Ambivalent connections: a qualitative study of the care experiences of non-psychotic chronic patients who are perceived as 'difficult' by professionals

Contains fulltext : 90688.pdf (publisher's version ) (Open Access)Background: Little is known about the perspectives of psychiatric patients who are perceived as 'difficult' by clinicians. The aim of this paper is to improve understanding of the connections between patients and professionals from patients' point of view. Methods: A Grounded Theory study using interviews with 21 patients from 12 outpatient departments of three mental health care facilities. Results: Patients reported on their own difficult behaviours and their difficulties with clinicians and services. Explanations varied but could be summarized as a perceived lack of recognition. Recognition referred to being seen as a patient and a person - not just as completely 'ill' or as completely 'healthy'. Also, we found that patients and professionals have very different expectations of one another, which may culminate in a difficult or ambivalent connection. In order to explicate patient's expectations, the patient-clinician contact was described by a stage model that differentiates between three stages of contact development, and three stages of substantial treatment. According to patients, in each stage there is a therapeutic window of optimal clinician behaviour and two wider spaces below and above that may be qualified as 'toxic' behaviour. Possible changes in clinicians' responses to 'difficult' patients were described using this model. Conclusions: The incongruence of patients' and professionals' expectations may result in power struggles that may make professionals perceive patients as 'difficult'. Explication of mutual expectations may be useful in such cases. The presented model gives some directions to clinicians how to do this.11 p

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Skewed X-inactivation is common in the general female population

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants

Recovery of Normal Body Weight in Adolescents with Anorexia Nervosa: The Nurses’ Perspective on Effective Interventions

Little is known about effective nursing interventions for adolescents with anorexia nervosa. The purpose of this study was to discover which aspects of nursing care are most effective, according to nurses, in recovery of normal body weight in adolescents with anorexia nervosa. METHODS: A qualitative descriptive research design was applied with individual in-depth interviews and a focus group. Thematic analysis was used to analyze the data. FINDINGS: Nurses state that they are in a key position in guiding patients with anorexia nervosa toward a path of weight recovery.A good therapeutic relationship is essential to the implementation of targeted nursing interventions in the areas of eating and exercising, social support, and parent counseling. CONCLUSIONS: The results of this research can be used to define more detailed nursing interventions, the effectiveness of which can be tested in follow-up research

Serrated adenomas and mixed polyposis caused by a splice acceptor deletion in the mouse Smad4 gene

Serrated adenomas, hyperplastic polyps, and admixed hyperplastic/adenomatous polyps form a distinct group of colorectal tumors, the molecular genetic basis of which is still poorly understood. We describe a novel mouse model for serrated adenomas and mixed polyposis, here referred to as Sad (serrated adenomas), caused by a spontaneously risen splice site mutation in the murine Smad4 gene. The Sad chromosomal region was identified by genetic linkage and loss of heterozygosity (LOH) analysis. Subsequently, several candidate genes were investigated by expression and mutation analysis. By use of genetic linkage and LOH analysis, we mapped the Sad candidate to mouse chromosome 18, 44-48 cM, syntenic to human chromosome band 18q21. Within this chromosomal interval, the Smad2, Smad4, and Smad7 genes were analyzed for the presence of a disease-causing mutation in affected animals. A single nucleotide (nt) deletion was identified in the intron 5/exon 6 splice acceptor site of the Smad4 gene. The single base deletion results in a frameshift and an early termination codon through activation of a cryptic splice site 4 nt downstream in exon 6. The resulting mRNA is unstable, and the Sad mutation is thus likely to represent a null allele. Identification of a Smad4 mutation in the Sad mouse model provides further support for the involvement of the Smad genes, and thus the TGFB pathway, in the serrated/hyperplastic route to colorectal cancer