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Several clinical trials have noted an association between hypoglycemia and major cardiovascular events; however, a direct link between antecedent hypoglycemia and worse cardiac outcomes has not been established. We hypothesized that antecedent recurrent hypoglycemia predisposes the heart to increased damage following a subsequent myocardial infarction. To test this hypothesis, adult Sprague Dawley rats were subjected to 3 days of recurrent insulin-induced hypoglycemia (25-30 mg/dl, 90 minutes each day; n = 6) or saline (control, n = 6) . On the following day, all rats underwent a myocardial infarction (MI) induced by occlusion of the left anterior descending artery for 30 minutes followed by reperfusion for 60 minutes. Electrocardiograms indicated ST elevation during the MI, which returned to normal sinus rhythm upon reperfusion. Hearts were removed immediately and analyzed for damage. MI induced ventricular damage from rats that underwent antecedent recurrent hypoglycemia (39 ± 5%) was significantly higher than control rats (16 ± 4%; p Disclosure C.G.Christensen: None. S.Fisher: None. C.M.Reno: None. Funding University of Utah’s Driving Out Diabetes, a Larry H. Miller Family Wellness InitiativeNational Institutes of Health (P30 DK020579) Juvenile Diabetes Research Foundation (1-FAC-2020-984-A-N)

To test the hypothesis that metoclopramide (a dopamine antagonist) may restore hypoglycemic counterregulation, 10-week old rats underwent recurrent (insulin-induced) hypoglycemia (RH) to induce a blunted sympathoadrenal response. RH rats were treated with vehicle or metoclopramide (RH+MET: 3 mg/kg IP) . A third control group did not undergo recurrent hypoglycemia (RS: recurrent saline) . MET was administered either during RH phase (concurrent protocol) or after RH (post-induction protocol) . All rats (n=7-14/group) underwent a hyperinsulinemic (50mU/kg/min) hypoglycemic (45±5 mg/dl) clamp. In the concurrent protocol, epinephrine response to hypoglycemia in RS (1434±275 pg/ml) was blunted in RH (460±1pg/ml, p In summary, 1) metoclopramide prevented the development of an impaired sympathoadrenal response to hypoglycemia, and 2) in rodents that had an impaired response to hypoglycemia, subsequent metoclopramide treatment restored the sympathoadrenal response. In conclusion, 1) dopaminergic signaling plays a role in the development of impaired counterregulation, and 2) post hoc treatment with metoclopramide improves the sympathoadrenal response to hypoglycemia. Disclosure M.H.Devore: None. S.Sharma: None. S.Fisher: None. Funding NIH R01DK118082

Point-of-care retinal imaging is effective at identifying diabetic retinopathy. However, appropriate follow-up, referral, and access to specialized eye care remains a barrier for the treatment of identified eye disease. We tested the hypothesis that rapid results and immediate referrals afforded by use of an automated diabetic retinopathy screening platform with AI technology (EyeArt) would result in greater patient follow up with ophthalmology specialists as compared to “traditional” tele-retinal screening (images acquired in clinic and transmitted electronically for interpretation by a vitreoretinal specialist) . All images were acquired during a patient’s regularly scheduled diabetes clinic visit. With traditional tele-retinal screening, the average turnaround time to patient notification of findings was days. Among the 357 patients that underwent traditional screening, 42 (12%) were found to have referable (more-than-mild) retinopathy, and of these, 32 (76%) followed up in ophthalmology clinic. In contrast, the fully autonomous diabetic retinopathy screening platform using AI technology provided an immediate assessment on the presence of retinopathy (within 60 seconds of photo acquisition) . Patients were given this point-of-care summary of their eye-exam findings. When indicated, an ophthalmology referral was ordered and patients were provided with contact information for the ophthalmology office. Of the 81 patients screened with AI technology, 22 (27%) had referable retinopathy detected, 15 (68%) of whom followed up in ophthalmology clinic. The higher detection rate with AI screening raises the question of “overcalling” the presence of disease. We conclude that although AI screening offers immediate results allowing for immediate ophthalmology referral, there remains a substantial barrier to ophthalmology follow up after a positive retinopathy screen identified by either screening method. Disclosure M.Wahl: None. R.Kiani: None. J.Neuberger: None. B.Wilson: None. M.Hartnett: None. S.Fisher: None.

Mechanisms underpinning neurotypical age-related variations in cortical thickness in the human brain remain insufficiently specified. Here we used cell-specific marker genes, followed by gene ontology and enrichment analyses, to quantify the association between gene-expression levels and inter-regional age-related variations in neurotypical cortical thinning using multicohort neuroimaging data from 14,248 individuals ages 4-89 years. We found that early-life (60 years) were associated with distinct patterns of association between inter-regional profiles of cortical thickness and expression profiles of markers genes for CA1 and S1 pyramidal cells, astrocytes, and microglia. Gene ontology and enrichment analyses indicated each of the three life-stages was associated with different biological processes and cellular components; these related to synaptic modeling in early life, neurotransmission in mid-life, and neurodegeneration in late-life. These findings provide mechanistic insights on age-related cortical thinning during typical development and ageing.

Worldwide, the majority of people prefer using the right hand for most motor tasks, including writing. Because of the link between handedness and language hemispheric dominance, handedness has been studied for association with language-related disorders. No clear pattern has emerged from these studies, and inconsistencies have been attributed to small sample sizes, publication bias, and heterogeneous criteria for the definition of handedness and disorders.Here, we assessed the frequency of non-right handedness (NRH) in 10 distinct cohorts not analysed before in this context. We identified N = 2,499 cases with reading and/or language impairment and N = 4,428 unique controls on the basis of a priori defined criteria. Overall, NRH was more frequent and more variable in the cases (8-24%) than in the controls (8-16%). Meta-analysis in the eight cohorts that met the inclusion criteria showed an increase of NRH in individuals with language/reading impairment compared to controls (OR = 1.21, CI = 1.06 - 1.37, p = 0.009). No moderator effects were detected for type of cohort (epidemiological versus clinical) and type of impairment (language versus reading). Our results support a genuine but modest association between NRH and reading and language impairments, suggesting shared biological pathways underlying brain lateralization, handedness, and cognitive functions.

Drug repurposing is promoted as a cost- and time-effective mechanism for providing new medicines. Often, however, there is insufficient consideration by academic researchers of the processes required to ensure that a repurposed drug can be used for a new indication. This may explain the inability of drug repurposing to fulfill its promise. Important aspects, often overlooked, include financial and intellectual property considerations, the clinical and regulatory path, and clinical equipoise, which provides ethical justification for randomized controlled trials. The goal of drug repurposing is to obtain a new regulator-approved label for an existing drug, and so, the trajectory for drug repurposing and traditional drug development is similar. Here, we discuss factors critical for a successful repurposed medicine to help academic investigators better identify drug repurposing opportunities.

Using a genome wide association study (GWAS), we identified a locus on the promoter of the human uromodulin (UMOD) gene associating with primary hypertension. In this study we aimed to identify genotype-differential protein binding partners which influence UMOD expression and to examine pathways linking UMOD expression to blood pressure variability in humans.We examined a variant on this locus, by incubating 50mer oligonucleotides featuring alternate alleles (C/G) with HEK-293 nuclear protein extract. Subsequently, we performed an electrophoretic mobility shift assay (EMSA) and purified protein complexes to analyse by Tandem-mass-spectroscopy (MS2). Filtering for peptide matches >20, we interpreted these data by Ingenuity Pathway Analysis (IPA). From a bank of 98 human renal biopsy samples, we assessed UMOD expression by qRT-PCR. RNA-seq was performed using the NextSeq-500 system on a subset of high and low UMOD expressors (n=3/ group). Differentially expressed (false-discovery-rate (FDR)

The COVID-19 pandemic affects many aspects of diabetes care including loss of access to healthcare due to clinic closures or insurance issues, fear of accessing care due to potential COVID exposures, and food/medication insecurity. Little is known about how ER visits for acute diabetic complications change as a result of this pandemic. An observational claims-based study was conducted to evaluate ER visits for DKA and hypoglycemia at the University of Michigan Health System. ER admissions with diagnoses of DKA and hypoglycemia were identified in 2020 and compared to 2017-19 (baseline). Since March 2020 (with the first COVID case identified in Michigan), the numbers of total ER admissions (both COVID and non-COVID related) have consistently remained lower than baseline (Figure 1A). While ER admission numbers for DKA (Figure 1B) and hypoglycemia (Figure 1C) were lower during the first wave of COVID (Mar-May), no consistent pattern has been observed in the second wave of COVID cases (Oct-). In summary, ER admissions for DKA and hypoglycemia decreased as much as 50% during the first, but not the second, waves of COVID cases. Further studies evaluating this complex psycho-social-medical phenomenon is in need.

