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  • Drug repurposing study finds lonafarnib effective against RSV

    Drug repurposing study finds lonafarnib effective against RSV

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    In a study published in the journal Nature Communications, researchers screened ReFRAME (short for repurposing, focused rescue, and accelerated Medchem), a drug-repurposing library, for drugs against respiratory syncytial virus (RSV). They identified lonafarnib as a potent inhibitor of RSV fusion protein and investigated its therapeutic potential against an RSV infection.

    Study: Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor. Image Credit: joshimerbin / ShutterstockStudy: Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor. Image Credit: joshimerbin / Shutterstock

    Background

    RSV causes severe lower respiratory tract infections in young children, immunosuppressed individuals, and older adults, with millions of annual hospital admissions and deaths. The recent coronavirus disease 2019 (COVID-19) pandemic and associated interventions have led to altered RSV epidemiology, with a transient suppression and resurgence of RSV circulation, raising concerns about increased infections.

    RSV infection treatment is currently symptomatic. While ribavirin shows in vitro efficacy, it is not very efficacious in patients. Palivizumab provides prophylaxis but is costly, offers only a partial reduction in hospitalization rates, and faces challenges like rapid resistance development. Although nirsevimab was recently approved for RSV prevention in newborns, there remains a dearth of therapeutic options.

    Various antiviral strategies against RSV, including immunoglobulins, are being developed. Repurposing libraries containing licensed drugs or compounds in clinical development serve as repositories with potential for accelerated therapeutic applications. Researchers in the present study screened the ReFRAME library and identified lonafarnib as an RSV fusion protein inhibitor while demonstrating its therapeutic ability.

    About the study

    The library (of 12,000 molecules) was screened using a recombinant RSV subtype A strain GFP (short for green fluorescent protein) reporter virus. Cell viability was determined using an MTT (short for 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The primary hit criteria were RSV infection ≤ 16% and cell viability ≥ 80%. Fourteen molecules met the primary criteria, and 16 additional molecules were selected. Two farnesyl-S-transferase inhibitors, lonafarnib, and tipifarnib, were evaluated and compared for their inhibitory effects on RSV infection. To identify the potential viral target of lonafarnib, passages of the RSV reporter virus were conducted with increasing doses of lonafarnib. The resulting virus populations were sequenced, and mutations were analyzed. The study additionally involved orthogonal infection assays, plaque reduction assays, RSV lentiviral pseudotype assays, and RSV F protein cell-to-cell membrane fusion assays. Surface plasmon resonance and crystallization experiments were conducted to investigate the interaction of lonafarnib with a recombinant RSV subtype A pre-fusion F protein.

    Therapeutic effects of lonafarnib were evaluated by inoculating A549 cells with HRSV-A-GFP, treating with lonafarnib or ribavirin 24 hours post-inoculation, and monitoring virus spread over time. The drug’s effect in a more natural model of RSV infection and cell entry was investigated using the immortalized human basal cell line BCi-NS1.1, which was further differentiated into the pseudostratified ciliated epithelium.

    Six mice were treated with oral lonafarnib or solvent control and infected with an RSV reporter virus. The animals’ weight was monitored, and on day 4, tissues were extracted, and lung RSV copy number was measured.

    A Screening and validation procedure. B HEp-2 cells were infected with rHRSV-A-GFP in presence of 5 µM compound. 48 hours later, infection and cell viability were quantified via GFP and MTT readouts. Dotted lines indicate primary hit criteria and dots represent means of two technical replicates. C HEp-2 cells were infected with HRSV-A-Luc at MOI 0.01 and treated with the indicated compound concentrations. 24 hours later, supernatant was transferred onto new cells for a second round of infection. Luminescence was quantified 24 hours post inoculation of both infection rounds. Cell viability was measured via MTT readout in treated, but uninfected cells. Mean ± SD of three independent experiments. Known RSV inhibitors (F protein: presatovir; N protein: RSV604, IMPDH inhibitors (AVN944, mycophenolic acid), HSP90 inhibitors (radiciol, HSP990). 4-Sulfocalix[6]arene Hydrate (4SC6AH, unknown target). Source data are provided as a Source Data file.A Screening and validation procedure. B HEp-2 cells were infected with rHRSV-A-GFP in presence of 5 µM compound. 48 hours later, infection and cell viability were quantified via GFP and MTT readouts. Dotted lines indicate primary hit criteria and dots represent means of two technical replicates. C HEp-2 cells were infected with HRSV-A-Luc at MOI 0.01 and treated with the indicated compound concentrations. 24 hours later, supernatant was transferred onto new cells for a second round of infection. Luminescence was quantified 24 hours post inoculation of both infection rounds. Cell viability was measured via MTT readout in treated, but uninfected cells. Mean ± SD of three independent experiments. Known RSV inhibitors (F protein: presatovir; N protein: RSV604, IMPDH inhibitors (AVN944, mycophenolic acid), HSP90 inhibitors (radiciol, HSP990). 4-Sulfocalix[6]arene Hydrate (4SC6AH, unknown target). Source data are provided as a Source Data file.

    Results and discussion

    Twenty-one molecules, including lonafarnib, demonstrated antiviral activity against RSV. Lonafarnib is approved for Hutchinson-Gilford progeria syndrome and is in phase III clinical trials for hepatitis delta virus infections. Lonafarnib, but not tipifarnib, demonstrated inhibition of RSV infection, as evidenced by reduced reporter virus activity, plaque reduction, and suppressed syncytia formation in infected cells. Further, lonafarnib, not tipifarnib, was found to interact with the pre-fusion F protein in a binding site that has been previously observed for other fusion inhibitors.

