Defining familial longevity and developing a familial longevity score for unbiased epigenetic studies in a birth cohort.

Aim: Longevity accumulating in families has genetic and epigenetic components. To study early and unbiased epigenetic predictors of longevity prospectively, a birth cohort would be ideal. However, the original family longevity selection score (FLoSS) focuses on populations of elderly only.Methods: In the German birth cohort KUNO-Kids we assessed when information for such scores may be best collected and how to calculate an adapted FLoSS.Results: A total of 551 families contributed to adapted FLoSS, with a mean score of -0.15 (SD 2.33). Adapted FLoSS ≥7 as a marker of exceptional longevity occurred in 3.3% of families, comparable to original FLoSS in elderly.Conclusion: An adapted FLoSS from data collectable postnatally may be a feasible tool to study unbiased epigenetic predictors for longevity.

In the German birth cohort KUNO-Kids we assessed if and how a family longevity selection score may best be calculated to study unbiased epigenetic predictors for longevity in the future.

Effect of mothers' health literacy on early childhood allergy prevention behaviours: results from the KUNO-Kids health study.

BACKGROUND: Parents can engage in several behaviours with regard to early childhood allergy prevention (ECAP). These can be related to diet of mother/child and the modification of the home environment; not all of them are justified by current evidence. Previous studies showed that parental health literacy (HL) is related to favourable health behaviours directed at the child. This study aimed to investigate the causal effect of mothers' HL on ECAP behaviours and to test different moderators of this effect. METHODS: One thousand six hundred sixty-two mothers participating in the KUNO-Kids health study in the area of Regensburg, Germany were surveyed on HL (assessed via the health care scale of the Health Literacy Survey-EU questionnaire, HLS-EU-Q47) and ECAP behaviours implemented during pregnancy and the child's first year of life. Patterns in ECAP behaviours were identified by latent class analysis. Multinomial regression modelling was performed with HL as exposure, ECAP as outcome variable, allergy risk, parental competence and bonding, anxiety and depression as moderators as well as potentially confounding variables. RESULTS: We identified three classes of ECAP behaviours (class 1: "breastfeeding " N = 871; class 2: "allergen-avoidance " N = 490; class 3: "mixed behaviours " N = 301). In univariable as well as fully adjusted regression models, compared to class 1, class 2 was negatively, and class 3 was not associated with HL. None of the tested moderating variables altered the association between HL and ECAP significantly. CONCLUSIONS: We found an effect of mothers' HL on ECAP behaviours: lower HL of mothers increased allergen-avoiding behaviour directed at their child, while decreasing the chance of exclusive breastfeeding. Improving HL could contribute to the implementation of recommended ECAP behaviours in families, especially to the reduction of allergen-avoiding behaviours.

Potential risk factors for reduced quality of life and increased health care utilization in ARDS survivors: results from the multicenter cohort study DACAPO.

AIM: To analyze the association of individual pre-ICU risk factors (obesity, physical and mental comorbidity, smoking status) on the long-term recovery process in survivors of the acute respiratory distress syndrome (ARDS; outcomes: health related quality of life, health care utilization; measured at 12, 24, and 36 months after ICU discharge). FINDINGS: Results show a possible causal link between pre-ICU risk factors and subsequent recovery of survivors of ARDS, especially with regard to mental health related quality of life. PURPOSE: Identifying relevant pre-existing risk factors, such as mental health problems, will enable the identification of at-risk patients, thus aiding in the improvement of long-term healthcare for survivors of critical illness.

Deriving acceptable limits for non-mutagenic impurities in medicinal products - Durational adjustments.

ICH Q3A/B guidelines are not intended for application during the clinical research phase of development and durationally adjusted qualification thresholds are not included. A central tenet of ICH Q3A is that lifetime exposure to 1 mg/day of an unqualified non-mutagenic impurity (NMI) is not a safety concern. An analysis of in vivo toxicology data from 4878 unique chemicals with established NO(A)ELs was conducted to determine whether durationally adjusted qualification limits can be supported. Although not recommended in ICH Q3A/B, a conservative approach was taken by using allometric scaling in the analysis. Following allometric scaling of the 5th percentile of the distribution of NO(A)ELs from available chronic toxicology studies, it was reconfirmed that there is a safety basis for the 1 mg/day qualification threshold in ICH Q3A. Additionally, allometric scaling of the 5th percentile of the distribution of NO(A)ELs from sub-acute and sub-chronic toxicology studies could support acceptable limits of 20 and 5 mg/day for an unqualified NMI for dosing durations of less than or greater than one month, respectively. This analysis supports durationally adjusted NMI qualification thresholds for pharmaceuticals that protect patient safety and contribute to 3Rs efforts for qualifying impurities using new approach methods.

Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study.

