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BACKGROUND AND OBJECTIVES: Transdiagnostic approaches have been promoted as a means of maximising preventative effects across multiple problems with depression and anxiety suitable targets as they appear to have highly interconnected systems in pathology development and maintenance. This study investigated long-term effects of two universal school-based programs, Emotion Regulation (ER) and Behavioral Activation (BA), that sought to prevent depression and anxiety by targeting worry (a transdiagnostic feature) to promote resilience. METHODS: This follow-up study captured data from 162 of 316 initial students (aged 8-13; 52.2% female), from six Australian schools. The original study design cluster randomised students by school into BA, ER, or a usual class control. Intervention conditions consisted of 8 × 50-min weekly sessions. This study measured the effects of these interventions after 24 months on resilience, worry, depression, and anxiety. Resilience was also examined as a potential mediator. RESULTS: At 24-month follow-up, there was no significant effect of either intervention on depression, anxiety, worry, or resilience levels. Significantly fewer participants in ER and BA met clinical thresholds for separation anxiety disorder (SAD) and obsessive-compulsive disorder (OCD) in the 24-month follow-up compared with baseline. No mediation effects were found. LIMITATIONS: Although self-report measures are common in universal, school-based research, this represents a study limitation. CONCLUSIONS: Both interventions may provide limited long-term protective effects on SAD and OCD symptoms, which appear to have a shelf-life shorter than 24 months. To maintain program effects, refresher sessions at shorter intervals may be a consideration for future research.
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INTRODUCTION: Milk fat globule membrane (MFGM) is a complex lipid-protein structure in mammalian milk and human milk that is largely absent from breastmilk substitutes. The objective of this trial is to investigate whether providing infant formula enriched with MFGM versus standard infant formula improves cognitive development at 12 months of age in exclusively formula-fed full-term infants. METHODS AND ANALYSIS: This is a randomised, controlled, clinician-blinded, researcher-blinded and participant-blinded trial of two parallel formula-fed groups and a breastfed reference group that were recruited in the suburban Adelaide (Australia) community by a single study centre (a medical research institute). Healthy, exclusively formula-fed, singleton, term-born infants under 8 weeks of age were randomised to either an MFGM-supplemented formula (intervention) or standard infant formula (control) from enrolment until 12 months of age. The reference group was not provided with formula. The primary outcome is the Cognitive Scale of the Bayley Scales of Infant Development, Fourth Edition (Bayley-IV) at 12 months. Secondary outcomes are the Bayley-IV Cognitive Scale at 24 months, other Bayley-IV domains (language, motor, emotional and behavioural development) at 12 and 24 months of age, infant attention at 4 and 9 months of age, parent-rated language at 12 and 24 months of age, parent-rated development at 6 and 18 months of age as well as growth, tolerance and safety of the study formula. To ensure at least 80% power to detect a 5-point difference in the mean Bayley-IV cognitive score, >200 infants were recruited in each group. ETHICS AND DISSEMINATION: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/19/WCHN/140). Caregivers gave written informed consent prior to enrolling in the trial. Findings of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12620000552987; Australian and New Zealand Clinical Trial Registry: anzctr.org.au.
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Desarrollo Infantil , Cognición , Glucolípidos , Glicoproteínas , Fórmulas Infantiles , Gotas Lipídicas , Humanos , Glucolípidos/administración & dosificación , Fórmulas Infantiles/química , Glicoproteínas/administración & dosificación , Cognición/efectos de los fármacos , Lactante , Femenino , Recién Nacido , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Suplementos Dietéticos , Lactancia Materna , Leche Humana/químicaRESUMEN
BACKGROUND: Acute Stanford type- A aortic dissections make up a large part of emergency cardiac surgery. They also carry a significant burden of morbidity. New techniques to aid aortic remodelling include the Ascyrus Medical Dissection Stent (AMDS): Its increasing use, looks to present a potential problem in cases where surgery involving the aortic arch may be required. CASE REPORT: We present the case of a 49-year-old male who underwent urgent redo-surgery for total arch replacement and de-branching following recent replacement of the ascending aorta for acute type-A dissection, where an AMDS stent was deployed. The patient underwent total arch replacement with a stented tri-furcate prosthesis and de-branching of arch vessels with the stent landed inside the previous AMDS, to good effect. CONCLUSION: This case highlights a possible approach to aortic arch surgery in patients who have previous had AMDS insertion.
