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Rationale: Severe pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is currently defined by an elevated mean pulmonary arterial pressure and strongly elevated pulmonary vascular resistance >5 wood units. Clinically, these patients show a male predominance, and usually present with very severe dyspnea, severe hypoxemia, strongly decreased exercise capacity and poor prognosis, even though the clinical picture is frequently associated with less severe airflow obstruction. Explanted lung samples of patients with COPD and severe PH show severe remodeling of small pulmonary arterioles, predominantly in the intima and media of the vessels. In this concise review, we discuss the clinical and histopathological evidence of severe PH in COPD.

Abstract Background Following SARS-CoV-2 infection, a relevant proportion of patients suffer from persistent or recurring sequela, even after initially mild primary illness. Many patients experience exhaustion and fatigue, rendering them incapable of working. Long COVID exerts a substantial burden on society and the healthcare system: at least 65 million people are currently affected worldwide. The underlying pathobiology is a complex derangement in several organ systems. To date, causal pharmaceutical therapies remain elusive. Waiting lists for specialist care are long. Rapidly scalable digital interventions offering support for the frequent subgroup of patients with mild to moderate impairment from Long COVID are urgently needed. The MiLoCoDaS study compares three intensities of a potentially rapidly scalable digital intervention aiming to accelerate recovery. The overall objective is to figure out if there is a difference in the effect sizes between these modalities. Methods The online intervention uses a learning platform (LMS, TYPO3 framework) comprising 12 sessions of medical, psychological, physiotherapeutic, and nutritional content. The three modalities differ as follows: patient information only (sham intervention, control), information plus interactive digital workbook including practical exercises (digital intervention), and the digital workbook augmented by once-weekly online seminars and discussion groups (person and peer-contact). Eligible patients are 18–67 years old satisfying Long COVID diagnostic criteria. Patients are recruited through primary care physicians and randomly allocated. The primary endpoint is the number of sick leave days during the 6-month observation period; secondary endpoints are patient-reported symptoms, quality of life, and work ability. The study size provides a power of 80% at a type I error of < 0.05 to show an effect size of Cohen = 0.3 between the augmented and the sham intervention (N = 152 per arm, total accounting for attrition N = 600). Discussion If one of the two interventions is superior to providing information alone, MiLoCoDaS would provide the starting point for a rapidly scalable digital intervention for the frequent and currently underserved patient group with mild to moderate impairment from Long COVID. Several caveats pertain to the heterogeneity of Long COVID manifestation and duration prior to inclusion. It is conceivable that the possible effect of the intervention may differ across subgroups. Therefore, a priori defined secondary analysis will be conducted. Trial registration German Clinical Trials Register (DRKS) DRKS00028964. Registered on 24 August 2022.

Abstract Pulmonary hypertension (PH) adds a substantial disease burden, including higher mortality, when associated with interstitial lung disease (ILD), a severe, chronic, progressive condition. Yet little is known of the lived experiences, perspectives, priorities, and viewpoints of patients and carers living with PH‐ILD. The Voice of the Patient meeting at the center of this qualitative research study aims to provide these difficult‐to‐obtain insights from a European perspective for the first time. The multistakeholder approach brought together four PH‐ILD patients, three primary caregivers, two patient associations, clinical experts, sponsor representatives, and a facilitator. Of the six major themes identified in the thematic analysis, symptoms, and physical limitations were the most impactful. Shortness of breath was the most bothersome symptom affecting patients daily. Further symptoms included fatigue, cough, dizziness, syncope, edema, and palpitations. Physical limitations focused on reduced mobility, impacting patients’ ability to perform daily tasks, hobbies, sports, and to enjoy travel. Existing antifibrotic and pulmonary arterial hypertension‐targeted treatments were perceived as beneficial. However, despite advances in treatment, severe disease burdens and high unmet medical needs persist from the perspectives of patients. Most meaningful to patients’ daily wellbeing was supplemental oxygen, enabling greater mobility. Patients and carers reported difficulties and barriers in navigating the healthcare system and obtaining adequate information to reduce their considerable uncertainties, documenting the substantial challenges that rare and complex conditions such as PH‐ILD pose for routine clinical practice beyond PH expert centers and indicating an urgent need for high‐quality patient‐ and clinician‐directed information to support patient‐centered care.

