Species-wide genetic incompatibility analysis identifies immune genes as hot spots of deleterious epistasis.

Intraspecific genetic incompatibilities prevent the assembly of specific alleles into single genotypes and influence genome- and species-wide patterns of sequence variation. A common incompatibility in plants is hybrid necrosis, characterized by autoimmune responses due to epistatic interactions between natural genetic variants. By systematically testing thousands of F1 hybrids of Arabidopsis thaliana strains, we identified a small number of incompatibility hot spots in the genome, often in regions densely populated by nucleotide-binding domain and leucine-rich repeat (NLR) immune receptor genes. In several cases, these immune receptor loci interact with each other, suggestive of conflict within the immune system. A particularly dangerous locus is a highly variable cluster of NLR genes, DM2, which causes multiple independent incompatibilities with genes that encode a range of biochemical functions, including NLRs. Our findings suggest that deleterious interactions of immune receptors limit the combinations of favorable disease resistance alleles accessible to plant genomes.

Deciphering the regulatory network of the NAC transcription factor FvRIF, a key regulator of strawberry (Fragaria vesca) fruit ripening.

The NAC transcription factor ripening inducing factor (RIF) was previously reported to be necessary for the ripening of octoploid strawberry (Fragaria × ananassa) fruit, but the mechanistic basis of RIF-mediated transcriptional regulation and how RIF activity is modulated remains elusive. Here, we show that FvRIF in diploid strawberry, Fragaria vesca, is a key regulator in the control of fruit ripening and that knockout mutations of FvRIF result in a complete block of fruit ripening. DNA affinity purification sequencing coupled with transcriptome deep sequencing suggests that 2,080 genes are direct targets of FvRIF-mediated regulation, including those related to various aspects of fruit ripening. We provide evidence that FvRIF modulates anthocyanin biosynthesis and fruit softening by directly regulating the related core genes. Moreover, we demonstrate that FvRIF interacts with and serves as a substrate of MAP kinase 6 (FvMAPK6), which regulates the transcriptional activation function of FvRIF by phosphorylating FvRIF at Thr-310. Our findings uncover the FvRIF-mediated transcriptional regulatory network in controlling strawberry fruit ripening and highlight the physiological significance of phosphorylation modification on FvRIF activity in ripening.

Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

BACKGROUND: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. METHODS: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. RESULTS: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. CONCLUSIONS: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

Diversity of the volatilome and the fruit size and shape in European woodland strawberry (Fragaria vesca).

Woodland strawberry (Fragaria vesca subsp. vesca) is a wild relative of cultivated strawberry (F. × ananassa) producing small and typically conical fruits with an intense flavor and aroma. The wild strawberry species, F. vesca, is a rich resource of genetic and metabolic variability, but its diversity remains largely unexplored and unexploited. In this study, we aim for an in-depth characterization of the fruit complex volatilome by GC-MS as well as the fruit size and shape using a European germplasm collection that represents the continental diversity of the species. We report characteristic volatilome footprints and fruit phenotypes of specific geographical areas. Thus, this study uncovers phenotypic variation linked to geographical distribution that will be valuable for further genetic studies to identify candidate genes or develop markers linked to volatile compounds or fruit shape and size traits.

The NAC transcription factor FaRIF controls fruit ripening in strawberry.

In contrast to climacteric fruits such as tomato, the knowledge on key regulatory genes controlling the ripening of strawberry, a nonclimacteric fruit, is still limited. NAC transcription factors (TFs) mediate different developmental processes in plants. Here, we identified and characterized Ripening Inducing Factor (FaRIF), a NAC TF that is highly expressed and induced in strawberry receptacles during ripening. Functional analyses based on stable transgenic lines aimed at silencing FaRIF by RNA interference, either from a constitutive promoter or the ripe receptacle-specific EXP2 promoter, as well as overexpression lines showed that FaRIF controls critical ripening-related processes such as fruit softening and pigment and sugar accumulation. Physiological, metabolome, and transcriptome analyses of receptacles of FaRIF-silenced and overexpression lines point to FaRIF as a key regulator of strawberry fruit ripening from early developmental stages, controlling abscisic acid biosynthesis and signaling, cell-wall degradation, and modification, the phenylpropanoid pathway, volatiles production, and the balance of the aerobic/anaerobic metabolism. FaRIF is therefore a target to be modified/edited to control the quality of strawberry fruits.

