Does screening or routine enquiry for adverse childhood experiences (ACEs) meet criteria for a screening programme? A rapid evidence summary.

BACKGROUND: Adverse childhood experiences (ACEs) are traumatic events in childhood that can have impacts throughout life. It has been suggested that ACEs should be 'screened' for, or routinely enquired about, in childhood or adulthood. The aim of this work is to review evidence for this against the United Kingdom National Screening Committee (UKNSC) programme criteria. METHODS: A rapid review of evidence on ACEs screening was conducted using the approach of the UKNSC. RESULTS: Good quality evidence was identified from meta-analyses for associations between ACEs and a wide range of adverse outcomes. There was no consistent evidence on the most suitable screening tool, setting of administration, and time or frequency of use. Routine enquiry among adults was feasible and acceptable to service users and professionals in various settings. A wide range of potentially effective interventions was identified. Limited evidence was available on the potential for screening or routine enquiry to reduce morbidity and mortality or possible harms of screening. CONCLUSIONS: Based on the application of available evidence to UKNSC screening criteria, there is currently insufficient evidence to recommend the implementation of a screening programme for ACEs. Further research is needed to determine whether routine enquiry can improve morbidity, mortality, health and wellbeing.

Adult encephalitis surveillance: experiences from an Australian prospective sentinel site study.

Few countries routinely collect comprehensive encephalitis data, yet understanding the epidemiology of this condition has value for clinical management, detecting novel and emerging pathogens, and guiding timely public health interventions. When this study was conducted there was no standardized diagnostic algorithm to aid identification of encephalitis or systematic surveillance for adult encephalitis. In July 2012 we tested three pragmatic surveillance options aimed at identifying possible adult encephalitis cases admitted to a major Australian hospital: hospital admissions searches, clinician notifications and laboratory test alerts (CSF herpes simplex virus requests). Eligible cases underwent structured laboratory investigation and a specialist panel arbitrated on the final diagnosis. One hundred and thirteen patients were initially recruited into the 10-month study; 20/113 (18%) met the study case definition, seven were diagnosed with infectious or immune-mediated encephalitis and the remainder were assigned alternative diagnoses. The laboratory alert identified 90% (102/113) of recruited cases including six of the seven cases of confirmed encephalitis suggesting that this may be a practical data source for case ascertainment. The application of a standardized diagnostic algorithm and specialist review by an expert clinical panel aided diagnosis of patients with encephalitis.

MAGNETOCALORIC RESPONSE OF NON-STOICHIOMETRIC Ni2MnGa ALLOYS AND THE INFLUENCE OF CRYSTALLOGRAPHIC TEXTURE.

Currently, there is significant interest in magnetocaloric materials for solid state refrigeration. In this work, polycrystalline Heusler alloys belonging to the Ni2+xMn1-xGa family, with x between 0.08 and 0.24, were evaluated for the purpose of finding composition(s) with an enhanced magnetocaloric effect (MCE) close to room temperature. Differential scanning calorimetry (DSC) was successfully used to screen alloy composition for simultaneous magnetic and structural phase transformations; this coupling needed for a giant MCE. The alloy with x = 0.16 showed an excellent match of transformation temperatures and exhibited the highest magnetic entropy change, ΔSM, in the as-annealed state. Furthermore, the MCE increased by up to 84 % with a 2 Tesla (T) field change when the samples were thermally cycled through the martensite to austenite transformation temperature while held under a constant mechanical load. The highest ΔSM measured for our x = 0.16 alloy for a 2 T magnetic field change was -18 J/kg-K. Texture measurements suggest that preferential orientation of martensite variants contributed to the enhanced MCE in the stress-assisted thermally cycled state.

Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand.

