De novo enhancer deletion of LMX1B produces a mild nail-patella clinical phenotype.

Critical genes involved in embryonic development are often transcription factors, regulating many downstream genes. LMX1B is a homeobox gene that is involved in formation of the limbs, eyes and kidneys, heterozygous loss-of-function sequence variants and deletions cause Nail-Patella syndrome. Most of the reported variants are localised within the gene's coding sequence, however, approximately 5%-10% of affected individuals do not have a pathogenic variant identified within this region. In this study, we present a family with four affected individuals across two generations with a deletion spanning a conserved upstream LMX1B-binding sequence. This deletion is de novo in the mother of three affected children. Furthermore, in this family, the manifestations appear limited to the nails and limbs, and therefore may reflect an attenuated phenotype of the classic Nail-Patella phenotype that includes ophthalmological and renal manifestations.

Integrated multi-omics for rapid rare disease diagnosis on a national scale.

Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.

Inequality in Immunization: Holding on to Equity as We 'Catch Up'.

Immunization, hailed as one of the most successful public health interventions in the world, has contributed to major advancements in health as well as social and economic development [...].

Inequalities in Immunization against Maternal and Neonatal Tetanus: A Cross-Sectional Analysis of Protection at Birth Coverage Using Household Health Survey Data from 76 Countries.

Substantial progress in maternal and neonatal tetanus elimination has been made in the past 40 years, with dramatic reductions in neonatal tetanus incidence and mortality. However, twelve countries have still not achieved maternal and neonatal tetanus elimination, and many countries that have achieved elimination do not meet key sustainability thresholds to ensure long-lasting elimination. As maternal and neonatal tetanus is a vaccine-preventable disease (with coverage of the infant conferred by maternal immunization during and prior to pregnancy), maternal tetanus immunization coverage is a key metric for monitoring progress towards, equity in, and sustainability of tetanus elimination. In this study, we examine inequalities in tetanus protection at birth, a measure of maternal immunization coverage, across 76 countries and four dimensions of inequality via disaggregated data and summary measures of inequality. We find that substantial inequalities in coverage exist for wealth (with lower coverage among poorer wealth quintiles), maternal age (with lower coverage among younger mothers), maternal education (with lower coverage among less educated mothers), and place of residence (with lower coverage in rural areas). Inequalities existed for all dimensions across low- and lower-middle-income countries, and across maternal education and place of residence across upper-middle-income countries. Though global coverage changed little over the time period 2001-2020, this obscured substantial heterogeneity across countries. Notably, several countries had substantial increases in coverage accompanied by decreases in inequality, highlighting the need for equity considerations in maternal and neonatal tetanus elimination and sustainability efforts.

Strengthening and expanding health inequality monitoring for the advancement of health equity: a review of WHO resources and contributions.

As part of its commitment to advance health equity, the World Health Organization (WHO) has a developed area of work to promote and strengthen health inequality monitoring. This includes an emphasis on the collection, analysis and use of disaggregated health data, which are central to evidence-informed decision making. The aim of this paper is to review WHO's work on health inequality monitoring, namely the 2022-27 Inequality monitoring and analysis strategy and corresponding activities, resources and tools. The strategy has three goals pertaining to: strengthening capacity for health inequality monitoring; generating and disseminating the latest evidence on health inequality and supporting data disaggregation; and developing and refining health inequality monitoring methods, resources and best practices. In alignment with these goals, WHO has published reference materials focused on conceptual approaches to health inequality monitoring, which are applied in the global State of Inequality report series. The Health Inequality Monitoring eLearning channel on OpenWHO and capacity building workshops and webinars facilitate the uptake and application of inequality monitoring practices across diverse settings and stakeholders. A key tool available to support the analysis and reporting aspects of health inequality monitoring is the Health Equity Assessment Toolkit (HEAT) application, which allows users to explore data interactively. The Health Inequality Data Repository, a collection of the largest publicly available database of disaggregated data from around the globe, further enables inequality monitoring and analyses. This collection of resources is an important contribution to promote health inequality monitoring across diverse settings. The uptake of evidence from health inequality monitoring remains crucial to the advancement of equity as part of global health and development initiatives.

