Cefadroxil and cephalexin pharmacokinetics and pharmacodynamics in children with musculoskeletal infections.

Cephalexin, a first-generation cephalosporin, is the first-line oral therapy for children with musculoskeletal infections due to methicillin-susceptible Staphylococcus aureus (MSSA). Cefadroxil, a similar first-generation cephalosporin, is an attractive alternative to cephalexin given its longer half-life. In this study, we describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of cephalexin and cefadroxil in children with musculoskeletal infections. Children aged 6 months to 18 years with a musculoskeletal infection were enrolled in a prospective, open-label, crossover PK study and given single oral doses of cefadroxil (50-75 mg/kg up to 2,000 mg) and cephalexin (50 mg/kg up to 1,375 mg). Population PK models were developed and used for dosing simulations. Our primary PD target was the achievement of free antibiotic concentrations above the minimum inhibitory concentration (fT >MIC) for 40% of the day for MICs ≤ 4 mg/L. PK of cephalexin (n = 15) and cefadroxil (n = 14) were best described using a one-compartment, first-order absorption model, with a lag time component for cefadroxil. PK parameters were notable for cefadroxil's longer half-life (1.61 h) than cephalexin's (1.10 h). For pediatric weight bands, our primary PD target was achieved by cephalexin 25 mg/kg/dose, maximum 750 mg/dose, administered three times daily and cefadroxil 40 mg/kg/dose, maximum 1,500 mg/dose, administered twice daily. More aggressive dosing was required to achieve higher PD targets. Among children with musculoskeletal infections, oral cephalexin and cefadroxil achieved PD targets for efficacy against MSSA. Given less frequent dosing, twice-daily cefadroxil should be further considered as an alternative to cephalexin for oral step-down therapy for serious infections due to MSSA.

No observed bidirectional effect between tenofovir diphosphate concentrations and gender-affirming hormone concentrations among transgender persons switching from tenofovir disoproxil fumarate/emtricitabine to tenofovir alafenamide/emtricitabine for HIV pre-exposure prophylaxis.

AIMS: Many transgender and gender diverse (TGD) individuals have expressed concerns about the potential for oral pre-exposure prophylaxis to affect hormonal concentrations achieved from taking gender-affirming hormone therapy (GAHT). The purpose of this study was to understand the bidirectional effects between hormone and intraerythrocytic tenofovir diphosphate concentrations when switching from tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) to tenofovir alafenamide/emtricitabine (TAF/FTC) in TGD users/nonusers of GAHT. METHODS: The study evaluated stored blood samples and dried blood spot cards from TGD adults without HIV who took ≥12 weeks of TDF/FTC and then switched to ≥12 weeks of TAF/FTC for pre-exposure prophylaxis. RESULTS: Thirty-nine individuals met the study inclusion criteria. Regardless of sex assigned at birth and the use of GAHT, there were no significant differences in hormone concentrations when individuals taking GAHT were taking TDF/FTC and then switched to TAF/FTC. Further, there was no significant difference in intraerythrocytic tenofovir diphosphate concentrations between users and nonusers of GAHT. CONCLUSION: There are no bidirectional effects between hormone and intraerythocytic tenofovir diphosphate concentrations when switching from TDF/FTC to TAF/FTC in TGD users/nonusers of GAHT.

Tenofovir-Diphosphate and Emtricitabine-Triphosphate Adherence Benchmarks in Dried Blood Spots for Persons with HIV Receiving Tenofovir Alafenamide and Emtricitabine-based Antiretroviral Therapy (QUANTI-TAF).

BACKGROUND: QUANTI-TAF aimed to establish tenofovir-diphosphate/emtricitabine-triphosphate (TFV-DP/FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with HIV (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART). METHODS: During a 16-week pharmacokinetic study, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TAF/FTC anabolites (TFV-DP/FTC-TP) in DBS were quantified by LC-MS/MS and summarized at steady-state (week 12 or 16) as median (IQR). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP. RESULTS: 84 participants (86% male, 11% female, and 4% transgender), predominantly receiving bictegravir/TAF/FTC (73%) enrolled. 92% completed week 12 or 16 (94% receiving unboosted ART). TFV-DP for <85% (7/72), ≥85%-<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039-4108), 3117 (2332-3339), and 3344 (2605-4293) fmol/punches. All participants with ≥85% cumulative adherence had TFV-DP ≥1800 fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower BMI, and in non-Blacks. FTC-TP for <85% (14/77), ≥85%-<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64-4.48), 4.58 (4.39-5.06), and 4.96 (4.21-6.26) pmol/punches. All participants with ≥85% 10-day adherence had FTC-TP ≥2.5 pmol/punches. Low-level viremia (HIV-1 RNA ≥20-<200 copies/mL) occurred at 60/335 (18%) visits in 33/84 (39%) participants (range: 20-149 copies/mL), with similar TFV-DP (3177 [2494-4149] fmol/punches) compared with HIV-1 RNA <20 copies/mL visits (3279 [2580-4407] fmol/punches). CONCLUSIONS: We propose PK-based TFV-DP (≥1800 fmol/punches)/FTC-TP (≥2.5 pmol/punches) benchmarks in DBS for PWH receiving unboosted TAF/FTC-based ART with ≥85% adherence. In the setting of high adherence, low-level viremia was common.

