Search Results (1,554)

Cutaneous graft-versus-host disease (GVHD) is a common complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). Despite established guidelines, discrepancies persist between clinical trial evidence and real-world practice, particularly for newer agents such as ruxolitinib. To characterize the phenotypic spectrum of cutaneous GVHD, evaluate real-world treatment strategies—with a specific focus on systemic and topical ruxolitinib—and assess adherence to national and international guidelines, we conducted a retrospective observational study of patients undergoing allo-HSCT between 2015 and 2025 who were referred to a dedicated dermato-haematology clinic. Clinical, histological, and therapeutic data were collected. Cutaneous manifestations were classified according to National Institutes of Health (NIH) and Italian Group for Blood and Marrow Transplantation (GITMO) criteria. Of 62 transplanted patients, 44 (71%) developed GVHD, with the skin as the most frequently involved organ. Acute GVHD predominantly presented with maculopapular eruptions, whereas chronic GVHD showed heterogeneous phenotypes, including sclerotic variants. First-line management was largely guideline-concordant. Systemic ruxolitinib was administered to 3% of patients in the aGVHD group and 3% in the cGVHD group. Steroid-refractory and steroid-dependent status was not systematically recorded; therefore, treatment eligibility could not be reliably determined, and the observed frequencies should not be interpreted as evidence of underuse. Topical ruxolitinib was not used and remains investigational for cutaneous GVHD. Interpretation should also consider that the study period encompassed changes in regulatory approval, reimbursement, and access to targeted therapies. Structured multidisciplinary assessment may support the management of complex cutaneous GVHD, although its effects on treatment decisions and patient outcomes require prospective evaluation. Full article

Nutritional deterioration in adults with acute myeloid leukemia (AML) may be present at diagnosis and may evolve rapidly during intensive chemotherapy, lower-intensity treatment, and allogeneic hematopoietic cell transplantation (allo-HCT). This structured narrative review critically examines nutritional screening and diagnostic instruments, anthropometry and body composition, laboratory-derived composite indices, and objective physical-function measures. PubMed was searched for publications from 1 January 2015 through 13 July 2026; Google Scholar and reference lists were used foradditional citation searching. Of 292 records screened, 52 full-text reports were assessed and 34 empirical studies were included. Methodological limitations were appraised with the 2018 Mixed Methods Appraisal Tool. Evidence was heterogeneous and predominantly observational. PG-SGA and NRS-2002 identified nutritional risk and nutrition-impact symptoms, but their classifications were not interchangeable with GLIM diagnosis, body-composition phenotyping, or prognostic indices. BMI alone did not capture muscle depletion. CT, quantitative CT, BIA-derived phase angle, skeletal muscle indices, and repeated anthropometry detected clinically relevant changes, although thresholds varied and fluid shifts may bias BIA. Albumin-based indices, including CONUT, sCONUT, NRI, GNRI, PNI, and the C-reactive protein/albumin ratio, were associated with outcomes in several retrospective cohorts, but largely reflect inflammation, disease burden, and treatment effects as well as nutrition; no head-to-head evidence establishes superiority. SPPB, gait speed, walking tests, chair stands, and grip strength provided prognostic information in selected older and transplant cohorts, including patients treated with hypomethylating agents plus venetoclax. The evidence supports repeated, multimodal assessment, while remaining insufficient to prove that any single tool or tool-guided intervention improves survival. Future studies require standardized definitions, sex-stratified validation, contemporary treatment cohorts, and trials integrating nutrition, symptom control, and exercise. Full article

