Bridlington Hospital

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

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This study is a report identifying actual and potential faecal leakage problems among ileostomists in relation to the use of different types of stoma appliances and accessories. A descriptive survey was conducted among 1035 respondents with an ileostomy. Fieldwork took place between August 2008 and September 2008. A structured questionnaire was mailed and returned by participants. This article offers a report of the findings, exploring the plight of the ileostomist in relation to the incidence and management of faecal leakage.

OBJECTIVE: To determine how examiners make decisions about candidates in the oral examination for membership in the Royal College of General Practitioners. DESIGN: Qualitative research using interpersonal process recall interviews with oral examiners immediately following examination of an Medical Research Council General Practitioner (MRCGP) candidate. SETTING: Summer 1999 sessions of the MRCGP examination in Edinburgh and London. PARTICIPANTS: Twenty-six examiners in a convenience sample from the panel of Royal College of General Practitioners (RCGP) oral examiners. RESULTS: Analysis of the transcripts revealed a three-stage process of decision-making consisting of a first impression, followed by a provisional grade and a final grade decision. The examiners used stem questions, exploratory questions and confirming questions during this process. Examiners produced lists of the attributes of successful and unsuccessful candidates, which resembled the grading guidelines provided by the examination committee. Some of the candidates' attributes which influenced the examiners' grading decisions related to personal qualities rather than knowledge or behaviours acquired in vocational training. When examiners were presented with the explanatory model arising from the analysis of the transcripts, they confirmed the validity of the observations. CONCLUSIONS: Decision-making by examiners during oral examinations is a complex process involving initial impressions, hypothesis generation and hypothesis testing. Candidates' knowledge, attitudes and performance influence the final outcome of the examination. Interpersonal process recall is a useful tool for exploring professional communication.

Annual cycles of development were studied in male and female Iceland scallops (Chlamys islandica) . Volume fractions of each germ cell type and other gonadal tissue were determined by histological and stereological techniques. Spawning occurs during a short period in late June and early July.

3,4-Diaminopyridine has shown promise in reversing botulinum intoxication, but poor pharmacokinetics and a narrow therapeutic window limit its clinical utility. Thus, we developed a pH-dependent oral delivery platform using club moss spore exines. These exine microcapsules slowed 3,4-diaminopyridine absorption, limited its seizure activity, and enabled delivery of doses which prolonged mouse survival after botulism neurotoxin A intoxication.

PURPOSE: To define the normal range of asymmetry in optic disc parameters measured by the Heidelberg Retina Tomograph (HRT II; Heidelberg Engineering GmbH, Dossenheim, Germany) in a normal elderly population. METHODS: Optic disc analysis of 918 eyes of 459 normal elderly patients was performed. All patients were consecutive in a cohort screened for eye disease. Normality was defined with a normal visual field on automated suprathreshold screening, intraocular pressure less than 22 mm Hg, and minimum corrected visual acuity of 6/12. Asymmetry measures were calculated by subtracting the values of the smaller disc from those of the larger disc. RESULTS: Subjects' mean age (262 female and 197 male) was 72.6 years (range, 65.5-89.3). There was no significant difference in disc area or rim area between the right and left eyes. Neither rim-to-disc area ratio asymmetry nor rim measurement asymmetries were significantly affected by age or sex. Rim-to-disc area ratio asymmetry was much less affected by the increasing difference in disc size than was absolute rim asymmetry. The 2.5th and 97.5th percentile limits of normality for the rim-to-disc area ratio asymmetry in the global and temporal-inferior analyses were -0.212 and 0.154, and -0.331 and 0.261, respectively. CONCLUSIONS: The normal range of parameter asymmetry in an age group relevant to glaucoma may be useful in the discrimination of normal from early glaucoma. Asymmetry analysis may improve discriminatory ability by reducing parameter variability based on disc size. The rim-to-disc area ratio asymmetry measure is likely to be the most useful parameter in describing normality with consistency.

increases the half-life of the polyene macrodiolide to the direct exposure to UV radiation by several orders of magnitude, thereby making this a potentially useful strategy for other light sensitive bioactive agents. In addition, we report that the SpECs can also be used to selectively extract culture broths that contain the marinomycins, which provides a significantly higher recovery than with conventional XAD resins and provides concomitant photoprotection.