    Lonafarnib-exposed virus populations accumulated two coding mutations (T335I and T400A) within the RSV fusion protein, leading to phenotypic resistance to lonafarnib. Further, lonafarnib was found to inhibit RSV’s entry into the cells by binding to the fusion protein and inhibiting membrane fusion. This inhibition was found to be overcome by resistance mutations in the fusion protein.

    In vitro, combinations of lonafarnib and ribavirin showed minor inhibitory or slightly synergistic activity at selected doses. Lonafarnib treatment post-inoculation in A549 cells restricted the spread of the HRSV GFP virus by 30% as compared to controls. In the BCi-NS1.1 cell culture model, prophylactic lonafarnib treatment from both the apical and basolateral sides dose-dependently inhibited RSV infection, resulting in a 10- to 15-fold reduction in virus load. Therapeutic application of lonafarnib only from the basolateral side also reduced virus load by approximately 50% in a clinical RSV isolate infection.

    In vivo, lonafarnib-treated animals showed a significantly reduced reporter virus signal in the lung and nose compared to controls. On day 4, a dose-dependent decline was observed in viral ribonucleic acid in the lungs of treated mice, and there was a lesser weight loss compared to controls. However, cellular infiltrates were observed in the lungs of lonafarnib-treated mice.

    Conclusion

    In conclusion, the study identified lonafarnib as a potential therapeutic candidate for RSV treatment, highlighting the utility of drug-repurposing studies. The findings demonstrate the promising antiviral activity of lonafarnib in cell culture as well as mice models of RSV infection. Further research is warranted to confirm the findings.

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  • Nutritional epigenetics education reduces ultra-processed food intake in parents of children with autism and ADHD

    Nutritional epigenetics education reduces ultra-processed food intake in parents of children with autism and ADHD

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    In a recent publication released by PubMed, American scientists led by Dr. Dufault at the Food Ingredient and Health Research Institute, reported the results of a clinical trial in which parents who received nutritional epigenetics education significantly reduced their consumption of ultra-processed foods while increasing their intake of whole and/or organic foods. The education intervention used curriculum focused on the constructs of the nutritional epigenetics model that explains how autism and attention deficit/hyperactivity disorder (ADHD) may develop from the excess consumption of ultra-processed foods.

    Consumption of ultra-processed foods leads to heavy metal exposures and dietary deficits that create mineral imbalances such as zinc and calcium losses. Inadequate zinc stores can disrupt the function of the metal transporter metallothionein (MT) gene preventing the elimination of heavy metals found in ultra-processed foods. The bioaccumulation of mercury and/or lead is common in children with autism and ADHD who are often zinc deficient. Mercury, lead, and other heavy metals are known to suppress the paraoxonase (PON1) gene. Paraoxonase is required by the body to detoxify the neurotoxic organophosphate pesticide residues found routinely in the food supply by the United States Department of Agriculture. Children with autism and ADHD are more susceptible to the harmful effects of organophosphate pesticide exposures.

    Parents who received nutritional epigenetics education learned how to reduce their children’s dietary exposures to heavy metal and organophosphate pesticide residues. The parents learned how to read food ingredient labels and changed their diet as they avoided buying foods with allowable heavy metal and pesticide residues. In learning how specific food ingredients contribute to heavy metal exposures, impact nutrient status and/or gene behavior, parents gained the knowledge they needed to feed themselves and their children a healthier diet. By the end of the education intervention, parents had changed their minds about their ability to control their child’s behavior through diet.

    Children behave better when they feel better. Because the severity of symptoms in autism and ADHD correlate directly to the heavy metal levels in blood, children with less heavy metal exposure show improvements in behavior and cognition. In addition, because heavy metals, in single or multi-metallic combination, create conditions for gut dysbiosis, improvements in diet can reduce inflammation and improve gut health. Reducing ultra-processed food consumption can alleviate symptoms associated with gut dysbiosis which is often a co-morbid condition found in children with autism and ADHD.

    Autism and ADHD are preventable, but the prevalence of these neurodevelopmental disorders will continue to increase in the United States until changes are made to reduce the allowable heavy metal residues in the ultra-processed food supply. The US Congress released two reports in 2021 on the problem of heavy metals in baby foods. The first report issued on February 4, 2021, revealed baby foods are tainted with dangerous levels of arsenic, lead, cadmium, and mercury. The second report, issued on September 29, 2021, confirmed new disclosures from manufacturers show dangerous levels of heavy metals in even more baby foods.

    Source:

    Food Ingredient and Health Research Institute

    Journal reference:

    Dufault, R. J., et al. (2024) Nutritional epigenetics education improves diet and attitude of parents of children with autism or attention deficit/hyperactivity disorder. World Journal of Psychiatry. doi.org/10.5498/wjp.v14.i1.159.

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  • Study finds digital CBT for children with anxiety delivers on par with traditional methods, lowers costs

    Study finds digital CBT for children with anxiety delivers on par with traditional methods, lowers costs

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    In a recent study published in The Lancet Psychiatry, a group of researchers evaluated if digitally augmented, therapist-supported, parent-led cognitive behavioral therapy (CBT) is a cost-effective and clinically effective alternative to standard care for treating childhood anxiety.

