Biological Age, Chronological Age and Survival in Pulmonary Fibrosis: A Causal Mediation Analysis.

RATIONALE: Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. OBJECTIVES: To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. METHODS: Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis (IPF) discovery cohort. Proteins mediating this relationship after adjustment for false discovery were advanced for testing in an independent ILD validation cohort and explored in a chronic obstructive pulmonary disease (COPD) cohort. A proteomic-based measure of biological age was constructed and survival analysis performed assessing the impact of biological age and peripheral blood telomere length on the chronological age-survival relationship. RESULTS: Twenty-two proteins mediated the chronological age-survival relationship after adjustment for false discovery in the IPF discovery cohort (n=874), with nineteen remaining significant mediators of this relationship in the ILD validation cohort (n=983) and one mediating this relationship in the COPD cohort. Latent transforming growth factor beta binding protein 2 and ectodysplasin A2 receptor showed the strongest mediation across cohorts. A proteomic measure of biological age completely attenuated the chronological age-survival association and better discriminated survival than chronological age. Results were robust to adjustment for peripheral blood telomere length, which did not mediate the chronological age-survival relationship. CONCLUSIONS: Molecular measures of aging completely mediate the relationship between chronological age and survival, suggesting that chronological age has no direct effect on ILD survival.

Machine Learning of Plasma Proteomics Classifies Diagnosis of Interstitial Lung Disease.

Rationale: Distinguishing connective tissue disease-associated interstitial lung disease (CTD-ILD) from idiopathic pulmonary fibrosis (IPF) can be clinically challenging. Objectives: To identify proteins that separate and classify patients with CTD-ILD and those with IPF. Methods: Four registries with 1,247 patients with IPF and 352 patients with CTD-ILD were included in analyses. Plasma samples were subjected to high-throughput proteomics assays. Protein features were prioritized using recursive feature elimination to construct a proteomic classifier. Multiple machine learning models, including support vector machine, LASSO (least absolute shrinkage and selection operator) regression, random forest, and imbalanced Random Forest, were trained and tested in independent cohorts. The validated models were used to classify each case iteratively in external datasets. Measurements and Main Results: A classifier with 37 proteins (proteomic classifier 37 [PC37]) was enriched in the biological process of bronchiole development and smooth muscle proliferation and immune responses. Four machine learning models used PC37 with sex and age score to generate continuous classification values. Receiver operating characteristic curve analyses of these scores demonstrated consistent areas under the curve of 0.85-0.90 in the test cohort and 0.94-0.96 in the single-sample dataset. Binary classification demonstrated 78.6-80.4% sensitivity and 76-84.4% specificity in the test cohort and 93.5-96.1% sensitivity and 69.5-77.6% specificity in the single-sample classification dataset. Composite analysis of all machine learning models confirmed 78.2% (194 of 248) accuracy in the test cohort and 82.9% (208 of 251) in the single-sample classification dataset. Conclusions: Multiple machine learning models trained with large cohort proteomic datasets consistently distinguished CTD-ILD from IPF. Many of the identified proteins are involved in immune pathways. We further developed a novel approach for single-sample classification, which could facilitate honing the differential diagnosis of ILD in challenging cases and improve clinical decision making.

Calcium and Phosphate Disorders: Core Curriculum 2024.

Maintaining normal calcium and phosphate homeostasis is essential for optimal cellular, metabolic, and organ function. Parathyroid hormone, fibroblast growth factor 23, and 1,25-dihydroxyvitamin D regulate calcium and phosphate homeostasis via multiple interlinked feedback loops, receptors, ion channels, and transporters. Following an initial overview of the stimuli and effects of the different hormonal regulators, this installment of AJKD's Core Curriculum in Nephrology reviews the physiology and pathophysiology of calcium and phosphate disorders through the lens of a series of illustrative cases. The cases span clinical conundrums commonly encountered by nephrologists in their daily clinical practice and other less common disorders. Some of the cases present in the outpatient clinic setting and others in the inpatient hospital setting. Patients with normal kidney function, chronic kidney disease, kidney failure, and acute kidney injury are all represented. Some of the disorders are iatrogenic, and some are due to native disease. All demonstrate key aspects of pathophysiology that are essential knowledge for nephrology clinicians of all career stages.

