Search results

A community-based intervention (the Omama Project) improves neurodevelopment in impoverished 2-year-old Roma children: a quasi-experimental observational study.

UNLABELLED: High rates of childhood neurodisability are reported among the Roma, Europe's largest ethnic minority community. Interventions targeting early child development (ECD) during the first 2 years of life can improve neurodevelopmental outcomes in vulnerable children; however, evidence from Roma preschoolers is scarce. In a quasi-experimental observational study, we compared neurodevelopmental outcomes at age 2 years, measured on the INTERGROWTH-21st Project Neurodevelopmental Assessment (INTER-NDA), between Roma children receiving a community-based ECD intervention (RI, n = 98), and age- and sex-matched Roma and non-Roma children (RC, n = 99 and NRC, n = 54, respectively) who did not receive the intervention in Eastern Slovakia. The intervention was delivered between 3 weeks and 20 months in weekly home-based sessions by trained Roma women from matched settlements to RIs. Compared with RC, RI had higher 2-year cognitive (B = 0.15; 95% CI, 0.04, 0.25), language (B = 0.25; 95% CI, 0.11, 0.38) and fine motor (B = 0.08; 95% CI, 0.01, 0.16) scores. After adjustment for covariates, cognitive delay decreased by 88% in RI compared with RC (aOR, 0.12; 95% CI, 0.03, 0.53). Linear growth at 24 months was a key predictor of developmental scores for both groups (range, B = 0.04-0.14; 95% CI, 0.01, 0.07 and 0.09, 0.20). CONCLUSIONS: Our results highlight that, without directly intervening on nutritional and poverty status, a community-based ECD intervention, delivered by trained Roma women to Roma children, can significantly improve neurodevelopmental outcomes at age 2 years. WHAT IS KNOWN: • The Roma are Europe's largest ethnic minority. High rates of neurodisability, malnutrition and poverty are reported in Roma preschoolers. • Optimal early child development (ECD) is foundational to lifecourse health and wellbeing. Early interventions improve ECD outcomes in vulnerable children; however, evidence from Roma communities is limited. WHAT IS NEW: • The Omama project is a community-based ECD intervention, delivered by trained Roma women to Roma children aged 3 weeks to 20 months living in impoverished settlements in Eastern Slovakia. • Roma children receiving the intervention had (i) higher cognitive, language and fine motor scores and (ii) lower rates of cognitive delay compared with controls.

Early neurophysiological markers of aberrant auditory processing associated with increased risk of autism spectrum disorder: A systematic review

Importance: There is a lack of reliable early diagnostic criteria for autism spectrum disorder (ASD), despite earlier diagnosis leading to better outcomes. Objective: To evaluate the association of aberrant auditory processing (AAP) as a potential early marker of ASD risk in children under 2 years old. Methods: A systematic review of studies published between 1985 and September 2024 was conducted by searching PubMed and Web of Science. Results: The review encompassed 18 studies with 140 231 participants, and a majority (76%) of these studies found evidence that early neurophysiological changes in auditory processing are associated with later ASD risk. Specifically, prolonged auditory brainstem response (ABR) latency, reduced social stimuli selectivity, and poorer auditory brain connectivity were correlated with ASD status in later childhood. Notably, auditory habituation did not differ significantly with ASD risk. It's important to recognize that the evidence was somewhat limited by heterogeneity, small sample sizes, and inadequate reporting. Interpretation: This review identified three early neurophysiological AAP markers associated with ASD risk: ABR latency, social stimuli selectivity, and auditory brain coherence. These markers show potential for aiding in earlier ASD risk assessment in young children, potentially leading to earlier interventions. However, to fully establish the association of these AAP markers with ASD as a reliable screening tool during early childhood, future research should focus on standardized experimental protocols and adequately powered prospective cohort studies.

Safety and humoral immunogenicity of the ChAdOx1 nCoV-19 vaccine administered as a fourth dose booster following two doses of ChAdOx1 nCoV-19 and a third dose of BNT162b2 (COV009): A prospective cohort study.

OBJECTIVES: Evaluation of the safety and humoral immunogenicity of ChAdOx1 nCoV-19 as a fourth dose booster in individuals who have had two initial doses of the vaccine and a third dose of BNT162b2. METHODS: COV009 is a safety follow-up study of volunteers enroled in the pivotal pre-licensure ChAdOx1 nCoV-19. In this sub-study, 149 eligible participants were given a fourth dose of ChAdOx1 nCoV-19. Primary outcomes were reactogenicity, safety, and humoral immunogenicity. Anti-spike IgG and pseudo-neutralising antibody against multiple variants were measured from pre-first dose to 28 days post-second and post-fourth dose (third dose samples were unavailable). RESULTS: A fourth dose of ChAdOx1 nCoV-19 had an acceptable safety profile with no vaccine-related serious adverse events. Humoral responses against various SARS CoV-2 variants post-fourth dose were significantly increased compared with the responses after the second dose (7- to 9-fold increase for anti-spike IgG responses across variants, all p<0.05). Those with lower antibody levels prior to the 4th dose had stronger responses to a 4th dose booster. Seropositivity by anti-nucleocapsid, or higher antibody responses pre-fourth dose correlated with lower infection risks six months thereafter (OR: 0.16, 95% CI: 0.05, 0.50). CONCLUSIONS: The ChAdOx1 nCoV-19 fourth dose is well tolerated and boosts humoral immunity; this was evident as an increased humoral response across multiple variants of concern. These data support its use as a booster dose against SARS-CoV-2 infection.

