Regional european genetic ancestry predicts type I interferon level and risk of severe viral infection.

BACKGROUND: Viral infection outcomes vary widely between individuals, ranging from mild symptoms to severe organ failure and death, and it is clear that host genetic factors play a role in this variability. Type I interferon (IFN) is a critical anti-viral cytokine, and we have previously noted differences in type I IFN levels between world populations. METHODS: In this study, we investigate the interrelationship between regional European genetic ancestry, type I IFN levels, and severe viral infection outcomes. RESULTS: In cohorts of European ancestry lupus patients living in Europe, we noted higher IFN in the Northwestern populations as compared to Southeastern populations. In an independent cohort of European ancestry lupus patients from the United States with varying proportional regional European genetic admixture, we observed the same Northwest vs. Southeast European ancestry IFN gradient. We developed a model to predict type I IFN level based on regional European ancestry (AUC = 0.73, p = 6.1e-6). Examining large databases containing serious viral outcomes data, we found that lower predicted IFN in the corresponding European country was significantly correlated with increased viral infection fatality rate, including COVID-19, viral hepatitis, and HIV [Correlation coefficients: -0.79 (p = 4e-2), -0.94 (p = 6e-3), and -0.96 (p = 8e-2) respectively]. CONCLUSIONS: This association between predicted type I IFN level and viral outcome severity suggests a potential causal relationship, as greater intrinsic type I IFN is beneficial in host defense against viruses. Genetic testing could provide insight into individual and population level risk of fatality due to viruses prior to infection, across a wide range of viral pathogens.

High Systemic Type I Interferon Activity Is Associated With Active Class III/IV Lupus Nephritis.

OBJECTIVE: Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN. METHODS: Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR. RESULTS: Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. CONCLUSION: Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.

A Four-Component Framework Toward Patient-Centered, Integrated Mental Healthcare in Kenya.

Background: How can we fast-track the global agenda of integrated mental healthcare in low- and middle-income countries (LMICs) such as Kenya? This is a question that has become increasingly important for individuals with lived experiences, policymakers, mental health advocates and health care providers at the local and international levels. Discussion: This narrative synthesis and perspective piece encompasses an overview of mental health care competencies, best practices and capacity building needed to fast track patient responsive services. In that vein we also review key policy developments like UHC to make a case for fast-tracking our four-step framework. Results: While there is an increasingly global impetus for integrated mental healthcare, there is a lack of clarity around what patient-responsive mental healthcare services should look like and how to measure and improve provider readiness appropriately. Here, our collaborative team of local and international experts proposes a simple four-step approach to integrating responsive mental healthcare in Kenya. Our recommended framework prioritizes a clear understanding and demonstration of multidimensional skills by the provider. The four steps are (1) provider sensitization, (2) continuous supervision, (3) continuous professional training, and (4) leadership empowerment. Conclusion: Our proposed framework can provide pointers to embracing patient-centered and provider empowerment focused quality of care improvements. Though elements of our proposed framework are well-known, it has not been sufficiently intertwined and therefore not been integrated. We think in the current times our integrated framework offers an opportunity to "building back better" mental health for all.

Single-cell expression quantitative trait loci (eQTL) analysis of SLE-risk loci in lupus patient monocytes.

BACKGROUND: We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. METHODS: Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14++CD16- CL and CD14dimCD16+ NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. RESULTS: The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. CONCLUSIONS: We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.

Lung mass density prediction using machine learning based on ultrasound surface wave elastography and pulmonary function testing.

OBJECTIVE: The objective of this study is to predict in vivo lung mass density for patients with interstitial lung disease using different gradient boosting decision tree (GBDT) algorithms based on measurements from lung ultrasound surface wave elastography (LUSWE) and pulmonary function testing (PFT). METHODS: Age and weight of study subjects (57 patients with interstitial lung disease and 20 healthy subjects), surface wave speeds at three vibration frequencies (100, 150, and 200 Hz) from LUSWE, and predicted forced expiratory volume (FEV1% pre) and ratio of forced expiratory volume to forced vital capacity (FEV1%/FVC%) from PFT were used as inputs while lung mass densities based on the Hounsfield Unit from high resolution computed tomography (HRCT) were used as labels to train the regressor in three GBDT algorithms, XGBoost, CatBoost, and LightGBM. 80% (20%) of the dataset was used for training (testing). RESULTS: The results showed that predictions using XGBoost regressor obtained an accuracy of 0.98 in the test dataset. CONCLUSION: The obtained results suggest that XGBoost regressor based on the measurements from LUSWE and PFT may be able to noninvasively assess lung mass density in vivo for patients with pulmonary disease.

