Effect of skin tone on the accuracy of the estimation of arterial oxygen saturation by pulse oximetry: a systematic review.

BACKGROUND: Pulse oximetry-derived oxygen saturation (SpO2) is an estimate of true arterial oxygen saturation (SaO2). The aim of this review was to evaluate available evidence determining the effect of skin tone on the ability of pulse oximeters to accurately estimate SaO2. METHODS: Published literature was screened to identify clinical and non-clinical studies enrolling adults and children when SpO2 was compared with a paired co-oximetry SaO2 value. We searched literature databases from their inception to March 20, 2023. Risk of bias (RoB) was assessed using the QUADAS-2 tool. Certainty of assessment was evaluated using the GRADE tool. RESULTS: Forty-four studies were selected reporting on at least 222 644 participants (6121 of whom were children) and 733 722 paired SpO2-SaO2 measurements. Methodologies included laboratory studies, prospective clinical, and retrospective clinical studies. A high RoB was detected in 64% of studies and there was considerable heterogeneity in study design, data analysis, and reporting metrics. Only 11 (25%) studies measured skin tone in 2353 (1.1%) participants; the remainder reported participant ethnicity: 68 930 (31.0%) participants were of non-White ethnicity or had non-light skin tones. The majority of studies reported overestimation of SaO2 by pulse oximetry in participants with darker skin tones or from ethnicities assumed to have darker skin tones. Several studies reported no inaccuracy related to skin tone. Meta-analysis of the data was not possible. CONCLUSIONS: Pulse oximetry can overestimate true SaO2 in people with darker skin tones. The clinical relevance of this bias remains unclear, but its magnitude is likely to be greater when SaO2 is lower. SYSTEMATIC REVIEW PROTOCOL: International Prospective Register of Systematic Reviews (PROSPERO): CRD42023390723.

Non-invasive detection of severe PH in lung disease using magnetic resonance imaging.

Introduction: Severe pulmonary hypertension (mean pulmonary artery pressure ≥35 mmHg) in chronic lung disease (PH-CLD) is associated with high mortality and morbidity. Data suggesting potential response to vasodilator therapy in patients with PH-CLD is emerging. The current diagnostic strategy utilises transthoracic Echocardiography (TTE), which can be technically challenging in some patients with advanced CLD. The aim of this study was to evaluate the diagnostic role of MRI models to diagnose severe PH in CLD. Methods: 167 patients with CLD referred for suspected PH who underwent baseline cardiac MRI, pulmonary function tests and right heart catheterisation were identified. In a derivation cohort (n = 67) a bi-logistic regression model was developed to identify severe PH and compared to a previously published multiparameter model (Whitfield model), which is based on interventricular septal angle, ventricular mass index and diastolic pulmonary artery area. The model was evaluated in a test cohort. Results: The CLD-PH MRI model [= (-13.104) + (13.059 * VMI)-(0.237 * PA RAC) + (0.083 * Systolic Septal Angle)], had high accuracy in the test cohort (area under the ROC curve (0.91) (p < 0.0001), sensitivity 92.3%, specificity 70.2%, PPV 77.4%, and NPV 89.2%. The Whitfield model also had high accuracy in the test cohort (area under the ROC curve (0.92) (p < 0.0001), sensitivity 80.8%, specificity 87.2%, PPV 87.5%, and NPV 80.4%. Conclusion: The CLD-PH MRI model and Whitfield model have high accuracy to detect severe PH in CLD, and have strong prognostic value.

Severe pulmonary hypertension associated with lung disease is characterised by a loss of small pulmonary vessels on quantitative computed tomography.

