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Background The efficacy of traditional rehabilitation interventions to improve locomotion post-stroke, including providing multiple exercises targeting impairments and activity limitations, is uncertain. Emerging evidence rather suggests attempts to prioritize stepping practice at higher cardiovascular intensities may facilitate greater locomotor outcomes. Objective The present study was designed to evaluate the comparative effectiveness of high-intensity training (HIT) to usual care during inpatient rehabilitation post-stroke. Methods Changes in stepping activity and functional outcomes were compared over 9 months during usual-care (n = 131 patients 2 analysis. Results Across all phases, admission scores were similar except for balance (usual-care>HIT; P Conclusions Greater efforts to prioritize walking and reach higher intensities during HIT led to increased steps/day, resulting in greater gains in locomotor and non-locomotor outcomes.

— Cryptocurrencies are being widely adopted by government and non-government organizations. A barrier that still exists to the widespread adoption is the high volatility of the cryptocurrencies. Stablecoins provide a solution for the high volatility of cryptocurrencies by providing price stability. There are two types of stablecoins, collateralized stablecoins and non-collateralized stablecoins. Collateralized stablecoins make use of other physical and digital assets to back up the cryptocurrency. Non-collateralized stablecoins make use of algorithms to deal with the price fluctuations. This paper introduces a non-collateralized stablecoin which will be pegged to the price of an Indian Rupee.

Evidence shows that reports of psychopathology symptoms by youth and their caregiver informants differ. To quantify youth-caregiver discrepancies in psychopathology symptoms and factors associated with such discrepancies, we investigated differences in how youth and their caregivers rated psychopathology symptoms. The sample (N = 5094) was extracted from the Philadelphia Neurodevelopmental Cohort, a community-based sample of youth and included participants ages 11-17 years old with both youth and caregiver reported symptom scores. Across psychopathology symptoms, youth-caregiver concordance was poor to fair (Cohens kappa for symptom items ranged between 0.03-0.41). Psychosis symptoms had the lowest concordance-Cohen's kappa ranged from 0.03 to 0.17 across psychosis symptoms. Discrepancies between youth and caregiver symptom reports were greater than average for Black youth and for youth of low socioeconomic status; discrepancies were also higher than average in youth with any psychiatric disorder when compared to typically developing youth. Network analysis of difference scores obtained by subtracting youth symptom scores from caregiver reported symptom scores showed that network connectivity (i.e., correlated difference scores) was sparsest for psychosis spectrum compared to other psychiatric disorders. Using a large sample, we show that youth and their caregiver informants tend to report psychopathology symptoms differently. Youth-caregiver discrepancies were the most pronounced for Black youth and youth of low socio-economic status. Race and socioeconomic status contribute to significant differences in how youth and their caregivers report such symptoms and are important factors that should be accounted for to facilitate accurate mental health symptom assessment and evaluation.

Objective This cohort investigation identified primary predictors of discharge walking function of nonambulatory individuals poststroke with high-intensity training (HIT) during inpatient rehabilitation. Design Observational cohort investigation. Setting Inpatient rehabilitation. Participants Data were collected from individuals (N=257) Intervention Clinical physical therapy interventions attempted to maximize stepping practice at higher intensities. Main Outcome Measures Primary outcomes included the discharge level of assistance required during walking (minimal or no assistance) and attainment of specific gait speed thresholds (0.4 and 0.8 m/s) during the 10-m walk test. Independent predictors were demographics, training interventions (including steps/day), baseline Berg Balance Scale (BBS), and paretic leg strength. Results Participants performed a median (interquartile range) of 1270 (533-2297) steps per day throughout inpatient rehabilitation, with significant differences between those who walked with versus without assistance at discharge. Logistic regressions indicate steps per day was a primary predictor of unassisted walking recovery; removal of steps per day resulted in primary predictors of baseline BBS and strength. Receiver operating characteristic (ROC) analyses indicate significant areas under the curve for BBS and relatively low cutoff scores of 5.5 points at admission to walk without assistance at any speed. ROC analyses performed using 1-week outcomes indicate BBS scores of 5-17 points were needed to achieve locomotor thresholds. Conclusion Stepping activity, BBS, and paretic leg strength were primary predictors of walking outcomes in patients performing HIT, and ROC analyses indicated recovery of independent walking could be achieved in low functioning patients early poststroke.