Background: Our knowledge about the attitudes of healthcare staff to palliative care in pediatric oncology is scarce. We aimed to assess their perceptions of palliative care in Hungary and find answers to the question of how to provide good palliative care for children. Method: Physicians (n = 30) and nurses (n = 43) working in the field of pediatric oncology (12 of them specialized in hospice care) were interviewed. Palliative care practice (communication, integration of palliative care, professionals’ feelings and attitudes, and opportunities for improvement) was assessed by semi-structured interviews evaluated in a mixed quantitative and qualitative way by narrative categorical content analysis and thematic analysis. Results: All providers displayed high negative emotions, positive evaluations, and used many active verbs. Nurses showed higher levels of denial, more self-references, and were more likely to highlight loss. Physicians emphasized the importance of communication regarding adequate or inadequate palliative care. Hospice specialists showed a higher passive verb rate, a lower self-reference, a lower need for psychological support, and a greater emphasis on teamwork and professional aspects. Conclusion: Our results show that nurses are more emotionally stressed than doctors in palliative care in pediatric oncology. To our knowledge, a study comparing doctors and nurses in this field has yet to be carried out. Our results suggest that pediatric oncological staff can positively evaluate a child’s palliative care despite the emotional strain. Regarding hospices, professional practice in palliative care may be a protective factor in reducing emotional distress and achieving professional well-being.

Abstract Background Pulmonary hypertension (PH) is a frequent complication in COPD and it is associated with decreased exercise capacity and poor prognosis. We hypothesized that even in COPD patients without significant PH at rest, abnormal pulmonary hemodynamics during exercise affect exercise capacity. Methods Consecutive COPD patients with clinically indicated right heart catheterization and resting mean pulmonary arterial pressure (mPAP)

ObjectivesPathways contributing to endothelial dysfunction in patients with limited cutaneous systemic sclerosis (lcSSc) are largely unknown. The aim of this study was to investigate potential associations of amino acids and parameters of bone metabolism with endothelial dysfunction and vasculopathy-related changes in patients with lcSSc and early-stage vasculopathy.MethodsAmino acids, calciotropic parameters, including 25-hydroxyvitamin D and parathyroid hormone (PTH), and bone turnover parameters, including osteocalcin and N-terminal peptide of procollagen-3 (P3NP), were measured in 38 lcSSc patients and 38 controls. Endothelial dysfunction was assessed by biochemical parameters, pulse-wave analysis, flow-mediated and nitroglycerine-mediated dilation. Additionally, vasculopathy-related and SSc-specific clinical changes including capillaroscopic, skin, renal, pulmonary, gastrointestinal and periodontal parameters were recorded.ResultsNo significant differences in amino acids, calciotropic and bone turnover parameters were observed between lcSSc patients and controls. In patients with lcSSc, several significant correlations were found between selected amino acids, parameters of endothelial dysfunction, vasculopathy-related and SSc-specific clinical changes (all with p

(1) Background: Long COVID syndrome (LCS) is a heterogeneous long-standing condition following COVID-19 infection. Treatment options are limited to symptomatic measures, and no specific medication has been established. Hyperbaric oxygenation (HBO) has been found to have a positive impact on the treatment of COVID-19 infection. This study evaluates both the feasibility and outcome of supportive HBO in patients with LCS. (2) Methods: Within 17 months, 70 patients with proven LCS were prospectively included. Each patient underwent a cycle of 10 subsequent HBO treatment sessions administered for 75 min at 2.2 atmospheres. Evaluation of the patients was performed before the first and after the last HBO session and 3 months afterwards. Statistical evaluation was based on an intention-to-treat analysis using Fisher’s exact test and Student’s t-test for paired samples. (3) Results: In total, 59 patients (33 females, 26 males; mean age: 43.9 years; range: 23–74 years; median: 45.0) were evaluable. After HBO, a statistically significant improvement of physical functioning (p < 0.001), physical role (p = 0.01), energy (p < 0.001), emotional well-being (p < 0.001), social functioning (p < 0.001), pain (p = 0.01) and reduced limitation of activities (p < 0.001) was confirmed. (4) Conclusions: Physical functioning and both the physical and emotional role improved significantly and sustainably, suggesting HBO as a promising supportive therapeutic tool for the treatment of LCS.