Krabbe disease is an autosomal recessive leukodystrophy caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC), responsible for the degradation of galactolipids, resulting in toxic psychosine accumulation and progressive demyelination of the central and peripheral nervous systems. Newborn screening (NBS) has increased recognition of later-onset Krabbe disease, although interpretation of complex GALC genotypes remains challenging, particularly in the presence of “pseudodeficiency” and modifier alleles. In this case report, we describe a child with late-infantile Krabbe disease identified through NBS with markedly reduced GALC activity and a homozygous GALC haplotype containing c.956A>G (p.Tyr319Cys; Y319C) and c.1685T>C (p.Ile562Thr; I562T), in addition to other benign variants. Retrospective analysis of the newborn screening specimen demonstrated mild psychosine elevation. Despite preserved neurodevelopment, longitudinal surveillance demonstrated progressive cerebral white matter abnormalities by 3 years and 9 months of age and psychosine elevation in erythrocytes (14 pmol/g Hb; controls < 5), prompting umbilical cord blood transplantation (UCBT). Following transplantation, GALC enzyme activity normalized, psychosine levels decreased, and serial neuroimaging demonstrated radiographic stability without neurologic regression at last follow-up (9 years old). This case expands the phenotypic spectrum associated with homozygosity for the p.Tyr319Cys variant and highlights the role of p.Ile562Thr in amplifying the pathogenic potential when in cis with p.Tyr319Cys. This GALC haplotype illustrates how “pseudodeficiency” and modifier alleles may collectively influence biochemical, radiologic, and clinical disease expression. These findings emphasize the importance of integrating genotype, psychosine, enzyme activity, and longitudinal neuroimaging when evaluating infants with NBS results positive for Krabbe disease. Full article

Human cytomegalovirus (CMV) remains a significant infectious complication after kidney transplantation, reflecting gaps in the understanding of the molecular and immunological mechanisms regulating the transition from latency to productive infection. Following primary infection, CMV establishes lifelong latency in hematopoietic and myeloid lineage cells, maintained by viral chromatin repression and robust CMV-specific immune surveillance. CMV reactivation is associated with graft dysfunction, increased risk of rejection, opportunistic infections, and reduced patient survival. In kidney transplantation, CMV reactivation is driven by the interplay between tissue injury, inflammation, and immunosuppression. Ischemia–reperfusion injury and peri-operative stress produce reactive oxygen species, DNA damage, and pro-inflammatory cytokines (e.g., TNF-α, IL-6), which activate transcription factors such as NF-κB and AP-1. These factors regulate the CMV major immediate-early promoter (MIEP), thereby triggering lytic viral gene expression. At the same time, immunosuppressive therapies impair antiviral immune surveillance and, in some cases, induce cytokine release, potentially contributing to the pro-inflammatory environment that favors viral reactivation. In this review, we summarize current molecular and immunologic mechanisms governing CMV latency and reactivation with a focus on how immunosuppressive strategies and injury-associated pathways converge to promote CMV reactivation. We also discuss implications of risk stratification and the development of targeted therapeutic strategies to prevent CMV reactivation in kidney transplant recipients (KTRs). Full article

Background: Hematologic malignancies (HMs) represent a growing global health burden, and HSCT remains a cornerstone of treatment for many HMs. Despite improvements in survival, transplantation-related physical deconditioning is a persistent clinical challenge, and evidence supporting structured inpatient exercise interventions is scarce. Objectives: To evaluate the effects of a self-directed aerobic exercise program on a cycle ergometer in inpatients under isolation precautions related to HSCT. Methods: In this single-center prospective, non-randomized controlled interventional study, 73 patients were enrolled in an intervention group (n = 43) performing daily aerobic exercise on a cycle ergometer, or a control group (n = 30) receiving standard care. Physical performance was assessed at baseline and at discharge using the 6-min walk test (6 MWT), Timed Up and Go test (TUG), and 30-s chair stand test (30 s-CST). Results: Significant group-by-time interactions were observed for the TUG (F(1,71) = 10.35; p = 0.001; ηp² = 0.13) and the 30 s-CST (F(1,71) = 21.61; p < 0.0001; ηp² = 0.23). No significant interaction was detected for the 6 MWT (F(1,71) = 2.01; p = 0.16; ηp² = 0.03), although the decline in walking distance was smaller in the intervention group than in the control group (−4.1% vs. −10.5%). Post hoc analyses demonstrated significant within-group deterioration only in the control group. Conclusions: Self-directed aerobic exercise during inpatient isolation may mitigate physical deconditioning in HSCT recipients, supporting its integration into routine care. Full article