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Aorta Torácica , Aneurisma de la Aorta Torácica , Disección Aórtica , Hematoma , Stents , Humanos , Masculino , Persona de Mediana Edad , Disección Aórtica/cirugía , Aorta Torácica/cirugía , Hematoma/cirugía , Hematoma/etiología , Aneurisma de la Aorta Torácica/cirugía , Implantación de Prótesis Vascular/métodos , Reoperación , Prótesis VascularRESUMEN
BACKGROUND: A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum, formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time. METHODS: We did a non-randomised, phase 1b, single-centre, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M in Bagamoyo, Tanzania. We recruited healthy adults (aged 18-45 years) and children (aged 5-17 months) to receive the RH5.1/Matrix-M vaccine candidate in the following three-dose regimens: 10 µg RH5.1 at 0, 1, and 2 months (Adults 10M), and the higher dose of 50 µg RH5.1 at 0 and 1 month and 10 µg RH5.1 at 6 months (delayed-fractional third dose regimen; Adults DFx). Children received either 10 µg RH5.1 at 0, 1, and 2 months (Children 10M) or 10 µg RH5.1 at 0, 1, and 6 months (delayed third dose regimen; Children 10D), and were recruited in parallel, followed by children who received the dose-escalation regimen (Children DFx) and children with higher malaria pre-exposure who also received the dose-escalation regimen (High Children DFx). All RH5.1 doses were formulated with 50 µg Matrix-M adjuvant. Primary outcomes for vaccine safety were solicited and unsolicited adverse events after each vaccination, along with any serious adverse events during the study period. The secondary outcome measures for immunogenicity were the concentration and avidity of anti-RH5.1 serum IgG antibodies and their percentage growth inhibition activity (GIA) in vitro, as well as cellular immunogenicity to RH5.1. All participants receiving at least one dose of vaccine were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT04318002, and is now complete. FINDINGS: Between Jan 25, 2021, and April 15, 2021, we recruited 12 adults (six [50%] in the Adults 10M group and six [50%] in the Adults DFx group) and 48 children (12 each in the Children 10M, Children 10D, Children DFx, and High Children DFx groups). 57 (95%) of 60 participants completed the vaccination series and 55 (92%) completed 22 months of follow-up following the third vaccination. Vaccinations were well-tolerated across both age groups. There were five serious adverse events involving four child participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum IgG antibody responses were induced by vaccination and purified total IgG showed in vitro GIA against P falciparum. We found similar functional quality (ie, GIA per µg RH5-specific IgG) across all age groups and dosing regimens at 14 days after the final vaccination; the concentration of RH5.1-specific polyclonal IgG required to give 50% GIA was 14·3 µg/mL (95% CI 13·4-15·2). 11 children were vaccinated with the delayed third dose regimen and showed the highest median anti-RH5 serum IgG concentration 14 days following the third vaccination (723 µg/mL [IQR 511-1000]), resulting in all 11 who received the full series showing greater than 60% GIA following dilution of total IgG to 2·5 mg/mL (median 88% [IQR 81-94]). INTERPRETATION: The RH5.1/Matrix-M vaccine candidate shows an acceptable safety and reactogenicity profile in both adults and 5-17-month-old children residing in a malaria-endemic area, with all children in the delayed third dose regimen reaching a level of GIA previously associated with protective outcome against blood-stage P falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African children. FUNDING: The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the UK Department for International Development; 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.
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PURPOSE: Tongue manometry (i.e., tongue pressure measurement) is a commonly used assessment for patients with suspected oral-motor involvement in swallowing disorders. Availability of lingual manometry has changed in recent years, with the introduction of the Tongueometer device being a more affordable tongue manometry system. The purpose of this study was to test concurrent (criterion) validity of the Tongueometer compared to the current standard reference device, the Iowa Oral Performance Instrument (IOPI). METHOD: Adults without dysphagia were recruited for participation in this study. Standard lingual measurements (swallowing-related pressures, maximum isometric pressure [MIP], and maximum isometric endurance) were recorded, with the bulb anteriorly placed, with both devices, in a randomized order. The Bland-Altman method was used to determine concurrent (criterion) validity of these measurements compared to the clinical standard IOPI device. A recently available suggested corrective value by Curtis et al. (2023) was also applied, with comparisons made between devices both with and without the Curtis correction. RESULTS: The final sample included 70 adult participants aged 20-89 years (Mage = 52.3 years). Measures with the Tongueometer device were significantly lower when compared with the same measures taken using the IOPI (p < .01) for all measures including MIP, endurance, and swallow pressures. The correction suggested by Curtis and colleagues did not ameliorate these differences. CONCLUSIONS: The Tongueometer lingual measurements were consistently lower compared to the IOPI. Clinical use of values taken with the Tongueometer device should be compared to normative data published for each specific device. Available features of each device (e.g., display, bulb texture, technology/application) should be considered when selecting which device to use with an individual patient.
