bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between different LDL-R mutations and response to ab-PCSK9 therapy in a group of patient with genetic diagnosis of Familial Hypercholesterolemia. Preliminary report
Authors: Buonaiuto A , Gentile M , Calcaterra I.L , Giacobbe C , Tripaldella M , Forte F , Iannuzzo G , Di Minno M.N.D , Fortunato G , Rubba P.O.F
Published: November 2020

Introduction

Familial hypercholesterolemia (FH) is an autosomal dominant disease that leads to premature cardiovascular disease (CAD). The availability of ab-PCSK9 has changed the approach to therapy.

Purpose

To evaluate the relationship between different types of mutations in LDLR gene and response to ab-PCSK9.

Methods

73 FH patients, 33 women and 40 men (53.9±13. yrs), in primary prevention (N=46) and secondary prevention (N=27), were recruited. This sample included patients with mutations in LDLR gene: heterozygotes for missense mutations (N=31), for null mutations (N=31), compound heterozygotes or homozygotes (N=11). At baseline, the whole sample had a maximally tolerated lipid lowering therapy (MT-LLT) without ab-PCSK9; 16 patients had MT-LLTs intolerance. After 160 days with ab-PCSK9 therapy we evaluated the achievement of a goal (LDL-C<70 mg/dL in primary prevention without Diabetes Mellitus, LDL-C<55 mg/dL).

Results

After 160 days of therapy with ab-PCSK9 (45 patients on Alirocumab, 28 patients on Evolocumab) and MT-LLT, 29/73 patients (39.7%) of the whole sample achieve the goal of LDL-C. Of them 14/29 (48.2%) were in primary prevention, 15/29 (51.7%) in secondary prevention, no difference in achievement of the goal. We then evaluated the percent of patients achieving the goal of LDL-C:

15/31 (48.3%) patients with missense mutation and 14/31 (45.1%) patients with null mutation, no significant difference among groups;

0/11 compound heterozygotes or homozygotes;

3/16 (18.7%) MT-LLTs intolerance.

The other main cardiovascular risk factors did not influence of the achievement the goal of LDL cholesterol.

Conclusions

Lack of correlation between type of mutation in heterozygous FH patients and ab-PCSK9 therapy response; response was significantly poorest in patients with compound heterozygosis or homozygosis mutation as compared to heterozygotes; the intolerance to MT-LLT was significant in the achievement of the goal of LDL-C.

Different between guideline 2016 vs 2019

Funding Acknowledgement

Type of funding source: None
Safety and efficacy of low-dose rivaroxaban in Asian patients with atrial fibrillation and chronic kidney disease
Authors: Liu L , Tseng Y.J , Lin P.L , Chiou W.R , Lee Y.H
Published: November 2020

Background

Low-dose rivaroxaban (10mg/day) has been commonly used in Asia for patients with atrial fibrillation (AF). However, its effectiveness and safety, particularly in patients with chronic kidney disease (CKD), is limited. Moreover, inappropriate low-dose rivaroxaban is frequently prescribed. We aimed to evaluate the effectiveness and safety of low-dose rivaroxaban in patients with or without CKD, compared to that of the standard dose in real-world practice.

Methods

3122 patients with AF treated with rivaroxaban between October 2012 and December 2016 were included in this retrospective multicenter study. We compared the different doses of rivaroxaban stratified according to renal function in this cohort. Bleeding events and major adverse cardiovascular events (MACE) including CV death, MI, stroke, and thromboembolism were recorded.

Results

1218 (39%) patients received standard-dose rivaroxaban (20mg/day). 1147 (36.7%) patients with eGFR>50 mL/min/1.73m2 and 757 (24.3%) patients with eGFR<50 mL/min/1.73m2 received low-dose rivaroxaban (10mg/day). The patients who received low-dose rivaroxaban were older, more likely to be female, and with more comorbidities. After adjustment, the use of low-dose rivaroxaban was significantly associated with increased risks of MACE in the patients without CKD compared to the patients with CKD (HR: 1.75; 95% CI: 1.07 to 2.89). Also, the risk of bleeding was highest in CKD patients despite low-dose rivaroxaban treatment. There was no difference in bleeding between the standard-dose and low-dose of rivaroxaban in patients without CKD (HR: 1.29; 95% CI: 0.8 to 2.08).

Conclusions

The use of inappropriate low-dose rivaroxaban in patients without CKD increased MACE significantly, compared to low-dose rivaroxaban in CKD patients. In addition, the risk of bleeding was strongly associated with CKD, not with the dose of rivaroxaban.

Cumulative Event Rates

Funding Acknowledgement

Type of funding source: None
Meta-analysis comparing the efficacy and safety of direct acting oral anticoagulants to warfarin in patients with atrial fibrillation with and without diabetes
Authors: Shetty S , Malik H
Published: November 2020

Background

Direct-acting oral anticoagulants (DOACs) are now the preferred choice over warfarin in patients with atrial fibrillation (AF). The comparative efficacy and safety of DOACs over warfarin in patients with and without diabetes mellitus (DM) has not been fully evaluated.

Purpose

To evaluate the efficacy and safety of DOACs compared to warfarin in patients with non-valvular atrial fibrillation with and without DM.

Methods

A comprehensive review of the literature was performed to identify RCTs with data on DOACs compared to warfarin in the subgroups of DM and nonN-DM. Our outcome of interest were stroke/systemic embolization (SSE) and major bleeding. A random-effects meta-analysis was performed. We further performed a network meta-analysis to assess the most effective of all the therapies for the above mentioned subgroups.

