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Though long-neglected, the right heart (RH) is now widely accepted as a pivotal player in heart failure (HF) either with reduced (HFrEF) or preserved (HFpEF) ejection fraction. The chronic overload of the pulmonary microcirculation results in an initial phase characterized by right ventricular (RV) hypertrophy, right atrial (RA) dilation, and diastolic dysfunction. This progresses to overt right heart failure (RHF) when RV dilation and systolic dysfunction lead to RV-pulmonary arterial uncoupling with low RV output. In the context of its established relevance to progression of HF, clinicians should consider assessment of the right heart with information from clinical assessment, biomarkers, and imaging. Notably, no single parameter can predict prognosis alone in HF. Assessments should simultaneously encompass RV systolic function, pulmonary pressures, an estimation of RV-PA coupling, and right heart morphology. Despite a large volume of evidence indicating the relevance of right heart function to the clinical syndrome of HF, evidence-based management strategies are lacking. Targeting RH dysfunction in HF should be an objective of future investigations, being an unmet need in the current management of HF.

Pulmonary arterial hypertension is a rare disease characterized by pulmonary microvasculature remodeling leading to right ventricular failure and death. Medical management of pulmonary hypertension has grown increasingly complex as more therapeutic agents have been developed. Evolving treatment strategies leveraging the endothelin, nitric oxide, and prostacyclin pathways lead to improved exercise capacity and outcomes in patients; however, significant opportunities for advancement remain.

In general, pulmonary vascular disease has important negative prognostic implications, regardless of the associated condition or underlying mechanism. In this regard, systemic sclerosis is of particular interest as it is the most common connective tissue disease associated with pulmonary hypertension, and a well-recognized at-risk population. In the setting of systemic sclerosis and unexplained dyspnea, the concept of using exercise to probe for underlying pulmonary vascular disease has acquired significant interest. In theory, a diagnosis of systemic sclerosis–associated exercise pulmonary hypertension may allow for earlier therapeutic intervention and a favorable alteration in the natural history of the pulmonary vascular disease. In the context of underlying systemic sclerosis, the purpose of this article is to provide a comprehensive review of the evolving definition of exercise pulmonary hypertension, the current role and methodologies for non-invasive and invasive exercise testing, and the importance of the right ventricle.

Sweet’s Syndrome (SS), also known as acute febrile neutrophilic dermatosis, is one of several cutaneous inflammatory disorders classified as neutrophilic dermatoses. Respiratory complications are described in

Smith-Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.(Glu1799Lys) variant. Limited phenotypic data impacts the quality of information delivered to families and the robustness of interpretation of novel MTOR missense variation. This study aims to improve our understanding of the SKS phenotype through the investigation of 16 further patients with the MTOR c.5395G>A p.(Glu1799Lys) variant. Through the careful phenotypic evaluation of these 16 patients and integration with data from 14 previously reported patients, we have defined major (100% patients) and frequent (>15%) SKS clinical characteristics and, using these data, proposed guidance for evidence-based management. In addition, in the absence of functional studies, we suggest that the combination of the SKS major clinical features of megalencephaly (where the head circumference is at least 3SD) and an intellectual disability with a de novo MTOR missense variant (absent from population databases) should be considered diagnostic for SKS.

Objective Data on the magnitude of benefit of modern therapies for pulmonary arterial hypertension (PAH) in connective tissue disease (CTD)–associated PAH are limited. In this study, we performed meta‐analyses of randomized, controlled trials (RCTs) and registries to quantify the benefit of these modern therapies in patients with CTD‐PAH. Methods The PubMed and Embase databases were searched for articles reporting data from RCTs or registries published between January 1, 2000 and November 25, 2019. Eligibility criteria included multicenter studies with ≥30 CTD‐PAH patients. For an RCT to be included, the trial had to evaluate an approved PAH therapy, and long‐term risks of clinical morbidity and mortality or 6‐minute walk distance had to be reported. For a registry to be included, survival rates had to be reported. Random‐effects models were used to pool the data. Results Eleven RCTs (total of 4,329 patients; 1,267 with CTD‐PAH) and 19 registries (total of 9,739 patients; 4,008 with CTD‐PAH) were included. Investigational therapy resulted in a 36% reduction in the risk of clinical morbidity/mortality events both in the overall PAH population (hazard ratio [HR] 0.64, 95% confidence interval [95% CI] 0.54, 0.75; P < 0.001) and in CTD‐PAH patients (HR 0.64, 95% CI 0.51, 0.81; P < 0.001) as compared to control subjects. The survival rate was lower in CTD‐PAH patients compared to all PAH patients (survival rate 62%, 95% CI 57, 67% versus 72%, 95% CI 69, 75% at 3 years). The survival rate in CTD‐PAH patients treated primarily after 2010 was higher than that in CTD‐PAH patients treated before 2010 (survival rate 73%, 95% CI 62, 81% versus 65%, 95% CI 59, 71% at 3 years). Conclusion Modern therapy provides a similar reduction in morbidity/mortality risk in patients with CTD‐PAH when compared to the PAH population overall. Risk of death is higher in CTD‐PAH patients than in those with PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and up‐front intensive treatment are warranted.

Alterations in sensorimotor functions are common in individuals with autism spectrum disorder (ASD). Such aberrations suggest the involvement of the thalamus due to its key role in modulating sensorimotor signaling in the cortex. Although previous research has linked atypical thalamocortical connectivity with ASD, investigations of this association in high-functioning adults with autism spectrum disorder (HFASD) are lacking. Here, for the first time, we investigated the resting-state functional connectivity of the thalamus, medial prefrontal, posterior cingulate, and left dorsolateral prefrontal cortices and its association with symptom severity in two matched cohorts of HFASD. The principal cohort consisted of 23 HFASD (mean[SD] 27.1[8.9] years, 39.1% female) and 20 age- and sex-matched typically developing controls (25.1[7.2] years, 30.0% female). The secondary cohort was a subset of the ABIDE database consisting of 58 HFASD (25.4[7.8] years, 37.9% female) and 51 typically developing controls (24.4[6.7] years, 39.2% female). Using seed-based connectivity analysis, between-group differences were revealed as hyperconnectivity in HFASD in the principal cohort between the right thalamus and bilateral precentral/postcentral gyri and between the right thalamus and the right superior parietal lobule. The former was associated with autism-spectrum quotient in a sex-specific manner, and was further validated in the secondary ABIDE cohort. Altogether, we present converging evidence for thalamocortical hyperconnectivity in HFASD that is associated with symptom severity. Our results fill an important knowledge gap regarding atypical thalamocortical connectivity in HFASD, previously only reported in younger cohorts.

BackgroundChronic lung allograft dysfunction (CLAD) phenotype determines prognosis and may have therapeutic implications. Despite the clarity achieved by recent consensus statement definitions, their reliance on radiologic interpretation introduces subjectivity. The Center for Computer Vision and Imaging Biomarkers at the University of California, Los Angeles (UCLA) has established protocols for chest high-resolution computed tomography (HRCT)-based computer-aided quantification of both interstitial disease and air-trapping. We applied quantitative image analysis (QIA) at CLAD onset to demonstrate radiographic phenotypes with clinical implications.MethodsWe studied 47 first bilateral lung transplant recipients at UCLA with chest HRCT performed within 90 d of CLAD onset and 47 no-CLAD control HRCTs. QIA determined the proportion of lung volume affected by interstitial disease and air-trapping in total lung capacity and residual volume images, respectively. We compared QIA scores between no-CLAD and CLAD, and between phenotypes. We also assigned radiographic phenotypes based solely on QIA, and compared their survival outcomes.ResultsCLAD onset HRCTs had more lung affected by the interstitial disease (P = 0.003) than no-CLAD controls. Bronchiolitis obliterans syndrome (BOS) cases had lower scores for interstitial disease as compared with probable restrictive allograft syndrome (RAS) (P < 0.0001) and mixed CLAD (P = 0.02) phenotypes. BOS cases had more air-trapping than probable RAS (P < 0.0001). Among phenotypes assigned by QIA, the relative risk of death was greatest for mixed (relative risk [RR] 11.81), followed by RAS (RR 6.27) and BOS (RR 3.15).ConclusionsChest HRCT QIA at CLAD onset appears promising as a method for precise determination of CLAD phenotypes with survival implications.

Background The most important determinant of long-term survival in patients with idiopathic pulmonary fibrosis is the right ventricular (RV) adaptation to the increased pulmonary vascular resistance. Our aim was to explore RV contractile reserve during stress echocardiography in early-stage IPF. Methods Fifty early-stage patients with IPF and 50 healthy control patients underwent rest and stress echocardiography, including RV two-dimensional speckle tracking echocardiography. At peak exertion, blood gas analysis and spirometry were also assessed. Results At rest, RV diameters were mildly increased in IPF; however, although RV conventional systolic function indexes were similar between the IPF and control groups, RV global longitudinal strain and RV lateral wall longitudinal strain (LWLS) were significantly reduced in the IPF cohort. During physical exercise, patients with IPF showed a reduced exercise tolerance with lower maximal workload (P o 2; P Conclusions RV myocardial dysfunction is already present at rest in early-stage IPF and worsens during exertion as detected by two-dimensional speckle-tracking echocardiography. The RV altered contractile reserve appears to be related to reduced exercise tolerability and impaired pulmonary hemodynamic.

