Diagnostic Evaluation of Autism Spectrum Disorder in Pediatric Primary Care.

BACKGROUND AND OBJECTIVES: Children with autism spectrum disorder (ASD) continue to experience significant delays in diagnosis and interventions. One of the main factors contributing to this delay is a shortage of developmental-behavioral specialists. Diagnostic evaluation of ASD by primary care pediatricians (PCPs) has been shown to be reliable and to decrease the interval from first concern to diagnosis. In this paper, we present the results of a primary care ASD diagnosis program in which the PCP serves as the primary diagnostician and leverages the infrastructure of the primary care medical home to support the child and family during the pre- and post-diagnostic periods, along with data on parental satisfaction with this model. METHODS: Retrospective data from a cohort of patients evaluated through this program were analyzed to determine the mean age at diagnosis and interval from referral for evaluation to diagnosis. We used survey methodology to obtain data from parents regarding their satisfaction with the process. RESULTS: Data from 8 of 20 children evaluated from April 2021 through May 2022 showed a median age of diagnosis of 34.5 months compared to the national average of 49 months. Mean interval from referral for evaluation to diagnosis was 3.5 months. Parental survey responses indicated high satisfaction. CONCLUSIONS: This model was successful in shortening the interval from referral to diagnosis resulting in significant decrease of age at diagnosis compared with the national average. Widespread implementation could improve access to timely diagnostic services and improve outcomes for children with ASD.

Participation of adolescents with and without physical disabilities and chronic diseases: A comprehensive conceptualization.

BACKGROUND: In 2001, the International Classification of Functioning and Disability (ICF) introduced participation as a main goal of rehabilitation processes. However, to date, a comprehensive concept of participation in the rehabilitative context is missing, particularly in German-speaking countries. We thus aimed to refine and extend the existing concepts of participation in this brief communication. METHODS: In preceding studies, we conducted semi-structured interviews with adolescents who either had chronic diseases and/or physical disabilities or had no impairments and focus groups with parents and experts. Based on these diverse perspectives and findings, we refine the term participation. RESULTS: Participation is a construct that is embedded in a social context and consists of objective (i.e., attendance) and subjective (i.e., satisfaction and involvement) dimensions. These dimensions are reflected in different domains and areas that are relevant to adolescents' lives. In addition, the subjective relevance of respective areas in life needs to be regarded as a weighing component when evaluating participation. CONCLUSION: Our results reflect international models on participation, refine the existing concept, and underline the multidimensional character of participation. These findings are urgently needed to develop appropriate instruments, for example, for assessing whether rehabilitative processes are effective regarding the goal of participation.

Design and validation of algorithms to identify venous thromboembolism in the French National Healthcare Database.

PURPOSE: This paper aims to introduce an algorithm designed to identify Venous Thromboembolism (VTE) in the French National Healthcare Database (SNDS) and to estimate its positive predictive value. METHODS: A case-identifying algorithm was designed using SNDS inpatient and outpatient encounters, including hospital stays with discharge diagnoses, imaging procedures and drugs dispensed, of French patients aged at least 18 years old to whom baricitinib or Tumor Necrosis Factor Inhibitors (TNFi) were dispensed between September 1, 2017, and December 31, 2018. An intra-database validation study was then conducted, drawing 150 cases identified as VTE by the algorithm and requesting four vascular specialists to assess them. Patient profiles used to conduct the case adjudication were reconstituted from de-identified pooled and formatted SNDS data (i.e., reconstituted electronic health records-rEHR) with a 6-month look-back period prior to the supposed VTE onset and a 12-month follow-up period after. The positive predictive value (PPV) with its 95% confidence interval (95% CI) was calculated as the number of expert-confirmed VTE divided by the number of algorithm-identified VTE. The PPV and its 95% CI were then recomputed among the same patient set initially drawn, once the VTE-identifying algorithm was updated based on expert recommendation. RESULTS: For the 150 patients identified with the first VTE-identifying algorithm, the adjudication committee confirmed 92 cases, resulting in a PPV of 61% (95% CI = [54-69]). The final VTE-identifying algorithm including expert suggestions showed a PPV of 92% (95% CI = [86-98]) with a total of 87 algorithm-identified cases, including 80 retrieved from the 92 confirmed by experts. CONCLUSION: The identification of VTE in the SNDS is possible with a good PPV.

