Search

Background: Bone scintigraphy (BS) is established as an accurate, non-invasive method for the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). In a real-life setting, however, some patients with no cardiac uptake on BS turn out to have cardiac-biopsy-confirmed ATTR-CM. We retrospectively included all patients diagnosed at the French Referral Center for ATTR-CM and who had data for BS and a cardiac biopsy., Results: Of 271 patients with positive cardiac biopsy, 14 (5%) had no cardiac uptake on 99m Tc-hydroxymethylene diphosphonate BS. Cardiac uptake was found in four of the seven patients who had a second BS assessment with 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD). A retrospective review of the BS data found low cardiac uptake in four patients (two with HMDP and two with both radiotracers). Ultimately, six of the 14 patients with a biopsy-confirmed diagnosis of ATTR-CM did not show any cardiac radiotracer uptake., Conclusions: An endomyocardial biopsy may be necessary for confirming the diagnosis of ATTR-CM in patients with clinical and imaging signs of cardiac amyloidosis but no cardiac radiotracer uptake in BS., (© 2024. The Author(s).)

Aims: The primary objectives of this study were to analyse the nationwide healthcare trajectories of heart failure (HF) patients in France, 2 years after their first hospitalization, and to measure sequence similarities. Secondary objectives were to identify the association between trajectories and the risk of mortality., Methods and Results: A retrospective, observational study was conducted using data extracted from the Echantillon Généraliste des Bénéficiaires database, covering the period from 1 January 2008 to 31 December 2018. Follow-up concluded upon death or at the end of the study. We developed a methodology specific to healthcare data by extracting frequent healthcare trajectories and measuring their similarity for use in a survival machine learning analysis. In total, 11 488 HF patients were included and followed up for an average of 2.9 ± 1.3 years. The mean age of the patients was 78.0 ± 13.2 years. The first-year mortality rate was 31.7% and increased to 78.8% at 5 years. Fifty per cent of patients experienced re-hospitalization for reasons related to cardiovascular diseases. We identified 1707 hospitalization sequences, and 21 sequences were associated with survival, while 15 sequences were linked to mortality. In all our models, age and gender emerged as the most significant predictors of mortality (permutation feature importance: 0.099 ± 0.00078 and 0.0087 ± 0.00018, respectively; weights could be interpreted in relative terms). Specifically, the age at initial hospitalization for HF was positively associated with mortality. Gender (male: 49.5%) was associated with poorer prognoses. Healthcare trajectories, including non-surgical device treatments, valve replacements, and atrial fibrillation ablation, were associated with a better prognosis (permutation feature importance: 0.0047 ± 0.00011, 0.0014 ± 0.000073, and 0.00095 ± 0.000097, respectively), except in cases where these invasive treatments preceded or followed hospitalization for cardiac decompensation. The predominant negative prognosis sequences were mostly those that included HF-related hospitalizations before or after other-related hospitalizations (permutation feature importance: 0.0007 ± 0.000091 and 0.00011 ± 0.000045, respectively)., Conclusions: We highlight the value of healthcare trajectories on frequent hospitalization sequences, mortality, and prognosis and indicate the necessary prognostic value of HF re-hospitalization. Our work may be an essential tool for better identification of at-risk patients in order to increase and improve personalized care in the future., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Protein disulfide isomerases (PDIs) are a family of chaperones resident in the endoplasmic reticulum (ER). In addition to holdase function, some members catalyze disulfide bond formation and isomerization, a crucial step for native folding and prevention of aggregation of misfolded proteins. PDIs are characterized by an arrangement of thioredoxin-like domains, with the canonical protein disulfide isomerase A1 (PDIA1) organized as four thioredoxin-like domains forming a horseshoe with two active sites, a and a ', at the extremities. We aimed to clarify important aspects underlying the catalytic cycle of PDIA1 in the context of the full pathways of oxidative protein folding operating in the ER. Results: Using two fluorescent redox sensors, redox green fluorescent protein 2 (roGFP2) and HyPer (circularly permutated yellow fluorescent protein containing the regulatory domain of the H 2 O 2 -sensing protein OxyR), either unfolded or native, as client substrates, we identified the N-terminal a active site of PDIA1 as the main oxidant of thiols. From there, electrons can flow to the C-terminal a ' active site, with the redox-dependent conformational flexibility of PDIA1 allowing the formation of an interdomain disulfide bond. The a ' active site then acts as a crossing point to redirect electrons to ER downstream oxidases or back to client proteins to reduce scrambled disulfide bonds. Innovation and Conclusions: The two active sites of PDIA1 work cooperatively as an interdomain redox relay mechanism that explains PDIA1 oxidative activity to form native disulfides and PDIA1 reductase activity to resolve scrambled disulfides. This mechanism suggests a new rationale for shutting down oxidative protein folding under ER redox imbalance. Whether it applies to physiological substrates in cells remains to be shown.

Aims: Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage., Methods and Results: This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision-making regarding therapy. Over the 12-year study period, among the 233 patients included, 133 were NYHA III-IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT-proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut-off values for Stage 1: hsTnT ≤ 107 ng/L and NT-proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT-proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT-proBNP then CB 4 μmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 μmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2-24]. At 1 year, 102 (44%) patients died and the Kaplan-Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11-18]) and stage 3, 6.6 months (95% CI [1-13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2., Conclusions: The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Peste des petits ruminants virus (PPRV) causes a highly infectious disease affecting mainly goats and sheep in large parts of Africa, Asia, and the Middle East and has an important impact on the global economy and food security. Full genome sequencing of PPRV strains has proved to be critical to increasing our understanding of PPR epidemiology and to inform the ongoing global efforts for its eradication. However, the number of full PPRV genomes published is still limited and with a heavy bias towards recent samples and genetic Lineage IV (LIV), which is only one of the four existing PPRV lineages. Here, we generated genome sequences for twenty-five recent (2010-6) and seven historical (1972-99) PPRV samples, focusing mainly on Lineage II (LII) in West Africa. This provided the first opportunity to compare the evolutionary pressures and history between the globally dominant PPRV genetic LIV and LII, which is endemic in West Africa. Phylogenomic analysis showed that the relationship between PPRV LII strains was complex and supported the extensive transboundary circulation of the virus within West Africa. In contrast, LIV sequences were clearly separated per region, with strains from West and Central Africa branched as a sister clade to all other LIV sequences, suggesting that this lineage also has an African origin. Estimates of the time to the most recent common ancestor place the divergence of modern LII and LIV strains in the 1960s-80s, suggesting that this period was particularly important for the diversification and spread of PPRV globally. Phylogenetic relationships among historical samples from LI, LII, and LIII and with more recent samples point towards a high genetic diversity for all these lineages in Africa until the 1970s-80s and possible bottleneck events shaping PPRV's evolution during this period. Molecular evolution analyses show that strains belonging to LII and LIV have evolved under different selection pressures. Differences in codon usage and adaptative selection pressures were observed in all viral genes between the two lineages. Our results confirm that comparative genomic analyses can provide new insights into PPRV's evolutionary history and molecular epidemiology. However, PPRV genome sequencing efforts must be ramped up to increase the resolution of such studies for their use in the development of efficient PPR control and surveillance strategies., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Although the plants of the genus Euphorbia are largely exploited by therapists in Morocco, the composition and antibacterial activities of propolis from these plants are still unknown. To address this gap, this study aimed to characterize the pollen type, the volatile compounds, and the phenolic and mineral profiles of three Euphorbia propolis samples collected in Morocco and evaluate their antimicrobial activities. The minimum inhibitory concentration of the propolis samples was determined by the microdilution method, and the anti-adherence activity was evaluated by the crystal violet assay. The examination of anti-quorum-sensing proprieties was performed using the biosensor Chromobacterium violaceum CV026. Pollen analysis revealed that Euphorbia resinifera pollen dominated in the P1 sample (58%), while E. officinarum pollen dominated in the P2 and P3 samples (44%). The volatile compounds were primarily composed of monoterpene hydrocarbons, constituting 35% in P1 and 31% in P2, with α-pinene being the major component in both cases, at 16% in P1 and 15% in P2. Calcium (Ca) was the predominant mineral element in both E. resinifera (P1) and E. officinarum (P2 and P3) propolis samples. Higher levels of phenols, flavonoids and dihydroflavonoids were detected in the E. officinarum P2 sample. The minimum inhibitory concentration (MIC) value ranged from 50 to 450 µL/mL against Gram-positive and Gram-negative bacteria. Euphorbia propolis displayed the ability to inhibit quorum sensing in the biosensor C. violaceum CV026 and disrupted bacterial biofilm formation, including that of resistant bacterial pathogens. In summary, the current study evidences the potential use of E. officinarum propolis (P2 and P3) to combat important features of resistant pathogenic bacteria, such as quorum sensing and biofilm formation.

