Long-term outcomes comparison of mitral valve repair or replacement for secondary mitral valve regurgitation. An updated systematic review and reconstructed time-to-event study-level meta-analysis.

BACKGROUND AND AIM: The ideal surgical intervention for secondary mitral regurgitation (SMR), a disease of the left ventricle not the mitral valve itself, is still debated. We performed an updated systematic review and study-level meta-analysis investigating mitral valve repair (MVr) versus mitral valve replacement (MVR) for adult patients with SMR, with or without coronary artery disease (CAD). METHODS: PubMed, CENTRAL and EMBASE were searched for studies comparing MVr versus MVR. Randomized trial or observational studies were considered eligible. Primary endpoint was long-term mortality for any cause. Kaplan-Meier survival curves were reconstructed and compared with Cox linear regression. Landmark analysis and time-varying hazard ratio (HR) were analyzed. Sensitivity analyses included meta-regression and separate sub-analysis. A random effects model was used. RESULTS: Twenty-three studies (MVr=3,727 and MVR=2,839) were included. One study was a randomized trial, and 19 studies were adjusted. The mean weighted follow-up was 3.7±2.8 years. MVR was associated with significative greater late mortality (HR=1.26; 95 % CI, 1.14-1.39; P<0.0001) at 10-year follow-up. There was a time-varying trend showing an increased risk of mortality in the first 2 years after MVR (HR=1.38; 95 % CI, 1.21-1.56; P<0.0001), after which this difference dissipated (HR=0.94; 95 % CI, 0.81-1.09; P=0.41). Separate sub-analyses showed comparable long-term mortality in patients with concomitant coronary surgery ≥90 %, left ventricle ejection fraction ≤40 %, and sub-valvular apparatus preservation rate of 100 %. CONCLUSIONS: Compared to repair, MVR is associated with higher probability of mortality in the first 2 years following surgery, after which the two procedures showed comparable late mortality rate.

Very Long-term Outcome of Bilateral Internal Thoracic Artery in Diabetic Patients: A Systematic Review and Reconstructed Time-To-Event Meta-analysis.

The benefits of single (SITA) and bilateral internal thoracic arteries (BITA) in diabetics undergoing coronary bypass grafting (CABG) are conflicting. We undertook a study-level meta-analysis to compare early and long-term outcomes of both CABG configurations. PubMed, CENTRAL, and EMBASE were searched for studies comparing BITA versus SITA for isolated CABG surgery in diabetics. Randomized trials or observational studies were considered eligible for the analysis. Kaplan-Meier curves of long-term survival were reconstructed and compared with Cox linear regression; incidence rate ratios (IRR) with 95% confidence intervals (CI) for long-term survival were calculated. Landmark analysis and time-varying hazard ratio (HR) were analyzed. Odds ratios (OR) were extracted for early mortality, postoperative stroke, deep sternal wound infection (DSWI), and myocardial infarction (MI). A random effects meta-analysis was performed. Sensitivity analyses included leave-one-out-analyses and meta-regression. Thirteen studies (7332 patients) were included. Overall, at 20-year follow-up, BITA was associated with higher survival (HR = 0.77; 95% CI, 0.71-0.84; P < 0.0001). Time-varying HR and landmark analysis reported BITA was associated with a higher rate of 10-year survival (HR = 0.75, 95% CI 0.68-0.82, P < 0.0001), while from 10 to 20-year follow-up no difference was revealed (HR = 0.99, 95% CI 0.82-1.19, P = 0.93). There was no increase in early mortality, postoperative MI, stroke, or DSWI between the groups. At meta-regression, the higher the age, the higher the long-term overall survival in patients with BITA. In diabetics, the BITA approach is associated with improved 10-year survival with no increase in early mortality, MI, stroke, or DSWI. In the 10-20-year timeframe, BITA and SITA showed comparable survival.

The response of Arabidopsis to the apocarotenoid ß-cyclocitric acid reveals a role for SIAMESE-RELATED 5 in root development and drought tolerance.

