RATIONALE: Lung volumes identify the susceptible smokers who progress to develop spirometric COPD. However, among susceptible smokers, development of spirometric COPD seems to be heterogeneous, suggesting the presence of different pathological mechanisms during early establishment of spirometric COPD. The objective of the present study was to determine the differential patterns of radiographic pathologies among susceptible smokers. METHODS: We categorised smokers with preserved spirometry (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0) in the Genetic Epidemiology of COPD (COPDGene) cohort based on tertiles (low, intermediate and high) of lung volumes (either total lung capacity (TLC), functional residual capacity FRC or FRC/TLC) at baseline visit. We then examined the differential patterns of change in spirometry and the associated prevalence of computed tomography measured pathologies of emphysema and airway disease with those categories of lung volumes. RESULTS: The pattern of spirometric change differed when participants were categorised by TLC versus FRC/TLC: those in the high TLC tertile showed stable forced expiratory volume in 1 s (FEV1), but enlarging forced vital capacity (FVC), while those in the high FRC/TLC tertile showed decline in both FEV1 and FVC. When participants from the high TLC and high FRC/TLC tertiles were partitioned into mutually exclusive groups, compared to those with high TLC, those with high FRC/TLC had lesser emphysema, but greater air trapping, more self-reported respiratory symptoms and exacerbation episodes and higher likelihood of progressing to more severe spirometric disease (GOLD stages 2-4 versus GOLD stage 1). CONCLUSIONS: Lung volumes identify distinct physiological and radiographic phenotypes in early disease among susceptible smokers and predict the rate of spirometric disease progression and the severity of symptoms in early COPD.

OBJECTIVES: Friedreich ataxia (FRDA) is a rare genetic disorder caused by mutations in the FXN gene, leading to progressive coordination loss and other symptoms. The recently approved omaveloxolone targets this condition but is limited to patients over 16 years of age, highlighting the need for pediatric treatments due to the disorders early onset and more rapid progression in children. This population also experiences increased non-neurological complications; the FACHILD study aimed to augment and expand the knowledge about the natural history of the disease and clinical outcome assessments for trials in children in FRDA. METHODS: The study enrolled 108 individuals aged 7-18 years with a confirmed FRDA diagnosis, with visits occurring from October 2017 to November 2022 across three institutions. Several measures were introduced to minimize the impact of the COVID-19 pandemic, including virtual visits. Outcome measures centered on the mFARS score and its subscores, and data were analyzed using mixed models for repeated measures. For context and to avoid misinterpretation, the analysis was augmented with data from patients enrolled in the Friedreichs Ataxia Clinical Outcome Measures Study. RESULTS: Results confirmed the general usefulness of the mFARS score in children, but also highlighted issues, particularly with the upper limb subscore (FARS B). Increased variability, limited homogeneity across study subgroups, and potential training effects might limit mFARS application in clinical trials in pediatric populations. INTERPRETATION: The FARS E (Upright Stability) score might be a preferred outcome measure in this patient population.

Friedreichs ataxia is a neurodegenerative disorder caused by reduced frataxin levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia, Friedreichs ataxia lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study proposes TUG1, a long non-coding RNA, as a promising blood-based biomarker for Friedreichs ataxia, which is known to regulate various cellular processes. In a previous study using a frataxin knockdown mouse model, we observed several hallmark Friedreichs ataxia symptoms. Building on this, we hypothesized that a dual-source approach-comparing the data from peripheral blood samples from Friedreichs ataxia patients with tissue samples from affected areas in Friedreichs ataxia knockdown mice, tissues usually unattainable from patients-would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of Friedreichs ataxia patients, carriers and controls and 192 tissue data sets from Friedreichs ataxia knockdown mice. Blood and tissue samples underwent RNA isolation and quantitative reverse transcription polymerase chain reaction, and frataxin knockdown was confirmed through enzyme-linked immunosorbent assays. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum samples on an independent set of 45 controls and 45 Friedreichs ataxia patients and in blood samples from 66 heterozygous carriers and 72 Friedreichs ataxia patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the Friedreichs ataxia knockdown mouse model (one-way ANOVA, P ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R 2 = 0.71 during depletion, R 2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1s downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of Friedreichs ataxia patients compared with controls (Wilcoxon signed-rank test, P < 0.05). Regression analyses revealed a negative correlation between TUG1 fold-change and disease onset (P < 0.0037) and positive correlations with disease duration and functional disability stage score (P < 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. This study identifies TUG1 as a potential blood-based biomarker for Friedreichs ataxia, showing consistent expression variance in human and mouse tissues related to disease severity and key Friedreichs ataxia pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for Friedreichs ataxia monitoring and therapeutic development, meriting additional research.

Background

The National Heart, Lung, and Blood Institute-sponsored IPF Clinical Research Network (IPFnet) studies enrolled subjects with idiopathic pulmonary fibrosis (IPF) to evaluate drug therapies in treatment trials. An adjudication committee (AC) provided a structured review of cases in which there was uncertainty or disagreement regarding diagnosis or clinical event classification. This article describes the diagnosis and adjudication processes.

Methods

The diagnostic process was based on review of clinical data and high-resolution CT scans with central review of lung biopsies when available. The AC worked closely with the data coordinating center to obtain clinical, radiologic, and histologic data and to communicate with the clinical centers. The AC used a multidisciplinary discussion model with four clinicians, one radiologist, and one pathologist to adjudicate diagnosis and outcome measures.