Fetal alcohol spectrum disorder and attention deficit hyperactivity disorder stimulant trial in children: an N-of-1 pilot trial to compare stimulant to placebo (FASST): protocol.

INTRODUCTION: Fetal alcohol spectrum disorder (FASD) is a neurodevelopmental disorder caused by alcohol exposure during pregnancy. FASD is associated with neurodevelopmental deviations, and 50%-94% of children with FASD meet the Diagnostic and Statistical Manual of Mental Disorders-fifth edition diagnostic criteria for attention deficit hyperactivity disorder (ADHD). There is a paucity of evidence around medication efficacy for ADHD symptoms in children with FASD. This series of N-of-1 trials aims to provide pilot data on the feasibility of conducting N-of-1 trials in children with FASD and ADHD. METHODS AND ANALYSIS: A pilot N-of-1 randomised trial design with 20 cycles of stimulant and placebo (four cycles of 2-week duration) for each child will be conducted (n=20) in Melbourne, Australia.Feasibility and tolerability will be assessed using recruitment and retention rates, protocol adherence, adverse events and parent ratings of side effects. Each child's treatment effect will be determined by analysing teacher ADHD ratings across stimulant and placebo conditions (Wilcoxon rank). N-of-1 data will be aggregated to provide an estimate of the cohort treatment effect as well as individual-level treatment effects. We will assess the sample size and number of cycles required for a future trial. Potential mediating factors will be explored to identify variables that might be associated with treatment response variability. ETHICS AND DISSEMINATION: The study was approved by the Hospital and Health Service Human Research Ethics Committee (HREC/74678/MonH-2021-269029), Monash (protocol V6, 25 June 2023).Individual outcome data will be summarised and provided to participating carers and practitioners to enhance care. Group-level findings will be presented at a local workshop to engage stakeholders. Findings will be presented at national and international conferences and published in peer-reviewed journals. All results will be reported so that they can be used to inform prior information for future trials. TRIAL REGISTRATION NUMBER: NCT04968522.

Parent screening questionnaires to detect cognitive and language delay at 2 years in high-risk infants: an analysis from the Victorian Infant Collaborative Study 2016-2017 cohort.

OBJECTIVE: To determine the accuracy of two developmental screening questionnaires to detect cognitive or language delay, defined using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III), in children born extremely preterm (EP: <28 weeks' gestation) or extremely low birth weight (ELBW: <1000 g). DESIGN: Prospective cohort study. SETTING: State of Victoria, Australia. PATIENTS: 211 infants born EP/ELBW assessed at 2 years' corrected age (mean 2.2, SD 0.2). MAIN OUTCOME MEASURES: Cognitive and language delay (<-1 SD) on the Bayley-III. The screening questionnaires were the Parent Report of Children's Abilities-Revised (PARCA-R) and the Ages & Stages Questionnaires Third Edition (ASQ-3). RESULTS: The PARCA-R performed better than the ASQ-3, but neither questionnaire had substantial agreement with the Bayley-III to detect cognitive delay; kappa (95% CI): PARCA-R 0.43 (0.23, 0.63); ASQ-3 0.15 (-0.05, 0.35); sensitivity (95% CI): PARCA-R 70% (53%, 84%) ASQ-3 62% (47%, 76%); specificity (95% CI): PARCA-R 73% (60%, 84%) ASQ-3 53% (38%, 68%). When both tools were used in combination (below cut-off on at least one assessment), sensitivity increased to 78% (60%, 91%) but specificity fell to 45% (29%, 62%). Similar trends were noted for language delay on the Bayley-III, although kappa values were better than for cognitive delay. CONCLUSIONS: Neither screening questionnaire identified cognitive delay well, but both were better at identifying language delay. The PARCA-R detects delay on the Bayley-III more accurately than the ASQ-3. Sensitivity for detecting delay is greatest when the PARCA-R and ASQ-3 were used in combination, but resulted in lower specificity.