Background: NT-proBNP and GDF-15 are established blood-derived biomarkers for risk assessment in pulmonary hypertension (PH), despite limited sensitivity and specificity. Apelin has a crucial function in endothelial homeostasis, thus it might represent a new biomarker for PH. However, there are numerous circulating apelin isoforms, and their potential role in this setting is unknown. This study evaluated different apelin isoforms in PH patients and prospectively evaluated the role of apelin-17 in comparison with NT-proBNP and GDF-15 as diagnostic marker in idiopathic pulmonary arterial hypertension (IPAH).Methods: Based on our pilot study, we performed a power calculation for apelin-13, apelin-17, apelin-36, as predictor of IPAH vs healthy controls. Apelin-17 provided the best discriminatory power, and accordingly, we enrolled n = 31 patients with IPAH and n = 31 matched healthy controls in a prospective study. NT-proBNP and GDF-15 was determined in all patients. ROC curve analysis was performed to assess the diagnostic value of the markers and their combinations.Results: Apelin-17, NT-proBNP, and GDF-15 were significantly elevated in IPAH patients as compared to controls (p < .001). Apelin-17 detected IPAH with a sensitivity of 68% and a specificity of 93% at a cut-off value of >1,480 pg/ml (AUC 0.86, 95%CI:0.76–0.95) as compared to GDF-15 (sensitivity 86%; specificity 72%, AUC 0.81 (95%CI:0.7–0.92)) and NT-proBNP (sensitivity 86%; specificity 72% (AUC 0.85, 95%CI:0.75–0.95)). Combinations of these markers could be used to increase either specificity or sensitivity.Conclusion: Apelin-17 appears to be suitable blood derived diagnostic marker for idiopathic pulmonary arterial hypertension.

In the recently published European Society of Cardiology/European Respiratory Society guidelines on the diagnosis and treatment of pulmonary hypertension (PH) the haemodynamic definitions of PH were updated and a new definition for exercise PH was introduced. Accordingly, exercise PH is characterised by a mean pulmonary arterial pressure/cardiac output (CO) slope >3 Wood units (WU) from rest to exercise. This threshold is supported by several studies demonstrating prognostic and diagnostic relevance of exercise haemodynamics in various patient cohorts. From a differential diagnostic point of view, an elevated pulmonary arterial wedge pressure/CO slope >2 WU may be suitable to identify post-capillary causes of exercise PH. Right heart catheterisation remains the gold standard to assess pulmonary haemodynamics both at rest and exercise. In this review, we discuss the evidence that led to the reintroduction of exercise PH in the PH definitions.

BackgroundMean pulmonary artery wedge pressure (PAWP) represents a right heart catheter (RHC) surrogate measure for mean left atrial (LA) pressure and is crucial for the clinical classification of pulmonary hypertension (PH). Hypothesizing that PAWP is related to acceleration of blood throughout the LA, we investigated whether an adequately introduced LA acceleration factor derived from magnetic resonance (MR) four-dimensional (4D) flow imaging could provide an estimate of PAWP in patients with known or suspected PH.MethodsLA 4D flow data of 62 patients with known or suspected PH who underwent RHC and near-term 1.5 T cardiac MR (ClinicalTrials.gov identifier: NCT00575692) were retrospectively analyzed. Early diastolic LA peak outflow velocity (vE) as well as systolic (vS) and early diastolic (vD) LA peak inflow velocities were determined with prototype software to calculate the LA acceleration factor (α) defined as α = vE/[(vS + vD)/2]. Correlation, regression and Bland-Altman analysis were employed to investigate the relationship between α and PAWP, α-based diagnosis of elevated PAWP (>15 mmHg) was analyzed by receiver operating characteristic curve analysis.Resultsα correlated very strongly with PAWP (r = 0.94). Standard deviation of differences between RHC-derived PAWP and PAWP estimated from linear regression model (α = 0.61 + 0.10·PAWP) was 2.0 mmHg. Employing the linear-regression-derived cut-off α = 2.10, the α-based diagnosis of elevated PAWP revealed the area under the curve 0.97 with sensitivity/specificity 93%/92%.ConclusionsThe very close relationship between the LA acceleration factor α and RHC-derived PAWP suggests α as potential non-invasive parameter for the estimation of PAWP and the distinction between pre- and post-capillary PH.

The clinical value of pulmonary hemodynamics during exercise has not been fully explored. In the last decade, several studies investigated the prognostic and diagnostic relevance of exercise hemodynamics and novel hemodynamic variables including the mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope and the pulmonary arterial wedge pressure (PAWP)/CO slope have been analyzed. These parameters describe the effects of pulmonary blood flow on the pulmonary pressure and were shown to be of prognostic relevance. In addition, they may also serve as tools to differentiate early forms of pulmonary vascular from left heart diseases. Right heart catheterization remains the gold standard to assess pulmonary hemodynamics both at rest and during exercise, while exercise echocardiography represents a promising non-invasive research tool. In this review, we provide an overview of the growing body of evidence on the clinical relevance of pulmonary hemodynamics during exercise and discuss its potential future role.

Abstract In this paper, a navigation and environment mapping method is presented for small exploration robots that use hopping motion. While previous research about hopping rovers mostly focuses on mobility and mechanical design, the motivation for the proposed method is to provide a fully autonomous navigation system using only a monocular camera. The method accurately estimates the hopping distance and reconstruct the 3D environment using Structure from Motion, proving that a monocular system is not only feasible, but accurate and robust at the same time. The relative scale problem of the reconstructed scene and trajectory is solved by the known gravity and parabolic motion constraints. After each hop, the error in landing position is corrected by a modified Iterative Closest Point algorithm with non-overlapping part elimination. The environmental point cloud is projected onto a 2D image, that is used to find the most suitable landing position for the next hop using protrusion based obstacle detection, and navigate the robot towards the goal direction. Both virtual environment simulations and real experiments confirm the feasibility and highlight the advantages of the presented method.

