RESUMEN
Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFß pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.
RESUMEN
INTRODUCTION: Studies suggest increased likelihood of atrial fibrillation (AF) recurrence after catheter ablation (CA) in women than in men, indicating that sex may be an independent risk factor for recurrence. Nevertheless, the influence of sex on AF recurrence and underlying mechanisms remains unclear. METHODS: Retrospective, single-centre study including patients undergoing AF CA between 2017 and 2021. Late recurrence (LR) was defined as AF recurrence ≥90 days after ablation, whereas early recurrence (ER) occurred within 90 days. RESULTS: 656 patients (32% women) were included, with a median follow-up period of 26 months. Compared to men, women undergoing CA were older, had higher body mass indexes, and had higher rates of hypertension, thyroid dysfunction, and valvular disease. Women also had increased LR risk after CA (HR 1.76, 95% CI [1.19, 2.59]). A time-split multivariable analysis at one year of follow-up showed no difference in LR risk during the first 12 months after CA (HR 1.19, 95% CI [0.73, 1.94]); however, LR risk increased in women (HR 2.90, 95% CI [1.68, 5.01]) after 12 months. In a sex-stratified analysis, coronary calcium score (CCS) >100 was associated with increased LR risk in men (HR 1.81, 95% CI [1.06, 3.08]), but not in women. Cardiac adipose tissue volume was not associated with increased LR risk. CONCLUSIONS: Fewer women underwent CA than men and LR was more frequent in women, particularly one year after the procedure. CCS was associated with increased LR risk in men.
Asunto(s)
Fibrilación Atrial , Ablación por Catéter , Venas Pulmonares , Recurrencia , Humanos , Fibrilación Atrial/cirugía , Fibrilación Atrial/epidemiología , Fibrilación Atrial/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Venas Pulmonares/cirugía , Ablación por Catéter/métodos , Ablación por Catéter/efectos adversos , Ablación por Catéter/tendencias , Anciano , Factores de Riesgo , Estudios de Seguimiento , Factores Sexuales , Caracteres SexualesRESUMEN
Background Opioids have long been the cornerstone of drugs used for perioperative analgesia. Sufentanil has an advantageous pharmacological profile for its use in continuous intravenous (IV) infusion, yet remains poorly described. Our institution has implemented analgesia protocols with IV sufentanil infusions for cancer surgery with appropriate monitoring. The aim of this study was to evaluate the efficacy and safety of IV sufentanil infusion. Methods A single-center retrospective cohort study was conducted through the analysis of patients' records and the acute pain service database. Inclusion criteria were adult patients admitted for elective cancer surgery and with postoperative IV sufentanil infusion during one year period. Descriptive and inferential statistical analysis was performed by using Software SPSS Statistics (IBM Corp., Armonk USA): Kruskal-Wallis, Mann-Whitney, Chi-square and Fisher tests; Bonferroni chi-square residual analysis, binary logistic regression; p<0.05. Results The study population of 304 patients had a median age of 66 years (22-91) and 229 (75.3%) were men. 38 (12.5%) were chronic opioid users. Head and neck/otorhinolaryngology (ORL) surgery was performed in 155 (51.0%) and abdominopelvic surgery in 123 (40.5%). The median days of IV sufentanil infusion were 2 (1-13). At rest and with movement, analgesia was considered good, i.e., over 90% of patients with visual analogue scale (VAS) pain score ≤ 3. We found that patients submitted to musculoskeletal surgery had higher VAS pain scores; this group also presented older patients with higher American Society of Anesthesiologists (ASA) physical status classification and more chronic opioid users (p<0.05). 144 patients (47.4%) had at least one adverse effect related to IV sufentanil infusion, notably transient and not requiring any specific treatment. These patients were older and had longer infusion periods (p<0.05). 237 (98.3%) of the adverse effects occurred during the first 3 days and the most common were: sedation (n=104, 42.8%), hypotension (n=32, 13.2%), hypoxemia (n=31, 12.8%) and nausea/vomiting (n=25, 10.3%). The reported incidence of respiratory depression was 2.9% (n=9), with three patients (1%) requiring advanced treatment. Conclusion Multimodal analgesic protocols with IV sufentanil infusions provided good postoperative analgesia for head and neck/ORL and abdominopelvic cancer surgeries. The adverse effects associated with the IV sufentanil infusions were mild and mainly managed with opioid dose reductions. Our study showed that this approach can be a safe option for postoperative multimodal analgesia in cancer surgery with appropriate monitoring in high-dependency units.
