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16 pages, 831 KB  
Article
Integrating the Neutrophil-to-Lymphocyte Ratio into a Clinicopathological Nomogram for Event-Free Survival Prediction in Cisplatin-Treated Muscle-Invasive Bladder Cancer
by Mariona Figols, Andrea González, Maria Fernandez-Saorín, Ana Bautista, Olatz Etxaniz, Ester Ruz, Jose Luis Gago, Daniela Gómez-Díaz, Juan Carlos Pardo, Marta Galí, Sergi Bernal, Cristina Camps, Lorena Rifa, Montserrat Domenech, Vicenç Ruiz de Porras, Anna Esteve and Albert Font
Cancers 2026, 18(13), 2054; https://doi.org/10.3390/cancers18132054 (registering DOI) - 24 Jun 2026
Abstract
Background/Objectives: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) is a standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC), yet baseline tools to refine prognostic stratification remain limited. We aimed to develop and internally validate a clinicopathological nomogram integrating the [...] Read more.
Background/Objectives: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) is a standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC), yet baseline tools to refine prognostic stratification remain limited. We aimed to develop and internally validate a clinicopathological nomogram integrating the neutrophil-to-lymphocyte ratio (NLR) to estimate event-free survival (EFS) in patients with MIBC treated with NAC. Methods: We retrospectively analyzed 210 patients with cT2–T4aN0–1M0 MIBC treated with cisplatin-based NAC at two Spanish institutions between 2010 and 2021. Candidate predictors included demographic, clinicopathological, and routine laboratory variables. A multivariable Cox model with backward selection based on the Akaike information criterion (AIC) was used to derive the final model, and internal validation was performed using 1000 bootstrap resamples. Results: Sex, age, prior non–muscle-invasive bladder cancer (NMIBC), and NLR were retained in the final nomogram. The model showed moderate discrimination, with a Harrell’s c-index of 0.60 and an optimism-corrected c-index of 0.58. The nomogram stratified patients into low-, intermediate-, and high-risk groups, with median EFS not reached, 47.5 months, and 18.0 months, respectively. High-risk patients also showed lower pathological complete response (pCR) rates. Conclusions: This exploratory nomogram integrates an accessible systemic inflammatory marker with baseline clinical variables to identify patients with poorer outcomes despite NAC. External validation in contemporary cohorts is warranted before clinical implementation. Full article
(This article belongs to the Special Issue Diagnosis and Therapy in Urothelial Cancer)
20 pages, 728 KB  
Article
Blood Phenylalanine Control in Paediatric and Adult Centres in the UK: Data from 2012–2018
by Alex Pinto, Catherine Ashmore, Jane Ash, Barbara Cochrane, Duncan Cole, Sarah Bailey, Clare Dale, Anne Daly, Charlotte Dawson, Sharon Evans, Sarah Firman, Suzanne Ford, Anne Grimsley, Diane Green, Tarekegn Geberhiwot, Sarah Howe, Inderdip Hunjan, Fatma Ilgaz, Richard Jackson, Nicola McStravick, Camille Newby, Natalia Oxley, Radha Ramachandran, Katie Rawlins, Louise Robertson, Danja Schulenburg-Brand, Kalpana Shah, Hugh Lemonde, Rachel Skeath, Allyson Terry, Gisela Wilcox, Alison Woodall, Karen Van Wyk, Júlio César Rocha and Anita MacDonaldadd Show full author list remove Hide full author list
Nutrients 2026, 18(13), 2069; https://doi.org/10.3390/nu18132069 (registering DOI) - 24 Jun 2026
Abstract
Background: Metabolic control in phenylketonuria (PKU) is known to deteriorate with age, but national-level data describing blood phenylalanine (Phe) control across the United Kingdom (UK) are limited. Objective: To characterise blood Phe control in individuals with PKU attending UK metabolic centres. Methods: Sixteen [...] Read more.
