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The Earth’s magnetosphere and its bow shock, which is formed by the interaction of the supersonic solar wind with the terrestrial magnetic field, constitute a rich natural laboratory enabling in situ investigations of universal plasma processes. Under suitable interplanetary magnetic field conditions, a foreshock with intense wave activity forms upstream of the bow shock. So-called 30 s waves, named after their typical period at Earth, are the dominant wave mode in the foreshock and play an important role in modulating the shape of the shock front and affect particle reflection at the shock. These waves are also observed inside the magnetosphere and down to the Earth’s surface, but how they are transmitted through the bow shock remains unknown. By combining state-of-the-art global numerical simulations and spacecraft observations, we demonstrate that the interaction of foreshock waves with the shock generates earthward-propagating, fast-mode waves, which reach the magnetosphere. These findings give crucial insight into the interaction of waves with collisionless shocks in general and their impact on the downstream medium.

Systemic administration of drugs that activate the noradrenergic or glucocorticoid system potentiates aversive memory consolidation and reconsolidation. The opposite happens with the stimulation of endocannabinoid signaling under certain conditions. An unbalance of these interacting neurotransmitters can lead to the formation and maintenance of traumatic memories, whose strength and specificity attributes are often maladaptive. Here we aimed to investigate whether originally low-intensity and precise contextual fear memories would turn similar to traumatic ones in rats systemically administered with adrenaline, corticosterone, and/or the cannabinoid type-1 receptor antagonist/inverse agonist AM251 during consolidation or reconsolidation. The high dose of each pharmacological agent evaluated significantly increased freezing times at test in the conditioning context one and nine days later when given alone post-acquisition or post-retrieval. Their respective low dose produced no relative changes when given separately, but co-treatment of adrenaline with corticosterone or AM251 and the three drugs combined, but not corticosterone with AM251, produced results equivalent to those mentioned initially. Neither the high nor the low dose of adrenaline, corticosterone, or AM251 altered freezing times at test in a novel, neutral context two and ten days later. In contrast, animals receiving the association of their low dose exhibited significantly higher freezing times than controls. Together, the results indicate that newly acquired and destabilized threat memory traces become more intense and generalized after a combined interference acting synergistically and mimicking that reported in patients presenting stress-related psychiatric conditions.

Objectives The aim of this AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial subgroup analysis was to examine rivaroxaban monotherapy benefits and their relation to the time between stenting and enrollment among patients after coronary stenting. Background Of 2,215 patients with atrial fibrillation and stable coronary artery disease in the AFIRE trial, rivaroxaban monotherapy was noninferior to rivaroxaban plus antiplatelet therapy (combination therapy) in terms of efficacy and superior for safety endpoints. However, thrombotic risk after antiplatelet therapy cessation remained a concern among 1,444 patients who had undergone coronary stenting >1 year before enrollment. Methods The benefits of rivaroxaban monotherapy in coronary stenting subgroups were assessed for efficacy (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death of any cause), safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria), ischemic endpoints, net adverse clinical event, and time between stenting and enrollment. Results Efficacy and safety endpoints for monotherapy were superior to combination therapy, with HRs of 0.70 for efficacy (95% CI: 0.50-0.98; P = 0.036) and 0.55 for safety (95% CI: 0.33-0.92; P = 0.019). For ischemic endpoints, the HR was 0.82 (95% CI: 0.58-1.15; P = 0.240). The HR became smaller with longer time between stenting and enrollment (efficacy, P for interaction = 0.158; safety, P = 0.097). Conclusions In patients with atrial fibrillation after coronary stenting, the benefits of rivaroxaban monotherapy for efficacy and safety endpoints were consistent with those in the whole AFIRE trial population. The benefits became apparent with longer time between stenting and enrollment. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study [AFIRE]; UMIN000016612 , NCT02642419 )

