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Introduction. Signs of pulmonary veno-occlusive disease (PVOD) may be found in patients with pulmonary arterial hypertension (PAH), particularly in systemic sclerosis (SSc)¹. This association (PVOD/PAH) remains poorly characterized in SSc. We aimed to compare the clinical, echocardiographic and hemodynamic profile of patients with SSc-PAH with and without a concomitant diagnosis of PVOD, and their potential response to vasodilators. Materials and Methods. We retrospectively analyzed 23 patients with SSc-PAH diagnosed by right heart catheterization, followed at our center between 2017 and 2023. Data collected at diagnosis and after 12 months included clinical, laboratory, functional and imaging parameters. Multidisciplinary assessment allowed the identification of cases with clinical and radiological features suggestive of PVOD/PAH¹. Patients were divided into two groups (PVOD/PAH and non-PVOD/PAH) and data were compared at baseline and 12-month follow-up. Results. Twenty-three patients with SSc-PAH were enrolled in the study, of whom 6 (26%) had signs of PVOD/PAH. At PAH diagnosis, PVOD/PAH patients had higher values of mean pulmonary arterial pressure compared to non-PVOD/PAH (47.5±5.3 vs. 36.7±8.8 mmHg, p=0.011), but similar pulmonary vascular resistance. Age, sex, cardiovascular risk factors, SSc features, echo findings as well as cardiac biomarker values were similar between the two groups (Table 1). At follow-up, most PVOD/PAH patients (67%) were on monotherapy with endothelin receptor antagonists (ERA), and 33% on dual therapy (ERA + phosphodiesterase inhibitors). Only one case of pulmonary edema was recorded. In the non-PVOD/PAH group, most patients (53%) were on dual vasodilator therapy. On echocardiography, PVOD/PAH patients showed higher tricuspid regurgitation velocity (4.10±0.68 vs. 3.07±0.91 m/s; p=0.035) and worse right ventricular function (FAC 25.6±8.4% vs. 33.9±6.8%; p=0.046). Changes in NT-proBNP levels from baseline differed between groups (p=0.012), showing a trend toward increase in PVOD/PAH (p=0.076) and reduction in non-PVOD/PAH (p=0.069). At 12 months, 5 hospitalizations for heart failure in each group, and a total of 5 deaths (2 PVOD/PAH and 3 non-PVOD/PAH) were recorded, with similar event-free survival (p=0.101). Conclusions. PVOD is frequently associated with PAH in SSc and does not seem to be associated with specific SSc features. Vasodilators, at least on monotherapy, should be considered in PVOD/PAH, as they seem to be well tolerated. Nevertheless, at follow-up these patients exhibit unfavorable laboratory and echo profiles compared to those with SSc-PAH alone, highlighting the importance of early referral for lung transplantation.

The loss of smell (anosmia) related to SARS-CoV-2 infection is one of the most common symptoms of COVID-19. Olfaction starts in the olfactory epithelium mainly composed of olfactory sensory neurons surrounded by supporting cells called sustentacular cells. It is now clear that the loss of smell is related to the massive infection by SARS-CoV-2 of the sustentacular cells in the olfactory epithelium leading to its desquamation. However, the molecular mechanism behind the destabilization of the olfactory epithelium is less clear. Using golden Syrian hamsters infected with an early circulating SARS-CoV-2 strain harboring the D614G mutation in the spike protein; we show here that rather than being related to a first wave of apoptosis as proposed in previous studies, the innate immune cells play a major role in the destruction of the olfactory epithelium. We observed that while apoptosis remains at a low level in the damaged area of the infected epithelium, the latter is invaded by Iba1(+) cells, neutrophils and macrophages. By depleting the neutrophil population or blocking the activity of neutrophil elastase-like proteinases, we could reduce the damage induced by the SARS-CoV-2 infection. Surprisingly, the impairment of neutrophil activity led to a decrease in SARS-CoV-2 infection levels in the olfactory epithelium. Our results indicate a counterproductive role of neutrophils leading to the release of infected cells in the lumen of the nasal cavity and thereby enhanced spreading of the virus in the early phase of the SARS-CoV-2 infection.

Pulmonary veno‐occlusive disease (PVOD) is a rare form of pulmonary vascular disease that is difficult to distinguish clinically from pulmonary arterial hypertension (PAH). Multiple genes have been implicated in disease pathogenesis in PAH and PVOD and the diseases are thought to be genetically distinct. In this report we present a case of first‐degree relatives with pathological evidence of PVOD and PAH. The index patient was diagnosed with PAH at age 42, was treated with escalating pulmonary vasodilator therapy, but eventually succumbed to her disease. On autopsy, her pathology was consistent with PAH. Her son was diagnosed with PAH at age 16, did well on pulmonary vasodilator therapy for over 10 years, but ultimately developed refractory right ventricular failure and received a heart and lung transplantation. Pathology of his explanted lung was consistent with PVOD, and genetic testing was negative for recognized variants that cause PAH or PVOD. We present a rare case of first‐degree relatives with pathologically proven PVOD and PAH. Genetic testing was negative for recognized variants that cause PAH or PVOD.

