Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterized by unexplained pulmonary vascular resistance, which can lead to persistent pulmonary arterial hypertension and eventually right heart failure. A targeted therapy for IPAH that can effectively reduce pulmonary artery pressure and improve survival and prognosis is urgently required. This study aimed to identify potential core genes and pathways involved in the pathogenesis of IPAH through a bioinformatics approach. Two publicly available gene expression datasets (GSE15197 and GSE130391) from the Gene Expression Omnibus were analyzed in this observational study, encompassing 22 IPAH and 17 control lung specimens. The GEO2R tool was employed to identify differentially expressed genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases were employed for the functional enrichment analysis of the identified differentially expressed genes. STRING and Cytoscape were used to construct and visualize a protein-protein interaction network, respectively, for the identification of hub genes. A total of 159 genes were identified, of which 56 were downregulated and 103 were upregulated. Their biological functions mainly focus on negative regulation of transcription (DNA-templated), positive regulation of RNA polymerase II promoter transcription, zinc ion binding, and protein heterodimerization activity. Enrichment mapping revealed that the phosphatidylinositol 3-kinase-protein kinase B axis and cancer pathways constituted the central regulatory networks for the differentially expressed gene cohort. Ten hub genes were identified, including the notably downregulated core gene vascular endothelial growth factor A. While this STROBE-compliant study was computational in nature, the 10 hub genes identified present promising candidates for future exploration in IPAH prevention, diagnostic strategies, and therapeutic development. These findings should be interpreted as generating hypotheses that necessitate confirmation through rigorous experimental validation to establish their biological significance. Notably, vascular endothelial growth factor A emerged as a particularly intriguing and unanticipated differentially expressed gene, with its downregulation potentially representing a distinctive feature of IPAH among pulmonary hypertension subtypes.

Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and COVID-19 are characterized by hyperinflammation, commonly referred to as "cytokine storm". The insulin-like growth factor (IGF) pathway, particularly the type 1 receptor (IGF1R), plays a critical role in lung homeostasis and has been implicated in the pathogenesis of pulmonary inflammatory diseases. In mice, widespread Igf1r deficiency attenuates lung inflammation and alveolar damage in bleomycin (BLM)-induced ALI.

We analyzed single-cell RNA sequencing datasets from lung tissue of COVID-19 cases and control donors as well as mouse lungs to determine Igf1r and IGF family expression across pulmonary cell types. Furthermore, we conducted bulk RNA sequencing on lungs from Igf1r-deficient mice three days after BLM or saline instillation, followed by differential expression and functional enrichment analyses. Findings were further tested through protein detection, assessment of DNA damage and methylation in lung tissues, and functional assays using Igf1r-deficient primary mouse embryonic fibroblasts (MEFs).

IGF1R was broadly expressed across multiple cell types in both human and mouse lungs under normal and pathological conditions. Other IGF family members showed cell-type-specific expression, which was modulated by lung injury. Transcriptomic profiling revealed differentially expressed genes between BLM-challenged and control mouse lungs, detecting biological processes and signaling pathways involved in ALI pathobiology. Igf1r deficiency in BLM-challenged mice reversed a large fraction of the transcriptional changes triggered by BLM, including "cytokine storm"-related gene expression. Functional enrichment analysis additionally revealed significant modulation of pathways related to DNA damage, metabolic reprogramming, mitochondrial homeostasis, and epigenetic regulation. In vitro, Igf1r-deficient MEFs exhibited decreased mitochondrial respiration and glycolysis, protection against BLM-induced nuclear damage and mitochondrial accumulation, and decreased histone H3 acetylation. Moreover, Igf1r-deficient mouse lungs displayed increased global DNA methylation following BLM challenge.

IGF1R is a key modulator of the inflammatory and molecular response to ALI pathogenesis. IGF1R deficiency dampens the "cytokine storm", modifies transcriptional and epigenetic profiles and promotes protective cellular responses. These findings highlight IGF1R signaling as a potential therapeutic target in ARDS and related lung injuries.

The paper presents the results of an ecological study completed within the warm seasonal period of 01/07/2024-31/10/2024. The aim is to assess the relationship between ambient air quality deterioration and acute respiratory incidents occurring in the inhabitants of Gliwice (Poland; Upper Silesian agglomeration). The number of daily medical services (MS) due to respiratory diseases and illnesses was obtained from the register of the National Health Fund (Silesian Voivodeship Branch in Katowice). The daily mean values of aerosanitary factors in Gliwice came from the mobile air pollution laboratory of the Silesian University of Technology in Poland. The relative risk (RR) of MS was estimated using a Poisson log-linear model considering independent environmental factors (meteorological factors and air pollutant concentrations) or confounding factors (astronomical season and day of the week). The highest number of MS due to respiratory diseases refers to acute nasopharyngitis and asthma exacerbation, mostly in children aged 0-9 years. A significant impact was observed in the case of particulate matter concentration increase and number of MS due to acute nasopharyngitis, laryngitis and tracheitis, pneumonia, asthma exacerbation, in the case of nitrogen oxides appropriately acute nasopharyngitis, bronchitis and/or bronchiolitis, pneumonia, asthma exacerbation. Additionally, a longer time of exposure was associated with a higher risk of MS due to respiratory incidents. The increase in wind speed and relative humidity was significantly associated with a higher number of bronchitis and asthma exacerbation while a higher temperature and higher 8-hour ozone concentration remain protective of both MS. The results are essential for effectively communicating environmental health risks, educating the public about potential threats, and pressuring legislators responsible for legislation and risk management.

