Clinical outcomes and mortality in patients with atrial fibrillation and recently diagnosed lung cancer in oncology outpatient settings.

INTRODUCTION: Our aim was to investigate the prevalence of atrial fibrillation (AF) and recently diagnosed lung cancer in the outpatient oncology clinic and to describe the clinical profile, management and outcomes of this population. METHODS: Among 6984 patients visited at the outpatient oncology clinics attending lung cancer patients in five university hospitals from 2017 to 2019, all consecutive subjects with recently diagnosed (<1 year) disease and AF were retrospectively selected and events in follow up were registered. RESULTS: A total of 269 patients (3.9 % of all attended, 71 ± 8 years, 91 % male) were included. Charlson, CHA2DS2-VASc and HAS-BLED indexes were 6.7 ± 2.9, 2.9 ± 1.5 y 2.5 ± 1.2, respectively. Tumour stage was I, II, III and IV in 11 %, 11 %, 33 % and 45 % of them, respectively. Anticoagulants were prescribed to 226 patients (84 %): direct anticoagulants (n = 99;44 %), low molecular weight heparins (n = 69;30 %) and vitamin K antagonists (n = 58;26 %). After 46 months of maximum follow-up, 186 patients died (69 %). Cumulative incidences of events at 3 years were 3.3 ± 1.3 % for stroke/systemic embolism (n = 7); 8.9 ± 2.2 % for thrombotic events (n = 18); 9.9 ± 2.6 % for major bleeding (n = 16), and 15.9 ± 3,0 % for cardiovascular events (n = 33). In patients with early stages of cancer (I-II), 2-year mortality was significantly higher in those with cardiovascular events or major bleeding (85 % vs 25 %, p = 0.01). CONCLUSION: Nearly 4 % or all outpatients in the oncology clinic attending lung cancer present recently diagnosed disease and AF. Major bleeding and cardiovascular event rates are high in this population, with an impact on mortality in early stages of cancer.

New severity criteria for tricuspid regurgitation in a broad population of "real life" patients: Prevalence and prognostic impact.

Introduction Our objective was to determine, in "real life" patients, the prevalence of massive and torrential regurgitation among patients diagnosed with severe tricuspid regurgitation (TR), as well as its impact on long-term prognosis. Methods In a single-center retrospective study, all patients with an echocardiographic diagnosis of severe TR attended at a tertiary care hospital of an European country from January 2008 to December 2017 were recruited. Images were analysed off-line to measure the maximum vena contracta (VC) and TR was classified into three groups: severe (VC ≥ 7 mm), massive (VC 14-20 mm), and torrential (VC ≥ 21 mm). The impact of this classification on the combined event of heart failure (HF) admission and all-cause death in follow-up was investigated. Results A total of 614 patients (70 ± 13 years, 72 % women) were included. 81.4 % had severe TR, 15.8 % massive TR, and 2.8 % torrential TR. The 5-year HF-free survival  was 42 %, 43 %, and 12 % (p = 0.001), for the different subgroups of severe TR, respectively. After adjusting for baseline characteristics, TR severity was an independent predictor of survival free of the combined end-point: HR 0.91 [95 % CI 0.70-1.18] p = 0.46, for massive TR; and HR 2.5 [95 % CI 1.49-4.21] p = 0.001, for torrential TR considering severe TR as reference. Conclusions The prevalence of massive and torrential TR is not negligible among patients with severe TR in real life. The prognosis is significantly worse for patients with torrential TR measured by the maximum VC.

Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy.

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity.

The Worsening of Heart Failure with Reduced Ejection Fraction: The Impact of the Number of Hospital Admissions in a Cohort of Patients.

