Experimental Schistosoma haematobium pulmonary hypertension.

Whether all Schistosoma species cause pulmonary hypertension (PH) is unclear. Experimentally exposing mice to Schistosoma haematobium eggs caused PH, which was less severe than that induced by S. mansoni exposure. These findings align with the relatively uncommon reports of pulmonary arterial hypertension associated with S. haematobium.

Is pulmonary arterial hypertension associated with schistosomiasis distinct from pulmonary arterial hypertension associated with portal hypertension?

Pulmonary arterial hypertension associated with schistosomiasis (SchPAH) and pulmonary arterial hypertension associated with portal hypertension (PoPAH) are lung diseases that develop in the presence of liver diseases. However, mechanistic pathways by which the underlying liver conditions and other drivers contribute to the development and progression of pulmonary arterial hypertension (PAH) are unclear for both etiologies. In turn, these unknowns limit certainty of strategies to prevent, diagnose, and reverse the resultant PAH. Here we consider specific mechanisms that contribute to SchPAH and PoPAH, identifying those that may be shared and those that appear to be unique to each etiology, in the hope that this exploration will both highlight known causal drivers and identify knowledge gaps appropriate for future research. Overall, the key pathophysiologic differences that we identify between SchPAH and PoPAH suggest that they are not variants of a single condition.

Dexamethasone prophylaxis protects from acute high-altitude illness by modifying the peripheral blood mononuclear cell inflammatory transcriptome.

Acute high-altitude (HA) exposure can induce several pathologies. Dexamethasone (DEX) can be taken prophylactically to prevent HA disease, but the mechanism by which it acts in this setting is unclear. We studied the transcriptome of peripheral blood mononuclear cells (PBMCs) from 16 subjects at low altitude (LA, 225 m) and then 3 days after acute travel to HA (3500 m) during the India-Leh-Dexamethasone-Expedition-2020 (INDEX2020). Half of the participants received oral DEX prophylaxis 4 mg twice daily in an unblinded manner, starting 1 day prior to travel to HA, and 12 h prior to the first PBMC collection. PBMC transcriptome data were obtained from 16 subjects, half of whom received DEX. The principal component analysis demonstrated a clear separation of the groups by altitude and treatment. HA exposure resulted in a large number of gene expression changes, particularly in pathways of inflammation or the regulation of cell division, translation, or transcription. DEX prophylaxis resulted in changes in fewer genes, particularly in immune pathways. The gene sets modulated by HA and DEX were distinct. Deconvolution analysis to assess PBMC subpopulations suggested changes in B-cell, T-cell, dendritic cell, and myeloid cell numbers with HA and DEX exposures. Acute HA travel and DEX prophylaxis induce significant changes in the PBMC transcriptome. The observed benefit of DEX prophylaxis against HA disease may be mediated by suppression of inflammatory pathways and changing leukocyte population distributions.

Repetitive schistosoma exposure causes perivascular lung fibrosis and persistent pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite antihelminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition. METHODS: Following intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis. RESULTS: Following intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7-14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition. CONCLUSIONS: Repeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease.

Exercise metabolomics in pulmonary arterial hypertension: Where pulmonary vascular metabolism meets exercise physiology.

Pulmonary arterial hypertension is an incurable disease marked by dysregulated metabolism, both at the cellular level in the pulmonary vasculature, and at the whole-body level characterized by impaired exercise oxygen consumption. Though both altered pulmonary vascular metabolism and abnormal exercise physiology are key markers of disease severity and pulmonary arterial remodeling, their precise interactions are relatively unknown. Herein we review normal pulmonary vascular physiology and the current understanding of pulmonary vascular cell metabolism and cardiopulmonary response to exercise in Pulmonary arterial hypertension. We additionally introduce a newly developed international collaborative effort aimed at quantifying exercise-induced changes in pulmonary vascular metabolism, which will inform about underlying pathophysiology and clinical management. We support our investigative approach by presenting preliminary data and discuss potential future applications of our research platform.

The role of brachytherapy in treatment of stage I esophageal cancer: A systematic review.