Background: Metabolic control in phenylketonuria (PKU) is known to deteriorate with age, but national-level data describing blood phenylalanine (Phe) control across the United Kingdom (UK) are limited. Objective: To characterise blood Phe control in individuals with PKU attending UK metabolic centres. Methods: Sixteen UK centres (nine paediatric, six adult, one mixed) retrospectively extracted blood Phe results collected between 2012 and 2018. Demographic, phenotypic and monitoring-related variables were analysed. Written consent for data collection was obtained from all patients or their caregivers. Results: Data were available for 871 individuals (55% female), of whom 744 (85%) were classified as follows: classical PKU, 75%, mild PKU, 22% and hyperphenylalaninaemia, 3%. Mean blood Phe concentrations were significantly higher in adults than children (491 ± 308 vs. 303 ± 199 µmol/L; p < 0.001), and the proportion of samples within target range declined steadily with age, from 78% in children <2 years to 36% in adults ≥41 years. Individuals with classical PKU had higher mean Phe concentrations and lower target attainment than those with HPA (386 vs. 300 µmol/L; 61% vs. 78%; p < 0.001), while mild PKU and HPA showed comparable control. Females generally demonstrated better metabolic control than males. More frequent dried blood spot sampling for blood Phe was strongly associated with improved metabolic control: weekly (254 ± 175 µmol/L; 82% within target), fortnightly (319 ± 207 µmol/L; 70%), monthly (397 ± 231 µmol/L; 61%), and less than monthly (624 ± 349 µmol/L; 44%). Nearly half of the blood Phe samples (47%) with recorded timing were taken in a non-fasting state. Conclusions: Achieving lifelong metabolic stability on a Phe-restricted diet alone remains challenging. These national data highlight the need for broader therapeutic options to support individuals with PKU across the lifespan. Full article
(This article belongs to the Special Issue Dietary Management for Patients with Inborn Errors of Metabolism)
12 pages, 422 KB  
Article
Perioperative Outcomes of Noncardiac Surgical and Interventional Procedures in Adults with Single-Ventricle Physiology: A Retrospective Cohort Study
by Montserrat Ribas-Ball, Laura González, Ekaterine Popova, Clara Bordes, Patricia Galan, Laura Villarino, Alfons Gómez, Maria Josefa Azpiroz, Marcos de Miguel, Laura Dos-Subirà and Miriam de Nadal
J. Clin. Med. 2026, 15(13), 4921; https://doi.org/10.3390/jcm15134921 (registering DOI) - 24 Jun 2026
Abstract
Background/Objectives: Adults with single-ventricle physiology (SVP) represent a growing population with complex cardiovascular conditions and an increasing need for noncardiac surgical and interventional procedures. However, perioperative outcomes in this group remain poorly characterized. This study aimed to provide a descriptive characteristic of perioperative [...] Read more.
Background/Objectives: Adults with single-ventricle physiology (SVP) represent a growing population with complex cardiovascular conditions and an increasing need for noncardiac surgical and interventional procedures. However, perioperative outcomes in this group remain poorly characterized. This study aimed to provide a descriptive characteristic of perioperative management, complications and mortality in adults with SVP undergoing noncardiac surgical and interventional procedures. Methods: We conducted a retrospective cohort study including all adult patients (≥18 years) with SVP who underwent noncardiac surgical and interventional procedures requiring anesthesia or sedation at a tertiary university hospital between 1 January 1995 and 30 November 2023. Demographic data, comorbidities, type of procedure and anesthetic technique were collected. Complications were defined as intraoperative or postoperative adverse events requiring intervention or associated with hemodynamic, respiratory, or cardiovascular instability. Primary outcomes were perioperative complications and all-cause mortality at 24 h, 30 days, and one year, with mortality reported at the patient level. Results: A total of 114 procedures were performed in 67 patients (mean age 32.3 ± 10.8 years). Most procedures were elective (78.9%) and minimally invasive, frequently performed under sedation, with or without local anesthesia (67.5%). Common comorbidities included arrhythmias (46.3%), liver disease (49.3%), and heart failure (17.9%). The overall complication rate was 6.1% (2.6% intraoperative, 3.5% postoperative). Mortality was 1.5% in 24 h, 2.9% in 30 days and 5.9% at one year. Most clinically relevant adverse events occurred in patients with earlier-stage palliation, advanced functional limitation or multiple comorbidities. Conclusions: Perioperative outcomes in adults with SVP undergoing noncardiac surgical and interventional procedures were acceptable when procedures were elective and managed in specialized settings. Risk remains heterogeneous and appears to be influenced by physiological status and stage of palliation. Full article
(This article belongs to the Section Cardiovascular Medicine)
14 pages, 5420 KB  
Article
Nectin-4 Expression in Muscle-Invasive Bladder Cancer Is Associated with Growth-Related and Inflammatory Signaling Pathways
by Sebastian Jersinovic, Marko Vukovic, Jörg Hennenlotter, Thomas Lütfrenk, Tilman Todenhöfer, Arnulf Stenzl, Igor Tsaur and Steffen Rausch
Int. J. Mol. Sci. 2026, 27(13), 5706; https://doi.org/10.3390/ijms27135706 (registering DOI) - 24 Jun 2026
Abstract
Nectin-4 has emerged as a clinically relevant target in muscle-invasive bladder cancer (MIBC), primarily because of its role in antibody–drug conjugate-based therapies. However, the broader biological context of Nectin-4 expression and its association with tumor-promoting signaling pathways in MIBC remain insufficiently characterized. In [...] Read more.
