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Ilene L Hollin,1 Anne EF Dimmock,2 John FP Bridges,3 Sonye K Danoff,4 Rebecca Bascom21Department of Health Services Administration and Policy, Temple University College of Public Health, Philadelphia, PA, USA; 2Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Penn State University College of Medicine, Hershey, PA, USA; 3Departments of Biomedical Informatics and Surgery, Ohio State University College of Medicine, Columbus, OH, USA; 4Division of Pulmonary Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USAPurpose: Rare diseases present challenges for accessing patient populations to conduct surveys. Clinical Data Research Networks (CDRNs) offer an opportunity to overcome those challenges by providing infrastructure for accessing patients and sharing data. This study aims to demonstrate the feasibility of collecting patient preference information for a rare disease in a CDRN, using idiopathic pulmonary fibrosis as proof of concept.Patients and methods: Utilizing a cohort of idiopathic pulmonary fibrosis (IPF) patients across a CDRN, a discrete choice experiment was administered via electronic and paper methods to collect patient preference information about benefits and risks of two therapeutic options. Survey data were augmented with data from electronic health records and patient-reported outcome surveys.Results: Thirty-three patients completed the preference experiment. The amount of choice attributable to a benefit of slowing of decline in lung function was 36%. Improving efficacy in terms of lung function was 2.16 times as important as improving efficacy in terms of shortness of breath. In terms of side effects, decreasing risk of gastrointestinal problems was 2.6 times as important as decreasing risk of sun sensitivity and 2.4 times as important as decreasing risk of liver injury. In terms of benefit-risk trade-offs, improving efficacy in terms of lung function was 1.6 times as important as decreasing risk of gastrointestinal problems.Conclusion: This study used IPF as a proof of concept to demonstrate the feasibility of collecting patient preference information in a CDRN. The network was advantageous to the study of patient preferences. Future research should continue to explore pathways for the collection and use of patient preference information across networks. The power of consolidated collection efforts may lead to the ability to use preference data to inform decision-making at the regional, specialty, or individual encounter level.Keywords: stated preference methods, discrete choice experiment, patient-centered outcomes research, benefit-risk trade-off

Microscopic polyangiitis (MPA) may present with a syndrome that resembles idiopathic pulmonary fibrosis (IPF). We describe an MPA patient with the clinical presentation of a 'pulmonary-muscle' syndrome in which interstitial lung disease antedated the onset of myopathy. Identification of vasculitis on muscle biopsy was instrumental in recognizing clinical, radiographic, and histopathologic features that were more characteristic of MPA than of IPF. Institution of glucocorticoid and cyclophosphamide therapy led to the induction of a complete remission. The histologic findings in this case implicate subclinical episodes of alveolar hemorrhage as the mechanism of interstitial lung disease in MPA. [ABSTRACT FROM AUTHOR]

The gene for TFII-I, a widely expressed transcription factor, has been localized to an interval of human chromosome 7q11.23 that is commonly deleted in Williams syndrome (WS). The clinical phenotype of WS includes elfin facies, infantile hypercalcemia, supravalvular aortic stenosis, hyperacusis and mental retardation. The WS cognitive profile (WSCP) is notable for the differential impairment of visual–spatial abilities with relative sparing of verbal–linguistic function. Fine mapping of individuals with WS has revealed a close association between deletion of TFII-I and the WSCP. To determine the plausibility of the hypothesis that hemizygous deletion of TFII-I contributes to the WSCP, we have examined the anatomic distribution of TFII-I RNA and protein isoforms in brains from adult and embryonic mice.Our studies show that early in development, TFII-I expression is widespread and nearly uniform throughout the brain. In adult brain, TFII-I protein is present exclusively in neurons. Highest levels of expression are observed in cerebellar Purkinje cells and in hippocampal interneurons. TFII-I immunoreactivity is distinct from that of the related protein, TFII-IRD1, which is also localized to the region of human chromosome 7 deleted in WS. The expression pattern of TFII-I in mouse brain parallels regions in human brain which have been shown to be anatomically and functionally altered in humans with WS. These observations are consistent with the hypothesis that deletion of the gene for TFII-I contributes to the cognitive impairments observed in WS. [Copyright &y& Elsevier]

Abstract Background General transcription factor (TFII-I) is a multi-functional transcription factor encoded by the Gtf2i gene, that has been demonstrated to regulate transcription of genes critical for development. Because of the broad range of genes regulated by TFII-I as well as its potential role in a significant neuro-developmental disorder, developing a comprehensive expression profile is critical to the study of this transcription factor. We sought to define the timing and pattern of expression of TFII-I in post-implantation embryos at a time during which many putative TFII-I target genes are expressed. Findings Antibodies to the N-terminus of TFII-I were used to probe embryonic mouse sections. TFII-I protein is widely expressed in the developing embryo. TFII-I is expressed throughout the period from E8-E16. However, within this period there are striking shifts in localization from cytoplasmic predominant to nuclear. TFII-I expression varies in both a spatial and temporal fashion. There is extensive expression in neural precursors at E8. This expression persists at later stages. TFII-I is expressed in developing lung, heart and gut structures. There is no evidence of isoform specific expression. Available data regarding expression patterns at both an RNA and protein level throughout development are also comprehensively reviewed. Conclusions Our immunohistochemical studies of the temporal and spatial expression patterns of TFII-I in mouse embryonic sections are consistent with the hypothesis that hemizygous deletion of GTF2I in individuals with Williams-Beuren Syndrome contributes to the distinct cognitive and physiological symptoms associated with the disorder.