RESUMEN
Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with high morbidity and increasing socio-economic burden, compounded by the lack of effective treatment options available to treat this disease. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have previously been shown to improve cardiovascular and renal outcomes in patients with type 2 diabetes and patients with heart failure with reduced ejection fraction (HFrEF). Recent major clinical trials with SGLT2 inhibitors, both empagliflozin and dapagliflozin, have now demonstrated improved cardiovascular outcomes in patients with HFpEF and a significant reduction in heart failure hospitalization. Current evidence shows a potential for cardiovascular benefits with SGLT2 inhibition that is consistent across the spectrum of ejection fraction, age, New York Heart Association (NYHA) functional class, natriuretic peptide levels and diabetes status. Although the cardioprotective mechanisms behind SGLT2 inhibition remain unclear, ongoing clinical studies aim to clarify the role of SGLT2 inhibitors on biomarkers of cardiac metabolism, diastolic function and exercise capacity in HFpEF. This article analyzes current clinical evidence from randomized controlled trials and meta-analyses and explores the potential cardioprotective mechanisms of SGLT2 inhibitors, while also looking towards the future of SGLT2 inhibition in HFpEF.
RESUMEN
BACKGROUND: Fibrotic hypersensitivity pneumonitis (fHP) is associated with significant morbidity and mortality. Interstitial lung disease-gender-age-physiology (ILD-GAP) performance in fHP outside the initial cohort was never performed. AIM: To assess the ILD-GAP index's ability to predict mortality in a Portuguese cohort of patients with fHP and analyse whether other clinical variables add value. METHODS: Retrospective analysis of fHP cohort in two Portuguese ILD centres. The baseline ILD-GAP index was calculated. Survival was analysed in months; mortality was the primary outcome. Univariate and multivariate analyses to identify mortality risk factors were performed. RESULTS: A total of 141 patients were included. Fifty-three patients (37.6%) died during the follow-up. The usual interstitial pneumonia (UIP) pattern was found in 49.6%, and their survival was inferior to non-UIP [32 months (interquartile range, IQR = 19, 60) versus 52 months (IQR = 28, 98), p = 0.048]. Patients with an ILD-GAP index higher than three double their risk of mortality [hazard ratio (HR) = 6.48, 95% confidence interval (CI) = (3.03-13.96)] when compared with the patients with an index between 2 and 3 [HR = 3.04, 95% CI = (1.62-5.71)] adjusting for acute exacerbation history. Even though UIP patients had worse survival, it did not reach statistical significance when UIP pattern was added to this model. Acute exacerbation history was an independent risk factor for mortality; however, ILD-GAP still predicted mortality after adjusting for this factor. PaO2 and 6-minute walk test desaturation were not significant risk factors. CONCLUSION: ILD-GAP index is a good predictor for mortality in fHP, even after adjusting for other mortality risk factors.