New regulatory functions in plant development and environmental stress responses have recently emerged for a number of apocarotenoids produced by enzymatic or nonenzymatic oxidation of carotenoids. ß-Cyclocitric acid (ß-CCA) is one such compound derived from ß-carotene, which triggers defense mechanisms leading to a marked enhancement of plant tolerance to drought stress. We show here that this response is associated with an inhibition of root growth affecting both root cell elongation and division. Remarkably, ß-CCA selectively induced cell cycle inhibitors of the SIAMESE-RELATED (SMR) family, especially SMR5, in root tip cells. Overexpression of the SMR5 gene in Arabidopsis induced molecular and physiological changes that mimicked in large part the effects of ß-CCA. In particular, the SMR5 overexpressors exhibited an inhibition of root development and a marked increase in drought tolerance which is not related to stomatal closure. SMR5 up-regulation induced changes in gene expression that strongly overlapped with the ß-CCA-induced transcriptomic changes. Both ß-CCA and SMR5 led to a down-regulation of many cell cycle activators (cyclins, cyclin-dependent kinases) and a concomitant up-regulation of genes related to water deprivation, cellular detoxification, and biosynthesis of lipid biopolymers such as suberin and lignin. This was correlated with an accumulation of suberin lipid polyesters in the roots and a decrease in nonstomatal leaf transpiration. Taken together, our results identify the ß-CCA-inducible and drought-inducible SMR5 gene as a key component of a stress-signaling pathway that reorients root metabolism from growth to multiple defense mechanisms leading to drought tolerance.

Extracorporeal life support in mitral papillary muscle rupture: Outcome of multicenter study.

BACKGROUND: Post-acute myocardial infarction papillary muscle rupture (post-AMI PMR) may present variable clinical scenarios and degree of emergency due to result of cardiogenic shock. Veno-arterial extracorporeal life support (V-A ECLS) has been proposed to improve extremely poor pre- or postoperative conditions. Information in this respect is scarce. METHODS: From the CAUTION (meChanical complicAtion of acUte myocardial infarcTion: an InternatiOnal multiceNter cohort study) database (16 different Centers, data from 2001 to 2018), we extracted adult patients who were surgically treated for post-AMI PMR and underwent pre- or/and postoperative V-A ECLS support. The end-points of this study were in-hospital survival and ECLS complications. RESULTS: From a total of 214 post-AMI PMR patients submitted to surgery, V-A ECLS was instituted in 23 (11%) patients. The median age was 61.7 years (range 46-81 years). Preoperatively, ECLS was commenced in 10 patients (43.5%), whereas intra/postoperative in the remaining 13. The most common V-A ECLS indication was post-cardiotomy shock, followed by preoperative cardiogenic shock and cardiac arrest. The median duration of V-A ECLS was 4 days. V-A ECLS complications occurred in more than half of the patients. Overall, in-hospital mortality was 39.2% (9/23), compared to 22% (42/219) for the non-ECLS group. CONCLUSIONS: In post-AMI PMR patients, V-A ECLS was used in almost 10% of the patients either to promote bridge to surgery or as postoperative support. Further investigations are required to better evaluate a potential for increased use and its effects of V-A ECLS in such a context based on the still high perioperative mortality.

The Geomagnetic Field (GMF) Is Required for Lima Bean Photosynthesis and Reactive Oxygen Species Production.

