Sleep disruption in patients with active and treated endogenous Cushing's syndrome.

CONTEXT: The hypothalamic-pituitary-adrenal axis is a critical regulator of circadian rhythm in humans. Impaired sleep adversely affects metabolic, emotional, and cognitive health. OBJECTIVE: To characterize sleep disturbances in patients with active and treated Cushing's syndrome (CS), and identify factors associated with impaired sleep in treated patients. DESIGN: Single-center cross-sectional study. METHODS: Patients with pituitary or adrenal CS enrolled in an observational study completed Nottingham Health Profile (NHP), CushingQoL, and Hospital Anxiety and Depression assessments. Cross-sectional analysis was conducted including patients with active and treated disease. RESULTS: 113 (94 female) patients with CS were included, 104 pituitary and 9 adrenal, with mean age at diagnosis of 43.9 ± 13.4 years. Mean and maximum duration of follow up was 5.1 and 23 years. Mean NHP sleep score was lower (i.e., improved) in patients with treated vs. active disease (29.6 ± 30.2 vs. 51.9 ± 30.9, p = 0.0005), as was CushingQoL sleep score (p = 0.015), but 41.5% of patients with treated disease stated they often or always had trouble sleeping. The proportion of treated vs. active patients taking medication for sleep, mood, or pain was not different. Neither NHP nor CushingQoL pain scores were lower in treated vs. active patients (p = 0.39 and 0.53). In patients with treated CS, anxiety and depression correlated with worse sleep scores. CONCLUSIONS: Patients with treated CS report improved sleep quality compared to those with active disease, but almost half of treated patients still report sleep challenges. The need for sleep medications, reported by one third of patients, was not different after CS treatment. Ongoing mood disturbances may play a role in persistent sleep disruption. Further work should focus on determinants of sleep impairments in treated CS patients.

Comparative Efficacy and Safety of Lorlatinib Versus Alectinib and Lorlatinib Versus Brigatinib for ALK-Positive Advanced/Metastatic NSCLC: Matching-Adjusted Indirect Comparisons.

INTRODUCTION: The comparative efficacy and safety of lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), versus second-generation ALK TKIs as a first-line treatment for ALK+ advanced/metastatic nonsmall cell lung cancer (NSCLC) remains uncertain as there are no head-to-head clinical trials. METHODS: Matching-adjusted indirect comparisons (MAICs) were conducted using phase III trial data demonstrating superior efficacy over crizotinib, a first-generation ALK TKI. MAICs were conducted to compare lorlatinib (CROWN) versus alectinib (ALEX and ALESIA) and brigatinib (ALTA-1L) with matching based on prespecified effect modifiers. Efficacy outcomes included progression-free survival (PFS), objective response (OR), and time to progression in the central nervous system (TTP-CNS). Safety outcomes included Grade ≥3 adverse events (AEs) and AEs leading to treatment discontinuation, dose reduction, or dose interruption. RESULTS: Lorlatinib was estimated to improve PFS compared to alectinib (ALEX) (HR: 0.54 [95% CI: 0.33, 0.88]) and brigatinib (ALTA-1L) (HR: 0.51 [95% CI: 0.31, 0.82]). Lorlatinib was estimated to improve TTP-CNS compared with brigatinib (HR: 0.19 [95% CI: 0.05, 0.71]). The estimated Grade ≥3 AE rate was higher with lorlatinib than with alectinib (RR: 1.48 [95% CI: 1.13, 1.94]); however, no differences were observed in other safety endpoints (ie, AEs leading to discontinuation, dose reduction, or interruption) or compared to brigatinib. CONCLUSION: Lorlatinib was estimated to have superior efficacy over first- and second-generation ALK-TKIs, but a higher rate of Grade ≥3 AEs compared to alectinib. These data support the use of lorlatinib as a first-line treatment for ALK+ advanced/metastatic NSCLC.

Clinical Impact of Telomere Length Testing for Interstitial Lung Disease.

