Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).

How do new crises impact HIV risk behaviour - exploring HIV risk behaviour according to COVID-19-related orphanhood status in South Africa?

The COVID-19 pandemic resulted in high death rates globally, and over 10.5 million children lost a parent or primary caregiver. Because HIV-related orphanhood has been associated with elevated HIV risk, we sought to examine HIV risk in children affected by COVID-19 orphanhood. Four hundred and twenty-one children and adolescents were interviewed, measuring seven HIV risk behaviours: condom use, age-disparate sex, transactional sex, multiple partners, sex associated with drugs/alcohol, mental health and social risks. Approximately 50% (211/421) experienced orphanhood due to COVID-19, 4.8% (20/421) reported living in an HIV-affected household, and 48.2% (203/421) did not know the HIV status of their household. The mean age of the sample was 12.7 years (SD:2.30), of whom 1.2% (5/421) were living with HIV. Eighty percent (337/421) reported at least one HIV risk behaviour. HIV sexual risk behaviours were more common among children living in HIV-affected households compared to those not living in HIV-affected households and those with unknown household status (35.0% vs. 13.6% vs.10.8%, X2 = 9.25, p = 0.01). Children living in HIV-affected households had poorer mental health and elevated substance use (70.0% vs. 48.5%, X2 = 6.21, p = 0.05; 35.0% vs. 19.9%, X2 = 4.02, p = 0.1306, respectively). HIV-affected households may require specific interventions to support the health and well-being of children and adolescents.

Hand hygiene perceptions, preferences, and practices among hospital staff in the Dominican Republic in the context of COVID-19: a qualitative study.

Background: Proper hand hygiene (HH), which includes sanitizing with alcohol-based hand rub (ABHR) (or handwashing with soap and water if ABHR is unavailable), is key for preventing healthcare-associated infections (HCAI), including COVID-19. Understanding drivers of HH is key to improving adherence. Aim: This study aims to explore drivers and barriers to HH practice at two hospitals in the Dominican Republic in the context of the COVID-19 pandemic to inform development of HH behaviour change interventions. Methods: We conducted in-depth interviews with 20 hospital staff during September 2021. We used the COM-B (capability, opportunity, motivation, behaviour) model to explore HH experiences and preferences. Interviews were recorded, transcribed, coded, and analysed using a thematic approach. Results: A total of 11 parent codes and 27 sub-codes were identified, and 1145 coded segments were analysed. Use of handwashing with soap and water and/or sanitizing with ABHR was reported by all participants; handwashing was generally preferred. Participants expressed knowledge of proper HH methods (capability), but inconsistent supplies and lack of time presented HH challenges (opportunity). Interviewees described practicing HH to protect themselves and their families from COVID-19 and other infections (reflective motivation) or out of habit (automatic motivation). Discussion: By understanding and addressing underlying factors affecting HH, hospitals can decrease the risk of HCAIs. Our findings suggest that interventions implemented to improve HH in these hospitals should target motivation and opportunity. These findings informed a multimodal intervention to increase ABHR access and implement message-tested communications campaigns; end-point assessments will provide insights into the intervention's impact.

Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL.

ABSTRACT: The phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard-of-care chemotherapy (SC). Here, we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n = 43; SC, n = 48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery were observed with InO vs SC in patients with BCR::ABL1-like ALL (85.7% [6/7] vs 0% [0/5]; P = .0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8]; P = .0047), and in the high-risk BCR::ABL1- (BCR::ABL1-like, low-hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P < .0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1-like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1-like subtype or harboring TP53 alterations is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT01564784.

Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL.

ABSTRACT: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO hyper-mutators resulting from error-prone DNA damage repair (nonhomologous/alternative end-joining repair, or mismatch repair deficiency), suggesting that hypermutation drove escape from CD22-directed therapy. CD22-mutant relapses occurred after InO and subsequent hematopoietic stem cell transplantation (HSCT), suggesting that InO eliminated the predominant clones, leaving subclones with acquired CD22 mutations that conferred resistance to InO and subsequently expanded. Acquired loss-of-function mutations in TP53, ATM, and CDKN2A were observed, consistent with a compromise of the G1/S DNA damage checkpoint as a mechanism for evading InO-induced apoptosis. Genome-wide CRISPR/Cas9 screening of cell lines identified DNTT (terminal deoxynucleotidyl transferase) loss as a marker of InO resistance. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. Our findings highlight the importance of defining the basis of CD22 escape and eradication of residual disease before HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss and provide opportunities to improve therapeutic approaches and overcome resistance. These trials were registered at www.ClinicalTrials.gov as NCT01134575, NCT01371630, and NCT03441061.

Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group.

