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Tetanus is a preventable, yet often fatal, disease affecting many species, including beef cattle. Vaccination for tetanus is recommended for calves at high risk of disease, but typical beef cattle management practices often make adherence to vaccine manufacturers' guidance for a second (booster) dose of vaccine difficult. This study examined the antibody response following a single dose of tetanus toxoid, as well as following booster vaccination at various intervals. Anti-tetanus IgG antibodies were detectable 25 days (D25) after a single dose, and rose following booster at either D25 D109 after initial vaccination. Antibody levels then declined numerically from D109 to D179 for calves boostered at D25 but rose on D179 for those receiving a second dose on D109. The relatively rapid response in IgG production, even in the absence of a booster vaccine, may suggest value in vaccinating calves for tetanus at time of greatest risk, even if a booster cannot be administered. The study also provides support for priming of the immune response lasting at least until D109 after primary immunization., Competing Interests: Conflict of interest None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To estimate the strength of association between exposure to selected classes of prescribed medications and the risk of developing iron deficiency anaemia (IDA), specifically considering oral anticoagulants (OACs), antidepressants, antiplatelet agents, proton pump inhibitors (PPIs) and non-steroidal anti-inflammatories., Design: A case-control study involving the analysis of community repeat prescriptions among subjects referred with IDA, and unmatched controls referred as gastroenterology fast-tracks for other indications. Multivariable logistic regression modelling was used to calculate ORs for the association between IDA presentation and each medication class, adjusted for age, sex and coprescribing. For those classes showing significance, it was also used to calculate risk differences between those in the IDA group with or without haemorrhagic lesions on investigation., Results: A total of 1210 cases were analysed-409 in the IDA group, and 801 in the control group. Significant associations were identified between presentation with IDA and long-term exposure to PPIs (OR 3.29, 95% CI: 2.47 to 4.41, p<0.001) and to OACs (OR 2.04, 95% CI: 1.29 to 3.24, p=0.002). IDA was not associated with long-term exposure to any of the other three drug classes. In contrast to the relationship with PPIs, the association with OACs was primarily in the IDA sub-group with haemorrhagic lesions., Conclusion: Long-term exposure to PPIs and OACs are independently associated with the risk of developing IDA. There are grounds for considering that these associations may be causal, though the underlying mechanisms probably differ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Characterizing sorbent affinity for a target compound (described by sorbent-water distribution coefficient, K sw ) is a necessary step in the sorbent selection and performance-testing process in the process of capturing aquatic contaminants. However, no standardized procedure exists to measure K sw , and studies display significant variations in set-up and performance. For per- and polyfluoroalkyl substances (PFAS), most K sw determinations employ batch experiments with small-scale water-sorbent mixtures, methanol-based spike of target compound(s), and analysis after assumed equilibrium, but methodological details of the above procedure differ and might cause artifacts in the determination of K sw . We conducted several batch experiments systematically varying a general procedure to characterize effects of sub-optimal experimental design. Using a selection of PFAS (6-carbon fluorinated chain length with differing functional groups) and two sorbents, we tested variations of solution:sorbent ratio, methanol content, and PFAS initial concentration, and compared derived K sw values. Each methodological component affected log(K sw ), usually by suppressing the value (by 0-48%) when compared with a "best design" procedure. Thus, we suggest (1) a reference procedure for PFAS and sorbents used here, and (2) general guidelines for batch experiment design with different compounds and sorbents. Additionally, we report well-constrained K sw values for 23 PFAS and two sorbents.

Per- and polyfluoroalkyl substances (PFAS) are a group of 4000+ man-made compounds of great concern due to their environmental ubiquity and adverse effects. Despite a general interest, few reliable detection tools for integrative passive sampling of PFAS in water are available. A microporous polyethylene tube with a hydrophilic-lipophilic balance sorbent could serve as a flow-resistant passive sampler for PFAS. The tube's sampling rate, Rs, was predicted based on either partitioning and diffusion, or solely diffusion. At 15 °C, the laboratory measured Rs for perfluorohexanoic acid of 100+/-81 mL day -1 were better predicted by a partitioning and diffusion model (48+/-1.8 mL day -1 ) across 10-60 cm s -1 water flow speeds (15+/-4.2 mL day -1 diffusion only). For perfluorohexane sulfonate, Rs at 15°C were similarly different (110+/-60 mL day -1 measured, 120+/- 63 versus 12+/-3.4 mL day -1 in respective models). Rs values from field deployments were in-between these estimates (46 +/-40 mL day -1 for perfluorohexanoic acid). PFAS uptake was not different for previously biofouled membranes in the laboratory, suggesting the general applicability of the sampler in environmental conditions. This research demonstrates that the polyethylene tube's sampling rates are sensitive to the parameterization of the models used here and partitioning-derived values should be used., Competing Interests: The authors declare no competing financial interest.