Systemic Sclerosis Portends Increased Risk of Conduction and Rhythm Abnormalities at Diagnosis and During Disease Course: A US Population-Based Cohort.

Objectives: To study the incidence, risk factors and outcomes of conduction and rhythm disorders in a population-based cohort of patients with systemic sclerosis (SSc) vs. non-SSc comparators. Methods: An incident cohort of patients with SSc (1980-2016) from Olmsted County, MN was compared to age- and sex-matched non-SSc subjects (1:2). Electrocardiograms (ECGs), Holter ECGs, and need for cardiac interventions were reviewed to determine the occurrence of any conduction or rhythm abnormalities. Results: 78 incident SSc cases and 156 comparators were identified (mean age 56 y, 91% female). The prevalence of any conduction disorder prior to SSc diagnosis compared to non-SSc subjects was 15% vs. 7% (p=0.06), and any rhythm disorder was 18% vs. 13% (p=0.33). During a median follow-up of 10.5 years in patients with SSc and 13.0 years in non-SSc comparators, conduction disorders developed in 25 patients with SSc with cumulative incidence of 20.5% (95% CI: 12.4-34.1%) vs. 28 non-SSc patients with cumulative incidence of 10.4% (95% CI: 6.2-17.4%) (HR: 2.57; 95% CI: 1.48-4.45), while rhythm disorders developed in 27 patients with SSc with cumulative incidence of 27.3% (95% CI: 17.9-41.6%) vs. 43 non-SSc patients with cumulative incidence of 18.0% (95% CI: 12.3-26.4%) (HR: 1.62; 95% CI: 1.00-2.64). Age, pulmonary hypertension and smoking were identified as risk factors. Conclusion: Patients with SSc have an increased risk of conduction and rhythm disorders both at disease onset and over time, compared to non-SSc patients. These findings warrant increased vigilance and screening for ECG abnormalities in SSc patients with pulmonary hypertension.

Hospitalization Rates Are Highest in the First 5 Years of Systemic Sclerosis: Results From a Population-based Cohort (1980-2016).

OBJECTIVE: Few studies have estimated the healthcare resource usage of patients with systemic sclerosis (SSc). The purpose of this study was to compare hospitalization among incident cases of SSc vs age- and sex-matched comparators. METHODS: A retrospective, population-based cohort of patients with SSc in Olmsted County, Minnesota, from January 1, 1980, to December 31, 2016, was assembled. A 2:1 cohort of age- and sex-matched patients without SSc from the same population was randomly selected for comparison. All hospitalizations in the geographic area from January 1, 1987, to September 30, 2018, were obtained. Rates of hospitalization, lengths of stay, and readmissions were compared between groups. RESULTS: There were 76 incident SSc cases and 155 non-SSc comparators (mean age 56 ± 16 yrs at diagnosis/index, 91% female) included. Rates of hospitalization among cases and comparators were 31.9 and 17.9 per 100 person-years, respectively (rate ratio [RR] 1.78, 95% CI 1.52-2.08). Hospitalization rates were higher in patients with SSc than comparators during the first 5 years after SSc diagnosis (RR 2.16, 95% CI 1.70-2.74). This difference decreased over time and was no longer significant at ≥ 15 years after SSc incidence/index. Lengths of stay (median [IQR] 4 [2-6] vs 3 [2-6], P = 0.52) and readmission rates (25% vs 23%, P = 0.51) were similar between groups. CONCLUSION: Patients with SSc were hospitalized more frequently than comparators, indicating high inpatient care needs in this population. Hospitalization rates were highest during the first 5 years following SSc diagnosis.

Untreated Takayasu arteritis: an unusual case of widespread disease.

