Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke.

BACKGROUND AND OBJECTIVES: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes. METHODS: We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage. RESULTS: We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (ß = 0.21; 95% CI 0.04-0.38, p = 0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (ß = -0.28; 95% CI -0.41 to -0.15, p < 0.001) and across multiple domains of function (ß = -0.14; 95% CI -0.22 to -0.06, p < 0.001). Brain age mediated 15% of the impact of lesion damage on sensorimotor performance (95% CI 3%-58%, p = 0.01). Greater brain resilience explained why people have better outcomes, given matched lesion damage (odds ratio 1.04, 95% CI 1.01-1.08, p = 0.004). DISCUSSION: We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets.

NITROGEN RESPONSE DEFICIENCY 1-mediated CHL1 induction contributes to optimized growth performance during altered nitrate availability in Arabidopsis.

Plants cannot fix nitrogen directly; they must absorb it from the soil through their roots, or in rare cases, form associations with nitrogen-fixing bacteria. The efficiency of nitrogen use in most domesticated crops is low, and more than half of the available nitrogen in the soil can leach into the environment. Understanding the nitrogen signaling pathways is essential for maximizing the efficiency of nitrogen use in crops. In the present study, we characterized the Myeloblastosis (Myb)-like gene NITROGEN RESPONSE DEFICIENCY 1 (NID1). We observed that the growth performance of nid1 knockout (KO) mutant Arabidopsis plants was better than that of wild-type Col-0 plants under very low-nitrate conditions, leading to improved growth performance in the nid1 KO plants. The results of chromatin immunoprecipitation and electrophoretic mobility shift assays indicated that NID1 binds to the promoter of the NITRATE TRANSPORTER (NRT)1.1 gene. Furthermore, nid1 KO plants exhibited similar growth performance to the nid1 KO/chl1-5 (nrt1.1 KO) double mutant and chl1-5 (nrt1.1 KO) plants in response to low-nitrate conditions. We suggest that NID1 plays a crucial role as a transcription factor in optimizing plant growth by modulating the transcript abundance of the nitrate transceptor CHL1, leading to enhanced ABA accumulation in low-nitrate conditions.

Non-vitamin K oral anticoagulants for coronary or peripheral artery disease: a systematic review and meta-analysis of mortality and major bleeding.

INTRODUCTION: Several high quality randomized controlled studies were recently published on non-vitamin K oral anticoagulants (NOACs) in patients with or at risk for coronary artery (CAD) or peripheral artery disease (PAD). While a reduction on cardiovascular event is known and an increase in moderate bleeding is expected, the effect of this strategy on survival is currently unknown. Accordingly, we performed a comprehensive systematic review and meta-analysis of randomized controlled trials to investigate the effect of NOAC on survival. EVIDENCE ACQUISITION: We searched Pubmed, EMBASE, Cochrane Central Register, and Clinicaltrials.gov (last updated March 31st 2019). The primary endpoint was all-cause mortality at the longest reported follow-up. Coprimary endpoint was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH) criterion. EVIDENCE SYNTHESIS: We included ten randomized controlled trials comparing NOACs versus control treatment (placebo, single platelet or dual antiplatelet therapy) enrolling 66665 patients with or at risk for CAD or PAD. NOACs were associated with a decreased risk of mortality (825/41655 [4.4%] versus 405/25010 [5.6%] RR 0.93 [95% CI: 0.87-1.00], P=0.04), and an increased risk for major bleeding (RR 1.62 [95% CI: 1.23-2.13], P=0.0005) when compared to control. Findings were robust to trial sequential, subgroup, and sensitivity analyses. Low doses NOACs were associated with a reduced mortality when compared to standard dose NOACs. CONCLUSIONS: NOACs reduced all-cause mortality in patients with or at risk for CAD or PAD, even though they increased the risk of major bleeding. Future studies regarding the best doses of NOACs are warranted.

Machine learning-based in-line holographic sensing of unstained malaria-infected red blood cells.