Background: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD)., Aim: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab., Results: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure., Conclusion: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Using two large datasets from Dorset, we previously reported an internally validated multivariable risk model for predicting the risk of GI malignancy in IDA-the IDIOM score. The aim of this retrospective observational study was to validate the IDIOM model using two independent external datasets., Methods: The external validation datasets were collected, in a secondary care setting, by different investigators from cohorts in Oxford and Sheffield derived under different circumstances, comprising 1117 and 474 patients with confirmed IDA respectively. The data were anonymised prior to analysis. The predictive performance of the original model was evaluated by estimating measures of calibration, discrimination and clinical utility using the validation datasets., Results: The discrimination of the original model using the external validation data was 70% (95% CI 65, 75) for the Oxford dataset and 70% (95% CI 61, 79) for the Sheffield dataset. The analysis of mean, weak, flexible and across the risk groups' calibration showed no tendency for under or over-estimated risks in the combined validation data. Decision curve analysis demonstrated the clinical value of the IDIOM model with a net benefit that is higher than 'investigate all' and 'investigate no-one' strategies up to a threshold of 18% in the combined validation data, using a risk cut-off of around 1.2% to categorise patients into the very low risk group showed that none of the patients stratified in this risk group proved to have GI cancer on investigation in the validation datasets., Conclusion: This external validation exercise has shown promising results for the IDIOM model in predicting the risk of underlying GI malignancy in independent IDA datasets collected in different clinical settings., (© 2021. The Author(s).)

It has been claimed that the National Institute of Mental Health (NIMH) budget, which traditionally has been evenly balanced between basic and clinical research, has shifted sharply and that 90% of NIMH resources are funding basic research. The authors used public data sources to assess this claim: the Research Condition and Disease Categorization Database, ClinicalTrials.gov, and the NIMH Strategic Plan for Research for 2020-2024. From 2016 to 2019, NIMH expenditures on bipolar disorder research decreased 25%, and those for schizophrenia research decreased 17.5%. From 2003 to 2019, NIMH support for treatment trials for schizophrenia, bipolar disorder, and major depressive disorder decreased 90%. NIMH's Strategic Plan for Research for 2020-2024 suggests that the shift toward basic research will continue. Because NIMH's primary purpose is to develop better treatments for current patients as well as future ones, the authors recommend that the ratio of basic to clinical research be readjusted to approximately 50:50.

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by urticarial plaques and/or vesicles and tense bullae. A unique presentation of BP can occur during pregnancy, the postpartum period after delivery, or with the initiation of contraception, in which case it is referred to as pemphigoid gestationis (PG). In rare instances, newborns born to mothers with PG may also present with blisters due to transplacental passage of maternal anti-bullous pemphigoid 180 (BP180) or 230 (BP230) immunoglobulin G (IgG). In this report, we present an unusual case of neonatal PG in an infant born to an asymptomatic mother without a previous diagnosis of PG., (© 2021 Wiley Periodicals LLC.)

Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments., Competing Interests: Competing interests: ILPB: Vifor advisory board, Pharmcosmos advisory board; PI for Feraccru studies. RL: Vifor Advisory Board, NHS England advisor. MP: Trio Medicines (research funding); IPSEN, Advanced Accelerator Applications, Mayoly Spindler laboratories (consultancies). AMV, WT, RS, CK, DC, NB, SS, AFG, JS: none declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Faecal occult blood (FOB) positivity and iron deficiency anaemia (IDA) are common manifestations of colorectal cancer (CRC) and both potentially facilitate diagnosis at an earlier, more treatable stage. It has been assumed that both are the consequence of low-grade blood loss from the tumour bed., Method: A retrospective analysis of 1121 cases of CRC diagnosed at a single centre between 2010 and 2016, comparing cases presenting via FOB-based Bowel Cancer Screening Programme (BCSP) and IDA pathways for a series of variables including age, sex, tumour location and prevalence of anaemia., Results: The BCSP and IDA pathways each accounted for about 15% of the total case load. There were significant differences between the BCSP and IDA sub-groups in median age (68 vs 78 years: p<0.001), median haemoglobin (138 vs 89 g/L: p<0.001) and proportion of lesions in right colon (31.1% vs 82.5%: p<0.001). The major disparity in the prevalence of anaemia (overall 20.0% vs 98.2%: p<0.001) persisted when controlled for tumour location., Conclusion: Paradoxically, CRC screening through the detection of FOB positivity and IDA identifies distinctly different sub-populations of cases. The theoretical implication is that an additional mechanism may be required to explain the development of IDA in CRC. The practical implication is that detection of IDA may have a complementary role to the BCSP in population screening for CRC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

