Tag: children

First gene therapy trial aims to restore hearing in children

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The aim of this clinical trial, which has just received approval in France, is to assess the safety and efficacy of a new gene therapy drug in children aged between 6 and 31 months with profound hearing loss. Audiogene was developed by a French consortium composed of teams from the Hearing Institute, an Institut Pasteur research center; the ENT Department and Pediatric Audiology Research Center at Necker-Enfants Malades Hospital (AP-HP); Sensorion and Fondation Pour l’Audition. The trial has also been submitted to other European countries and is currently undergoing assessment.

Audiogene is the first clinical trial in France to test a gene therapy drug, SENS-501, developed by the biotech company Sensorion, to treat children with DFNB9, a form of hereditary deafness caused by mutations in the OTOF gene, which encodes a protein called otoferlin. The usual treatment for this form of hearing loss is a bilateral cochlear implant.

The aim of this treatment is to restore hearing. It works by injecting a copy of the normal otoferlin gene into the child’s impaired inner ear. The SENS-501 drug is designed to correct the genetic abnormality in the inner ear cells of children with hearing loss and restore inner ear cell function and hearing in these children.

The first step in the clinical trial will be to test two doses of SENS-501 so that the optimal dose can be selected for the rest of the trial.

In practice, the SENS-501 gene therapy drug will be directly injected into the inner ear of the child with DFNB9 deafness. The drug is injected into the round window in the inner ear, in a similar way to cochlear implantation surgery. The procedure will be performed under general anesthetic by a lead ENT surgeon. The drug will be administered using an injection system developed in partnership with the company EVEON, so that the injected dose can be measured precisely and the inner ear structures can be preserved.

This gene therapy for hearing loss patients with an otoferlin deficiency was developed as part of the RHU AUDINNOVE project, involving a consortium composed of scientists from the Hearing Institute, an Institut Pasteur research center; physicians from the ENT Department and Pediatric Audiology Research Center at Necker-Enfants Malades Hospital (AP-HP); and teams from Sensorion and Fondation Pour l’Audition.

A collective effort that thrills the AUDINNOVE stakeholders

The launch of the Audiogene clinical trial is a major step forward for deaf children with otoferlin defects and their parents but also brings hope to people with genetic deafness. We are very proud that our long-time support to French innovation and to the teams of Prof. Petit at the Hearing Institute, an Institut Pasteur research center, and Prof. Loundon, at the Clinical Center for Research in Pediatric Audiology at AP-HP Necker hospital, translates now into a trial.”

Denis Le Squer, Executive Director of Fondation Pour l’Audition

Alain Chédotal, Chair of the Scientific Committee at Fondation Pour l’Audition: “The launch of the first gene therapy clinical trial for a deafness in France is a major milestone for Fondation Pour l’Audition, which supported the project from its beginning. It embodies our high-level scientific and medical actions and positions France as a key player in this field at an international level. It also embraces our strong ambition to speed up the development of therapies for individuals with hearing disorders.”

Nawal Ouzren, Chief Executive Officer of Sensorion, said: “The launch of the Audiogene clinical trial is a significant milestone in the development program of SENS-501, a pioneering drug candidate in the field of gene therapies for genetic hearing loss. We are delighted to be continuing our collaboration with the team at the Fondation Pour l’Audition, the research teams at the Hearing Institute and the clinical team at the Pediatric Audiology Research Center at Necker-Enfants Malades Hospital (AP-HP), as part of the AUDINNOVE consortium. This consortium, composed of leading stakeholders, is currently one of the few players worldwide capable of bringing about a technological and medical revolution that offers real hope for all children with congenital hearing loss.”

Natalie Loundon, Director of the Pediatric Audiology Research Center and a Pediatric Otolaryngologist and Head and Neck Surgeon at Necker-Enfants Malades Hospital (AP-HP), who is the Audiogene clinical trial coordinator investigator, comments: “This project is incredibly innovative and represents a first in the field, raising high hopes for patients with hearing loss. The project heralds the advent of a revolution in the future treatment of hearing loss patients. For this study, DFNB9 patients will be offered an alternative to cochlear implantation. We are already working on widening the indications to include other causes of hearing loss.”

Christine Petit, Professor at the Institut Pasteur and Professor Emeritus at the Collège de France, added: “This clinical trial, which aims to correct the deficiency in a gene responsible for congenital hearing loss to restore hearing, is based on the pioneering research carried out at the Institut Pasteur in our Genetics and Physiology of Hearing Unit, which involved identifying the genes responsible, elucidating the defective mechanisms and demonstrating the possible reversal of hearing loss in the laboratory. We have been performing research on DFNB9 deafness for around 20 years now. Audiogene assembles a wide range of expertise so that these discoveries can be applied for the benefit of people with hearing loss. There is currently no treatment for hearing loss. The success of this clinical trial should serve as a catalyst in the search for much-needed therapeutic solutions for a whole series of hearing impairments and vestibular disorders.”

Anne-Lise Giraud, Director of the Hearing Institute, an Institut Pasteur center, concluded: “The Hearing Institute is delighted with this major first, to which its teams, especially those led by Christine Petit and Saaid Safieddine, have made a huge contribution by paving the way for the translation of basic research into therapeutic applications.”