BACKGROUND: Worsening heart failure (WFH) includes heart failure (HF) hospitalisation, representing a strong predictor of mortality in patients with heart failure with reduced ejection fraction (HFrEF). However, there is little evidence analysing the impact of the number of previous HF admissions. Our main objective was to analyse the clinical profile according to the number of previous admissions for HF and its prognostic impact in the medium and long term. METHODS: A retrospective study of a cohort of patients with HFrEF, classified according to previous admissions: cohort-1 (0-1 previous admission) and cohort-2 (≥2 previous admissions). Clinical, echocardiographic and therapeutic variables were analysed, and the medium- and long-term impacts in terms of hospital readmissions and cardiovascular mortality were assessed. A total of 406 patients were analysed. RESULTS: The mean age was 67.3 ± 12.6 years, with male predominance (73.9%). Some 88.9% (361 patients) were included in cohort-1, and 45 patients (11.1%) were included in cohort-2. Cohort-2 had a higher proportion of atrial fibrillation (49.9% vs. 73.3%; p = 0.003), chronic kidney disease (36.3% vs. 82.2%; p < 0.001), and anaemia (28.8% vs. 53.3%; p = 0.001). Despite having similar baseline ventricular structural parameters, cohort-1 showed better reverse remodelling. With a median follow-up of 60 months, cohort-1 had longer survival free of hospital readmissions for HF (37.5% vs. 92%; p < 0.001) and cardiovascular mortality (26.2% vs. 71.9%; p < 0.001), with differences from the first month. CONCLUSIONS: Patients with HFrEF and ≥2 previous admissions for HF have a higher proportion of comorbidities. These patients are associated with worse reverse remodelling and worse medium- and long-term prognoses from the early stages, wherein early identification is essential for close follow-up and optimal intensive treatment.

Sick and depressed? The causal impact of a diabetes diagnosis on depression.

BACKGROUND: There is sparse evidence on the impact of health information on mental health as well as on the mechanisms governing this relationship. We estimate the causal impact of health information on mental health via the effect of a diabetes diagnosis on depression. METHODS: We employ a fuzzy regression discontinuity design (RDD) exploiting the exogenous cut-off value of a biomarker used to diagnose type-2 diabetes (glycated haemoglobin, HbA1c) and information on psycometrically validated measures of diagnosed clinical depression drawn from rich administrative longitudinal individual-level data from a large municipality in Spain. This approach allows estimating the causal impact of a type-2 diabetes diagnosis on clinica ldepression. RESULTS: We find that overall a type-2 diabetes diagnosis increases the probability of becoming depressed, however this effect appears to be driven mostly by women, and in particular those who are relatively younger and obese. Results also appear to differ by changes in lifestyle induced by the diabetes diagnosis: while women who did not lose weight are more likely to develop depression, men who did lose weight present a reduced probability of being depressed. Results are robust to alternative parametric and non-parametric specifications and placebo tests. CONCLUSIONS: The study provides novel empirical evidence on the causal impact of health information on mental health, shedding light on gender-based differences in such effects and potential mechanisms through changes in lifestyle behaviours.

Improvement of left ventricular ejection fraction in patients with heart failure with reduced ejection fraction: Predictors and clinical impact / Impacto clínico a medio plazo de la mejoría de la fracción de eyección ventricular izquierda en pacientes con insuficiencia cardiaca con fracción de eyección reducida

Background A percentage of patients with heart failure with reduced ejection fraction (HFrEF) improve left ventricular ejection fraction (LVEF) in the evolution. This entity, defined for the first time in an international consensus as heart failure with improved ejection fraction (HFimpEF), could have a different clinical profile and prognosis than HFrEF. Our main aim was to analyze the differential clinical profile between the two entities, as well as the mid-term prognosis. Material-methods Prospective study of a cohort of patients with HFrEF who had echocardiographic data at baseline and follow-up. A comparative analysis of patients who improved LVEF with those who did not was made. Clinical, echocardiographic and therapeutic variables were analyzed, and the mid-term impact in terms of mortality and hospital readmissions for HF was assessed. Results Ninety patients were analyzed. Mean age was 66.5(10.4) years, with a male predominance (72.2%). Forty five patients (50%) improved LVEF (Group-1,HFimpEF) and forty five patients (50%) sustained reduced LVEF (Group-2,HFsrEF). The mean time to LVEF improvement in Group-1 was 12.6(5.7) months. Group-1 had a more favorable clinical profile: lower prevalence of cardiovascular risk factors, higher prevalence of de novo HF (75.6% vs. 42.2%; p<0.05), lower prevalence of ischemic etiology (22.2% vs. 42.2%; p<0.05), with less basal dilatation of the left ventricle. At the end of follow-up (mean 19(1) months) Group-1 had a lower hospital readmission rate (3.1% vs. 26.7%; p<0.01), as well as lower mortality (0% vs. 24.4%; p<0.01). Conclusion Patients with HFimpEF seem to have a better mid-term prognosis in terms of reduced mortality and hospital admissions. This improvement could be conditioned by the clinical profile of patients HFimpEF (AU)