Results

Our search identified 4 RCTs with 71,683 randomized patients, of which 22,087 were DM and 49,596 were non-DM. The mean duration of follow up was 2.3 years. Our results showed that the DOACS were associated with lower odds for SSE in diabetics (OR 0.80; 95% CI 0.67–0.95; p-value=0.01) and non-diabetics (OR 0.81; 95% CI 0.71–0.92; p-value<0.01). For major bleeding, DOACs were non-inferior to warfarin in DM (OR 0.94; 95% CI 0.80–1.09; p-value=0.42) and non-DM (OR 0.82; 95% CI 0.62–1.07; p-value=0.15). (Fig 1) Network meta-analysis showed that dabigatran was the most effective for the outcome of SSE irrespective of DM status. However, edoxaban and apixaban were the safest of the DOACs for the outcome of major bleeding (Table 1)

Conclusion

In this meta-analysis of RCT, we found that DOACs are more effective and similarly safe compared to warfarin irrespective of the diabetic status of the patient.

Funding Acknowledgement

Type of funding source: None
Implications of presenting to hospital with AF: the REVIEW AF study
Authors: Gallagher C , Wong C.X , Hendriks J.M , Bednarz J , Elliott A.D , Linz D , Middeldorp M.E , Mahajan R , Lau D.H , Sanders P
Published: November 2020

Background

There is a growing burden of hospitalizations due to atrial fibrillation (AF). The implications of hospitalisation to the individual with AF has not been well characterized.

Purpose

To characterise the consequences of presenting to hospital with AF.

Methods

Individuals presenting to the emergency department (ED) of three hospitals in South Australia from March 2013 to February 2014 with a primary diagnosis of AF were enrolled. Based on coding and individual electronic medical record review all re-presentations over follow up were characterised as: 1) AF related; 2) cardiovascular related (excluding AF); or 3) all other causes. Mortality over follow up was also determined.

Results

The study cohort comprised of 437 individuals with an AF related index presentation. Mean age was 69±15 years and 49.9% were male. Individuals were followed for a mean of 3.7±0.4 years. There were 2304 unplanned presentations over follow up. The percentage of the study cohort who presented to the ED or were admitted to hospital over follow up is detailed in Figure 1. Compared to individuals who did not have a hospital admission for AF over follow up, those who were readmitted for AF were more likely to be hypertensive (63.2% vs 49.3%, p<0.001); and have a higher CHA2DS2-VASc score (3.2±1.8 vs 2.7±1.9, p=0.002) and HAS-BLED score (2.0±1.0 vs 1.5±1.1, p<0.001). A total of 71 individuals (16.2%) died during the follow-up period (annual mortality rate of 3.78%).

Conclusions

A hospital presentation with a primary diagnosis of AF identifies individuals at high risk of repeat hospitalisations and death. Urgent studies are needed to improve management of this high-risk cohort.

Figure 1. Repeat hospital presentations in AF

Funding Acknowledgement

Type of funding source: None
A combined digital and organizational approach dramatically improves access to outpatient care in cardiology
Authors: Jamal F , Boiron F , Tettoni C , Couvert I , Ielissof C , Fasciani S , Zebrowski P.A , Dussardier F , Schloter N , Amaral A
Published: November 2020

We have previously shown that digital preconsultation saves medical time and may improve outcome. But waiting times for a cardiology consultation are still growing mainly due to chronic diseases, aging and a growing demand for prevention.

Purpose

We aimed to evaluate the impact of a combined approach using digital tools and a novel outpatient team organization on access to care, in real life

Methods

We implemented a full digital solution and a dedicated team in a new outpatient cardiology center (Figure). The organization was schematically divided in five parts: (1) digital PRECONSULTATION completed by the patient with an assistant and nurse support if necessary; (2) digital AI-NALYSIS of this data with a trained nurse validation to define the risk level; (3) Medical CONSULTATION either physical or using teleconsultation; (4) RESULTS: directly accessible to the patient and his GP; (5) FOLLOW-UP if relevant mainly based on digital tools and trained nurses. Activity was monitored for 9 months. The following parameters were measured: waiting time (from demand to consultation); medical efficiency (number of consultations/hour of work); patient overall satisfaction

Results

2867 consultations were performed between April and December 2019, with a waiting time of 4.3±1.6 days (compared to a national average of 61 days). Efficiency averaged 2.3 patients/hour. Patient satisfaction averaged 4.84 over 5.

In addition, 160 possible consultations in the emergency room were avoided (mainly mild palpitations and non-cardiac chest pain)

Conclusion

A specific digital platform and a dedicated medical team and organization improved the access to care and the medical efficiency. We believe this is a promising way to decrease the demand burden in the emergency room, to decrease the professional burnout risk and to improve prevention.

Figure 1. A Phygital care path

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): Cardioparc, Izycardio
Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?
Authors: Ademi Z , Norman R , Pang J , Liew D , Zoungas S , Sijbrands E , Ference B.A , Wiegman A , Watts G
Published: November 2020

Background

There are no studies that have specifically investigated the cost-effectiveness of cascade screening of children for heterozygous familial hypercholesterolemia (FH) and treatment of affected individuals with statins to prevent coronary heart disease (CHD).

