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24 pages, 1028 KiB  
Review
Biocontrol of Phage Resistance in Pseudomonas Infections: Insights into Directed Breaking of Spontaneous Evolutionary Selection in Phage Therapy
by Jumpei Fujiki, Daigo Yokoyama, Haruka Yamamoto, Nana Kimura, Manaho Shimizu, Hinatsu Kobayashi, Keisuke Nakamura and Hidetomo Iwano
Viruses 2025, 17(8), 1080; https://doi.org/10.3390/v17081080 - 4 Aug 2025
Abstract
Phage therapy, long overshadowed by antibiotics in Western medicine, has a well-established history in some Eastern European countries and is now being revitalized as a promising strategy against antimicrobial resistance (AMR). This resurgence of phage therapy is driven by the urgent need for [...] Read more.
Phage therapy, long overshadowed by antibiotics in Western medicine, has a well-established history in some Eastern European countries and is now being revitalized as a promising strategy against antimicrobial resistance (AMR). This resurgence of phage therapy is driven by the urgent need for innovative countermeasures to AMR, which will cause an estimated 10 million deaths annually by 2050. However, the emergence of phage-resistant variants presents challenges similar to AMR, thus necessitating a deeper understanding of phage resistance mechanisms and control strategies. The highest priority must be to prevent the emergence of phage resistance. Although phage cocktails targeting multiple receptors have demonstrated a certain level of phage resistance suppression, they cannot completely suppress resistance in clinical settings. This highlights the need for strategies beyond simple resistance suppression. Notably, recent studies examining fitness trade-offs associated with phage resistance have opened new avenues in phage therapy that offer the potential of restoring antibiotic susceptibility and attenuating pathogen virulence despite phage resistance. Thus, controlling phage resistance may rely on both its suppression and strategic redirection. This review summarizes key concepts in the control of phage resistance and explores evolutionary engineering as a means of optimizing phage therapy, with a particular focus on Pseudomonas infections. Harnessing evolutionary dynamics by intentionally breaking the spontaneous evolutionary trajectories of target bacterial pathogens could potentially reshape bacterial adaptation by acquisition of phage resistance, unlocking potential in the application of phage therapy. Full article
(This article belongs to the Section Bacterial Viruses)
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20 pages, 1918 KiB  
Review
Leveraging the Tumor Microenvironment as a Target for Cancer Therapeutics: A Review of Emerging Opportunities
by Hakan Guven and Zoltán Székely
Pharmaceutics 2025, 17(8), 980; https://doi.org/10.3390/pharmaceutics17080980 - 29 Jul 2025
Viewed by 323
Abstract
Cancer has remained one of the leading causes of death worldwide throughout history despite significant advancements in drug development, radiation therapy, and surgery. Traditional chemotherapeutic small molecules are often hindered by narrow therapeutic indices and limited specificity, leading to suboptimal clinical outcomes. On [...] Read more.
Cancer has remained one of the leading causes of death worldwide throughout history despite significant advancements in drug development, radiation therapy, and surgery. Traditional chemotherapeutic small molecules are often hindered by narrow therapeutic indices and limited specificity, leading to suboptimal clinical outcomes. On the other hand, more advanced approaches, such as antibody–drug conjugates (ADCs), frequently encounter obstacles, including poor tumor penetration and prohibitive production costs. The tumor-forming and metastatic capacity of cancer further challenges currently available cancer therapies by creating a biochemical milieu known as the tumor microenvironment (TME). Although solid tumor development presents significant obstacles, it also opens new avenues for innovative therapeutic approaches. It is well-documented that as tumors grow beyond 1–2 mm3 in size, they undergo profound changes in their microenvironment, including alterations in oxygen levels, pH, enzymatic activity, surface antigen expression, and the cellular composition of the stroma. These changes create unique opportunities that can be exploited to develop novel and innovative therapeutics. Currently, numerous ADCs, small-molecule–drug conjugates (SMDCs), and prodrugs are being developed to target specific aspects of these microenvironmental changes. In this review, we explore five TME parameters in detail, with a focus on their relevance to specific cancer types, phenotypic identifiers, and preferred methods of therapeutic targeting. Additionally, we examine the chemical moieties available to target these changes, providing a framework for design strategies that exploit the dynamics of the tumor microenvironment. Full article
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12 pages, 480 KiB  
Brief Report
Treated but Uncontrolled: Characterizing Hypertension in a Sample of 357 Older Adults in the Southeastern United States
by Rachel Helms, Laura A. Robinson, Paul S. Fiore, Kelly P. Strickland, Sarah O. Watts, Felicia J. Tuggle, Jennifer L. Slay, Jeanna Sewell and Andrew D. Frugé
Geriatrics 2025, 10(4), 101; https://doi.org/10.3390/geriatrics10040101 - 26 Jul 2025
Viewed by 160
Abstract
Background/Objectives: Hypertension (HTN) continues to be a leading cause of death and disability in older adults, especially in the southeastern United States. A cross-sectional study was conducted to evaluate the relationships among measured, diagnosed, and treated (HTN) in community-dwelling adults participating in [...] Read more.
