NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.

B cell progenitor acute lymphoblastic leukemia (B-ALL) treatment has been revolutionized by T cell-based immunotherapies-including chimeric antigen receptor T cell therapy (CAR-T) and the bispecific T cell engager therapeutic, blinatumomab-targeting surface glycoprotein CD19. Unfortunately, many patients with B-ALL will fail immunotherapy due to 'antigen escape'-the loss or absence of leukemic CD19 targeted by anti-leukemic T cells. In the present study, we utilized a genome-wide CRISPR-Cas9 screening approach to identify modulators of CD19 abundance on human B-ALL blasts. These studies identified a critical role for the transcriptional activator ZNF143 in CD19 promoter activation. Conversely, the RNA-binding protein, NUDT21, limited expression of CD19 by regulating CD19 messenger RNA polyadenylation and stability. NUDT21 deletion in B-ALL cells increased the expression of CD19 and the sensitivity to CD19-specific CAR-T and blinatumomab. In human B-ALL patients treated with CAR-T and blinatumomab, upregulation of NUDT21 mRNA coincided with CD19 loss at disease relapse. Together, these studies identify new CD19 modulators in human B-ALL.

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.).

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 patients with ETV6::RUNX1 or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies.

Children with ETV6::RUNX1 or high-hyperdiploid B-acute lymphoblastic leukemia (B-ALL) have favorable outcomes. The St. Jude (SJ) classification considers these patients low-risk, regardless of their National Cancer Institute (NCI) risk, except when there is slow minimal residual disease (MRD) response or central nervous system/testicular involvement. We analyzed outcomes in children (aged 1-18.99 years) with these genotypes in the SJ Total XV and XVI studies (2000-2017). Patients with ETV6::RUNX1 (n = 222) or high-hyperdiploid (n = 296) B-ALL had 5-year event-free survival (EFS) of 97.7% ± 1.1% and 94.7% ± 1.4%, respectively. For ETV6::RUNX1, EFS was comparable for NCI standard-risk and high-risk patients (97.8% ± 1.2% and 97.5% ± 2.6%, respectively; P = 0.917) and for SJ low-risk and standard-risk patients (97.4% ± 1.2% and 100.0%; P = 0.360). Thirty-seven of 40 NCI high-risk patients who received SJ low-risk therapy had excellent EFS (97.3% ± 2.8%). For high-hyperdiploid B-ALL, EFS was worse for NCI high-risk patients than for standard-risk patients (87.6% ± 4.5% and 96.4% ± 1.3%; P = 0.016). EFS was similar for NCI standard-risk and high-risk patients classified as SJ low-risk (96.0% ± 1.5% and 96.9% ± 3.2%; P = 0.719); however, EFS was worse for NCI high-risk patients than for NCI standard-risk patients receiving SJ standard/high-risk therapy (77.4% ± 8.2% and 98.0% ± 2.2%; P = 0.004). NCI high-risk patients with ETV6::RUNX1 or high-hyperdiploid B-ALL who received SJ low-risk therapy had lower incidences of thrombosis (P = 0.013) and pancreatitis (P = 0.011) than those who received SJ standard/high-risk therapy. Contemporary MRD-directed therapy yielded excellent outcomes, except for NCI high-risk high-hyperdiploid B-ALL patients with slow MRD response, who require new treatment approaches. Among NCI high-risk patients, 93% with ETV6::RUNX1 and 54% with high-hyperdiploid B-ALL experienced excellent outcomes with a low-intensity regimen. These trials were registered at www.clinicaltrials.gov as #NCT00137111 and #NCT00549848.

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.

Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia.

Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, we used integrated whole-genome (WGS) and -transcriptome sequencing (RNA-seq), enhancer mapping, and chromatin topology analysis to identify previously unrecognized genomic drivers in B-ALL. Newly diagnosed (n = 3221) and relapsed (n = 177) B-ALL cases with tumor RNA-seq were studied. WGS was performed to detect mutations, structural variants, and copy number alterations. Integrated analysis of histone 3 lysine 27 acetylation and chromatin looping was performed using HiChIP. We identified a subset of 17 newly diagnosed and 5 relapsed B-ALL cases with a distinct gene expression profile and 2 universal and unique genomic alterations resulting from aberrant recombination-activating gene activation: a focal deletion downstream of PAN3 at 13q12.2 resulting in CDX2 deregulation by the PAN3 enhancer and a focal deletion of exons 18-21 of UBTF at 17q21.31 resulting in a chimeric fusion, UBTF::ATXN7L3. A subset of cases also had rearrangement and increased expression of the PAX5 gene, which is otherwise uncommon in B-ALL. Patients were more commonly female and young adult with median age 35 (range,12-70 years). The immunophenotype was characterized by CD10 negativity and immunoglobulin M positivity. Among 16 patients with known clinical response, 9 (56.3%) had high-risk features including relapse (n = 4) or minimal residual disease >1% at the end of remission induction (n = 5). CDX2-deregulated, UBTF::ATXN7L3 rearranged (CDX2/UBTF) B-ALL is a high-risk subtype of leukemia in young adults for which novel therapeutic approaches are required.

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.

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.

Monitoring Temporal Changes in SARS-CoV-2 Spike Antibody Levels and Variant-Specific Risk for Infection, Dominican Republic, March 2021-August 2022.

To assess changes in SARS-CoV-2 spike binding antibody prevalence in the Dominican Republic and implications for immunologic protection against variants of concern, we prospectively enrolled 2,300 patients with undifferentiated febrile illnesses in a study during March 2021-August 2022. We tested serum samples for spike antibodies and tested nasopharyngeal samples for acute SARS-CoV-2 infection using a reverse transcription PCR nucleic acid amplification test. Geometric mean spike antibody titers increased from 6.6 (95% CI 5.1-8.7) binding antibody units (BAU)/mL during March-June 2021 to 1,332 (95% CI 1,055-1,682) BAU/mL during May-August 2022. Multivariable binomial odds ratios for acute infection were 0.55 (95% CI 0.40-0.74), 0.38 (95% CI 0.27-0.55), and 0.27 (95% CI 0.18-0.40) for the second, third, and fourth versus the first anti-spike quartile; findings were similar by viral strain. Combining serologic and virologic screening might enable monitoring of discrete population immunologic markers and their implications for emergent variant transmission.

Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL.

Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 [75%] of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19- relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19- relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure.

Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia.

CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) accounts for more than half of Philadelphia chromosome-like (Ph-like) ALL and is associated with a poor outcome in children and adults. Overexpression of CRLF2 results in activation of Janus kinase (JAK)-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of JAKs show variable and limited efficacy. Here, we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAKs. Solving the structure of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled the rational design and optimization of a series of cereblon (CRBN)-directed JAK PROTACs utilizing derivatives of JAK inhibitors, linkers, and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation, and activity was tested in a panel of leukemia/lymphoma cell lines and xenograft models of kinase-driven ALL. Multiple PROTACs were developed that degraded JAKs and potently killed CRLF2r cell lines, the most active of which also degraded the known CRBN neosubstrate GSPT1 and suppressed proliferation of CRLF2r ALL in vivo, e.g. compound 7 (SJ988497). Although dual JAK/GSPT1-degrading PROTACs were the most potent, the development and evaluation of multiple PROTACs in an extended panel of xenografts identified a potent JAK2-degrading, GSPT1-sparing PROTAC that demonstrated efficacy in the majority of kinase-driven xenografts that were otherwise unresponsive to type I JAK inhibitors, e.g. compound 8 (SJ1008030). Together, these data show the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT-driven ALL and highlight the interplay of JAK and GSPT1 degradation activity in this context.

The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13.

B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B-cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL-initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL-initiating cells prolonged murine survival, whereas high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13 axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.

Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL.

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

Does pre-COVID impulsive behaviour predict adherence to hygiene and social distancing measures in youths following the COVID-19 pandemic onset? Evidence from a South African longitudinal study.

