A Mixed Methods Study of Adherence to Prophylactic Treatment Among Young People With Haemophilia

Introduction Haemophilia is an inherited bleeding disorder caused by a deficiency in one of the coagulation or blood clotting factors in the blood. When injured someone with haemophilia does not bleed more intensely than a person without haemophilia, but they tend to bleed for a much longer time. For people affected by severe haemophilia, the deficiency in coagulation factor can cause spontaneous internal bleeding in joints and muscles, as well as intracranial bleeding, and bleeding in soft tissues (e.g. nosebleeds or bleeding gums). The most common form is Haemophilia A which is caused by a deficiency in factor VIII. Haemophilia B is caused by a deficiency of factor IX and tends to be less severe than haemophilia A. Haemophilia is treated by replacing the deficient coagulation factor in the blood through intravenous injections of factor concentrate. Treatment can be on-demand, where medication is used to treat a bleeding episode; or preventative, where factor replacement treatment is used to increase the concentration of coagulation factor in the blood to prevent bleeding. Most young people with severe haemophilia in the UK follow a preventative treatment regimen (prophylactic treatment or prophylaxis). Patients with severe haemophilia A usually take 3 or 4 injections per week on alternate days, whereas patients with severe haemophilia B usually take 2 or 3 injections per week. There is good evidence that prophylaxis reduces bleeds and joint damage, whilst also improving quality of life. Therefore it is imperative for future health and functioning that young people with haemophilia (YPH) follow the prophylactic regimen they agreed with their haemophilia team. However, reported adherence levels among YPH vary widely (17 - 93%). Additionally, drivers of (non)adherence among YPH specifically have not been evidenced. Aims The overall aim of the research described in this thesis was to gain a better understanding of the extent to which YPH adhere to their prophylactic treatment, and better understand what drives their (non-)adherence. The aims of the quantitative questionnaire study were to measure levels of adherence among YPH, and to assess whether psychosocial factors that have been shown to be associated with adherence among young people with other chronic illnesses, such as self-efficacy and social support, are also associated with adherence among YPH. Based on previous research on adherence and social cognitive models of illness, it was hypothesised that: - there would be differences between adolescents and young adults in relation to psychosocial correlates of adherence. - higher perceptions of pain and impact of pain would be associated with better adherence (De Moerloose, Urbancik, Van Den Berg, & Richards, 2008; Treil, Rice, & Leissinger, 2007). - higher perceptions of chronicity, consequences and treatment control would be predictive of higher adherence (Chilcot et al., 2010; Horne & Weinman, 2002). - greater perception of necessity of prophylaxis would be predictive of higher adherence whereas concerns about prophylaxis would not be predictive (de Thurah, Nørgaard, Harder, & Stengaard-Pedersen, 2010; Horne et al., 2013; Horne & Weinman, 1999; Llewellyn, Miners, Lee, Harrington, & Weinman, 2003; Wileman et al., 2014). - greater negative mood would be associated with lower adherence scores (Cox & Hunt, 2015; Helgeson, Siminerio, Escobar, & Becker, 2009; Snell, Fernandes, Bujoreanu, & Garcia, 2014). In addition, based on evidence that lower adherence results in worse disease outcomes (Berntorp, 2009; M. J. Manco-Johnson et al., 2007), it was anticipated that non-adherence to prophylaxis would be associated with higher numbers of bleeds and hospital visits. The aims of the qualitative interview studies with YPH, parents of YPH, and haemophilia healthcare professionals were to examine perceptions and experiences in relation to prophylaxis and how they make sense of these experiences. It was anticipated that this would provide evidence to gain a better understanding of the complexities surrounding prophylaxis and of the barriers and facilitators to adherence among YPH

Emerging Processes Within Peer-Support Hearing Voices Groups: A Qualitative Study in the Dutch Context