A 38-year-old man with no medical history presented with bilateral flank and epigastric abdominal pain. CT abdomen and pelvis demonstrated diffuse nodules and lymphadenopathy, which were biopsied and showed chronic inflammatory changes. He later presented with pleuritic chest pain and was sent for a CT chest angiogram, which revealed perivascular inflammation involving the thoracic aortic arch, supra-aortic branch vessels and descending thoracic aorta. Further work-up showed vasculitic involvement of the coeliac, superior mesenteric and femoral arteries with heavy collateralisation. These findings were most consistent with widespread Takayasu arteritis that had been untreated for nearly 20 years. It was necessary to define the degree of active inflammation and need for immediate therapy, as the patient had a concomitant latent tuberculosis infection that precluded the use of immunosuppressive medications. This report illustrates an unusual case of Takayasu arteritis and highlights the presentation, diagnosis and work-up of suspected cases.

Cardiovascular Risk Factors and Atherosclerotic Cardiovascular Events Among Incident Cases of Systemic Sclerosis: Results From a Population-Based Cohort (1980-2016).

OBJECTIVE: To characterize cardiovascular (CV) risk factors and outcomes among incident cases of systemic sclerosis (SSc) in a population-based cohort. METHODS: Medical records of patients with SSc diagnosed in Olmsted County, Minnesota, between January 1, 1980, and December 31, 2016, were reviewed to identify 78 incident SSc cases. The comparators were 156 sex- and age-matched individuals from the same population. Data for SSc characteristics, traditional CV risk factors, and CV events were collected. Cumulative incidence was adjusted for the competing risk for death. RESULTS: During a median follow-up of 9.8 (SSc) and 9.2 years (non-SSc), 21 patients with SSc and 17 patients without SSc developed CV events, corresponding to 10-year cumulative incidence of 24.4% and 15.2%, respectively. The risk for incident CV disease was increased by 2-fold (hazard ratio, 2.38; 95% CI, 1.28-4.43) in patients with SSc vs comparators, predominately due to coronary artery disease (hazard ratio, 2.35; 95% CI, 1.17-4.71). Mean body mass index and prevalence of diabetes mellitus were lower in SSc vs non-SSc. There was no significant difference in smoking, hypertension, or hyperlipidemia. Observed CV events were increased compared with CV events predicted by the Framingham Risk Score and American College of Cardiology/American Heart Association score with standardized incident ratios of 4.16 (95% CI, 2.16-7.99) and 5.69 (95% CI, 2.71-11.94), respectively. CONCLUSION: Patients with SSc are at >2-fold increased risk for experiencing a CV event compared with persons without SSc. Framingham Risk Score and American College of Cardiology/American Heart Association score dramatically underestimate CV risk in SSc.

Ultrasound Surface Wave Elastography for Assessing Scleroderma.

Scleroderma, or systemic sclerosis (SSc), is a multi-organ connective tissue disease characterized by immune dysregulation and tissue fibrosis. Skin disease is both a disabling feature of SSc and a predictor of visceral involvement and increased mortality. The Modified Rodnan Skin Score (MRSS) is currently the most common clinical method for assessing skin. We developed ultrasound surface wave elastography (USWE) techniques to measure skin surface wave speeds and analyze skin viscoelasticity. The objective of this research was to determine the correlations of skin surface wave speed and skin viscoelasticity with MRSS. Twenty-six SSc patients were studied using USWE and the MRSS. The subject was tested in a sitting position while his or her left or right forearm and upper arm were placed horizontally on a pillow in a relaxed state. The skin of both left and right forearms and upper arms of patients was tested using USWE. Surface wave speeds are positively correlated with the MRSS. Skin elasticity is also positively correlated with the MRSS. However, there was no correlation between skin viscosity and the MRSS for these SSc patients. We will further study if skin viscosity is sensitive enough to detect early edema from inflammation changes of SSc.

Type I Interferon Predicts an Alternate Immune System Phenotype in Systemic Lupus Erythematosus.

OBJECTIVE: Type I interferon (IFN) is important to systemic lupus erythematosus (SLE) pathogenesis, but it is not clear how chronic elevations in IFN alter immune function. We compared cytokine responses after whole blood stimulation with Toll-like receptor (TLR) agonists in high- and low-IFN SLE patient subgroups. METHODS: SLE patients and nonautoimmune controls were recruited, and SLE patients were categorized as either high or low IFN. Whole blood was dispensed into tubes coated with lipopolysaccharide (LPS), oligonucleotides with cytosine-guanine repeats, Resiquimod, IFN-α, and IFN-α + LPS. Cytokine production in patient sera and after whole blood TLR stimulation was measured by multiplex assay, and type I IFN was assessed using a functional assay. RESULTS: Circulating plasmacytoid dendritic cell numbers were specifically reduced in high-IFN SLE patients and not in low-IFN SLE patients. In serum, we observed that the correlations between cytokines in serum differed to a much greater degree between the high- and low-IFN groups (P < 0.0001) than the absolute cytokine levels differed between these same groups. In stimulated conditions, the high-IFN patients had less cytokine production in response to TLR ligation than the low-IFN SLE patients. LPS produced the most diverse response, and a number of interactions between type I IFN and LPS were observed. CONCLUSION: We find striking differences in resting and stimulated cytokine patterns in high- vs. low-IFN SLE patients, which supports the biological importance of these patient subsets. These data could inform personalized treatment approaches and the pathogenesis of SLE flare following infection.