Long-standing research in animal models and humans with stroke or incomplete spinal cord injury (iSCI) indicate that specific physical training variables, such as the specificity and amount of practice, may influence neurologic recovery and locomotor function. More recent data highlight the contributions of exercise intensity, as estimated indirectly by cardiovascular exertion, as potentially more important than previously considered. The effects of exercise intensity are well described in neurologically intact individuals, although confusion regarding the definitions of intensity and safety concerns have limited its implementation during physical rehabilitation of patients with neurologic injury. The purpose of this review is to delineate some of the evidence regarding the effects of exercise intensity during locomotor training in patients with stroke and iSCI. We provide specific definitions of exercise intensity used within the literature, describe methods used to ensure appropriate levels of exertion, and discuss potential adverse events and safety concerns during its application. Further details on the effects of locomotor training intensity on clinical outcomes, and on neuromuscular and cardiovascular function will be addressed as available. Existing literature across multiple studies and meta-analyses reveals that exercise training intensity is likely a major factor that can influence locomotor function after neurologic injury. To extend these findings, we describe previous attempts to implement moderate to high intensity interventions during physical rehabilitation of patients with neurologic injury, including the utility of specific strategies to facilitate implementation, and to navigate potential barriers that may arise during implementation efforts.

The failure of cancer treatments, including immunotherapy, continues to be a major obstacle in preventing durable remission. This failure often results from tumor evolution, both genotypic and phenotypic, away from sensitive cell states. Here, we propose a mathematical framework for studying the dynamics of adaptive immune evasion that tracks the number of tumor-associated antigens available for immune targeting. We solve for the unique optimal cancer evasion strategy using stochastic dynamic programming and demonstrate that this policy results in increased cancer evasion rates compared to a passive, fixed strategy. Our foundational model relates the likelihood and temporal dynamics of cancer evasion to features of the immune microenvironment, where tumor immunogenicity reflects a balance between cancer adaptation and host recognition. In contrast with a passive strategy, optimally adaptive evaders navigating varying selective environments result in substantially heterogeneous post-escape tumor antigenicity, giving rise to immunogenically hot and cold tumors.

S4. E-cadherin induces E- to N-cadherin switching in sarcoma cells.

CDH1 (also known as E-cadherin), an epithelial-specific cell–cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-to-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-to-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB1 (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell–cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth.Implications:We highlight how E-cadherin can restrict aggressive behavior in sarcomas through both biochemical signaling and biomechanical effects.

Supplementary Data

The dynamic interactions between an evolving malignancy and the adaptive immune system generate diverse evolutionary trajectories that ultimately result in tumor clearance or immune escape. Here, we create a simple mathematical model coupling T-cell recognition with an evolving cancer population that may randomly produce evasive subclones, imparting transient protection against the effector T cells. T-cell turnover declines and evasion rates together explained differences in early incidence data across almost all cancer types. Fitting the model to TRACERx evolutionary data argued in favor of substantial and sustained immune pressure exerted upon a developing tumor, suggesting that clinically observed incidence is a small proportion of all cancer initiation events. This dynamical model promises to increase our quantitative understanding of many immune escape contexts, including cancer progression and intracellular pathogenic infections.Significance:The early cancer–immune interaction sculpts intratumor heterogeneity through the selection of immune-evasive clones. This study provides a mathematical framework for investigating the coevolution between an immune-evasive cancer population and the adaptive immune system.

The table lists the phosphorylation values for the array of peptides containing tyrosine or serine/threonine phosphorylation sites. This array was used to compare lysates from HME2 parental cells, TGF-beta-induced EMT and lapatinib-induced EMT.