Nectin-4 has emerged as a clinically relevant target in muscle-invasive bladder cancer (MIBC), primarily because of its role in antibody–drug conjugate-based therapies. However, the broader biological context of Nectin-4 expression and its association with tumor-promoting signaling pathways in MIBC remain insufficiently characterized. In this single-institution study, Nectin-4 expression (H-score 0–300) was assessed by immunohistochemistry in two independent MIBC cohorts. Associations between Nectin-4 expression and key markers related to growth signaling, metabolic regulation, and inflammation were analyzed alongside clinicopathological characteristics. Nectin-4 expression was significantly higher in malignant tissue than in non-malignant tissue (p = 0.0016 and p = 0.0302, respectively). Nectin-4 expression was not associated with demographic or clinicopathological parameters; however, a trend toward lower expression in more advanced disease stages was observed. Significant positive correlations were identified between Nectin-4 expression and protein kinase B (p = 0.0004), cytoplasmic (p = 0.0115) and membranous somatostatin receptor 2 (p = 0.0125), insulin receptor substrate 1 (p = 0.03), and interleukin-1 receptor antagonist (IL-1RA; p = 0.0045). In contrast, a negative correlation was observed with the IL-1β/IL-1RA ratio (p = 0.0246). Although Nectin-4 expression was not significantly associated with cancer-specific or overall survival, a trend toward shorter relapse-free survival was observed in patients with lower Nectin-4 expression (p = 0.0531). In multivariate analysis, patient age, but not Nectin-4 expression, emerged as an independent prognostic factor. Although Nectin-4 expression does not appear to have independent prognostic value, its biological associations suggest that it reflects an integrated tumor-related signaling context. These findings support further investigation of Nectin-4 as part of rational, biology-driven therapeutic strategies in bladder cancer. Full article
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22 pages, 1457 KB  
Systematic Review
Open and Percutaneous Fixation of Traumatic Sacral Fracture–Dislocation with Spinopelvic Dissociation: Two Adolescent Cases and a Systematic Literature Review
by Angelo Carosini, Calogero Velluto, Maria Ilaria Borruto, Laura Scaramuzzo, Maurizio Genitiempo, Felice Minutillo, Giulio Maccauro and Luca Proietti
J. Clin. Med. 2026, 15(13), 4914; https://doi.org/10.3390/jcm15134914 (registering DOI) - 24 Jun 2026
Abstract
Background: Spinopelvic dissociation secondary to sacral fracture–dislocation is a rare but severe injury, most often resulting from high-energy trauma. Management remains challenging, particularly in adolescents, and the optimal choice between open and percutaneous fixation is still debated. Methods: We present two adolescent cases [...] Read more.
Background: Spinopelvic dissociation secondary to sacral fracture–dislocation is a rare but severe injury, most often resulting from high-energy trauma. Management remains challenging, particularly in adolescents, and the optimal choice between open and percutaneous fixation is still debated. Methods: We present two adolescent cases of traumatic sacral fracture–dislocation with spinopelvic dissociation, one treated with percutaneous fixation and one with open lumbopelvic stabilization both with the use of navigation. The systematic literature review included 29 published studies. Together with the present two-patient case series, the overall analysis comprised 30 studies/series and 739 patients. Data on demographics, mechanisms of injury, neurological involvement, treatment strategies, and outcomes were extracted and analyzed. Results: Case 1 (18 years) was managed with closed reduction and percutaneous fixation, achieving complete neurological and functional recovery at 6 months. Case 2 (14 years) underwent open reduction, decompression, and lumbopelvic fixation, with favorable radiological outcomes but residual sphincter dysfunction at follow-up. In the literature, the weighted mean age was 40.6 years (range 5–91), with 48.6% presenting neurological deficits, most frequently cauda equina syndrome. Surgical management was performed in nearly all cases, with mean time to fixation ranging from 3.6 to 8.6 days. Open techniques were predominantly used in patients with severe displacement or neurological compromise, whereas percutaneous fixation was associated with reduced surgical morbidity and satisfactory neurological recovery in selected patients. Permanent bladder and bowel dysfunction persisted in up to 33% of cases. Conclusions: Spinopelvic dissociation following sacral fracture–dislocation remains a rare and highly unstable injury with frequent neurological impairment. Early surgical stabilization may be beneficial when the patient’s clinical condition permits, and the choice between open and percutaneous fixation should be individualized according to fracture morphology, neurological status, and the need for direct decompression. Our adolescent cases highlight both the potential for complete recovery and the risk of residual dysfunction, reflecting the complexity of these injuries. Full article
12 pages, 487 KB  
Article
Prevalence of ABO Blood Groups and Their Relationship with Vascular Access Thrombosis and Mortality in Hemodialysis Patients
by Can Hüzmeli, Ayşe Şeker, Hatice Ortaç and Nurettin Yeral
Medicina 2026, 62(7), 1227; https://doi.org/10.3390/medicina62071227 (registering DOI) - 24 Jun 2026
Abstract
Background and Objectives: ABO and Rh blood group systems represent clinically relevant genetic polymorphisms with established associations beyond transfusion medicine, including thrombotic risk. We investigated the prevalence of ABO and Rh blood group phenotypes in hemodialysis patients and their associations with documented vascular [...] Read more.