Background/Objectives: Hypertension (HTN) continues to be a leading cause of death and disability in older adults, especially in the southeastern United States. A cross-sectional study was conducted to evaluate the relationships among measured, diagnosed, and treated (HTN) in community-dwelling adults participating in student-led health screenings in eastern Alabama. Methods: Between 2017 and 2019, students from health-related disciplines facilitated screenings at 23 community and independent living sites to conduct health assessments, including measuring blood pressure (BP), obtaining medical history, and evaluating current prescriptions. Statistical analyses including chi-square tests, t-tests, and backward stepwise linear regression were performed. Results: The current sample includes data from 357 adults aged 60 to 99 years (mean age 74.6 ± 8.7), who were 70.9% females, 60.8% identifying as Black/African American (BA), and 36.8% residing in rural areas. The majority of clients had a prior HTN diagnosis (71.1%) and/or currently measured HTN (78.7%). Forty-three percent of adults screened had measured, diagnosed, and pharmaceutically treated HTN, while 31% had measured but untreated HTN. Black clients had higher measured systolic and diastolic BP and were more likely to also have been diagnosed with HTN (p < 0.05 for all). Linear regression indicated that lower systolic BP was predicted by not living alone (p = 0.003), White race (p = 0.004), and previous HTN diagnosis (p = 0.012), while female gender (p = 0.079) and decreasing body mass index (p = 0.053) had marginal predictive value. Conclusions: These results indicate that awareness and screening of HTN in this population are noteworthy, though management of the disease through ongoing screening and referrals is essential to reduce disparities. Full article
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14 pages, 242 KiB  
Article
Factors Associated with Successful Smoking Cessation Among Adults in Saudi Arabia—A Cross-Sectional Study
by Nada A. Alyousefi, Reema S. Alquraini, Lina F. Alyahya, Norah M. Bin Hamad, Deema K. Aljuribah and Kadi K. Aldossari
Healthcare 2025, 13(15), 1813; https://doi.org/10.3390/healthcare13151813 - 25 Jul 2025
Viewed by 332
Abstract
Purpose: Smoking is a major preventable cause of illness and death. Quitting smoking can reduce related health complications. Numerous factors, including age, socioeconomic status, smoking habits, and availability of support, influence smoking cessation success. Despite anti-smoking measures and smoking cessation clinics in Saudi [...] Read more.
Purpose: Smoking is a major preventable cause of illness and death. Quitting smoking can reduce related health complications. Numerous factors, including age, socioeconomic status, smoking habits, and availability of support, influence smoking cessation success. Despite anti-smoking measures and smoking cessation clinics in Saudi Arabia, smoking-related deaths are increasing. This study aimed to identify factors influencing successful smoking cessation among Saudi adults and examine the relationship between cessation methods and success rates. Patients and methods: A cross-sectional study was conducted through an online survey targeting Saudi adults who had attempted to quit smoking of all types, whether traditional cigarettes, e-cigarettes, shisha, or others. Success was defined as quitting for at least six months. The data collected included sociodemographic details, smoking history, and experiences with cessation. Logistic regression analysis was used to identify factors associated with successful cessation. Results: Of 364 participants, 18.4% were successful quitters, with a mean age of 34.94. Occupation was a key predictor; freelance workers had significantly higher odds of unsuccessful quitting (OR = 12.96, 95% CI: 2.08–80.79, p = 0.006). Those who continued smoking despite illness were less likely to quit successfully (OR = 2.33, 95% CI: 1.16–4.68, p = 0.018). Early initiation of smoking also negatively impacted cessation success (OR = 1.10, 95% CI: 1.03–1.17, p = 0.006). Successful quitters reported fewer adverse symptoms during their attempts (p = 0.018) and employed behavioral strategies, such as disposing of tobacco products (p < 0.001), avoiding smoking triggers (p = 0.002), and engaging in exercise (p < 0.001). Confidence in quitting significantly contributed to success (p < 0.001). Conclusions: This study highlights the role of individual, social, and environmental factors in smoking cessation. Tailored interventions that address socioeconomic, psychological, and lifestyle factors are crucial for enhancing cessation success among Saudi adults. Full article
13 pages, 1916 KiB  
Case Report
Beyond Comorbidity: Pulmonary Adenocarcinoma in a Patient with Rheumatoid Arthritis—A Case Report and Literature Review
by Ancuța-Alina Constantin, Mihai Alexandru Arghir, Dana Avasilcăi and Florin-Dumitru Mihălțan
Life 2025, 15(7), 1118; https://doi.org/10.3390/life15071118 - 17 Jul 2025
Viewed by 349
Abstract
Lung cancer is one of the most common and deadly forms of cancer worldwide, despite sustained efforts to encourage smoking cessation and raise awareness of the risk factors. In Romania, lung cancer is a significant health challenge, being the leading cause of death [...] Read more.