BACKGROUND: Shortened telomere length (TL) is a genomic risk factor for fibrotic interstitial lung disease (ILD), but its role in clinical management is unknown. RESEARCH QUESTION: What is the clinical impact of TL testing on the management of ILD? STUDY DESIGN AND METHODS: Patients were evaluated in the Columbia University ILD clinic and underwent Clinical Laboratory Improvement Amendments-certified TL testing by flow cytometry and fluorescence in situ hybridization (FlowFISH) as part of clinical treatment. Short TL was defined as below the 10th age-adjusted percentile for either granulocytes or lymphocytes by FlowFISH. Patients were offered genetic counseling and testing if they had short TL or a family history of ILD. FlowFISH TL was compared with research quantitative polymerase chain reaction (qPCR) TL measurement. RESULTS: A total of 108 patients underwent TL testing, including those with clinical features of short telomere syndrome such as familial pulmonary fibrosis (50%) or extrapulmonary manifestations in the patient (25%) or a relative (41%). The overall prevalence of short TL was 46% and was similar across clinical ILD diagnoses. The number of short telomere clinical features was independently associated with detecting short TL (OR, 2.00; 95% CI, 1.27-3.32). TL testing led to clinical treatment changes for 35 patients (32%), most commonly resulting in reduction or avoidance of immunosuppression. Of the patients who underwent genetic testing (n = 34), a positive or candidate diagnostic finding in telomere-related genes was identified in 10 patients (29%). Inclusion of TL testing below the 1st percentile helped reclassify eight of nine variants of uncertain significance into actionable findings. The qPCR test correlated with FlowFISH, but age-adjusted percentile cutoffs may not be equivalent between the two assays. INTERPRETATION: Incorporating TL testing in ILD impacted clinical management and led to the discovery of new actionable genetic variants.

Alternatives to Conventional Topical Dosage Forms for Targeted Skin Penetration of Diclofenac Sodium.

Skin penetration of an active pharmaceutical ingredient is key to developing topical drugs. This penetration can be adjusted for greater efficacy and/or safety through the selection of dosage form. Two emerging dosage forms, cream-gel and gel-in-oil emulsion, were tested for their ability to deliver diclofenac into the skin, with the target of maximising skin retention while limiting systemic exposure. Prototypes with varying amounts of solvents and emollients were formulated and evaluated by in vitro penetration testing on human skin. Cream-gel formulas showed better skin penetration than the emulgel benchmark drug even without added solvent, while gel-in-oil emulsions resulted in reduced diffusion of the active into the receptor fluid. Adding propylene glycol and diethylene glycol monoethyl ether as penetration enhancers resulted in different diclofenac penetration profiles depending on the dosage form and whether they were added to the disperse or continuous phase. Rheological characterisation of the prototypes revealed similar profiles of cream-gel and emulgel benchmark, whereas gel-in-oil emulsion demonstrated flow characteristics suitable for massaging product into the skin. This study underlined the potential of cream-gel and gel-in-oil emulsions for adjusting active penetration into the skin, broadening the range of choices available to topical formulation scientists.

Antiaging, Brightening, and Antioxidant Efficacy of Fermented Bilberry Extract (Vaccinium myrtillus): A Randomized, Double-Blind, Placebo-Controlled Trial.

Strategies for successful aging, including the use of food supplements, are part of the approach to support skin youthfulness. To demonstrate the efficacy of fermented bilberry extract (FBE) against skin aging and uneven complexion, a clinical trial was carried out on 66 subjects with visible "crow's feet" wrinkles, mild-to-moderate skin slackness, and uneven skin tone. The wrinkle depth, skin smoothness (Ra) and roughness (Rz), skin firmness (R0) and elasticity (R2), skin coloration (ITA°), and skin antioxidant capacity were measured before and after 28 (D28), 56 (D56), and 84 (D84) days of product use (either FBE or a placebo). These parameters were also integrated with a clinical evaluation, carried out by a dermatologist, and a self-assessment questionnaire to align the measured efficacy with the visual or perceived efficacy. At D84, the wrinkle depth had decreased by 10.6%, Ra had improved by 7.9%, Rz had decreased by 7.3%, R0 had improved by 13.3%, R2 had improved by 12.4%, and skin antioxidant capacity had increased by 20.8%. ITA° increased by 20.8% and was accompanied by a decrease in the skin's redness component by 16.8% and an increase in the lightness component by 2.2%. The variation of all the above-mentioned parameters was statistically significant between the FBE and PL groups. Our findings demonstrate the efficacy of FBE in improving skin aging and complexion evenness.

Improved pulmonary function and exercise tolerance despite persistent pulmonary fibrosis over 1 year after severe COVID-19 infection.

We conducted a prospective single-centre cohort study of 104 multi-ethnic severe COVID-19 survivors from the first wave of the pandemic 15 months after hospitalisation. Of those who were assessed at 4 and 15 months, improvement of ground glass opacities correlated with worsened fibrotic reticulations. Despite a high prevalence of fibrotic patterns (64%), pulmonary function, grip strength, 6 min walk distance and frailty normalised. Overall, dyspnoea, cough and exhaustion did not improve and were not correlated with pulmonary function or radiographic fibrosis at 15 months, suggesting non-respiratory aetiologies. Monitoring persistent, and often subclinical, fibrotic interstitial abnormalities will be needed to determine their potential for future progression.

Efficacy of a wheat polar lipid complex in reducing hair loss and improving hair growth in healthy women: A randomized, double-blind, placebo-controlled clinical study.

OBJECTIVE: Hair loss is a major source of psychological distress for affected people. Safe and natural ingredients are therefore needed to help reduce hair loss and stimulate hair growth. This pilot clinical study aimed at exploring the efficacy of a wheat polar lipid complex (WPLC, Ceramosides™), containing sphingolipids and digalactosyl diglycerides, on hair characteristics improvement in women showing acute hair shedding. METHODS: Sixty-six women presenting a proportion of hair in the telogen phase greater than 15% were recruited and allocated to two groups, each including at least 10 postmenopausal women. For 84 days, participants consumed 30 mg/day of the WPLC supplement, or the placebo. Their hair characteristics were assessed after 56 and 84 days using phototrichogram evaluations of hairs in anagen/telogen phases, measuring hair shedding by a pull test, hair diameter and elongation at break point, hair growth and scalp sebum content. Hair density and volume were also clinically evaluated. All these parameters were also investigated in the subgroup of postmenopausal women. RESULTS: WPLC supplementation decreased telogen hair density/proportion while increasing the anagen hair density/proportion. These effects were significant compared with the placebo as early as within 56 days. It also led to reduced hair shedding upon pull test analyses. If no changes were evidenced in hair diameter, WPLC improved hair growth and resistance to breakage after 84 days. Clinical evaluations also showed hair density and volume improvement. Furthermore, supplementation decreased scalp sebum content in women with oily hair. The beneficial effects were also observed in the subgroup of postmenopausal women. Finally, WPLC supplementation improved participants' perception of their hair conditions. CONCLUSION: Through a reducing effect on hair shedding and a stimulating effect on hair reappearance and growth, WPLC dietary supplementation was shown to significantly reduce hair loss in women.

