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Background Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing NUP93 variants suggest these could be a significant cause of paediatric onset SRNS. We report NUP93 cases in the UK and demonstrate in vivo functional effects of Nup93 depletion in a fly (Drosophila melanogaster) nephrocyte model. Methods Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS). D. melanogaster Nup93 knockdown was achieved by RNA interference using nephrocyte-restricted drivers. Results Six novel homozygous and compound heterozygous NUP93 variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12 months from clinical diagnosis. Silencing of the two orthologs of human NUP93 expressed in D. melanogaster, Nup93-1, and Nup93-2 resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in Nup93-1 and Nup93-2 silenced flies surviving to adulthood. Conclusion We expand the spectrum of NUP93 variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either D. melanogaster Nup93 ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information

This chapter describes the anaesthetic management of the patient with those neurological or muscular disorders which are relevant to anaesthetic practice, including malignant hyperthermia (MH). Other topics covered include epilepsy, cerebrovascular disease; Parkinson’s disease; spinal cord lesions; myasthenia gravis; multiple sclerosis; Guillain-Barré syndrome; motor neuron disease; dystrophia myotonica and the muscular dystrophies. For each topic, pre-operative investigation and optimisation, treatment, and anaesthetic management are described.

Case report - Introduction Bacterial community-acquired atypical pneumonia is sometimes complicated by myositis or by renal parenchymal disease. They can present with myositis and present with muscle weakness, pain or swelling, and elevated muscle enzymes. We present the case of a patient with lower limb weakness and raised creatinine kinase with atypical pneumonia caused by Legionella pneumophila. Case report - Case description A 76-year-old Caucasian man, who was previously fit and independent and walked 3 miles every day presented with a 1-week history of progressive leg weakness, and inability to mobilize. He had a fall and was on the floor for 2 hours. He had a background history of hypercholesterolemia and was on atorvastatin for 15 years. On his vital observation, he was found tachypnoeic, tachycardic, and hypoxic. He had a right upper lobe crackle but he didn’t have respiratory symptoms. His muscle power in his leg was 3/5 with carpet burns on knees and elbow. Initial investigation showed raised inflammatory marker CRP 412mg/L, AKI stage 1, and CK 43400 IU/L. His CXR showed dense right upper lobe consolidation. Legionella urinary antigen was positive. Myositis myoblot, ANA, ANCA negative. COVID-19 swab negative. Treated with IV antibiotic, supplemental oxygen, and IV fluid. Transferred to ITU due to worsening of hypoxia and kidney function. Interestingly, the CK level had improved significantly within 48 hours along with clinical improvement in his symptoms. There was no role of steroid or immunosuppressant due to his significant clinical improvement. On day 7 he was off oxygen, kidney function improved, had physiotherapy, and transferred to ward and on day 10 he was ambulant and discharged home. Case report - Discussion To date, very few case reports of myositis in a patient with atypical pneumonia have been reported. The mechanism underlying acute myositis in atypical pneumonia is still unknown. The present analysis points out that the organism underlying atypical bacterial pneumonia may occasionally invade the muscle tissue thereby inducing both myositis and secondary kidney damage. Case report - Key learning points We should be aware of this rare complication of atypical pneumonia and the resolution of symptoms that occur with the treatment of pneumonia. This would avoid unnecessary investigation and use of steroid.

ObjectiveMyocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischaemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes.Approach and ResultsWe retrospectively analysed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (pConclusionsRapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.Graphical AbstractHighlights3-5 bullet points that summarize the major findings of the study.Circulating non classical monocytes show a rapid fall in STEMI patients within 90 minutes of re-opening the culprit coronary artery.The extent of the drop in non classical monocytes correlates with loss of cardiac function and increased infarct size.A mouse model of cardiac ischaemia and reperfusion shows rapid margination of monocytes to the coronary vasculature

Eileen Hunt Botting’s exciting new monograph reads Mary Shelley’s Frankenstein as a literary thought experiment on the rights of the child. Botting’s meticulously argued and deeply researched work ...