Lung cancer is one of the most common and deadly forms of cancer worldwide, despite sustained efforts to encourage smoking cessation and raise awareness of the risk factors. In Romania, lung cancer is a significant health challenge, being the leading cause of death caused by cancer, especially amongst men. The incidence of lung cancer in connective tissue disease (CTD) varies in different studies from 4.5% in rheumatoid arthritis (RA), to 4.4% in polymyositis or dermatomyositis, and up to 11.1% in systemic sclerosis. However, older studies have shown an increased risk of cancer in patients with rheumatoid arthritis (RA), ranging from 10% to 30% compared to the general population, particularly in those undergoing methotrexate therapy. Rheumatoid arthritis affects approximately 40 per 100,000 people annually worldwide, with a three- to four-fold higher incidence in women. Non-small cell lung cancer (NSCLC), the most common lung cancer subtype, has been linked to RA, yet the association remains poorly defined, with limited insight into the underlying molecular mechanisms. We present the case of a 61-year-old male with a 49-pack-year smoking history and a known diagnosis of rheumatoid arthritis, currently managed with methotrexate therapy. He was admitted for evaluation due to a progressive decline in general condition, characterized by worsening dyspnea and chest pain, symptoms that had been longstanding but had markedly exacerbated over the past two weeks. Based on a chest CT performed prior to the patient’s admission to our clinic, subsequent diagnostic investigations established the diagnosis of pulmonary adenocarcinoma. The diagnostic process proved to be particularly challenging due to the presence of multiple comorbidities, which significantly impacted both the diagnostic approach and the overall clinical trajectory. Full article
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17 pages, 1413 KiB  
Article
Sensitivity and Cross-Reactivity Analysis of Serotype-Specific Anti-NS1 Serological Assays for Dengue Virus Using Optical Modulation Biosensing
by Sophie Terenteva, Linoy Golani-Zaidie, Shira Avivi, Yaniv Lustig, Victoria Indenbaum, Ravit Koren, Tran Mai Hoa, Tong Thi Kim Tuyen, Ma Thi Huyen, Nguyen Minh Hoan, Le Thi Hoi, Nguyen Vu Trung, Eli Schwartz and Amos Danielli
Biosensors 2025, 15(7), 453; https://doi.org/10.3390/bios15070453 - 14 Jul 2025
Viewed by 531
Abstract
Dengue virus (DENV) poses a major global health concern, with over 6.5 million cases and 7300 deaths reported in 2023. Accurate serological assays are essential for tracking infection history, evaluating disease severity, and guiding vaccination strategies. However, existing assays are limited in their [...] Read more.
Dengue virus (DENV) poses a major global health concern, with over 6.5 million cases and 7300 deaths reported in 2023. Accurate serological assays are essential for tracking infection history, evaluating disease severity, and guiding vaccination strategies. However, existing assays are limited in their specificity, sensitivity, and cross-reactivity. Using optical modulation biosensing (OMB) technology and non-structural protein 1 (NS1) antigens from DENV-1–3, we developed highly sensitive and quantitative serotype-specific anti-DENV NS1 IgG serological assays. The OMB-based assays offered a wide dynamic range (~4-log), low detection limits (~400 ng/L), fast turnaround (1.5 h), and a simplified workflow. Using samples from endemic (Vietnam) and non-endemic (Israel) regions, we assessed intra-DENV and inter-Flavivirus cross-reactivity. Each assay detected DENV infection with a 100% sensitivity for the corresponding serotype and 64% to 90% for other serotypes. Cross-reactivity with Zika, Japanese encephalitis, and West Nile viruses ranged from 21% to 65%, reflecting NS1 antigen conservation. Our study provides valuable insights into the cross-reactivity of DENV NS1 antigens widely used in research and highlights the potential of OMB-based assays for quantitative and epidemiological studies. Ongoing efforts should aim to minimize cross-reactivity while maintaining sensitivity and explore integration with complementary platforms for improved diagnostic precision. Full article
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19 pages, 794 KiB  
Article
Maternal Death: Retrospective Autopsy Study in Southwestern Colombia, 2000–2023
by Jhoan Sebastian Cruz-Barbosa, Andrés Felipe Valencia-Cardona, Armando Daniel Cortés-Buelvas and Yamil Liscano
Int. J. Environ. Res. Public Health 2025, 22(7), 1105; https://doi.org/10.3390/ijerph22071105 - 14 Jul 2025
Viewed by 562
Abstract
Background and aim: The death of a woman while pregnant or within 42 days of delivery, regardless of the cause of death, or even up to one year after the end of the pregnancy, due to causes related to or aggravated by pregnancy [...] Read more.