Migrants detained by US Immigration and Customs Enforcement (ICE) are at risk of preventable infections from crowding and limited health care. Postpandemic risk remains unclear as detention increases.

To assess epidemiological patterns of 3 vaccine-preventable diseases within ICE facilities.

This case series study examined data from January 2019 through October 2023 from ICE facilities managed by ICE Health Services Corp during the study period. All cases of influenza, mumps, and hepatitis A among persons detained in reporting ICE facilities were included.

Diagnosis of influenza, mumps, or hepatitis A during ICE detention.

The primary outcomes were monthly case counts and estimated case rates (per 100 000 person-months), outbreak occurrence and duration, and seasonal and geospatial patterns. Outbreaks were defined as 3 or more cases within a facility over at least 1 month. Seasonal variation was assessed through variations in mean monthly case rates across years with analysis of variance, and Tukey tests were used to compare monthly pairwise permutations for statistical significance. Geospatial trends were evaluated using global and local Moran I analyses of annual facility-level case rates.

From 2019 to 2023, at a total of 20 ICE facilities, there were 2035 influenza cases (mean [SD] age, 33.1 [10.8] years; 1804 [88.6%] men), with a mean of 35.1 cases monthly (range, 0.0-276.0 cases monthly). The mean facility-level monthly case rate was 17.3 cases per 100 000 persons (range, 0.0-720.0 cases per 100 000 persons), lower than national rates. December had the highest case rate (mean [SD], 59.4 [142.0] cases per 100 000 persons) and September the lowest (mean [SD], 6.1 [11.9] cases per 100 000 persons), paralleling national trends. Across 15 facilities, 79 outbreaks occurred involving 1739 cases with a mean duration of 2.5 months (range, 1.0-13.0 months). For mumps, 252 cases were reported (mean [SD] age, 34.3 [9.2] years; 235 [93.3%] men), with a mean of 4.3 cases monthly (range, 0.0-61.0 cases monthly). The mean facility-level monthly case rate was 1.5 cases per 100 000 persons (range, 0.0-160.2 cases per 100 000 persons). June had the highest mean case rate (3.1 cases per 100 000 persons) and February the lowest (0.1 cases per 100 000 persons); 16 outbreaks across 8 facilities involved 177 cases with a mean duration of 1.8 months (range, 1.0-6.0 months). For hepatitis A, there were 486 reported cases (mean [SD] age, 39.2 [10.8] years; 408 [84.0%] men), with a mean of 8.4 cases monthly (range, 0.0-40.0 cases monthly). The mean facility-level monthly case rate was 6.0 cases per 100 000 persons (range, 0.0-273.4 cases per 100 000 persons). July had the highest mean case rate (13.8 cases) and November the lowest (2.3 cases); 33 outbreaks across 11 facilities involved 158 cases with a mean duration of 1.2 months (range, 1.0-2.0 months). No geospatial clusters were found.

This case series found that vaccine-preventable infectious disease burden among individuals detained by ICE varied by season and facility. Mitigation could include decongregation, reduced crowding, vaccinations, and improved infection control procedures to protect migrants and staff.

Exposure to air pollution is known to contribute to the development and exacerbation of asthma symptoms, impacting respiratory health through complex, not yet fully understood biological mechanisms. It is hypothesized that DNA methylation (DNAm) changes triggered by air pollutants may mediate these effects on asthma symptom control.

We aimed to investigate the effects of air pollution on DNAm in peripheral blood and asthma control. We also explored whether DNAm could potentially mediate the relationship between air pollution exposure and asthma control.

This study included 651 participants with asthma exposed to ambient air pollutants, NO₂, PM_2.5, PM₁₀, O₃, elemental carbon (EC), and NOx. Self-reported Asthma Control Test (ACT) scores for the preceding six-month period were used to assess asthma symptom control. DNAm was quantified using the Infinium HumanMethylation450 BeadChip array in whole blood and CD4 + naive T cells. An Epigenome-Wide Association Study (EWAS) was conducted to identify CpGs associated with air pollutants, with sample sizes ranging from 169 to 329. The Causal Inference Test (CIT) was employed to examine whether DNAm mediates the effects of air pollution exposure on asthma control.