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Deglución , Manometría , Lengua , Humanos , Lengua/fisiología , Persona de Mediana Edad , Adulto , Anciano , Manometría/instrumentación , Femenino , Masculino , Anciano de 80 o más Años , Reproducibilidad de los Resultados , Adulto Joven , Deglución/fisiología , Presión , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/fisiopatología , Diseño de Equipo , Valor Predictivo de las PruebasRESUMEN
Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII are associated with lysosomal accumulation of heparan sulphate and manifest with neurological deterioration. Most of these neurological MPS currently lack effective treatments. Here, we report that, compared to controls, neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and in mouse models of MPS I, II, IIIA, IIIB and IIIC, but not of other neurological lysosomal disorders not presenting with heparan sulphate storage. We further show that accumulated heparan sulphate disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), ß-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) necessary to maintain enzyme activity, and that NEU1 deficiency is linked to partial deficiencies of GLB1 and GALNS in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brain samples of human MPS III patients and MPS IIIC mice implicated insufficient processing of brain N-linked sialylated glycans, except for polysialic acid, which was reduced in the brains of MPS IIIC mice. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of the excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1-/PSD95-positive puncta in cortical neurons derived from iPSC of an MPS IIIA patient. Together, our data demonstrate that heparan sulphate-induced secondary NEU1 deficiency and aberrant sialylation of glycoproteins implicated in synaptogenesis, memory, and behaviour constitute a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology.
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It is not yet understood whether, and to what extent, craniosynostosis impacts the development of Attention Deficit/Hyperactivity Disorder (ADHD). This PRISMA compliant and PROSPERO pre-registered (ID: CRD42023458640) systematic review and meta-analysis examines the association of single-suture, non-syndromic craniosynostosis with ADHD and inattention/hyperactivity symptoms. Data from 17 independent studies (Nparticipants = 2,389; Mage = 7.3 years) were analyzed, taking into consideration suture location, surgical status, age, and measures administered, where feasible. Few differences were found between cases and controls, but some studies reported high symptom levels. Additional research is required utilizing larger sample sizes and more comprehensive assessment of ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Craneosinostosis , Humanos , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/etiología , Craneosinostosis/complicaciones , NiñoRESUMEN
OBJECTIVES: Children and adolescents with intellectual disabilities (ID) have high rates of mental health disorders, particularly anxiety disorders. Cognitive behavior therapy (CBT) has largely remained unexamined as a treatment option for this population. Fearless Me! © is an adapted CBT treatment program specifically designed for children and adolescents with ID. METHOD: Eleven children, aged between eight and 17, completed 10 therapy sessions. Measures of anxiety were completed pre and posttreatment and at 3 and 12-month follow-ups by both the children and parents. RESULTS: Six children reported significant reductions in anxiety, with all showing significant reductions in parent-reported child anxiety at either posttreatment assessment, 3-month follow-up, or 12-month follow-up. Results varied across the six children as all parents reported heightened anxiety, but not all children reported high levels of anxiety for themselves. CONCLUSION: Overall, this evaluation provides a sound basis for continued investigation and research into the use of the Fearless Me! © modified CBT program to treat children with ID and anxiety.
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Trastornos de Ansiedad , Terapia Cognitivo-Conductual , Discapacidad Intelectual , Humanos , Niño , Masculino , Femenino , Discapacidad Intelectual/terapia , Discapacidad Intelectual/psicología , Adolescente , Terapia Cognitivo-Conductual/métodos , Trastornos de Ansiedad/terapia , Resultado del Tratamiento , Ansiedad/terapia , Estudios de SeguimientoRESUMEN
The genetic landscape of neurodegenerative diseases encompasses genes affecting multiple cellular pathways which exert effects in an array of neuronal and glial cell-types. Deconvolution of the roles of genes implicated in disease and the effects of disease-associated variants remains a vital step in the understanding of neurodegeneration and the development of therapeutics. Disease modelling using patient induced pluripotent stem cells (iPSCs) has enabled the generation of key cell-types associated with disease whilst maintaining the genomic variants that predispose to neurodegeneration. The use of CRISPR interference (CRISPRi), alongside other CRISPR-perturbations, allows the modelling of the effects of these disease-associated variants or identifying genes which modify disease phenotypes. This review summarises the current applications of CRISPRi in iPSC-derived neuronal models, such as fluorescence-activated cell sorting (FACS)-based screens, and discusses the future opportunities for disease modelling, identification of disease risk modifiers and target/drug discovery in neurodegeneration.