In this study, a distributed acoustic sensor (DAS) was numerically modeled based on the non-ideal optical components with their noises and imperfections. This model is used to compare the response of DAS systems to standard single-mode fibers and ultra-low loss-enhanced backscattering (ULEB) fibers, a fiber with an array of high reflective points equally spaced along its length. It is shown that using ULEB fibers with highly reflective points improves the signal-to-noise ratio and linearity of the measurement, compared with the measurement based on standard single-mode fibers.

Iron deficiency anaemia (IDA) is common in colorectal cancer (CRC), especially, in right-sided CRC which is known to have an overall worse prognosis. The associations between diagnostic pathway (Bowel Cancer Screening Programme (BCSP), IDA, symptomatic) and tumour side/stage was assessed using logistic regression models in 1138 CRC cases presenting during 2010-2016 at a single secondary-care centre in the UK. In the IDA sub-group, the relationship between CRC stage and the event of having a blood count prior to CRC diagnosis was examined using Bayesian parametric survival model. IDA was found as the only significant predictor of right-sided CRC (OR 10.61, 95% CI 7.02-16.52). Early-stage CRC was associated with both the IDA (OR 1.65, 95% CI 1.18-2.29) and BCSP pathway (OR 2.42, 95% CI 1.75-3.37). At any age, the risk of detecting CRC at late-stage was higher in those without a previous blood count check (hazard ratio 1.53, 95% credibility interval 1.08-2.14). The findings of this retrospective observational study suggest a benefit from diagnosing CRC through the detection of IDA, and warrant further research into the prognosis benefit of systematic approach to blood count monitoring of the at-risk population.

In 2008 the National Institutes of Health established the Research, Condition and Disease Categorization Database (RCDC) that reports the amount spent by NIH institutes for each disease. Its goal is to allow the public "to know how the NIH spends their tax dollars," but it has been little used. The RCDC for 2018 was used to assess 428 schizophrenia-related research projects funded by the National Institute of Mental Health. Three senior psychiatrists independently rated each on its likelihood ("likely", "possible", "very unlikely") of improving the symptoms and/or quality of life for individuals with schizophrenia within 20 years. At least one reviewer rated 386 (90%), and all three reviewers rated 302 (71%), of the research projects as very unlikely to provide clinical improvement within 20 years. Reviewer agreement for the "very unlikely" category was good; for the "possible" category was intermediate; and for the "likely" category was poor. At least one reviewer rated 30 (7%) of the research projects as likely to provide clinical improvement within 20 years. The cost of the 30 projects was 5.5% of the total NIMH schizophrenia-related portfolio or 0.6% of the total NIMH budget. Study results confirm previous 2016 criticisms that the NIMH schizophrenia-related research portfolio disproportionately underfunds clinical research that might help people currently affected. Although the results are preliminary, since the RCDC database has not previously been used in this manner and because of the subjective nature of the assessment, the database would appear to be a useful tool for disease advocates who wish to ascertain how NIH spends its public funds., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: John Rush: A. John Rush has received consulting fees from Akili, Brain Resource Inc., Compass Inc., Curbstone Consultant LLC, Emmes Corp., Johnson and Johnson (Janssen), Liva-Nova, Mind Linc, Otsuka-US, Sunovion; speaking fees from Liva-Nova; and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). He is also named co-inventor on two patents: U.S. Patent No. 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS; and U.S. Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors have no disclosures or competing interests.