Background/Objectives: CAR T-cell therapy is a highly efficacious therapy option for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), but its widespread use is currently limited by safety concerns and high healthcare costs. Methods: We evaluated 66 patients with R/R LBCL treated with tisagenlecleucel or axicabtagene ciloleucel between 2016 and 2022 at a single institution to identify factors associated with increased healthcare utilization. Results: The median age of our cohort was 59.5 years, with 22.7% over the age of 70. The median length of stay (LOS) during the initial hospitalization was 12 days (range, 7–62 days). Longer initial hospital LOS was linked to higher age-adjusted HCT-CI score (IRR 1.08; 95% CI, 1.01 to 1.15; p = 0.0203), thrombocytopenia grade 3–4 (IRR 1.32; 95% CI, 1.07 to 1.63; p = 0.0091), and first ICU admission (IRR 1.81; 95% CI, 1.37 to 2.38; p < 0.00001). Thirty- and 90-day readmission rates post-discharge after receiving CAR T-cell therapy were 21.2% and 28.8%, respectively. Multiple readmissions within 90 days after initial hospital discharge were observed in 15% of patients. Longer 30-day readmission LOS was linked to initial hospital LOS (IRR 1.23; 95% CI, 1.11 to 1.35; p < 0.0001) but outpatient follow-up was associated with shorter 30-day readmission LOS (IRR 0.43; 95% CI, 0.26–0.69; p = 0.0005). Factors associated with longer 90-day readmission LOS included a greater number of ER visits within 60 days of CAR T-cell therapy (IRR 3.10; 95% CI, 2.15–4.46), prior 30-day readmission LOS (IRR 1.35; 95% CI, 1.14–1.60), and SUVmax at Day 30 (IRR 1.06; 95% CI, 1.03–1.09) (all p-values < 0.0001). Conclusions: Our findings identify key clinical and utilization variables associated with initial and repeat hospitalizations post-CAR T-cell therapy, emphasizing the need for targeted interventions to reduce readmissions and optimize post-discharge care. Full article

Multiple myeloma (MM) is a malignant plasma cell disorder and one of the most common tumors of lymphoid origin. In the process of oncogenesis, there is a significant change in the immune balance in the body, which leads to the suppression of the immune response to the tumor. This immune suppression is one of the reasons why the tumor can progress and cause serious health problems for the patient. One of the key factors that affect immune balance is innate lymphoid cells (ILCs). ILCs play an important role in regulating the immune response and can both promote and hinder the development of tumor processes, depending on their functional state and interaction with other cells of the immune system. Among ILCs, ILC1 mainly exert antitumour activity, but ILC2 and ILC3 are usually protumorigenic. One of the standard treatments for MM is autologous hematopoietic stem cell transplantation (auto-HSCT), and the aim of our study was to evaluate the effect of auto-HSCT on ILCs in MM. We assessed the number and subpopulation composition of ILCs in MM patients before and after auto-HSCT. In MM patients, an increase in the proportion of ILC2 and a decrease in ILC1 are observed before auto-HSCT compared to healthy controls. The subpopulation composition of ILCs changes in patients with multiple myeloma after auto-HSCT, with an increase in ILC1 and a decrease in ILC2 compared to pre-auto-HSCT values. No differences were observed in the relative number of different types of ILC in MM patients after auto-HSCT and in healthy controls. It has been shown that the number of immature CD5⁺ILC2s in the peripheral blood of patients with multiple myeloma is comparable to that of healthy individuals. However, in MM patients, HSCT leads to an increase in the relative number of CD5⁺ILC2s. Full article

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy arising from a single-nucleotide transversion (GAG → GTG) at codon six of the HBB gene on chromosome 11, substituting glutamic acid with valine in the β-globin chain and producing hemoglobin S (HbS). Under hypoxic conditions, HbS polymerizes and distorts erythrocytes into the characteristic sickle shape, initiating a cascade of vaso-occlusion, chronic hemolytic anemia, and progressive multi-organ damage that defines the clinical burden of this disease. Although SCD has ancient origins in sub-Saharan Africa, the Indian subcontinent, the Middle East, and the Mediterranean, regions where it conferred heterozygous resistance to malaria, the ease of human migration has long since made it a global health concern, affecting an estimated 300,000–400,000 newborns annually. Advances in molecular and genomic research have deepened our understanding of SCD pathophysiology, revealing the central contributions of hemoglobin polymerization, oxidative stress, endothelial inflammation, and nitric oxide depletion to disease progression. Current management rests on supportive pharmacological interventions, including hydroxyurea, chronic transfusion therapy, L-glutamine, and multimodal pain management, complemented by lifestyle modifications. Curative approaches have advanced substantially: hematopoietic stem cell transplantation (HSCT) remains the established standard of cure, while the regulatory approvals in late 2023 of the CRISPR/Cas9-based exagamglogene autotemcel (Casgevy) and the lentiviral vector-based lovotibeglogene autotemcel (Lyfgenia) represent the most transformative development in the history of SCD therapeutics. This review traces the disease from its ancient origins and molecular characterization through to its clinical manifestations, inheritance patterns, screening strategies, and the full spectrum of current and emerging therapies. Persistent challenges, prohibitive treatment costs, healthcare inequities, the ethical dimensions of genome editing, and the urgent need for long-term safety data, are examined critically, with a view to informing the research and policy agenda that must accompany these remarkable scientific advances. Full article