Background: Early cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed., Aim: To reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period., Methods: This was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA., Results: Overall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010-2012 to 308 in 2019-2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013-2014 to 45.9% in 2019-2020). Lastly, among patients diagnosed with ATTRv in 2019-2020, 83.9% had ATTR Val122Ile cardiac phenotype., Conclusions: This study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background and Aims: Self-reported questionnaires are useful for estimating the health-related quality of life (HR-QoL), impact of interventions, and prognosis. To our knowledge, no HR-QoL questionnaire has been developed for cardiac amyloidosis (CA). This study aimed to validate Amylo-AFFECT-QOL questionnaire to assess HR-QoL and its prognostic value in CA., Methods: A self-reported questionnaire, "Amylo-AFFECT" had been designed and validated for CA symptoms evaluation and screening by physicians. It was adapted here to assess HR-QoL (Amylo-AFFECT-QOL) and its prognostic value in CA. To validate the theoretical model, internal consistency and convergent validity were assessed, particularly correlations between Amylo-AFFECT-QOL and the HR-QoL Minnesota Living Heart Failure (MLHF) questionnaire., Results: Amylo-AFFECT-QOL was completed by 515 patients, 425 of whom (82.5%) had CA. Wild-type and hereditary transthyretin amyloidosis (ATTRwt and ATTRv) and immunoglobulin light-chain amyloidosis (AL) were diagnosed in 47.8, 14.7, and 18.8% of cases, respectively. The best HR-QoL evaluation was obtained with five dimensions: "Heart failure," "Vascular dysautonomia," "Neuropathy," "Ear, gastrointestinal, and urinary dysautonomia," and "Skin or mucosal involvement." The global Amylo-AFFECT-QOL and MLHF scores showed significant positive correlations (rs = 0.72, p < 0.05). Patients with a final diagnosis of CA had a global Amylo-AFFECT-QOL score significantly higher than the control group composed by patients with other diagnoses (22.2 ± 13.6 vs. 16.2 ± 13.8, respectively, p -value < 0.01). According to the Amylo-AFFECT-QOL global results, ATTRv patients' QoL was more affected than AL patients' QoL or ATTRwt patients' QoL. Patients with a higher HR-QoL score had a greater risk of death or heart transplant after 1 year of follow-up (log-rank < 0.01)., Conclusion: Amylo-AFFECT-QOL demonstrates good psychometric properties and is useful for quantifying HR-QoL and estimating CA prognosis. Its use may help to improve overall management of patients with CA., Competing Interests: TD received grants or consultancy fees from Akcea, Alnylam, Pfizer, and GSK. SO received honoraria from Pfizer. BF received consultancy fees from Pfizer. EI received honoraria from Pfizer and Janssen-Cilag. RG received honoraria from SANOFI. AB received consultancy fees from Pfizer, Novartis, Vifor Pharma, and AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kharoubi, Bézard, Broussier, Galat, Gounot, Poullot, Molinier-Frenkel, Fanen, Funalot, Itti, Lemonnier, Sing Chadha, Guendouz, Mallet, Zaroui, Audard, Audureau, Le Corvoisier, Hittinger, Planté Bordeneuve, Lefaucheur, Amiot, Bequignon, Bartier, Leroy, Teiger, Oghina and Damy.)

Data regarding renal involvement in patients with hereditary transthyretin (ATTRv) amyloidosis are scarce and the natural course of chronic kidney disease (CKD) in this population remains unclear. This observational study, including adult patients diagnosed with ATTRv amyloidosis at the French Reference Centre for Cardiac Amyloidosis, investigated renal function outcome and its determinants. Multivariable logistic regression models identified factors associated with CKD at baseline. Determinants of the change in estimated glomerular filtration rate (eGFR) over 24 months of follow-up were assessed with a multivariable linear mixed-effects model. In total, 232 patients (78 women [34%], mean age: 64 years) with ATTRv amyloidosis were classified on the basis of their TTR variants: ATTRV122I (37%), ATTRV30M (29%), and other variants (34%). Median baseline eGFR was 78 ml/min/1.73 m 2 . Seventy-two patients (31%) had an eGFR below 60 ml/min/1.73m 2 and 27/137 patients (20%) had significant proteinuria (urine protein/creatinine ratio ≥30 mg/mmol). Renal biopsy, performed in four cases, found typical Congo red-positive and TTR-labelled amyloid deposits in all cases. Older age (OR 1.07, p  < .001) and a prior history of hypertension (OR 2.09, p  = .04) were associated with a higher prevalence of CKD at baseline, whereas higher left ventricular global longitudinal strain (LVGLS) (OR 0.83, p  < .001) was associated with a lower prevalence. The estimated change in eGFR was -7.12 [-9.61, -4.63] and -8.21 [-10.81, -5.60] ml/min/1.73 m 2 after 12 and 24 months of follow-up, respectively. eGFR decline was independently associated with older age ((67-74], coefficient= -14.35 mL/min/1.73 m 2 , p  < .01, >74, coefficient = -22.93 mL/min/1.73 m 2 , p  < .001, versus <56), ATTRV122I (coefficient = -17.17 mL/min/1.73m 2 , p  < .01, versus ATTRV30M) and LVGLS (coefficient = 1.22, p  < .01). These data suggest that CKD is a common finding in patients with ATTRv amyloidosis, and that eGFR decline is rapid during the first year of evaluation. Older age, lower LVGLS and ATTRV122I were associated with a worse renal outcome. Further studies are now needed to evaluate effects of new targeted therapies on long term renal function.

Objective: To evaluate the real-life use of a modified Gillmore algorithm with a "one-stop-shop" approach, bone scintigraphy (BS), a monoclonal gammopathy test (GT), a salivary gland biopsy (SGB), and genetic testing performed at the same time for the diagnosis of cardiac amyloidosis at the French National Reference Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Créteil, France)., Methods: This retrospective cohort study included a total of 1222 patients with suspected amyloidosis who underwent BS and GT between June 2008 and May 2019., Results: Of 1222 patients, 349 had no cardiac uptake on BS and negative GT (BS-/GT-), 276 were BS-/GT positive (GT+), 420 patients were BS+/GT-, and 177 were BS+/GT+. Our one-stop-shop check-up enabled us to diagnose 892 (72.9%) patients; 330 (27.0%) patients required additional examinations, such as mass spectrometry and/or a cardiac biopsy. This subset notably included 112 patients with amyloid light chain amyloidosis. More than 64% of the patients with transthyretin amyloidosis or another type of amyloidosis were diagnosed during the one-stop shop visit. Sensitivity and specificity of BS for transthyretin amyloidosis diagnosis was 99% and 96%, respectively. For amyloid light chain diagnosis, sensitivity and specificity were 100% and 76%, respectively, for GT and 54% and 100%, respectively, for SGB. Of 910 transthyretin genetic tests, 205 (17%) detected mutations., Conclusion: The results of our real-life cohort study confirmed the ability of a one-stop-shop approach with a modified Gillmore algorithm to diagnose cardiac amyloidosis and the interest of simultaneous testing for earlier diagnosis. The SGB has diagnostic value because it is easy, quick, and less invasive than a cardiac biopsy., (Copyright © 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Production of peste des petits ruminants (PPR) vaccines in Russia is based on two attenuated virus strains ("45G37/35-k" and "ARRIAH") of common origin. Here, the identity of the strain PPRV/45G37/35-k was investigated using a full genome, Illumina deep sequencing approach. Phylogenomic analysis showed that PPRV/45G37/35-k belongs to the same lineage as the widely used PPRV vaccine strain Nigeria/75/1 (lineage II). However, 248 nucleotide differences separate the genomes of these vaccine strains, indicating that the PPRV vaccine strains produced in Russia are new strains not yet recognised by the World Organization for Animal Health (WOAH). Detailed information on the safety and efficacy of these vaccines should be provided to the WOAH before further national and international distribution., (© 2022. The Author(s).)