Background: Pulmonary hypertension (PH) in patients with chronic lung disease (CLD) predicts reduced functional status, clinical worsening and increased mortality, with patients with severe PH-CLD (≥35 mmHg) having a significantly worse prognosis than mild to moderate PH-CLD (21-34 mmHg). The aim of this cross-sectional study was to assess the association between computed tomography (CT)-derived quantitative pulmonary vessel volume, PH severity and disease aetiology in CLD. Methods: Treatment-naïve patients with CLD who underwent CT pulmonary angiography, lung function testing and right heart catheterisation were identified from the ASPIRE registry between October 2012 and July 2018. Quantitative assessments of total pulmonary vessel and small pulmonary vessel volume were performed. Results: 90 patients had PH-CLD including 44 associated with COPD/emphysema and 46 with interstitial lung disease (ILD). Patients with severe PH-CLD (n=40) had lower small pulmonary vessel volume compared to patients with mild to moderate PH-CLD (n=50). Patients with PH-ILD had significantly reduced small pulmonary blood vessel volume, compared to PH-COPD/emphysema. Higher mortality was identified in patients with lower small pulmonary vessel volume. Conclusion: Patients with severe PH-CLD, regardless of aetiology, have lower small pulmonary vessel volume compared to patients with mild-moderate PH-CLD, and this is associated with a higher mortality. Whether pulmonary vessel changes quantified by CT are a marker of remodelling of the distal pulmonary vasculature requires further study.

Training and clinical testing of artificial intelligence derived right atrial cardiovascular magnetic resonance measurements.

BACKGROUND: Right atrial (RA) area predicts mortality in patients with pulmonary hypertension, and is recommended by the European Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. The advent of deep learning may allow more reliable measurement of RA areas to improve clinical assessments. The aim of this study was to automate cardiovascular magnetic resonance (CMR) RA area measurements and evaluate the clinical utility by assessing repeatability, correlation with invasive haemodynamics and prognostic value. METHODS: A deep learning RA area CMR contouring model was trained in a multicentre cohort of 365 patients with pulmonary hypertension, left ventricular pathology and healthy subjects. Inter-study repeatability (intraclass correlation coefficient (ICC)) and agreement of contours (DICE similarity coefficient (DSC)) were assessed in a prospective cohort (n = 36). Clinical testing and mortality prediction was performed in n = 400 patients that were not used in the training nor prospective cohort, and the correlation of automatic and manual RA measurements with invasive haemodynamics assessed in n = 212/400. Radiologist quality control (QC) was performed in the ASPIRE registry, n = 3795 patients. The primary QC observer evaluated all the segmentations and recorded them as satisfactory, suboptimal or failure. A second QC observer analysed a random subcohort to assess QC agreement (n = 1018). RESULTS: All deep learning RA measurements showed higher interstudy repeatability (ICC 0.91 to 0.95) compared to manual RA measurements (1st observer ICC 0.82 to 0.88, 2nd observer ICC 0.88 to 0.91). DSC showed high agreement comparing automatic artificial intelligence and manual CMR readers. Maximal RA area mean and standard deviation (SD) DSC metric for observer 1 vs observer 2, automatic measurements vs observer 1 and automatic measurements vs observer 2 is 92.4 ± 3.5 cm2, 91.2 ± 4.5 cm2 and 93.2 ± 3.2 cm2, respectively. Minimal RA area mean and SD DSC metric for observer 1 vs observer 2, automatic measurements vs observer 1 and automatic measurements vs observer 2 was 89.8 ± 3.9 cm2, 87.0 ± 5.8 cm2 and 91.8 ± 4.8 cm2. Automatic RA area measurements all showed moderate correlation with invasive parameters (r = 0.45 to 0.66), manual (r = 0.36 to 0.57). Maximal RA area could accurately predict elevated mean RA pressure low and high-risk thresholds (area under the receiver operating characteristic curve artificial intelligence = 0.82/0.87 vs manual = 0.78/0.83), and predicted mortality similar to manual measurements, both p < 0.01. In the QC evaluation, artificial intelligence segmentations were suboptimal at 108/3795 and a low failure rate of 16/3795. In a subcohort (n = 1018), agreement by two QC observers was excellent, kappa 0.84. CONCLUSION: Automatic artificial intelligence CMR derived RA size and function are accurate, have excellent repeatability, moderate associations with invasive haemodynamics and predict mortality.

