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Objective: To compare the linear growth and nutritional parameters of a group of Malaysian children with cerebral palsy (CP) against a group of controls, and to determine the nutritional, medical and sociodemographic factors associated with poor growth in children with CP. Methodology: The linear growth of 101 children with CP and of their healthy controls matched for age, sex and ethnicity was measured using upper-arm length (UAL). Nutritional parameters of weight, triceps skin-fold thickness and mid-arm circumference were also measured. Total caloric intake was assessed using a 24-h recall of a 3-day food intake and calculated as a percentage of the Recommended Daily Allowance. Multiple regression analysis was used to determine nutritional, medical and sociodemographic factors associated with poor growth (using z-scores of UAL) in children with CP. Results: Compared with the controls, children with CP had significantly lower mean UAL measurements (difference between means –;1.1, 95% confidence interval –;1.65 to –; 0.59), weight (difference between means –;6.0, 95% CI –;7.66 to –;4.34), mid-arm circumference (difference between means –;1.3, 95% CI –;2.06 to –;0.56) and triceps skin-fold thickness (difference between means –;2.5, 95% CI –;3.5 to –;1.43). Factors associated with low z-scores of UAL were a lower percentage of median weight (P < 0.001), tube feeding (P < 0.001) and increasing age (P < 0.001). Conclusion: A large proportion of Malaysian children with CP have poor nutritional status and linear growth. Nutritional assessment and management at an early age might help this group of children achieve adequate growth. [ABSTRACT FROM AUTHOR]

Purpose: Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy., Methods: The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy. Only patients with Grade (G) 0-1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30 min prior to and continuing up to 90 min after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0-2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy., Results: Eighty-three patients were enrolled over a period of 18 months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 and above, indicating that the procedure was comfortable, upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3 weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation., Conclusion: SCT is well tolerated in an Asian-predominant population. Among women with breast or gynaecological cancers receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: A computer game-based epilepsy educational programme (Epigame) can potentially improve the awareness, knowledge and attitude (AKA) and quality of life (QOL) of children with epilepsy (CWE). Our study among Malaysian CWE aimed to assess the: i) baseline level of epilepsy AKA and potential characteristics associated with poor levels of AKA, ii) effectiveness of Epigame in improving AKA and QOL of CWE., Method: Prospective cohort study on CWE age 7-18 years old with no comorbidities. Epilepsy education was delivered using Epigame. CWE completed AKA questionnaire before (time point 1 [TP1]), immediately after (TP2), 3 months (TP3) after provision of Epigame. Child self-report Health-Related Quality of Life Measurement for Children with Epilepsy (CHEQOL-25) questionnaire was completed at TP1 and TP3., Results: Total of 106 CWE participated in this study (mean age of 13.3 years). Baseline (TP1) AKA was rated "very low to moderate" for awareness domain in 95.3 %, "very low to moderate" for knowledge domain in 67 %, "negative to indifferent" for attitude domain in 54.7 %, and "very poor to moderate' for total AKA score domain in 84 %. "Positive to very positive" for child attitude domain was significantly associated with parents with "positive to very positive" for attitude domain (OR 10.6, 95 % CI 3.23-34.66). "Good to excellent" for total child AKA domain was significantly associated with parents with "Good to excellent" for total AKA domain (OR 5.2, 95 % CI 1.16-15.02) and with < 2 antiseizure medication (OR 5.0, 95 % CI 1.34-18.98). The scores in the knowledge, attitude and total AKA score domains improved significantly after the introduction of Epigame at TP3. There were no significant improvements in the CHEQOL-25 scores over time except for the "Quest for Normality" subscale score (mean of score difference between TP1 and TP3 = 1.0, 95 % CI 0.19-1.81)., Conclusion: Majority of Malaysian CWE had low levels of epilepsy AKA, particularly among parents with "negative to indifferent" for attitude domain, parents with "very poor to moderate" for total AKA domain and on polytherapy. Introduction of Epigame was effective in improving scores of the knowledge, attitude and total AKA domains, and the QOL "Quest for Normality" domain of the CHEQOL-25., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Mesenchymal stromal cells (MSCs) have broad potential as a cell therapy including for the treatment of drug-resistant inflammatory conditions with abnormal T cell proliferation such as graft-versus-host disease (GVHD). Clinical success, however, has been complicated by the heterogeneity of culture-expanded MSCs as well as donor variability. Here, we devise culture conditions that promote expansion of MSCs with enhanced immunomodulatory functions both in vitro and in animal models of GVHD., Methods: Human bone marrow-derived MSCs were expanded at high-confluency (MSC HC ) and low-confluency state (MSC LC ). Their immunomodulatory properties were evaluated with in vitro co-culture assays based on suppression of activated T cell proliferation and secretion of pro-inflammatory cytokines from activated T cells. Metabolic state of these cells was determined, while RNA sequencing was performed to explore transcriptome of these MSCs. Ex vivo expanded MSC HC or MSC LC was injected into human peripheral blood mononuclear cells (PBMC)-induced GVHD mouse model to determine their in vivo therapeutic efficacy based on clinical grade scoring, human CD45 +  blood count and histopathological examination., Results: As compared to MSC LC , MSC HC significantly reduced both the proliferation of anti-CD3/CD28-activated T cells and secretion of pro-inflammatory cytokines upon MSC HC co-culture across several donors even in the absence of cytokine priming. Mechanistically, metabolic analysis of MSC HC prior to co-culture with activated T cells showed increased glycolytic metabolism and lactate secretion compared to MSC LC , consistent with their ability to inhibit T cell proliferation. Transcriptome analysis further revealed differential expression of immunomodulatory genes including TRIM29, BPIFB4, MMP3 and SPP1 in MSC HC as well as enriched pathways including cytokine-cytokine receptor interactions, cell adhesion and PI3K-AKT signalling . Lastly, we demonstrate in a human PBMC-induced GVHD mouse model that delivery of MSC HC showed greater suppression of inflammation and improved outcomes compared to MSC LC and saline controls., Conclusion: Our study provides evidence that ex vivo expansion of MSCs at high confluency alters the metabolic and transcriptomic states of these cells. Importantly, this approach maximizes the production of MSCs with enhanced immunomodulatory functions without priming, thus providing a non-invasive and generalizable strategy for improving the use of MSCs for the treatment of inflammatory diseases., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Pediatric central nervous system tumor survivors (CNSTS) experience late effects that may affect their health-related quality of life (HRQOL). The study aims: i) compare HRQOL among Malaysian CNSTS with acute lymphoblastic leukemia survivors (ALLS) and healthy children, and ii) explore factors associated with low HRQOL. We performed a comparative cross-sectional HRQOL study of 46 CNSTS aged 5-18 years and 90 ALLS (age and gender-matched) who completed treatment for >1 year, and a published cohort of healthy children. Pediatric Quality of Life Inventory (PedsQL) was used for all groups and PedsQL Cancer Module for CNSTS and ALLS. Multiple regression analysis was used to determine factors associated with low HRQOL. Mean PedsQL total scale score, physical health score and psychosocial health score of CNSTS were 69.0 (SD 20.3), 68.7 (SD 27.9) and 69.2 (SD 19.2) respectively. These scores were significantly lower in all domains particularly in teenagers compared with healthy children and ALLS. The median PedsQL Cancer Module score of CNSTS was significantly lower than ALLS in total scale, cognitive problems and communication. Physical impairment was associated with lower PedsQL scores in all 3 domains; special education placement was associated with lower PedsQL total scale and physical health scores and clinically significant internalizing behavioral difficulties score was associated with lower PedsQL psychosocial health scores. CNSTS reported lower PedsQL scores in all domains than ALLS and healthy children. Clinicians need to be vigilant of HRQOL needs among CNSTS, especially those with risk factors of special education needs, physical impairment, and internalizing behavioral difficulties.

