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At present, there is no available method to study the in vivo microstructures of the airway wall (epithelium, smooth muscle, adventitia, basement membrane, glands, cartilage). Currently, we rely on ex vivo histologic evaluation of airway biopsies. To overcome this obstacle, we have developed an endoscopic ultrahigh-resolution diffractive optical coherence tomography (OCT) system, operating at a wavelength of 800 nm, to non-invasively study the in vivo microstructures of the airway wall. Prior to human study, validation of diffractive OCT's ability to quantitate airway microstructural components is required.To validate and demonstrate the accuracy of this OCT system, we used an ovine model to image small airways (∼ 2 mm in diameter). Histologic samples and correlated OCT images were matched. The cross-sectional area of the airway wall, lumen, and other microstructures were measured and compared.A total of 27 sheep were studied from which we identified 39 paired OCT-histology airway images. We found strong correlations between the OCT and the histology measurements of the airway wall area and the microstructural area measurements of the epithelium, basement membrane, airway smooth muscle, glands, cartilage, and adventitia. The correlations ranged from r=0.61 (p0.001) for the epithelium to r=0.86 (p0.001) for the adventitia with the correlation between the OCT and the histology measurements for the entire airway wall of r=0.76 (p0.001).Given the high degree of correlation, these data validate the ability to acquire and quantify in vivo microscopic level imaging with this newly developed 800nm ultra-high resolution diffractive OCT system.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene (SOD1) are associated with ∼20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouseSod1gene, leading to mutant SOD1G85Rprotein expression. HeterozygousSod1G85Rmutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygousSod1G85Rmice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar toSod1knock-out mice, suggesting theSod1G85Rphenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected humanTgSOD1G93Atransgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. TheSod1G85Rknock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis is a devastating disease involving the progressive loss of motor neurons and motor function for which there is currently no cure. Understanding biological mechanisms leading to motor neuron death is critical for developing new treatments. Using a new knock-in mutant mouse model carrying aSod1mutation that causes ALS in patients, and in the mouse, causes a limited neurodegenerative phenotype similar toSod1loss-of-function, we show that cholesterol synthesis pathway genes are up-regulated in mutant motor neurons, whereas the same genes are down-regulated in transgenicSOD1mice with a severe phenotype. Our data implicate dysregulation of cholesterol or other related lipid genes in ALS pathogenesis and provide new insights that could contribute to strategies for disease intervention.

Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 10

Background: HIV is associated with accelerated decline in lung function and increased risk for chronic obstructive pulmonary disease (COPD). Recently, there has been growing attention toward the impairment in the diffusing capacity of the lungs for carbon monoxide (DLCO), a marker of pulmonary gas exchange, observed among persons living with HIV. Although increased emphysema can contribute to the DLCO impairment observed, other factors may drive this association. Methods: Using cross-sectional data from the Study of HIV in the Etiology of Lung Disease, we studied the association between HIV and DLCO independent of emphysema. We also analyzed the joint influence of HIV and COPD on DLCO impairment. An analysis was conducted among 339 participants (229 with HIV) with lung function and chest CT imaging data. Multivariable regression models were generated with percent predicted DLCO and odds of DLCO impairment as outcomes. Results: After adjusting for confounders, including emphysema severity, HIV was associated with lower DLCO (β −4.02%; P = 0.020) and higher odds of DLCO impairment (odds ratio 1.93; P = 0.017). Even among those without COPD, HIV was independently associated with lower DLCO (β −3.89%; P = 0.049). Compared with HIV-uninfected participants without COPD, those with both HIV and COPD experienced the greatest impairment in DLCO (β −14.81; P < 0.001). Conclusions: HIV is associated with impaired pulmonary gas exchange independent of emphysema severity. Our data also suggest a potentially additive influence between HIV and COPD on DLCO impairment. Further studies should investigate the other factors, including pulmonary vascular disease, which may contribute to DLCO impairment among persons living with HIV.

Supplementary Fig 1: Tumor volume determination by high resolution computed tomography (HRCT) scan. Supplementary Fig 2: Quantification of tumor perfusion by contrast enhanced CT imaging.