Multiple technological innovations

A gene can only enter inner ear cells if it is transported by a viral vector that is capable of crossing the cell membrane. In this case the adeno-associated virus (AAV) is used to deliver the gene. As the OTOF gene is so big, it is divided into two DNA fragments, each transported by an AAV, which are then assembled inside the inner ear cells. This is referred to as a dual AAV vector technology. AAV vectors are harmless and non-pathogenic; they are reliable, well known and do not cause diseases. They are produced using the highest applicable industry standards and approved by health authorities for use in humans. Some are already in use and have been marketed as treatments.

This work was supported by the French National Research Agency which is funding the France 2030 program entitled RHU AUDINNOVE, ANR-18-RHUS-0007.

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February 5, 2024
Has a decade of maternal pertussis vaccination reduced its effectiveness?
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In a recent modeling and meta-analysis study published in the journal Nature Communications, researchers evaluated if maternal immunization against pertussis, a highly contagious bacterial respiratory infection, experienced reduced efficacy (‘blunting’) due to prolonged use. They reviewed four studies with up to six years of follow-up and designed a novel mathematical model to evaluate immunization’s short- and long-term effects on disease transmission dynamics. While incapable of ruling out minor reductions in vaccine effectiveness (VE), their findings highlight that maternal immunizations are (and will continue to be) essential in preventing pertussis transmission and, more importantly, saving the lives of unvaccinated newborns.

Study: Maternal pertussis immunization and the blunting of routine vaccine effectiveness: a meta-analysis and modeling study. Image Credit: Kateryna Kon / Shutterstock

Pertussis and the results of global immunization efforts

Pertussis, colloquially called ‘whooping cough,’ is a highly contagious respiratory illness caused by the bacteria Bordetella pertussis. Its symptoms included chronic or severe cough, general fatigue and fever, nausea, and difficulty breathing. It is characterized by its severe hacking cough from which the name “whooping” is obtained. Pertussis infections are most severe in children, especially newborns, and were a significant cause of childhood mortality before the 1940s.

Thankfully, pertussis is easily preventable via vaccines. Global large-scale immunization efforts in the 1940s reduced transmission rates by 90% in most countries. Unfortunately, for reasons hitherto unknown, pertussis has been staging a comeback over the past two decades. This has prompted a resurgence into pertussis-centric research aimed at evaluating the mechanisms underpinning rising transmission rates.

Infants, especially newborns, are the cohort most vulnerable to the disease, given their suboptimal immune development and lack of immunization. To counter this, numerous nations (since 2012) and the World Health Organization (since 2015) have recommended and initiated maternal immunization programs. Vaccinating women during the gestation period has been clinically revealed to transfer its protective effects to their unborn infants, resulting in an estimated 70% reduction in newborn mortality.

“However, the downstream consequences of maternal immunization, when infants receive their routine pertussis vaccines, are poorly understood. Specifically, there has been long-standing concern regarding potential immunological blunting, i.e., the interference of maternally transferred antibodies with the infant immune response.”

Understanding if current vaccination protocols are resulting in immunization blunting, and if so, to what extent, will allow for the revision of present immunization policies and may require an overhaul of the vaccines used or the process itself.

About the study

In the present study, researchers conducted a meta-analysis to investigate if prolonged (2012 to 2023) maternal immunization has reduced vaccine effectiveness (VE). The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Data collection was initiated by collating relevant publications from three online databases (PubMed, Web of Science, and Scopus) from database initiation till August 25, 2023. This search revealed 374 articles across databases, 146 of which were duplicate records. Of the 228 remaining publications, abstract screening revealed 69 potential articles, which full-text screening further narrowed down to the final sample set – four.

“To be included in our review, studies had to provide an estimate of the relative risk (RR) of pertussis in infants having received at least one dose of their primary immunization from vaccinated vs. unvaccinated mothers. We selected only those studies that used laboratory-confirmed diagnosis of pertussis.”

Each of the four included studies reported at least five pertussis relative risk estimates in comparing vaccinated and unvaccinated mothers. Study analyses were carried out using two steps – Firstly, to account for different metrics used in the included studies, standard relative risks were calculated and applied to each included metric. Secondly, the meta-analyses were carried out. The meta-regression used herein was corrected to account for ‘population’ as a random intercept.

Finally, researchers devised a novel mathematical model based on the Susceptible-Exposed-Infected-Recovery (SEIR) model, explicitly testing for VE accounting for immunization blunting. The model had two outcome measures – 1. failure in “take” (if the primary vaccine failed), and 2. failure in duration (loss or reduction of vaccine protection). The model works in a hierarchical compartmentalization framework comprising three levels, each with their own ‘paths.’

Level 1: “These three possible paths or compartments start from their mother’s immunization status during pregnancy, followed by an infant immunization schedule that resembles that of the empirical studies.” Level 2: “…newborns can be born in three possible compartments: from vaccinated mothers whose immunization succeeded, mothers whose immunization failed (i.e., who received the vaccine but whose infant remained unprotected), or unvaccinated mothers.” Level 3: “Each of the three compartments is followed by a compartment for successful primary infant immunization and a compartment for failed primary infant immunization, thereby becoming susceptible, or no immunization thereby also becoming susceptible.”