Abstract Background Systemic sclerosis (SSc) is a severe rheumatic disease of the interstitial tissue, in which heart and lung involvement can lead to disease-specific mortality. Our study tests the hypothesis that in addition to established prognostic factors, cardiopulmonary exercise testing (CPET) parameters, particularly peak oxygen uptake (peakVO2) and ventilation/carbon dioxide (VE/VCO2)-slope, can predict survival in patients with SSc. Subjects and methods We retrospectively assessed 210 patients (80.9% female) in 6 centres over 10 years with pulmonary testing and CPET. Survival was analysed with Cox regression analysis (adjusted for age and gender) by age, comorbidity (Charlson-Index), body weight, body-mass index, extensive interstitial lung disease, pulmonary artery pressure (measured by echocardiography and invasively), and haemodynamic, pulmonary and CPET parameters. Results Five- and ten-year survival of SSc patients was 93.8 and 86.9%, respectively. There was no difference in survival between patients with diffuse (dcSSc) and limited cutaneous manifestation (lcSSc; p = 0.3). Pulmonary and CPET parameters were significantly impaired. Prognosis was worst for patients with pulmonary hypertension (p = 0.007), 6-min walking distance 35. Age (hazard ratio HR = 1.23; 95% confidence interval CI: 1.14;1.41), VE/VCO2-slope (HR = 0.9; CI 0.82;0.98), diffusion capacity (Krogh factor, HR = 0.92; CI 0.86;0.98), forced vital capacity (FVC, HR = 0.91; CI 0.86;0.96), and peakVO2 (HR = 0.87; CI 0.81;0.94) were significantly linked to survival in multivariate analyses (Harrell’s C = 0.95). Summary This is the first large study with SSc patients that demonstrates the prognostic value of peakVO2 35.

The definition of pulmonary hypertension (PH) is based on a growing body of evidence and represents the result of ongoing discussions within the PH community over the past 50 years. In 2018, the most recent World Symposium on Pulmonary Hypertension introduced significant changes in the definition of PH by lowering the mean pulmonary arterial pressure threshold to >20 mmHg and (re)introducing the pulmonary vascular resistance ≥3 WU cut-off for all forms of pre-capillary PH. These changes and their potential clinical impact have been the subject of lively discussions in the community and some important questions and controversies have been identified. In this review we aim to present the development of the definition of PH over the past decades and discuss the main arguments that led to relevant modifications. In addition, we address the practical implications of the most recent changes and controversies that still exist. Educational aims To review the historical development of the definition of pulmonary hypertension. To discuss practical implications and current controversies of the currently recommended definitions of pulmonary hypertension and pulmonary arterial hypertension.

Pulmonary hypertension (PH) commonly affects patients with systemic sclerosis (SSc) and is associated with significant morbidity and increased mortality. PH is a heterogenous condition and several different forms can be associated with SSc, including pulmonary arterial hypertension (PAH) resulting from a pulmonary arterial vasculopathy, PH due to left heart disease and PH due to interstitial lung disease. The incidence of pulmonary veno-occlusive disease is also increased. Accurate and early diagnosis to allow optimal treatment is, therefore, essential. Recent changes to diagnostic haemodynamic criteria at the 6th World Symposium on Pulmonary Hypertension have resulted in therapeutic uncertainty regarding patients with borderline pulmonary haemodynamics. Furthermore, the optimal pulmonary vascular resistance threshold for diagnosing PAH and the role of exercise in identifying early disease require further elucidation. In this article we review the epidemiology, diagnosis, outcomes and treatment of the spectrum of pulmonary vascular phenotypes associated with SSc.

