Dose escalation study of a personalized peptide-based neoantigen vaccine (EVX-01) in patients with metastatic melanoma.

BACKGROUND: Neoantigens can serve as targets for T cell-mediated antitumor immunity via personalized neopeptide vaccines. Interim data from our clinical study NCT03715985 showed that the personalized peptide-based neoantigen vaccine EVX-01, formulated in the liposomal adjuvant, CAF09b, was safe and able to elicit EVX-01-specific T cell responses in patients with metastatic melanoma. Here, we present results from the dose-escalation part of the study, evaluating the feasibility, safety, efficacy, and immunogenicity of EVX-01 in addition to anti-PD-1 therapy. METHODS: Patients with metastatic melanoma on anti-PD-1 therapy were treated in three cohorts with increasing vaccine dosages (twofold and fourfold). Tumor-derived neoantigens were selected by the AI platform PIONEER and used in personalized therapeutic cancer peptide vaccines EVX-01. Vaccines were administered at 2-week intervals for a total of three intraperitoneal and three intramuscular injections. The study's primary endpoint was safety and tolerability. Additional endpoints were immunological responses, survival, and objective response rates. RESULTS: Compared with the base dose level previously reported, no new vaccine-related serious adverse events were observed during dose escalation of EVX-01 in combination with an anti-PD-1 agent given according to local guidelines. Two patients at the third dose level (fourfold dose) developed grade 3 toxicity, most likely related to pembrolizumab. Overall, 8 out of the 12 patients had objective clinical responses (6 partial response (PR) and 2 CR), with all 4 patients at the highest dose level having a CR (1 CR, 3 PR). EVX-01 induced peptide-specific CD4+ and/or CD8+T cell responses in all treated patients, with CD4+T cells as the dominating responses. The magnitude of immune responses measured by IFN-γ ELISpot assay correlated with individual peptide doses. A significant correlation between the PIONEER quality score and induced T cell immunogenicity was detected, while better CRs correlated with both the number of immunogenic EVX-01 peptides and the PIONEER quality score. CONCLUSION: Immunization with EVX-01-CAF09b in addition to anti-PD-1 therapy was shown to be safe and well tolerated and elicit vaccine neoantigen-specific CD4+and CD8+ T cell responses at all dose levels. In addition, objective tumor responses were observed in 67% of patients. The results encourage further assessment of the antitumor efficacy of EVX-01 in combination with anti-PD-1 therapy.

Risk factors for rebleeding and mortality following prophylactic transarterial embolization for patients with high-risk peptic ulcer bleeding: a single-center retrospective cohort study.

BACKGROUND: To investigate factors associated with risk for rebleeding and 30-day mortality following prophylactic transarterial embolization in patients with high-risk peptic ulcer bleeding. METHODS: We retrospectively reviewed medical records and included all patients who had undergone prophylactic embolization of the gastroduodenal artery at Rigshospitalet, Denmark, following an endoscopy-verified and treated peptic Sulcer bleeding, from 2016 to 2021. Data were collected from electronic health records and imaging from the embolization procedures. Primary outcomes were rebleeding and 30-day mortality. We performed logistical regression analyses for both outcomes with possible risk factors. Risk factors included: active bleeding; visible hemoclips; Rockall-score; anatomical variants; standardized embolization procedure; and number of endoscopies prior to embolization. RESULTS: We included 176 patients. Rebleeding occurred in 25% following embolization and 30-day mortality was 15%. Not undergoing a standardized embolization procedure increased the odds of both rebleeding (odds ratio 3.029, 95% confidence interval (CI) 1.395-6.579) and 30-day overall mortality by 3.262 (1.252-8.497). More than one endoscopy was associated with increased odds of rebleeding (odds ratio 2.369, 95% CI 1.088-5.158). High Rockall-score increased the odds of 30-day mortality (odds ratio 2.587, 95% CI 1.243-5.386). Active bleeding, visible hemoclips, and anatomical variants did not affect risk of rebleeding or 30-day mortality. Reasons for deviation from standard embolization procedure were anatomical variations, targeted treatment without embolizing the gastroduodenal artery, and technical failure. CONCLUSIONS: Deviation from the standard embolization procedure increased the risk of rebleeding and 30-day mortality, more than one endoscopy prior to embolization was associated with higher odds of rebleeding, and a high Rockall-score increased the risk of 30-day mortality. We suggest that patients with these risk factors are monitored closely following embolization. Early detection of rebleeding may allow for proper and early re-intervention.