Local heterogeneity of normal lung parenchyma and small airways disease are associated with COPD severity and progression.

BACKGROUND: Small airways disease (SAD) is a major cause of airflow obstruction in COPD patients and has been identified as a precursor to emphysema. Although the amount of SAD in the lungs can be quantified using our Parametric Response Mapping (PRM) approach, the full breadth of this readout as a measure of emphysema and COPD progression has yet to be explored. We evaluated topological features of PRM-derived normal parenchyma and SAD as surrogates of emphysema and predictors of spirometric decline. METHODS: PRM metrics of normal lung (PRMNorm) and functional SAD (PRMfSAD) were generated from CT scans collected as part of the COPDGene study (n = 8956). Volume density (V) and Euler-Poincaré Characteristic (χ) image maps, measures of the extent and coalescence of pocket formations (i.e., topologies), respectively, were determined for both PRMNorm and PRMfSAD. Association with COPD severity, emphysema, and spirometric measures were assessed via multivariable regression models. Readouts were evaluated as inputs for predicting FEV1 decline using a machine learning model. RESULTS: Multivariable cross-sectional analysis of COPD subjects showed that V and χ measures for PRMfSAD and PRMNorm were independently associated with the amount of emphysema. Readouts χfSAD (ß of 0.106, p < 0.001) and VfSAD (ß of 0.065, p = 0.004) were also independently associated with FEV1% predicted. The machine learning model using PRM topologies as inputs predicted FEV1 decline over five years with an AUC of 0.69. CONCLUSIONS: We demonstrated that V and χ of fSAD and Norm have independent value when associated with lung function and emphysema. In addition, we demonstrated that these readouts are predictive of spirometric decline when used as inputs in a ML model. Our topological PRM approach using PRMfSAD and PRMNorm may show promise as an early indicator of emphysema onset and COPD progression.

τ $$ \tau $$ -Inflated beta regression model for censored recurrent events.

This research introduces a multivariate τ $$ \tau $$ -inflated beta regression ( τ $$ \tau $$ -IBR) modeling approach for the analysis of censored recurrent event data that is particularly useful when there is a mixture of (a) individuals who are generally less susceptible to recurrent events and (b) heterogeneity in duration of event-free periods amongst those who experience events. The modeling approach is applied to a restructured version of the recurrent event data that consists of censored longitudinal times-to-first-event in τ $$ \tau $$ length follow-up windows that potentially overlap. Multiple imputation (MI) and expectation-solution (ES) approaches appropriate for censored data are developed as part of the model fitting process. A suite of useful analysis outputs are provided from the τ $$ \tau $$ -IBR model that include parameter estimates to help interpret the (a) and (b) mixture of event times in the data, estimates of mean τ $$ \tau $$ -restricted event-free duration in a τ $$ \tau $$ -length follow-up window based on a patient's covariate profile, and heat maps of raw τ $$ \tau $$ -restricted event-free durations observed in the data with censored observations augmented via averages across MI datasets. Simulations indicate good statistical performance of the proposed τ $$ \tau $$ -IBR approach to modeling censored recurrent event data. An example is given based on the Azithromycin for Prevention of COPD Exacerbations Trial.

Change in motivational bias during treatment predicts outcome in anorexia nervosa.