Purpose/Aims: This study aimed to gain insight into the value of Hearing Voices Groups (HVGs) in the Dutch context. Specifically, we aimed to learn more about the meaning of HVG participation, as well as the aspects that contribute to that meaning, from the perspective of participants' experiences. Method: The study used a qualitative design with in-depth interviews to explore the experiences of 30 members within seven HVGs in the Netherlands. Interviews were recorded, transcribed, and analyzed using interpretative analysis inspired by the Grounded Theory method. Findings: The individual-level analysis revealed four different group processes that appear to determine the value that HVGs have for their participants: (i) peer-to-peer validation, (ii) exchanging information and sharing self-accumulated knowledge, (iii) connection and social support, and (iv) engaging in mutual self-reflection. We found that specific characteristics of HVGs facilitate these group processes and lead to specific personal outcomes. Combining the interview data from people who joined the same HVG reveals that, although all four described group processes occur in all groups, each group's emphasis differs. Three related factors are described: (i) the composition of the group, (ii) the style of the facilitators, and (iii) the interaction between group processes and individual processes. Implications: Unique processes, for which there is little to no place within regular mental health care (MHC), occur within HVGs. MHC professionals should be more aware of the opportunities HVG can offer voice-hearers. Essential matters regarding the implementation of HVGs are discussed

Early adversity and 5-HTT-BDNF genes: new evidences of gene-environment interactions on depressive symptoms in a general population

Adverse childhood experiences have been described as one of the major environmental risk factors for depressive disorder. Likewise, the deleterious impact of early traumatic experiences on depression seems to be moderated by individual genetic variability. Serotonin transporter (5-HTT) and the Brain-Derived Neurotrophic Factor (BDNF) seem to modulate the effect of childhood adversity on adult depression, although inconsistencies across studies have been found. Moreover, the GxE interaction concerning the different types of childhood adversity remains poorly understood. The aim of this study is to analyse the putative interaction between the 5-HTT gene (5- HTTLPR polymorphism), BDNF gene (Val66Met polymorphism) and childhood adversity in accounting for adult depressive symptoms Method A sample of 534 healthy individuals filled in self-report questionnaires of depressive symptomatology [the Symptom Check List 90 Revised (SCL-90-R)] and different types of childhood adversities [the Childhood Trauma Questionnaire (CTQ)]. The 5-HTTLPR polymorphism (5-HTT gene) and the Val66Met polymorphism (BDNF gene) were genotyped in the whole sample. Results Total childhood adversity (β=0.27, p<0.001), childhood sexual abuse (CSA; β=0.17, p<0.001), childhood emotional abuse (β=0.27,p<0.001) and childhood emotional neglect (β=0.22, p<0.001) had an impact on adult depressive symptoms. CSA had a greater impact on depressive symptoms in Met allele carriers of the BDNF gene than in the Val/Val group (F=5.87, p<0.0001), and in S carriers of the 5-HTTLPR polymorphism (5-HTT gene) (F=5.80, p<0.0001). Conclusions Childhood adversity per se predicted higher levels of adult depressive symptoms. In addition, BDNF Val66Met and 5-HTTLPR polymorphisms seemed to moderate the effect of CSA on adult depressive symptom

Short-term protein restriction at advanced age stimulates FGF21 signalling, energy expenditure and browning of white adipose tissue

Dietary protein restriction has been demonstrated to improve metabolic health under various conditions. However, the relevance of ageing and age-related decline in metabolic flexibility on the effects of dietary protein restriction has not been addressed. Therefore, we investigated the effect of short-term dietary protein restriction on metabolic health in young and aged mice. Young adult (3 months old) and aged (18 months old) C57Bl/6J mice were subjected to a 3-month dietary protein restriction. Outcome parameters included fibroblast growth factor 21 (FGF21) levels, muscle strength, glucose tolerance, energy expenditure (EE) and transcriptomics of brown and white adipose tissue (WAT). Here, we report that a low-protein diet had beneficial effects in aged mice by reducing some aspects of age-related metabolic decline. These effects were characterized by increased plasma levels of FGF21, browning of subcutaneous WAT, increased body temperature and EE, while no changes were observed in glucose homeostasis and insulin sensitivity. Moreover, the low-protein diet used in this study was well-tolerated in aged mice indicated by the absence of adverse effects on body weight, locomotor activity and muscle performance. In conclusion, our study demonstrates that a short-term reduction in dietary protein intake can impact age-related metabolic health alongside increased FGF21 signalling, without negatively affecting muscle function. These findings highlight the potential of protein restriction as a strategy to induce EE and browning of WAT in aged individuals

