Can primary health care mitigate the effects of economic crises on child health in Latin America? An integrated multicountry evaluation and forecasting analysis.

BACKGROUND: Latin American and Caribbean countries are dealing with the combined challenges of pandemic-induced socicoeconomic stress and increasing public debt, potentially leading to reductions in welfare and health-care services, including primary care. We aimed to evaluate the impact of primary health-care coverage on child mortality in Latin America over the past two decades and to forecast the potential effects of primary health-care mitigation during the current economic crisis. METHODS: This multicountry study integrated retrospective impact evaluations in Brazil, Colombia, Ecuador, and Mexico from 2000 to 2019 with forecasting models covering up to 2030. We estimated the impact of coverage of primary health care on mortality rates in children younger than 5 years (hereafter referred to as under-5 mortality) across different age groups and causes of death, adjusting for all relevant demographic, socioeconomic, and health-care factors, with fixed-effects multivariable negative binomial models in 5647 municipalities with an adequate quality of vital statistics. We also performed several sensitivity and triangulation analyses. We integrated previous longitudinal datasets with validated dynamic microsimulation models and projected trends in under-5 mortality rates under alternative policy response scenarios until 2030. FINDINGS: High primary health-care coverage was associated with substantial reductions in post-neonatal mortality rates (rate ratio [RR] 0·72, 95% CI 0·71-0·74), toddler (ie, aged between 1 year and <5 years) mortality rates (0·75, 0·73-0·76), and under-5 mortality rates (0·81, 0·80-0·82), preventing 305 890 (95% CI 251 826-360 517) deaths of children younger than 5 years over the period 2000-19. High primary health-care coverage was also associated with lower under-5 mortality rates from nutritional deficiencies (RR 0·55, 95% CI 0·52-0·58), anaemia (0·64, 0·57-0·72), vaccine-preventable and vaccine-sensitive conditions (0·70, 0·68-0·72), and infectious gastroenteritis (0·78, 0·73-0·84). Considering a scenario of moderate economic crisis, a mitigation response strategy implemented in the period 2020-30 that increases primary health-care coverage could reduce the under-5 mortality rate by up to 23% (RR 0·77, 95% CI 0·72-0·84) when compared with a fiscal austerity response, and this strategy would avoid 142 285 (95% CI 120 217-164 378) child deaths by 2030 in Brazil, Colombia, Ecuador, and Mexico. INTERPRETATION: The improvement in primary health-care coverage in Brazil, Colombia, Ecuador, and Mexico over the past two decades has substantially contributed to improving child survival. Expansion of primary health-care coverage should be considered an effective strategy to mitigate the health effects of the current economic crisis and to achieve Sustainable Development Goals related to child health. FUNDING: UK Medical Research Council. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Down-regulation of wheat Rubisco activase isoforms expression by virus-induced gene silencing.

Rubisco activase (Rca) is an essential photosynthetic enzyme that removes inhibitors from the catalytic sites of the carboxylating enzyme Rubisco. In wheat, Rca is composed of one longer 46 kDa α-isoform and two shorter 42 kDa ß-isoforms encoded by the genes TaRca1 and TaRca2. TaRca1 produces a single transcript from which a short 1ß-isoform is expressed, whereas two alternative transcripts are generated from TaRca2 directing expression of either a long 2α-isoform or a short 2ß-isoform. The 2ß isoform is similar but not identical to 1ß. Here, virus-induced gene silencing (VIGS) was used to silence the different TaRca transcripts. Abundance of the transcripts and the respective protein isoforms was then evaluated in the VIGS-treated and control plants. Remarkably, treatment with the construct specifically targeting TaRca1 efficiently decreased expression not only of TaRca1 but also of the two alternative TaRca2 transcripts. Similarly, specific targeting of the TaRca2 transcript encoding a long isoform TaRca2α resulted in silencing of both TaRca2 alternative transcripts. The corresponding protein isoforms decreased in abundance. These findings indicate concomitant down-regulation of TaRca1 and TaRca2 at both transcript and protein levels and may impact the feasibility of altering the relative abundance of Rca isoforms in wheat.

Construction and Evaluation of a Realistic Low-Cost Model for Training in Chest-Tube Insertion.