Purpose

This study explores the cost-effectiveness of this strategy from the perspective of the Australian public healthcare system.

Methods

A lifetime Markov model with four health states (Alive without CHD, Alive with CHD, Dead from fatal CHD, and Dead from other causes) was developed to simulate the progression of ten- year-old children screened for FH and treated immediately with statins if found to have FH. The underlying prevalence of FH in this target population was assumed to be 56.8%, and the sensitivity and specificity of testing was 100%. The comparator was usual care, which assumed that subjects started statins spontaneously at a later point or when they experienced a cardiovascular event. The effect of reducing low-density lipoprotein cholesterol (LDL-C) on the risk of a first event at each age assumed that risk was proportional to total lifetime exposure and was implemented using Mendelian randomisation analysis data. Cost and other outcome data were sourced from published sources. Outcome of interests were costs in Australian dollars (AUD), life years gained (LYG) and quality-adjusted life years (QALYs) gained, as well as incremental cost-effectiveness ratios (ICERs) of costs per LYG and per QALY gained. All future costs and outcomes were discounted by 5% annually.

Results

Undiscounted results showed that compared with usual care, cascade screening of ten year-old children for FH and initiation of treatment of affected individuals saved 7.77 LYG and 7.53 QALYs per person over a lifetime. With 5% annual discounting, there were 0.97 LYG and 1.07 QALYs gained per person, at an additional cost of $3,244. These equated to ICERs of $3334 per LYG and $3023 per QALY gained. The equivalent ICERs in USD would be $5089 per LYG gained and $4615 per QALY gained. Sensitivity analysis showed the results to be robust.

Conclusions

Compared to usual care, cascade screening of ten year old children for FH and treating affected individuals is likely to be highly cost-effective.

Table 1. Granular cost and benefit data

Funding Acknowledgement

Type of funding source: None
Cholinergic regulation of cardiac pacemaker activity by l-type cav1.3 channels
Authors: Talssi L , Bidaud I , Mesirca P , Mangoni M
Published: November 2020

Introduction

The cholinergic regulation of heart rate (HR) is mediated by acetylcholine (ACh)-dependent activation of M2-receptors (M2R). Activated M2R promote release of the βγ-subunit of G-proteins to directly gate GIRK1/4 channels (underlying the cardiac IKACh current), while αi-subunits inhibit adenylate cyclase (AC) activity. AC inhibition reduces the intracellular concentration of cAMP, decreasing the activity of ion channels involved in pacemaking, including “funny” f-(HCN4) and L-type Cav1.3 calcium channels.

Purpose

To determine the importance of L-type Cav1.3 channels in the cholinergic regulation of heart rate.

Methods

We recorded the frequency and the position of the pacemaker leading site in ex vivo sinus nodes and the HR of isolated Langendorff perfused hearts of mice in control or during ACh perfusion. We used control wild type (WT) mice, and five genetically modified mouse models: Cav1.3 knockout (KO, ablated Cav1.3-mediated L-type current), GIRK4KO (ablated IKACh current), HCN4-CNBD (selective deletion of cAMP-dependent regulation of HCN4), GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO.

Results

Data from optical mapping experiments showed that, under basal conditions, perfusion of 3 μM ACh significantly reduced the frequency of action potentials in WT (44%), HCN4-CNBD (38%), Cav1.3KO (65%) and GIRK4KO (8%) isolated mouse sinus node tissues. ACh application did not significantly affect the frequency of action potentials recorded in tissue from GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO animals. Furthermore, in all the sinus node tissues tested, regardless of the genotypes, ACh shifted the pacemaker leading site from its normal position by at least 0.7 mm.

Upon stimulation of the β-adrenergic pathway by Isoproterenol, to reproduce conditions of accentuated antagonism, 3μM ACh reduced HR in isolated hearts from WT (43.8%), HCN4-CNBD (38.7%), Cav1.3KO (25,4%), GIRK4KO (16.9%) and GIRK4KO/HCN4-CNBD (16.4%) mice. No significant HR reduction was recorded in hearts from GIRK4KO/Cav1.3KO animals.

Conclusion

Our data indicate that L-type Cav1.3 channels are involved in cholinergic regulation of heart rate in mice. In addition, when the intracellular concentration of cAMP is elevated (i.e. under conditions of accentuated antagonism), the cholinergic regulation of sinus node pacemaking is predominantly ensured by Cav1.3 and KACh channels.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): “Fondation pour la recherche medicale” FRM
Usefulness of collaboration between mathematical models and cell engineering for elucidating complex disease mechanisms and discover effective drugs
Authors: Kohjitani H , Kashiwa A , Makiyama T , Toyoda F , Yamamoto Y , Wuriyanghai Y , Ohno S , Aizawa T , Imamura T , Shizuta S , Kimura T
Published: November 2020

Background

A missense mutation, CACNA1C-E1115K, located in the cardiac L-type calcium channel (LTCC), was recently reported to be associated with diverse arrhythmias. Several studies reported in-vivo and in-vitro modeling of this mutation, but actual mechanism and target drug of this disease has not been clarified due to its complex ion-mechanisms.

Objective

To reveal the mechanism of this diverse arrhythmogenic phenotype using combination of in-vitro and in-silico model.

Methods and results

Cell-Engineering Phase: We generated human induced pluripotent stem cell (hiPSC) from a patient carrying heterozygous CACNA1C-E1115K and differentiated into cardiomyocytes. Spontaneous APs were recorded from spontaneously beating single cardiomyocytes by using the perforated patch-clamp technique.