Encephalitis is a complex neurological syndrome caused by inflammation of the brain parenchyma. The management of encephalitis is challenging because: the differential diagnosis of encephalopathy is broad; there is often rapid disease progression; it often requires intensive supportive management; and there are many aetiologic agents for which there is no definitive treatment. Patients with possible meningoencephalitis are often encountered in the emergency care environment where clinicians must consider differential diagnoses, perform appropriate investigations and initiate empiric antimicrobials. For patients who require admission to hospital and in whom encephalitis is likely, a staged approach to investigation and management is preferred with the potential involvement of multiple medical specialties. Key considerations in the investigation and management of patients with encephalitis addressed in this guideline include: Which first-line investigations should be performed?; Which aetiologies should be considered possible based on clinical features, risk factors and radiological features?; What tests should be arranged in order to diagnose the common causes of encephalitis?; When to consider empiric antimicrobials and immune modulatory therapies?; and What is the role of brain biopsy?

The relationship between deprivation and alcohol-related presentation at Accident and Emergency (A&E) over a three-month period.

OBJECTIVES: To identify any relationship between deprivation and the level of presentation to Accident and Emergency with alcohol-related conditions in a busy East Coast teaching hospital in Scotland. METHODS: Over an 87-day-period initial screening to determine whether alcohol played a part in each presentation was conducted at triage. These patients were then streamed according to their Paddington Alcohol Test (Pat) score into Pat +ve and Pat -ve groups. The postcode of each patient was recorded before they were assigned deprivation levels using the DepCat scoring system. This information was then compiled in Microsoft Excel 2003 and a graph showing the differences in the number of presentations across the social spectrum was constructed. RESULTS: Nine hundred and forty four patients were screened as attending due to alcohol with 43.86% being Pat +ve and 56.14% being Pat -ve. Overall 66.42% of the Pat +ve group and 54.42% of Pat -ve were from deprived or very deprived areas. CONCLUSIONS: The use of electronic-based screening was effective at highlighting patients presenting to Accident and Emergency with alcohol-related problems, and these presentations highlighted a direct link between the level of deprivation and attendances.

A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.

OBJECTIVES: In patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine, in which their immunogenicity is potentiated by tissue transglutaminase (tTG) and T-helper type 1-mediated immune responses are triggered. Tight junction disassembly and paracellular permeability are believed to have an important role in the transport of gluten peptides to the lamina propria. Larazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease. METHODS: In this dose-ranging, placebo-controlled study, 86 patients with celiac disease controlled through diet were randomly assigned to larazotide acetate (0.25, 1, 4, or 8 mg) or placebo three times per day with or without gluten challenge (2.4 g/day) for 14 days. The primary efficacy outcome was the urinary lactulose/mannitol (LAMA) fractional excretion ratio. Secondary endpoints included gastrointestinal symptom severity, quality-of-life measures, and antibodies to tTG. RESULTS: LAMA measurements were highly variable in the outpatient setting. The increase in LAMA ratio associated with the gluten challenge was not statistically significantly greater than the increase in the gluten-free control. Among patients receiving the gluten challenge, the difference in the LAMA ratios for the larazotide acetate and placebo groups was not statistically significant. However, larazotide acetate appeared to limit gluten-induced worsening of gastrointestinal symptom severity as measured by the Gastrointestinal Symptom Rating Scale at some lower doses but not at the higher dose. Symptoms worsened significantly in the gluten challenge-placebo arm compared with the placebo-placebo arm, suggesting that 2.4 g of gluten per day is sufficient to induce reproducible gluten toxicity. Larazotide acetate was generally well tolerated. No serious adverse events were observed. The most common adverse events were headache and urinary tract infection. CONCLUSIONS: LAMA variability in the outpatient setting precluded accurate assessment of the effect of larazotide acetate on intestinal permeability. However, some lower doses of larazotide acetate appeared to prevent the increase in gastrointestinal symptom severity induced by gluten challenge.

Episodic growth of the Gondwana supercontinent from hafnium and oxygen isotopes in zircon.