REG-1α, a secreted protein containing a C-type lectin domain, is expressed in various organs and plays different roles in digestive system cells in physiological and pathological conditions. Like other members of the Reg family, REG-1α is expressed also in the brain where it has different functions. For instance, we previously reported that REG-1α regulates neurite outgrowth and is overexpressed during the very early stages of Alzheimer's disease (AD). However, REG-1α function in neural cells during neural degeneration remains unknown. First, REG-1α and phosphorylated tau expression were assessed in tissue sections from the hippocampus, representing neurofibrillary tangles (NFTs), from patients with AD, and from basal ganglia, representing subcortical NFTs, from patients with progressive supranuclear palsy (PSP). We found an association between REG-1α expression, tau hyperphosphorylation and NFTs in human brain samples from patients with these neurodegenerative diseases. Then, the effects of REG-1α overexpression on tau phosphorylation and axonal morphology were investigated i) in primary cultures of rat neurons that express human tau P301L and ii) in a transgenic zebrafish model of tauopathy that expresses human tau P301L. In the tau P301L cell model, REG-1α overexpression increased tau phosphorylation at the S202/T205 and S396 residues (early and late stages of abnormal phosphorylation, respectively) through the AKT/GSK3-β pathway. This effect was associated with axonal defects both in tau P301L-expressing rat neurons and zebrafish embryos. Our findings suggest a functional role for REG-1α during tauopathy development and progression and, specifically, its involvement in the modification of tau phosphorylation temporal sequence.

Magnetic resonance imaging (MRI) is an emerging tool for diagnosis and treatment monitoring of chronic thromboembolic pulmonary hypertension (CTEPH). The current study aims to identify central pulmonary arterial hemodynamic parameters that reflect clinical, cardiac and pulmonary changes after PEA. 31 CTEPH patients, who underwent PEA and received pre- and postoperative MRI, were analyzed retrospectively. Central pulmonary arterial blood flow, lung perfusion and right heart function data were derived from MRI. Mean pulmonary arterial pressure (mPAP) and 5-month follow-up six-minute walk-distance (6MWD) were assessed. After PEA, mPAP decreased significantly and patients achieved a higher 6MWD. Central pulmonary arterial blood flow velocities, pulmonary blood flow (PBF) and right ventricular function increased significantly. Two-dimensional (2D) phase-contrast (PC) MRI-derived average mean velocity, maximum mean velocity and deceleration volume changes after PEA correlated with changes of 6MWD and right heart ejection fraction (RVEF). Deceleration volume is a novel 2D PC MRI parameter showing further correlation with PBF changes. In conclusion, 2D PC MRI-derived main pulmonary hemodynamic changes reflect changes of RVEF, PBF and 5-month follow-up 6MWD and may be used for future CTEPH patient monitoring after PEA.

Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2, ATP13A3, AQP1 and SOX17.

Systemic sclerosis (SSc) is an intractable autoimmune disease characterized by vasculopathy and organ fibrosis. Autologous hematopoietic stem cell transplantation (AHSCT) should be considered for the treatment of selected patients with rapid progressive SSc at high risk of organ failure. It, however, remains elusive whether immunosuppressive therapies such as rituximab (RTX) are still necessary for such patients after AHSCT, especially in those with bad outcomes. In the present report, a 43-year-old man with diffuse cutaneous SSc received AHSCT. Despite AHSCT, SSc further progressed with progressive symptomatic heart failure with newly developed concomitant mitral and tricuspid valve insufficiency, thus the patient started on RTX 8 months after AHSCT. Shortly after initiation of RTX, clinical symptoms and organ functions ameliorated subsequently. Heart valve regurgitations were reversible after initiation of RTX treatment. Currently, the patient remains in a stable condition with significant improvement of clinical symptoms and organ functions. Reporting about therapies after AHSCT in SSc is a very important issue, as randomized controlled trials are lacking, and therefore this report adds to evidence that RTX can be considered as a treatment option in patients with SSc that do not respond to AHSCT.

The diagnosis of idiopathic pulmonary arterial hypertension (iPAH) is complex and, besides invasive hemodynamic evaluation, includes several diagnostic steps to exclude any underlying diseases. The role of a decreased diffusion capacity of the lung for carbon monoxide (DLCO) is a matter of discussion. Here, we present a 76-year-old man with a smoking history of 30 pack-years who was diagnosed with iPAH after chronic thromboembolic pulmonary hypertension was excluded based on a negative perfusion scan, an underlying heart disease was excluded based on echocardiography and right heart catheterization, and a significant lung disease was excluded based on lung function test (FVC = 101% predicted, FEV1 = 104% predicted, FEV1/FVC = 77, TLC = 97% predicted) and thin-slice computed tomography (CT) scan. Just DLCO was reduced to 40% predicted, suggesting a possible structural lung disease. Postmortem examination demonstrated severe interstitial lung fibrosis combined with microscopic emphysema. This indicates that both CT imaging and pulmonary function test may be insensitive to a diffuse peripheral combined pattern of fibrosis and emphysema and that DLCO may be the only sensitive marker of this significant lung pathology.