Background: Patients with asthma often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral reinfections., Objective: Because the development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitization on the development of virus-specific lung resident memory T cells and viral clearance., Methods: Mice were sensitized with house dust mite extract followed by priming with X47 and a subsequent secondary influenza infection. Antiviral memory T-cell response and protection to viral infection was assessed before and after secondary influenza infection, respectively. Gene set variation analysis was performed on data sets from the U-BIOPRED asthma cohort using an IFN-γ-induced epithelial cell signature and a tissue resident memory T-cell signature., Results: Viral loads were higher in lungs of sensitized compared with nonsensitized mice after secondary infection, indicating reduced virus clearance. X47 priming induced fewer antiviral lung resident memory CD8 T cells and resulted in lower pulmonary IFN-γ levels in the lungs of sensitized as compared with nonsensitized mice. Using data from the U-BIOPRED cohort, we found that patients with enrichment of epithelial IFN-γ-induced genes in nasal brushings and bronchial biopsies were also enriched in resident memory T-cell-associated genes, had more epithelial CD8 T cells, and reported significantly fewer exacerbations., Conclusions: The allergen-sensitized lung microenvironment interferes with the formation of antiviral resident memory CD8 T cells in lungs and virus clearance. Defective antiviral memory response might contribute to increased susceptibility of patients with asthma to viral exacerbations., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate parental perception of advance care plan (ACP) discussions in families of Malaysian children with bilateral cerebral palsy (CP) classified in Gross Motor Function Classification System levels IV or V for (1) acceptance of the ACP discussion, (2) feedback on the usefulness of ACP discussion, and (3) exploration of possible factors related to parental acceptance of ACP., Method: This was a prospective pre- and post-ACP discussion questionnaire study for parents of children with bilateral CP., Results: Sixty-nine patients were recruited to the study; 64 (93%) had at least one additional comorbidity. The median age was 8 years (interquartile range 5 years 1 month-11 years 6 months). Fifty-seven (82.6%) parents found the ACP discussion acceptable, and most reported positive feedback on various components of the discussion (88.4-97.1%). One-third of participants were not comfortable discussing end-of-life care plans. On multivariate analysis, parents who were comfortable discussing end-of-life care plans were more likely to find the ACP discussion acceptable (odds ratio 27.78, 95% confidence interval 2.9-265.1, p = 0.004)., Interpretation: Most parents of Malaysian children with bilateral CP reported the ACP discussion as both acceptable and beneficial. Parents need to be comfortable about discussing end-of-life care plans for their child to enable the ACP discussion to be an acceptable experience., (© 2022 Mac Keith Press.)

The fate of tissue-resident memory CD4 T cells (Trm) has been incompletely investigated. Here we show that intranasal, but not parenteral, immunization with CTA1-3M2e-DD stimulated M2e-specific Th17 Trm cells, which conferred strong protection against influenza virus infection in the lung. These cells rapidly expanded upon infection and effectively restricted virus replication as determined by CD4 T cell depletion studies. Single-cell RNAseq transcriptomic and TCR VDJ-analysis of M2e-tetramer-sorted CD4 T cells on day 3 and 8 post infection revealed complete Th17-lineage dominance (no Th1 or Tregs) with extensive functional diversity and expression of gene markers signifying mature resident Trm cells (Cd69, Nfkbid, Brd2, FosB). Unexpectedly, the same TCR clonotype hosted cells with different Th17 subcluster functions (IL-17, IL-22), regulatory and cytotoxic cells, suggesting a tissue and context-dependent differentiation of reactivated Th17 Trm cells. A gene set enrichment analysis demonstrated up-regulation of regulatory genes (Lag3, Tigit, Ctla4, Pdcd1) in M2e-specific Trm cells on day 8, indicating a tissue damage preventing function. Thus, contrary to current thinking, lung M2e-specific Th17 Trm cells are sufficient for controlling infection and for protecting against tissue injury. These findings will have strong implications for vaccine development against respiratory virus infections and influenza virus infections, in particular., (© 2022. The Author(s).)

Previous work showed that interferon-λ (IFN-λ) can trigger the synthesis of thymic stromal lymphopoietin (TSLP) by specialized epithelial cells in the upper airways of mice, thereby improving the performance of intranasally administered influenza vaccines. Here we demonstrate that protein-only influenza vaccines containing either IFN-λ or TSLP boosted antigen-specific IgG1 and IgA responses and enhanced the resistance of mice to influenza virus challenge, irrespective of whether the vaccines were applied via the intranasal or the rectal route. TSLP receptor deficiency negatively influenced vaccine-induced antiviral immunity by impairing the migration of dendritic cells from the airways to the draining lymph nodes of immunized mice, thereby restraining follicular helper T cell and germinal center B cell responses. As previously observed during intranasal vaccination, the adjuvant effect of IFN-λ on a rectally administered influenza vaccine was no longer observed when TSLP receptor-deficient mice were used for immunization, highlighting the central role of the IFN-λ/TSLP axis for vaccine-induced antiviral immunity in the mucosa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ye, Schnepf, Ohnemus, Ong, Gad, Hartmann, Lycke and Staeheli.)

Objective: Describe the outcome of a Malaysian cohort of children with acute necrotising encephalopathy (ANE)., Method: Retrospective study of children with ANE seen at University of Malaya Medical Centre from 2014 to 2019. All clinical details including ANE-severity score (ANE-SS), immunomodulation treatment and neurodevelopmental long-term outcome were collected., Results: Thirteen patients had ANE and brainstem death occurred in 5. In 10 patients (77%) viruses were isolated contributing to ANE: 8 influenza virus, 1 acute dengue infection, and 1 acute varicella zoster infection. The ANE-SS ranged 2-7: 9 were high risk and 4 were medium risk. Among the 8 survivors; 1 was lost to follow-up. Follow-up duration was 1-6 years (median 2.2). At follow-up among the 4 high-risk ANE-SS: 2 who were in a vegetative state, 1 remained unchanged and 1 improved to severe disability; the other 2 with severe disability improved to moderate and mild disability respectively. At follow-up all 3 medium-risk ANE-SS improved: 2 with severe disability improved to moderate and mild disability respectively, while 1 in a vegetative state improved to severe disability. Early treatment with immunomodulation did not affect outcome., Conclusion: Our ANE series reiterates that ANE is a serious cause of encephalopathy with mortality of 38.5%. All survivors were in a vegetative state or had severe disability at discharge. Most of the survivors made a degree of recovery but good recovery was seen in 2. Follow-up of at least 12 months is recommended for accurate prognostication. Dengue virus infection needs to be considered in dengue endemic areas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