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder caused by biallelic loss-of-function mutations in the ADA2 gene (formerly CECR1). First described in 2014, DADA2 has emerged as a paradigm for monogenic vasculitis, bridging the gap between primary immunodeficiencies and systemic vasculitides. The disease is characterized by a remarkably broad clinical spectrum encompassing early-onset lacunar stroke, systemic vasculitis resembling polyarteritis nodosa (PAN), hematologic abnormalities ranging from pure red cell aplasia to pancytopenia, humoral immunodeficiency, and variable lymphoproliferation. ADA2, predominantly secreted by myeloid cells, serves dual functions as a growth factor for endothelial cells and a modulator of extracellular adenosine metabolism. Its deficiency leads to a proinflammatory state driven by macrophage dysregulation, excessive tumor necrosis factor (TNF) production, neutrophil extracellular trap (NET) formation, and endothelial dysfunction. The genotype–phenotype correlation is complex, with certain mutations predisposing to vasculitic versus hematologic-predominant phenotypes. Emerging evidence further links ADA2 deficiency to cellular senescence and inflammaging pathways, suggesting a connection between monogenic vasculitis and aging-related biological mechanisms. Anti-TNF therapy has revolutionized disease management, achieving sustained remission in the majority of vasculitic manifestations. Hematopoietic stem cell transplantation (HSCT) offers a definitive cure for severe hematologic disease, while gene therapy approaches are under active investigation. This review synthesizes current knowledge on the immunopathogenesis, clinical heterogeneity, genotype–phenotype correlations, multi-omics insights, and evolving precision therapeutic strategies for DADA2, positioning it as an instructive model for understanding monogenic immune vasculopathy. Despite this progress, fundamental questions remain—including the relative contribution of ADA2 enzymatic versus growth factor functions to disease pathogenesis, the mechanisms underlying tissue-specific vulnerability, the basis of differential treatment responsiveness, and the identity of genetic and environmental modifiers that determine phenotypic heterogeneity—that define the frontier of current DADA2 research. This review critically evaluates both established knowledge and persistent uncertainties, positioning DADA2 as an instructive model for the study of monogenic immune vasculopathy. Full article

Intestinal microbiome dysbiosis has been associated with transplant-related mortality and graft-versus-host disease in allo-HSCT patients. We assessed how pre-transplant antibiotic and antineoplastic exposures, together with multidrug-resistant colonization, are associated with baseline gut microbiome diversity at allo-HSCT. We conducted a prospective, single-center cohort study at Fundeni Clinical Institute (Bucharest, Romania) between August 2024 and June 2025, enrolling 52 allo-HSCT recipients and 27 healthy controls. Fecal samples were collected before conditioning. Gut microbiome composition was assessed via 16S rRNA gene sequencing and analyzed using QIIME2 and R. Associations were evaluated using Wilcoxon test, multivariable linear regression, and PERMANOVA. Shannon diversity was significantly lower in patients (median 4.71, IQR 3.97–5.44) than in healthy controls (median 6.09, IQR 5.87–6.28; p < 0.001). In bivariate analyses, carbapenem (p adj = 0.02) and oxazolidinone exposure (p adj = 0.005) were associated with reduced diversity, while immunotherapy was associated with higher diversity (p adj = 0.042). Broad-spectrum penicillin (p adj = 0.062) and ESBL colonization (p adj = 0.066) did not reach significance. In the multivariable antibiotic model, although the overall model was statistically significant (model p = 0.039), no individual antibiotic class remained significantly associated with Shannon diversity after adjustment for co-exposures. Beta diversity differed modestly with carbapenem exposure (R² = 0.033, p = 0.019). Pre-transplant antibiotic exposures were associated with lower gut microbiome diversity at allo-HSCT admission, with patterns consistent with a cumulative rather than a class-specific association. These findings support antibiotic stewardship in pre-transplant care. Full article