It is thought that continental crust existed as early as 150 million years after planetary accretion, but assessing the rates and processes of subsequent crustal growth requires linking the apparently contradictory information from the igneous and sedimentary rock records. For example, the striking global peaks in juvenile igneous activity 2.7, 1.9 and 1.2 Gyr ago imply rapid crustal generation in response to the emplacement of mantle 'super-plumes', rather than by the continuous process of subduction. Yet uncertainties persist over whether these age peaks are artefacts of selective preservation, and over how to reconcile episodic crust formation with the smooth crustal evolution curves inferred from neodymium isotope variations of sedimentary rocks. Detrital zircons encapsulate a more representative record of igneous events than the exposed geology and their hafnium isotope ratios reflect the time since the source of the parental magmas separated from the mantle. These 'model' ages are only meaningful if the host magma lacked a mixed or sedimentary source component, but the latter can be diagnosed by oxygen isotopes, which are strongly fractionated by rock-hydrosphere interactions. Here we report the first study that integrates hafnium and oxygen isotopes, all measured in situ on the same, precisely dated detrital zircon grains. The data reveal that crust generation in part of Gondwana was limited to major pulses at 1.9 and 3.3 Gyr ago, and that the zircons crystallized during repeated reworking of crust formed at these times. The implication is that the mechanisms of crust formation differed from those of crustal differentiation in ancient orogenic belts.

Complete nucleotide sequence and deduced polypeptide sequence of a nonmuscle myosin heavy chain gene from Acanthamoeba: evidence of a hinge in the rodlike tail.

We have completely sequenced a gene encoding the heavy chain of myosin II, a nonmuscle myosin from the soil ameba Acanthamoeba castellanii. The gene spans 6 kb, is split by three small introns, and encodes a 1,509-residue heavy chain polypeptide. The positions of the three introns are largely conserved relative to characterized vertebrate and invertebrate muscle myosin genes. The deduced myosin II globular head amino acid sequence shows a high degree of similarity with the globular head sequences of the rat embryonic skeletal muscle and nematode unc 54 muscle myosins. By contrast, there is no unique way to align the deduced myosin II rod amino acid sequence with the rod sequence of these muscle myosins. Nevertheless, the periodicities of hydrophobic and charged residues in the myosin II rod sequence, which dictate the coiled-coil structure of the rod and its associations within the myosin filament, are very similar to those of the muscle myosins. We conclude that this ameba nonmuscle myosin shares with the muscle myosins of vertebrates and invertebrates an ancestral heavy chain gene. The low level of direct sequence similarity between the rod sequences of myosin II and muscle myosins probably reflects a general tolerance for residue changes in the rod domain (as long as the periodicities of hydrophobic and charged residues are largely maintained), the relative evolutionary "ages" of these myosins, and specific differences between the filament properties of myosin II and muscle myosins. Finally, sequence analysis and electron microscopy reveal the presence within the myosin II rodlike tail of a well-defined hinge region where sharp bending can occur. We speculate that this hinge may play a key role in mediating the effect of heavy chain phosphorylation on enzymatic activity.

alpha-Cardiac actin is the major sarcomeric isoform expressed in embryonic avian skeletal muscle.

A primer extension assay that is diagnostic for the messenger RNA's (mRNA's) transcribed from the beta-cytoplasmic, alpha-cardiac, and alpha-skeletal actin genes of the chicken was used to measure the mRNA levels for these actin isoforms. Measurements were made in chicken breast muscle during myogenesis in vivo and in vitro. alpha-Cardiac actin mRNA accounts for more than 90 percent of the sarcomeric actin transcripts expressed in avian embryonic breast muscle. Five weeks after hatching, alpha-skeletal actin mRNA is the only detectable sarcomeric actin transcript.

Molecular cloning of a gene sequence regulated by nerve growth factor.