Exposure to short-term PM₁₀ was associated with poorer asthma control. We identified DNA methylation changes linked to air pollution in both whole blood and CD4 + cells, with associations observed for PM₁₀, EC and NOx in whole blood, and for PM₁₀, NO₂ and PM_2.5 in CD4 + cells. Three CpG sites in whole blood-cg04605532 (p = 0.0004), cg05492904 (p = 0.0008), and cg23622322 (p = 0.001)- and one CpG in CD4 + cells -cg10022248 (p = 0.0084)-were associated with air pollution exposure and linked to asthma control. Additionally, CIT-based mediation analysis identified two CpG sites, cg02324789 (p = 0.05) and cg10758278 (p = 0.06), as potential mediators in the relationship between short-term exposure to PM₁₀ and asthma control.

These findings suggest that air pollution-associated changes in DNA methylation may affect asthma control for some loci, thus help elucidate underlying mechanisms in asthmatic patients. These epigenetic alterations highlight potential targets for understanding the pathophysiology of asthma due to air pollution. While our findings suggest possible links between air pollution, DNA methylation, and asthma control, more evidence is needed to establish causal relationships and unravel the complexities of these connections.

Obesity triggers chronic low-grade inflammation contributing to cardiovascular and metabolic diseases. Over-release of adipokines and pro-inflammatory mediators by white adipose tissue (WAT) enhances inflammation through a feedforward loop involving endothelial and immune cells, promoting atherosclerosis. Our previous studies showed that in vivo gene transfer of the longevity-associated variant (LAV) of BPIFB4 restores endothelial and cardiac function and reduces systemic inflammation in mouse models. Here we investigated the anti-inflammatory potential of orally administered recombinant rhLAV-BPIFB4 in ApoE-/- mice fed a high-fat diet to elucidate its role in modulating endothelial dysfunction primed by adipose tissue inflammation. We studied n = 5 ApoE-/- mice on standard diet (SD), n = 5 (VEH-HFD) and n = 6 (LAV-HFD) ApoE-/- mice fed high-fat diet without or with rhLAV-BPIFB4 protein. Primary pre-adipocyte cultures were established from epididymal WAT to evaluate CD45+CD38+ leukocyte infiltration, inflammatory profile of pre-adipocytes, and ex vivo effects of conditioned media on vessels. Oral administration of rhLAV-BPIFB4 in ApoE-/- mice fed high-fat diet dampens atherosclerosis by preserving endothelial integrity and reducing ICAM+ and CD68+ cell infiltration. Despite unchanged adiposity, systemically rhLAV-BPIFB4 reduces pro-inflammatory cytokines (IL-1α/β, TNF-α, IL-6) while mildly increasing IL-10 levels. Supernatants from pre-adipocytes treated with rhLAV-BPIFB4 demonstrate similar anti-inflammatory cytokine profiles. Conditioned media from rhLAV-treated eWAT ex vivo restores endothelial function in dysfunctional arteries (VEH-HFD vs LAV-HFD, ***p < 0.001). Collectively our data show that targeting adipocyte-associated inflammation, LAV-BPIFB4 emerges as a promising therapeutic strategy to counteract endothelial dysfunction in obesity.

Many end-stage kidney disease (ESKD) patients frequently suffer from both aggressive vascular access stenosis in the venous segment of arteriovenous fistula or arteriovenous graft, and widespread cardiovascular disease (CVD) or peripheral arterial disease (PAD). Despite the magnitude of these clinical problems, the pathogenic role of the uremic state in both these conditions remains unclear. To investigate the underlying mechanisms, we used porcine-derived arterial smooth muscle cells (ApSMCs) and venous smooth muscle cells (VpSMCs) to examine several key aspects of cell behavior in response to uremic serum. The MTT assay demonstrated that 30% of uremic serum was able to stimulate proliferation of both subtypes of cells equally. Cell migration, measured by the scratch assay, showed that uremic serum increased migration of both cells, but was more robust in VpSMCs. Importantly, uremic serum induced phenotypic switching (e.g., dedifferentiation) in both subtypes of cells, as indicated by increased PCNA expression and reduced calponin expression. Intriguingly, we found that several key aspects of this uremia-induced phenotypic switch were stronger in ApSMCs as compared to VpSMCs, including the production of extracellular matrix (ECM) proteins, such as fibronectin, cellular calcification (high expression of RUNX family transcription factor 2 (Runx2), alkaline phosphatase (ALP) and kruppel-like factor 4 (KLF-4)), and a proinflammatory state (high expression of tumor necrosis factor α (TNFα) and interleukin 6 (IL-6)). Our findings suggest that uremia plays an important role in both the aggressive arteriovenous stenosis and CVD/PAD that affect many hemodialysis patients. This information could contribute to the development of novel uremia-specific therapies for both vascular access dysfunction and CVD/PAD in ESKD patients.