OBJECTIF: La chute de cheveux est une source importante de détresse psychologique pour les personnes concernées. Des ingrédients naturels et sûrs sont nécessaires pour permettre de réduire la chute et stimuler la croissance des cheveux. Cette étude clinique pilote avait pour objectif d'étudier la capacité d'un complexe de lipides polaires extraits du blé (WPLC), composé de sphingolipides et de digalactosyl diglycerides, à améliorer la qualité des cheveux chez des femmes présentant une chute de cheveux diffuse et aiguë. MÉTHODES: Soixante­six femmes présentant un taux de cheveux en phase télogène supérieur à 15% ont été recrutées et séparées en deux groupes, chacun comprenant au moins dix femmes ménopausées. Pendant 84 jours, les volontaires ont consommé le supplément à une dose de 30 mg/jour, ou le placebo. Leur chevelure a été évaluée après 56 et 84 jours de supplémentation en quantifiant les cheveux en phase anagène/télogène grâce à un phototrichogramme, en évaluant la chute de cheveux grâce à un test de traction, en mesurant le diamètre, l'élongation et la croissance des cheveux, et en quantifiant le taux de sébum du cuir chevelu. La densité et le volume de la chevelure ont été évalués cliniquement. Tous ces paramètres ont également été analysés dans le sous­groupe de femmes ménopausées. RÉSULTATS: Une diminution de la densité et de la proportion des cheveux en phase télogène a été observée, en association avec une augmentation de la densité et de la proportion des cheveux en phase anagène. Ces résultats sont statistiquement significatifs en comparaison avec le placebo, et ce, dès 56 jours. La chute de cheveux, mesurée par le test de traction, a également été significativement réduite. Bien qu'aucun changement n'ait été observé concernant le diamètre des cheveux, le supplément a amélioré la résistance à la casse et la croissance des cheveux après 84 jours d'utilisation. L'évaluation clinique a montré une amélioration de la densité et du volume de la chevelure. De plus, la supplémentation a entraîné une réduction du taux de sébum du cuir chevelu chez les femmes présentant des cheveux à tendance grasse. Les effets bénéfiques de la supplémentation ont également été observés dans le sous­groupe des femmes ménopausées. Enfin, la prise du supplément a également été associée à une amélioration de la perception des volontaires concernant la qualité de leurs cheveux. CONCLUSION: Grâce à un effet réducteur sur la chute de cheveux et un effet stimulateur sur la repousse et la croissance des cheveux, cette étude a démontré l'efficacité de la supplémentation nutritionnelle avec WPLC à atténuer la perte de cheveux chez la femme.

Top Ten Tips Palliative Care Clinicians Should Know About Caring for Filipino American and Korean American Patients.

As of 2019, there are 4.2 million Filipino Americans (FAs) and 1.9 million Korean Americans (KAs) in the United States, largely concentrated in New York, California, Texas, Illinois, and Washington. In both populations, similar to the broader U.S. culture, one can find health literacy gaps around understanding and utilizing palliative care. In this article, we provide 10 cultural pearls to guide clinicians on how to sensitively approach FA and KA groups when addressing palliative and end-of-life (EOL) discussions. We fully celebrate that every person is an individual and care should be tailored to each person's goals, values, and preference. In addition, there are several cultural norms that, when appreciated and celebrated, may help clinicians to improve serious illness care and EOL discussions for members of these populations.

Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Dietary supplementation with a wheat polar lipid complex improves skin conditions in women with dry skin and mild-to-moderate skin aging.

BACKGROUND: Aging, menopause, and seasonal changes alter the lipid composition of the outermost skin layer, the stratum corneum, resulting in dry and itchy skin. AIMS: This clinical trial aimed at evaluating the effects of a wheat polar lipid complex (WPLC) on skin characteristics in women showing dry and wrinkled skin, investigating its effects in a subgroup of postmenopausal women, and assessing if benefits were maintained after supplementation. METHODS: Seventy-two women with dry and wrinkled skin were recruited in this double-blind, randomized, parallel-group study, and allocated to three groups of 24 subjects, each including at least 10 postmenopausal women. For 56 days, subjects consumed the WPLC supplement (oil or powder), or the placebo. Skin hydration, transepidermal water loss (TEWL), elasticity, and profilometry were evaluated at baseline, after 14, 28, and 56 days of supplementation, and 56 days after the end of supplementation. Additionally, a lipidomic analysis was performed to examine changes in superficial skin layers over 56 days. RESULTS: Dietary supplementation with WPLC rapidly improved all parameters. It increased skin hydration, smoothness, and elasticity while decreasing TEWL, roughness, and wrinkle depth after only 14 days of supplementation. These effects were also observed in the subpopulation of postmenopausal women and led to an improved self-perception of skin. For all the parameters, outcomes were not maintained after the supplementation was stopped. The lipidomic analysis revealed 10 compounds evolving over the 56 days of WPLC supplementation. CONCLUSION: WPLC supplementation improved skin hydration, smoothness, elasticity, and wrinkledness within 14 days and, as expected, did not last after supplementation was stopped.