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Sistemas CRISPR-Cas , Células Madre Pluripotentes Inducidas , Enfermedades Neurodegenerativas , Neuronas , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Humanos , Enfermedades Neurodegenerativas/terapia , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Neuronas/metabolismo , Neuronas/citología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Animales , Edición GénicaRESUMEN
Targeted alpha therapy (TAT) is a promising form of oncology treatment utilising alpha-emitting radionuclides that can specifically accumulate at disease sites. The high energy and high linear energy transfer associated with alpha emissions causes localised damage at target sites whilst minimising that to surrounding healthy tissue. The lack of appropriate radionuclides has inhibited research in TAT. The identification of appropriate radionuclides should be primarily a function of the radionuclide's nuclear decay properties, and not their biochemistry or economic factors since these last two factors can change; however, the nuclear decay properties are fixed to that nuclide. This study has defined and applied a criterion based on nuclear decay properties useful for TAT. This down-selection exercise concluded that the most appropriate radionuclides are: 149 Tb, 211 At/ 211 Po, 212 Pb/ 212 Bi/ 212 Po, 213 Bi/ 213 Po, 224 Ra, 225 Ra/ 225 Ac/ 221 Fr, 226 Ac/ 226 Th, 227 Th/ 223 Ra/ 219 Rn, 229 U, 230 U/ 226 Th, and 253 Fm, the majority of which have previously been considered for TAT. 229 U and 253 Fm have been newly identified and could become new radionuclides of interest for TAT, depending on their decay chain progeny.
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Partículas alfa , Radioisótopos , Partículas alfa/uso terapéutico , Radioisótopos/uso terapéutico , Humanos , RadioquímicaRESUMEN
BACKGROUND: Dissociation is a feature of Borderline Personality Disorder (BPD), but rarely a focus for research, particularly in the perinatal literature. BPD partly has its aetiology in childhood and is characterised by emotional changes and difficulty with self-coherence that impacts on the processes of caregiving. METHODS: A scoping review was conducted to synthesise current perspectives on the effect of dissociation in caregivers with BPD, particularly regarding the impact of caregiver dissociation on the interactional quality of relationship within parent-child dyads. Studies were included if they explicitly mentioned dissociation in the target population, or if dissociation was implied. A thematic analysis was conducted. RESULTS: 20 studies were included; 10 experimental or quasi-experimental; 2 presenting case material; and 8 non-systematic review articles. 4 studies used the Dissociative Experiences Scale (DES) to measure dissociation, while 2 studies included a 'dissociative behaviour' subscale as part of an observational measure. The remaining studies did not measure dissociation but referenced directly or indirectly a concept of dissociation. CONCLUSIONS: Findings suggested there was some evidence that dissociation plays a unique role in BPD caregivers' interactions with their offspring, however any findings should be interpreted with caution as the concept has been poorly operationalised and defined.
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AIM: Mindfulness-based interventions have been tested as preventive programs for childhood internalizing difficulties, but most research has been at a 'universal' level with small to null effects. Mindfulness-Based Cognitive Therapy for Children (MBCT-C) has similar effects to Cognitive Behaviour Therapy (CBT) when used as a small-group, targeted preventive program. Knowledge gaps include the longer-term effectiveness of MBCT-C relative to CBT and the benefits of adding a parent module. This trial aims to compare MCBT-C to traditional CBT, including a parent module, to 15-months post-intervention and to test the feasibility and acceptability of adding a parent module. METHODS: Participants will be recruited from primary schools in areas of socio-economic disadvantage in South Australia (n = 194). Children (aged 9-12) years with signs of internalizing difficulties (e.g., shy, withdrawn, worried), and their parents, will be eligible for this two-armed randomized controlled non-inferiority trial (RCT). Children will participate in 10 group sessions of MBCT-C or CBT, facilitated by psychologists, and parents from both conditions will participate in two parent-only group sessions. Child self-report measures include depression and anxiety, as well as attention, mindfulness and self-compassion. Parent measures include symptoms of depression and anxiety, mindfulness, and parent-child relationship strength. The primary outcome will be child anxiety and depression (Revised Child Anxiety and Depression Scale-25). Measures will be collected pre and post intervention, and at 3, 6, 12 and 15-month follow up. RESULTS: Schools will be recruited from October 2022. Nomination of children will commence from February 2023. Program implementation will begin May 2023. CONCLUSIONS: This trial will have implications for the feasibility of involving parents in preventative programs, as well as whether mindfulness-based interventions prevent internalizing difficulties over time.