Introducción Un porcentaje de pacientes con insuficiencia cardiaca y fracción de eyección reducida (IC-FEr) mejoran la fracción de eyección ventricular izquierda (FEVI) en la evolución. Esta entidad se ha definido por primera vez en un consenso internacional como insuficiencia cardiaca y fracción de eyección mejorada (IC-FEm), y podría tener un perfil y pronóstico diferente que IC-FEr. Nuestro objetivo fue analizar el perfil de ambas entidades y su pronóstico a medio plazo. Material y métodos Estudio prospective de una cohorte de pacientes con IC-FEr que tenían datos ecocardiográficos basales y en el seguimiento. Se hizo un análisis comparativo de pacientes con IC-FEm y pacientes con insuficiencia cardiaca y IC-FEpr. Se analizaron variables clínicas, ecocardiográficas y de tratamiento; el impacto clínico a medio plazo se analizó en términos de mortalidad y reingresos hospitalarios por insuficiencia cardiaca. Resultados Se analizaron 90 pacientes, edad media 66,5 (10,4) años (72,2% mujeres). La mitad de los pacientes mejoraron su FEVI, con un tiempo medio hasta la mejoría de 12,6 (5,7) meses. El grupo IC-FEm tenía un perfil clínico más favorable: menor proporción de factores de riesgo cardiovascular, prevalencia más elevada de IC-novo (75,6 vs. 42,2%; p < 0,05), y menor proporción de isquemia (22,2 vs. 42.2%; p < 0,05). Los pacientes con IC-FEm en el seguimiento a medio plazo tenían menor tasa de reingresos (3,1 vs. 26,7%; p < 0,01), y mortalidad (0 vs. 24,4%; p < 0,01). Conclusión Pacientes con IC-FEm parecen tener un mejor pronóstico en términos de mortalidad y reingresos hospitalarios por insuficiencia cardiaca (IC). Esta mejoría clínica podría estar condicionada por el perfil de los pacientes con IC-FEm (AU)

Improvement of left ventricular ejection fraction in patients with heart failure with reduced ejection fraction: Predictors and clinical impact.

BACKGROUND: A percentage of patients with heart failure with reduced ejection fraction (HFrEF) improve left ventricular ejection fraction (LVEF) in the evolution. This entity, defined for the first time in an international consensus as heart failure with improved ejection fraction (HFimpEF), could have a different clinical profile and prognosis than HFrEF. Our main aim was to analyze the differential clinical profile between the two entities, as well as the mid-term prognosis. MATERIAL-METHODS: Prospective study of a cohort of patients with HFrEF who had echocardiographic data at baseline and follow-up. A comparative analysis of patients who improved LVEF with those who did not was made. Clinical, echocardiographic and therapeutic variables were analyzed, and the mid-term impact in terms of mortality and hospital readmissions for HF was assessed. RESULTS: Ninety patients were analyzed. Mean age was 66.5(10.4) years, with a male predominance (72.2%). Forty five patients (50%) improved LVEF (Group-1,HFimpEF) and forty five patients (50%) sustained reduced LVEF (Group-2,HFsrEF). The mean time to LVEF improvement in Group-1 was 12.6(5.7) months. Group-1 had a more favorable clinical profile: lower prevalence of cardiovascular risk factors, higher prevalence of de novo HF (75.6% vs. 42.2%; p<0.05), lower prevalence of ischemic etiology (22.2% vs. 42.2%; p<0.05), with less basal dilatation of the left ventricle. At the end of follow-up (mean 19(1) months) Group-1 had a lower hospital readmission rate (3.1% vs. 26.7%; p<0.01), as well as lower mortality (0% vs. 24.4%; p<0.01). CONCLUSION: Patients with HFimpEF seem to have a better mid-term prognosis in terms of reduced mortality and hospital admissions. This improvement could be conditioned by the clinical profile of patients HFimpEF.

Risk scores for predicting incident heart failure admission in patients with chronic coronary syndromes: Validation in a prospective, monocentric, long-term, cohort study.