Intravenous iron supplementation in pulmonary hypertension groups 1 to 4.

Background: Iron deficiency (ID) is common in patients with pulmonary arterial hypertension and has been associated with increased morbidity and mortality. We aimed to evaluate the therapeutic effects of iron supplementation in iron deficient patients with group 1 to 4 pulmonary hypertension (PH). Methods: A total of 85 PH patients (mean age 69.8 ± 12.0 years, 56.5% female) were included in this prospective trial. Patients were screened for ID at baseline. PH patients with ID received intravenous iron supplementation (500-1000 mg ferric carboxymaltose). PH patients without ID served as control group. At baseline and 16-week follow up, six-minute walk test (6MWT), laboratory testing and echocardiography were performed. Additionally, World Health Organization (WHO) functional class, fatigue score and quality of life (QoL) by the SF-36 questionnaire were assessed. Results: Overall, ID was present in 26.7% (n=8/30), 37.5% (n=9/24), 45.5% (n=10/22) and 44.4% (n=4/9) of patients in PH groups 1-4, respectively. In the total study population, iron restoration led to a significant mitigation of fatigue (p=0.01). However, 6MWT, WHO function class, NT-proBNP levels, QoL and right ventricular function did not change significantly. With regard to the underlying PH group, only PH group 3 patients experienced significant improvements in 6MWT distance (p=0.019), WHO functional class (p=0.017), fatigue (p=0.009) and some QoL domains, as compared to controls. Conclusions: ID was common in PH groups 1 to 4. Though intravenous iron supplementation adequately restored iron status and improved fatigue throughout all patients, in the underlying PH groups treatment was accompanied by improvements in exercise capacity, WHO function class and fatigue only in group 3 PH.

Response to biologic therapy in patients with asthma and reduced pulmonary diffusion capacity.

Introduction Asthma patients with a smoking history are usually excluded from asthma trials, to exclude smoking-related comorbidities like chronic obstructive pulmonary disease (COPD). Therefore, little is known about the efficacy of biologic therapy in asthma patients with reduced diffusing capacity of the lungs for carbon monoxide (DLCO). Methods This study aimed to assess the response to biologic therapy in asthma patients with reduced DLCO. A total of 77 consecutive patients undergoing biologic therapy in a routine clinical setting were included in the analysis and divided into three groups (1. DLCO ≥60%, 2. DLCO <60% and <10 pack-years, 3. DLCO <60% and ≥10 pack-years = asthma and COPD comorbidity). Follow-up evaluations were conducted after a minimum of 6 months of therapy. Results After 34.0 ± 10.2 weeks, comparable therapeutic responses were observed between the three groups. There were no differences between the groups in terms of reduction in the annual acute exacerbation rate (AE median -3 [25%-percentile -5; 75%-percentile -1] vs. -6.1 [-11.3;-2.2] vs. -3 [-6;-2], p=0.067), oral corticosteroid (OCS) doses (-5 [-10;0] vs. -1 [-7.5;0] vs. -7.5 [-10;-4] mg, p=0.136), improvement in asthma control test (ACT) scores (4 [0;9.3] vs. 3 [-1;6] vs. 4 [3;10], p=0.276) or forced expiratory volume in one second (FEV1) improvement (5.5 [-2;21.5] vs. 0.5 [-2.8;9.3] vs. 5 [0;16] %predicted, p=0.328). Linear regression analysis revealed no significant correlation between DLCO levels and changes in OCS dosage or AE rate, nor between DLCO and improvements in ACT scores or FEV1. Notably, a smaller proportion of patients exhibited a reduced transfer coefficient (DLCO/VA) (n=13, 16.9%). This parameter did not significantly impact therapy response either. Conclusion Our findings suggest that biologic therapy can effectively manage asthma irrespective of DLCO measurements. Thus, reduced DLCO values should not preclude thorough asthma diagnosis and treatment. Further investigation into the utility of DLCO/VA assessment in this context is warranted.

Sleep-disordered breathing and lung function abnormalities in adults with congenital heart disease.