Analysis of problems and potentials for increasing pandemic resilience in public health administrations in Saxony-Anhalt, Germany-a mixed-methods approach.

INTRODUCTION: The COVID-19 pandemic has shown the importance of resilient, modern, and well-equipped public health administrations from national to communal levels. In Germany, the surveillance, contact tracing, and local adaptions went through local health offices, revealing both their important role and also their lack of equipment and general preparation for health crises. Research on the mode of operation of the public health service (PHS), especially in a time of crisis, is rare. The present study aims to qualitatively and quantitatively assess problem areas, conflict potentials, and challenges that have become apparent for the PHS of Saxony-Anhalt during the pandemic. It focuses on the individual insight of employees of the PHS of Saxony-Anhalt and its 14 health offices to derive concrete needs and fields of action for increasing pandemic preparedness. Furthermore, the prospective personnel and resource-based requirements as well as the necessary structural and organisational changes of the public health departments are to be considered. METHODS AND ANALYSIS: The study will follow a sequential mixed-methods approach. Introductory expert interviews (n=12) with leading staff of Saxony-Anhalt's PHS will be conducted, followed by focus group interviews (n=4) with personnel from all departments involved in the pandemic response. Thereafter, a quantitative survey will be carried out to validate and complement the results of the qualitative phase. ETHICS AND DISSEMINATION: Ethical approval was obtained by the Martin-Luther-Universität Halle-Wittenberg ethics commission (Ref number 2023-102). The authors will submit the results of the study to relevant peer-reviewed journals and give national and international oral presentations to researchers, members of the PHS, and policymakers.

COVID-19 and pregnancy: A European study on pre- and post-infection medication use.

PURPOSE: The COVID-19 pandemic has impacted medication needs and prescribing practices, including those affecting pregnant women. Our goal was to investigate patterns of medication use among pregnant women with COVID-19, focusing on variations by trimester of infection and location. METHODS: We conducted an observational study using six electronic healthcare databases from six European regions (Aragon/Spain; France; Norway; Tuscany, Italy; Valencia/Spain; and Wales/UK). The prevalence of primary care prescribing or dispensing was compared in the 30-day periods before and after a positive COVID-19 test or diagnosis. RESULTS: The study included 294,126 pregnant women, of whom 8943 (3.0%) tested positive for, or were diagnosed with, COVID-19 during their pregnancy. A significantly higher use of antithrombotic medications was observed particularly after COVID-19 infection in the second and third trimesters. The highest increase was observed in the Valencia region where use of antithrombotic medications in the third trimester increased from 3.8% before COVID-19 to 61.9% after the infection. Increases in other countries were lower; for example, in Norway, the prevalence of antithrombotic medication use changed from around 1-2% before to around 6% after COVID-19 in the third trimester. Smaller and less consistent increases were observed in the use of other drug classes, such as antimicrobials and systemic corticosteroids. CONCLUSION: Our findings highlight the substantial impact of COVID-19 on primary care medication use among pregnant women, with a marked increase in the use of antithrombotic medications post-COVID-19. These results underscore the need for further research to understand the broader implications of these patterns on maternal and neonatal/fetal health outcomes.

Management and use of healthcare resources in patients with chronic lymphocytic leukemia initiating venetoclax in routine clinical practice.

Venetoclax is a first-in-class B-cell lymphoma-2 (BCL-2) inhibitor approved as continuous monotherapy and in combination with rituximab as fixed-treatment duration for relapsed and refractory chronic lymphocytic leukemia (R/R CLL). DEVOTE was a 24-week, multicenter observational study (NCT03310190) evaluating the safety, healthcare resource utilization (HCRU) and health-related quality of life (HRQoL) of patients initiating venetoclax for R/R CLL in Canada. Overall, 89 patients received 1 dose of venetoclax; 80% had prior exposure (42% resistant) to ibrutinib. Biochemical tumor lysis syndrome (TLS) occurred in five patients. We observed differences in hospitalization across Canadian provinces including in patients at low risk for TLS with no clear impact on TLS incidence. Additionally, a rapid and sustained improvement in several domains of HRQoL was observed during venetoclax initiation. Early adoption of venetoclax was mainly for R/R CLL patients with few treatment options; nonetheless, acceptable toxicity and a positive impact on HRQoL were observed.

