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Background Alpha-1 antitrypsin deficiency (AATD) is a rare disease that is associated with an increased risk of pulmonary emphysema. The European AATD Research Collaboration (EARCO) international registry was founded with the objective of characterising the individuals with AATD and investigating their natural history. Methods The EARCO registry is an international, observational and prospective study of individuals with AATD, defined as AAT serum levels < 11 μM and/or proteinase inhibitor genotypes PI*ZZ, PI*SZ and compound heterozygotes or homozygotes of other rare deficient variants. We describe the characteristics of the individuals included from February 2020 to May 2022. Results A total of 1044 individuals from 15 countries were analysed. The most frequent genotype was PI*ZZ (60.2%), followed by PI*SZ (29.2%). Among PI*ZZ patients, emphysema was the most frequent lung disease (57.2%) followed by COPD (57.2%) and bronchiectasis (22%). Up to 76.4% had concordant values of FEV1(%) and KCO(%). Those with impairment in FEV1(%) alone had more frequently bronchiectasis and asthma and those with impairment in KCO(%) alone had more frequent emphysema and liver disease. Multivariate analysis showed that advanced age, male sex, exacerbations, increased blood platelets and neutrophils, augmentation and lower AAT serum levels were associated with worse FEV1(%). Conclusions EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registration www.clinicaltrials.gov (ID: NCT04180319)

Quantifying physical activity in chronic obstructive pulmonary disease (COPD) with questionnaires and activity monitors in clinical practice is challenging. The aim of the present study was to analyse the discriminant validity of a single clinical question for the screening of inactive individuals living with COPD. A multicentre study was carried out in stable COPD individuals both in primary and tertiary care. Patients wore the accelerometer for 8 days and then answered 5 physical activity questions developed for the study, referring to the week in which their physical activity was monitored. Receiver operating characteristic (ROC) curve analysis with physical activity level (PAL) as the gold standard reference was used to determine the best cut-off point for each of the 5 clinical physical activity questions tested. A total of 86 COPD participants were analysed (males 68.6%; mean (SD) age 66.6 (8.5) years; FEV 50.9 (17.3)% predicted; mean of 7305 (3906) steps/day). Forty-two (48.8%) participants were considered physically inactive (PAL ≤1.69). Answers to 4 out of 5 questions significantly differed in active vs inactive patients. The Kappa index and ROC curves showed that the answer to the question \"On average, how many minutes per day do you walk briskly?\" had the best discriminative capacity for inactivity, with an area under the curve (AUC) (95% Confidence interval (CI)) of 0.73 (0.63-0.84) and 30 min/day was identified as the best cut-off value (sensitivity (95% CI): 0.75 (0.60-0.87); specificity: 0.76 (0.61-0.88)). The present results indicate that self-reported brisk walk time lower than 30 min/day may be a valid tool for the screening of inactivity in individuals living with COPD in routine care, if more detailed physical activity measures are not feasible.

Background Control in COPD is a dynamic concept that can reflect changes in patients’ clinical status that may have prognostic implications, but there is no information about changes in control status and its long-term consequences. Methods We classified 798 patients with COPD from the CHAIN cohort as controlled/uncontrolled at baseline and over 5 years. We describe the changes in control status in patients over long-term follow-up and analyze the factors that were associated with longitudinal control patterns and related survival using the Cox hazard analysis. Results 134 patients (16.8%) were considered persistently controlled, 248 (31.1%) persistently uncontrolled and 416 (52.1%) changed control status during follow-up. The variables significantly associated with persistent control were not requiring triple therapy at baseline and having a better quality of life. Annual changes in outcomes (health status, psychological status, airflow limitation) did not differ in patients, regardless of clinical control status. All-cause mortality was lower in persistently controlled patients (5.5% versus 19.1%, p = 0.001). The hazard ratio for all-cause mortality was 2.274 (95% CI 1.394–3.708; p = 0.001). Regarding pharmacological treatment, triple inhaled therapy was the most common option in persistently uncontrolled patients (72.2%). Patients with persistent disease control more frequently used bronchodilators for monotherapy (53%) at recruitment, although by the end of the follow-up period, 20% had scaled up their treatment, with triple therapy being the most frequent therapeutic pattern. Conclusions The evaluation of COPD control status provides relevant prognostic information on survival. There is important variability in clinical control status and only a small proportion of the patients had persistently good control. Changes in the treatment pattern may be relevant in the longitudinal pattern of COPD clinical control. Further studies in other populations should validate our results. Trial registration: Clinical Trials.gov: identifier NCT01122758.

The α-1 antitrypsin (AAT) protease inhibitor PiMZ is a moderately deficient genotype, until recently considered of little or negligible risk. However, a growing number of studies show that MZ carriers have an increased risk of developing lung and liver diseases, if exposed to smoking or other airborne or industrial pollutants, and hepatotoxic substances. We used the epidemiological studies performed to determine the frequencies of PiM and PiZ worldwide, based on the following criteria: 1) samples representative of the general population; 2) AAT phenotyping or genotyping characterized by adequate methods, including isoelectric focusing and polymerase chain reaction; and 3) studies with reliable results assessed with a coefficient of variation calculated from the sample size and 95% confidence intervals, to measure the precision of the results in terms of dispersion of the data around the mean. The present review reveals an impressive number of MZs of more than 35 million in 74 countries of the world with available data. Seventy-five percent of them are people of Caucasian European heritage, mostly living in Europe, America, Australia and New Zealand. Twenty percent of the remaining MZs live in Asia, with the highest concentrations in the Middle East, Eastern¸ Southern, and South-eastern regions of the Asian continent. The remaining five percent are Africans residing in Western and Eastern Africa. Considering the high rate of smoking, the outdoor and the indoor air pollution from solid fuels used in cooking and heating, and the exposure to industrial dusts and chemicals in many of these countries, these figures are very worrying, and hence the importance of adequately assessing MZ subjects, recommending them rigorous preventive measures based on the adoption of healthy lifestyles, including avoidance of smoking and alcohol.