Study findings

Exploring the historical landscape of VE in infant pertussis via the novel model revealed that infant (maternal) immunization substantially decreased disease incidence. However, consistent with global reports, this was followed by a gradual rebound in pertussis persistence. This is consistent with the previously described “end-of-honeymoon” effect and is expected in most diseases managed using imperfect yet highly efficient vaccines. These results validate model reliability.

Analyzing the sample dataset using this model revealed that the first vaccine dose in infants following maternal immunization is highly effective against pertussis contraction, but the second and third doses are much more uncertain, consistent with previous uncertainty regarding blunting effects. The model demonstrated the presence of a decade-long lag phase following the introduction of maternal immunization, during which time blunting effects are liable to be underestimated in trial studies.

Encouragingly, quantifying the blunting effects suggests that they are minor and pale compared to the infant mortality-saving that maternal immunization provides. These findings support the public health decisions of many countries (55 as of 2021) to continue maternal immunization efforts and recommend that other nations follow suit.

Conclusions

The present study conducted a meta-regression analysis of four epidemiological publications to investigate the potential blunting effect of decade-long maternal immunization efforts. They further devised and implemented a mathematical model to interpret pertussis relative risk while explicitly accounting for vaccine efficacy blunting.

Their findings reveal the presence of a transient decade-long lag phase following maternal immunization, characterized by the masking and underestimation of blunting effects, thereby explaining previous inconsistencies in the literature. More importantly, the study highlights that while moderate levels of VE loss via blunting do exist, they are far outweighed by the infant mortality savings that maternal vaccination provides.
Journal reference:

Briga, M., Goult, E., Brett, T. S., & Rohani, P. (2024). Maternal pertussis immunization and the blunting of routine vaccine effectiveness: A meta-analysis and modeling study. Nature Communications, 15(1), 1-11., DOI – 10.1038/s41467-024-44943-7, https://www.nature.com/articles/s41467-024-44943-7
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February 4, 2024
Global study finds one child may be the new norm

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In a recent study published in the journal Proceedings of the National Academy of Sciences, researchers conceptualized empirical measurements for family ideals comprising ten family characteristics, a significant increase from previous studies’ evaluation of just one characteristic. Against the backdrop of the worst low-fertility period in modern history, they recruited participants from eight low-fertility nations. They conducted a factorial survey experiment (FSE) to evaluate what the ideal family means to people from different cultural contexts and institutional settings.

Their findings revealed both expected and surprising results. As expected, childlessness is a shared concern across nations and is often looked upon in poor light. However, the common notion that multiple children are preferable over a single child, with two being the ideal, was found to be a misconception. This study highlights that while a few country- and culture-specific characteristics differ across nations, most family ideals across industrialized countries remain uniform.

Study: Family ideals in an era of low fertility. Image Credit: IndianFaces / Shutterstock

The changing concept of the ideal family in a modernized world

Families are the fundamental unit of social organization, but the concept of family may mean substantially different things to different respondents. A multitude of reasons unpin this observation – culture, society, religion, and media influences all shape the holistic interpretation of the ideal family. This is evident in the world around us – today’s family landscape radically differs from that of our great-grandparents’ generation. While intergenerational differences in opinion are expected, the magnitude of recent demographic transitions is arguably unprecedented.

Titled ‘The Second Demographic Transition (SDT)’, Van de Kaa and Lesthaeghe’s interpretation of Inglehart’s ideas hypothesize that value systems have fundamentally shifted, which, in tandem with the relatively novel focus on self-realization, have made traditional family structures in modern society rare. Examples of this include the growing popularity of single-person households and cohabitation, divorce, and re-partnering, and the ever-increasing prevalence of children raised by single parents and nonmarried couples.

Alarmingly, one of the observable outcomes of these shifts is a rapid increase in low fertility rates, especially across industrialized nations. Understanding the role of family values and ideals on fertility rates in these changing times presents the first step to stabilizing the global fertility crisis and the focus of current research. While previous studies have explored the concept of family ideals, they suffer from one common demerit – dimensionality.

The concept of an ideal family is a multidimensional one, incorporating different characteristics (e.g., the ideal number of children, family versus career obligations, and the division of domestic work) with different relative contributions to the observable trend (low fertility rate). Unfortunately, most research in the field has focused on the ideal number of children (the fertility ideal), a single dimension. Despite this research establishing two children as the global ideal, it is plagued by numerous potentially biasing traits and may be less accurate than believed.

“…traditional survey questions force respondents to state a single ideal number of children (e.g., one or two or three children), thus masking potential variation in the strength of such preferences… because fertility ideals or preferences are not asked in direct relation to other dimensions of family life, the importance of fertility cannot be established relative to a host of other relevant family dimensions, including the division of labor within the family, career aspirations, financial resources, and the possibility of extended family support.”

About the study

In the first comprehensive examination of the multidimensional family characteristics across diverse national backgrounds, researchers reviewed classical theories of family behavior to conceptualize and empirically measure ten characteristics of the ideal family. The online factorial survey experiment (FSE) comprised 20,141 participants from urban areas of China, South Korea, Japan, Singapore, Italy, the United States (US), Norway, and Spain.