Pulmonary arterial hypertension (PAH), whether idiopathic PAH (IPAH), heritable PAH, or associated with other conditions, is a rare and potentially lethal disease characterized by progressive vascular changes. To date, there is limited data on the genetic basis of PAH in the Arab region, and none from Saudi Arabian patients. This study aims to identify genetic variations and to evaluate the frequency of risk genes associated to PAH, in Saudi Arabian patients. Adult PAH patients, diagnosed with IPAH and pulmonary veno-occlusive disease, of Saudi Arabian origin, were enrolled in this study. Forty-eight patients were subjected to whole-exome sequencing, with screening of 26 genes suggested to be associated with the disease. The median age at diagnosis was 29.5 years of age, with females accounting for 89.5% of our cohort population. Overall, we identified variations in nine genes previously associated with PAH, in 16 patients. Fourteen of these variants have not been described before. Plausible deleterious variants in risk genes were identified in 33.3% (n = 16/48) of our entire cohort and 25% of these cases carried variants in BMPR2 (n = 4/16). Our results highlight the genetic etiology of PAH in Saudi Arabia patients and provides new insights for the genetic diagnosis of familial and IPAH as well as for the identification of the biological pathways of the disease. This will enable the development of new target therapeutic strategies, for a disease with a high rate of morbidity and mortality.

Fermented beetroots can be osmotically dehydrated and then dried to make a nutritious snack known as fermented beet chips. To ensure the best product quality, it is necessary to determine optimal parameters of osmotic dehydration. Therefore, the aim of this study was to determine the optimal parameters of pulsed vacuum osmotic dehydration (PVOD) of fermented beetroot slices. The response surface methodology (RSM) was employed to optimize PVOD and improve the efficiency of the process. The experimental parameters considered: (T) processing temperature (20 < T < 40 °C), (SC) sugar concentration (40 < SC < 60%), (VT) vacuum impregnation time (10 < VT < 50 min), and (ST) slice thickness (2 < ST < 6 mm). PVOD was optimized in terms of properties of beetroot tissue (hardness, HT, redness, a*T, water loss, WL, solid gain, SG) and osmotic solution (dry matter content, DMS, redness, a*S). The optimum qualities of beetroot tissue (HT = 202.0 N, a*T = 11.8, WL = 55.5%, SG = 7.1%) and osmotic solution (DMS = 57.3%, a*S = 38.9) were obtained at T = 20 °C, SC = 60%, VT = 10 min, ST = 6 mm and T = 40 °C, SC = 60%, VT = 50 min, ST = 2 mm, respectively. The beet tissue obtained by PVOD in optimal parameters was characterized by 2.58 ± 0.21 kg H2O/kg DM moisture content (MCF), 4.64 ± 0.37 mg GA/g DM total polyphenols (TPC), 2.2 ± 0.2 mg TE/g DM ferric reducing antioxidant power (FRAP), 1125 ± 10 kg/m3 density (ρT), and 4.29 ± 0.24 total color change (ΔE*) compared to material before PVOD. 2D and 3D images of the beetroot surface structure allowed to observe the collapse of the structure and the appearance of a semi-transparent coating (most likely a sugar solution) on the material after PVOD.

Pulmonary capillary hemangiomatosis (PCH) is a very rare and refractory disease characterized by capillary angioproliferation. The updated classification of pulmonary hypertension categorizes PCH into a subgroup of pulmonary arterial hypertension (PAH) alongside pulmonary veno-occlusive disease (PVOD). However, the definitive diagnosis of PCH only with noninvasive tools remains difficult. The aim of this study was to elucidate the radiological and physiological characteristics of PCH. We searched for cases of pathologically confirmed PCH in the English literature published between 2000 and 2018. We identified 26 cases among 39 studies. Then, we extracted and evaluated the relevant clinical information in all cases with available data. On chest computed tomography (CT), ground-glass opacities (GGOs) were observed in 92% of the cases, in which poorly defined nodular pattern was the most common (88%). GGOs in a bat-wing distribution were observed in one case. Septal lines and lymph node enlargement were observed less frequently (each 19%, 12%). Seven cases (27%) had overlapping abnormalities. Diffusing capacity of the lung for carbon monoxide (DLCO) was remarkably decreased. Alveolar hemorrhage by histological findings or bronchoalveolar lavage (BAL) was observed in seven cases. The present study showed that the most characteristic findings of CT in PCH was centrilobular GGOs with a poorly defined nodular pattern, and septal lines and lymph node enlargement were seen less frequently. Alveolar hemorrhage detected by BAL and decreased DLCO may also be helpful to recognize the possibility of PCH like PVOD.