The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial–mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal–epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells.Significance:These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy.See related commentary by Farrington and Narla, p. 1756

This file contains the SI, including: TableS1 - evidence that our model outperforms random models); FigureS1 - additional examples of normalization applied to relevant datasets; TableS2 - additional EMT score categorizations on samples with a priori known phenotypes; FigureS2 - qPCR for relevant transcription factors for cell lines that were predicted to be hybrid E/M by our model; FigureS3 - A second experimental sample for flow cytometric cell sorting of cells that were predicted to be hybrid E/M by our model; FigureS4 - Survival analysis via separation of patients based on median VIM/CDH1 levels applied to samples detected with significant difference by our original model; FigureS5 - Survival analysis using a similar model as ours with only CDH1 and VIM as predictors applied to samples detected with significant difference by our original model; FigureS6 - Empirical EMT score distributions for large sample datasets.

Proangiogenic function of post-EMT tumor cells.

This file contains the Supplementary Data not to be included in the SI as a separate figure, but as a data file which can be downloaded and accessed. Sheet 1 contains a list of EMT-relevant gene products created by a review of the literature. Genes are organized into columns based on the relevant citation last name on the top of each column. Those entries in color represent either epithelial (peach) or mesenchymal (blue) genes. Sheet 2 contains the total (non-redundant) list of possible predictors, along with ratios of two predictors for prominent EMT-related genes. For example, VIM/CDH1. Sheet 3 includes the top 50 normalizers selected based on their inability to resolve E,E/M and M groups (i.e. the EMT-independent normalization gene signature). Sheet 4 contains the regression coefficients for the top model CLDN7, VIM/CDH1 as used in Equations 2-4. Sheet 5 contains the primer design used in Figure S2.

Metastases are responsible for the majority of breast cancer–associated deaths. The contribution of epithelial-to-mesenchymal transition (EMT) in the establishment of metastases is still controversial. To obtain in vivo evidence of EMT in metastasis, we established an EMT lineage tracing (Tri-PyMT) model, in which tumor cells undergoing EMT would irreversibly switch their fluorescent marker from RFP+ to GFP+ due to mesenchymal-specific Cre expression. Surprisingly, we found that lung metastases were predominantly derived from the epithelial compartment of breast tumors. However, concerns were raised on the fidelity and sensitivity of RFP-to-GFP switch of this model in reporting EMT of metastatic tumor cells. Here, we evaluated Tri-PyMT cells at the single-cell level using single-cell RNA-sequencing and found that the Tri-PyMT cells exhibited a spectrum of EMT phenotypes, with EMT-related genes concomitantly expressed with the activation of GFP. The fluorescent color switch in these cells precisely marked an unequivocal change in EMT status, defining the pre-EMT and post-EMT compartments within the tumor. Consistently, the pre-EMT cells played dominant roles in metastasis, while the post-EMT cells were supportive in promoting tumor invasion and angiogenesis. Importantly, the post-EMT (GFP+) cells in the Tri-PyMT model were not permanently committed to the mesenchymal phenotype; they were still capable of reverting to the epithelial phenotype and giving rise to secondary tumors, suggesting their persistent EMT plasticity. Our study addressed major concerns with the Tri-PyMT EMT lineage tracing model, which provides us with a powerful tool to investigate the dynamic EMT process in tumor biology.Significance:These findings confirm the fidelity and sensitivity of the EMT lineage tracing (Tri-PyMT) model and highlight the differential contributions of pre- and post-EMT tumor cells in breast cancer metastasis.See related commentary by Bunz, p. 153

This file contain supplemental figures S1 through S4. These figures present additional immunoblot and replicate immune fluorescent frames to further support the conclusions made from the data presented in the main manuscript.