Objective We aimed to support service transformation by developing a core capabilities framework for first contact practitioners working with people who have musculoskeletal conditions. Methods We conducted a modified three-round Delphi study with a multi-professional panel of 41 experts nominated through 18 national professional and patient organizations. Qualitative data from an open-ended question in round one were analysed using a thematic approach and combined with existing literature to shape a draft framework. Participants rated their agreement with each of the proposed 142 outcomes within 14 capabilities on a 10-point Likert scale in round two. The final round combined round two results with a wider online survey. Results Rounds two and three of the Delphi survey were completed by 37 and 27 participants, respectively. Ninety practitioners responded to the wider online survey. The final framework contains 105 outcomes within 14 capabilities, separated into four domains (person-centred approaches; assessment, investigation and diagnosis; condition management, intervention and prevention; and service and professional development). The median agreement for all 105 outcomes was at least nine on the 10-point Likert scale in the final round. Conclusion The framework outlines the core capabilities required for practitioners working as the first point of contact for people with musculoskeletal conditions. It provides a standard structure and language across professions, with greater consistency and portability of musculoskeletal core capabilities. Agreement on each of the 105 outcomes was universally high amongst the expert panel, and the framework is now being disseminated by Health Education England, NHS England and Skills for Health.

Introduction Primary percutaneous coronary intervention (PPCI) is the standard care for treatment of acute myocardial infarction, reducing both mortality and morbidity. However, ischaemia/reperfusion (I/R) injury remains an important complication, contributing up to 50% of the final infarct size. Evidence from our clinical studies suggests that lymphocytes expressing the fractalkine receptor (CX3CR1) are associated with microvascular obstruction and hence poorer long-term patient outcomes. This project aims to investigate the role of fractalkine in lymphocyte-mediated myocardial I/R injury and evaluate whether this damage can be reduced by inhibiting fractalkine/receptor (CX3CL1/CX3CR1) interaction. Methods We are using a mouse model of myocardial I/R injury to study lymphocyte infiltration following MI. Multicolour flow cytometry, immunofluorescence staining, qPCR, imaging mass cytometry and magnetic resonance imaging (MRI) are used to evaluate T cell recruitment and cardiac function in a CX3CR1 knockout mouse line. Results CX3CR1 knockout leads to over 30% reduction in immune cell infiltration at the site of cardiac ischaemic injury 2 hours after reperfusion, both in heterozygous (p ≤ 0.01) and knockout (p ≤ 0.001) mice. By 24 hours I/R, infiltration of CD45+ cells in heterozygous and knockout animals returns to, and surpasses, wild type (WT) levels (p ≤ 0.05). Despite the 20% increase in leukocyte infiltration at 24 hours, we see a 2-fold decrease in T cells at the site of I/R injury in the knockout animals, compared to both WT (p ≤ 0.001) and heterozygous mice (p ≤ 0.0001). T cell infiltration in the knockout is also reduced (although not significantly) when heart infiltrates at 24h reperfusion are investigated by an alternative method: flow cytometry analysis of digested cardiac tissue. Furthermore, our studies show a reduction of 30% in the number of CX3CR1-expressing T cells (p ≤ 0.0001) and 50% in total CX3CR1+ cells (p ≤ 0.01) that infiltrate the left ventricle wall in knockout mice, compared to heterozygous animals. Functional studies using cardiac MRI show no difference between heterozygous and KO mice 6 weeks following I/R injury. Conclusion These findings suggest that knockout of CX3CR1 leads to delayed recruitment of leukocytes following cardiac I/R. This results in an altered immune cell infiltrate including reduced number of T cells in the injured tissue. In addition, the role for CX3CR1-expressing T cells in myocardial I/R is supported by our data showing that the number of CX3CR1+ CD3+ cells is significantly reduced from heterozygous to knockout animals following injury. Conflict of interest None