Predictors of severity of SARS-CoV-2 infections in Brazil: Post hoc analyses of a randomised controlled trial.

OBJECTIVES: To identify demographic, clinical and immunological factors associated with adverse COVID-19 outcomes. METHODS: A large randomised controlled trial of ChAdOx1 nCoV-19 was undertaken in Brazil. Participants were randomised 1:1 either to receive ChAdOx1 nCov-19 or to a control group. COVID-19 infections were confirmed by nucleic acid amplification test (NAAT) and classified using the WHO clinical progression scale. Anti-spike antibody responses and serum neutralising activity were measured 28 days after second vaccination in some participants. Exploratory analyses were conducted into factors associated with COVID-19 infection severity and hospitalisation, using logistic regression models adjusted for demographic and clinical factors. RESULTS: 10,416 participants were enrolled; 1790 had NAAT-positive COVID-19 infection; 63 cases required hospitalisation. More severe infection was associated with greater body-mass index (BMI) (odds ratio [OR] = 1.06 [95 %CI: 1.01-1.10], p = 0.01) and diabetes (OR = 3.67 [1.59-8.07], p = 0.003). Hospitalisation risk increased with greater age (OR = 1.06 [1.03-1.08], p 180 days after last vaccination. In the fully vaccinated subgroup (n = 841), only greater age predicted hospitalisation (OR = 1.07 [1.03-1.12], p 

Ebola disease: bridging scientific discoveries and clinical application.

The west Africa Ebola disease epidemic (2014-16) marked a historic change of course for patient care during emerging infectious disease outbreaks. The epidemic response was a failure in many ways-a slow, cumbersome, and disjointed effort by a global architecture that was not fit for purpose for a rapidly spreading outbreak. In the most affected countries, health-care workers and other responders felt helpless-dealing with an overwhelming number of patients but with few, if any, tools at their disposal to provide high-quality care. These inadequacies, however, led to attention and innovation. The decade since then has seen remarkable achievements in clinical care for Ebola disease, including the approval of the first vaccines and treatments. In this paper, the first in a two-part Series, we reflect on this progress and provide expert summary of the modern landscape of Ebola disease, highlighting the priorities and ongoing activities aimed at further improving patient survival and wellbeing in the years ahead.

Safety and efficacy of the blood-stage malaria vaccine RH5.1/Matrix-M in Burkina Faso: interim results of a double-blind, randomised, controlled, phase 2b trial in children.