Main SI file: This file contains all supplementary information, including detailed mathematical derivations and supplemental figures: SF1: Probability densities for the inter-temporal clone arrival times SF2: Escape and elimination probabilities as a function of cycle number assuming clearance probabilities that decline as a function of cycle number. SF3: Escape probabilities as a function of cycle number assuming constant clearance probability as well as clearance probabilities that decline as a function of current clone size. SF4: Simulated population trajectories as a function of time for both the deterministic and adaptive immune recognition assumptions SF5: Simulated population trajectories as a function of time conditioned on ultimate escape. SF6: Empirical cancer incidence as a function of age. SF7: Changes in early cancer incidence as a function of per-cell mutation rate SF8: General features of the co-evolutionary framework, including initiation, branching, recognition, ultimate elimination, and ultimate escape. SF9: Example simulated trajectories as a function of time for various clearance probabilities and branching parameters. SF10: Detection size and mean dispersion assuming adaptive recognition as a function of the adaptive immune detection parameter and per-cell growth rate SF11: Mean recognition cycles and escape probabilities as a function of clearance probability and branching parameter. SF12: Cycle number and escape probability as a function of clearance probability and branching parameter, assuming mean cycle numbers +/- 1 standard deviation of estimated cycle number. ST1: TRACERx empirical mutational burden partitioned by lung cancer subtype.

The list of differentially expressed genes in the GFP+ and RFP+ Tri-PyMT cells.

Metastasis is a significant contributor to morbidity and mortality for many cancer patients and remains a major obstacle for effective treatment. In many tissue types, metastasis is fueled by the epithelial-to-mesenchymal transition (EMT)—a dynamic process characterized by phenotypic and morphologic changes concomitant with increased migratory and invasive potential. Recent experimental and theoretical evidence suggests that cells can be stably halted en route to EMT in a hybrid E/M phenotype. Cells in this phenotype tend to move collectively, forming clusters of circulating tumor cells that are key tumor-initiating agents. Here, we developed an inferential model built on the gene expression of multiple cancer subtypes to devise an EMT metric that characterizes the degree to which a given cell line exhibits hybrid E/M features. Our model identified drivers and fine-tuners of epithelial–mesenchymal plasticity and recapitulated the behavior observed in multiple in vitro experiments across cancer types. We also predicted and experimentally validated the hybrid E/M status of certain cancer cell lines, including DU145 and A549. Finally, we demonstrated the relevance of predicted EMT scores to patient survival and observed that the role of the hybrid E/M phenotype in characterizing tumor aggressiveness is tissue and subtype specific. Our algorithm is a promising tool to quantify the EMT spectrum, to investigate the correlation of EMT score with cancer treatment response and survival, and to provide an important metric for systematic clinical risk stratification and treatment. Cancer Res; 77(22); 6415–28. ©2017 AACR.

Background Blockade of the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high‐affinity monoclonal blocking antibody to LOX‐1. Methods and Results This phase 1, first‐in‐human, placebo‐controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive single ascending doses (10, 30, 90, 250, or 500 mg) or multiple ascending doses (90, 150, or 250 mg once monthly for 3 months) of MEDI6570 or placebo. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX‐1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half‐life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target‐mediated drug disposition. Dose‐dependent reductions in mean soluble LOX‐1 levels from baseline were observed (>66% at 4 weeks and 71.61–82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (−13.45 mm 3 versus −8.25 mm 3 ). Conclusions MEDI6570 was well tolerated and demonstrated dose‐dependent soluble LOX‐1 suppression and a pharmacokinetic profile consistent with once‐monthly dosing. Registration URL: https://clinicaltrials.gov/ ; Unique identifier: NCT03654313.