A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention.

BACKGROUND: On-demand topical products could be an important tool for HIV prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG; 16 mg/20 mg) insert administered rectally. METHODS: MTN-039 was a Phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid (RF), and rectal tissue (RT) were collected over 72 hours (hr) following rectal administration of one and two TAF/EVG inserts for each participant. ClinicalTrials.gov Identifier: NCT04047420. RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. RT EVG peaked at 2-hr (median 2 inserts= 9 ng/mg) but declined to BLQ in the majority of samples at 24-hr, whereas TFV-DP remained high >2,000 fmol/million cells for 72-hr with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each timepoint for both 1 and 2 inserts (p<0.065 and p<0.039, respectively). DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.

Concordance between daily diary reported PrEP intake and intraerythrocytic tenofovir diphosphate (TFV-DP) in the Amsterdam PrEP demonstration project.

OBJECTIVE: We assessed the association and concordance between self-reported oral preexposure prophylaxis (PrEP) intake in a diary app and intraerythrocytic drug metabolite concentrations. DESIGN: AMPrEP was a prospective demonstration study providing daily and event-driven PrEP to MSM in Amsterdam, the Netherlands (2015-2020). METHODS: Participants could record their PrEP intake in a diary app. Dried blood spots (DBS) were taken at 6, 12, 24, and 48 months and analysed for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations. We included TFV-DP measurements preceded by diary completion on at least 90% of days in the 6 weeks prior. We examined the association between self-reported PrEP intake (i.e. number of pills) and TFV-DP concentrations using tobit regression with a random intercept per participant. We also calculated concordance between categorized PrEP intake (i.e. <2, 2-3, 4-6 or 7 pills per week) and categorized TFV-DP concentrations (i.e. <350, 350-699,700-1249 or ≥1250 fmol/punch) using weighted Cohen's kappa. Last, we calculated concordance between self-reported recent PrEP intake (yes/no, in past 2 days) and quantifiability of FTC-TP (yes/no) using Cohen's kappa. RESULTS: Seven hundred and fifty-nine DBS measurements from 282 MSM were included. Self-reported PrEP intake was strongly and positively associated with TFV-DP concentration (ß = 0.77, 95% CI = 0.70-0.84, P < 0.0001). Concordance between categorized PrEP intake and TFV-DP concentration was moderate (κ = 0.44, 95% CI = 0.39-0.50). Concordance between self-reported recent PrEP intake and FTC-TP quantifiability was perfect (κ = 0.83, 95% CI 0.76-0.90). CONCLUSION: Self-reported PrEP intake in a diary app is strongly correlated with actual use, and therefore reliable for comparing PrEP adherence between groups. Still, suboptimal criterion validity according to clinically relevant categories warrants caution when assessing 6-week reported adherence for individuals.

Proximal Motives of Sexual Arousal, Power, and Relationship for Sexual Aggression: Supporting the Millennial Shift.

We examined three proximal motives for sexual aggression (sexual persistence after a turn down): sexual arousal, power, and relationship. The MTurk sample consisted of 264 adults: 92 Millennial men (35%), 51 Millennial women (19%), 82 Gen X men (31%) and 39 Gen X women (15%). The motive data, measured by the Sexual Aggression Motive Assessment (SAMA), were unanalyzed data extracted from the authors' previous study of the Millennial shift, a phenomenon in which Millennial women, as compared to older generation women, showed higher levels of sexual aggression, while Millennial men, in comparison to older generation men, demonstrated lower levels of sexual aggression. For all respondents combined, the most chosen motive category was sexual arousal (95%), followed by relationship (49%), and then by power (18%) with 50% choosing two or more motive categories. Providing conceptual support for the Millennial shift, significantly more Millennial women than Gen X women chose motives of sexual arousal and power as reasons for perpetrating sexual aggression. An important finding for the relationship motive is that substantial numbers of both men and women engaged in sexual aggression because they felt that having sex would make the person like them.

Satisfaction with Control of Mild to Moderate Atopic Dermatitis with Ruxolitinib Cream: US Physician and Patient Perspectives.