Objective. The nephron (pro)renin receptor may play a pathophysiological role in renal disorders in hypertension or diabetes. The aim of this study was to determine the relationship of (pro)renin receptors and transdifferentiation between the renin-negative and renin-positive SMCs in the afferent arteriole by estimating the distribution of (pro)renin receptors in renin-positive and renin-negative SMCs of the afferent arteriole of kidneys in normal and streptozotocin- (STZ-) induced diabetic rats. Therefore in diabetes the renin granulation of afferent arterioles is different as in normal, the diabetes model for finding the differences to normal in distribution of (pro)renin receptors of afferent arterioles was used. Method. To estimate the number of (pro)renin receptors in arteriolar SMCs a special protocol of immunohistochemistry to stereology was followed. Results. Our results showed that on the surface of renin-positive SMCs the number of (pro)renin receptors was upregulated, while in the cytoplasm of SMCs there was downregulation in comparison to renin-negative SMCs. There is a significant difference between the number of (pro)renin receptors on the surface and in the cytoplasm of renin-positive SMCs in normal rats. These differences in the number of (pro)renin receptors were not present in rats with STZ-induced diabetes. Any other differences in the number of (pro)renin receptors between the STZ-induced diabetic and normal rats were not detected. The tissue level of angiotensin II did not change in the kidneys of STZ-induced diabetic rats. Conclusion. The distribution of (pro)renin receptors in afferent arteriolar SMCs is related to renin granulation of SMCs, but independent of angiotensin II plasma or tissue levels in the kidney.

Severe pulmonary hypertension (PH) is rare in chronic obstructive pulmonary disease (COPD). Pulmonary arterial hypertension drugs are vasodilators and may cause severe side effects in these patients. Hence, they are not recommended except in right heart failure on an individual basis. Imatinib, a tyrosine-kinase-inhibitor, has no direct vasodilator effects but significantly improved hemodynamics and exercise capacity in PAH but its use was associated with an increased risk for subdural hematomas in anticoagulated patients. We report on a COPD patient with right heart failure who did not recover with a phosphodiesterase-5-inhibitor or a soluble-guanylate-cyclasestimulator alone but with imatinib as add-on therapy. After one year of treatment, pulmonary vascular resistance (10.8 WU to 2.9 WU), NT-proBNP (4144 pg/mL to 363 pg/mL), and symptoms (WHO FC IV to III, 6MWD bedridden to 303 m) improved without major side effects. Imatinib may be a therapy option in patients with severe PH due to lung disease and right heart failure where other drugs have failed.

The peak oxygen consumption (VO2 peak) serves as a prognostic factor in cardio-respiratory diseases and plays an important role in cancer patients. The long-term prognostic relevance of VO2 peak in lung cancer patients has not been investigated extensively. The aim of this study was to evaluate the impact of the preoperative VO2 peak on the postoperative long-term survival in patients with operated lung cancer. Retrospective analysis of 342 patients with curatively resected non-small-cell lung cancer using a multivariate Cox proportional hazard model. Results: Preoperative VO2 peak ranged from 10.2 to 51.8 mL/kg/min (mean: 18.3 ± 4.6), VO2 peak % of predicted ranged from 32 to 172% (mean: 65.2 ± 18.0%). Overall 10-year survival was 23%. A Log-rank test comparing predicted VO2 peak ≥ 60% with predicted VO2 peak < 60% showed overall survival of 30% and 17%, respectively (p < 0.001) and non-tumour-related survival of 71% and 51% (p = 0.001) at 10 years. In multivariable Cox analysis, overall 10-year survival correlated with a high predicted VO2 peak% (p = 0.001) and low N-stage corresponding to N0 and N1 (p < 0.001). Non-tumour-related death correlated with low VO2 peak% of predicted (p = 0.001), and age (p < 0.001). Low preoperative VO2 peak was associated with both decreased postoperative overall survival and decreased non-tumour-related survival during the 10-year follow-up.

Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) associated with high morbidity and mortality. There are several biomarkers of SSc-PAH, reflecting endothelial physiology, inflammation, immune activation, extracellular matrix, metabolic changes, or cardiac involvement. Biomarkers associated with diagnosis, disease severity and progression have been identified, however, very few have been tested in a prospective setting. Some antinuclear antibodies such as nucleosome antibodies (NUC), anti-centromere antibodies (CENP-A/B) and anti-U3-ribonucleoprotein (anti-U3-RNP) are associated with PAH while anti-U1-ribonucleoprotein (anti-U1-RNP) is associated with a reduced PAH risk. Anti-endothelin receptor and angiotensin-1 receptor antibodies might be good markers of SSc-PAH and progression of pulmonary vasculopathy. Regarding the markers reflecting immune activation and inflammation, there are many inconsistent results. CXCL-4 was associated with SSc progression including PAH and lung fibrosis. Growth differentiation factor (GDF)-15 was associated with PAH and mortality but is not specific for SSc. Among the metabolites, kynurenine was identified as diagnostic marker for PAH, however, its pathologic role in the disease is unclear. Endostatin, an angiostatic factor, was associated with heart failure and poor prognosis. Established heart related markers, such as N-terminal fragment of A-type natriuretic peptide/brain natriuretic peptide (NT-proANP, NT-proBNP) or troponin I/T are elevated in SSc-PAH but are not specific for the right ventricle and may be increased to the same extent in left heart disease. Taken together, there is no universal specific biomarker for SSc-PAH, however, there is a pattern of markers that is strongly associated with a risk of vascular complications in SSc patients. Further comprehensive, multicenter and prospective studies are warranted to develop reliable algorithms for detection and prognosis of SSc-PAH.