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Terapia Cognitivo-Conductual , Atención Plena , Niño , Humanos , Terapia Cognitivo-Conductual/métodos , Estudios de Equivalencia como Asunto , Atención Plena/métodos , Padres/psicología , Estudios de FactibilidadRESUMEN
BACKGROUND: Cranial ultrasound is frequently performed in neonatal intensive care units and acquiring 2-dimensional (D) images requires significant training. Three-D ultrasound images can be acquired semi-automatically. OBJECTIVE: This proof-of-concept study aimed to demonstrate that 3-D study image quality compares well with 2-D. If this is successful, 3-D images could be acquired in remote areas and read remotely by experts. MATERIALS AND METHODS: This was a prospective study of 20 neonates, who underwent both routine 2-D and 3-D cranial ultrasounds. Images were reconstructed into standard views extracted from the 3-D volume and evaluated by three radiologists blinded to the acquisition method. The radiologists assessed for the presence of anatomical landmarks and overall image quality. RESULTS: More anatomical structures were identified in the 3-D studies (P<0.01). There was a trend that 3-D ultrasound demonstrated better image quality in the coronal plane, and 2-D in the sagittal plane, only reaching statistical significance for two coronal views and two sagittal views. CONCLUSION: Overall, this study has demonstrated that 3-D cranial ultrasound performs similarly to 2-D and could be implemented into neonatal practice.
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Imagenología Tridimensional , Humanos , Recién Nacido , Imagenología Tridimensional/métodos , Estudios Prospectivos , Femenino , Masculino , Ecoencefalografía/métodos , Prueba de Estudio Conceptual , Unidades de Cuidado Intensivo NeonatalRESUMEN
Endosomes are specialized organelles that function in the secretory and endocytic protein sorting pathways. Endocytosed cell surface receptors and transporters destined for lysosomal degradation are sorted into intraluminal vesicles (ILVs) at endosomes by endosomal sorting complexes required for transport (ESCRT) proteins. The endosomes (multivesicular bodies, MVBs) then fuse with the lysosome. During endosomal maturation, the number of ILVs increases, but the size of endosomes does not decrease despite the consumption of the limiting membrane during ILV formation. Vesicle-mediated trafficking is thought to provide lipids to support MVB biogenesis. However, we have uncovered an unexpected contribution of a large bridge-like lipid transfer protein, Vps13, in this process. Here, we reveal that Vps13-mediated lipid transfer at ER-endosome contact sites is required for the ESCRT pathway. We propose that Vps13 may play a critical role in supplying lipids to the endosome, ensuring continuous ESCRT-mediated sorting during MVB biogenesis.
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Complejos de Clasificación Endosomal Requeridos para el Transporte , Endosomas , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Endocitosis , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Endosomas/genética , Lípidos , Cuerpos Multivesiculares , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Transporte de ProteínasRESUMEN
BACKGROUND: Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. METHODS: We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5-36 months) were enrolled and randomly assigned (2:1) to receive 5 µg R21 plus 50 µg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing. FINDINGS: From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71-79; p<0·0001) at the seasonal sites and 68% (61-74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71-78; p<0·0001) at the seasonal sites and 67% (59-73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762-974) cases per 1000 children-years at seasonal sites and 296 (231-362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5-17 month age group compared with 18-36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73-84]; p<0·001) and standard (75% [65-83]; p<0·001) sites. INTERPRETATION: R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. FUNDING: The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.