BACKGROUND: Two pre-erythrocytic vaccines (R21/Matrix-M and RTS,S/AS01) are now approved for Plasmodium falciparum malaria. However, neither induces blood-stage immunity against parasites that break through from the liver. RH5.1/Matrix-M, a blood-stage P falciparum malaria vaccine candidate, was highly immunogenic in Tanzanian adults and children. We therefore assessed the safety and efficacy of RH5.1/Matrix-M in Burkinabe children. METHODS: In this double-blind, randomised, controlled, phase 2b trial, RH5.1/Matrix-M was given to children aged 5-17 months in Nanoro, Burkina Faso, a seasonal malaria transmission setting. Children received either three intramuscular vaccinations with 10 μg RH5.1 protein with 50 μg Matrix-M adjuvant or three doses of rabies control vaccine, Rabivax-S, given either in a delayed third-dose (0, 1, and 5 month) regimen (first cohort) or a 0, 1, and 2 month regimen (second cohort). Vaccinations were completed part way through the malaria season. Children were randomly assigned 2:1 within each cohort to receive RH5.1/Matrix-M or Rabivax-S. Participants were assigned according to a random allocation list generated by an independent statistician using block randomisation with variable block sizes. Participants, their families, and the study teams were masked to group allocation; only pharmacists who prepared the vaccines were unmasked. Vaccine safety, immunogenicity, and efficacy were evaluated. The coprimary outcomes assessed were: first, the safety and reactogenicity of RH5.1/Matrix-M; and second, the protective efficacy of RH5.1/Matrix-M against clinical malaria (measured as time to first episode of clinical malaria, using a Cox regression model) from 14 days to 6 months after the third vaccination in the per-protocol sample. This ongoing trial is registered with ClinicalTrials.gov (NCT05790889). FINDINGS: From April 6 to 13 and July 3 to 7, 2023, 412 children aged 5-17 months were screened, and 51 were excluded. A total of 361 children were enrolled in this study. In the first cohort, 119 were assigned to the RH5.1/Matrix-M delayed third-dose group, and 62 to the equivalent rabies control group. The second cohort included 120 children in the monthly RH5.1/Matrix-M group and 60 in the equivalent rabies control group. The final vaccination was administered to all groups from Sept 4 to 21, 2023. RH5.1/Matrix-M in both cohorts had a favourable safety profile and was well tolerated. Most adverse events were mild, with the most common being local swelling and fever. No serious adverse events were reported. Comparing the RH5.1/Matrix-M delayed third-dose regimen with the pooled control groups resulted in a vaccine efficacy of 55% (95% CI 20 to 75%; p=0·0071). The same analysis showed a vaccine efficacy of 40% (-3 to 65%; p=0·066) when comparing the monthly regimen with the pooled control groups. Participants vaccinated with RH5.1/Matrix-M in both cohorts showed high concentrations of anti-RH5.1 serum IgG antibodies 14 days after the third vaccination, and the purified IgG showed high levels of in vitro growth inhibition activity against P falciparum; these responses were higher in patients who received the RH5.1/Matrix-M vaccine delayed third-dose regimen, as opposed to monthly regimen (growth inhibition activity 79·0% [SD 14·3] vs 74·2% [SD 15·9]; p=0·016). INTERPRETATION: RH5.1/Matrix-M appears safe and highly immunogenic in African children and shows promising efficacy against clinical malaria when given in a delayed third-dose regimen. This trial is ongoing to further monitor efficacy over time. FUNDING: The European and Developing Countries Clinical Trials Partnership, the UK Medical Research Council, the National Institute for Health and Care Research Oxford Biomedical Research Centre, the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, the US Agency for International Development, and the Wellcome Trust.

uORF-targeting steric block antisense oligonucleotides do not reproducibly increase RNASEH1 expression

Immunogenicity and safety of beta variant COVID-19 vaccine AZD2816 and AZD1222 (ChAdOx1 nCoV-19) as primary-series vaccination for previously unvaccinated adults in Brazil, South Africa, Poland, and the UK: a randomised, partly double-blinded, phase 2/3 non-inferiority immunobridging study.

BACKGROUND: AZD2816 is a variant-adapted COVID-19 vaccine that expresses the full-length SARS-CoV-2 beta variant spike protein but is otherwise similar to AZD1222 (ChAdOx1 nCoV-19). This study aimed to evaluate the safety and immunogenicity of AZD1222 or AZD2816 (or both) primary-series vaccination in a cohort of adult participants who were previously unvaccinated. METHODS: In this phase 2/3, randomised, multinational, active-controlled, non-inferiority, immunobridging study, adult participants previously unvaccinated for COVID-19 were enrolled at 16 study sites in Brazil, South Africa, Poland, and the UK. Participants were stratified by age, sex, and comorbidity and randomly assigned 5:5:5:2 to receive a primary series of AZD1222 (AZD1222 group), AZD2816 (AZD2816 [4-week] group), or AZD1222-AZD2816 (AZD1222-AZD2816 group) at 4-week dosing intervals, or AZD2816 at a 12-week interval (AZD2816 [12-week] group) and evaluated for safety and immunogenicity through 180 days after dose 2. Primary outcomes were safety (rates of solicited adverse events occurring during 7 days and unsolicited adverse events occurring during 28 days after each dose) and immunogenicity (non-inferiority of pseudovirus neutralising antibody geometric mean titre [GMT], GMT ratio margin of 0·67, and seroresponse rate, rate difference margin of -10%, recorded 28 days after dose 2 with AZD2816 [4-week interval] against beta vs AZD1222 against ancestral SARS-CoV-2) in participants who were seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04973449, and is completed. FINDINGS: Between July 7 and Nov 12, 2021, 1449 participants were assigned to the AZD1222 group (n=413), the AZD2816 (4-week) group (n=415), the AZD1222-AZD2816 group (n=412), and the AZD2816 (12-week) group (n=209). Ten (2·6%) of 378 participants who were seronegative at baseline in the AZD1222 group, nine (2·4%) of 379 in the AZD2816 (4-week) group, eight (2·1%) of 380 in the AZD1222-AZD2816 group, and 11 (5·8%) of 191 in the AZD2816 (12-week) group had vaccine-related unsolicited adverse events. Serious adverse events were recorded in one (0·3%) participant in the AZD1222 group, one (0·3%) in the AZD2816 (4-week) group, two (0·5%) in the AZD1222-AZD2816 group, and none in the AZD2816 (12-week) group. Co-primary immunogenicity endpoints were met: neutralising antibody GMT (ratio 1·19 [95% CI 1·08-1·32]; lower bound greater than 0·67) and seroresponse rate (difference 1·7% [-3·1 to 6·5]; lower bound greater than -10%) at 28 days after dose 2 were non-inferior in the AZD2816 (4-week) group against beta versus in the AZD1222 group against ancestral SARS-CoV-2. Seroresponse rates were highest with AZD2816 against beta (12-week interval 94·3% [95% CI 89·4-97·3]; 4-week interval 85·7% [81·5-89·2]) and with AZD1222 (84·6% [80·3-88·2]) against ancestral SARS-CoV-2. INTERPRETATION: Primary series of AZD1222 and AZD2816 were well tolerated, with no emergent safety concerns. Both vaccines elicited robust immunogenicity against beta and ancestral SARS-CoV-2 with greater responses demonstrated when testing against SARS-CoV-2 strains that matched those targeted by the respective vaccine. These findings demonstrate the continued importance of ancestral COVID-19 vaccines in protecting against severe COVID-19 and highlight the feasibility of using the ChAdOx1 platform to develop COVID-19 vaccines against future SARS-CoV-2 variants. FUNDING: AstraZeneca.