PURPOSE: Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019. METHODS: We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials. RESULTS: Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 103/µL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005). CONCLUSION: Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.

Associations of formal childcare use with health and human capital development for adolescent mothers and their children in South Africa: A cross-sectional study.

AIM: This study aims to investigate associations of formal childcare with maternal and child outcomes in a large sample of adolescent mothers. BACKGROUND: Forty percent of adolescent girls in Africa are mothers. Increasing evidence shows positive impacts of formal childcare use for adult women, but no known studies in the Global South examine associations for adolescent mothers and their children. METHODS: We interviewed 1046 adolescent mothers and completed developmental assessments with their children (n = 1139) in South Africa's Eastern Cape between 2017 and 2019. Questionnaires measured childcare use, maternal and child outcomes and socio-demographic background variables. Using cross-sectional data, associations between formal childcare use and outcomes were estimated in multivariate multi-level analyses that accounted for individual-level and family-level clustering. RESULTS: Childcare use was associated with higher odds of being in education or employment (AOR: 4.01, 95% CIs: 2.59-6.21, p < .001), grade promotion (AOR: 2.08, 95% CIs: 1.42-3.05, p < .001) and positive future ideation (AOR: 1.58, 95% CIs: 1.01-2.49, p = .047) but no differences in mental health. Childcare use was also associated with better parenting on all measures: positive parenting (AOR: 1.66, 95% CIs: 1.16-2.38, p = .006), better parental limit-setting (AOR: 2.00, 95% CIs: 1.37-2.93, p < .001) and better positive discipline (AOR: 1.77, 95% CIs: 1.21-2.59, p = .003). For the children, there were no differences in temperament or illness, but a significant interaction showed stronger associations between childcare use and better cognitive, language and motor scores with increasing child age (AOR: 5.04, 95% CIs: 1.59-15.96, p = .006). CONCLUSIONS: Adolescent mothers might benefit substantially from formal childcare, but causal links need to be explored further. Childcare use was also associated with improved parenting and better child development over time, suggesting positive pathways for children. At an average of $9 per month, childcare provisions for adolescent mothers may offer low-cost opportunities to achieve high returns on health and human capital outcomes in Sub-Saharan African contexts.

Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL.

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response to InO. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed tumor samples. There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included protein truncation, protein destabilization, and epitope alteration. Hypermutation by error-prone DNA damage repair (alternative end-joining, mismatch repair deficiency) drove CD22 escape. Acquired loss-of-function mutations in TP53 , ATM and CDKN2A were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The escape strategies within and beyond antigen loss to CD22-targeted therapy elucidated in this study provide insights into improving therapeutic approaches and overcoming resistance. KEY POINTS: We identified multiple mechanisms of CD22 antigen escape from inotuzumab ozogamicin, including protein truncation, protein destabilization, and epitope alteration.Hypermutation caused by error-prone DNA damage repair was a driver of CD22 mutation and escape.

Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

PURPOSE: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease. METHODS: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts. RESULTS: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], P =9.5 x 10 -5 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], P =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating LMO2 activation and inactivating STAG2 inactivation ( STAG2/LMO2 ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine. CONCLUSION: γδ T-ALL in children under the age of three is extremely high-risk and enriched for STAG2/LMO2 ALL. STAG2 loss perturbs chromatin conformation and differentiation, and STAG2/LMO2 ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL. SUPPORT: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.

Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL.

PURPOSE: High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain. METHODS: We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs. RESULTS: Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% v 86.8%; P = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% v 8.8%; P = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17. CONCLUSION: Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.

Key normative, legal, and policy considerations for supporting pregnant and postpartum adolescents in high HIV-burden settings: a critical analysis.

Rates of adolescent pregnancy within sub-Saharan Africa are increasing. Adolescent mothers ages 10-19 years face a distinct set of risks to their own and their children's health, compounded by many economic, social, and epidemiological challenges, such as living with HIV. In navigating this complex developmental period, many adolescent mothers face structural barriers impeding safe transitions to adulthood and motherhood. Drawing on existing literature and emerging data, we outline three normative, legal, and policy issues - violence and gender inequity, access to sexual and reproductive health services, and access to social and structural supports - which affect the health, wellbeing and development of adolescent mothers and their children. We also highlight emergent evidence about programming and policy changes that can better support adolescent mothers and their children. These key proposed responses include removing barriers to SRH and HIV service integration; ensuring implementation of return-to-school policies; and extending social protection systems to cater for adolescent mothers. Despite ongoing global crises and shifts in funding priorities, these normative, legal, and policy considerations remain critical to safeguard the health and wellbeing of adolescent mothers and their children.

Sydenham chorea in the top end of Australia's Northern Territory: A 20-year retrospective case series.