During pregnancy, the uterine spiral arteries undergo major vascular remodeling to ensure sufficient uteroplacental perfusion to support the fetus. In pregnancies complicated by hypertensive disorders, this remodeling is deficient leading to impaired uteroplacental blood flow and poor maternal and fetal outcomes. The underlying genetic mechanisms for failed vascular remodeling are not fully understood. This study aimed to examine the early-pregnancy-associated gene changes in the uterine arteries of spontaneously hypertensive stroke-prone rats (SHRSP) compared with their normotensive counterparts, Wistar–Kyoto rats (WKY). Uterine arteries from gestational day 6.5 WKY and SHRSP were processed for RNA-sequencing, along with virgin, age-matched controls for each strain. Gene expression changes were identified and biological pathways were implicated and interpretated using ingenuity pathway analysis (IPA). This study found that WKY uterine arteries from early pregnancy exhibit a gene expression pattern that is suggestive of a pregnancy-dependent reduction in Ca2+ handling and renin-angiotensin-aldosterone system (RAAS) components and an increase in ATP production. In contrast, the expression pattern of pregnant SHRSP uterine arteries was dominated by an elevated immune response and increased production of reactive oxygen species (ROS) and downstream effectors of the RAAS. These results suggest that in a rat model, hypertension during pregnancy impacts uterine artery gene expression patterns as early as the first week of pregnancy. The pathway changes involved may underlie or contribute to the adverse vascular remodeling and resultant placental ischemia and systemic vascular dysfunction observed in SHRSP in late gestation.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown.We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48 % male) derived from 15 distinct MRI scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers – the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

The 5HT1B receptor (5HT1BR) contributes to the pathogenic effects of serotonin in pulmonary arterial hypertension. Here, we determine the effect of a microRNA96 (miR96) mimic delivered directly to the lungs on development of severe pulmonary hypertension in rats. Female rats were dosed with sugen (30 mg/kg) and subjected to 3 weeks of hypobaric hypoxia. In normoxia, rats were dosed with either a 5HT1BR antagonist SB216641 (7.5 mg/kg/day for 3 weeks), miR96, or scramble sequence (50 μg per rat), delivered by intratracheal (i.t) administration, once a week for 3 weeks. Cardiac hemodynamics were determined, pulmonary vascular remodeling was assessed, and gene expression was assessed by qRT-PCR, and in situ hybridization and protein expression were assessed by western blot and ELISA. miR96 expression was increased in pulmonary arteries and associated with a downregulation of the 5HT1BR protein in the lung. miR96 reduced progression of right ventricular systolic pressure, pulmonary arterial remodeling, right ventricular hypertrophy, and the occurrence of occlusive pulmonary lesions. Importantly, miR96 had no off-target effects and did not affect fibrotic markers of liver and kidney function. In conclusion, direct delivery of miR96 to the lungs was effective, reducing progression of sugen/hypoxia-induced pulmonary hypertension with no measured off-target effects. miR96 may be a novel therapy for pulmonary arterial hypertension, acting through downregulation of 5HT1BR., Graphical Abstract, Serotonin, acting through the 5HT1B receptor contributes to the pathophysiology of pulmonary hypertension. In a model of pulmonary hypertension, miR96 delivered directly to the lungs decreased expression of the lung 5HT1B receptor and reversed pulmonary hypertension without causing any inflammation or loss of liver or kidney function.

An open question is how individual sensory experiences acquire different subjective aesthetic values. Variability in visual aesthetic value is known to be formed and shaped over a lifetime, with individual experiences playing a crucial role. However, whether the formation of visual aesthetic value is solely influenced by environmental exposure is still a matter of debate. Here, we considered differences in aesthetic value emerging across three visual domains; abstract images, scenes and faces. We examined variability in two major dimensions of ordinary aesthetic experiences: similarity between each individual’s preferences and the group’s average (taste-typicality) and the overall aesthetic value evoked by visual images (evaluation-bias). We build on a discovery sample from the Australian Twin Registry originally analysed by Germine et al. (2015), and validate our findings in a partially overlapping sample analysed by Sutherland et al. (2020), where respectively 1547 and 1243 monozygotic and dizygotic twins rated visual images belonging to the three domains. First, we revealed that the three visual domains evoked different degrees of individual variability in preferences. We then showed that genetic influences could explain 25% to 41% of the variance in taste-typicality and evaluation-bias. Multivariate analyses showed that genetic effects were partially shared across visual domains. Results indicate that major dimensions of aesthetic evaluations are comparably heritable to other complex human traits. The exception was taste-typicality for abstract images for which we found only shared and unique environmental influences. Our study reveals that diverse sources of variation, both genetic and environmental, influence the formation of aesthetic value across distinct visual domains.

The valve and operating system had reached the end of its asset life and the tower was showing signs of structural distress. The wet tower arrangement required a full drawdown of the reservoir basin to allow surveys of the valve, pipework and tower condition. A pro-active silt management system was required to discharge into the downstream watercourse that flows into sinkholes. The paper covers the development of the scheme through to selection of the preferred solution.

Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on modest sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last four years, the ENIGMA-Laterality Working Group has published six studies of brain structural asymmetry based on total sample sizes of between roughly 3,500 and 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average brain asymmetry was achieved, including an intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA’s multi-dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for brain asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: Autism Spectrum Disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; Pediatric Obsessive-Compulsive Disorder was associated with altered subcortical asymmetry; Major Depressive Disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.

Specific language impairment (SLI) is defined as an inability to develop appropriate language skills without explanatory medical conditions, low intelligence or lack of opportunity. Previously, a genome scan of 98 families affected by SLI was completed by the SLI Consortium, resulting in the identification of two quantitative trait loci (QTL) on chromosomes 16q (SLI1) and 19q (SLI2). This was followed by a replication of both regions in an additional 86 families. Both these studies applied linkage methods to one phenotypic trait at a time. However, investigations have suggested that simultaneous analysis of several traits may offer more power. The current study therefore applied a multivariate variance-components approach to the SLI Consortium dataset using additional phenotypic data. A multivariate genome scan was completed and supported the importance of the SLI1 and SLI2 loci, whilst highlighting a possible novel QTL on chromosome 10. Further investigation implied that the effect of SLI1 on non-word repetition was equally as strong on reading and spelling phenotypes. In contrast, SLI2 appeared to have influences on a selection of expressive and receptive language phenotypes in addition to non-word repetition, but did not show linkage to literacy phenotypes. © 2007 The Authors Journal compilation © 2007 University College London.

Spiritual care may be said to be universally recognized as an important aspect of palliative care and yet its effectiveness is notoriously difficult to evaluate. This article traces the experience of a group of three hospice services in East Kent. It describes the formulation of a multidisciplinary policy for spiritual care based on the best available evidence. Clinical and non-clinical staff were encouraged through training to adopt an approach to spiritual care for all patients recognizing that their spiritual needs are broader than religious needs, The outcome of the training was audited and showed that the principles of the policy had been understood and put into practice. Lessons learned through the audit were then used to update the policy, adapt practice and plan a fresh round of training.

The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.

Purpose of review This review considers the biliary complications associated with liver transplantation using donation after cardiac death (DCD) donor grafts. Recent findings The increasing use of DCD liver grafts with their increased incidence of biliary complications is discussed. The ethics of this greater use is briefly analysed. Recent animal and human study evidence to support the peribiliary vascular plexus' role in ischaemic cholangiopathy is reviewed. Recent advances in in-vivo and ex-vivo perfusion are explored. In particular, the latest theories regarding perfusion's peribiliary plexus preserving effects and the mechanism by which biliary regeneration may be promoted as a consequence are discussed. Summary This article explores the need for DCD liver graft use and the associated biliary complications. The current theories regarding the cause of DCD biliary complications are reviewed, as are the current strategies to reduce them.