This is a proof-of-principle study demonstrating that the combination of a cholera toxin derived adjuvant, CTA1-DD, and lipid nanoparticles (LNP) can significantly improve the immunogenicity and protective capacity of an intranasal vaccine. We explored the self-adjuvanted universal influenza vaccine candidate, CTA1-3M2e-DD (FPM2e), linked to LNPs. We found that the combined vector greatly enhanced survival against a highly virulent PR8 strain of influenza virus as compared to when mice were immunized with FPM2e alone. The combined vaccine vector enhanced early endosomal processing and peptide presentation in dendritic cells and upregulated co-stimulation. The augmenting effect was CTA1-enzyme dependent. Whereas systemic anti-M2e antibody and CD4 + T-cell responses were comparable to those of the soluble protein, the local respiratory tract IgA and the specific Th1 and Th17 responses were strongly enhanced. Surprisingly, the lung tissue did not exhibit gross pathology upon recovery from infection and M2e-specific lung resident CD4 + T cells were threefold higher than in FPM2e-immunized mice. This study conveys optimism as to the protective ability of a combination vaccine based on LNPs and various forms of the CTA1-DD adjuvant platform, in general, and, more specifically, an important way forward to develop a universal vaccine against influenza.

The complement alternative pathway (AP) is tightly regulated and changes in two important AP components, factor B (FB) and factor H (FH) are linked to severe dengue in humans. Here, a mouse model of dengue was investigated to define the changes in FB and FH and assess the utility of this model to study the role of the AP in severe dengue. Throughout the period of viremia in the AG129 IFN signalling-deficient mouse, an increase in FB and a decrease in FH was observed following dengue virus (DENV) infection, with the former only seen in a model of more severe disease associated with antibody-dependent enhancement (ADE). Terminal disease was associated with a decrease in FB and FH, with greater changes during ADE, and accompanied by increased C3 degradation consistent with complement activation. In silico analysis of NFκΒ, signal transducer and activator of transcription (STAT) and IFN-driven FB and FH promoter elements to reflect the likely impact of the lack of IFN-responses in AG129 mice, demonstrated that these elements differed markedly between human and mouse, notably with mouse FH lacking NFκΒ and key IFN-stimulated response elements (ISRE), and FB with many more NFκΒ and STAT-responsive elements than human FB. Thus, the AG129 mouse offers utility in demonstrating changes in FB and FH that, similar to humans, are associated with severe disease, but lack predicted important human-specific and IFN-dependent responses of FB and FH to DENV-infection that are likely to regulate the subtleties of the overall AP response during dengue disease in humans.

Dengue is a major public health concern in the tropical and subtropical world, with no effective treatment. The controversial live attenuated virus vaccine Dengvaxia has boosted the pursuit of subunit vaccine approaches, and nonstructural protein 1 (NS1) has recently emerged as a promising candidate. However, we found that NS1 immunization or passive transfer of NS1 antibodies failed to confer protection in symptomatic dengue mouse models using two non-mouse-adapted DENV2 strains that are highly virulent. Exogenous administration of purified NS1 also failed to worsen in vivo vascular leakage in sublethally infected mice. Neither method of NS1 immune neutralization changed the disease outcome of a chimeric strain expressing a vascular leak-potent NS1. Instead, virus chimerization involving the prME structural region indicated that these proteins play a critical role in driving in vivo fitness and virulence of the virus, through induction of key proinflammatory cytokines. This work highlights that the pathogenic role of NS1 is DENV strain dependent, which warrants reevaluation of NS1 as a universal dengue vaccine candidate., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2020 Lee et al.)

Study Design: Cross-sectional study., Objective: To determine the prevalence and potential risk factors of vitamin D deficiency and insufficiency among Malaysian children with spina bifida., Setting: Four Malaysian tertiary hospitals., Methods: Children with spina bifida were assessed for potential demographic, disease severity and lifestyle risk factors for vitamin D deficiency and insufficiency. Blood for 25-hydroxy vitamin D (25(OH)D) was taken. Vitamin D deficiency was defined as 25(OH)D levels ≤ 37.5 nmol/L and insufficiency as 37.6-50 nmol/L., Results: Eighty children aged 2-18 years (42 males) participated in the study. Vitamin D levels ranged from 14 to 105 nmol/L (mean 52.8, SD 19.1). Vitamin D deficiency was identified in 18 (22.5%) and insufficiency in 26 (32.5%) children. Logistic regression analysis showed that skin exposure to sunlight ≤ 21% body surface area (OR: 6.2, CI 1.7-22.9) and duration of sun exposure ≤ 35 min/day (OR: 4.0, CI 1.2-14.1) were significant risk factors for vitamin D deficiency and insufficiency, respectively., Conclusions: Over half (55%) of Malaysian children with spina bifida seen in urban tertiary hospitals have vitamin D insufficiency and deficiency. Lifestyle sun exposure behaviours were risk factors for vitamin D deficiency and insufficiency.

Aim: To evaluate the microstructural abnormalities of the white matter tracts (WMT) using diffusion tensor imaging (DTI) in children with global developmental delay (GDD)., Materials and Methods: Sixteen children with GDD underwent magnetic resonance imaging (MRI) and cross-sectional DTI. Formal developmental assessment of all GDD patients was performed using the Mullen Scales of Early Learning. An automated processing pipeline for the WMT assessment was implemented. The DTI-derived metrics of the children with GDD were compared to healthy children with normal development (ND)., Results: Only two out of the 17 WMT demonstrated significant differences (p<0.05) in DTI parameters between the GDD and ND group. In the uncinate fasciculus (UF), the GDD group had lower mean values for fractional anisotropy (FA; 0.40 versus 0.44), higher values for mean diffusivity (0.96 versus 0.91×10 -3 mm 2 /s) and radial diffusivity (0.75 versus 0.68×10 -3 mm 2 /s) compared to the ND group. In the superior cerebellar peduncle (SCP), mean FA values were lower for the GDD group (0.38 versus 0.40). Normal myelination pattern of DTI parameters was deviated against age for GDD group for UF and SCP., Conclusion: The UF and SCP WMT showed microstructural changes suggestive of compromised white matter maturation in children with GDD. The DTI metrics have potential as imaging markers for inadequate white matter maturation in GDD children., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Dengue virus (DENV) infection is associated with clinical ocular presentations and here DENV infection of the eye was assessed in mice. In an AG129 mouse model of antibody-dependent enhancement of DENV infection, DENV RNA was detected in the eye and vascular changes were present in the retinae. Intraocular CD8 and IFN-γ mRNA were increased in mice born to DENV-naïve, but not DENV-immune mothers, while TNF-α mRNA was induced and significantly higher in mice born to DENV-immune than DENV-naïve mothers. DENV RNA was detected in the eye following intracranial DENV infection and CD8 mRNA but not IFN-γ nor TNF-α were induced. In all models, viperin was increased following DENV infection. Thus, DENV in the circulation or the brain can infect the eye and stimulate innate immune responses, with induction of viperin as one response that consistently occurs in multiple DENV eye-infection models in both an IFN-dependent and independent manner.

