Core Outcome Set for IgE-mediated food allergy clinical trials and observational studies of interventions: International Delphi consensus study 'COMFA'.

BACKGROUND: IgE-mediated food allergy (FA) is a global health concern with substantial individual and societal implications. While diverse intervention strategies have been researched, inconsistencies in reported outcomes limit evaluations of FA treatments. To streamline evaluations and promote consistent reporting, the Core Outcome Measures for Food Allergy (COMFA) initiative aimed to establish a Core Outcome Set (COS) for FA clinical trials and observational studies of interventions. METHODS: The project involved a review of published clinical trials, trial protocols and qualitative literature. Outcomes found as a result of review were categorized and classified, informing a two-round online-modified Delphi process followed by hybrid consensus meeting to finalize the COS. RESULTS: The literature review, taxonomy mapping and iterative discussions with diverse COMFA group yielded an initial list of 39 outcomes. The iterative online and in-person meetings reduced the list to 13 outcomes for voting in the formal Delphi process. One more outcome was added based on participant suggestions after the first Delphi round. A total of 778 participants from 52 countries participated, with 442 participating in both Delphi rounds. No outcome met a priori criteria for inclusion, and one was excluded as a result of the Delphi. Thirteen outcomes were brought to the hybrid consensus meeting as a result of Delphi and two outcomes, 'allergic symptoms' and 'quality of life' achieved consensus for inclusion as 'core' outcomes. CONCLUSION: In addition to the mandatory reporting of adverse events for FA clinical trials or observational studies of interventions, allergic symptoms and quality of life should be measured as core outcomes. Future work by COMFA will define how best to measure these core outcomes.

Substituting Book Reading for Screen Time Benefits Preschoolers' Sleep Health: Results from the Ulm SPATZ Health Study.

Purpose: Healthy sleep is essential for the physical, cognitive, and social development of children. Several studies have reported the increase in digital media use in preschool children and its association with impaired sleep. However, there is relatively little evidence on the effects of book reading as a potentially safe alternative. The objective of this study, therefore, was to investigate whether sleep in children could benefit from book reading, and whether the negative effects of media use on sleep can be mitigated by substituting book reading for screen time. Participants and Methods: We used longitudinal data from three consecutive waves of the SPATZ Health study, including children at the ages of 4 (n=581), 5 (n=508), and 6 (n=426) years. All data were collected by self-administered questionnaires. Parent-reported child sleep was assessed by the Children's Sleep Habits Questionnaire. Results: Across the three waves, screen-based media use increased and was associated with lower sleep quality. In contrast, the time spent with book reading decreased; however, book reading appeared to be beneficial for children's sleep. Substitution models revealed that the theoretical substitution of an equal amount of book reading for 50% of the time spent with screen-based media benefits several domains of preschoolers' sleep health, including parasomnias, sleep anxiety, daytime sleepiness, and sleep onset delay. Conclusion: Besides implications for population-wide and individual prevention, book reading may also be incorporated as a useful intervention to improve sleep quality in children who are already affected by sleep problems. Given that book reading is perceived as a safe alternative, the presented evidence may suffice to support recommendations in this direction.

RMST-based multiple contrast tests in general factorial designs.

Several methods in survival analysis are based on the proportional hazards assumption. However, this assumption is very restrictive and often not justifiable in practice. Therefore, effect estimands that do not rely on the proportional hazards assumption are highly desirable in practical applications. One popular example for this is the restricted mean survival time (RMST). It is defined as the area under the survival curve up to a prespecified time point and, thus, summarizes the survival curve into a meaningful estimand. For two-sample comparisons based on the RMST, previous research found the inflation of the type I error of the asymptotic test for small samples and, therefore, a two-sample permutation test has already been developed. The first goal of the present paper is to further extend the permutation test for general factorial designs and general contrast hypotheses by considering a Wald-type test statistic and its asymptotic behavior. Additionally, a groupwise bootstrap approach is considered. Moreover, when a global test detects a significant difference by comparing the RMSTs of more than two groups, it is of interest which specific RMST differences cause the result. However, global tests do not provide this information. Therefore, multiple tests for the RMST are developed in a second step to infer several null hypotheses simultaneously. Hereby, the asymptotically exact dependence structure between the local test statistics is incorporated to gain more power. Finally, the small sample performance of the proposed global and multiple testing procedures is analyzed in simulations and illustrated in a real data example.