Background/Objectives: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has expanded donor availability for patients with acute myeloid leukemia; however, it is associated with a high risk of endothelial complications. Among them, sinusoidal obstruction syndrome (SOS) and transplant-associated thrombotic microangiopathy (TA-TMA) are life-threatening conditions with overlapping clinical features, making early diagnosis and management challenging. Case Presentation: We report the case of a 47-year-old woman with acute myeloid leukemia who underwent haploidentical HSCT and developed sequential endothelial complications. On day +11 post-transplant, she presented with weight gain (>5%), hyperbilirubinemia (44 μmol/L), elevated liver enzymes (ALT 2228 U/L and AST 3477 U/L), and multi-organ dysfunction, consistent with probable SOS according to EBMT criteria. Intensive supportive care, glucocorticosteroids, and hemodiafiltration resulted in partial clinical improvement. Subsequently, on day +22, the patient developed progressive thrombocytopenia, hemolytic anemia (hemoglobin 71 g/L), elevated lactate dehydrogenase (3129 U/L), undetectable haptoglobin, and schistocytosis (up to 3.9%), accompanied by neurological symptoms, leading to the diagnosis of TA-TMA. Results: Management included discontinuation of tacrolimus, initiation of plasma exchange, and complement inhibition with eculizumab, along with ruxolitinib for graft-versus-host disease prophylaxis. This approach resulted in rapid clinical and laboratory improvement, including resolution of hemolysis, reduction in schistocytes (to 1%), normalization of lactate dehydrogenase, and regression of neurological symptoms. The patient was discharged in stable condition, although requiring ongoing renal replacement therapy. Conclusions: This case highlights the complexity of diagnosing and managing sequential endothelial complications after haplo-HSCT. SOS and TA-TMA may reflect overlapping manifestations of endothelial injury rather than entirely isolated complications. Full article

Serratia species are Gram-negative pathogens responsible for a wide range of nosocomial infections. This multicenter nationwide retrospective study aimed to describe the epidemiology, clinical characteristics, antimicrobial susceptibility, and outcomes of Serratia infections in pediatric oncology patients and hematopoietic stem cell transplantation (HSCT) recipients in Poland between 2012 and 2023. A total of 36 Serratia infection episodes were identified in patients under 20 years of age, including 30 cases (83.3%) in the oncological (OHD) group and six (16.7%) among HSCT recipients. The median age was 4.30 years. The most common underlying diseases were acute lymphoblastic leukemia (36.1%) and central nervous system tumors (16.7%). Bloodstream infections predominated in OHD patients (33.3%), whereas urinary tract infections were most frequent in HSCT recipients (83.3%). S. marcescens was the most commonly isolated species. More than half of isolates (53.3%) showed antimicrobial resistance, with extended-spectrum β-lactamase (ESBL)-producing strains in 26.7% and AmpC β-lactamase-producing strains in 13.3%. Multidrug resistance occurred in 30%. Treatment most often included amikacin, piperacillin/tazobactam, and carbapenems. Five deaths occurred in the OHD group and one in the HSCT group, none directly related to Serratia infection. Although uncommon, Serratia infections remain clinically relevant due to their high antimicrobial resistance, underscoring the need for antimicrobial stewardship. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by a block of differentiation and uncontrolled expansion of myeloid progenitor cells. Standard treatment includes intensive induction chemotherapy, typically with cytarabine and anthracycline, followed by consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. However, these approaches are often associated with relapse and treatment-related toxicity. Accumulating evidence highlights a critical role for epigenetic dysregulation in driving disease initiation, progression, and therapeutic resistance. In this review, we examine an integrated framework of epigenetic regulation in AML, encompassing DNA methylation, histone post-translational modifications, chromatin remodeling, and RNA-mediated epigenetics. We discuss how alterations in key epigenetic regulators, such as DNMT3A, TET2, IDH1/2, EZH2, and histone-modifying enzymes, reshape the transcriptional and epigenetic landscape of leukemic cells. Particular emphasis is placed on epigenetically defined AML subtypes, including NPM1-mutated, DNMT3A-mutated, and KMT2A-rearranged AML, which illustrate distinct mechanisms of transcriptional and epigenetic dysregulation and confer unique therapeutic vulnerabilities. We further summarize current and emerging therapeutic strategies, ranging from conventional chemotherapy to molecularly targeted agents, epigenetic drugs, and immunotherapeutic approaches. Despite these advances, durable responses remain limited, highlighting the need to better understand epigenetic mechanisms to overcome resistance and improve patient outcomes. Full article