Sarcoidosis is a multisystemic granulomatous disorder that can affect virtually any organ. However, pulmonary and thoracic lymph node involvement predominates; abnormalities on chest radiographs are present in 80 to 90% of patients with sarcoidosis. High-resolution computed tomographic (HRCT) scans are superior to chest X-rays in assessing extent of disease, and some CT features may discriminate an active inflammatory component (which may be amenable to therapy) from fibrosis (for which therapy is not indicated). Typical findings on HRCT include micronodules, perilymphatic and bronchocentric distribution, perihilar opacities, and varying degrees of fibrosis. Less common findings on CT include mass-like or alveolar opacities, miliary opacities, mosaic attenuation, honeycomb cysts, and cavitation. With progressive disease, fibrosis, architectural distortion, upper lobe volume loss with hilar retraction, coarse linear bands, cysts, and bullae may be observed. We discuss the salient CT findings in patients with sarcoidosis (with a major focus on pulmonary features) and present classical radiographic and histopathological images of a few extrapulmonary sites.

Objectives Sarcopenia is characterized by the loss of skeletal muscle mass, strength and performance. The study aimed to provide cut off values of various Sarcopenia parameters [computerized tomography skeletal muscle index (SMI), handgrip strength (HGS), gait velocity and chair stand] to predict mortality in end-stage liver disease (ESLD). Methods The inclusion criteria were age 18-75 years, model for end-stage liver disease > 15. All patients with advanced heart, lung, kidney diseases, active malignancy were excluded from the study. Sarcopenia indices were compared between survivors and non-survivors to find cut off value for prediction of mortality in ESLD patients. Results One hundred sixty-one subjects suffering from ESLD were enrolled. The cutoff value of the SMI to identify high risk of mortality in sarcopenia patients is ≤21.2 cm/m, area under the curve (AUC) 0.537 [95% confidence interval (CI) 0.456-0.616]. The cutoff value of the hand grip strength to identify high-risk mortality is ≤25.3 kilogram-force, AUC 0.682 (95% CI 0.604-0.753). The cutoff value of the gait velocity for the same is as ≤0.84 m/s, AUC 0.551 (95% CI 0.459-0.641). The cutoff value of the chair stand is ≥20.9 seconds, AUC 0.956 (95% CI 0.910-0.983). In the multivariate analysis, HGS, gait velocity and chair stand correlated with mortality. Conclusion The current study is a comprehensive Asian study that gives the cut off values of Sarcopenia: muscle mass, strength and performance which identify high risk of mortality in ESLD patients. Muscle strength and performance correlated with mortality.

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger’s Diagnostic Scale–Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water’s relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

Background/Aims: Opioid-induced bowel dysfunction includes nausea, vomiting, constipation and abdominal distension. We describe patients presenting with gastrointestinal (GI) ulcers and ulcerated strictures secondary to opioid abuse, an entity not well described in literature.Methods: This retrospective observational study included patients with opioid abuse gastroenteropathy presenting to Dayanand Medical College and Hospital, Ludhiana, India between January 2013 and December 2018. Opioid abuse gastroenteropathy was defined as gastric or small bowel ulcers and ulcerated strictures in patients abusing opioids, where all other possible etiologies of GI ulcers/strictures were excluded. Clinical, biochemical, endoscopic, radiological and histological parameters as well as response to treatment were assessed.Results: During the study period, 20 patients (mean age, 38.5±14.2 years; 100% males) were diagnosed to have opioid induced GI ulcers and/or ulcerated strictures. The mean duration of opioid consumption was 6.2±3.4 years. The mean duration of symptoms at presentation was 222.1±392.3 days. Thirteen patients (65%) had gastroduodenal involvement, 6 (30%) had a jejunoileal disease and 1 (5%) had an ileocecal stricture. Two patients (10%) presented with upper GI bleeding, 11 (55%) had features of gastric outlet obstruction and 7 (35%) presented with small bowel obstruction. Abdominal pain and iron deficiency anemia were the most common presentations. Only 1 patient (5%) responded to proton pump inhibitors, 3 (15%) had a lasting response to endoscopic balloon dilatation, while all other (80%) required surgical intervention.Conclusions: Opioid abuse gastroenteropathy presents as ulcers and ulcerated strictures which respond poorly to medical management and endoscopic balloon dilatation. A majority of these cases need surgical intervention.

Exercise Doppler echocardiography (EDE) is a well-validated tool in ischemic and valvular heart diseases. However, its use in the assessment of the right heart and pulmonary circulation unit (RH-PCU) is limited. The aim of this study is to assess the semi-recumbent bicycle EDE feasibility for the evaluation of RH-PCU in a large multi-center population, from healthy individuals and elite athletes to patients with overt or at risk of developing pulmonary hypertension (PH). From January 2019 to July 2019, 954 subjects [mean age 54.2 ± 16.4years, range 16–96, 430 women] underwent standardized semi-recumbent bicycle EDE with an incremental workload of 25 watts every 2min, were prospectively enrolled among 7 centers participating to the RIGHT Heart International NETwork (RIGHT-NET). EDE parameters of right heart structure, function and pressures were obtained according to current recommendations. Right ventricular (RV) function at peak exercise was feasible in 903/940 (96%) by tricuspid annular plane systolic excursion (TAPSE), 667/751 (89%) by tissue Doppler-derived tricuspid lateral annular systolic velocity (S′) and 445/672 (66.2%) by right ventricular fractional area change (RVFAC). RV—right atrial pressure gradient [RV–RA gradient = 4 × tricuspid regurgitation velocity2 (TRV)] was feasible in 894/954 patients (93.7%) at rest and in 816/954 (85.5%) at peak exercise. The feasibility rate in estimating pulmonary artery pressure improved to more than 95%, if both TRV and/or right ventricular outflow tract acceleration time (RVOT AcT) were considered. In high specialized echocardiography laboratories semi-recumbent bicycle EDE is a feasible tool for the assessment of the RH-PCU pressure and function.