Background and Objectives: ABO and Rh blood group systems represent clinically relevant genetic polymorphisms with established associations beyond transfusion medicine, including thrombotic risk. We investigated the prevalence of ABO and Rh blood group phenotypes in hemodialysis patients and their associations with documented vascular access thrombosis and all-cause mortality. Materials and Methods: This retrospective cohort study analyzed 3027 patients receiving maintenance hemodialysis in Hatay province, Türkiye, between January 2010 and April 2025. Data included ABO and Rh blood group determination, demographics, comorbidities, dialysis vintage, vascular access type, vascular access thrombosis events, and mortality. Multivariable binary logistic regression was used to identify independent factors associated with documented vascular access thrombosis. Multivariable Cox proportional hazards regression with vascular access thrombosis modeled as a time-dependent covariate was used to identify independent predictors of all-cause mortality. Results: Mean patient age was 63.95 ± 13.74 years; 58.3% were men. Blood group A was most prevalent (41.4%), followed by O (35.8%), B (15.9%), and AB (6.9%); 92.7% were Rh-positive. Documented vascular access thrombosis differed significantly by ABO group (p = 0.027), with the highest rate in group A (14.1%). In multivariable logistic regression, non-O blood group (OR 1.34, 95% CI 1.06–1.70; p = 0.014) and longer dialysis vintage (OR 1.01 per month, 95% CI 1.00–1.01; p < 0.001) were independently associated with documented vascular access thrombosis. In multivariable Cox regression, time-dependent vascular access thrombosis was independently associated with higher all-cause mortality (HR 1.33, 95% CI 1.12–1.59; p = 0.002), as were age (HR 1.02; p < 0.001), diabetes mellitus (HR 1.49; p < 0.001), coronary artery disease (HR 1.34; p < 0.001), and hypertension (HR 1.19; p < 0.001). Arteriovenous fistula was associated with lower mortality compared with temporary catheter (HR 0.46, 95% CI 0.37–0.58; p < 0.001). Blood group phenotype was not independently associated with all-cause mortality (all p > 0.5 vs. group O). Conclusions: In hemodialysis patients, non-O blood groups were modestly but independently associated with documented vascular access thrombosis, and vascular access thrombosis was independently associated with increased mortality when modeled as a time-dependent exposure. Blood group phenotype was not independently associated with mortality after adjustment for established risk factors. Blood group may contribute incrementally to vascular access risk awareness alongside established clinical risk factors, but its modest absolute risk difference limits standalone clinical utility. Full article
(This article belongs to the Special Issue End-Stage Kidney Disease (ESKD))
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11 pages, 488 KB  
Article
Prognostic Factors in Medullary Thyroid Cancer: A Real-World Study in a Referral Center
by Rosa Lauretta, Giulia Puliani, Irene Terrenato, Marta Bianchini, Marilda Mormando and Marialuisa Appetecchia
Biomedicines 2026, 14(7), 1431; https://doi.org/10.3390/biomedicines14071431 (registering DOI) - 24 Jun 2026
Abstract
Background: Several factors have been reported to influence the prognosis of medullary thyroid cancer (MTC). This study aimed to identify prognostic variables associated with progression-free survival (PFS) and overall survival (OS) in a cohort of patients treated at our institution. Patients and [...] Read more.
Background: Several factors have been reported to influence the prognosis of medullary thyroid cancer (MTC). This study aimed to identify prognostic variables associated with progression-free survival (PFS) and overall survival (OS) in a cohort of patients treated at our institution. Patients and Methods: We performed a retrospective analysis of 107 consecutive patients with histologically confirmed MTC who were followed for at least 12 months. Demographic, clinical, and pathological data were retrieved from medical records. The association between baseline variables and survival outcomes was evaluated using univariate Cox proportional hazards regression models. The study was approved by the local ethics committee. Results: The median age at diagnosis was 56 years (range, 10–80 years), and 63% of the patients were female. Germline REarranged during Transfection (RET) mutations were identified in 10% of cases. The median follow-up duration was 100 months (range, 12–464 months). At diagnosis, disease stages were distributed as follows: stage I, 52%; stage II, 12%; stage III, 17%; and stage IV, 19%. Female patients showed significantly longer PFS compared with males (Hazard Ratio (HR) = 0.41, 95% Confidence Interval (CI) (0.21–0.82); p = 0.012). Factors associated with PFS by Cox regression models were post-operative serum calcitonin (CT) values after 1 and 3 months of surgery (HR = 0.08, 95% CI (0.03–0.20); p < 0.001; HR = 0.03, 95% CI (0.01–0.11); p < 0.001, respectively), Tumor, Node, and Metastasis (TNM) stage III–IV (HR = 16.86, 95% CI (5.87–48.44); p < 0.001), presence of lymph nodes metastasis at diagnosis (HR = 9.6, 95% CI (3.59–25.63); p < 0.001), multifocal disease (HR = 2.37, 95% CI (1.07–5.28); p = 0.034) and capsular invasion (HR = 10.72, 95% CI (4.45–25.87); p < 0.001). Factors associated with OS by Cox regression models were age at diagnosis (HR = 1.07, 95% CI (1.01–1.12); p = 0.019) and TNM Classification of Malignant Tumours stage III-IV (HR = 6.69, 95% CI (1.42–31.62); p = 0.016). Although lymph node metastasis and capsular invasion were not significantly associated with overall survival (p = 0.178 and p = 0.094, respectively), both variables showed a trend toward an association with OS. Conclusions: The study confirmed that post-operative serum CT values, male sex, lymph nodes metastasis at diagnosis, TNM stage III and IV and capsular invasion were all associated with a lower PFS. Factors associated with OS were age at diagnosis, presence of lymph nodes metastasis, TNM stage III–IV and capsular invasion. Full article
(This article belongs to the Special Issue New Insights in Thyroid Cancer)
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13 pages, 685 KB  
Article
Resilience in Gastroparesis Is Not Associated with Symptom Severity or Healthcare Utilization: An Exploratory Pilot Analysis
by Elina Stoffel, John William Blackett, Alexa Choy, Dakota Ma, Wynette Almeida, Brad Kuo, Daniela Jodorkovsky and Sydney Pomenti
Gastrointest. Disord. 2026, 8(3), 31; https://doi.org/10.3390/gidisord8030031 (registering DOI) - 24 Jun 2026
Abstract
Background: Gastroparesis presents with frequently debilitating symptoms of nausea, vomiting, abdominal pain, bloating and early satiety, resulting in high healthcare utilization. Resilience, defined as the inherent and modifiable ability of an individual to adapt and recover positively to stress, is crucial for [...] Read more.