Objective: To report our cumulative experience from a dedicated iron deficiency anaemia (IDA) clinic over the last 15 years-with particular emphasis on referral rate, uptake of investigation, impact on endoscopy services, diagnostic yield of gastrointestinal (GI) investigation and the issue of recurrent IDA., Method: A series of analyses of a register of 2808 referrals to the Poole IDA clinic between 2004 and 2018., Results: The study population of 2808 had a sex ratio of 1.9 (female/male ratio) and a median age of 72 years (IQR: 60-79). A rising referral rate over the study period appears to be plateauing at around 2 cases per 1000 population per annum. On the basis of a snapshot audit, investigation of IDA may now account for over 20% of all diagnostic endoscopies.Overall, 86% of cases underwent examination of the upper and lower GI tract. Significant GI pathology was identified in 27% of the investigated cohort. Adenocarcinoma of the upper or lower GI tract was found in 8.3%, the majority in the right colon. The prevalence of recurrent IDA was estimated at 12.4%, and the results of investigation of this subgroup are reported., Conclusion: Unexplained IDA is common, particularly in those over 60 years, and may be the first indication of underlying GI malignancy in over 8% of cases. Unresolved challenges include accommodating the resulting endoscopy workload, establishing a risk/benefit ratio for investigating those with major comorbidities and the management of recurrent IDA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To refine and validate a model for predicting the risk of gastrointestinal (GI) cancer in iron deficiency anaemia (IDA) and to develop an app to facilitate use in clinical practice., Design: Three elements: (1) analysis of a dataset of 2390 cases of IDA to validate the predictive value of age, sex, blood haemoglobin concentration (Hb), mean cell volume (MCV) and iron studies on the probability of underlying GI cancer; (2) a pilot study of the benefit of adding faecal immunochemical testing (FIT) into the model; and (3) development of an app based on the model., Results: Age, sex and Hb were all strong, independent predictors of the risk of GI cancer, with ORs (95% CI) of 1.05 per year (1.03 to 1.07, p<0.00001), 2.86 for men (2.03 to 4.06, p<0.00001) and 1.03 for each g/L reduction in Hb (1.01 to 1.04, p<0.0001) respectively. An association with MCV was also revealed, with an OR of 1.03 for each fl reduction (1.01 to 1.05, p<0.02). The model was confirmed to be robust by an internal validation exercise. In the pilot study of high-risk cases, FIT was also predictive of GI cancer (OR 6.6, 95% CI 1.6 to 51.8), but the sensitivity was low at 23.5% (95% CI 6.8% to 49.9%). An app based on the model was developed., Conclusion: This predictive model may help rationalise the use of investigational resources in IDA, by fast-tracking high-risk cases and, with appropriate safeguards, avoiding invasive investigation altogether in those at ultra-low predicted risk., Competing Interests: Competing interests: SS and EW have received honoraria for speaking at educational meetings sponsored by Pharmacosmos., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To document changes in the clinical features of coeliac disease (CD) at presentation over the last 25 years., Design: Observational study., Patients: 802 subjects diagnosed between 1993 and 2017 at a single general hospital., Outcome Measures: Date of diagnosis, age, sex, postcode, symptoms, haematinic deficiency, smoking status, serology, family history and autoimmune phenomena., Results: The incidence of diagnosed CD rose threefold during the course of the study, with a rising prevalence of positive coeliac serology and positive family history of CD, and a falling prevalence of symptoms and haematinic deficiencies. There was little change in the female predominance, age at diagnosis or high prevalence of other autoimmune conditions over the 25 years, and a paucity throughout of cigarette smokers, particularly heavy smokers. A cohort of patients with seronegative CD was identified who shared many of the characteristics of seropositive CD, but with a significantly older age at diagnosis and a higher prevalence of cigarette smokers., Conclusion: There have been major changes in the epidemiology of CD over the last 25 years, of relevance to both our understanding of the aetiopathogenesis of CD and the requirement for service provision. The implications are discussed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Delayed effects of a 20-min crushed ice application on knee joint position sense assessed by a functional task during a re-warming period., Introduction: The effect of cryotherapy on joint positioning presents conflicting debates as to whether individuals are at an increased risk of injury when returning to play following cryotherapy application at the lower limb., Objectives: The aim of this study was to investigate whether a 20 min application of crushed ice at the knee affects knee joint kinematics immediately post and up to 20 mins post ice removal, during a small knee bend., Method: 17 healthy male participants took part in the study performing a functional task. Using three-dimensional motion analysis (Qualisys Medical AB Gothenburg, Sweden), kinematics of the knee were measured during a weight bearing functional task pre and immediately post, 5, 10, 15 and 20 min post cryotherapy intervention. Skin surface temperature (T sk ) cooling was measured via infrared non-contact thermal imaging (Flir Systems, Danderyd, Sweden) over the anterior and medial aspect of the knee., Results: Results demonstrated significant reductions in the ability to accurately replicate knee joint positioning. A significant increase (P ≧ 0.05) in rotational movement in the transverse plane occurred, 20 min post ice removal., Discussion: A 20-min application of crushed ice to the anterior aspect of the non-dominant knee has an adverse effect on knee joint repositioning and dynamic stability, 20 min after ice is removed. In consideration of returning a land-based athlete to dynamic functional activities, post cryotherapeutic intervention at the knee, clinicians should consider these findings due to the potential increase risk of injury., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Innovation in kidney diseases is not commensurate with the effect of these diseases on human health and mortality or innovation in other key therapeutic areas. A primary cause of the dearth in innovation is that kidney diseases disproportionately affect a demographic that is largely disenfranchised, lacking sufficient advocacy, public attention, and funding. A secondary and likely consequent cause is that the existing infrastructure supporting nephrology research pales in comparison with those for other internal medicine specialties, especially cardiology and oncology. Citing such inequities, however, is not enough. Changing the status quo will require a coordinated effort to identify and redress the existing deficits. Specifically, these deficits relate to the need to further develop and improve the following: understanding of the disease mechanisms and pathophysiology, patient engagement and activism, clinical trial infrastructure, and investigational clinical trial designs as well as coordinated efforts among critical stakeholders. This paper identifies potential solutions to these barriers, some of which are already underway through the Kidney Health Initiative. The Kidney Health Initiative is unique and will serve as a current and future platform from which to overcome these barriers to innovation in nephrology., (Copyright © 2016 by the American Society of Nephrology.)