Background and aim: The death of a woman while pregnant or within 42 days of delivery, regardless of the cause of death, or even up to one year after the end of the pregnancy, due to causes related to or aggravated by pregnancy remains a critical public health problem globally and in Colombia. While the country shows a general decreasing trend (preliminary Maternal Mortality Ratio 38.6/100,000 live births in 2023), significant regional disparities persist. Understanding precise underlying causes, especially in high-complexity referral centers, is vital. This study describes the sociodemographic and anatomopathological characteristics associated with autopsy-verified maternal mortality cases at a Level-4 hospital in southwestern Colombia (2000–2023). Methodology: A descriptive observational retrospective study analyzed 42 maternal mortality cases verified by clinical autopsy (2000–2023) at the Pathology Department of Universidad del Valle, a Level-4 referral center in Cali, Colombia. Cases met the WHO definition. Data on sociodemographic, clinical, and pathological characteristics were retrospectively extracted from clinical records and autopsy reports. Results: The analysis of 42 autopsies (2000–2023) showed that 85.7% were early maternal deaths. Indirect causes predominated (57.1%, n = 24) over direct (42.9%, n = 18). Septic shock was the main indirect cause (65.2% of indirect), often from endemic infections. Hypovolemic shock due to PPH was the main direct cause (50% of direct). A high proportion were from subsidized/uninsured schemes (65.7%) and had a migratory history (20%). Discussion and conclusions: This study highlights the value of autopsy in revealing maternal mortality etiologies, showing a predominance of indirect/infectious causes and endemic diseases often missed clinically, despite PPH remaining the main direct cause. Findings reaffirm the strong link between maternal death and social/economic inequity, access barriers, and regional/migratory vulnerabilities. Effectively reducing maternal mortality necessitates rigorous clinical management, regionalized public health strategies addressing inequities, and integrating pathological data for targeted surveillance. Full article
(This article belongs to the Special Issue Sexual, Reproductive and Maternal Health)
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31 pages, 3002 KiB  
Review
Difficult Airway Management in the Intensive Care Unit: A Narrative Review of Algorithms and Strategies
by Talha Liaqat, Mohammad Asim Amjad and Sujith V. Cherian
J. Clin. Med. 2025, 14(14), 4930; https://doi.org/10.3390/jcm14144930 - 11 Jul 2025
Viewed by 1655
Abstract
Background: The management of difficult airways is one of the most critical and challenging aspects of emergency and ICU care. Despite technological advances, unanticipated airway difficulty can result in serious complications, including hypoxia, brain injury, and death. This comprehensive narrative review aims to [...] Read more.
Background: The management of difficult airways is one of the most critical and challenging aspects of emergency and ICU care. Despite technological advances, unanticipated airway difficulty can result in serious complications, including hypoxia, brain injury, and death. This comprehensive narrative review aims to consolidate current algorithms and evidence-based strategies to guide clinicians in the assessment and management of difficult airways. Methods: A comprehensive literature review was conducted using PubMed, Embase, and Google Scholar to identify relevant studies, clinical guidelines, and expert consensus documents related to difficult airway management. The focus was placed on both pre-intubation assessment tools and intervention strategies used in various clinical contexts. Results: Airway difficulty is best anticipated through a combination of history, physical examination, and validated tools such as the Mallampati score. Several algorithms, including those from the American Society of Anesthesiologists (ASA) and the Difficult Airway Society (DAS), provide structured approaches that emphasize preoxygenation, preparedness for failed intubation, and the use of adjuncts such as video laryngoscopy, supraglottic airway devices, and awake intubation techniques. Crisis algorithms such as the Vortex approach help simplify decision-making during emergencies. It is important to have adjuncts available in cases of anticipated difficult airways, such as fiberoptic intubation, while surgical airway access is an important component of a stepwise airway management algorithm when critical scenarios are encountered. Conclusions: Effective difficult airway management requires anticipation, a structured plan, familiarity with advanced airway tools, and adherence to validated algorithms. Training in crisis resource management and multidisciplinary rehearsal of airway scenarios are essential to improving outcomes. Full article
(This article belongs to the Section Respiratory Medicine)
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15 pages, 959 KiB  
Article
Growth Differentiation Factor 15 Predicts Cardiovascular Events in Peripheral Artery Disease
by Ben Li, Farah Shaikh, Houssam Younes, Batool Abuhalimeh, Abdelrahman Zamzam, Rawand Abdin and Mohammad Qadura
Biomolecules 2025, 15(7), 991; https://doi.org/10.3390/biom15070991 - 11 Jul 2025
Viewed by 423
Abstract
Peripheral artery disease (PAD) is associated with an elevated risk of major adverse cardiovascular events (MACE). Despite this, few reliable biomarkers exist to identify patients at heightened risk of MACE. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine implicated in inflammation, atherosclerosis, and [...] Read more.