Increased Subclinical Coronary Artery Pathology in Type 2 Diabetes With Albuminuria.

Diabetes affects the kidneys, and the presence of albuminuria reflects widespread vascular damage and is a risk factor for cardiovascular disease (CVD). Still, the pathophysiological association between albuminuria and CVD remains incompletely understood. Recent advances in noninvasive imaging enable functional assessment of coronary artery pathology and present an opportunity to explore the association between albuminuria and CVD. In this cross-sectional study, we evaluated the presence of subclinical coronary artery pathology in people with type 2 diabetes, free of overt CVD. Using multimodal imaging, we assessed the coronary microcalcification activity (18F-sodium fluoride positron emission tomography/computed tomography [PET/CT], plaque inflammation [64Cu-DOTATATE PET/CT], and myocardial flow reserve [82Rb PET/CT]). The study population consisted of 90 participants, stratified by albuminuria; 60 had historic or current albuminuria (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g]), and 30 had normoalbuminuria (UACR <30 mg/g). We demonstrated that any albuminuria (historic or current) was associated with a more severe phenotype, in particular, higher levels of microcalcifications and impaired myocardial microvascular function; however, coronary inflammation activity was similar in people with and without albuminuria. Our findings establish a potential underlying mechanism connecting cardiovascular and kidney diseases and could indicate the initial stages of the cardiorenal syndrome.

Patient-reported outcomes used actively in cancer patients undergoing antineoplastic treatment: A mini-review of the Danish landscape.

Introduction: Many studies using Patient-reported outcomes (PRO) data have been conducted to monitor symptoms and health-related quality of life during follow-up after cancer treatment. However new ways of using (e)PROs have emerged. We aimed to explore the Danish landscape of the use of PRO in a research setting, where PRO is used actively in cancer patients undergoing treatment, and give an overview of how it is embraced by patients and clinicians. Methods and materials: A literature search was performed in June 2023, using the keywords Denmark, cancer, and patient-reported outcomes. An expert on literature searches identified the search terms, and double screening was performed at both abstract and screening levels and full-text stage. The software tool Covidence was used. Results: 467 articles were retrieved and 19 studies were included. They described the type of ePRO instrument used and the application of active ePRO i.e. a dialogue tool in the clinical encounter, release of alerts to clinicians, and enhancement of self-management. Finally, a development in the use of active ePROs over time is elucidated and we show how it is embraced by patients and clinicians. Conclusion: This mini-review gives an overview of how ePRO solutions are tested in oncological research in Denmark and embraced by patients and clinicians. ePRO solutions in a Danish setting seem well-suited for self-management. However, if more impact is warranted, clinicians need to engage in reviewing and using ePROs. Moreover, for successful implementation, the integration of ePROs in electronic health records must be supported by IT specialists and management.

Uptake of signposting to web-based resources: pregnant women's use of a preventive web-based intervention.

BACKGROUND: Signposting to web-based interventions is becoming increasingly popular in primary care. Most resources are focused on individuals with clinical problems, but less is known about the uptake of general practice (GP) signposted web-based interventions. GPs in Denmark are responsible for scheduled preventive care during pregnancy and the child's first five years. In the "Family Well-being in General Practice" trial the web-based intervention "Resilientchild.dk" is introduced at these consultations. Resilientchild.dk is designed to improve the capacity of parents to understand the mental state of themselves, their partners, and their children. In this study we assess the uptake and use of this web-based intervention. OBJECTIVE: To describe participant and practice characteristics associated with the use of a web-based psychoeducational intervention. Eligible participants were pregnant women presenting at their first antenatal assessment, usually around 6-10 gestational weeks. METHODS: The study was nested in a cluster randomised trial of resilientchild.dk. We conducted a relative importance analysis, which allows for determination of the variables most strongly associated with website use. To assess the direction and magnitude of the influences of the identified variables, we applied multinomial generalized linear mixed modelling. A practice random effect allows us to account for clustering of women within practices. RESULTS: Parity and the absence of a nurse or midwife in the practice were important factors driving a decrease in the likelihood of using resilientchild.dk. Being a student or living outside the capital city were important factors driving an increase in the likelihood of using resilientchild.dk. CONCLUSION: The data offer unique opportunities to assess the utilisation of a web-based mental health-promotion intervention following advice from a clinician. This study draws conclusions about which patients are likely to access similar resources and which practice characteristics encourage their use. TRIAL REGISTRATION: Registered in clinicaltrials.gov, Trial number: NCT04129359 Date of registration: 16/10/2019 ( https://clinicaltrials.gov/ct2/show/NCT04129359 ).