BACKGROUND: Heart failure (HF) admission in chronic coronary syndrome (CCS) patients has a prognostic impact. Stratification schemes have been described for predicting this endpoint, but none of them has been externally validated. OBJECTIVES: Our aim was to develop point scores for predicting incident HF admission with data from previous studies, to perform an external validation in an independent prospective cohort and to compare their discriminative ability for this event. METHODS: Independent predictive variables of HF admission in CCS patients without baseline HF were selected from four previous prospective studies (CARE, PEACE, CORONOR and CLARIFY), generating scores based on the relative magnitude of the coefficients of Cox of each variable. Finally, the scores were validated and compared in a monocentric prospective cohort. RESULTS: The validation cohort included 1212 patients followed for up to 17 years, with 171 patients suffering at least one HF admission in the follow-up. Discriminative ability for predicting HF admission was statistically significant for all, and paired comparisons among them were all nonsignificant except for CORONOR score was superior to CLARIFY score (C-statistic 0.73, 95%CI 0.69-0.76 vs. 0.69, 95% CI 0.65-0.73; p = 0.03). CONCLUSION: All tested scores showed significant discriminative ability for predicting incident HF admission in this independent validation study. Their discriminative ability was similar, with significant differences only between the two scores with higher and lower performance.

Long-Term Prognostic Impact of Sex in Patients with Chronic Coronary Syndrome: A 17-Year Prospective Cohort Study.

Background: Women and men with chronic coronary syndrome (CCS) have different clinical features and management, and studies on mid-term prognosis have reported conflicting results. Our objective was to investigate the impact of the female sex in the prognosis of the disease in the very long term. Methods and Results: We investigated differential features and very long-term prognosis in 1268 consecutive outpatients with CCS (337 [27%] women and 931 [73%] men). Women were older than men, more likely to have hypertension, diabetes, angina, and atrial fibrillation, and less likely to be exsmoker/active smoker and to have been treated with coronary revascularization (p < 0.05 for all). The prescription of statins, antiplatelets, and betablockers was similar in both groups. After up to 17 years of follow-up (median = 11 years, interquartile range = 4-15 years), cumulative incidences of acute myocardial infarction (10.2% vs. 11.8%) or stroke (11% vs. 10%) at median follow-up were similar, but the risks of major cardiovascular events (acute myocardial infarction, stroke, or cardiovascular death, 41.2% vs. 33.6%), hospital admission for heart failure (20.9% vs. 11.9%), or cardiovascular death (32.3% vs. 22.1%) were significantly higher for women (p < 0.0005), with a nonsignificant trend to higher overall mortality (45.2% vs. 39.1%, p = 0.07). However, after multivariate adjustment, all these differences disappeared. Conclusion: Although women and men with CCS presented a different clinical profile, and crude rates of major cardiovascular events, heart failure and cardiovascular death were higher in women, female sex was not an independent prognostic factor in this study with up to 17 years of follow-up.

Health System Decentralization: Creating as Many Problems Than It Solves? Comment on "The Effects of Health Sector Fiscal Decentralisation on Availability, Accessibility, and Utilisation of Healthcare Services: A Panel Data Analysis".

This comment draws on the study by Rotulo et al about the effects of fiscal decentralization on access, utilization and availability of healthcare resources across Italian regions. We start by discussing the recent trends in health system decentralization worldwide, and then reflect on the rationale and main benefits and the key complexities and challenges of this much debated reform. We address these issues with reference to the recent experience of Italy as well as that of other comparable highly decentralized countries, most notably Spain, paying particular attention to their similarities and contrasts. We conclude that decentralization of health services poses complex challenges and trade-offs which may require careful design of equalisation mechanisms, framework regulation and efficient coordination mechanisms by central and sub central governments.

Waiting times in healthcare: equal treatment for equal need?

BACKGROUND: In many universal health systems, waiting times act as a non-monetary rationing mechanism, one that should be based on clinical need rather than the ability to pay. However, there is growing evidence that among patients with similar levels of need, waiting times often differ according to socioeconomic status. The mechanisms underlying inequality in access remain unclear. METHODS: Using data for Spain, we study whether waiting times for primary and specialist care depend on patients' socioeconomic status (SES). Additionally, we make use of the continuous nature of our data to explore whether the SES-related differences in waiting times found for specialist consultations vary among different points of the waiting time distribution. RESULTS: Our results reveal the presence of a SES gradient in waiting times for specialist services explained on the basis of education, employment status and income. In addition, for primary care, we found evidence of a slightly more moderate SES gradient mostly based on employment status. Furthermore, although quantile regression estimates indicated the presence of a SES gradient within the distribution of waiting times for specialist visits, the SES differences attenuated in the context of longer waiting times in the public sector but did not disappear. CONCLUSION: Our findings suggest the principle of equal treatment for equal need, assumed to be inherent to national health systems such as the Spanish system, is not applied in practice. Determining the mechanism(s) underlying this selective barrier to healthcare is of crucial importance for policymakers, especially in the current COVID-19 health and economic crises, which could exacerbate these inequalities as increasing numbers of treatments are having to be postponed.

