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Successful integration of point-of-care testing (POCT) into clinical settings requires improved assay sensitivity and precision to match laboratory standards. Here, we show how innovations in amplified biosensing, imaging, and data processing, coupled with deep learning, can help improve POCT. To demonstrate the performance of our approach, we present a rapid and cost-effective paper-based high-sensitivity vertical flow assay (hs-VFA) for quantitative measurement of cardiac troponin I (cTnI), a biomarker widely used for measuring acute cardiac damage and assessing cardiovascular risk. The hs-VFA includes a colorimetric paper-based sensor, a portable reader with time-lapse imaging, and computational algorithms for digital assay validation and outlier detection. Operating at the level of a rapid at-home test, the hs-VFA enabled the accurate quantification of cTnI using 50 μL of serum within 15 min per test and achieved a detection limit of 0.2 pg/mL, enabled by gold ion amplification chemistry and time-lapse imaging. It also achieved high precision with a coefficient of variation of

Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration. Unexpectedly, Toci-secreting CD19 CAR-T cells exhibit superior in vivo antitumor efficacy compared with conventional CD19 CAR-T cells. scRNA-seq analysis of immune cells recovered from tumor-bearing humanized mice revealed treatment with Toci-secreting CD19 CAR-T cells enriches for cytotoxic T cells while retaining memory T-cell phenotype, suggesting Toci secretion not only reduces toxicity but also significantly alters the overall T-cell composition. This approach of engineering T cells to self-regulate inflammatory cytokine production is a clinically compatible strategy with the potential to simultaneously enhance safety and efficacy of CAR-T cell therapy for cancer.

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

Methods integrating genetics with transcriptomic reference panels prioritize risk genes and mechanisms at only a fraction of trait-associated genetic loci, due in part to an overreliance on total gene expression as a molecular outcome measure. This challenge is particularly relevant for the brain, in which extensive splicing generates multiple distinct transcript-isoforms per gene. Due to complex correlation structures, isoform-level modeling from cis-window variants requires methodological innovation. Here we introduce isoTWAS, a multivariate, stepwise framework integrating genetics, isoform-level expression and phenotypic associations. Compared to gene-level methods, isoTWAS improves both isoform and gene expression prediction, yielding more testable genes, and increased power for discovery of trait associations within genome-wide association study loci across 15 neuropsychiatric traits. We illustrate multiple isoTWAS associations undetectable at the gene-level, prioritizing isoforms of AKT3, CUL3 and HSPD1 in schizophrenia and PCLO with multiple disorders. Results highlight the importance of incorporating isoform-level resolution within integrative approaches to increase discovery of trait associations, especially for brain-relevant traits.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values

BackgroundIncreased expression of the complement component 4A (C4A) gene is associated with a greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear the extent to which upregulation of C4A alters brain development or is associated with the risk for psychotic symptoms in childhood. Here, we perform a multi-ancestry phenome-wide association study in 7789 children aged 9-12 years to examine the relationship between genetically regulated expression (GREx) of C4A, childhood brain structure, cognition, and psychiatric symptoms.ResultsWhile C4A GREx is not related to childhood psychotic experiences, cognition, or global measures of brain structure, it is associated with a localized reduction in regional surface area (SA) of the entorhinal cortex. Furthermore, we show that reduced entorhinal cortex SA at 9-10 years predicts a greater number and severity of psychosis-like events at 1-year and 2-year follow-up time points. We also demonstrate that the effects of C4A on the entorhinal cortex are independent of genome-wide polygenic risk for schizophrenia.ConclusionsOur results suggest neurodevelopmental effects of C4A on childhood medial temporal lobe structure, which may serve as a biomarker for schizophrenia risk prior to symptom onset.

BackgroundChildhood sleep problems are common and among the most frequent and impairing comorbidities of childhood psychiatric disorders. In adults, sleep disturbances are heritable and show strong genetic associations with brain morphology; however, little is known about the genetic architecture of childhood sleep and potential etiological links between sleep, brain development, and pediatric-onset psychiatric symptoms.MethodsUsing data from the Adolescent Brain Cognitive Development Study (n Phenotype = 4428 for discovery/replication, n Genetics = 4728; age 9-10 years), we assessed phenotypic relationships, heritability, and genetic correlations between childhood sleep disturbances (insomnia, arousal, breathing, somnolence, hyperhidrosis, sleep-wake transitions), brain size (surface area, cortical thickness, volume), and dimensional psychopathology.ResultsSleep disturbances showed widespread positive associations with multiple domains of childhood psychopathology; however, only insomnia showed replicable associations with smaller brain surface area. Among the sleep disturbances assessed, only insomnia showed significant heritability (h 2 SNP = 0.15, p < .05) and showed substantial genetic correlations with externalizing and attention-deficit/hyperactivity disorder symptomatology (r G s > 0.80, ps < .05). We found no evidence of genetic correlation between childhood insomnia and brain size. Furthermore, polygenic risk scores calculated from genome-wide association studies of adult insomnia and adult brain size did not predict childhood insomnia; instead, polygenic risk scores trained using attention-deficit/hyperactivity disorder genome-wide association studies predicted decreased surface area at baseline as well as insomnia and externalizing symptoms longitudinally.ConclusionsFindings demonstrate a distinct genetic architecture underlying childhood insomnia and brain size and suggest genetic overlap between childhood insomnia and attention-deficit/hyperactivity disorder symptomatology. Additional research is needed to examine how genetic risk manifests in altered developmental trajectories and comorbid sleep/psychiatric symptoms across adolescence.