PURPOSE: Despite advancements in the early detection of esophageal cancer, optimal radiotherapy methods for treatment of early disease have not yet been determined. Moreover, the benefit of intraluminal brachytherapy on local control or survival remains controversial. We performed a systematic review to establish the role of brachytherapy as boost therapy in stage I esophageal squamous cell carcinoma, and to evaluate associated survival outcomes. METHODS AND MATERIALS: A systematic search of three bibliographic databases from January 1950 to January 2019 was conducted. All studies investigating brachytherapy for curative intent were included and palliative treatment was excluded. Primary outcomes included overall survival and disease-free survival (DFS). Secondary outcomes included loco-regional control (LRC) and toxicity grades and/or complications. Two reviewers independently abstracted data and evaluated study quality using grading of recommendations assessment, development, and evaluation, pooled results were presented through risk ratios. RESULTS: A total of 12 retrospective studies met inclusion criteria. The overall quality of evidence yielded a Grade 1C rating (strong recommendation, low quality evidence). Of 525 included patients, 325 patients received both external beam radiation (EBRT), and brachytherapy, 132 underwent EBRT only, and 68 received brachytherapy with and/or without chemoradiation. For patient group treated with EBRT and brachytherapy, 5-year mortality, DFS and LRC were: 43% (27-59%), 63% (49-76%) and 72% (63-80%) respectively. Rates of complications reported included 82.1% Grade 1 esophagitis for a combined external beam radiation and brachytherapy cohort, 12.3% ulcerations, and 3.3% fistulae. CONCLUSIONS: Brachytherapy as a combined modality is encouraging, given its relative safety and effectiveness. Further prospective analysis using higher quality evidence is warranted to evaluate oncologic outcomes and survival advantage.

The role of macrophages in right ventricular remodeling in experimental pulmonary hypertension.

Right ventricular (RV) failure is the primary cause of death in pulmonary hypertension (PH), but the mechanisms of RV failure are not well understood. We hypothesized macrophages in the RV contribute to the RV response in PH. We induced PH in mice with hypoxia (FiO2 10%) and Schistosoma mansoni exposure, and in rats with SU5416-hypoxia. We quantified cardiac macrophages in mice using flow cytometry. Parabiosis between congenic CD45.1/.2 mice or Cx3cr1-green fluorescent protein and wild-type mice was used to quantify circulation-derived macrophages in experimental PH conditions. We administered clodronate liposomes to Sugen hypoxia (SU-Hx) exposed rats to deplete macrophages and evaluated the effect on the extracellular matrix (ECM) and capillary network in the RV. In hypoxia exposed mice, the overall number of macrophages did not significantly change but two macrophage subpopulations increased. Parabiosis identified populations of RV macrophages that at steady state is derived from the circulation, with one subpopulation that significantly increased with PH stimuli. Clodronate treatment of SU-Hx rats resulted in a change in the RV ECM, without altering the RV vasculature, and correlated with improved RV function. Populations of RV macrophages increase and contribute to RV remodeling in PH, including through regulation of the RV ECM.

Contribution of fatty acid oxidation to the pathogenesis of pulmonary hypertension.

Dysregulated metabolism characterizes both animal and human forms of pulmonary hypertension (PH). Enzymes involved in fatty acid metabolism have previously not been assessed in human pulmonary arteries affected by pulmonary arterial hypertension (PAH), and how inhibition of fatty acid oxidation (FAO) may attenuate PH remains unclear. Fatty acid metabolism gene transcription was quantified in laser-dissected pulmonary arteries from 10 explanted lungs with advanced PAH (5 idiopathic, 5 associated with systemic sclerosis), and 5 donors without lung diseases. Effects of oxfenicine, a FAO inhibitor, on female Sugen 5416-chronic hypoxia (SuHx) rats were studied in vivo using right heart catheterization, and ex vivo using perfused lungs and pulmonary artery ring segments. The impact of pharmacologic (oxfenicine) and genetic (carnitine palmitoyltransferase 1a heterozygosity) FAO suppression was additionally probed in mouse models of Schistosoma and hypoxia-induced PH. Potential mechanisms underlying FAO-induced PH pathogenesis were examined by quantifying ATP and mitochondrial mass in oxfenicine-treated SuHx pulmonary arterial cells, and by assessing pulmonary arterial macrophage infiltration with immunohistochemistry. We found upregulated pulmonary arterial transcription of 26 and 13 FAO genes in idiopathic and systemic sclerosis-associated PAH, respectively. In addition to promoting de-remodeling of pulmonary arteries in SuHx rats, oxfenicine attenuated endothelin-1-induced vasoconstriction. FAO inhibition also conferred modest benefit in the two mouse models of PH. Oxfenicine increased mitochondrial mass in cultured rat pulmonary arterial cells, and decreased the density of perivascular macrophage infiltration in pulmonary arteries of treated SuHx rats. In summary, FAO inhibition attenuated experimental PH, and may be beneficial in human PAH.