Heart transplantation in cardiac amyloidosis (CA) patients is possible and generally considered for transplantation if other organs are not affected. In this study, we aimed to describe and assess outcome in patients following heart transplantations at our CA referral center., Methods: We assessed all CA patients that had heart transplantations at our center between 2005 and 2018. Patients with New York Heart Association status 3 out of 4, with poor short-term prognosis due to heart failure, despite treatment, and without multiple myeloma, systemic disease, severe neuropathic/digestive comorbidities, cancer, or worsening infections were eligible for transplantation. Hearts were transplanted by bicaval technique. Standard induction and immunosuppressive therapies were used. Survival outcome of CA patients after transplantation was compared with recipients with nonamyloid pathologies in France., Results: Between 2005 and 2018, 23 CA patients had heart transplants: 17 (74%) had light chain (light chain amyloidosis [AL]) and 6 (26%) had hereditary transthyretin (hereditary transthyretin amyloidosis [ATTRv]) CA. Also, 13 (57%) were male, and the mean age at diagnosis was 56.5 y (range, 47.7-62.8). Among AL patients, 13 had heart-only and 5 had heart-kidney transplantations. Among ATTRv patients, 1 had heart-only and 5 had heart-liver transplantations. The 1-y survival rate after transplantation was 78%, 70% with AL, and 100% with ATTRv. At 2 y, 74% were alive: 65% with AL and 100% with ATTRv., Conclusion: After heart transplantation, French CA and nonamyloid patients have similar survival outcomes. Among CA patients, ATTRv patients have better prognosis than those with AL, possibly due to the combined heart-liver transplantation. Selected CA patients should be considered for heart transplantations., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: The three main cardiac amyloidosis (CA) types have different progression and prognosis. Little is known about the mode of death (MOD) which is commonly attributed to cardiovascular causes in CA. Improving MOD's knowledge could allow to adapt patient care., Objective: This retrospective study describes the MOD that occurred during long-term follow-up in CA patients in light-chain (AL), transthyretin hereditary (ATTRv) or wild-type (ATTRwt)., Material and Methods: Patients referred to and cared for, at the French referral centre for CA, Henri Mondor Hospital, Créteil between 2010 and 2016 were included. Clinical information surrounding patient deaths were investigated and centrally evaluated by two blinded clinical committees which classified MOD as cardiovascular, non-cardiovascular or unknown and sub-classified it depending on its subtype., Results: From the 566 patients included, 187 had AL, 206 ATTRv and 173 ATTRwt. During the 864 patient-year follow-up, 160 (28%) deaths occurred, with median survival time of 17.3 months (interquartile range 5.1-35.4). The most frequent MOD was cardiovascular (64%) of which worsening heart failure occurred most frequently and for which, 69% were of AL subtype, 79% ATTRv and 76% ATTRwt. Sudden death also occurred more frequently in AL subtype accounting for 29% of AL deaths. Non-cardiovascular MOD occurred in 26% of patients overall. Among these, infection was the most common non-cardiovascular MOD in any type of CA (80%)., Conclusions: Mortality is high during natural course of CA and differs between subtypes. The main MOD were worsening heart failure, sudden death and infection, opening room to optimise management.

The demand for more suitable eco-friendly extraction processes has grown over the last few decades and driven research to develop efficient extraction processes with low energy consumption and low costs, but always assuring the quality of the volatile oils (VOs). The present study estimated the kinetic extraction and energy consumption of simultaneous hydro- and steam-distillation (SHSD), and SHSD assisted by carbon dioxide (SHSDACD), using an adopted modelling approach. The two isolation methods influenced the VOs yield, chemical composition and biological activities, namely, antioxidant, anti-glucosidase, anti-acetylcholinesterase and anti-inflammatory properties. SHSDACD provided higher VOs yields than the SHSD at a shorter extraction time: 2.8% at 30 min vs. 2.0% at 120 min, respectively, for Rosmarinus officinalis, 1.5% at 28 min vs. 1.2% at 100 min, respectively, for Lavandula angustifolia, and 1.7% at 20 min vs. 1.6% at 60 min, respectively, for Origanum compactum. The first order and sigmoid model fitted to SHSD and SHSDACD, respectively, with R2 value at 96% and with mean square error (MSE) < 5%, where the k distillation rate constant of SHSDACD was fivefold higher and the energy consumption 10 times lower than the SHSD. The rosemary SHSD and SHSDACD VOs chemical composition were similar and dominated by 1,8-cineole (50% and 48%, respectively), and camphor (15% and 12%, respectively). However, the lavender and oregano SHSDACD VOs were richer in linalyl acetate and carvacrol, respectively, than the SHSD VOs. The SHSDACD VOs generally showed better capacity for scavenging the nitric oxide and superoxide anions free radicals as well as for inhibiting α-glucosidase, acetylcholinesterase, and lipoxygenase.

Aims: Cardiac amyloidosis (CA) has a poor prognosis which is aggravated by diagnostic delay. Amyloidosis extracardiac and cardiac events (AECE and ACE) may help improve CA diagnosis and typing. The aim of this study was to compare AECE and ACE between different CA types and assess their relationship with survival., Methods and Results: This retrospective cohort study conducted in France from June 2008 to May 2019, at the Henry Mondor Hospital. This cohort included 983 patients with CA. Mean age at inclusion was 73.1 ± 11.4 years, 726 (75.1%) were male and the mean body mass index was 24.5 ± 4.1 kg/m 2 . Among them, 321 had immunoglobulin light chain (AL) amyloidosis, 434 had wild-type transthyretin (ATTRwt), and 212 had hereditary transthyretin (ATTRv). The first AECE and/or ACE occurred at a mean age of 63 ± 11 years for AL and ATTRv, and 70 ± 12 years for ATTRwt (P < 0.01). The median (Q1-Q3) delay between declaration of the first events and diagnosis varied from 11.1 (5.9; 34.8) months for AL to 92.2 (39.0; 174.7) months for ATTRwt (P < 0.01). The nature of the onset of AECE or ACE varied based on amyloidosis type, heart failure symptoms for AL (26%) and integumentary symptoms for ATTRv with cardiologic or mixed phenotype (39%) and ATTRwt (42%). In AL and ATTRwt, a short delay between the onset of the first AECE or ACE and diagnosis was associated with reduced survival rate (log-rank test P-value <0.01)., Conclusions: This study highlights the impact of amyloidosis type and evolution on diagnostic delay and on prognosis. Physicians must be aware and vigilant in front of extracardiac and cardiac events to considerably improve early diagnosis of amyloidosis., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: Due to improved therapy in childhood, many patients with congenital heart disease reach adulthood and are termed adults with congenital heart disease (ACHD). ACHD often develop heart failure (HF) as a consequence of initial palliative surgery or complex anatomy and subsequently require advanced HF therapy. ACHD are usually excluded from trials evaluating heart failure therapies, and in this context, more data about heart failure trajectories in ACHD are needed to guide the management of ACHD suffering from HF., Methods and Results: The pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R) will collect data from ACHD evaluated or listed for heart or heart-combined organ transplantation from 16 countries in Europe and the Asia/Pacific region. We plan retrospective collection of data from 1989-2020 and will include patients prospectively. Additional organizations and hospitals in charge of transplantation of ACHD will be asked in the future to contribute data to the register. The primary outcome is the combined endpoint of delisting due to clinical worsening or death on the waiting list. The secondary outcome is delisting due to clinical improvement while on the waiting list. All-cause mortality following transplantation will also be assessed. The data will be entered into an electronic database with access to the investigators participating in the register. All variables of the register reflect key components important for listing of the patients or assessing current HF treatment., Conclusion: The ARTORIA-R will provide robust information on current management and outcomes of adults with congenital heart disease suffering from advanced heart failure., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Circulating miRNAs (c-miRNAs) are found in most, if not all, biological fluids and are becoming well-established non-invasive biomarkers of many human pathologies. However, their features in non-pathological contexts and whether their expression profiles reflect normal life history events have received little attention, especially in non-mammalian species. The aim of the present study was to investigate the potential of c-miRNAs to serve as biomarkers of reproductive and metabolic states in fish., Results: The blood plasma was sampled throughout the reproductive cycle of female rainbow trout subjected to two different feeding regimes that triggered contrasting metabolic states. In addition, ovarian fluid was sampled at ovulation, and all samples were subjected to small RNA-seq analysis, leading to the establishment of a comprehensive miRNA repertoire (i.e., miRNAome) and enabling subsequent comparative analyses to a panel of RNA-seq libraries from a wide variety of tissues and organs. We showed that biological fluid miRNAomes are complex and encompass a high proportion of the overall rainbow trout miRNAome. While sharing a high proportion of common miRNAs, the blood plasma and ovarian fluid miRNAomes exhibited strong fluid-specific signatures. We further revealed that the blood plasma miRNAome significantly changed depending on metabolic and reproductive states. We subsequently identified three evolutionarily conserved muscle-specific miRNAs or myomiRs (miR-1-1/2-3p, miR-133a-1/2-3p, and miR-206-3p) that accumulated in the blood plasma in response to high feeding rates, making these myomiRs strong candidate biomarkers of active myogenesis. We also identified miR-202-5p as a candidate biomarker for reproductive success that could be used to predict ovulation and/or egg quality., Conclusions: Together, these promising results reveal the high potential of c-miRNAs, including evolutionarily conserved myomiRs, as physiologically relevant biomarker candidates and pave the way for the use of c-miRNAs for non-invasive phenotyping in various fish species., (© 2021. The Author(s).)