INTRODUCTION: The 2021 US approval of ruxolitinib cream for treatment of atopic dermatitis (AD) in patients aged ≥ 12 years was based on the results of two pivotal phase 3 studies. Currently, real-world data to describe effectiveness of ruxolitinib cream and physician satisfaction with treatment remain limited. Our objective is to describe disease control among adults with mild to moderate AD prescribed ruxolitinib cream and physician satisfaction with treatment. METHODS: Data were from the Adelphi AD Disease Specific Programme™, a US real-world, cross-sectional survey of physician-reported data, undertaken between August 2022 and March 2023. For patients aged ≥ 18 years, physicians reported patient demographics, clinical characteristics, treatment patterns, and physician satisfaction with disease control. Descriptive analysis of data for patients with mild to moderate AD prior to the initiation of ruxolitinib cream and treated with ruxolitinib cream for ≥ 1 month was undertaken. RESULTS: Among physician-reported data from 1360 patients with AD, 149 patients had received ruxolitinib cream (in combination or as monotherapy) for ≥ 1 month, including 59 patients receiving monotherapy. Prior to treatment with ruxolitinib cream, 84.6% of patients had moderate AD (Investigator's Global Assessment, IGA of 3), whereas after treatment (median duration, 26 weeks), only 21.5% had an IGA of 3, with 48.3% of patients having clear or almost clear skin (IGA of 0/1). For these patients, 81.2% were not currently experiencing a flare, and physicians were satisfied with disease control for 87.3%. Results were similar in patients receiving monotherapy. The most frequent physician-reported reasons for prescribing ruxolitinib cream included relieving itch, improving lesion redness/thickness, achieving disease control, and reducing/controlling flares. CONCLUSIONS: These real-world findings demonstrate effective disease control and physician satisfaction with ruxolitinib cream for the treatment of AD in adults in a clinical practice setting. Outcomes were similar whether ruxolitinib cream was prescribed as monotherapy or in combination regimens, suggesting a role for ruxolitinib cream across the spectrum of disease.

Atopic dermatitis (AD) is a disease in which skin can be itchy, inflamed, and cracked. Traditional therapies for mild to moderate AD can be limited by side effects and long-term safety issues. After US approval of ruxolitinib cream for the treatment of mild to moderate AD in 2021, the goal of this study was to describe disease control and doctor satisfaction with ruxolitinib cream in a real-world setting. The Adelphi AD Disease Specific Programme™ surveyed 159 doctors who treated people with AD between August 2022 and March 2023. Doctors reported records from 1360 patients with mild to moderate AD. In these patients, ruxolitinib cream was used for at least 1 month in 149 patients and was used alone in 59 patients. Before the use of ruxolitinib cream, nearly 85% of the 149 patients had moderate AD. After the use of ruxolitinib cream, about 20% had moderate AD, with half having clear or almost clear skin. About 80% were not currently experiencing flares. Doctors were satisfied with disease control in more than 85% of patients. Patients applying ruxolitinib cream alone had similar results. Doctors most often prescribed ruxolitinib cream for itch relief, disease control, and to reduce or control flares. In summary, when ruxolitinib cream was used by patients, it provided good disease control, and doctors were satisfied with results. Outcomes were similar in patients who applied ruxolitinib cream alone or with another treatment. This suggests that ruxolitinib cream may be useful for patients with AD of differing levels of severity.

Low to moderate prenatal alcohol exposure and neurodevelopment in a prospective cohort of early school aged children.

Evidence is strong for adverse fetal effects of high level or chronic prenatal alcohol exposure (PAE), but many pregnant women continue to drink at lower levels. The 'Asking Questions about Alcohol in pregnancy' prospective cohort aimed to determine the neurodevelopmental consequences at 6-8 years of age of low to moderate PAE. 1570 women from seven public antenatal clinics in Melbourne, Australia, provided information on frequency and quantity of alcohol use, and obstetric, lifestyle and socio-environmental confounders at four gestation timepoints. PAE was classified into five trajectories plus controls. At 6-8 years, 802 of 1342 eligible families took part and completed a questionnaire (60%) and 696 children completed neuropsychological assessments (52%). Multiple linear regressions examined mean outcome differences between groups using complete case and multiple imputation models. No meaningful relationships were found between any of the PAE trajectories and general cognition, academic skills, motor functioning, behaviour, social skills, social communication, and executive function. Maternal education most strongly influenced general cognition and academic skills. Parenting behaviours and financial situation were associated with academic skills, behaviour, social skills and/or executive function. The lack of association between PAE and neurodevelopment at 6-8 years may partly be explained by cumulative positive effects of socio-environmental factors.

Associations between low-moderate prenatal alcohol exposure and brain development in childhood.