Abortion stigma among abortion seekers, healthcare professionals and the public in high-income countries: A mixed-methods systematic review protocol.

INTRODUCTION: Abortion is a crucial sexual and reproductive right. However, the legal situation of pregnancy termination is rather heterogeneous across countries and regions. The political climate and cultural perception may result in abortion-related stigma. This mixed-methods systematic review protocol aims to detail the proposed methods for assessing the current state of research on abortion stigma in high-income countries from an abortion seeker, healthcare provider and public perspective. METHODS AND ANALYSIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guideline, we conducted a systematic literature search of peer-reviewed studies from high-income countries in relevant electronic databases: PubMed, CINHAL, PsycINFO, LIVIVO and Cochrane Library. Qualitative, quantitative and mixed-method studies that measured or examined abortion-related stigma in abortion seekers, healthcare professionals and the general public will be included. Assessment of risk of bias, data synthesis and qualitative meta-aggregation will be carried out. ETHICS AND DISSEMINATION: The results of the systematic review will be submitted to peer-reviewed journals and presented at relevant conferences.

Cardiovascular and renal diseases in type 2 diabetes patients: 5-year cumulative incidence of the first occurred manifestation and hospitalization cost: a cohort within the French SNDS nationwide claims database.

BACKGROUND: Myocardial infarction (MI), stroke, peripheral arterial disease (PAD), heart failure (HF) and chronic kidney disease (CKD) are common cardiovascular renal diseases (CVRD) manifestations for type 2 diabetes. The objective was to estimate the incidence of the first occurring CVRD manifestation and cumulative hospitalization costs of each CVRD manifestation for type 2 diabetes without CVRD history. METHODS: A cohort study of all type 2 diabetes free of CVRD as of January 1st 2014, was identified and followed-up for 5 years within the French SNDS nationwide claims database. The cumulative incidence of the first occurring CVRD manifestation was estimated using the cumulative incidence function, with death as a competing risk. Cumulative hospitalization costs of each CVRD manifestations were estimated from the perspective of all payers. RESULTS: From 2,079,089 type 2 diabetes without cancer or transplantation, 76.5% were free of CVRD at baseline with a mean age of 65 years, 52% of women and 7% with microvascular complications history. The cumulative incidence of a first CVRD manifestation was 15.3% after 5 years of follow-up with a constant linear increase over time for all CVRD manifestations: The most frequent was CKD representing 40.6% of first occurred CVRD manifestation, followed by HF (23.0%), then PAD (13.5%), stroke (13.2%) and MI (9.7%). HF and CKD together reached about one patient out of ten after 5 years and represented 63.6% of first CVRD manifestations. The 5-year global cost of all CVRD hospitalizations was 3.9 billion euros (B€), i.e. 2,450€ per patient of the whole cohort, with an exponential increase over time for each specific CVRD manifestation. The costliest was CKD (2.0 B€), followed by HF (1.2 B€), then PAD (0.7 B€), stroke (0.6 B€) and MI (0.3 B€). CONCLUSIONS/INTERPRETATION: While MI, stroke and PAD remain classic major risks of complications for CVRD-free type 2 diabetes, HF and CKD nowadays represent individually a higher risk and cost than each of these classic manifestations, and jointly represents a risk and a cost twice as high as these three classic manifestations all together. This should encourage the development of specific HF and CKD preventive strategies.

A pilot study to develop a participation self-assessment tool for adolescents: The Social Participation Inventory (SPI).

