Factors that influence health-related quality of life in adolescents with sickle cell disease

The chronic course of sickle cell disease (SCD) can be particularly burdensome for adolescents and can have a negative impact on health-related quality of life (HRQOL) during the time of transitioning from childhood to adulthood. Additionally, family functioning has been identified as an important predictor for how well children and adolescents cope with and adapt to SCD. Although there have been major medical advances that have benefited affected individuals, SCD imposes significant demands on affected children and their families. In light of the progress in management and treatment of SCD, and the developmental challenges associated with adolescence, it is an opportune time to assess HRQOL and family functioning in this population. The aims of the research were to: (1) appraise existing research related to family functioning and child outcomes in families of children and adolescents with SCD, (2) identify measures used to assess HRQOL, and (3) describe factors that influence HRQOL in adolescents with SCD. This is a manuscript style dissertation including 3 manuscripts encompassing a single program of research In manuscript 1, a total of 23 family functioning studies were identified. The findings indicated that families with high levels of family functioning were associated with affected children who had better adaptive outcomes. Low levels of family functioning were associated with children who had poorer adaptive outcomes. Family functioning assessments were influenced by issues such as number and relationships of informants, study designs, family functioning measures, and coping mechanisms. A total of seven HRQOL measures were identified among 25 studies in manuscript 2. The PedsQL emerged as the most flexible and useful HRQOL measurement for children and adolescents with SCD. Finally, in manuscript 3, a secondary data analysis was conducted on 482 adolescents to determine inter-relationships of HRQOL and influencing factors. Findings indicated that factors associated with reduced HRQOL included: (1) female gender compared to male gender, and (2) history of transfusions compared to no history. Factors associated with better HRQOL included: (1) mild disease severity compared to severe, (2) private health insurance compared to Medicaid/Medicare, and (3) other or no health insurance compared to Medicaid/Medicare

Does Attendance at a Sickle Cell Educational Conference Improve Clinician Knowledge and Attitude Toward Patients with Sickle Cell Disease?

Sickle cell disease (SCD) is a genetic disease associated with both chronic pain and acute painful events referred to as vaso-occlusive crisis. Individuals suffer from a multitude of medical complications in addition to pain. Patients are often stigmatized as “drug-seeking” and receive inadequate pain management

Care Seeking for Pain in Young Adults with Sickle Cell Disease

In individuals with sickle cell disease (SCD), recognizing the cues to an acute pain episode and responding appropriately are important. The purpose of this mixed-methods pilot study is to identify preliminary factors that influence care seeking for pain in young adults with SCD. Responses were received from 69 young adults with SCD, age 18-35 years. The majority of respondents (88%) wait until the pain intensity is an average of 8.7 (± 1.2) on a scale of 1 to 10 before seeking care. Prominent themes influencing care seeking for pain include: trying to treat pain at home, avoiding the emergency department because of past treatment experiences, the desire to avoid admission to the hospital, and the importance of time in the lives of the young adults with SCD. Young adults with SCD need additional support from family and healthcare providers in order to make timely, appropriate decisions regarding care seeking

Over 35 years, integrated pest management has reduced pest risks and pesticide use

Pests and their interactions with crops, ecological landscapes and animals are in continuous flux — they are never static. Pest severity increases or decreases depending on environmental conditions and changes in production or pest control practices. Pest management is made even more challenging by exotic and newly invasive pests. Over its 35-year history, the UC Agriculture and Natural Resources Statewide IPM Program has supported research and extension that has decreased risks of crop losses, improved treatment programs for invasive and endemic pests, and reduced the use of pesticides and their impact on the environment and human health. Its publications are widely used among growers, pest control advisers, research institutions, state agencies, agricultural organizations and gardeners; and integrated pest management has been adopted statewide in agriculture, as well as in managed landscapes and urban areas.

Establishment of a Bluetongue Virus Infection Model in Mice that Are Deficient in the Alpha/Beta Interferon Receptor

Bluetongue (BT) is a noncontagious, insect-transmitted disease of ruminants caused by the bluetongue virus (BTV). A laboratory animal model would greatly facilitate the studies of pathogenesis, immune response and vaccination against BTV. Herein, we show that adult mice deficient in type I IFN receptor (IFNAR(−/−)) are highly susceptible to BTV-4 and BTV-8 infection when the virus is administered intravenously. Disease was characterized by ocular discharges and apathy, starting at 48 hours post-infection and quickly leading to animal death within 60 hours of inoculation. Infectious virus was recovered from the spleen, lung, thymus, and lymph nodes indicating a systemic infection. In addition, a lymphoid depletion in spleen, and severe pneumonia were observed in the infected mice. Furthermore, IFNAR(−/−) adult mice immunized with a BTV-4 inactivated vaccine showed the induction of neutralizing antibodies against BTV-4 and complete protection against challenge with a lethal dose of this virus. The data indicate that this mouse model may facilitate the study of BTV pathogenesis, and the development of new effective vaccines for BTV

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder