Who Cared for the Carers? A Study of the Occupational Health of General and Mental Health Nurses 1890 to 1948

This thesis set out to explore the neglected field of nurses’ occupational health. Evidence from the three case study hospitals confirms that attitudes toward nurses’ health changed between 1888 and 1948. The health of nurses was an issue that was always taken seriously but each institution approached the problem differently and responses showed much variation over time. There were good reasons for this but the failure to adopt a coherent and consistent policy worked to the detriment of nurse health. This difficulty helps explain the ambiguous treatment of occupational health within wider histories of nursing. This can lead to the erroneous conclusion that occupational health was somehow neglected by contemporary actors, thereby facilitating the omission of the subject from historical studies concentrating on professional projects and the wider politics of nursing. This study takes a different approach showing that occupational health issues were inexorably connected to these nursing debates. Occupational health cannot be understood without reference to professional projects. This is as true in debates where occupational health was obscured as it was in cases of overt concern. The history of the occupational health of nurses is also important because it offers a new perspective on two other themes central to nursing history, particularly class and gender. This focus helps understand why attitudes towards the care of sick nurses changed over time and varied between different types of institutions. By concentrating on individual nurses’ experiences we reveal something new about the way national conversations affected ordinary nurses’ lives. Recognition that nursing presents a serious occupational health risk is a relatively recent phenomenon; it was not until the 1990s that most nurses had access to occupational health units. This study not only sheds light on why nurses’ health attracted little attention before the Second World War but also explains why this situation began to change from the 1940s.Wellcome Trus

Rheumatoid arthritis - clinical aspects: 134. Predictors of Joint Damage in South Africans with Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) causes progressive joint damage and functional disability. Studies on factors affecting joint damage as clinical outcome are lacking in Africa. The aim of the present study was to identify predictors of joint damage in adult South Africans with established RA. Methods: A cross-sectional study of 100 black patients with RA of >5 years were assessed for joint damage using a validated clinical method, the RA articular damage (RAAD) score. Potential predictors of joint damage that were documented included socio-demographics, smoking, body mass index (BMI), disease duration, delay in disease modifying antirheumatic drug (DMARD) initiation, global disease activity as measured by the disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and autoantibody status. The predictive value of variables was assessed by univariate and stepwise multivariate regression analyses. A p value <0.05 was considered significant. Results: The mean (SD) age was 56 (9.8) years, disease duration 17.5 (8.5) years, educational level 7.5 (3.5) years and DMARD lag was 9 (8.8) years. Female to male ratio was 10:1. The mean (SD) DAS28 was 4.9 (1.5) and total RAAD score was 28.3 (12.8). The mean (SD) BMI was 27.2 kg/m2 (6.2) and 93% of patients were rheumatoid factor (RF) positive. More than 90% of patients received between 2 to 3 DMARDs. Significant univariate predictors of a poor RAAD score were increasing age (p = 0.001), lower education level (p = 0.019), longer disease duration (p < 0.001), longer DMARD lag (p = 0.014), lower BMI (p = 0.025), high RF titre (p < 0.001) and high ESR (p = 0.008). The multivariate regression analysis showed that the only independent significant predictors of a higher mean RAAD score were older age at disease onset (p = 0.04), disease duration (p < 0.001) and RF titre (p < 0.001). There was also a negative association between BMI and the mean total RAAD score (p = 0.049). Conclusions: Patients with longstanding established RA have more severe irreversible joint damage as measured by the clinical RAAD score, contrary to other studies in Africa. This is largely reflected by a delay in the initiation of early effective treatment. Independent of disease duration, older age at disease onset and a higher RF titre are strongly associated with more joint damage. The inverse association between BMI and articular damage in RA has been observed in several studies using radiographic damage scores. The mechanisms underlying this paradoxical association are still widely unknown but adipokines have recently been suggested to play a role. Disclosure statement: C.I. has received a research grant from the Connective Tissue Diseases Research Fund, University of the Witwatersrand. All other authors have declared no conflicts of interes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Who cared for the carers? : a study of the occupational health of general and mental health nurses 1890 to 1948