Objective: The 6-min walk test (6MWT) is a simple test widely used to assess sub-maximal exercise capacity in chronic respiratory diseases. We explored the relationship of 6-min walk distance (6MWD) with measurements of physiological, clinical, radiographic measures in patients with myositis-associated interstitial lung disease (MA-ILD)., Method: We analyzed data from the Abatacept in Myositis Associated Interstitial lung disease (Attack My-ILD) study, a 48-week multicentre randomized trial of patients with anti-synthetase antibodies and active MA-ILD. 6MWD, forced vital capacity (FVC), diffusing capacity (DLCO), high resolution CT, and various physician/patient reported outcome measures were obtained during the trial. Spearman's correlations and repeated-measures analysis with linear mixed-effects models were used to estimate the associations between 6MWD and various physiologic, clinical and radiographic parameters both cross-sectionally and longitudinally., Results: Twenty participants with a median age of 57, 55% male and 85% white were analyzed. Baseline 6MWD did not associate with baseline PFTs. Repeated-measures analysis showed 6MWD over time associated with FVC over time, but not with DLCO. 6MWD over time also correlated with UCSD dyspnea score, Borg scores, as well as global disease activity and muscle strength over time. Emotional role functioning, vitality, general health and physical functioning scores by short form 36 also correlated with 6MWD over time., Conclusions: : Exploratory work in a small cohort of MA-ILD demonstrated 6MWD over time associated with parallel changes in FVC and patient reported outcomes of dyspnea, but not with DLCO. Larger studies are needed to validate the reliability, responsiveness and utility of the 6MWT in MA-ILD., Clinical Trial Registration: ClinicalTrials.gov, NCT03215927., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Interstitial lung disease due to rheumatoid arthritis (RA-ILD) affects a substantial minority of patients with RA, inducing life-altering symptoms, impairing quality of life (QOL) and forcing patients to confront the potential for shortened survival. Dyspnoea is the predominant respiratory symptom of RA-ILD and a strong driver of QOL impairment in patients with it. The D12 is a 12-item questionnaire that assesses the physical and affective components of dyspnoea. It was one of a battery of patient-reported outcomes used in the double-blind, placebo-controlled TRAIL 1 trial of pirfenidone for RA-ILD. There is little information on the reliability, validity or responsiveness of the D12 in RA-ILD., Methods: In accordance with COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) methodology, we conducted analyses on data from the TRAIL 1 trial to assess the measurement properties of the D12., Results: Internal consistency (α=0.95, 0.95, 0.95, 0.95 and 0.96 at baseline, 13, 26, 39 and 52 weeks) and test-retest reliability 0.85 (0.71 to 0.92) exceeded acceptability criteria. Well over the 75% benchmark of hypotheses (43/46=93%) around D12 measurement properties were confirmed. Known-groups validity was supported by significant differences between subgroups of patients with differing levels of dyspnoea (eg, St. George's Respiratory Questionnaire (SGRQ) Activity score ≥50 vs <50, 9.36 (1.27) points, p<0.0001, with a large effect size=1.7) and physiological impairment at baseline. Longitudinal validity was supported by significant associations between D12 and anchor scores over time (eg, at 52 weeks, correlation between D12 change and SGRQ Activity change was 0.54, p<0.0001; between D12 change and Routine Assessment of Patient Index Data (RAPID) Functioning Component was 0.41, p<0.0001). A battery of analyses confirmed the responsiveness of D12 scores for capturing change in dyspnoea over time. We estimated the minimal within-patient change threshold for worsening as 3 points., Conclusions: D12 scores possess acceptable measurement properties in RA-ILD, such that it can be used with confidence in this population to assess dyspnoea severity defined by its physical and affective components. As validation is an ongoing process, and never accomplished in a single study, additional research on the psychometric properties of the D12 in RA-ILD is encouraged., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study investigates cancer risk in idiopathic inflammatory myopathy (IIM) relative to the general population., Methods: We conducted a single-center, retrospective cohort study of IIM patients and malignancy. Myositis-specific and -associated autoantibodies were determined by Euroimmun line blot, enzyme-linked immunosorbent assay, and immunoprecipitation. We calculated standardized prevalence ratios (SPRs) and adjusted for calendar year, age, sex, race, and ethnicity by comparing observed cancers in IIM patients versus expected cancers in the general population using the Surveillance, Epidemiology, and End Results registry., Results: Of 1,172 IIM patients, 203 (17%) patients with a cancer history were studied. Over a median follow-up of 5.2 years, the observed number of IIM patients diagnosed with cancer was increased 1.43-fold (SPR 1.43 [95% confidence interval (95% CI) 1.15-1.77]; P = 0.002). Within 3 years of IIM symptom onset, an increased SPR was observed for anti-transcription intermediary factor 1γ (anti-TIF1γ)-positive patients for ovarian and breast cancer (ovarian SPR 18.39 [95% CI 5.01-47.08], P < 0.001; breast SPR 3.84 [95% CI 1.99-6.71], P < 0.001). As expected, anti-TIF1γ positivity was associated with a significantly elevated SPR; however, only 55% (36 of 66) of all cancers within 3 years of dermatomyositis onset were observed in anti-TIF1γ-positive patients. Other myositis-specific autoantibodies, including anti-Mi-2, anti-small ubiquitin-like modifier activating enzyme (SAE), and anti-nuclear matrix protein 2 (NXP-2), accounted for 26% (17 of 66) of cancers diagnosed within 3 years of dermatomyositis onset. No cancer association, positive or negative, was observed for patients with antisynthetase, anti-melanoma differentiation-associated protein 5 (anti-MDA-5), or anti-hydroxymethylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies., Conclusion: In a tertiary referral center population, anti-TIF1γ was most strongly associated with breast and ovarian cancer. Patients with antisynthetase, anti-MDA-5, or anti-HMGCR antibodies had the same cancer risk as the general population., (© 2022 American College of Rheumatology.)

This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate initial diagnosis being of paramount importance in ensuring appropriate initial management. Equally, case-by-case decisions on monitoring and management are essential, given the varying presentations of F-ILDs and the varying rates of progression. The value of diagnostic tests in risk stratification at presentation and, separately, the importance of a logical monitoring strategy, tailored to manage the risk of progression, are also stressed. The term "progressive pulmonary fibrosis" (PPF) exactly describes the entity that clinicians often face in practice. The importance of using antifibrotic therapy early in PPF (once initial management has failed to prevent progression) is increasingly supported by evidence. Artificial intelligence software for high-resolution computed tomography analysis, although an exciting tool for the future, awaits validation. Guidance is provided on pulmonary rehabilitation, oxygen and the use of non-invasive ventilation focused specifically on the needs of ILD patients with progressive disease. PPF should be differentiated from acute deterioration due to drug-induced lung toxicity or other forms of acute exacerbations. Referral criteria for a lung transplant are discussed and applied to patient needs in severe diseases where transplantation is not realistic, either due to access limitations or transplantation contraindications. In conclusion, expert group consensus guidance is provided on the diagnosis, treatment and monitoring of F-ILDs with specific focus on the recognition of PPF and the management of pulmonary fibrosis progressing despite initial management., Competing Interests: Conflict of interest: S.K. Rajan reports grants to their institution, consulting fees and lecture fees from Cipla and Boehringer Ingelheim; speaker fees from the Indian Chest Society; and support from Cipla to attend a European Respiratory Society meeting, all in the 36 months prior to manuscript submission. V. Cottin reports an unrestricted grant to their institution from Boehringer Ingelheim; consulting fees from Boehringer Ingelheim, Roche, Galapagos, Galecto, Shionogi, Fibrogen, RedX Pharma and PureTech; payment or honoraria and support for attending meetings from Boehringer Ingelheim and Roche; and participation on a data safety monitoring board or advisory board for Roche/Promedior, Celgene/Bristol Myers Squibb and Galapagos, all in the 36 months prior to manuscript submission. R. Dhar reports external expert contracts from Cipla and Boehringer Ingelheim; speaker fees from the Indian Chest Society, Cipla and Boehringer Ingelheim; and support for attendance at a European Respiratory Society meeting from Cipla. S. Danoff reports grant funding from Bristol Myers Squibb (Myositis ILD Trial), Boehringer Ingelheim (INBUILD and INBUILD-ON Trials) and Roche/Genentech (TRAIL Trial); royalties from UpToDate; advisory board fees from Boehringer Ingelheim and Lupin Pharma; payment for presentations from the France Foundation; funding for travel to present lectures from Boehringer Ingelheim; and participation on data safety monitoring boards for Galecto and Galapagos, all in the 36 months prior to manuscript submission; as well as a role as senior medical adviser and interim CMO for the Pulmonary Fibrosis Foundation and membership of the board of directors of the American Thoracic Society. K.R. Flaherty reports research grants paid to their institution by Boehringer Ingelheim; and consulting fees paid to them by Boehringer Ingelheim, Roche/Genentech, Blade Therapeutics, Shionogi, DevPro, AstraZeneca, Pure Health, Fibrogen, Sun Pharmaceuticals, Pliant, United Therapeutics, Arrowhead, Lupin, Polarean and PureTech, all in the 36 months prior to manuscript submission. K.K. Brown reports lung fibrosis research grants from the National Heart, Lung, and Blood Institute; being an external science advisor to AbbVie, CSL Behring, Dispersol, Huitai Biomedicine, Lilly, RedX Pharma, Theravance and Translate Bio; being a DMC chair for Biogen; scientific advisory board membership for Blade Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, DevPro Biopharma, Galapagos NV, Galecto, Open Source Imaging Consortium, Pliant, Sanofi and Third Pole; DMC membership for Humanetics; and a scientific collaboration with Sekisui Medical Co., all in the 36 months prior to manuscript submission; as well as leadership or fiduciary roles for the Fleischner Society and Open Source Imaging Consortium. A. Mohan declares no competing interests. E. Renzoni declares a research contract payment and advisory board meeting payment to their institution by Boehringer Ingelheim; lecture fees paid to their institution by Boehringer Ingelheim, Roche and Chiesi; and registration and travel expenses for the American Thoracic Society conference, paid by Boehringer Ingelheim, all in the 36 months prior to manuscript submission. M. Mohan reports no competing interests. Z. Udwadia reports no competing interests. P. Shenoy reports no competing interests. D. Currow reports intellectual property payments and royalties from Mayne Pharma International Pty Ltd, a manufacturer of sustained-release morphine; and consulting fees from Helsinn Pharmaceuticals, in the 36 months prior to manuscript submission; as well as leadership or fiduciary roles for the Dust Diseases Board of New South Wales and the Board of the Cancer Institute NSW. A. Devraj reports consulting fees from Boehringer Ingelheim, Roche, Galecto, Galapagos, Brainomix and Vicore, all in the 36 months prior to manuscript submission. B. Jankharia reports payment or honoraria to their institution from Cipla India, Lupin India, Boehringer Ingelheim and German Remedies India, all in the 36 months prior to manuscript submission; as well as being a past president of the Indian Musculoskeletal Society and the Indian Radiology and Imaging Association. R. Kulshrestha reports no competing interests. S. Jones reports grants to their institution from Boehringer Ingelheim and Trevi for being Chair of Action for Pulmonary Fibrosis (APF) and President of the European Pulmonary Fibrosis Federation (EU-IPFF) (both these organisations implement projects in partnership with industry; the author is not involved in these projects and does not gain personally); reports payment or honoraria from Boehringer Ingelheim, Vicore and Roche (paid to their institution); and participation on a data safety monitoring board or advisory board as Galecto DSMB for an anti-fibrotic therapy, in the 36 months prior to manuscript submission. C. Ravaglia reports no competing interests. S. Quadrelli reports speaker fees from Boehringer Ingelheim in the 36 months prior to manuscript submission. R. Iyer reports no competing interests. S. Dhooria reports no competing interests. M. Kolb reports research funding for pre-clinical work from Boehringer Ingelheim and Pieris; research funding for a clinical project from Roche; consulting fees from Boehringer Ingelheim, Roche, Horizon, Cipla, AbbVie, Belerophon, Algernon, CSL Behring, United Therapeutics and AstraZeneca; payment or honoraria from Novartis, Boehringer Ingelheim and Roche; payment for court testimony from Roche; participation on a data safety monitoring board or advisory board for Covance and United Therapeutics; and an allowance paid to their institution from the European Respiratory Society relating to their duties as European Respiratory Journal Chief Editor, all in the 36 months prior to manuscript submission. A.U. Wells reports payments or honoraria from Boehringer Ingelheim and Roche; and participation on a data safety monitoring board or advisory board for Boehringer Ingelheim, Roche and Veracyte, all in the 36 months prior to manuscript submission., (Copyright ©The authors 2023.)