Age-related susceptibility to insulin resistance arises from a combination of CPT1B decline and lipid overload

Abstract Background The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD). Results As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet. Conclusion We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR

Eosinophil Morphology Eosinophil granules and degranulation

Endogenous DNA damage is causally associated with the functional decline and transformation of stem cells that characterize aging. DNA lesions that have escaped DNA repair can induce replication stress and genomic breaks that induce senescence and apoptosis. It is not clear how stem and proliferating cells cope with accumulating endogenous DNA lesions and how these ultimately affect the physiology of cells and tissues. Here we have addressed these questions by investigating the hematopoietic system of mice deficient for Rev1, a core factor in DNA translesion synthesis (TLS), the postreplicative bypass of damaged nucleotides. Rev1 hematopoietic stem and progenitor cells displayed compromised proliferation, and replication stress that could be rescued with an antioxidant. The additional disruption of Xpc, essential for global-genome nucleotide excision repair (ggNER) of helix-distorting nucleotide lesions, resulted in the perinatal loss of hematopoietic stem cells, progressive loss of bone marrow, and fatal aplastic anemia between 3 and 4 months of age. This was associated with replication stress, genomic breaks, DNA damage signaling, senescence, and apoptosis in bone marrow. Surprisingly, the collapse of the Rev1Xpc bone marrow was associated with progressive mitochondrial dysfunction and consequent exacerbation of oxidative stress. These data reveal that, to protect its genomic and functional integrity, the hematopoietic system critically depends on the combined activities of repair and replication of helix-distorting oxidative nucleotide lesions by ggNER and Rev1-dependent TLS, respectively. The error-prone nature of TLS may provide mechanistic understanding of the accumulation of mutations in the hematopoietic system upon aging

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Climate change effects on phytoplankton depend on cell size and food web structure

We investigated the effects of warming on a natural phytoplankton community from the Baltic Sea, based on six mesocosm experiments conducted 2005–2009. We focused on differences in the dynamics of three phytoplankton size groups which are grazed to a variable extent by different zooplankton groups. While small-sized algae were mostly grazer-controlled, light and nutrient availability largely determined the growth of medium- and large-sized algae. Thus, the latter groups dominated at increased light levels. Warming increased mesozooplankton grazing on medium-sized algae, reducing their biomass. The biomass of small-sized algae was not affected by temperature, probably due to an interplay between indirect effects spreading through the food web. Thus, under the higher temperature and lower light levels anticipated for the next decades in the southern Baltic Sea, a higher share of smaller phytoplankton is expected. We conclude that considering the size structure of the phytoplankton community strongly improves the reliability of projections of climate change effects

Ubiquitous LEA29Y Expression Blocks T Cell Co-Stimulation but Permits Sexual Reproduction in Genetically Modified Pigs

We have successfully established and characterized a genetically modified pig line with ubiquitous expression of LEA29Y, a human CTLA4-Ig derivate. LEA29Y binds human B7.1/CD80 and B7.2/CD86 with high affinity and is thus a potent inhibitor of T cell co-stimulation via this pathway. We have characterized the expression pattern and the biological function of the transgene as well as its impact on the porcine immune system and have evaluated the potential of these transgenic pigs to propagate via assisted breeding methods. The analysis of LEA29Y expression in serum and multiple organs of CAG-LEA transgenic pigs revealed that these animals produce a biologically active transgenic product at a considerable level. They present with an immune system affected by transgene expression, but can be maintained until sexual maturity and propagated by assisted reproduction techniques. Based on previous experience with pancreatic islets expressing LEA29Y, tissues from CAG-LEA29Y transgenic pigs should be protected against rejection by human T cells. Furthermore, their immune-compromised phenotype makes CAG-LEA29Y transgenic pigs an interesting large animal model for testing human cell therapies and will provide an important tool for further clarifying the LEA29Y mode of action