INTRODUCTION: Emergency thoracostomy is applied in life-threatening situations. Simulation plays a pivotal role in training in invasive techniques used mainly in stressful situations. Currently available commercial simulation models for thoracostomy have various drawbacks. METHODS: We designed a thoracostomy phantom from discarded hospital materials and pigskin with underlying flesh. The phantom can be used alone for developing technical skills or mounted on an actor in simulation scenarios. Medical students, intensive care unit (ICU) and emergency department teams, and thoracostomy experts evaluated its technical fidelity and usefulness for achieving learning objectives in workshops. RESULTS: The materials used to construct the phantom cost €47. A total of 12 experts in chest-tube placement and 73 workshop participants (12 ICU physicians and nurses, 20 emergency physicians and nurses, and 41 fourth-year medical students) evaluated the model. All groups rated the model's usefulness and the sensation of perforating the pleura highly. Experts rated the air release after pleura perforation lower than other groups. Lung reexpansion was the lowest rated item in all groups. Ratings of the appearance and feel of the model correlated strongly among all groups and experts. The ICU professionals rated the resistance encountered in introducing the chest drain lower than the other groups. CONCLUSIONS: This low-cost, reusable, transportable, and highly realistic model is an attractive alternative to commercial models for training in chest-tube insertion skills.

Removal of redox-sensitive Rubisco Activase does not alter Rubisco regulation in soybean.

Rubisco activase (Rca) facilitates the catalytic repair of Rubisco, the CO2-fixing enzyme of photosynthesis, following periods of darkness, low to high light transitions or stress. Removal of the redox-regulated isoform of Rubisco activase, Rca-α, enhances photosynthetic induction in Arabidopsis and has been suggested as a strategy for the improvement of crops, which may experience frequent light transitions in the field; however, this has never been tested in a crop species. Therefore, we used RNAi to reduce the Rca-α content of soybean (Glycine max cv. Williams 82) below detectable levels and then characterized the growth, photosynthesis, and Rubisco activity of the resulting transgenics, in both growth chamber and field conditions. Under a 16 h sine wave photoperiod, the reduction of Rca-α contents had no impact on morphological characteristics, leaf expansion rate, or total biomass. Photosynthetic induction rates were unaltered in both chamber-grown and field-grown plants. Plants with reduced Rca-α content maintained the ability to regulate Rubisco activity in low light just as in control plants. This result suggests that in soybean, Rca-α is not as centrally involved in the regulation of Rca oligomer activity as it is in Arabidopsis. The isoform stoichiometry supports this conclusion, as Rca-α comprises only ~ 10% of the Rubisco activase content of soybean, compared to ~ 50% in Arabidopsis. This is likely to hold true in other species that contain a low ratio of Rca-α to Rca-ß isoforms.

Reactivación de la enfermedad de Chagas después de trasplante autólogo de progenitores hematopoyéticos. Reporte de caso y revisión de la literatura / Chagas disease reactivation after autologous stem cell transplant. Case report and literature review

Introducción. La enfermedad de Chagas es una parasitosis endémica en Latinoamérica transmitida por triatominos. Está asociada a factores de riesgo como la pobreza y la ruralidad. Después de la infección aguda, un tercio de los pacientes presenta compromiso del corazón, el aparato digestivo o el sistema nervioso central, en tanto que los dos tercios restantes no presentan este tipo de compromiso secundario. La inmunosupresión farmacológica rompe el equilibrio entre el sistema inmunitario y el parásito, lo cual favorece su reactivación. Caso clínico. Se presenta el caso de un hombre de 58 años procedente de un área rural colombiana, con diagnóstico de mieloma múltiple resistente a los fármacos de primera línea de tratamiento, que requirió un nuevo esquema de quimioterapia y consolidación con trasplante autólogo de células madre. Después del trasplante, presentó neutropenia febril. Los estudios microbiológicos iniciales fueron negativos. En el frotis de sangre periférica, se demostraron tripomastigotes y se diagnosticó enfermedad de Chagas aguda posterior al trasplante. Se inició el tratamiento con benznidazol. La evolución del paciente fue satisfactoria. Conclusiones. La serología positiva para Chagas previa a un trasplante obliga a descartar la reactivación de la enfermedad en caso de neutropenia febril. Se requieren más estudios para determinar las herramientas que permitan estimar la probabilidad de reactivación de la enfermedad y decidir sobre la mejor opción de relación entre costo, riesgo y beneficio de la terapia profiláctica.