Phosphorylation of 'SDT-like' motifs in ATRX mediates its interaction with the MRN complex and is important for ALT pathway suppression.

Approximately 10-15% of human cancers are telomerase-negative and maintain their telomeres through a recombination-based process known as the alternative lengthening of telomeres (ALT) pathway. Loss of the alpha-thalassemia/mental retardation, X-linked (ATRX) chromatin remodeller is a common event in ALT-positive cancers, but is generally insufficient to drive ALT induction in isolation. We previously demonstrated that ATRX binds to the MRN complex, which is also known to be important in the ALT pathway, but the molecular basis of this interaction remained elusive. Here, we demonstrate that the interaction between ATRX and MRN is dependent on the N-terminal forkhead-associated and BRCA1 C-terminal domains of NBS1, analogous to the previously reported NBS1-MDC1 interaction. A number of conserved 'SDT-like' motifs (serine and threonine residues with aspartic/glutamic acid residues at proximal positions) in the central unstructured region of ATRX were found to be crucial for the ATRX-MRN interaction. Furthermore, treatment with a casein kinase 2 inhibitor prevented the ability of ATRX to bind MRN, suggesting that phosphorylation of these residues by casein kinase 2 is also important for the interaction. Finally, we show that a functional ATRX-MRN interaction is important for the ability of ATRX to prevent induction of ALT hallmarks in the presence of chemotherapeutically induced DNA-protein crosslinks, and might also have implications for individuals with ATR-X syndrome.

Biomarkers of vaccine safety and efficacy in vulnerable populations: Lessons from the fourth international precision vaccines conference

Vaccination has been a cornerstone of public health, substantially reducing the global burden of infectious diseases, notably evident during the COVID-19 pandemic caused by SARS-CoV-2. However, vulnerable populations (VPs), including those in extreme age groups and those with underlying health conditions, have borne a disproportionate burden of morbidity and mortality from infectious diseases. Understanding vaccine immunogenicity in these populations is crucial for developing effective vaccines. Characterizing vaccine responses in VPs presents unique challenges due to under-vaccination, sub-optimal vaccine responses, and distinct mechanisms of vaccine-induced protection. To address these challenges, experts convened at the 4th International Precision Vaccines Conference in Rome. Co-hosted by the Precision Vaccines Program of Boston Children's Hospital and Ospedale Pediatrico Bambino Gesù, the conference focused on biomarkers of vaccine safety and efficacy in vulnerable populations. Discussions at the conference emphasized the need for multidisciplinary strategies and international collaborations to optimize vaccine development. Key areas of focus included assessing vaccine safety, defining biomarkers for vaccine immunogenicity, developing human in vitro assay models, and accelerating the selection of novel vaccine formulations and adjuvants tailored for vulnerable populations. The conference provided a platform for experts from diverse fields, including immunology, paediatrics, and vaccinology, to exchange ideas and advance research in precision vaccines. This manuscript highlights key concepts discussed at the conference and underscores the importance of precision vaccines in addressing the unique needs of vulnerable populations.