Plants evolved in the presence of the Earth's magnetic field (or geomagnetic field, GMF). Variations in MF intensity and inclination are perceived by plants as an abiotic stress condition with responses at the genomic and metabolic level, with changes in growth and developmental processes. The reduction of GMF to near null magnetic field (NNMF) values by the use of a triaxial Helmholtz coils system was used to evaluate the requirement of the GMF for Lima bean (Phaseolus lunatus L.) photosynthesis and reactive oxygen species (ROS) production. The leaf area, stomatal density, chloroplast ultrastructure and some biochemical parameters including leaf carbohydrate, total carbon, protein content and δ13C were affected by NNMF conditions, as were the chlorophyll and carotenoid levels. RubisCO activity and content were also reduced in NNMF. The GMF was required for the reaction center's efficiency and for the reduction of quinones. NNMF conditions downregulated the expression of the MagR homologs PlIScA2 and PlcpIScA, implying a connection between magnetoreception and photosynthetic efficiency. Finally, we showed that the GMF induced a higher expression of genes involved in ROS production, with increased contents of both H2O2 and other peroxides. Our results show that, in Lima bean, the GMF is required for photosynthesis and that PlIScA2 and PlcpIScA may play a role in the modulation of MF-dependent responses of photosynthesis and plant oxidative stress.

Arabidopsis ANAC102, Chloroplastic or Nucleocytosolic Localization?

ANAC102 is a transcription factor involved in stress response and brassinosteroids signaling, with circadian regulation controlled by phytochromes. ANAC102 has been proposed to have a role in downregulating chloroplast transcription, which may be very useful in reducing photosynthesis and chloroplast energy demand under stress conditions. However, its localization in the chloroplast has mainly been demonstrated by using constitutive promoters. In this work, we recapitulate the literature, clarify which are ANAC102 isoforms in Arabidopsis and analyze their expressions under control conditions and in response to stress. Based on our results, the most highly expressed ANAC102 isoform encodes for a nucleocytoplasmic protein and the N-terminal chloroplast-targeting peptide appears to be present only in Brassicaceae, and not involved in stress response.

Redo Surgical Aortic Valve Replacement versus Valve-In-Valve Transcatheter Aortic Valve Implantation: A Systematic Review and Reconstructed Time-To-Event Meta-Analysis.

Objective. Valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) has emerged as a useful alternative intervention to redo-surgical aortic valve replacement (Redo-SVAR) for the treatment of degenerated bioprosthesis valve. However, there is no robust evidence about the long-term outcome of both treatments. The aim of this meta-analysis was to analyze the long-term outcomes of Redo-SVAR versus ViV-TAVI by reconstructing the time-to-event data. Methods. The search strategy consisted of a comprehensive review of relevant studies published between 1 January 2000 and 30 September 2022 in three electronic databases, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and EMBASE. Relevant studies were retrieved for the analysis. The primary endpoint was the long-term mortality for all death. The comparisons were made by the Cox regression model and by landmark analysis and a fully parametric model. A random-effect method was applied to perform the meta-analysis. Results. Twelve studies fulfilled the eligibility criteria and were included in the final analysis. A total of 3547 patients were included. Redo-SAVR group included 1783 patients, and ViV-TAVI included 1764 subjects. Redo-SAVR showed a higher incidence of all-cause mortality within 30-days [Hazard ratio (HR) 2.12; 95% CI = 1.49−3.03; p < 0.0001)], whereas no difference was observed between 30 days and 1 year (HR = 1.03; 95% CI = 0.78−1.33; p = 0.92). From one year, Redo-SAVR showed a longer benefit (HR = 0.52; 95% CI = 0.40−0.67; p < 0.0001). These results were confirmed for cardiovascular death (HR = 2.04; 95% CI = 1.29−3.22; p = 0.001 within one month from intervention; HR = 0.35; 95% CI = 0.18−0.71; p = 0.003 at 4-years follow-up). Conclusions. Although the long-term outcomes seem similar between Redo-SAVR and ViV-TAVI at a five-year follow-up, ViV-TAVI shows significative lower mortality within 30 days. This advantage disappeared between 30 days and 1 year and reversed in favor of redo-SAVR 1 year after the intervention.

Survival effect of radial artery usage in addition to bilateral internal thoracic arterial grafting: A meta-analysis.