Aims: Multimodal imaging has allowed cardiac amyloidosis (CA) to be increasingly recognised as a treatable cause of heart failure with preserved ejection fraction, but its prognosis remains poor due to late diagnosis. To assess the left ventricular diastolic function (LVDF) patterns in a large contemporary CA cohort according to the current recommendations and to identify their determinants., Methods and Results: We conducted a monocentric, observational study on a cohort of CA patients from a tertiary CA referral centre. Diastolic function was analysed using standard echocardiography and clinical, laboratory and survival parameters were collected. Four hundred and sixty-four patients with one of the three main type of CA were included: 41% had grade III diastolic dysfunction (restrictive mitral pattern), 25% had grade II diastolic dysfunction, and 25% had grade I diastolic dysfunction; 9% were unclassified. No difference was found between the main CA types. After multivariate analyses, grades II and III were independently associated with dyspnoea, elevated NT-proBNP, cardiac infiltration and systolic dysfunction (global longitudinal strain). Grade I patients had a better prognosis., Conclusions: All LVDF patterns can be observed in CA. One quarter of CA patients have grade I LVDF, reflecting the emergence of earlier stage-related phenotypes with a better prognosis.

Background: We assesse the evolution and prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (cTnT-HS) in transthyretin amyloid cardiomyopathy (ATTR-CA) before and after tafamidis treatment., Methods and Results: 454 ATTR-CA patients without tafamidis (Cohort A) and 248 ATTR-CA with tafamidis (Cohort B) were enrolled. Event-free survival (EFS) events were death, heart transplant, or acute heart failure. In Cohort A, 27% of patients maintained NT-proBNP < 3000 ng/L and 14% cTnT-HS < 50 ng/L at 12 months relative to baseline levels. In Cohort B, the proportions were 49% and 29%, respectively. In Cohort A, among the 333 patients without an increased NT-proBNP > 50% relative to baseline EFS was extended compared to the 121 patients with an increased NT-proBNP > 50% (HR: 0.75 [0.57; 0.98]; p = 0.032). In Cohort A, baseline NT-proBNP > 3000 ng/L and cTnT-HS > 50 ng/L and a relative increase of NT-proBNP > 50% during follow-up were independent prognostic factors of EFS. The slopes of logs NT-proBNP and cTnT-HS increased with time before and stabilized after tafamidis., Conclusion: ATTR-CA patients with increasing NT-proBNP had an increased risk of EFS. Tafamidis stabilize NT-proBNP and cTnT-HS increasing, even if initial NT-proBNP levels were >3000 ng/L. Thus suggesting that all patients, irrespective of baseline NT-proBNP levels, may benefit from tafamidis.

Background: Cardiac light chain amyloidosis (AL-CA) patients often die within three months of starting chemotherapy. Chemotherapy for non-immunoglobulin M gammopathy with AL-CA frequently includes bortezomib (Bor), cyclophosphamide (Cy), and dexamethasone (D). We previously reported that NT-ProBNP levels can double within 24h of dexamethasone administration, suggesting a deleterious impact on cardiac function. In this study, we evaluate the role of dexamethasone in early cardiovascular mortality during treatment., Methods and Findings: We retrospectively assessed 100 de novo cardiac AL patients (62% male, mean age 68 years) treated at our institute between 2009 and 2018 following three chemotherapy regimens: CyBorDComb (all initiated on day 1; 34 patients), DCyBorSeq (D, day 1; Cy, day 8; Bor, day 15; 17 patients), and CyBorDSeq (Cy, day 1; Bor, day 8; D, day 15; 49 patients). The primary endpoint was cardiovascular mortality and cardiac transplantation at days 22 and 455. At day 22, mortality was 20.6% with CyBorDComb, 23.5% with DCyBorSeq, and 0% with CyBorDSeq (p = 0.003). At day 455, mortality was not significantly different between regimens (p = 0.195). Acute toxicity of dexamethasone was evaluated on myocardial function using a rat model of isolated perfused heart. Administration of dexamethasone induced a decrease in left ventricular myocardium contractility and relaxation (p<0.05), supporting a potential negative inotropic effect of dexamethasone in AL-CA patients with severe cardiac involvement., Conclusion: Delaying dexamethasone during the first chemotherapy cycle reduces the number of early deaths without extending survival. It is clear that dexamethasone is beneficial in the long-term treatment of patients with AL-CA. However, the initial introduction of dexamethasone during treatment is critical, but may be associated with early cardiac deaths in severe CA. Thus, it is important to consider the dosage and timing of dexamethasone introduction on a patient-severity basis. The impact of dexamethasone in the treatment of AL-CA needs further investigation., Competing Interests: Pr Vincent Audard received consulting fees from Addmedica not related to the submitted work. Dr Silvia Oghina reported personal fees from Pfizer, outside of the submitted work. Pr Thibaud Damy received grant and/or consulting fees from PFIZER, AKCEA, ALNYLAM, PROTHENA, and JANSSEN outside the submitted work. The other authors declared no conflict of interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Interest in the use of essential oils (EOs) in the biomedical and food industries have seen growing over the last decades due to their richness in bioactive compounds. The challenges in developing an EO extraction process that assure an efficient levels of monoterpenes with impact on biological activities have driven the present study, in which the EO extraction process of rosemary, lavender and citrus was performed by simultaneous hydrodistillation-steam distillation, and the influence of EO composition on biological activities, namely antioxidant, anti-inflammatory, antidiabetic, anti-acetylcholinesterase, anti-tyrosinase, antibacterial, and antibiofilm activity, were evaluated. The EO yields of combinations were generally higher than the individual plants ( R. officinalis ( Ro ), L. angustifolia ( La ), and C. aurantium ( Ca )) extracted by the conventional hydrodistillation. The EOs obtained by this process generally had a better capacity for scavenging the free radicals, inhibiting α-glucosidase, and acetylcholinesterase activities than the individual EOs. The combination of EOs did not improve the ability for scavenging peroxide hydrogen or the capacity for inhibiting lipoxygenase activity. The antioxidant activity or the enzyme inhibition activity could not only be attributed to their major compounds because they presented lower activities than the EOs. The chemical composition of the combination Ro : La : Ca , at the ratio 1/6:1/6:2/3, was enriched in 1,8-cineole, linalool, and linalyl acetate and resulted in lower MIC values for all tested strains in comparison with the ratio 1/6:2/3:1/6 that was deprived on those components. The biofilm formation of Gram positive and Gram negative bacteria was impaired by the combination Ro : La : Ca at a sub-inhibitory concentration.