OBJECTIVE: Reward and punishment sensitivity are known to be altered in anorexia nervosa (AN). Most research has examined these constructs separately although motivated behavior is influenced by considering both the potential for reward and risk of punishment. The present study sought to compare the relative balance of reward and punishment sensitivity in AN versus healthy controls (HCs) and examine whether motivational bias is associated with AN symptoms and treatment outcomes. METHODS: Adolescents and adults with AN (n = 262) in a partial hospitalization program completed the Eating Disorders Examination Questionnaire (EDE-Q), Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scales, and Sensitivity to Punishment/Sensitivity to Reward Questionnaire (SPSRQ) at admission and discharge. HCs (HC; n = 90) completed the BIS/BAS and SPSRQ. Motivational Bias Scores were calculated to reflect the dominance of reward versus punishment sensitivity. RESULTS: Individuals with AN demonstrated significantly greater bias toward punishment sensitivity than HC. In AN, a bias toward punishment was associated with higher EDE-Q Global score at admission. Change in motivational bias during treatment predicted EDE-Q Global scores, but not BMI, at discharge, with greater increases in reward sensitivity or greater decreases in punishment sensitivity during treatment predicting lower eating pathology. Similar findings were observed using the BIS/BAS and SPSRQ. DISCUSSION: Change in motivational bias during treatment is associated with improved outcomes in AN. However, it appears that much of the change in motivational bias can be attributed to changes in punishment sensitivity, rather than reward sensitivity. Future research should examine the mechanisms underlying punishment sensitivity decreases during treatment. PUBLIC SIGNIFICANCE: Sensitivity to reward and punishment may be important treatment targets for individuals with anorexia nervosa (AN). To date, most research has considered reward and punishment sensitivity separately, rather than examining their relationship to each other. We found that the balance of reward and punishment sensitivity (i.e., motivational bias) differs between healthy controls and those with AN and that this bias is associated with eating disorder symptoms and treatment outcome.

Market making and the production of nurses for export: a case study of India-UK health worker migration.

BACKGROUND: High-income countries increasingly look to the international recruitment of health workers to address domestic shortages, especially from low-income and middle-income countries. We adapt conceptual frameworks from migration studies to examine the networked and commercialised nature of the Indian market for nurse migration to the UK. METHODS: We draw on data from 27 expert interviews conducted with migration intermediaries, healthcare providers and policymakers in India and the UK. FINDINGS: India-UK nurse migration occurs within a complex and evolving market encompassing ways to educate, train and recruit nursing candidates. For-profit actors shape the international orientation of nursing curricula, broker on-the-job training and offer language, exam and specialised clinical training. Rather than merely facilitate travel, these brokers produce both generic, emigratory nurses as well as more customised nurses ready to meet specific shortages in the UK. DISCUSSION: The dialectic of producing emigratory and customised nurses is similar to that seen in the Post-Fordist manufacturing model characterised by flexible specialisation and a networked structure. As the commodity in this case are people attempting to improve their position in life, these markets require attention from health policy makers. Nurse production regimes based on international market opportunities are liable to change, subjecting nurses to the risk of having trained for a market that can no longer accommodate them. The commercial nature of activities further entrenches existing socioeconomic inequalities in the Indian nurse force. Negative repercussions for the source healthcare system can be anticipated as highly qualified, specialised nurses leave to work in healthcare systems abroad.

Chronic inflammation is associated with worsening working memory performance: Preliminary evidence from a diverse, longitudinal cohort of adolescents and young adults.

Many depressed individuals experience cognitive difficulties that persist when depression is in remission. Inflammation is hypothesized to play a role in cognitive dysfunction in depression; however, many aspects of this relationship are not well characterized. The current study examined whether inflammation is associated with specific cognitive deficits in individuals with a history of depression and with progressively worsening working memory over time. Adolescents who participated in a prospective, longitudinal study of adolescent-onset depression were recruited to complete a follow-up cognitive assessment. The sample was comprised of 82 participants (52.4% female; 37.8% white; 42.7% low socioeconomic status) who were aged 22.61 years (SD = 1.50) at the time of the follow-up cognitive assessment. Prior to the follow-up cognitive assessment, they had completed an average of 6.24 (SD = 1.80) prior annual assessments over 6.24 years (SD = 2.08) as part of the parent longitudinal study in which C-reactive protein (CRP), depressive symptoms, and working memory were assessed repeatedly. First, using linear regression, we tested whether individuals exhibiting inflammation (CRP ≥3 mg/L) at multiple timepoints and a history of likely depression (Children's Depression Inventory ≥19) exhibited differentially worse executive functioning, episodic memory, or psychomotor speed. Second, using hierarchical linear modeling, we tested whether the combination of inflammation and likely past depression was associated with poorer working memory over time. Chronic inflammation was associated with worsening working memory over time, but no significant associations were observed in cross-sectional analyses. These preliminary data indicate that chronic inflammation may lead to progressive decline in working memory over time.