Core outcome measurement set for research and clinical practice in post-COVID-19 condition (long COVID) in children and young people: an international Delphi consensus study "PC-COS Children".

The coronavirus disease 2019 (COVID-19) pandemic substantially impacted different age groups, with children and young people not exempted. Many have experienced enduring health consequences. Presently, there is no consensus on the health outcomes to assess in children and young people with post-COVID-19 condition. Furthermore, it is unclear which measurement instruments are appropriate for use in research and clinical management of children and young people with post-COVID-19. To address these unmet needs, we conducted a consensus study, aiming to develop a core outcome set (COS) and an associated core outcome measurement set (COMS) for evaluating post-COVID-19 condition in children and young people. Our methodology comprised of two phases. In phase 1 (to create a COS), we performed an extensive literature review and categorisation of outcomes, and prioritised those outcomes in a two-round online modified Delphi process followed by a consensus meeting. In phase 2 (to create the COMS), we performed another modified Delphi consensus process to evaluate measurement instruments for previously defined core outcomes from phase 1, followed by an online consensus workshop to finalise recommendations regarding the most appropriate instruments for each core outcome. In phase 1, 214 participants from 37 countries participated, with 154 (72%) contributing to both Delphi rounds. The subsequent online consensus meeting resulted in a final COS which encompassed seven critical outcomes: fatigue; post-exertion symptoms; work/occupational and study changes; as well as functional changes, symptoms, and conditions relating to cardiovascular, neuro-cognitive, gastrointestinal and physical outcomes. In phase 2, 11 international experts were involved in a modified Delphi process, selecting measurement instruments for a subsequent online consensus workshop where 30 voting participants discussed and independently scored the selected instruments. As a result of this consensus process, four instruments met a priori consensus criteria for inclusion: PedsQL multidimensional fatigue scale for "fatigue"; PedsQL gastrointestinal symptom scales for "gastrointestinal"; PedsQL cognitive functioning scale for "neurocognitive" and EQ-5D for "physical functioning". Despite proposing outcome measurement instruments for the remaining three core outcomes ("cardiovascular", "post-exertional malaise", "work/occupational and study changes"), a consensus was not achieved. Our international, consensus-based initiative presents a robust framework for evaluating post-COVID-19 condition in children and young people in research and clinical practice via a rigorously defined COS and associated COMS. It will aid in the uniform measurement and reporting of relevant health outcomes worldwide.

Event rates and incidence of post-COVID-19 condition in hospitalised SARS-CoV-2 positive children and young people and controls across different pandemic waves: exposure-stratified prospective cohort study in Moscow (StopCOVID).

BACKGROUND: Long-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections. METHODS: A prospective exposure-stratified cohort study of individuals under 18 years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the 'exposed cohorts' and 'reference cohort' was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC. RESULTS: Of 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final 'matched' analysis. The median follow-up time post-discharge was 6.7 months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3-120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9-21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts. CONCLUSIONS: Wuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants.

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.

[Suicides among children, adolescents, and young adults during the COVID-19 pandemic - An analysis of police data from three German federal states]. / Suizide unter Kindern, Jugendlichen und jungen Erwachsenen während der COVID-19-Pandemie ­ Eine Analyse von Polizeidaten aus drei Bundesländern.