BACKGROUND: The effects of low-moderate prenatal alcohol exposure (PAE) on brain development have been infrequently studied. AIM: To compare cortical and white matter structure between children aged 6 to 8 years with low-moderate PAE in trimester 1 only, low-moderate PAE throughout gestation, or no PAE. METHODS: Women reported quantity and frequency of alcohol consumption before and during pregnancy. Magnetic resonance imaging was undertaken for 143 children aged 6 to 8 years with PAE during trimester 1 only (n = 44), PAE throughout gestation (n = 58), and no PAE (n = 41). T1-weighted images were processed using FreeSurfer, obtaining brain volume, area, and thickness of 34 cortical regions per hemisphere. Fibre density (FD), fibre cross-section (FC) and fibre density and cross-section (FDC) metrics were computed for diffusion images. Brain measures were compared between PAE groups adjusted for age and sex, then additionally for intracranial volume. RESULTS: After adjustments, the right caudal anterior cingulate cortex volume (pFDR = 0.045) and area (pFDR = 0.008), and right cingulum tract cross-sectional area (pFWE < 0.05) were smaller in children exposed to alcohol throughout gestation compared with no PAE. CONCLUSION: This study reports a relationship between low-moderate PAE throughout gestation and cingulate cortex and cingulum tract alterations, suggesting a teratogenic vulnerability. Further investigation is warranted.

Updates to the Melbourne Children's Regional Infant Brain Software Package (M-CRIB-S).

The delineation of cortical areas on magnetic resonance images (MRI) is important for understanding the complexities of the developing human brain. The previous version of the Melbourne Children's Regional Infant Brain (M-CRIB-S) (Adamson et al. Scientific Reports, 10(1), 10, 2020) is a software package that performs whole-brain segmentation, cortical surface extraction and parcellation of the neonatal brain. Available cortical parcellation schemes in the M-CRIB-S are the adult-compatible 34- and 31-region per hemisphere Desikan-Killiany (DK) and Desikan-Killiany-Tourville (DKT), respectively. We present a major update to the software package which achieves two aims: 1) to make the voxel-based segmentation outputs derived from the Freesurfer-compatible M-CRIB scheme, and 2) to improve the accuracy of whole-brain segmentation and cortical surface extraction. Cortical surface extraction has been improved with additional steps to improve penetration of the inner surface into thin gyri. The improved cortical surface extraction is shown to increase the robustness of measures such as surface area, cortical thickness, and cortical volume.

Associations between physical activity and development in preschool-aged children born <30 weeks' gestation: a cohort study.

OBJECTIVE: To investigate the effect of physical activity (PA) on development (motor, cognitive, social-emotional) in children 4-5 years old born <30 weeks' gestation, and to describe subgroups of children at risk of low PA in this cohort. DESIGN: Longitudinal cohort study. PATIENTS: 123 children born <30 weeks were recruited at birth and assessed between 4 and 5 years' corrected age. MAIN OUTCOME MEASURES: Development was assessed using the Movement Assessment Battery for Children, Second Edition (MABC-2), Little Developmental Coordination Disorder Questionnaire (L-DCDQ), Wechsler Preschool and Primary Scale of Intelligence (Fourth Edition; WPPSI-IV), and Strengths and Difficulties Questionnaire (SDQ). To measure PA, children wore an accelerometer and parents completed a diary for 7 days. Effects of PA on developmental outcomes, and associations between perinatal risk factors and PA, were estimated using linear regression. RESULTS: More accelerometer-measured PA was associated with better MABC-2 aiming and catching scores (average standard score increase per hour increase in PA: 0.54, 95% CI 0.11, 0.96; p=0.013), and lower WPPSI-IV processing speed index scores (average composite score decrease per hour increase in PA: -2.36, 95% CI -4.19 to -0.53; p=0.012). Higher accelerometer-measured PA was associated with better SDQ prosocial scores. Major brain injury in the neonatal period was associated with less moderate-vigorous and less unstructured PA at 4-5 years. CONCLUSIONS: Higher levels of PA are associated with aspects of motor, cognitive and social-emotional skill development in children 4-5 years old born <30 weeks. Those with major brain injury in the neonatal period may be more vulnerable to low PA at preschool age.

Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants.

