Individual and stable autoantibody repertoires in healthy individuals

In the era towards precision medicine, we here present the individual specific autoantibody signatures of 193 healthy individuals. The self-reactive IgG signatures are stable over time in a way that each individual profile is recognized in longitudinal sampling. The IgG autoantibody reactivity towards an antigen array comprising 335 protein fragments, representing 204 human proteins with potential relevance to autoimmune disorders, was measured in longitudinal plasma samples from 193 healthy individuals. This analysis resulted in unique autoantibody barcodes for each individual that were maintained over one year's time. The reactivity profiles, or signatures, are person specific in regards to the number of reactivities and antigen specificity. Two independent data sets were consistent in that each healthy individual displayed reactivity towards 0-16 antigens, with a median of six. Subsequently, four selected individuals were profiled on in-house produced high-density protein arrays containing 23,000 protein fragments representing 14,000 unique protein coding genes. Based on a unique, broad and deep longitudinal profiling of autoantibody reactivities, our results demonstrate a unique autoreactive profile in each analyzed healthy individual. The need and interest for broad-ranged and high-resolution molecular profiling of healthy individuals is rising. We have here generated and assessed an initial perspective on the global distribution of the self-reactive IgG repertoire in healthy individuals, by investigating 193 well-characterized healthy individuals.Peer reviewe

Dynamics of the normal gut microbiota: A longitudinal one-year population study in Sweden

Temporal dynamics of the gut microbiota potentially limit the identification of microbial features associated with health status. Here, we used whole-genome metagenomic and 16S rRNA gene sequencing to characterize the intra- and inter-individual variations of gut microbiota composition and functional potential of a disease-free Swedish population (n = 75) over one year. We found that 23% of the total compositional variance was explained by intra-individual variation. The degree of intra-individual compositional variability was negatively associated with the abundance of Faecalibacterium prausnitzii (a butyrate producer) and two Bifidobacterium species. By contrast, the abundance of facultative anaerobes and aerotolerant bacteria such as Escherichia coli and Lactobacillus acidophilus varied extensively, independent of compositional stability. The contribution of intra-individual variance to the total variance was greater for functional pathways than for microbial species. Thus, reliable quantification of microbial features requires repeated samples to address the issue of intra-individual variations of the gut microbiota

Developmental trajectory of the healthy human gut microbiota during the first 5 years of life

The gut is inhabited by a densely populated ecosystem, the gut microbiota, that is established at birth. However, the succession by which different bacteria are incorporated into the gut microbiota is still relatively unknown. Here, we analyze the microbiota from 471 Swedish children followed from birth to 5 years of age, collecting samples after 4 and 12 months and at 3 and 5 years of age as well as from their mothers at birth using 16S rRNA gene profiling. We also compare their microbiota to an adult Swedish population. Genera follow 4 different colonization patterns during establishment where Methanobrevibacter and Christensenellaceae colonize late and do not reached adult levels at 5 years. These late colonizers correlate with increased alpha diversity in both children and adults. By following the children through age-specific community types, we observe that children have individual dynamics in the gut microbiota development trajectory

Facets of individual-specific health signatures determined from longitudinal plasma proteome profiling

Background: Precision medicine approaches aim to tackle diseases on an individual level through molecular profiling. Despite the growing knowledge about diseases and the reported diversity of molecular phenotypes, the descriptions of human health on an individual level have been far less elaborate. Methods: To provide insights into the longitudinal protein signatures of well-being, we profiled blood plasma collected over one year from 101 clinically healthy individuals using multiplexed antibody assays. After applying an antibody validation scheme, we utilized > 700 protein profiles for in-depth analyses of the individuals’ short-term health trajectories. <p<Findings: We found signatures of circulating proteomes to be highly individual-specific. Considering technical and longitudinal variability, we observed that 49% of the protein profiles were stable over one year. We also identified eight networks of proteins in which 11 242 proteins covaried over time. For each participant, there were unique protein profiles of which some could be explained by associations to genetic variants. Interpretation: This observational and non-interventional study identifyed noticeable diversity among clinically healthy subjects, and facets of individual-specific signatures emerged by monitoring the variability of the circulating proteomes over time. To enable more personal hence precise assessments of health states, longitudinal profiling of circulating proteomes can provide a valuable component for precision medicine approaches

Integration of molecular profiles in a longitudinal wellness profiling cohort

An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine

The human secretome

The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, whereas another large group of proteins were identified that are predicted to be retained locally at the tissue of expression and not secreted into the blood. Proteins detected in the human blood by mass spectrometry-based proteomics and antibody-based immuno-assays are also presented with estimates of their concentrations in the blood. The results are presented in an updated version 19 of the Human Protein Atlas in which each gene encoding a secretome protein is annotated to provide an open-access knowledge resource of the human secretome, including body-wide expression data, spatial localization data down to the single-cell and subcellular levels, and data about the presence of proteins that are detectable in the blood

Pathogenesis of Obesity and Effects of Treatment. Clinical and Molecular Studies on Body Fat, Energy Balance, and Weight Loss.