SUMMARY Purpose: The present study evaluated the color-matching ability of a structural colored resin composite to compare it with resin composites employing pigments. Methods and Materials: A structural colored resin composite (Omnichroma [OMC]), a supranano-filled resin composite (Estelite ∑ Quick [ELQ]), and a nano-filled resin composite (Filtek Supreme Ultra [FSU]) were used. Each resin composite was packed into a Teflon mold and pressed down with a clear strip under a glass slide. The specimens were light irradiated through the slide with a light-emitting diode curing unit. The thickness of the specimens (n=6) was measured with a digital caliper before being transferred to distilled water and stored at 37°C for 24 hours. The measurements of the optical characteristics of the specimens on a black-and-white background were performed using a spectrophotometer. D65 (CIE D65) was used as a light source for the spectrophotometer. Measurements were repeated three times for each specimen under each color-measurement condition, and average values for three same-shade specimens were calculated. One-way analysis of variance and Tukey post hoc tests were used (α=0.05). To determine its ability to match the color of artificial teeth, each shade of resin composite was placed in a cavity before performing color measurements. Using a spectrophotometer (CMS-35F S/C) with a flexible sensor, L*, a*, and b* values were obtained. Results: The spectral reflectance curve of OMC showed that it reflected light wavelengths from 430–700 nm regardless of the background color and thickness of the specimens. The percentage of reflectance of ELQ decreased near wavelengths of 550–580 nm. Regarding the influence of background color on CIE L*, a*, b* values, the L* level showed significantly higher values for all tested materials with white backgrounds, and OMC was most affected by the difference in background color. However, a* values of ELQ and FSU were significantly higher with a black background than with a white background, and OMC showed a significantly higher value with a white background than with a black background. The b* values were higher with a white background than with a black background and were significantly higher for all three products, and these tendencies were much greater for ELQ and FSU. Conclusions: The ability of OMC to match the color of artificial teeth showed acceptable color compatibility, regardless of the shade of the artificial teeth and the depth of the cavity. However, ELQ and FSU showed reduced color compatibility, especially for a cavity depth of 3.0 mm. Excellent color matching ability was confirmed for the structural colored resin composite OMC, resulting in reduced color differences and therefore improving the esthetic appearance of the restoration, simplifying shade matching, and compensating for any color mismatch.

Background The role of antithrombotic chemoprophylaxis in prevention of venous thromboembolism (VTE) in laparoscopic surgery for gastric and colorectal malignancies is unknown. This study compared the addition of enoxaparin following intermittent pneumatic compression (IPC) with IPC alone in patients undergoing laparoscopic surgery for gastrointestinal malignancy. Methods In this multicentre RCT, eligible patients were older than 40 years and had a WHO performance status of 0 or 1. Exclusion criteria were prescription of antiplatelet or anticoagulant drugs and history of VTE. Patients were allocated to IPC or to ICP with enoxaparin in a 1 : 1 ratio. Stratification factors included sex, location of cancer, age 61 years and over, and institution. Enoxaparin was administered on days 1–7 after surgery. Primary outcome was VTE, evaluated by multidetector CT on day 7. Results Of 448 patients randomized, 208 in the IPC group and 182 in the IPC with enoxaparin group were evaluated. VTE occurred in ten patients (4·8 per cent) in the IPC group and six (3·3 per cent) in the IPC with enoxaparin group (P = 0·453). Proximal deep vein thrombosis and/or pulmonary embolism occurred in seven patients (3·4 per cent) in the IPC group and one patient (0·5 per cent) in the IPC with enoxaparin group (P = 0·050). All VTE events were asymptomatic and non‐fatal. Bleeding occurred in 11 of 202 patients in the IPC with enoxaparin group, and one patient needed a transfusion. All bleeding events were managed by discontinuation of the drug. Conclusion IPC with enoxaparin after laparoscopic surgery for gastric and colorectal malignancies did not reduce the rate of VTE. Registration number: UMIN000011667 ( https://www.umin.ac.jp/)., This RCT compared intermittent pneumatic compression (IPC) alone with IPC plus enoxaparin for 1 week after surgery in the prevention of venous thromboembolism (VTE) in patients undergoing laparoscopic surgery for gastric or colorectal malignancy. Although VTE occurred in 4·8 per cent of the ICP‐alone group and 3·3 per cent of the ICP with enoxaparin group (P = 0·453), the occurrence of proximal deep vein thrombosis and/or pulmonary embolism was reduced from 3·4 to 0·5 per cent by the addition of enoxaparin (P = 0·050). No additional value of enoxaparin in patients who recover uneventful