Asunto(s)
Alveolitis Alérgica Extrínseca , Enfermedades Pulmonares Intersticiales , Humanos , Estudios Retrospectivos , Alveolitis Alérgica Extrínseca/diagnósticoRESUMEN
INTRODUCTION: Approximately 500.000 people in Europe sustain cardiac arrest (CA) every year, being myocardial infarction the main etiology. Interest has been raised in a new approach to refractory cardiac arrest (rCA) using extra-corporeal oxygenation (ECMO). In settings where it can be rapidly implemented, ECMO assisted resuscitation (ECPR) may be considered. Additionally, donation after circulatory death, which seeks to obtain solid organs donation from patients suffering rCA, has increased its role effectively increasing the pool of donors. Combined programs with integration of ECPR and uncontrolled donation after circulatory determination of death (uDCDD) are worldwide limited and experience integrating these two techniques is lacking. METHODS: We report a 24 months experience of ECPR and uDCDD kidney transplantation based on a management protocol in a university teaching hospital in the urban area of Lisbon. RESULTS: Over a period of 24 months, 58 patients were admitted to our ICU with rCA, 6 (10%) in the ECPR program and 52 (90%) in the uDCDD. Seventy-eight percent of patients were male, with an average age of 49 year-old. CA was witnessed in 83% of cases and initial rhythm was ventricular fibrillation in 20 cases (35%). 13 (25%) patients were effective organ donors. Refusal for effective donation was mainly due to prior comorbidities. DISCUSSION: The development of an integrated program for ECPR and uDCDD is feasible and requires a well-established and efficient activation program. In an era of significant organ shortage, it provides a viable option for increasing the organ donation pool, with promising results.
RESUMEN
Lung cancer is a highly prevalent pathology and a leading cause of cancer-related deaths. Most patients are diagnosed when the disease has manifested itself, which usually is a sign of lung cancer in an advanced stage and, as a consequence, the 5-year survival rates are low. To increase the chances of survival, improving the cancer early detection capacity is crucial, for which computed tomography (CT) scans represent a key role. The manual evaluation of the CTs is a time-consuming task and computer-aided diagnosis (CAD) systems can help relieve that burden. The segmentation of the lung is one of the first steps in these systems, yet it is very challenging given the heterogeneity of lung diseases usually present and associated with cancer development. In our previous work, a segmentation model based on a ResNet34 and U-Net combination was developed on a cross-cohort dataset that yielded good segmentation masks for multiple pathological conditions but misclassified some of the lung nodules. The multiple datasets used for the model development were originated from different annotation protocols, which generated inconsistencies for the learning process, and the annotations are usually not adequate for lung cancer studies since they did not comprise lung nodules. In addition, the initial datasets used for training presented a reduced number of nodules, which was showed not to be enough to allow the segmentation model to learn to include them as a lung part. In this work, an objective protocol for the lung mask's segmentation was defined and the previous annotations were carefully reviewed and corrected to create consistent and adequate ground-truth masks for the development of the segmentation model. Data augmentation with domain knowledge was used to create lung nodules in the cases used to train the model. The model developed achieved a Dice similarity coefficient (DSC) above 0.9350 for all test datasets and it showed an ability to cope, not only with a variety of lung patterns, but also with the presence of lung nodules as well. This study shows the importance of using consistent annotations for the supervised learning process, which is a very time-consuming task, but that has great importance to healthcare applications. Due to the lack of massive datasets in the medical field, which consequently brings a lack of wide representativity, data augmentation with domain knowledge could represent a promising help to overcome this limitation for learning models development.
Asunto(s)
Neoplasias Pulmonares , Tomografía Computarizada por Rayos X , Diagnóstico por Computador , Humanos , Procesamiento de Imagen Asistido por Computador , Pulmón/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , TóraxRESUMEN
Advancements in the development of computer-aided decision (CAD) systems for clinical routines provide unquestionable benefits in connecting human medical expertise with machine intelligence, to achieve better quality healthcare. Considering the large number of incidences and mortality numbers associated with lung cancer, there is a need for the most accurate clinical procedures; thus, the possibility of using artificial intelligence (AI) tools for decision support is becoming a closer reality. At any stage of the lung cancer clinical pathway, specific obstacles are identified and "motivate" the application of innovative AI solutions. This work provides a comprehensive review of the most recent research dedicated toward the development of CAD tools using computed tomography images for lung cancer-related tasks. We discuss the major challenges and provide critical perspectives on future directions. Although we focus on lung cancer in this review, we also provide a more clear definition of the path used to integrate AI in healthcare, emphasizing fundamental research points that are crucial for overcoming current barriers.