Mathematical-Modeling Phase: We newly developed ICaL-mutation mathematical model, fitted into experimental data, including its impaired ion selectivity. Furthermore, we installed this mathematical model into hiPSC-CM simulation model.

Collaboration Phase: Mutant in-silico model showed APD prolongation and frequent early afterdepolarization (EAD), which are same as in-vitro model. In-silico model revealed this EAD was mostly related to robust late-mode of sodium current occurred by Na+ overload and suggested that mexiletine is capable of reducing arrhythmia. Afterward, we applicated mexiletine onto hiPSC-CMs mutant model and found mexiletine suppress EADs.

Conclusions

Precise in-silico disease model can elucidate complicated ion currents and contribute predicting result of drug-testing.

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists
MicroRNA-330-5p inhibits NLRP3 inflammasome-mediated myocardial ischemia-reperfusion injury by targeting TIM3
Authors: Zuo W , Tian R , Chen Q , Wang L , Gu Q , Huang C.M , Yang X.L , Xu L.H , Zhang B , Liu Z.Y
Published: November 2020

Background

Myocardial ischemia-reperfusion injury (MIRI) is one of the leading causes of human death. Nod-like receptor protein-3 (NLRP3) inflammasome signaling pathway involved in the pathogenesis of MIRI. However, the upstream regulating mechanisms of NLRP3 at molecular level remains unknown.

Purpose

This study investigated the role of microRNA330-5p (miR-330-5p) in NLRP3 inflammasome-mediated MIRI and the associated mechanism.

Methods

Mice underwent 45 min occlusion of the left anterior descending coronary artery followed by different times of reperfusion. Myocardial miR-330-5p expression was examined by quantitative polymerase chain reaction (PCR), and miR-330-5p antagomir and agomir were used to regulate miR-330-5p expression. To evaluate the role of miR-330-5p in MIRI, Evans Blue (EB)/2, 3, 5-triphenyltetrazolium chloride (TTC) staining, echocardiography, and immunoblotting were used to assess infarct volume, cardiac function, and NLRP3 inflammasome activation, respectively. Further, in vitro myocardial ischemia-reperfusion model was established in cardiomyocytes (H9C2 cell line). A luciferase binding assay was used to examine whether miR-330-5p directly bound to T-cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM3). Finally, the role of miR-330-5p/TIM3 axis in regulating apoptosis and NLRP3 inflammasome formation were evaluated using flow cytometry assay and immunofluorescence staining.

Results

Compared to the model group, inhibiting miR-330-5p significantly aggravated MIRI resulting in increased infarct volume (58.09±6.39% vs. 37.82±8.86%, P<0.01) and more severe cardiac dysfunction (left ventricular ejection fraction [LVEF] 12.77%±6.07% vs. 27.44%±4.47%, P<0.01; left ventricular end-diastolic volume [LVEDV] 147.18±25.82 vs. 101.31±33.20, P<0.05; left ventricular end-systolic volume [LVESV] 129.11±30.17 vs. 74.29±28.54, P<0.05). Moreover, inhibiting miR-330-5p significantly increased the levels of NLRP3 inflammasome related proteins including caspase-1 (0.80±0.083 vs. 0.60±0.062, P<0.05), interleukin (IL)-1β (0.87±0.053 vs. 0.79±0.083, P<0.05), IL-18 (0.52±0.063 vs. 0.49±0.098, P<0.05) and tissue necrosis factor (TNF)-α (1.47±0.17 vs. 1.03±0.11, P<0.05). Furthermore, TIM3 was confirmed as a potential target of miR-330-5p. As predicted, suppression of TIM3 by small interfering RNA (siRNA) ameliorated the anti-miR-330-5p-mediated apoptosis of cardiomyocytes and activation of NLRP3 inflammasome signaling pathway (Figure 1).

Conclusion

Overall, our study indicated that miR-330-5p/TIM3 axis involved in the regulating mechanism of NLRP3 inflammasome-mediated myocardial ischemia-reperfusion injury.

Figure 1

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China Grants
Systemic mesenchymal stem cell-derived exosomes reduce myocardial infarct size: characterization with MRI in a porcine model
Authors: Charles C.J , Li R.R , Yeung T , Mazlan S.M.I , Lai R.C , De Kleijn D.P.V , Lim S.K , Richards A.M
Published: November 2020

Background

Mesenchymal stem cells (MSCs) have been shown to exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes.

Purpose

To determine whether MSC-derived exosomes administered systemically by the convenient method of intravenous (IV) bolus injection reduce infarct size and improve cardiac function in an established porcine model of myocardial infarction (MI).

Methods

A total of 20 pigs underwent experimental MI by permanent ligation of the left circumflex coronary artery (LCX). Ten pigs (exosome treated) received twice daily IV injection of exosomes (1000ug protein equivalent) for 7 days. The remaining 10 pigs received vehicle control injections. Cardiac structure and function were measured by MRI which was performed at baseline (pre-MI) and repeated on days 7 and 28 post-MI. Infarct size was also confirmed post-mortem. Blood samples were drawn over first 7 days for measurement of hs Troponin T. The study followed the principles of laboratory animal care and was approved by our institution's IACUC.