Results

The IPFnet trials screened 1,015 subjects; of these, 23 cases required review by the AC to establish eligibility. The most common diagnosis for exclusion was suspected chronic hypersensitivity pneumonitis. The AC reviewed 88 suspected acute exacerbations (AExs), 93 nonelective hospitalizations, and 16 cases of bleeding. Determination of AEx presented practical challenges to adjudicators, as necessary clinical data were often not collected, particularly when subjects were evaluated outside of the primary study site.

Conclusions

The IPFnet diagnostic process was generally efficient, but a multidisciplinary adjudication committee was critical to assure correct phenotype for study enrollment. The AC was key in adjudicating all adverse outcomes in two IPFnet studies terminated early because of safety issues. Future clinical trials in IPF should consider logistical and cost issues as they incorporate AExs and hospitalizations as outcome measures.

Trial registry

ClinicalTrials.gov; No.: NCT00517933, NCT00650091, NCT00957242; URL: www.clinicaltrials.gov.

Purpose

To develop a deep learning-based algorithm to stage the severity of chronic obstructive pulmonary disease (COPD) through quantification of emphysema and air trapping on CT images and to assess the ability of the proposed stages to prognosticate 5-year progression and mortality.

Materials and methods

In this retrospective study, an algorithm using co-registration and lung segmentation was developed in-house to automate quantification of emphysema and air trapping from inspiratory and expiratory CT images. The algorithm was then tested in a separate group of 8951 patients from the COPD Genetic Epidemiology study (date range, 2007-2017). With measurements of emphysema and air trapping, bivariable thresholds were determined to define CT stages of severity (mild, moderate, severe, and very severe) and were evaluated for their ability to prognosticate disease progression and mortality using logistic regression and Cox regression.

Results

On the basis of CT stages, the odds of disease progression were greatest among patients with very severe disease (odds ratio [OR], 2.67; 95% CI: 2.02, 3.53; P < .001) and were elevated in patients with moderate disease (OR, 1.50; 95% CI: 1.22, 1.84; P = .001). The hazard ratio of mortality for very severe disease at CT was 2.23 times the normal ratio (95% CI: 1.93, 2.58; P < .001). When combined with Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging, patients with GOLD stage 2 disease had the greatest odds of disease progression when the CT stage was severe (OR, 4.48; 95% CI: 3.18, 6.31; P < .001) or very severe (OR, 4.72; 95% CI: 3.13, 7.13; P < .001).

Conclusion

Automated CT algorithms can facilitate staging of COPD severity, have diagnostic performance comparable with that of spirometric GOLD staging, and provide further prognostic value when used in conjunction with GOLD staging.Supplemental material is available for this article.© RSNA, 2021See also commentary by Kalra and Ebrahimian in this issue.

Background

Collaborative data sharing between research groups provides an opportunity to explore the basis for the heterogeneity in cognitive training outcomes reported in the schizophrenia literature. The current analyses focused on the contribution of site and participant characteristics to these heterogeneous outcomes.

Methods

Data from two independent studies, from New York (NY) and Los Angeles (LA), were combined to yield a sample of 132 outpatient adults with schizophrenia/schizoaffective disorder. While similar treatment doses, cognitive exercises and outcome measures were used, sites differed in use of coaching, group discussion and compensation. Between-site differences in participant demographic and baseline clinical characteristics were tested. Regression examined predictors of change in cognition (MCCB) and functional capacity (UPSA) which could explain site differences in treatment effects.

Results

Medium to large treatment effect size differences in MCCB and UPSA favored the NY site over LA. When the studies were combined, the effect of site was significant for both outcomes with a medium effect size difference. After controlling for background characteristics, the effect of site was reduced for both outcomes, but remained significant for cognition. Improvement in UPSA was associated with better baseline MCCB (p < 0.001), lower baseline UPSA (p < 0.001) and younger age (p = 0.019). The overall model with site, baseline scores, and participant background characteristics explained about 30% to 40% of the variance in outcomes.

Discussion

Participant and treatment characteristics are both predictive of outcomes, but treatment characteristics may be more consequential to cognitive gain, while participant characteristics may be more consequential to change in functional capacity.

Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.

OBJECTIVE: Friedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age-specific prevalence of FA-associated DM and its impact on neurologic outcomes. RESEARCH DESIGN AND METHODS: Participants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS). Physical function was assessed, using validated instruments. Multivariable regression analyses examined the independent association of DM with outcomes. RESULTS: Mean age of participants was 30.1 years (SD 15.3, range: 7-82), 50% were female, and 94% were non-Hispanic white. 9% (42/459) of adults and 3% (10/352) of children had DM. Individuals with FA-associated DM were older (P < 0.001), had longer GAA repeat length on the least affected FXN allele (P = 0.037), and more severe FA (P = 0.0001). Of individuals with DM, 65% (34/52) were taking insulin. Even after accounting statistically for both age and GAA repeat length, DM was independently associated with greater FA symptom burden (P = 0.010), reduced capacity to perform activities of daily living (P = 0.021), and a decrease of 0.33 SDs on a composite performance measure (95% CI: -0.56-0.11, P = 0.004); the relative impact of DM was most apparent in younger individuals. CONCLUSIONS: DM-associated FA has an independent adverse impact on well-being in affected individuals, particularly at younger ages. In future, evidence-based approaches for identification and management of FA-related DM may improve both health and function.