Objectives: In dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with an increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies., Methods: Phage ImmunoPrecipitation Sequencing using sera from 43 patients with DM suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins patients with myositis (255 with DM, 28 with antisynthetase syndrome, 40 with immune-mediated necrotising myopathy, 29 with inclusion body myositis and 19 with polymyositis), 80 rheumatological disease controls (25 with Sjogren's syndrome, 25 with systemic lupus erythematosus and 30 with rheumatoid arthritis (RA)) and 200 healthy comparators were screened for anti-SP4 autoantibodies by ELISA. A validation cohort of 46 anti-TIF1γ-positive patient sera from the University of Pittsburgh was also screened for anti-Sp4 autoantibodies., Results: Anti-Sp4 autoantibodies were present in 27 (10.5%) patients with DM and 1 (3.3%) patient with RA but not in other clinical groups. In patients with DM, 96.3% of anti-Sp4 autoantibodies were detected in those with anti-TIF1γ autoantibodies. Among 26 TIF1γ-positive patients with anti-Sp4 autoantibodies, none (0%) had cancer. In contrast, among 35 TIF1γ-positive patients without anti-Sp4 autoantibodies, 5 (14%, p=0.04) had cancer. In the validation cohort, among 15 TIF1γ-positive patients with anti-Sp4 autoantibodies, 2 (13.3%) had cancer. By comparison, among 31 TIF1γ-positive patients without anti-Sp4 autoantibodies, 21 (67.7%, p<0.001) had cancer., Conclusions: Anti-Sp4 autoantibodies appear to identify a subgroup of anti-TIF1γ-positive DM patients with lower cancer risk., Competing Interests: Competing interests: YJ, IP-F, KP, MC-D, MJK, JA, TEL, ET, CVO, SM-K, CC-R, JCM, JMG-J, AS-O'C and ALM report no competing interests. CAM has received support from NIH grant 1K23AR075898 and the Jerome L. Greene Foundation; reconsulting fees from Guidepoint Consultations and Boehringer Ingelheim; and payment for expert testimony from the Department of Justice–Vaccine Injury Compensation Program. BMW received support from NIH grant Z01-DE000704. SD received support grants or contract from BMS, Boehringer-Ingelheim and Genentech/Roche; royalties or licences from UpToDate; consulting fees from Boehringer-Ingelheim; payment for presentations from France Foundation; support for travel from Boehringer-Ingelheim; participates in an advisory board for Galecto and Galapagos; and is a senior medical advisor for the Pulmonary Fibrosis Foundation and the American Thoracic Society. JJP received support from NIH grant K23AR073927; grants or contracts from Pfizer, Kezer and Corbus; royalties from UpToDate; and consulting fees from Pfizer, Kezar, EMD Serono, Proivant and Guidepoint Consultation. RA received grants or contracts from Mallinckrodt, Q32, Pfizer, EMD-Serono and Bristol Myers-Squibb; and consulting fees from Mallinckrodt, EMD Serono, Octapharma, Kezar, CSL Behring, Pfizer, Bristol Myers-Squibb, Astrazeneca, Alexion, Boehringer-Ingelheim, Argenx, Corbus, Roivant, Jannsen, Merck, Kyverna, Galapagos, Actigraph, Abbvie, Scipher, Horizon Therapeutics, Teva and Beigene. LC-S received grants or contracts from Pfizer, Corbus and Kezar; royalties from Inova Diagnostics; consulting fees from Janssen, Boehringer-Ingelheim, Mallinckrodt, EMD-Serono, Argenx, Allogene and Horizon Therapeutics; expert testimony for Bendin Sumrall and Ladner LLC, Feldman, Kleidman Coffey, & Sappe LLP Downs Ward Bender Hauptmann & Herzog, P.A., and Sulloway and Hollis; and patents from Inova Diagnostics and RDL. HBL received support from NIH grant R01GM136724; is a founder of ImmuneID, Portal Bioscience and Alchemab; and is an advisor to TScan Therapeutics., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Patients with anti-melanoma-differentiation-associated 5 (anti-MDA5)-positive dermatomyositis (DM) share several striking similarities to patients with SARS-CoV-2. Our objective was to assess the prevalence of anti-angiotensin converting enzyme-2 (ACE2) immunoglobulin M (IgM) antibodies, found in patients with severe SARS-CoV-2, in two independent anti-MDA5-positive DM cohorts., Methods: Anti-ACE2 IgM antibodies were assayed by enzyme-linked immunosorbent assay (ELISA) in two anti-MDA5-positive DM cohorts: a predominantly outpatient North American cohort (n = 52) and a Japanese cohort enriched for new-onset disease (n = 32). Additionally, 118 patients with SARS-CoV-2 with a spectrum of clinical severity were tested for anti-MDA5 antibodies by ELISA., Results: Five of fifty-two (9.6%) North American patients and five of thirty-two (15%) Japanese patients were positive for anti-ACE2 IgM. In the North American cohort, all five patients with anti-ACE2 IgM antibodies had proximal muscle weakness, had interstitial lung disease, were significantly more likely to receive pulse dose methylprednisolone (80% vs 30%, P = 0.043), and had worse forced vital capacity (median 59% predicted vs 78%, P = 0.056) compared with the anti-ACE2-IgM-negative group. In the Japanese cohort, all five anti-ACE2-IgM-positive patients also required pulse dose methylprednisolone, and three of five (60%) patients died. Japanese patients with anti-ACE2 IgM had significantly worse oxygenation, as defined by a lower partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (233 vs 390, P = 0.021), and a higher alveolar-arterial oxygenation gradient (91 vs 23 mm Hg, P = 0.024) than the IgM-negative group., Conclusion: We describe anti-ACE2 IgM autoantibodies in two independent cohorts with anti-MDA5-positive DM. These autoantibodies may be biomarkers for severe disease and provide insight into disease pathogenesis., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Rationale: Transbronchial lung cryobiopsy (TBLC) has emerged as a less invasive method to obtain a tissue diagnosis in patients with interstitial lung disease (ILD). The diagnostic yield of TBLC compared to surgical lung biopsy (SLB) remains uncertain., Objectives: The aim of this study was to determine the diagnostic accuracy of forceps transbronchial lung biopsy (TBLB) and TBLC compared to SLB when making the final diagnosis based on multidisciplinary discussion (MDD)., Methods: Patients enrolled in the study underwent sequential TBLB and TBLC followed immediately by SLB. De-identified cases, with blinding of the biopsy method, were reviewed by a blinded pathologist and then discussed at a multidisciplinary conference., Main Results: Between August 2013 and October 2017, we enrolled 16 patients. The raw agreement between TBLC and SLB for the MDD final diagnosis was 68.75% with a Cohen's kappa of 0.6 (95% CI 0.39, 0.81). Raw agreement and Cohen's kappa of TBLB versus TBLC and TBLB versus SLB for the MDD final diagnosis were much lower (50%, 0.21 [95% CI 0, 0.42] and 18.75%, 0.08 [95% CI -0.03, 0.19], respectively). TBLC was associated with mild bleeding (grade 1 bleeding requiring suction to clear) in 56.2% of patients., Conclusions: In patients with ILD who have an uncertain type based on clinical and radiographic data and require tissue sampling to obtain a specific diagnosis, TBLC showed moderate correlation with SLB when making the diagnosis with MDD guidance. TBLB showed poor concordance with both TBLC and SLB MDD diagnoses., (© 2021 S. Karger AG, Basel.)