Obesity discrimination in employment and recruitment has become a topic of focus for research examination with increasing reports of discrimination by colleagues and managers. Whilst a limited number of legal cases have emerged, disability law is consulted in line with the expectation of anti-discriminatory practices at work. In line with disability law, whether obesity is defined as a disability or not has an impact on the outcome of a court ruling. Ambiguity when defining obesity through either the medical or social model means there are many questions that remain unanswered which might lead to inconsistency in court rulings.

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory., (© 2015 Shakya et al.)

Blood transfusion is widely used in the management of acute upper gastrointestinal haemorrhage (AUGIH). Trial data suggests that excessive transfusion may be detrimental, yet overtransfusion remains commonplace. This study reports the impact of introducing a simple cross-match policy in a district general hospital, which resulted in a substantial fall in the prevalence of overtransfusion (odds ratio 0.43; 95% confidence interval 0.19-0.98), with potential patient benefits in terms of rebleeding, and a reduction in the total blood transfused from 162 to 121 units per 100 patients with AUGIH. For the cost of blood alone, this corresponds to projected savings across the NHS in England in excess of £2 million per annum., (© Royal College of Physicians 2015. All rights reserved.)

Background: Coeliac disease (CD) results from mucosal exposure to dietary gluten in genetically predisposed individuals, although other environmental factors may be involved. The seroprevalence of CD is approximately 1%, with a high ratio of undiagnosed to diagnosed cases, leading to the concept of a 'coeliac iceberg'., Aim: To provide contemporary estimates of the incidence of diagnosed CD and the size of the submerged 'coeliac iceberg', and to seek evidence of disease clustering., Design: Prospective observational study in a defined local population., Methods: Data were collected prospectively for all biopsy-proven cases diagnosed at Poole Hospital, 1993-2002. Age-specific incidence was calculated and point prevalence estimated for cases within the defined study zone. Evidence of disease clustering was sought using a space-time scan statistic based on a Poisson model., Results: The overall incidence of CD was 8.7 cases/100,000/year (95%CI 7.4-10.1), with a median age at diagnosis of 53 years. Incidence increased progressively during the study period, and the estimated point prevalence of biopsy-proven CD rose from 0.18% to 0.4%. An area of significant space-time clustering was identified, with an incidence of 22.9 cases/100,000/year (95%CI 16.1-31.6), but there was no evidence of seasonality., Discussion: The submerged component of the 'coeliac iceberg' may be diminishing due to increasing case ascertainment, with a projected ratio of undiagnosed to diagnosed cases as low as 1.5:1. Our identification of clustering must be interpreted with caution, but suggests that an additional environmental factor may influence the pathogenesis of CD.

Objective: To determine geriatricians' experience of and views on living wills, National Health Service Trusts' support of advance end-of-life health care planning and geriatricians' views on related legal changes in the Mental Capacity Act., Design: Anonymous postal questionnaire survey of all 1,426 British Geriatrics Society members in England, Wales and Northern Ireland., Results: A total of 842 (59%) questionnaires were returned. Of 811 geriatricians, 454 (56%) had cared for patients with living wills. Of the 280 who cared for patients when the living will had come into effect, 108 (39%) had changed treatment because of the living will and 84 (78%) of those felt that decisions had been easier to make. Living wills not already in effect made discussions with patients [171 of 178 (96%)] and families [135 of 178 (76%)] easier. Of 779 geriatricians, 713 (92%) saw advantages of older people using living wills; 467 of these also expressed concerns. Only 16 (2%) geriatricians who had concerns said that there were no advantages. A total of 214 (27%) were aware that their Trust had a form to help with discussions about cardiopulmonary resuscitation. Fewer [126 of 781 (16%)] were aware of a Trust policy on living wills. The proposal, in the Mental Capacity Bill, for advance refusals of treatment was supported by 59% (476 of 801), yet the proposal for a lasting power of attorney (LPA) covering health care was only supported by 47% (382 of 806)., Conclusion: Many geriatricians have positive experiences of caring for patients with living wills. Despite recognising potential problems, most geriatricians support the use of living wills by older people. However, most believe that their Trust does not have a policy to support advance health care planning. Geriatricians have reservations about LPAs covering health care.