Introduction Aside from their patrolling behaviour, the early functions of CX3CR1hi non-classical (NC) monocytes following acute myocardial ischemia-reperfusion (I/R) are largely unknown. NC monocyte behaviour is orchestrated in part by their high expression of the fractalkine receptor, CX3CR1, however the signalling pathways activated by fractalkine stimulation remain largely undefined. Increasing evidence has now implicated the CX3CR1/CX3CL1 system in myocardial I/R injury, which conclusively suggest that fractalkine has a detrimental effect on myocardial ischemia and accelerates the progress of heart failure. Neutralization of the receptor is successful in improving cardiac function in a mouse model of MI, and STEMI patient CX3CL1 concentration is a prognostic marker following MI. The first aim of this project was therefore to characterise circulating CX3CR1hi NC monocyte dynamics in ST elevation MI (STEMI) patients immediately following reperfusion, and evaluate their prognostic value. Using a mouse model of cardiac I/R, we evaluated the effect of genetic CX3CR1 knockout on non-classical monocyte recruitment into the injured myocardium at 2h and 24h post-I/R. Since contemporary efforts to promote myocardial repair have failed to translate into clinical therapies thus far, we hypothesize that CX3CR1 may be a prime candidate to target myocardial repair following I/R. Method Flow Cytometry (FC) quantified monocyte subpopulations in the blood of 59 STEMI patients pre and post PPCI. Infarct size and microvascular obstruction (MVO) were assessed using cardiac MRI. Monocytes were quantified in a second study of 14 STEMI patients. A mouse model of cardiac I/R injury was used to study monocyte infiltration following MI. The recruitment of classical monocytes [CD11b+ GFPmid CCR2hi] and NC monocytes [CD11b+ GFPhi CCR2lo] into the injured myocardium at 2h and 24h post-IR was studied by immunofluorescence in CX3CR1+/GFP CX3CR1GFP/GFP mice. FC quantified absolute monocyte subset counts in mouse blood at 2h and 24h post-IR. Results STEMI patients showed a 46%(±4) drop in circulating CX3CR1hi CD16++ NC monocytes (p Conclusion & Future Work: NC monocytes appear to specifically respond to cardiac I/R, and may be predictive of cardiac function following STEMI. The 2-fold reduction in CX3CR1hi LY6Clo NC monocyte infiltration in CX3CR1GFP/GFP mice suggests that CX3CR1 has an important function in the NC monocyte response to cardiac I/R. Conflict of Interest non

The success of cell therapy approaches is greatly dependent on the ability to precisely deliver and monitor transplanted stem cell grafts at treated sites. Iron oxide particles, traditionally used in vivo for magnetic resonance imaging (MRI), have been shown to also represent a safe and efficient in vitro labelling agent for mesenchymal stem cells (MSCs). Here, stem cells were labelled with magnetic particles, and their resulting response to magnetic forces was studied using 2D and 3D models. Labelled cells exhibited magnetic responsiveness, which promoted localised retention and patterned cell seeding when exposed to magnet arrangements in vitro. Directed migration was observed in 2D culture when adherent cells were exposed to a magnetic field, and also when cells were seeded into a 3D gel. Finally, a model of cell injection into the rodent leg was used to test the enhanced localised retention of labelled stem cells when applying magnetic forces, using whole body imaging to confirm the potential use of magnetic particles in strategies seeking to better control cell distribution for in vivo cell delivery.

Haitian women have the highest incidence of cervical cancer within the Western hemisphere. Intravaginal hygiene practices have been linked with human papilloma virus (HPV) infection and cervical dysplasia. These practices, known as 'twalet deba' in Haitian Creole, are common among Haitian women and are performed with various natural and synthetic agents. As part of a community-based participatory research initiative aimed at reducing cervical cancer disparities in rural Haiti, we explored the use of intravaginal agents and their associations with high-risk HPV infection.Community Health Workers recruited 416 women for cervical self-sampling from two neighborhoods within Thomonde, Haiti. Participants were interviewed regarding intravaginal hygiene practices and completed a cervical self-sampling procedure. Cervical samples were analyzed for the presence of high-risk HPV infection. Associations between each intravaginal agent and high-risk HPV infection were examined via univariate logistic regression analyses, as well as via multivariate analyses controlling for sociodemographic factors and concurrent agent use.Nearly all women (97.1%) performed twalet deba, using a variety of herbal and commercially produced intravaginal agents. Approximately 11% of the participants tested positive for high-risk HPV. Pigeon pea and lime juice were the only agents found to be associated with high-risk HPV in the univariate analyses, with women who used these agents being approximately twice as likely to have high-risk HPV as those who did not. Only pigeon pea remained significantly associated with high-risk HPV after controlling for sociodemographic factors and concurrent agent use.Two agents, pigeon pea and lime juice, may contribute to risk for HPV infection in this population. Results suggest that in addition to cervical cancer screening interventions, future preventive initiatives should focus on minimizing risk by advocating for the use of less-toxic twalet deba alternatives.