OBJECTIVE: Participation is one of the key goals of re/habilitative processes. Since participation impacts adolescents' social-emotional development and overall health, this goal is particularly important for them. However, to date, no German-speaking self-assessment tool for participation among adolescents is available. This study sought therefore to develop such a tool and to test its psychometric properties. METHODS: Based on a preliminary qualitative study, we developed 133 items for a pilot version of the Social Participation Inventory (SPI). The SPI assesses the objective dimension (i.e., attendance) and the subjective dimension (i.e., involvement and satisfaction) of participation. To test the psychometric properties of the SPI, we conducted a quantitative cross-sectional survey and applied the SPI to n = 151 adolescents with and without disabilities and/or chronic diseases. RESULTS: By using principal component analyses, we examined the SPI's consistency and verified the theoretical considerations regarding the two components of participation (i.e., objective and subjective dimensions). Items that did not load sufficiently on components were removed after careful theoretical-based consideration. The condensed version of the SPI consists of 39 items that assess participation and 18 items to assess the perceived importance of respective areas of life. The SPI shows very good overall reliability (Cronbach's α = .920) and good validity. CONCLUSION: This study provides a new psychometrically tested participation self-assessment scale for adolescence with and without disabilities and/or chronic diseases. Further research is needed to re-evaluate its psychometric properties and to evaluate the application of the SPI in clinical and scientific contexts.

What does social participation mean? A qualitative study exploring the concept of participation from the perspectives of experts and parents.

OBJECTIVES: This study aimed to assess the theoretical framework regarding social participation from the perspectives of experts and parents of youth aged between 10 and 17 years, and therefore, provides new insights into the concept of social participation. DESIGN: A qualitative study was conducted to understand the construct of social participation in more detail. Eight focus groups were held with experts (n=21) and parents (n=24) and analysed based on content analysis. PARTICIPANTS: We used purposive and snowball sampling to obtain a comprehensive sample of (A) parents of adolescents with and without chronic and/or physical-motor impairments and (B) experts involved in participatory research and/or treatment of adolescents with chronic and/or physical-motor impairments. The final sample consisted of 3 focus groups with a total of 21 experts and 5 focus groups with 24 parents. This included 10 parents who had disabled children. RESULTS: The concept of social participation consists of subjective and objective components. The focus from the experts' perspective is clearly on the subjective level; that is, revolving around the question 'Does the adolescent feel involved?' In contrast, the parents' focus is more on normative expectations. The possibility of participation in all areas of life through the adjustment of environmental factors was identified as a central factor. CONCLUSIONS: The results underline the importance of the subjective feelings of adolescents, as well as the significance of normative requirements. To capture the subjective component of participation, suitable measurements are needed. TRIAL REGISTRATION NUMBER: DRKS00014739.

The impact of nucleoside base modification in mRNA vaccine is influenced by the chemistry of its lipid nanoparticle delivery system.

The use of modified nucleosides is an important approach to mitigate the intrinsic immunostimulatory activity of exogenous mRNA and to increase its translation for mRNA therapeutic applications. However, for vaccine applications, the intrinsic immunostimulatory nature of unmodified mRNA could help induce productive immunity. Additionally, the ionizable lipid nanoparticles (LNPs) used to deliver mRNA vaccines can possess immunostimulatory properties that may influence the impact of nucleoside modification. Here we show that uridine replacement with N1-methylpseudouridine in an mRNA vaccine encoding influenza hemagglutinin had a significant impact on the induction of innate chemokines/cytokines and a positive impact on the induction of functional antibody titers in mice and macaques when MC3 or KC2 LNPs were used as delivery systems, while it impacted only minimally the titers obtained with L319 LNPs, indicating that the impact of nucleoside modification on mRNA vaccine efficacy varies with LNP composition. In line with previous observations, we noticed an inverse correlation between the induction of high innate IFN-α titers in the macaques and antigen-specific immune responses. Furthermore, and consistent with the species specificity of pathogen recognition receptors, we found that the effect of uridine replacement did not strictly translate from mice to non-human primates.

Study protocol: Hypersexual and hyposexual behavior among adults diagnosed with alcohol- and substance use disorders-Associations between traumatic experiences and problematic sexual behavior.