    Study: Digitally augmented, parent-led CBT versus treatment as usual for child anxiety problems in child mental health services in England and Northern Ireland: a pragmatic, non-inferiority, clinical effectiveness and cost-effectiveness randomised controlled trial. Image Credit: Ground Picture/Shutterstock.comStudy: Digitally augmented, parent-led CBT versus treatment as usual for child anxiety problems in child mental health services in England and Northern Ireland: a pragmatic, non-inferiority, clinical effectiveness and cost-effectiveness randomised controlled trial. Image Credit: Ground Picture/Shutterstock.com

    Background

    Child mental health services worldwide struggle to meet demand, highlighting the need for more accessible care. Digital treatments could significantly expand service capacity, but their full integration into routine care is pending.

    Recognizing the urgency, entities like England’s National Institute for Health and Care Excellence (NICE) emphasize the importance of digital solutions for youth mental health. Anxiety, affecting a significant portion of the population from an early age, leads to major personal and economic impacts.

    CBT, especially in brief, parent-led formats supported by therapists, offers a viable solution by overcoming barriers to access and engaging families directly.

    Digital platforms like the Online Support and Intervention (OSI) for child anxiety, co-developed with families and therapists, show promise in making effective treatments more accessible. However, further research is crucial to evaluate their cost-effectiveness and potential for widespread use in varied clinical contexts.

    About the study 

    The present study was registered and followed a published protocol, sought to involve sites that were part of the National Health Service (NHS) or local authorities, totaling 34 participating sites. These included a diverse mix of NHS Trusts and local authority or voluntary or community sector providers, encompassing 73 Child Mental Health Teams.

    Eligibility criteria for children included being aged 5–12 years with a primary anxiety problem, alongside their parents having sufficient English language proficiency, internet access, and willingness to consent.

    Exclusions applied to children with certain comorbid conditions or those involved in child protection concerns, as well as parents with significant intellectual impairments or severe mental health issues.

    The study acknowledged the unique context of the coronavirus disease 2019 (COVID-19) pandemic, which necessitated a rapid shift to remote service delivery, influencing the trial’s approach to what constituted “treatment as usual.”

    Randomization was carefully managed using a web-based system, ensuring balanced allocation across intervention and control groups, albeit blinding to intervention was not feasible for participants.

    The trial’s procedures were thorough, with families being identified, consented, and assessed online, followed by a structured engagement with the treatment process across both arms.

    Qualitative interviews were conducted to gauge the acceptability of OSI plus therapist support, providing rich insights into participants’ experiences.

    The primary outcome focused on the impact of child anxiety on family life, using the Child Anxiety Impact Scale–Parent Report (CAIS-P), with a comprehensive suite of secondary outcomes to capture a broad spectrum of effects. 

    Study results 

    Between December 5, 2020, and August 3, 2022, 706 families were referred, and out of these referrals, 444 families met the inclusion criteria, provided consent, and were randomized equally between the two study arms.

    Despite initial plans, only 79% of these participants started their allocated treatment within the stipulated 12-week period post-randomization.

    By the end of the trial, completion rates for the 14-week and 26-week assessments were 79% and 74%, respectively, in the OSI plus therapist support and treatment as usual groups.

    The participant demographic was predominantly White-British, with a slight majority of girls over boys and an average child age of 9.20 years. Treatment as usual, primarily consisted of CBT, often delivered through parents.

    Before treatment, parents across both groups had similar expectations regarding the logical nature and potential success of the interventions. However, parents initially felt more confident in the success of the OSI, plus therapist support.

    Post-treatment, therapists felt more comfortable delivering traditional treatment than OSI, expressing hesitancy about future use of OSI, largely due to its novelty and their temporary access during the trial.

    The study found OSI plus therapist support to be non-inferior to traditional treatments across all primary and secondary outcomes, demonstrating minimal differences in effectiveness. This was consistent across various sensitivity analyses.

    Furthermore, there was little difference in utility scores and Quality-Adjusted Life Years (QALYs) between the groups.

    However, the OSI plus therapist support arm showed lower associated costs, primarily due to reduced delivery time. Despite some uncertainty, cost-utility analyses suggested that OSI plus therapist support could be cost-effective under certain scenarios.

    Health economic results revealed minor differences in treatment and resource use outcomes, suggesting the potential cost-effectiveness of OSI plus therapist support, though with noted uncertainty.

    Despite this uncertainty and the absence of serious adverse events, the trial highlighted the feasibility of OSI plus therapist support as an effective and potentially more efficient alternative to traditional treatment methods for child anxiety problems.

    This finding underscores the value of further exploring digitally augmented treatments within child mental health services.

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  • Vaccines safe for pregnant women with HIV but show reduced immune response

    Vaccines safe for pregnant women with HIV but show reduced immune response

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    In a recent study published in the journal eClinicalMedicine, researchers performed a meta-analysis on the immunogenicity and safety of vaccines for pregnant women living with human immunodeficiency virus (HIV) infections (PWLWH), comparing their immunogenicity effect to those without HIV infections (PWWH).

    Increased access to lifelong combined antiretroviral therapy (cART) has significantly aided the global reduction in mother-to-child HIV transmission. HIV-exposed uninfected (HEU) infants have a higher burden of infectious diseases than HIV-unexposed and uninfected (HUU). Immunization of PWLWH individuals could potentially reduce the severity of infectious diseases in early infancy. However, previous reports indicate that maternal vaccines given to PWLWH may be less immunogenic than those administered to PWWH. Most HEU children live in low- and middle-income countries, particularly SSA, where the HIV burden is highest. The World Health Organization (WHO) recommends tetanus vaccines for pregnancy, and evidence from clinical trials supports the safety and immunogenicity of other maternal vaccines. However, data on safety and immunogenicity in pregnant women is scarce.

    Study: The safety and immunogenicity of vaccines administered to pregnant women living with HIV: a systematic review and meta-analysis. Image Credit: Hit Stop Media / ShutterstockStudy: The safety and immunogenicity of vaccines administered to pregnant women living with HIV: a systematic review and meta-analysis. Image Credit: Hit Stop Media / Shutterstock

    About the study

    In the present meta-analysis, researchers examined the immunogenicity and safety of vaccines for HIV-exposed pregnant women.

    The team searched the Embase, MEDLINE, Web of Science, Cochrane, and Virtual Health Library databases from study inception through January 31, 2022, and re-ran the search without language restrictions between February 1, 2022, and September 6, 2023. In addition, they searched the references to the relevant studies to identify additional records.

    The study included observational studies and randomized clinical trials administering vaccines to expecting women living with HIV infections and groups of HIV-uninfected women for comparison. They excluded animal studies, reviews, conference abstracts, and case series. Two researchers independently screened titles and abstracts, and a third researcher resolved disagreements.

    The researchers followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for analysis. They used the Newcastle-Ottawa Scale (NOS) to assess the methodological quality of non-randomized controlled trials. Three researchers evaluated bias risks related to generating random sequences, allocation concealing, personnel and participant blinding, outcome assessment blinding, selective reporting, and inadequate outcome data. They assessed publication bias based on funnel plot asymmetries.

    The team performed random effects modeling for the meta-analyses, assessing geometric mean titers (GMT) to compute effect sizes using the inverse variance-weighted method and report it as the mean difference. They used the I2 statistic to assess study heterogeneity. They performed group-stratified analyses, including HIV status and vaccine subtypes.

    Results

    The initial data search yielded 96,160 records, of which 75 underwent full-text screening, and 12 were eligible for the meta-analysis, including 3,744 expecting females, of which 1,714 were PWLWH. They identified three vaccines in the study, i.e., those for group B streptococci (GBS), influenza virus, and pneumococci. They rated the overall bias risk as low, but outcome assessment blinding-related bias as unclear.

    Five studies, including 3,456 PWLWH women, reported safety outcomes, with no increase in adverse events reported in PWLWH compared to PWWH. The GMT increase from baseline to weeks 28-35 post-vaccination in HA units ranged between 12 and 239. The pooled geometric mean difference in hemagglutination inhibition (HAI) titers following influenza vaccination was 56. The increase was less in PWLWH compared to PWWH: −142. The team observed the most significant difference in women receiving B strains (−166) and the most negligible difference among those receiving A/ H3N1 vaccinations (−112).

    One study documented one or more severe local reactions in four percent of PWLWH, whereas 19% had one or more severe systemic reactions a week post-vaccination. Compared to PWWH, five percent reported one or more severe local reactions, and 15% reported one or more severe systemic reactions. One study documented an increased frequency of injection-area adverse reactions with double-dosage influenza vaccinations among expecting women living with HIV infections. The most frequent serious adverse event was preterm birth, with higher rates among HIV-infected expecting women compared to their HIV-uninfected counterparts.

    Five studies evaluated immunogenicity for pneumococcal, influenza, and GBS vaccines, all reporting elevated antibody titers after four weeks of vaccination among PWLWH compared to baseline; however, antibody titers were lower compared to PWWH. Three studies on influenza vaccinations had adequate comparison information for meta-analytic research stratified by vaccine subtypes (A/H1N1 virus, A/H3N2 virus, B/Victoria virus, and B/Yamagata virus). The mean differences in antibody titers 28 to 35 days after influenza vaccinations were significantly higher in PWLWH than in PWWH.

    Overall, the study findings showed that there is limited data on the immunogenicity and safety of vaccines administered to HIV-infected expecting women. There was no difference in vaccine safety between PWLWH and PWWH concerning influenza, pneumococcal, and investigational GBS vaccines, but there was a significant elevation in antibody titers four weeks post-vaccination; however, the increase was lower in PWLWH compared to PWWH. The findings underscore the potential challenges for vaccine policy in countries with high HIV burdens and the need for PWLWH inclusion in maternal vaccine trials to promote vaccine confidence.

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  • Exploring the dynamic between dog ownership and child activity levels

    Exploring the dynamic between dog ownership and child activity levels

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    In a recent study published in the International Journal of Behavioural Nutrition and Physical Activity, a group of researchers examined the longitudinal effects of changes in dog ownership on children’s physical activity and movement behaviors using data from the Play Spaces and Environments for Children’s Physical Activity (PLAYCE) cohort study.

    Study: Longitudinal effects of dog ownership, dog acquisition, and dog loss on children’s movement behaviours: findings from the PLAYCE cohort study. Image Credit: Dmytro Vietrov/Shutterstock.com
    Study: Longitudinal effects of dog ownership, dog acquisition, and dog loss on children’s movement behaviours: findings from the PLAYCE cohort study. Image Credit: Dmytro Vietrov/Shutterstock.com

    Background 

    Despite the importance of physical activity for children’s health, many fail to meet activity guidelines. Dog ownership in places like Australia is linked to higher physical activity levels in children, as owning a dog encourages more walking and play. Yet, the impact of dog ownership on children’s screen time and sleep remains unclear, and there’s a lack of longitudinal research. Ethical constraints limit the feasibility of randomized trials, underscoring the value of natural experiments or observational studies to explore this relationship. There is a crucial need for further study using advanced methods to accurately assess the effects of dog ownership on various aspects of children’s movement behaviors.