OBJECTIVE: The COVID-19 pandemic severely affected young people, resulting in increased psychological distress and rising prevalence rates for mental disorders. There is concern that completed suicides have increased in addition to the observed increase in suicide attempts. METHOD: The study is based on the police crime statistics (01/2017 to 12/2022) of three federal states in Germany, representing 13% of Germany's overall population. Suicide counts and rates for the child, teenage, adolescent, and young adult age groups were compared between the pre-pandemic and pandemic periods using chi-squared tests. RESULTS: 860 people under age 30 died from suicide. Suicide rates did not differ between the pre-pandemic and pandemic periods in any of the age groups studied. CONCLUSION: So far, there has been no discernible increase in suicides among young Germans. Ongoing suicide monitoring is recommended.

Suicide trends in Germany during the COVID-19 pandemic and the war in Ukraine.

AIMS: The later phase of the COVID-19 pandemic overlaps with geopolitical and economic consequences from the Ukraine war. Financial hardship and concerns about gas supply may add to pandemic factors and lead to increased suicide rates in Germany. METHODS: Age- and sex-stratified suicide data from police crime statistics covering 35 % of the German population were used for an interrupted time-series analysis and for a projection of total German suicides in 2022. RESULTS: For both sexes, a trend reversal from constant or declining suicide rates to an increase was observed. This increase is particularly pronounced in 2022 and mainly relates to the 60+ age group that is highly vulnerable to suicide. The projection of the overall German suicide rate is at a level last observed in 2015. CONCLUSIONS: The key challenge now is to combat potential causes of this rise in suicide rates to avert the emerging upward trend.

A descriptive analysis of human milk dispensed by the Leipzig Donor Human Milk Bank for neonates between 2012 and 2019.

Background: Human milk banking has become an important aspect of Nutritional medicine. It is not just about the provision of mother's own milk (MOM) or donor human milk (DHM) in the hospital, but also a strategy to encourage breastfeeding in the clinical setting and beyond. Objective: To describe the feeding patterns of hospitalised infants including human milk dispensed by the Leipzig Donor Human Milk Bank (LMB). Design: A descriptive analysis of daily data on milk feeds dispensed by LMB for hospitalised infants distinguishing between MOM or DHM, either fresh or frozen, and raw/pasteurised milk from 2012-2019. Results: We included 2,562 infants with median hospitalisation of 23 days, for whom human milk was dispensed on median 76% of those days and other nutrition on the remaining days. Raw MOM and raw DHM comprised 52% and 8% of the dispensed milk, respectively. Dispensing exclusive DHM instead of MOM for at least one full day was required for 55% of the infants, mostly at the beginning but also later during hospitalisation. Exclusive raw DHM was dispensed on at least 1 day for 37% of the infants, in different birthweight strata <1,000 g: 10%, 1,000-1500 g: 11%, 1,500-2500 g: 13% and > 2,500 g: 3%. At discharge, MOM was dispensed for more than 60% of the infants. Conclusion: During an infant's hospital stay, LMB dispenses various human milk feeds with interspersed DHM resulting in complex intra-individual and time-variant feeding patterns. LMB dispenses raw MOM and especially raw DHM with the intention to retain the properties of human milk unlike a diet containing pasteurised DHM and/or formula. Although raw DHM comprises a small percentage of all dispensed milk, raw DHM is dispensed for a substantial portion of infants. Our results document that dispensing raw DHM, is possible in routine settings.

Association of breastfeeding with mental disorders in mother and child: a systematic review and meta-analysis.