Peripheral artery disease (PAD) is associated with an elevated risk of major adverse cardiovascular events (MACE). Despite this, few reliable biomarkers exist to identify patients at heightened risk of MACE. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine implicated in inflammation, atherosclerosis, and thrombosis, has been broadly studied in cardiovascular disease but remains underexplored in PAD. This study aimed to evaluate the prognostic utility of GDF15 for predicting 2-year MACE in PAD patients using explainable statistical and machine learning approaches. We conducted a prospective analysis of 1192 individuals (454 with PAD and 738 without PAD). At study entry, patient plasma GDF15 concentrations were measured using a validated multiplex immunoassay. The cohort was followed for two years to monitor the occurrence of MACE, defined as stroke, myocardial infarction, or death. Baseline GDF15 levels were compared between PAD and non-PAD participants using the Mann–Whitney U test. A machine learning model based on extreme gradient boosting (XGBoost) was trained to predict 2-year MACE using 10-fold cross-validation, incorporating GDF15 and clinical variables including age, sex, comorbidities (hypertension, diabetes, dyslipidemia, congestive heart failure, coronary artery disease, and previous stroke or transient ischemic attack), smoking history, and cardioprotective medication use. The model’s primary evaluation metric was the F1 score, a validated measurement of the harmonic mean of the precision and recall values of the prediction model. Secondary model performance metrics included precision, recall, positive likelihood ratio (LR+), and negative likelihood ratio (LR-). A prediction probability histogram and Shapley additive explanations (SHAP) analysis were used to assess model discrimination and interpretability. The mean participant age was 70 ± SD 11 years, with 32% (n = 386) female representation. Median plasma GDF15 levels were significantly higher in PAD patients compared to the levels in non-PAD patients (1.29 [IQR 0.77–2.22] vs. 0.99 [IQR 0.61–1.63] pg/mL; p < 0.001). During the 2-year follow-up period, 219 individuals (18.4%) experienced MACE. The XGBoost model demonstrated strong predictive performance for 2-year MACE (F1 score = 0.83; precision = 82.0%; recall = 83.7%; LR+ = 1.88; LR− = 0.83). The prediction histogram revealed distinct stratification between those who did vs. did not experience 2-year MACE. SHAP analysis identified GDF15 as the most influential predictive feature, surpassing traditional clinical predictors such as age, cardiovascular history, and smoking status. This study highlights GDF15 as a strong prognostic biomarker for 2-year MACE in patients with PAD. When combined with clinical variables in an interpretable machine learning model, GDF15 supports the early identification of patients at high risk for systemic cardiovascular events, facilitating personalized treatment strategies including multidisciplinary specialist referrals and aggressive cardiovascular risk reduction therapy. This biomarker-guided approach offers a promising pathway for improving cardiovascular outcomes in the PAD population through precision risk stratification. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cardiology 2025)
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15 pages, 638 KiB  
Article
Efficacy, Toxicity and Effect of Pretreatment Cardiologic Consultation on Outcomes of Ibrutinib Therapy for Chronic Lymphocytic Leukemia—A KroHem Study
by Inga Mandac Smoljanović, Igor Aurer, Nikola Bulj, Barbara Dreta, Antonija Miljak, Fran Petričević, Marija Ivić, Sandra Bašić-Kinda, Viktor Zatezalo, Sanja Madunić, Dubravka Čaržavec, Jasminka Sinčić-Petričević, Dragana Grohovac, Ozren Jakšić, Ivan Krečak, Martina Morić-Perić, Božena Coha, Petra Berneš, Neno Živković and Vlatko Pejša
Cancers 2025, 17(14), 2302; https://doi.org/10.3390/cancers17142302 - 10 Jul 2025
Viewed by 319
Abstract
Background/Objectives: Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia but has off-target side effects, most notably cardiac. In order to evaluate the efficacy and toxicity of ibrutinib treatment, risk factors for adverse outcomes and the influence of pretreatment cardiologic evaluation, KroHem collected [...] Read more.
Background/Objectives: Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia but has off-target side effects, most notably cardiac. In order to evaluate the efficacy and toxicity of ibrutinib treatment, risk factors for adverse outcomes and the influence of pretreatment cardiologic evaluation, KroHem collected data on Croatian patients with chronic lymphocytic leukemia treated with this drug. Methods: This is a retrospective survey performed in order to analyze the efficacy and toxicity of ibrutinib in a real-life setting. Patients starting therapy with ibrutinib for chronic lymphocytic leukemia between the time the drug became reimbursable in 2015 and 31 December 2021 were included, irrespective of treatment line. Results: We identified 436 patients fulfilling entry criteria; 404 (92.7%) responded to treatment. Cardiovascular side effects occurred in 25.0% of patients and hemorrhagic in 15.6%. The dose of ibrutinib was permanently reduced in 22.2% of patients. Median follow-up of the cohort was 29 months (IQR 18–41 months), estimated median overall survival 75 months (IQR 36 months–not reached), progression-free survival 54 months (IQR 24–81 months) and time on ibrutinib treatment 44 months (IQR 14–78 months). Factors significantly related to overall survival in multivariate analysis were stage, treatment line and age. Factors significantly related to progression-free survival in multivariate analysis were treatment line, age and pretreatment history or ECG finding of cardiac arrhythmia. Factors significantly related to time on ibrutinib treatment in multivariate analysis were age, pretreatment history or ECG finding of cardiac arrhythmia, and permanent dose reduction for toxicity. Sex, FISH and the presence of arterial hypertension were not independently significantly related to any of these outcomes. Pretreatment cardiologic consultation did not improve time on ibrutinib therapy, progression-free survival, overall survival, risk of stopping treatment due to cardiovascular side effects or risk of cardiovascular or sudden death, neither in the whole cohort nor in the subgroup of patients with and without pretreatment cardiac arrhythmia. Conclusions: Our analysis confirms the efficacy and tolerability of ibrutinib for the treatment of chronic lymphocytic leukemia. Patients older than 75 do significantly less well. Routine pretreatment cardiologic consultation does not improve outcomes and should not be considered part of standard pretreatment assessment without additional proof of its usefulness. Future investigations should aim at identifying predictive factors, mechanisms, and preventive strategies for reducing cardiotoxicity in chronic lymphocytic leukemia patients taking Bruton tyrosine kinase inhibitors. Full article
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16 pages, 576 KiB  
Article
The Prognostic Potential of Insulin-like Growth Factor-Binding Protein 1 for Cardiovascular Complications in Peripheral Artery Disease
by Ben Li, Farah Shaikh, Houssam Younes, Batool Abuhalimeh, Abdelrahman Zamzam, Rawand Abdin and Mohammad Qadura
J. Cardiovasc. Dev. Dis. 2025, 12(7), 253; https://doi.org/10.3390/jcdd12070253 - 1 Jul 2025
Viewed by 408
Abstract
Background/Objectives: Patients with peripheral artery disease (PAD) have a heightened risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and death. Despite this, limited progress has been made in identifying reliable biomarkers to prognosticate such outcomes. Circulating growth factors, known to [...] Read more.