RATIONALE: Early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. OBJECTIVES: To assess the accuracy of gas chromatography-mass spectrometry based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. METHODS: This study encompassed a discovery (SysPharmPediA) and validation phase (U-BIOPRED, PANDA). Firstly, exhaled VOCs that discriminated asthma control levels were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled, based on asthma control test scores and number of severe attacks in the past year. Additionally, potential of VOCs in predicting two or more future severe asthma attacks in SysPharmPediA was evaluated. MEASUREMENTS AND MAIN RESULTS: Complete data were available for 196 children (SysPharmPediA=100, U-BIOPRED=49, PANDA=47). In SysPharmPediA, after randomly splitting the population into training (n=51) and test sets (n=49), three compounds (acetophenone, ethylbenzene, and styrene) distinguished between uncontrolled and controlled asthmatics. The area under the receiver operating characteristic curve (AUROCC) for training and test sets were respectively: 0.83 (95% CI: 0.65-1.00) and 0.77 (95% CI: 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ±0.06 (UBIOPRED) and 0.68 ±0.05 (PANDA). Attacks prediction tests, resulted in AUROCCs of 0.71 (95% CI 0.51-0.91) and 0.71 (95% CI 0.52-0.90) for training and test sets. CONCLUSIONS: Exhaled metabolites analysis might enable asthma control classification in children. This should stimulate further development of exhaled metabolites-based point-of-care tests in asthma.

Health Literacy in Pediatric Consultations on Allergy Prevention.

BACKGROUND: The first 3 years of life offer an opportunity to prevent allergic diseases. Pediatricians are an important source of health information for parents. However, a certain degree of health literacy is necessary to understand, appraise, and apply preventive behavior, which can be supported by health literacy (HL) sensitive consultations and a HL friendly environment. OBJECTIVE: In this study, we want to shed light on how pediatricians in outpatient care in Germany advise on early childhood allergy prevention (ECAP) and how they consider parental HL. METHODS: We conducted 19 semi-standardized telephone interviews with pediatricians from North-Rhine-Westphalia and Bavaria. The interviews were audio-recorded, transcribed, pseudonymized, and subjected to content analysis. KEY RESULTS: Current ECAP recommendations were well known among our sample. Despite the shift of evidence from avoidance of allergens toward early exposure, providing advice on ECAP was considered non-controversial and it was widely assumed that recommendations were easy to understand and apply for parents. However, ECAP was treated as an implicit topic resonating among others like infant nutrition and hygiene. Regarding HL, our interview partners were not aware of HL as a concept. However, they deemed it necessary to somehow assess parental information level and ability to understand provided information. Formal HL screening was not applied, but implicit strategies based on intuition and experience. Concerning effective HL-sensitive communication techniques, interviewees named the adaptation of language and visual support of explanations. More advanced techniques like Teach Back were considered too time-consuming. Medical assistants were considered important in providing an HL-sensitive environment. Time constraints and the high amount of information were considered major barriers regarding HL-sensitive ECAP counseling. CONCLUSION: It seems warranted to enhance professional education and training for pediatricians in HL and HL-sensitive communication, to reach all parents with HL-sensitive ECAP counseling. [HLRP: Health Literacy Research and Practice. 2024;8(2):e47-e61.].

PLAIN LANGUAGE SUMMARY: We asked pediatricians how they advise parents on prevention of allergy in children. We found that pediatricians were well aware of the recommendations on allergy prevention, but they did not pass on all the information to parents. The HL of parents (that is the ability to find, understand, appraise, and apply health information) was not an important issue for the doctors.

Directed acyclic graph for epidemiological studies in childhood food allergy: Construction, user's guide, and application.

Understanding modifiable prenatal and early life causal determinants of food allergy is important for the prevention of the disease. Randomized clinical trials studying environmental and dietary determinants of food allergy may not always be feasible. Identifying risk/protective factors for early-life food allergy often relies on observational studies, which may be affected by confounding bias. The directed acyclic graph (DAG) is a causal diagram useful to guide causal inference from observational epidemiological research. To date, research on food allergy has made little use of this promising method. We performed a literature review of existing evidence with a systematic search, synthesized 32 known risk/protective factors, and constructed a comprehensive DAG for early-life food allergy development. We present an easy-to-use online tool for researchers to re-construct, amend, and modify the DAG along with a user's guide to minimize confounding bias. We estimated that adjustment strategies in 57% of previous observational studies on modifiable factors of childhood food allergy could be improved if the researchers determined their adjustment sets by DAG. Future researchers who are interested in the causal inference of food allergy development in early life can apply the DAG to identify covariates that should and should not be controlled in observational studies.

M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation.

The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by Fcγ receptors (FcγR) ligand-dependent CD137 activation, respectively. M9657 was engineered as a tetravalent bispecific antibody (mAb2) in a human IgG1 backbone with LALA mutations to reduce binding to FCγRs. Here, we report that M9657 selectively binds to mesothelin (MSLN) and CD137 with similar affinity in humans and cynomolgus monkeys. In a cellular functional assay, M9657 enhanced CD8+ T cell-mediated cytotoxicity and cytokine release in the presence of tumor cells, which was dependent on both MSLN expression and T-cell receptor/CD3 activation. Both FS122m, a murine surrogate with the same protein structure as M9657, and chimeric M9657, a modified M9657 antibody with the Fab portion replaced with an anti-murine MSLN motif, demonstrated in vivo antitumor efficacy against various tumors in wild-type and human CD137 knock-in mice, and this was accompanied by activated CD8+ T-cell infiltration in the tumor microenvironment. The antitumor immunity of M9657 and FS122m depended on MSLN expression density and the mAb2 structure. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.