A critical examination of Danish norms for the Strengths and Difficulties Questionnaire (SDQ).

OBJECTIVE: The objective was to describe observed differences between the official Danish Strengths and Difficulties Questionnaire (SDQ)-norms and data from a sample based on the Danish National Birth Cohort (DNBC) including children born between 1996 and 2003. We compared the risk classification, cut-off bandings and the group sizes between the Danish norms and the values found in our sample at ages 7, 11 and 18 years. RESULTS: Two sets of norms are used in Denmark: Arnfred's norms, based on a sample from one single Danish municipality and Niclasen's norms, based on multiple Danish cohorts, including the DNBC. Inconsistencies were found between banding scores in the two existing norms and the banding scores identified in our sample from DNBC: discrepancies included banding scores for several of the problem scales for children and preadolescents. For adolescents, we found less apparent inconsistencies between Arnfred's sample and the DNBC. Results demonstrate that the existing SDQ norms do not apply well to a large-scale cohort sample in Denmark. The usefulness of the SDQ as a screening instrument for mental health problems depends on appropriate norms. We therefore urge that the current Danish SDQ norms are used with caution, and preferably they should be revised.

Significance of lipids, lipoproteins, and apolipoproteins during the first 14-16 months of life.

BACKGROUND AND AIMS: The aims of this study were to investigate lipid parameters during the first 14-16 months of life, to identify influential factors, and to test whether high concentrations at birth predict high concentrations at 2- and 14-16 months. METHODS: The Copenhagen Baby Heart Study, including 13,354 umbilical cord blood samples and parallel venous blood samples from children and parents at birth (n = 444), 2 months (n = 364), and 14-16 months (n = 168), was used. RESULTS: Concentrations of lipids, lipoproteins, and apolipoproteins in umbilical cord blood samples correlated highly with venous blood samples from newborns. Concentrations of low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, and lipoprotein(a) increased stepwise from birth to 2 months to 14-16 months. Linear mixed models showed that concentrations of LDL cholesterol, non-HDL cholesterol, and lipoprotein(a) above the 80th percentile at birth were associated with significantly higher concentrations at 2 and 14-16 months. Finally, lipid concentrations differed according to sex, gestational age, birth weight, breastfeeding, and parental lipid concentrations. CONCLUSIONS: Lipid parameters changed during the first 14-16 months of life, and sex, gestational age, birth weight, breastfeeding, and high parental concentrations influenced concentrations. Children with high concentrations of atherogenic lipid traits at birth had higher concentrations at 2 and 14-16 months. These findings increase our knowledge of how lipid traits develop over the first 14-16 months of life and may help in deciding the optimal child age for universal familial hypercholesterolaemia screening.

Modifiable cardiovascular risk factors and genetics for targeted prevention of dementia.

Dementia is a major global challenge for health and social care in the 21st century. A third of individuals >65 years of age die with dementia, and worldwide incidence numbers are projected to be higher than 150 million by 2050. Dementia is, however, not an inevitable consequence of old age; 40% of dementia may theoretically be preventable. Alzheimer's disease (AD) accounts for approximately two-thirds of dementia cases and the major pathological hallmark of AD is accumulation of amyloid-ß. Nevertheless, the exact pathological mechanisms of AD remain unknown. Cardiovascular disease and dementia share several risk factors and dementia often coexists with cerebrovascular disease. In a public health perspective, prevention is crucial, and it is suggested that a 10% reduction in prevalence of cardiovascular risk factors could prevent more than nine million dementia cases worldwide by 2050. Yet this assumes causality between cardiovascular risk factors and dementia and adherence to the interventions over decades for a large number of individuals. Using genome-wide association studies, the entire genome can be scanned for disease/trait associated loci in a hypothesis-free manner, and the compiled genetic information is not only useful for pinpointing novel pathogenic pathways but also for risk assessments. This enables identification of individuals at high risk, who likely will benefit the most from a targeted intervention. Further optimization of the risk stratification can be done by adding cardiovascular risk factors. Additional studies are, however, highly needed to elucidate dementia pathogenesis and potential shared causal risk factors between cardiovascular disease and dementia.