Rationale and design of a screening study to detect schistosomiasis-associated pulmonary hypertension in Ethiopia and Zambia.

Schistosomiasis is a major cause of pulmonary arterial hypertension (PAH) worldwide, but the prevalence and risk factors for schistosomiasis-associated PAH (SchPAH) development are not well understood. Schistosomiasis-associated hepatosplenic disease (SchHSD) is thought to be a major risk factor for PAH development. Herein, we describe our plans for prospectively screening SchHSD subjects for clinical evidence of PAH at two major academic medical centers and national referral hospitals in Addis Ababa, Ethiopia and Lusaka, Zambia. The screening study will primarily be conducted by echocardiography, in addition to clinical assessments. Plasma samples will be drawn and banked for subsequent analysis based on preclinical animal model rationale. If successful, this study will demonstrate feasibility of conducting prospective cohort studies of SchPAH screening in schistosomiasis-endemic regions of Africa, and provide initial data on clinic-based disease prevalence and potential mechanistic biomarkers underlying disease pathogenesis.

Experimental Schistosoma japonicum-induced pulmonary hypertension.

BACKGROUND: Schistosomiasis, a major cause of pulmonary arterial hypertension (PAH) worldwide, is most clearly described complicating infection by one species, Schistosoma mansoni. Controlled exposure of mice can be used to induce Type 2 inflammation-dependent S. mansoni pulmonary hypertension (PH). We sought to determine if another common species, S. japonicum, can also cause experimental PH. METHODS: Schistosome eggs were obtained from infected mice, and administered by intraperitoneal sensitization followed by intravenous challenge to experimental mice, which underwent right heart catheterization and tissue analysis. RESULTS: S. japonicum sensitized and challenged mice developed PH, which was milder than that following S. mansoni sensitization and challenge. The degree of pulmonary vascular remodeling and Type 2 inflammation in the lungs was similarly proportionate. Cross-sensitization revealed that antigens from either species are sufficient to sensitize for intravenous challenge with either egg, and the degree of PH severity depended on primarily the species used for intravenous challenge. Compared to a relatively uniform distribution of S. mansoni eggs, S. japonicum eggs were observed in clusters in the lungs. CONCLUSIONS: S. japonicum can induce experimental PH, which is milder than that resulting from comparable S. mansoni exposure. This difference may result from the distribution of eggs in the lungs, and is independent of which species is used for sensitization. This result is consistent with the clearer association between S. mansoni infection and the development of schistosomiasis-associated PAH in humans.

A Systematic Review and Bibliometric Analysis of Applications of Artificial Intelligence and Machine Learning in Vascular Surgery.