OBJECTIVE: Little evidence shows whether the radial artery (RA) as third arterial graft provides superior outcomes compared with the use of the bilateral internal thoracic artery (BITA) and saphenous vein (SV) graft in patients undergoing coronary artery bypass grafting. A meta-analysis of propensity score-matched observational studies that compared the long-term outcomes of coronary artery bypass grafting with the use of BITA and the RA (BITA + RA) versus BITA and SV (BITA + SV) was performed. METHODS: Electronic databases from January 2000 to November 2020 were screened. Studies that reported long-term mortality were analyzed. The primary outcome was long-term overall mortality. A secondary end point was in-hospital/30-day mortality. Pooled hazard ratio with 95% confidence interval (CI) were calculated for survival and time-to-event analysis according to a random effect model. Differences were expressed as odds ratio with 95% CI for in-hospital/30-day mortality. RESULTS: Six propensity score-matched studies that reported on 2500 matched patients (BITA + RA: 1250; BITA + SV: 1250) were identified for comparison. The use of BITA + RA was not statistically associated with early mortality (odds ratio, 0.90; 95% CI, 0.36-2.28; P = .83). The mean follow-up time ranged from 7.5 to 12 years. The pooled analysis of long-term survival revealed a significant difference between the 2 groups favoring BITA + RA treatment (hazard ratio, 0.71; 95% CI, 0.50-0.91; P = .031). The survival rate for BITA + RA versus BITA + SV at 5, 10, and 15 years were: 96.2% versus 94.8%, 88.9% versus 87.4%, and 83% versus 77.9%, respectively (log rank test, P = .02). CONCLUSIONS: In patients with coronary artery bypass grafting, BITA + RA usage is not associated with higher rates of operative risk and is associated with superior long-term overall survival.

Iron-sulfur complex assembly: Potential players of magnetic induction in plants.

Iron-sulfur (Fe-S) clusters are involved in fundamental biological reactions and represent a highly regulated process involving a complex sequence of mitochondrial, cytosolic and nuclear-catalyzed protein-protein interactions. Iron-sulfur complex assembly (ISCA) scaffold proteins are involved in Fe-S cluster biosynthesis, nitrogen and sulfur metabolism. ISCA proteins are involved in abiotic stress responses and in the pigeon they act as a magnetic sensor by forming a magnetosensor (MagS) complex with cryptochrome (Cry). MagR gene exists in the genomes of humans, plants, and microorganisms and the interaction between Cry and MagR is highly conserved. Owing to the extensive presence of ISCA proteins in plants and the occurrence of homology between animal and human MagR with at least four Arabidopsis ISCAs and several ISCAs from different plant species, we believe that a mechanism similar to pigeon magnetoperception might be present in plants. We suggest that plant ISCA proteins, homologous of the animal MagR, are good candidates and could contribute to a better understanding of plant magnetic induction. We thus urge more studies in this regard to fully uncover the plant molecular mechanisms underlying MagR/Cry mediated magnetic induction and the possible coupling between light and magnetic induction.

The impact of coronary artery bypass grafting added to aortic valve replacement on long-term outcomes in octogenarian patients: a reconstructed time-to-event meta-analysis.

The long-term results in studies comparing octogenarian patients who received either isolated surgical aortic valve replacement (i-SAVR) or coronary artery bypass grafting (CABG) in addition to SAVR are still debated. We performed a reconstructed time-to-event data meta-analysis of studies comparing i-SAVR and CABG+SAVR to evaluate the impact of CABG and to analyse the time-varying effects on long-term outcome. We performed a systematic review of the literature from January 2000 through November 2021, including studies comparing i-SAVR and CABG+SAVR, which reported at least 3-year follow-up and that plotted Kaplan-Meier curves of overall survival. The primary endpoint was overall long-term survival; secondary endpoints were in-hospital/30-day mortality and postoperative outcomes. The pooled hazard ratio (HR) and odds ratio) with 95% confidence interval (CI) were calculated for primary and secondary endpoints, respectively. Random-effect model was used in all analyses. Sixteen retrospective studies were included (5382 patients, i-SAVR = 2568 and CABG+SAVR = 2814). I-SAVR showed a lower incidence of in-hospital mortality compared to CABG+SAVR (odds ratio = 0.73; 95% CI= 0.60-0.89; P = 0.002). Landmark analyses showed a significantly higher all-cause mortality within 1 year from surgery in CABG+SAVR (HR = 1.17; 95% CI = 1.01-1.36; P = 0.03); after 1 year, no significant difference was observed (HR = 0.95; 95% CI = 0.87-1.04; P = 0.35). Landmark analysis was confirmed by time-varying trend of HR. Late survival of octogenarians did not differ significantly between the 2 interventions. Interestingly, CABG added to SAVR was associated with both higher in-hospital and within 1-year mortality after surgery, whereas this difference was statistically non-significant at long-term follow-up.