The World's First Acne Dysbiosis-like Model of Human 3D Ex Vivo Sebaceous Gland Colonized with Cutibacterium acnes and Staphylococcus epidermidis.

Acne-prone skin is associated with dysbiosis involving Cutibacterium acnes (C. acnes) and Staphylococcus epidermidis (S. epidermidis) causing increased seborrhea in sebaceous glands (SG) and inflammation. Human primary sebocytes were cultivated using 1.106 UFC/mL C. acnes Type IA (facial acne, ATCC6919) and/or 1.105 UFC/mL S. epidermidis (unknown origin, ATCC12228) for 48 h in our SEB4GLN-optimized media without antibiotics. Bacteria and sebocytes were enumerated and assessed to determine their viability. Lipid production was imaged and quantified via Nile Red staining. SG with hair follicles were microdissected from healthy skin and cultured using 1.105 UFC/mL C. acnes Type 1A and/or 1.104 UFC/mL S. epidermidis (wild-type facial skin strain) through prior fixation and immunostaining for MC5R, C. acnes and nuclei (DAPI) via Z-stack confocal microscopy bioimaging (Leica SP5X & FIJI software, Version 2.9.0). C. acnes growth was not impacted when co-cultivated with sebocytes (2D) or SG (3D) models. Phylotype IA stimulated sebocyte lipid production, which had no impact on viability. The S. epidermidis reference strain overproliferated, inducing sebocyte mortality. For 3D SG model, culture conditions were optimized using a wild-type facial skin strain at a lower concentration, 1:10 ratio to C. acnes, reduced contact time, sequential inoculation and rinsing step. Bioimaging revealed strong C. acnes labeling in the active areas of the pilosebaceous unit. S. epidermidis formed biofilm, which was distributed across the SG via non-specific fluorescence imaging. We developed an innovative model of a sebaceous gland that mimics acne-prone skin with lipid overproduction and virulent phylotype IA C. acnes inoculation.

Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease.

BACKGROUND: Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD). METHODS: A retrospective, multicentre cohort analysis was performed in fibrotic hypersensitivity pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease (CTD)-ILD patients from five centres. LTL was measured by quantitative PCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on 2-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure. RESULTS: The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. fHP and uILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality hazard ratio (HR) 4.97, 95% CI 2.26-10.92; p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77; p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (discovery pinteraction=0.013; replication pinteraction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for CTD-ILD. CONCLUSION: Similar to IPF, fHP and uILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.

A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities.

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10-95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

Fibrotic-Like Pulmonary Radiographic Patterns Are Not Associated With Adverse Outcomes in COVID-19 Chronic Critical Illness.

OBJECTIVES: Pulmonary fibrosis is a feared complication of COVID-19. To characterize the risks and outcomes associated with fibrotic-like radiographic abnormalities in patients with COVID-19-related acute respiratory distress syndrome (ARDS) and chronic critical illness. DESIGN: Single-center prospective cohort study. SETTING: We examined chest CT scans performed between ICU discharge and 30 days after hospital discharge using established methods to quantify nonfibrotic and fibrotic-like patterns. PATIENTS: Adults hospitalized with COVID-19-related ARDS and chronic critical illness (> 21 d of mechanical ventilation, tracheostomy, and survival to ICU discharge) between March 2020 and May 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We tested associations of fibrotic-like patterns with clinical characteristics and biomarkers, and with time to mechanical ventilator liberation and 6-month survival, controlling for demographics, comorbidities, and COVID-19 therapies. A total of 141 of 616 adults (23%) with COVID-19-related ARDS developed chronic critical illness, and 64 of 141 (46%) had a chest CT a median (interquartile range) 66 days (42-82 d) after intubation. Fifty-five percent had fibrotic-like patterns characterized by reticulations and/or traction bronchiectasis. In adjusted analyses, interleukin-6 level on the day of intubation was associated with fibrotic-like patterns (odds ratio, 4.40 per quartile change; 95% CI, 1.90-10.1 per quartile change). Other inflammatory biomarkers, Sequential Organ Failure Assessment score, age, tidal volume, driving pressure, and ventilator days were not. Fibrotic-like patterns were not associated with longer time to mechanical ventilator liberation or worse 6-month survival. CONCLUSIONS: Approximately half of adults with COVID-19-associated chronic critical illness have fibrotic-like patterns that are associated with higher interleukin-6 levels at intubation. Fibrotic-like patterns are not associated with longer time to liberation from mechanical ventilation or worse 6-month survival.