Molecular manipulation and analysis are the cornerstone of life sciences. With the recent advances in molecular data storage and computing, it has become an increasingly exciting and viable alternative for the post-CMOS scaling era. Widespread use of molecular manipulation/analysis and data storage/computing requires a scalable and low-cost platform for hybrid molecular-electronics systems. This enables us to build on the best of what molecular and electronics systems can offer. In this article, we present PurpleDrop, a full-stack digital microfluidic platform for hybrid molecular-electronic systems in multiple domains, and focus on DNA data storage as a use case. We describe its design principles and relevant aspects such as closed-loop operation with computer vision and capacitive sensing, on-board magnetic bead extraction, and polymerase chain reaction, among other primitives. Importantly, we emphasize the ability to express and execute protocols and computation that include molecular and computational components.

Purpose This study aimed to quantify the coverage probability for esophageal cancer radiotherapy as a function of a preset margin for online MR-guided and (CB)CT-guided radiotherapy. Methods Thirty esophageal cancer patients underwent six T2-weighted MRI scans, 1 prior to treatment and 5 during neoadjuvant chemoradiotherapy at weekly intervals. Gross tumor volume (GTV) and clinical target volume (CTV) were delineated on each individual scan. Follow-up scans were rigidly aligned to the bony anatomy and to the clinical target volume itself, mimicking two online set-up correction strategies: a conventional CBCT-guided set-up and a MR-guided set-up, respectively. Geometric coverage probability of the propagated CTVs was assessed for both set-up strategies by expanding the reference CTV with an isotropic margin varying from 0 mm to 15 mm with an increment of 1 mm. Results A margin of 10 mm could resolve the interfractional changes for 118 out of the 132 (89%) analyzed fractions when applying a bone-match registration, whereas the CTV was adequately covered in 123 (93%) fractions when the registration was directly performed at the CTV itself (soft-tissue registration). Closer analyses revealed that target coverage violation predominantly occurred for distal tumors near the junction and into the cardia. Conclusion Online MR-guided soft-tissue registration protocols exhibited modest improvements of the geometric target coverage probability as compared to online CBCT-guided bone match protocols. Therefore, highly conformal target irradiation using online MR-guidance can only be achieved by implementing on-table adaptive workflows where new treatment plans are daily generated based on the anatomy of the day.

DNA has recently emerged as an attractive medium for archival data storage. Recent work has demonstrated proof-of-principle prototype systems; however, very uneven (biased) sequencing coverage has been reported, which indicates inefficiencies in the storage process. Deviations from the average coverage in the sequence copy distribution can either cause wasteful provisioning in sequencing or excessive number of missing sequences. Here, we use millions of unique sequences from a DNA-based digital data archival system to study the oligonucleotide copy unevenness problem and show that the two paramount sources of bias are the synthesis and amplification (PCR) processes. Based on these findings, we develop a statistical model for each molecular process as well as the overall process. We further use our model to explore the trade-offs between synthesis bias, storage physical density, logical redundancy, and sequencing redundancy, providing insights for engineering efficient, robust DNA data storage systems., DNA is an attractive digital data storing medium due to high information density and longevity. Here the authors use millions of sequences to investigate inherent biases in DNA synthesis and PCR amplification.

Background: Neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer causes tumor regression during treatment. Tumor regression can induce changes in the thoracic anatomy, with smaller target vol...