Phylogeny of gracillariid leaf-mining moths: evolution of larval behaviour inferred from phylogenomic and Sanger data.

Gracillariidae is the most taxonomically diverse cosmopolitan leaf-mining moth family, consisting of nearly 2000 named species in 105 described genera, classified into eight extant subfamilies. The majority of gracillariid species are internal plant feeders as larvae, creating mines and galls in plant tissue. Despite their diversity and ecological adaptations, their phylogenetic relationships, especially among subfamilies, remain uncertain. Genomic data (83 taxa, 589 loci) were integrated with Sanger data (130 taxa, 22 loci), to reconstruct a phylogeny of Gracillariidae. Based on analyses of both datasets combined and analyzed separately, monophyly of Gracillariidae and all its subfamilies, monophyly of the clade "LAMPO" (subfamilies: Lithocolletinae, Acrocercopinae, Marmarinae, Phyllocnistinae, and Oecophyllembiinae) and relationships of its subclade "AMO" (subfamilies: Acrocercopinae, Marmarinae, and Oecophyllembiinae) were strongly supported. A sister-group relationship of Ornixolinae to the remainder of the family, and a monophyletic leaf roller lineage (Callicercops Vári + Parornichinae) + Gracillariinae, as sister to the "LAMPO" clade were supported by the most likely tree. Dating analyses indicate a mid-Cretaceous (105.3 Ma) origin of the family, followed by a rapid diversification into the nine subfamilies predating the Cretaceous-Palaeogene extinction. We hypothesize that advanced larval behaviours, such as making keeled or tentiform blotch mines, rolling leaves and galling, allowed gracillariids to better avoid larval parasitoids allowing them to further diversify. Finally, we stabilize the classification by formally re-establishing the subfamily ranks of Marmarinae stat.rev., Oecophyllembiinae stat.rev. and Parornichinae stat.rev., and erect a new subfamily, Callicercopinae Li, Ohshima and Kawahara to accommodate the enigmatic genus Callicercops.

Semi-automatic thresholding of RV trabeculation improves repeatability and diagnostic value in suspected pulmonary hypertension.

Objectives: Right ventricle (RV) mass is an imaging biomarker of mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR). Some methods of RV mass measurement on cardiac MRI (CMR) exclude RV trabeculation. This study assessed the reproducibility of measurement methods and evaluated whether the inclusion of trabeculation in RV mass affects diagnostic accuracy in suspected pulmonary hypertension (PH). Materials and methods: Two populations were enrolled prospectively. (i) A total of 144 patients with suspected PH who underwent CMR followed by right heart catheterization (RHC). Total RV mass (including trabeculation) and compacted RV mass (excluding trabeculation) were measured on the end-diastolic CMR images using both semi-automated pixel-intensity-based thresholding and manual contouring techniques. (ii) A total of 15 healthy volunteers and 15 patients with known PH. Interobserver agreement and scan-scan reproducibility were evaluated for RV mass measurements using the semi-automated thresholding and manual contouring techniques. Results: Total RV mass correlated more strongly with MPAP and PVR (r = 0.59 and 0.63) than compacted RV mass (r = 0.25 and 0.38). Using a diagnostic threshold of MPAP ≥ 25 mmHg, ROC analysis showed better performance for total RV mass (AUC 0.77 and 0.81) compared to compacted RV mass (AUC 0.61 and 0.66) when both parameters were indexed for LV mass. Semi-automated thresholding was twice as fast as manual contouring (p < 0.001). Conclusion: Using a semi-automated thresholding technique, inclusion of trabecular mass and indexing RV mass for LV mass (ventricular mass index), improves the diagnostic accuracy of CMR measurements in suspected PH.

Xenon ventilation MRI in difficult asthma: initial experience in a clinical setting.