BACKGROUND: Artificial intelligence (AI) and machine learning (ML) have seen increasingly intimate integration with medicine and healthcare in the last 2 decades. The objective of this study was to summarize all current applications of AI and ML in the vascular surgery literature and to conduct a bibliometric analysis of published studies. METHODS: A comprehensive literature search was conducted through Embase, MEDLINE, and Ovid HealthStar from inception until February 19, 2021. Reporting of this study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Title and abstract screening, full-text screening, and data extraction were conducted in duplicate. Data extracted included study metadata, the clinical area of study within vascular surgery, type of AI/ML method used, dataset, and the application of AI/ML. Publishing journals were classified as having either a clinical scope or technical scope. The author academic background was classified as clinical, nonclinical (e.g., engineering), or both, depending on author affiliation. RESULTS: The initial search identified 7,434 studies, of which 249 were included for a final analysis. The rate of publications is exponentially increasing, with 158 (63%) studies being published in the last 5 years alone. Studies were most commonly related to carotid artery disease (118, 47%), abdominal aortic aneurysms (51, 20%), and peripheral arterial disease (26, 10%). Study authors employed an average of 1.50 (range: 1-6) distinct AI methods in their studies. The application of AI/ML methods broadly related to predictive models (54, 22%), image segmentation (49, 19.4%), diagnostic methods (46, 18%), or multiple combined applications (91, 37%). The most commonly used AI/ML methods were artificial neural networks (155/378 use cases, 41%), support vector machines (64, 17%), k-nearest neighbors algorithm (26, 7%), and random forests (23, 6%). Datasets to which these AI/ML methods were applied frequently involved ultrasound images (87, 35%), computed tomography (CT) images (42, 17%), clinical data (34, 14%), or multiple datasets (36, 14%). Overall, 22 (9%) studies were published in journals specific to vascular surgery, with the majority (147/249, 59%) being published in journals with a scope related to computer science or engineering. Among 1,576 publishing authors, 46% had exclusively a clinical background, 48% a nonclinical background, and 5% had both a clinical and nonclinical background. CONCLUSIONS: There is an exponentially growing body of literature describing the use of AI and ML in vascular surgery. There is a focus on carotid artery disease and abdominal aortic disease, with many other areas of vascular surgery under-represented. Neural networks and support vector machines composed most AI methods in the literature. As AI/ML continue to see expanded applications in the field, it is important that vascular surgeons appreciate its potential and limitations. In addition, as it sees increasing use, there is a need for clinicians with expertise in AI/ML methods who can optimize its transition into daily practice.

Role of Adjuvant Therapy in Esophageal Cancer Patients After Neoadjuvant Therapy and Esophagectomy: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to analyze esophageal cancer patients who previously underwent neoadjuvant therapy followed by a curative resection to determine whether additional adjuvant therapy is associated with improved survival outcomes. SUMMARY BACKGROUND DATA: Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal cancer, whereas adjuvant therapy is typically employed for patients with residual disease. However, the role of adjuvant therapy after a curative resection is still uncertain. METHODS: MEDLINE, EMBASE, and CENTRAL databases were searched for studies comparing patients with esophageal cancer who underwent neoadjuvant therapy and curative resection with and without adjuvant therapy. Primary outcome was overall survival (OS), and random effects meta-analysis was conducted where appropriate. Grading of recommendations, assessment, development, and evaluation was used to assess the certainty of evidence. RESULTS: Ten studies involving 6462 patients were included. When compared to patients who received neoadjuvant therapy and esophagectomy alone, adjuvant therapy groups experienced a significant decrease in mortality by 48% at 1 year (Risk Ratio (RR) 0.52, 95% confidence interval [CI] 0.41-0.65, P < 0.001, moderate certainty). This reduction in mortality was carried through to 5-year follow-up (RR 0.91, 95% CI 0.86-0.96, P < 0.001, moderate certainty). The difference between the adjuvant therapy and the control group was uncertain regarding the secondary outcomes. CONCLUSION: Adjuvant therapy after neoadjuvant treatment and esophagectomy with negative resection margins provide an improved OS at 1 and 5 years with moderate to high certainty of evidence, but the benefit for disease-free survival and locoregional/distal recurrence remain uncertain due to limited reporting of these outcomes.

Growth factors for treating chronic venous leg ulcers: A systematic review and meta-analysis.