Honey is a natural food product very famous for its health benefits for being an important source of antioxidant and phenolic compounds. Euphorbia honeys obtained from different regions of Morocco were evaluated for their ability to inhibit acetylcholinesterase, lipoxygenase, tyrosinase and xanthine oxidase activities. Their antioxidant properties were evaluated using the: 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging capacity, nitric oxide scavenging activity (NO) and scavenging ability of superoxide anion radical. Then, the phenolic extracts of the same entire honey samples were evaluated by liquid chromatography coupled to diode array detection and mass spectrometry (LC-DAD-MS) and tested for the biological activities previously evaluated on the entire honeys, in order to conduct a comparative study between both (honey and phenolic extracts). The chromatographic profiles for the studied Euphorbia honey extracts were different. Phenolic compounds gallic acid, 4-hydroxybenzoic acid and p -coumaric acid were detected in all samples, whereas kampferol was only present in two samples. Physicochemical parameters and total phenolic content were also determined. Entire honey that recorded the highest rate of phenols was sample M6 ( E. resinifera ) = 69.25 mg GAE/100 g. On the other hand, the phenolic extracts had better antioxidant and enzyme inhibitory activities than the entire honeys, regardless the monofloral honey type. In conclusion, the studied Euphorbia honeys may have a great potential as antioxidant, anti-inflammatory and anti-tyrosinase sources for pharmaceutical and cosmetic applications.

Background CT can provide information regarding myocardial perfusion and expansion of the extracellular space, which is relevant to patients with cardiac amyloidosis (CA). Purpose To evaluate the role of CT in the diagnosis and prognosis of CA. Materials and Methods In this prospective study (Commission National de l'Informatique et des Libertés registration no. 1431858), participants with CA, participants with nonamyloid cardiac hypertrophy (NACH), and participants without hypertrophy were included between April 2017 and December 2018. The confirmed diagnosis of CA was determined according to established criteria (ie, proven with positive bone scintigraphy or endomyocardial biopsy). All participants were imaged with dynamic CT perfusion imaging at whole-heart cardiac CT. Extracellular volume measured at CT and myocardial perfusion parameters calculated on CT perfusion maps were compared among different participant groups. Differences between continuous data were tested using the unpaired t test, Mann-Whitney rank-sum test, or the Kruskal-Wallis test. Results A total of 84 participants with CA, 43 participants with NACH, and 33 participants without hypertrophy were included. Participants with CA exhibited a higher value of extracellular volume measured at CT (mean, 54.7% ± 9.7 [standard deviation]) than participants with NACH (mean, 34.6% ± 9.1; P < .001) and participants without hypertrophy (mean, 35.9% ± 9.9; P = .001). Mean myocardial blood volume and mean myocardial blood flow were lower in participants with CA (mean myocardial blood volume: 4.05 mL/100 g of myocardium ± 0.80; mean myocardial blood flow: 73.2 mL/100 g of myocardium per minute ± 25.7) compared to participants with NACH (mean myocardial blood volume: 5.38 mL/100 g of myocardium ± 1.20, P < .001; mean myocardial blood flow: 89.6 mL/100 g of myocardium per minute ± 31.3, P = .007) and participants without hypertrophy (mean myocardial blood volume: 5.68 mL/100 g of myocardium ± 1.05; mean myocardial blood flow: 106.3 mL/100 g of myocardium per minute ± 29.8; P < .001 for both). Extracellular volume measured at CT (hazard ratio >0.56 vs ≤0.56 = 4.2 [95% CI: 1.4, 11.8]), mean slope (hazard ratio ≤3.0 sec -1 vs >3.0 sec -1 = 0.2 [95% CI: 0.1, 0.8]), and time to peak (hazard ratio >20 seconds vs ≤20 seconds = 11.6 [95% CI: 1.3, 101.6]) were predictive of mortality in participants with CA. Conclusion Participants with cardiac amyloidosis exhibited an increase in extracellular volume at CT and abnormal CT perfusion parameters. Extracellular volume and several perfusion parameters were predictive of mortality. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Zimmerman in this issue.

Peste des petits ruminants (PPR) is a viral disease of goats and sheep that occurs in Africa, the Middle East and Asia with a severe impact on livelihoods and livestock trade. Many wild artiodactyls are susceptible to PPR virus (PPRV) infection, and some outbreaks have threatened endangered wild populations. The role of wild species in PPRV epidemiology is unclear, which is a knowledge gap for the Global Strategy for the Control and Eradication of PPR. These studies aimed to investigate PPRV infection in wild artiodactyls in the Greater Serengeti and Amboseli ecosystems of Kenya and Tanzania. Out of 132 animals purposively sampled in 2015-2016, 19.7% were PPRV seropositive by ID Screen PPR competition enzyme-linked immunosorbent assay (cELISA; IDvet, France) from the following species: African buffalo, wildebeest, topi, kongoni, Grant's gazelle, impala, Thomson's gazelle, warthog and gerenuk, while waterbuck and lesser kudu were seronegative. In 2018-2019, a cross-sectional survey of randomly selected African buffalo and Grant's gazelle herds was conducted. The weighted estimate of PPRV seroprevalence was 12.0% out of 191 African buffalo and 1.1% out of 139 Grant's gazelles. All ocular and nasal swabs and faeces were negative by PPRV real-time reverse transcription-polymerase chain reaction (RT-qPCR). Investigations of a PPR-like disease in sheep and goats confirmed PPRV circulation in the area by rapid detection test and/or RT-qPCR. These results demonstrated serological evidence of PPRV infection in wild artiodactyl species at the wildlife-livestock interface in this ecosystem where PPRV is endemic in domestic small ruminants. Exposure to PPRV could be via spillover from infected small ruminants or from transmission between wild animals, while the relatively low seroprevalence suggests that sustained transmission is unlikely. Further studies of other major wild artiodactyls in this ecosystem are required, such as impala, Thomson's gazelle and wildebeest.

Aims: The prevalence of autonomic neuropathy (AN) is high in patients with hereditary transthyretin amyloidosis but remains unknown in transthyretin wild-type cardiac amyloidosis (ATTRwt-CA). This study aimed to determine the prevalence of AN in patients with ATTRwt-CA using Sudoscan®, a non-invasive method used to provide evidence of AN in clinical practice and based on measurement of electrochemical skin conductance at the hands and feet (fESC)., Methods and Results: A series of 62 non-diabetic patients with ATTRwt-CA was prospectively included over 2 years and compared with healthy elderly subjects, matched by age, gender, and body mass index. The presence of AN was defined as electrochemical skin conductance at the hands <60 μS and/or fESC <70 μS, and conductances were analysed according to clinical, biological, and echocardiographic data. Mean fESC was significantly lower in patients with ATTRwt-CA compared with elderly controls: 68.3 (64.1-72.5) vs. 76.9 (75.6-78.1) μS (P < 0.0001), respectively. Prevalence of fESC <70 μS was higher in ATTRwt-CA patients than in controls: 48.4% vs. 19.9%, P < 0.05. Univariate analysis showed that fESC, N-terminal pro-B-type natriuretic peptide, creatinine plasma levels, and echocardiographic global longitudinal strain were associated with decompensated cardiac failure and death. Multivariate analysis revealed that fESC was an independent prognostic factor, and Kaplan-Meier estimator evidenced a greater occurrence of cardiac decompensation and death in patients with fESC <70 μS, P = 0.046., Conclusions: Reduced fESC was observed in almost 50% of patients with ATTRwt-CA and was associated with a worse prognosis. Sudoscan® could easily be used to screen ATTRwt-CA patients for the presence of AN and identify patients at higher risk for a poor outcome., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Available data on clinical presentation and mortality of coronavirus disease-2019 (COVID-19) in heart transplant (HT) recipients remain limited. We report a case series of laboratory-confirmed COVID-19 in 39 HT recipients from 3 French heart transplant centres (mean age 54.4 ± 14.8 years; 66.7% males). Hospital admission was required for 35 (89.7%) cases including 14/39 (35.9%) cases being admitted in intensive care unit. Immunosuppressive medications were reduced or discontinued in 74.4% of the patients. After a median follow-up of 54 (19-80) days, death and death or need for mechanical ventilation occurred in 25.6% and 33.3% of patients, respectively. Elevated C-reactive protein and lung involvement ≥50% on chest computed tomography (CT) at admission were associated with an increased risk of death or need for mechanical ventilation. Mortality rate from March to June in the entire 3-centre HT recipient cohort was 56% higher in 2020 compared to the time-matched 2019 cohort (2% vs. 1.28%, P = 0.15). In a meta-analysis including 4 studies, pre-existing diabetes mellitus (OR 3.60, 95% CI 1.43-9.06, I 2  = 0%, P = 0.006) and chronic kidney disease stage III or higher (OR 3.79, 95% CI 1.39-10.31, I 2  = 0%, P = 0.009) were associated with increased mortality. These findings highlight the aggressive clinical course of COVID-19 in HT recipients., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