Results from randomized trial of pirfenidone in patients with chronic rejection (STOP-CLAD study).

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading long-term cause of poor outcomes after transplant and manifests by fibrotic remodeling of small airways and/or pleuroparenchymal fibroelastosis. This study evaluated the effect of pirfenidone on quantitative radiographic and pulmonary function assessment in patients with CLAD. METHODS: We performed a single-center, 6-month, randomized, placebo-controlled trial of pirfenidone in patients with CLAD. Randomization was stratified by CLAD phenotype. The primary outcome for this study was change in radiographic assessment of small airways disease, quantified as percentage of lung volume using parametric response mapping analysis of computed tomography scans (PRMfSAD); secondary outcomes included change in forced expiratory volume in 1 second (FEV1), change in forced vital capacity (FVC), and change in radiographic quantification of parenchymal disease (PRMPD). Linear mixed models were used to evaluate the treatment effect on outcome measures. RESULTS: The goal enrollment of 60 patients was not met due to the coronavirus disease of 2019 pandemic, with 23 patients included in the analysis. There was no significant difference over the study period between the pirfenidone vs placebo groups with regards to the observed change in PRMfSAD (+4.2% vs -0.4%; p = 0.22), FEV1 (-3.5% vs -3.6%; p = 0.97), FVC (-1.9% vs -4.6%; p = 0.41), or PRMPD (-0.6% vs -2.5%; p = 0.30). The study treatment tolerance and adverse events were generally similar between the pirfenidone and placebo groups. CONCLUSIONS: Pirfenidone had no apparent impact on radiographic evidence of allograft dysfunction or pulmonary function decline in a single-center randomized trial of CLAD patients that did not meet enrollment goals but had an acceptable tolerance and side-effect profile.

Exacerbation-like events in the 12 months prior to identification of chronic respiratory conditions in a primary care population.

Initial chronic obstructive lung disease (COPD) pharmacotherapy is based on symptom burden and exacerbation history. Inclusion of inhaled cortico-steroids (ICS) is recommended only for those with a history of exacerbations. This brief report highlights that among individuals with previously unrecognized COPD about 1 in 5 have one or more exacerbation-like events and about 1 in 10 have two or more events in the prior 12 months whether or not they self-report concomitant asthma. Closer attention to prior exacerbation-like event history might lead to more guideline concordant care. In addition, there are two other groups that have impaired but non-obstructive spirometry, some with significant respiratory symptom burden who have frequencies of exacerbation-like events similar to those meeting COPD spirometry criteria. To date we have little guidance for treatment of these individuals.

Familial Variability of Disease Severity in Adult Patients With ADPKD.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity. Methods: To better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity. Results: Marked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = <0.001). Conclusion: Using objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.

Association between CFTR modulators and changes in iron deficiency markers in cystic fibrosis.