PURPOSE: Advances in treatment enables most patients with congenital heart diseases (CHD) to survive into adulthood, implying the need to address comorbid conditions in this growing cohort of patients. The aim of this study was to evaluate the prevalence of sleep-disordered breathing (SDB) and lung function abnormalities in patients with adult congenital heart disease (ACHD). METHODS: Patients with ACHD underwent level 3 sleep testing (Embletta MPR polygraphy) and pulmonary function testing. Results were stratified by the underlying haemodynamic ACHD lesion group. RESULTS: Patients with ACHD (n = 100) were middle-aged (42.3 ± 14.6 years), 54% male and slightly overweight (BMI 25.9 ± 5.5 kg/m2). Polygraphy revealed a prevalence of sleep apnoea of 39% with 15% of patients presenting with predominantly obstructive apnoeic episodes, while 23% of patients presenting primarily with central sleep apnoea. The distribution of mild, moderate, and severe sleep apnoea in the total study population was 26%, 7% and 6%, respectively. Comparison of apnoea-hypopnoea index, presence of sleep apnoea, and apnoea severity did not offer significant differences between the four ACHD lesion groups (p = 0.29, p = 0.41 and p = 0.18, respectively). Pulmonary function testing revealed obstructive lung disease in 19 of 100 patients. Concomitant chronic obstructive pulmonary disease and obstructive sleep apnoea were diagnosed in 3% of patients and were associated with profound nocturnal desaturation. CONCLUSION: The findings suggest a mild propensity amongst patients with ACHD to develop SDB that seems to be unaffected by the specific underlying congenital lesion.

Exploring pulmonary involvement in newly diagnosed rheumatoid arthritis, and psoriatic arthritis: a single center study.

OBJECTIVES: This cross-sectional study aimed to determine the prevalence, manifestation, and risk factors of pulmonary involvement in newly diagnosed, untreated rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients, and to evaluate the efficacy of various diagnostic tools in screening for pulmonary involvement. METHODS: Untreated, newly diagnosed patients with RA and PsA underwent an extensive multimodal diagnostic approach including clinical and laboratory assessment, pulmonary function tests, and chest radiography. RESULTS: We recruited 50 arthritis patients (26 RA, 24 PsA) and 26 control subjects. Respiratory symptoms were found in 36.0 % of arthritis patients and 11.5 % of controls (p = 0.031). Pathologically reduced breathing width (< 3.0 cm) was significantly more common in arthritis patients (64.0 %) than in controls (23.1 %) (p < 0.001). Pulmonary function test results did not differ significantly between groups. Chest radiography revealed pulmonary involvement in 37.0 % of arthritis patients, higher in RA (50.0 %) than in PsA (22.7 %). Notably, only 35.3 % of arthritis patients with radiographic pulmonary involvement were symptomatic, with 64.7 % being asymptomatic. Radiographic pulmonary involvement was associated with advanced age (p = 0.002) and increased rheumatoid factor levels (p = 0.024). CONCLUSION: Our research underscores the significant prevalence of largely asymptomatic pulmonary involvement in newly diagnosed RA and PsA patients. These findings highlight the importance of an early, multidisciplinary screening approach, particularly for high-risk individuals. Further large-scale studies are needed to develop comprehensive screening protocols to improve early detection and treatment of pulmonary involvement in arthritis.

Assessing sleep-related breathing disorders among newly diagnosed rheumatoid and psoriatic arthritis patients: a cross-sectional study.

OBJECTIVES: This cross-sectional study aimed to determine the prevalence and risk factors for sleep-related breathing disorders (SRBD) in newly diagnosed, untreated rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients, and to develop a screening algorithm for early detection. METHODS: We evaluated newly diagnosed RA or PsA patients using the Epworth Sleepiness Scale (ESS) questionnaire, cardiorespiratory polygraphy (RPG), and clinical and laboratory assessments. Sleep apnea syndrome (SAS) was diagnosed based on pathological RPG findings excessive daytime sleepiness, defined as ESS score above 10. RESULTS: The study included 39 patients (22 RA, 17 PsA) and 23 controls. In RPG, SRBD was identified in 38.5% of arthritis patients compared to 39.1% of controls (p = 1.00), with male gender (p = .004) and age (p < .001) identified as risk factors. Excessive daytime sleepiness was noted in 36.4% of RA patients, 17.6% of PsA patients, and 21.7% of controls. Of the 24 patients diagnosed with SRBD, 41.6% met the criteria for SAS. SAS prevalence was 31.8% among RA patients, 0% in PsA patients, and 13% in controls. A significant association was observed between excessive daytime sleepiness and SRBD (p = .036). CONCLUSION: Our findings reveal a high prevalence of SRBD in newly diagnosed, untreated RA and PsA patients in ESS and RPG, with excessive daytime sleepiness being a reliable predictor of SRBD. Patients with RA exhibited a higher predisposition to SAS. We therefore suggest incorporating ESS and RPG as screening tools in RA or PsA for early detection and management of SRBD.