Introduction: Chagas disease is an endemic parasitic infection in Latin America transmitted by triatomines. It is associated with risk factors such as poverty and rurality. After acute infection, a third of patients will present target organ involvement (heart, digestive tract, central nervous system). The remaining two thirds remain asymptomatic throughout their life. Pharmacological immunosuppression breaks the balance between the immune system and the parasite, favoring its reactivation. Clinical case: We present the case of a 58-year-old man from a Colombian rural area with a diagnosis of multiple myeloma refractory to the first line of treatment who required a new chemotherapy scheme and consolidation with autologous stem cell transplant. During the post-transplant period, he suffered from febrile neutropenia. Initial microbiological studies were negative but the peripheral blood smear evidenced trypomastigotes in blood. With a diagnosis of acute Chagas disease in a post-transplant patient, benznidazole was started. The evolution of the patient was satisfactory. Conclusions: Positive serology prior to transplantation makes it necessary to rule out reactivation of the pathology in the setting of febrile neutropenia. More studies are required to determine tools for estimating the probability of reactivation of the disease and defining the best cost-risk-benefit relation for the prophylactic therapy.

Feasibility of a Multimodal Prehabilitation Programme in Patients Undergoing Cytoreductive Surgery for Advanced Ovarian Cancer: A Pilot Study.

INTRODUCTION: Treatment for advanced ovarian cancer (AOC) comprises cytoreductive surgery combined with chemotherapy. Multimodal prehabilitation programmes before surgery have demonstrated efficacy in postoperative outcomes in non-gynaecological surgeries. However, the viability and effects of these programmes on patients with AOC are unknown. We aimed to evaluate the feasibility and postoperative impact of a multimodal prehabilitation programme in AOC patients undergoing surgery. METHODS: This single-centre, before-and-after intervention pilot study included 34 patients in two cohorts: the prehabilitation cohort prospectively included 15 patients receiving supervised exercise, nutritional optimisation, and psychological preparation from December 2019 to January 2021; the control cohort included 19 consecutive patients between January 2018 and November 2019. Enhanced Recovery After Surgery guidelines were followed. RESULTS: The overall adherence to the multimodal prehabilitation programme was 80%, with 86.7% adherence to exercise training, 100% adherence to nutritional optimisation, and 80% adherence to psychological preparation. The median hospital stay was shorter in the prehabilitation cohort (5 (IQR, 4-6) vs. 7 days (IQR, 5-9) in the control cohort, p = 0.04). Differences in postoperative complications using the comprehensive complication index (CCI) were not significant (CCI score: 9.3 (SD 12.12) in the prehabilitation cohort vs. 16.61 (SD 16.89) in the control cohort, p = 0.08). The median time to starting chemotherapy was shorter in the prehabilitation cohort (25 (IQR, 23-25) vs. 35 days (IQR, 28-45) in the control cohort, p = 0.03). CONCLUSIONS: A multimodal prehabilitation programme before cytoreductive surgery is feasible in AOC patients with no major adverse effects, and results in significantly shorter hospital stays and time to starting chemotherapy.

Preintervention imaging and intraoperative management care of the hypertrophic obstructive cardiomyopathy patient.

With an estimated overall mortality of less than 1 percent per year, hypertrophic cardiomyopathy, is the most common genetic cardiomyopathy. Intraoperative transesophageal echocardiography is the standard of care for assessing patients with hypertrophic obstructive cardiomyopathy undergoing surgical septal myectomy, allowing surgical planning, intraoperative hemodynamic monitoring, and postprocedural assessment of the repair, including detection of immediate complications. At various phases during surgical septal myectomy, the changing hemodynamic conditions may lead to worsening or improvement in left ventricle outflow tract obstruction by change in preload or afterload, systolic anterior motion of the mitral valve, or sympathetic stimulation. These characteristics represent unique challenges in the management of these patients, requiring a comprehensive understanding of the management of all the conditions required to decrease the left ventricle outflow tract gradient avoiding obstruction, which include the maintenance of sinus rhythm, adequate rate avoiding tachycardia and bradycardia, and avoidance of systemic hypotension preserving preload and afterload, with adequate vasoactive agents. The aim of this review is to summarize the perioperative assessment and management of patients undergoing hypertrophic obstructive myopathy surgery.

Apoptosis Pathways Triggered by a Potent Antiproliferative Hybrid Chalcone on Human Melanoma Cells.