Evaluation of the Danish version of the prenatal parental reflective functioning questionnaire in early pregnancy as a screening tool.

Parental reflective functioning (PRF) is the capacity to focus on feelings and experiences in oneself as a parent and in the child. Research has demonstrated that, the better the PRF the better outcomes for the child. This paper evaluated the Danish version of the prenatal parental reflective functioning questionnaire (P-PRFQ). We used data from a cluster-randomized trial of pregnant women recruited from Danish general practice. The sample included 605 mothers. Factor structure and internal consistency were investigated. Linear regression analysis was used to examine the associations between the P-PRFQ score and the five most predictive variables. The confirmatory factor analyses supported the three-factor model. The P-PRFQ had moderate internal consistency. The regression analysis showed a decrease in the P-PRFQ score with increasing age, increasing parity, current employment, better self-reported health, lower anxiety score, and fewer negative life events with persistent impact. The directions of the associations between P-PRFQ score and the predictive variables were opposite of what was hypothesized raising questions about whether the P-PRFQ can be used as an early pregnancy screening tool assessing prenatal PRF. Further validation studies are required to assess the extent to which the P-PRFQ truly measures reflective functioning.

El funcionamiento con reflexión de los padres es la capacidad de enfocarse en sentimientos y experiencias en uno mismo como progenitor y en el niño. La investigación ha demostrado que mientras mejor es el funcionamiento con reflexión, mejores son los resultados para el niño. Este ensayo evalúa la versión danesa del cuestionario prenatal del funcionamiento con reflexión de los progenitores (P-PRFQ). Usamos datos de un ensayo con un grupo al azar de mujeres embarazadas reclutadas de la práctica general danesa. El grupo muestra estaba compuesto de 605 madres. Se investigaron la estructura de factores y la consistencia interna. Se usaron análisis de regresión lineal para examinar la asociación entre los puntajes del P-PRFQ y las cinco variables más predictivas. Los análisis de factores confirmatorios apoyaron el modelo de tres factores. El P-PRFQ presentó una consistencia interna moderada. Los análisis de regresión mostraron una baja en los puntajes del P-PRFQ con el aumento de la edad, el aumento de la paridad, el empleo actual, una mejor auto reportada salud, más bajo puntaje de ansiedad y menos eventos negativos en la vida con impacto persistente. Las direcciones de las asociaciones entre el puntaje del P-PRFQ y las variables predictivas resultaros lo opuesto de la hipótesis propuesta, lo cual genera preguntas sobre si se puede usar el P-PRFQ como una herramienta de examen temprano del embarazo para evaluar el funcionamiento con reflexión prenatal de los progenitores. Se requieren estudios posteriores de validación para evaluar hasta qué punto el P-PRFQ mide verdaderamente el funcionamiento con reflexión.

La fonction réflexive parentale est la capacité à se focaliser sur ses propres sentiments et ses expériences en tant que parent et chez l'enfant. Les recherches ont démontré que mieux fonctionne la fonction réflexive parentale, mieux s'avère le résultat pour l'enfant. Cet article a évalué la version danoise du questionnaire de la fonction réflexive parentale prénatale (P-PRFQ). Nous avons utilisé des données d'un essai randomisé par grappes de femmes enceintes recrutées dans un service de médecine générale au Danemark. L'échantillon a inclus 605 mères. La structure de facteur et la cohérence interne ont fait l'objet des recherches. Une analyse par régression linéaire a été utilisée afin d'examiner les liens entre le score P-PRFQ et les cinq variables les plus prédictives. Les analyses factorielles confirmatoires ont soutenu le modèle à trois facteurs. Le P-PRFQ a eu une cohérence internet. L'analyse par régression a montré une baisse dans le score P-PRFQ avec un âge plus avancé, une parité augmentée, un emploi courant, une meilleure santé auto-rapportée, un score d'anxiété plus bas et moins d'événements négatifs de la vie ayant un impact persistent. Les directions des liens entre le score P-PRFQ et les variables prédictives étaient à l'opposé de l'hypothèse, soulevant des questions sur si le P-PRFQ peut être utilisé en tant qu'outil de dépistage au début de la grossesse pour évaluer la fonction réflexive parentale prénatale. Des études de validation supplémentaires sont nécessaires pour évaluer dans quelle mesure le P-PRFQ mesure vraiment la fonction réflexive.

Association of self-reported mother-infant relationship with child and adolescent mental health.