Does health information affect lifestyle behaviours? The impact of a diabetes diagnosis.

Despite an increasing interest in the effect of health information on health-behaviours, evidence on the causal impact of a diagnosis on lifestyle factors is still mixed and does not often account for long-term effects. We explore the role of health information in individual health-related decisions by identifying the causal impact of a type-2 diabetes diagnosis on body mass index (BMI) and lifestyle behaviours. We employ a fuzzy regression discontinuity design (RDD) exploiting the exogenous cut-off value in the diagnosis of type-2 diabetes provided by a biomarker (glycated haemoglobin) drawn from unique administrative longitudinal data from Spain. We find that following a type-2 diabetes diagnosis individuals appear to reduce their weight in the short-term. Differently from previous studies, we also provide evidence of statistically significant long-term impacts of a type-2 diabetes diagnosis on BMI up to three years from the diagnosis. We do not find perceivable effects of a type-2 diabetes diagnosis on quitting smoking or drinking. Overall, health information appears to have a sustained causal impact on weight reduction, a key lifestyle and risk factor among individuals with type-2 diabetes.

Freedom of choice and health services' performance: Evidence from a national health system.

Public policies fostering the freedom of choice of provider in the healthcare sector are increasingly common in many countries and regions, where policymakers wish to empower patients and improve health service performance. However, in the literature there is not clear consensus about the impact of expanded patient choice on healthcare quality yet. This study investigates whether increasing patients' freedom of choice influences health system outcomes in terms of various non-clinical aspects of care, a dimension often overlooked by researchers in this field. Our study considers a "natural experiment" that took place within the Spanish National Health System in 2009 under which citizens of the Community (region) of Madrid were allowed to freely choose among any GP and/or specialist in their region. The empirical analysis was conducted by using Spanish microdata for the period 2002-2016 and used synthetic control estimation techniques. The key findings show the reform had a strong and long-lasting impact, reducing average waiting times and increasing patients' satisfaction with the specialist attention received. We did not detect any statistically significant impact of the reform on the other responsiveness domains analysed. Our analysis shows that freedom of choice policies could improve health system performance if they are combined with appropriate economic incentives for health providers.

Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias.

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.

The Role of Left Atrial Longitudinal Strain in the Diagnosis of Acute Cellular Rejection in Heart Transplant Recipients.

Our aim was to investigate the role of left atrial longitudinal strain (LALS) in the non-invasive diagnosis of acute cellular rejection (ACR) episodes in heart transplant (HTx) recipients. Methods: We performed successive echocardiographic exams in 18 consecutive adult HTx recipients in their first year after HTx within 3 h of the routine surveillance endomyocardial biopsies (EMB) in a single center. LALS parameters were analyzed with two different software. We investigated LALS association with ACR presence, as well as inter-vendor variability in comparable LALS values. Results: A total of 147 pairs of EMB and echo exams were carried out. Lower values of LALS were significantly associated with any grade of ACR presence. Peak atrial longitudinal strain (PALS) offered the best diagnostic value for any grade of ACR, with a C statistic of 0.77 using one software (95% CI 0.68−0.84, p < 0.0005) and 0.64 with the other (95% CI 0.54−0.73, p = 0.013) (p = 0.02 for comparison between both curves). Reproducibility between comparable LALS parameters was poor (intraclass correlation coefficients were 0.60 for PALS, 95% CI 0.42−0.73, p < 0.0005; and 0.42 for PALS rate, 95% CI −0.13−0.68, p < 0.0005). Conclusions: LALS variables might be a sensitive marker of ACR in HTx recipients, principally discriminating between those studies without rejection and those with any grade of ACR. Inter-vendor variability was significant.

Effect of the COVID-19 pandemic on depression in older adults: A panel data analysis.