PurposeThis study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork.MethodsAll participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S’), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e’) and left ventricular ejection fraction (LVEF) were measured.ResultsThe accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e’ = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S’ = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%.ConclusionsWhen performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.

Despite advances in targeted medical therapy, pulmonary arterial hypertension (PAH) remains a fatal disease because of progressive right ventricular dysfunction. For patients who are refractory to medical therapy, heart-lung and lung transplantation are important treatment options. Because of longer waiting time, surgical interventions including extracorporeal lung support and atrial septostomy can be used in PAH patients bridging to transplantation.

Diffuse pulmonary lung disease and chronic obstructive pulmonary disease is a heterogeneous population that can manifest pulmonary hypertension. These subgroups are classified as primarily World Health Organization group 3. Available data suggest that the impact of pulmonary hypertension targeted therapy in diffuse pulmonary lung disease and chronic obstructive pulmonary disease is limited and survival is poor despite attempted treatment.

Exercise stress testing of the pulmonary circulation for the diagnosis of latent or early-stage pulmonary hypertension (PH) is gaining acceptance. There is emerging consensus to define exercise-induced PH by a mean pulmonary artery pressure > 30 mm Hg at a cardiac output 3 Wood units at maximum exercise, in the absence of PH at rest. Exercise-induced PH has been reported in association with a bone morphogenetic receptor-2 gene mutation, in systemic sclerosis, in left heart conditions, in chronic lung diseases, and in chronic pulmonary thromboembolism. Exercise-induced PH is a cause of decreased exercise capacity, may precede the development of manifest PH in a proportion of patients, and is associated with a decreased life expectancy. Exercise stress testing of the pulmonary circulation has to be dynamic and rely on measurements of the components of the pulmonary vascular equation during, not after exercise. Noninvasive imaging measurements may be sufficiently accurate in experienced hands, but suffer from lack of precision, so that invasive measurements are required for individual decision-making. Exercise-induced PH is caused either by pulmonary vasoconstriction, pulmonary vascular remodeling, or by increased upstream transmission of pulmonary venous pressure. This differential diagnosis is clinical. Left heart disease as a cause of exercise-induced PH can be further ascertained by a pulmonary artery wedge pressure above or below 20 mm Hg at a cardiac output

The Right Heart International Network is a multicenter international study aiming to prospectively collect exercise Doppler echocardiography tests of the right heart pulmonary circulation unit (RHPCU) in large cohorts of healthy subjects, elite athletes, and individuals at risk of or with overt pulmonary hypertension. It is going to provide standardization of exercise stress echocardiography of RHPCU and explore the full physiopathologic response.

Sarcoidosis is a poorly understood granulomatous disease that involves the lungs and/or intrathoracic lymph nodes in more than 90% of cases. Although pulmonary sarcoidosis is the leading cause of mortality in this disease, this review focuses on three sites of extrapulmonary involvement (heart, nervous system, and eyes), since involvement of any of these sites can be catastrophic, leading to death, debilitation, or blindness. Patients with cardiac, ocular and neurosarcoidosis necessitate a multidisciplinary approach with careful and long-term follow-up. Prompt diagnosis with imaging and/or biopsy and treatment is required to avoid irreversible damage. Corticosteroids are the mainstay of therapy and are often associated with rapid and durable remissions. Immunosuppressive or biologic agents are reserved for patients failing or experiencing side effects from steroids. Managing sarcoidosis requires vigilance, judgement, and awareness of the vagaries of this fascinating disease.

Background Some interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable efficacy in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD). We hypothesize that Nintedanib targeted molecular pathways will be augmented to a similar degree across PF-ILD regardless of aetiology. Methods We collected explanted lung tissue at the time of lung transplantation from 130 PF-ILD patients (99 (76%) IPF, 14 (11%) SSc-ILD, 17 (13%) other PF-ILD), and wedge biopsies from 200 donor lungs and measured PDGF, FGF, VEGF and M-CSF concentrations by Luminex. Findings The concentrations of PDGF-AA, PDGF-BB, FGF-2, VEGF and M-CSF were significantly increased in PF-ILD lungs compared to donor lungs (PDGF-AA 93·0 pg/ml [±97·2] vs. 37·5 pg/ml [±35·4], p

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a “phenotype first” approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.