Background/Objectives: Patients with peripheral artery disease (PAD) have a heightened risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and death. Despite this, limited progress has been made in identifying reliable biomarkers to prognosticate such outcomes. Circulating growth factors, known to influence endothelial function and the progression of atherosclerosis, may hold prognostic value in this context. The objective of this research was to evaluate a broad range of blood-based growth factors to investigate their potential as predictors of MACE in patients diagnosed with PAD. Methods: A total of 465 patients with PAD were enrolled in a prospective cohort study. Baseline plasma levels of five different growth factors were measured, and participants were monitored over a two-year period. The primary outcome was the occurrence of MACE within those two years. Comparative analysis of protein levels between patients who did and did not experience MACE was performed using the Mann–Whitney U test. To assess the individual prognostic significance of each protein for predicting MACE within two years, Cox proportional hazards regression was performed, adjusting for clinical and demographic factors including a history of coronary and cerebrovascular disease. Subgroup analysis was performed to assess the prognostic value of these proteins in females, who may be at higher risk of PAD-related adverse events. Net reclassification improvement (NRI), integrated discrimination improvement (IDI), and area under the receiver operating characteristic curve (AUROC) were calculated to assess the added value of significant biomarkers to model performance for predicting 2-year MACE when compared to using demographic/clinical features alone. Kaplan–Meier curves stratified by IGFBP-1 tertiles compared using log-rank tests and Cox proportional hazards analysis were used to assess 2-year MACE risk trajectory based on plasma protein levels. Results: The average participant age was 71 years (SD 10); 31.1% were female and 47.2% had diabetes. By the end of the two-year follow-up, 18.1% (n = 84) had experienced MACE. Of all proteins studied, only insulin-like growth factor-binding protein 1 (IGFBP-1) showed a significant elevation among patients who suffered MACE versus those who remained event-free (20.66 [SD 3.91] vs. 13.94 [SD 3.80] pg/mL; p = 0.012). IGFBP-1 remained a significant independent predictor of 2-year MACE occurrence in the multivariable Cox analysis (adjusted hazard ratio [HR] 1.57, 95% CI 1.21–1.97; p = 0.012). Subgroup analyses revealed that IGFBP-1 was significantly associated with 2-year MACE occurrence in both females (adjusted HR 1.52, 95% CI 1.16–1.97; p = 0.015) and males (adjusted HR 1.04, 95% CI 1.02–1.22; p = 0.045). Incorporating IGFBP-1 into the clinical risk prediction model significantly enhanced its predictive performance, with an increase in the AUROC from 0.73 (95% CI 0.71–0.75) to 0.79 (95% CI 0.77–0.81; p = 0.01), an NRI of 0.21 (95% CI 0.07–0.36; p = 0.014), and an IDI of 0.041 (95% CI 0.015–0.066; p = 0.008), highlighting the prognostic value of IGFBP-1. Kaplan–Meier analysis showed an increase in the cumulative incidence of 2-year MACE across IGFBP-1 tertiles. Patients in the highest IGFBP-1 tertile experienced a significantly higher event rate compared to those in the lowest tertile (log-rank p = 0.008). In the Cox proportional hazards analysis, the highest tertile of IGFBP-1 was associated with increased 2-year MACE risk compared to the lowest tertile (adjusted HR 1.81; 95% CI: 1.31–2.65; p = 0.001). Conclusions: Among the growth factors analyzed, IGFBP-1 emerged as the sole biomarker independently linked to the development of MACE over a two-year span in both female and male PAD patients. The addition of IGFBP-1 to clinical features significantly improved model predictive performance for 2-year MACE. Measuring IGFBP-1 levels may enhance risk stratification and guide the intensity of therapeutic interventions and referrals to cardiovascular specialists, ultimately supporting more personalized and effective management strategies for patients with PAD to reduce systemic vascular risk. Full article
(This article belongs to the Section Cardiovascular Clinical Research)
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16 pages, 2665 KiB  
Study Protocol
Usefulness of Respiratory Stability Time-Guided Management to Prevent Readmission of Chronic Heart Failure Patients at Home: A Multicenter, Single-Arm, Open-Label Clinical Study (ITMETHOD-HF-III)
by Teruhiko Imamura, Yasuhiro Akazawa, Shunsuke Saito, Yasushi Sakata, Shigeru Miyagawa, Tomomi Yamada, Hidetsugu Asanoi and Koichiro Kinugawa
J. Clin. Med. 2025, 14(13), 4653; https://doi.org/10.3390/jcm14134653 - 1 Jul 2025
Viewed by 355
Abstract
Background: Telemonitoring aimed at detecting subclinical heart failure and facilitating medication up-titration offers a promising approach to reducing heart failure hospitalizations. Our team has recently developed a non-invasive metric called “respiratory stability time (RST)”, which quantifies respiratory instability, a surrogate marker of [...] Read more.