BACKGROUND: This paper investigates the impact of the COVID-19 pandemic on depression in the older population, an especially vulnerable group for which to date there is limited empirical research. METHODS: We employ a panel data consisting of seven waves of the English Longitudinal Study of Ageing (2010-2020). The breadth and depth of the data considered enabled us to control for individual fixed effects, to adjust for pre-pandemic trends in depression levels and to perform a heterogeneity analysis, depending on the intensity of the lockdown measures implemented and relevant socioeconomic characteristics. RESULTS: We find that, following the COVID-19 pandemic, study participants reported a statistically significant increase in the depressive symptoms by around 0.7 over 8 points as measured by the Centre for Epidemiologic Studies Depression (CES-D) index. The estimated coefficients were larger in November than in July, for individuals who lost their job, retired and women. Interestingly, we observed that mental health has worsened substantially relative to the pre-pandemic period across all income groups of the older population, suggesting a limited role of income as a protective mechanism for mental health. CONCLUSIONS: Our findings provide compelling evidence that depression levels amongst older adults have worsened considerably following the COVID-19 pandemic, and that factors other than income, such as social interactions, may be highly relevant for well-being in later life.

Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3.

Peroxiredoxin 3 (PRDX3) encodes a mitochondrial antioxidant protein, which is essential for the control of reactive oxygen species homeostasis. So far, PRDX3 mutations are involved in mild-to-moderate progressive juvenile onset cerebellar ataxia. We aimed to unravel the molecular bases underlying the disease in an infant suffering from cerebellar ataxia that started at 19 months old and presented severe cerebellar atrophy and peripheral neuropathy early in the course of disease. By whole exome sequencing, we identified a novel homozygous mutation, PRDX3 p.D163E, which impaired the mitochondrial ROS defense system. In mouse primary cortical neurons, the exogenous expression of PRDX3 p.D163E was reduced and triggered alterations in neurite morphology and in mitochondria. Mitochondrial computational parameters showed that p.D163E led to serious mitochondrial alterations. In transfected HeLa cells expressing the mutation, mitochondria accumulation was detected by correlative light electron microscopy. Mitochondrial morphology showed severe changes, including extremely damaged outer and inner membranes with a notable cristae disorganization. Moreover, spherical structures compatible with lipid droplets were identified, which can be associated with a generalized response to stress and can be involved in the removal of unfolded proteins. In the patient's fibroblasts, PRDX3 expression was nearly absent. The biochemical analysis suggested that the mutation p.D163E would result in an unstable structure tending to form aggregates that trigger unfolded protein responses via mitochondria and endoplasmic reticulum. Altogether, our findings broaden the clinical spectrum of the recently described PRDX3-associated neurodegeneration and provide new insight into the pathological mechanisms underlying this new form of cerebellar ataxia.

Electrocardiographic features and need for pacemaker in cardiac amyloidosis: Analysis of 58 cases. / Alteraciones electrocardiográficas y necesidad de marcapasos en amiloidosis cardiaca: análisis de 58 casos.

AIM: Amyloidosis is a disease in which amyloid fibrils can be deposited in different cardiac structures, and several electrocardiographic abnormalities can be produced by this phenomenon. The objective of this study was to describe the most common basal electrocardiographic alterations in patients diagnosed with cardiac amyloidosis (CA) and to determine if these abnormalities have an impact on the need of pacemaker. METHODS: This retrospective study included patients who had an established diagnosis of CA [light-chain cardiac amyloidosis (LA-CA) or transthyretin cardiac amyloidosis (TTR-CA)] between January 2013 and March 2021. The baseline heart rate, the percentage of patients with a pseudo-infarct pattern, low-voltage pattern or cardiac conductions disturbances, and the impact of these factors on the need of pacemaker were analysed. RESULTS: Fifty-eight patients with CA (20 with LA-CA and 38 with TTR-CA) were included, and the majority were male (69.0%). Twenty-one patients had atrial fibrillation (AF) at diagnosis. Thirty-five patients had a pseudo-infarct pattern, 35% had a low-voltage pattern, and 22% had criteria for ventricular hypertrophy. Two hirds had a conduction disorder: 18 patients with first degree atrioventricular block, 12 right bundle branch block, 3 left bundle branch block and 25 with a branch hemiblock. There were no differences between LA-CA and TTR-CA. Patients with TTR-CA had a greater need for pacemakers in the folow-up (39±40 meses). Bundle branch block was a predictor of the need for a permanent pacemaker (HR: 23.43; CI 95%: 4.09.134.09; P=.01). CONCLUSIONS: Electrocardiographic abnormalities in patients diagnosed wich CA are heterogeneus. Most frecuent is the presence of conduction disorders, the pseudoinfarction pattern, followed by the low voltage pattern. Patients with any bundle branch block at the baseline electrocardiogram need more frecuent to require a pacemaker during follow-up, especially in TTR-CA.