The early and long-term outcomes of coronary artery bypass grafting added to aortic valve replacement compared to isolated aortic valve replacement in elderly patients: a systematic review and meta-analysis.

In aged population, the early and long-term outcomes of coronary revascularization (CABG) added to surgical aortic valve replacement (SAVR) compared to isolated SAVR (i-SAVR) are conflicting. To address this limitation, a meta-analysis comparing the early and late outcomes of SAVR plus CABG with i-SAVR was performed. Electronic databases from January 2000 to November 2021 were screened. Studies reporting early-term and long-term comparison between the two treatments in patients over 75 years were analyzed. The primary endpoints were in-hospital/30-day mortality and overall long-term survival. The pooled odd ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) were calculated for in-early outcome and long-term survival, respectively. Random-effect model was used in all analyses. Forty-four retrospective observational studies reporting on 74,560 patients (i-SAVR = 36,062; SAVR + CABG = 38,498) were included for comparison. The pooled analysis revealed that i-SAVR was significantly associated with lower rate of early mortality compared to SAVR plus CABG (OR = 0.70, 95% CI 0.66-0.75; p < 0.0001) and with lower incidence of postoperative acute renal failure (OR = 0.65; 95% CI 0.50-0.91; p = 0.02), need for dialysis (OR = 0.65; 95% CI 0.50-0.86; p = 0.002) and prolonged mechanical ventilation (OR = 0.57; 95% CI 0.42-0.77; p < 0.0001). Twenty-two studies reported data of long-term follow-up. No differences were reported between the two groups in long-term survival (HR = 0.95; 95% CI 0.87-1.03; p = 0.23). CABG added to SAVR is associated with worse early outcomes in terms of early mortality, postoperative acute renal failure, and prolonged mechanical ventilation. Long-term survival was comparable between the two treatments.

MoBiFC: development of a modular bimolecular fluorescence complementation toolkit for the analysis of chloroplast protein-protein interactions.

BACKGROUND: The bimolecular fluorescence complementation (BiFC) assay has emerged as one of the most popular methods for analysing protein-protein interactions (PPIs) in plant biology. This includes its increasing use as a tool for dissecting the molecular mechanisms of chloroplast function. However, the construction of chloroplast fusion proteins for BiFC can be difficult, and the availability and selection of appropriate controls is not trivial. Furthermore, the challenges of performing BiFC in restricted cellular compartments has not been specifically addressed. RESULTS: Here we describe the development of a flexible modular cloning-based toolkit for BiFC (MoBiFC) and proximity labelling in the chloroplast and other cellular compartments using synthetic biology principles. We used pairs of chloroplast proteins previously shown to interact (HSP21/HSP21 and HSP21/PTAC5) and a negative control (HSP21/ΔPTAC5) to develop standardised Goldengate-compatible modules for the assembly of protein fusions with fluorescent protein (FP) fragments for BiFC expressed from a single multigenic T-DNA. Using synthetic biology principles and transient expression in Nicotiana benthamiana, we iteratively improved the approach by testing different FP fragments, promoters, reference FPs for ratiometric quantification, and cell types. A generic negative control (mCHERRY) was also tested, and modules for the identification of proximal proteins by Turbo-ID labelling were developed and validated. CONCLUSIONS: MoBiFC facilitates the cloning process for organelle-targeted proteins, allows robust ratiometric quantification, and makes available model positive and negative controls. Development of MoBiFC underlines how Goldengate cloning approaches accelerate the development and enrichment of new toolsets, and highlights several potential pitfalls in designing BiFC experiments including the choice of FP split, negative controls, cell type, and reference FP. We discuss how MoBiFC could be further improved and extended to other compartments of the plant cell and to high throughput cloning approaches.