Background: Telemonitoring aimed at detecting subclinical heart failure and facilitating medication up-titration offers a promising approach to reducing heart failure hospitalizations. Our team has recently developed a non-invasive metric called “respiratory stability time (RST)”, which quantifies respiratory instability, a surrogate marker of subclinical worsening heart failure. A decrease in RST below 20 s predicts the onset of worsening heart failure within 28 days. However, the clinical utility of RST-guided management in reducing mortality and heart failure hospitalizations remains uncertain. Methods: The Innovative Tele-Monitoring Environment To Halt Ongoing Deterioration of Heart Failure-III (ITMETHOD-HF-III) is a non-blinded, interventional, multicenter, single-arm study. Eighty heart failure patients with a history of at least two prior hospitalizations for heart failure will be enrolled. After validating the robustness of RST measurements, participants will be monitored for 1.5 years through daily RST measurements. Mandatory up-titration of heart failure medications will be started if RST values decrease below 20 s for two consecutive days or decrease progressively below 30 s over 10–90 days from RST values above 45 s maintained for over 1 month, irrespective of the presence of heart failure signs/symptoms. Medication adjustment will continue until RST exceeds 30 s. The study will compare a composite endpoint of heart failure hospitalization and cardiac death between the present RST-guided group and a historical control group from the ITMETHOD-HF-II trial, in which management was based on patients’ symptoms. Results: We anticipate that the precent ITMETHOD-HF-III study will demonstrate that mandatory, RST-guided heart failure management significantly reduces the incidence of the primary composite endpoint—heart failure hospitalization and cardiac death—compared with symptom-guided standard care in the historical control group (ITMETHOD-HF-II). Conclusions: The ITMETHOD-HF-III study aims to demonstrate the clinical efficacy of RST-guided management in reducing heart failure hospitalization rates and cardiac mortality by enabling early detection of subclinical heart failure and facilitating timely medication adjustments, irrespective of heart failure signs/symptoms. If successful, RST-guided management could establish a new standard for telemonitoring heart failure patients in outpatient settings. Full article
(This article belongs to the Special Issue Clinical Challenges in Heart Failure Management)
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13 pages, 1167 KiB  
Article
A New High Penetrant Intronic Pathogenic Variant Related to Long QT Syndrome Type 2
by Manuel Rodríguez-Junquera, Alberto Alén, Francisco González-Urbistondo, José Julián Rodríguez-Reguero, Bárbara Fernández, Rut Álvarez-Velasco, Daniel Vazquez-Coto, Lorena M. Vega-Prado, Pablo Avanzas, Eliecer Coto, Juan Gómez and Rebeca Lorca
J. Clin. Med. 2025, 14(13), 4646; https://doi.org/10.3390/jcm14134646 - 1 Jul 2025
Viewed by 370
Abstract
Background/Objectives: Long QT Syndrome type 2 (LQT2) is a cardiac channelopathy linked to pathogenic variants in the KCNH2 gene, which encodes the Kv11.1 potassium channel, essential for cardiac repolarization. Variants affecting splice sites disrupt potassium ion flow, prolong QT interval, and increase [...] Read more.