RESUMEN
BACKGROUND: Chronic benzodiazepine use is a challenge in primary care practice. Protocols to support safe discontinuation are still needed, especially in countries with high utilization rates. OBJECTIVES: To evaluate the feasibility, effectiveness, and safety of a benzodiazepine discontinuation protocol in primary care setting. METHODS: Nonrandomized, single-arm interventional study, at primary care units. Family physicians (FPs) recruited patients (18-85 years-old) with benzodiazepine dependence and chronic daily use ≥3 months. Patients with daily dosages ≥30 mg diazepam-equivalent, taking zolpidem, with a history of other substance abuse or major psychiatric disease were excluded. After the switch to diazepam, the dosage was gradually tapered according to a standardized protocol. Primary endpoint was the percentage of patients who stopped benzodiazepine at the intervention last visit. Dosage reduction, withdrawal symptoms, patients' and FPs' satisfaction with the protocol were evaluated. RESULTS: From 66 enrolled patients (74% female; 66.7% aged >64 years; median time of benzodiazepine use was 120 months), 2 withdrew due to medical reasons and 3 presented protocol deviations. Overall, 59.4% of participants successfully stopped benzodiazepine (60.7% when excluding protocol deviations). Men had higher probability of success (relative risk = 0.51, P = 0.001). A total of 31 patients reported at least 1 withdrawal symptom, most frequently insomnia and anxiety. Most of participating FP considered the clinical protocol useful and feasible in daily practice. Among patients completing the protocol, 77% were satisfied. For the patients who reduced dosage, 85% kept without benzodiazepines after 12 months. CONCLUSION: The discontinuation protocol with standardized dosage reduction was feasible at primary care and showed long-term effectiveness.
Asunto(s)
Ansiolíticos , Síndrome de Abstinencia a Sustancias , Trastornos Relacionados con Sustancias , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ansiolíticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Diazepam/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atención Primaria de Salud/métodos , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/psicología , Adulto JovenRESUMEN
BACKGROUND: Post-operative atrial fibrillation (POAF) is a relevant complication after surgery. Several studies have shown that POAF has important consequences for long-term morbidity and mortality, by increasing the risk of thromboembolic events. However, the use of oral anticoagulation (OAC) is not well established in this context. METHODS: We searched MEDLINE, CENTRAL, PsycInfo and Web of Science for clinical trials and observational studies evaluating anticoagulation vs. no anticoagulation in patients with POAF (after cardiac or non-cardiac surgery). Data were screened and extracted by two independent reviewers. We performed a random- effects model to estimate the pooled odds ratio (OR) with 95% Confidence Intervals (CI), and heterogeneity was evaluated by I2 statistics. The outcomes of interest were all-cause mortality, thromboembolic events, and bleeding events. RESULTS: Overall, 10 observational retrospective studies were included: 5 studies with 203,946 cardiac surgery POAF patients, and 5 studies with 29,566 patients with POAF after non-cardiac surgery. In cardiac surgery POAF, the OAC use was associated with lower risk of thromboembolic events (OR 0.68; 95%CI 0.47-0.96, I2 = 31%; 4 studies) and the bleeding risk was significantly increased (OR 4.30; 95%CI 3.69 to 5.02, 1 study). In non-cardiac surgery POAF, OAC did not significantly reduce the risk of thromboembolic events (OR 0.71, 95%CI 0.33-1.15; I2 = 79%; 5 studies) but was associated with increased risk of bleeding (OR 1.20, 95%CI 1.10-1.32, I2 = 0%; 3 studies). Mortality was not significantly reduced in both cardiac and non-cardiac surgery POAF. CONCLUSION: Oral anticoagulation was associated with a lower risk of thromboembolic events in patients with POAF following cardiac surgery but not in non-cardiac surgery. Bleeding risk was increased in both settings. The confidence on pooled results is at most low, and further data, namely randomized controlled trials are necessary to derive robust conclusions.