This research is aimed at determining the physicochemical properties (resin, wax, balsams, pH, moisture, ash, and mineral contents) of propolis samples collected from different geographical areas in Morocco, as well as evaluating the antioxidant and antibacterial activities of these samples. The results showed the following values for physicochemical analysis: resin (17.42-58.01%), wax (21.31-70.12%), balsam (0.27-2.12%), pH (3.7-5.3), moisture (1.02-3.65%), and ash (0.72-5.01%). The phenolic and flavone/flavonol contents of samples were ranged between 6.74 mg FAE/g and 149.13 mg FAE/g and between 1.19 mg QE/g and 108.11 mg QE/g, respectively. The sample P3 presented also the strongest radical scavenging activity toward DPPH, ABTS free radicals, and FRAP assay with IC 50 values of 0.021, 0.026, and 0.042 mg/mL, respectively. All propolis samples showed significant inhibitory effects against all tested microorganisms with MICs ranging from 0.28 mg/mL to 1.12 mg/mL for Gram-negative strains and from 0.002 mg/mL to 1.12 mg/mL for Gram-positive strains. A strong correlation was found between resin, total phenolic compounds, flavones/flavonols, and antioxidant activity. Linear discriminant analysis revealed that the samples studied were divided into two groups which were differentiated by the data of antioxidant activity, mineral contents, and antibacterial activity. It can be concluded that the physicochemical properties, mineral content, and biological activities of Moroccan propolis depend on their geographical and botanical origin., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Naoual El Menyiy et al.)

The actinobacteria Streptomyces sp. AV05 appears to be a potential biocontrol agent (BCA) against mycotoxigenic fungi. It was found to significantly inhibit F. verticillioides growth and mycotoxin production during their co-cultivation. F. verticillioides growth was durably affected while the decrease of the toxin production levels was reversible, suggesting different BCA actions. The study of both transcriptomes brought useful information on the microbial interaction. RNA-seq data indicated that the dual interaction modified genetic expression of both microorganisms as 18.5 % of the genes were differentially expressed for the fungus against 3.8 % for the actinobacteria. Fungal differentially expressed genes (DEGs) were equally up and down regulated while bacterial ones were mainly upregulated. We especially focused the analysis of DEGs on fungal defense reaction to bacterial attack. For example, if this potential BCA implements a strategy of antibiosis with the over expression of 'siderophore-interacting protein' linked to the production of bacteriocins, the fungus in a state of stress is able to adapt its metabolism by up-regulation of amidase. It could correspond to the induction of resistance gene clusters and suggest a detoxification process. Moreover fumonisins-related pathway appears underexpressed in the presence of Streptomyces that explain the reduction of fumonisin accumulation observed., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2019 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

Aims: Hereditary (ATTRv) and wild-type (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral nerves (or both). Since 2012, tafamidis has been used in France to treat patients with ATTRv with neuropathy (alone or combined with cardiomyopathy). Recently, the Phase III ATTR-ACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real-life population in comparison to the population included in the ATTR-ACT trial and to assess the impact of tafamidis treatment on major cardiovascular outcome (MCO)-free survival time without cardiac decompensation, heart transplant, or death., Methods and Results: From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. A total of 467 (72%) patients matched the inclusion criteria of the ATTR-ACT trial. For the 631 patients with cardiomyopathy, tafamidis treatment was associated with a longer median MCO-free survival time (n = 98): 1565 (1010-2400) days vs. 771 (686-895) days without treatment (log-rank P < 0.001). This association was confirmed after considering confounding factors (age at inclusion, N-terminal pro-B-type natriuretic peptide and amyloidosis type) with a propensity score (hazard ratio 0.546; P = 0.0132)., Conclusion: In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTR-ACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcomes in a real-life population., (© 2020 European Society of Cardiology.)

Natural products may be applied in a wide range of domains, from agriculture to food and pharmaceutical industries. In this study, the antioxidant properties and the capacity to inhibit some enzymatic activities of Euphorbia resinifera and Euphorbia officinarum aqueous extracts and honeys were assessed. The physicochemical characteristics were also evaluated. Higher amounts of iron, copper and aluminium were detected in E. officinarum honey, which may indicate environmental pollution around the beehives or inadequate storage of honey samples. This honey sample showed higher amounts of total phenols and better capacity for scavenging superoxide anion free radicals and DPPH free radicals as compared with E. resinifera honey, but poorer capacity for inhibiting lipoxygenase, acetylcholinesterase, tyrosinase and xanthine oxidase. The ratio plant mass:solvent volume (1:100) and extraction time (1 - 2 h) were associated with higher total phenols and better antioxidant activities and lipoxygenase, acetylcholinesterase and tyrosinase inhibitory activities, regardless of the plant species. The aqueous extracts had systematically higher in vitro activities than the respective honey samples.

This study compared the capacity of propolis extract (PE) and thyme waste extract (TWE) to prevent the oxidation of oil in water (O/W) emulsion, as well as their impact on emulsion apparent viscosity (AV) in the presence of wheat germ and almond oils as lipid phase. For this, central composite design (CCD) and principal component analysis (PCA) were performed. Oxidation process was monitored by evaluating the formation of primary and secondary lipid oxidation products, at the same time the AV behavior was determined evaluating consistency index and flow behavior index. The results revealed that the increase of PE% and TWE% decreases TBARS (Thiobarbituric Acid Reactive Substances) and hydroperoxides formation. Viscosity increases with the rise of TWE% over (0.04%), whereas lower concentrations of PE% decreases it. Those results have been confirmed in the PCA analysis. TWE showed higher resistance to oxidation, although PE was more effective as antioxidant than TWE.

Purpose: Increased cardiac uptake (CU) on early-phase 99m Tc-HMDP scintigraphy has demonstrated diagnostic and prognostic values in amyloid transthyretin (ATTR) cardiac amyloidosis (CA). Extracardiac uptake (ECU) has been poorly studied. We assessed the clinical value of ECU, in combination with CU, on 99m Tc-HMDP scintigraphy using a novel Methodological Amyloidosis Diagnostic Index (MADI)., Methods: We reviewed all patients referred for suspicion of CA, who underwent 99m Tc-HMDP scintigraphy over an 8-year period. ECU, CU, and MADI were determined: MADI0 = neither ECU or CU, MADI1 = ECU alone, MADI2 = CU alone, and MADI3 = ECU + CU., Results: Of 308 eligible patients, 247 had CA, including 75 ATTRv, 107 ATTRwt, and 65 light-chain (AL), while 61 had another cardiopathy (controls). ECU was observed in 29% of CA and 3% of controls. Most frequent sites of ECU were pleuropulmonary (16% of CA, 3% of controls) followed by the digestive tract and subcutaneous tissues. The liver and spleen ECU was only observed in AL-CA (n = 8). CU was only observed in CA patients (n = 187), of whom 182 had ATTR-CA vs. 5 AL-CA, P < 0.001. MADI0 was only observed in controls (97%) and in AL-CA (60%). MADI1 was mainly observed in AL-CA (positive predictive value, PPV = 91%) while MADI2/3 were more frequent in ATTR-CA (PPV = 97%), P < 0.0001. MADI > 0 vs. MADI0 in AL and MADI3 vs. MADI2 in ATTR were associated with a worse prognosis (P = 0.03 and P = 0.002, respectively)., Conclusions: ECU combined with CU demonstrates high diagnostic and prognostic values in CA patients. MADI seems an easy and reliable score in clinical practice.

Background and Aim: Hexavalent chromium (Cr (VI)) compounds have been shown to induce nephrotoxicity associated with oxidative stress in humans and animals. The aim of the present study was to investigate the nephroprotective effect of bee propolis, as highly antioxidant natural product, in vivo using an animal model., Materials and Methods: First of all, total phenol and flavonoid contents of propolis sample were estimated in vitro . Afterward, to study the protective effect of propolis on renal damages caused by an injection of a single dose of potassium dichromate (15 mg/kg b.wt), 24 male Wister rats were divided into test and control groups. Propolis treatment was performed by oral gavage of 100 mg/kg b.wt/day, while the control groups received water instead. The 24 h urine was collected and blood samples were withdrawn before and after each treatment for further analysis., Results: Propolis revealed to be rich in polyphenols and flavonoids. Chromate provoked a nephrotoxic effect expressed by a drastic decrease in glomerular filtration assessed by creatinine clearance. However, the administration of propolis attenuated the renal damages induced by the chromate. This attenuation can be seen by the increase of creatinine clearance when comparing propolis treated group to the non-treated group., Conclusion: Propolis showed a protective potential against chromate-induced nephrotoxicity through the amelioration of chromate's toxic effects. It might be concluded that propolis could be effective as chemoprotectant in the management of potassium dichromate-induced nephrotoxicity., (Copyright: © El-Guendouz, et al.)