Accurate and immediate diagnosis of malaria is important for medication of the infectious disease. Conventional methods for diagnosing malaria are time consuming and rely on the skill of experts. Therefore, an automatic and simple diagnostic modality is essential for healthcare in developing countries that lack the expertise of trained microscopists. In the present study, a new automatic sensing method using digital in-line holographic microscopy (DIHM) combined with machine learning algorithms was proposed to sensitively detect unstained malaria-infected red blood cells (iRBCs). To identify the RBC characteristics, 13 descriptors were extracted from segmented holograms of individual RBCs. Among the 13 descriptors, 10 features were highly statistically different between healthy RBCs (hRBCs) and iRBCs. Six machine learning algorithms were applied to effectively combine the dominant features and to greatly improve the diagnostic capacity of the present method. Among the classification models trained by the 6 tested algorithms, the model trained by the support vector machine (SVM) showed the best accuracy in separating hRBCs and iRBCs for training (n = 280, 96.78%) and testing sets (n = 120, 97.50%). This DIHM-based artificial intelligence methodology is simple and does not require blood staining. Thus, it will be beneficial and valuable in the diagnosis of malaria.

Regulation and function of MeCP2 Ser421 phosphorylation in U50488-induced conditioned place aversion in mice.

RATIONALE: Phosphorylation of the methyl DNA-binding protein MeCP2 at Ser421 (pMeCP2-S421) is induced in corticolimbic brain regions during exposure to drugs of abuse and modulates reward-driven behaviors. However, whether pMeCP2-S421 is also involved in behavioral adaptations to aversive drugs is unknown. OBJECTIVES: Our goal was to establish the role and regulation of pMeCP2-S421 in corticolimbic brain regions of mice upon acute treatment with the kappa opioid receptor agonist U50488 and during the expression of U50488-induced conditioned place aversion (CPA). METHODS: pMeCP2-S421 levels were measured in the nucleus accumbens (NAc), prelimbic cortex, infralimbic cortex (ILC), and basolateral amygdala (BLA) of male mice after intraperitoneal administration of U50488 and upon the expression of U50488-induced CPA. Fos was measured as marker of neural activity in the same brain regions. U50488-induced CPA and Fos levels were compared between knockin (KI) mice that lack pMeCP2-S421 and their wild-type (WT) littermates. RESULTS: U50488 administration acutely induced pMeCP2-S421 and Fos selectively in the NAc but did not alter MeCP2 levels in any brain region. U50488-induced CPA was associated with decreased pMeCP2-S421 in the ILC and BLA and induced Fos in the BLA. MeCP2 KI mice showed CPA indistinguishable from their WT littermates, but they also showed less BLA Fos induction upon CPA. CONCLUSION: These data are the first to show that pMeCP2-S421 is induced in the brain acutely after U50488 administration but not upon U50488-induced CPA. Although pMeCP2-S421 is not required for U50488-induced CPA, this phosphorylation event may contribute to molecular plasticities in brain regions that govern aversive behaviors.

Comparison of digital tomosynthesis and chest radiography for the detection of pulmonary nodules: systematic review and meta-analysis.

OBJECTIVE: To compare the diagnostic accuracy of digital tomosynthesis (DTS) with that of chest radiography for the detection of pulmonary nodules by meta-analysis. METHODS: A systematic literature search was performed to identify relevant original studies from 1 January 1 1976 to 31 August 31 2016. The quality of included studies was assessed by quality assessment of diagnostic accuracy studies-2. Per-patient data were used to calculate the sensitivity and specificity and per-lesion data were used to calculate the detection rate. Summary receiver-operating characteristic curves were drawn for pulmonary nodule detection. RESULTS: 16 studies met the inclusion criteria. 1017 patients on a per-patient basis and 2159 lesions on a per-lesion basis from 16 eligible studies were evaluated. The pooled patient-based sensitivity of DTS was 0.85 [95% confidence interval (CI) 0.83-0.88] and the specificity was 0.95 (0.93-0.96). The pooled sensitivity and specificity of chest radiography were 0.47 (0.44-0.51) and 0.37 (0.34-0.40), respectively. The per-lesion detection rate was 2.90 (95% CI 2.63-3.19). CONCLUSION: DTS has higher diagnostic accuracy than chest radiography for detection of pulmonary nodules. Chest radiography has low sensitivity but similar specificity, comparable with that of DTS. Advances in knowledge: DTS has higher diagnostic accuracy than chest radiography for the detection of pulmonary nodules.