Asunto(s)
Fibrilación Atrial , Tromboembolia , Anticoagulantes/efectos adversos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/etiología , Humanos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Factores de Riesgo , Tromboembolia/etiología , Tromboembolia/prevención & controlRESUMEN
The cognitive deficits associated with Parkinson's disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson's disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson's disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson's might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson's Disease. Seventeen participants with Parkinson's disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson's group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially oriented to the instruction slides or when discrimination trials were performed. Concomitantly, Magnetic Resonance Spectroscopy showed reduced gamma-Aminobutyric acid levels within the mid-dorsolateral prefrontal cortices of individuals who made misbinding errors. These results demonstrate, for the first time, that a subset of early-to-mid stage people with Parkinson's show substantial deficits when binding new task rules in working memory. Given the ubiquity of instruction-based learning, these deficits are likely to impede daily living. They will also confound clinical assessment of other cognitive processes. Future work should determine the value of instruction-based learning as a sensitive early marker of cognitive decline and as a measure of responsiveness to therapy in Parkinson's disease.
RESUMEN
The majority of biopsies in both basic research and translational cancer studies are preserved in the format of archived formalin-fixed paraffin-embedded (FFPE) samples. Profiling histone modifications in archived FFPE tissues is critically important to understand gene regulation in human disease. The required input for current genome-wide histone modification profiling studies from FFPE samples is either 10-20 tissue sections or whole tissue blocks, which prevents better resolved analyses. But it is desirable to consume a minimal amount of FFPE tissue sections in the analysis as clinical tissues of interest are limited. Here, we present FFPE tissue with antibody-guided chromatin tagmentation with sequencing (FACT-seq), the first highly sensitive method to efficiently profile histone modifications in FFPE tissues by combining a novel fusion protein of hyperactive Tn5 transposase and protein A (T7-pA-Tn5) transposition and T7 in vitro transcription. FACT-seq generates high-quality chromatin profiles from different histone modifications with low number of FFPE nuclei. We proved a very small piece of FFPE tissue section containing â¼4000 nuclei is sufficient to decode H3K27ac modifications with FACT-seq. H3K27ac FACT-seq revealed disease-specific super enhancers in the archived FFPE human colorectal and human glioblastoma cancer tissue. In summary, FACT-seq allows decoding the histone modifications in archival FFPE tissues with high sensitivity and help researchers to better understand epigenetic regulation in cancer and human disease.
Asunto(s)
Cromatina/metabolismo , Epigénesis Genética , Histonas/análisis , Animales , Línea Celular , Humanos , Ratones , Procesamiento Proteico-Postraduccional , Proteína Estafilocócica A/metabolismo , Transposasas/metabolismoRESUMEN
Epigenetic mechanisms are potential mediators of the physiological response to abuse by altering the genetic predisposition of the cellular response to the environment, leading to changes in the regulation of multiple organ systems. This study was established to review the epigenetic mechanisms associated with childhood abuse as well as the long-term determinants that these epigenetic changes may have on future illness. We retrospectively analysed the effect of exposure to adverse childhood experiences (ACEs, specifically those relating to childhood maltreatment) between the ages of 0 and 16 years on the human epigenome, as well as possible clinical associations. After meeting inclusion and exclusion criteria, 36 articles were included in this systematic review. Eight of these studies did not find a relationship between childhood maltreatment and DNA methylation. Of the remaining 28 studies, nine were genome-wide association studies, whereas the rest were candidate gene studies, mainly studying effects on neuroendocrine, serotoninergic and immunoregulatory systems. Meta-analysis of correlation coefficients from candidate gene studies estimated an association of childhood adversity and DNA methylation variation at r = 0.291 (P < 0.0001), and meta-analysis of two epigenome-wide association studies (EWASs) identified 44 differentially methylated CpG sites. In conclusion, childhood maltreatment may mediate epigenetic mechanisms through DNA methylation, thereby affecting physiological responses and conferring a predisposition to an increased risk for psychopathology and forensic repercussions. Similar evidence for somatic illnesses is not yet available. KEY POINTSAdverse childhood experiences are associated with increased mortality partly explained by acquired epigenetic changesThere is a positive correlation between childhood abuse and DNA methylation at specific gene sitesThe cumulative effect of different types of childhood abuse and neglect may lead to changes in DNA methylationEpigenome changes associated with childhood abuse appear to be involved in the development of psychiatric illness in adulthoodStudying epigenetic changes may have important public health and forensic applications in the future.