The World Health Organization reported that approximately 324,000 new cases of melanoma skin cancer were diagnosed worldwide in 2020. The incidence of melanoma has been increasing over the past decades. Targeting apoptotic pathways is a potential therapeutic strategy in the transition to preclinical models and clinical trials. Some naturally occurring products and synthetic derivatives are apoptosis inducers and may represent a realistic option in the fight against the disease. Thus, chalcones have received considerable attention due to their potential cytotoxicity against cancer cells. We have previously reported a chalcone containing an indole and a pyridine heterocyclic rings and an α-bromoacryloylamido radical which displays potent antiproliferative activity against several tumor cell lines. In this study, we report that this chalcone is a potent apoptotic inducer for human melanoma cell lines SK-MEL-1 and MEL-HO. Cell death was associated with mitochondrial cytochrome c release and poly(ADP-ribose) polymerase cleavage and was prevented by a non-specific caspase inhibitor. Using SK-MEL-1 as a model, we found that the mechanism of cell death involves (i) the generation of reactive oxygen species, (ii) activation of the extrinsic and intrinsic apoptotic and mitogen-activated protein kinase pathways, (iii) upregulation of TRAIL, DR4 and DR5, (iv) downregulation of p21Cip1/WAF1 and, inhibition of the NF-κB pathway.

The pharmacogenetics of treatment with olanzapine.

Genetic polymorphism in olanzapine-metabolizing enzymes, transporters and drug targets is associated with alterations in safety and efficacy. The aim of this systematic review is to describe all clinically relevant pharmacogenetic information on olanzapine and to propose clinically actionable variants. Two hundred and eighty-four studies were screened; 76 complied with the inclusion criteria and presented significant associations. DRD2 Taq1A (rs1800497) *A1, LEP -2548 (rs7799039) G and CYP1A2*1F alleles were related to olanzapine effectiveness and safety variability in several studies, with a high level of evidence. DRD2 -141 (rs1799732) Ins, A-241G (rs1799978) G, DRD3 Ser9Gly (rs6280) Gly, HTR2A rs7997012 A, ABCB1 C3435T (rs1045642) T and G2677T/A (rs2032582) T and UGT1A4*3 alleles were related to safety, effectiveness and/or pharmacokinetic variability with moderated level of evidence.

Outcomes of Septal Myectomy beyond 65 Years, with and without Concomitant Procedures.

INTRODUCTION AND OBJECTIVES: Septal myectomy remains the first septal reduction therapy for hypertrophic obstructive cardiomyopathy in young patients and those requiring concomitant procedures. Its role in advanced ages is questioned due to perceived increased risk. We assess the outcomes of surgical relief of obstruction in patients beyond 65 years old. METHODS: A single-center retrospective review of patients ≥ 65 years old undergoing septal myectomy through median sternotomy between April 2015 and February 2020. RESULTS: We identified 52 patients. Mean age was 71.8 ± 4.9 years; 36 (69.2%) were females. All were symptomatic. Mean highest LVOT gradient was 90 ± 39 mmHg. All patients had systolic anterior motion (SAM) of the mitral valve and 36 (69.2%) ≥ moderate mitral regurgitation. Additional LVOT interventions beyond myectomy were performed in 34 (65.4%). At least one other cardiac concomitant procedure was performed 44 (84.6%). No perioperative mortality in elective surgery occurred. One patient (1.9%) developed atrio-ventricular block. Postoperative mean gradient was 4.3 ± 1.9 mmHg, with 46 (88.4%) achieving complete resolution of obstruction. Mitral regurgitation was reduced to grade ≤ I in 46 (88.5%). Mean follow-up time was 2.3 ± 1.2 years and 82% of patients were in NYHA I. Survival at 2 years was 98%. CONCLUSION: Septal myectomy in the elderly is a safe and effective operation despite the need for concomitant procedures. LVOT interventions beyond septal myectomy to relieve obstruction are common in this advanced cohort of hypertrophic cardiomyopathy patients. This operation carried at experienced centers seems an unmatched therapeutic option.

The relative abundance of wheat Rubisco activase isoforms is post-transcriptionally regulated.