Immunogenicity of MVA-BN vaccine deployed as mpox prophylaxis: a prospective cohort study and analysis of transcriptomic predictors of response

Background: Since 2022, mpox has emerged as a global health threat, with two clades (I and II) causing outbreaks of international public health concern. The third generation smallpox vaccine modified vaccinia Ankara, manufactured by Bavarian Nordic (MVA-BN), has emerged as a key component of mpox prevention. To date, the immunogenicity of this vaccine, including determinants of response has been incompletely described, especially when MVA-BN has been administered intradermally at 1/5th the registered dose (‘fractionated dosing’), as recommended as a dose-sparing strategy. The aim of this study was to explore the immunogenicity of MVA-BN, and baseline determinants of vaccine response in an observational public-health response setting. Methods: We conducted a prospective cohort study and immunological analysis of responses to MVA-BN in patients attending a sexual health vaccination clinic in Oxford, UK. Blood samples were taken at baseline, day 14, and day 28 after first vaccine, and 28 and 90 days following a second vaccine. A sub-cohort had additional blood samples collected day 1 following their first vaccine (optional timepoint). We assessed IgG responses to mpox/vaccinia antigens using Luminex assay (‘MpoxPlex’) via generalised linear mixed modelling, and T-cell responses using interferon- enzyme linked immunospot and activation induced marker assay. Associations between blood transcriptomic signatures (baseline, day 1) and immunogenicity were assessed using differential expression analysis and gene set enrichment methods. Findings: We recruited 34 participants of whom 33 received fractionated dosing. Of those without prior smallpox vaccination (n=30), 50% seroconverted by day 28, and while this increased to 89% by day 90 post second vaccination, individuals seronegative on day 28 demonstrated persistently lower responses compared to day 28 seropositive individuals. Serological response on day 28 positively associated with type I and II interferon signatures day one post-vaccination (n=18 samples) but negatively associated with these signatures at baseline. Interpretation: Baseline inflammatory states may inhibit MVA-BN serological immunogenicity by inhibiting the upregulation of MVA-induced innate immune signalling. If confirmed mechanistically these insights may inform improved vaccination strategies against mpox in diverse geographic and demographic settings. Given the likelihood of vaccine supply limitations in the current context and in future outbreak settings, the utility of dose-sparing vaccine strategies as a general approach to maximising population benefit warrants further study

The Epidemiology, Clinical, and Economic Burdens of Respiratory Syncytial Virus Infections Amongst Hospitalized Children Under 5 Years of Age in Jordan: A National Multi-Center Cross-Sectional Study

Respiratory syncytial virus (RSV) has been recognized as a highly important cause of morbidity and mortality among children and adults. A cross-sectional study at representative sites in Jordan was undertaken to provide an assessment of the epidemiology and health and economic burdens of RSV and influenza infections in Jordan amongst hospitalized children under 5 years old for the period between 15 November 2022 and 14 April 2023. This study involved 1000 patients with a mean age of 17.10 (SD: 16.57) months. Of these, half (n = 506, 50.6%) had positive results for RSV. Furthermore, 33% and 17.4% of the participants had positive results for RSV-B and RSV-A, respectively. The findings underscore the severity of RSV infections, where a significant proportion of the children experienced severe respiratory distress, which led to bronchiolitis and pneumonia. This study meticulously documented the clinical outcomes, including the need for intensive care, mechanical ventilation, and prolonged hospital stays. There was no statistically significant difference in the financial burdens between the RSV-positive and RSV-negative patients. This study revealed the urgent need for preventive measures to control the substantial burden of RSV among children under 5 years old in Jordan.

COVID-19 testing and reporting behaviours in England across different sociodemographic groups: a population-based study using testing data and data from community prevalence surveillance surveys.