Background: Pulmonary hypertension (PH) is a rare complication of sarcoidosis, although it is not uncommon in advanced disease. Methods: A retrospective series of 22 sarcoidosis patients (16 men) of mean (SD) age 46 (13) years with PH was divided into two groups depending on the absence (stage 0: n = 2, stage II: n = 4, stage III: n = 1) or presence (n = 15) of radiographic pulmonary fibrosis at the time of PH diagnosis. Results: In both groups PH was moderate to severe and there was no response to acute vasodilator challenge. In non-fibrotic cases no other cause of PH was found, suggesting a specific sarcoidosis vasculopathy, although no histological specimens were available. In cases with fibrosis there was no correlation between haemodynamics and lung volumes or arterial oxygen tensions, suggesting other mechanisms for PH in addition to pulmonary destruction and hypoxaemia. These included extrinsic arterial compression by lymphadenopathies in three cases and histologically proven pulmonary veno-occlusive disease in the five patients who underwent lung transplantation. Ten patients received high doses of oral prednisone for PH (stage 0: n  =  1, stage II: n  =  4 and stage IV: n  =  5); three patients without pulmonary fibrosis experienced a sustained haemodynamic response. Survival of the overall population was poor (59% at 5 years). Mortality was associated with NYHA functional class IV but not with haemodynamic parameters or with lung function. Conclusion: Two very different phenotypes of sarcoidosis combined with PH are observed depending on the presence or absence of pulmonary fibrosis. PH is a severe complication of sarcoidosis.

Background Pulmonary veno-occlusive disease (PVOD) is a rare, progressive, and oft-fatal condition of pulmonary arterial hypertension that is typically difficult to diagnose and treat. However, with the development of next-generation sequencing technology, an increasing number of patients with PVOD are being diagnosed. Methods Initially, we used whole exome sequencing (WES) to identify the proband as a rare compound heterozygous mutation of EIF2AK4 in PVOD. Subsequently, the parents of patient underwent EIF2AK4 screening by Sanger sequencing. Results In this study, we describe the family tree of a patient with PVOD with a rare compound heterozygous EIF2AK4 mutation. Moreover, we identified a new EIF2AK4 mutation, c.2236_2237insAAGTCCTTCT, in exon 12 of the proband and his mother. This frameshift mutation led to premature termination of the coding protein sequence and widespread loss of protein function, which promoted the development of PVOD. Conclusions Our results expand our understanding of the EIF2AK4 mutation spectrum in patients with PVOD, as well as highlight the clinical applicability of WES.

Background Variants in the gene encoding bone morphogenetic protein receptor type II ( BMPR2 ) are the most common genetic cause of pulmonary arterial hypertension (PAH), whereas biallelic variants in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH). Racial background may influence the clinical characteristics of patients diagnosed with PAH or PVOD/PCH. Here, we compared the clinical characteristics and survival between patients with BMPR2 variants or EIF2AK4 variants in a Chinese population. Methods Heterozygous variants in BMPR2 and homozygous or compound heterozygous biallelic EIF2AK4 variants predicted to be deleterious were identified as potentially causal. Clinical and radiological data were collected and analysed. The primary outcomes were death or lung transplantation. Hazard ratios (HRs) for death or transplantation associated with the presence of BMPR2 or biallelic EIF2AK4 variants were calculated using Cox proportional hazards models to analyse patient survival. Results Two hundred thirty-two patients with PAH were enrolled for genetic testing, and PAH patients with associated conditions were excluded from the study. Forty-five patients with BMPR2 variants and 11 patients with biallelic EIF2AK4 variants were recruited. PAH patients with BMPR2 or biallelic EIF2AK4 variants presented symptoms at the ages of 25.57 ± 10.17 years and 31.6 ± 9.38 years, respectively. The whole group of patients showed female dominance either with BMPR2 variants or biallelic EIF2AK4 variants. Specific radiological abnormalities are more prominent in EIF2AK4 variant carriers but can also be found in some patients with BMPR2 variants. Biallelic EIF2AK4 variant carriers had worse survival than BMPR2 variant carriers ( p  < 0.0001). Conclusions Clinical pictures of PAH patients with BMPR2 and biallelic EIF2AK4 variants in the Chinese population differ from other populations by a younger age at diagnosis and demonstrate female dominance in the whole patient group. High-resolution chest CT can help assist in differentiating PAH with PVOD/PCH . BMPR2 variants and biallelic EIF2AK4 variants are associated with adverse outcomes, but the survival of patients with biallelic EIF2AK4 variants is dismal.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast to PAH, PVOD is characterized by a particular remodeling of the pulmonary venous system and the obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation. The pathobiological knowledge of PVOD is poor, explaining the absence of medical therapy for PVOD. Lung transplantation remains the only therapy for eligible PVOD patients. As we recently demonstrated, respiratory diseases, chronic obstructive pulmonary disease, or cystic fibrosis exhibit lipointoxication signatures characterized by excessive levels of saturated phospholipids contributing to the pathological features of these diseases, including endoplasmic reticulum stress, pro-inflammatory cytokines production, and bronchoconstriction. In this study, we investigated and compared the clinical data and lung lipid signature of control (10 patients), idiopathic PAH (7 patients), heritable PAH (9 BMPR2 mutations carriers), hPVOD (10 EIF2AK4 mutation carriers), and sPVOD (6 non-carriers) subjects. Mass spectrometry analyses demonstrated lung lipointoxication only in hPVOD patients, characterized by an increased abundance of saturated phosphatidylcholine (PC) at the expense of the polyunsaturated species in the lungs of hPVOD patients. The present data suggest that lipointoxication could be a potential player in the etiology of PVOD.