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

The differential cross sections of the Σ^{-}p→Λn reaction were measured accurately for the Σ^{-} momentum (p_{Σ}) ranging from 470 to 650 MeV/c at the J-PARC Hadron Experimental Facility. Precise angular information about the Σ^{-}p→Λn reaction was obtained for the first time by detecting approximately 100 reaction events at each angular step of Δcosθ=0.1. The obtained differential cross sections show a slightly forward-peaking structure in the measured momentum regions. The cross sections integrated for -0.7≤cosθ≤1.0 were obtained as 22.5±0.68 [statistical error(stat.)] ±0.65 [systematic error(syst.)] mb and 15.8±0.83(stat)±0.52(syst) mb for 470p_{Σ}(MeV/c)550 and 550p_{Σ}(MeV/c)650, respectively. These results show a drastic improvement compared with past measurements of the hyperon-proton scattering experiments. They will play essential roles in updating the theoretical models of the baryon-baryon interactions.

Description, A demonstration of DNA synthesis control at over 1000x higher density shows the path to large scale DNA data storage., Synthetic DNA is an attractive medium for long-term data storage because of its density, ease of copying, sustainability, and longevity. Recent advances have focused on the development of new encoding algorithms, automation, preservation, and sequencing technologies. Despite progress in these areas, the most challenging hurdle in deployment of DNA data storage remains the write throughput, which limits data storage capacity. We have developed the first nanoscale DNA storage writer, which we expect to scale DNA write density to 25 × 106 sequences per square centimeter, three orders of magnitude improvement over existing DNA synthesis arrays. We show confinement of DNA synthesis to an area under 1 square micrometer, parallelized over millions of nanoelectrode wells and then successfully write and decode a message in DNA. DNA synthesis on this scale will enable write throughputs to reach megabytes per second and is a key enabler to a practical DNA data storage system.

Background and objective Percutaneous coronary intervention (PCI) with metallic coronary stent (bare-metal stents [BMS] and drug-eluting stents [DES]) implantation is most frequently performed therapeutic procedures for coronary artery disease. In-stent restenosis (ISR) is a critical drawback of metallic coronary stents. Incidence of ISR has been reported in up to 30% after BMS implantation. The use of DES has greatly reduced the proportion of restenosis compared with the BMS. However, ISR still remains the primary concern after PCI even in the contemporary DES era, and thought to be associated with worse clinical outcomes. However, comparative data on ISR and de novo lesions are rare. Purpose The aim of the present study was to compare the clinical outcomes after PCI for the de novo lesion and the ISR lesion. Methods We performed a retrospective analysis of patients who underwent PCI between 2013 and 2020. The incidences of major adverse cardiac and cerebrovascular events (MACCE) and all-cause death were evaluated. MACCE was defined as composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Results In this study, 1538 patients were enrolled and divided into two groups: PCI for de novo lesion group (n=1258, 81.8%), and PCI for ISR lesion group (n=280, 18.2%). Patients in the ISR lesion group were significantly older and had higher prevalence of hypertension, diabetes mellitus, dyslipidemia and chronic kidney disease than patients in the de novo lesion group. During a median follow-up period of 1.9 years, Kaplan-Meier curves showed no significant differences in the incidences of MACCE (log-rank, p=0.86) and all-cause death (p=0.84) between two groups. After adjustment for other covariates, PCI for ISR lesion were not significantly associated with MACCE (hazard ratio [HR], 1.10; 95% confidential interval [CI], 0.61–1.97; p=0.76) and all-cause death (HR, 0.93; 95% CI, 0.56–1.56; p=0.79) Conclusion PCI for the ISR lesion was not associated with worse clinical outcomes compared with PCI for the de novo lesion. Funding Acknowledgement Type of funding sources: None.