Coordination of Chloroplast Activity with Plant Growth: Clues Point to TOR.

Photosynthesis is the defining function of most autotrophic organisms. In the plantae kingdom, chloroplasts host this function and ensure growth. However, these organelles are very sensitive to stressful conditions and the photosynthetic process can cause photooxidative damage if not perfectly regulated. In addition, their function is energivorous in terms of both chemical energy and nutrients. To coordinate chloroplast activity with the cell's need, continuous signaling is required: from chloroplasts to cytoplasm and from nucleus to chloroplasts. In this opinion article, several mechanisms that ensure this communication are reported and the many clues that point to an important role of the Target of Rapamycin (TOR) kinase in the coordination between the eukaryotic and prokaryotic sides of plants are highlighted.

A guanosine tetraphosphate (ppGpp) mediated brake on photosynthesis is required for acclimation to nitrogen limitation in Arabidopsis.

Guanosine pentaphosphate and tetraphosphate (together referred to as ppGpp) are hyperphosphorylated nucleotides found in bacteria and the chloroplasts of plants and algae. In plants and algae artificial ppGpp accumulation can inhibit chloroplast gene expression, and influence photosynthesis, nutrient remobilization, growth, and immunity. However, it is so far unknown whether ppGpp is required for abiotic stress acclimation in plants. Here, we demonstrate that ppGpp biosynthesis is necessary for acclimation to nitrogen starvation in Arabidopsis. We show that ppGpp is required for remodeling the photosynthetic electron transport chain to downregulate photosynthetic activity and for protection against oxidative stress. Furthermore, we demonstrate that ppGpp is required for coupling chloroplastic and nuclear gene expression during nitrogen starvation. Altogether, our work indicates that ppGpp is a pivotal regulator of chloroplast activity for stress acclimation in plants.

Surgical treatment for post-infarction papillary muscle rupture: a multicentre study.

OBJECTIVES: Papillary muscle rupture (PMR) is a rare but potentially fatal complication of acute myocardial infarction. The aim of this study was to analyse the patient characteristics and early outcomes of the surgical management of post-infarction PMR from an international multicentre registry. METHODS: Patients underwent surgery for post-infarction PMR between 2001 through 2019 were retrieved from database of the CAUTION study. The primary end point was in-hospital mortality. RESULTS: A total of 214 patients were included with a mean age of 66.9 (standard deviation: 10.5) years. The posteromedial papillary muscle was the most frequent rupture location (71.9%); the rupture was complete in 67.3% of patients. Mitral valve replacement was performed in 82.7% of cases. One hundred twenty-two patients (57%) had concomitant coronary artery bypass grafting. In-hospital mortality was 24.8%. Temporal trends revealed no apparent improvement in in-hospital mortality during the study period. Multivariable analysis showed that preoperative chronic kidney disfunction [odds ratio (OR): 2.62, 95% confidence interval (CI): 1.07-6.45, P = 0.036], cardiac arrest (OR: 3.99, 95% CI: 1.02-15.61, P = 0.046) and cardiopulmonary bypass duration (OR: 1.01, 95% CI: 1.00-1.02, P = 0.04) were independently associated with an increased risk of in-hospital death, whereas concomitant coronary artery bypass grafting was identified as an independent predictor of early survival (OR: 0.38, 95% CI: 0.16-0.92, P = 0.031). CONCLUSIONS: Surgical treatment for post-infarction PMR carries a high in-hospital mortality rate, which did not improve during the study period. Because concomitant coronary artery bypass grafting confers a survival benefit, this additional procedure should be performed, whenever possible, in an attempt to improve the outcome. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov: NCT03848429.