'Noisy, restless and incoherent' : puerperal insanity at Dundee Lunatic Asylum

This research is supported by the Strathmartine Trust Scottish History Scholarship, St Andrews.Puerperal insanity has been described as a nineteenth-century diagnosis, entrenched in contemporary expectations of proper womanly behaviour. Drawing on detailed study of establishment registers and patient case notes, this paper examines the puerperal insanity diagnosis at Dundee Lunatic Asylum between 1820 and 1860. In particular, the study aims to consider whether the class or social status of the patients had a bearing on how their conditions were perceived and rationalized, and how far the puerperal insanity diagnosis, coloured by the values assigned to it by the medical officers, may have been reserved for some women and not for others. This examination of the diagnosis in a Scottish community, suggesting a contrast in the way that middle-class and working-class women were diagnosed at Dundee, engages with and expands on work on puerperal insanity elsewhere.PostprintPeer reviewe

‘This distressing malady’ : childbirth and mental illness in Scotland 1820 – 1930

My thesis explores the experiences of women who suffered from mental disorder related to childbirth and pregnancy, looking in particular at Dundee, Fife and Forfarshire in the north-east of Scotland, during the period 1820 to 1930. This study offers a new perspective on women’s lives, wellbeing and healthcare in this region by examining at a local level the ideas surrounding postpartum mental illness. By the mid-nineteenth century, the term ‘puerperal insanity’ was widely known and much discussed and deliberated in medical literature. However, the day-to-day care and treatment of postpartum women suffering from mental disorder was not straightforward. My findings demonstrate that the diagnosis and treatment of postpartum mental illness in nineteenth- and early twentieth-century Scotland was a complex issue influenced as much by social and economic factors as by medical ideas. Using records from the chartered asylums at Montrose and Dundee, court and prison records, and newspaper accounts, I have uncovered how childbearing-related mental illness was recognised, accepted and supported by families, neighbours, friends and authorities. Within the asylum, I have revealed how physicians assessed their patients’ characters and status as much as their physical conditions, but nevertheless in many cases provided positive medical care and much-needed rest and nourishment. In criminal cases, my study has looked beyond legislation and verdicts to reveal a positive and constructive approach to the care and custody of women who had committed child murder. Awareness of postpartum mental illness in the community was developed through a collaboration of medical and lay knowledge, acquired through interactions between physicians, families and communities, and filtered through pre-existing understandings and ideas. I have identified a lay understanding and accepted discourse which guided the ideas and actions of friends, family and community in dealing with the problems associated with mental illness among postpartum women

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Pathways and practice : the general practitioner in nineteenth-century Dundee

Although the care of the basic medical needs of much of the population, or what might be termed general medicine, accounted by the mid nineteenth century for the work of the majority of medical men in Britain, those who practiced within this field were an irregular group of practitioners who had evolved from the surgeon- apothecaries and man midwives of the eighteenth century, and who formed an unspecific mix of medical men with different qualifications, training and experiences. Increasing legislation forced the radical development of the medical profession by the end of the century and, in a changing climate of education and opportunity, medical men competed for professional survival. This they did through the cultivation and exploitation of ‘community niches’ to gain professional recognition (Digby, 1999, p. 261). The medical establishment in mid-nineteenth-century Dundee was made up of a diverse group of practitioners, in terms of education, qualification and experience, much of which still reflected the pathways and practices of the late eighteenth century. Dominated by leading medical families and intricate social networks, the medical community increasingly established itself in a distinct quarter within the city, and entrenched itself in the wider community through public appointments and civic office. This paper will explore the landscape of medical practice in this local ‘niche’, examining the ways in which the resident medical men created themselves both as individual practitioners with status and influence – the newly emerging ‘general practitioners’ – and as a distinct and respected professional community.Publisher PDFPeer reviewe