Type I and type III interferons (IFNs) can promote adaptive immune responses in mice and improve vaccine-induced resistance to viral infections. The adjuvant effect of type III IFN (IFN-λ) specifically boosts mucosal immunity by an indirect mechanism, involving IFN-λ-induced production of thymic stromal lymphopoietin (TSLP), a cytokine that activates immune cells. To date, it remained unclear whether the previously described adjuvant effect of type I IFN (IFN-α/β) would also depend on TSLP and whether type I IFN stimulates different antibody subtypes. Here, we show that after infection with a live attenuated influenza virus, mice lacking functional type I IFN receptors failed to produce normal amounts of virus-specific IgG2c and IgA antibodies. In contrast, mice lacking functional IFN-λ receptors contained normal levels of virus-specific IgG2c but had reduced IgG1 and IgA antibody levels. When applied together with protein antigen, IFN-α stimulated the production of antigen-specific IgA and IgG2c to a greater extent than IgG1, irrespective of whether the mice expressed functional TSLP receptors and irrespective of whether the vaccine was applied by the intranasal or the intraperitoneal route. Taken together, these results demonstrate that the adjuvant activities of type I and type III IFNs are mechanistically distinct. IMPORTANCE Interferons can shape antiviral immune responses, but it is not well understood how they influence vaccine efficacy. We find that type I IFN preferentially promotes the production of antigen-specific IgG2c and IgA antibodies after infection with a live attenuated influenza virus or after immunization with influenza subunit vaccines. In contrast, type III IFN specifically enhances influenza virus-specific IgG1 and IgA production. The adjuvant effect of type I IFN was not dependent on TSLP, which is essential for the adjuvant effect of type III IFN. Type I IFN boosted vaccine-induced antibody production after immunization by the intranasal or the intraperitoneal route, whereas type III IFN exhibited its adjuvant activity only when the vaccine was delivered by the mucosal route. Our findings demonstrate that type I and type III IFNs trigger distinct pathways to enhance the efficacy of vaccines. This knowledge might be used to design more efficient vaccines against infectious diseases., (Copyright © 2019 American Society for Microbiology.)

Aim: Evaluation of impaired quality of life (QOL) of Malaysian children with tuberous sclerosis complex (TSC) and its possible risk factors., Method: Cross-sectional study on 68 parents of Malaysian children aged 2-18 years with TSC. QOL was assessed using proxy-report Paediatric Quality of Life Inventory (PedsQL) V.4.0, and scores compared with those from a previous cohort of healthy children. Parents also completed questionnaires on child behaviour (child behaviour checklist (CBCL)) and parenting stress (parenting stress index-short form). Multiple regression analysis was used to determine sociodemographic, medical, parenting stress and behavioural factors that impacted on QOL., Results: The mean proxy-report PedsQL V.4.0 total scale score, physical health summary score and psychosocial health summary score of the patients were 60.6 (SD 20.11), 65.9 (SD 28.05) and 57.8 (SD 19.48), respectively. Compared with healthy children, TSC patients had significantly lower mean PedsQL V.4.0 total scale, physical health and psychosocial health summary scores (mean difference (95% CI): 24 (18-29), 20 (12-27) and 26 (21-31) respectively). Lower total scale scores were associated with clinically significant CBCL internalising behaviour scores, age 8-18 years and Chinese ethnicity. Lower psychosocial health summary scale scores were associated with clinically significant CBCL internalising behaviour scores, Chinese ethnicity or >1 antiepileptic drug (AED)., Conclusion: Parents of children with TSC reported lower PedsQL V.4.0 QOL scores in all domains, with psychosocial health most affected. Older children, those with internalising behaviour problems, of Chinese ethnicity or on >1 AED was at higher risk of lower QOL. Clinicians need to be vigilant of QOL needs among children with TSC particularly with these additional risk factors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: An information technology (IT)-based epilepsy educational program, the Interactive Animated Epilepsy Education Programme (IAEEP), can potentially help improve awareness, knowledge, and attitude (AKA) of parents of children with epilepsy (CWE) enabling CWE to lead a normal life. Our study aimed to assess the following: i) baseline level of epilepsy AKA of Malaysian parents of CWE and explore potential characteristics associated with low levels of AKA; ii) effectiveness of the IAEEP in improving parental AKA, and whether these effects remained stable over time; and iii) effects of the IAEEP on parental mental state and perception of their child's quality of life., Methods: This prospective study includes parents of CWE aged 8-18 years old with no comorbidities. Epilepsy education was delivered using the IAEEP. Parents completed an AKA questionnaire before (time point 1 [TP1]), immediately after (TP2), and 4-6 months (TP3) after the provision of IAEEP. Parent proxy report of Health-Related Quality of Life Measurement for Children with Epilepsy (CHEQOL)-25 questionnaire and Depression, Anxiety, and Stress Scale (DASS)-21 questionnaire was completed at TP1 and TP3., Results: A total of 78 parents participated in the study. At baseline (TP1), parental responses were rated as "moderate" for awareness domain, "high" for knowledge domain, "very positive" for attitude domain, and "good" for total AKA score domain. No epilepsy or parental characteristics were associated with the low baseline parental AKA levels. After IAEEP intervention, there was a significant increase in all AKA subdomain scores. Post-IAEEP, the AKA of parents were rated as "very high" for awareness domain, "very high" for knowledge domain, "very positive" for attitude domain, and "excellent" for total AKA domain at both TP2 and TP3. Parent proxy CHEQOL-25 report showed significant increments in interpersonal/social and secrecy scale scores between TP1 and TP3. There were no significant differences in the DASS-21 scores between TP1 and TP3., Conclusion: The IAEEP is an effective epilepsy educational tool to increase the levels of AKA among parents of CWE. Following the use of the IAEEP, parents of CWE also reported an improvement of their child's quality of life in the interpersonal/social and epilepsy secrecy CHEQOL-25 domains. There was no impact on parental mental health following exposure to the IAEEP., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Because of the nature of epilepsy, and the unpredictability of seizure recurrence, epilepsy requires long-term treatment with medications. As a consequence, epilepsy has a negative pervasive impact in children with epilepsy (CWE), and their parents. Hence, our aim was to explore the needs and challenges of parents and their CWE. In-depth interviews (IDIs) were conducted with 15 families (12 mothers and 3 fathers) and 15 CWE (aged 8-18 years). Data were transcribed verbatim and thematically analyzed using the descriptive phenomenology approach. The experiences of parents and their CWE could be divided into two time frames: "experiences during a child's first seizure" and "experiences whilst growing up with epilepsy". Parents' main concerns and worries were regarding their child's physical health, psychological and emotional wellbeing, academic achievement, and future. The children's main concerns were restrictions imposed, their interpersonal relationship with peers, and being independent in the future. Parents reported that they needed epilepsy-related information, continuity of care, and a parental support group, while CWE reported that their main needs were independence and autonomy. The views of parents and their child with epilepsy were similar in physical functioning and academic achievement. However, parents and children had different views on how epilepsy impacted on the child emotionally, as well as behavioral and interpersonal relationship with peers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Children with epilepsy (CWE) are at risk of impaired quality of life (QOL), and achieving a good QOL is an important treatment goal among CWE. To date, there are no published multiethnic QOL studies in Asia. Our study aimed to: i) investigate the QOL of multiethnic CWE in Malaysia as reported by both the child and parent; ii) determine the level of agreement between child-self report and parent-proxy report QOL; and iii) explore potential correlates of sociodemographic, epilepsy characteristics, and family functioning with QOL in CWE., Methods: Cross-sectional study of all CWE aged 8-18years old with at least 6months' duration of epilepsy, minimum reading level of primary school education Year 1, and attending mainstream education. Quality of life was measured using the parent-proxy and child self-report of Quality of Life Measurement for Children with Epilepsy (CHEQOL-25) questionnaire. Total and subscale CHEQOL-25 scores were obtained. The levels of parent-child agreement were determined using intraclass correlation coefficients (ICC). Family functioning was assessed using the General functioning subscale (GF-12)., Results: A total of 115 CWE and their parents participated in the study. In general, Malaysian parents rated children's total CHEQOL-25 scores poorer than the children themselves [mean total parent score: 68.56 (SD: 10.86); mean total child score: 71.82 (SD: 9.55)]. Agreement between child and parent on the CHEQOL-25 was poor to moderate (ICC ranged from 0.31-0.54), with greatest discordance in the epilepsy secrecy domain (ICC=0.31, p=0.026). Parent and child were more likely to agree on more external domains: intrapersonal/social (ICC=0.54, p<0.001) and interpersonal/emotional (ICC=0.50, p<0.001). Malay ethnicity, focal seizure and high seizure frequency (≥1 seizure per month) were associated with lower CHEQOL-25 scores. There was a significant but weak correlation between GF-12 and parent-proxy CHEQOL-25 Total Scores (r=-0.186, p=0.046)., Conclusion: Our results emphasize the importance to have the child's perspective of their QOL as the level of agreement between the parent and child reported scores were poor to moderate. Malaysian CWE of Malay ethnicity, those with focal seizures or high seizure frequency are at risk of poorer QOL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Dengue virus (DENV) infection imposes enormous health and economic burden worldwide with no approved treatment. Several small molecules, including lovastatin, celgosivir, balapiravir and chloroquine have been tested for potential anti-dengue activity in clinical trials; none of these have demonstrated a protective effect. Recently, based on identification and characterization of cross-serotype neutralizing antibodies, there is increasing attention on the potential for dengue immunotherapy. Here, we tested the ability of VIS513, an engineered cross-neutralizing humanized antibody targeting the DENV E protein domain III, to overcome antibody-enhanced infection and high but brief viremia, which are commonly encountered in dengue patients, in various in vitro and in vivo models. We observed that VIS513 efficiently neutralizes DENV at clinically relevant viral loads or in the presence of enhancing levels of DENV immune sera. Single therapeutic administration of VIS513 in mouse models of primary infection or lethal secondary antibody-enhanced infection, reduces DENV titers and protects from lethal infection. Finally, VIS513 administration does not readily lead to resistance, either in cell culture systems or in animal models of dengue infection. The findings suggest that rapid viral reduction during acute DENV infection with a monoclonal antibody is feasible.