Background: Gastroparesis presents with frequently debilitating symptoms of nausea, vomiting, abdominal pain, bloating and early satiety, resulting in high healthcare utilization. Resilience, defined as the inherent and modifiable ability of an individual to adapt and recover positively to stress, is crucial for patients with chronic diseases but has not been studied in gastroparesis. We aimed to investigate if resilience correlates with acute care utilization and symptom severity in patients with gastroparesis. Methods: We conducted a single-center prospective observational study of patients with gastroparesis. Resilience was assessed using the 10-item Connor–Davidson Resilience scale (CD-RISC). Symptom severity was assessed through the Gastroparesis Cardinal Symptom Index (GCSI). Gastric emptying severity using scintigraphy or wireless motility capsule was categorized as mild, moderate, or severe based on consensus recommendations. Acute care utilization and hospitalizations in the last 12 months, comorbidities, medications, and demographic information were collected. Count outcomes were modeled using negative binomial regression due to overdispersion. Models were adjusted for age, sex, and symptom severity. Results: Among 40 consecutive patients (mean age 39 ± 16, 88% female), gastric emptying severity was mild in 35%, moderate in 15%, severe in 30%, and unknown in 20%. Mean resilience score was 29 ± 8 and mean GCSI was 2.96 ± 1.14. Gastroparesis symptoms did not correlate with gastric emptying severity (p = 0.5). In a linear regression model, no statistically significant correlation was observed between resilience and mean GCSI score in unadjusted or adjusted models. In negative binomial regression models, greater symptom severity was strongly associated with higher Emergency Department (ED)/urgent care visits (IRR 3.12; 95% CI 1.60–6.98; p < 0.001) and hospitalization rates (IRR 3.36; 95% CI 1.62–8.57, p = 0.006). Resilience was not a significant predictor of either (IRR 1.07; 0.95–1.22; p = 0.2 and IRR 1.02; 0.89–1.18; p = 0.7). Conclusions: Among patients with gastroparesis, no statistically significant association was detected between resilience and symptom severity, gastric emptying, or acute-care utilization after accounting for clinical and demographic factors. Symptom severity was the dominant predictor of ED visits and hospitalizations. These findings suggest that symptomatic disease burden, rather than objective gastric emptying severity, is the primary driver of acute healthcare utilization in this cohort. Full article
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17 pages, 824 KB  
Article
Real-World Administration Practices of Sapropterin in Paediatric and Adults with Phenylketonuria: Results from a United Kingdom Cross-Sectional Survey
by Martina Tosi, Sharon Evans, Alex Pinto, Richard Jackson, Catherine Ashmore, Anne Daly, Suzanne Ford, Sharon Buckley, Annabelle G. Skidmore and Anita MacDonald
Nutrients 2026, 18(13), 2057; https://doi.org/10.3390/nu18132057 (registering DOI) - 24 Jun 2026
Abstract
Background/Objectives: Sapropterin dihydrochloride is an established treatment option for individuals with phenylketonuria (PKU) who demonstrate responsiveness, but uncertainty persists regarding dosing frequency, timing relative to meals, the influence of dietary composition, and efficacy of different formulations. Despite widespread use in the UK, [...] Read more.