Background In patients with acute myocardial infarction (MI), monocytes are rapidly recruited to the injured tissue, where they contribute to the inflammatory milieu. Different monocyte subsets exhibit distinct roles. Classical monocytes (CD16-CCR2 +CX3CR1-) migrate to sites of injury in response to CCL2 and differentiate into inflammatory macrophage, whilst non-classical monocytes (CD16 +CCR2- CX3CR1+) patrol the endothelium where they potentially interact with Fractalkine. The aim of this project was to characterise these circulating monocyte subpopulations dynamics in ST elevation MI patients immediately following reperfusion, and evaluate their prognostic value. Methods Flow Cytometry was used to quantify monocyte subpopulations in the blood of 59 STEMI patients the time of primary percutaneous coronary intervention for acute MI and at different times thereafter. Infarct size and microvascular obstruction (MVO) were assessed using cardiac MRI. Results STEMI patients showed a significant drop in circulating CD16 ++monocyte counts at 90 min post-reperfusion, whereas the CD16- monocyte counts remained unchanged at this early stage. This rapid decrease in CD16 ++monocytes was greater in individuals with a larger infarct size and lower left ventricular ejection fraction (LVEF). Conclusion This data suggests that CD16 ++monocytes during the acute phase post-MI may hold predictive value for myocardial injury and long-term patient outcome. Further work using a CX3CR1-GFP mouse model of ischemia-reperfusion (IR) is being used to investigate monocyte recruitment to the injured myocardium at 2 and 24 hours post IR and the role of Fractalkine signalling.

The term Outreach is used to define the process of extending critical care services beyond the current or usual limits. Its purpose is to ‘break down the walls’ of critical care, by extending intensive care to sick patients outside of intensive care boundaries so preventing unnecessary morbidity and mortality in ward patients. The objectives were outlined by the Department of Health in their 2000 publication ‘Comprehensive Critical Care’

Neuromuscular disorders are a heterogeneous group of diseases that share a number of important issues with regard to generic anaesthetic management. However, it is important to remember that each disease state has its own distinct pathophysiology that requires individually tailored perioperative care. This article will discuss both hereditary and acquired neuromuscular disorders, paying particular attention to the specific management of each disease when undergoing anaesthesia (Tables 1 and 2).

Patients with neuromuscular disorders are a concern for anaesthetists and intensivists alike, as well as their parent medical or surgical team. Although it is impossible to negate risk altogether in these patients, an understanding of the pathophysiology underlying each condition facilitates preoperative, perioperative, and postoperative planning. A precise diagnosis before anaesthesia is ideal, but this is not always possible—anaesthesia may be required for muscle biopsy to complete investigations. Complications associated with high morbidity and mortality should be planned for with regard to prevention and subsequent management should they arise. This article follows on from a previous article in this journal Anaesthesia for Children with Neuromuscular Disease by detailing the anaesthetic management for patients with generic neuromuscular disorders and the anaesthetic management of specific neuromuscular disorders in the accompanying article. These together should provide both paediatric and adult anaesthetists with a core level of information on how to proceed.

In 2000, all 191 United Nations member states agreed to work toward the achievement of a set of health and development goals by 2015. The achievement of these eight goals, the Millennium Development goals (MDGs) is highly dependent on improving the status of women, who play a key role in health and education in families and communities around the world. Yet structural violence, defined as the systematic exclusion of a group from the resources needed to develop their full human potential, remains a significant barrier against women's development and threatens the achievement of the MDGs. Although sound evidence has long existed for improving women's survival, the will to address women's health concretely and holistically is only recently gaining the advocacy needed to change policy. Concrete examples of the integration of approaches to mitigate structural violence within the delivery of health services do exist and should be incorporated into global advocacy for women's health.

Tissues from sequential-kill time course studies of bovine spongiform encephalopathy (BSE) were examined to define PrP immunohistochemical labeling forms and map disease-specific labeling over the disease course after oral exposure to the BSE agent at two dose levels. Study was confined to brainstem, spinal cord, and certain peripheral nervous system ganglia—tissues implicated in pathogenesis and diagnosis or disease control strategies. Disease-specific labeling in the brainstem in 39 of 220 test animals showed the forms and patterns observed in natural disease and invariably preceded spongiform changes. A precise temporal pattern of increase in labeling was not apparent, but labeling was generally most widespread in clinical cases, and it always involved neuroanatomic locations in the medulla oblongata. In two cases, sparse labeling was confined to one or more neuroanatomic nuclei of the medulla oblongata. When involved, the spinal cord was affected at all levels, providing no indication of temporal spread within the cord axis or relative to the brainstem. Where minimal PrP labeling occurred in the thoracic spinal cord, it was consistent with initial involvement of general visceral efferent neurons. Labeling of ganglia involved only sensory ganglia and only when PrP was present in the brainstem and spinal cord. These experimental transmissions mimicked the neuropathologic findings in BSE-C field cases, independent of dose of agent or stage of disease. The model supports current diagnostic sampling approaches and control measures for the removal and destruction of nervous system tissues in slaughtered cattle.