Results

All LCX ligations resulted in permanent ischaemia with MI as evidenced by pallor of the myocardium, ECG changes including ST segment elevation and increases in plasma hs Troponin T. Exosomes administered IV for 7 days resulted in clear reduction (30–40%) of infarct size measured at both 7 (p<0.05) and 28 days (p<0.01) post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning (p<0.01) in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening (p<0.01) compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments.

Conclusion

Taken together, our results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs.

Figure 1

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): STaR Award (AM Richards), National Medical Research Council, Singapore. IAF-ICP, National Research Foundation, Singapore (RC Lai and SK Lim).
Haematopoietic PI3-kinase delta deficiency profoundly impairs regulatory T-cell biology and thereby protection against atherosclerosis
Authors: Zierden M , Millarg C , Berghausen E.M , Feik L , Baldus S , Vantler M , Rosenkranz S
Published: November 2020

Introduction and purpose

Atherosclerosis is a chronic inflammatory disease of arteries, critically involving leukocytes like macrophages as well as T and B lymphocytes. Macrophages are major drivers of disease through the ingestion of lipoproteins, foam cell formation, and secretion of inflammatory mediators. Although macrophages outnumber other leukocytes in atherosclerotic plaques, T and B cells can shape the course of disease by promoting or mitigating inflammatory responses. Leukocytes highly express the phosphoinositide 3-kinase isoform delta (PI3Kd), exerting a key role in the regulation of immune responses including activation, proliferation, differentiation, and effector functions. Therefore, PI3Kd represents a promising target for the modulation of inflammatory diseases. Consequently, we aimed to analyse the role of PI3Kd in leukocytes during atherogenesis.

Methods and results

To investigate the role of PI3Kd in atherosclerosis, bone marrow from PI3Kd−/− or PI3Kd+/+ mice was transplanted into LDLR−/− mice. After a 6-weeks-challenge by high fat diet, PI3Kd−/− recipient LDLR−/− mice displayed profoundly impaired CD4+ and CD8+ T-cell numbers, CD4+ T-cell activation, CD4+ effector T-cell differentiation, and proatherogenic CD4+ T-helper (Th) 1 responses in para-aortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the net effect of PI3Kd deficiency was a substantial increase of aortic inflammation and atherosclerosis in LDLR−/− mice. Whereas plaque content and functions of macrophages including foam cell formation, efferocytosis, and cytokine secretion remained unaffected, haematopoietic PI3Kd ablation strongly reduced mature B cells and serum immunoglobulins in LDLR−/− mice. Importantly, PI3Kd deficiency severely impaired numbers and immunosuppressive functions of regulatory CD4+ T cells (Tregs) in spleen, para-aortic lymph nodes, and plaques of LDLR−/− mice. Consequently, adoptive transfer of PI3Kd+/+ Tregs fully constrained the plaque burden in PI3Kd−/− transplanted LDLR−/− mice without affecting B-cell numbers and serum immunoglobulins, whereas adoptively transferred PI3Kd−/− Tregs were unable to relieve atherosclerosis progression.

Conclusions

Here, we demonstrate that PI3Kd plays a crucial role in Tregs, Th1 cells, and B cells during atherogenesis. Lack of PI3Kd signalling specifically in atheroprotective Treg responses outplays its impact on proatherogenic Th1 and B-cell responses, thus leading to aggravated atherosclerosis. Hence, PI3Kd is a key regulator of Treg biology and thereby protects against atherosclerosis.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): Marga and Walter Boll Foundation
Sirt6 regulates autophagy in AGE-treated endothelial cells via KLF4
Authors: Tong J , Chen F , Tang J.N , Ye Z , Liu X.B
Published: November 2020

Aims

To explore Sirt6 regulating autophagy in endothelial cells and the specific mechanism of this function with involvement of KLF4.

Materials and methods

Human umbilical vein endothelial cells were cultured with advanced glycation end products (AGE) treatment. Adv-Sirt6, LV-Sirt6 and LV-KLF4 were used to knockup Sirt6 and knockdown Sirt6 and KLF4 respectively. qPCR and Western Blotting were used to detect the mRNA and protein expression of Sirt6 and KLF4. Laser scanning confocal microscope was used to observe the LC3-II marked autophagosomes. Wildlife BALB/c mice were treated with STZ to produce diabetic mice model. AAV-Sirt6 was injected by tail vein injection to achieve Sirt6 knockdown. HE staining and scanning electron microscope were used to observe the aortic intima condition and autophagosomes number respectively.

Results

In AGE treated HUVECs, knockdown of Sirt6 led to impaired autophagy level along with less expression of autophagic markers LC3-II, Beclin-1, Lamp2 and autophagic marker p62. Knockdown and knockup of Sirt6 directly affected KLF4 expression level but KLF4 didn't have any effect on Sirt6 expression. Knockout of KLF4 offset the augmented autophagy caused by overexpression of Sirt6. In high-fat fed diabetic mice, downregulation of Sirt6 led to better cardiac function along with less autophagosomes and impaired aortic intima integrity.