Background/Objectives: Long QT Syndrome type 2 (LQT2) is a cardiac channelopathy linked to pathogenic variants in the KCNH2 gene, which encodes the Kv11.1 potassium channel, essential for cardiac repolarization. Variants affecting splice sites disrupt potassium ion flow, prolong QT interval, and increase the risk of arrhythmias and sudden cardiac death (SCD). Understanding genotype–phenotype correlations is key, given the variability of clinical manifestations even within families sharing the same variant. We aimed to evaluate new pathogenic variants by analyzing genotype–phenotype correlations in informative families. Methods: Genetic and clinical assessments were performed on index cases and family members carrying KCNH2 pathogenic variants, referred for genetic testing between 2010 and June 2023. The next-generation sequencing (NGS) of 210 cardiovascular-related genes was conducted. Clinical data, including demographic details, family history, arrhythmic events, electrocardiographic parameters, and treatments, were collected. Results: Among 390 patients (152 probands) tested for LQTS, only 2 KCNH2 variants had over 5 carriers. The detailed clinical information of 22 carriers of this KCNH2 p.Ser261fs. has already been reported by our research group. Moreover, we identified 12 carriers of the KCNH2 c.77-2del variant, predicted to disrupt a splice site and not previously reported. Segregation analysis showed its high penetrance, supporting its classification as pathogenic. Conclusions: The newly identified KCNH2 c.77-2del variant is a pathogenic, as strongly supported by the segregation analysis. Our findings underscore the importance of further research into splice site variants to enhance clinical management and genetic counseling for affected families. Full article
(This article belongs to the Section Cardiology)
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15 pages, 285 KiB  
Article
A Quasi-Experimental Study: Social Support in Group Prenatal Care’s Impact on Postpartum Depression in Black and Hispanic Women
by Keisha A. Robinson, Tarnisha Ebony Hemphill and Robert O. Atlas
Int. J. Environ. Res. Public Health 2025, 22(7), 1046; https://doi.org/10.3390/ijerph22071046 - 30 Jun 2025
Viewed by 846
Abstract
Depression is a widespread mental health condition that affects millions of women globally. In the United States (U.S.), more than half of maternal mental health-related deaths occur during the postpartum period, making it the leading cause of mortality during this time. This urban [...] Read more.
Depression is a widespread mental health condition that affects millions of women globally. In the United States (U.S.), more than half of maternal mental health-related deaths occur during the postpartum period, making it the leading cause of mortality during this time. This urban U.S. single-site quasi-experimental study aimed to evaluate the effectiveness of social support integrated into group prenatal care as an intervention for postpartum depression. The study employed a dual methodological approach, combining prospective participant recruitment with a retrospective analysis of medical records. It compared the Edinburgh Postnatal Depression Scale (EPDS) scores from group prenatal care to those from traditional individualized prenatal care, specifically focusing on Black and Hispanic women. In all, 200 postpartum women participated in the study, comprising (n = 100) group prenatal care and (n = 100) traditional individualized care. Most participants were Black (97%), with an average age of 26.8 years (SD = 5.9). At six weeks postpartum, 97% of the participants underwent depression screening, which indicated a mean EPDS score of 3.79 (SD = 4.7). Among the participants, 25% exhibited mild to moderate postpartum depression, while 3% experienced severe depression. No significant differences were observed between the models of care in terms of total scores (T = 2.0, p = 0.46) or score ranges (χ2 = 5.8, p = 0.12). It is noteworthy that no severe cases of depression were identified within the group prenatal care model. Suggesting group prenatal care may still benefit Black and Hispanic women in urban areas with a history of anxiety or depression. Full article
(This article belongs to the Special Issue Improving the Quality of Maternity Care)
8 pages, 229 KiB  
Article
Predictive Factors for Recurrence of Choledocholithiasis After ERCP with Sphincterotomy in Benign Biliary Tract Disease: A Retrospective Study
by Mercedes Ibáñez-García, Juan Ramon Gómez-López, Jean Carlo Trujillo-Díaz, Pilar Concejo-Cutoli, Carlos Vaquero-Puerta and Juan Carlos Martín-del Olmo
Gastrointest. Disord. 2025, 7(3), 44; https://doi.org/10.3390/gidisord7030044 - 30 Jun 2025
Viewed by 395
Abstract
Objectives: To analyze the factors associated with recurrent choledocholithiasis following endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy (BS). Methods: A retrospective, observational, and analytical cohort study was conducted. Patients who underwent ERCP with BS for benign biliary pathology and were followed for a [...] Read more.
Objectives: To analyze the factors associated with recurrent choledocholithiasis following endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy (BS). Methods: A retrospective, observational, and analytical cohort study was conducted. Patients who underwent ERCP with BS for benign biliary pathology and were followed for a minimum of two years were included. Demographic and clinical data were collected, including the indication for the procedure, endoscopic findings, performance and timing of cholecystectomy (before or after ERCP), and the need for repeat procedures. Episodes of choledocholithiasis were defined as those occurring at least six months after the initial ERCP. Follow-up continued until patient death, loss of follow-up, or the conclusion of the study. Results: A total of 576 patients were included, with a mean age of 71 years and an average follow-up duration of 131 months. Sixty-nine cases of recurrent choledocholithiasis were documented (11.96%). Multivariate analysis identified the following predictive factors for recurrence: age over 50 years, bile duct dilation upon initial evaluation, history of biliary surgery, cytology sampling, placement of biliary stents, repeated ERCP, biliary diversion procedures, and cholecystectomy prior to the index ERCP. Conclusions: Biliary duct dilation, advanced age, and any previous manipulation of the biliary tree are associated with an increased risk of recurrent choledocholithiasis. Cholecystectomy performed after the initial ERCP was not associated with a reduced recurrence risk. Full article
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