Chronic venous leg ulcers (VLU) are wounds that commonly occur due to venous insufficiency. Many growth factors have been introduced over the past two decades to treat VLU. This systematic review and meta-analysis evaluates the impact of growth factor treatments of VLU in comparison to control for complete wound healing, percent reduction in wound area, time to wound healing, and adverse events. A systematic review and meta-analysis of randomised trials was conducted. MEDLINE and EMBASE were searched up to December 2020. Studies were included if they compared a growth factor versus placebo or standard care in patients with VLU. From 1645 articles, 13 trials were included (n = 991). There was a significant difference between any growth factor and placebo in complete wound healing (P = 0.04). Any growth factor compared to placebo significantly increased the likelihood of percent wound reduction by 48.80% (P = <0.00001). There was no difference in overall adverse event rate. Most comparisons have low certainty of evidence according to Grading of Recommendations, Assessment, Development, and Evaluation. This meta-analysis suggests that growth factors have a beneficial effect in complete wound healing of VLU. Growth factors may also increase percent reduction in wound area. The suggestion of benefit for growth factors identified in this review is not a strong one based on the low quality of evidence.

Prognostic value of blood pressure in ambulatory heart failure: a meta-analysis and systematic review. Ambulatory blood pressure predicts heart failure prognosis.

Previous primary studies have explored the association between blood pressure (BP) and mortality in ambulatory heart failure (HF) patients reporting varying and contrasting associations. The aim is to determine the pooled BP prognostic value and explore potential reasons for between-study inconsistency. We searched Medline, Cochrane, EMBASE and CINAHL from January 2005 to October 2018 for studies with ≥ 50 events (mortality and/or hospitalization) and included BP in a multivariable model in ambulatory HF patients. We pooled hazard ratios (random effects model) for systolic BP (SBP) or diastolic BP (DBP) effect on mortality and/or hospitalization risk. We used a priori defined sub-group analyses to explore heterogeneity and GRADE approach to assess the certainty of the evidence. Seventy-one eligible articles (239,467 screened) at low to moderate risk of bias included 235,752 participants. Higher SBP was associated with reduced all-cause mortality (HR 0.93, 95%CI 0.91-0.95, I2 = 87.13%, moderate certainty), all-cause hospitalization events (HR 0.91, 95%CI 0.88-0.93, I2 = 44.4%, high certainty) and their composite endpoint (HR 0.93 per 10 mmHg, 95%CI 0.91-0.94, I2 = 86.3%, high certainty). DBP did not demonstrate a statistically significant effect for all outcomes. The association strength was significantly weaker in studies following patients with either LVEF > 40%, higher average SBP (> 130 mmHg), increasing age and diabetes. All other a priori subgroup hypotheses did not explain between study differences. Higher ambulatory SBP is associated with reduced risk of all-cause mortality and hospitalization. Patients with lower BP and reduced LVEF are in a high-risk group of developing adverse events with moderate certainty of evidence.

Siderophore-mediated zinc acquisition enhances enterobacterial colonization of the inflamed gut.

Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or "Nissle") exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactin's affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae.

Endothelial cell PHD2-HIF1α-PFKFB3 contributes to right ventricle vascular adaptation in pulmonary hypertension.

Humans and animals with pulmonary hypertension (PH) show right ventricular (RV) capillary growth, which positively correlates with overall RV hypertrophy. However, molecular drivers of RV vascular augmentation in PH are unknown. Prolyl hydroxylase (PHD2) is a regulator of hypoxia-inducible factors (HIFs), which transcriptionally activates several proangiogenic genes, including the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). We hypothesized that a signaling axis of PHD2-HIF1α-PFKFB3 contributes to adaptive coupling between the RV vasculature and tissue volume to maintain appropriate vascular density in PH. We used design-based stereology to analyze endothelial cell (EC) proliferation and the absolute length of the vascular network in the RV free wall, relative to the tissue volume in mice challenged with hypoxic PH. We observed increased RV EC proliferation starting after 6 h of hypoxia challenge. Using parabiotic mice, we found no evidence for a contribution of circulating EC precursors to the RV vascular network. Mice with transgenic deletion or pharmacological inhibition of PHD2, HIF1α, or PFKFB3 all had evidence of impaired RV vascular adaptation following hypoxia PH challenge. PHD2-HIF1α-PFKFB3 contributes to structural coupling between the RV vascular length and tissue volume in hypoxic mice, consistent with homeostatic mechanisms that maintain appropriate vascular density. Activating this pathway could help augment the RV vasculature and preserve RV substrate delivery in PH, as an approach to promote RV function.