Background Sickle-cell trait (SCT) is historically regarded as a benign carrier state, although emerging evidence from athletic and military cohorts suggests increased vulnerability during physiological stress. In this study, we aimed to identify the incidence of acute renal and hemodynamic complications in adolescent and younger adult patients with SCT or sickle-cell disease (SCD) and compare these risks against propensity-matched controls from the general non-sickle-cell population. Methods A retrospective analysis of the TriNetX global network was performed. Patients aged 13-40 years with SCD or SCT were identified and propensity-score matched to non-sickle-cell controls based on age, sex, race, comorbidities, and medication use. Univariate analyses and Kaplan-Meier survival analysis assessed relative risk and time-to-event for rhabdomyolysis, heat-related illness, acute kidney failure, dehydration, electrolyte imbalance, syncope/collapse, and hemodynamic shock within five years. Subgroup analysis of differences in outcomes between SCD and SCT patients was performed. Results A total of 24,178 patients remained per cohort (SCD/SCT and no SCD/SCT) after matching. Compared to controls, the sickle-cell cohort exhibited significantly higher risks of dehydration (RR = 1.62, 95% CI 1.48-1.77), acute kidney failure (RR = 1.76, 95% CI 1.56-1.98), electrolyte imbalance (RR = 1.66, 95% CI 1.55-1.78), and hypotension/volume-depletion shock (RR = 1.71, 95% CI 1.47-1.99) (all P < 0.001). In subgroup analysis, SCD showed higher risk than SCT for most outcomes, but they experienced less syncope/collapse (RR = 0.74, 95% CI 0.64-0.85, P < 0.001). Conclusion Adolescents and young adults with sickle-cell hemoglobinopathies face significant renal and hemodynamic vulnerabilities. Higher collapse incidence in SCT suggests unique susceptibility to acute hemodynamic failure. These findings have generated hypotheses that are worth prospective investigations, including the development of universal-precaution protocols and monitoring key subclinical biomarkers, which might help identify patients undergoing significant physiological strain before a clinical crisis develops. However, further prospective research incorporating detailed laboratory data and extended observation periods is necessary to determine if such strategies can be effectively translated into evidence-based care for the wider young-adult sickle-cell population.

Sickle cell disease (SCD) has long been associated with high childhood mortality and reduced life expectancy; however, advances in newborn screening, disease-modifying therapies, and comprehensive care have substantially improved survival. As increasing numbers of women with SCD reach midlife, new challenges are emerging that extend beyond the traditional focus on fertility and pregnancy. Despite growing recognition of reproductive health issues in SCD, menopause remains an underexplored and underrecognized phase of the disease trajectory. In this Perspective, we propose a lifespan framework for women's health in SCD that extends from menarche through menopause and healthy aging. We discuss how the underlying pathophysiology of SCD-including chronic hemolysis, inflammation, endothelial dysfunction, and progressive organ injury-intersects with reproductive transitions across the female life course. We highlight emerging evidence suggesting earlier menopause in women with SCD and examine the potential implications for pain burden, cognitive health, bone health, cardiovascular risk, iron overload, and quality of life. We further explore how symptom overlap between menopause and SCD may contribute to underdiagnosis and undertreatment during midlife. At the same time, we highlight the role of protective factors-including comprehensive multidisciplinary care, the development and evaluation of menopause-specific interventions through dedicated clinical trials in individuals with SCD, reproductive health services, and coordinated lifespan care models-in supporting healthy aging and improving long-term outcomes. Finally, we argue that menopause should be recognized as a critical component of comprehensive SCD care and research. Integrating reproductive aging into clinical practice, research agendas, and health policy represents an important opportunity to improve lifelong health outcomes, strengthen women-centered care, and advance health equity for women living with SCD worldwide.