A spinal cord injury usually spares some components of the locomotor circuitry. Deep brain stimulation (DBS) of the midbrain locomotor region and epidural electrical stimulation of the lumbar spinal cord (EES) are being used to tap into this spared circuitry to enable locomotion in humans with spinal cord injury. While appealing, the potential synergy between DBS and EES remains unknown. Here, we report the synergistic facilitation of locomotion when DBS is combined with EES in a rat model of severe contusion spinal cord injury leading to leg paralysis. However, this synergy requires high amplitudes of DBS, which triggers forced locomotion associated with stress responses. To suppress these undesired responses, we link DBS to the intention to walk, decoded from cortical activity using a robust, rapidly calibrated unsupervised learning algorithm. This contingency amplifies the supraspinal descending command while empowering the rats into volitional walking. However, the resulting improvements may not outweigh the complex technological framework necessary to establish viable therapeutic conditions. Deep brain stimulation and epidural electrical stimulation of the spinal cord enable locomotion in humans with spinal cord injury (SCI) but the potential synergy between both approaches is unclear. The authors show that a complex technological approach is required to enable volitional walking in rats with SCI.

Neurons in the pedunculopontine nucleus (PPN) exhibit a wide heterogeneity in terms of their neurochemical nature, their discharge properties, and their connectivity. Such characteristics are reflected in their functional properties and the behaviors in which they are involved, ranging from motor to cognitive functions, and the regulation of brain states. A clue to understand this functional versatility arises from the internal organization of the PPN. Thus, two main areas of the PPN have been described, the rostral and the caudal, which display remarkable differences in terms of the distribution of neurons with similar phenotype and the projections that originate from them. Here we review these differences with the premise that in order to understand the function of the PPN it is necessary to understand its intricate connectivity. We support the case that the PPN should not be considered as a homogeneous structure and conclude that the differences between rostral and caudal PPN, along with their intrinsic connectivity, may underlie the basis of its complexity.

Lung cancer (LC) is the leading cause of cancer deaths, and chronic obstructive pulmonary disease (COPD) can increase LC risk. Metallomics may provide insights into both of these tobacco-related diseases and their shared etiology. We conducted an observational study of 191 human serum samples, including those of healthy controls, LC patients, COPD patients, and patients with both COPD and LC. We found 18 elements (V, Al, As, Mn, Co, Cu, Zn, Cd, Se, W, Mo, Sb, Pb, Tl, Cr, Mg, Ni, and U) in these samples. In addition, we evaluated the elemental profiles of COPD cases of varying severity. The ratios and associations between the elements were also studied as possible signatures of the diseases. COPD severity and LC have a significant impact on the elemental composition of human serum. The severity of COPD was found to reduce the serum concentrations of As, Cd, and Tl and increased the serum concentrations of Mn and Sb compared with healthy control samples, while LC was found to increase Al, As, Mn, and Pb concentrations. This study provides new insights into the effects of LC and COPD on the human serum elemental profile that will pave the way for the potential use of elements as biomarkers for diagnosis and prognosis. It also sheds light on the potential link between the two diseases, i.e., the evolution of COPD to LC.

Working in coal mines is a risk factor for pneumoconiosis and COPD. There still exist, however, doubts and debates about the risk involved in such work for tuberculosis and lung cancer. The aim of this study was to clarify some of these uncertainties through the study of a cohort group. The cohort comprises 2,579 miners. An initial medical examination was carried out when they began to work in the mine, and three further examinations were performed over the 20 years of the study. The follow-up failure rate was 23.7%. Ninety-nine workers (3.8%) developed round opacities (category 1) that were significantly related to the kind of work in a crude analysis (p = 0.045), with a greater frequency (7.3%) among rock workers, who have greater exposure to silica, and were almost significantly related to tobacco use (p = 0.092). These round opacities also show a significant relation to smoking, being more frequent (4.9%) among smokers, both in the crude analysis (p = 0.028) and in the multivariable analysis (p = 0.001) controlling for rock work. In 240 workers (12.7%), accelerated FEV1 decreases were observed with significant relations to tobacco use (p = 0.001) and rock work (p = 0.044). Pulmonary tuberculosis was diagnosed in four cases, with an incidence of eight in 105 person-years. This rate falls within the limits expected for the region. No case of lung cancer was observed. In summary, our results showed the following: round opacities (category 1) were related to smoking and, probably, to rock work; accelerated FEV1 decreases were related to rock work and tobacco consumption. There was no identified increase in tuberculosis or lung cancer in this cohort.

Background Although bronchiectasis has been recognised as a feature of some patients with Alpha1-Antitrypsin deficiency the prevalence and characteristics are not widely known. We wished to determine the prevalence of bronchiectasis and patient characteristics. The first cohort of patients recruited to the EARCO (European Alpha1 Research Collaboration) International Registry data base by the end of 2021 was analysed for radiological evidence of both emphysema and bronchiectasis as well as baseline demographic features. Results Of the first 505 patients with the PiZZ genotype entered into the data base 418 (82.8%) had a reported CT scan. There were 77 (18.4%) with a normal scan and 38 (9.1%) with bronchiectasis alone. These 2 groups were predominantly female never smokers and had lung function in the normal range. The remaining 303 (72.5%) ZZ patients all had emphysema on the scan and 113 (27%) had additional evidence of bronchiectasis. Conclusions The data indicates the bronchiectasis alone is a feature of 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency but although emphysema is the dominant lung pathology bronchiectasis is also present in 27% of emphysema cases and may require a different treatment strategy.