The role of viral infections in the aetiopathogenesis of polymyositis remains speculative. We report a case of profound subacute polymyositis with incipient ventilatory failure following serologically confirmed infection by respiratory syncytial virus (RSV), with a dramatic and sustained response to pulse corticosteroid therapy. We suggest a possible autoimmune mechanism to account for this sequence of events.

Elevated cholesteryl ester transfer protein (CETP) activity has been reported in type 1 diabetic subjects and may be one cause of the high incidence of macrovascular complications in these patients. LDL delivers arachidonic acid (AA), in the form of cholesteryl ester (CE), to cells such as monocytes and fibroblasts, as precursor for eicosanoid synthesis. We discovered that AA content in LDL CE was significantly correlated with CETP activity, even after controlling for CETP concentration, in type 1 diabetic children. The production of LTB(4), a potent chemotactic and pro-inflammatory factor which plays a role in atherogenesis, has been shown to be increased in type 1 diabetic patients. We hypothesized that in these subjects, increased AA content in LDL CE, resulting from increased CETP activity and transient hyperinsulinemia, may lead to enhanced synthesis of LTB(4) and subsequently the higher incidence of cardiovascular disease.

The effects of apolipoprotein E (apoE) phenotype and glycemic regulation on plasma levels of lipids and lipoproteins, low density lipoprotein (LDL) composition, LDL particle size, and LDL oxidation were examined in 35 type 1 diabetic children aged 5-12 years. All subjects were classified according to glycemic regulation (HbA(1c)<8% vs. HbA(1c)>8%). ApoE phenotypes were identified by isoelectric focusing (IEF) followed by immunoblotting. Results from two-way analysis of variance (ANOVA) showed that subjects with apoE 4/3 and HbA(1c)>8% had higher concentrations of total cholesterol (TC), LDL-cholesterol (LDL-C), and LDL-cholesterol ester (LDL-CE) than subjects with the same apoE phenotype and HbA(1c)<8%. LDL particles in all subjects were classified as the subclass pattern A. Both LDL particle size and susceptibility of LDL to oxidation were not different among subjects stratified by apoE phenotype. In conclusion, children with type 1 diabetes mellitus included in this study did not have high-risk lipoprotein profiles at this early stage of life. However, there was some indication that those with the apoE 4/3 phenotype were more likely to have more favorable lipid profiles when HbA(1c) levels were <8%.

In order to investigate the role of cholesteryl ester transfer protein (CETP) in the cholesterolaemic response to dietary fats, we analysed plasma lipid profiles of CETP-transgenic and control C57BL/6 mice fed standard chow (AIN-93G; AIN), a low-fat diet, and diets high in butter (saturated fatty acids; SFA), high-oleic acid safflower oil (monounsaturated fatty acids; MUFA), and safflower oil (polyunsaturated fatty acids; PUFA) for 5 weeks. Each group contained four or five mice. There were significant diet and dietxgenotype effects on plasma total cholesterol (TC; and respectively), liver TC ( and respectively), and esterified cholesterol (EC; and respectively); diet effects on plasma triacylglycerol liver free cholesterol and body weight a genotype effect on body-weight gain and a dietxgenotype effect on energy intake In transgenic mice the SFA diet caused significantly higher plasma TC than the PUFA diet In control mice MUFA and PUFA diets, but not the SFA diet, caused significantly higher plasma TC than the low-fat and AIN diets Transgenic mice fed PUFA had lower plasma TC while transgenic mice fed MUFA had lower LDL+VLDL-cholesterol than controls in the same dietary groups. Transgenic mice fed MUFA and PUFA diets also had significantly higher liver TC and respectively) and EC and respectively) than controls fed the same diets. In the present study we showed that: (1) CETP transgenic mice had a cholesterolaemic response to dietary fats similar to that in human subjects; (2) CETP transgenic mice fed PUFA showed significantly lower plasma TC, while those fed MUFA had lower LDL+VLDL-cholesterol than controls; (3) hepatic accumulation of cholesterol, possibly resulting from the combination of the enhanced cholesteryl ester transfer to apolipoprotein B-containing lipoproteins and increased hepatic uptake of cholesterol, may contribute to the cholesterol-lowering effect of MUFA and PUFA in CETP-transgenic mice; (4) CETP may play a role in appetite and/or energy regulation.