Dexamethasone, Remdesivir and Azithromycin modulate ACE2 and IL-6 in Lung Epithelial Cells.

BACKGROUND: The optimal use of steroids in COVID-19 patients remains challenging. Current S3-guidelines "Recommendations for patients with COVID-19" recommend dexamethasone (DEX) for patients requiring respiratory support, remdesivir (RD) in the early disease phase and azythromycin (AZ) is no longer recommended. We investigated effects of DEX, RD and AZ in a lipopolysaccharide induced inflammation in lung cells in vitro and analyzed publicly available datasets with a focus on the Angiotensin-converting enzyme 2 (ACE2) to better understand drugs' mechanisms of action. METHODS: human bronchial (Calu) and alveolar (A549) lung epithelial cells were treated with DEX, AZ or RDV in the presence of lipopolysaccharides (LPS). Gene expression (GE) of ACE2, IL-6 and the IL-6 protein release were measured. Publicly available GE data from lung tissues of COVID-19 patients and from lung cells treated with DEX were analyzed for the GE of ACE2. RESULTS: DEX increased and RDV and AZ reduced the GE of ACE2 in LPS-stimulated bronchial and alveolar epithelial cells. Only DEX significantly reduced LPS-induced IL-6 releases in alveolar cells substantially. The database analyses showed an, albeit not always significant, increase in ACE2 for lung tissue or cell lines treated with DEX. Lung tissue from patients after COVID-19 infection as well as bronchial cell cultures after COVID-19 infection showed lower GEs of ACE2. DISCUSSION AND CONCLUSION: DEX can increase ACE2 expression in vitro and thereby the portal of entry of SARS-CoV-2 into lung cells during an LPS induced inflammation. Simultaneously the inflammatory marker IL-6 is reduced. Comparative database analyses indicate that these processes can also take place in vivo.

Identity and functional characterisation of the transporter supporting the Na+ -dependent high-affinity NO3 - uptake in Zostera marina L.

Zostera marina is a seagrass, a group of angiosperms that evolved from land to live submerged in seawater, an environment of high salinity, alkaline pH and usually very low NO3 - . In 2000, we reported the first physiological evidence for the Na+ -dependent high-affinity NO3 - uptake in this plant. Now, to determine the molecular identity of this process, we searched for NO3 - transporters common to other vascular plants encoded in Z. marina's genome. We cloned two candidates, ZosmaNPF6.3 and ZosmaNRT2 with its partner protein ZosmaNAR2. ZosmaNAR2 expression levels increase up to 4.5-fold in Z. marina leaves under NO3 - -deficiency, while ZosmaNRT2 and ZosmaNPF6.3 expressions were low and unaffected by NO3 - . NO3 - transport capacity, kinetic properties and H+ or Na+ -dependence were examined by heterologous expression in the Hansenula polymorpha high-affinity NO3 - transporter gene disrupted strain (∆ynt1). ZosmaNPF6.3 functions as a H+ -dependent NO3 - transporter, without functionality at alkaline pH and apparent dual kinetics (KM = 11.1 µM at NO3 - concentrations below 50 µM). ZosmaNRT2 transports NO3 - in a H+ -independent but Na+ -dependent manner (KM = 1 mM Na+ ), with low NO3 - affinity (KM = 30 µM). When ZosmaNRT2 and ZosmaNAR2 are co-expressed, a Na+ -dependent high-affinity NO3 - transport occurs (KM = 5.7 µM NO3 - ), mimicking the in vivo value. These results are discussed in the physiological context, providing evidence that ZosmaNRT2 is a Na+ -dependent high-affinity NO3 - transporter, the first of its kind to be functionally characterised in a vascular plant, that requires ZosmaNAR2 to achieve the necessary high-affinity for nitrate uptake from seawater.

Non-climacteric fruit development and ripening regulation: 'the phytohormones show'.

