Enhanced Risk Stratification for Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia: A Children's Oncology Group Report.

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PICOG) that maximized discrimination of the predictive model. Patients with higher PICOG have higher predicted relapse risk. The PICOG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PICOG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PICOG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PICOG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PICOG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.

The interplay between the impact of household's and children's education on the risk of type 2 diabetes and death among older adults: a Danish register-based cohort study.

OBJECTIVES: This study aims to assess the association of household's and children's education on the risk of type 2 diabetes (T2D) and subsequent death. STUDY DESIGN: Danish register-based cohort study. METHODS: In total, 1,021,557 adults were included at their 65th birthday between 2000 and 2018. A multistate survival model was performed to estimate the association of household's and children's education on the transition between the three states: 1) 65th birthday; 2) diagnosis of T2D; and 3) all-cause death. RESULTS: The incidence rates per 1000 person-years were 9.1 for T2D, 18.4 for death without T2D, and 45.0 for death with T2D. Compared to long household's education and children's education, long household's education combined with either short-medium children's education or no children were associated with a 1.49- (95% confidence interval [CI]: 1.44; 1.54] and 1.69-times (95% CI: 1.61;1.78) higher hazard of T2D, respectively. Short-medium household's education combined with either long children's education or no children were associated with 0.64- (95% CI: 0.62; 0.66) and 0.77-times (95% CI: 0.74; 0.79) lower hazard of T2D, respectively. Compared to long household's education and children's education, any other combination of household's and children's education was associated with higher hazards of death both without and with T2D. CONCLUSION: Older adults living in households with long education with no children or children with short-medium education had higher hazards of T2D. Households with short-medium education and no children or children with long education were associated with lower hazards of T2D. Both household's and children's education were associated with higher hazard of death without and with T2D.

Re-constructing parental identity after parents face their offspring's suicidal behaviour: An interview study.

INTRODUCTION: Parents are affected when their offspring engages in non-fatal suicidal behaviour. Although research exists on parents' mental and emotional state when they realise this behaviour, relatively little attention has been devoted to exploring how their parental identity is affected. PURPOSE: To explore how parents re-constructed and negotiated their parental identity after realising that their offspring was suicidal. METHOD: A qualitative exploratory design was adopted. We conducted semi-structured interviews with 21 Danish parents who self-identified as having offspring at risk of suicidal death. Interviews were transcribed, analysed thematically and interpreted by drawing on the interactionist concepts of negotiated identity and moral career. FINDINGS: Parents' perspectives on their parental identity were conceptualised as a moral career encompassing three distinct stages. Each stage was negotiated through social interaction with other people and the wider society. Entry into the first stage, disrupted parental identity, occurred when parents realised that they could lose their offspring to suicide. At this stage, parents trusted their own abilities to resolve the situation and keep their offspring safe and alive. This trust was gradually undermined by social encounters, which caused career movement. In the second stage, impasse, parents lost faith in their ability to help their offspring and to change the situation. Whereas some parents gradually resigned entirely to impasse, others regained their trust in their own abilities through social interaction in the third stage, restored parental agency. CONCLUSION: Offspring's suicidal behaviour disrupted parents' self-identity. Social interaction was fundamental if parents were to re-construct their disrupted parental identity. This study contributes with knowledge about the stages characterising the reconstructive process of parents' self-identity and sense of agency.

Direct observation of ultrafast exciton localization in an organic semiconductor with soft X-ray transient absorption spectroscopy.

The localization dynamics of excitons in organic semiconductors influence the efficiency of charge transfer and separation in these materials. Here we apply time-resolved X-ray absorption spectroscopy to track photoinduced dynamics of a paradigmatic crystalline conjugated polymer: poly(3-hexylthiophene) (P3HT) commonly used in solar cell devices. The π→π* transition, the first step of solar energy conversion, is pumped with a 15 fs optical pulse and the dynamics are probed by an attosecond soft X-ray pulse at the carbon K-edge. We observe X-ray spectroscopic signatures of the initially hot excitonic state, indicating that it is delocalized over multiple polymer chains. This undergoes a rapid evolution on a sub 50 fs timescale which can be directly associated with cooling and localization to form either a localized exciton or polaron pair.

