood around the body. This study compared the effects of spironolactone and eplerenone on the echocardiographic variables of the left ventricular (LV) function in symptomatic patients diagnosed with new-onset systolic HF.

This study was a randomised controlled trial, including 85 symptomatic patients with new-onset systolic HF (namely, dilated cardiomyopathy). The patients were then randomly assigned to two groups in a 11 ratio and received either spironolactone or eplerenone in addition to optimal HF therapy for 6 months. Echocardiography was performed to visualise alterations in two-dimensional, pulse Doppler, tissue Doppler, and deformation indices of LV function.

The results revealed that the group receiving eplerenone had a significantly greater increase in LV ejection fraction (LVEF) and a decrease in end-systolic LV internal diameter compared with the group receiving spironolith new-onset systolic HF.
What are the relative effects of group-based exercise, individual exercise and home-based exercise on clinical outcomes and costs in patients with subacromial pain?

Multicentre, three-arm, randomised controlled trial with concealed allocation and intention-to-treat analysis.

A total of 208 patients referred to municipal rehabilitation for management of subacromial pain in six municipalities in the Central Denmark Region.

Patients were randomly allocated to group-based exercise rehabilitation (GE), individual exercise rehabilitation (IE) or home exercise rehabilitation (HE) for a period of 8 weeks.

The primary outcome measure was the shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire (Quick-DASH). The secondary outcome measures included the EQ-5D-5L index, pain intensity, fear avoidance, psychological wellbeing, and the participant's perception of improvement and satisfaction. Healthcare and productivity costs were extracted from national health and social registers.

There was no important between-group difference in Quick-DASH scores at 6 months adjusted mean differences GE minus IE-2 (95% CI-9 to 5), GE minus HE-2 (95% CI-9 to 5) and HE minus IE 1 (95% CI-6 to 7).