Background: Systemic sclerosis (SSc) is a heterogeneous disorder that results in multiorgan dysfunction. The most common pulmonary manifestations are pulmonary hypertension (PH) and interstitial lung disease (ILD). Systemic sclerosis may be complicated by World Health Organization (WHO) Group 1 PH (SSc-PAH), which is the most well-studied subtype. The PH associated with SSc may also be secondary to underlying left heart disease (SSc-PH-LHD) or ILD (SSc-PH-ILD), and these subgroups are classified as WHO Group 2 and Group 3 PH, respectively. These non-WHO Group 1 PH subsets are notoriously under-studied. Available data suggest that the impact of PH-specific therapy in SSc-PH-LHD and SSc-PH-ILD is limited and survival is poor despite attempted treatment. Implication for clinicians: Most research and clinical trials surrounding PH in SSc have thus far focused on WHO Group 1 SSc-PAH. There are limited data surrounding therapeutic options for WHO Group 2 (SSc-PH-LHD) and Group 3 PH (SSc-PH-ILD) phenotypes. This review aims to summarize and consolidate the data surrounding these 2 distinct clinical phenotypes and to emphasize the available prognostic and treatment considerations. Conclusions: Given the unique pathophysiology, prognostic implications, and poor response to treatment of WHO Group 2 and 3 SSc-PH phenotypes, there is an overwhelming need for more data to best understand optimal management strategies. The focus should be individual patient-level prognostication, how and when to initiate and manage PH-specific therapy, and appropriate triage with regard to the timing of lung (or heart-lung) transplantation.

The cardiopulmonary vascular system represents a key determinant of prognosis in several cardiorespiratory diseases. Although right heart catheterization is considered the gold standard for assessing pulmonary hemodynamics, a comprehensive noninvasive evaluation including left and right ventricular reserve and function and cardiopulmonary interactions remains highly attractive. Stress echocardiography is crucial in the evaluation of many cardiac conditions, typically coronary artery disease but also heart failure and valvular heart disease. In stress echocardiographic applications beyond coronary artery disease, the assessment of the cardiopulmonary vascular system is a cornerstone. The possibility of coupling the left and right ventricles with the pulmonary circuit during stress can provide significant insight into cardiopulmonary physiology in healthy and diseased subjects, can support the diagnosis of the etiology of pulmonary hypertension and other conditions, and can offer valuable prognostic information. In this state-of-the-art document, the topic of stress echocardiography applied to the cardiopulmonary vascular system is thoroughly addressed, from pathophysiology to different stress modalities and echocardiographic parameters, from clinical applications to limitations and future directions.

International audience; GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype-phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.

Background: Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined. Methods: In vitro assessment of BOLA3 regulation and gain- and loss-of-function assays were performed in human pulmonary artery endothelial cells using siRNA and lentiviral vectors expressing the mitochondrial isoform of BOLA3. Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice. Overexpression of pulmonary vascular BOLA3 was performed by orotracheal transgene delivery of adeno-associated virus in mouse models of PH. Results: In cultured hypoxic pulmonary artery endothelial cells, lung from human patients with Group 1 and 3 PH, and multiple rodent models of PH, endothelial BOLA3 expression was downregulated, which involved hypoxia inducible factor-2-dependent transcriptional repression via histone deacetylase 1-mediated histone deacetylation. In vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration. In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction while decreasing angiogenic potential. In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH. Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation. Conclusions: BOLA3 acts as a crucial lynchpin connecting Fe-S-dependent oxidative respiration and glycine homeostasis with endothelial metabolic reprogramming critical to PH pathogenesis. These results provide a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders. These findings also identify novel metabolic targets, including those involved in epigenetics, Fe-S biogenesis, and glycine biology, for diagnostic and therapeutic development., National Institutes of Health (U.S.) (Grant R01 HL124021), National Institutes of Health (U.S.) (Grant HL 122596), National Institutes of Health (U.S.) (Grant HL 138437), National Institutes of Health (U.S.) (Grant UH2 TR002073)

Context: Electrophysiological and hemodynamic data can be integrated to accurately identify the generators of abnormal electrical activity in drug-resistant focal epilepsy. Arterial Spin Labeling (ASL), a magnetic resonance imaging (MRI) technique for quantitative noninvasive measurement of cerebral blood flow (CBF), can provide a direct measure of variations in cerebral perfusion associated with the epileptogenic zone. Aims: 1. To evaluate usefulness of ASL for detecting interictal temporal hypoperfusion to localize the epileptogenic zone in patients of drug resistant mesial temporal lobe epilepsy (MTLE). 2. Correlation of localization of epileptogenic zone on ASL MR perfusion with structural MRI and EEG. Methods and Materials: 30 patients with MTLE and10 age and gender matched normal controls were studied. All patients underwent ictal video EEG monitoring non-invasively, MR imaging with epilepsy protocol and pseudocontinuous ASL (PCASL) perfusion study. Relative CBF (rCBF) values in bilateral mesial temporal lobes were measured utilizing quantitative analysis of perfusion images. A perfusion asymmetry index (AI) was calculated for each region. Results: In patients, ipsilateral mesial temporal rCBF was significantly decreased compared with contralateral mesial temporal rCBF (p = 0.021). Mesial temporal blood flow was more asymmetric in patients than in normal control participants (p = 0.000). Clear perfusion asymmetry on PCASL-MRI was identified despite normal structural-MRI in 5 cases, agreeing with EEG laterality. Conclusions: Pseudo-continuous ASL offers a promising approach to detect interictal hypoperfusion in TLE and as a clinical alternative to SPECT and PET due to non-invasiveness and easy accessibility. Incorporation of ASL into routine pre-surgical evaluation protocols can help to localize epileptogenic zone in surgical candidates.