Lysosomal Storage Diseases (LSDs) include roughly 70 inherited metabolic disorders, most of which are expressed in an autosomal recessive pattern. These conditions arise from mutations in genes encoding lysosomal enzymes, leading to intracellular buildup of substrates and subsequent lysosomal dysfunction. LSDs can be broadly classified based on the nature of the stored substrate, encompassing Sphingolipidoses, Mucopolysaccharidoses, Lysosomal Glycogen Storage Disease, Oligosaccharidoses, Mucolipidoses, and Lysosomal Proteinoses. Although individually rare, LSDs collectively affect approximately 1 in 5000 live births. They usually manifest in childhood, but adult-onset types are also detected. Clinical manifestations are heterogeneous and may involve the central nervous system, skeletal system, skin, heart, muscles, kidneys, and other organs. Several therapeutic strategies are available for LSDs, including Enzyme Replacement Therapy to restore deficient enzymes, Hematopoietic Stem Cell Transplantation to provide functional donor-derived cells, Substrate Reduction Therapy and pharmacological chaperones to modulate substrate turnover or enhance enzyme stability, alongside symptomatic and supportive treatments. Ongoing research is also exploring gene therapy-based strategies. Current diagnostic criteria remain insufficient for reliable presymptomatic diagnosis, highlighting the need for more sensitive and specific approaches. In this context, untargeted metabolomics is a powerful strategy to investigate pathogenic pathways, identify novel diagnostic and prognostic biomarkers, and uncover potential therapeutic targets. Accordingly, this review provides an overview of LSDs, focusing on untargeted metabolomics studies and their contribution to the discovery of novel biomarkers and previously unrecognised pathogenic mechanisms relevant to diagnostic and therapeutic innovation. Full article

Genetically modified hematopoietic stem cell therapy using gene-modified autologous hematopoietic stem cells has evolved over the last 30 years as an alternative approach to circumvent the limitations of donor availability, risks of excessive regimen related toxicity, prolonged immune suppression and graft-versus-host disease associated with allogeneic hematopoietic cell transplantation. Gene replacement therapy based on viral insertion of transgene into host genome was developed as one of the main methods for gene modification of autologous cells. Unfortunately, many cases of oncogenesis were directly caused by genetically modified hematopoietic stem cell therapy. The purpose of the present review is the description of cases of leukemogenesis in gene replacement therapy in hematopoietic stem cells, elucidation of the causes, and overview of the risk mitigation strategies. It aims to elucidate the main risk factors in gene replacement therapy in hematopoietic stem cells. The insertional mutagenesis leads to activation of proto-oncogenes, mostly LMO2 and MECOM-EVI1. γ-retroviral vectors are dangerous in this case, as they contain long terminal repeats with strong promotor activity and are prone to integration near transcription initiation sites. Therefore, safer self-inactivating lentiviral vectors were developed, with long terminal repeats modified to reduce their promoter activity and with safer integration pattern. Nevertheless, the risk of leukemogenesis remains because the promoter integrated into the transgene expression cassette may still influence nearby gene expression. Another risk factor is monosomy 7, either pre-existing or caused by MECOM-EVI1 activation, which may contribute directly to leukemogenesis. Thus, oncogenesis in HSPC gene replacement therapy does not have a single definitive cause; rather, multiple factors may contribute, and each may be sufficient under specific conditions. Full article