Broadly neutralizing antibody responses in the longitudinal primary HIV-1 infection Short Pulse Anti-Retroviral Therapy at Seroconversion cohort

OBJECTIVE: Development of immunogens that elicit an anti-HIV-1 broadly neutralizing antibody (bnAb) response will be a key step in the development of an effective HIV-1 vaccine. Although HIV-1 bnAb epitopes have been identified and mechanisms of action studied, current HIV-1 envelope-based immunogens do not elicit HIV-1 bnAbs in humans or animal models. A better understanding of how HIV-1 bnAbs arise during infection and the clinical factors associated with bnAb development may be critical for HIV-1 immunogen design efforts. DESIGN AND METHODS: Longitudinal plasma samples from the treatment-naive control arm of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) primary HIV-1 infection cohort were used in an HIV-1 pseudotype neutralization assay to measure the neutralization breadth, potency and specificity of bnAb responses over time. RESULTS: In the SPARTAC cohort, development of plasma neutralization breadth and potency correlates with duration of HIV infection and high viral loads, and typically takes 3-4 years to arise. bnAb activity was mostly directed to one or two bnAb epitopes per donor and more than 60% of donors with the highest plasma neutralization having bnAbs targeted towards glycan-dependent epitopes. CONCLUSION: This study highlights the SPARTAC cohort as an important resource for more in-depth analysis of bnAb developmental pathways

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterized by extreme morbidity and mortality

Background: The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored. Methods and results: We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent-offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic. Conclusion: Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Castan Centre human rights report 2015

Summarises some key human rights issues facing Australia and the world in 2015. Foreword Since our inaugural Castan Centre Human Rights Report last April, it has felt as if the number of human rights issues facing people around the world is overwhelming. The Castan Centre has found itself working on a number of fronts to promote and protect human rights. Some of those areas will be very familiar to our supporters, and some will be quite novel. Indigenous Australians continue to face enormous obstacles to ‘closing the gap’ in the face of large budget cuts and entrenched bureaucratic barriers. For example, a multi-year research project by Castan Centre staff has revealed that unregistered births, which disproportionately affect Indigenous people, can increase imprisonment rates. The assault on asylum seekers’ human rights continues unabated. In this report, two pieces look at the latest legislative and policy changes. Entrenched political opinion on this issue may make it seem futile to address refugee rights at this time. However, there will likely be consequences for the perpetration of such grave human rights abuses, as mentioned in my introductory piece. Prisoners’ rights is another topic that rarely draws sympathy from the general public. As prisons are so far from the public eye and prisoners so susceptible to abuse, it is a vital human rights issue nonetheless. In this report, we look at how lawyers and judges often fail to use human rights laws to protect prisoners, while in other cases novel methods are being used to hold prison authorities to account. The nexus between human rights here and overseas has never been greater – from commercial surrogacy to LGBT rights, land grabs and international criminal law to the death penalty, Australians are increasingly grappling with complex human rights issues. This report – which covers just some of the many issues facing humanity today – reminds us that there has rarely been a more important time to stand up for human rights, both here and around the world. The report coincides with our annual appeal, and we hope that you will choose to support us at this crucial moment