BACKGROUND: Infants born preterm are at increased risk of cognitive and motor impairments compared with infants born at term. Early developmental interventions for preterm infants are targeted at the infant or the parent-infant relationship, or both, and may focus on different aspects of early development. They aim to improve developmental outcomes for these infants, but the long-term benefits remain unclear. This is an update of a Cochrane review first published in 2007 and updated in 2012 and 2015. OBJECTIVES: Primary objective To assess the effect of early developmental interventions compared with standard care in prevention of motor or cognitive impairment for preterm infants in infancy (zero to < three years), preschool age (three to < five years), and school age (five to < 18 years). Secondary objective To assess the effect of early developmental interventions compared with standard care on motor or cognitive impairment for subgroups of preterm infants, including groups based on gestational age, birthweight, brain injury, timing or focus of intervention and study quality. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO and trial registries in July 2023. We cross-referenced relevant literature, including identified trials and existing review articles. SELECTION CRITERIA: Studies included randomised, quasi-randomised controlled trials (RCTs) or cluster-randomised trials of early developmental intervention programmes that began within the first 12 months of life for infants born before 37 weeks' gestational age (GA). Interventions could commence as an inpatient but had to include a post discharge component for inclusion in this review. Outcome measures were not prespecified, other than that they had to assess cognitive outcomes, motor outcomes or both. The control groups in the studies could receive standard care that would normally be provided. DATA COLLECTION AND ANALYSIS: Data were extracted from the included studies regarding study and participant characteristics, timing and focus of interventions and cognitive and motor outcomes. Meta-analysis using RevMan was carried out to determine the effects of early developmental interventions at each age range: infancy (zero to < three years), preschool age (three to < five years) and school age (five to < 18 years) on cognitive and motor outcomes. Subgroup analyses focused on GA, birthweight, brain injury, time of commencement of the intervention, focus of the intervention and study quality. We used standard methodological procedures expected by Cochrane to collect data and evaluate bias. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Forty-four studies met the inclusion criteria (5051 randomly assigned participants). There were 19 new studies identified in this update (600 participants) and a further 17 studies awaiting outcomes. Three previously included studies had new data. There was variability in the focus and intensity of the interventions, participant characteristics, and length of follow-up. All included studies were either single or multicentre trials and the number of participants varied from fewer than 20 to up to 915 in one study. The trials included in this review were mainly undertaken in middle- or high-income countries. The majority of studies commenced in the hospital, with fewer commencing once the infant was home. The focus of the intervention programmes for new included studies was increasingly targeted at both the infant and the parent-infant relationship. The intensity and dosages of interventions varied between studies, which is important when considering the applicability of any programme in a clinical setting. Meta-analysis demonstrated that early developmental intervention may improve cognitive outcomes in infancy (developmental quotient (DQ): standardised mean difference (SMD) 0.27 standard deviations (SDs), 95% confidence interval (CI) 0.15 to 0.40; P < 0.001; 25 studies; 3132 participants, low-certainty evidence), and improves cognitive outcomes at preschool age (intelligence quotient (IQ); SMD 0.39 SD, 95% CI 0.29 to 0.50; P < 0.001; 9 studies; 1524 participants, high-certainty evidence). However, early developmental intervention may not improve cognitive outcomes at school age (IQ: SMD 0.16 SD, 95% CI -0.06 to 0.38; P = 0.15; 6 studies; 1453 participants, low-certainty evidence). Heterogeneity between studies for cognitive outcomes in infancy and preschool age was moderate and at school age was substantial. Regarding motor function, meta-analysis of 23 studies showed that early developmental interventions may improve motor outcomes in infancy (motor scale DQ: SMD 0.12 SD, 95% CI 0.04 to 0.19; P = 0.003; 23 studies; 2737 participants, low-certainty evidence). At preschool age, the intervention probably did not improve motor outcomes (motor scale: SMD 0.08 SD, 95% CI -0.16 to 0.32; P = 0.53; 3 studies; 264 participants, moderate-certainty evidence). The evidence at school age for both continuous (motor scale: SMD -0.06 SD, 95% CI -0.31 to 0.18; P = 0.61; three studies; 265 participants, low-certainty evidence) and dichotomous outcome measures (low score on Movement Assessment Battery for Children (ABC) : RR 1.04, 95% CI 0.82 to 1.32; P = 0.74; 3 studies; 413 participants, low-certainty evidence) suggests that intervention may not improve motor outcome. The main source of bias was performance bias, where there was a lack of blinding of participants and personnel, which was unavoidable in this type of intervention study. Other biases in some studies included attrition bias where the outcome data were incomplete, and inadequate allocation concealment or selection bias. The GRADE assessment identified a lower certainty of evidence in the cognitive and motor outcomes at school age. Cognitive outcomes at preschool age demonstrated a high certainty due to more consistency and a larger treatment effect. AUTHORS' CONCLUSIONS: Early developmental intervention programmes for preterm infants probably improve cognitive and motor outcomes during infancy (low-certainty evidence) while, at preschool age, intervention is shown to improve cognitive outcomes (high-certainty evidence). Considerable heterogeneity exists between studies due to variations in aspects of the intervention programmes, the population and outcome measures utilised. Further research is needed to determine which types of early developmental interventions are most effective in improving cognitive and motor outcomes, and in particular to discern whether there is a longer-term benefit from these programmes.