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Microbial electrosynthesis (MES) has been highlighted as a means to valorize inorganic gaseous carbon, such as CO2, into value-added chemicals using electricity as the reducing power. Electrode-based electron transfer delivers respiratory electrons to a live-cell biocatalyst through a biofilm matrix or via electron shuttle molecules. The addition of artificial mediators, such as neutral red (NR) and 2-hydroxy-1,4-naphthoquinone (HNQ), increased acetate synthesis significantly, suggesting that these mediators improve the electron transport capability between the suspended cells and electrode. Regular media replacement also improves MES by adapting mediator-utilizing species in the reactor. MES without a mediator initially produced acetate at a reasonable rate (5.1 ± 0.2 mmol/l/day), but the rate became negligible in the later stage. In contrast, MES with NR or HNQ showed a higher acetate production rate (4.6 ± 0.4 vs. 7.4 ± 0.4 mmol/l/day, respectively) as the media replacement progressed. Confocal laser scanning microscopy and 3D imaging showed that the biofilm matrix consisted of live and dead cells, while the composition was different in the MES with and without a mediator. Microbial community analysis by next-generation sequencing (NGS) showed that acetogenic Acetobacterium (in suspension) and Sporomusa (in both suspension and biofilm) were dominant during the 96 days of operation. The biofilm and planktonic community interacted dynamically under MES conditions. This result provides a realistic model of biofilms and planktonic cells in the MES. The interaction of the suspended cells with the biofilm-forming electrode via electron shuttles could improve volumetric acetate production and stabilize the MES performance.

Magnetism and spin-orbit coupling are two quintessential ingredients underlying topological transport phenomena in itinerant ferromagnets. When spin-polarized bands support nodal points/lines with band degeneracy that can be lifted by spin-orbit coupling, the nodal structures become a source of Berry curvature, leading to a large anomalous Hall effect. However, two-dimensional systems can possess stable nodal structures only when proper crystalline symmetry exists. Here we show that two-dimensional spin-polarized band structures of perovskite oxides generally support symmetry-protected nodal lines and points that govern both the sign and the magnitude of the anomalous Hall effect. To demonstrate this, we performed angle-resolved photoemission studies of ultrathin films of SrRuO3, a representative metallic ferromagnet with spin-orbit coupling. We show that the sign-changing anomalous Hall effect upon variation in the film thickness, magnetization and chemical potential can be well explained by theoretical models. Our work may facilitate new switchable devices based on ferromagnetic ultrathin films.

The most significant common variant association for schizophrenia (SCZ) reflects increased expression of the complement component 4A (C4A). Yet, it remains unclear how C4A interacts with other SCZ risk genes or whether the complement system more broadly is implicated in SCZ pathogenesis. Here, we integrate several existing, large-scale genetic and transcriptomic datasets to interrogate the functional role of the complement system and C4A in the human brain. Unexpectedly, we find no significant genetic enrichment among known complement system genes for SCZ. Conversely, brain co-expression network analyses using C4A as a seed gene reveal that genes downregulated when C4A expression increases exhibit strong and specific genetic enrichment for SCZ risk. This convergent genomic signal reflects synaptic processes, is sexually dimorphic and most prominent in frontal cortical brain regions, and is accentuated by smoking. Overall, these results indicate that synaptic pathways-rather than the complement system-are the driving force conferring SCZ risk.

The most significant common variant association for schizophrenia (SCZ) reflects increased expression of the complement component 4A (C4A). Yet, it remains unclear how C4A interacts with other SCZ risk genes or whether the complement system more broadly is implicated in SCZ pathogenesis. Here, we integrate several existing, large-scale genetic and transcriptomic datasets to interrogate the functional role of the complement system and C4A in the human brain. Unexpectedly, we find no significant genetic enrichment among known complement system genes for SCZ. Conversely, brain co-expression network analyses using C4A as a seed gene reveal that genes downregulated when C4A expression increases exhibit strong and specific genetic enrichment for SCZ risk. This convergent genomic signal reflects synaptic processes, is sexually dimorphic and most prominent in frontal cortical brain regions, and is accentuated by smoking. Overall, these results indicate that synaptic pathways-rather than the complement system-are the driving force conferring SCZ risk.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Alkali metal dosing (AMD) has been widely used as a way to control doping without chemical substitution. This technique, in combination with angle resolved photoemission spectroscopy (ARPES), often provides an opportunity to observe unexpected phenomena. However, the amount of transferred charge and the corresponding change in the electronic structure vary significantly depending on the material. Here, we report study on the correlation between the sample work function and alkali metal induced electronic structure change for three iron-based superconductors: FeSe, Ba(Fe0.94Co0.06)2As2 and NaFeAs which share a similar Fermi surface topology. Electronic structure change upon monolayer of alkali metal dosing and the sample work function were measured by ARPES. Our results show that the degree of electronic structure change is proportional to the difference between the work function of the sample and Mulliken's absolute electronegativity of the dosed alkali metal. This finding provides a possible way to estimate the AMD induced electronic structure change.