Pulmonary emphysema subtypes defined by unsupervised machine learning on CT scans.

BACKGROUND: Treatment and preventative advances for chronic obstructive pulmonary disease (COPD) have been slow due, in part, to limited subphenotypes. We tested if unsupervised machine learning on CT images would discover CT emphysema subtypes with distinct characteristics, prognoses and genetic associations. METHODS: New CT emphysema subtypes were identified by unsupervised machine learning on only the texture and location of emphysematous regions on CT scans from 2853 participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a COPD case-control study, followed by data reduction. Subtypes were compared with symptoms and physiology among 2949 participants in the population-based Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study and with prognosis among 6658 MESA participants. Associations with genome-wide single-nucleotide-polymorphisms were examined. RESULTS: The algorithm discovered six reproducible (interlearner intraclass correlation coefficient, 0.91-1.00) CT emphysema subtypes. The most common subtype in SPIROMICS, the combined bronchitis-apical subtype, was associated with chronic bronchitis, accelerated lung function decline, hospitalisations, deaths, incident airflow limitation and a gene variant near DRD1, which is implicated in mucin hypersecretion (p=1.1 ×10-8). The second, the diffuse subtype was associated with lower weight, respiratory hospitalisations and deaths, and incident airflow limitation. The third was associated with age only. The fourth and fifth visually resembled combined pulmonary fibrosis emphysema and had distinct symptoms, physiology, prognosis and genetic associations. The sixth visually resembled vanishing lung syndrome. CONCLUSION: Large-scale unsupervised machine learning on CT scans defined six reproducible, familiar CT emphysema subtypes that suggest paths to specific diagnosis and personalised therapies in COPD and pre-COPD.

Incidence of Interstitial Lung Abnormalities: The MESA Lung Study.

The incidence of newly developed interstitial lung abnormalities (ILA) and fibrotic ILA have not been previously reported.Trained thoracic radiologists evaluated 13 944 cardiac CT scans for the presence of ILA in 6197 Multi-Ethnic Study of Atherosclerosis longitudinal cohort study participants >45 years of age from 2000 to 2012. 5% of the scans were re-read by the same or a different observer in a blinded fashion. After exclusion of participants with ILA at baseline, incidence rates and incidence rate ratios for ILA and fibrotic ILA were calculated.The intra-reader agreement of ILA was 92.0% (Gwet AC1=0.912, ICC=0.982) and the inter-reader agreement of ILA was 83.5% (Gwet AC1=0.814; ICC=0.969). Incidence of ILA and fibrotic ILA was estimated to be 13.1 cases/1000 person-years and 3.5/1000 person-years, respectively. In multivariable analyses, age (HR 1.06 (1.05, 1.08), p <0.001; HR 1.08 (1.06, 1.11), p <0.001), high attenuation area (HAA) at baseline (HR 1.05 (1.03, 1.07), p <0.001; HR 1.06 (1.02, 1.10), p=0.002), and the MUC5B promoter SNP (HR 1.73 (1.17, 2.56) p=0.01; HR 4.96 (2.68, 9.15), p <0.001) were associated with incident ILA and fibrotic ILA, respectively. Ever smoking (HR 2.31 (1.34, 3.96), p= 0.002) and an IPF polygenic risk score (HR 2.09 (1.61-2.71), p<0.001) were associated only with incident fibrotic ILA.Incident ILA and fibrotic ILA were estimated by review of cardiac imaging studies. These findings may lead to wider application of a screening tool for atherosclerosis to identify preclinical lung disease.

