Long-term follow-up of renal function in patients treated with migalastat for Fabry disease

The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)-naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m 2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m 2) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFR were − 1.6 mL/min/1.73 m 2 overall and − 1.8 mL/min/1.73 m 2 and − 1.4 mL/min/1.73 m 2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFR were − 1.6 mL/min/1.73 m 2 overall and − 2.6 mL/min/1.73 m 2 and − 0.8 mL/min/1.73 m 2 in male and female patients, respectively. Mean annualized rate of change in eGFR in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was −1.7 mL/min/1.73 m 2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFR change was minimal (mean: −0.1 and 0.1 mL/min/1.73 m 2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype

Functional Implications of Human-Specific Changes in Great Ape microRNAs

microRNAs are crucial post-transcriptional regulators of gene expression involved in a wide range of biological processes. Although microRNAs are highly conserved among species, the functional implications of existing lineage-specific changes and their role in determining differences between humans and other great apes have not been specifically addressed. We analyzed the recent evolutionary history of 1,595 human microRNAs by looking at their intra-and inter-species variation in great apes using high-coverage sequenced genomes of 82 individuals including gorillas, orangutans, bonobos, chimpanzees and humans. We explored the strength of purifying selection among microRNA regions and found that the seed and mature regions are under similar and stronger constraint than the precursor region. We further constructed a comprehensive catalogue of microRNA species-specific nucleotide substitutions among great apes and, for the first time, investigated the biological relevance that human-specific changes in microRNAs may have had in great ape evolution. Expression and functional analyses of four microRNAs (miR-299-3p, miR-503-3p, miR508-3p and miR-541-3p) revealed that lineage-specific nucleotide substitutions and changes in the length of these microRNAs alter their expression as well as the repertoires of target genes and regulatory networks. We suggest that the studied molecular changes could have modified crucial microRNA functions shaping phenotypes that, ultimately, became human-specific. Our work provides a frame to study the impact that regulatory changes may have in the recent evolution of our species.Peer reviewe

Factors affecting the relationship between psychological status and quality of life in COPD patients

<p>Abstract</p> <p>Background</p> <p>This study aims to (i) evaluate the association between anxiety and depressive symptoms and health-related quality of life (HRQoL); and (ii) identify the effect modifiers of this relationship in patients with chronic obstructive pulmonary disease (COPD).</p> <p>Methods</p> <p>A total of 337 clinically stable COPD patients answered the St. George's Respiratory Questionnaire (SGRQ) (assessing HRQoL) and the Hospital Anxiety and Depression Scale (HADS). Socio-demographic information, lung function, and other clinical data were collected.</p> <p>Results</p> <p>Most patients (93%) were male; they had a mean (SD) age of 68 (9) years and mild to very severe COPD (post-bronchodilator FEV₁52 (16)% predicted). Multivariate analyses showed that anxiety, depression, or both conditions were associated with poor HRQoL (for all SGRQ domains). The association between anxiety and total HRQoL score was 6.7 points higher (indicating a worse HRQoL) in current workers than in retired individuals. Estimates for patients with "both anxiety and depression" were 5.8 points lower in stage I-II than in stage III-IV COPD, and 10.2 points higher in patients with other comorbidities than in those with only COPD.</p> <p>Conclusions</p> <p>This study shows a significant association between anxiety, depression, or both conditions and impaired HRQoL. Clinically relevant factors affecting the magnitude of this association include work status, COPD severity, and the presence of comorbidities.</p

Impact of high-flow oxygen therapy during exercise in idiopathic pulmonary fibrosis: a pilot crossover clinical trial

[Background] Supplemental oxygen delivered with standard oxygen therapy (SOT) improves exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). Although high-flow nasal cannula oxygen therapy (HFNC) improves oxygenation in other respiratory diseases, its impact on exercise performance has never been evaluated in IPF patients. We hypothesized that HFNC may improve exercise capacity in IPF subjects compared to SOT.[Methods] This was a prospective, crossover, pilot randomized trial that compared both oxygenation methods during a constant submaximal cardiopulmonary exercise test (CPET) in IPF patients with exertional oxygen saturation (SpO2) ≤ 85% in the 6-min walking test. The primary outcome was endurance time (Tlim). Secondary outcomes were muscle oxygen saturation (StO2) and respiratory and leg symptoms.[Results] Ten IPF patients [71.7 (6) years old, 90% males] were included. FVC and DLCO were 58 ± 11% and 31 ± 13% pred. respectively. Tlim during CPET was significantly greater using HFNC compared to SOT [494 ± 173 vs. 381 ± 137 s, p = 0.01]. HFNC also associated with a higher increase in inspiratory capacity (IC) [19.4 ± 14.2 vs. 7.1 ± 8.9%, respectively; p = 0.04], and a similar trend was observed in StO2 during exercise. No differences were found in respiratory or leg symptoms between the two oxygen devices.[Conclusions] This is the first study demonstrating that HFNC oxygen therapy improves exercise tolerance better than SOT in IPF patients with exertional desaturation. This might be explained by changes in ventilatory mechanics and muscle oxygenation. Further and larger studies are needed to confirm the benefits of HFNC in IPF patients and its potential usefulness in rehabilitation programs.This study has been funded by SEPAR 2017 (Fellowship) and Rio Hortega; ISCIII (Project and fellowship).Peer reviewe

Validation of walking trails for the Urban Training of chronic obstructive pulmonary disease patients.