Nudging hand hygiene compliance: a large-scale field experiment on hospital visitors.

BACKGROUND: Hospital-care-associated infections (HCAIs) represent the most frequent adverse event during care delivery, affecting hundreds of millions of patients around the world. Implementing and ensuring conformity to standard precautions, particularly best hand hygiene practices, is regarded as one of the most important and cheapest strategies for preventing HCAIs. However, despite consistent efforts at increasing conformity to standard hand hygiene practices at hospitals, research has repeatedly documented low conformity levels amongst staff, patients and visitors alike. AIM: The behavioural sciences have documented the potential of adjusting seemingly irrelevant contextual features in order to 'nudge' people to conform to desirable behaviours such as hand hygiene compliance (HHC). In this field experiment we investigate the effect on HHC amongst visitors upon entry of a hospital by varying such features. METHODS: Over 50 days, we observed the HHC of a total of 46,435 hospital visitors upon their entry to the hospital in a field experimental design covering eight variations over the salience, placement and assertion of the hand sanitizer in the foyer, including the presence of the yearly national HHC campaign and a follow up during the COVID-19 pandemic. FINDINGS: Our experiment found that varying seemingly irrelevant features increased HHC from a baseline of 0.4%-19.7% (47.6% during COVID-19). The experiment also found that the national HHC-campaign had no direct statistically significant effect on HHC. CONCLUSION: Varying seemingly irrelevant contextual features provides an effective, generic, cheap and easy to scale approach to increasing HHC relative to sanitizing one's hands at hospitals.

HLA-DRB1 polymorphism in recurrent pregnancy loss: New evidence for an association to HLA-DRB1*07.

Many cases of recurrent pregnancy loss (RPL) defined as ≥3 consecutive pregnancy losses are suggested to be caused by an aberrant maternal immune response against the fetus or trophoblast. Human leukocyte antigen (HLA)-DRB1 and -DQB1 polymorphisms are associated with most autoimmune disorders and studies of HLA-DBB1 polymorphism in RPL patients are thus relevant. In previous studies, the HLA-DRB1*03 allele was found with increased prevalence in RPL patients. We wanted to clarify whether HLA-DRB1 alleles indeed were associated with RPL among women of Caucasian descent. A total of 1078 women with unexplained RPL and 2066 bone marrow donors were HLA-DRB1-typed and subsets were also HLA-DQB1 typed. All patients were initially HLA-DRB1-typed by DNA-based low-resolution techniques and subsets of patients and all controls were typed by high-resolution techniques. Among patients, the HLA-DRB1*07 allele frequency was significantly increased compared with controls; OR 1.29 (95 % CI 1.09-1.52), p < 0.0025; after correction for multiple comparisons pc = 0.031. The HLA-DRB1*07/*07 genotype was highly increased in patients with RPL compared with controls: OR 2.27 (1.31-3.93), p = 0.0027. The frequency of the HLA-DRB1*07 phenotype in RPL patients had increased significantly (p = 0.002) in three studies from our group published 1994-2021. The allele frequency of HLA-DRB1*03 was not increased in RPL patients compared with controls; OR 0.96 (0.83-1.12). In conclusion, the previous association between HLA-DRB1*03 and RPL could not be confirmed in our study whereas an association to HLA-DRB1*07 was detected for the first time. Since the latter association is a new finding, it should be confirmed in future studies.

C-reactive protein is associated with cognitive performance in a large cohort of euthymic patients with bipolar disorder.