Evaluation of Pulmonary Fibrosis Outcomes by Race and Ethnicity in US Adults.

Importance: Pulmonary fibrosis (PF) is characterized by progressive scarring of lung tissue and poor survival. Racial and ethnic minority populations face the greatest risk of morbidity and mortality from disparities impacting respiratory health, but the pattern of age at clinically relevant outcomes across diverse racial and ethnic populations with PF is unknown. Objective: To compare the age at PF-related outcomes and the heterogeneity in survival patterns among Hispanic, non-Hispanic Black, and non-Hispanic White participants. Design, Setting, and Participants: This cohort study included adult patients with a PF diagnosis and used data from prospective clinical registries: the Pulmonary Fibrosis Foundation Registry (PFFR) for the primary cohort and registries from 4 geographically distinct tertiary hospitals in the US for the external multicenter validation (EMV) cohort. Patients were followed between January 2003 and April 2021. Exposures: Race and ethnicity comparisons between Black, Hispanic, and White participants with PF. Main Outcomes and Measures: Age and sex distribution of participants were measured at the time of study enrollment. All-cause mortality and age at PF diagnosis, hospitalization, lung transplant, and death were assessed in participants over 14 389 person-years. Differences between racial and ethnic groups were compared using Wilcoxon rank sum tests, Bartlett 1-way analysis of variance, and χ2 tests, and crude mortality rates and rate ratios were assessed across racial and ethnic categories using Cox proportional hazards regression models. Results: In total, 4792 participants with PF were assessed (mean [SD] age, 66.1 [11.2] years; 2779 [58.0%] male; 488 [10.2%] Black, 319 [6.7%] Hispanic, and 3985 [83.2%] White); 1904 were in the PFFR and 2888 in the EMV cohort. Black patients with PF were consistently younger than White patients (mean [SD] age at baseline, 57.9 [12.0] vs 68.6 [9.6] years; P < .001). Hispanic and White patients were predominantly male (Hispanic: PFFR, 73 of 124 [58.9%] and EMV, 109 of 195 [55.9%]; and White: PFFR, 1090 of 1675 [65.1%] and EMV, 1373 of 2310 [59.4%]), while Black patients were less likely to be male (PFFR, 32 of 105 [30.5%] and EMV, 102 of 383 [26.6%]). Compared with White patients, Black patients had a lower crude mortality rate ratio (0.57 [95% CI, 0.31-0.97), but for Hispanic patients, the mortality rate ratio was similar to that of White patients (0.89; 95% CI, 0.57-1.35). Mean (SD) hospitalization events per person were highest among Black patients compared with Hispanic and White patients (Black: 3.6 [5.0]; Hispanic, 1.8 [1.4]; and White, 1.7 [1.3]; P < .001). Black patients were consistently younger than Hispanic and White patients at first hospitalization (mean [SD] age: Black, 59.4 [11.7] years; Hispanic, 67.5 [9.8] years; and White, 70.0 [9.3] years; P < .001), lung transplant (Black, 58.6 [8.6] years; Hispanic, 60.5 [6.1] years; and White, 66.9 [6.7] years; P < .001), and death (Black, 68.7 [8.4] years; Hispanic, 72.9 [7.6] years; and White, 73.5 [8.7] years; P < .001). These findings remained consistent in the replication cohort and in sensitivity analyses within prespecified deciles of age groups. Conclusions and Relevance: In this cohort study of participants with PF, racial and ethnic disparities, especially among Black patients, were found in PF-related outcomes, including earlier onset of death. Further research is essential to identify and mitigate the underlying responsible factors.