AIM: Sydenham chorea is an immune-mediated neuropsychiatric condition, and a major criterion for diagnosis of acute rheumatic fever (ARF). Children in remote Northern Australia experience disproportionately high rates of ARF, yet studies looking at the epidemiology, clinical presentation and management of Sydenham chorea are limited in this population. METHODS: We conducted a retrospective case series from January 2002 to April 2022 of all paediatric patients aged ≤18 years admitted to Royal Darwin Hospital with Sydenham chorea. Cases were identified using the hospital's clinical coding system (ICD10). Medical records were reviewed and data on demographics, clinical presentation, investigation results, treatment and outcome were extracted, deidentified and analysed. RESULTS: One hundred ten presentations of Sydenham chorea occurred between 2002 and 2022, 109 (99%) of these were in First Nations children, with 85% residing in very remote locations. Most commonly, chorea presented as a generalised movement disorder affecting all four limbs (49%). Neuropsychiatric symptoms were reported in 33 (30%), and there was evidence of rheumatic heart disease on echocardiogram in 86 (78%) at presentation. All patients received benzathine penicillin, but there was significant variation in management of chorea, ranging from supportive management, to symptomatic management with anticonvulsants, to immunomodulatory medications including corticosteroids. CONCLUSION: This case series highlights the significant burden of Sydenham chorea among First Nations children living in Northern Australia and demonstrates wide variation in treatment approaches. High-quality clinical trials are required to determine the best treatment for this disabling condition.

Creating Connections: A Feasibility Study of a Technology-Based Intervention to Support Mothers of Newborns during Pediatric Well-Visits.

Objective: Intervention in the earliest period of parenthood can make a strong, positive impact on parenting, yet engaging parents of newborns in parenting interventions can be difficult. Technological adaptation of important interventions can improve early engagement. This study reports the initial feasibility of the Creating Connections intervention, a technology-based intervention developed to support mothers of newborns, and feasibility of evaluating the intervention through a randomized clinical trial in pediatric primary care. The intervention includes: 1) a brief tablet-based intervention delivered during a newborn well-child pediatric check-up, and 2) tailored text messages delivered thereafter to boost intervention content. Intervention content includes empirically-supported aspects of parenting behaviors known to positively influence children's social-emotional development. Methods: Project recruitment took place in an ambulatory care pediatric clinic in a large Midwestern city. Mothers received information about infant soothing, book sharing, or both. Results: One hundred and three parents learned about the program and 72 participated. Mothers were primarily Black/African American with incomes at or below $30,000. Only 50% of mothers that received text messages through the program completed follow-up, but these mothers gave overall positive ratings of text messages. Conclusions: Program engagement and ratings of parents support feasibility, but retention rates need improvement. Based on barriers and successes of this investigation, lessons learned about feasibility and acceptability are discussed.

Protocol for the OCAY study: a cohort study of orphanhood and caregiver loss in the COVID-19 era to explore the impact on children and adolescents.

INTRODUCTION: Globally, no person has been untouched by the COVID-19 pandemic. Yet, little attention has been given to children and adolescents in policy, provision and services. Moreover, there is a dearth of knowledge regarding the impact of COVID-19-associated orphanhood and caregiver loss on children. This study aims to provide early insights into the mental health and well-being of children and adolescents experiencing orphanhood or caregiver loss in South Africa. METHODS AND ANALYSIS: Data will be drawn from a quantitative longitudinal study in Cape Town, South Africa. A sample of children and adolescents between the ages of 9 and 18 years, experiencing parental or caregiver loss from COVID-19, will be recruited together with a comparison group of children in similar environments who did not experience loss. The study aims to recruit 500 children in both groups. Mental health and well-being among children will be explored through the use of validated and study-specific measures. Participants will be interviewed at two time points, with follow-up data being collected 12-18 months after baseline. A combination of analytical techniques (including descriptive statistics, regression modelling and structural equation modelling) will be used to understand the experience and inform future policy and service provision. ETHICS AND DISSEMINATION: This study received ethical approval from the Health Research Ethics Committee at Stellenbosch University (N 22/04/040). Results will be disseminated via academic and policy publications, as well as national and international presentations including high-level meetings with technical experts. Findings will also be disseminated at a community level via various platforms.

How Is Functional Neurological Disorder Managed in Australian Hospitals? A Multi-Site Study Conducted on Acute Inpatient and Inpatient Rehabilitation Wards.