BACKGROUND: Hyperpolarised gas magnetic resonance imaging (MRI) can be used to assess ventilation patterns. Previous studies have shown the image-derived metric of ventilation defect per cent (VDP) to correlate with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1 in asthma. OBJECTIVES: The aim of this study was to explore the utility of hyperpolarised xenon-129 (129Xe) ventilation MRI in clinical care and examine its relationship with spirometry and other clinical metrics in people seen in a severe asthma service. METHODS: 26 people referred from a severe asthma clinic for MRI scanning were assessed by contemporaneous 129Xe MRI and spirometry. A subgroup of 18 patients also underwent reversibility testing with spirometry and MRI. Quantitative MRI measures of ventilation were calculated, VDP and the ventilation heterogeneity index (VHI), and compared to spirometry, Asthma Control Questionnaire 7 (ACQ7) and blood eosinophil count. Images were reviewed by a multidisciplinary team. RESULTS: VDP and VHI correlated with FEV1, FEV1/FVC and forced expiratory flow between 25% and 75% of FVC but not with ACQ7 or blood eosinophil count. Discordance of MRI imaging and symptoms and/or pulmonary function tests also occurred, prompting diagnostic re-evaluation in some cases. CONCLUSION: Hyperpolarised gas MRI provides a complementary method of assessment in people with difficult to manage asthma in a clinical setting. When used as a tool supporting clinical care in a severe asthma service, occurrences of discordance between symptoms, spirometry and MRI scanning indicate how MRI scanning may add to a management pathway.

Revision of the Hawaiian endemic leaf-mining moth genus Philodoria Walsingham (Lepidoptera: Gracillariidae): its conservation status, host plants and descriptions of thirteen new species.

Philodoria Walsingham, 1907 is a threatened, Hawaiian endemic genus of leaf-mining gracillariid moths that feeds as larvae on many threatened and endangered Hawaiian endemic plants. These moths are poorly studied and species lack detailed descriptions of morphology, distribution data, and natural history information of adults and immatures. Based on extensive fieldwork from 2013 to 2016, and examination of museum specimens, we describe or redescribe 51 species, 13 which are new species and provide biological and distribution data for 41 species. The 13 new species and their host plants are: P. alakaiensis Kobayashi, Johns Kawahara, sp. n. (Asteraceae: Dubautia sp.), P. funkae Kobayashi, Johns Kawahara, sp. n. (Asteraceae: Wilkesia gymnoxiphium), P. haelaauensis Kobayashi, Johns Kawahara, sp. n. (Urticaceae: Pipturus albidus, P. rockii, Pipturus sp.), P. hesperomanniella Kobayashi, Johns Kawahara, sp. n. (Asteraceae: Hesperomannia arborescens and H. swezeyi), P. keaensis Kobayashi, Johns Kawahara, sp. n. (host unknown), P. keahii Kobayashi, Johns Kawahara, sp. n. (Asteraceae: Remya mauiensis), P. knudseniiella Kobayashi, Johns Kawahara, sp. n. (Asteraceae: Dubautia knudsenii subsp. nagate and D. latifolia), P. lama Kobayashi, Johns Kawahara, sp. n. (Ebanaceae: Diospyros sandwicensis and/or D. hillebrandii), P. limahuliensis Kobayashi, Johns Kawahara, sp. n. (Malvaceae: Hibiscus waimeae subsp. hannerae), P. napaliensis Kobayashi, Johns Kawahara, sp. n. (Ebanaceae: Diospyros sandwicensis and/or D. hillebrandii), P. obamaorum Kobayashi, Johns Kawahara, sp. n. (Urticaceae: Pipturus albidus, Pipturus sp.), P. opuhe Kobayashi, Johns Kawahara, sp. n. (Urticaceae: Urera kaalae and U. sandvicensis) and P. platyphylliella Kobayashi, Johns Kawahara, sp. n. (Asteraceae: Dubautia platyphylla). Types of 30 species were examined, lectotypes of 16 species are designated, and a key to all Philodoria species and all Hawaiian leaf-mining moths are provided. We also present a new Hawaiian name for Philodoria, which we call Hunelele 'elilau, meaning "tiny flier, leaf excavator", referring to their life history and behavior. Philodoria feeds on five herbraceous and woody host plant families, and 41 species persist in localized populations in Hawaii as of 2016. Twelve species (P. alakaiensis, P. funkae, P. haelaauensis, P. hespermanniella, P. kauaulaensis, P. keaensis, P. keahii, P. knudsniiella, P. limahuliensis, P. platyphylliella, P. sciallactis, P. wilkesiella) appear to be severely threatened, as these species are rare or feed exclusively on plants that are endangered or rare. We were unable to document 10 species (P. costalis, P. lipochaetaella, P. micropetala, P. nigrella, P. nigrelloides, P. opuhe, P. pipturiana, P. pipturicola, P. pittosporella, P. spilota) after many efforts to sample in or near their historical habitats. We believe these species may be extinct. Given their restricted distribution and the fact that many species feed on rare and endangered plants, there is a risk that many more Philodoria species may go extinct unless immediate conservation measures are taken.