Data support the notion that 40-60% of patients with bipolar disorder (BD) have neurocognitive deficits. It is increasingly accepted that functioning in BD is negatively impacted by these deficits, yet they have not been a successful target for treatment. The biomarkers that predict cognitive deficits in BD are largely unknown, however recent evidence suggests that inflammation may be associated with poorer cognitive outcomes in BD. We measured C-reactive protein (CRP), a marker of systemic inflammation and risk of inflammatory disease, in 222 euthymic BD patients and 52 healthy controls. Within the patient sample, using multivariate analyses of covariance (MANCOVA) we compared cognitive performance of those with high CRP (≥5 mg/L) versus the remaining subjects (<5 mg/L) on a battery of cognitive tests. We evaluated relationships with several other relevant clinical features. We also examined the role of CRP in cognitive decline using a proxy cognitive decline metric, defined as the difference between premorbid and current IQ estimates, in a logistic regression analysis. Approximately 80% of our sample were BD-I, and the remainder were BD-II and 42.6% of our sample had a history of psychosis. We found a statistically significant effect of CRP on cognitive performance on a broad range of tests; participants with CRP ≥ 5 mg/L had worse performance on several measures of executive functioning, MATRICS processing speed and MATRICS reasoning and problem solving relative to those with lower CRP. We also identified CRP as a significant positive predictor of proxy cognitive decline. Our results indicate that elevated CRP is associated with a broad cognitive dysfunction in affectively remitted BD patients. These results may point to a subgroup of patients who might benefit from treatments to reduce inflammation.

Relatives' experiences of providing care for individuals with suicidal behaviour conceptualized as a moral career: A meta-ethnographic study.

BACKGROUND: An increasing number of qualitative research articles have reported on relatives' experiences of providing care for individuals displaying suicidal behaviour. To contribute more fully to theory and practice, these reported experiences must be synthesized. OBJECTIVES: To identify original qualitative studies of relatives' experiences of providing care for individuals with non-fatal suicidal behaviour and to systematically review and synthesize this research using a meta-ethnographic approach. DESIGN: Systematic review and meta-ethnography. DATA SOURCES: Literature searches were undertaken in six bibliographic databases (PubMed, CINAHL, Embase, PsycINFO, Web of Science and Scopus) and limited to peer-reviewed original studies. Eligible studies reported relatives' experiences of providing care for individuals with suicidal behaviour, published in English or a Scandinavian language. REVIEW METHODS: One reviewer screened the titles, abstracts and full texts and then collaborated with another reviewer on excluding ineligible studies. A two-step strategy was used while reviewing publications: 1) appraising study quality, and 2) classifying study findings according to degree of data interpretation. This strategy was used for each study by two independent reviewers who subsequently reached a shared decision on inclusion. Noblit and Hare's methodology for translation and synthesis was followed in developing a novel theoretical interpretation of relatives' experiences. The concept of moral career was adopted in producing this synthesis. RESULTS: Of 7,334 publications screened, 12 studies were eligible for inclusion. The synthesis conveyed relatives' moral career as comprising four stages, each depicting relatives' different perspectives on life and felt identities. First, relatives negotiated conventional ideas about normalcy and positioned themselves as living abnormal family lives in the stage from normal to abnormal. The first career movement could be mediated by social interactions with professionals in the stage feeling helpful or feeling unhelpful. For some relatives, this negotiated perspective of abnormality got stuck in an impasse. They did not interact with their surroundings in ways that would enable them to renegotiate these fixed views, and this stage was named stuck in abnormality. For other relatives, career movement took place as relatives re-positioned themselves as negotiating an alternative perspective of normalcy in the stage from abnormal to normal. CONCLUSIONS: Interactions with other people facing similar difficulties enabled relatives to shift perspectives and alleviated experiences of distress.

Generation and measurement of isolated attosecond pulses with enhanced flux using a two colour synthesized laser field.

We have generated isolated attosecond pulses and performed attosecond streaking measurements using a two-colour synthesized laser field consisting of a strong near-infrared few-cycle pulse and a weaker multi-cycle pulse centred at 400 nm. An actively stabilized interferometer was used to coherently combine the two pulses. Using attosecond streaking we characterised the electric fields of the two pulses and accurately retrieved the spectrum of the multi-cycle pulse. We demonstrated a two-fold increase in the flux of isolated attosecond pulses produced and show that their duration was minimally affected by the presence of the weaker field due to spectral filtering by a multilayer mirror.