Background Near-infrared spectroscopy (NIRS) and intravascular ultrasound (IVUS) are useful imaging modalities to identify lipid-rich plaque (LRP) which is associated with an increased risk of future cardiovascular events in individuals undergoing PCI. Pathological studies have raised concerns that treating LRP with stents may impair vascular healing. However, the impact of stent implantation to LRP lesions was less known. Moreover, little information is available about changes in the extent of LRP at before and after PCI. Purpose The aim of this study was to investigate changes in LRP by NIRS between pre- and post-stent implantation, and to evaluate an association among impact of LRP by NIRS at pre- and post-stenting and late lumen loss (LLL) by angiography. Methods We studied 175 lesions in 149 patients who underwent PCI under NIRS-IVUS guidance and follow-up angiography at 8-month later from 2017 to 2020. Plaque characteristics on IVUS, the extent of LRP [defined as a long segment with a 4-mm maximum lipid core burden index (maxLCBI4mm)] on NIRS, and quantitative coronary angiography measurements were analyzed. We evaluated a change of the extent of LRP between pre- and post-stenting at index PCI procedure, and association between the extent of LRP and a 8-month LLL at follow-up coronary angiography. A large LRP was defined as maxLCBI4mm>400 at pre-stenting. Results Mean age was 64.5 years old, and 123 (82%) patients were male. The prevalence of large LRP was 51% and median plaque burden at minimum lumen area was 81%. The extent of LRP at culprit lesion significantly decreased from pre- to post-stenting (median maxLCBI4mm [interquartile range (IQR)]: 407 [199, 580] to 133 [13, 319], p0.05). Median LLL at follow-up angiogram was 0.17 [0.07–0.35] mm. Both the extent of pre- and post-stenting LRP were not associated with LLL (r=0.018, p=0.80 and r=0.022, p=0.76, respectively) (Figure 2). In addition, there was no significant difference in LLL between the post-stenting large and non-large LRP (median [IQR] 0.18 [0.08–0.35] vs. 0.17 [0.07–0.35]; P=0.95). Conclusions This study showed coronary stent implantation significantly reduced the NIRS-derived LRP in patients undergoing PCI. Although the extent of pre-stenting LRP and IVUS plaque burden predicted the reduction of LRP, the extent of pre- and post-stenting LRP were not associated with LLL. These findings suggest that stent implantation for LRP, even in a large LRP, is safe and does not affect LLL. Funding Acknowledgement Type of funding sources: None. Figure 1. Scatter plotsFigure 2. CENTRAL Figure

Background Asians have a much lower incidence of adverse coronary events than Caucasians, and the characteristics of vulnerable plaque might be different among the ethnics. Purpose The aim of this study was to investigate the clinical characteristics of lipid-rich plaque (LRP) in the Asian population and we also aimed to distinguish the characteristics of an acute coronary syndrome (ACS) culprit lesion and a chronic coronary syndrome (CCS) culprit lesion. Furthermore, we evaluated the association between lipid core burden index (LCBI) and cardiovascular risk factors, lipid profiles, and inflammatory biomarkers, as determined in vivo by near infrared spectroscopy intravascular ultrasound (NIRS-IVUS) imaging in patients undergoing percutaneous coronary intervention (PCI). Methods We evaluated 207 patients (ACS, n=75; CCS, n=132) who underwent PCI under NIRS-IVUS. Plaque characteristics and the extent of LRP [defined as a long segment with a 4-mm maximum LCBI (maxLCBI4mm)] on NIRS in de-novo culprit and non-culprit segments were analyzed. Results The mean age was 65 years old and 82% of patients were male. The ACS culprit lesions had a significantly higher maxLCBI4mm (median [interquartile range (IQR)]: 533 [385–745] vs. 361 [174–527], p Conclusions We confirmed that NIRS-IVUS plaque assessment could be useful to differentiate ACS from CCS culprit lesions, and that a threshold maxLCBI4mm ≥400 was clinically suitable in Japanese patients. No systemic surrogate markers were found to be associated with the extent of LRP by NIRS in culprit and non-culprit segments. Consequently, we believe that direct intravascular evaluation of coronary plaque characteristics remains important for identification of high-risk LRP. Funding Acknowledgement Type of funding sources: None. Figure 1. The difference of maxLCBI4mmFigure 2. ROC curve