Introduction: Children with epilepsy on long-term antiepileptic drugs (AEDs) are at risk of low bone mineral density (BMD). The aims of our study were to evaluate the prevalence and determinants of low BMD among Malaysian children with epilepsy., Method: Cross-sectional study of ambulant children with epilepsy on long-term AEDs for >1 year seen in a tertiary hospital in Malaysia from 2014 to 2015. Detailed assessment of anthropometric measurements; environmental lifestyle risk factors; serum vitamin D, calcium and parathyroid hormone levels; genotyping of single nucleotide polymorphisms of genes in vitamin D and calcium metabolism; and lumbar spine BMD were obtained. Low BMD was defined as BMD Z-score ≤ -2.0 SD., Results: Eighty-seven children with mean age of 11.9 years (56 males) participated in the study. The prevalence of low lumbar BMD was 21.8% (19 patients). Multivariate logistic regression analysis identified polytherapy >2 AEDs (OR: 7.86; 95% CI 1.03-59.96), small frame size with wrist breadth of <15th centile (OR 14.73; 95% CI 2.21-98.40), and body mass index Z-score < -2.0 (OR 8.73, 95% CI 1.17-65.19) as significant risk factors for low BMD., Conclusion: One-fifth of Malaysian children with epilepsy on long-term AEDs had low BMD. Targeted BMD should be performed for those who are on >2 AEDs, underweight or with small frame size as they are at higher risk of having low BMD., (Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Paediatric neurodiagnostic investigations, including brain neuroimaging and electroencephalography (EEG), play an important role in the assessment of neurodevelopmental disorders. The use of an appropriate sedative agent is important to ensure the successful completion of the neurodiagnostic procedures, particularly in children, who are usually unable to remain still throughout the procedure., Objectives: To assess the effectiveness and adverse effects of chloral hydrate as a sedative agent for non-invasive neurodiagnostic procedures in children., Search Methods: We used the standard search strategy of the Cochrane Epilepsy Group. We searched MEDLINE (OVID SP) (1950 to July 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 7, 2017), Embase (1980 to July 2017), and the Cochrane Epilepsy Group Specialized Register (via CENTRAL) using a combination of keywords and MeSH headings., Selection Criteria: We included randomised controlled trials that assessed chloral hydrate agent against other sedative agent(s), non-drug agent(s), or placebo for children undergoing non-invasive neurodiagnostic procedures., Data Collection and Analysis: Two review authors independently assessed the studies for their eligibility, extracted data, and assessed risk of bias. Results were expressed in terms of risk ratio (RR) for dichotomous data, mean difference (MD) for continuous data, with 95% confidence intervals (CIs)., Main Results: We included 13 studies with a total of 2390 children. The studies were all conducted in hospitals that provided neurodiagnostic services. Most studies assessed the proportion of sedation failure during the neurodiagnostic procedure, time for adequate sedation, and potential adverse effects associated with the sedative agent.The methodological quality of the included studies was mixed, as reflected by a wide variation in their 'Risk of bias' profiles. Blinding of the participants and personnel was not achieved in most of the included studies, and three of the 13 studies had high risk of bias for selective reporting. Evaluation of the efficacy of the sedative agents was also underpowered, with all the comparisons performed in single small studies.Children who received oral chloral hydrate had lower sedation failure when compared with oral promethazine (RR 0.11, 95% CI 0.01 to 0.82; 1 study, moderate-quality evidence). Children who received oral chloral hydrate had a higher risk of sedation failure after one dose compared to those who received intravenous pentobarbital (RR 4.33, 95% CI 1.35 to 13.89; 1 study, low-quality evidence), but after two doses there was no evidence of a significant difference between the two groups (RR 3.00, 95% CI 0.33 to 27.46; 1 study, very low-quality evidence). Children who received oral chloral hydrate appeared to have more sedation failure when compared with music therapy, but the quality of evidence was very low for this outcome (RR 17.00, 95% CI 2.37 to 122.14; 1 study). Sedation failure rates were similar between oral chloral hydrate, oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam.Children who received oral chloral hydrate had a shorter time to achieve adequate sedation when compared with those who received oral dexmedetomidine (MD -3.86, 95% CI -5.12 to -2.6; 1 study, moderate-quality evidence), oral hydroxyzine hydrochloride (MD -7.5, 95% CI -7.85 to -7.15; 1 study, moderate-quality evidence), oral promethazine (MD -12.11, 95% CI -18.48 to -5.74; 1 study, moderate-quality evidence), and rectal midazolam (MD -95.70, 95% CI -114.51 to -76.89; 1 study). However, children with oral chloral hydrate took longer to achieve adequate sedation when compared with intravenous pentobarbital (MD 19, 95% CI 16.61 to 21.39; 1 study, low-quality evidence) and intranasal midazolam (MD 12.83, 95% CI 7.22 to 18.44; 1 study, moderate-quality evidence).No data were available to assess the proportion of children with successful completion of neurodiagnostic procedure without interruption by the child awakening. Most trials did not assess adequate sedation as measured by specific validated scales, except in the comparison of chloral hydrate versus intranasal midazolam and oral promethazine.Compared to dexmedetomidine, chloral hydrate was associated with a higher risk of nausea and vomiting (RR 12.04 95% CI 1.58 to 91.96). No other adverse events were significantly associated with chloral hydrate (including behavioural change, oxygen desaturation) although there was an increased risk of adverse events overall (RR 7.66, 95% CI 1.78 to 32.91; 1 study, low-quality evidence)., Authors' Conclusions: The quality of evidence for the comparisons of oral chloral hydrate against several other methods of sedation was very variable. Oral chloral hydrate appears to have a lower sedation failure rate when compared with oral promethazine for children undergoing paediatric neurodiagnostic procedures. The sedation failure was similar for other comparisons such as oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam. When compared with intravenous pentobarbital and music therapy, oral chloral hydrate had a higher sedation failure rate. However, it must be noted that the evidence for the outcomes for the comparisons of oral chloral hydrate against intravenous pentobarbital and music therapy was of very low to low quality, therefore the corresponding findings should be interpreted with caution.Further research should determine the effects of oral chloral hydrate on major clinical outcomes such as successful completion of procedures, requirements for additional sedative agent, and degree of sedation measured using validated scales, which were rarely assessed in the studies included in this review. The safety profile of chloral hydrate should be studied further, especially the risk of major adverse effects such as bradycardia, hypotension, and oxygen desaturation.

