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Background: The 2022 European Society of Cardiology/European Respiratory Society guidelines define pulmonary hypertension (PH) as a resting mean pulmonary artery pressure (mPAP) > 20 mm Hg at right heart catheterization (RHC). Previously, patients with an mPAP between 21 and 24 mm Hg were classified in a "gray zone" of unclear clinical significance., Research Question: What is the diagnostic performance of the main parameters used for PH screening in detecting patients with systemic sclerosis (SSc) with an mPAP of 21 to 24 mm Hg at RHC?, Study Design and Methods: Patients with SSc from the European Scleroderma Trials and Research (EUSTAR) database with available tricuspid annular plane systolic excursion (TAPSE), systolic PAP (sPAP), and mPAP data were included. Patients with mPAP 21 to 24 mm Hg and patients with mPAP ≤ 20 mm Hg were considered for the analysis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated., Results: TAPSE/sPAP was lower in the group of patients with SSc with mPAP 21 to 24 mm Hg than in the non-PH group (0.58 [0.46-0.72] vs 0.69 [0.57-0.81] mm/mm Hg, respectively; P < .01). No difference was found in other parameters between the two groups. Diffusing capacity of the lungs for carbon monoxide < 80% of the predicted value had the highest sensitivity (88.9%) and NPV (80%), but the lowest specificity (18.2%) and PPV (30.8%) in detecting patients with SSc with mPAP 21 to 24 mm Hg. TAPSE/sPAP < 0.55 mm/mm Hg had the highest specificity (78.9%), PPV (50%), and accuracy (68.1%); its NPV was 75.4%, and its sensitivity was 45.1%., Interpretation: In this study, diffusing capacity of the lungs for carbon monoxide < 80% of the predicted value was the parameter with the highest sensitivity and NPV in detecting patients with SSc with mPAP 21 to 24 mm Hg. TAPSE/sPAP < 0.55 mm/mm Hg had the highest specificity, PPV, and accuracy and, therefore, can be a useful additional parameter to decrease the number of unnecessary RHCs., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: V. S. is senior clinical investigator of the Research Foundation—Flanders (Belgium): (FWO) (1.8.029.20N). This funding source had no role in the literature review and the synthesis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication. C. B. received grants from Boehringer-Ingelheim, consulting fees from Janssen, honoraria for lectures from Novartis, and travel grants from Kyverna, which were not related to this project. E. Z. received speaking and lecture fees from Janssen and consulting fees from Janssen and GSK. F. I. received honoraria and speaking fees from AbbVie, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB outside this work. C. P. S. A. received consulting fees and support for attending meetings from Janssen-Cilag SAS, Boehringer Ingelheim Ltd and MSD. None declared (A. C., E. H., C. P., G. R., J. H., D. L., A. M., A. M. G., M.-E. T., S. O., M. V., F. D. G., E. R.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The study aim was to evaluate the predictive role of the echocardiography-derived tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio for pulmonary hypertension (PH) diagnosis and mortality in the European Scleroderma Trials and Research (EUSTAR) cohort., Methods: Eligible patients were systemic sclerosis (SSc) patients registered in the EUSTAR database with at least one visit recording TAPSE and sPAP data. Individual centres were required to provide TAPSE and sPAP data at 12 ± 3 months before right heart catheterization (RHC). Logistic regression analysis was applied to analyse the predictive ability of TAPSE/sPAP ratio for PH diagnosis. Cox regression analysis was performed to evaluate TAPSE/sPAP ratio as a predictive factor for all-cause mortality., Results: 2555 SSc patients met the inclusion criteria for this study with 355 SSc patients having available RHC data at baseline. PH was confirmed by RHC in 195 SSc patients (54.9%). TAPSE/sPAP ratio < 0.55 mm/mmHg [OR 0.251 (95% CI 0.084-0.753), p < 0.05] and FVC/DL CO [OR 2.568 (95% CI 1.227-5.375), p < 0.05] were significantly associated with PH diagnosis. In logistic regression analysis with echocardiographic parameters at 12 ± 3 months before RHC, TAPSE/sPAP ratio < 0.55 mm/mmHg [OR 0.265 (95% CI 0.102-0.685), p < 0.01] and FVC/DL CO [OR 2.529 (95% CI 1.358-4.711), p < 0.01] were associated with PH diagnosis. In multivariate Cox regression analysis, TAPSE/sPAP ratio ≤ 0.32 mm/mmHg [HR 0.310 (0.164-0.585), p < 0.001] was the most significant predictive factor for death., Conclusions: TAPSE/sPAP ratio < 0.55 mm/mmHg is a predictive risk factor for PH. TAPSE/sPAP ratio ≤ 0.32 mm/mmHg is a predictive risk marker for all-cause mortality., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ivan Castellvi’ reports a relationship with Janssen-Cilag SAS that includes: consulting or advisory and funding grants. Ivan Castellvi’ reports a relationship with Boehringer Ingelheim Ltd. that includes: consulting or advisory and funding grants. Ivan Castellvi’ reports a relationship with Genentech that includes: consulting or advisory and funding grants. Ivan Castellvi’ reports a relationship with Kern Pharma SL that includes: funding grants. Paolo Airo’ reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory and travel reimbursement. Paolo Airo’ reports a relationship with Boehringer Ingelheim Ltd. that includes: consulting or advisory. Paolo Airo’ reports a relationship with Novartis that includes: consulting or advisory. Paolo Airo’ reports a relationship with CSL Behring LLC that includes: travel reimbursement. Paolo Airo’ reports a relationship with Janssen Pharmaceuticals Inc. that includes: travel reimbursement. Paolo Airo’ reports a relationship with Roche that includes: travel reimbursement. I.C. has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Janssen-Cilag, Genentech/Roche and Kern in the area of potential treatments of scleroderma and its complications. P.A. received consulting fees from Bristol Myers Squibb; payments or honoraria from Bristol Myers Squibb, Bohringer Ingelheim, and Novartis; and support for attending meetings and travel from CSL Behring, Janssen, Roche, and Bristol Myers Squibb., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The spectrum of kidney involvement in systemic sclerosis (SSc) includes scleroderma renal crisis, widely recognized as the most severe renal-vascular complication, but also several forms of chronic renal vasculopathy and reduced renal function are complications of scleroderma. Scleroderma renal crisis, myeloperoxidase-antineutrophil cytoplasmic antibody associated glomerulonephritis, penicillamine-associated renal disease, abnormal urinalysis, alteration of vascular endothelial markers, scleroderma associated-vasculopathy with abnormal renal resistance indices and cardiorenal syndromes type 5 were also reported in SSc patients. A frequent form of renal involvement in SSc patients is a subclinical renal vasculopathy, characterized by vascular damage and normal renal function. Indeed, asymptomatic renal changes, expressed by increase of intrarenal stiffness, are often non-progressive in SSc patients but can lead to a reduction in renal functional reserve. The purpose of this review is to provide an assessment of kidney involvement in SSc, from SRC to subclinical renal vasculopathy., Competing Interests: Declaration of Competing Interest The author has no financial or other conflicts of interest to disclose., (Copyright © 2022 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

The lysosomal cysteine hydrolase N-acylethanolamine acid amidase (NAAA) deactivates palmitoylethanolamide (PEA), a lipid-derived PPAR-α agonist that is critically involved in the control of pain and inflammation. In this study, we asked whether NAAA-regulated PEA signaling might contribute to dopamine neuron degeneration and parkinsonism induced by the mitochondrial neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In vitro experiments showed that 6-OHDA and MPTP enhanced NAAA expression and lowered PEA content in human SH-SY5Y cells. A similar effect was observed in mouse midbrain dopamine neurons following intra-striatal 6-OHDA injection. Importantly, deletion of the Naaa gene or pharmacological inhibition of NAAA activity substantially attenuated both dopamine neuron death and parkinsonian symptoms in mice treated with 6-OHDA or MPTP. Moreover, NAAA expression was elevated in postmortem brain cortex and premortem blood-derived exosomes from persons with Parkinson's disease