Fruit ripening involves numerous physiological, structural, and metabolic changes that result in the formation of edible fruits. This process is controlled at different molecular levels, with essential roles for phytohormones, transcription factors, and epigenetic modifications. Fleshy fruits are classified as either climacteric or non-climacteric species. Climacteric fruits are characterized by a burst in respiration and ethylene production at the onset of ripening, while regulation of non-climacteric fruit ripening has been commonly attributed to abscisic acid (ABA). However, there is controversy as to whether mechanisms regulating fruit ripening are shared between non-climacteric species, and to what extent other hormones contribute alongside ABA. In this review, we summarize classic and recent studies on the accumulation profile and role of ABA and other important hormones in the regulation of non-climacteric fruit development and ripening, as well as their crosstalk, paying special attention to the two main non-climacteric plant models, strawberry and grape. We highlight both the common and different roles of these regulators in these two crops, and discuss the importance of the transcriptional and environmental regulation of fruit ripening, as well as the need to optimize genetic transformation methodologies to facilitate gene functional analyses.

Allelic Variation of MYB10 Is the Major Force Controlling Natural Variation in Skin and Flesh Color in Strawberry (Fragaria spp.) Fruit.

The fruits of diploid and octoploid strawberry (Fragaria spp) show substantial natural variation in color due to distinct anthocyanin accumulation and distribution patterns. Anthocyanin biosynthesis is controlled by a clade of R2R3 MYB transcription factors, among which MYB10 is the main activator in strawberry fruit. Here, we show that mutations in MYB10 cause most of the variation in anthocyanin accumulation and distribution observed in diploid woodland strawberry (F. vesca) and octoploid cultivated strawberry (F ×ananassa). Using a mapping-by-sequencing approach, we identified a gypsy-transposon in MYB10 that truncates the protein and knocks out anthocyanin biosynthesis in a white-fruited F. vesca ecotype. Two additional loss-of-function mutations in MYB10 were identified among geographically diverse white-fruited F. vesca ecotypes. Genetic and transcriptomic analyses of octoploid Fragaria spp revealed that FaMYB10-2, one of three MYB10 homoeologs identified, regulates anthocyanin biosynthesis in developing fruit. Furthermore, independent mutations in MYB10-2 are the underlying cause of natural variation in fruit skin and flesh color in octoploid strawberry. We identified a CACTA-like transposon (FaEnSpm-2) insertion in the MYB10-2 promoter of red-fleshed accessions that was associated with enhanced expression. Our findings suggest that cis-regulatory elements in FaEnSpm-2 are responsible for enhanced MYB10-2 expression and anthocyanin biosynthesis in strawberry fruit flesh.

Cardiac autonomic dysfunction in adult congenital heart disease.

PURPOSE: Due to recent advances in diagnosis and treatment, the number of adults with congenital heart disease (ACHD) has substantially increased. This achievement is mitigated by rhythm disorders. Here, we sought to determine alterations in heart rate variability (HRV) and their prognostic value in ACHD. METHODS: Ninety seven ACHD patients (39.2 ± 14.1 years, 51.5% female) and 19 controls (39.7 ± 15.0 years, 47.4% female) underwent 24-h Holter monitoring. RESULTS: As compared to controls, ACHD patients offered a significantly higher burden of premature ventricular contractions (p = 0.02) and decreased HRV indices (natural logarithmic transformation of very low frequency (lnVLF): 7.46 ± 0.76 ms2 vs. 7.91 ± 0.92ms2, p = 0.03; natural logarithmic transformation of low frequency (lnLF): 6.39 ± 0.95ms2 vs. 7.01 ± 1.07ms2, p = 0.01; natural logarithmic transformation of the ratio of low to high frequency spectra (lnLF/HF): 0.81 ± 0.74 vs. 1.17 ± 0.51, p = 0.04). No differences in HRV measures were observed across ACHD lesion groups. NT-proBNP levels were significantly related to both time and frequency domain indices (natural logarithmic transformation of the standard deviation of NN intervals (lnSDNN): Spearman´s rho = -0.32, p = 0.001; natural logarithmic transformation of the standard deviation of the average NN intervals for each 5-min segment of a 24-h Holter monitoring (lnSDANN): Spearman´s rho: -0.33, p = 0.001; natural logarithmic transformation of the total power (lnTP): Spearman´s rho: -0.25, p = 0.01; lnVLF: Spearman´s rho: -0.33, p = 0.001; lnLF: Spearman´s rho: -0.35, p < 0.001; lnLF/HF: Spearman´s rho: -0.34, p = 0.001). After a mean follow-up of 3.9 ± 0.7 years, 8 patients died and 3 patients survived sudden cardiac death (SCD). Several HRV parameters were significantly higher in event-free ACHD patients than in those who died or survived SCD (natural logarithmic transformation of the average of the standard deviations of NN intervals for each 5-min segment of a 24-h Holter monitoring (lnASDNN): p = 0.04; lnPNN30: p = 0.04; lnVFL: p = 0.03; lnLF: p < 0.01). On univariate Cox regression analysis, the time domain indices lnSDNN, lnASDNN and lnPNN30, as well as the frequency domain parameters lnTP, lnVLF and lnLF were associated with death and survived cardiac arrest. CONCLUSION: ACHD is accompanied by HRV impairment that carries prognostic implications on ACHD mortality and survived SCD.