    About the study 

    The present study, initiated in Perth, recruited children aged 2 to 5 from early childhood education and care services. The study sought participation from a diverse socio-economic background, collecting baseline data from 2015 to 2018. As these children transitioned to full-time school, they were followed up until 2021, provided they met the eligibility criteria, resulting in a sample of 641 children aged 5 to 7 for wave 2, with 600 children having complete data on dog ownership across both waves. This setup created a natural experiment with four distinct groups based on dog ownership changes, allowing for a comparison of physical activity levels and other movement behaviors over time.

    Children’s physical activity was rigorously measured using ActiGraph GT3X+ accelerometers, processed through a machine learning model to categorize activity intensity accurately. Additionally, parents reported on screen time, sleep duration, and physical activity, offering a comprehensive view of the children’s movement behaviors. The study also considered various covariates like parental education and household characteristics to adjust for potential confounders.

    Analytical approaches included linear mixed effects models to explore differences in movement behaviors over time and by dog ownership status, adjusting for a range of variables and the context of the coronavirus disease 2019 (COVID-19) pandemic. 

    Study results 

    The PLAYCE cohort study detailed the characteristics and movement behaviors of children across different dog ownership statuses. Approximately half of the participants were girls, with a median age of 3.2 years at the study’s outset. Notably, socioeconomic factors such as the mother’s education level, employment status, and living conditions varied significantly across dog ownership groups, influencing the study’s context.

    Initial assessments revealed no significant differences in movement behaviors measured by devices among the dog ownership groups. However, when looking at unstructured physical activity, children in the dog owner and dog loss groups engaged in more physical activities than their counterparts without dogs. Interestingly, these differences were primarily due to dog-related activities. Screen time and sleep duration also varied, indicating nuanced influences of dog ownership on children’s daily routines.

    As children transitioned from preschool to full-time school, changes in their movement behaviors were observed, with variations depending on whether they acquired or lost a dog during this period. For girls, acquiring a dog positively impacted light intensity activities, whereas losing a dog led to reductions in both light intensity activities and total physical activity. Conversely, boys in the dog owner group saw an increase in energetic play, highlighting the gender-specific effects of dog ownership on children’s physical activities.

    The acquisition of a dog also positively affected both girls’ and boys’ unstructured physical activity, emphasizing the role of dog-facilitated activities in promoting physical engagement. These findings suggest that changes in dog ownership status can significantly impact children’s movement behaviors, with the loss of a dog particularly affecting girls’ physical activity levels.

    Screen time trends further illustrated these effects, with no significant changes observed in girls who acquired or lost a dog, but a distinct trajectory for girls in the dog owner group compared to non-dog owners. This divergence underscores the complex relationship between dog ownership and screen time, possibly reflecting lifestyle or behavioral adjustments associated with having a pet.

    Lastly, the study highlighted significant shifts in physical activity and screen time among children experiencing changes in dog ownership status. These results point to the potential of dog ownership to positively influence children’s physical activity, with implications for public health strategies aimed at enhancing physical engagement among young populations. 

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  • New treatment target found for CDKL5 deficiency disorder

    New treatment target found for CDKL5 deficiency disorder

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    Scientists at the Francis Crick Institute have found a new treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy. 

    CDD causes seizures and impaired development in children, and medications are limited to managing symptoms rather than tackling the root cause of the disease. The disorder involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function.

    Following recent research from the same lab showing that a calcium channel could be a target for therapy for CDD, the team has now identified a new way to potentially treat CDD by boosting another enzyme’s activity to compensate for the loss of CDKL5. 

    In research published today in Molecular Psychiatry, the scientists studied mice that don’t make the CDKL5 enzyme. These mice show similar symptoms to people with CDD like impaired learning or social interaction. 

    The researchers first identified that CDKL5 is active in nerve cells in mice but not in another type of brain cell called an astrocyte. In the nerve cells, they measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 isn’t produced. 

    Interestingly, even in mice that don’t produce CDKL5, there was still some EB2 phosphorylation taking place, which suggested that another similar enzyme must also be able to phosphorylate it.

    By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons. In mice without both CDKL5 and CDKL2, the remaining EB2 phosphorylation almost fully dropped off.

    The researchers concluded that, although most activity comes from CDKL5, about 15% is from CDKL2, and the remaining <5% from another enzyme yet to be identified. 

    Their research suggests that increasing the level of CDKL2 in people who are deficient in CDKL5 could potentially treat some of the effects on the brain in early development. 

    CDD is a devastating condition that impacts young children from birth, and we don’t know a huge amount about why losing this one enzyme is so disastrous for the developing brain. Through this research, we’ve identified a potential way to compensate for the loss of CDKL5. If we can increase levels of CDKL2, we might one day be able to stop symptoms from developing or getting worse.”


    Sila Ultanir, Group Leader of the Kinases and Brain Development Laboratory, The Francis Crick Institute

    The researchers are now investigating if mice without CDKL5 can be treated by stimulating their brain cells to produce more CDKL2. The lab is also working with biotechnology companies to identify molecules that increase CDKL2 for potential new medicines for CDD. 

    Margaux Silvestre, former PhD student at the Crick and now postdoctoral researcher at the Max Planck Institute for Brain Research in Frankfurt, said: “Our discoveries offer fresh insights into the expression and regulation of CDKL5 in the brain. Moreover, the identification of CDKL2 as a potential compensatory enzyme provides hope for uncovering better treatments that could truly make a difference in the lives of the children with this devastating condition. This research owes its success to all the authors involved in the publication but also the unwavering support we received from the technical teams at the Crick – a big shoutout to them!”