BACKGROUND: Understanding underlying mechanisms of heterogeneity in test-seeking and reporting behaviour during an infectious disease outbreak can help to protect vulnerable populations and guide equity-driven interventions. The COVID-19 pandemic probably exerted different stresses on individuals in different sociodemographic groups and ensuring fair access to and usage of COVID-19 tests was a crucial element of England's testing programme. We aimed to investigate the relationship between sociodemographic factors and COVID-19 testing behaviours in England during the COVID-19 pandemic. METHODS: We did a population-based study of COVID-19 testing behaviours with mass COVID-19 testing data for England and data from community prevalence surveillance surveys (REACT-1 and ONS-CIS) from Oct 1, 2020, to March 30, 2022. We used mass testing data for lateral flow device (LFD; data for approximately 290 million tests performed and reported) and PCR (data for approximately 107 million tests performed and returned from the laboratory) tests made available for the general public and provided by date and self-reported age and ethnicity at the lower tier local authority (LTLA) level. We also used publicly available data on mean population size estimates for individual LTLAs, and data on ethnic groups, age groups, and deprivation indices for LTLAs. We did not have access to REACT-1 or ONS-CIS prevalence data disaggregated by sex or gender. Using a mechanistic causal model to debias the PCR testing data, we obtained estimates of weekly SARS-CoV-2 prevalence by both self-reported ethnic groups and age groups for LTLAs in England. This approach to debiasing the PCR (or LFD) testing data also estimated a testing bias parameter defined as the odds of testing in infected versus not infected individuals, which would be close to zero if the likelihood of test seeking (or seeking and reporting) was the same regardless of infection status. With confirmatory PCR data, we estimated false positivity rates, sensitivity, specificity, and the rate of decline in detection probability subsequent to reporting a positive LFD for PCR tests by sociodemographic groups. We also estimated the daily incidence, allowing us to calculate the fraction of cases captured by the testing programme. FINDINGS: From March, 2021 onwards, individuals in the most deprived regions reported approximately half as many LFD tests per capita as individuals in the least deprived areas (median ratio 0·50 [IQR 0·44-0·54]). During the period October, 2020, to June, 2021, PCR testing patterns showed the opposite trend, with individuals in the most deprived areas performing almost double the number of PCR tests per capita than those in the least deprived areas (1·8 [1·7-1·9]). Infection prevalences in Asian or Asian British individuals were considerably higher than those of other ethnic groups during the alpha (B.1.1.7) and omicron (B.1.1.529) BA.1 waves. Our estimates indicate that the England Pillar 2 COVID-19 testing programme detected 26-40% of all cases (including asymptomatic cases) over the study period with no consistent differences by deprivation levels or ethnic groups. Testing biases for PCR were generally higher than those for LFDs, in line with the general policy of symptomatic and asymptomatic use of these tests. Deprivation and age were associated with testing biases on average; however, the uncertainty intervals overlapped across deprivation levels, although the age-specific patterns were more distinct. We also found that ethnic minorities and older individuals were less likely to use confirmatory PCR tests through most of the pandemic and that delays in reporting a positive LFD test were possibly longer in populations self-reporting as "Black; African; Black British or Caribbean". INTERPRETATION: Differences in testing behaviours across sociodemographic groups might be reflective of the higher costs of self-isolation to vulnerable populations, differences in test accessibility, differences in digital literacy, and differing perceptions about the utility of tests and risks posed by infection. This study shows how mass testing data can be used in conjunction with surveillance surveys to identify gaps in the uptake of public health interventions both at fine-scale levels and across sociodemographic groups. It provides a framework for monitoring local interventions and yields valuable lessons for policy makers in ensuring an equitable response to future pandemics. FUNDING: UK Health Security Agency.

Cognitive function and skeletal size and mineral density at age 6-7 years: Findings from the Southampton Women's Survey.

INTRODUCTION: Poor cognitive function and osteoporosis commonly co-exist in later life. In women, this is often attributed to post-menopausal estrogen loss. However, a common early life origin for these conditions and the associations between cognitive function and bone mineral density (BMD) in childhood have not previously been explored. We examined these relationships at age 6-7 years in the Southampton Women's Survey (SWS) mother-offspring cohort. METHODS: Child occipitofrontal circumference (OFC), a proxy for brain volume, intelligence quotient (IQ) [Wechsler Abbreviated Scale of Intelligence] and visual recognition and working memory [CANTAB® Delayed Matching to Sample (DMS) and Spatial Span Length (SSP), respectively] were assessed. Whole-body-less-head (WBLH) and lumbar spine dual-energy X-ray absorptiometry [Hologic Discovery] (DXA) were performed to measure bone area (BA), bone mineral content (BMC), BMD and bone mineral apparent density (BMAD). Linear regression was used to examine associations between age and sex standardized variables (β represent standard deviation (SD) difference per SD of cognitive function). RESULTS: DXA was performed in 1331 children (mean (SD) age 6.8 (0.33) years, 51.5 % male), with OFC, IQ, DMS and SSP assessed in 1250, 551, 490 and 460, respectively. OFC (β = 0.25 SD/SD, 95%CI 0.20,0.30), IQ (β = 0.11 SD/SD, 95%CI 0.02,0.19), and DMS (β = 0.11, SD/SD, 95%CI 0.01,0.20) were positively associated with WBLH BA, with similar associations for lumbar spine BA. OFC and DMS were also positively associated with WBLH BMC, but only OFC was associated with BMD (WBLH: β = 0.38 SD/SD, 95%CI 0.33,0.43; LS: β = 0.19 SD/SD, 95%CI 0.13,0.24). CONCLUSION: Childhood brain volume was positively associated with measures of skeletal size and BMD, whereas IQ and memory were associated only with skeletal size. These findings suggest that common early life determinants for skeletal growth and BMD and cognitive function should be explored to identify potential early-life approaches to preventing osteoporosis and cognitive decline.

Focal epilepsy features in a child with Congenital Zika Syndrome.

Zika virus (ZIKV) is a mosquito-borne, single-stranded DNA flavivirus that is teratogenic and neurotropic. Similar to the teratogenic effects of other TORCH infections, ZIKV infection during pregnancy can have an adverse impact on fetal and neonatal development. Epilepsy is detected in 48-96% of children with Congenital Zika Syndrome (CZS) and microcephaly. Early epilepsy surveillance is needed in children with prenatal ZIKV exposure; yet, most ZIKV-endemic regions do not have specialist epilepsy care. Here, we describe the demographic, clinical, imaging, and EEG characteristics of a 2-year-old child with CZS and microcephaly who presented with focal epileptiform activity, suboptimal growth, and severe neurodevelopmental delays. Administration of a brief seizure questionnaire by allied health professionals to the patient's caregiver helped to characterize the child's seizure semiology and differentiate focal from generalized seizure features. A telemedicine EEG interpretation platform provided valuable diagnostic information for the patient's local pediatrician to integrate into her treatment plan. This case illustrates that CZS can present with focal epilepsy features and that a telemedicine approach can be used to bridge the gap between epilepsy specialists and local care providers in resource limited ZIKV-endemic regions to achieve better seizure control in children with CZS.