RESUMEN
Treatment and prevention of cardiovascular diseases often rely on Electrocardiogram (ECG) interpretation. Dependent on the physician's variability, ECG interpretation is subjective and prone to errors. Machine learning models are often developed and used to support doctors; however, their lack of interpretability stands as one of the main drawbacks of their widespread operation. This paper focuses on an Explainable Artificial Intelligence (XAI) solution to make heartbeat classification more explainable using several state-of-the-art model-agnostic methods. We introduce a high-level conceptual framework for explainable time series and propose an original method that adds temporal dependency between time samples using the time series' derivative. The results were validated in the MIT-BIH arrhythmia dataset: we performed a performance's analysis to evaluate whether the explanations fit the model's behaviour; and employed the 1-D Jaccard's index to compare the subsequences extracted from an interpretable model and the XAI methods used. Our results show that the use of the raw signal and its derivative includes temporal dependency between samples to promote classification explanation. A small but informative user study concludes this study to evaluate the potential of the visual explanations produced by our original method for being adopted in real-world clinical settings, either as diagnostic aids or training resource.
Asunto(s)
Inteligencia Artificial , Electrocardiografía , Arritmias Cardíacas/diagnóstico , Frecuencia Cardíaca , Humanos , Aprendizaje AutomáticoRESUMEN
Extemporaneous suspensions are often marketed with several administration devices that can be freely used by patients/caregivers. The homogeneity of suspensions requires shaking before use. Hence, it is crucial to assess the precision of all devices and the users' awareness of the shaking procedure. This study was conducted at University Institute Egas Moniz with 40 pharmacy students who were asked to measure 2.5 and 5 mL of two extemporaneous azithromycin suspensions. Formulation A is marketed with a double-dosing spoon and oral syringe, whereas B includes a transparent dosing spoon. Both have a reconstitution cup. The user's preference for administration devices, the degree of compliance with the 'shake before use' instruction and the accuracy of the manipulation were assessed. The double-dosing spoon was the preferred device. The "shake before use" instruction was overlooked by most volunteers. The average measured volumes obtained with the double-dosing spoon were significantly different from the ones obtained with the oral syringe (p < 0.001) and significantly lower than the reference dose (p < 0.001). The oral syringe originates significantly higher values than the reference dose (p < 0.001). The dosing spoons values were significantly different from each other (p < 0.001). Liquid medicines containing several administration devices may be a challenge since they are nonequivalent.
RESUMEN
The topic of interstitial pneumonia with autoimmune features (IPAF) is a research classification proposed by the European Respiratory Society/American Thoracic Society Task Force: this includes patients with idiopathic interstitial pneumonia (IIP) and clinical features, suggesting an underlying autoimmune process, but who do not meet established criteria for a connective tissue disease (CTD). We aimed to perform a detailed characterization of clinical, serological, and radiological features for our patients with IPAF criteria. Six patients were included, and a comprehensive description of these cases revealed a heterogeneous group in terms of clinical and treatment options. In most patients, it was possible to identify other features and disorders with an autoimmune "background," which may support the inclusion of these patients in the IPAF classification. No deaths or significant decline in lung function occurred, and thus no definitive diagnosis of CTD could be found over 35 months of median follow-up. Therefore, IPAF is a recent concept, with many questions still open in regard to its usage in the ILD field.