Ahmad Kharoufeh

Background/Objectives: Pulmonary arterial hypertension (PAH) management is evolving beyond conventional vasoactive therapies toward strategies targeting pathways implicated in pulmonary vascular remodeling. Despite advances in combination therapy, substantial residual risk persists. The clinical introduction of sotatercept, targeting activin signaling, has expanded the therapeutic landscape. This narrative review critically evaluates the evidence supporting remodeling-directed treatment and examines how established recommendations, individualized therapeutic considerations, and investigational strategies can be distinguished within risk-guided PAH management. Methods: Clinical, translational, and mechanistic evidence was narratively synthesized, prioritizing randomized controlled trials, prospective investigations, major guidelines, and relevant mechanistic studies. Particular attention was given to differences in trial populations, endpoints, background treatment, safety, and evidence maturity. Results: Sotatercept has demonstrated incremental clinical benefits across functional, hemodynamic, and clinical-outcome measures in studied PAH populations, although trial heterogeneity limits indirect comparisons and long-term disease modification remains unproven. Other remodeling-directed approaches, including growth-factor inhibition, BMPR2 restoration, immune modulation, and metabolic targeting, remain investigational, with variable and frequently preliminary evidence. The proposed synthesis distinguishes guideline-supported therapeutic escalation from individualized clinical considerations and research hypotheses, emphasizing residual risk, treatment tolerability, and demonstrated incremental benefit. Conclusions: Remodeling-directed therapy expands the treatment options for PAH but does not replace established vasoactive treatment or risk-based escalation. Future priorities include defining optimal therapeutic sequencing, identifying responsive patient populations, and determining whether sustained clinical improvements translate into modification of disease progression.

Acute coronary syndromes (ACS) are biologically and clinically heterogeneous, with substantial variation in mechanisms of coronary instability, coronary anatomy, ischemic and bleeding risk, and residual cardiovascular risk. Although advances in imaging, risk stratification, and targeted therapies have expanded opportunities for individualized care, their clinical actionability remains uneven. This narrative review proposes a longitudinal precision-medicine framework integrating four interconnected domains—mechanism, anatomy, ischemic–bleeding risk, and residual biological risk—to examine how patient characterization can inform treatment selection and reassessment. Contemporary evidence on mechanistic phenotyping, coronary imaging, revascularization, antithrombotic therapy, and residual cardiovascular risk is critically synthesized, with particular emphasis on distinguishing strategies supported by randomized clinical-outcome evidence from those supported primarily by mechanistic, imaging, biomarker, or other surrogate endpoints. Mechanistic and imaging-based characterization can refine ACS phenotyping, while coronary anatomy and clinical characteristics inform revascularization decisions. Dynamic assessment of ischemic and bleeding risk supports individualized antithrombotic strategies, and lipid-related, inflammatory, thrombotic, and cardiometabolic phenotypes inform residual-risk assessment and secondary prevention. However, the evidence supporting phenotype-guided treatment remains heterogeneous. Several anatomy- and risk-informed strategies have demonstrated clinical benefit, whereas morphology-guided intervention, biomarker-directed treatment, molecular phenotyping, and artificial-intelligence-assisted decision support require further validation before routine implementation. The proposed framework distinguishes clinically actionable information from findings that remain primarily prognostic or hypothesis-generating. Diagnostic precision currently exceeds therapeutic precision in several areas of ACS care. A longitudinal framework integrating mechanism, anatomy, ischemic–bleeding risk, and residual biological risk may help connect patient phenotyping to evidence-based treatment decisions, identify where treatment-effect evidence remains insufficient, and support reassessment as clinical and biological risk evolves. Precision ACS care should therefore prioritize demonstrated clinical benefit rather than diagnostic sophistication alone.