This article contains a series of reports on recent research developments in the field of heart failure. Reports of key presentations made at the European Society of Cardiology meeting, held in Vienna, Austria, between 30 August and 3 September 2003 are reported. In the CHARM study, candesartan reduced cardiovascular deaths and hospital admissions for heart failure, both in patients who were already taking an ACE-inhibitor and in those who were ACE intolerant. However, results in patients with preserved left ventricular function were less conclusive. The BASEL study supports the use of B-type natriuretic peptide testing to confirm the diagnosis of heart failure in patients presenting with acute dyspnoea. In EUROPA, the largest ever study of secondary prevention of coronary artery disease, long-term treatment with perindopril reduced the incidence of cardiovascular death, myocardial infarction (MI) and cardiac arrest. The ESTEEM study showed that the oral thrombin inhibitor ximelagatran plus aspirin was more effective than aspirin alone in the prophylaxis of major cardiovascular events following MI.

Contamination of waterways is of increasing concern, with recent studies demonstrating elevated levels of antibiotics, antidepressants, household, agricultural and industrial chemicals in freshwater systems. Thus, there is a growing demand for methods to rapidly and conveniently monitor contaminants in waterways. Here we demonstrate how a combination of paper microfluidic devices and handheld mobile technology can be used by citizen scientists to carry out a sustained water monitoring campaign. We have developed a paper-based analytical device and a 3 minute sampling workflow that requires no more than a container, a test device and a smartphone app. The contaminant measured in these pilots are phosphates, detectable down to 3 mg L-1. Together these allow volunteers to successfully carry out cost-effective, high frequency, phosphate monitoring over an extended geographies and periods.

Phased array antennas, in both communications and radar systems, are increasingly being favoured over conventional mechanically-scanned systems. In their active form, particularly in military scenarios, the acronym AESA (active electronically-scanned arrays) is frequently encountered. By definition these types of antennas specifically demand a source (or sources) of microwave power. Today and forseeably into the future RF semiconductor power amplifiers (mainly MMICs) are implemented to supply the required power to each individual element in the active array. In this paper some examples of active phased arrays are reviewed-both existing and those under development. The paper presents and critiques the current state-of-the-art with suitable GaAs MMIC power amplifiers (power versus frequency, efficiency, suppliers, etc.). GaN and SiC MESFET devices and MMICs are also considered-again with references to power versus frequency, efficiency, suppliers, etc

<h3>Abstract</h3> Neurobiological pain models propose that the transition from acute to chronic pain is accompanied by neuropathological adaptations that mediate progressive pain processing dysfunctions. In contrast, meta-analytic studies on neurofunctional dysregulations in chronic pain have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta-analysis combined three different meta-analytic approaches with stringent study selection criteria for case-control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders (i.e., fibromyalgia, irritable bowel syndrome, chronic low back pain, neuropathic pain; n = 295 patients, n = 211 controls; 86 foci). Across the meta-analytic approaches, convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex, with study characteristics indicating generalized pain processing abnormalities. Seed-based resting-state functional connectivity based on a large publicly available dataset combined with a meta-analytic task-based approach identified the anterior insular region as a key node of an extended bilateral insula-fronto-cingular network, resembling the salience network. Moreover, the meta-analytic decoding showed that this region presents a high probability to be specifically activated during pain-related processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.

BACKGROUND: Distraction techniques are a form of coping strategies used in cognitive behavioural techniques. They may be of value as an adjunctive treatment for people with schizophrenia or schizophrenia-like illnesses. OBJECTIVES: To review the effects of distraction techniques for people with schizophrenia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (October 2003), manually searched reference lists and contacted relevant authors. SELECTION CRITERIA: We included all randomised controlled trials comparing distraction techniques with other treatments for schizophrenia. DATA COLLECTION AND ANALYSIS: We reliably selected, quality assessed and data extracted studies. We excluded data where more than 50% of participants in any group were lost to follow up. For binary outcomes, we calculated a fixed effects risk ratio (RR) and its 95% confidence interval (CI), along with the number needed to treat/harm (NNT/H). For continuous data we calculated the weighted mean difference (WMD). MAIN RESULTS: In terms of mental state, distraction techniques did not have a clear effect (n=60, 1 RCT, MD endpoint BPRS 1.60 CI -0.49 to 3.69). Distraction does not obviously engage people in the studies (n=159, 5 RCTs, RR leaving the study before completion 1.08 CI 0.72 to 1.63). AUTHORS' CONCLUSIONS: Clinicians, researchers, policy makers and recipients of care cannot be confident of the effects of distraction techniques from the findings of this review. The few pioneering studies are small, short and poorly reported. Further data from already completed trials might help inform practice, but more trials do seem to be justified as some of these potentially simple techniques, even if their effect is negligible, could be widely implemented and prove more acceptable than other more intrusive treatments.