BACKGROUND: Engagement in protective behaviours relating to the COVID-19 pandemic has been proposed to be key to infection control. This is particularly the case for youths as key drivers of infections. A range of factors influencing adherence have been identified, including impulsivity and risk taking. We assessed the association between pre-COVID impulsivity levels and engagement in preventative measures during the COVID-19 pandemic in a longitudinal South African sample, in order to inform future pandemic planning. METHODS: Data were collected from N = 214 youths (mean age at baseline: M = 17.81 (SD = .71), 55.6% female) living in a South African peri-urban settlement characterised by high poverty and deprivation. Baseline assessments were taken in 2018/19 and the COVID follow-up was conducted in June-October 2020 via remote data collection. Impulsivity was assessed using the Balloon Analogue Task (BART), while hygiene and social distancing behaviours were captured through self-report. Stepwise hierarchical regression analyses were performed to estimate effects of impulsivity on measure adherence. RESULTS: Self-rated engagement in hygiene behaviours was high (67.1-86.1% "most of the time", except for "coughing/sneezing into one's elbow" at 33.3%), while engagement in social distancing behaviours varied (22.4-57.8% "most of the time"). Higher impulsivity predicted lower levels of hygiene (ß = .14, p = .041) but not social distancing behaviours (ß = -.02, p = .82). This association was retained when controlling for a range of demographic and COVID-related factors (ß = .14, p = .047) and was slightly reduced when including the effects of a life-skills interventions on hygiene behaviour (ß = -.13, p = .073). CONCLUSIONS: Our data indicate that impulsivity may predict adolescent engagement in hygiene behaviours post COVID-19 pandemic onset in a high risk, sub-Saharan African setting, albeit with a small effect size. For future pandemics, it is important to understand predictors of engagement, particularly in the context of adversity, where adherence may be challenging. Limitations include a small sample size and potential measure shortcomings.

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.

Exploring the cognitive development of children born to adolescent mothers in South Africa.

This study explores the cognitive development of children born to adolescent mothers within South Africa compared to existing reference data, and explores development by child age bands to examine relative levels of development. Cross-sectional analyses present data from 954 adolescents (10-19 years) and their first-born children (0-68 months). All adolescents completed questionnaires relating to themselves and their children, and standardized child cognitive assessments (Mullen Scales of Early Learning) were undertaken. Cognitive development scores of the sample were lower than USA reference population scores and relative performance compared to the reference population was found to decline with increasing child age. When compared to children born to adult mothers in the sub-Saharan African region, children born to adolescent mothers (human immunodeficiency virus [HIV] unexposed; n = 724) were found to have lower cognitive development scores. Findings identify critical periods of development where intervention may be required to bolster outcomes for children born to adolescent mothers. Highlights: An exploration of the cognitive development of children born to adolescent mothers within South Africa utilizing the Mullen Scales of Early Learning.Cognitive development scores of children born to adolescent mothers within South Africa were lower compared to USA norm reference data and declined with child age.Previous studies utilizing the Mullen Scales of Early Learning within sub-Saharan Africa were summarized, and comparisons were made with the current sample.Findings highlight a potential risk of developmental delay among children born to adolescent mothers compared to children of adult mothers in the sub-Saharan African region.

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.

Adolescent Motherhood and HIV in South Africa: Examining Prevalence of Common Mental Disorder.

The mental health of adolescents (10-19 years) remains an overlooked global health issue, particularly within the context of syndemic conditions such as HIV and pregnancy. Rates of pregnancy and HIV among adolescents within South Africa are some of the highest in the world. Experiencing pregnancy and living with HIV during adolescence have both been found to be associated with poor mental health within separate explorations. Yet, examinations of mental health among adolescents living with HIV who have experienced pregnancy/parenthood remain absent from the literature. As such, there exists no evidence-based policy or programming relating to mental health for this group. These analyses aim to identify the prevalence of probable common mental disorder among adolescent mothers and, among adolescents experiencing the syndemic of motherhood and HIV. Analyses utilise data from interviews undertaken with 723 female adolescents drawn from a prospective longitudinal cohort study of adolescents living with HIV (n = 1059) and a comparison group of adolescents without HIV (n = 467) undertaken within the Eastern Cape Province, South Africa. Detailed study questionnaires included validated and study specific measures relating to HIV, adolescent motherhood, and mental health. Four self-reported measures of mental health (depressive, anxiety, posttraumatic stress, and suicidality symptomology) were used to explore the concept of likely common mental disorder and mental health comorbidities (experiencing two or more common mental disorders concurrently). Chi-square tests (Fisher's exact test, where appropriate) and Kruskal Wallis tests were used to assess differences in sample characteristics (inclusive of mental health status) according to HIV status and motherhood status. Logistic regression models were used to explore the cross-sectional associations between combined motherhood and HIV status and, likely common mental disorder/mental health comorbidities. 70.5% of participants were living with HIV and 15.2% were mothers. 8.4% were mothers living with HIV. A tenth (10.9%) of the sample were classified as reporting a probable common mental disorder and 2.8% as experiencing likely mental health comorbidities. Three core findings emerge: (1) poor mental health was elevated among adolescent mothers compared to never pregnant adolescents (measures of likely common mental disorder, mental health comorbidities, depressive, anxiety and suicidality symptoms), (2) prevalence of probable common mental disorder was highest among mothers living with HIV (23.0%) compared to other groups (Range:8.5-12.8%; Χ2 = 12.54, p = 0.006) and, (3) prevalence of probable mental health comorbidities was higher among mothers, regardless of HIV status (HIV & motherhood = 8.2%, No HIV & motherhood = 8.2%, Χ2 = 14.5, p = 0.002). Results identify higher mental health burden among adolescent mothers compared to never-pregnant adolescents, an increased prevalence of mental health burden among adolescent mothers living with HIV compared to other groups, and an elevated prevalence of mental health comorbidities among adolescent mothers irrespective of HIV status. These findings address a critical evidence gap, highlighting the commonality of mental health burden within the context of adolescent motherhood and HIV within South Africa as well as the urgent need for support and further research to ensure effective evidence-based programming is made available for this group. Existing antenatal, postnatal, and HIV care may provide an opportunity for mental health screening, monitoring, and referral.