Importance: Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. Objective: To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient’s lifetime. Design, Setting, and Participants: Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. Interventions: Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. Main Outcomes and Measures: The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient’s lifetime for the primary outcome and the secondary outcome of death from any cause. Results: A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. Conclusions and Relevance: These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. Trial registration: ClinicalTrials.gov Identifier: NCT03036124.

Noradrenergic degeneration in the locus coeruleus (LC) seems a convergent neuropathological marker of different neurodegenerative diseases. Herein, we investigated the temporal development of apoptotic signaling activation in the LC, noradrenergic dysfunction and behavioral impairments in rats following the noradrenergic lesion of the LC. For this purpose, the dopamine reuptake inhibitor nomifensine was administered 1 h before the stereotaxic bilateral injections of 6-hydroxydopamine (6-OHDA; 5, 10 or 20 μg/hem) into the LC. The behavioral and neurochemical analyses were performed at 7, 21 and 42 days after 6-OHDA injections. All doses of 6-OHDA induced neuronal death in LC, but only the highest dose (20 μg/hem) disrupted the motor function. 6-OHDA (5 μg/hem) injection induced short-term memory deficits in all periods, olfactory discrimination and long-term memory impairments at 7 days, and depressive-like behaviors at 21 and 42 days after injection. Moreover, 6-OHDA infusion increased Bax/Bcl2 ratio and caspase 3 levels, and decreased the dopamine β-hydroxylase immunocontent in the LC. Noradrenergic neurotransmission dysfunction was observed in the LC, olfactory bulb, prefrontal cortex, hippocampus and striatum. The intranasal (i.n.) noradrenaline (NA) infusion restored the impairments in the olfactory discrimination, short-term memory and depressive-like behavior of 6-OHDA-lesioned rats. In addition, these effects were blocked by the prior i.n. infusion of the β3-adrenergic receptor antagonist SR59230A. These findings indicate that the 6-OHDA injection into the LC induced the apoptosis signaling activation, noradrenergic neurotransmission dysfunction and behavioral impairments that were restored via β3-adrenergic receptors activation mediated by the i.n. NA administration.

Attention deficit and hyperactivity disorder (ADHD) is characterized by impaired levels of hyperactivity, impulsivity, and inattention. Adenosine and endocannabinoid systems tightly interact in the modulation of dopamine signaling, involved in the neurobiology of ADHD. In this study, we evaluated the modulating effects of the cannabinoid and adenosine systems in a tolerance to delay of reward task using the most widely used animal model of ADHD. Spontaneous Hypertensive Rats (SHR) and Wistar-Kyoto rats were treated chronically or acutely with caffeine, a non-selective adenosine receptor antagonist, or acutely with a cannabinoid agonist (WIN55212-2, WIN) or antagonist (AM251). Subsequently, animals were tested in the tolerance to delay of reward task, in which they had to choose between a small, but immediate, or a large, but delayed, reward. Treatment with WIN decreased, whereas treatment with AM251 increased the choices of the large reward, selectively in SHR rats, indicating a CB1 receptor-mediated increase in impulsive behavior. An acute pre-treatment with caffeine blocked WIN effects. Conversely, a chronic treatment with caffeine increased the impulsive phenotype and potentiated the WIN effects. The results indicate that both cannabinoid and adenosine receptors modulate impulsive behavior in SHR: the antagonism of cannabinoid receptors might be effective in reducing impulsive symptoms present in ADHD; in addition, caffeine showed the opposite effects on impulsive behavior depending on the length of treatment. These observations are of particular importance to consider when therapeutic manipulation of CB1 receptors is applied to ADHD patients who consume coffee.