Prevalence of sleep-disordered breathing in patients with mitral regurgitation and the effect of mitral valve repair.

PURPOSE: The relationship between chronic heart failure and sleep-disordered breathing (SDB) has been frequently described. However, little is known about the association of mitral regurgitation (MR) and SDB or the impact of transcatheter mitral valve repair (TMVR) on SDB. Our aims were first to determine the prevalence of SDB in patients with MR, and second to determine the effect of TMVR on SDB. METHODS: Patients with MR being evaluated for TMVR at the University Hospital Bonn underwent polygraphy (PG) to determine the prevalence of SDB. After TMVR, a subset of patients was followed up with transthoracic echocardiography (TTE) and PG to evaluate the effect of TMVR on SDB. RESULTS: In 53 patients, mean age was 76.0 ± 8.5 years and 62% were male. Patients predominantly had more than moderate mitral regurgitation (94%). SDB was highly prevalent (68%) with predominantly central sleep apnoea (CSA, 67%). After TMVR in 15 patients, the apnoea/hypopnoea index (AHI) and central apnoea index (AI) were significantly reduced among patients with SDB (AHI - 8.0/h, p = 0.021; central AI - 6.9/h, p = 0.046). The left atrial volume index (LAVI) at baseline was significantly higher in patients with CSA than in patients with obstructive sleep apnoea (OSA) and was significantly reduced after TMVR (63.5 ml/m2 ± 27.2 vs. 38.3 ml/m2 ± 13.0; - 18.4 ml/m2, p = 0.027). CONCLUSION: SDB, especially CSA, is highly prevalent in patients with mitral regurgitation. In the follow-up cohort TMVR led to a significant reduction of the AHI, predominantly of central events. The findings of the study suggest that TMVR may be a suitable therapy not only for MR but also for the accompanying CSA. LAVI may be a useful indicator for CSA in patients with MR.

Preclinical atherosclerotic burden in carotid and lower extremity arteries in adults with congenital heart disease.

Background: Over 90% of patients with congenital heart defects now reach adulthood, due to significant medical advances in recent decades. With advancing age, the risk of acquired cardiovascular diseases increases in addition to the already existing risk due to the congenital defect. The aim of this study was to evaluate the prevalence of atherosclerotic lesions in carotid and lower extremity arteries in adults with congenital heart disease (ACHD). Patients and methods: A total number of 108 ACHD patients (40.6±15.0 years, 50.0% male) and 22 healthy controls (39.3±16.6 years, 40.9% male) were included in this prospective study and underwent a comprehensive angiological examination that included vascular strain analysis on the common carotid artery. Results were stratified by the underlying ACHD lesion groups: shunt lesions (n=26), left-sided obstructive lesions (n=29), right-sided lesions (n=26) and complex lesions (n=27). Results: Colour-coded duplex sonography revealed atherosclerotic lesions in lower extremity arteries in 19 ACHD patients (17.6%). This prevalence did not significantly differ from the one assessed in controls (13.6%, p=0.77). All cases were asymptomatic and therefore classified as Fontaine stage I. 20.4% of ACHD patients presented atherosclerotic lesions in extracranial carotid arteries; amongst controls, the corresponding proportion was 18.4% (p=1.00). No significant differences were observed in atherosclerotic burden in extracranial carotid and lower limb arteries across the four ACHD patient groups (p=0.67 and p=0.89, respectively). Vascular strain analysis revealed no differences between patients and controls. Though circumferential strain varied over ACHD groups (p<0.05), comparison of strain measurements across all specific underlying defect subgroups revealed no significant difference for any of the studied strain parameters. Conclusions: ACHD patients present an atherosclerotic burden in extracranial carotid and lower limb arteries and a vascular stiffness that is comparable to healthy controls.