BACKGROUND: Iron deficiency (ID) is a common extrapulmonary manifestation in cystic fibrosis (CF). CF transmembrane conductance regulator (CFTR) modulator therapies, particularly highly-effective modulator therapy (HEMT), have drastically improved health status in a majority of people with CF. We hypothesize that CFTR modulator use is associated with improved markers of ID. METHODS: In a multicenter retrospective cohort study across 4 United States CF centers 2012-2022, the association between modulator therapies and ID laboratory outcomes was estimated using multivariable linear mixed effects models overall and by key subgroups. Summary statistics describe the prevalence and trends of ID, defined a priori as transferrin saturation (TSAT) <20 % or serum iron <60 µg/dL (<10.7 µmol/L). RESULTS: A total of 568 patients with 2571 person-years of follow-up were included in analyses. Compared to off modulator therapy, HEMT was associated with +8.4 % TSAT (95 % confidence interval [CI], +6.3-10.6 %; p < 0.0001) and +34.4 µg/dL serum iron (95 % CI, +26.7-42.1 µg/dL; p < 0.0001) overall; +5.4 % TSAT (95 % CI, +2.8-8.0 %; p = 0.0001) and +22.1 µg/dL serum iron (95 % CI, +13.5-30.8 µg/dL; p < 0.0001) in females; and +11.4 % TSAT (95 % CI, +7.9-14.8 %; p < 0.0001) and +46.0 µg/dL serum iron (95 % CI, +33.3-58.8 µg/dL; p < 0.0001) in males. Ferritin was not different in those taking modulator therapy relative to off modulator therapy. Hemoglobin was overall higher with use of modulator therapy. The prevalence of ID was high throughout the study period (32.8 % in those treated with HEMT). CONCLUSIONS: ID remains a prevalent comorbidity in CF, despite availability of HEMT. Modulator use, particularly of HEMT, is associated with improved markers for ID (TSAT, serum iron) and anemia (hemoglobin).

Design of the SPIROMICS Study of Early COPD Progression: SOURCE Study.

The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Accord-ingly, with National Heart, Lung and Blood Institute support, we initiated the SPIROMICS Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups 0-2 or with Preserved Ratio Impaired Spirometry (PRISm); and an additional n=40 never-smoker controls. Participants undergo baseline and three-year follow-up visits, each including high-resolution computed tomography; respiratory oscillometry and spirometry (pre- and post-bronchodilator administration), exhaled breath condensate (baseline only); and extensive biospecimen collection, including sputum induction. Symptoms, interim healthcare utilization, and exacerbations are captured every six months via follow-up phone calls. An embedded bronchoscopy sub-study involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.

Following the Science? Examining the Issuance of Stay-At-Home Orders Related to COVID-19 by U.S. Governors.

Informed by the public health policymaking literature, this study's objective is to identify scientific, political, social, economic, and external factors related to U.S. governors' decisions to issue stay-at-home orders (SAHOs) in response to the first wave of the COVID-19 pandemic. Public health experts advocate for social distancing to slow the spread of infectious diseases, but government mandates to social distance can impose substantial social and economic costs. This study uses event history analysis to investigate the issuance of COVID-19-related gubernatorial SAHOs during a 41-day period in the 50 U.S. states. The findings indicate that scientific, political, and economic factors were associated with the issuance of SAHOs, but that external considerations played the largest role, particularly those related to the timing of other governors' decisions. This study offers evidence about how some U.S. political leaders balance public health concerns against other considerations and, more broadly, how state governments address crisis-level issues.

Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease.

Chronic kidney disease (CKD) is a global health epidemic that significantly increases mortality due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiac injury in CKD. High serum levels of fibroblast growth factor (FGF) 23 in patients with CKD may contribute mechanistically to the pathogenesis of LVH by activating FGF receptor (FGFR) 4 signaling in cardiac myocytes. Mitochondrial dysfunction and cardiac metabolic remodeling are early features of cardiac injury that predate development of hypertrophy, but these mechanisms of disease have been insufficiently studied in models of CKD. Wild-type mice with CKD induced by adenine diet developed LVH that was preceded by morphological changes in mitochondrial structure and evidence of cardiac mitochondrial and metabolic dysfunction. In bioengineered cardio-bundles and neonatal rat ventricular myocytes grown in vitro, FGF23-mediated activation of FGFR4 caused a mitochondrial pathology, characterized by increased bioenergetic stress and increased glycolysis, that preceded the development of cellular hypertrophy. The cardiac metabolic changes and associated mitochondrial alterations in mice with CKD were prevented by global or cardiac-specific deletion of FGFR4. These findings indicate that metabolic remodeling and eventually mitochondrial dysfunction are early cardiac complications of CKD that precede structural remodeling of the heart. Mechanistically, FGF23-mediated activation of FGFR4 causes mitochondrial dysfunction, suggesting that early pharmacologic inhibition of FGFR4 might serve as novel therapeutic intervention to prevent development of LVH and heart failure in patients with CKD.