Conclusions

Sirt6 improves autophagy both in vivo and in vitro and Sirt6 regulates autophagy via KLF4 in HUVECs.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Natural Science Foundation of China
The role of matrix metalloproteinase-2 on age-dependent arterial stiffness
Authors: Puspitasari Y.M , Diaz-Canestro C , Sudano I , Flammer A , Bonetti N.R , Wuest P , Liberale L , Constantino S , Paneni F , Ruschitzka F , Beer J.H , Hermann M , Luscher T.F , Camici G.G
Published: November 2020

Introduction

Arterial stiffness is a well-characterized sign of vascular aging. It strongly predicts the development of several cardiovascular diseases (CVD), such as hypertension, stroke and heart failure. The age-dependent stiffening of elastic arteries is primarily attributed to the loss of interlaminar elastic fibers and the increase of collagen fibers. This process is regulated by matrix metalloproteinases (MMPs), including MMP-2. A strong correlation between MMP-2 levels and arterial stiffness has been previously described. However, the causative link between age-dependent arterial stiffness and MMP-2 remains unclear.

Purpose

In this study, we aimed to prospectively investigate the effect of MMP-2 gene silencing on the development of age-dependent carotid stiffness in wild type (WT) mice.

Methods

Pulse Wave Velocity (PWV), as the gold standard technique to assess arterial stiffness, was assessed in the right common carotid artery (RCCA) of C57BL/6 WT mice of various ages ranging between 3 and 25 months. Plasma and vascular levels of MMP-2 on RCCA were also measured and correlate with PWV. Moreover, aged WT male mice (18–21-month-old) were treated for 4 weeks with either MMP-2 siRNA or Scr siRNA via tail vein injection every 4 days and PWV was assessed at baseline, 2 and 4 weeks.

Results

Mouse carotid PWV increased and was positively correlated with age in our in vivo longitudinal study. Increases of vascular and circulating MMP-2 levels were also observed in this study. MMP-2 knockdown by siRNA treatment reduced vascular MMP-2 level (Fig. 1), which in turn attenuated age-dependent carotid stiffening (data not shown). siMMP-2 treated animals also showed an increase of elastin to collagen ratio. Furthermore, enhanced phosphorylation of the activatory eNOS Ser1177 was observed in the siMMP-2 group without affecting the level of total eNOS and Akt phosphorylation. Interestingly, co-immunoprecipitation experiments demonstrated that MMP-2 directly interacts with eNOS and this interaction is augmented with age.

Conclusion

The silencing of MMP-2 attenuates age-dependent carotid stiffness by affecting elastin to collagen ratio and interfering with eNOS activation. Thus, MMP-2 may mediate ECM remodeling and endothelial-dependent vasorelaxation in the development of age-dependent vascular stiffness.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): Swiss National Science Foundation, Foundation for Cardiovascular Research-Zurich Heart House
A case report of cardiac toxicity from barracuda ingestion in Mexico
Authors: Haouzi Alice , Khraishah Haitham , Diamond Jamie , Pinto Duane S
Published: November 2020

Background

Ciguatera toxicity is a fish-borne illness that initially manifests with gastrointestinal symptoms, followed by bizarre neurological symptoms including heat-cold sensation alteration, peculiar feeling of loose teeth, and peripheral neuropathy. However, cardiac manifestations are rare and underreported in the literature.

Case summary

A 73-year-old man presented with symptomatic bradycardia and hypotension after ingestion of barracuda fish in Mexico. He received atropine and dopamine with subsequent improvement in his symptoms, but continued to experience peripheral neuropathic and other odd sensations. Four of his family members ingested the same fish and had similar symptoms. He was managed conservatively and did not require temporary or permanent pacing. Within 1 week from toxin exposure, bradycardia had improved. Heart rate was 40–50 b.p.m. at rest, and he was discharged with an ambulatory monitor. Heart rate had increased to 77 b.p.m. at 1-month follow-up on repeat electrocardiogram (ECG).

Discussion

Although the predominant manifestations of ciguatera toxicity are neurological, cardiac complications tend to be more acute and require attention. Unlike neurological symptoms, bradycardia and hypotension are short-lived, often resolving within a week. Treatment continues to be largely supportive, and patients may require temporary treatment with positive chronotropic agents such as atropine or dopamine.
Assessment of Cognitive-Motor Performance Costs, Task Prioritization, and Adaptation to Dishwashing Under Increased Demand in Older Women With Arthritis
Authors: Mejía Shannon T , Nielsen Karen E , Raichur Vineet , Carmichael Alicia G , Tavares Eugene , Jarvis Jennie , Smith Jacqui , Gonzalez Richard
Published: November 2020

Background and Objectives

Hand arthritis can limit upper-limb instrumental activities of daily living (IADLs) and require the recruitment of additional cognitive and motor resources to support performance. We devised a dual-task protocol for dishwashing to examine cognitive-motor performance costs and prioritizations under increased demands, processes of adaptation, and individual differences in performance costs.

Research Design and Methods

Sixty women with hand arthritis (aged 60–91) completed a standardized dishwashing protocol. Motor demand was increased via the properties of the soap dispenser. Cognitive demand was increased using audial attention and response inhibition tasks. The protocol was completed twice per lab visit on 3 occasions. Response time and dishwashing time provided measures of cognitive and motor task performance. Prioritization was determined by comparing the magnitude of dual-task cost (DTC) across tasks. Adaptation to the dishwashing protocol and novel dispenser was assessed by change in DTC across lab visits. Individual differences in cognitive and physical ability were assessed with the trail making B test and gait speed.

Results

Estimates from linear mixed-effects models revealed that response time increased, whereas dishwashing time decreased, during the dual-task study stages. Cognitive-motor prioritization effects were most pronounced among women with lower cognitive and physical ability. Evidence of prioritization and individual differences in DTC diminished across lab visits.