Nerve growth factor (NGF) is essential for the development and differentiation of sympathetic or sensory neurons. A complementary DNA was cloned that corresponds to a gene sequence induced more than 50-fold in a cultured target cell line of pheochromocytoma cells (PC12 cells) 5 hours after the addition of NGF. The induced messenger RNA encodes a 90,000-dalton polypeptide that may represent one of the primary events in NGF-induced differentiation of neurons.

Requirement of MADS domain transcription factor D-MEF2 for muscle formation in Drosophila.

Members of the myocyte enhancer binding factor-2 (MEF2) family of MADS (MCM1, agamous, deficiens, and serum response factor) box transcription factors are expressed in the skeletal, cardiac, and smooth muscle lineages of vertebrate and Drosophila embryos. These factors bind an adenine-thymidine-rich DNA sequence associated with muscle-specific genes. The function of MEF2 was determined by generating a loss-of-function of the single mef2 gene in Drosophila (D-mef2). In loss-of-function embryos, somatic, cardiac, and visceral muscle cells did not differentiate, but myoblasts were normally specified and positioned. These results demonstrate that different muscle cell types share a common myogenic differentiation program controlled by MEF2.

Introduction of the Liverpool Care Pathway for end of life care to emergency medicine.

AIM: To improve the care of patients presenting to the emergency department who are acutely dying or those in whom further disease-modifying treatment is not appropriate. DESIGN: A quality improvement report on the implementation of a modified Liverpool Care Pathway for the Dying Patient (LCP) in an emergency medicine department. SETTING: The emergency medicine department of Ninewells Hospital, Dundee. Ninewells Hospital is the tertiary referral and teaching hospital for the east coast of Scotland and North East Fife. KEY MEASURES FOR IMPROVEMENT: The pathway was introduced after a 2001 study and a 2003 audit showed that the department had an increasing role in the care of the acutely dying, but some inconsistency in approach. Key measures for improvement were to improve communication between staff, improve the consistency of care and improve the perceived quality of care given. Senior decision making remains a crucial element of the pathway. STRATEGIES FOR CHANGE: A modified LCP was developed and launched in November 2005. Change was managed via a series of meetings and a pilot process. Serial review and audit allowed ongoing quality review of the pathway and improvements. RESULTS: The care of the dying patient has become a more consistent and positive endeavour. Nursing staff are very satisfied with its use, and it is hoped that the LCP pathway can be developed further within the organisation. CONCLUSIONS: It has been a rewarding undertaking to improve the care of dying patients, but one which has taken time and has required consistent management of change to promote the positive outcomes.

The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study.

BACKGROUND: Lifelong adherence to a strict gluten-free diet is the cornerstone of coeliac disease treatment. Elucidation of disease pathogenesis has created opportunities for novel therapeutic approaches to coeliac disease. AT-1001 is an inhibitor of paracellular permeability whose structure is derived from a protein secreted by Vibrio cholerae. AIM: To determine the safety and tolerability of 12 mg doses of AT-1001 in coeliac disease subjects challenged with gluten. METHODS: An in-patient, double-blind, randomized placebo-controlled safety study utilizing intestinal permeability, measured via fractional excretions of lactulose and mannitol, as an exploratory measure of drug efficacy. RESULTS: Compared to placebo, no increase in adverse events occurred in patients exposed to AT-1001. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while none was seen in the AT-1001 group. Interferon-gamma levels increased in four of seven patients (57%) of the placebo group, but only in four of 14 patients (29%) of the AT-1001 group. Gastrointestinal symptoms were more frequently detected in the placebo group when compared to the AT-1001 group (P = 0.018). CONCLUSIONS: AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure.

Cell cycle regulation of a mouse histone H4 gene requires the H4 promoter.