Atypical scrapie is a relatively recent discovery, and it was unknown whether it was a new phenomenon or whether it had existed undetected in the United Kingdom national flock. Before 1998, the routine statutory diagnosis of transmissible spongiform encephalopathy (TSE) in sheep relied on the presence of TSE vacuolation in the brainstem. This method would not have been effective for the detection of atypical scrapie. Currently, immunohistochemistry (IHC) and Western blot are commonly used for the differential diagnosis of classical and atypical scrapie. The IHC pattern of PrP d deposition in atypical scrapie is very different from that in classical scrapie using the same antibody. It is thus possible that because of a lack of suitable diagnostic techniques and awareness of this form of the disease, historic cases of atypical scrapie remain undiagnosed. Immunohistochemistry was performed on selected formalin-fixed, paraffin-embedded (FFPE) blocks of ovine brain from the Veterinary Laboratories Agency archives that were submitted for various reasons, including suspect neurological disorders, between 1980 and 1989. It was found that PrP d deposits in a single case were consistent with atypical scrapie. A method was developed to obtain a PrP genotype from FFPE tissues and was applied to material from this single case, which was shown to be AHQ/AHQ. This animal was a scrapie suspect from 1987, but diagnosis was not confirmed by the available techniques at that time.

Readers frequently have wondered if Oscar Wilde's fairy tales were intended for adults or for children. Through its analysis of "The Devoted Friend" (1888), this essay describes Wilde's promotion of a moral code consistent with his developing socialist politics to both children and adults in Victorian England.

This is the third of three articles describing the work of the Birth Place Choices (BPC) Project, a Department of Health funded project carried out between May 2003 and May 2005 as a collaboration between Southampton University Hospitals NHS Trust and Portsmouth Hospitals NHS Trust. The BPC Project had three aims: 1. To identify factors which influence women's decisions about where to give birth. 2. To determine whether the introduction of specially designed information and educational initiatives increase women's knowledge of choices for place of birth. 3. To determine whether implementation of these initiatives was associated with an increase in the number of women choosing to give birth outside main consultant-led maternity units. This article describes the evaluation process carried out during phase two of the BPC Project, as well as the key successes of the BPC Project and the barriers which limited its effectiveness.

The Birth Place Choices (BPC) Project was carried out between May 2003 and May 2005 as a collaboration between Southampton University Hospitals NHS Trust and Portsmouth Hospitals NHS Trust. The BPC Project had three aims: 1. To identify factors that influence women's decisions about where to give birth. 2. To determine whether the introduction of specially designed information and educational initiatives increase women's knowledge of choices for place of birth. 3. To determine whether implementation of these initiatives was associated with an increase in the number of women choosing to give birth outside main consultant-led maternity units. This article describes the educational, marketing and change management initiatives that were carried out as part of phase two of the BPC Project. These included a marketing campaign for local Midwifery-Led Units, the provision of a maternity service user leaflet on local birthplace choices, and the development of a multi-professional guideline on place of birth. Midwife practice educators were employed to help disseminate the leaflet and guideline as well as implement educational initiatives for local midwives on and around informed choice and place of birth.

The Birth Place Choices (BPC) Project was carried out between May 2003 and May 2005 as a collaboration between Southampton University Hospitals NHS Trust and Portsmouth Hospitals NHS Trust. The BPC Project had three aims: 1. To identify factors that influence women's decisions about where to give birth 2. To determine whether the introduction of specially designed information and educational initiatives increase women's knowledge of choices for place of birth 3. To determine whether implementation of these initiatives was associated with an increase in the number of women choosing to give birth outside main consultant-led maternity units. Phase one of the BPC Project, described here, addressed the first aim. This is the first of three articles describing the work of the BPC Project. Following a literature review and an analysis of locally collected routine statistics relating to birthplace, a cross-sectional survey of local women and focus groups involving local women and midwives were carried out. The findings revealed that, compared to other health professionals, midwives had the greatest influence on maternity service users with regard to their birth place choices, yet were perhaps not using their influence effectively to ensure local women were aware of all their birthplace options, including midwifery-led units and home birth.