Whether you exercise a desire to experience surgery abroad during your student elective or whether you want to take the opportunity to enhance your career aspirations in far-flung regions, knowledge of common surgi­cal presentations of tropical disease is a prerequisite. Moreover, with the ability conferred by modern jet travel to translocate to almost any area of the globe within 48h, you may well encounter these conditions in your local general hospital clinic or emergency department, in visitors to the country or in travellers returning home from foreign excursions. This chapter tests you on your knowledge of presentations, investi­gations, and management of diseases such as malaria, schistosomiasis, amoebiasis, and filariasis, conditions native to a variety of geographical locations. Some diseases such as hydatid still remain endemic in regions closer to the UK. A sound understanding of parasitic life cycles, modes of exposure to, and manifestations of infection, and principles of treatment, will help you to diagnose and manage these conditions whether they are encountered unexpectedly, or prevalent in your geographical location.

Understanding that children are not small adults, and that they come in different sizes and stages of development, is fundamental to paediatric surgery. Knowledge of a child’s weight is crucial when considering fluid and medication administration. Moreover, babies have immature physiology and less functional reserve compared to older children. Understanding basic embryology will unravel some of the mysteries of developmental pathology encoun­tered by the paediatric surgeon, such as oesophageal atresia, malrotation of the gut, annular pancreas, and maldescent of the testis. The paediatric surgeon deals with some of the same surgical condi­tions that affect adults, but even management of a common condition such as inguinal hernia, has different therapeutic implications in children and adults. Paediatric surgery demands gentle tissue handling and deli­cate technique. Good communication skills are a prerequisite for dealing with the distraught or ill child and anxious parents, and the surgeon often retains a clinical interest in his or her patient, well into young adulthood. This chapter will test your knowledge of principles of surgical manage­ment of sick children and your understanding of presentations of some of the more commonplace conditions encountered by surgeons in this demanding, yet rewarding, discipline.

When the student contemplates potential causes of urinary tract obstruction, considering the anatomy of the drainage system from renal pelvis to urethral meatus and appreciation of potential causes of block­age will provide a useful diagnostic screen and will help one to review the breadth of conditions which may affect the renal tract. These include extrinsic compression, (for instance, due to retroperitoneal fibrosis or prostatic hypertrophy), mural involvement (infection, inflammation and transitional cell carcinoma), or luminal obstruction, (blood clot, stone, or valve). A firm grasp of appropriate investigations for urinary tract disease will aid diagnostic accuracy. Urological surgery encompasses various aspects of neoplasia and developmental conditions. This chapter will test your knowledge of the presentation, diagnosis, management, and pathology of common urological malignancies including renal adenocarcinoma, transitional cell tumours, testicular tumours, and carcinoma of the prostate. Urological conditions often occur in patients who may have other co-morbidities. Understanding the causes, investigation, and management of renal failure, appreciating the significance of haematuria, and knowing how to deal with an urological emergency of acute urinary obstruction will add to the medical student’s or trainee surgeon’s breadth of compe­tence in general surgical practice.

Management of the cardiothoracic patient is diagnostically and techni­cally demanding. Cardiothoracic surgery comprises cardiac and thoracic components. Whilst overlap exists between treatment of pulmonary conditions including lung neoplasia, infection and ventilatory dysfunction, and treatment of cardiac disease, progressively surgeons tend to special­ize in one area or the other. Boundaries between cardiac surgery and interventional cardiology are also diminishing as new endovascular interventions—for instance, in coronary artery angioplasty, stenting, and valve replacement—achieve growing therapeutic prominence and compete with open surgical procedures. A firm grasp of cardiopulmonary physiology underpins understanding of cardiovascular function and of the pathologies affecting these systems. This chapter will test you on aspects of pulmonary pathology, cardiovas­cular physiology, and on ischaemic heart disease and valvular dysfunc­tion. This should help you to revise key aspects in this demanding and rapidly evolving area of surgery.