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Expansions of a G(4)C(2) repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Using C9-ALS/FTD patient derived cells and C9ORF72 BAC transgenic mice, we have generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G(4)C(2) repeat containing transcripts and effectively suppress tissue levels of polyGP dipeptides. ASOs with reduced phosphorothioate content showed improved tolerability without sacrificing efficacy. In a single patient harboring mutant C9ORF72 with the G(4)C(2) repeat expansion, repeated dosing by intrathecal delivery of the optimal ASO was well tolerated, leading to significant reductions in levels of CSF polyGP. This report provides insight into the impact of nucleic acid chemistry on toxicity and for the first time demonstrates the feasibility of clinical suppression of the C9ORF72 gene. Further clinical trials will be required to demonstrate safety and efficacy of this therapy in patients with C9ORF72 gene mutations.

ALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize mutant SOD1 in vitro. Further, SOD1 expression levels were enhanced and the physiological subcellular localization of mutant SOD1 was restored upon co-expression of anti-SOD1 nanobodies in immortalized cells. In human motor neurons harboring the SOD1 A4V mutation, anti-SOD1 nanobody expression promoted neurite outgrowth, demonstrating a protective effect of anti-SOD1 nanobodies in otherwise unhealthy cells. In vitro assays revealed that an anti-SOD1 nanobody exhibited selectivity for human mutant SOD1 over endogenous murine SOD1, thus supporting the preclinical utility of anti-SOD1 nanobodies for testing in animal models of ALS. In sum, the anti-SOD1 nanobodies developed and presented herein represent viable biologics for further preclinical testing in human and mouse models of ALS.

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability. Analysis of age of onset and disease duration in a large, international cohort of people with SOD1-ALS shows that there is a distinct phenotype and that onset and progression are decoupled., United Kingdom, Medical Research Council; Economic and Social Research Council; European Community’s Health Seventh Framework Programme; European Research Council (ERC); Horizon 2020; Framework Programme; Programme Grants for Applied Research; Research and Innovation Programme; Avexis/Novartis; United Kingdom Dementia Research Institute; National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust; King’s College London; Motor Neurone Disease Association; ALS Association; Psychiatry Research Trust; Health Holland, Top Sector Life Sciences & Health; ALS Foundation Netherlands

Introduction: Antiplatelet therapy has been associated with fewer exacerbations and reduced respiratory symptoms in chronic obstructive pulmonary disease (COPD). Whether platelet activation is associated with respiratory symptoms in COPD is unknown. Methods: Former smokers with spirometry-confirmed COPD had urine 11-dehydro-thromboxane B2 (11dTxB2), plasma soluble CD40L (sCD40L), and soluble P-selectin (sP-selectin) repeatedly measured during a 6- to 9-month study period. Multivariate mixed-effects models adjusted for demographics, clinical characteristics, and medication use evaluated the association of each biomarker with respiratory symptoms, health status, and quality of life. Results: Among 169 participants (average age 66.5±8.2 years, 51.5% female, 47.5±31 pack years, forced expiratory volume in 1 second percent predicted 53.8±17.1), a 100% increase in 11dTxB2 was associated with worse respiratory symptoms reflected by higher scores on the COPD Assessment Test (β 0.77, 95% confidence interval [CI]: 0.11–1.4) and Ease of Cough and Sputum Clearance Questionnaire β 0.77, 95%CI: 0.38–1.2, worse health status (Clinical COPD Questionnaire β 0.13, 95%CI: 0.03-0.23) and worse quality of life (St George’s Respiratory Questionnaire β 1.9, 95%CI: 0.39-3.4). No statistically significant associations were observed for sCD40L or sP-selectin. There was no consistent statistically significant effect modification of the relationship between urine 11dTxB2 and respiratory outcomes by history of cardiovascular disease, subclinical coronary artery disease, antiplatelet therapy, or COPD severity. Conclusions: In stable moderate-severe COPD, elevated urinary11dTxB2, a metabolite of the platelet activation product thromboxane A2, was associated with worse respiratory symptoms, health status, and quality of life.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease for which there is currently no robust therapy. Recent progress in understanding ALS disease mechanisms and genetics in combination with innovations in gene modulation strategies creates promising new options for the development of ALS therapies. In recent years, six gene modulation therapies have been tested in ALS patients. These target gain-of-function pathology of the most common ALS genes, SOD1, C9ORF72, FUS, and ATXN2, using adeno-associated virus (AAV)-mediated microRNAs and antisense oligonucleotides (ASOs). Here, we review the latest clinical and preclinical advances in gene modulation approaches for ALS, including gene silencing, gene correction, and gene augmentation. These techniques have the potential to positively impact the direction of future research trials and transform ALS treatments for this grave disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01285-w.