Diurnal rhythms and light availability affect transcription-translation feedback loops that regulate the synthesis of photosynthetic proteins. The CO2-fixing enzyme Rubisco is the most abundant protein in the leaves of major crop species and its activity depends on interaction with the molecular chaperone Rubisco activase (Rca). In Triticum aestivum L. (wheat), three Rca isoforms are present that differ in their regulatory properties. Here, we tested the hypothesis that the relative abundance of the redox-sensitive and redox-insensitive Rca isoforms could be differentially regulated throughout light-dark diel cycle in wheat. While TaRca1-ß expression was consistently negligible throughout the day, transcript levels of both TaRca2-ß and TaRca2-α were higher and increased at the start of the day, with peak levels occurring at the middle of the photoperiod. Abundance of TaRca-ß protein was maximal 1.5 h after the peak in TaRca2-ß expression, but the abundance of TaRca-α remained constant during the entire photoperiod. The redox-sensitive TaRca-α isoform was less abundant, representing 85% of the redox-insensitive TaRca-ß at the transcript level and 12.5% at the protein level. Expression of Rubisco large and small subunit genes did not show a consistent pattern throughout the diel cycle, but the abundance of Rubisco decreased by up to 20% during the dark period in fully expanded wheat leaves. These results, combined with a lack of correlation between transcript and protein abundance for both Rca isoforms and Rubisco throughout the entire diel cycle, suggest that the abundance of these photosynthetic enzymes is post-transcriptionally regulated.

Multimodal prehabilitation as strategy for reduction of postoperative complications after cardiac surgery: a randomised controlled trial protocol.

INTRODUCTION: Prehabilitation programmes that combine exercise training, nutritional support and emotional reinforcement (multimodal prehabilitation) have demonstrated efficacy reducing postoperative complications in the context of abdominal surgery. However, such programmes have seldom been studied in cardiac surgery, one of the surgeries associated with higher postoperative morbidity and mortality. This trial will assess the feasibility and efficacy in terms of reduction of postoperative complications and cost-effectiveness of a multimodal prehabilitation programme comparing to the standard of care in cardiac surgical patients. METHODS AND ANALYSIS: This is a single-centre, randomised, open-label, controlled trial with a 1:1 ratio. Consecutive 160 elective valve replacement and/or coronary revascularisation surgical patients will be randomised to either standard of care or 4-6 weeks of multimodal prehabilitation that will consist in (1) two times/week supervised endurance and strength exercise training sessions, (2) promotion of physical activity and healthy lifestyle, (3) respiratory physiotherapy, (4) nutrition counselling and supplementation if needed, and (5) weekly mindfulness sessions. Baseline, preoperative and 3-month postoperative data will be collected by an independent blinded evaluator. The primary outcome of this study will be the incidence of postoperative complications. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of Clinical investigation of Hospital Clinic de Barcelona (HCB/2017/0708). The results will be disseminated in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03466606.

In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation.

BACKGROUND: COVID-19 is associated with a substantial risk of venous thrombotic events, even in the presence of adequate thromboprophylactic therapy. OBJECTIVES: We aimed to better characterize the hypercoagulable state of COVID-19 patients in patients receiving anticoagulant therapy. METHODS: We took plasma samples of 23 patients with COVID-19 who were on prophylactic or intensified anticoagulant therapy. Twenty healthy volunteers were included to establish reference ranges. RESULTS: COVID-19 patients had a mildly prolonged prothrombin time, high von Willebrand factor levels and low ADAMTS13 activity. Most rotational thromboelastometry parameters were normal, with a hypercoagulable maximum clot firmness in part of the patients. Despite detectable anti-activated factor X activity in the majority of patients, ex vivo thrombin generation was normal, and in vivo thrombin generation elevated as evidenced by elevated levels of thrombin-antithrombin complexes and D-dimers. Plasma levels of activated factor VII were lower in patients, and levels of the platelet activation marker soluble CD40 ligand were similar in patients and controls. Plasmin-antiplasmin complex levels were also increased in patients despite an in vitro hypofibrinolytic profile. CONCLUSIONS: COVID-19 patients are characterized by normal in vitro thrombin generation and enhanced clot formation and decreased fibrinolytic potential despite the presence of heparin in the sample. Anticoagulated COVID-19 patients have persistent in vivo activation of coagulation and fibrinolysis, but no evidence of excessive platelet activation. Ongoing activation of coagulation despite normal to intensified anticoagulant therapy indicates studies on alternative antithrombotic strategies are urgently required.

Melatonin Induces Melanogenesis in Human SK-MEL-1 Melanoma Cells Involving Glycogen Synthase Kinase-3 and Reactive Oxygen Species.