There is very little research into patients who suffer from a terminal and progressive illness making decisions about health care in a hospice setting. What decision-making means to the inpatients in a hospice could be better understood by staff caring for this patient group. The aim of this small qualitative study was to explore the nature of decisions and the process of decision-making with patients who had been admitted to a hospice with a progressive terminal illness. A phenomenological approach was taken using a theoretical framework to explore the patients’ life world and its existential meaning, and interviews were conducted with six inpatients. The decisions that came to the fore for the participants were around the driving force behind admission, which was often pain. Beyond this often traumatic event they were able to be robust in decision-making about day-to-day issues. Other decisions related to the purpose of the admission such as symptom control, achieving independence, whether to have further treatment, communication with their families and returning to the community. Patients had an increased awareness of the fragility of their existence, which was brought into focus by the decision to be admitted to the hospice. The findings give an insight into the driving forces behind decision-making and the kind of decisions that are important to the patients in this sample, which staff caring for this patient group may find valuable.

Low birth weight (LBW) is an important risk factor for type 2 diabetes. We have developed a mouse model of LBW resulting from undernutrition during pregnancy. Restriction of maternal food intake from day 12.5 to 18.5 of pregnancy results in a 23% decrease in birth weight (P0.001), with normalization after birth. However, offspring of undernutrition pregnancies develop progressive, severe glucose intolerance by 6 months. To identify early defects that are responsible for this phenotype, we analyzed mice of undernutrition pregnancies at age 2 months, before the onset of glucose intolerance. Fed insulin levels were 1.7-fold higher in mice of undernutrition pregnancies (P = 0.01 vs. controls). However, insulin sensitivity was normal in mice of undernutrition pregnancies, with normal insulin tolerance, insulin-stimulated glucose disposal, and isolated muscle and adipose glucose uptake. Although insulin clearance was mildly impaired in mice of undernutrition pregnancies, the major metabolic phenotype in young mice of undernutrition pregnancies was dysregulation of insulin secretion. Despite normal beta-cell mass, islets from normoglycemic mice of undernutrition pregnancies showed basal hypersecretion of insulin, complete lack of responsiveness to glucose, and a 2.5-fold increase in hexokinase activity. Taken together, these data suggest that, at least in mice, primary beta-cell dysfunction may play a significant role in the pathogenesis of LBW-associated type 2 diabetes.

Introduction The remit of the National Audit Tools Group (NATG) is to produce a set of core audit tools to enable hospices to evidence compliance with national standards of care, irrespective of their processes or documentation systems. Quality impact analysis, feedback from workshops, training days and consultation with hospices identified a need for audit tools specific to community services. Aims Development of a comprehensive family of audit tools to measure quality of hospice care in the community against validated standards. Methods A NATG subgroup was formed drawing on expertise from different community areas, in particular Community Nurse Specialist and Hospice at Home. To inform the development and structure of the tools, it critically reviewed: statutory and regulatory requirements, relevant national standards and guidelines, range and scope of community services provided by hospices. Because of the size and complexity of the project, topics were grouped to reflect different community areas, each requiring specialist input and ensuring multi professional collaboration. Results Five audit tools under development are: Referral Management, Initial Assessment, Follow-up Assessment, Assessment Domains, Cooperation with Other Providers. Further tools are planned to include: Advance Care Planning, Communication, Confidentiality, Education and Training, Rapid Response, Documentation and Recording. Discussion The diversity of community service provision and the different work patterns across hospices presented a number of challenges in ensuring that the tools under development are fit for purpose and meet local needs. Conclusion Following testing and critical review, the first tool will be available by the end of 2011 and will be published on Help the Hospices website as a free download. Other tools will follow during 2012.