Can a combination of interventions accelerate outcomes to deliver on the Sustainable Development Goals for young children? Evidence from a longitudinal study in South Africa and Malawi.

BACKGROUND: This study aimed to identify possible entry points for interventions that can act as development accelerators for children and adolescents in South Africa and Malawi. METHODS: This study was a secondary data analysis. Data were sourced from the Child Community Care longitudinal study which tracked child well-being outcomes among 989 children (4-13 years) and their caregivers affected by HIV and enrolled in community-based organizations in South Africa and Malawi. We examined associations between five hypothesized accelerating services/household provisions-measured as access at baseline and follow-up and 12 child outcomes that relate to indicators within the Sustainable Development Goals (SDGs) framework. We calculated the adjusted probabilities of experiencing each SDG aligned outcome conditional on receipt of single, combined or all identified accelerators. RESULTS: The results show household food security is associated with positive child education and cognitive development outcomes. Cash grants were positively associated with nutrition and cognitive development outcomes. Living in a safe community was positively associated with all mental health outcomes. Experiencing a combination of two factors was associated with higher probability of positive child outcomes. However, experiencing all three accelerators was associated with better child outcomes, compared with any of the individual factors by themselves with substantial improvements noted in child education outcomes. CONCLUSIONS: Combined delivery of specific interventions or services may yield greater improvements in child outcomes across different developmental domains. It is recommended that multiple support avenues in combination like improving food security and safe communities, as well as social protection grants, should be provided for vulnerable children to maximize the impact.

Which factors affect postpartum educational enrollment of adolescent mothers in South Africa? A latent class analysis.

Interrupted education of adolescent mothers remains a major concern, but limited evidence-based programming exists to support postpartum schooling of this group. This study aimed to better understand the factors that render some adolescent mothers vulnerable to school non-enrollment, and how to reduce these risks. Data from 1,046 adolescent and young mothers (10-24 years) from rural and urban communities in South Africa's Eastern Cape was obtained through a questionnaire containing validated and study-specific measures relating to sociodemographic characteristics, schooling, relationships, violence exposure, and health. Using latent class analysis, we explored emerging latent groups and their relationship to mothers' enrollment in school, college, or tertiary education. The analyses revealed three distinct groups of mothers: The 'most disadvantaged' subgroup (39%) experienced multiple risks, including food insecurity, living in informal housing, lacking positive relationships with their caregiver, and the highest distance to school; The 'disadvantaged' subgroup (44%) did not experience food insecurity whilst reporting better caregiver relationships and lower distance to school. However, this group still showed high probabilities of residing in informal housing and in communities that expose them to violence; A 'least disadvantaged' subgroup (17%) was largely unaffected by economic and community risks and experienced good caregiver relationships. Compared to the most disadvantaged mothers, the least disadvantaged mothers showed the highest probability of being enrolled in education (65% versus 45%). Adolescent motherhood can impede continued enrollment in education and individual-centered interventions alone might not be sufficient to mitigate the risks for non-enrollment. Services and provisions that address severe poverty and improve family relationships might provide an opportunity to positively influence schooling among adolescent mothers.