Diagnostic accuracy of CT pulmonary angiography in suspected pulmonary hypertension.

OBJECTIVES: Computed tomography (CT) pulmonary angiography is widely used in patients with suspected pulmonary hypertension (PH). However, the diagnostic and prognostic significance remains unclear. The aim of this study was to (a) build a diagnostic CT model and (b) test its prognostic significance. METHODS: Consecutive patients with suspected PH undergoing routine CT pulmonary angiography and right heart catheterisation (RHC) were identified. Axial and reconstructed images were used to derive CT metrics. Multivariate regression analysis was performed in the derivation cohort to identify a diagnostic CT model to predict mPAP ≥ 25 mmHg (the existing ESC guideline definition of PH) and > 20 mmHg (the new threshold proposed at the 6th World Symposium on PH). In the validation cohort, sensitivity, specificity and compromise CT thresholds were identified with receiver operating characteristic (ROC) analysis. The prognostic value of the CT model was assessed using Kaplan-Meier analysis. RESULTS: Between 2012 and 2016, 491 patients were identified. In the derivation cohort (n = 247), a CT model was identified including pulmonary artery diameter, right ventricular outflow tract thickness, septal angle and left ventricular area. In the validation cohort (n = 244), the model was diagnostic, with an area under the ROC curve of 0.94/0.91 for mPAP ≥ 25/> 20 mmHg respectively. In the validation cohort, 93 patients died; mean follow-up was 42 months. The diagnostic thresholds for the CT model were prognostic, log rank, all p < 0.01. DISCUSSION: In suspected PH, a diagnostic CT model had diagnostic and prognostic utility. KEY POINTS: • Diagnostic CT models have high diagnostic accuracy in a tertiary referral population of with suspected PH. • Diagnostic CT models stratify patients by mortality in suspected PH.

Diagnostic and prognostic significance of cardiovascular magnetic resonance native myocardial T1 mapping in patients with pulmonary hypertension.