The survey was conducted between December 2021 and February 2022. Data collection comprised of participants’ demographic data and the completed FSE-based questionnaire. Collected age 925 TO 39; 40 TO 50) and gender (male or female) data were used to stratify the pooled national populations into four cohorts per nation. Participants were further categorized based on the presence of at least one child. Each cohort was subjected to a separately analyzed questionnaire with questions modified to reflect the presence (or absence) of children.

FSE provides at least three advantages over traditional study approaches – “First, the experimental design ensures that respondents’ characteristics are independent of the dimensions of the vignette they are asked to evaluate. Second, respondents in FSE studies are asked to evaluate vignettes that vary along multiple dimensions. This has the advantage of allowing us to test various combinations, including some which occur only rarely in reality Third, the multidimensionality of the FSE reduces concerns about respondents providing socially desirable answers because the variations across vignettes make it relatively more difficult to identify the purpose of the study”

The contents of the questionnaire involved participants’ numerically scaled responses to the question, “How well does this describe an ideal family?” for a vignette made by randomly combining different levels of the conceptualized characteristics. These characteristics consist of union status, household income (relative to the national mean), number of children, level of respect received by the family within the community, gender roles, work-family conflict, communication (nuclear and extended family communication, measured separately), savings for the child(ren)’s support, and child(ren)’s desired education attainment level.

“Among the 1,440 (864 + 576) unique vignettes, 240 (144 + 96) decks (i.e., questionnaire versions) were constructed with each containing six randomly selected vignettes. Pooling across eight countries, each vignette was rated by 84.23 (SD = 5.11) respondents. For each country, each vignette was rated by 11.83 (SD = 3.03) respondents, which exceeds the common suggestion of 5 in the literature and thus ensures the robustness of the result.”

Statistical analysis was hierarchically structured to account for the multidimensional structuring of vignettes and nationalities. Dependant variables were treated as continuous, and a multilevel linear regression model was used to compute and interpret results.

Study findings and conclusions

The present study reveals that consistent with previous work, parenthood remains one of the most valued family attributes. However, contrasting previous literature, analyses found that, following the birth of the first child, the number of additional children was inconsequential to study participants. The study highlights that parents may prefer one child over the ‘ideal’ of having two, especially when resources are scarce. Cross-referencing these findings against population-trends data from countries like Norway validates their accuracy, with the fertility rate substantially lower than the expected two-child-ideal rate.

Country contexts were revealed to matter for some dimensions, such as household income – while low-income families received a low rating irrespective of respondent nationality, the high-income families were not given a high rating in Italy, Spain, and Norway, potentially due to the high level of welfare support received in these countries. In contrast, most characteristics and their corresponding scores were indistinguishable across national cohorts, suggesting that education and urbanization play strong roles in formulating ideals about family compared to region and cultural background.

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February 4, 2024
CRISPR-Cas9 gene-editing tool repairs defective T cells to treat rare hereditary disease

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Some hereditary genetic defects cause an exaggerated immune response that can be fatal. Using the CRISPR-Cas9 gene-editing tool, such defects can be corrected, thus normalizing the immune response, as researchers led by Klaus Rajewsky from the Max Delbrück Center now report in “Science Immunology.”

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of the immune system that usually occurs in infants and young children under the age of 18 months. The condition is severe and has a high mortality rate. It is caused by various gene mutations that prevent cytotoxic T cells from functioning normally. These are a group of immune cells that kill virus-infected cells or otherwise altered cells. If a child with FHL contracts a virus – such as the Epstein-Barr virus (EBV), but also other viruses – the cytotoxic T cells cannot eliminate the infected cells. Instead, the immune response gets out of control. This leads to a cytokine storm and an excessive inflammatory reaction that affects the entire organism.

“Doctors treat FHL with a combination of chemotherapy, immunosuppression and bone marrow transplantation, but many children still die of the disease,” says Professor Klaus Rajewsky, who heads the Immune Regulation and Cancer Lab at the Max Delbrück Center. He and his team have therefore developed a new therapeutic strategy. Using the CRISPR-Cas9 gene-editing tool, the researchers succeeded in repairing defective T cells from mice and from two critically ill infants. The repaired cytotoxic T cells then functioned normally, with the mice recovering from hemophagocytic lymphohistiocytosis. Rajewsky and his team have now published their findings in the journal “Science Immunology.”

Gene repair strategy works in mice

The starting point for the study were mice in which the team could mimic EBV infections. In these animals, the researchers altered a gene called perforin so that its function was completely lost or severely compromised – a common genetic defect in patients with FHL. When they then elicited a condition resembling an EBV infection, the affected B cells multiplied uncontrollably because the defective cytotoxic T cells were unable to eliminate them. As a result, the immune response went into overdrive and the mice developed hemophagocytic lymphohistiocytosis.

The team next collected T memory stem cells – that is, long-lived T cells from which active cytotoxic T cells can mature – from the blood of the mice. The researchers used the CRISPR-Cas9 gene-editing tool to repair the defective perforin gene in the memory T cells and then injected the corrected cells back into the mice. The immune response in the animals quieted down and their symptoms disappeared.