BACKGROUND: Breastfeeding has long been associated with numerous benefits for both mothers and infants. While some observational studies have explored the relationship between breastfeeding and mental health outcomes in mothers and children, a systematic review of the available evidence is lacking. The purpose of this study is to systematically evaluate the association between breastfeeding and mental health disorders in mothers and children. METHODS: We systematically searched MEDLINE and EMBASE from inception to June 2, 2023. The inclusion criteria consisted of all studies evaluating links between breastfeeding and development of mental health disorders in children and mothers. Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) while grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of evidence. A random-effects meta-analysis was used if possible, to estimate the odds ratio for the association between breastfeeding and mental health outcomes. The Mantel-Haenszel method was utilised for pooling ORs across studies. Study heterogeneity was assessed using the I2 statistic. RESULTS: Our review identified twenty-one original study. Of these, 18 focused on the association between breastfeeding and child health, assessing depressive disorders, schizophrenia, anxiety disorders, eating disorders and borderline personality disorder. Three studies evaluated the associations between breastfeeding and maternal mental health disorders. Three studies looking at outcomes in children showed no significant association between breastfeeding and occurrence of schizophrenia later in life (OR 0.98; 95% CI 0.57-1.71; I2 = 29%). For depressive disorders (5 studies) and anxiety disorders (3 studies), we found conflicting evidence with some studies showing a small protective effect while others found no effect. The GRADE certainty for all these findings was very low due to multiple limitations. Three studies looking at association between breastfeeding and maternal mental health, were too heterogeneous to draw any firm conclusions. CONCLUSIONS: We found limited evidence to support a protective association between breastfeeding and the development of mental health disorders in children later in life. The data regarding the association between breastfeeding and maternal mental health beyond the postnatal period is also limited. The methodological limitations of the published literature prevent definitive conclusions, and further research is needed to better understand the relationship between breastfeeding and mental health in mothers and children.

Timing of complementary feeding for early childhood allergy prevention: An overview of systematic reviews.

OBJECTIVE: To summarise and critically appraise systematic review (SR) evidence on the effects of timing of complementary feeding (CF) on the occurrence of allergic sensitisation and disease. DESIGN: Overview of SRs. AMSTAR-2 and ROBIS were used to assess methodological quality and risk of bias (RoB) of SRs. RoB 2 Tool was used to assess RoB of primary randomised controlled trials (RCTs) (or extracted). The certainty of evidence (CoE) was assessed using GRADE. Findings were synthesised narratively. DATA SOURCES: MEDLINE (via PubMed and Ovid), the Cochrane Library and Web of Science Core Collection (2010 to 27 February 2023). ELIGIBILITY CRITERIA: SRs investigating the effects of timing of CF in infants or young children (0-3 years) on risk of developing food allergy (FA), allergic sensitisation, asthma, allergic rhinitis, atopic eczema and adverse events based on RCT evidence. RESULTS: Eleven SRs were included. Only two SRs had low RoB; common issues were failure to report on funding of primary studies and failure to provide a list of excluded trials. Common limitations of included trials were lack of blinding of outcome assessment or detailed trial preregistration, and inadequate handling of high loss to follow up. Primary study overlap was very high for specific FA and slight to moderate for FA in general and other primary outcomes. Introducing specific foods (peanut, cooked egg) early probably reduces the risk of specific FA. Evidence for other allergic outcomes was mostly very uncertain and based on few primary studies. Trials varied regarding timing of CF, nature of complementary foods and population risk, which limited comparability between SRs. CONCLUSIONS: For developing guidelines to support decision-making on the timing of CF as a preventive strategy, early introduction of specific foods (i.e. egg and peanut) seems promising and safe, whereas more extensive research is required regarding other allergic outcomes and potential adverse events.

Potential sex differences in human milk fatty acids and their association with atopic dermatitis: Results of the Ulm SPATZ health study.

BACKGROUND: Polyunsaturated fatty acids (PUFAs) in human milk are essential in immune system maturation and might play a role in the development of allergic conditions, such as atopic dermatitis (AD) in infants. Immune system responses are modulated by sex, but data on the sex-specific associations with PUFAs are limited. We therefore explored sex-specific differences in human milk PUFAs and their association with AD up to 2 years. METHODS: PUFAs were measured in human milk samples from the Ulm SPATZ Health Study at 6 weeks (n = 512) and 6 months (n = 367). Associations with AD up to 2 years were evaluated using crude and multivariable logistic regression. Interactions between infant sex and PUFAs were explored by including the product term. RESULTS: No significant associations were observed with 6-week data. At 6 months, the median relative proportion of docosahexaenoic acid (DHA) was significantly higher in milk for female than male infants (p = .001). Female infants whose milk was lower in quintile proportions of alpha-linolenic acid (ALA) at 6 months had lower odds of AD compared to males [first vs. fifth quintile OR (95% confidence interval): 0.13 (0.02, 0.66), p = .02]. This interaction was not significant when correcting for multiple testing (α threshold: p = .004). No other statistically significant associations were observed. CONCLUSION: Individual quintile PUFA proportions in human milk were not associated with AD, overall and in a sex-specific manner. More comprehensive and statistically powered longitudinal studies are needed to determine whether potential sex differences in human milk, if any, could be of clinical relevance for infants including the investigation of mediating factors.