    The research was funded by the Loulou Foundation, a private foundation dedicated to the development of therapeutics and eventual cures for CDD.

    Source:

    The Francis Crick Institute

    Journal reference:

    Silvestre, M., et al. (2024). Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain. Molecular Psychiatry. doi.org/10.1038/s41380-024-02434-7.

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  • Virginia Tech food safety expert offers tips for selecting the right charcuterie meats

    Virginia Tech food safety expert offers tips for selecting the right charcuterie meats

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    Whether it’s building out a big spread for the Super Bowl or planning a Valentine’s Day meal, lots of people will be heading to the store these next few weeks to stock up on food. One item many might be considering is charcuterie. A recent Salmonella outbreak linked to charcuterie meats has raised some concerns, but Virginia Tech food safety expert Katheryn Parraga-Estrada explains that not all charcuterie products are involved in this outbreak and offers tips for selecting the right meats.

    What do people need to know before buying charcuterie meats?

    If you plan on buying or consuming charcuterie, make sure that you do not buy products from the brands implicated in the recent outbreak until the recall is over. If you have these products at home, discard them and thoroughly wash and disinfect any surfaces that may have come into contact with the products. 

    For reference, the charcuterie products involved in the recent outbreak include:

    Busseto brand Charcuterie Sampler

    – Has prosciutto, sweet soppressata, and dry coppa

    – Sold at Sam’s Club

    – Comes in a twin-pack (2 x 9oz)

     – Any lot code

    Fratelli Beretta brand Antipasto Gran Beretta

    – Has black pepper coated dry salami, Italian dry salami, dry coppa, and prosciutto

    – Sold at Costco

    – Comes in a twin-pack (2 x 12oz)

    – Any lot code

    The duration of a CDC investigation varies depending on the outbreak, and it may be extended. Each time an individual reports symptoms, it takes 3 to 4 weeks to determine if it is linked to an outbreak. As part of your responsibility, you will need to keep informed as additional brands may be implicated in this recall.

    How can people avoid Salmonella?

    Salmonella is a bacteria that lives in the intestines of people and animals and can cause a gastrointestinal illness and fever called salmonellosis. Salmonella can contaminate food or drinking water due to poor hygiene of employees who handle the food or through cross-contamination from raw products, such as poultry products to cooked or ready-to-eat products. Every year, there are about 420 deaths due to salmonellosis and about 26,500 people get hospitalized because of this bacteria. 

    People can prevent getting sick with salmonellosis by following these recommendations:

    Wash your hands properly and sanitize them after touching pets, including poultry and reptiles, which are natural carriers of Salmonella.

    • When preparing food at home, make sure to wash and sanitize surfaces that might be contaminated with Salmonella.

    • If you have children, elderly individuals, pregnant women, or people with weakened immune systems at home, ensure you fully cook all foods, especially meats.

    What are the symptoms of Salmonella?

    Symptoms can develop within 6 hours to 6 days after consuming the food contaminated or swallowing the bacteria. While healthy individuals typically recover without treatment after 4 to 7 days, those with weakened immune systems, children under 5 years old, and adults above 65 years old may experience more severe symptoms requiring medical treatment or hospitalization.

    If you experience these symptoms, make sure to keep hydrated by drinking fluids and getting rest. Dehydration can occur due to diarrhea; if symptoms are severe (bloody diarrhea, severe diarrhea for more than 3 days, high fever (>102 °F), vomiting, signs of dehydration), contact your doctor. In some cases, antibiotics may be prescribed.

    About Parraga-Estrada

    Katheryn Parraga-Estrada joined the faculty at Virginia Seafood Agricultural Research and Extension Center and Virginia Tech’s Department of Food Science and Technology in September of 2021. Her extension work focuses on improving the understanding and application of food safety research through education, training, and technical guidance for the production of safe and quality foods. In addition, she is an active member of the International Association of Food Protection, Gamma Sigma Delta Honor Society, and Phi Tau Sigma Honor Society.

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  • Media stories on parental vaccine hesitancy drive a false narrative, distort reality

    Media stories on parental vaccine hesitancy drive a false narrative, distort reality

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    Media stories focusing on vaccine hesitancy can distort reality and drive a false narrative that a large percentage of parents are refusing to get their children vaccinated, according to an editorial in the New England Journal of Medicine by two pediatricians from the University of Colorado Anschutz Medical Campus.

    The article, published online Saturday in the Perspective section of the prestigious medical journal, said stories indicating widespread vaccine hesitancy among parents are at odds with the facts and can have long-term consequences.

    The algorithms that shape our media diets have been promoting the idea that parental hesitancy about routine childhood vaccines has become commonplace in the United States. The data, however, are undeniable: apart from important challenges with influenza and Covid­19 vaccina­tion, the vast majority of parents in the United States continue to choose to have their children vac­cinated according to the vaccina­tion schedule recommended by the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics.”


    Sean O’Leary, MD, MPH, and David Higgins, MD, MPH, of the University of Colorado School of Medicine and Children’s Hospital Colorado

    According to the authors, a recent poll from the Pew Research Center found 88% of adults have robust confidence in the value of childhood vaccines such as those for measles, mumps, and rubella. The poll also showed little change in the numbers of adults who say the value of vaccines outweigh any associated risk.