This work presents the investigation on a MEMS based optomechanical transducer for displacements or vibration regarding its cross-sensitivities to multidirectional input excitations. The principle of the optomechanical transducer is based on the modulation of the light flux passing through one static and one movable micromechanical aperture. This kind of transducer is of increasing interest for MEMS sensors since it has inherent benefits and can compete with state-ofthe- art readout concepts regarding its resolution. We have experimentally proven that the sensitivities of the device is 3.3 × 107 V/m in x-direction, 8.23 × 106 V/m in y-direction, while it is negligible in z-direction.

This paper reports a MEMS gradiometer consisting of two independent, laterally oscillating masses on a single chip with integrated optical readout featuring a responsitivity of 35V/T at resonant operation. The symmetrical design of the two masses offers high accuracy and low cost by using conventional MEMS batch fabrication technology. The sensing principle is based on lateral displacement of the masses actuated by Lorentz forces which modulates a light flux passing through a stationary mask and the moving mask integrated in the masses. Phase and intensity detected by photodiodes reveal information about the uniformity of an external applied magnetic field, hence, enables the measurement of gradient-, homogeneous- and offset gradient magnetic fields.

The functional principle of an optical gradient magnetic field sensor consisting of two independent laterally oscillating masses on a single chip is reported. These oscillations are caused by the Lorentz forces resulting from an alternating current through the masses interacting with a static magnetic field. Light is modulated by relative in-plane movement of the masses and a fixed frame and subsequently detected by two photodiodes. Evaluation of magnitude and phase of the output signal reveals information about the uniformity of the magnetic field. The sensor is capable of detecting uniaxially strength and direction of magnetic gradient fields, offset gradient fields and homogeneous fields.

We report on a new optical sensing principle for measuring the electric field strength based on MEMS technology. This method allows for distortion-free and point-like measurements with high stability regarding temperature. The main focus of this paper rests on an enhanced measurement set-up and the thereby obtained measurement results. These results reveal an improved resolution limit and point to the limitations of the current characterization approach. A resolution limit of 222 V/m was achieved while a further improvement of roughly one order of magnitude is feasible.

There is a broad consensus that pulmonary hypertension (PH) is to be diagnosed by right heart catheterization (RHC) and that the most important non-invasive tool is echocardiography. However, the role of simple non-invasive tools in the work-up of PH is not clearly defined. We hypothesized that the use of simple non-invasive techniques may help to guide important decisions in the diagnostics of pulmonary hypertension.We aimed to develop an algorithm with the use of simple, non-invasive tools in order to identify patients with very high or very low likelihood of PH.We retrospectively analyzed all consecutive patients undergoing RHC between 2005 and 2010 in our center and performed logistic regression of simple non-invasive parameters regarding detection and exclusion of PH and derived a two-step algorithm. In a prospective study we evaluated this algorithm between 2011 and 2013.The retrospective cohort consisted of n = 394 patients of which 49% presented with PH. Right axis deviation in the ECG was present in 90/394 patients and had a positive predictive value (PPV) of 93% for PH. The combination of non-right axis deviation, N-terminal pro brain natriuretic peptide (NT-proBNP)

To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and 2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment ≤24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo(immuno)therapy combinations in patients with an early relapse does not offer any benefit when compared to less intensive therapies. Trial identifier: NCT00281918, ISRCTN75653261, ISRCTN36294212, NCT00274989 and NCT00147901.