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Vacunas contra la Malaria , Malaria , Nanopartículas , Saponinas , Preescolar , Femenino , Humanos , Lactante , Masculino , Anticuerpos Antivirales , Burkina Faso , Método Doble Ciego , Inmunización , Malaria/tratamiento farmacológico , Vacunas contra la Malaria/efectos adversosRESUMEN
This review aimed to identify the post-graduation training pathways available for both clinicians and trainers in the assessment and diagnosis of Autism Spectrum Disorder (ASD). The study was guided by two research questions: What is known about ASD-specific educational, training, or other pathways available to support clinicians of any discipline, post-graduation, to meet the required expertise relevant to assessments of ASD concerns? What is known about the educational pathways available to clinicians seeking to provide training to other clinicians, post-graduation, in the assessment of ASD concerns? A scoping review was undertaken with searches completed across five databases (PubMed, PsycINFO, PsycEXTRA, ERIC and CINAHL). A Google search strategy was also executed using the "advanced" search function. Eligible records were literature, written in English, that examined post-graduation training and/ or education of clinicians to assess and/ or diagnose ASD. Fourteen relevant records were identified. Post-graduate training has the potential to enhance clinician confidence and service provision in ASD assessment and diagnosis. System-wide training approaches show promise in building large-scale, diagnostic capacity and the use of tele-mentoring offers a cost-effective, convenient mode of training delivery. A lack of evidence to support ASD diagnostic training pathways was found and may pose a challenge for clinicians and service users. The limited evidence found suggests that high quality research will be fundamental in determining how to build clinician capacity in ASD assessment and diagnosis and to ascertain whether training pathways are a necessary component.
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Currently, more than half of the world's human population lives in urban areas, which are increasingly affected by climate hazards. Little is known about how multi-hazard environments affect people, especially those living in urban areas in northern latitudes. This study surveyed homeowners in Anchorage and Fairbanks, USA, Alaska's largest urban centers, to measure individual risk perceptions, mitigation response, and damages related to wildfire, surface ice hazards, and permafrost thaw. Up to one third of residents reported being affected by all three hazards, with surface ice hazards being the most widely distributed, related to an estimated $25 million in annual damages. Behavioral risk response, policy recommendations for rapidly changing urban environments, and the challenges to local governments in mitigation efforts are discussed.
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Hielos Perennes , Incendios Forestales , Humanos , Hielo , Clima , Cambio Climático , Regiones ÁrticasRESUMEN
Importance: Children born at less than 29 weeks' gestation are at risk of behavioral difficulties. This may be due in part to the lack of transplacental supply of docosahexaenoic acid (DHA), a key fatty acid with structural and functional roles in the brain. Objective: To determine whether meeting the neonatal DHA requirement through supplementation is associated with improved behavioral functioning of children born at less than 29 weeks' gestation. Design, Setting and Participants: This was a follow-up of children from 10 Australian participating centers in a multi-center, blinded, parallel group randomized clinical trial of infants born at less than 29 weeks' gestation conducted from June 2012 and September 2015, excluding those with additional fatty acid supplementation or major congenital or chromosomal abnormalities. Follow-up took place from August 2018 to May 2021. Parents of surviving children who had not withdrawn from the original trial were invited to complete questionnaires when the child turned 5 years' corrected age. Interventions: Infants were randomized to receive daily enteral emulsions providing 60 mg/kg/d of DHA or a soy-oil emulsion (with no DHA) from within the first 3 days of enteral feeding until 36 weeks' postmenstrual age or discharge home, whichever occurred first. Main Outcomes and Measures: The primary outcome of this follow-up was parent-rated behavior and emotional functioning as indicated by the Total Difficulties score of the Strengths and Difficulties Questionnaire. Parents also completed questionnaires about their child's behavioral manifestations of executive functioning, as well as a range of health outcomes to assess potential longer-term side effects of DHA intervention. Results: Primary outcome data were available for 731 children (76% of 958 surviving eligible children; 361 in the intervention group and 370 in the control group). Of these 731, 452 (47%) were female, and the mean (SD) corrected age at follow-up was 5.4 (0.5) years. Following imputation for missing data, the mean Total Difficulties score was the same in both groups (intervention group, n = 465; mean [SD], 11.8 [6.3]; control group, n = 493; mean [SD], 11.8 [6.0]; mean difference adjusted for sex, gestational age stratum, and hospital, 0.01; 95% CI, -0.87 to 0.89; P = .98). There was no evidence for differences between the groups in any secondary outcomes of behavior, executive functioning, or health. Conclusions and Relevance: In this follow-up of a randomized clinical trial, enteral DHA supplementation at the equivalent of the estimated in utero dose for infants born at less than 29 weeks' gestation did not improve behavioral functioning at age 5 years. There were no indications of adverse effects with DHA supplementation. Trial Registration: Australian New Zealand Clinical Trial Registry: ACTRN12612000503820.