Objective: To determine the relative incidence and characteristics of endomysial antibody (EMA)-negative coeliac disease in adults., Design: Retrospective analysis of prospectively collected data on adults with newly diagnosed coeliac disease, with determination of EMA status before gluten withdrawal., Setting: District general hospital (secondary care institution)., Participants: Sixty consecutive incident cases., Main Outcome Measures: (i) Proportion of cases who were EMA-negative; (ii) comparison of clinical and laboratory variables at diagnosis for EMA-positive and EMA-negative subjects., Results: Fifteen subjects (25%, 95% CI 15-38%) were EMA negative, of whom only two were IgA deficient. There was clinical evidence in all 15 patients and histological evidence in 13 patients of a response to gluten withdrawal. No significant differences were found between EMA-positive and EMA-negative subjects with respect to histological features, age, gender, clinical manifestations, concurrent autoimmune disorders, family history of coeliac disease, or haemoglobin and albumin concentrations at diagnosis. However, EMA-negative status at diagnosis was associated strongly with current or recent cigarette smoking (OR 7.0, 95% CI 1.7-31.5, P= 0.003)., Conclusions: A substantial minority of patients with otherwise typical coeliac disease are EMA negative, and most of these are IgA replete. The value of EMA as a screening tool is therefore limited. EMA status in untreated coeliac disease correlates strongly with cigarette smoking history: this may be of pathogenic significance, given the previously demonstrated association between smoking and the risk of coeliac disease.

The activities of two crucial enzymes of reverse cholesterol transport, cholesterol ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), and their relationships with lipid profile and fasting plasma glucose were examined in 35 type 1 diabetic children. The CETP and LCAT activities were significantly lower (p<0.05) in the 4 subjects with normal fasting plasma glucose levels (<6.39 mmol/l) than in the 28 with high plasma glucose levels (CEPT activity, 10.63+/-3.81 vs. 32.18+/-13.94 nmol/ml h; LCAT activity, 25.52+/-4.53 vs. 39.52+/-12.52 nmol/ml h; both p<0.05). The subjects with high plasma glucose levels also had higher total and LDL-cholesterol than those with normal glucose levels. CETP activity was positively correlated with fasting plasma glucose, CETP concentration, LCAT activity, total cholesterol, free cholesterol, LDL-C, and LDL-cholesteryl ester, while negatively correlated with cholesteryl ester to free cholesterol ratio, LDL triglyceride to protein ratio, and LDL triglyceride to cholesteryl ester ratio. LCAT activity was found to positively correlate with CETP activity, total cholesterol, free cholesterol, LDL-C, CETP concentration, and LDL-cholesteryl ester, while it negatively correlated with cholesteryl ester to free cholesterol ratio. The results observed in type 1 diabetic subjects suggest that (1) accelerated LCAT and CETP activities may result in the accumulation of LDL-cholesteryl ester; and (2) fasting plasma glucose may be a major determinant of CETP activity.

Medium-chain triglycerides (MCT) are often used in specialized formula diets or designer fats because of their special properties. Yet their influence on lipid metabolism is not completely understood. In this two-period cross-over study, the effects of MCT (8:0 + 10:0) in contrast to a similar saturated fatty acid (12:0) were compared. Eighteen healthy women ate a baseline diet [polyunsaturated (PUFA)/saturated fat = 0.9] for 1 wk. Then, they consumed test diets (PUFA/saturated fat = 0.2) for 4 wk. Monounsaturated fat and cholesterol were constant in baseline and treatment diets. MCT and 12:0, substituted for part of the PUFA, provided 14 energy (en)% of the test diets. In comparison to the PUFA baseline diet, a 16% increase in mean serum low density lipoprotein (LDL)-cholesterol (C) on the 12:0 diet was accompanied by a 21% decrease in mean receptor-mediated degradation of LDL by freshly isolated mononuclear cells (MNC) in vitro. The MNC assay theoretically gives an indication of receptor-mediated degradation of LDL. In contrast, the MCT diet raised mean receptor-mediated degradation of LDL by 42%, a finding out of line with the mean 11% increase in serum LDL-C. Perhaps MCT, by increasing the rate of LDL-C production, overcame the rate of LDL-C clearance. The 12:0 diet enhanced some factors involved in reverse cholesterol transport (e.g., high density lipoprotein fractions) while MCT had a different or less pronounced effect. The overall effects of MCT on cholesterol metabolism may or may not be desirable, whereas those of 12:0 appear largely undesirable as previously reported.