Objectives: The effect of propolis collected in Morocco on blood glucose, lipid profile, liver enzymes, and kidney function was investigated in control and diabetic rats., Materials and Methods: Antioxidant activity of propolis was evaluated with the use of DPPH, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS•+), ferric reducing power and total antioxidant activity assay. To study its effect in streptozotocin (STZ)-induced diabetes, the rats were divided into eight groups; four control and four diabetics. The animals received distilled water, glibenclamide, or propolis extract, 50 mg/kg/BW) or 100 mg/kg/b.wt, daily for 15 days. Blood glucose, triglyceride, lactic acid dehydrogenase, liver enzymes, creatinine, blood urea, lipid profile, and body weight were measured on day 15 after commencement of the treatment., Results: Propolis has a strong antioxidant activity and high total flavonoids and polyphenols content. Glibenclamide and propolis have no significant effect on lipid parameters, and renal and hepatic function in non-diabetic rats. However, propolis or glibenclamide caused a significant lowering of blood glucose after a single administration and at day 15 after daily administration in diabetic rats ( P <0.05). Both interventions significantly lowered lactic acid dehydrogenase, increased body weight, and ameliorated dyslipidemia and abnormal liver and kidney function caused by diabetes. The effect of propolis was dose-dependent and in a high dose it was more potent than glibenclamide., Conclusion: Propolis exhibited strong antihyperglycemic, antihyperlipidemic, and hepato-renal protective effects in diabetes, and significantly lowered the elevated lactic acid dehydrogenase. The study demonstrated for the first-time the effect of Moroccan propolis in diabetes and it will pave the way for clinical investigations.

Peste des Petits Ruminants (PPR) is a highly infectious disease caused by a virus of the Morbillivirus genus. The current PPR eradication effort relies mainly on the implementation of massive vaccination campaigns. One of the most widely used PPR vaccines is the Nigeria 75/1 strain obtained after attenuation by 75 serial passages of the wild type isolate in cell cultures. Here we use high throughput deep sequencing of the historical passages that led to the Nigeria 75/1 attenuated strain to understand the evolution of PPRV attenuation and to assess the risk of reversal in different cell types. Comparison of the consensus sequences of the wild type and vaccine strains showed that only 18 fixed mutations separate the two strains. At the earliest attenuation passage at our disposal (passage 47), 12 out of the 18 mutations were already present at a frequency of 100%. Low-frequency variants were identified along the genome in all passages. Sequencing of passages after the vaccine strain showed evidence of genetic drift during cell passages, especially in cells expressing the SLAM receptor targeted by PPRV. However, 15 out of the 18 mutations related to attenuation remained fixed in the population. In vitro experiments suggest that one mutation in the leader region of the PPRV genome affects virus replication. Our results suggest that only a few mutations can have a serious impact on the pathogenicity of PPRV. Risk of reversion to virulence of the attenuated PPRV strain Nigeria 75/1 during serial passages in cell cultures seems low but limiting the number of passages during vaccine production is recommended.

Thymus vulgaris (thyme) is an aromatic plant and its essential oil has been applied as antimicrobial and antioxidant due to the presence of phenolic compounds. However, after steam distillation, the deodorized plant material is rejected, despite the possible presence of bioactive compounds. Ethanolic thyme waste extract revealed the presence of benzoic acid, 4-hydroxybenzoic acid, ferulic acid, caffeic acid, and sinapic acid. This waste thyme extract had the capacity for preventing the formation of primary and secondary lipid oxidation products in emulsions O/W (oil in water), constituted by diverse proportions of wheat and almond oils, without interfering with the viscosity parameters, for 10 weeks, at 37 °C. The increasing proportion of almond oil (≥50%) in the emulsion increases its resistance to oxidation, which is improved with the presence of an optimal concentration of tested thyme waste extract (0.02% and 0.04%). The waste thyme extract can, therefore, be used as an antioxidant either in food or pharmaceutical emulsions O/W, replacing the synthetic antioxidants.

Microbial fuel cells (MFCs) are a promising technology that generates electricity from several biodegradable substrates and wastes. The main drawback of these devices is the need of using a catalyst for the oxygen reduction reaction at the cathode, which makes the process relatively expensive. In this work, two low cost materials are tested as catalysts in MFCs. A novel iron complex based on the ligand n-phenyledenparaethoxy aniline has been synthesized and its performance as catalyst in single chamber MFCs containing ionic liquids has been compared with a commercial inorganic material such as Raney nickel. The results show that both materials are suitable for bioenergy production and wastewater treatment in the systems. Raney nickel cathodes allow MFCs to reach a maximum power output of 160 mW.m -3 anode , while the iron complex offers lower values. Regarding the wastewater treatment capacity, MFCs working with Raney nickel-based cathodes reach higher values of chemical oxygen demand removal (76%) compared with the performance displayed by the cathodes based on Fe-complex (56%).

This review updates the information upon the chemical composition of propolis from all Mediterranean countries as well as their biological properties and applications. The non-volatile fraction of propolis was characterized by the presence of phenolic acids and their esters and flavonoids. Nevertheless, in some countries, diterpenes were also present: Sicily (Italy), Croatia, Malta, Creta (Greece), Turkey, Cyprus, Egypt, Libya, Algeria and Morocco. The volatile fraction of propolis was characterized by the presence of benzoic acid and its esters, mono- and sesquiterpenes, being the oxygenated sesquiterpene β-eudesmol characteristic of poplar propolis, whereas the hydrocarbon monoterpene α-pinene has been related with the presence of conifers. Regardless the chemical composition, there are common biological properties attributed to propolis. Owing to these attributes, propolis has been target of study for applications in diverse areas, such as food, medicine and livestock., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production., Methods: To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant., Results: The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P <0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P <0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell-mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access., Conclusions: Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization., (Copyright © 2019 by the American Society of Nephrology.)

Objective: To describe the prevalence of and risk factors for renal infarction (RI) in patients with cardiac amyloidosis., Patients and Methods: We evaluated 87 patients with cardiac amyloidosis who underwent renal technetium-99m-labeled dimercaptosuccinic acid scintigraphy in the Amyloidosis Referral Center of Henri-Mondor Hospital from October 1, 2015, through February 28, 2018., Results: Three groups of patients were identified according to the underlying amyloidosis disorder: AL amyloidosis in 24 patients, mutated-transthyretin amyloidosis in 24 patients, and wild-type transthyretin amyloidosis in 39 patients. Patients with wild-type transthyretin amyloidosis were older (P<.001), more likely to be men (P=.02), to have arrhythmic heart diseases (P<.001), and to be receiving anticoagulation treatment (P<.001). Patients with AL amyloidosis had significantly higher N-terminal pro-B-type natriuretic peptide levels (P=.02) and were more likely to have nephrotic syndrome (P<.001). Renal infarction was detected in 18 patients (20.7%), at similar frequencies in the various groups. Baseline urinary protein to creatinine ratio was the only parameter for which a significant difference (P=.03) was found between patients with and without RI diagnoses. The likelihood of RI diagnosis was 47.1% (8 of 17) in the presence of AKI and 14.5% (10 of 69) in its absence (P=.003). Overall, heart transplant-censored patient survival did not differ significantly between patients with and without RI (P=.64), but death- and heart transplant-censored renal survival was significantly lower in patients with RI (P<.001)., Conclusion: Our study suggests that prevalence of RI in patients with cardiac amyloidosis is higher than previously thought, regardless of the underlying amyloidosis disorder. Acute kidney injury in a patient with cardiac amyloidosis should alert clinicians to the possibility of RI., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Propolis is known to possess antioxidant activity. However, there is no information on this activity in emulsions O/W. The protective effect of propolis on the oxidation and rheological properties of emulsions O/W containing wheat germ and almond oils was evaluated. Emulsions O/W were prepared with different concentration of propolis extract, almond oil and wheat germ oil. All emulsions physically stable without phase separation were stored at 37 °C for 9 weeks. Chemical composition of propolis was established by Gas chromatography coupled to mass spectrometry. Rheological characterization of different emulsions was performed evaluating consistency index and flow behavior index. The oxidation was monitored by measuring the lipid hydroperoxides and thiobarbituric acid-reactive substances (TBARS) methods. Flavonoids, phenolic acid esters, and aromatic acids were the main groups of compounds found in propolis. The results showed that popolis was good antioxidant in the concentration of 0.02 and 0.04% when lipid phase was constituted by almond oil. The rheological behavior is typical of a non-Newtonian fluid, being almond oil more adequate for having a higher stable O/W emulsion.