Grainyhead-like 2 interacts with noggin to regulate tissue fusion in mouse.

Defective tissue fusion during mammalian embryogenesis results in congenital anomalies, such as exencephaly, spina bifida and cleft lip and/or palate. The highly conserved transcription factor grainyhead-like 2 (Grhl2) is a crucial regulator of tissue fusion, with mouse models lacking GRHL2 function presenting with a fully penetrant open cranial neural tube, facial and abdominal clefting (abdominoschisis), and an open posterior neuropore. Here, we show that GRHL2 interacts with the soluble morphogen protein and bone morphogenetic protein (BMP) inhibitor noggin (NOG) to impact tissue fusion during development. The maxillary prominence epithelium in embryos lacking Grhl2 shows substantial morphological abnormalities and significant upregulation of NOG expression, together with aberrantly distributed pSMAD5-positive cells within the neural crest cell-derived maxillary prominence mesenchyme, indicative of disrupted BMP signalling. Reducing this elevated NOG expression (by generating Grhl2-/-;Nog+/- embryos) results in delayed embryonic lethality, partial tissue fusion rescue, and restoration of tissue form within the craniofacial epithelia. These data suggest that aberrant epithelial maintenance, partially regulated by noggin-mediated regulation of BMP-SMAD pathways, may underpin tissue fusion defects in Grhl2-/- mice.

Exploring Working Memory Capacity and Efficiency Processes to Understand Working Memory Training Outcomes in Primary School Children.

Despite the abundance of research evaluating working memory training outcomes in children, few studies have examined the underlying cognitive mechanisms. This study aimed to contribute understanding by exploring whether working memory capacity (maximum span) and/or efficiency (basic and cognitive processing speeds), two proposed cognitive mechanisms, are associated with children's working memory performance immediately and 6-months post-intervention. We used data from a previous trial in primary school children (7-11 years) who completed working memory training (n = 52) or an active control (n = 36), comprising 10 sessions (each 20-minutes) in class over two weeks. Children completed five working memory measures at baseline, immediately and 6-months post-intervention: two Backwards Span and two Following Instructions measures (same paradigms as training activities), and one n-back measure (different paradigm). Maximum span, basic and cognitive processing speeds, and performance were calculated for each measure. Associations between change in maximum span, processing speeds and change in performance on the working memory measures from baseline to immediately and 6-months post-intervention did not differ between groups (all p < .05). Maximum span, processing speeds and performance on working memory measures did not differ between groups. Findings provide little evidence that the studied capacity or efficiency processes contribute to understanding working memory training outcomes in primary school children. Furthermore, working memory training did not have benefits for children's working capacity, efficiency or performance up to 6-months post-intervention. It is of interest for future studies to explore cognitive mechanisms, including strategy use, maximum span and information processing, in datasets where training effects are observed.

The Knowledge Translation of Early Cerebral Palsy (KiTE CP) study: Implementing Screening among a High-risk Prospective Cohort of Australian Infants.

OBJECTIVE: To describe the implementation of the international guidelines for the early diagnosis of cerebral palsy (CP) and engagement in the screening process in an Australian cohort of infants with neonatal risk factors for CP. STUDY DESIGN: Prospective cohort study of infants with neonatal risk factors recruited at <6 months corrected age from 11 sites in the states of Victoria, New South Wales, and Queensland, Australia. First, we implemented a multimodal knowledge translation strategy including barrier identification, technology integration, and special interest groups. Screening was implemented as follows: infants with clinical indications for neuroimaging underwent magnetic resonance imaging and/or cranial ultrasound. The Prechtl General Movements Assessment (GMA) was recorded clinically or using an app (Baby Moves). Infants with absent or abnormal fidgety movements on GMA videos were offered further assessment using the Hammersmith Infant Neurological Examination (HINE). Infants with atypical findings on 2/3 assessments met criteria for high risk of CP. RESULTS: Of the 597 infants (56% male) recruited, 95% (n = 565) received neuroimaging, 90% (n = 537) had scorable GMA videos (2% unscorable/8% no video), and 25% (n = 149) HINE. Overall, 19% of the cohort (n = 114/597) met criteria for high risk of CP, 57% (340/597) had at least 2 normal assessments (of neuroimaging, GMA or HINE), and 24% (n = 143/597) had insufficient assessments. CONCLUSIONS: Early CP screening was implemented across participating sites using a multimodal knowledge translation strategy. Although the COVID-19 pandemic affected recruitment rates, there was high engagement in the screening process. Reasons for engagement in early screening from parents and clinicians warrant further contextualization and investigation.