Cellular transport homeostasis evolved as a universal strategy linking the dynamic interactions between membrane transport, metabolism and biosynthesis in all cells. The entangled nature of these interactions, together with the effects from additional processes influencing homeostatic variables generate complexities that render intuition an unreliable interpreter and predictor of cell responses often prompting for modelling help. The main variables in transport homeostasis are membrane potentials, cell volume, ion and neutral solute fluxes through active and passive membrane transporters, cytoplasmic amounts and concentrations of soluble ions and neutral solutes, charge and concentrations of impermeant cytoplasmic solutes, charge and osmotic coefficient of cytoplasmic proteins, and cytoplasmic H[+], Ca[2+] and Mg[2+] buffering. Models of cellular transport homeostasis developed to explain puzzling, unexpected or conflicting observations in epithelia, red blood cells, malaria-infected red blood cells, reticulocytes, sickle cells, and plant guard cells proved essential for explaining underlying mechanisms in many experimental, physiological and pathological contexts and for elucidating conflicts greatly expanding our knowledge of the cell systems investigated thus far. The transport homeostasis loop is an ancient circuit that preserves cellular integrity. In this cycle, metabolic ATP powers families of membrane pumps that sustain ionic gradients across plasma membranes. These gradients act as secondary sources of energy for the passive transport of ions through channels and through ion-coupled solute carriers. These, in turn, supply the substrates for metabolic ATP production and for the biosynthesis of proteins, lipids, RNA and DNA that replace decayed membrane transporters, closing the transport homeostasis loop. This review outlines the foundational principles applied when developing models of this dynamic circuit and of the achievements resulting from their application in different cell types.

As survival for people with sickle cell disease (SCD) improves, fertility and family-building have become increasing priorities. This shift is especially important with the broader use of disease-modifying treatments that impact fertility. This qualitative study assessed pediatric hematologists' perspectives and practices regarding adolescents with SCD who may have fertility and family-building concerns. We interviewed 20 hematology providers about their roles, perceived barriers and facilitators, and recommendations for reproductive healthcare for adolescents with SCD. Ten participants (n = 5 men; n = 5 women; n = 5 within 5 years post-fellowship) specifically discussed fertility and family-building. We transcribed the interviews and coded them using applied thematic analysis. Three major themes emerged: the impact of disease-modifying, curative, and transformative therapies; patient-level factors that influence the timing and scope of fertility discussions; and the importance of multidisciplinary collaboration. Participants described uncertainty about the evidence surrounding fertility risks of treatments and the need to balance these with health benefits, patient age, and their care journey. Conversations about fertility and family-building in SCD are nuanced and benefit from multidisciplinary expertise. Future work should create standardized, age-based counseling and train clinic teams to address fertility concerns among adolescents with SCD.

Sickle cell disease (SCD) in India is often linked to the Arab-Indian haplotype, characterized by elevated fetal hemoglobin (HbF) levels and a relatively mild phenotype. However, data on genetic heterogeneity and genotype-phenotype correlations in Eastern India remain limited. This hospital-based cross-sectional study at Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, included 204 participants: 94 with SCD, 80 with sickle cell trait, and 30 healthy controls. Clinical, hematological, and socio-demographic data were analyzed. Among SCD patients (57 males, 37 females; mean age 24.2 years), 85.1% had a monthly household income ≤ ₹10,000, and 55.3% reported consanguinity. Geospatial mapping revealed clustering in North 24 Parganas, South 24 Parganas, and Kolkata. The predominant genotype was HbS-β thalassemia (62.8%). The median values for hemoglobin, HbF, platelet count, and leukocyte count were 8.7 g/dL, 17.4%, 214 × 10[9]/L, and 8.8 × 10[9]/L, respectively. HbF expression showed marked inter-individual variability, ranging from 7.7% to 49.6%. HbF levels showed a significant inverse correlation with leukocyte count (ρ=-0.733, p < 0.001), annual transfusion frequency (r=-0.387, 95% CI [-0.546, -0.200], p < 0.001), and vaso-occlusive crisis (VOC) frequency (r=-0.364, 95% CI [-0.528, -0.175], p < 0.001). In conclusion, SCD in West Bengal shows marked genetic and clinical heterogeneity, with HbS-β thalassemia as the predominant genotype. Higher HbF levels were associated with lower leukocyte counts, fewer transfusions, and fewer VOCs, supporting its role as a disease modifier. However, persistent variability suggests additional genetic and environmental influences, highlighting the need for region-specific screening and individualized management.

Gene therapy for individuals living with sickle cell disease is a transformative therapy, ameliorating many of its severe symptoms. Nevertheless, ex vivo administration of gene therapy coupled with sickle cell disease specific obstacles, complicate and limit widespread adoption. In this review, we discuss current strategies to develop in vivo gene delivery technologies, highlighting different approaches and their potential benefits and limitations in the context of sickle cell disease. Additionally, we examine editing challenges and outline how in vivo gene editing may be evaluated for therapeutic benefit.