BACKGROUND: Native T1 may be a sensitive, contrast-free, non-invasive cardiovascular magnetic resonance (CMR) marker of myocardial tissue changes in patients with pulmonary artery hypertension. However, the diagnostic and prognostic value of native T1 mapping in this patient group has not been fully explored. The aim of this work was to determine whether elevation of native T1 in myocardial tissue in pulmonary hypertension: (a) varies according to pulmonary hypertension subtype; (b) has prognostic value and (c) is associated with ventricular function and interaction. METHODS: Data were retrospectively collected from a total of 490 consecutive patients during their clinical 1.5 T CMR assessment at a pulmonary hypertension referral centre in 2015. Three hundred sixty-nine patients had pulmonary hypertension [58 ± 15 years; 66% female], an additional 39 had pulmonary hypertension due to left heart disease [68 ± 13 years; 60% female], 82 patients did not have pulmonary hypertension [55 ± 18; 68% female]. Twenty five healthy subjects were also recruited [58 ±4 years); 51% female]. T1 mapping was performed with a MOdified Look-Locker Inversion Recovery (MOLLI) sequence. T1 prognostic value in patients with pulmonary arterial hypertension was assessed using multivariate Cox proportional hazards regression analysis. RESULTS: Patients with pulmonary artery hypertension had elevated T1 in the right ventricular (RV) insertion point (pulmonary hypertension patients: T1 = 1060 ± 90 ms; No pulmonary hypertension patients: T1 = 1020 ± 80 ms p < 0.001; healthy subjects T1 = 940 ± 50 ms p < 0.001) with no significant difference between the major pulmonary hypertension subtypes. The RV insertion point was the most successful T1 region for discriminating patients with pulmonary hypertension from healthy subjects (area under the curve = 0.863) however it could not accurately discriminate between patients with and without pulmonary hypertension (area under the curve = 0.654). T1 metrics did not contribute to prediction of overall mortality (septal: p = 0.552; RV insertion point: p = 0.688; left ventricular free wall: p = 0.258). Systolic interventricular septal angle was a significant predictor of T1 in patients with pulmonary hypertension (p < 0.001). CONCLUSIONS: Elevated myocardial native T1 was found to a similar extent in pulmonary hypertension patient subgroups and is independently associated with increased interventricular septal angle. Native T1 mapping may not be of additive value in the diagnostic or prognostic evaluation of patients with pulmonary artery hypertension.

Origin and macroevolution of micro-moths on sunken Hawaiian Islands.

The origins and evolution of Hawaiian biodiversity are a matter of controversy, and the mechanisms of lineage diversification for many organisms on this remote archipelago remain unclear. Here we focus on the poorly known endemic leaf-mining moth genus Philodoria (Lepidoptera, Gracillariidae), whose species feed on a diversity of Hawaiian plant lineages, many of which are critically endangered. We use anchored hybrid enrichment to assemble the first phylogenomic dataset (507 loci) for any Hawaiian animal taxon. To uncover the timing and pattern of diversification of these moths, we apply two frequently used dating calibration strategies, biogeographic calibrations and secondary calibrations. Island calibrations on their own resulted in much younger and unrealistic dates compared to strategies that relied on secondary calibrations. Philodoria probably originated on the now partially sunken islands of Laysan or Lisianski, approximately 21 Ma, and were associated with host plants in the families Ebenaceae, Malvaceae or Primulaceae. Major feeding groups associated with specific host-plant families originated soon after the plants colonized the islands. Allopatric isolation and host shifts, in concert and independently, probably play major roles in the diversification of Philodoria Our dating results indicate that Philodoria is among the oldest known Hawaiian arthropod lineages, and that island calibrations alone can lead to unrealistically young dates.

Hawaiian Philodoria (Lepidoptera, Gracillariidae, Ornixolinae) leaf mining moths on Myrsine (Primulaceae): two new species and biological data.

This paper provides new taxonomic and biological data on a complex of gracillariid moths in the endemic genus Philodoria Walsingham, 1907 that are associated with Myrsine (Primulaceae) in the Hawaiian Islands, United States. Two new species, Philodoria kauaulaensis Kobayashi, Johns & Kawahara, sp. n. (host: Myrsine lanaiensis, M. lessertiana, and M. sandwicensis) and P. kolea Kobayashi, Johns & Kawahara, sp. n. (host: M. lessertiana) are described. Biological data are provided for two previously described species that also feed on Myrsine: P. auromagnifica Walsingham, 1907 and P. succedanea Walsingham, 1907. For the first time we detail and illustrate genital structures, immature stages, biology, and host plants of P. auromagnifica and P. succedanea. Philodoria kolea, P. auromagnifica, and P. succedanea occur in sympatry on the island of Hawaii (Big Island), but each species differs in behavioral characters: P. kolea utilizes leaves of seedlings and forms a serpentine mine, whereas the latter two utilize leaves of larger plants, and form linear or serpentine to blotch mines. More broadly, leaf mine forms and diagnostic characteristics of the Myrsine-feeding species complex of Philodoria (as currently known) are reviewed and illustrated.