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Ácidos Docosahexaenoicos , Recien Nacido Prematuro , Preescolar , Femenino , Humanos , Recién Nacido , Masculino , Embarazo , Australia , Suplementos Dietéticos , Estudios de Seguimiento , Edad GestacionalRESUMEN
BACKGROUND: People with Parkinson's disease (PwP) often report problems with their handwriting before they receive a formal diagnosis. Many PwP suffer from deteriorating handwriting throughout their illness, which has detrimental effects on many aspects of their quality of life. AIMS: To assess a 6-week online training programme aimed at improving handwriting of PwP. METHODS: Handwriting samples from a community-based cohort of PwP (n = 48) were analysed using systematic detection of writing problems (SOS-PD) by two independent raters, before and after a 6-week remotely monitored physiotherapy-led training programme. Inter-rater variability on multiple measures of handwriting quality was analysed. The handwriting data was analysed using pre-/post-design in the same individuals. Multiple aspects of the handwriting samples were assessed, including writing fluency, transitions between letters, regularity in letter size, word spacing, and straightness of lines. RESULTS: Analysis of inter-rater reliability showed high agreement for total handwriting scores and letter size, as well as speed and legibility scores, whereas there were mixed levels of inter-rater reliability for other handwriting measures. Overall handwriting quality (p = 0.001) and legibility (p = 0.009) significantly improved, while letter size (p = 0.012), fluency (p = 0.001), regularity of letter size (p = 0.009), and straightness of lines (p = 0.036) were also enhanced. CONCLUSIONS: The results of this study show that this 6-week intensive remotely-monitored physiotherapy-led handwriting programme improved handwriting in PwP. This is the first study of its kind to use this tool remotely, and it demonstrated that the SOS-PD is reliable for measuring handwriting in PwP.
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Enfermedad de Parkinson , Humanos , Reproducibilidad de los Resultados , Calidad de Vida , Escritura ManualRESUMEN
BACKGROUND: Indigenous Australian children and adolescents experience profound levels of preventable dental disease. The application of silver fluoride (AgF) to active dental caries is a noninvasive alternative to traditional dental treatment approaches. There is particular utility among Indigenous children and young people with dental fear, who may not have access to timely or culturally safe dental service provisions. OBJECTIVE: The aims of this study are to: (1) assess levels of active dental caries among Indigenous children and young people in 6 Australian states and territories; (2) determine if an AgF intervention reduces levels of active disease over 12-24 months; (3) measure the impact of improved oral health on social and emotional well-being (SEWB) and oral health-related quality of life; and (4) calculate the cost-effectiveness of implementing such an initiative. METHODS: The study will use a 2-arm, parallel cluster randomized controlled trial design. Approximately 1140 Indigenous children and youth aged between 2 and 18 years will be recruited. Each state or territory will have 2 clusters. The intervention group will receive the AgF intervention at the start of the study, with the delayed intervention group receiving the AgF intervention 12 months after study commencement. The primary outcome will be the arrest of active carious lesions, with arrested caries defined as nonpenetration by a dental probe. Secondary outcomes will include SEWB, oral health-related quality of life, and dental anxiety, with covariates including dental behaviors (brushing and dental visits). Effectiveness measures for the economic evaluation will include the number of children and young people managed in primary oral health care without the need for specialist referral, changes in SEWB, the numbers and types of treatments provided, and caries increments. RESULTS: Participant recruitment will commence in May 2023. The first results are expected to be submitted for publication 1 year after a 24-month follow-up. CONCLUSIONS: Our findings have the potential to change the way in which active dental disease among Indigenous children and young people can be managed through the inclusion of specifically tailored AgF applications to improve dental health and SEWB delivered by Indigenous health care workers. Desired impacts include cost savings on expensive dental treatments; improved SEWB, nutrition, social, and learning outcomes; and improved quality of life for both children and young people and their caregivers and the broader Indigenous community. The AgF application could be easily implemented into the training program of Indigenous health workers and yield critical information in the management armamentarium of health and well-being recommendations for Australia's First Peoples. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/48558.