Lung US Surface Wave Elastography in Interstitial Lung Disease Staging.

Background Lung US surface wave elastography (SWE) can noninvasively quantify lung surface stiffness or fibrosis by evaluating the rate of surface wave propagation. Purpose To assess the utility of lung US SWE for evaluation of interstitial lung disease. Materials and Methods In this prospective study, lung US SWE was used to assess 91 participants (women, 51; men, 40; mean age ± standard deviation [SD], 62.4 years ± 12.9) with interstitial lung disease and 30 healthy subjects (women, 16; men, 14; mean age, 45.4 years ± 14.6) from February 2016 through May 2017. Severity of interstitial lung disease was graded as none (healthy lung [F0]), mild (F1), moderate (F2), or severe (F3) based on pulmonary function tests, high-resolution CT, and clinical assessments. We propagated surface waves on the lung through gentle mechanical excitation of the external chest wall and measured the lung surface wave speed with a US probe. Lung US SWE performance was assessed, and the optimal cutoff wave speed values for fibrosis grades F0 through F3 were determined with receiver operating characteristic (ROC) curve analysis. Results Lung US SWE had a sensitivity of 92% (95% confidence intervals [CI]: 84%, 96%; P < .001) and a specificity of 89% (95% CI: 81%, 94%; P < .001) for differentiating between healthy subjects (F0) and participants with any grade of interstitial lung disease (F1-F3). It had a sensitivity of 50% and a specificity of 81% for differentiating interstitial lung disease grades F0-F2 from F3. The sensitivity was 88% and the specificity was 97% for differentiating between F0 and F1. The highest area under the ROC curve (AUC) values were obtained at 200 Hz and ranged from 0.83 to 0.94 to distinguish between healthy subjects and study participants with any interstitial lung disease. Conclusion Lung US surface wave elastography may be adjunct to high-resolution CT for noninvasive evaluation of interstitial lung disease. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

A quantitative method for measuring the changes of lung surface wave speed for assessing disease progression of interstitial lung disease.

Lung ultrasound surface wave elastography (LUSWE) is a novel non-invasive technique for measuring superficial lung tissue stiffness. The purpose of the study described here was to develop LUSWE for assessment of progression in patients with interstitial lung disease (ILD). In this study, LUSWE was used to measure changes in lung surface wave speeds at 100, 150 and 200 Hz through six intercostal lung spaces for 52 patients with ILD. The mean age was 63.1 ± 12.0 y (range: 20-85, 23 male and 29 female). The follow-up interval was 9.2 ± 3.5 mo depending on each patient's return appointment and availability. For each patient, disease progression between the baseline and follow-up tests was evaluated clinically using a 7-point Likert scale comprising three grades of improvement (mild, moderate, marked), unchanged status and three grades of worsening (mild, moderate, marked). Clinical assessments were based on changes in pulmonary function tests together with high-resolution computed tomography, echocardiography and clinical evaluations. This study illustrates the correlations between changes in lung surface wave speed and clinical assessments. Correlations of changes in lung surface wave speed at lower lateral and posterior portions of the lung portions with clinical assessments were good. LUSWE provides quantitative global and regional changes in lung surface wave speed that may be useful for quantitative assessment of progression of ILD.

Assessment of Interstitial Lung Disease Using Lung Ultrasound Surface Wave Elastography: A Novel Technique With Clinicoradiologic Correlates.