Within-Country Inequality in COVID-19 Vaccination Coverage: A Scoping Review of Academic Literature.

Since December 2020, COVID-19 vaccines have become increasingly available to populations around the globe. A growing body of research has characterised inequalities in COVID-19 vaccination coverage. This scoping review aims to locate, select and assess research articles that report on within-country inequalities in COVID-19 vaccination coverage, and to provide a preliminary overview of inequality trends for selected dimensions of inequality. We applied a systematic search strategy across electronic databases with no language or date restrictions. Our inclusion criteria specified research articles or reports that analysed inequality in COVID-19 vaccination coverage according to one or more socioeconomic, demographic or geographic dimension of inequality. We developed a data extraction template to compile findings. The scoping review was carried out using the PRISMA-ScR checklist. A total of 167 articles met our inclusion criteria, of which half (n = 83) were conducted in the United States. Articles focused on vaccine initiation, full vaccination and/or receipt of booster. Diverse dimensions of inequality were explored, most frequently relating to age (n = 127 articles), race/ethnicity (n = 117 articles) and sex/gender (n = 103 articles). Preliminary assessments of inequality trends showed higher coverage among older population groups, with mixed findings for sex/gender. Global research efforts should be expanded across settings to understand patterns of inequality and strengthen equity in vaccine policies, planning and implementation.

Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma.

We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.

Expanding the Allelic Heterogeneity of ANO10-Associated Autosomal Recessive Cerebellar Ataxia.

Background and Objectives: The term autosomal recessive cerebellar ataxia (ARCA) encompasses a diverse group of heterogeneous degenerative disorders of the cerebellum. Spinocerebellar ataxia autosomal recessive 10 (SCAR10) is a distinct classification of cerebellar ataxia caused by variants in the ANO10 gene. Little is known about the molecular role of ANO10 or its role in disease. There is a wide phenotypic spectrum among patients, even among those with the same or similar genetic variants. This study aimed to characterize the molecular consequences of variants in ANO10 and determine their pathologic significance in patients diagnosed with SCAR10. Methods: We presented 4 patients from 4 families diagnosed with spinocerebellar ataxia with potential pathogenic variants in the ANO10 gene. Patients underwent either clinical whole-exome sequencing or screening of a panel of known neuromuscular disease genes. Effects on splicing were studied using reverse transcriptase PCR to analyze complementary DNA. Western blots were used to examine protein expression. Results: One individual who presented clinically at a much earlier age than typical was homozygous for an ANO10 variant (c.1864A > G [p.Met622Val]) that produces 2 transcription products by altering an exonic enhancer site. Two patients, both of Lebanese descent, had a homozygous intronic splicing variant in ANO10 (c.1163-9A > G) that introduced a cryptic splice site acceptor, producing 2 alternative transcription products and no detectable wild-type protein. Both these variants have not yet been associated with SCAR10. The remaining patient was found to have compound heterozygous variants in ANO10 previously associated with SCAR10 (c.132dupA [p.Asp45Argfs*9] and c.1537T > C [p.Cys513Arg]). Discussion: We presented rare pathogenic variants adding to the growing list of ANO10 variants associated with SCAR10. In addition, we described an individual with a much earlier age at onset than usually associated with ANO10 variants. This expands the phenotypic and allelic heterogeneity of ANO10-associated ARCA.

Global state of education-related inequality in COVID-19 vaccine coverage, structural barriers, vaccine hesitancy, and vaccine refusal: findings from the Global COVID-19 Trends and Impact Survey.