The existing far infrared spectroscopy beam line at the Daresbury Laboratory Synchrotron Radiation Source (SRS) has been adapted to provide intense collimated radiation for a mid infrared microscope. The SRS beam is focused by the microscope onto an area of the sample only 20 X 30 microns in size and this allows the collection of high fidelity data from samples smaller than 10 microns across. At these dimensions, signal-to-noise is significantly greater than with a conventional infrared source. This new facility is now finding applications with a wide range of users in areas such as materials science, conservation, and biomedicine. As part of a collaboration between Daresbury Laboratory, Nottingham University and University Hospital, Nottingham, the instrument is being applied to investigate the subtle chemical differences which occur between normal and cancerous cells on a cell-by-cell basis. Significant spectral shifts, some of which have previously only been observed in macroscopic samples, can be identified in single cells. The enhanced ability to make such measurements by using synchrotron radiation as the IR source has potential to provide a clearer understanding of the changes occurring in cancerous and pre-cancerous cells.

This paper describes how an experimental full services access network has been constructed at BT Labs and presents views on how its performance could be improved to meet the reliability and traffic loading requirements expected in real applications such as fiber to the business and fiber to the cabinet. The experimental network included: asynchronous transfer mode (ATM) switch, an ATM passive optical network (PON), very high speed digital subscriber loop (VDSL) customer drop and ATM forum 25 Mbit/s customer network. The design and realization of the VDSL customer drop, the signaling system and the interfaces between the system elements formed a major part of the design and construction work at BT Labs. The ability to cope with varying service demand and achieving the necessary quality of service are important requirements for roll-out systems. This paper describes how these requirements could be met in the design of future proprietary equipment.© (1997) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Next-generation sequencing is set to transform the discovery of genes underlying neurodevelopmental disorders, and so off er important insights into the biological bases of spoken language. Success will depend on functional assessments in neuronal cell lines, animal models and humans themselves.

Background ‘NHS fast tract’ enables urgent care allocation to a patient whose primary health need is classified as ‘rapidly deteriorating condition with an increasing level of dependency and approaching end of life care’. The guidance states clearly that life expectancy does not form a part of the eligibility criteria under fast tract route. This approach aims to ensure that the individual in question with get the care they require and this be their preferred place of care and be in place within 48 h. Aim To explore the possibility that the fast track process can act as a useful aide memoire when professionals are trying to predict prognosis in individuals with progressive, life limiting conditions. Methodology A retrospective case note review as well as fast track documentation within a hospice setting over 3 months. Results Fourty-two patients identified who applied for the ‘NHS fast tract’ process with 41 applications approved. In 39/42 (93%) applications a decision was reached within 48 h with the remaining applications getting a decision in 72 h. In terms of accuracy of prediction: 36/42 (86%) died with 12 weeks of approval.28/42 (67%) achieved their preferred place of care (PPoC) and death (PPoD) with 6/42 (14%) not able to have the conversation regarding PPoC/D. Conclusion The possibility that the Fast Track process may help clinicians in trying to build an approach in aiding prognostication and facilitating individuals to be cared for and die in their preferred setting is promising. The use of an existing process that can timely facilitate end of life care in individuals with the helpfulness of timelines can only help manage resources that are currently so limited. We aim to use this approach with additional data methods to try and gain further knowledge in best planning end of life care.

Steroids are commonly used medications in palliative care patients. It is well known that inappropriate or prolonged prescribing of steroids could be harmful for patients. An Audit of documentation of steroid usage in in-patients was completed in 2007 at three hospices with 90 patients. This recommended (1) every patient on steroids must have indication, dose, response and planned length of treatment documented. It may be feasible to record this in both case notes and drug chart. (2) All patients on steroids and NSAIDs should be on a PPI. (3) All patients discharged on steroids should have a management plan documented. Aim To evaluate our current practice against the recommendations from the 2007 audit. Methodology Retrospective, case notes &drug chart review of all the patients discharged from two inpatients9 units from November 2010 to May 2011 with 32 beds in total. Results Total patients: 133, patients discharged on steroids: 60 (30%). Indication documented: 52/60; Response clearly documented: 37/60.Planned duration documented: 40/60.Patient on steroids and NSAIDs not on PPI: 2/5. No documented plans about steroids in discharge letter: 28/60. Conclusion A significant number of patients are discharged on steroids from inpatients9 units. However, the documentation of indications, planned length of use, response to the treatment and reduction plans needs further improvement. One of the main findings from the audit is that the documentation regarding steroid prescription and planned reduction in discharge summaries needs to be significantly improved. It is recommended that a separate box be added to the discharge letters regarding steroids and plans of reduction and introduce steroid card for the patients to carry to alert the professionals. To re-audit in 2 years time to check progress.