Risk factors during pregnancy and birth-related complications in HIV-positive versus HIV-negative women in Denmark, 2002-2014.

OBJECTIVES: We aimed to compare risk factors for adverse pregnancy outcomes in women living with HIV (WLWH) with those in women of the general population (WGP) in Denmark. Further, we estimated risk of pregnancy- or birth-related complications. METHODS: A retrospective cohort study including all WLWH who delivered a live-born child from 2002 to 2014 and WGP, matched by origin, age, year and parity, was carried out. We compared risk factors during pregnancy and estimated risk of pregnancy- and birth-related complications using multivariate logistic regression. RESULTS: A total of 2334 pregnancies in 304 WLWH and 1945 WGP were included in the study. WLWH had more risk factors present than WGP during pregnancy: previous caesarean section (CS) (24.7% versus 16.3%, respectively; P = 0.0001), smoking (14.2% versus 7.5%, respectively; P = 0.0001) and previous perinatal/neonatal death (2.3% versus 0.9%, respectively; P = 0.03). We found no difference between groups regarding gestational diabetes, hypertensive disorders, low birth weights or premature delivery. More children of WLWH had intrauterine growth retardation (IUGR) [adjusted odds ratio (aOR) 1.9; 95% confidence interval (CI) 1.1-3.2; P = 0.02]. Median gestational age and birth weight were lower in children born to WLWH. WLWH had a higher risk of emergency CS (EmCS) (aOR 1.6; 95% CI 1.2-2.1; P = 0.0005) and postpartum haemorrhage (aOR 1.4; 95% CI 1.0-1.9; P = 0.02) but not infection, amniotomy, failure to progress, low activity-pulse-grimace-appearance-respiration (APGAR) score or signs of asphyxia. CONCLUSIONS: WLWH had more risk factors present during pregnancy, similar risks of most pregnancy- and birth-related complications but a higher risk of postpartum haemorrhage and EmCS compared with WGP. Children born to WLWH had lower median birth weights and gestational ages and were at higher risk of IUGR.

Loneliness, health and mortality.

AIMS: Literature suggests an association between loneliness and mortality for both males and females. Yet, the linkage of loneliness to mortality is not thoroughly examined, and need to be replicated with a long follow-up time. This study assessed the association between loneliness and mortality, including associations to gender, in 1363 adult swedes. METHODS: This community-based prospective cohort study from the Swedish Lundby Study included 1363 individuals of whom 296 individuals (21.7%) were identified as lonely with use of semi-structured interviews in 1997. The cohort was followed until 2011 and survival analyses were used to estimate the relative risk of death. RESULTS: Death occurred with an incidence rate of 2.63 per 100 person-years and 2.09 per 100 person-years for lonely and non-lonely individuals, respectively. In crude analysis, loneliness was associated with a significant increased mortality risk of 27% compared with non-lonely individuals [hazard ratio (HR) 1.27; 95% CI 1.01-1.60]. Unadjusted, lonely females had a significant increased risk (HR 1.76; 95% CI 1.31-2.34) and adjusted insignificant increased mortality risk of 27% (HR 1.27; 95% CI 0.92-1.74), compared with non-lonely females. Lonely males were found to have an adjusted significant decreased risk of mortality (HR 0.50; 95% CI 0.32-0.80), compared with non-lonely males. CONCLUSIONS: Findings suggest an association between loneliness and increased risk of mortality and that gender differences may exist, which have not been previously reported. If replicated, our results indicate that loneliness may have differential physical implications in some subgroups. Future studies are needed to further investigate the influence of gender on the relationship.

Social cognition moderates the relationship between neurocognition and community functioning in bipolar disorder.