This thesis set out to explore the neglected field of nurses’ occupational health. Evidence from the three case study hospitals confirms that attitudes toward nurses’ health changed between 1888 and 1948. The health of nurses was an issue that was always taken seriously but each institution approached the problem differently and responses showed much variation over time. There were good reasons for this but the failure to adopt a coherent and consistent policy worked to the detriment of nurse health. This difficulty helps explain the ambiguous treatment of occupational health within wider histories of nursing. This can lead to the erroneous conclusion that occupational health was somehow neglected by contemporary actors, thereby facilitating the omission of the subject from historical studies concentrating on professional projects and the wider politics of nursing. This study takes a different approach showing that occupational health issues were inexorably connected to these nursing debates. Occupational health cannot be understood without reference to professional projects. This is as true in debates where occupational health was obscured as it was in cases of overt concern. The history of the occupational health of nurses is also important because it offers a new perspective on two other themes central to nursing history, particularly class and gender. This focus helps understand why attitudes towards the care of sick nurses changed over time and varied between different types of institutions. By concentrating on individual nurses’ experiences we reveal something new about the way national conversations affected ordinary nurses’ lives. Recognition that nursing presents a serious occupational health risk is a relatively recent phenomenon; it was not until the 1990s that most nurses had access to occupational health units. This study not only sheds light on why nurses’ health attracted little attention before the Second World War but also explains why this situation began to change from the 1940s.EThOS - Electronic Theses Online ServiceWellcome TrustGBUnited Kingdo

Associations of autozygosity with a broad range of human phenotypes

Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

INTRODUCTION: Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS) that often presents in young adults. Over the past decade, certain elements of the genetic architecture of susceptibility have gradually emerged, but most of the genetic risk for MS remained unknown. RATIONALE: Earlier versions of the MS genetic map had highlighted the role of the adaptive arm of the immune system, implicating multiple different T cell subsets. We expanded our knowledge of MS susceptibility by performing a genetic association study in MS that leveraged genotype data from 47,429 MS cases and 68,374 control subjects. We enhanced this analysis with an in-depth and comprehensive evaluation of the functional impact of the susceptibility variants that we uncovered. RESULTS: We identified 233 statistically independent associations with MS susceptibility that are genome-wide significant. The major histocompatibility complex (MHC) contains 32 of these associations, and one, the first MS locus on a sex chromosome, is found in chromosome X. The remaining 200 associations are found in the autosomal non-MHC genome. Our genome-wide partitioning approach and large-scale replication effort allowed the evaluation of other variants that did not meet our strict threshold of significance, such as 416 variants that had evidence of statistical replication but did not reach the level of genome-wide statistical significance. Many of these loci are likely to be true susceptibility loci. The genome-wide and suggestive effects jointly explain ~48% of the estimated heritability for MS. Using atlases of gene expression patterns and epigenomic features, we documented that enrichment for MS susceptibility loci was apparent in many different immune cell types and tissues, whereas there was an absence of enrichment in tissue-level brain profiles. We extended the annotation analyses by analyzing new data generated from human induced pluripotent stem cell–derived neurons as well as from purified primary human astrocytes and microglia, observing that enrichment for MS genes is seen in human microglia, the resident immune cells of the brain, but not in astrocytes or neurons. Further, we have characterized the functional consequences of many MS susceptibility variants by identifying those that influence the expression of nearby genes in immune cells or brain. Last, we applied an ensemble of methods to prioritize 551 putative MS susceptibility genes that may be the target of the MS variants that meet a threshold of genome-wide significance. This extensive list of MS susceptibility genes expands our knowledge more than twofold and highlights processes relating to the development, maturation, and terminal differentiation of B, T, natural killer, and myeloid cells that may contribute to the onset of MS. These analyses focus our attention on a number of different cells in which the function of MS variants should be further investigated. Using reference protein-protein interaction maps, these MS genes can also be assembled into 13 communities of genes encoding proteins that interact with one another; this higher-order architecture begins to assemble groups of susceptibility variants whose functional consequences may converge on certain protein complexes that can be prioritized for further evaluation as targets for MS prevention strategies. CONCLUSION: We report a detailed genetic and genomic map of MS susceptibility, one that explains almost half of this disease’s heritability. We highlight the importance of several cells of the peripheral and brain resident immune systems—implicating both the adaptive and innate arms—in the translation of MS genetic risk into an auto-immune inflammatory process that targets the CNS and triggers a neurodegenerative cascade. In particular, the myeloid component highlights a possible role for microglia that requires further investigation, and the B cell component connects to the narrative of effective B cell–directed therapies in MS. These insights set the stage for a new generation of functional studies to uncover the sequence of molecular events that lead to disease onset. This perspective on the trajectory of disease onset will lay the foundation for developing primary prevention strategies that mitigate the risk of developing MS

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.

BACKGROUND Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). INTERPRETATION We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. FUNDING UK Medical Research Council and University of Milan-Bicocca

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p&lt;0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p&lt;0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p&lt;0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p&lt;0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79–0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=–0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). Interpretation: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. Funding: UK Medical Research Council and University of Milan-Bicocca