    At the same time, a recent study from the CDC showed 93% of kindergarten students received state-required vaccines. Another study revealed that vaccination coverage for children at age 2 remained high and stable throughout the pandemic,

    “The headlines say vaccine resistance is through the roof, the sky is falling,” said O’Leary, professor of pediatrics and infectious diseases at the CU School of Medicine and Children’s Hospital Colorado. “There is a real risk of the community buying into this and treating it as the norm.”

    Higgins, a fellow and instructor in pediatrics at the CU School of Medicine and the Adult & Child Center for Outcomes Research & Delivery Science (ACCORDS) at the CU School of Medicine, said constant focus on vaccine hesitancy could become a “dangerous, self-fulfilling prophecy.”

    He said perceived social norms, or what people consider typical behavior, can powerfully influence their health care decisions.

    “The most important thing we can do is normalize vaccinations. That’s what the majority of parents do, vaccinate their children,” Higgins said. “We in the scientific community need to better communicate the value of vaccinations.”

    Studies show that vaccine recommendations from physicians are more effective when framed in a way that presumes parents want their kids vaccinated. If clinicians expect resistance, the recommendations may be less effective.

     “Legitimate inquiries about vaccines don’t necessarily indicate major parental vaccine hesitancy. In our experience, most parents with such inquiries aren’t `antivaccine;’ they believe vaccines are essential to their child’s health. One of the best parts of being a pediatrician is partnering with parents to address these good­faith questions,” the authors wrote.

    O’Leary, chair of the Committee on Infectious Diseases for the American Academy of Pediatrics, said not only do most adults support vaccinating their children, but since the onset of the pandemic and contrary to many media stories, pediatricians have told him that parents who had previously refused to vaccinate their kids are coming in to get the inoculations.

    Neither doctor is suggesting that vaccine hesitancy isn’t a significant health threat in the U.S.

    “We believe it will be essential to double down on efforts to increase confidence and trust in vaccines, including in populations that have experienced mistreatment by the medical community,” O’Leary and Higgins wrote. “Because of the complexity of this issue, addressing parental vaccine hesitancy requires partnerships among academic experts in vari­ous disciplines, community lead­ers, policymakers, public health professionals and parents.”

    Source:

    University of Colorado Anschutz Medical Campus

    Journal reference:

    Higgins, D. M., & O’Leary, S. T. (2024). The Risks of Normalizing Parental Vaccine Hesitancy. The New England Journal of Medicine. doi.org/10.1056/nejmp2313742.

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  • Retrospective study shows decrease in kindergarten readiness

    Retrospective study shows decrease in kindergarten readiness

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    Primary care screening visits for young children serve as useful sources of data for assessing social and developmental markers. It is not clear how these screening data can be used to predict whether children are school ready.

    Study: arly Correlates of School Readiness Before and During the COVID-19 Pandemic Linking Health and School Data. Image Credit: FamVeld/Shutterstock.com
    Study: Early Correlates of School Readiness Before and During the COVID-19 Pandemic Linking Health and School Data. Image Credit: FamVeld/Shutterstock.com

    A new study appeared in JAMA Pediatrics that explored associations between school district early Kindergarten Readiness Assessment (KRA) and electronic health records (EHR) data and linked KRA scores with the changes occurring during the coronavirus disease 2019 (COVID-19) pandemic.

    Background

    Childhood is a watershed period for developing social skills, healthy physical and brain development, and becoming ready for school. Multiple factors may interfere with the acquisition of these skills which are essential in school life, such as social training, emotional regulation, as well as math and literacy skills. These may include socioeconomic and racial characteristics.

    In some regions, up to 4 out of 10 new kindergartners are not ready to enter school. Since there has been no systematic attempt to identify which children are at risk of entering kindergarten without readiness, it is not clear how and which risk factors can be modified to change this situation.

    The COVID-19 pandemic negatively impacted learning in school-age children, but its effect on development in children under five years remains to be described. This motivated the current study that uses KRA scores before and during the pandemic with the EHR data from a cohort of students in a large school district with about 36,000 students.

    The KRA scores are linked to reading proficiency in the third grade and include four skill categories: preliteracy, premath, motor skills, and social-emotional skills.

    What did the study show?

    The study included over 3,000 patients who were screened at primary care level. The mean age was 67 months, with the majority being Black (80%) vs 8% Whites. The passing KRA score was set at 270.

    When correlated with the pandemic dates, the mean KRA scores were significantly lower in 2021, at 260, vs ~263 in 2019 and 2018. About a fifth of students scored above passing levels in 2021, demonstrating school readiness, vs ~30% in 2019 and 32% in 2018.

    About one in four parents said they rarely read to their child, that is, one or less days a week, at least once during the period of the study. About 27% of children were unable to meet ASQ scores at least once, while 12% of the children sometimes experienced food insecurity.

    The risk factors for a low KRA score were one or more failures in the ASQ between 18 and 54 months, being Hispanic, not speaking the language of the healthcare professional during screening visits, being male and being seldom read to, as well as having food insecurity. Only 23% of boys were school-ready vs 32% of girls.

    Having Medicaid insurance, indicative of low socioeconomic status, was associated with school readiness in ~27% of children, vs ~51% if Medicaid was never used.

    Other socioeconomic factors, like housing insecurity, race, depression among the caregivers, and difficulty of any sort in obtaining benefits, did not show an association with the KRA scores. 

    “To interpret our findings using a hypothetical clinical example, starting with the expected score of 270.8 in the adjusted model (equivalent to demonstrating readiness): a boy who is Medicaid insured, who once failed an ASQ, who infrequently reported food insecurity, and was not read to as an infant lost an average of 15 points on the KRA, placing him in bottom category of emerging readiness (score below 257).”