Background: Hypersexual and hyposexual behaviors are common concomitant of substance use disorders (SUD). On the one hand, the regular consumption of alcohol or illegal drugs can lead to hypersexual or hyposexual behavior due to its effects on the organism; on the other hand, the use of psychotropic substances is also used as a coping strategy concerning already existing sexual impairments. The aforementioned disorders show similarities in terms of their etiology, as traumatic experiences get special attention as potential risk factors for the development of addictions, hypersexual, and hyposexual behavior. Objectives: The study aims to explore the association between SUD characteristics and hypersexual/hyposexual behavior, and a potential moderating effect of early traumatic life events by answering the following research questions: (1) Do people with SUD differ from a sample of people with other psychiatric disorders regarding hypersexual and hyposexual behavior? (2) What are the associations between the presence of sexual problems and different characteristics of the SUD (e.g., mono vs. polysubstance use, type of addictive substance, intensity of the disorder)? (3) What influence do traumatic experiences in childhood and adolescence have on the existence of sexual disorders among adults with a diagnosed SUD? Method: The target group of this cross-sectional ex-post-facto study comprises adults diagnosed with an alcohol- and/or substance use disorder. Data will be collected with an online survey, which will be promoted via several support and networking services for people diagnosed with SUD. Two control groups will be surveyed, one consisting of people with other psychiatric disorders than SUD and traumatic experiences, and one healthy group. Relations between the dependent variables (hypersexual and hyposexual behavior) and independent variables (sociodemographic information, medical and psychiatric status, intensity of the prevalent SUD, traumatic experiences, and symptoms of posttraumatic stress disorder) will be initially calculated via correlations and linear regression. Risk factors will be identified via multivariate regression. Discussion: Gaining relevant knowledge promises new perspectives for prevention, diagnosis, case conception, and therapy of SUDs as well as problematic sexual behaviors. The results can provide more information about the importance of psychosexual impairments regarding the development and maintenance of SUDs.

Chemokine modulation in microscopic and submicroscopic Plasmodium falciparum malaria infection in women at delivery in Yaoundé, Cameroon.

In pregnancy-associated malaria, chemokines such as CXCL-4, CXCL-13, CXCL-16, and CCL-24 play critical roles in leucocyte trafficking to tissue sites in the infected placenta where inflammatory reactions are active. However, how plasma levels of these chemokines associate with Plasmodium falciparum placental malaria and pregnancy outcomes remains not well understood. The present study analyzed the plasma levels of CXCL-4, CXCL-13, CXCL-16, and CCL-24 chemokines in matched peripheral, placental and cord blood in relation with placental malaria (PM), and with submicroscopic parasitaemia. This was a retrospective case-control study (1:3 ratio) involving samples from 134 women (34 PM+ and 100 PM-) enrolled at delivery at the Marie Reine Health Center in Yaoundé, Cameroon between June 2013 and October 2018. Samples were collected just after delivery and used to diagnose microscopic and submicroscopic Plasmodium falciparum infections. Submicroscopic infections were detected by reverse transcription LAMP whereas chemokine levels were determined by Magnetic Luminex Screening Assay. Overall, PM was associated with increased plasma levels of CXCL-13 and CXCL-16 and low levels of CXCL-4 and CCL-24 in both peripheral and placental blood (0.0002 ≤ p ≤ 0.042). Similarly, CCL-24 levels in peripheral and placental blood samples were significantly lower in submicroscopically infected women compared to healthy controls (p = 0.04 and 0.02, respectively). Maternal hemoglobin levels increased with peripheral plasma levels of CXCL-4 (p = 0.005), CXCL-16 (p = 0.03), and CCL-24 (p = 0.002) while birth weight was lower for babies born from women with high levels of peripheral CXCL-13 (p = 0.0006) and low levels of cord CXCL-4 and CCL-24 (p = 0.02 and 0.08, respectively). Together the data suggest that low levels of CXCL-4 and CCL-24 coupled with high plasma levels of CXCL-13 and for a lesser extend CXCL-16 represent signatures of PM in the study population. These findings are relevant for understanding the immunopathogenesis of PM and developing new therapeutic or preventive strategies against severe PM outcomes.

Variations in foam collapse and thin film stability with constant interfacial and bulk properties.