Obesity is common and related to many health problems including various forms of cancer. The condition arises from the imbalance between food intake and energy expenditure, and is strongly influenced by genetic factors. Weight loss has several health benefits, but for many of the obesity-related diseases such as cancer, the impact of obesity treatment is not clarified. Unfortunately, weight loss is in most cases difficult to sustain, and obesity treatment today is insufficient. The adipose tissue and the gastrointestinal tract play active roles in the regulation of whole-body energy balance, and therapeutic targets for the treatment of obesity may be found within these sites. Also, these organs may be responsible for mediating some of the adverse effects of obesity. Special attention has been drawn to visceral adipose tissue, i.e. the fat surrounding the intestines, as being particularly harmful. The aim of this thesis was to increase our understanding of the mechanisms behind human obesity and the consequences of obesity treatment. We used population-based cross-sectional studies, as well as longitudinal intervention studies with short- and long-term weight loss. CIDEA and CIDEC are two genes with putative functions in adipose tissue, and we therefore studied their transcriptional regulation in relation to energy balance and body composition as an attempt to elucidate their role in human obesity. The genes were predominantly expressed in adipose tissue as compared to other human tissues, both CIDEA and CIDEC gene transcription were highly responsive to changes in energy availability, and CIDEA correlated with body fat and insulin levels. CIDEA expression also correlated with basal metabolic rate and uncoupling protein 1, suggesting a role in the regulation of energy expenditure. In gene silencing experiments in cultured adipocytes, we showed that CIDEC is involved in the regulation of basal as well as stimulated lipolysis, and mitochondrial fatty acid oxidation. Together, our results support a role of CIDEC and CIDEA in human obesity. There are indications that impaired intestinal barrier with increased passage of gut-derived antigens may drive visceral adipose tissue accumulation, and we therefore investigated if increased intestinal permeability is associated with visceral obesity in humans. Study subjects were recruited from a population-based cohort of Swedish women. Intestinal permeability was assessed using the urinary excretion of orally ingested sucralose and mannitol. We used computed tomography to measure visceral and liver fat. Intestinal permeability of the large intestine correlated with visceral fat area (P=0.0003) and liver fat content (P=0.004). The results indicate that gut leakiness should be further explored as a possible cause of visceral fat accumulation. The Swedish Obese Subjects (SOS) study in combination with the Swedish National Cancer Register makes it possible to, for the first time, study the effects of bariatric surgery on cancer incidence in a prospective, controlled study setting. The SOS study started in 1987 and involves severely obese subjects, 2010 of which underwent bariatric surgery, and 2037 contemporaneously matched obese controls who received conventional treatment. Bariatric surgery resulted in a sustained weight reduction, whereas the average weight change in the control group was minimal. In women, the number of first-time cancers during on average 11 years after inclusion was lower in the surgery group compared to the control group (HR= 0.58, 95% CI: 0.44-0.77, p<0.001). In men, we could not detect any difference between treatment groups (HR=0.97, p=0.91). In summary, the results of this thesis suggest that the CIDEA and CIDEC genes play a role in obesity, impaired intestinal barrier function contributes to visceral fat accumulation, and bariatric surgery reduces the risk of developing cancer in severely obese women

Coercion as care : Patients’ experiences of coercive care and coercive interventions – a literature review

Background For patients in need for psychiatric care who refuse treatment, coercive care might be necessary due to The Law of Psychiatric Compulsory Care, LPT. The purpose of this law is to make sure the patient later on will be able to increase autonomy. The most frequent patients in coercive care suffer from psychosis, heavy depression or having high risk of committing suicide. One of the most important tasks in the nurse profession is to increase patients’ autonomy. Therefore having ethical judgment is necessary to know when to use paternalism. To take note of patients’ experiences may increase awareness, making care more patient-centered. Aim To describe patients’ experiences of coercive care and coercive interventions in psychiatric care. Method A literature review has been conducted in order to compile what is currently known about the topic at hand. The result is based on ten scientific articles with findings responding to the aim of this study. The articles have been analyzed by identifying similarities and differences that have synthesized to a new whole.   Result The literature review yielded a profound view of patients’ experiences when being in coercive care. Three main themes were found to cover the phenomenon. Those were Coercive Care - limits and possibilities, The care relationship is fundamental and From abuse to life saving. Discussion The result has been discussed using the theory about Care Suffering, as described by Katie Eriksson. This theory is applicable on the context of interest. The findings has also been discussed using earlier studies concerning coercive care, as well as studies emphasizing the perspective of the nurse’s using coercive restraint. Key words Coercive care, coercive interventions, psychiatric care, patients’ experiences