Extrinsic compression of the left main coronary artery (LMCA) by a dilated pulmonary artery (PA) in the setting of pulmonary arterial hypertension (PAH) is an increasingly recognized disease entity. LMCA compression has been associated with angina, arrhythmia, heart failure, and sudden cardiac death in patients with PAH. Recent studies suggest that at least 6% of patients with PAH have significant LMCA compression. Screening for LMCA compression can be achieved with computed coronary tomography angiography, with a particular emphasis on assessment of PA size and any associated downward displacement and reduced takeoff angle of the LMCA. Indeed, evidence of a dilated PA (>40 mm), a reduced LMCA takeoff angle (

Background CTD-PAH has historically represented a PAH subtype with poor prognosis. New therapies, as well as combination therapy approaches targeting multiple pathways have been approved for PAH based on RCTs. CTD-PAH patients comprise a subgroup of the RCT populations and efficacy analyses are based on subgroup analyses which can be less reliable than the overall analysis. We conducted a meta-analysis of RCTs of approved PAH therapies to evaluate outcomes of patients with CTD-PAH. Purpose To use meta-analysis to determine response to treatment in patients with CTD-PAH. Methods The PubMed and EMBASE databases were searched for English-only articles published between January 1, 2000 and November 25, 2019. Inclusion criteria were multicenter RCTs that enrolled adults with WHO group 1 pulmonary hypertension (PAH); enrollment in 2000 or later; long-term clinical morbidity and/or mortality event or 6-minute walk distance (6MWD) as an efficacy endpoint reported for ≥30 patients with CTD-PAH; and evaluation of a US Food and Drug Administration-approved PAH therapy. The primary outcomes were treatment effect as measured by the study time to first morbidity or morality event and change in 6MWD from baseline to between 3–6 months, per the data provided in each article. Results from individual studies were combined using a random-effects model for overall study population (PAH patients) and the subgroup of CTD-PAH patients. Results Ten RCTs (N=4329 PAH patients; n=1263 (29%) with CTD-PAH) met inclusion criteria and were included in the meta-analysis. At baseline, PAH patients had a mean age of 50 years, approximately 78% were female, and approximately 58% had functional class III or IV disease. These characteristics were balanced between treatment and control groups. Baseline 6MWD was 356 m for the overall population and 337 m for patients with CTD-PAH. Five RCTs (N=3172; n=941 with CTD-PAH [30%]) reported hazard ratios (HRs) for time to a morbidity or mortality event by drug treatment and PAH etiology: overall population HR=0.63 (95% confidence interval [CI], 0.56–0.72; P Conclusions The improvement in 6MWD in patients with CTD-PAH is smaller than in those with other types of PAH, perhaps reflecting comorbidities and CTD-induced mobility constraints, independent of their cardiopulmonary capacity. Data from long term clinical morbidity/mortality endpoint studies in this large group of patients with CTD-PAH demonstrate that these patients derive significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH. Treatment effect on morbidity/mortality Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Actelion Pharmaceuticals US, Inc.

Primary haemochromatosis (PH) is a genetic disorder of iron metabolism with multiorgan involvement due to mutations in HFE or more rarely haemojuvelin (HJV) gene. Cardiac involvement results in dilated cardiomyopathy with reduced ejection fraction and progressive heart failure. PH is rarely reported from India and cardiomyopathy due to PH from HJV mutations is thought to be uncommon. We report two families with cardiomyopathy resulting from PH. Diagnosis was suspected on the basis of skin pigmentation, markedly elevated serum ferritin and transferring saturation. Genetic testing revealed a rare mutation in HJV gene in one family. Being a treatable condition, PH should be suspected and investigated in cardiomyopathy patients in Indian subcontinent. If HFE is negative, analysis of non-HFE mutation should always be considered.