High prevalence of peripheral and carotid artery disease in patients with interstitial lung diseases.

Background: Interstitial lung diseases (ILD) are a heterogenous group of diseases, which have pulmonary fibrosis, restrictive lung disease, and decreased diffusion capacity as a common final path. Premature death frequently results not from ILD itself but from comorbidities. Peripheral artery disease (PAD) is a common comorbid disease in different chronic lung diseases. The focus of the present study is to clarify the prevalence of PAD in ILD. Patients and methods: A total of 97 patients with ILD and 30 controls were included in the study. Patients with ILD were subdivided into two groups according to the progression of pulmonary fibrosis: progressive fibrosing and non-progressive fibrosing ILD (PF-ILD and nPF-ILD, respectively). All participants underwent standard angiological and pneumological diagnostic procedures including six-minute walking test, measurement of ankle-brachial-index, and colour-coded duplex sonography. Results: We observed no relevant differences in the baseline characteristics except age. Both, PF-ILD and nPF-ILD patients, presented with a highly increased incidence of atherosclerotic lesions compared to the control group (p<0.001). PAD was present in all patients with PF-ILD and in 73% of patients with nPF-ILD. These results were confirmed by age-adjusted regression analyses. Conclusions: The present results indicate that ILD is an independent risk factor for atherosclerosis. Patients with PF-ILD are more severely affected than nPF-ILD patients with age as a confounding variable. Atherogenesis in ILD may be mediated by increased cardiovascular risk, systemic inflammation and chronic hypoxemia.

[Haemoptysis]. / Hämoptysen.

Haemoptysis describes the expectoration of blood originating from the tracheobronchial tree and lung. Its presentation varies from mild to massive haemoptysis, the latter entailing the risk of asphyxia and thus requiring rapid intervention that spans multiple specialties.

Impact of short-term pausing of oral corticosteroids on blood eosinophil count in patients with severe asthma.

BACKGROUND: The peripheral blood eosinophil count (BEC) is a well-established and easily accessible biomarker for asthma patients and crucial for the therapeutic decision regarding monoclonal antibody (mAB) therapy. Oral corticosteroid therapy frequently hinders the correct evaluation of BEC in patients with severe asthma, but a discontinuation of such therapy frequently comes along with severe side effects. Therefore, we examined the effect of a short 24-hour pause of OCS treatment on BEC in patients with severe asthma and followed-up whether patients with a then increased eosinophil count benefited from mAB-therapy, as expected. METHODS: In this multicentre study we retrospectively included 24 patients with severe asthma and OCS therapy and determined their BEC count. Ten patients, where BEC count was obtained in the morning before taking medication (a de-facto 24-hour OCS pause), were assigned to group 1. Fourteen patients, where BEC was obtained after OCS tapering were assigned to group 2. Those who then received mAB treatment were followed up for treatment response (OCS dose, annual acute exacerbations, increase in forced expiratory volume in one second [FEV1] and asthma control test [ACT]) after ≥3 months. RESULTS: We included 24 patients with a median age of 60.5 [IQR: 17.3] years. Regarding all baseline characteristics except FEV1 (l), both groups did not differ significantly.Among all 24 patients, after pausing OCS therapy for 2 [5.5] days the BEC increased significantly from 125.0/µl [125] to 300/µl [232.5] (p<0.001). In both individual groups BEC increased significantly as well (150 [123] to 325 [305], p=0.005 and 70 [150] to 280 [255], p<0.001), with no significant difference for increase (BEC +170/µl [205.0] vs. +195 [222.5], p=0.886). Of all 24 patients, 13 (54.2%) reached eosinophil levels ≥300/µl, while 12 of them had not exceeded this threshold before.Subsequently, 20 patients (83.3%) received mAB-therapy with 55.5% demonstrating a good treatment response within 6 [1.5] months. The response rate in patients with BEC count ≥300/µl was even higher (75.0%). There was no difference in the treatment response rate between group 1 and 2 (p=0.092). CONCLUSION: After just a short 24-hour pause of OCS therapy it was possible to demask a relevant eosinophilia in asthma patients, without risking severe side effects. In this manner, we enabled the possibility of achieving successful targeted mAB-therapy, according to the patient's individual asthma phenotype.