How long protection lasts is uncertain

The first author of the paper, Dr Xun Li, used blood samples from two sick infants to test whether the strategy also works in humans. One had a defective perforin gene, the other a different defective gene.

Our gene repair technique is more precise than previous methods, and the T cells are virtually unchanged after undergoing gene editing. It was also fascinating to see how effectively the memory T cells could be multiplied and repaired from even a small amount of blood.”

Dr Xun Li, First Author

Cell culture experiments showed that the infants’ repaired T memory cells were capable of a normal cytotoxic T cell response.

This means the therapeutic mechanism works in principle. But before patients can benefit from this discovery, the team needs to first resolve open questions and test the treatment concept in clinical trials. “It is still uncertain how long the protective effect lasts,” says Dr Christine Kocks, a scientist in Rajewsky’s team. “Since the T memory stem cells remain in the body for a long time, we hope the therapy provides long-term or even permanent protection. It is also conceivable that patients could be treated with their repaired T cells over and over again.”

The procedure is minimally invasive since only a small amount of blood is needed, and the mice did not require any preparatory treatment – unlike, for example, with a bone marrow transplant. “We very much hope that our mechanism of action is a breakthrough in treating FHL,” says Rajewsky, “either to gain more time for a successful bone marrow transplant or even as a treatment itself.”

Source:

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Journal reference:

Li, X., et al. (2024) Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis. Science Immunology. doi.org/10.1126/sciimmunol.adi0042.

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February 3, 2024
Study says parents may overshoot fluoride toothpaste dose for toddlers, risking dental fluorosis
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In a recent study published in the journal BDJ Open, researchers in Canada and Germany tested the doses of fluoride toothpaste that parents gave to children up to two years old. Their results indicate that many parents may give their children significantly more toothpaste than optimal and should adopt fluoride-free alternatives to avoid fluoride consumption.

Image Credit: Inna Reznik / Shutterstock

Background

While good oral hygiene during childhood is critical to prevent dental caries and other oral diseases, the fluoride present in toothpaste has raised toxicological concerns about its safety for infants and toddlers.

Studies have also observed that despite fluorides being used frequently around the world, dental caries continue to be prevalent, with global estimates suggesting that they affect nearly half of all children.

Fluoride may cause chronic toxicity and other adverse long-term effects. For this reason, guidelines in different parts of the world suggest limiting the dose of fluoride for young children to a small smear or the size of a single grain of rice (up to 24 months of age) or a pea (for children under six).

However, young children may swallow 64-100% of their toothpaste, putting them at risk of dental fluorosis since they are being systematically exposed to fluoride. Therefore, it is crucial to collect more information on how much toothpaste their parents are giving them.

About the study

In this study, researchers hypothesized that parents would find it challenging to follow guidelines recommending giving children aged up to two years one grain’s rice worth of toothpaste. They tested this hypothesis by testing the real-life doses of toothpaste given by parents to their children.

The study was undertaken across five daycare centers in Germany, where parents were given two commercially available brands of toothpaste containing 1,000 ppm of fluoride and suitable for children and asked to dose them as they usually did at home.

Photograph of the reference doses (i.e., a grain of rice-size amount of toothpaste as recommended for toothpastes for children aged up to 24 months with 1000 ppm fluoride) of toothpaste A (left) and toothpaste B (right) on children’s toothbrushes. A natural grain of rice was used as model. Both amounts were dosed by an experienced dentist.

To be included in the study, they needed to use fluoride toothpaste for children at home regularly. Parents of children older than two years were asked to provide a dose based on what they did before the child’s second birthday. This was considered to be representative of how much they would give their children at home.

The weight of each dose was determined and compared with the ‘optimal’ recommendation of one grain. Parents were also asked to state how frequently their child’s teeth were brushed every day to calculate fluoride exposure, as well as their knowledge of the optimal doses.

Findings

The children were, on average, 24 months old at the time of the study, and 61 parents met the inclusion criteria. More than 60% of parents said that their children brushed twice daily, while about 23% said they brushed thrice daily.

The average value of a reference dose of fluoride was 0.039-0.045g; however, parents dosed their children with 0.263-0.281g of fluoride on average. The overdose factor was between 5.6 and 8.2.

More than 60% of parents did not know about fluoride health warnings or conditions for its use. Nearly 15% used fluoride tablets in addition to fluoride toothpaste for their child.

Conclusions

These findings show that children may be receiving overdoses of fluoride from their parents. The authors noted that they may be underestimating children’s exposure to the substance, as fluoride is also present in foods such as rice, cow milk, and bananas, as well as drinking water and sometimes salt.

However, even fluoride intake through toothpaste exceeded what is considered to be an upper limit to avoid dental fluorosis. Further research should undertake a comprehensive risk assessment, including other sources of fluorides, and also consider the possibility of neurotoxicity as an outcome. It should also take socioeconomic factors into account.

One of the reasons for large dose sizes could be that television commercials often showcase excess amounts of toothpaste on brushes. For example, previous studies had shown that most advertisements depicted a large swirl of paste that covered the entire head of the brush, far exceeding the recommended dose. The flavor of toothpaste may also be palatable to children, leading them to ingest more.

Since dispensing a rice grain’s worth of fluoride may be challenging for parents, the researchers suggest using fluoride-free toothpaste varieties, including some other anti-caries substances.