Purpose: To systematically examine published literature which assessed the prevalence of academic difficulties in children with epilepsy (CWE) of normal intelligence, and its associating factors., Methods: A search was conducted on five databases for articles published in English from 1980 till March 2015. Included were studies who recruited children (aged 5-18 years), with a diagnosis or newly/recurrent epilepsy, an intelligent quotient (IQ) of ≥70 or attending regular school, with or without a control group, which measured academic achievement using a standardised objective measure, and published in English. Excluded were children with learning difficulties, intellectual disabilities (IQ<70) and other comorbidities such as attention deficits hyperactive disorder or autism. Two pairs of reviewers extracted the data, and met to resolve any differences from the data extraction process., Results: Twenty studies were included. The majority of the studies assessed "low achievement" whist only two studies used the IQ-achievement discrepancy definition of "underachievement". Fourteen studies (70%) reported that CWE had significantly lower academic achievement scores compared to healthy controls, children with asthma or reported norms. The remaining six studies (30%) did not report any differences. CWE had stable academic achievement scores over time (2-4 years), even among those whose seizure frequency improved. Higher parental education and children with higher IQ, and had better attention or had a positive attitude towards epilepsy, were associated with higher academic achievement score. Older children were found to have lower academic achievement score., Conclusions: In CWE of normal intelligence, the majority of published literature found that academic achievement was lower than controls or reported norms. The high percentages of low achievement in CWE, especially in the older age group, and the stability of scores even as seizure frequency improved, highlights the need for early screening of learning problems, and continued surveillance., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Sudden unexpected death in epilepsy (SUDEP) is an important cause of mortality in epilepsy. To date, there is only one published UK study evaluating information provision of SUDEP among parents of children with epilepsy (CWE), and there are no studies published from Asia. Although SUDEP information provision is recommended among parents of CWE, it is uncertain if these recommendations are applicable to Asian countries due to the different cultural attitude towards epilepsy. Our prospective cohort study consisted of multiethnic parents of children with epilepsy (CWE) seen in a tertiary hospital in Malaysia. Information on SUDEP was delivered to parents using an epilepsy educational software program. Participants completed a set of standardized questionnaire and Depression Anxiety Stress Scales-Short Form (DASS-21) immediately after and retested 3-6months after the SUDEP information provision. A total of 127 parents (84 mothers) participated in the study. The CWE consisted of 3 ethnic groups (38% Malay, 30% Chinese, 32% Indian) with a mean age of 9.6years. Majority (70.9%) felt positive after SUDEP information provision, 90.6% wanted SUDEP discussion for themselves with 70.1% wanted SUDEP discussion with their child, and a lower proportion (58.3%) would discuss SUDEP with their child. None of the participants reported increased symptoms of depression, stress or anxiety attributed to SUDEP information provision. Most parents took steps to reduce SUDEP risk, and most parents did not report an impact on their own functioning. However, there was an increase in parental report over time of impact on their child's functioning following SUDEP information (P<0.05). In conclusion, most Malaysian parents of CWE wanted SUDEP information. Following SUDEP information disclosure, majority did not report negative emotions; however, an increase in parents over time reported an impact on their child. Our findings reiterate that provision of SUDEP information should form part of care of CWE and parents should receive ongoing support as they undergo a period of parenting adjustment when dealing with the information provided., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: The objectives of this study were to compare the quality-of-life scores of Malaysian children with CHD and their healthy siblings, to determine the level of agreement between proxy-reports and child self-reports, and to examine variables that have an impact on quality of life in those with CHD., Methods: Parental-proxy scores of the Pediatric Quality of Life Inventory 4.0 core scales were obtained for 179 children with CHD and 172 siblings. Intra-class coefficients were derived to determine the levels of proxy-child agreement in 66 children aged 8-18 years. Multiple regression analysis was used to determine factors that impacted Pediatric Quality of Life Inventory scores., Results: Proxy scores were lower in children with CHD than siblings for all scales except physical health. Maximum differences were noted in children aged 5-7 years, whereas there were no significant differences in the 2-4 and 13-18 years age groups. Good levels of proxy-child agreement were found in children aged 8-12 years for total, psychosocial health, social, and school functioning scales (correlation coefficients 0.7-0.8). In children aged 13-18 years, the level of agreement was poor to fair for emotional and social functioning. The need for future surgery and severity of symptoms were associated with lower scores., Conclusion: Differences in proxy perception of quality of life appear to be age related. The level of proxy-child agreement was higher compared with other reported studies, with lower levels of agreement in teenagers. Facilitating access to surgery and optimising control of symptoms may improve quality of life in this group of children.