BACKGROUND: Schizophrenia (SZ) studies suggest that neurocognition predicts functional outcome and that social cognition mediates this relationship. Bipolar disorder (BD) patients also have cognitive, social, and functional impairments but the relationship among these factors in BD is not well established. We assessed whether social cognition modulates the influence of neurocognition on community functioning in BD, as found in SZ. METHODS: 200 BD patients and 49 healthy controls (HC) were administered and compared on a battery of tests assessing neurocognition, social cognition, and community functioning. We conducted a series of regression analyses to investigate potential mediation or moderation of social cognition on the relationship between neurocognition and community functioning. RESULTS: BD patients performed worse on neurocognitive domains of processing speed, attention, verbal learning, and global neurocognition. Also, BD patients performed worse on theory of mind, the social cognition composite score, and community functioning. Neurocognition did not significantly predict functional outcome in our BD sample. However, we found a moderating effect of social cognition: among patients with poor social cognition, better neurocognition was associated with better community functioning, a relationship not seen in BD patients with good social cognition. LIMITATIONS: The study was limited by a relatively small HC group and assessing one subtype of functioning status. CONCLUSIONS: The relationship between neurocognition and community functioning in BD may be dependent on social cognition status, implying the presence of social cognitive heterogeneity. Results may be relevant to choosing proper treatment interventions depending on the patient's social cognitive level.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Neurocognitive subtypes in patients with bipolar disorder and their unaffected siblings.

BACKGROUND: Our previous work revealed substantial heterogeneity in the cognitive profile of bipolar disorder (BD) due to the presence of three underlying cognitive subgroups characterized as: globally impaired, selectively impaired, or cognitively intact. In an effort to determine whether these subgroups are differentially related to genetic risk for the illness, we investigated whether cognitive deficits were more pronounced in unaffected siblings (UAS) of BD probands within identified clusters. METHODS: Cluster analysis was used to identify cognitive clusters in BD (N = 60). UAS (N = 49) were classified into groups according to their proband sibling's cluster assignment; comparisons were made across all clusters and healthy controls (HCs; N = 71). RESULTS: Three cognitive clusters in BD emerged: a globally impaired (36.7%), a selectively impaired (30%), and a cognitively intact cluster (33.3%). UAS showed a qualitatively similar pattern to their BD siblings; UAS of the globally impaired BD cluster showed verbal memory and general cognitive impairments relative to HCs. In contrast, UAS of the other two clusters did not differ from HCs. CONCLUSIONS: This study corroborates findings from prior work regarding the presence of cognitive heterogeneity in BD. UAS of subjects in the globally impaired BD cluster presented with a qualitatively similar cognitive profile to their siblings and performed worse than all other BD clusters and UAS groups. This suggests that inherited risk factors may be contributing to cognitive deficits more notably in one subgroup of patients with BD, pointing toward differential causes of cognitive deficits in discrete subgroups of patients with the disorder.

Chlorhexidine gluconate or polyhexamethylene biguanide disc dressing to reduce the incidence of central-line-associated bloodstream infection: a feasibility randomized controlled trial (the CLABSI trial).

BACKGROUND: A number of antimicrobial-impregnated discs to prevent central-line-associated bloodstream infection (CLABSI) are marketed but it is unclear which disc is most effective. AIM: To investigate the feasibility and safety of comparing two antimicrobial-impregnated discs to prevent CLABSI. METHODS: A single-centre, parallel group, randomized controlled trial was conducted in a 929-bed tertiary referral hospital. Hospital inpatients requiring a peripherally inserted central catheter were randomized to chlorhexidine gluconate (CHG) or polyhexamethylene biguanide (PHMB) disc dressing group. Dressings were replaced every seven days, or earlier, if clinically required. Participants were followed until device removal or hospital discharge. Feasibility outcomes included: proportion of potentially eligible participants who were enrolled; proportion of protocol violations; and proportion of patients lost to follow-up. Clinical outcomes were: CLABSI incidence, diagnosed by a blinded infection control practitioner; all-cause bloodstream infection (BSI); and product-related adverse events. FINDINGS: Of 143 patients screened, 101 (71%) were eligible. Five (3.5%) declined participation. There was one post-randomization exclusion. Two (2%) protocol violations occurred in the CHG group. No patients were lost to follow-up. Three (3%) BSIs occurred; two (2%) were confirmed CLABSIs (one in each group) and one a mucosal barrier injury-related BSI. A total of 1217 device-days were studied, resulting in 1.64 CLABSIs per 1000 catheter-days. One (1%) disc-related adverse event occurred in the CHG group. CONCLUSION: Disc dressings containing PHMB are safe to use for infection prevention at catheter insertion sites. An adequately powered trial to compare PHMB and CHG discs is feasible.