Background: Interstitial lung disease-associated antisynthetase syndrome (AS-ILD) carries significant morbidity and mortality. Corticosteroids and immunosuppressive drugs are the mainstay of treatment. Human immunoglobulin (IVIg), an immunomodulator without immunosuppressive properties, is effective in myositis but the evidence supporting its use in ILD is scarce., Objective: To describe clinical outcomes of AS-ILD patients receiving IVIg., Methods: Retrospective analysis of AS-ILD patients. Linear mixed models using restricted maximum likelihood estimation was used to estimate the change in lung function and corticosteroid dose over time., Results: Data from 17 patients was analyzed. Median follow-up was 24.6 months. Fourteen patients had refractory disease. The mean percent-predicted forced vital capacity (FVC%) (p = 0.048) and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (p = 0.0223) increased over time, while the mean prednisone dose (p < 0.001) decreased over time. Seven patients achieved a >10% increase in FVC%, including two who used IVIg as initial treatment. Five patients showed a >10% increase in DLCO% and TLC%. Nine (53%) patients experienced side effects., Conclusions: IVIg may be a useful complementary therapy in active progressive AS-ILD but is associated with potential side effects. Fssssurther investigation is required to determine the value of IVIg as an initial treatment in AS-ILD., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose: Myositis-associated interstitial lung disease (MA-ILD) is associated with increased mortality, but no prognostic model exists in this population. The ILD-GAP index was developed to predict mortality risk across all subtypes of chronic ILD. The purpose of this study was to validate the ILD-GAP risk prediction model in patients with MA-ILD., Procedures: We completed a retrospective cross-sectional study of patients enrolled in the Johns Hopkins Myositis Center database between 2006 and 2017. Cumulative mortality rates were estimated using the Kaplan-Meier test. Model calibration was determined by using standardized mortality ratios of observed versus expected deaths., Main Findings: 179 participants with MA-ILD were included. The mean baseline percent predicted forced vital capacity was 65.2 ± 20.6%, forced expiratory volume in the first second 65.4 ± 20.4%, and carbon monoxide diffusing capacity 61.6 ± 20.0%. Thirty-two participants died (17.9%). The ILD-GAP model had poor discriminative performance and calibration., Conclusions: The ILD-GAP risk prediction model is a poor predictor of mortality among individuals with MA-ILD. The identification of a better predictive model for MA-ILD is needed to help guide care in this patient population., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Immune checkpoint inhibitors (ICIs) are newer, immunotherapy-based drugs that have been shown to improve survival in advanced non-small cell lung cancer (NSCLC). Unlike traditional chemotherapeutic agents, ICIs work by boosting the body's natural tumor killing response. However, this unique mechanism of action has also led to the recognition of class-specific side effects. Labeled immune-related adverse events, these toxicities can affect multiple organ systems including the lungs. Immune-mediated lung injury because of ICI use, termed checkpoint inhibitor pneumonitis (CIP), occurs in about 3% to 5% of patients receiving ICIs; however, the real-world incidence of this entity may be higher, especially now that ICIs are being used in nonclinical trial settings. In this review, we briefly introduce the biology of ICIs and the indications for ICI use in NSCLC and then discuss the epidemiology and clinical and radiologic manifestations of CIP. Next, we discuss management strategies for CIP, including the current consensus on management of steroid-refractory CIP. Given the nascent nature of this field, we highlight areas of uncertainty and emerging research questions in the burgeoning field of checkpoint inhibitor pulmonary toxicity., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Pirfenidone was approved in October 2014 in the USA for the treatment of idiopathic pulmonary fibrosis. Although not included in the adverse events published in the CAPACITY-1 and CAPACITY-2 or ASCEND trials, hyponatraemia was reported in supplementary data with rate of 3.4% in the active therapy arm versus 0.3% in the placebo arm. We performed a retrospective analysis of patients who were initiated on pirfenidone or nintedanib for the treatment of pulmonary fibrosis at our centre. Of the 52 patients who were started on pirfenidone, three (5.8%) developed severe hyponatraemia. Of the 29 patients who were started on nintedanib, none developed hyponatraemia. Laboratory data suggested syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by pirfenidone and the medication was discontinued. Hyponatraemia is a possible significant adverse effect of pirfenidone, able to induce SIADH in patients taking the medication., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Pulmonary vascular involvement due to rheumatoid arthritis, presenting as diffuse alveolar haemorrhage (DAH), is a rare phenomenon, especially if there are no signs of systemic vasculitides. Furthermore, how to proceed with the management of these patients is challenging, as in the case of our patient, who had recurrent DAH. We present a case of a patient with known rheumatoid arthritis who had recurrence of DAH that spanned over several years, often presenting with life-threatening respiratory failure. While her DAH presentation improved with high-dose glucocorticoids, to resolve her recurrence, we opted to initiate treatment with rituximab, with a short course of azathioprine. After the second round of rituximab, the patient continues to do well without any further DAH-related complications. We also summarise prior cases of such patients to highlight variable treatment options., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: Among patients with autoimmune myositis, associated interstitial lung disease (MA-ILD) is a known contributor of excess morbidity and mortality. Recent data on survival in idiopathic inflammatory myopathies originate primarily in Asia and Europe and vary widely. We sought to examine mortality in a large U.S. myositis cohort focusing in particular on the impact of associated ILD., Methods: A cross-sectional analysis of participants from the Johns Hopkins Myositis Center with autoimmune myositis (polymyositis [PM], dermatomyositis [DM], or clinically amyopathic dermatomyositis [CADM]) was conducted. The primary outcome assessed was all-cause mortality. Cumulative mortality rates were estimated using the Kaplan-Meier test; the Cox proportional hazards model was used to compare group differences in survival., Results: Eight hundred and thirty-one participants were included with a median follow-up time of 4.5 years. Four hundred thirty-eight (53 %) had PM, 362 (43 %) had DM, and 31 (4 %) had CADM. Ninety-four (11 %) participants had clinically evident ILD. Overall, 51 participants died (6 %). In those without ILD, the survival rates at 1, 5, and 10 years were 99, 95, and 90 %, respectively. In those with ILD, the survival rates at 1, 5, and 10 years were 97, 91, and 81 %, respectively. The risk of death was statistically significantly higher among participants with ILD compared to those without ILD (HR 2.13. 95 % CI 1.06-4.25; p = 0.03)., Conclusions: We analyzed one of the largest known cohorts of patients with autoimmune myositis and found significantly higher mortality rates among those with clinically evident ILD compared to those without clinically evident ILD. Our results suggest that ILD remains an important and significant source of mortality in patients with inflammatory myopathies and as such should be screened for and treated aggressively.