Single-walled carbon nanotubes (SWCNTs) are carbon-based nanomaterials that possess immense industrial potential. Despite accumulating evidence that exposure to SWCNTs might be toxic to humans, our understanding of the mechanisms for cellular toxicity of SWCNTs remain limited. Here, we demonstrated that acute exposure of short (1-3μm) and regular-length (5-30μm) pristine, carboxylated or hydroxylated SWCNTs inhibited cell proliferation in human somatic and human stem cells in a cell type-dependent manner. The toxicity of regular-length pristine SWCNT was most evidenced in NP69>CYT00086>MCF-10A>MRC-5>HaCaT > HEK-293T>HepG2. In contrast, the short pristine SWCNTs were relatively less toxic in most of the cells being tested, except for NP69 which is more sensitive to short pristine SWCNTs as compared to regular-length pristine SWCNTs. Interestingly, carboxylation and hydroxylation of regular-length SWCNTs, but not the short SWCNTs, significantly reduced the cytotoxicity. Exposure of SWCNTs also induced caspase 3 and 9 activities, mitochondrial membrane depolarization, and significant apoptosis and necrosis in MRC-5 embryonic lung fibroblasts. In contrast, SWCNTs inhibited the proliferation of HaCaT human keratinocytes without inducing cell death. Further analyses by gene expression profiling and Connectivity Map analysis showed that SWCNTs induced a gene expression signature characteristic of heat shock protein 90 (HSP90) inhibition in MRC-5 cells, suggesting that SWCNTs may inhibit the HSP90 signaling pathway. Indeed, exposure of MRC-5 cells to SWCNTs results in a dose-dependent decrease in HSP90 client proteins (AKT, CDK4 and BCL2) and a concomitant increase in HSP70 expression. In addition, SWCNTs also significantly inhibited HSP90-dependent protein refolding. Finally, we showed that ectopic expression of HSP90, but not HSP40 or HSP70, completely abrogated the cytotoxic effects of SWCNTs, suggesting that SWCNT-induced cellular toxicity is HSP90 dependent. In summary, our findings suggest that the toxic effects of SWCNTs are mediated through inhibition of HSP90 in human lung fibroblasts and keratinocytes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Vincristine, an essential component of childhood acute lymphoblastic leukaemia (ALL) therapeutic protocols, is associated with dose-dependent neurotoxicity, but its long-term morbidity in treated children has not been clearly elucidated. The aim of this study is to determine the prevalence of vincristine-induced peripheral neuropathy (VIPN) among Malaysian childhood ALL survivors and its impact on motor function and quality of life., Procedure: Survivors of childhood ALL aged 4-18 years who had completed chemotherapy for 2 years or more were evaluated for VIPN using both the clinical Total Neuropathy Score (cTNS) and nerve conduction studies. Motor function and quality of life of the survivors were assessed via the Bruininks-Oseretsky Test of Motor Proficiency Brief Form, Second Edition (BOT-2 Brief Form) and the Paediatric Quality of Life version 4.0 Generic Core Scales (PedsQL4.0) questionnaire, respectively., Results: One hundred and one survivors with a duration of follow-up ranging from 2.0 to 10.3 years were recruited. Twenty-seven (26.7%) had abnormal cTNS scores and 69 (68.3%) had electrophysiological evidence of neuropathy. Of these, 16 (15.8%) had combined clinical and electrophysiological neuropathy (VIPN). Those previously treated on the intermediate- or high-risk treatment stratification arms had a higher risk of developing VIPN (67.3 vs. 32.7%; odds ratio [OR]: 9.06, 95% confidence interval [CI]: 1.14-71.86; P = 0.014). Survivors with VIPN had significantly lower quality of life scores in the physical (P = 0.024) and social domains (P = 0.039) compared with peers without VIPN, but no association with poorer motor function was observed., Conclusions: Sixteen percent of ALL survivors had VIPN. VIPN should be increasingly recognised as a late effect of chemotherapy, as it significantly affects physical and social function quality of life., (© 2017 Wiley Periodicals, Inc.)

Objective: Long-term use of antiepileptic drugs (AEDs) is a significant risk factor for vitamin D deficiency in children with epilepsy. The aims of our study were to evaluate the prevalence and risk factors for vitamin D deficiency among Malaysian children with epilepsy., Methods: Cross-sectional study of ambulant children with epilepsy on long-term AEDs for >1 year seen in three tertiary hospitals in Malaysia from April 2014 to April 2015. Detailed assessment of pubertal status, skin pigmentation, sunshine exposure behavior, physical activity, dietary vitamin D and calcium intake, anthropometric measurements and bone health blood tests (vitamin D, alkaline phosphatase, calcium, phosphate, and parathyroid hormone levels) were obtained on all patients. Vitamin D deficiency was defined as 25-hydroxy vitamin D [25(OH)D] levels ≤35 nmol/L and insufficiency as 25(OH)D levels of 36-50 nmol/L., Results: A total of 244 children (146 male) participated in the study. Ages ranged between 3.7 and 18.8 years (mean 12.3 years). 25(OH)D levels ranged between 7.5 and 140.9 nmol/L (mean 53.9 nmol/L). Vitamin D deficiency was identified in 55 patients (22.5%), and a further 48 (19.7%) had vitamin D insufficiency. Multivariate logistic regression analysis identified polytherapy >1 AED (odds ratio [OR] 2.16, 95% confidence interval [CI] 1.07-4.36), age >12 years (OR 4.16, 95% CI 1.13-15.30), Indian ethnicity (OR 6.97, 95% CI 2.48-19.55), sun exposure time 30-60 min/day (OR 2.44, 95% CI 1.05-5.67), sun exposure time <30 min/day (OR 3.83, 95% CI 1.61-9.09), and female (OR 2.61, 95% CI 1.31-5.20) as statistically significant (p < 0.05) risk factors for vitamin D deficiency., Significance: Despite living in the tropics, a high proportion of Malaysian children with epilepsy are at risk of vitamin D deficiency. Targeted strategies including vitamin D supplementation and lifestyle advice of healthy sunlight exposure behavior should be implemented among children with epilepsy, particularly for those at high risk of having vitamin D deficiency., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Dengue virus (DENV) causes a spectrum of diseases ranging from self-limiting dengue fever to severe conditions such as haemorrhagic fever and dengue shock syndrome. Antibody-dependent enhancement (ADE) is thought to explain the occurrence of severe dengue whereby pre-existing binding but non-neutralising antibodies enhance DENV infection. The ADE phenomenon is supported by epidemiological findings that infants that born to dengue immune mothers are at greater risk to develop severe dengue upon primary infection. The role of maternally acquired dengue-specific antibodies in disease enhancement was recently recapitulated in a mouse model where mice born to DENV1-immune mothers experienced enhanced disease severity upon DENV2 infection. Here, this study investigates the relative contribution of maternal dengue-specific antibodies acquired during gestation and breastfeeding in dengue disease. Using a surrogate breastfeeding mother experimental approach, we showed that majority of the maternal dengue-specific antibodies were acquired during breastfeeding and conferred an extended enhancement window. On the other hand, in the context of homologous infection, breastfeeding conferred protection. Furthermore, measurement of dengue-specific antibody titres over time in mice born to dengue immune mothers revealed a biphasic pattern of antibody decay as reported in humans. Our work provides evidence of the potential contribution of breast milk-acquired dengue-specific IgG antibodies in enhancement and protection against dengue. Should such contribution be established in humans as well, it may have important implications for the development of guidelines to dengue-immune breastfeeding mothers.