Wake and light therapy for moderate-to-severe depression - a randomized controlled trial.

OBJECTIVE: To examine the efficacy of using wake and light therapy as a supplement to standard treatment of hospitalized patients with depression. METHOD: In this randomized, controlled study, 64 patients with moderate-to-severe depression were allocated to standard treatment or to the intervention, which additionally consisted of three wake therapy sessions in one week, 30-min daily light treatment and sleep time stabilization over the entire nine-week study period. RESULTS: Patients in the wake therapy group had a significant decrease in depressive symptoms in week one as measured by HAM-D17 , 17.39 (CI 15.6-19.2) vs. 20.19 (CI 18.3-22.09) (P = 0.04), whereas no statistically significant differences were found between the groups in weeks two to nine. At week nine, the wake therapy group had a significantly larger increase in general self-efficacy (P = 0.001), and waking up during nights was a significantly less frequent problem (1.9 times vs. 3.2) (P = 0.0008). In most weeks, significantly fewer patients in the wake therapy group slept during the daytime, and if they slept, their naps were shorter (week three: 66 min vs. 117 min P = 0.02). CONCLUSION: The antidepressant effect initially achieved could not be maintained during the nine-week study period. However, sleep and general self-efficacy improved.

Nueva estrategia terapéutica en cáncer de recto localmente avanzado / A new therapeutic approach of locally advanced rectal cancer

El cáncer de recto es una enfermedad frecuente en la población, siendo un problema de salud importante a nivel nacional, con un probable aumento en la incidencia junto con la transición demográfica y epidemiológica de los últimos años. La cirugía ha sido históricamente el pilar fundamental en el tratamiento de esta patología, pero asociándose a una alta tasa de recurrencia, tanto locorregional como a distancia, como único tratamiento. Es por esto que se ha estudiado el agregar terapias adyuvantes a la cirugía, como lo es la radioterapia y quimioterapia. La evidencia ha demostrado que la adyuvancia con radioterapia más quimioterapia se asocia a mayor sobrevida global y menor recurrencia local y a distancia en comparación con la cirugía exclusiva. En el presente artículo se realiza una revisión de los principales estudios que evidencian la ventaja, tanto en sobrevida global como libre de enfermedad, del uso de la adyuvancia con radioterapia más quimioterapia, mencionando la última evidencia disponible sobre el tratamiento del cáncer de recto localmente avanzado y las perspectivas a futuro.

Rectal cancer is a common disease in general population, being a major health problem in our nation, with a likely increase in incidence associated to demographic and epidemiological transition in recent years. Historically, the surgery has been the mainstay in the treatment of this disease, but surgery alone is associated to a high rate of recurrence, both locoregional and distant. This is why it has been studied adding adjuvant therapies to surgery, as is radiotherapy and chemotherapy. The evidence has shown that adjuvant radiotherapy and chemotherapy is associated with increased overall survival and less local and distant recurrence compared to surgery alone. This article is a review of major studies that demonstrate the advantage of using adjuvant radiotherapy and chemotherapy in both overall and disease-free survival, mentioning the last evidence available in treatment of locally advanced rectal cancer.

Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia.

The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 × 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 × 10-5, model with SNPs HR=1.31, P=0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.

Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy.

Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome-wide association study to identify loci associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation, and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2.5 × 10-8 ). The PNPLA3 rs738409 variant explained 3.8% of the variability in ALT, and partly explained race-related differences in ALT. The PNPLA3 rs738409 association was replicated in an independent cohort of 2,285 patients treated on Children's Oncology Group protocol AALL0232 (P = 0.024). This is an example of a pharmacogenetic variant overlapping with a disease risk variant.