BACKGROUND: The quality of the relationship between mother and infant may have profound implications for the development of a child. Early indicators of psychological vulnerability may allow targeting of support for the child's cognitive, emotional and social development. A challenging mother-infant relationship could be one indicator of risk. AIMS: This study examined variations in psychological well-being and psychopathology among boys and girls according to early maternal perception of the mother-infant relationship. METHOD: This study is based on 64 663 mother-infant pairs from the Danish National Birth Cohort, for which data on the mother-infant relationship were collected at 6 months postpartum. Behavioural problems were assessed with the Danish version of the Strengths and Difficulties Questionnaire (SDQ) at child ages 7, 11 and 18 years, and we retrieved information on diagnosed childhood and adolescent psychiatric disorders and prescriptions of psychotropic drugs from Danish registries. RESULTS: Children in the challenging mother-infant relationship group had higher odds of behavioural problems at age 7 among both boys and girls. The same pattern of elevated estimates was identified for boys across all SDQ domains and for girls in three of five SDQ domains. All associations were attenuated at age 18, but increased odds of behavioural problems still existed. A challenging early mother-infant relationship increased the offspring's risk of being diagnosed with a psychiatric disorder or being prescribed a psychotropic drug before the age of 18. CONCLUSION: A challenging self-reported mother-infant relationship was associated with later psychopathological difficulties. Routine clinical enquiry may be useful in identification of future vulnerability.

Family wellbeing in general practice: a study protocol for a cluster-randomised trial of the web-based resilience programme on early child development.

BACKGROUND: Social, emotional and behavioural problems in early childhood are associated with increased risk for a wide range of poor outcomes associated with substantial cost and impact on society as a whole. Some of these problems are rooted in the early mother-infant relationship and might be prevented. In Denmark, primary health care has a central role in preventive care during pregnancy and the first years of the child's life and general practice provides opportunities to promote a healthy mother-infant relationship in early parenthood. OBJECTIVE: In the context of standardised antenatal and child development assessments focused on psychosocial wellbeing, we examine the impact of a complex intervention designed to improve maternal mentalisation skills, involving training of general practice clinicians and signposting towards a web-based resource. Joint main outcomes are child socio-emotional and language development at age 30 months measured by parentally reported questionnaires (Communicative Development Inventory and Strengths and Difficulties Questionnaire). METHODS: The study is a cluster-randomised controlled trial based in general practices in the Capital Region and the Zealand Region of Denmark. Seventy practices were included. Practices were randomised by a computer algorithm in a ratio of 1:1 to intervention or control groups. Each practice was asked to recruit up to 30 women consecutively at their first scheduled antenatal assessment. Clinicians in both groups received one day of training in preventive antenatal and child development consultations with added focus on parental psychosocial well-being, social support, and parent-child interaction. These preventive consultations delivered in both trial arms require enhanced data recording about psychosocial factors. In intervention clinics, clinicians were asked to signpost a web page at three scheduled antenatal consultations and at four scheduled consultations when the child is 5 weeks, 5 months, 1 and 2 years. DISCUSSION: We hypothesise that the intervention will increase mothers' ability to be sensitive to their child's mental state to an extent that improves the child's language and mental state at 30 months of age measured by parent-reported questionnaires. TRIAL REGISTRATION: ClinicalTrials.gov NCT04129359. Registered on Oct 16 2019.

Red blood cell parameters in early childhood: a prospective cohort study.

OBJECTIVES: Red blood cell parameters are frequently used biomarkers when assessing clinical status in newborns and in early childhood. Cell counts, amounts, and concentrations of these parameters change through gestation and after birth. Robust age-specific reference intervals are needed to optimize clinical decision making. METHODS: The Copenhagen Baby Heart Study (CBHS) and the COMPARE study are prospective cohort studies including red blood cell parameters from 7,938 umbilical cord blood samples and 295 parallel venous blood samples from newborns with follow-up at two and at 14-16 months after birth. RESULTS: For venous blood at birth, reference intervals for hemoglobin, erythrocytes, and hematocrit were 145-224 g/L, 4.1-6.4 × 1012/L, and 0.44-0.64, respectively. Hemoglobin, erythrocytes, and hematocrit were lower at birth in children delivered by prelabor cesarean section compared to vaginal delivery. Conversion algorithms based on term newborns were: venous hemoglobin=(umbilical cord hemoglobin-86.4)/0.39; venous erythrocytes=(umbilical cord erythrocytes-2.20)/0.44; and venous hematocrit=(umbilical cord hematocrit-0.24)/0.45. CONCLUSIONS: This study presents new reference intervals for red blood cell parameters in early childhood, describes the impact of delivery mode, and provide exact functions for converting umbilical cord to venous blood measurements for term newborns. These findings may improve clinical decision making within neonatology and infancy and enhance our clinical understanding of red blood cell parameters for health and diseases in early life.