The stability of foams is commonly linked to the interfacial properties of the proteins and other surfactants used. This study aimed to use these relationships to explain differences in foam stability observed among similar beer samples from different breweries. The foam stability was different for each sample (Nibem foam stability ranged from 206 to 300 s), but ranking was similar for all three foaming methods used, thus independent of the method, gas, etc. Differences in foam stability were dominated by differences in coalescence, as illustrated by the correlation with the stability of single bubbles and thin liquid films. The differences in coalescence stability could not be explained by the measured interfacial properties (e.g. surface pressure, adsorption rate, dilatational modulus and surface shear viscosity), or the bulk properties (concentration, pH, ionic strength, viscosity), since they were similar for all samples. The drainage rates and disjoining pressure isotherms measured in thin liquid films were also similar for all samples, further limiting the options to explain the differences in foam stability using known arguments. The differences in coalescence stability of the thin films was shown to depend on the liquid in between the adsorbed layers of the thin film, using a modified capillary cell to exchange this liquid (to a buffer, or one of the other samples). This illustrates the need to review our current understanding and to develop new methods both for experimental study and theoretical description, to better understand foam stability in the future.

The Adolescent Concept of Social Participation-A Qualitative Study on the Concept of Social Participation from Adolescents with and without Physical Disabilities.

PURPOSE: The construct of social participation is still not clearly defined. To reach a better understanding of social participation, the perspectives of adolescents must be taken into account. This study explores the adolescent concept of social participation and expands knowledge of the meaning of subjective components of the term. METHODS: Thirty-four semi-structured interviews were conducted with adolescents with and without physical disabilities or chronic diseases between the ages of 12 and 17 and analyzed according to grounded theory. RESULTS: Adolescents describe social participation as involving reflexive interaction with their social environment. Furthermore, forming a social environment plays an important role. All components of the concept are embedded in a context that influences the ways adolescents participate. Adolescents differentiate between active and passive forms of social participation. The concept of reflexive interaction is situated within an interdependent structure of components such as the "feeling of belonging" and the feeling of "well-being" among adolescents. CONCLUSION: The results expand the current state of knowledge regarding the theoretical differentiation of social participation by exploring subjective components of the term. This offers the possibility of supplementing the theoretical frameworks of social participation and supports the understanding of the critical importance of social participation for adolescents.

Nonclinical safety evaluation of two vaccine candidates for herpes simplex virus type 2 to support combined administration in humans.

Herpes simplex virus type 2 (HSV-2) is the most common cause of genital disease worldwide. The development of an effective HSV-2 vaccine would significantly impact global health based on the psychological distress caused by genital herpes for some individuals, the risk transmitting the infection from mother to infant, and the elevated risk of acquiring HIV-1. Five nonclinical safety studies were conducted with the replication defective HSV529 vaccine, alone or adjuvanted with GLA-SE, and the G103 subunit vaccine containing GLA-SE. A biodistribution study was conducted in guinea pigs to evaluate distribution, persistence, and shedding of HSV529. A preliminary immunogenicity study was conducted in rabbits to demonstrate HSV529-specific humoral response and its enhancement by GLA-SE. Three repeated-dose toxicity studies, one in guinea pigs and two in rabbits, were conducted to assess systemic toxicity and local tolerance of HSV529, alone or adjuvanted with GLA-SE, or G103 containing GLA-SE. Data from these studies show that both vaccines are safe and well tolerated and support the ongoing HSV-2 clinical trial in which the two vaccine candidates will be given either sequentially or concomitantly to explore their potential synergistic and incremental effects.

Cancer prevention in females with and without obesity: Does perceived and internalised weight bias determine cancer prevention behaviour?

BACKGROUND: Women with obesity are not only at higher risk of developing cancer such as gynaecological malignancies but are also less likely to attend cancer prevention screenings (CPS). In this study, we aimed to obtain a better database for Germany and to investigate whether women with obesity are less likely to undergo CPS compared to women without obesity. Moreover, we aimed to identify factors that determine CPS behaviour. METHODS: A quantitative cross-sectional telephone survey was conducted that assessed data of 1003 females in the general public with obesity (BMI ≥ 30 kg/m2; n = 500) and without obesity (BMI < 30 kg/m2; n = 503). We assessed participants' utilisation of cervical, breast, and colorectal CPS. Group differences were investigated by using Chi-Square tests, whereas influencing factors that might determine CPS behaviour were examined by multivariate logistic regression analyses. Therefore, logistic regression models for (a) the full sample and (b) the obese sample were conducted. Explanatory factors (i.e., cancer awareness, the internalisation of weight bias (WBIS) and perceived weight-based discrimination) were included. Confounding factors such as sociodemographic variables were included in the multivariate analysis. RESULTS: Women with obesity were less likely to undergo Pap smear (χ2(1) = 13.90, p < 0.001) and clinical breast examination (χ2(4) = 14.41, p < 0.01) compared to women without obesity. In contrast, the utilisation of all other CPS methods did not differ between women with and without obesity. Logistic regression analyses revealed neither an association between CPS behaviour and WBI nor perceived weight bias. Instead, previous cancer diagnoses and knowledge about CPS forms were found to reinforce CPS behaviour. CONCLUSION: Although data did not suggest that internalised or perceived weight bias deter women with obesity from undergoing CPS, the role of weight bias has not yet been conclusively clarified. Future studies should address potential methodological limitations and evaluate the effectiveness of most recently established cancer prevention programs and in particular how they affect CPS behaviour in women with obesity.