PURPOSE: Optimal strategies to detect early interstitial lung disease (ILD) are unknown. ILD is frequently subpleural in distribution and affects lung elasticity. Lung ultrasound surface wave elastography (LUSWE) is a noninvasive method of quantifying superficial lung tissue elastic properties. In LUWSE a handheld device applied at the intercostal space vibrates the chest at a set frequency, and the lung surface wave velocity is measured by an ultrasound probe 5 mm away in the same intercostal space. We explored LUWSE's ability to detect ILD and correlated LUSWE velocity with physiological, quantitative, and visual radiologic features of subjects with known ILD and of healthy controls. MATERIALS AND METHODS: Seventy-seven subjects with ILD, mostly caused by connective tissue disease, and 19 healthy controls were recruited. LUSWE was performed on all subjects in 3 intercostal lung regions bilaterally. Comparison of LUSWE velocities pulmonary function testing, visual assessment, and quantitative analysis of recent computed tomographic imaging with Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) software. RESULTS: Sonographic velocities were higher in all lung regions for cases, with the greatest difference in the lateral lower lung. Median velocity in m/s was 5.84 versus 4.11 and 5.96 versus 4.27 (P<0.00001) for cases versus controls, left and right lateral lower lung zones, respectively. LUSWE velocity correlated negatively with vital capacity and positively with radiologist and CALIPER-detected interstitial abnormalities. CONCLUSIONS: LUSWE is a safe and noninvasive technique that shows high sensitivity to detect ILD and correlated with clinical, physiological, radiologic, and quantitative assessments of ILD. Prospective study in detecting ILD is indicated.

Lung Ultrasound Surface Wave Elastography for Assessing Interstitial Lung Disease.

OBJECTIVE: Our goal is to translate lung ultrasound surface wave elastography (LUSWE) for assessing patients with interstitial lung disease (ILD) and various connective tissue diseases including systemic sclerosis (SSc). METHODS: LUSWE was used to measure the surface wave speed of lung at 100, 150, and 200 Hz through six intercostal lung spaces for 91 patients with ILD and 30 healthy control subjects. In addition, skin viscoelasticity was measured on both forearms and upper arms for patients and controls. RESULTS: The surface wave speeds of patients' lungs were significantly higher than those of control subjects. Patient skin elasticity and viscosity were significantly higher than those of control subjects. In dividing ILD patients into two groups, ILD with SSc patients and ILD without SSc patients, significant differences between each patient group with the control group were found for both the lung and skin. No significant differences were found between the two patient groups, although there were some differences at a few locations and at 100 Hz for skin viscoelasticity. CONCLUSION: Significant differences of surface wave speed were found between ILD patients and healthy control subjects for both the lung and skin. SIGNIFICANCE: LUSWE may be useful for assessing ILD and SSc and screening early stage patients.

An Ultrasound Surface Wave Technique for Assessing Skin and Lung Diseases.

Systemic sclerosis (SSc) is a multi-organ connective tissue disease characterized by immune dysregulation and organ fibrosis. Severe organ involvement, especially of the skin and lung, is the cause of morbidity and mortality in SSc. Interstitial lung disease (ILD) includes multiple lung disorders in which the lung tissue is fibrotic and stiffened. The purpose of this study was to translate ultrasound surface wave elastography (USWE) for assessing patients with SSc and/or ILD via measuring surface wave speeds of both skin and superficial lung tissue. Forty-one patients with both SSc and ILD and 30 healthy patients were enrolled in this study. An external harmonic vibration was used to generate the wave propagation on the skin or lung. Three excitation frequencies of 100, 150 and 200 Hz were used. An ultrasound probe was used to measure the wave propagation in the tissue non-invasively. Surface wave speeds were measured on the forearm and upper arm of both left and right arm, as well as the upper and lower lungs, through six intercostal spaces of patients and healthy patients. Viscoelasticity of the skin was calculated by the wave speed dispersion with frequency using the Voigt model. The magnitudes of surface wave speed and viscoelasticity of patients' skin were significantly higher than those of healthy patients (p <0.0001) for each location and each frequency. The surface wave speeds of patients' lung were significantly higher than those of healthy patients (p <0.0001) for each location and each frequency. USWE is a non-invasive and non-ionizing technique for measuring both skin and lung surface wave speed and may be useful for quantitative assessment of SSc and/or ILD.

Single-cell gene expression patterns in lupus monocytes independently indicate disease activity, interferon and therapy.