Post-hemorrhagic hydrocephalus (PHH) is a serious neurological sequela of severe intraventricular hemorrhage (IVH) in premature infants and remains one of the leading indications for ventriculoperitoneal (VP) shunt placement. Evaluating possible VP shunt-related complications can be challenging because clinical manifestations are often nonspecific, neuroimaging may initially appear unchanged, and microbiological cultures may remain negative. We report the case of a 19-month-old male born at 28 weeks’ gestation who developed Grade IV germinal matrix/intraventricular hemorrhage with bilateral intraparenchymal extension, early periventricular cystic leukomalacia, and post-hemorrhagic communicating hydrocephalus requiring multiple cerebrospinal fluid diversion procedures culminating in long-term VP shunt dependence. His medical history was notable for recurrent neonatal meningitis, secondary epilepsy with previous episodes of status epilepticus, secondary adrenal insufficiency, and severe global developmental delay. He presented with fever, recurrent coffee-ground vomiting, abdominal distension, progressive lethargy, reduced responsiveness, and localized erythematous swelling over the cranial VP shunt reservoir, raising concern for possible shunt-related pathology. During hospitalization, he deteriorated with status epilepticus and respiratory failure, with clinical concern for increased intracranial pressure, requiring admission to the Pediatric Intensive Care Unit (PICU). Laboratory investigations demonstrated leukocytosis, elevated C-reactive protein, cerebrospinal fluid pleocytosis, markedly elevated CSF protein, and CSF glucose of 2.0 mmol/L, for which a paired serum glucose value was unavailable, while repeated blood, urine, wound, and CSF cultures remained negative. Initial computed tomography (CT) demonstrated no significant interval change in the chronic hydrocephalus despite progressive neurological deterioration; however, serial neuroimaging later revealed progressive bilateral extra-axial fluid collections with radiological features suggestive of an evolving subacute subdural hemorrhage. The patient was managed with empirical broad-spectrum intravenous antibiotics, aggressive seizure control, stress-dose corticosteroids, respiratory support, and continuous multidisciplinary monitoring. His neurological and respiratory status subsequently improved, and he returned to his pre-admission neurological baseline before discharge with planned further evaluation at a tertiary pediatric neurosurgical center. This case highlights the diagnostic uncertainty surrounding acute neurological deterioration in a child with shunt-dependent PHH. VP shunt-related infection or malfunction remained important but unconfirmed diagnostic considerations, alongside competing or potentially overlapping contributors including status epilepticus, evolving extra-axial collections, respiratory infection, and endocrine or metabolic decompensation. No single etiology was definitively established. The case emphasizes the importance of serial neurological assessment, consideration of alternative diagnoses, repeat neuroimaging, and multidisciplinary evaluation when initial investigations do not establish the cause of deterioration.

Background/Objectives: Recurrent urinary tract infection (rUTI) is common after menopause, but estrogen deficiency alone does not explain variation in recurrence, symptoms, and microbial profiles. This study aimed to synthesize evidence on the interactions among estrogen deficiency, urogenital microbial ecology, diabetes, obesity, microbial reservoirs, and anatomical, neurological, and functional modifiers of postmenopausal rUTI susceptibility. Methods: PubMed and Scopus were searched for original studies published from 1 January 2021 to 15 June 2026. A structured narrative synthesis included 62 original reports comprising clinical interventions, observational cohorts, microbiome and multi-omic studies, and cellular and animal experiments. Evidence was interpreted according to study design, population relevance, and biological directness. Results: Menopause was associated with reduced Lactobacillus dominance, higher vaginal pH, and altered vaginal or urinary communities, although findings were heterogeneous. Vaginal estrogen reduced recurrence and improved the local urogenital environment, but microbiome restoration is not established as its sole mechanism. Gut, rectal, vaginal, urinary, and bladder-wall reservoirs may contribute to persistence or repeated exposure. Diabetes was linked to dysbiosis and impaired urothelial defence, whereas obesity evidence remained less direct. Pelvic organ prolapse with incomplete emptying, elevated postvoid residual urine, age-related detrusor dysfunction, stroke, immobility, functional dependence, incontinence, and catheter exposure may further modify susceptibility. Conclusions: Postmenopausal rUTI is multifactorial. The urogenital microbiome–metabolic interface is a useful integrative framework, but not a validated causal or diagnostic model. Vaginal estrogen, urine culture, metabolic and bladder-function assessment, and antimicrobial stewardship remain the clinical foundation; microbiome-directed strategies require prospective validation.