Discussion and Implications

The pattern of results suggests that older women with arthritis prioritize the motor over cognitive components of dishwashing, a common IADL. Adaptation across lab visits resulted in improved performance, reduced evidence of prioritization, and attenuated differences in DTC across physical and cognitive abilities.
Altruistic Attitudes Among Older Adults: Examining Construct Validity and Measurement Invariance of a New Scale
Authors: Bhatta Tirth R , Kahana Eva , Lekhak Nirmala , Kahana Boaz , Midlarsky Elizabeth
Published: November 2020

Background and Objectives

Scholarly research has established the role of altruism in facilitating human cooperation and prosocial behaviors and highlighted its contribution to psychological well-being. Given the health significance of altruistic attitudes and orientations, we developed a valid and reliable measure of this construct that is suitable for use with older adults.

Research Design and Methods

Based on data from a long-term panel study on adaptation to frailty among older adults (n = 366; mean age = 86 years), we used confirmatory factor analysis to perform construct validation of a five-item Elderly Care Research Center Altruism Scale among older adults (e.g., “Seeing others prosper makes me happy”). Moreover, we examined the invariance of the scale’s factor structure across time and gender using nested models.

Results

Composite reliability (coefficient omega = 0.78), factor loadings (>0.45 with eigenvalue = 2.84) from exploratory factor analysis, and model fit indices (e.g., comparative fit index = 0.999) from confirmatory factor analysis suggest a single factor, supporting a unidimensional reliable construct of altruistic orientation at baseline. The results provided support for configural, metric, and scalar invariance across time. Findings pertaining to measurement invariance across gender confirmed full configural invariance but only offered support for partial metric, scalar, and residual invariance at baseline. Strong correlations among the altruism scale, salient personality traits, psychological well-being, religiosity, and meaning in life help establish construct validity.

Discussion and Implications

The availability of a reliable and valid measure of altruistic attitudes enables a comprehensive evaluation of altruism’s influence on later-life health and well-being.
COVID-19 Pandemic Planning: Simulation Models to Predict Biochemistry Test Capacity for Patient Surges
Authors: Lyon Martha E , Bajkov Andrew , Haugrud Diane , Kyle Barry D , Wu Fang , Lyon Andrew W
Published: November 2020

Background

Patient surges beyond hospital capacity during the initial phase of the COVID-19 pandemic emphasized a need for clinical laboratories to prepare test processes to support future patient care. The objective of this study was to determine if current instrumentation in local hospital laboratories can accommodate the anticipated workload from COVID-19 infected patients in hospitals and a proposed field hospital in addition to testing for non-infected patients.

Methods

Simulation models predicted instrument throughput and turn-around-time for chemistry, ion-selective-electrode, and immunoassay tests using vendor-developed software with different workload scenarios. The expanded workload included tests from anticipated COVID patients in 2 local hospitals and a proposed field hospital with a COVID-specific test menu in addition to the pre-pandemic workload.

Results

Instrumentation throughput and turn-around time at each site was predicted. With additional COVID-patient beds in each hospital, the maximum throughput was approached with no impact on turnaround time. Addition of the field hospital workload led to significantly increased test turnaround times at each site.

Conclusions

Simulation models depicted the analytic capacity and turn-around times for laboratory tests at each site and identified the laboratory best suited for field hospital laboratory support during the pandemic.
Revisiting the Legal Effect of General Assembly Resolutions: Can an Authorising Competence for the Assembly be Grounded in the Assembly’s ‘Established Practice’, ‘Subsequent Practice’ or Customary International Law?
Authors: Barber Rebecca
Published: November 2020

The Security Council’s recent intractability in the face of human rights and humanitarian crises has directed increased attention to the General Assembly’s secondary responsibility for international peace and security. Despite considerable academic attention to the issue, however, significant questions remain regarding the scope of the Assembly’s powers. One of the most significant of these questions is whether the Assembly may authorise conduct that would otherwise be unlawful. This question is important, because while there is good authority to support the proposition that the Assembly may recommend measures up to and including the use of force, if the Assembly is not also competent to authorise such measures, we are left with the unsatisfactory scenario in which the Assembly is legally competent to make recommendations that States may not legally be able to act upon. Drawing on the International Law Commission’s 2018 Draft Articles on Subsequent Agreement and Subsequent Practice, as well as those on Identification of Customary International Law, this article explores whether an authorising competence on the part of the General Assembly can be grounded in the Assembly’s practice. Specifically, it considers whether the Assembly’s practice of recommending and seemingly purporting to authorise coercive measures may amount to ‘established practice’, thus forming part of the ‘rules of the organisation’ within the meaning of the Vienna Convention on the Law of Treaties (VCLT); or alternatively if it can be considered ‘subsequent practice’ within the meaning of the VCLT; or alternatively it may attest to a rule of customary international law.
Using mixture models to examine group difference among jurors: an illustration involving the perceived strength of forensic science evidence
Authors: Kaplan-Damary Naomi , C. Thompson William , Hofstein Grady Rebecca , Stern Hal S
Published: November 2020