BACKGROUND: COVID-19 vaccine coverage and experiences of structural and attitudinal barriers to vaccination vary across populations. Education-related inequality in COVID-19 vaccine coverage and barriers within and between countries can provide insight into the hypothesised role of education as a correlate of vaccine access and acceptability. We aimed to characterise patterns of within-country education-related inequality in COVID-19 vaccine indicators across 90 countries. METHODS: This study used data from the University of Maryland Social Data Science Center Global COVID-19 Trends and Impact Survey. Data from 90 countries (more than 14 million participants aged 18 years and older) were included in our analyses. We assessed education-related inequalities globally, across country-income groupings, and nationally for four indicators (self-reported receipt of COVID-19 vaccine, structural barriers to vaccination, vaccine hesitancy, and vaccine refusal) for the study period June 1-Dec 31, 2021. We calculated an absolute summary measure of inequality to assess the latest situation of inequality and time trends and explored the association between government vaccine availability policies and education-related inequality. FINDINGS: Nearly all countries had higher self-reported receipt of a COVID-19 vaccine among the most educated respondents than the least educated respondents. Education-related inequality in structural barriers, vaccine hesitancy, and vaccine refusal varied across countries, and was most pronounced in high-income countries, overall. Low-income and lower-middle-income countries reported widespread experiences of structural barriers and high levels of vaccine hesitancy alongside low levels of education-related inequality. Globally, vaccine hesitancy in unvaccinated people was higher among those with lower education and vaccine refusal was higher among those with higher education, especially in high-income countries. Over the study period, education-related inequalities in self-reported receipt of a COVID-19 vaccine declined, globally and across all country income groupings. Government policies expanding vaccine availability were associated with lower education-related inequality in self-reported receipt of vaccine. INTERPRETATION: This study serves as a baseline for continued inequality monitoring and could help to inform targeted actions for the equitable uptake of vaccines. FUNDING: Gavi, the Vaccine Alliance.

Education-related inequalities in beliefs and behaviors pertaining to COVID-19 non-pharmaceutical interventions.

BACKGROUND: The coronavirus pandemic has exposed existing social inequalities in relation to disease preventive behaviors, risk of exposure, testing and healthcare access, and consequences as a result of illness and containment measures across different population groups. However, due to a lack of data, to date there has been limited evidence of the extent of such within-country inequalities globally. METHODS: We examined education-related inequalities in four COVID-19 prevention and testing indicators within 90 countries, using data from the University of Maryland Social Data Science Center Global COVID-19 Trends and Impact Survey, in partnership with Facebook, over the period 1 June 2021 to 31 December 2021. The overall level of education-related inequalities, as well as how they differ across country income groups and how they have changed over time were analyzed using the Slope Index of Inequality (SII) and the Relative Index of Inequality (RII). We also assessed whether these education-related inequalities were associated with government policies and responses. RESULTS: Education-related inequalities in beliefs, mask wearing, social distancing and testing varied across the study countries. Mask wearing and beliefs in the effectiveness of social distancing and mask wearing were overall more common among people with a higher level of education. Even after controlling for other sociodemographic and health-related factors, social distancing practice was higher among the most educated in low/lower middle income countries, but was higher overall among the least educated in high income countries. Overall there were low education-related inequalities in COVID-19 testing, though there was variation across countries. CONCLUSIONS: The study highlights important within-country education-related differences in COVID-19 beliefs, preventive behaviors and testing, as well as differing trends across country income groups. This has implications for considering and targeting specific population groups when designing public health interventions and messaging during the COVID-19 pandemic and future health emergencies.

Understanding maternity waiting home uptake and scale-up within low-income and middle-income countries: a programme theory from a realist review and synthesis.

INTRODUCTION: Maternity waiting homes (MWHs) link pregnant women to skilled birth attendance at health facilities. Research suggests that some MWH-facility birth interventions are more success at meeting the needs and expectations of their intended users than others. We aimed to develop theory regarding what resources work to support uptake and scale-up of MHW-facility birth interventions, how, for whom, in what contexts and why. METHODS: A four-step realist review was conducted which included development of an initial programme theory; searches for evidence; selection, appraisal and extraction of data; and analysis and data synthesis. RESULTS: A programme theory was developed from 106 secondary sources and 12 primary interviews with MWH implementers. The theory demonstrated that uptake and scale-up of the MWH-facility birth intervention depends on complex interactions between three adopter groups: health system stakeholders, community gatekeepers and pregnant women and their families. It describes relationships between 19 contexts, 11 mechanisms and 31 outcomes accross nine context-mechanism-outcome configurations (CMOCs) which were grouped into 3 themes: (1) Engaging stakeholders to develop, integrate, and sustain MWH-facility birth interventions, (2) Promoting and enabling MWH-facility birth utilisation and (3) Creating positive and memorable MWH-facility birth user experiences. Belief, trust, empowerment, health literacy and perceptions of safety, comfort and dignity were mechanisms that supported diffusion and adoption of the intervention within communities and health systems. Examples of resources provided by implementers to trigger mechanisms associated with each CMOC were identified. CONCLUSIONS: Implementers of MWHs cannot merely assume that communities will collectively value an MWH-facility birth experience over delivery at home. We posit that MWH-facility birth interventions become vulnerable to under-utilisation when implementers fail to: (1) remove barriers that hinder women's access to MWH and (2) ensure that conditions and interactions experienced within the MWH and its affiliated health facility support women to feel treated with compassion, dignity and respect. PROSPERO REGISTRATION NUMBER: CRD42020173595.