The mouse histone H4 gene, when stably transformed into L cells on the PSV2gpt shuttle vector, is cell cycle regulated in parallel with the endogenous H4 genes. This was determined in exponentially growing pools of transformants fractionated into cell cycle-specific stages by centrifugal elutriation, a method for purifying cells at each stage of the cell cycle without the use of treatments that arrest growth. Linker additions in the 5' noncoding region of the H4 RNA or in the coding region of the gene did not affect the cell cycle-regulated expression of the modified H4 gene even though the overall level of expression was altered. However, replacing the H4 promoter with the human alpha-2 globin promoter, so that the histone transcript produced by the chimeric gene remains essentially unchanged, resulted in the constitutive expression of H4 mRNA during all phases of the cell cycle with no net increase in H4 mRNA levels during the G1-to-S transition. From these results we conclude that all the information necessary for the cell cycle-regulated expression of the H4 gene is contained in the 5.2-kilobase subclone used in these studies with 228 nucleotides of 5'-flanking DNA and that the increase in H4 mRNA during the G1-to-S transition in the cell cycle is mediated by the H4 promoter and not by the increased stability of the H4 RNA.

Approximately 1 kilobase of sequence 5' to the two myosin light-chain 1f/3f gene cap sites is sufficient for differentiation-dependent expression.

Approximately 1 kilobase of genomic DNA from the chicken fast myosin light-chain 1f/3f gene 5' to the transcriptional start sites for each light-chain mRNA was sufficient for differentiation-dependent, tissue-restricted expression. This was determined in primary chick myoblast cultures transfected with the chloramphenicol acetyltransferase (CAT) expression vector p8CAT containing these 5'-flanking sequences. The expression of CAT activity from both light-chain promoters was 10- to 20-fold higher in differentiated myotubes than in fibroblasts or myoblasts grown in bromodeoxyuridine. In contrast, the beta-actin and Rous sarcoma virus promoters joined to the CAT gene were expressed equally in all cell backgrounds tested. Even though the relative timing of light-chain 1f and 3f expression was altered, tissue-restricted, differentiation-dependent expression of the light-chain mRNAs was maintained with these 5' cis-acting sequence elements.

Identification of two nuclear factor-binding domains on the chicken cardiac actin promoter: implications for regulation of the gene.

The cis-acting regions that appear to be involved in negative regulation of the chicken alpha-cardiac actin promoter both in vivo and in vitro have been identified. A nuclear factor(s) binding to the proximal region mapped over the TATA element between nucleotides -50 and -25. In the distal region, binding spanned nucleotides -136 to -112, a region that included a second CArG box (CArG2) 5' to the more familiar CCAAT-box (CArG1) consensus sequence. Nuclear factors binding to these different domains were found in both muscle and nonmuscle preparations but were detectable at considerably lower levels in tissues expressing the alpha-cardiac actin gene. In contrast, concentrations of the beta-actin CCAAT-box binding activity were similar in all extracts tested. The role of these factor-binding domains on the activity of the cardiac actin promoter in vivo and in vitro and the prevalence of the binding factors in nonmuscle extracts are consistent with the idea that these binding domains and their associated factors are involved in the tissue-restricted expression of cardiac actin through both positive and negative regulatory mechanisms. In the absence of negative regulatory factors, these same binding domains act synergistically, via other factors, to activate the cardiac actin promoter during myogenesis.

E-box- and MEF-2-independent muscle-specific expression, positive autoregulation, and cross-activation of the chicken MyoD (CMD1) promoter reveal an indirect regulatory pathway.