These could include calcium sodium phosphosilicate or hydroxyapatite, of which the latter has been clinically shown to be protective against caries. It is safe for infants and toddlers if swallowed and can reduce bacterial colonization on the surface of teeth. Encouraging parents to replace fluoride toothpaste with efficient and safe alternatives can promote oral care in young children – and keep them safe from fluorosis.
Journal reference:

Doses of fluoride toothpaste for children up to 24 months. Sudradjat, H., Meyer, F., Fandrich, P., Schulze sur Wiesche, E., Limeback, H., Enax, J. BDJ Open (2024). DOI: 10.1038/s41405-024-00187-7, https://www.nature.com/articles/s41405-024-00187-7
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February 2, 2024
US Congress grilled Big Tech leaders on child online safety

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Tech executives at a congressional hearing, including: Shou Chew at TikTok, Linda Yaccarino at X and Mark Zuckerberg at Meta

UPI / Alamy Stock Photo

Families confronted Meta CEO Mark Zuckerberg with pictures of their dead children, prompting an apology from the executive during a hearing in front of the US Congress on 31 January. The children had been sexually exploited or otherwise harmed through social media prior to their deaths.

“You have blood on your hands,” said Senator Lindsay Graham to executives from TikTok, Snap, Discord, Meta and X (formerly Twitter), who were being questioned…

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January 31, 2024
High diet quality in early life associated with reduced risk of IBD

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A high quality diet at the age of 1 may curb the subsequent risk of inflammatory bowel disease, suggests a large long term study, published online in the journal Gut.

Plenty of fish and vegetables and minimal consumption of sugar-sweetened drinks at this age may be key to protection, the findings indicate.

A linked editorial suggests that it may now be time for doctors to recommend a ‘preventive’ diet for infants, given the mounting evidence indicative of biological plausibility.

Cases of inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, are increasing globally. Although there is no obvious explanation for this trend, changes in dietary patterns are thought to have a contributory role, because of their impact on the gut microbiome.

While various studies have looked at the influence of diet on IBD risk in adults, there is little in the way of research on the potential influence of early childhood diet on risk.

In a bid to plug this knowledge gap, the researchers drew on survey data from the All Babies in Southeast Sweden study (ABIS) and The Norwegian Mother, Father and Child Cohort Study (MoBa).

ABIS includes 21,700 children born between October 1997 and October 1999; MoBa includes 114, 500 children, 95,200 mothers, and 75,200 fathers recruited from across Norway between 1999 and 2008.

Parents were asked specific questions about their children’s diet when they were aged 12-18 months and 30-36 months. The final analysis included dietary information for 81,280 1 year olds: 11,013 (48% girls) from ABIS and 70, 267 (49% girls) from MoBa.

Diet quality, gleaned from measuring intake of meat, fish, fruit, vegetables, dairy, sweets, snacks, and drinks, was assessed using a modified version of the Healthy Eating Index (HEI) scoring system, adapted for children. The weekly frequency of specific food groups was also assessed.

Higher diet quality-;a higher intake of vegetables, fruit, and fish, and a lower intake of meat, sweets, snacks, and drinks-;was reflected in a higher HEI score.The total score was divided into thirds to indicate a low, medium, or high quality diet.

Data on age at weaning, antibiotic use, and formula feed intake were also reported at age 12 (ABIS) and 18 months (MoBa).

The children’s health was monitored for an average of 21 (ABIS) and 15 (MoBa) years from the age of 1 until 31 December 2020-21.

During this period, 307 children were diagnosed with IBD (131 with Crohn’s disease; 97 with ulcerative colitis; and 79 with unclassified IBD). The average age at diagnosis was 17 (ABIS) and 12 (MoB).

Medium and high quality diets at the age of 1 were associated with an overall 25% lower risk of IBD compared with a low quality diet at this age, after adjusting for potentially influential factors, such as parental history of IBD, the child’s sex, ethnic origin, and education and co-existing conditions in the mother.

Specifically, high fish intake at the age of 1 was associated with a lower overall risk compared with its opposite, and a 54% lower risk of ulcerative colitis in particular.

Higher vegetable intake at 1 year of age was also associated with a reduced risk of IBD. On the other hand, consumption of sugar-sweetened drinks was associated with a 42% heightened risk.

There were no obvious associations between any of the other food groups, including meat, dairy, fruit, grains, potatoes and foods high in sugar and/or fat, and overall IBD or Crohn’s disease or ulcerative colitis risks.

By the age of 3, only high fish intake was associated with reduced IBD risk, and ulcerative colitis in particular.

The findings remained unchanged after accounting for household income and the child’s formula intake and antibiotic use by the age of 1.

This is an observational study, and as such, can’t establish cause. And the researchers acknowledge that while the ABIS participation rate was high (79%), it was only 41% for MoBa. And because Sweden and Norway are two high-income countries, findings may not be generalisable to low- or middle-income countries with other dietary habits, they add.

“While non-causal explanations for our results cannot be ruled out, these novel findings are consistent with the hypothesis that early-life diet, possibly mediated through changes in the gut microbiome, may affect the risk of developing IBD,” they conclude.