BACKGROUND: In recent years there have been concerns regarding the prescribing of antipsychotic drugs to patients with dementia in nursing homes, due to adverse effects, inappropriate indications and insufficient review. Our practice decided to look at this difficult area more closely. AIM: The aim of this audit was to assess whether our prescribing of antipsychotic drugs in nursing homes was appropriate. METHOD: Our audit criteria for appropriate prescribing were based on National Institute for Health and Clinical Excellence (NICE) recommendations: 1 there is a clear recorded indication or target symptom (standard 100%) 2 there is a documented review of the prescription in the past six months by a GP or psychiatrist (standard 100%). Patients in nursing homes receiving antipsychotic drugs were identified from electronic case notes, using a specific nursing home Read code and British National Formulary chapter. RESULTS: The first data collection (July 2008) revealed we had 81 patients in nursing homes and 22 (27%) were prescribed antipsychotic drugs. There was a clear recorded indication or target symptom in only 11 patients (50%) and a documented review of the prescription in the past six months by a general practitioner (GP) or psychiatrist in only 14 patients (64%). We discussed the results with our practice team and decided to introduce a review checklist for antipsychotic prescribing in nursing homes. The second data collection (December 2008) showed that the number of patients prescribed antipsychotic drugs had fallen to 15 (19% of total 80) and both audit criteria were met in 100% of cases. CONCLUSION: The introduction of the checklist and six-monthly review led to an improvement in the recording of a clear indication for the antipsychotic drug and of documented review. As a practice we were pleased with the modest reduction in the prescribing of antipsychotic drugs in nursing home patients. We were satisfied that the patients who remain on these drugs are being reviewed appropriately and that the benefit of prescribing outweighs the risk.

Water (and its deteriorating quality) may be the most severe stress on the exponentially growing human population in the next century. Problems are becoming increasingly complex and diverse and require more and more specific knowledge, and efficient integration across various disciplines, sectors, countries, and societies. The major challenge addressed is whether we are prepared to realize the desired integration and to resolve the large amount of existing gaps and barriers. The paper analyzes major past and desired future trends in water quality management. A number of issues are selected such as the identification, occurrence, and perception of various problems (e.g. eutrophication, acidification, global warming), pollution control types, wastewater treatment, modeling and monitoring, planning and environmental impact assessment, legislation and institutions, the notion of sustainable development, and the role of science and engineering. The past two decades showed tremendous developments in water quality management. In spite of these, the focus of the present discussion lies mostly on pitfalls to disseminate lessons and questions which are crucial to likely future problems and desired improvements.