Objective: The impact and natural history of connective tissue disease related interstitial lung disease (CTD-ILD) are poorly understood; and have not been previously described from the patient's perspective. This investigation sought insight into CTD-ILD from the patients' perspective to add to our knowledge of CTD-ILD, identify disease-specific areas of unmet need and gather potentially meaningful information towards development of disease-specific patient-reported outcome measures (PROMs)., Methods: A mixed methods design incorporating patient focus groups (FGs) querying disease progression and life impact followed by questionnaires with items of importance generated by >250 ILD specialists were implemented among CTD-ILD patients with rheumatoid arthritis, idiopathic inflammatory myopathies, systemic sclerosis, and other CTD subtypes. FG data were analyzed through inductive analysis with five independent analysts, including a patient research partner. Questionnaires were analyzed through Fisher's Exact tests and hierarchal cluster analysis., Results: Six multicenter FGs included 45 patients. Biophysiologic themes were cough and dyspnea, both pervasively impacting health related quality of life (HRQoL). Language indicating dyspnea was unexpected, unique and contextual. Psycho-social themes were Living with Uncertainty, Struggle over Self-Identity, and Self-Efficacy - with education and clinician communication strongly emphasised. All questionnaire items were rated 'moderately' to 'extremely' important with 10 items of highest importance identified by cluster analysis., Conclusion: Patients with CTD-ILD informed our understanding of symptoms and impact on HRQoL. Cough and dyspnea are central to the CTD-ILD experience. Initial FGs have provided disease-specific content, context and language essential for reliable PROM development with questionnaires adding value in recognition of patients' concerns.