Background/Objectives: Sapropterin dihydrochloride is an established treatment option for individuals with phenylketonuria (PKU) who demonstrate responsiveness, but uncertainty persists regarding dosing frequency, timing relative to meals, the influence of dietary composition, and efficacy of different formulations. Despite widespread use in the UK, real-world administration behaviours have not previously been characterised. This study aimed to characterise sapropterin administration behaviours among people with PKU in the UK. Methods: A 31-item questionnaire was developed and disseminated via the National Society for Phenylketonuria website and social media channels. The survey captured demographic information, dosing schedules, formulation use, administration techniques, co-ingestion with food, and changes in natural protein tolerance following initiation of generic sapropterin. Results: 124 current sapropterin users completed the survey. Most respondents were caregivers of children or adolescents (68.5% aged 0–18 years). Once-daily dosing was most common (66.1%, n = 82), typically administered at breakfast, followed by twice-daily (32.3%, n = 40) and three-times-daily (1.6%, n = 2). Tablets were the predominant formulation (92.7%, n = 115); 50.4% (n = 58/115) swallowed tablets whole, while the remaining (49.6%, n = 57/115) crushed or dissolved them in water or juice. Nine respondents (7.3%, n = 9/124) used powder sachets. Most participants (75%, n = 93/124) took sapropterin with food, with both low-fat (36.6%, n = 34/93) and high-fat (26.9%, n = 24/93) meals reported. Over a third of participants (33.9%, n = 42/124) tolerated a natural protein intake >30 g/day when this was measured, and a further 15.3% (n = 19) were able to maintain a fully unrestricted protein intake without protein substitute supplementation. The magnitude of protein intake improvement was significantly greater among adults (p < 0.001), those with higher baseline natural protein intake (≥30 exchanges/day) (p < 0.001), and individuals who swallowed sapropterin tablets whole (p = 0.038). Although 71.8% (n = 89/124) were pleased with their increased natural protein allowance, many expressed a desire for further improvement. Conclusions: Substantial heterogeneity in dosing schedules, formulation handling, and co-ingestion practices highlights the absence of standardised guidance. These findings emphasise the need for clearer clinical recommendations to optimise treatment effectiveness and support consistent, equitable care. Full article
(This article belongs to the Section Nutrition and Metabolism)
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19 pages, 309 KB  
Article
Ultrasound-Based Staging and Its Impact on Clinical Management of Hepatic Hydatid Cysts in an Endemic Setting: A Cross-Sectional Study in Eastern Afghanistan
by Samiullah Sajjad, Parnpen Viriyavejakul, Dorn Watthanakulpanich, Sant Muangnoicharoen, Paron Dekumyoy, Wirongrong Chierakul, Chayasin Mansaguan and Prakaykaew Charunwatthana
Trop. Med. Infect. Dis. 2026, 11(7), 172; https://doi.org/10.3390/tropicalmed11070172 (registering DOI) - 24 Jun 2026
Abstract
Background: Hydatid disease, caused by Echinococcus granulosus, remains a significant public health concern in endemic regions. This study aimed to evaluate the role of ultrasound in the diagnosis, staging, and clinical management of liver hydatid cysts in the eastern city of Jalalabad, [...] Read more.
Background: Hydatid disease, caused by Echinococcus granulosus, remains a significant public health concern in endemic regions. This study aimed to evaluate the role of ultrasound in the diagnosis, staging, and clinical management of liver hydatid cysts in the eastern city of Jalalabad, Afghanistan. Method: A cross-sectional study was conducted between February and November 2024 among 159 patients diagnosed with liver hydatid cysts. Demographic, clinical, laboratory, and imaging data were collected. Cysts were classified according to the WHO Informal Working Group on Echinococcosis (WHO-IWGE) and Gharbi systems. Ultrasound findings were compared with computed tomography (CT), and their association with treatment decisions was assessed. Result: A total of 159 patients with liver hydatid cysts were included in the study. Among them, 91 (57.2%) were female, 80 (50.3%) were aged 20–39 years, and 128 (80.5%) resided in rural areas. Most patients presented with a single cyst (144/159, 90.6%), while multiple cysts were observed in 15 (9.4%). The majority of cysts measured 5–9.9 cm in diameter (43.4%), followed by 1–4.9 cm (42.1%) and ≥10 cm (14.5%). According to the WHO-IWGE classification, CE1 (25.8%) and CE4 (24.5%) were the most common stages, followed by CE2 (17.6%), CE3a (13.8%), CE3b (11.3%), and CE5 (7.0%). Common exposure-related factors included dog ownership, poor hygiene practices, and consumption of raw vegetables. Ultrasound accurately identified cyst stages and demonstrated a significant association between WHO-IWGE staging and treatment modality (χ2 = 63.56, p < 0.001). Almost perfect agreement was observed between ultrasound and CT for cyst classification (Cohen’s κ > 0.90), although CT provided additional anatomical information in selected complex cases. Conclusions: Ultrasound is an accessible, accurate, and reliable imaging modality for the diagnosis, staging, and management of liver hydatid cysts. In resource-limited settings, it serves as the primary imaging modality for guiding clinical decision-making, with CT reserved for complex or uncertain cases. Full article
29 pages, 3854 KB  
Article
Real-World Pharmacotherapy-Driven Cardiovascular Risk Prediction Using Interpretable Machine Learning and Jordanian EHR Data
by Said Moshawih, Lobna Gharaibeh, Islam Alfreahat and Abeer Jabra Shnoudeh
Med. Sci. 2026, 14(3), 343; https://doi.org/10.3390/medsci14030343 (registering DOI) - 24 Jun 2026
Abstract
Background: Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with over 75% of deaths occurring in low- and middle-income countries, where conventional risk models often demonstrate poor calibration and limited generalizability. Objective: This study aimed to develop an interpretable, pharmacotherapy-informed machine [...] Read more.