The head-down tilt position decreases vasopressor requirement during hypotension following induction of anaesthesia in patients undergoing elective coronary artery bypass graft and valvular heart surgeries.

BACKGROUND AND OBJECTIVE: Previous studies have failed to demonstrate that the head-down tilt position confers benefits in hypovolaemic hypotensive patients. The aim of this study was to evaluate the haemodynamic effect and vasopressor use by this position in hypotensive patients after the induction of general anaesthesia. METHODS: This prospective randomised study involved 98 patients scheduled for elective cardiac surgery and 40 patients (40.1%) developed hypotension after anaesthesia induction. Upon occurrence of hypotension, patients were randomly allocated to the supine (n = 19) or head-down tilt (n = 21) groups (15° head-down tilt position). Blood pressure, heart rate, cardiac index and stroke volume index were recorded at 1-min interval for 10 min from the occurrence of hypotension. Vasopressors were administered to treat hypotension in both groups. RESULTS: No haemodynamic difference was observed between the supine and head-down tilt groups except for SBP changes from baseline at 1 min (-3.98 ± 6.31 vs. 1.84 ± 8.25%, P = 0.004) and 2 min (1.51 ± 14.34 vs. 9.37 ± 10.57%, P = 0.032). The number of vasopressor administrations and percentage of the patients requiring vasopressors in the supine group were greater than that in the head-down tilt group [median 1 (range 1-5) vs. median 0 (range 0-2), P = 0.002, 19/19 (100%) vs. 10/21 (47.6%), P < 0.001]. CONCLUSION: The head-down tilt position in hypotensive patients following anaesthesia induction reduced vasopressor requirement by almost one third. Minimal haemodynamic effect may be caused by different vasopressor administrations. This result suggests that the head-down tilt position may enable more stable anaesthesia induction in patients undergoing elective coronary artery bypass graft or valvular heart surgeries.

Prognostic significance of insulin growth factor-I receptor and insulin growth factor binding protein-3 expression in primary breast cancer.

We analyzed insulin-like growth factor receptor I (IGF-IR) and insulin growth factor binding protein-3 (IGFBP-3) expression with respect to overall survival and relapse-free survival (RFS) in 460 patients with primary invasive breast cancer using immunohistochemistry. IGF-IR expression had a significant positive correlation with positive estrogen receptor (ER), positive progesterone receptor (PR) and Bcl-2 expression. Univariate analysis showed significantly better overall survival (p=0.000) and RFS (p=0.004), in the IGF-IR-positive group. Multivariate analysis showed a significant reduction in relative risk for overall survival (p=0.019, HR=0.221, 95% CI=0.062-0.780) and RFS (p=0.026, HR=0.462, 95% CI=0.234-0.913) in the IGF-IR-positive group. IGF-IR expression in primary breast cancer is an independent favorable prognostic factor. IGFBP-3 expression in breast cancer is associated with poor outcome.

Inhibitory effects of alpha- and beta-carotene on croton oil-induced or enzymatic lipid peroxidation and hydroperoxide production in mouse skin epidermis.

1. The effects of carotenes (alpha- and beta-) on edema, MDA contents and peroxidizability of croton oil-treated mouse skin epidermis, hydroperoxide production and enzymatic lipid peroxidation of epidermal homogenates were studied. Edema was determined as ear punch weight and the intensity of lipid peroxidation was measured using malondialdehyde formation. 2. Carotenes (alpha- and beta-) significantly suppressed edema formation, hydroperoxide production, lipid peroxidation caused by croton oil, Fe + 3-ADP/NADPH or paraquat/NADPH in vivo as well as in vitro. 3. These results indicate that both alpha- and beta-carotene have chemopreventive effects on croton oil-induced tumor promotion in skin tumorigenesis by scavenging oxygen free radicals, indirectly determined as carotene inhibition of lipid peroxidation and hydroperoxide formation.