Background: Longitudinal extensive transverse myelitis associated with dengue infection is rare with no reported paediatric cases., Methods: We report a 12-year-old girl who presented with flaccid quadriplegia 8 days after onset of acute dengue fever. MRI spine showed T2 hyperintensity associated with epidural hematoma at C3-C6 level of the spinal cord. Transcranial magnetic brain stimulation revealed absent motor evoked potentials bilaterally. We also summarise and compare the reported cases of transverse myelitis associated with dengue infection., Results: Immunomodulatory treatment was given which included pulse methylprednisolone, intravenous immunoglobulin and plasmapharesis. Six months post-admission, there was a good (near-complete) clinical recovery with the repeat MRI showing mild residual hyperintensity at C4 level and complete resolution of epidural haematoma., Conclusion: This is the first reported paediatric case of longitudinal extensive transverse myelitis following dengue infection. It is also the first to illustrate that in patients with concomitant epidural haematoma a good outcome is possible despite not having surgical decompression. Clinicians should be aware of parainfectious dengue-related longitudinal extensive transverse myelitis in children and consider prompt immunomodulatory treatment., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Aim: This cross-sectional study aimed to determine the prevalence, frequency, and intensity of parent-reported pain among non-verbal children with cerebral palsy (CP) and explore associations with medical, demographic, and parental psychosocial factors., Method: Participants were parents of non-verbal outpatients (aged 2-20y) with CP at University of Malaya Medical Centre, Kuala Lumpur and two community centres. Parents answered the Caregiver Priorities and Child Health Index of Life with Disabilities Questionnaire and a pro forma regarding parent-reported frequency and intensity of pain during the preceding 4 weeks. Parental psychosocial well-being was assessed via the Depression, Anxiety and Stress Scale and Multidimensional Scale of Perceived Social Support., Results: The response rate was 94%; 104 children (54 males, 50 females) were studied. The majority (51%) were in Gross Motor Function Classification System level V and 65% had spastic quadriplegia. Parents reported pain in 65%, intense pain in 17%, and daily pain in 28%. Intense and frequent pain was reported during physiotherapy. More intense pain was reported in older children (p=0.016) and those with spastic quadriplegia (p=0.020)., Interpretation: Caregivers of non-verbal children with CP report a high frequency of pain. Pain intensity is associated with patient factors but not parental psychosocial factors., (© 2015 Mac Keith Press.)

Epidemiological studies have reported that most of the severe dengue cases occur upon a secondary heterologous infection. Furthermore, babies born to dengue immune mothers are at greater risk of developing severe disease upon primary infection with a heterologous or homologous dengue virus (DENV) serotype when maternal antibodies reach sub-neutralizing concentrations. These observations have been explained by the antibody mediated disease enhancement (ADE) phenomenon whereby heterologous antibodies or sub-neutralizing homologous antibodies bind to but fail to neutralize DENV particles, allowing Fc-receptor mediated entry of the virus-antibody complexes into host cells. This eventually results in enhanced viral replication and heightened inflammatory responses. In an attempt to replicate this ADE phenomenon in a mouse model, we previously reported that upon DENV2 infection 5-week old type I and II interferon (IFN) receptors-deficient mice (AG129) born to DENV1-immune mothers displayed enhancement of disease severity characterized by increased virus titers and extensive vascular leakage which eventually led to the animals' death. However, as dengue occurs in immune competent individuals, we sought to reproduce this mouse model in a less immunocompromised background. Here, we report an ADE model that is mediated by maternal antibodies in type I IFN receptor-deficient A129 mice. We show that 5-week old A129 mice born to DENV1-immune mothers succumbed to a DENV2 infection within 4 days that was sub-lethal in mice born to naïve mothers. Clinical manifestations included extensive hepatocyte vacuolation, moderate vascular leakage, lymphopenia, and thrombocytopenia. Anti-TNFα therapy totally protected the mice and correlated with healthy hepatocytes. In contrast, blocking IL-6 did not impact the virus titers or disease outcome. This A129 mouse model of ADE may help dissecting the mechanisms involved in dengue pathogenesis and evaluate the efficacy of vaccine and therapeutic candidates.

Early diagnosis of low grade glioma has been a challenge to clinicians. Positron Emission Tomography (PET) using 18F-FDG as a radio-tracer has limited utility in this area because of the high background in normal brain tissue. Other radiotracers such as 18F-Fluorocholine (18F-FCH) could provide better contrast between tumor and normal brain tissue but with high incidence of false positives. In this study, the potential application of a dual tracer 18F-FCH/18F-FDG-PET is investigated in order to improve the sensitivity of PET imaging for low grade glioma diagnosis based on a mouse orthotopic xenograft model. BALB/c nude mice with and without orthotopic glioma xenografts from U87 MG-luc2 glioma cell line are used for the study. The animals are subjected to 18F-FCH and 18F-FDG PET imaging, and images acquired from two separate scans are superimposed for analysis. The 18F-FCH counts are subtracted from the merged images to identify the tumor. Micro-CT, bioluminescence imaging (BLI), histology and measurement of the tumor diameter are also conducted for comparison. Results show that there is a significant contrast in 18F-FCH uptake between tumor and normal brain tissue (2.65 ± 0.98), but with a high false positive rate of 28.6%. The difficulty of identifying the tumor by 18F-FDG only is also proved in this study. All the tumors can be detected based on the dual tracer technique of 18F-FCH/18F-FDG-PET imaging in this study, while the false-positive caused by 18F-FCH can be eliminated. Dual tracer 18F-FCH/18F-FDG PET imaging has the potential to improve the visualization of low grade glioma. 18F-FCH delineates tumor areas and the tumor can be identified by subtracting the 18F-FCH counts. The sensitivity was over 95%. Further studies are required to evaluate the possibility of applying this technique in clinical trials.

Carbon nanotubes (CNTs) are an important class of nanomaterials, which have numerous novel properties that make them useful in technology and industry. Generally, there are two types of CNTs: single-walled nanotubes (SWNTs) and multi-walled nanotubes. SWNTs, in particular, possess unique electrical, mechanical, and thermal properties, allowing for a wide range of applications in various fields, including the electronic, computer, aerospace, and biomedical industries. However, the use of SWNTs has come under scrutiny, not only due to their peculiar nanotoxicological profile, but also due to the forecasted increase in SWNT production in the near future. As such, the risk of human exposure is likely to be increased substantially. Yet, our understanding of the toxicological risk of SWNTs in human biology remains limited. This review seeks to examine representative data on the nanotoxicity of SWNTs by first considering how SWNTs are absorbed, distributed, accumulated and excreted in a biological system, and how SWNTs induce organ-specific toxicity in the body. The contradictory findings of numerous studies with regards to the potential hazards of SWNT exposure are discussed in this review. The possible mechanisms and molecular pathways associated with SWNT nanotoxicity in target organs and specific cell types are presented. We hope that this review will stimulate further research into the fundamental aspects of CNTs, especially the biological interactions which arise due to the unique intrinsic characteristics of CNTs.

Despite 70 years of research that has intensified in the past decade, a safe and efficacious dengue vaccine has yet to be available. In addition to the expected challenges such as identifying immune correlates of protection, the dengue vaccine field has faced additional hurdles including the necessity to design a tetravalent formulation and the risk of antibody-mediated disease enhancement. Nevertheless, tetravalent live attenuated vaccine candidates have reached efficacy trials and demonstrated some benefit, despite imbalanced immunogenicity and incomplete protection against the four serotypes. Meanwhile, the development of sub-unit dengue vaccines has gained momentum. As the target of most of the neutralizing antibodies so far reported, the virus envelope E protein has been the focus of much effort and represents the leading dengue sub-unit vaccine candidate. However, its notorious poor immunogenicity has prompted the development of innovative approaches to make E-derived constructs part of the second generation dengue vaccines portfolio.