Background: Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with over 75% of deaths occurring in low- and middle-income countries, where conventional risk models often demonstrate poor calibration and limited generalizability. Objective: This study aimed to develop an interpretable, pharmacotherapy-informed machine learning model for cardiovascular risk prediction using national electronic health record (EHR) data from Jordan. Methods: A retrospective cohort study was conducted using approximately 600,000 individuals from the national Hakeem EHR system (2018–2022). Demographic, clinical, blood pressure, laboratory, and medication data were integrated to construct three datasets reflecting varying levels of feature completeness. Multiple machine learning models were benchmarked, followed by optimization, hybrid modeling, and probability calibration. Model interpretability was assessed using SHAP analysis. Results: The national cohort demonstrated a high cardiometabolic burden, with prevalence of hypertension (50.2%), hyperlipidemia (54.9%), and diabetes (47.9%). Antihypertensive and lipid-lowering therapies were more frequently used among CVD patients (56.9% and 49.6%, respectively). Treatment patterns were dominated by amlodipine (19.9%) and atorvastatin (74.4%). The final calibrated seed-bagged gradient boosting model achieved robust performance (ROC-AUC 0.844; PR-AUC 0.813) with consistent generalization across datasets. Key predictors included antihyperlipidemic therapy, systolic blood pressure variability, age, and sex. Conclusions: This study presents JoRisk, a calibrated and interpretable machine learning framework that integrates pharmacotherapy and clinical data for short-term cardiovascular risk prediction. The model demonstrates strong performance using routinely available EHR variables and offers a scalable decision-support tool for risk stratification in resource-constrained healthcare systems. Full article
(This article belongs to the Special Issue Artificial Intelligence (AI) in Cardiovascular Medicine)
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9 pages, 3073 KB  
Article
Trans-Gastric Versus Trans-Duodenal Endoscopic Ultrasound-Guided Gallbladder Drainage: Which Is the Optimal Access Route?
by Serena Stigliano, Claudia Marinaccio, Benedetto Neri, Nicolò Citterio, Marta Pettinelli, Dario Biasutto and Francesco Maria Di Matteo
Biomedicines 2026, 14(7), 1429; https://doi.org/10.3390/biomedicines14071429 (registering DOI) - 24 Jun 2026
Abstract
Background/Objectives: Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) with Lumen-Apposing Metal Stent (LAMS) is an established option for high-surgical-risk patients, with high technical and clinical success. Indications include acute cholecystitis and palliation of jaundice in malignant distal biliary obstruction (MDBO). Both trans-gastric and trans-duodenal [...] Read more.
Background/Objectives: Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) with Lumen-Apposing Metal Stent (LAMS) is an established option for high-surgical-risk patients, with high technical and clinical success. Indications include acute cholecystitis and palliation of jaundice in malignant distal biliary obstruction (MDBO). Both trans-gastric and trans-duodenal approaches are used, but the optimal route remains debated. The aim of the study was to compare trans-gastric and trans-duodenal access in terms of technical success, adverse events, readmissions, and reinterventions. Methods: We implemented a single-centre retrospective study of consecutive EUS-GBD procedures with LAMS at a tertiary endoscopy unit (January 2020–January 2026). Demographic, clinical, and procedural data were analyzed using appropriate statistical tests. Results: Seventy patients were included (51.4% male; mean age 77 ± 12 years). Indications were acute cholecystitis (64.3%) and MDBO (35.7%). Trans-gastric access was used in 48.5% of cases. A Hot-Axios LAMS was deployed in 77.2% of cases, mostly >10 mm. Technical success was achieved in 98.5% of cases. Naso-cystic drainage (NCD) was used through the LAMS in 47.1% of patients, while a double pig-tail plastic stent was used in 7.2% of patients. Adverse events were rare (1.4% misdeployment). LAMS obstruction occurred in 10% of patients, with reintervention required in 12.8% of patients. No differences were found between access routes in indication, technical success, LAMS type/size, or adjunctive drainage. However, trans-gastric access was associated with a higher reintervention rate (p = 0.01). Conclusions: EUS-GBD is a safe and effective procedure. While both approaches are comparable in most outcomes, the trans-gastric route may carry a higher risk of reintervention and should be avoided when alternative access is feasible. Full article
(This article belongs to the Special Issue Next-Generation Approaches to Hepatobiliary Disorders)
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15 pages, 1253 KB  
Article
Automated Extraction of Pulsatile Stiffness and Wall Asymmetry from Aortic M-Mode Ultrasound Images
by Cheong-Ah Lee, Dong-Guk Paeng and Joon Hyouk Choi
Bioengineering 2026, 13(7), 727; https://doi.org/10.3390/bioengineering13070727 (registering DOI) - 24 Jun 2026
Abstract
Conventional ultrasound-based assessment of aortic stiffness relies on two-point distension metrics using maximum and minimum vessel diameters within a cardiac cycle, which may not fully reflect time-resolved aortic wall dynamics. This retrospective pilot study investigated the feasibility and clinical relevance of a time-series-based [...] Read more.