Pre- and early postpartum psychosocial stress trajectories in mothers and child body mass index at 3 years: a birth cohort study.

BACKGROUND: Child overweight remains a prevalent public health concern, but the impact of maternal psychosocial stress and related constructs, the timing, and possible trajectories on child body mass index (BMI) is controversial. We aimed to investigate the association of maternal stress, depression and anxiety symptoms, and maternal hair cortisol concentrations (HCC) at delivery, 6, and 12 months postpartum with child BMI and age- and sex-standardized BMI (BMI-SDS) at age 3 years. METHODS: Data were derived from the Ulm SPATZ Health Study with a baseline examination between 04/2012 and 05/2013 at the University Medical Centre Ulm, Germany, the only maternity clinic in Ulm, with a good representation of the source population. Adjusted regression analyses based on BMI/BMI-SDS (dependent) and trajectories of stress, depression, and anxiety (independent variables) were investigated in 596 mothers and children. Multiple imputation of missing covariates was performed. RESULTS: Various trajectories in independent variables were identified, trajectories of maternal anxiety symptom differed between child sexes. We did not find an association between trajectories of maternal chronic stress, depression symptoms, or HCC and child BMI/BMI-SDS. However, trajectories of low-increasing maternal anxiety symptoms were linked to higher child BMI compared to a low-stable trajectory group (b = 0.58 kg/m2, 95% Confidence Interval: 0.11; 1.04) in girls. CONCLUSIONS: Trajectories of maternal anxiety symptoms were associated with the child's BMI/BMI-SDS in girls at age 3 years. However, further large scale studies should include variables to determine the causal pathway and enlighten sex-specific differences.

Trajectories of child mental health, physical activity and screen-time during the COVID-19 pandemic considering different family situations: results from a longitudinal birth cohort.

BACKGROUND: Many authors have described a significant mental health burden on children and adolescents during the COVID-19 pandemic, possibly moderated by social disparities. This analysis explores whether pre-pandemic family circumstances might be related to different aspects of child health during the pandemic. METHODS: We analyzed trajectories of health-related outcomes in children aged 5 to 9 years (T7 to T11) using the Ulm SPATZ Health study, a population based birth cohort study (baseline 04/2012-05/2013) conducted in the South of Germany. Outcomes were children's mental health, quality of life, and lifestyle, such as screen time and physical activity. We conducted descriptive statistics of maternal and child characteristics before and throughout the pandemic. We defined three different groups of pre-pandemic family situations and used adjusted mixed models to estimate differences in means associated with the time during the pandemic vs. before the pandemic in (a) all children and in (b) children belonging to specific pre-pandemic family situations. RESULTS: We analyzed data from n = 588 children from whom at least one questionnaire was completed between T7 and T11. When not considering the pre-pandemic family situation, adjusted mixed models showed statistically significant lower mean scores of health-related quality of life among girls during vs. before the COVID-19 pandemic (difference in means (b): - 3.9 (95% confidence interval (CI): - 6.4, - 1.4). There were no substantial differences in mental health, screen time, or physical activity in boys or girls. When considering pre-pandemic family situations, boys with mothers having symptoms of depression or anxiety showed a substantial loss of health-related quality of life on the subscale of friends (b: - 10.5 (95% CI: - 19.7, - 1.4)). Among girls in this group, 60% of the 15 assessed outcomes were negatively associated with a remarkable loss in health-related quality of life (e.g., KINDL-physical well-being difference in means: - 12.2 (95% CI: - 18.9, - 5.4)). Furthermore, a substantial increase in screen time was found (+ 2.9 h (95% CI: 0.3, 5.6)). CONCLUSION: Our results suggest that the health (and behavior) of primary school-aged children is possibly impacted by the COVID-19 pandemic, with adverse consequences differing by gender and very likely by the pre-pandemic family situation. Especially in girls having a mother with depression or anxiety symptoms, the adverse consequences of the pandemic on mental health seem to be aggregated. Boys showed fewer adverse trajectories, and it needs to be further assessed which factors exactly are behind the (socio-economic) factors, such as maternal working habits and limited living space, when analyzing the effect of the pandemic on children's health.