In a linked editorial, gastroenterologist Dr Ashwin Ananthakrishnan of Massachusetts General Hospital, Boston, USA, cautions that the questionnaires didn’t capture elements, such as additives and emulsifiers which are common in baby food, and which may contribute to the development of IBD.

Accurate measures of food intake in infants and young children are inherently fraught with difficulty, he adds.

But he goes on to say that it may nevertheless be time to recommend a ‘preventive’ diet, particularly as this is likely to have other health benefits.

“Despite the absence of gold standard interventional data demonstrating a benefit of dietary interventions in preventing disease, in my opinion, it may still be reasonable to suggest such interventions to motivated individuals that incorporate several of the dietary patterns associated with lower risk of IBD from this and other studies.

“This includes ensuring adequate dietary fiber, particularly from fruit and vegetables, intake of fish, minimizing sugar-sweetened beverages and preferring fresh over processed and ultra-processed foods and snacks.”

Source:

Journal reference:

Guo, A., et al. (2024). Early-life diet and risk of inflammatory bowel disease: a pooled study in two Scandinavian birth cohorts. Gut. doi.org/10.1136/gutjnl-2023-330971.

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January 31, 2024
Medical clowns boost sleep quality and reduce hospital stay for children, study finds

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In a recent study published in Scientific Reports, a group of researchers evaluated the impact of medical clown interventions on sleep quality and hospital stay duration in pediatric patients.

Study: Medical clowns improve sleep and shorten hospitalization duration in hospitalized children. Image Credit: AnnaStills/Shutterstock.com

Background

Sleep is crucial for recovery, yet hospital environments often disrupt it, particularly affecting pediatric patients. Hospitalized children experience late bedtimes, frequent awakenings, and reduced sleep time, intensifying their anxiety and discomfort.

Medical clowns, a non-pharmacologic intervention, have demonstrated potential in reducing stress and anxiety, enhancing overall well-being and cooperation in pediatric care, yet further research is essential to conclusively establish their effectiveness in improving sleep quality and overall recovery outcomes in hospitalized children.

About the study

This single-center, prospective observational study, conducted at The Lady Davis Carmel Medical Center in Israel from July 2019 to January 2022, involved pediatric patients aged 2-18 years, predicted to stay for at least two nights. Patients were recruited based on admission order and matched 1:1 for age and clinical condition with controls. Exclusions included children under 2 or over 18, those with sleep disorders, on sleep-altering medication, chronic conditions, a fear of clowns, or expected one-day hospitalizations. Participants were excluded if discharged or transferred within one night or if they removed the Actigraph sleep-monitoring device prematurely.

The study group received standard medical care and a session with a medical clown at bedtime, using relaxation techniques like music or guided imagination for 15–30 minutes. The control group, matched by medical condition, age, and if possible, gender, received standard care without clown intervention. Both groups wore Actigraph devices to measure sleep and were accompanied by a primary caregiver who completed a three-part questionnaire about the child’s sleep at home, during hospitalization, and, for the clown group, the perceived effect of the clown on sleep.

Data from Actigraph devices were compared with parents’ questionnaires, and each study participant’s data was compared with their control group counterparts. An independent unpaired two-tailed t-test was used for statistical analysis, with a paired t-test for within-group comparisons across two hospital days. A p-value of less than 0.05 indicated statistical significance. Ethical approval was granted by the Carmel Medical Center IRB, with informed consent obtained from all participant caregivers.

Study results

In the present study, 57 children were initially recruited, but 15 were dropped for not completing the required two-night protocol, leaving 42 participants divided into a clown group (n = 21) and a control group (n = 21). Children were matched by age and clinical characteristics, averaging around 10.8 years, with a nearly equal gender distribution. Medical conditions varied, including acute appendicitis and abdominal pain, among others.

The sleep habits of both groups were initially similar. However, the study revealed significant differences in sleep patterns post-intervention. The clown group, exposed to a medical clown intervention before bedtime, showed a delayed wake-up time by approximately 27 minutes compared to the control group. This group also experienced longer time in bed and total sleep time as assessed by both objective measures and parental estimates.

Interestingly, the total wake time during the night was slightly shorter in the clown group. The mean sleeping period was longer in the clown group by 72 minutes, though this did not reach statistical significance. Sleep efficiency was marginally higher in the clown group. The mean number of awakenings during the night was lower in the clown group, but this also did not reach statistical significance.

A notable finding was within the clown group itself. When comparing the two nights for each child in this group, the night following the clown intervention showed a significant increase in total sleep time by 54 minutes, reduced total wake time, and improved sleep efficiency by 4.3%. These changes were mainly attributed to a reduction in the wake period after sleep onset.

Beyond sleep parameters, the study also observed general characteristics of the children’s hospital stay. A remarkable outcome was that the length of hospitalization was significantly shorter in the clown group compared to the control group, with an average reduction of nearly a full day.

Conclusions

The study found significant improvements in sleep parameters for the clown group, including later wake-up times, reduced wakefulness during the night, and increased sleep efficiency. This improvement was particularly notable when comparing nights with and without the clown intervention within the same group. Moreover, the study discovered a substantial reduction in hospital stay duration for children who interacted with the clowns. These findings suggest that medical clowns not only improve sleep quality but also potentially expedite overall recovery.