This study was performed to evaluate the total phenols, flavonoids, and antioxidant activities of twenty-four propolis samples from different regions of Morocco. In addition, two samples were screened regarding the antibacterial effect against four Staphylococcus aureus strains. Gas chromatography coupled to mass spectra (GC-MS) analysis was done for propolis samples used in antibacterial tests. The minimum inhibitory and minimum bactericidal concentration (MIC, MBC) were determined. The potential to acquire the resistance after sequential exposure of bacterial strains and the impact of adaptation to propolis on virulence using the Galleria mellonella were evaluated. Additionally, the effects of propolis extract on the bacterial adherence ability and its ability to inhibit the quorum sensing activity were also examined. Among the twenty-four extracts studied, the samples from Sefrou, Outat el Haj, and the two samples marketed in Morocco were the best for scavenging DPPH, ABTS, NO, peroxyl, and superoxide radicals as well as in scavenging of hydrogen peroxide. A strong correlation was found between the amounts of phenols, flavonoids, and antioxidant activities. Propolis extract at the MIC value (0.36 mg/mL) significantly reduced ( p < 0.001) the virulence potential of S. aureus ATCC 6538 and the MRSA strains without leading to the development of resistance in the sequence of continuous exposure. It was able to impair the bacterial biofilm formation. The results have revealed that sample 1 reduces violacein production in a concentration dependent manner, indicating inhibition of quorum sensing. This extract has as main group of secondary metabolites flavonoids (31.9%), diterpenes (21.5%), and phenolic acid esters (16.5%).

Assessment of potential donors is an essential part of heart transplantation. Despite the shortage of donor hearts, donor heart procurement from brain-dead organ donors remains low in France, which may be explained by the increasing proportion of high-risk donors, as well as the mismatch between donor assessment and the transplant team's expectations. Improving donor and donor heart assessment is essential to improve the low utilization rate of available donor hearts without increasing post-transplant recipient mortality. This document provides information to practitioners involved in brain-dead donor management, evaluation and selection, concerning the place of medical history, electrocardiography, cardiac imaging, biomarkers and haemodynamic and arrhythmia assessment in the characterization of potential heart donors., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Details of the Clinical Case: An aortic valve thrombus (AVT) is a rare complication after HeartMate II implantation. In a 44-year-old man, a large AVT was discovered 6 weeks after implantation of a HeartMate II for severe dilated cardiomyopathy. The aortic valve was permanently closed., Discussion: After a followup of 3 months without embolic events, the patient started a cardiac rehabilitation (CR) program involving aerobic exercise, resistance exercises, group gymnastics, and relaxation exercise, and completed the program without any complications, resulting in a significant functional benefit., Summary: CR might not be systematically contraindicated in patients with HeartMate II and an AVT, in particular, if there is no opening of the aortic valve at rest.

Objective: To study the antioxidant properties of Capparis spinosa (C. spinosa) honey and propolis and the effect of combined honey and propolis administration on urine volume and electrolytes in rats., Methods: C. spinosa honey [1000 mg/kg body weight (b.wt)], propolis (100 mg/kg b.wt), honey/propolis mixture (C. spinosa honey 1000 mg/kg b.wt/ propolis extract 100 mg/kg b.wt ), distilled water (1 mL/kg b.wt) and furosemide (10 mg/kg b.wt) were orally administered to five groups of rats for 21 d. Urine volume, blood and urine sodium, potassium and chloride were measured. The antioxidant activity of propolis and honey was assessed and their total phenols and flavonoids were determined., Results: Propolis and C. spinosa honey contain polyphenols including flavonoids and propolis demonstrated higher antioxidant activities than honey. Honey significantly increased urine volume and urine electrolyte excretion. Propolis had no significant effect on urine volume, but co-administration of propolis and honey caused significant diuresis. No major changes were observed in plasma electrolytes with the use of honey, propolis or their combination., Conclusions: Honey and propolis have antioxidant activity and contain polyphenols including flavonoids that are more pronounced in propolis. Honey has a significant diuretic activity alone or in combination with propolis. This is the first study comparing the diuretic effect of co-administration of propolis and C. spinosa honey with furosemide., (Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.)

Chemotherapy combining cyclophosphamide, bortezomib and dexamethasone is widely used in light-chain amyloidosis. The benefit is limited in patients with cardiac amyloidosis mainly because of adverse cardiac events. Retrospective analysis of our cohort showed that 39 patients died with 42% during the first month. A new escalation-sequential regimen was set to improve the outcomes. Nine newly-diagnosed patients were prospectively treated with close monitoring of serum N-terminal pro-brain natriuretic peptide, troponin-T and free light chains. The results show that corticoids may destabilise the heart through fluid retention. Thus, a sequential protocol may be a promising approach to treat these patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A genome-wide assessment of diversity is provided for wild Mediterranean brown trout Salmo trutta populations from headwater tributaries of the Orb River and from Atlantic and Mediterranean hatchery-reared strains that have been used for stocking. Double-digest restriction-site-associated DNA sequencing (dd-RADseq) was performed and the efficiency of de novo and reference-mapping approaches to obtain individual genotypes was compared. Large numbers of single nucleotide polymorphism (SNP) markers with similar genome-wide distributions were discovered using both approaches (196 639 v. 121 016 SNPs, respectively), with c. 80% of the loci detected de novo being also found with reference mapping, using the Atlantic salmon Salmo salar genome as a reference. Lower mapping density but larger nucleotide diversity (π) was generally observed near extremities of linkage groups, consistent with regions of residual tetrasomic inheritance observed in salmonids. Genome-wide diversity estimates revealed reduced polymorphism in hatchery strains (π = 0·0040 and π = 0·0029 in Atlantic and Mediterranean strains, respectively) compared to wild populations (π = 0·0049), a pattern that was congruent with allelic richness estimated from microsatellite markers. Finally, pronounced heterozygote deficiency was found in hatchery strains (Atlantic F IS = 0·18; Mediterranean F IS = 0·42), indicating that stocking practices may affect the genetic diversity in wild populations. These new genomic resources will provide important tools to define better conservation strategies in S. trutta., (© 2016 The Fisheries Society of the British Isles.)

Aims: Serial invasive endomyocardial biopsies (EMB) remain the gold standard for acute cellular rejection (ACR) diagnosis. However histological grading has several limitations. We aimed to explore the value of myocardial Gene Expression Profiling (GEP) for diagnosing and identifying predictive biomarkers of ACR., Methods: A case-control study nested within a retrospective heart transplant patients cohort included 126 patients with median (IQR) age 50 (41-57) years and 111 (88%) males. Among 1157 EMB performed, 467 were eligible (i.e, corresponding to either ISHLT grade 0 or ≥3A), among which 36 were selected for GEP according to the grading: 0 (CISHLT, n = 13); rejection ≥3A (RISHLT, n = 13); 0 one month before ACR (BRISHLT, n = 10)., Results: We found 294 genes differentially expressed between CISHLT and RISHLT, mainly involved in immune activation, and inflammation. Hierarchical clustering showed a clear segregation of CISHLT and RISHLT groups and heterogeneity of GEP within RISHLT. All EMB presented immune activation, but some RISHLT EMB were strongly subject to inflammation, whereas others, closer to CISHLT, were characterized by structural modifications with lower inflammation level. We identified 15 probes significantly different between BRISHLT and CISHLT, including the gene of the muscular protein TTN. This result suggests that structural alterations precede inflammation in ACR. Linear Discriminant Analysis based on these 15 probes was able to identify the histological status of every 36 samples., Conclusion: Myocardial GEP is a helpful method to accurately diagnose ACR, and predicts rejection one month before its histological occurrence. These results should be considered in cardiac allograft recipients' care., Competing Interests: The authors have declared that no competing interests exist.