Melatonin is present in all living organisms where it displays a diversity of physiological functions. Attenuation of melanogenesis by melatonin has been reported in some mammals and also in rodent melanoma cells. However, melatonin may also stimulate melanogenesis in human melanoma cells through mechanisms that have not yet been revealed. Using the human melanoma cells SK-MEL-1 as a model, an increase in both tyrosinase activity and melanin was already observed at 24 h after melatonin treatment with maximal levels of both being detected at 72 h. This effect was associated with the induction in the expression of the enzymes involved in the synthesis of melanin. In this scenario, glycogen synthase kinase-3ß seems to play a significant function since melatonin decreased its phosphorylation and preincubation with specific inhibitors of this protein kinase (lithium or BIO) reduced the expression and activity of tyrosinase. Blocking of PI3K/AKT pathway stimulated melanogenesis and the effect was suppressed by the inhibitors of glycogen synthase kinase-3ß. Although melatonin is a recognized antioxidant, we found that it stimulates reactive oxygen species generation in SK-MEL-1 cells. These chemical species seem to be an important signal in activating the melanogenic process since the antioxidants N-acetyl-l-cysteine and glutathione decreased both the level and activity of tyrosinase stimulated by melatonin. Our results support the view that regulation of melanogenesis involves a cross-talk between several signaling pathways.

Seguridad y resultados del implante de MitraClip en insuficiencia mitral funcional según el grado de disfunción ventricular izquierda / Safety and outcomes of MitraClip implantation in functional mitral regurgitation according to degree of left ventricular dysfunction

INTRODUCCIÓN Y OBJETIVOS: Recientemente se han presentado 2 estudios aleatorizados con resultados confrontados sobre la reparación percutánea de la válvula mitral con dispositivo MitraClip en pacientes con insuficiencia mitral funcional (IMF). El objetivo del presente estudio es evaluar la seguridad y el impacto en el pronóstico del tratamiento de la IMF con MitraClip en función del estado del ventrículo izquierdo (VI). MÉTODOS: Se realizó un cribado retrospectivo de los pacientes con IMF tratada con MitraClip en nuestro centro, dividiéndolos en 2 grupos según la fracción de eyección del VI (FEVI) y el diámetro telediastólico del VI: «VI extremo» (FEVI ≤ 20% y/o diámetro telediastólico del VI ≥ 70 mm) y «VI no extremo» (FEVI> 20% y diámetro telediastólico del VI <70 mm). Se realizó un análisis de supervivencia por eventos cardiovasculares que incluía ingreso hospitalario por insuficiencia cardiaca, trasplante cardiaco o muerte cardiovascular. Asimismo se compararon la clase funcional y el número de ingresos por insuficiencia cardiaca durante los años previo y posterior al implante del dispositivo. RESULTADOS: Se incluyó a 58 pacientes con IMF consecutivos (28 con VI extremo y 30 con VI no extremo). El seguimiento medio fue de 19,5±13 meses. Los pacientes con VI no extremo mostraron una supervivencia libre de eventos cardiovasculares significativamente mayor (log-rank, 3,706; p = 0,010). Al año de la intervención, ambos grupos mostraron una mejoría de los síntomas. La mayoría de los pacientes se encontraban entonces en clase funcional I-II de la New York Heart Asssociation (el 100% del grupo de VI no extremo y el 84% del grupo de VI extremo) y se observó una reducción del número de ingresos hospitalarios por insuficiencia cardiaca en ambos grupos. CONCLUSIONES: El implante del dispositivo MitraClip parece ser seguro y efectivo en la reducción de la IMF. Pese a que los pacientes con FEVI muy baja y/o VI muy dilatado parecen tener un peor pronóstico cardiovascular, la intervención en ellos fue segura y mejoró sus síntomas