In vivo imaging and quantification of the microstructures of small airways in three dimensions (3D) allows a better understanding and management of airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). At present, the resolution and contrast of the currently available conventional optical coherence tomography (OCT) imaging technologies operating at 1300 nm remain challenging to directly visualize the fine microstructures of small airways in vivo.We developed an ultrahigh-resolution diffractive endoscopic OCT at 800 nm to afford a resolving power of 1.7 µm (in tissue) with an improved contrast and a custom deep residual learning based image segmentation framework to perform accurate and automated 3D quantification of airway anatomy.The 800-nm diffractive OCT enabled the direct delineation of the structural components in the small airway wall in vivo. We further first demonstrated the 3D anatomic quantification of critical tissue compartments of small airways in sheep using the automated segmentation method.The deep learning assisted diffractive OCT provides a unique ability to access the small airways, directly visualize and quantify the important tissue compartments, such as airway smooth muscle, in the airway wall in vivo in 3D.These pilot results suggest a potential technology for calculating volumetric measurements of small airways in patients in vivo.

A large G4C2-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing transcripts in multiple cellular models and C9BAC transgenic mice. We optimize stereopure oligonucleotides that act through this site, and we demonstrate that their preferential activity depends on both backbone stereochemistry and asymmetric wing design. In mice, stereopure oligonucleotides produce durable depletion of pathogenic signatures without disrupting protein expression. These oligonucleotides selectively protect motor neurons harboring C9orf72-expansion mutation from glutamate-induced toxicity. We hypothesize that targeting C9orf72 with stereopure oligonucleotides may be a viable therapeutic approach for the treatment of C9orf72-associated neurodegenerative disorders., C9orf72 expansion mutations are the most common genetic cause of ALS and FTD, which have limited therapies. The authors generate stereopure oligonucleotides that selectively deplete expansion-containing transcripts and protect against expansion-associated pathologies in preclinical models.

The Losartan Effects on Emphysema Progression (LEEP) trial was designed to test the hypothesis that losartan slows progression of emphysema in chronic obstructive pulmonary disease (COPD) patients (NCT00720226). It was conducted by the Pulmonary Trials Cooperative consortium, in collaboration with the American Lung Association Airways Clinical Research Centers network. We describe the design of the trial and challenges for recruitment and follow-up of participants. LEEP is a placebo-controlled, parallel randomized trial, allocation ratio of 1:1, with a planned sample size of 220. Primary eligibility criteria were mild emphysema based on high-resolution computed tomography (HRCT) scans with 5% to 35% voxels

A hexanucleotide repeat expansion (HRE) consisting of GGGGCC24+ in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are fatal neurodegenerative diseases with no current approved treatments that significantly slow disease progression or extend life expectancy. Several hypotheses have emerged to explain how this HRE causes neuronal death, including C9ORF72 haploinsufficiency, sequestration of RNA-binding proteins in the nucleus, and production of dipeptide repeat proteins. In the present study we used a CRISPR/Cas9 gene-editing approach to remove the HRE from the C9ORF72 genomic locus, designing guide RNAs (gRNAs) flanking the HRE, and delivered Cas9 and gRNAs using adeno-associated virus serotype 9 (AAV9) vectors. Here, we demonstrate successful excision of the HRE in C9ORF72 in primary cortical neurons and brains of three mouse models containing the C9ORF72 expanded HRE (ranging from 500-600 repeats) as well as in patient-derived iPSC motor neurons and brain organoids (450 repeats). This resulted in a reduction of RNA foci, poly-dipeptides and haploinsufficiency, the major hallmarks of C9-ALS/FTD, making this an extremely attractive therapeutic approach to these diseases.