The adaptive immune system plays a crucial role in the pathophysiology and progression of Alzheimer's disease (AD).1 In this context, we read with great interest the recent publication by Gericke et al.,2 who reported a positive association of CD8+ CD45RA-reactivated T effector memory (TEMRA) cells with the presence of brain β-amyloid and AD-specific changes in plasma biomarkers in ∼180 cognitively healthy individuals. While an increase of TEMRA cells had been reported previously in clinically affected AD patients compared to controls (e.g., ref.3), the results by Gericke et al.2 extended these findings to the pre-clinical disease phase. In the current study, we investigated whether the alteration of TEMRA cells may manifest even earlier in the course of the disease, that is, in younger and in older, cognitively healthy adults at high genetic risk of AD based on polygenic risk score (PRS) analyses. Detailed methods can be found in the Supplementary methods. Briefly, quality-controlled genome-wide single nucleotide polymorphism (SNP) data (n = 7,536,015)4 and CD8+ TEMRA cell proportions of total CD8+ T cells in blood (Table S1)5 were available for 370 cognitively healthy individuals comprising a group of young adults (n = 120, mean age: 29 years, range 23–35) and a group of older people (n = 250, mean age: 69 years, range 60–82). All participants were recruited as part of the Berlin Aging Study II (BASE-II), a multi-institutional and multidisciplinary project aimed to characterize the individual changes of healthy participants (at the time of recruitment) in the aging process.6 All participants included here had a Mini-Mental State Examination score ≥27. The PRS was calculated using R and PRSice-27 and was based on apolipoprotein E (APOE) e4 (rs429358) and 70 of the 83 genome-wide significantly associated (α = 5.0E-8), independent SNPs from the largest AD genome-wide association studies (GWAS) to date based on 487,511 individuals.8 For each age group, we performed linear regression analyses of TEMRA cells (log-transformed; Figure S1) on the AD PRS as a continuous score. In addition, we performed linear regression analyses on the established AD risk variants e4 and e2 (rs7412) in APOE. As a positive control, we performed linear regression analyses of TEMRA cell counts on anti-cytomegalovirus (CMV) antibody titer status and older versus young age.9, 10 All analyses were adjusted for sex and four principal components. Significance was defined as α = 0.05. We performed a range of sensitivity analyses by using an optimized AD PRS that explained the largest amount of variance of the TEMRA cell counts, adjusting for CMV as additional covariate, contrasting the top versus lower PRS quintile to allow for a non-linear model, and using arcsinh transformation of the TEMRA cell data as applied in the original study.2 As expected, we observed a strong and statistically significant increase of CD8+ TEMRA cells in CMV-seropositive participants (young adults: p = 1.17E-15, older: p = 2.46E-24) as well as with increasing age (p = 3.78E-13, Table 1, Figure S2). However, the PRS on genome-wide significant AD risk SNPs did not show statistically significant association with CD8+ TEMRA cells, neither in young adults (incremental phenotypic variance explained [ΔR2] = 0.00003, p = 0.954) nor in the older (ΔR2 = 0.0007, p = 0.670, Table 1, Figure S2). Furthermore, and in contrast to the original study,2 APOE rs429358 and rs7412 also failed to show significant associations with the number of TEMRA cells (Table 1, Figure S2). These results did not change in sensitivity analyses: Optimizing the PRS resulted in a score composed of 7234 SNPs (threshold for variant selection: p = 4.15E-03) in young adults and 76,312 SNPs (p-value threshold = 9.71E-02) in older adults, but the analysis still yielded non-significant results. None of the other sensitivity analyses, including contrasting PGS extremes, changed the results substantially (Table 1). In summary, we did not detect a statistically significant increase of TEMRA cells in cognitively healthy younger or older adults with a high genetic risk of AD. While we cannot exclude a lack of power to detect small effects, we investigated a substantially larger sample compared to that of Gericke et al.,2 observed the well-established effects of CMV status and age on TEMRA cell counts, and performed a range of carefully executed additional analyses, all of which showed null effects. Thus, while prior work2 suggests that the increase of TEMRA cells in the blood occurs shortly before the clinical onset of AD, that is, specifically when pathology is already present in the brain, our study shows that this increase does not manifest in cognitively healthy participants at increased genetic AD risk earlier in life. Further functional studies are needed to fully characterize the mechanisms and timing underlying the dynamic and intricate role of CD8+ TEMRA cells in AD. We are grateful to all BASE-II participants. The BASE-II research project (co-PIs: Lars Bertram, Ilja Demuth, Denis Gerstorf, Ulman Lindenberger, Graham Pawelec, Elisabeth Steinhagen-Thiessen, and Gert G. Wagner) has been supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) under grant numbers #16SV5536K, #16SV5537, #16SV5538, #16SV5837, #01UW0808, 01GL1716A, and 01GL1716B, and by the Max Planck Institute for Human Development, Berlin, Germany. Additional contributions (e.g., equipment, logistics, personnel) are made from each of the other participating sites. The responsibility for the contents of this publication lies with its authors. C.M.L. was supported by the Cure Alzheimer's Fund and the Heisenberg program of the German Research Foundation (DFG; LI 2654/4-1). The authors declare no conflicts of interest. Author disclosures are available in the Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