Conventional ultrasound-based assessment of aortic stiffness relies on two-point distension metrics using maximum and minimum vessel diameters within a cardiac cycle, which may not fully reflect time-resolved aortic wall dynamics. This retrospective pilot study investigated the feasibility and clinical relevance of a time-series-based stiffness parameter, termed pulsatile stiffness-β, derived from automated segmentation of archived aortic M-mode ultrasound images. Seventy-nine cases with available aortic M-mode images were analyzed. Automated image processing was used to segment the anterior and posterior aortic walls and reconstruct diameter waveforms. Conventional stiffness-β, pulsatile stiffness-β, and wall asymmetry-related parameters were calculated and compared with demographic, tonometry-derived, hemodynamic, coronary burden, cardiovascular risk, and echocardiographic variables. Conventional and pulsatile stiffness-β were strongly correlated and showed directionally consistent associations with established vascular functional parameters, including systolic blood pressure, pulse pressure, augmentation pressure, age, and cardiovascular risk burden. Pulsatile stiffness-β demonstrated association patterns broadly comparable to conventional stiffness-β, suggesting its role as a waveform-informed extension rather than a superior alternative. Wall asymmetry-related parameters were associated with the Syntax score. Automated analysis of archived aortic M-mode images may provide feasible time-resolved vascular biomarkers for stiffness and wall motion assessment. Full article
(This article belongs to the Section Biosignal Processing)
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13 pages, 938 KB  
Article
Differential Binding and Neutralising Antibody Responses Across COVID-19 Severity in a Saudi Multicentre Cohort
by Mariam M. AlEissa, Nada Saleh, Ahdab A. Alsaieedi, Raghad A. AlQurashi, Esraa A. Hawsa, Muath ben Shaded, Amer M. Alshehri, Eyad Y. Abu Sarhan, Osamah T. Khojah, Walid A. Nouh, Sami S. Almudarra, Khaled I. AlAbdulkareem, Ghada Garaween, Maha Alzayer, Yusra Alyafee, Monera Alrukhayes, Reema Alduaiji, Fahad A. Almsned and Abdullah M. Assiri
Viruses 2026, 18(7), 696; https://doi.org/10.3390/v18070696 (registering DOI) - 24 Jun 2026
Abstract
Background: Humoral immune responses to SARS-CoV-2 are well documented, yet the immunopathogenic mechanisms distinguishing severe from critical disease remain incompletely defined, particularly in Middle Eastern populations. We investigated antibody responses across levels of clinical severity in a Saudi Arabian cohort. Methods: In this [...] Read more.
Background: Humoral immune responses to SARS-CoV-2 are well documented, yet the immunopathogenic mechanisms distinguishing severe from critical disease remain incompletely defined, particularly in Middle Eastern populations. We investigated antibody responses across levels of clinical severity in a Saudi Arabian cohort. Methods: In this multicentre study, we analysed 406 participants stratified into five clinical groups: controls, asymptomatic, mild, severe, and critically ill requiring intensive care unit (ICU) admission. SARS-CoV-2-specific IgG and IgM levels were quantified alongside surrogate ACE2-RBD neutralisation activity. Associations between humoral markers, demographic factors, comorbidities, and disease severity were assessed. Results: SARS-CoV-2-specific IgG and IgM levels differed significantly across disease severity groups (p < 0.001), with higher levels observed in groups with greater clinical severity. No significant difference in IgG or IgM levels was observed between the severe and ICU groups (IgG p = 0.384; IgM p = 0.768). While binding antibody levels were associated with severity, surrogate ACE2-RBD neutralising activity did not differ significantly across groups (p = 0.209). Increasing age (χ2 = 44.5) and the presence of comorbidities (χ2 = 31.9) were associated with more severe clinical categories, whereas sex was not. Conclusions: These findings suggest that antibody levels provide useful information about exposure and immune activation, but antibody quantity alone does not fully explain the transition from severe to critical disease. The results support interpreting serological measures alongside clinical factors such as age and chronic illness. Full article
(This article belongs to the Special Issue COVID-19 Complications and Co-Infections: 2nd Edition)
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21 pages, 906 KB  
Review
Alkaline Water and Muscle Health in Aging: A Systematic Evidence Map and Translational Appraisal of Human Evidence
by Tariq A. Alalwan, Giuseppe Mazzola, Lucia Chiesa, Mariangela Rondanelli and Simone Perna
J. Ageing Longev. 2026, 6(3), 49; https://doi.org/10.3390/jal6030049 (registering DOI) - 24 Jun 2026
Abstract
Alkaline water is increasingly marketed for musculoskeletal and recovery benefits, yet its relevance to healthy aging, sarcopenia prevention, and functional capacity in older adults remains largely unexplored. This systematic evidence map and translational appraisal examined whether the available comparative human evidence on alkaline [...] Read more.
Alkaline water is increasingly marketed for musculoskeletal and recovery benefits, yet its relevance to healthy aging, sarcopenia prevention, and functional capacity in older adults remains largely unexplored. This systematic evidence map and translational appraisal examined whether the available comparative human evidence on alkaline water is applicable to aging populations and longevity research. Following PRISMA guidance, PubMed and Scopus were searched from January 2005 to September 2025. Eligible studies were controlled or comparative observational human studies reporting muscle strength, physical performance, or recovery outcomes. Risk of bias was assessed using RoB 2, ROBINS-I, and JBI criteria; evidence certainty was judged narratively using GRADE-informed principles. Ten studies met the inclusion criteria. Most enrolled young athletic populations; only two had partial relevance to aging cohorts. Crucially, no study included participants aged 65 years or older or assessed primary sarcopenia-relevant endpoints such as appendicular lean mass, gait speed, or chair-rise performance; this total absence of data in the target demographic represents the central limitation of the current literature. Risk of bias ranged from some concerns to serious. The most consistent signals were short-term improvements in lactate clearance and perceived exertion in young male athletes. Evidence for strength, functional performance, and safety in older adults was absent or indirect. Current evidence, rated low to very low certainty for aging-relevant outcomes, does not support alkaline water as an evidence-based strategy for healthy aging or muscle preservation in older adults. Age-appropriate trials using EWGSOP2-aligned outcomes are urgently needed. Full article
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