Introduction: Hydatid disease of the bone is a parasitic infestation in the form of cystic echinococcosis by a tapeworm echinococcus granulosus. Its manifestation in the bone is relatively low and has the ability to mimic other skeletal pathologies. Case Report: We came across a 30-year-old male farmer with complaints of sero-purulent discharge from a sinus tract wound in the axilla for the past 3 years. He had been previously evaluated elsewhere with blood investigations, pus culture/sensitivity tests, MRI, and CT scans. Blood reports and culture/sensitivity tests were inconclusive and imaging tests were suggestive of a sinus tract originating from the right scapula. He was incorrectly diagnosed as a case of Tuberculosis of the Scapula and started on anti-tubercular medications for 9 months which was ineffective. To confirm the diagnosis, a biopsy was taken from the scapular lesion through a posterior approach. Histological tests revealed a cystic lesion composed of trilaminar membrane consisting of dead and degenerating scolices consistent with “Hydatid Cyst of Bone.” Conclusion: Hydatid disease of the bone has an inconsistent clinical picture which makes diagnosing this rare disease even more difficult. A high suspicion for hydatid infestation in bone pathologies could help in diagnosing the disease at the earliest.

Epithelial–mesenchymal transition (EMT) and its reverse mesenchymal–epithelial transition (MET) are critical during embryonic development, wound healing and cancer metastasis. While phenotypic changes during short-term EMT induction are reversible, long-term EMT induction has been often associated with irreversibility. Here, we show that phenotypic changes seen in MCF10A cells upon long-term EMT induction by TGF β need not be irreversible, but have relatively longer time scales of reversibility than those seen in short-term induction. Next, using a phenomenological mathematical model to account for the chromatin-mediated epigenetic silencing of the miR-200 family by ZEB family, we highlight how the epigenetic memory gained during long-term EMT induction can slow the recovery to the epithelial state post-TGF β withdrawal. Our results suggest that epigenetic modifiers can govern the extent and time scale of EMT reversibility and advise caution against labelling phenotypic changes seen in long-term EMT induction as ‘irreversible’.

BackgroundPatients with Crohn’s disease (CD) are predisposed to nonalcoholic fatty liver disease (NAFLD). CD management often includes thiopurines which can promote hepatotoxicity. We aimed to identify the role of NAFLD on the risk of developing liver injury from thiopurines in CD.MethodsIn this prospective cohort analysis, CD patients at a single center were recruited 6/2017–5/2018. Patients with alternative liver diseases were excluded. The primary outcome was time to elevation of liver enzymes. Patients underwent MRI with assessment of proton density fat fraction (PDFF) on enrollment, where NAFLD was defined as PDFF >5.5%. Statistical analysis was performed using a Cox-proportional hazards model.ResultsOf the 311 CD patients studied, 116 (37%) were treated with thiopurines, 54 (47%) of which were found to have NAFLD. At follow-up, there were 44 total cases of elevated liver enzymes in those treated with thiopurines. Multivariable analysis demonstrated that NAFLD was a predictor of elevated liver enzymes in patients with CD treated with thiopurines (HR 3.0, 95% CI 1.2–7.3, P = .018) independent of age, body mass index, hypertension, and type 2 diabetes. Steatosis severity by PDFF positively correlated with peak alanine aminotransferase (ALT) at follow-up. Kaplan–Meier analysis demonstrated poorer complication-free survival (log-rank 13.1, P < .001).ConclusionsNAFLD at baseline is a risk factor for thiopurine-induced hepatotoxicity in patients with CD. The degree of liver fat positively correlated with the degree of ALT elevation. These data suggest that evaluation for hepatic steatosis be considered in patients with liver enzyme elevations with thiopurine therapy.

Background Youth mental health disorders are strong predictors of adult mental health disorders. Early identification of mental health disorders in youth is important as it could aid early intervention and prevention. In a disorder agnostic manner, we aimed to identify influential psychopathology symptoms that could impact mental health in youth. Methods This study sampled 6063 participants from the Philadelphia Neurodevelopmental Cohort and comprised of youth of ages 12–21 years. A mixed graphical model was used to estimate the network structure of 115 symptoms corresponding to 16 psychopathology domains. Importance of individual symptoms in the network were assessed using node influence measures such as strength centrality and predictability. Results The generated network had stronger associations between symptoms within a psychopathological domain; overall had no negative associations. A conduct disorder symptom eliciting threatening others and a depression symptom - persistent sadness or depressed mood - had the greatest strength centralities (β = 2.85). Fear of traveling in a car and compulsively going in and out a door had the largest predictability (classification accuracy = 0.99). Conduct disorder, depression, and obsessive compulsive disorder symptoms generally had the largest strength centralities. Suicidal thoughts had the largest bridge strength centrality (β = 2.85). Subgroup networks revealed that network structure differed by socioeconomic status (low versus high, p = 0.04) and network connectivity patterns differed by sex (p = 0.01), but not for age or race. Conclusions Psychopathology symptom networks offer insights that could be leveraged for early identification, intervention, and possibly prevention of mental health disorders.