compared to age-matched controls. The results identify NAAA-regulated PEA signaling as a molecular control point for dopaminergic neuron survival and a potential target for neuroprotective intervention., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Imaging studies have revealed cortical thinning and subcortical atrophy occurring in Parkinson's disease (PD); however, the topographical distribution and clinical associations related to advancing stages of PD remains unclear., Objective: We aimed to investigate the topographical distribution of cortical and subcortical morphometric changes, and their clinical associations, related to increasing disease severity., Methods: In this cross-sectional imaging study, T1-weighted structural magnetic resonance imaging data for 80 non-demented PD patients and 30 age-matched healthy controls were analysed using FreeSurfer software suite to derive morphometric changes using whole-brain vertex-wise analysis, and surface-based (cortical) and volume-based (subcortical) parcellation maps. PD patients were divided into three groups of mild (n = 27), moderate (n = 27), and severe (n = 26) PD based disease duration and Hoehn and Yahr and Unified Parkinson's Disease Rating Scale Part-III motor severity scores., Results: Whole-brain vertex-wise analysis revealed cortical thinning in the orbitofrontal cortex in early PD (P = .011), and in the superior frontal (P = .002), caudal middle frontal gyrus (P = .001) and inferior parietal cortex (P = .006) in moderate PD. Severe PD patients showed additional cortical thinning in temporal and occipital cortices (P < .005). Subcortical volume loss was detected in the thalamus (P = .012) and hippocampus (P = .032) in moderate PD, which extended to the caudate (P = .012), putamen (P = .042) and amygdala (P = .008) in severe PD. Increasing disease duration and motor severity scores, correlated with cortical thinning in frontal, temporal, parietal and occipital cortices, and subcortical volumetric loss in the thalamus, caudate, putamen, amygdala and hippocampus. Lower global cognitive status, measured with MMSE, correlated with cortical thinning in temporal, parietal, frontal and cingulate cortices, and with volumetric loss in the hippocampus (r = 0.31; P = .009); suggesting subclinical pathogenic changes occur prior to the onset of cognitive impairment., Conclusion: In conclusion, in more severe disease stages PD patients exhibit progressive cortical thinning and subcortical volume loss which could have relevance to the development of cognitive impairment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite of previous evidence supporting the association between impulse control disorder (ICD) and several demographic, clinical and therapeutic features in Parkinson's disease (PD), the relationships between pathological gambling (PG) or other variants of ICD (ICD-NOS) and specific neuropsychiatric or cognitive domains are not entirely defined. In this study, 155 PD patients without dementia or cognitive impairment underwent: i. the ICD diagnoses, using the Questionnaire for Impulsive-Compulsive Disorders, ii. the mood and anxiety disorders diagnoses, according to the DSM-IV-TR criteria, and iii. a comprehensive battery for measuring severity of psychopathology and neuropsychology domains. Patients were divided in those with pathological gambling (PG), ICDs not otherwise specified (ICD-NOS), or the lack of ICD (No-ICD). There was a progression in age and age at onset from the younger PG subjects throughout ICD-NOS to No-ICD. PG and ICD-NOS subjects had longer disease duration and were taking significantly higher dosages of antiparkinsonian drugs than No-ICD ones. PG subjects had significantly higher severity of depressive and anxious symptoms with respect to the other 2 groups. Both PG and ICD-NOS subjects suffer from increased severity of psychotic symptoms than No-ICD ones. The 3 groups did not differ in any cognitive measure. Our results support the concept that the different sociodemographic and neuropsychiatric profiles of PD patients are associated with different ICDs. Moreover, we clearly demonstrate the lack of relationship between ICD and cognitive performances in undemented PD patients., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)