The way in which jurors perceive reports of forensic evidence is of critical importance, especially in cases of forensic identification evidence that require examiners to compare items and assess whether they originate from a common source. The current study discusses methods for studying group differences among mock jurors and illustrates them using a reanalysis of data regarding lay perceptions of forensic science evidence. Conventional approaches that consider subpopulations defined a priori are compared with mixture models that infer group structure from the data, allowing detection of subgroups that cohere in unexpected ways. Mixture models allow researchers to determine whether a population comprises subpopulations that respond to evidence differently and then to consider how those subpopulations might be characterized. The reanalysis reported here shows that mixture models can enhance understanding of lay perceptions of an important type of forensic science evidence (DNA and fingerprint comparisons), providing insight into how the perceived strength of that evidence varies as a function of the language forensic experts use to describe their findings. This novel application of mixture models illustrates how such models can be used, more generally, to explore the importance of juror characteristics in jury decision making.
High-cadence, early-time observations of core-collapse supernovae from the TESS prime mission
Authors: Vallely P J , Kochanek C S , Stanek K Z , Fausnaugh M , Shappee B J
Published: November 2020

We present observations from the Transiting Exoplanet Survey Satellite (TESS) of twenty bright core-collapse supernovae with peak TESS-band magnitudes ≲18 mag. We reduce this data with an implementation of the image subtraction pipeline used by the All-Sky Automated Survey for Supernovae (ASAS-SN) optimized for use with the TESS images. In empirical fits to the rising light curves, we do not find strong correlations between the fit parameters and the peak luminosity. Existing semi-analytic models fit the light curves of the Type II supernovae well, but do not yield reasonable estimates of the progenitor radius or explosion energy, likely because they are derived for use with ultraviolet observations while TESS observes in the near-infrared. If we instead fit the data with numerically simulated light curves, the rising light curves of the Type II supernovae are consistent with the explosions of red supergiants. While we do not identify shock breakout emission for any individual event, when we combine the fit residuals of the Type II supernovae in our sample, we do find a >5σ flux excess in the ∼1 d before the start of the light-curve rise. It is likely that this excess is due to shock breakout emission, and that during its extended mission TESS will observe a Type II supernova bright enough for this signal to be detected directly.
Tidally excited oscillations in hot white dwarfs
Authors: Yu Hang , Fuller Jim , Burdge Kevin B
Published: November 2020

We study the flux variation in helium white dwarfs (WDs) induced by dynamical tides for a variety of WD models with effective temperatures ranging from $T=10\, {\rm kK}$ to $T=26\, {\rm kK}$. At linear order, we find the dynamical tide can significantly perturb the observed flux in hot WDs. If the temperature $T\gtrsim 14\, {\rm kK}$, then the dynamical tide may induce a fractional change in the flux by $\gt 1{{\ \rm per\ cent}}$ when the orbital period is $P_{\rm orb}\simeq 20{\!-\!}60\, {\rm min}$. The ratio between the flux modulation due to the dynamical tide and that due to the equilibrium tide (i.e. ellipsoidal variability) increases as the WD’s radius decreases, and it could exceed $\mathcal {O}(10)$ if the WD has a radius R ≲ 0.03 R⊙. Unlike the ellipsoidal variability which is in phase with the orbital motion, the pulsation caused by the dynamical tide may have a substantial phase shift. A cold WD with $T\simeq 10\, {\rm kK}$, on the other hand, is unlikely to show observable pulsations due to the dynamical tide. At shorter orbital periods, the dynamical tide may break and become highly non-linear. We approximate this regime by treating the waves as one-way travelling waves and find the flux variation is typically reduced to 0.1–1 per cent and the excess phase is ∼90° (though with large uncertainty). Even in the travelling-wave limit, the flux perturbation due to dynamical tide could still exceed the ellipsoidal variability for compact WDs with R ≲ 0.02 R⊙. We further estimate the non-linear flux perturbations oscillating at four times the orbital frequency dominated by a self-coupled parent g-mode driving low-order daughter p modes. The non-linear flux variation could be nearly $50{{\ \rm per\ cent}}$ of the linear variation for very hot WD models with $T\gtrsim 26\, {\rm kK}$ and $1{{\ \rm per\ cent}}$ linear flux variation. We thus predict that both the linear and non-linear flux variations due to dynamical tides are likely to have significant observational signatures.
Satellites and central galaxies in SDSS: the influence of interactions on their properties
Authors: Mesa Valeria , Alonso Sol , Coldwell Georgina , Lambas Diego García , Nilo Castellon J L
Published: November 2020

We use SDSS-DR14 to construct a sample of galaxy systems consisting of a central object and two satellites. We adopt projected distance and radial velocity difference criteria and impose an isolation criterion to avoid membership in larger structures. We also classify the interaction between the members of each system through a visual inspection of galaxy images, finding ${\sim}80{{\ \rm per\ cent}}$ of the systems lack evidence of interactions whilst the remaining ${\sim}20{{\ \rm per\ cent}}$ involve some kind of interaction, as inferred from their observed distorted morphology. We have considered separately, samples of satellites and central galaxies, and each of these samples were tested against suitable control sets to analyse the results. We find that central galaxies showing signs of interactions present evidence of enhanced star formation activity and younger stellar populations. As a counterpart, satellite samples show these galaxies presenting older stellar populations with a lower star formation rate than the control sample. The observed trends correlate with the stellar mass content of the galaxies and with the projected distance between the members involved in the interaction. The most massive systems are less affected since they show no star formation excess, possibly due to their more evolved stage and less gas available to form new stars. Our results suggest that it is arguably a transfer of material during interactions, with satellites acting as donors to the central galaxy. As a consequence of the interactions, satellite stellar population ages rapidly and new bursts of star formation may frequently occur in the central galaxy.