Over the past decade, large-scale genetic studies have successfully identified hundreds of genetic variants robustly associated with risk for psychiatric disorders. However, mechanistic insight and clinical translation continue to lag the pace of risk variant identification, hindered by the sheer number of targets and their predominant noncoding localization, as well as pervasive pleiotropy and incomplete penetrance. Successful next steps require identification of "causal" genetic variants and their proximal biological consequences; placing variants within biologically defined functional contexts, reflecting specific molecular pathways, cell types, circuits, and developmental windows; and characterizing the downstream, convergent neurobiological impact of polygenicity within an individual. Here, we discuss opportunities and challenges of high-throughput transcriptomic profiling in the human brain, and how transcriptomic approaches can help pinpoint mechanisms underlying genetic risk for psychiatric disorders at a scale necessary to tackle daunting levels of polygenicity. These include transcriptome-wide association studies for risk gene prioritization through integration of genome-wide association studies with expression quantitative trait loci. We outline transcriptomic results that inform our understanding of the brain-level molecular pathology of psychiatric disorders, including autism spectrum disorder, bipolar disorder, major depressive disorder, and schizophrenia. Finally, we discuss systems-level approaches for integration of distinct genetic, genomic, and phenotypic levels, including combining spatially resolved gene expression and human neuroimaging maps. Results highlight the importance of understanding gene expression (dys)regulation across human brain development as a major contributor to psychiatric disease pathogenesis, from common variants acting as expression quantitative trait loci to rare variants enriched for gene expression regulatory pathways.

Rotation of MO6 (M = transition metal) octahedra is a key determinant of the physical properties of perovskite materials. Therefore, tuning physical properties, one of the most important goals in condensed matter research, may be accomplished by controlling octahedral rotation (OR). In this study, it is demonstrated that OR can be driven by an electric field in Sr2RuO4. Rotated octahedra in the surface layer of Sr2RuO4 are restored to the unrotated bulk structure upon dosing the surface with K. Theoretical investigation shows that OR in Sr2RuO4 originates from the surface electric field, which can be tuned via the screening effect of the overlaid K layer. This work establishes not only that variation in the OR angle can be induced by an electric field, but also provides a way to control OR, which is an important step toward in situ control of the physical properties of perovskite oxides.

Motivated by the novel insulating state of Sr_{2}IrO_{4} from strong spin-orbit coupling (SOC), we investigate, by means of angle resolved photoemission, the metal-insulator transition (MIT) mechanism in Sr_{2-x}La_{x}RhO_{4} whose mother compound is isovalent and isostructural but has smaller SOC strength compared to Sr_{2}IrO_{4}. Transport and angle resolved photoemission results from single crystalline Sr_{2-x}La_{x}RhO_{4} revealed that the MIT occurs coincidentally with a multi- to single-band transition (Lifshitz transition) at x=0.4. Starting from x=0.4, there is a gradual but anomalous enhancement in the band gap size with additional electron doping, suggesting that the insulating phase in Sr_{2-x}La_{x}RhO_{4} is a new type which has been rarely investigated. These results suggest that the insulating phase in Sr_{2-x}La_{x}RhO_{4} is likely induced by the moderate SOC strength and electron doping effect from the La. Our findings not only elucidate the MIT mechanism in Sr_{2-x}La_{x}RhO_{4}, but may also open new avenues for novel MIT research in moderate SOC regimes.

Motivated by the novel insulating state of Sr_{2}IrO_{4} from strong spin-orbit coupling (SOC), we investigate, by means of angle resolved photoemission, the metal-insulator transition (MIT) mechanism in Sr_{2-x}La_{x}RhO_{4} whose mother compound is isovalent and isostructural but has smaller SOC strength compared to Sr_{2}IrO_{4}. Transport and angle resolved photoemission results from single crystalline Sr_{2-x}La_{x}RhO_{4} revealed that the MIT occurs coincidentally with a multi- to single-band transition (Lifshitz transition) at x=0.4. Starting from x=0.4, there is a gradual but anomalous enhancement in the band gap size with additional electron doping, suggesting that the insulating phase in Sr_{2-x}La_{x}RhO_{4} is a new type which has been rarely investigated. These results suggest that the insulating phase in Sr_{2-x}La_{x}RhO_{4} is likely induced by the moderate SOC strength and electron doping effect from the La. Our findings not only elucidate the MIT mechanism in Sr_{2-x}La_{x}RhO_{4}, but may also open new avenues for novel MIT research in moderate SOC regimes.

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

BackgroundImmunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.ObjectiveThis analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.MethodsClinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.ResultsWe confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.ConclusionsPatients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

BACKGROUND:Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE:This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS:Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS:We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS:Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.