    What are the implications?

    This is among the earliest studies to report that there might have been “a deleterious association of the COVID-19 pandemic with early learning and development.” It is also one of the largest studies to correlate primary care data to outcomes in public schools.

    While other researchers have found conflicting evidence regarding childhood development during the pandemic, multiple factors have been at work, impacting the validity of observed associations. For example, school enrolment was lower during the period. However, the association of lower school readiness with not being read to as an infant has been well documented, as well as with low developmental scores and food insecurity.

    Danger signals picked up in this way could help provide appropriate interventions in early life, whether by speech and language therapy, promoting learning by enrolment in good early childhood education programs, or facilitating library access.

    “These findings suggest substantial untapped potential for primary care pediatrics and school districts to work more closely together given that risks for kindergarten readiness are evident much earlier in primary care.”

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  • Maternal happiness in pregnancy boosts child brain development, study finds

    Maternal happiness in pregnancy boosts child brain development, study finds

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    A new study in the journal Nature Mental Health explores how a mother’s positive state of mind during pregnancy affects the structure and function of the developing fetal brain by measuring these parameters by 7.5 years of age.

    Study: Maternal positive mental health during pregnancy impacts the hippocampus and functional brain networks in children. Image Credit: Dean Drobot / Shutterstock.com Study: Maternal positive mental health during pregnancy impacts the hippocampus and functional brain networks in children. Image Credit: Dean Drobot / Shutterstock.com

    How does the maternal emotional state affect fetal development?

    During pregnancy, which is a time of significant physical, mental, and social change, anxiety, depression, and other stress-related mental health disorders are frequently reported. These mental health issues have been associated with a durable and adverse effect on fetal brain development.

    For example, previous research has shown that these mental disorders can lead to changes in the growth rate of the fetal hippocampus and a lower density of gray matter in the prefrontal and medial temporal lobes in early childhood. These children may also exhibit altered structure and function of emotion-regulating cortico-limbic networks, which are important for stress management.

    At certain stages, these changes appear to be more significant in girls than boys. Notably, it is not necessary that the mother be clinically anxious or depressed for these alterations to manifest.

    As a key component of mental health, positive maternal emotions like happiness can affect multiple outcomes, including maternal-infant bonding, parenting approaches, and child development. Furthermore, maternal happiness during pregnancy also impacts the long-term health of both the mother and child; however, it remains unclear how positive maternal emotions affect prenatal development.

    About the study

    The current study used data from the Growing Up in Singapore Towards Health Outcomes (GUSTO) cohort. Both structural and functional magnetic resonance imaging (MRI) were performed on children to explore the association of maternal happiness during pregnancy with brain development.

    The researchers developed their own tool to measure positive maternal mental health during pregnancy. This was based on a mental health questionnaire given to pregnant women at 26-28 weeks.

    What did the study show?

    At 7.5 years of age, children are experiencing a vital phase of development during which the brain shifts towards different patterns of activity and cognitive processes develop in new ways. As a result, this period was chosen as the focus of the study.

    Brain areas involved in perceiving and regulating emotions include the hippocampus and amygdala, as well as various functional networks like the visual networks, default mode network (DMN), and functional network. These regions of the brain have also been directly correlated with how the mother cares for the child.

    A composite measure from multiple mental health scales was used for assessing positive maternal emotions during pregnancy. Other potential contributing factors such as socioeconomic status, stress levels, family and friend relationships, and death of close relatives in the two years before and after pregnancy were also recorded to determine a socio-environmental adversity factor. Maternal parenting stress was also assessed when the child was six years of age.

    Interestingly, girls born to mothers who reported feeling happy during pregnancy had larger hippocampus volumes, whereas both boys and girls born to happy mothers exhibited altered functional connectivity of multiple networks.

    When categorized by task-negative and task-positive networks, reduced connectivity between task-negative networks was observed among girls born to mothers with increased positive emotions during pregnancy. Conversely, increased connectivity between task-positive networks was associated with greater maternal happiness during pregnancy.

    Since these findings were absent when explored in relation to depression or anxiety in the mother during pregnancy, the observed changes in functional connectivity may occur specifically with greater maternal positive emotion in pregnancy. This may indicate that maternal happiness transmits to the developing child’s brain through neural changes.

    What are the implications?

    The study findings suggest that feeling happy during pregnancy not only reduces the risk of psychiatric illness in the mother but also potentially acts as a protective factor for fetal brain development.

    Previous studies have shown that anxious and stressed mothers are more likely to have children with hippocampal changes, which may affect the developing brain and lead to impaired stress responses in the future. By encouraging mothers to have positive emotions during pregnancy, hippocampal development in the offspring may be promoted, with better structure and functional networks during the time when children typically begin to attend school.

    Importantly, better hippocampal development is associated with greater childhood resilience, thus serving as an early marker for psychological vulnerability and greater potential for behavioral and emotional problems when encountering stressful circumstances. However, the period of fetal development at which maternal positive emotions occur may modify the impact.

    Future studies are needed to establish and extend these findings, especially to understand the neural basis of prenatal-maternal interactions during psychoneurological development. These studies could support the development of preventive strategies to help mothers feel happy during pregnancy and ultimately promote the mental health of their children.

    Journal reference:

    • Qiu, A., Shen, C., Lopez-Vicente, M., et al. (2024). Maternal positive mental health during pregnancy impacts the hippocampus and functional brain networks in children. Nature Mental Health. doi:10.1038/s44220-024-00202-8.

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