INTRODUCTION: Tackling malnutrition in infants aged under 6 months (u6m) is a major global priority yet evidence around this vulnerable group is weak. We aimed to support the rollout of new 2023 WHO guidelines by examining the burden of infant malnutrition and potential programme caseloads with new enrolment criteria. METHODS: Secondary analysis of Demographic and Health Survey (DHS) datasets. We calculated the number of underweight (low weight-for-age), wasting (low weight-for-length), stunting (low length-for-age) and low birth weight (LBW) infants. We assessed data quality by recording extreme or missing values. We calculated the population-weighted prevalence of anthropometric deficit and extrapolated to all low- and middle-income countries (LMICs). We regressed being underweight and wasti on infant, maternal and household characteristics using logistic regression. RESULTS: We analysed 56 DHS surveys. There were more extreme (flagged) values for length-based measures (7.5% flagged for weight-for-length, 3.8% for length-for-age) than for weight-for-age (0.6% flagged). Overall, 17.4% of infants (95% CI: 16.9 to 18.0) were underweight, 15.5% (15.0-16.0) were wasted, 19.9% (19.3-20.5) were stunted and 15.0% (14.5-15.5) were LBW. This corresponds to an estimated burden in LMICs of 10.3 million underweight infants (4.1 million severely underweight), 9.2 million wasted (4.0 million severely wasted), 11.8 million stunted (5.4 million severely stunted) and 8.9 million LBW infants. Overlap of the indicators varied markedly in different regions/countries. Numerous factors were associated with both underweight and wasting; associations tended to be stronger and have greater biological plausibility with being underweight. CONCLUSION: Malnutrition in infants u6m is a major problem in LMICs. Local epidemiology should inform case identification in contextualised care services across health and nutrition. Data quality and stronger associations with health and social characteristics support the use of underweight as a key enrolment criterion. Since vulnerability may be due to or exacerbated by multiple factors, management must go beyond feeding support to address wider infant, maternal and mental health and social circumstances through integrated, multidisciplinary care systems.

ABSTRACT One of the most misunderstood aspects of journal management is the effect of journal title changes on the ThomsonScientific impact factor. This study analyses journals that changed their title in 1994 and 1995 and ascertains the period of time taken to recover the impact factor. Effects of subject classification and of the size of the journal are also investigated to see if recovery time depends on them. The analysis shows that recovery times are longer than predicted. Suggestions are made on how publishers may approach communication of journal title changes to minimize the effects on the impact factor.

Abstract

The therapeutic efficacy of long acting diltiazem 300 mg od (Tildiem LA) was compared with sustained release nifedipine 20 mg bd and bendrofluazide 5 mg od in a multicentre study with 230 patients diagnosed with mild to moderate essential hypertension, with 77, 77 and 76 randomized to the diltiazem, nifedipine SR and bendrofluazide groups respectively. Patients were entered into this randomised, single (investigator) blind, parallel-group multicentre study if the systolic and diastolic blood pressures were > or = 145 mm Hg and/or 95 mm Hg respectively at the admission visit. Twenty-one general practitioners and two hospital physicians monitored patients at baseline and at four and eight weeks of continuous dosing. After eight weeks of therapy, clinically acceptable control of blood pressure was seen in all groups: reductions were 19.2/13.5 mm Hg, 20.4/14 mm Hg and 18.5/10.8 mm Hg for the Tildiem, nifedipine and bendrofluazide groups respectively. Significant differences were shown between bendrofluazide and the other two groups on diastolic pressures (p = 0.01). The non-significant trend was for systolic pressures to mirror these effects. Significantly higher withdrawals caused by adverse events were seen with nifedipine. These were as follows: 14 patients receiving nifedipine (18%), 5 patients receiving diltiazem (6%) and 4 patients receiving bendrofluazide (5%). The difference in this withdrawal rate between treatments was statistically significant (p = 0.01). Post hoc tests revealed that both diltiazem and bendrofluazide had statistically significant lower withdrawals for adverse events than the nifedipine group (p = 0.047). Nifedipine was associated with a marginal increase in standing apex pulse rate and only diltiazem LA significantly maintained serum potassium levels. These results indicate that diltiazem 300 mg is an effective antihypertensive agent and is equivalent in efficacy to nifedipine SR 20 mg and both are superior to bendrofluazide. Nifedipine SR was however the worst tolerated and had the highest withdrawal rate (p = 0.013).