CT derived left atrial size identifies left heart disease in suspected pulmonary hypertension: Derivation and validation of predictive thresholds.

BACKGROUND: Patients with pulmonary hypertension due to left heart disease (PH-LHD) have overlapping clinical features with pulmonary arterial hypertension making diagnosis reliant on right heart catheterization (RHC). This study aimed to investigate computed tomography pulmonary angiography (CTPA) derived cardiopulmonary structural metrics, in comparison to magnetic resonance imaging (MRI) for the diagnosis of left heart disease in patients with suspected pulmonary hypertension. METHODS: Patients with suspected pulmonary hypertension who underwent CTPA, MRI and RHC were identified. Measurements of the cardiac chambers and vessels were recorded from CTPA and MRI. The diagnostic thresholds of individual measurements to detect elevated pulmonary arterial wedge pressure (PAWP) were identified in a derivation cohort (n = 235). Individual CT and MRI derived metrics were tested in validation cohort (n = 211). RESULTS: 446 patients, of which 88 had left heart disease. Left atrial area was a strong predictor of elevated PAWP>15 mm Hg and PAWP>18 mm Hg, area under curve (AUC) 0.854, and AUC 0.873 respectively. Similar accuracy was also identified for MRI derived LA volume, AUC 0.852 and AUC 0.878 for PAWP > 15 and 18 mm Hg, respectively. Left atrial area of 26.8 cm2 and 30.0 cm2 were optimal specific thresholds for identification of PAWP > 15 and 18 mm Hg, had sensitivity of 60%/53% and specificity 89%/94%, respectively in a validation cohort. CONCLUSIONS: CTPA and MRI derived left atrial size identifies left heart disease in suspected pulmonary hypertension with high specificity. The proposed diagnostic thresholds for elevated left atrial area on routine CTPA may be a useful to indicate the diagnosis of left heart disease in suspected pulmonary hypertension.

Magnetic Resonance Imaging in the Prognostic Evaluation of Patients with Pulmonary Arterial Hypertension.

RATIONALE: Prognostication is important when counseling patients and defining treatment strategies in pulmonary arterial hypertension (PAH). OBJECTIVES: To determine the value of magnetic resonance imaging (MRI) metrics for prediction of mortality in PAH. METHODS: Consecutive patients with PAH undergoing MRI were identified from the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre) pulmonary hypertension registry. MEASUREMENTS AND MAIN RESULTS: During the follow-up period of 42 (range, 17-142) months 576 patients were studied and 221 (38%) died. A derivation cohort (n = 288; 115 deaths) and validation cohort (n = 288; 106 deaths) were identified. We used multivariate Cox regression and found two independent MRI predictors of death (P < 0.01): right ventricular end-systolic volume index adjusted for age and sex, and the relative area change of the pulmonary artery. A model of MRI and clinical data constructed from the derivation cohort predicted mortality in the validation cohort at 1 year (sensitivity, 70 [95% confidence interval (CI), 53-83]; specificity, 62 [95% CI, 62-68]; positive predictive value [PPV], 24 [95% CI, 16-32]; negative predictive value [NPV], 92 [95% CI, 87-96]) and at 3 years (sensitivity, 77 [95% CI, 67-85]; specificity, 73 [95% CI, 66-85]; PPV, 56 [95% CI, 47-65]; and NPV, 87 [95% CI, 81-92]). The model was more accurate in patients with idiopathic PAH at 3 years (sensitivity, 89 [95% CI, 65-84]; specificity, 76 [95% CI, 65-84]; PPV, 60 [95% CI, 46-74]; and NPV, 94 [95% CI, 85-98]). CONCLUSIONS: MRI measurements reflecting right ventricular structure and stiffness of the proximal pulmonary vasculature are independent predictors of outcome in PAH. In combination with clinical data MRI has moderate prognostic accuracy in the evaluation of patients with PAH.

TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer.

The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N'-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50% of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-beta-mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-beta-dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-beta are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that both tumor cell-autonomous mechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.