Neurosensory, cognitive and academic outcomes at 8 years in children born 22-23 weeks' gestation compared with more mature births.

Despite providing intensive care to more infants born <24 weeks' gestation, data on school-age outcomes, critical for counselling and decision-making, are sparse. OBJECTIVE: To compare major neurosensory, cognitive and academic impairment among school-aged children born extremely preterm at 22-23 weeks' gestation (EP22-23) with those born 24-25 weeks (EP24-25), 26-27 weeks (EP26-27) and term (≥37 weeks). DESIGN: Three prospective longitudinal cohorts. SETTING: Victoria, Australia. PARTICIPANTS: All EP live births (22-27 weeks) and term-born controls born in 1991-1992, 1997 and 2005. MAIN OUTCOME MEASURES: At 8 years, major neurosensory disability (any of moderate/severe cerebral palsy, IQ <-2 SD relative to controls, blindness or deafness), motor, cognitive and academic impairment, executive dysfunction and poor health utility. Risk ratios (RRs) and risk differences between EP22-23 (reference) and other gestational age groups were estimated using generalised linear models, adjusted for era of birth, social risk and multiple birth. RESULTS: The risk of major neurosensory disability was higher for EP22-23 (n=21) than more mature groups (168 EP24-25; 312 EP26-27; 576 term), with increasing magnitude of difference as the gestation increased (adjusted RR (95% CI) compared with EP24-25: 1.39 (0.70 to 2.76), p=0.35; EP26-27: 1.85 (0.95 to 3.61), p=0.07; term: 13.9 (5.75 to 33.7), p<0.001). Similar trends were seen with other outcomes. Two-thirds of EP22-23 survivors were free of major neurosensory disability. CONCLUSIONS: Although children born EP22-23 experienced higher rates of disability and impairment at 8 years than children born more maturely, many were free of major neurosensory disability. These data support providing active care to infants born EP22-23.

Pheromonal variation and mating between two mitotypes of fall armyworm (Spodoptera frugiperda) in Africa.

In the Americas, the fall armyworm (Spodoptera frugiperda) exists in two genetically distinct strains, the corn (C) and rice (R) strains. Despite their names, these strains are not associated with host plant preferences but have been shown to vary in pheromone composition and male responses. Recently, S. frugiperda was detected in Africa as an invasive species, but knowledge about variation in strain types, pheromone composition and inter-strain mating of populations of the pest in the continent has not been fully examined. Therefore, this study aimed to investigate variations, if any in the pheromone composition of female moths, male moth responses, and mating between C and R mitotypes of S. frugiperda populations in Kenya, as well as their geographic distribution. Strains (mitotypes) of S. frugiperda were identified using mitochondrial DNA (mtDNA) markers, and their pheromonal composition determined by coupled gas chromatography-mass spectrometric (GC-MS) analysis. Male moth responses to these compounds were evaluated using GC-electroantennographic detection (EAD), electroantennogram (EAG), and wind tunnel assays. Oviposition assays were used to determine whether R and C mitotype moths could mate and produce eggs. The results showed that both the R and C mitotypes were present, and there were no statistically significant differences in their distribution across all sampled locations. Five pheromone compounds including (Z)-7-dodecenyl acetate (Z7-12:OAc), (Z)-7-tetradecenyl acetate (Z7-14:OAc), (Z)-9-tetradecenyl acetate (Z9-14:OAc), (Z)-11-tetradecenyl acetate (Z11-14:OAc) and (Z)-11-hexadecenyl acetate (Z11-16:OAc), were detected in the pheromone glands of female moths of both mitotypes, with Z9-14:OAc being the most abundant. The relative percentage composition of Z9-14:OAc was similar in both mitotypes. However, the R mitotype had a 2.7 times higher relative percentage composition of Z7-12:OAc compared to the C mitotype moth, while the C mitotype moth had a 2.4 times higher relative percentage composition of Z11-16:OAc than the R mitotype moth. Male moths of both mitotypes exhibited similar responses to the pheromone compounds, showing the strongest responses to Z9-14:OAc and Z7-12:OAc in electrophysiological and behavioural assays. There was mating between R and C mitotypes with egg production comparable to mating within the same mitotype. Our results revealed that differences between the two S. frugiperda mitotypes are characterized by female moth pheromone composition rather than male moth responses to the pheromones, and that this does not prevent hybridisation between the mitotypes, which may have implications for their management.