Purpose Accessible interventions to train patients with chronic obstructive pulmonary disease (COPD) are needed. We designed urban trails of different intensities (low, moderate and high) in different types of public spaces (boulevard, beach and park). We aimed to validate the trails' design by assessing the physiological response to unsupervised walking trails of: (1) different intensities in COPD patients, and (2) same intensity from different public spaces in healthy adults. Methods On different days and under standardized conditions, 10 COPD patients walked the three intensity trails designed in a boulevard space, and 10 healthy subjects walked the three intensity trails in three different spaces. We measured physiological response and energy expenditure using a gas analyzer. We compared outcomes across trails intensity and/or spaces using mixed-effects linear regression. Results In COPD patients, physiological response and energy expenditure increased significantly according to the trails intensity: mean (SD) peak O2 15.9 (3.5), 17.4 (4.7), and 17.7 (4.4) mL/min/kg (p-trend = 0.02), and MET-min 60 (23), 64 (26), 72 (31) (p-trend<0.01) in low, moderate and high intensity trails, respectively. In healthy subjects there were no differences in physiological response to walking trails of the same intensity across different spaces. Conclusions We validated the trails design for the training of COPD patients by showing that the physiological response to and energy expenditure on unsupervised walking these trails increased according to the predefined trails' intensity and did not change across trails of the same intensity in different public space. Walkable public spaces allow the design of trails that could be used for the training of COPD patients in the community

Predictors and changes of physical activity in idiopathic pulmonary fibrosis

Background Different clinical predictors of physical activity (PA) have been described in idiopathic pulmonary fibrosis (IPF), but studies are lacking evaluating the potential role of muscle strength and anxiety and depression symptoms in PA limitation. Moreover, little is known about the impact of changes in PA in the course of the disease. The aim of the present study was to investigate the relationship between baseline PA and a wide range of variables in IPF, to assess its longitudinal changes at 12 months and its impact on progression free-survival. Methods PA was assessed by accelerometer and physiological, clinical, psychological factors and health-related quality of life were evaluated in subjects with IPF at baseline and at 12 month follow-up. Predictors of PA were determined at baseline, evolution of PA parameters was described and the prognostic role of PA evolution was also established. Results Forty participants with IPF were included and 22 completed the follow-up. At baseline, subjects performed 5765 (3442) daily steps and spent 64 (44) minutes/day in moderate to vigorous PA. Multivariate regression models showed that at baseline, a lower six-minute walked distance, lower quadriceps strength (QMVC), and a higher depression score in the Hospital Anxiety and Depression scale were associated to lower daily step number. In addition, being in (Gender-Age-Physiology) GAP III stage, having a BMI >= 25 kg/m(2) and lower QMVC or maximum inspiratory pressure were factors associated with sedentary behaviour. Adjusted for age, gender and forced vital capacity (FVC) (%pred.) a lower progression-free survival was evidenced in those subjects that decreased PA compared to those that maintained, or even increased it, at 12 months [HR 12.1 (95% CI, 1.9-78.8); p = 0.009]. Conclusion Among a wide range of variables, muscle strength and depression symptoms have a predominant role in PA in IPF patients. Daily PA behaviour and its evolution should be considered in IPF clinical assessment and as a potential complementary indicator of disease prognosis

Changes in the stool and oropharyngeal microbiome in obsessive-compulsive disorder