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January 31, 2024
Maternal happiness during pregnancy linked to child’s brain development
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In a recent study published in the journal Nature Mental Health, researchers explored the relationship between maternal mental health and children’s brain development. Their results contribute to the medical understanding of the importance of the intrauterine environment and suggest that in addition to positive outcomes for the mother, emotional well-being during pregnancy can be an important protective factor for brain development in children.

Study: Maternal positive mental health during pregnancy impacts the hippocampus and functional brain networks in children. Image Credit: Prostock-studio / Shutterstock

Background

Research suggests that depression, anxiety, and stress during pregnancy can have enduring adverse effects on the child’s brain development. Maternal anxiety and depression have been found to affect gray matter density in the medial temporal and prefrontal cortex as well as hippocampal growth.

Maternal health factors can also modify the cortico-limbic system, which helps regulate stress responses and emotional states. These widespread effects have been observed to be more prominent in female children between birth and early childhood. These findings highlight the need to address prenatal mental health to promote brain development in children.

However, emotional well-being is not merely the absence of mental illness but also includes the experience of positive emotions and mental affect. While the effect of positive maternal emotions on parenting behavior, mother-infant bonding, long-term mental health, and child development has been studied, its impacts on brain development have not been explored.

About the study

The study followed a longitudinal prospective birth cohort design to investigate the relationship between maternal well-being and brain development in 7.5-year-old children using magnetic resonance imaging (MRI). This age was chosen because it is a key neurodevelopmental period when significant cognitive processes and brain changes occur.

Participants in the study included pregnant Asian (Malay, Indian, or Chinese) women in their first trimester who were recruited while they antenatal care at an ultrasound scan clinic in Singapore. For the MRI, children were included if they had a gestational age of more than 30 weeks and a birth weight of more than 2 kg to avoid the confounding effects of birth complications.

The authors hypothesized that positive emotions during pregnancy would be associated with significant differences in brain structures, such as the amygdala and hippocampus as well as functional networks, such as the default mode and visual networks. The mental health of the mothers was assessed using the Beck Depression Inventory, the Edinburgh Postnatal Depression Scale, and the State-Trait Anxiety Inventory.

Additionally, the survey included questions on socioeconomic status, relationships with friends and family, life stress, and other topics related to prenatal health and well-being. This information was used to construct an overall socio-environmental adversity factor and scores for four risk domains – personal, interpersonal, socioeconomic, and life stress.

Findings

The sample of participants who underwent the structural MRI included 381 children, of whom 369 also underwent the functional MRI procedure. After controlling for the overall socio-environmental adversity factor and the child’s age during the MRI, researchers found that more positive maternal emotions during the prenatal period were associated with a larger bilateral hippocampal volume in female children but not males. However, maternal positive emotions were not seen to be associated with cortical thickness or volumes of the thalamus, amygdala, lateral ventricles, or basal ganglia.

In terms of functional networks, more maternal positive emotions were associated with higher functional connectivity between the right frontoparietal and visual association networks, salience and thalamo-hippocampal networks, and posterior default mode and attention networks. Notably, these results were significant after controlling for child sex and age as well as postnatal parenting stress and other risk factors. These outcomes were not, however, associated with anxiety or depressive symptoms during pregnancy.

Conclusions

These findings indicate that there may be a neural basis through which positive emotions during pregnancy are transmitted from the mother to her offspring during the early development of the brain. Of the significantly associated outcomes, only the change in the bilateral hippocampi differed between male and female children. This research implies that ensuring mothers’ mental health could lead to sustained benefits for offspring in terms of neural development.

While the study has several strengths and offers novel insights, the authors acknowledged some limitations. While brain development was assessed through neuroimaging, data on maternal mood and well-being were collected through subjective reports and may, therefore, be subject to biases related to recall and social desirability. Self-reports of positive emotions may not be an adequate proxy for psychological well-being, a complex and multifaceted issue. The study participants were all Asian, leading to a lack of generalizability to other populations.

Future studies can build on these findings by including individuals of other races and factoring in positive emotions during other stages (such as during the postnatal period). This work adds to a growing body of literature showing the transgenerational nature of mental health outcomes and the importance of ensuring that mothers and children are not just healthy but happy, too.
Journal reference:

Maternal positive mental health during pregnancy impacts the hippocampus and functional brain networks in children. Qui, A., Shen, C., López-Vicente, M., Szekely, E., Chong, Y., White, T., Wazana, A. Nature Mental Health (2024). DOI: 10.1038/s44220-024-00202-8, https://www.nature.com/articles/s44220-024-00202-8
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January 31, 2024
Premature babies could be treated with an artificial uterus in 2024

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The EXTEND system has kept more than 300 preterm lambs alive

Partridge, E., Davey, M., Hornick, M. et al. (2023)

The groundwork is being laid for the first human trial of an artificial uterus, which could get the go-ahead from the US Food and Drug Administration (FDA) some time in 2024.

Artificial uteruses are designed to mimic the environment of the womb as closely as possible and may help support babies who are born extremely prematurely, at around 23 or 24 weeks’ gestation.

“The idea is to bridge the rough patch when they’re really struggling and carry them through to a point when they can do…

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December 27, 2023