Background Interleukin-6 blockade (IL-6) has become a focus of therapeutic investigation for the coronavirus disease 2019 (COVID-19). Methods We report a case of a 34-year-old with COVID-19 pneumonia receiving an IL-6 receptor antagonist (IL-6Ra) who developed spontaneous colonic perforation. This perforation occurred despite a benign abdominal exam and in the absence of other known risk factors associated with colonic perforation. Results Examination of the colon by electron microscopy revealed numerous intact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions abutting the microvilli of the colonic mucosa. Multiplex immunofluorescent staining revealed the presence of the SARS-CoV-2 spike protein on the brush borders of colonic enterocytes that expressed angiotensin-converting enzyme 2. However, no viral particles were observed within the enterocytes to suggest direct viral injury as the cause of colonic perforation. Conclusions These data and absence of known risk factors for spontaneous colonic perforation implicate IL-6Ra therapy as the potential mediator of colonic injury in this case. Furthermore, this report provides the first in situ visual evidence of the virus in the colon of a patient presenting with colonic perforation adding to growing evidence that intact infectious virus can be present in the stool.

Purpose: Several reports have demonstrated similar effects on oxygenation between inhaled epoprostenol (iEPO) compared to inhaled nitric oxide (iNO) for acute respiratory distress syndrome (ARDS). Previous studies directly comparing oxygenation and clinical outcomes between iEPO and iNO exclusively in an adult ARDS patient population utilized a weight-based dosing strategy. The purpose of this study was to compare the clinical and economic impact between iNO and fixed-dosed iEPO for ARDS in adult intensive care unit (ICU) patients. Methods: This retrospective cohort study was conducted at a major academic medical center between January 1, 2014, and October 31, 2018. Patients ≥18 years of age with moderate-to-severe ARDS were included. The primary end point was to compare the mean change in partial arterial oxygen pressure to fraction of inspired oxygen (Pao 2: Fio 2) at 4 hours from baseline between iEPO and iNO. Other secondary aims were total acquisition drug costs, in-hospital mortality, ICU and hospital length of stay, and duration of mechanical ventilation. Results: A total of 239 patients were included with 139 (58.2%) and 100 (41.8%) in the iEPO and iNO groups, respectively. The mean change in Pao 2: Fio 2 at 4 hours from baseline in the iEPO and iNO groups were 31.4 ± 54.6 and 32.4 ± 42.7 mm Hg, respectively ( P = .88). The responder rate at 4 hours was similar between iEPO and iNO groups (64.7% and 66.0%, respectively, P = .84). Clinical outcomes including mortality, overall hospital and ICU length of stay, and mechanical ventilation duration were similar between iEPO and iNO groups. Estimated annual cost-savings realized with iEPO was USD1 074 433. Conclusion: Fixed-dose iEPO was comparable to iNO in patients with moderate-to-severe ARDS for oxygenation and ventilation parameters as well as clinical outcomes. Significant cost-savings were realized with iEPO use.

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management., Familial myeloid malignancies have recently been classified as separate disease entities. Here, using whole-exome sequencing of affected pedigrees - the authors highlight genetic variants associated with these conditions.

The authors retrospectively reviewed charts of the children with basal ganglia stroke who either had preceding minor head injury or showed basal ganglia calcification on computed tomography (CT) scan. Twenty children, 14 boys and 6 girls were identified. Eighteen were aged between 7 months to 17 months. Presentation was with hemiparesis in 17 and seizures in 3. Preceding minor head trauma was noted in 18. Family history was positive in 1 case. Bilateral basal ganglia calcification on CT scan was noted in 18. Brain magnetic resonance imaging done in 18 infants showed acute or chronic infarcts in basal ganglia. Results of other laboratory and radiological investigations were normal. Four infants were lost to follow-up, 9 achieved complete or nearly completely recovery, and 7 had persistent neurological deficits. Basal ganglia calcification likely represents mineralized lenticulostriate arteries, a marker of lenticulostriate vasculopathy. Abnormal lenticulostriate vessels are vulnerable to injury and thrombosis after minor head trauma resulting in stroke.

Acute cardiothoracic and respiratory diseases frequently remain a challenge to diagnose and differentiate in the emergency setting. The main diseases that manifest with chest pain include ischaemic heart disease, myocarditis, acute pericarditis, aortic dissection/rupture and pulmonary embolism (PE). Diseases that primarily present with dyspnoea include heart failure (HF), acute respiratory distress syndrome (ARDS), pneumonia, asthma exacerbations and chronic obstructive pulmonary disease. Pre-test probabilities of clinical findings play a vital part in diagnostic decisions, and the use of a Bayesian approach to these greatly improves the ability to stratify patients more accurately. However, blood tests (biomarkers) are increasingly used to assist in rapid decision-making in the emergency setting in combination with imaging methods such as chest radiograph, ultrasound and increasingly computed tomography, as well as physiological tests such as the electrocardiogram in addition to physical examination. Specific tests for ischaemic heart disease and myocarditis (cardiac troponins), HF (B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP)), aortic dissection (smooth muscle markers) and PE (D-dimer) have been developed. Surfactant protein-D and interleukin-8 have been developed for ARDS. Additionally, circulating microRNAs have emerged as promising biomarker candidates in cardiovascular disease. With this increasing array of biochemical markers to aid in the diagnosis of chest diseases presenting with chest pain and dyspnoea, we herein review the clinical usefulness of these markers, in particular in differentiating cardiac from pulmonary diseases. A symptom-oriented assessment as necessary for use in the critical setting is described in addition to discussion of individual biomarkers.