Evaluation of the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) in 2 year-old children.

BACKGROUND: The INTER-NDA is a novel assessment of early child development measuring cognition, language, motor skills, behaviour, attention, and socio-emotional reactivity in 2 year olds in 15 minutes. Here, we present the results of an evaluation of the INTER-NDA against the Bayley Scales of Infant Development III edition (BSID-III), its sensitivity and specificity and its psychometric properties. METHODS: Eighty-one infants from Oxford, UK, aged 23.1-28.3 months, were evaluated using the INTER-NDA and the BSID-III. The agreement between the INTER-NDA and the BSID-III was assessed using interclass correlations (for absolute agreement), Bland-Altman analyses (for bias and limits of agreement), and sensitivity and specificity analyses (for accuracy). The internal consistency of the INTER-NDA and uni-dimensionality of its subscales were also determined. RESULTS: The interclass correlation coefficients between the BSID-III and the INTER-NDA cognitive, motor and behaviour scores ranged between 0.745 and 0.883 (p<0.001). The Bland-Altman analysis showed little to no bias in the aforementioned subscales. The sensitivity and specificity of INTER-NDA cognitive scores ≤1 SD below the mean are 66.7% and 98.6% respectively, with moderate agreement between INTER-NDA and BSID-III classifications (κ = 0.72, p<0.001). The sensitivity and specificity of INTER-NDA scores <2 SD below the mean, in predicting low BSID-III scores (<70), are 100% each for cognition, and 25% and 100% respectively for language. More than 97% of children who scored in the normal range of the INTER-NDA (<1SD below mean) also scored in the normal range in the BSID-III (≥85). The INTER-NDA demonstrates satisfactory internal consistency and its subscales demonstrate good unidimensionality. CONCLUSION: The INTER-NDA shows good agreement with the BSID-III, and demonstrates satisfactory psychometric properties, for the assessment of ECD at 22-28 months.

The INTERGROWTH-21st Project Neurodevelopment Package: a novel method for the multi-dimensional assessment of neurodevelopment in pre-school age children.

BACKGROUND: The International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Project is a population-based, longitudinal study describing early growth and development in an optimally healthy cohort of 4607 mothers and newborns. At 24 months, children are assessed for neurodevelopmental outcomes with the INTERGROWTH-21st Neurodevelopment Package. This paper describes neurodevelopment tools for preschoolers and the systematic approach leading to the development of the Package. METHODS: An advisory panel shortlisted project-specific criteria (such as multi-dimensional assessments and suitability for international populations) to be fulfilled by a neurodevelopment instrument. A literature review of well-established tools for preschoolers revealed 47 candidates, none of which fulfilled all the project's criteria. A multi-dimensional assessment was, therefore, compiled using a package-based approach by: (i) categorizing desired outcomes into domains, (ii) devising domain-specific criteria for tool selection, and (iii) selecting the most appropriate measure for each domain. RESULTS: The Package measures vision (Cardiff tests); cortical auditory processing (auditory evoked potentials to a novelty oddball paradigm); and cognition, language skills, behavior, motor skills and attention (the INTERGROWTH-21st Neurodevelopment Assessment) in 35-45 minutes. Sleep-wake patterns (actigraphy) are also assessed. Tablet-based applications with integrated quality checks and automated, wireless electroencephalography make the Package easy to administer in the field by non-specialist staff. The Package is in use in Brazil, India, Italy, Kenya and the United Kingdom. CONCLUSIONS: The INTERGROWTH-21st Neurodevelopment Package is a multi-dimensional instrument measuring early child development (ECD). Its developmental approach may be useful to those involved in large-scale ECD research and surveillance efforts.

Pre and postnatal exposure to Chikungunya virus does not affect child neurodevelopmental outcomes at two years of age.