Background: A subset of rheumatoid arthritis (RA) patients have detectable antibodies directed against the peptidyl-arginine deiminase (PAD) enzyme isoforms 3 and 4. Anti-PAD3/4 cross-reactive antibodies (anti-PAD3/4XR) have been shown to lower the calcium threshold required for PAD4 activation, an effect potentially relevant to the pathogenesis of RA-associated interstitial lung disease (ILD)., Methods: RA patients underwent multi-detector computed tomography (MDCT) of the chest with interpretation by a pulmonary radiologist for ILD features. A semi-quantitative ILD Score (range 0-32) was calculated. Concurrent serum samples were assessed for antibodies against PAD by immunoprecipitation with radiolabeled PAD3 and PAD4., Results: Among the 176 RA patients studied, any ILD was observed in 58 (33%) and anti-PAD3/4XR was detected in 19 (11%). The frequency of any ILD among those with anti-PAD3/4XR was 68% vs. 29% among those with no anti-PAD (crude OR = 5.39; p = 0.002) and vs. 27% among those with anti-PAD4 that was not cross-reactive with PAD3 (crude OR = 5.74; p = 0.001). Both associations were stronger after adjustment for relevant confounders (adjusted ORs = 7.22 and 6.61, respectively; both p-values<0.01). Among ever smokers with anti-PAD3/4XR, the adjusted frequency of any ILD was 93% vs. 17% for never smokers without the antibody (adjusted OR = 61.4; p = 0.001, p-value for the interaction of smoking with anti-PAD3/4XR<0.05)., Conclusions: The prevalence and extent of ILD was markedly higher among RA patients with anti-PAD3/4 cross-reactive antibodies, even after accounting for relevant confounders, particularly among ever smokers. These findings may suggest etiopathologic mechanisms of RA-ILD, and their clinical utility for predicting ILD warrants additional study.

Rationale: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities., Methods: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF)., Results: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed., Conclusion: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.

Pergolide is an ergot-derived dopamine agonist used in Parkinson's disease and, increasingly, in restless legs syndrome. We report a patient with a 2.5-year history of weight loss, pleuropulmonary fibrosis, and exudative pleural effusion that developed insidiously while taking this medication. The extensive and invasive workup that preceded the diagnosis highlights the difficulty in attributing such a process to a drug reaction. This is the second report of such a reaction to pergolide, which is one of the increasing number of ergot-derived compounds in common clinical use.

The Inositol 1,4,5-trisphosphate receptor (IP3R) is an intracellular calcium channel involved in coupling cell membrane receptors to calcium signal transduction pathways within the cell. We have cloned a cDNA for the human type 1 inositol 1,4,5-trisphosphate receptor. The sequence contains the S2 splice site which appears to be the region most divergent between rat and human. We now report an additional alternatively spliced region in the coupling domain, that is 9 amino acids long, which we term S3. Alternatively spliced forms are found in both human and rat. PCR analysis of brain and peripheral tissues from human and rat shows both transcripts of the type 1 inositol 1,4,5-trisphosphate receptor in all tissues. The long form predominates in most brain regions (except the cerebellum) while the short form predominates in peripheral tissues. The sequence of the longer form in human appears to create an additional consensus protein kinase C phosphorylation site.

1. The phosphatidyl inositol (PI) second messenger system has been extensively investigated in the past decade. This complex pathway results in the production of two second messengers, one of which, inositol 1,4,5-trisphosphate, will be the focus of this review. 2. The intracellular receptor for this second messenger (IP3R) has been purified, reconstituted and extensively characterized in both brain and peripheral tissues. 3. Localization and functional studies show that IP3 binding causes the receptor to release portions of the intracellular calcium stores. 4. Multiple modulators of the receptor have been identified, including pH, calcium concentration, adenine nucleotide concentration and phosphorylation. 5. The cDNA for this molecule has been cloned from a number of sources. Studies of the molecular structure of the receptor have revealed additional levels of complexity including multiple alternative splicing events in the initially cloned cerebellar (Type I) receptor, as well as the existence of highly related but distinct cDNAs which likely reflect a gene family. 6. There is suggestive evidence linking the PI system, and thus the IP3R, to bipolar disorder and the actions of lithium.

Prolonged endotracheal intubation has become the standard of care in most neonatal units for maintenance of mechanical ventilation in the presence of respiratory distress. Unfortunately this approach has become associated with significant complications, including acquired subglottic stenosis. We have successfully used nasal continuous positive airway pressure to avoid or decrease the incidence and duration of endotracheal intubation. With use of this technique we have been able to significantly reduce sequelae (i.e., bronchopulmonary dysplasia, chronic lung disease, intraventricular hemorrhage) and have not encountered subglottic stenosis in more than 200 cases. The use of this technique may be of significant value in preventing or reducing the incidence of acquired subglottic stenosis.

One source of diversity in the inositol (1,4,5)-trisphosphate receptors (IP3Rs) is generated at the level of alternative splicing. Our previous studies of splice isoforms of the receptor in various tissues suggested that some tissues, specifically those containing neurons, selectively express a 40 amino acid insert located between 2 sites for phosphorylation by cyclic AMP-dependent protein kinase (PKA), and that the presence of this insert changes the preferred site of phosphorylation of the receptor. Studies of the mouse receptor have also suggested the existence of intermediately spliced forms containing partial versions of the splice and exhibiting different brain distributions. In this study, we have investigated the alternative splicing of the rat receptor in greater detail using RNase protection and PCR analysis. We find little evidence for the existence of intermediately spliced forms in rat, raising the possibility that the degree of alternative splicing at this site differs in the brains of two very similar species. Our screen of tissue distribution supports the selectively neuronal expression of the long spliced form, and suggests that regulation of this receptor in neurons may be different than in other tissues.

Three inositol 1,4,5-trisphosphate receptor (IP3R) cDNAs, designated IP3R-II, -III, and -IV, were cloned from a mouse placenta cDNA library. All three display strong homology in membrane-spanning domains M7 and M8 to the originally cloned cerebellar IP3R-I, with divergences predominantly in cytoplasmic domains. Levels of mRNA for the three additional IP3Rs in general are substantially lower than for IP3R-I, though in the gastrointestinal tract the levels of IP3R-III may be comparable to IP3R-I. Cerebellar Purkinje cells express at least two and possibly three distinct IP3Rs, suggesting heterogeneity of IP3 action within a single cell.