Health Inequality Monitoring channel on OpenWHO: capacity strengthening through eLearning.

BACKGROUND: Health inequality monitoring can generate important evidence to inform and motivate changes to policy, programmes and practices. However, the potential of health inequality monitoring practices to quantify inequalities between population subgroups and track progress on the advancement of health equity is under-realized. Capacity strengthening on health inequality monitoring can play an important role in enhancing political will for the generation and use of disaggregated data and for wider adoption of this practice to inform health decision-making. There is a lack of widely available and accessible training materials related to health inequality monitoring that may be used by a range of stakeholders. OBJECTIVE: In this paper, we describe the design, development and implementation of the Health Inequality Monitoring channel on the OpenWHO eLearning platform. We discuss the anticipated impact and potential opportunities for these eLearning courses to contribute to strengthened health inequality monitoring practices. RESULTS: The Health Inequality Monitoring channel on the OpenWHO platform is a self-directed learning environment, designed to meet the immediate learning needs of users. The channel contains three series of courses: health inequality monitoring foundations courses; topic-specific health inequality monitoring courses; and health inequality monitoring skill building courses. Courses are primarily targeted to monitoring and evaluation officers, data analysts, academics and researchers, public health professionals, medical and public health students, and others with a general interest in health data and inequality monitoring. CONCLUSIONS: WHO eLearning courses on health inequality monitoring are addressing the need for capacity strengthening in the collection, analysis and reporting of inequality data. They introduce learners to the foundational concepts, best practices, tools and skills required to conduct health inequality monitoring. The courses on the Health Inequality Monitoring channel demonstrate how technical information can be simplified and presented to broad audiences in a manner that is highly accessible to learners. The Health Inequality Monitoring channel on OpenWHO is an innovative and necessary addition to existing tools and resources to support the advancement of health equity.

CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development.

CDKL5 deficiency disorder (CDD) is an X-linked brain disorder of young children and is caused by pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene. Individuals with CDD suffer infantile onset, drug-resistant seizures, severe neurodevelopmental impairment and profound lifelong disability. The CDKL5 protein is a kinase that regulates key phosphorylation events vital to the development of the complex neuronal network of the brain. Pathogenic variants identified in patients may either result in loss of CDKL5 catalytic activity or are hypomorphic leading to partial loss of function. Whilst the progressive nature of CDD provides an excellent opportunity for disease intervention, we cannot develop effective therapeutics without in-depth knowledge of CDKL5 function in human neurons. In this mini review, we summarize new findings on the function of CDKL5. These include CDKL5 phosphorylation targets and the consequence of disruptions on signaling pathways in the human brain. This new knowledge of CDKL5 biology may be leveraged to advance targeted drug discovery and rapid development of treatments for CDD. Continued development of effective humanized models will further propel our understanding of CDD biology and may permit the development and testing of therapies that will significantly alter CDD disease trajectory in young children.

Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency.