A pre-post intervention study: Knowledge among parents about child infections and antibiotic use facilitated by maternal and child health nurses.

AIMS: To investigate parent's knowledge and beliefs of common infections and antibiotics in children before and after an educational intervention provided by maternal and child health nurses. Second, to investigate sociodemographic differences in parent's knowledge before and following the intervention. DESIGN: A prospective pre-post intervention study. The intervention consisted of a booklet with information about childhood infections delivered by maternal and child health nurses. METHODS: The study population included 344 parents with a child born during 2017 and residing in three Danish municipalities. Knowledge about infections and antibiotics were collected quantitatively through an online questionnaire before and after the intervention (August 2017-November 2018) and analysed using linear mixed models. RESULTS: Parental knowledge increased after the intervention. Parents with lower education and born in Denmark compared to parents with higher education and born in other countries experienced a higher increase in knowledge from baseline to follow-up.

In vivo molecular imaging of cardiac angiogenesis in persons with and without type 2 diabetes: A cross-sectional 68 Ga-RGD-PET study.

AIMS: To assess cardiac angiogenesis in type 2 diabetes by positron emission tomography (PET) tracer [68 Ga]Ga-NODAGA-E[(cRGDyK)]2 (68 Ga-RGD) imaging. METHODS: Cross-sectional study including 20 persons with type 2 diabetes and 10 non-diabetic controls (CONs). Primary prespecified outcome was difference in cardiac angiogenesis (cardiac 68 Ga-RGD mean target-to-background ratio [TBRmean ]) between type 2 diabetes and CONs. Secondary outcome was to investigate associations between cardiac angiogenesis and kidney function and other risk factors. RESULTS: Participants with type 2 diabetes had a mean ± SD age of 61 ± 9 years, 30% were women, median (IQR) diabetes duration of 11 (6-19) years and 3 (15%) had a history of cardiovascular disease. The CONs had comparable age and sex distribution to the participants with type 2 diabetes, and none had a history of coronary artery disease. Myocardial flow reserve was lower in type 2 diabetes (2.7 ± 0.6) compared with CONs (3.4 ± 1.2) ( p  = 0.03) and coronary artery calcium score was higher (562 [142-905] vs. 1 [0-150] p  = 0.04). Cardiac 68 Ga-RGD TBRmean was similar in participants with type 2 diabetes (0.89 ± 0.09) and CONs (0.89 ± 0.10) ( p  = 0.92). Cardiac 68 Ga-RGD TBRmean was not associated with estimated glomerular filtration rate, urine albumin creatinine ratio, cardiovascular disease, coronary artery calcium score or baroreflex sensitivity, neither in pooled analyses nor in type 2 diabetes. CONCLUSIONS: Cardiac angiogenesis, evaluated with 68 Ga-RGD PET, was similar in type 2 diabetes and CONs. Cardiac angiogenesis was not associated with kidney function or other risk markers in pooled analyses or in analyses restricted to type 2 diabetes.

Markers of Kidney Function in Early Childhood and Association With Maternal Comorbidity.