Validation of a Harmonized Enzyme-Linked-Lectin-Assay (ELLA-NI) Based Neuraminidase Inhibition Assay Standard Operating Procedure (SOP) for Quantification of N1 Influenza Antibodies and the Use of a Calibrator to Improve the Reproducibility of the ELLA-NI With Reverse Genetics Viral and Recombinant Neuraminidase Antigens: A FLUCOP Collaborative Study.

Current vaccination strategies against influenza focus on generating an antibody response against the viral haemagglutination surface protein, however there is increasing interest in neuraminidase (NA) as a target for vaccine development. A critical tool for development of vaccines that target NA or include an NA component is available validated serology assays for quantifying anti-NA antibodies. Additionally serology assays have a critical role in defining correlates of protection in vaccine development and licensure. Standardisation of these assays is important for consistent and accurate results. In this study we first validated a harmonized enzyme-linked lectin assay (ELLA)- Neuraminidase Inhibition (NI) SOP for N1 influenza antigen and demonstrated the assay was precise, linear, specific and robust within classical acceptance criteria for neutralization assays for vaccine testing. Secondly we tested this SOP with NA from influenza B viruses and showed the assay performed consistently with both influenza A and B antigens. Third, we demonstrated that recombinant NA (rNA) could be used as a source of antigen in ELLA-NI. In addition to validating a harmonized SOP we finally demonstrated a clear improvement in inter-laboratory agreement across several studies by using a calibrator. Importantly we showed that the use of a calibrator significantly improved agreement when using different sources of antigen in ELLA-NI, namely reverse genetics viruses and recombinant NA. We provide a freely available and detailed harmonized SOP for ELLA-NI. Our results add to the growing body of evidence in support of developing biological standards for influenza serology.

Nonclinical safety evaluation of a novel ionizable lipid for mRNA delivery.

mRNA vaccines hold tremendous potential in disease control and prevention for their flexibility with respect to production, application, and design. Recent breakthroughs in mRNA vaccination would have not been possible without major advances in lipid nanoparticles (LNPs) technologies. We developed an LNP containing a novel ionizable cationic lipid, Lipid-1, and three well known excipients. An in silico toxicity hazard assessment for genotoxicity, a genotoxicity assessment, and a dose range finding toxicity study were performed to characterize the safety profile of Lipid-1. The in silico toxicity hazard assessment, utilizing two prediction systems DEREK and Leadscope, did not find any structural alert for mutagenicity and clastogenicity, and prediction in the statistical models were all negative. In addition, applying a read-across approach a structurally very similar compound was tested negative in two in vitro assays confirming the low genotoxicity potential of Lipid-1. A dose range finding toxicity study in rabbits, receiving a single intramuscular injection of either different doses of an mRNA encoding Influenza Hemagglutinin H3 antigen encapsulated in the LNP containing Lipid-1 or the empty LNP, evaluated local tolerance and systemic toxicity during a 2-week observation period. Only rabbits exposed to the vaccine were able to develop a specific IgG response, indicating an appropriate vaccine take. The vaccine was well tolerated up to 250 µg mRNA/injection, which was defined as the No Observed Adverse Effect Level (NOAEL). These results support the use of the LNP containing Lipid-1 as an mRNA delivery system for different vaccine formulations and its deployment into clinical trials.