Background: Successful management for functional neurological disorder (FND) requires multidisciplinary involvement starting with providing a definitive diagnosis. Objectives: To observe clinical management of patients with FND during hospital admission. Methods: A prospective observational study was conducted over six Australian hospitals over a 4-month period. Data collected included patient demographics, communication of the diagnosis of FND, access to the multidisciplinary team, hospital length of stay (LOS), and emergency department (ED) presentations. Results: A total of 113 patients were included. Median LOS was 6 (interquartile range, 3-14) days. Thirty-five (31%) presented to ED with 9 (8%) re-presenting two or more times after hospital discharge. Total hospital utilization cost was AUD$3.5million. A new diagnosis was made in 82 (73%) patients. Inpatient referrals were made to neurology (81, 72%), psychology (29, 26%), psychiatry (27, 24%), and physiotherapy (100, 88%). Forty-four (54%) were not told of the diagnosis. Twenty (24%) did not have their diagnosis documented in their medical record. Of the 19 (23%) not reviewed by neurology on non-neurosciences wards, 17 (89%) did not have their diagnosis communicated and 11 (58%) did not have it documented. Twenty-five (42%) referred to neurology were not provided with a diagnosis. Conclusions: Current gaps in service provision during inpatient hospital admissions in Australia include low rates of communication of a diagnosis, particularly when patients are not located on a neurosciences ward, and limited and variable access to inpatient multidisciplinary teams. Specialized services are needed to improve education, clinical pathways, communication, and health outcomes while reducing healthcare system costs.

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

Parenting in Adversity: Effects of Older Caregivers, Biological Carers and Troubled Carers on Child Outcomes in High HIV-Affected Communities.

Caregiving by older adults is a common phenomenon, enhanced in the era of HIV infection. This longitudinal study was set up to examine the effect of caregiver age, relationship and mental wellbeing on child (4-13 years) outcomes (psychosocial and cognitive) in a sample of 808 caregiver- child dyads in South Africa and Malawi. Respondents were drawn from consecutive attenders at Community Based Organisations (CBOs) and interviewed with standardised inventories at baseline and followed up 12-15 months later. Analysis focused on three separate aspects of the caregiver; age, relationship to the child, and mental wellbeing, results are stratified with regard to these factors. Results showed that compared to younger caregivers, over 50 years were carrying a heavy load of childcare, but caregiver age for the most part was not associated with child outcomes. Being biologically related to the child (such as biological grandparenting) was also not a significant factor in child outcomes measured. However, irrespective of age and relationship, caregiver mental health was associated with differences in child outcome - those children of caregivers with a greater mental health burden were found to report experiencing more physical and psychologically violent discipline. Over time, the use of violent discipline was found to reduce. These data suggest that older caregivers and grandparents are providing comparable care to younger caregivers, for young children in the face of the HIV epidemic and that interventions should focus on mental health support for all caregivers, irrespective of age or relationship to the child.

Philadelphia-Like Genetic Rearrangements in Adults With B-Cell ALL: Refractoriness to Chemotherapy and Response to Tyrosine Kinase Inhibitor in ABL Class Rearrangements.

PURPOSE: Philadelphia-like (Ph-like) B-cell ALL is a high-risk subtype of B-cell ALL that shares a gene expression profile with Ph-positive ALL, but without a BCR::ABL1 fusion. A subgroup of these patients have fusions or rearrangements involving genes such as ABL1, ABL2, PDGFRß, JAK2, and EPOR, some of which are potentially sensitive to tyrosine kinase inhibitors (TKIs). Prompt identification of these genetic aberrations are important for prognostication and treatment decisions. PATIENTS AND METHODS: We performed a retrospective review of patients with B-cell ALL treated at MD Anderson Cancer Center to identify recurrent genetic fusions commonly seen in Ph-like ALL and focus on patients treated with TKI. RESULTS: We identified 23 patients with recurrent genetic fusions commonly seen in Ph-like ALL; 14 had ABL class fusions (eight ABL1, one ABL2, and five PDGFRß) and nine had JAK2 class fusions (five JAK2 and four EPOR). Notably, several of these fusions were cryptic by conventional cytogenetics and fluorescent in situ hybridization (FISH) assays and identified only by multiplex fusion assay. Thirteen of these 23 patients received a TKI as part of their treatment; this included ABL1 fusion (n = 8), PDGFRß fusion (n = 4), and EPOR fusion (n = 1). All four patients with ABL1 fusions who received TKI with induction chemotherapy are alive in first remission. CONCLUSION: Understanding the genomics of B-cell ALL is important for disease prognostication and for precise treatment planning. Besides conventional cytogenetics and directed FISH testing, multiplex fusion assays can help identify recurrent chromosomal translocations that are seen in patients with Ph-like ALL. Early initiation of TKI appears beneficial; larger studies are required to fully understand the benefit of TKI and to design rational combination therapies for these patients.