Importance: Kidney functional capacity is low at birth but doubles during the first 2 weeks of life and reaches near-adult levels at age 1 to 2 years. Existing reference intervals for markers of kidney function in newborns are mostly based on preterm newborns, newborns with illness, or small cohorts of term newborns, and the consequences of maternal comorbidities for newborn kidney function are sparsely described. Objective: To establish robust reference intervals for creatinine and urea in healthy children in early childhood and to assess whether maternal comorbidity is associated with newborn creatinine and urea concentrations. Design, Setting, and Participants: This multicenter, prospective, population-based cohort study assessed data and umbilical cord blood samples from participants in the Copenhagen Baby Heart Study (CBHS) who were born between April 1, 2016, and October 31, 2018, and venous blood samples from a subsample of CBHS participants who were enrolled in the COMPARE study between May 3, 2017, and November 4, 2018. Cord blood samples of 13 354 newborns from the CBHS and corresponding venous blood samples of 444 of those newborns from the COMPARE study were included. Blood samples were collected at birth, age 2 months, and age 14 to 16 months, with follow-up completed on February 12, 2020. Healthy nonadmitted term newborns from maternity wards at 3 hospitals in the Capital Region of Denmark were included. Exposures: Maternal comorbidity. Main Outcomes and Measures: Creatinine and urea concentrations. Results: Among 13 354 newborns in the CBHS cohort, characteristics of 12 938 children were stratified by sex and gestational age (GA). Of those, 6567 children (50.8%) were male; 5259 children (40.6%) were born at 37 to 39 weeks' GA, and 7679 children (59.4%) were born at 40 to 42 weeks' GA. Compared with children born at 40 to 42 weeks' GA, those born at 37 to 39 weeks' GA had lower birth weight, Apgar scores at 5 minutes, placental weight, and placental-fetal weight ratio. Children born at 37 to 39 weeks' GA vs those born at 40 to 42 weeks' GA were more frequently small for GA at birth and more likely to have placental insufficiency and exposure to maternal preeclampsia, maternal diabetes, maternal kidney disease, and maternal hypertension. Among children born at 37 to 39 weeks' GA, reference intervals were 0.54 to 1.08 mg/dL for creatinine and 5.32 to 14.67 mg/dL for urea; among children born at 40 to 42 weeks' GA, reference intervals were 0.57 to 1.19 mg/dL for creatinine and 5.60 to 14.85 mg/dL for urea. At birth, multifactorially adjusted odds ratios among children exposed to preeclampsia were 9.40 (95% CI, 1.68-52.54) for a venous creatinine concentration higher than the upper reference limit, 4.29 (95% CI, 1.32-13.93) for a venous creatinine concentration higher than the 90th percentile, and 3.10 (95% CI, 1.14-8.46) for a venous creatinine concentration higher than the 80th percentile. Conclusions and Relevance: In this study, improved reference intervals for creatinine and urea concentrations were generated. Preeclampsia was associated with an increased risk of high newborn creatinine concentrations, suggesting that newborns of mothers with preeclampsia need closer observation of their kidney function.

Physical activity in leisure time and at work and risk of dementia: A prospective cohort study of 117,616 individuals.

BACKGROUND AND AIMS: Up to 40% of all dementia cases may be preventable, primarily by treating or acting on well-established cardiovascular risk factors such as diabetes, hypertension, smoking, and physical inactivity. Whether physical inactivity is associated with risk of non-Alzheimer's dementia - a disease influenced by cardiovascular risk factors - and whether a given association differs for physical activity in leisure time and at work remains unknown. METHODS: We conducted a prospective cohort study including 117,616 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study with up to 43 years of follow-up. RESULTS: Multifactorially adjusted hazard ratios for low versus high physical activity at leisure time was 1.60 (95% confidence interval 1.40-1.83) for non-Alzheimer's dementia and 0.94 (0.80-1.11) for Alzheimer's disease. Corresponding values for non-Alzheimer's dementia after additional adjustment for physical activity at work or apolipoprotein E (APOE) genotype were 1.60 (1.40-1.83) and 1.82 (1.34-2.15). Multifactorially and APOE adjusted hazard ratios for high versus low physical activity at work were 1.50 (1.10-2.05) for non-Alzheimer's dementia and 1.62 (1.14-2.31) for Alzheimer's disease. When combining the two types of physical activity, physical activity in leisure time had the strongest relationship with risk of non-Alzheimer's dementia. CONCLUSIONS: Physical inactivity in leisure time was associated with increased risk of non-Alzheimer's dementia, independent of modifiable risk factors and physical activity at work. The present study thus provides evidence for public health advice on physical activity in leisure time for the vascular part of dementia.

Individualizing the Oncological Treatment of Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma by Using Gene Sequencing and Patient-Reported Outcomes: Protocol for the INDIGO Study.

