Survival, cardiorespiratory fitness and quality of life after renal transplantation in childhood: Data from the HENT study

Renal transplantation (tx) restores kidney function temporarily and improves the prospects of a normal life as compared to dialysis. During the last forty years great progress has been made in renal transplantation and its follow up treatment. However, preserving long-term graft function is still a major challenge. Therefore, it is crucial to review our practices in pediatric transplantation and to evaluate patient outcome as the first step in enhancing future prospects. Following renal tx a chronic multifactorial physical and mental condition persists both for the child and its caregivers. Life-long dependence on immunosuppressive treatment (IS) and concomitant comorbidities after tx (e.g. progressive decline in renal function, hypertension, hyperlipidemia and excessive weight gain) render these children at increased risk for future cardiovascular (CV) morbidity and mortality. Based on structural and functional echocardiographic findings post-tx, these children have been forecast a rather gloomy CV prognosis including cardiomyopathy and heart failure in adult life. However, little attention has so far been paid to the levels of physical activity and cardiorespiratory fitness (CR fitness, V02peak) as global markers of CV health and physical functioning in tx children and adult survivors. Furthermore, more knowledge is required of the impact of tx on health related quality of life (HRQOL) for the child and its caregivers following, predominantly, parental kidney donation

The effects of water temperature and photoperiod: Investigating the cause of early activation of the BPG axis in male Atlantic salmon (Salmo salar) during the freshwater stages of development

Early sexual maturation of Atlantic salmon (Salmo salar) post-smolts has been a major issue over the years and has recently become a prevalent issue in land-based production systems like the recirculating aquaculture systems (RAS), where early maturation is more prevalent in males. Atlantic salmon that mature early experience a loss of growth, may have a higher risk of infections and are at risk of dying if they are kept in sea water during maturation, and the aquaculture companies experience a loss of profit and altered production schedules. Male Atlantic salmon were exposed to two different temperatures regimes of 12.5℃ and 15℃ and photoperiod regimes, where all salmon were exposed to long light, LL (LD 24:0) prior half being exposed to a winter signal period, WS for 5 weeks (LD: 12:12) and then LL. Body weight and condition factor (K) was measured and calculated to examine changes in growth and the gonadosomatic index (GSI) was calculated to discern maturation levels in the four experimental groups (12.5℃-WS, 12.5℃-LL, 15℃-LL and 15℃ WS). Gene expression profiles were calculated as relative mRNA abundance, where diencephalon expressions of gnrh2, gpr54, gniha, gnihb, and dio2b and pituitary tshβb expression were analyzed to ascertain their potential influence on maturation. The salmon in all experimental groups grew steadily throughout the experiment, and condition factor mainly increased in all groups suggesting the salmon did not smoltify normally. Early maturation was observed in the 15℃-LL group, indicating that exposure to a higher water temperature and continuous light may trigger early onset maturation in Atlantic salmon. Temperature was the key factor influencing changes in diencephalon expression of gnrh2, gpr54, gniha and gnihb over time, where a possible effect of the onset of maturation may be stimulated by exposure to LL and inhibited by exposure to WS. Photoperiod was the key regulator on the pituitary expression levels tshβb, which increased in only the 15℃-WS group and 12.5℃-WS group following exposure to LL. Results indicate that there is a TSH-DIO2 signaling system in Atlantic salmon, but its role related to maturation is not as clear as in mammals and birds. The lack of a tshβb expression peak in the salmon exposed to continuous lights suggest that this light regime disrupts the physiology during freshwater development and emphasizes the importance of subjecting salmon to a winter signal during freshwater development. Further studies are needed to elucidate the possible role of TSH in smoltification and maturation in Atlantic salmon. Of the tested photoperiod and temperature regimes, exposure to a water temperature of 12.5℃ and a winter signal period presents as the best option to avoid early post-smolt maturation in Atlantic salmon.Masteroppgave i biologiBIO399MAMN-BIOMAMN-HAVS

Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases: Results From the First Multi-Center European Survey

Malalties metabòliques hereditàries; Malaltia rara; Procés de transicióEnfermedades metabólicas hereditarias; Enfermedad rara; Proceso de transición:esInherited metabolic disease(s); Rare disease; Transition processInherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called “transition.” The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe.This work was generated within the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), co-funded by the European Union within the framework of the Third Health Programme ERN-2016 - Framework Partnership Agreement 2017–2021, Project ID No. 739543

The prevalence and clinical relevance of hyperhomocysteinemia suggesting vitamin B12 deficiency in presumed healthy infants

Background Previous studies have demonstrated a high prevalence of biochemical vitamin B12 deficiency in infants in Norway. Increased total homocysteine (tHcy) is the most important marker of B12 deficiency in infants. There is a need to evaluate its clinical relevance. Aims To investigate the prevalence of hyperhomocysteinemia (S-tHcy > 8 μmol/L) suggestive of suboptimal B12 status and the prevalence of clinically relevant hyperhomocysteinemia in presumed healthy infants in Norway. Further, to evaluate risk factors, presence of symptoms and psychomotor development in these children. Methods In a prospective study we clinically examined 252 infants aged 3–7 months using standardized neurological and psychomotor tests prior to analyzing biochemical B12 deficiency markers in 250 infants. Results Twenty-five of 250 (10%) infants had hyperhomocysteinemia combined with clinically relevant symptoms suggestive of B12 deficiency. Hyperhomocysteinemia was associated with tremor, excessive sleep, and sub-normal scores in the fine motor section of the Ages and Stages Questionnaire. One-hundred and fourteen of 250 (46%) infants had hyperhomocysteinemia. Multiple regression analysis showed months of infant formula use as the strongest negative predictor for hyperhomocysteinemia. Conclusion We have demonstrated associations between symptoms suggestive of infant B12 deficiency and increased levels of tHcy in presumed healthy infants The combination of hyperhomocysteinemia and associated relevant symptoms suggestive of B12 deficiency was a common finding, albeit most infants with hyperhomocysteinemia did not show symptoms.publishedVersio

Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases : Results From the First Multi-Center European Survey

Inherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called "transition." The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe

Kidney transplantation in childhood: mental health and quality of life of children and caregivers

Our objective was to assess the mental health and health-related quality of life (HRQOL) in children and their parents after renal transplantation (TX) compared to healthy controls and children with acute lymphoblastic leukemia (ALL) and to identify possible health status variables associated with impaired mental health and HRQOL. Thirty-eight TX children with a median age of 13 (range 3–19) years were investigated. Mental health was assessed by the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and the Strength and Difficulties Questionnaire (SDQ-20). Each mother’s own mental health and QOL were assessed by the General Health Questionnaire (GHQ-30) and the Quality of Life Scale (QOLS). Forty children with ALL [median age 11 (8.5–15.4) years] and 42 healthy children [median age 11 (8.9– 15) years] served as controls. Treadmill exercise results from 22 of the 38 patients were included in the analysis. TX children showed significantly higher levels of mental health problems and lower HRQOL at 2 to 16 years after transplantation compared to both control groups. Body mass index and maximal oxygen uptake (n = 22/38) were significant predictors of child mental health (SDQ) and child QOL (PedsQL), respectively. Based on these results, we suggest that rehabilitation after TX should include a focus on physical activity and QOL to reduce interconnected physical and psychological morbidity in kidney TX children

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic

Incentivizing the Dynamic Workforce: Learning Contracts in the Gig-Economy

In principal-agent models, a principal offers a contract to an agent to perform a certain task. The agent exerts a level of effort that maximizes her utility. The principal is oblivious to the agent's chosen level of effort, and conditions her wage only on possible outcomes. In this work, we consider a model in which the principal is unaware of the agent's utility and action space. She sequentially offers contracts to identical agents, and observes the resulting outcomes. We present an algorithm for learning the optimal contract under mild assumptions. We bound the number of samples needed for the principal obtain a contract that is within $\epsilon$ of her optimal net profit for every $\epsilon>0$

The effects of water temperature and photoperiod: Investigating the cause of early activation of the BPG axis in male Atlantic salmon (Salmo salar) during the freshwater stages of development

Early sexual maturation of Atlantic salmon (Salmo salar) post-smolts has been a major issue over the years and has recently become a prevalent issue in land-based production systems like the recirculating aquaculture systems (RAS), where early maturation is more prevalent in males. Atlantic salmon that mature early experience a loss of growth, may have a higher risk of infections and are at risk of dying if they are kept in sea water during maturation, and the aquaculture companies experience a loss of profit and altered production schedules. Male Atlantic salmon were exposed to two different temperatures regimes of 12.5℃ and 15℃ and photoperiod regimes, where all salmon were exposed to long light, LL (LD 24:0) prior half being exposed to a winter signal period, WS for 5 weeks (LD: 12:12) and then LL. Body weight and condition factor (K) was measured and calculated to examine changes in growth and the gonadosomatic index (GSI) was calculated to discern maturation levels in the four experimental groups (12.5℃-WS, 12.5℃-LL, 15℃-LL and 15℃ WS). Gene expression profiles were calculated as relative mRNA abundance, where diencephalon expressions of gnrh2, gpr54, gniha, gnihb, and dio2b and pituitary tshβb expression were analyzed to ascertain their potential influence on maturation. The salmon in all experimental groups grew steadily throughout the experiment, and condition factor mainly increased in all groups suggesting the salmon did not smoltify normally. Early maturation was observed in the 15℃-LL group, indicating that exposure to a higher water temperature and continuous light may trigger early onset maturation in Atlantic salmon. Temperature was the key factor influencing changes in diencephalon expression of gnrh2, gpr54, gniha and gnihb over time, where a possible effect of the onset of maturation may be stimulated by exposure to LL and inhibited by exposure to WS. Photoperiod was the key regulator on the pituitary expression levels tshβb, which increased in only the 15℃-WS group and 12.5℃-WS group following exposure to LL. Results indicate that there is a TSH-DIO2 signaling system in Atlantic salmon, but its role related to maturation is not as clear as in mammals and birds. The lack of a tshβb expression peak in the salmon exposed to continuous lights suggest that this light regime disrupts the physiology during freshwater development and emphasizes the importance of subjecting salmon to a winter signal during freshwater development. Further studies are needed to elucidate the possible role of TSH in smoltification and maturation in Atlantic salmon. Of the tested photoperiod and temperature regimes, exposure to a water temperature of 12.5℃ and a winter signal period presents as the best option to avoid early post-smolt maturation in Atlantic salmon