Objectives: To determine relative effects of diets high in synthetic sources of myristic (14:0), palmitic (16:0) or stearic (18:0) acid on concentrations and metabolism of serum lipoproteins., Design: Eighteen healthy women participated in a three-way cross-over study for five week periods separated by seven week washout periods, diets were assigned in random order., Subjects: Premenopausal women, not on medication, were from three races (Caucasian, African-American, Asian) and four apolipoprotein E phenotype groups (3/3, 3/2, 4/3, and 4/2)., Intervention: During the first week the subjects consumed a baseline diet providing 11 energy (en)% saturated fat, 10en% polyunsaturated fat and 14en% monounsaturated fat. Followed by test diets with 19en% saturated fat (including 14en% test saturated fatty acid), 3en% polyunsaturated fat, and 14en% monounsaturated fat for four weeks. Synthetic fats (trimyristin, tripalmitin, and tristearin) were used in blends with natural fats and oils., Results: Mean concentrations of serum total, esterified and LDL cholesterol were significantly lower after 18:0 than after 16:0 (n = 16-18, P < 0.01 for treatment effect). Myristic acid (14:0) had an intermediate effect. Receptor-mediated degradation of 125I-LDL in mononuclear cells obtained from the subjects was lower after 16:0 than after 14:0 and 18:0 (n = 16-18, P=0.05 for treatment effect). Differences in the digestibilities of the fats were not a major factor in the results. Strong cholesterolemic responses to the 16:0 diet were partly explained by apoE phenotype., Conclusions: As noted previously, stearic acid was neutral compared to 14:0 and 16:0. In contrast to studies involving natural fats, 14:0, fed as a synthetic triglyceride, was less cholesterolemic than 16:0 in a majority of subjects. ApoE phenotype influenced the cholesterolemic response particularly when diets high in 16:0 were eaten.

Objectives: Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesterol to apoB-containing lipoproteins. Its mass and activity are increased in several pro-atherogenic conditions. The objective of this study is to develop a cost- and time-effective sandwich ELISA for plasma CETP concentration., Design and Methods: Monoclonal anti-CETP, TP20, was used as the capture antibody, while the other biotinylated monoclonal anti-CETP, TP2, was used for detection. The results were expressed in an arbitrary unit, ng biotin-TP2 bound per microl plasma. Plasma CETP concentrations, activities and their relationship were assessed in 35 IDDM children., Results: The assay had an intra-assay CV of 8.75% and an inter-assay CV under 10%. Plasma CETP concentration of these subjects ranged from 0.36-1.89 ng biotin-TP2/microL. CETP concentration was significantly correlated with CETP activity (r = 0.51, p < 0.01)., Conclusion: The sandwich ELISA we have developed carried sufficient sensitivity for assaying plasma CETP concentration in human.

This report summarizes two studies which investigated the effects of apolipoprotein E (apoE) polymorphism on the serum total cholesterol (TC) and lipoprotein cholesterol responses to 8:0 + 10:0 and 12:0 diets (Study I) and 14:0, 16:0 and 18:0 diets (Study II). Eighteen healthy premenopausal women (3 apoE 3/2, 12 apoE 3/3, 3 apoE 4/3) in study I and another 18 healthy premenopausal women (4 apoE 3/2, 10 apoE 3/3, 3 apoE 4/3, 1 apoE 4/2) in study II consumed a baseline diet providing 40 en% total fat, 11 en% 18:2, 15 en% 18:1, 11.5 en% saturated fat for the first week of each 5-wk period. The experimental diets for both studies provided 40 en% total fat, 13-14 en% as one of five test saturated fatty acids (SFA), 14-16 en% 18:1, and 3-4 en% 18:2. Analysis by apoE phenotypes showed that both the 8:0 + 10:0 diet and the 12:0 diet in Study I induced significant increases in serum TC in subjects with different apoE phenotypes with the exception of apoE 3/2 in the medium-chain triglyceride group. In contrast, in Study II, individuals with apoE 4/3 consuming the 14:0 diet showed significant increases in serum TC, high density lipoprotein-cholesterol (HDL-C), and HDL2-C, but the same subjects consuming the 16:0 diet showed significant increases in serum TC and low density lipoprotein-cholesterol. The findings from both studies indicated serum lipoprotein responses to SFA were different and the variation of responsiveness may be regulated, at least in part, by apoE polymorphism, especially when 14:0, 16:0, or 18:0 was consumed.