STRUCTURED ABSTRACTBackground and ObjectivesMuscular dystrophies associated with decreased sarcolemma integrity lack validated clinical measures of sarcolemma fragility that can be used to assess disease progression and the effects of therapies designed to reduce sarcolemma fragility. We conducted a pilot study to test the hypothesis that physical activity leads to significant changes in muscle-derived plasma enzymes in participants with “fragile sarcolemmal muscular dystrophies” (FSMD).MethodsWe enrolled ambulatory individuals clinically affected with genetically confirmed FSMD neither taking anti-inflammatory medications nor having relevant co-morbidities for an inpatient study. Over five days, blood samples at 20 time points were obtained. Plasma enzymes alanine and aspartate aminotransferase (ALT, AST), creatine kinase (CK), and lactate dehydrogenase (LDH), all found in muscle, were measured before and after routine morning activities and motor function testing. Analysis of Z-transformed time series data led to feature and kinetic models that revealed activity-dependent feature and kinetic parameters.ResultsAmong the 11 enrolled participants, (LGMD Type 2B/R2 Dysferlin-related (4F/1M), LGMD Type 2L/R12 Anoctamin-5-related (3F/2M), LGMD Type 2I/R9 FKRP-related (1M)), plasma enzymes increased with activity. The average % change +/- SEM with morning activity across all participants was ALT 12.8 ± 2.8%, AST 11.6 ± 2.9%, CK 12.9 ± 2.8%, and LDH 12.2 ± 3.9%, suggesting the increases originate from the same stimulated source, presumably skeletal muscle. For ALT, AST, CK, and LDH, characteristic kinetic features include (a) elevated enzyme activities on arrival that decreased overnight; (b) a longer decay trend observed over the week, and (c) for ALT, AST, and CK, a similar decay trend observed with post-morning activity blood draws.DiscussionControlled activity-dependent changes in plasma ALT, AST, and CK on time scales of days to weeks can serve as common outcome measures for sarcolemma integrity and may be efficient and effective tools for monitoring disease progression and treatment efficacy for both individuals and patient populations. In addition, this study provides data that may benefit patient management as it can inform guidance on duration and type of activity that minimizes muscle damage.

Background Chronic respiratory disease represents an important comorbidity for persons living with HIV (PLWH). HIV itself is associated with greater impairment in lung function. We aimed to determine the association between declining lung function and both quality of life (QOL) and health care utilization for PLWH. Methods Using longitudinal data from the Study of HIV Infection in the Etiology of Lung Disease 2009-2017, we studied the association between changes in lung function and both QOL and acute care events (emergency department visit or hospitalization). The Medical Outcomes Studies-HIV Questionnaire provided QOL domains. Multivariable regression models were performed with generalized estimating equations accounting for 1499 participants, 485 with HIV, contributing 10,825 spirometry visits. Results Among PLWH, decreased FEV1 was associated with worse physical health for those with higher viral load [β: -1.66, 95% confidence interval (CI): -3.11 to -0.39] compared to those with viral suppression (β: -0.58, 95% CI: -1.06 to -0.162), even in those without airflow obstruction. Lower FEV1 was also associated with increased odds of both emergency department (odds ratio: 1.21, 95% CI: 1.09 to 1.34) and inpatient (odds ratio: 1.26, 95% CI: 1.12 to 1.42) hospitalizations for PLWH. Lung function was not associated with increased odds of acute care events for HIV-uninfected participants. Conclusions FEV1 declines represent an independent predictor of QOL and acute care events among PLWH. Although the generalizability of these results may be limited, because of the high-risk population included, findings suggest that care for PLWH should involve monitoring FEV1 over time, especially in those with poor virologic control, with emphasis on the development and implementation of interventions to mitigate lung function decline.

Significance MicroRNAs (miRNAs) are abundant inside cells, where they regulate gene expression posttranscriptionally, but are also found in circulation as remarkably stable extracellular constituents of body fluids such as human blood plasma and cerebrospinal fluid. We observed that these circulating miRNAs are predominantly associated with free Argonaut 2 (AGO2) complexes that are accessible to immunoprecipitation by AGO2 antibodies and are able to base-pair with complementary target RNAs, suggesting that, under normal physiological conditions, circulating miRNAs are largely contained in functional miRNA-mediated silencing complexes (miRISCs). However, we observe that, under certain pathological conditions, more miRNAs become associated with complexes other than free AGO2/miRISC, suggesting that the assortment of circulating miRNAs into distinct complexes offers a potential new dimension to miRNA-based diagnostics., MicroRNAs (miRNAs) function cell-intrinsically to regulate gene expression by base-pairing to complementary mRNA targets while in association with Argonaute, the effector protein of the miRNA-mediated silencing complex (miRISC). A relatively dilute population of miRNAs can be found extracellularly in body fluids such as human blood plasma and cerebrospinal fluid (CSF). The remarkable stability of circulating miRNAs in such harsh extracellular environments can be attributed to their association with protective macromolecular complexes, including extracellular vesicles (EVs), proteins such as Argonaut 2 (AGO2), or high-density lipoproteins. The precise origins and the potential biological significance of various forms of miRNA-containing extracellular complexes are poorly understood. It is also not known whether extracellular miRNAs in their native state may retain the capacity for miRISC-mediated target RNA binding. To explore the potential functionality of circulating extracellular miRNAs, we comprehensively investigated the association between circulating miRNAs and the miRISC Argonaute AGO2. Using AGO2 immunoprecipitation (IP) followed by small-RNA sequencing, we find that miRNAs in circulation are primarily associated with antibody-accessible miRISC/AGO2 complexes. Moreover, we show that circulating miRNAs can base-pair with a target mimic in a seed-based manner, and that the target-bound AGO2 can be recovered from blood plasma in an ∼1:1 ratio with the respective miRNA. Our findings suggest that miRNAs in circulation are largely contained in functional miRISC/AGO2 complexes under normal physiological conditions. However, we find that, in human CSF, the assortment of certain extracellular miRNAs into free miRISC/AGO2 complexes can be affected by pathological conditions such as amyotrophic lateral sclerosis.

Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS.

Objective To investigate neurodegenerative and inflammatory biomarkers in people with amyotrophic lateral sclerosis (PALS), evaluate their predictive value for ALS progression rates, and assess their utility as pharmacodynamic biomarkers for monitoring treatment effects. Methods De‐identified, longitudinal plasma, and cerebrospinal fluid (CSF) samples from PALS (n = 108; 85 with samples from ≥2 visits) and controls without neurological disease (n = 41) were obtained from the Northeast ALS Consortium (NEALS) Biofluid Repository. Seventeen of 108 PALS had familial ALS, of whom 10 had C9orf72 mutations. Additional healthy control CSF samples (n = 35) were obtained from multiple sources. We stratified PALS into fast‐ and slow‐progression subgroups using the ALS Functional Rating Scale‐Revised change rate. We compared cytokines/chemokines and neurofilament (NF) levels between PALS and controls, among progression subgroups, and in those with C9orf72 mutations. Results We found significant elevations of cytokines, including MCP‐1, IL‐18, and neurofilaments (NFs), indicators of neurodegeneration, in PALS versus controls. Among PALS, these cytokines and NFs were significantly higher in fast‐progression and C9orf72 mutation subgroups versus slow progressors. Analyte levels were generally stable over time, a key feature for monitoring treatment effects. We demonstrated that CSF/plasma neurofilament light chain (NFL) levels may predict disease progression, and stratification by NFL levels can enrich for more homogeneous patient groups. Interpretation Longitudinal stability of cytokines and NFs in PALS support their use for monitoring responses to immunomodulatory and neuroprotective treatments. NFs also have prognostic value for fast‐progression patients and may be used to select similar patient subsets in clinical trials.

Rationale: Permanent lung function impairment after active tuberculosis infection is relatively common. It remains unclear which spirometric pattern is most prevalent after tuberculosis. Objectives: Our objective was to elucidate the impact of active tuberculosis survival on lung health in the Strong Heart Study (SHS), a population of American Indians historically highly impacted by tuberculosis. As arsenic exposure has also been related to lung function in the SHS, we also assessed the joint effect between arsenic exposure and past active tuberculosis. Methods: The SHS is an ongoing population-based, prospective study of cardiovascular disease and its risk factors in American Indian adults. This study uses tuberculosis data and spirometry data from the Visit 2 examination (1993–1995). Prior active tuberculosis was ascertained by a review of medical records. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), and FEV(1)/FVC were measured by spirometry. An additional analysis was conducted to evaluate the potential association between active tuberculosis and arsenic exposure. Results: A history of active tuberculosis was associated with reduced percent predicted FVC and FEV(1), an increased odds of airflow obstruction (odds ratio = 1.45, 95% confidence interval = 1.08–1.95), and spirometric restrictive pattern (odds ratio = 1.73, 95% confidence interval = 1.24–2.40). These associations persisted after adjustment for diabetes and other risk factors, including smoking. We also observed the presence of cough, phlegm, and exertional dyspnea after a history of active tuberculosis. In the additional analysis, increasing urinary arsenic concentrations were associated with decreasing lung function in those with a history of active tuberculosis, but a reduced odds of active tuberculosis was found with elevated arsenic. Conclusions: Our findings support existing knowledge that a history of active tuberculosis is a risk factor for long-term respiratory impairment. Arsenic exposure, although inversely associated with prior active tuberculosis, was associated with a further decrease in lung function among those with a prior active tuberculosis history. The possible interaction between arsenic and tuberculosis, as well as the reduced odds of tuberculosis associated with arsenic exposure, warrants further investigation, as many populations at risk of developing active tuberculosis are also exposed to arsenic-contaminated water.