Members of the MyoD family of gene-regulatory proteins (MyoD, myogenin, myf5, and MRF4) have all been shown not only to regulate the transcription of numerous muscle-specific genes but also to positively autoregulate and cross activate each other's transcription. In the case of muscle-specific genes, this transcriptional regulation can often be correlated with the presence of a DNA consensus in the regulatory region CANNTG, known as an E box. Little is known about the regulatory interactions of the myogenic factors themselves; however, these interactions are thought to be important for the activation and maintenance of the muscle phenotype. We have identified the minimal region in the chicken MyoD (CMD1) promoter necessary for muscle-specific transcription in primary cultures of embryonic chicken skeletal muscle. The CMD1 promoter is silent in primary chick fibroblast cultures and in muscle cell cultures treated with the thymidine analog bromodeoxyuridine. However, CMD1 and chicken myogenin, as well as, to a lesser degree, chicken Myf5 and MRF4, expressed in trans can activate transcription from the minimal CMD1 promoter in these primary fibroblast cultures. Here we show that the CMD1 promoter contains numerous E-box binding sites for CMD1 and the other myogenic factors, as well as a MEF-2 binding site. Surprisingly, neither muscle-specific and the other myogenic factors, as well as a MEF-2 binding site. Surprisingly, neither muscle-specific expression, autoregulation, or cross activation depends upon the presence of of these E-box or MEF-2 binding sites in the CMD1 promoter. These results demonstrate that the autoregulation and cross activation of the chicken MyoD promoter through the putative direct binding of the myogenic basic helix-loop-helix regulatory factors is mediated through an indirect pathway that involves unidentified regulatory elements and/or ancillary factors.

Provision of mouth-care in long-term care facilities: an educational trial.

OBJECTIVES: This randomized clinical trial aimed to assess the effectiveness of a pyramid-based education for improving the oral health of elders in long-term care (LTC) facilities. METHODS: Fourteen facilities matched for size were assigned randomly to an active or control group. At baseline in each facility, care-aides in the active group participated with a full-time nurse educator in a seminar about oral health care, and had unlimited access to the educator for oral health-related advice throughout the 3-month trial. Care-aides in the control group participated in a similar seminar with a dental hygienist but they received no additional advice. The residents in the facilities at baseline and after 3 months were examined clinically to measure their oral hygiene, gingival health, masticatory potential, Body Mass Index and Malnutrition Indicator Score, and asked to report on chewing difficulties. RESULTS: Clinical measures after 3 months were not significantly different from baseline in either group, indicating that education neither influenced the oral health nor the dental hygiene of the residents. CONCLUSIONS: A pyramid-based educational scheme with nurses and care-aides did not improve the oral health of frail elders in this urban sample of LTC facilities.

Introduction of an electronic debrief and governance tool in prehospital care.

BACKGROUND: The Tayside Trauma Team is a mobile medical team that is deployed from Ninewells Hospital, Dundee, UK at the request of the ambulance service. AIM: To describe the implementation of a formal debrief and governance tool to ensure the ongoing provision of a high-quality prehospital service. METHODS: A questionnaire was devised to examine key issues relating to clinical governance and distributed to all members of staff involved in the provision of prehospital care. RESULTS: A number of areas of concern were revealed, including a lack of understanding on how to report critical incidents occurring in this field and a low level of opportunity to fully discuss events and vocalise concerns. These areas of concern were used to formulate an electronic debrief tool to be available to staff after each incident attended. Reports were considered and actioned and data collected for audit purposes and to provide a framework for discussion at monthly morbidity and mortality meetings. CONCLUSION: Any patient requiring the services of a healthcare professional in the prehospital setting has a right to expect the same level of quality of care that they would receive within the hospital. The development of a debrief tool will achieve ongoing quality of care in this specialised area of healthcare.

End tidal carbon dioxide monitoring in prehospital and retrieval medicine: a review.

End tidal carbon dioxide (ETCO2) monitoring is the non-invasive measurement of exhaled CO2. The Intensive Care Society guidelines include (ETCO2) monitoring as one of the objective standards required for monitoring patients in transport, and the American Heart Association recommends that all intubations must be confirmed by some form of ETCO2 measurement. The physiological principles and technology underlying ETCO2 measurement and the clinical indication for its use in the prehospital environment are reviewed. ETCO2 monitoring has been widely established in the prehospital environment and is of particular use for verification of endotracheal tube placement. It is non-invasive and easy to apply to breathing circuits. The units now available are compact and rugged, with extended battery operating times, which are ideally suited for prehospital use and should be considered as an essential item for advanced airway management.