Although the etiology of obsessive-compulsive disorder (OCD) is largely unknown, it is accepted that OCD is a complex disorder. There is a known bi-directional interaction between the gut microbiome and brain activity. Several authors have reported associations between changes in gut microbiota and neuropsychiatric disorders, including depression or autism. Furthermore, a pediatric-onset neuropsychiatric OCD-related syndrome occurs after streptococcal infection, which might indicate that exposure to certain microbes could be involved in OCD susceptibility. However, only one study has investigated the microbiome of OCD patients to date. We performed 16S ribosomal RNA gene-based metagenomic sequencing to analyze the stool and oropharyngeal microbiome composition of 32 OCD cases and 32 age and gender matched controls. We estimated different α- and β-diversity measures and performed LEfSe and Wilcoxon tests to assess differences in bacterial distribution. OCD stool samples showed a trend towards lower bacterial α-diversity, as well as an increase of the relative abundance of Rikenellaceae, particularly of the genus Alistipes, and lower relative abundance of Prevotellaceae, and two genera within the Lachnospiraceae: Agathobacer and Coprococcus. However, we did not observe a different Bacteroidetes to Firmicutes ratio between OCD cases and controls. Analysis of the oropharyngeal microbiome composition showed a lower Fusobacteria to Actinobacteria ratio in OCD cases. In conclusion, we observed an imbalance in the gut and oropharyngeal microbiomes of OCD cases, including, in stool, an increase of bacteria from the Rikenellaceae family, associated with gut inflammation, and a decrease of bacteria from the Coprococcus genus, associated with DOPAC synthesis

Natural Course of the Diffusing Capacity of the Lungs for Carbon Monoxide in COPD: Importance of Sex

[Background] The value of the single-breath diffusing capacity of the lungs for carbon monoxide (Dlco) relates to outcomes for patients with COPD. However, little is known about the natural course of Dlco over time, intersubject variability, and factors that may influence Dlco progression.[Research Question] What is the natural course of Dlco in patients with COPD over time, and which other factors, including sex differences, could influence this progression?[Study Design and Methods] We phenotyped 602 smokers (women, 33%), of whom 506 (84%) had COPD and 96 (16%) had no airflow limitation. Lung function, including Dlco, was monitored annually over 5 years. A random coefficients model was used to evaluate Dlco changes over time.[Results] The mean (± SE) yearly decline in Dlco % in patients with COPD was 1.34% ± 0.015%/y. This was steeper compared with non-COPD control subjects (0.04% ± 0.032%/y; P = .004). Sixteen percent of the patients with COPD, vs 4.3% of the control subjects, had a statistically significant Dlco % slope annual decline (4.14%/y). At baseline, women with COPD had lower Dlco values (11.37% ± 2.27%; P < .001) in spite of a higher FEV1 % than men. Compared with men, women with COPD had a steeper Dlco annual decline of 0.89% ± 0.42%/y (P = .039).[Interpretation] Patients with COPD have an accelerated decline in Dlco compared with smokers without the disease. However, the decline is slow, and a testing interval of 3 to 4 years may be clinically informative. The lower and more rapid decline in Dlco values in women, compared with men, suggests a differential impact of sex in gas exchange function.[Trial Registry] ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.govThis study was funded in part by an unrestricted grant from AstraZeneca, and also by the COPD Research Program of the Spanish Respiratory Society (PII de EPOC of SEPAR).Peer reviewe

New GOLD classification: longitudinal data on group assignment

Rationale: Little is known about the longitudinal changes associated with using the 2013 update of the multidimensional GOLD strategy for chronic obstructive pulmonary disease (COPD). Objective: To determine the COPD patient distribution of the new GOLD proposal and evaluate how this classification changes over one year compared with the previous GOLD staging based on spirometry only. Methods: We analyzed data from the CHAIN study, a multicenter observational Spanish cohort of COPD patients who are monitored annually. Categories were defined according to the proposed GOLD: FEV1%, mMRC dyspnea, COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ), and exacerbations-hospitalizations. One-year follow-up information was available for all variables except CCQ data. Results: At baseline, 828 stable COPD patients were evaluated. On the basis of mMRC dyspnea versus CAT, the patients were distributed as follows: 38.2% vs. 27.2% in group A, 17.6% vs. 28.3% in group B, 15.8% vs. 12.9% in group C, and 28.4% vs. 31.6% in group D. Information was available for 526 patients at one year: 64.2% of patients remained in the same group but groups C and D show different degrees of variability. The annual progression by group was mainly associated with one-year changes in CAT scores (RR, 1.138; 95%CI: 1.074-1.206) and BODE index values (RR, 2.012; 95%CI: 1.487-2.722). Conclusions: In the new GOLD grading classification, the type of tool used to determine the level of symptoms can substantially alter the group assignment. A change in category after one year was associated with longitudinal changes in the CAT and BODE index

Riduzione delle emissioni di ammoniaca nell’agricoltura mediterranea attraverso tecniche innovative di fertirrigazione con liquami (LIFE16 ENV/ES/000400)

Esta publicación ha sido elaborada como resultado de los trabajos realizados dentro del proyecto LIFE ARIMEDA: Reducción de emisiones de amoníaco en la agricultura mediterránea a través de técnicas innovadoras de fertirrigación con purín (LIFE16 ENV/ES/000400). El proyecto LIFE ARIMEDA ha recibido fondos del Programa LIFE de la Unión Europea.Publishe