Background/Objectives: Post-hemorrhagic hydrocephalus (PHH) is a major complication of extreme prematurity associated with significant neurodevelopmental morbidity. Although post-hemorrhagic ventricular dilatation (PHVD) is a recognized consequence of intraventricular hemorrhage (IVH), progression from an apparently low-grade IVH to severe shunt-dependent disease with imaging features suggestive—but not diagnostic—of a non-communicating hydrocephalus pattern is uncommon and presents important diagnostic and management challenges. We report such a case. Case Presentation: A male infant born at 26 weeks’ gestation developed an initially documented Grade II intraventricular hemorrhage that subsequently evolved into progressive post-hemorrhagic ventricular dilatation. Serial cranial ultrasonography demonstrated progressive ventriculomegaly, later confirmed by computed tomography showing marked dilatation of the lateral and third ventricles with severe cortical mantle thinning and a relatively preserved fourth ventricle, raising suspicion of a non-communicating hydrocephalus pattern. Clinical deterioration with progressive macrocephaly and neurological manifestations necessitated temporizing ventricular cerebrospinal fluid drainage, followed by ventriculoperitoneal shunt placement after stabilization and management of secondary complications. Management throughout the clinical course relied on serial neuroimaging, multidisciplinary decision-making, and individualized neurosurgical intervention. Conclusions: This case illustrates that an apparently low-grade neonatal intraventricular hemorrhage may evolve into severe shunt-dependent PHVD and emphasizes the importance of serial neuroimaging surveillance, objective assessment of ventricular progression, and cautious interpretation of imaging findings suggestive—but not diagnostic—of a non-communicating hydrocephalus pattern. It further highlights the diagnostic and therapeutic challenges encountered when atypical radiological evolution complicates the management of PHVD in extremely premature infants.

Pediatric drug therapy remains fundamentally challenged by profound interindividual variability driven by dynamic development, genetic, and environmental factors. Although dosing strategies based on age, body weight, or body surface area remain important starting points in pediatric pharmacotherapy, they may not fully capture ontogeny-dependent variability in drug disposition and response. Consequently, clinically relevant differences in efficacy and toxicity may still occur among children receiving similar weight-adjusted doses. Pharmacogenomics offers a promising framework for individualized therapy; however, its clinical translation in pediatrics is limited by developmental variability in gene expression and enzyme activity. Emerging evidence highlights the pivotal role of epigenetic regulation, including DNA methylation, histone modifications, and microRNAs, in modulating pharmacogenetic expression across developmental stages, thereby reshaping drug response trajectories. Concurrently, advances in artificial intelligence and next-generation sequencing enable integration of multidimensional datasets, facilitating predictive modeling of drug efficacy and toxicity. This narrative review provides a comprehensive synthesis of developmental pharmacology, pharmacogenomics, and epigenetic mechanisms, while critically evaluating current translational gaps and implementation challenges. Importantly, it proposes an integrative precision framework that incorporates genetic, epigenetic, and computational insights to optimize pediatric pharmacotherapy. By bridging mechanistic biology with emerging digital health technologies, this work advances a paradigm shift from empirical prescribing toward predictive, adaptive, and individualized therapeutic strategies. The proposed approach holds significant potential to enhance clinical outcomes, minimize adverse effects, and accelerate the realization of precision medicine in pediatric populations.

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for the management of obesity and type 2 diabetes, particularly among women of reproductive age. Emerging evidence suggests potential effects on ovulation, fertility, and pregnancy outcomes. This narrative review aims to synthesize current evidence on the reproductive safety of GLP-1RAs, with a focus on their implications for conception, unintended pregnancy, and maternal–fetal outcomes. Methods: A narrative literature review was conducted using PubMed and relevant bibliographic sources to identify studies published between 2020 and 2025. The search included clinical trials, observational studies, registry data, case reports, and selected preclinical evidence. Studies addressing reproductive outcomes, including ovulation, fertility, pregnancy exposure, and fetal safety, were included. Evidence was synthesized descriptively in accordance with recommended approaches for narrative reviews. Results: Available evidence indicates that GLP-1RAs may improve ovulatory function and menstrual regularity, particularly in women with obesity or polycystic ovary syndrome, potentially increasing the likelihood of conception. However, human data on pregnancy exposure remain limited. While current evidence does not consistently demonstrate a strong teratogenic signal, findings are based on small samples and heterogeneous study designs. Concerns persist regarding unintended pregnancies due to improved fertility and the absence of robust safety data during early gestation. Conclusions: GLP-1RAs present a complex clinical scenario in women of reproductive age, with potential benefits for metabolic and reproductive health but uncertain safety during pregnancy. Clinicians should exercise caution, provide appropriate contraceptive counseling, and carefully weigh the risks and benefits when prescribing these agents. Further large-scale, prospective studies are needed to clarify reproductive safety and inform evidence-based clinical guidelines.