This paper aims to clarify the mechanism of action of Cardiac Contractility Modulation in heart failure treatment, synthesize key clinical evidence supporting the combination of Cardiac Contractility Modulation and implantable cardioverter-defibrillators for managing heart failure with reduced ejection fraction, and explore potential challenges and future applications pertaining to this combined therapy.

Recent studies indicate that cardiac contractility modulation therapy improves ventricular function without elevating myocardial oxygen consumption, promotes recovery of diastolic and systolic function, augments myocardial contractility, and exhibits substantial efficacy in drug-refractory chronic heart failure. Additionally, cardiac contractility modulation markedly improves left ventricular function, reduces hospitalization frequency, and enhances quality of life in patients with heart failure with reduced ejection fraction and a QRS duration of 120-149 ms. It may also serve as a pivotal strategy to arrest progression of heart failure with preserved ejection fraction. Combining implantable cardioverter-defibrillators with cardiac contractility modulation addresses a critical gap in the clinical management of patients with heart failure with reduced ejection fraction. These individuals meet criteria for left ventricular assist devices but are ineligible for cardiac resynchronization therapy and fail to derive long-term survival benefits from implantable cardioverter-defibrillator monotherapy. This review demonstrates that combining cardiac contractility modulation and implantable cardioverter-defibrillators shows potential for improving outcomes in specific populations with heart failure with reduced ejection fraction by addressing limitations of single-therapy approaches. A key implication is that this combined strategy may offer a valuable therapeutic option for patients underserved by current guidelines. However, further rigorous clinical investigations are needed to fully establish its long-term efficacy, safety, and optimal patient selection criteria. These findings highlight the need for future research to refine the application of this combined therapy and expand its evidence base, which may inform future treatment guidelines for heart failure with reduced ejection fraction.

This review aims to provide an updated overview of the clinical management of heart failure and comorbidities in transthyretin amyloid cardiomyopathy (ATTR-CM). We sought to address key unanswered questions and current uncertainties regarding treatment response, prognosis, and optimization of care in this complex population.

Once considered rare, ATTR-CM is now increasingly recognized due to greater awareness and the possibility of non-invasive diagnosis. Patients are often identified at earlier stages, with lower mortality than historically observed. Disease-modifying therapies with proven efficacy in randomized trials are now available, yet many patients experience disease progression. In real-world practice, ATTR-CM patients are typically older and have multiple cardiac and extracardiac comorbidities, often representing exclusion criteria of clinical trials, which may influence treatment response and efficacy. Modern management of ATTR-CM should integrate heart failure treatment with tailored approaches to comorbidity care. Earlier diagnosis, real-world evidence, and strategies for patients outside trial populations will be essential to improve prognosis and guide future research.

Varicocele is characterized by abnormally dilated and tortuous veins in the pampiniform plexus. Treatment options are varied, including open surgery, laparoscopic surgery, microscopic varicocelectomy, and sclero-embolization. However, no consensus exists on the optimal treatment. This systematic review and meta-analysis aim to compare the effectiveness and safety of sclero-embolization versus surgical ligation for varicocele.

In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched PubMed, Web of Science, EMBASE, and MEDLINE for relevant studies up to October 14, 2023. Study selection followed the Patient, Intervention, Comparison, Outcome, Study type (PICOS) framework. The quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies and the Cochrane Risk of Bias Tool (CCTARB) for randomized controlled trials. Data analysis was performed using Review Manager (RevMan) version 5.4.

Thirty studies were included in the final analysis. Regarding recurrence rates, sclero-embolization was associated with a statistically higher recurrence rate compared to high ligation (OR = 1.37, 95% CI 1.03-1.82, p = 0.03). For sperm concentration, a non-significant trend favoring sclero-embolization was observed (MD = 7.09, 95% CI -0.14 to 14.31, p = 0.05). Sclero-embolization demonstrated a more favorable safety profile, with lower overall complication rates (OR = 0.65, 95% CI 0.47-0.91, p = 0.01) and significantly reduced incidence of hydrocele (OR = 0.19, 95% CI 0.10-0.35, p < 0.00001) compared to surgical ligation.

This meta-analysis reveals a nuanced trade-off between sclero-embolization and surgical ligation for varicocele treatment. Sclero-embolization is associated with higher recurrence rates but a more favorable safety profile, while its effect on sperm concentration remains marginal and inconclusive. Surgical ligation, particularly the high ligation approach, demonstrates superior efficacy in preventing recurrence but carries a higher risk of complications. The choice of technique should therefore be individualized based on patient-specific factors. These findings warrant validation through further high-quality, prospective studies.