Trichobezoars are compact mass of hair occupying the gastric cavity that if left untreated can cause developmental delay, malnutrition, obstruction or perforation. The treatment options include extraction by conventional laparotomy, laparoscopy, gastrotomy or endoscopy. Since they are almost always associated with trichotillomania and trichophagia or other psychiatric disorders, psychiatric consultation is necessary to prevent relapses. We reviewed the medical charts of two patients with trichobezoar who were treated at Lord Mahavir, Civil Hospital, Ludhiana. Both the cases, aged 14 and 19 years were females and presented at the hospital with a history of epigastric discomfort, pain and vomiting. Both the girls were lean, underweight and pale skinned. First patient had trichotillomania and trichophagia for 1 year prior to presentation. The parents were unaware of patient’s trichophagia but the girl revealed that she ate hair during the night. The second patient had no history of trichophagia and the bilateral loss of scalp hair indicated nocturnal involuntary eating of hair during sleep. The large palpable mass in both the cases was non-tender, hard, smooth and mobile on examination. The abdominal imaging with CT revealed the mass occupying most of the gastric cavity, and turned out to be trichobezoars. The masses were successfully extracted by laparotomy and gastrotomy. A trichobezoar represents a serious surgical condition. It is important to consider such diagnosis in face of suggestive symptoms, even if signs of trichotillomania are not present. Gastrotomy was found to be very successful for the surgical removal of trichobezoars. The behavioral assessment and psychiatric counselling also plays a useful role in patient management and prevention of recurrence.

Pulmonary hypertension (PH) may complicate connective tissue disease (CTD; particularly systemic sclerosis [scleroderma]), and is associated with increased mortality. More than 70% of cases of PH complicating CTD occur in patients with systemic sclerosis (SSc), which is the major focus of this article. Pulmonary complications (i.e., interstitial lung disease [ILD] and PH) are the leading causes of SSc-related deaths. “Isolated” PH (i.e., without ILD) complicates SSc in 7.5 to 20% of cases; secondary PH may also occur in patients with SSc-associated ILD. Several clinical markers and specific autoantibody profiles have been associated with PH in SSc. The role of PH-specific therapy in improving CTD-PH outcomes is under investigation, as prognosis and responsiveness to therapy appear to be worse in SSc-associated PH compared with idiopathic pulmonary arterial hypertension. We discuss medical therapies for CTD-associated PH and the role of lung transplantation for patients who fail medical therapy.

Objective Patients with pulmonary hypertension and right heart failure have a high risk of clinical deterioration and death during or soon after endotracheal intubation. The effects of sedation, hypoxia, hypoventilation, and changes in intrathoracic pressure can lead to severe hemodynamic instability. In search for safer approach to endotracheal intubation in this cohort of patients, we evaluate the safety and feasibility of an alternative intubation technique. Data sources Retrospective data analysis. Study selection Two medical ICUs in large university hospitals in the United States. Data extraction We report a case series of nine nonconsecutive patients with compromised right heart function, pulmonary hypertension, and severe acute hypoxemic respiratory failure who underwent endotracheal intubation with a novel technique combining awake bronchoscopic intubation supported with nasally delivered noninvasive positive pressure ventilation or high-flow nasal cannula. Data synthesis All patients were intubated in the first attempt without major complications and eight patients (88%) were alive 24 hours after intubation. Systemic hypotension was the most frequent complication following the procedure. Conclusions Awake bronchoscopic intubation supported with a noninvasive positive pressure delivery systems may be feasible alternative to standard direct laryngoscopy approach. Further studies are needed to better assess its safety and applicability.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a disease process wherein tumor cells are thought to embolize to the pulmonary circulation causing pulmonary hypertension (PH) and death from right heart failure. Presented herein are clinical, laboratory, radiographic, and histologic features across seven cases of PTTM. Highlighted in this publication are also involvement of pulmonary venules and clinical features distinguishing PTTM from clinical mimics. We conducted a retrospective chart review of seven cases of PTTM from hospitals in the greater Los Angeles metropolitan area. Patients in this series exhibited: symptoms of cough and progressive dyspnea; PH and/or heart failure on physical exam; laboratory abnormalities of anemia, thrombocytopenia, elevated LDH, and elevated D-dimer; chest computed tomography (CT) showing diffuse septal thickening, mediastinal and hilar lymphadenopathy and nodules; elevated pulmonary artery pressures on transthoracic echocardiogram and/or right heart catheterization; and presence of malignancy. Tumor emboli and fibrocellular intimal proliferation were seen in pulmonary arterioles, while two patients had pulmonary venopathy. PTTM is a devastating disease occurring in patients with metastatic carcinoma. An early diagnosis is challenging. Understanding the clinical presentation of PTTM and distinguishing PTTM from clinical mimics may help achieve an early diagnosis and allow time for initiation of treatment.