Health and nutrition claims for infant formula: international cross sectional survey.

OBJECTIVES: To review available health and nutrition claims for infant formula products in multiple countries and to evaluate the validity of the evidence used for substantiation of claims. DESIGN: International cross sectional survey. SETTING: Public facing and healthcare professional facing company owned or company managed formula industry websites providing information about products marketed for healthy infants delivered at full term in 15 countries: Australia, Canada, Germany, India, Italy, Japan, Nigeria, Norway, Pakistan, Russia, Saudi Arabia, South Africa, Spain, the United Kingdom, and the United States in 2020-22. MAIN OUTCOME MEASURES: Number and type of claims made for each product and ingredient. References cited were reviewed and risk of bias was assessed for registered clinical trials using the Cochrane risk of bias tool, and for systematic reviews using the Risk Of Bias in Systematic reviews tool. RESULTS: 757 infant formula products were identified, each with a median of two claims (range from 1 (Australia) to 4 (US)), and 31 types of claims across all products. Of 608 products with ≥1 claims, the most common claim types were "helps/supports development of brain and/or eyes and/or nervous system" (323 (53%) products, 13 ingredients), "strengthens/supports a healthy immune system" (239 (39%) products, 12 ingredients), and "helps/supports growth and development" (224 (37%) products, 20 ingredients). 41 groups of ingredients were associated with ≥1claims, but many claims were made without reference to a specific ingredient (307 (50%) products). The most common groups of ingredients cited in claims were long chain polyunsaturated fatty acids (278 (46%) products, 9 different claims); prebiotics, probiotics, or synbiotics (225 (37%) products, 19 claims); and hydrolysed protein (120 (20%) products, 9 claims). 161/608 (26%) products with ≥1 claims provided a scientific reference to support the claim-266 unique references were cited for 24 different claim types for 161 products. The reference types most frequently cited were clinical trials (50%, 134/266) and reviews (20%, 52/266). 28% (38/134) of referenced clinical trials were registered, 14% (19/134) prospectively. 58 claims referred to 32 registered clinical trials, of which 51 claims (27 trials) related to a randomised comparison. 46 of 51 claims (90%) referenced registered clinical trial outcomes at high risk of bias, and all cited systematic reviews and pooled analyses, carried a high risk of bias. CONCLUSIONS: Most infant formula products had at least one health and nutrition claim. Multiple ingredients were claimed to achieve similar health or nutrition effects, multiple claims were made for the same ingredient type, most products did not provide scientific references to support claims, and referenced claims were not supported by robust clinical trial evidence.

CASANOVA: Permutation inference in factorial survival designs.

We propose inference procedures for general factorial designs with time-to-event endpoints. Similar to additive Aalen models, null hypotheses are formulated in terms of cumulative hazards. Deviations are measured in terms of quadratic forms in Nelson-Aalen-type integrals. Different from existing approaches, this allows to work without restrictive model assumptions as proportional hazards. In particular, crossing survival or hazard curves can be detected without a significant loss of power. For a distribution-free application of the method, a permutation strategy is suggested. The resulting procedures' asymptotic validity is proven and small sample performances are analyzed in extensive simulations. The analysis of a data set on asthma illustrates the applicability.