High-affinity, membrane-associated inositol 1,3,4,5-tetrakisphosphate (IP4) and inositol hexakisphosphate (IP6) binding proteins were solubilized and isolated utilizing a heparin-agarose resin followed by an IP4 affinity resin. The IP6 receptor comprises a protein complex of 115-, 105-, and 50-kDa subunits, all of which comigrate under native conditions. The Kd of the receptor for IP6 is 12 nM, whereas inositol 1,3,4,5,6-pentakisphosphate (IP5), IP4, and inositol 1,4,5-trisphosphate (IP3) are 50%, 30%, and 15%, respectively, as potent. Two protein complexes copurify with the IP4 receptor fraction. A 182/123-kDa complex elutes first from the affinity column followed by a 174/84-kDa protein complex, which elutes at higher salt. Both complexes show high affinity for IP4 (Kd = 3-4 nM). IP5, IP6, and IP3 display approximately 25%, 10%, and 0.1%, respectively, the affinity of IP4. Ligand binding to IP6 and IP4 receptors is inhibited 50% by heparin at 0.1 microgram/ml. IP4 receptor proteins are stoichiometrically phosphorylated by cyclic AMP-dependent protein kinase and protein kinase C, whereas negligible phosphorylation is observed for the IP6 receptor.

We have identified two distinct transcripts of inositol 1,4,5-trisphosphate receptor by using the PCR on first-strand cDNAs from various rat tissues. The longer form, corresponding to the previously cloned adult rat brain inositol 1,4,5-trisphosphate receptor, contains a 120-nucleotide insert between the two cAMP-dependent protein kinase phosphorylation consensus sequences. The shorter form (lacking the insert) predominates in fetal brain and peripheral tissues and appears to represent a nonneuronal receptor, whereas the longer form is found in adult brain and appears to be exclusively neuronal. The phosphorylation kinetics by cAMP-dependent protein kinase and the phosphopeptide maps differ for inositol 1,4,5-trisphosphate receptors purified from tissues predominantly expressing different forms of the transcript.

The two inositol phosphate-binding proteins, the Ins(1,4,5)P3 (InsP3) and Ins(1,3,4,5)P4 (InsP4) receptors, and the two particulate InsP3-metabolizing enzymes, InsP3 5-phosphatase and InsP3 3-kinase, were solubilized with detergent from rat cerebellar membranes. These four activities are shown to be distinct molecular species by separation using a variety of protein chromatographic steps. The pharmacology of the partially purified InsP4-binding site indicates that the binding has a high affinity and selectivity for InsP4 over InsP3. These results suggest the existence of a distinct specific InsP4-binding protein which may represent the receptor for this putative second messenger.

Rheological parameters were measured in 10 pairs of mothers and newborns. Whole blood viscosity was similar despite a higher fetal hematocrit (47.0 +/- 5.1 versus 35.5 +/- 12.0%, mean +/- SD, p less than 0.05). When the hematocrit of the suspension of red cells in plasma was adjusted to 45%, the viscosity was significantly lower in the fetal blood over a wide range of shear rates (0.52-208 S-1). The main reason for the lower viscosity in the fetal blood was the lower plasma viscosity as compared to the maternal blood (1.08 +/- 0.05 versus 1.37 +/- 0.08 centipoise, p less than 0.05); this in turn was attributable to a lower total plasma protein concentration (4.74 +/- 0.71 versus 6.47 +/- 0.64 g/dl, p less than 0.05). All protein fractions were lower in the fetal plasma. The assessment of red cell deformability by filtration through polycarbonate sieves revealed that the resistance of a fetal red cell was three times higher than that of a maternal red cell in a 2.6-micron pore, but there was no significant difference in resistance for these red cells in 6.9-micron pores. This higher filtration resistance of fetal red cells through the small pores was mainly due to their large volume (115.4 +/- 10.8 versus 93.5 +/- 5.9 fl, p less than 0.001). Measurements on membrane-free hemoglobin solutions indicated that the internal viscosity of these two types of red cells was not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Inositol 1,4,5-trisphosphate (InsP3) is a component of the phosphoinositide second-messenger system which mobilizes Ca2+ from intracellular stores. Recently, an InsP3 receptor binding protein from rat cerebellar membranes was solubilized and purified to homogeneity. The potent inhibition by Ca2+ of [3H]InsP3 binding to the InsP3 receptor in cellular membranes is not apparent in the purified receptor. The Ca2+-dependent inhibition of [3H]InsP3 binding in the crude homogenate (concn. giving 50% inhibition = 300 nM) can be restored by addition of solubilized cerebellar membranes to the purified receptor. In the present study, we further characterize the protein in solubilized membranes which confers Ca2+-sensitivity to the receptor, and which we term 'calmedin'. Calmedin appears to be a neutral membrane protein with an estimated Mr of 300,000 by gel filtration in the presence of Triton X-100. Calmedin confers a Ca2+-sensitivity to InsP3 receptor binding, which can be completely reversed by 10 min incubation with EDTA and therefore does not represent Ca2+-dependent proteinase action. Calmedin effects on the purified InsP3 receptor depend on Ca2+ binding to the calmedin, although Ca2+ also binds directly to the InsP3 receptor. The regional distribution of calmedin differs from that of the InsP3 receptor in the brain, suggesting that it also mediates other Ca2+-dependent functions. Calmedin activity in peripheral tissues is much lower than in brain.

A newly developed capillary viscometer (capillary diameter 496 micron, length 10 cm) was tested and used for measurement of blood viscosity. The determination of pressure drop along the capillary during a constant flow allowed the calculation of the apparent viscosity. By changing the flow rate, the shear rate could be varied from 0.67 to 590 sec-1. A sample of 0.5 ml was sufficient for readings to be made at 10 shear rates in this range. Measurements of distilled water and standard oils were in good agreement with the expected values. Measurements on adult human plasma and umbilical cord blood were compared with simultaneous readings by Couette viscometer. For whole blood at various shear rates, regression analysis between the viscosity obtained from the capillary viscometer and that from the Couette viscometer yielded excellent correlation (r = 0.968, p less than 0.001). This capillary viscometer with high precision for very small samples is useful for various clinical applications.