INTRODUCTION AND OBJECTIVES: Recent randomized trials of the MitraClip system have reported controversial results in the treatment of patients with functional mitral regurgitation (FMR). The aim of the present study was to evaluate the safety and impact of MitraClip implantation on outcomes in FMR according to left ventricular (LV) status. METHODS: Patients with FMR undergoing MitraClip implantation in our center were retrospectively screened and divided into 2 groups according to LV ejection fraction (LVEF) and LV end-diastolic dimension: "very poor LV" (LVEF ≤ 20% and/or LV end-diastolic dimension ≥ 70 mm) and "poor LV" (LVEF> 20% and LV end-diastolic dimension <70 mm). Survival analysis of cardiovascular outcomes included hospital admission due to congestive heart failure, heart transplant, and cardiovascular death. Likewise, we compared the number of hospital admissions and functional class the year before and after the intervention. RESULTS: Fifty-eight consecutive patients with FMR were included (28 with very poor LV and 30 with poor LV). The mean follow-up was 19.5± 13 months. Patients with poor LV showed a significantly better event-free survival for cardiovascular events (log-rank 3.706, P=.010). One year after the intervention, both groups showed symptom improvement. Most of the patients were in New York Heart Association functional class I-II (100% poor LV and 84% very poor LV) and both groups showed a decrease in the number of hospital admissions due to congestive heart failure. CONCLUSIONS: MitraClip implantation seems to be safe and effective in reducing FMR. Although patients with very low LVEF and/or very enlarged LV seemed to have worse cardiovascular outcomes, the intervention was safe and resulted in symptom improvement

Safety and outcomes of MitraClip implantation in functional mitral regurgitation according to degree of left ventricular dysfunction.

INTRODUCTION AND OBJECTIVES: Recent randomized trials of the MitraClip system have reported controversial results in the treatment of patients with functional mitral regurgitation (FMR). The aim of the present study was to evaluate the safety and impact of MitraClip implantation on outcomes in FMR according to left ventricular (LV) status. METHODS: Patients with FMR undergoing MitraClip implantation in our center were retrospectively screened and divided into 2 groups according to LV ejection fraction (LVEF) and LV end-diastolic dimension: "very poor LV" (LVEF ≤ 20% and/or LV end-diastolic dimension ≥ 70 mm) and "poor LV" (LVEF> 20% and LV end-diastolic dimension <70 mm). Survival analysis of cardiovascular outcomes included hospital admission due to congestive heart failure, heart transplant, and cardiovascular death. Likewise, we compared the number of hospital admissions and functional class the year before and after the intervention. RESULTS: Fifty-eight consecutive patients with FMR were included (28 with very poor LV and 30 with poor LV). The mean follow-up was 19.5± 13 months. Patients with poor LV showed a significantly better event-free survival for cardiovascular events (log-rank 3.706, P=.010). One year after the intervention, both groups showed symptom improvement. Most of the patients were in New York Heart Association functional class I-II (100% poor LV and 84% very poor LV) and both groups showed a decrease in the number of hospital admissions due to congestive heart failure. CONCLUSIONS: MitraClip implantation seems to be safe and effective in reducing FMR. Although patients with very low LVEF and/or very enlarged LV seemed to have worse cardiovascular outcomes, the intervention was safe and resulted in symptom improvement.

Rubisco activation by wheat Rubisco activase isoform 2ß is insensitive to inhibition by ADP.

Rubisco activase (Rca) is a catalytic chaperone that remodels the active site, promotes the release of inhibitors and restores catalytic competence to Rubisco. Rca activity and its consequent effect on Rubisco activation and photosynthesis are modulated by changes to the chloroplast environment induced by fluctuations in light levels that reach the leaf, including redox status and adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio. The Triticum aestivum (wheat) genome encodes for three Rca protein isoforms: 1ß (42.7 kDa), 2ß (42.2 kDa) and 2α (46.0 kDa). The regulatory properties of these isoforms were characterised by measuring rates of Rubisco activation and ATP hydrolysis by purified recombinant Rca proteins in the presence of physiological ADP/ATP ratios. ATP hydrolysis by all three isoforms was sensitive to inhibition by increasing amounts of ADP in the assay. In contrast, Rubisco activation activity of Rca 2ß was insensitive to ADP inhibition, while Rca 1ß and 2α were inhibited. Two double and one quadruple site-directed mutants were designed to elucidate if differences in the amino acid sequences between Rca 1ß and 2ß could explain the differences in ADP sensitivity. Changing two amino acids in Rca 2ß to the corresponding residues in 1ß (T358K & Q362E) resulted in significant inhibition of Rubisco activation in presence of ADP. The results show that the wheat Rca isoforms differ in their regulatory properties and that amino acid changes in the C domain influence ADP sensitivity. Advances in the understanding of Rubisco regulation will aid efforts to improve the efficiency of photosynthetic CO2 assimilation.