The central cofactors NAD(P)H are prone to damage by hydration, resulting in formation of redox-inactive derivatives designated NAD(P)HX. The highly conserved enzymes NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) function to repair intracellular NAD(P)HX. Recently, pathogenic variants in both the NAXD and NAXE genes were associated with rapid deterioration and death after an otherwise trivial fever, infection, or illness in young patients. As more patients are identified, distinct clinical features are emerging depending on the location of the pathogenic variant. In this review, we carefully catalogued the clinical features of all published NAXD deficiency patients and found distinct patterns in clinical presentations depending on which subcellular compartment is affected by the enzymatic deficiency. Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2. NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions. Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration. This suggests that cytosolic NAD(P)HX repair may protect from neurological damage, whereas muscle fibres may be more sensitive to mitochondrial NAD(P)HX damage. A deeper understanding of the clinical phenotype may facilitate rapid identification of new cases and allow earlier therapeutic intervention. Niacin-based therapies are promising, but advances in disease modelling for both NAXD and NAXE deficiency may identify more specific compounds as targeted treatments. In this review, we found distinct patterns in the clinical presentations of NAXD deficiency patients based on the location of the pathogenic variant, which determines the subcellular compartment that is affected by the enzymatic deficiency.

Maternal social support and health facility delivery in Southwest Ethiopia.

BACKGROUND: Maternal mortality continues to decrease in the world but remain the most important health problems in low-income countries. Although evidence indicates that social support is an important factor influencing health facility delivery, it has not been extensively studied in Ethiopia. Therefore, this study aimed to assess the effect of maternal social support and related factors on health facility delivery in southwest Ethiopia. METHODS: A cross-sectional survey data on 3304 women aged 15-47 years in three districts of Ethiopia, were analyzed. Using multivariable logistic regression, we assessed the association between health facility birth, social support, and socio-demography variables. Adjusted odds ratios with 95% confidence intervals were used to identify statistically significant associations at 5% alpha level. RESULT: Overall, 46.9% of women delivered at health facility in their last pregnancy. Average travel time from closest health facility (AOR: 1.51, 95% CI 1.21 to 2.90), mean perception score of health facility use (AOR: 1.83, 95% CI 1.44 to 2.33), involvement in final decision to identify their place of childbirth (AOR: 2.12, 95% CI 1.73 to 2.58) had significantly higher odds of health facility childbirth. From social support variables, women who perceived there were family members and husband to help them during childbirth (AOR: 3.62, 95% CI 2.74 to 4.79), women who received continuous support (AOR: 1.97, 95% CI 1.20 to 3.23), women with companions for facility visits (AOR: 1.63, 95% CI 1.34 to 2.00) and women who received support from friends (AOR: 1.62, 95% CI 1.16 to 3.23) had significantly higher odds of health facility childbirth. CONCLUSIONS: Social support was critical to enhance health facility delivery, especially if women's close ties help facility delivery. An intervention to increase facility delivery uptake should target not only the women's general social supports, but also continuous support during childbirth from close ties including family members and close friends as these are influential in place of childbirth. Also actions that increase women's healthcare decision could be effective in improving health facility delivery.

Economic-Related Inequalities in Zero-Dose Children: A Study of Non-Receipt of Diphtheria-Tetanus-Pertussis Immunization Using Household Health Survey Data from 89 Low- and Middle-Income Countries.

Despite advances in scaling up new vaccines in low- and middle-income countries, the global number of unvaccinated children has remained high over the past decade. We used 2000-2019 household survey data from 154 surveys representing 89 low- and middle-income countries to assess within-country, economic-related inequality in the prevalence of one-year-old children with zero doses of diphtheria-tetanus-pertussis (DTP) vaccine. Zero-dose DTP prevalence data were disaggregated by household wealth quintile. Difference, ratio, slope index of inequality, concentration index, and excess change measures were calculated to assess the latest situation and change over time, by country income grouping for 17 countries with high zero-dose DTP numbers and prevalence. Across 89 countries, the median prevalence of zero-dose DTP was 7.6%. Within-country inequalities mostly favored the richest quintile, with 19 of 89 countries reporting a rich-poor gap of ≥20.0 percentage points. Low-income countries had higher inequality than lower-middle-income countries and upper-middle-income countries (difference between the median prevalence in the poorest and richest quintiles: 14.4, 8.9, and 2.7 percentage points, respectively). Zero-dose DTP prevalence among the poorest households of low-income countries declined between 2000 and 2009 and between 2010 and 2019, yet economic-related inequality remained high in many countries. Widespread economic-related inequalities in zero-dose DTP prevalence are particularly pronounced in low-income countries and have remained high over the previous decade.