ObjectiveAdvances in genetics has led to a better understanding of both genetic and environmental contributions to psychiatric mental health disorders. But psychiatric genetics research is predominantly Eurocentric, and individuals of non-European ancestry continue to be significantly underrepresented in research studies. The objective of this study was to examine factors associated with genetic study participation in a schizophrenia sample.MethodsThe study sample was extracted from the Clinical Antipsychotics Trial of Intervention Effectiveness (CATIE) schizophrenia study which enrolled patients with schizophrenia between the ages of 18-65 and incorporated an optional genetic sub-study. Using regression models, we examined sociodemographic and clinical factors that were independently associated with participation in the genetic sub-study.ResultsThe genetic sub-study had a lower proportion of Black (30% in genetic vs 40% in CATIE overall) and Other race (4% vs 6%) participants. Severe psychopathology symptoms (odds ratio [OR]=0.78, p=0.004) and better reasoning scores (OR = 1.16,p= 0.036) influenced the odds of genetic study participation. Compared to Black participants, White participants were significantly more likely to participate in the genetic sub-study (OR=1.43, p=0.009)ConclusionRace and clinical variables significantly impact genetic study participation of individuals with schizophrenia. Future studies should examine the interactive effects of race and clinical variables for a nuanced understanding of how individuals diagnosed with severe psychiatric illnesses choose to participate in genetics studies.

Reactive oxygen species comprise oxygen-based free radicals and non-radical species such as peroxynitrite and electronically excited (singlet) oxygen. These reactive species often have short lifetimes, and much of our understanding of their formation and reactivity in biological and especially medical environments has come from complimentary fast reaction methods involving pulsed lasers and high-energy radiation techniques. These and related methods, such as EPR, are discussed with particular reference to singlet oxygen, hydroxy radicals, the superoxide radical anion, and their roles in medical aspects, such as cancer, vision and skin disorders, and especially pro- and anti-oxidative processes.

International audience; Aims: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death.Methods and results: A mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time-dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin-to-creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated.Conclusions: Changes in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population.

Moringa oleifera Lam. is an important plant with multiple benefits for humans, and has been termed “the miracle plant” by many. This study presents a bibliometric analysis of M. oleifera (MO) in the last two decades with data indexed on the Scopus database. The objective is to evaluate how research outputs on the plant have evolved within the period with a focus on country, institution, journal and author participation. The analysis was limited to the search command - article title “Moringa oleifera”, for original research articles and conference presentations. The search output was 2,345 documents, representing 97% of all time published reports on the subject. A data analysis software – VOSviewer 1.6.15 (Leiden, Netherlands) was used to analyze the data generated from Scopus. So far, 98 countries have contributed to research publications on MO, with India leading the pack. The most productive author is Rosângela Bergamasco of the Universidade Estadual de Maringa in Brazil with 60 published articles on MO. This institution is also the leading contributor to research outputs on the plant. The most cited author – Farooq Anwar is affiliated with the University of Sargodha, Pakistan with 1091 citations distributed over 11 publications on the plant. The South African Journal of Botany continues to lead in terms of the publication number with 64 original articles on MO while the Journal of Ethnopharmacology's published articles had the most citations (1166). VOSviewer analysis established Egypt, Nigeria and India as the countries with the best international link strength. The research areas on the plant are mainly on the pharmacological, food and nutritional uses as well as its applications in water treatment, environmental management and biofuel production.