Heterogeneous phenotypes of complex disorders pose a great challenge for genetic association studies and for the development of personalized treatment strategies. Cluster analysis of phenotypic data has been recently proposed as a reliable auxiliary method for such studies. A cohort of 236 treatment-seeking smokers was investigated after overnight nicotine abstinence. Alpha4 nicotinic acetylcholine receptor (nAChR) subunit-related phenotypes were assessed by the Fagerström Test for Nicotine Dependence (FTND), exhaled carbon monoxide (CO) measurements, the Minnesota Nicotine Withdrawal Scale (MNWS) and the Zung Self-Rating Depression Scale (ZSDS). Seven tag SNPs (single-nucleotide polymorphisms) across CHRNA4 (the gene encoding alpha4 subunit of the nicotinic acetylcholine receptor) were genotyped and two-step cluster analysis was used for phenotypic cluster characterization. Haplotype estimation was determined by HapStat module of R 2.0 software. Three different phenotypic clusters were identified and the C3 cluster was characterized by the highest ZSDS and MNWS scores compared to others. Furthermore, lifetime prevalence of major depression was significantly higher in the C3 cluster (p = 0.019). In genetic association tests, this cluster was also significantly associated with rs3787138 genotypes (p = 0.004) while haplotype analyses of three SNPs (rs3787138, rs1044396, rs3787140) revealed that the risk for C3 phenotype was almost three times higher in GCC haplotype carriers compared to others (pperm = 0.013). This is the first report on a significant association between CHRNA4 variants and a subgroup of smokers characterized by massive withdrawal symptoms and affective vulnerability. Identification of such a phenotypic cluster can be a pivotal step for further pharmacogenetic studies on ligands of the alpha4 nAChR subunit. Our results suggest that performing cluster analysis in genetic association studies can be proposed for complex disorders.

Pulmonary hypertension (PH) can result in vascular pruning and increased tortuosity of the blood vessels. In this study we examined whether automatic extraction of lung vessels from contrast-enhanced thoracic computed tomography (CT) scans and calculation of tortuosity as well as 3D fractal dimension of the segmented lung vessels results in measures associated with PH. In this pilot study, 24 patients (18 with and 6 without PH) were examined with thorax CT following their diagnostic or follow-up right-sided heart catheterisation (RHC). Images of the whole thorax were acquired with a 128-slice dual-energy CT scanner. After lung identification, a vessel enhancement filter was used to estimate the lung vessel centerlines. From these, the vascular trees were generated. For each vessel segment the tortuosity was calculated using distance metric. Fractal dimension was computed using 3D box counting. Hemodynamic data from RHC was used for correlation analysis. Distance metric, the readout of vessel tortuosity, correlated with mean pulmonary arterial pressure (Spearman correlation coefficient: ρ = 0.60) and other relevant parameters, like pulmonary vascular resistance (ρ = 0.59), arterio-venous difference in oxygen (ρ = 0.54), arterial (ρ = -0.54) and venous oxygen saturation (ρ = -0.68). Moreover, distance metric increased with increase of WHO functional class. In contrast, 3D fractal dimension was only significantly correlated with arterial oxygen saturation (ρ = 0.47). Automatic detection of the lung vascular tree can provide clinically relevant measures of blood vessel morphology. Non-invasive quantification of pulmonary vessel tortuosity may provide a tool to evaluate the severity of pulmonary hypertension.ClinicalTrials.gov NCT01607489.

PURPOSE: Three-dimensional (3D) magnetic resonance phase contrast imaging (PC-MRI) allows non-invasive diagnosis of pulmonary hypertension (PH) and estimation of elevated mean pulmonary arterial pressure (mPAP) based on vortical motion of blood in the main pulmonary artery. The purpose of the present study was to compare the presence and duration of PH-associated vortices derived from different flow visualization techniques with special respect to their performance for non-invasive assessment of elevated mPAP and diagnosis of PH. METHODS: Fifty patients with suspected PH (23 patients with and 27 without PH) were investigated by right heart catheterization and time-resolved PC-MRI of the main pulmonary artery. PC-MRI data were visualized with dedicated prototype software, providing 3D vector, multi-planar reformatted (MPR) 2D vector, streamline, and particle trace representation of flow patterns. Persistence of PH-associated vortical blood flow (tvortex) was evaluated with all visualization techniques. Dependencies of tvortex on visualization techniques were analyzed by means of correlation and receiver operating characteristic (ROC) curve analysis. RESULTS: tvortex values from 3D vector visualization correlated strongly with those from other visualization techniques (r = 0.98, 0.98 and 0.97 for MPR, streamline and particle trace visualization, respectively). Areas under ROC curves for diagnosis of PH based on tvortex did not differ significantly and were 0.998 for 3D vector, MPR vector and particle trace visualization and 0.999 for streamline visualization. Correlations between elevated mPAP and tvortex in patients with PH were r = 0.96, 0.93, 0.95 and 0.92 for 3D vector, MPR vector, streamline and particle trace visualization, respectively. Corresponding standard deviations from the linear regression lines ranged between 3 and 4 mmHg. CONCLUSION: 3D vector, MPR vector, streamline as well as particle trace visualization of time-resolved 3D PC-MRI data of the main pulmonary artery can be employed for accurate vortex-based diagnosis of PH and estimation of elevated mPAP.