BACKGROUND: No phase 3 studies have yet been conducted for patients with non-clear cell (CC) renal cell carcinoma (RCC) exclusively due to the rare occurrence of the disease and the heterogenicity in tumor morphology. Consequently, there is no evidence of the optimal treatment, and new approaches are needed. One approach is individualizing treatment based on the gene sequencing of tumor tissue. Additionally, recent studies involving the patient-reported outcomes (PROs) of patients treated for metastatic cancer have shown significant benefits for quality of life, median overall survival, and overall survival. The use of gene sequencing and PROs can be of great importance to patients with rare cancer types, including patients with non-CC RCC, and should be investigated in clinical trials, especially for cases where evidence based on phase 3 studies is difficult to obtain. OBJECTIVE: We describe the INDIGO study, in which patients, based on gene analyses, will be allocated into 4 treatment arms containing 14 treatments and use electronic PROs. We aim to improve the treatment of patients with non-CC RCC. The end points in the study will be the overall response rate (complete and partial) in the total patient population, which will be based on the RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria, and the time to treatment failure. METHODS: INDIGO is a prospective phase 2 trial, and 30 patients will be enrolled. The patients will receive systemic treatment based on genetic analyses of their tumor tissue. All patients will receive electronic questionnaires in a dedicated app-a questionnaire regarding symptoms and side effects and another regarding health-related quality of life. Depending on the treatment regimen, the patients will be seen by a medical doctor every third, fourth, or sixth week, and the effect of the systemic treatment will be evaluated every 6 weeks via a computed tomography scan. The study has been approved by the Danish Medicines Agency and the National Committee on Health Research Ethics (approval number: H-19041833), complies with good clinical practice guidelines, follows the General Data Protection Regulation, and is registered at the Capital Region of Denmark. RESULTS: Recruitment started in March 2020, and at the time of submitting this paper (June 2022), a total of 9 patients have been enrolled. CONCLUSIONS: We aim to explore methods for improving the treatment outcomes of patients with non-CC RCC, and the INDIGO study will contribute further data on personalized medicine for rare types of RCC and provide new knowledge on the active use of electronic PROs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04644432, https://clinicaltrials.gov/ct2/show/NCT04644432 ; European Union Drug Regulating Authorities Clinical Trials Database 2019-001316-38, https://tinyurl.com/2p8mb4aw. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36632.

Chicken IgY reduces the risk of Pseudomonas aeruginosa urinary tract infections in a murine model.

Introduction: Urinary tract infections (UTIs) with Pseudomonas aeruginosa are a severe problem in disposed patients in modern healthcare. Pseudomonas aeruginosa establishes recalcitrant biofilm infections and can develop antibiotic resistance. Gargling with avian egg yolk anti-Pseudomonas antibodies (IgY) has shown clinical effect in preventing onset of chronic P. aeruginosa lung infections in patients with cystic fibrosis (CF). Therefore, we speculated whether passive intravesically administered IgY immunotherapy could be a novel strategy against P. aeruginosa UTIs. Aim: To evaluate if prophylactic repurposing of anti-Pseudomonas IgY can prevent UTIs with P. aeruginosa in a UTI mouse model. Materials and methods: In vitro, P. aeruginosa (PAO1 and PAO3) was mixed with increasing concentrations of specific anti-Pseudomonas IgY (sIgY) or non-specific control IgY (cIgY) and/or freshly isolated human neutrophils. Bacterial growth was evaluated by the optical density at 600 nm. In vivo, via a temporary transurethral catheter, 10-week-old female Balb/c mice were intravesically infected with 50 ml of a bacterial suspension and sIgY, cIgY, or isotonic NaCl. IgY and NaCl were either co-instilled with the bacteria, or instilled prophylactically, 30 min prior to infection. The animals were euthanized 20 h after infection. Vesical bacteriology was quantified, and cytokine expression in the bladder homogenate was measured by multiplex cytokine assay. Results: In vitro, sIgY concentrations above 2.5% reduced bacterial growth in a dose-dependent manner. In vivo, a UTI lasting for minimum 7 days was established by installing 5 × 106 colony-forming units (CFU) of P. aeruginosa PAO1. sIgY reduced vesical bacterial load if co-installed with P. aeruginosa PAO1. Prophylactic sIgY and cIgY reduced bacterial load when compared to isotonic NaCl. CXCL2 and G-CSF were both increased in infected bladders compared to non-infected controls which had non-detectable levels. Co-installation of sIgY and bacteria nearly completely inhibited the inflammatory response. However, the cytokine levels in the bladder did not change after prophylactic administration of sIgY or cIgY. Conclusion: Prophylactic sIgY significantly reduces the amount of bacteria in the bladder in a mouse model of P. aeruginosa cystitis and may serve as a novel non-antibiotic strategy in preventing P. aeruginosa UTIs.