BACKGROUND: The 2005-06 chikungunya virus (CHIKV) outbreak in La Réunion suggested that mothers could transmit CHIKV to their neonates while viremic during the intrapartum period, and more than half of the infected neonates showed impaired neurodevelopment at two years of age. However, data sparsity precluded an overview of the developmental impact of vertical infection within the whole prenatal period. OBJECTIVE & METHODS: The current study assessed two-year old children born to mothers who were infected during the 2014 CHIKV outbreak in Grenada to determine the neurodevelopmental impact of perinatal CHIKV infection throughout gestation. Mother and child infection status were confirmed by serologic testing (IgG and IgM) for CHIKV. Cognitive, fine motor, gross motor, language and behavioral outcomes were assessed at two years of age on the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA). RESULTS: No differences in neurodevelopmental outcomes were observed between two-year-old children born to mothers infected with CHIKV during gestation (n = 149) and those born to mothers not infected with CHIKV (n = 161). No differences were found in INTER-NDA scores between children infected with CHIKV (n = 47) and children not infected with CHIKV (n = 592). Likewise, there were no differences between children infected with CHIKV post-partum (n = 19) versus children not infected with CHIKV (n = 592). CONCLUSION: Our findings suggest that children exposed and/or infected with CHIKV outside of the intrapartum period experience no significant neurodevelopmental delay at two years of age, as measured by the INTER-NDA, compared to their unexposed and/or uninfected peers. These results complement those of previous studies which showed a neurodevelopmental risk only for children infected during the intrapartum period, while the mother was highly viremic. These results might be reassuring for women of childbearing age and public health officials in CHIKV-endemic regions.

Foetal exposure to maternal depression predicts cortisol responses in infants: findings from rural South India.

BACKGROUND: Maternal depression during pregnancy is associated with an increased risk of adverse child outcomes. One potential mechanism is the influence of antenatal depression on the foetal hypothalamic-pituitary-adrenal axis. This can be observed as disturbances in baseline cortisol secretion during childhood. The influence of antenatal depression on infant cortisol reactivity to a stressor may provide further insight into this association. In addition, the dose-response relationship between foetal exposure to antenatal depression and infant cortisol reactivity is unclear. METHODS: A consecutive sample of 133 pregnant women in their third trimester was recruited from an antenatal clinic in Karnataka, South India. Women were assessed for depression before and after birth on the Edinburgh Postnatal Depression Scale (EPDS) and the Kessler 10 Scale. Salivary cortisol response to immunization was measured in 58 infants at 2 months of age. We aimed (i) to investigate the association between antenatal depression and infant cortisol reactivity to immunization and (ii) to explore whether the relationship is dose-dependent. RESULTS: Exposure to antenatal depression independently predicted elevated infant cortisol responses to immunization (β = 0.53, P = 0.04). The association was found to be U-shaped, for antenatal depression measured on the EPDS, with the infants exposed to the highest and lowest levels of maternal antenatal EPDS scores during intra-uterine life showing elevated cortisol responses to immunization (R(2) = 0.20, P = 0.02). Infants exposed to moderate levels of maternal antenatal depression showed the lowest cortisol response to immunization. CONCLUSIONS: These findings suggest that the association between antenatal depression and infant cortisol reactivity is dose-dependent and U-shaped, implying that infants exposed to both low and high levels of maternal depression showed greater reactivity. The study provides the first evidence of such an association from a low-income setting.

Are fetal growth impairment and preterm birth causally related to child attention problems and ADHD? Evidence from a comparison between high-income and middle-income cohorts.

BACKGROUND: Cross-cohort comparison is an established method for improving causal inference. This study compared 2 cohorts, 1 from a high-income country and another from a middle-income country, to (1) establish whether birth exposures may play a causal role in the development of childhood attention problems; and (2) identify whether confounding structures play a different role in parent-reported attention difficulties compared with attention deficit hyperactivity disorder (ADHD) diagnoses. METHODS: Birth exposures included low birth weight (LBW), small-for-gestational age (SGA), small head circumference (HC) and preterm birth (PTB)). Outcomes of interest were attention difficulties (Strengths and Difficulties Questionnaire, SDQ) and ADHD (Development and Well-Being Assessment, DAWBA). Associations between exposures and outcomes were compared between 7-year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK (N=6849) and the 2004 Pelotas cohort in Brazil (N=3509). RESULTS: For attention difficulties (SDQ), the pattern of association with birth exposures was similar between cohorts: following adjustment, attention difficulties were associated with SGA (OR=1.59, 95% CI 1.20 to 2.19) and small HC (OR=1.64, 95% CI 1.11 to 2.41) in ALSPAC and SGA (OR=1.35, 95% CI 1.04 to 1.75) in Pelotas. For ADHD, however, the pattern of association following adjustment differed markedly between cohorts. In ALSPAC, ADHD was associated with LBW (OR=2.29, 95% CI 1.09 to 4.80) and PTB (OR=2.33, 95% CI 1.23 to 4.42). In the Pelotas cohort, however, ADHD was associated with SGA (OR=1.69, 95% CI 1.02 to 2.82). CONCLUSIONS: The findings suggest that fetal growth impairment may play a causal role in the development of attention difficulties in childhood, as similar associations were identified across both cohorts. Confounding structures, however, appear to play a greater role in determining whether a child meets the full diagnostic criteria for ADHD.