OBJECTIVES: Important findings can be masked in gene expression studies of mixed cell populations. We examined single-cell gene expression in SLE patient monocytes in the context of clinical and immunological features. METHODS: Monocytes were purified from patients with SLE and controls, and individually isolated for single-cell gene expression measurement. A panel of monocyte-related transcripts were measured in individual classical (CL) and non-classical (NCL) monocytes. RESULTS: Analyses of both CL and NCL monocytes demonstrated that many genes had a lower expression rate in SLE monocytes than in controls. Unsupervised hierarchical clustering of the CL and NCL data sets demonstrated independent clusters of cells from the patients with SLE that were related to disease activity, type I interferon (IFN) and medication use. Thus, each of these factors exerted a different impact on monocyte gene expression that could be identified separately, and a number of genes correlated uniquely with disease activity. We found within-cell correlations between genes directly induced by type I IFN-induced and other non-IFN-induced genes, suggesting the downstream biological effects of type I IFN in individual human SLE monocytes which differed between CLs and NCLs. CONCLUSIONS: In summary, single-cell gene expression in monocytes was associated with a wide range of clinical and biological features in SLE, providing much greater detail and insight into the cellular biology underlying the disease than previous mixed-cell population studies.

Lung Ultrasound Surface Wave Elastography: A Pilot Clinical Study.

A lung ultrasound surface wave elastography (LUSWE) technique is developed to measure superficial lung tissue elastic properties. The purpose of this paper was to translate LUSWE into clinical studies for assessing patients with interstitial lung disease (ILD) and present the pilot data from lung measurements on 10 healthy subjects and 10 patients with ILD. ILD includes multiple lung disorders in which the lung tissue is distorted and stiffened by tissue fibrosis. Chest radiography and computed tomography are the most commonly used techniques for assessing lung disease, but they are associated with radiation and cannot directly measure lung elastic properties. LUSWE provides a noninvasive and nonionizing technique to measure the elastic properties of superficial lung tissue. LUSWE was used to measure regions of both lungs through six intercostal spaces for patients and healthy subjects. The data are presented as wave speed at 100, 150, and 200 Hz at the six intercostal spaces. As an example, the surface wave speeds are, respectively, 1.88 ± 0.11 m/s at 100 Hz, 2.74 ± 0.26 m/s at 150 Hz, and 3.62 ± 0.13 m/s at 200 Hz for a healthy subject in the upper right lung; this is in comparison to measurements from an ILD patient of 3.3 ± 0.37 m/s at 100 Hz, 4.38 ± 0.33 m/s at 150 Hz, and 5.24 ± 0.44 m/s at 200 Hz in the same lung space. Significant differences in wave speed between healthy subjects and ILD patients were found. LUSWE is a safe and noninvasive technique which may be useful for assessing ILD.

Lupus-Associated Functional Polymorphism in PNP Causes Cell Cycle Abnormalities and Interferon Pathway Activation in Human Immune Cells.

OBJECTIVE: Systemic lupus erythematosus (SLE) is frequently characterized by activation of the type I interferon (IFN) pathway. We previously observed that a missense single-nucleotide polymorphism (rs1049564) in the purine nucleoside phosphorylase (PNP) gene was associated with high levels of IFN in SLE. PNP is a key enzyme involved in purine metabolism. In this study, we performed functional follow-up of this polymorphism in human cells. METHODS: Type I IFN was measured in patient sera, using a reporter cell assay. Structural modeling of the PNP variant was performed using PyMOL software. PNP messenger RNA (mRNA) and protein levels and type I IFN-induced gene expression were measured in lymphoblastoid cell lines with known PNP rs1049564 genotypes. The cell cycle was assayed using flow cytometry. RESULTS: Structural modeling indicated no major disruption in folding related to rs1049564. We observed that homozygous rs1049564 TT lymphoblastoid cells had decreased PNP mRNA expression and protein levels, and that cells with the TT genotype had reduced PNP enzymatic activity even when the amount of PNP was controlled. Cells with the TT genotype had a 2-fold increase in S-phase block as compared with cells with the homozygous CC phenotype. The S-phase block could be pharmacologically reversed with hypoxanthine and adenosine, supporting the notion that relative PNP deficiency is the cause of the S-phase block. Type I IFN-induced transcripts were increased in a dose-response manner related to the rs1049564 T allele, at both baseline and after type I IFN stimulation. CONCLUSION: The PNP rs1049564 T allele is a loss-of-function variant that induces S-phase block and IFN pathway activation in lymphocytes. The S-phase block could be rescued in our in vitro experiments, suggesting the potential for personalized treatment.