Background Excessive respiratory secretions are common at the end of life. A Cochrane review concluded that there was no current evidence of effectiveness of current interventions but it is a symptom that relatives find distressing in end of life care. Therefore clinicians need to balance the available evidence with the distress remarked on by relatives. Aim To compare audits on the management of ‘death rattle’ in two hospices against national guidelines. Methodology Retrospective, case note review of inpatients who died over a 5 month period in 2010 (Unit 1) and in 2011 (Unit 2). Results Unit 1: 73 patients: 66 had antisecretory medication prescribed. Twenty-four patients needed the medication. 27/66 had incorrect doses prescribed. 21/24 had response assessed/documented. 18/24 patients documented benefit from the antisecretory drug. Non-Pharmacological measures, 2/24 patients had evidence of re-positioning only with no documentation of communication with the family (0/24). 20/24 patients died within 48 h of the first dose of antisecretory medication. Results Unit 2: 72 patients: 65 had antisecretory medication prescribed. 36 patients needed the medication. 16/65 had incorrect doses prescribed.29/36 response assessed/documented. 24/29 patients had documented benefit from the antisecretory drug. Non-Pharmacological measures, 3/36 patients had evidence of re-positioning with 4/36 documentation of communication with the family. 22/36 patients died within 48 h of the first dose of antisecretory medication. Conclusion Patterns of antisecretory medication appears very similar pattern in both hospices. In the majority of cases, documentation supported adherence to the national guidelines. Of note is the considerable dose variation in the drugs prescribed. This has been highlighted as an education and training issue. The supporting documentation to evidence the use of non-pharmacological measures but also in communicating with the relatives about the ‘death rattle’ needs further work.

‘Noisy breathing’ also known as death rattle, is common in end of life care situations and can be distressing for the family given it9s unpleasant resonance. A recent Cochrane review by Wee et al (2009 review) concluded that there is no evidence to show any intervention was superior to placebo; it is very difficult to subsequently manage. Aim To evaluate current practice against national guidelines on the use of antisecretory medications in end of life care. Methodology Retrospective, case notes review of all the patients died in the author9s unit (Jan 2011–May 2011). Results Seventy-two patients were identified with 65 patients having antisecretory drugs prescribed and 36 patients requiring medications. 49/65 had complied with the recommended guidance with only 29/36 having a documentation of a response. 7/36 patients with no documentation of assessment. 24/29 patients had documented benefit from the antisecretory drug and a syringe driver started in 24/36 cases. Apart from drugs evidence of other modalities used was lacking: 3/36 patients evidence of re-positioning only. Documentation of communication with family was only in 4/36. 22/36 patients died within 48 h from 1st dose of antisecretory given and 16/24 patients died within 24 h of the syringe driver starting. Conclusion In a majority of patients medications used appropriately and response assessment completed. However, documentation of communication with family and other approaches needs to be improved. Interestingly when antisecretory drugs were used death ensued within 48 hrs for the majority. Education of all staff members is extremely important along with regular audit.

The object of this paper is to present a thematic and analytical account of the present scope and limits of the doctrine of direct effect of secondary legislation in European Community Law. It is thirty years since the doctrine of direct effect was first clearly established in the leading case of NV AIgemene Transport en Expeditie Van Gend en Loos v. Nederlandse administratie der belastingen1 and hence it is appropriate that an analysis of the present day doctrine of direct effect is undertaken. Many fields of judicial doctrine, whether in public law or private law, have been developed in an incremental or ad hoc basis where the courts first lay down the principles of the doctrine and subsequently refine them as the case law develops. As part of this process the criteria laid down by the European Court of Justice in determining whether or not a given provision of European Community Law has direct effect will be isolated. This will provide a springboard then, to examine the types of secondary Community legal provisions which have direct effect. This analysis will show the importance and emphasis placed by the European Court on the development and refinement of judicial doctrine giving content and application to the principle of direct effect. The outcome of this process will be to identify the factors and influences that contribute to the orderly and rational development, as well as enhancement, of European Community Law.