Patient-reported outcome measures show FIT as an acceptable investigation to rule out colorectal cancer in the two-week wait cohort.

INTRODUCTION: Use of faecal immunochemical testing (FIT) for symptomatic patients is increasing. FIT is recommended as a triage tool from primary care to the two-week wait (TWW) suspected cancer pathway, but there is still little known about patient attitudes. AIM: The aim of this study was to explore patient opinions of FIT and how it might be applied in the TWW pathway. METHODS: A telephone survey was conducted for patients from the TWW pathway who had undergone both conventional colonic investigation and FIT. Five questions explored expectations, attitudes towards results and experience of the investigations using a Likert scale 1-5. Differences in opinion were compared using median and mode scores and visualised using bar charts. RESULTS: One hundred and nine TWW patients agreed to answer the five questions. All had taken a stool sample for FIT, 50 underwent colonoscopy, 51 had a CT colonography and 8 underwent flexible sigmoidoscopy. Most patients (85%) scored 5 (completely satisfied) with these conventional colonic investigation methods they underwent for ruling out colorectal cancer (median 5). However, 30% of patients scored 5 (completely satisfied) if using a negative FIT to not require additional colonic investigation. The median score to perform FIT was 5 (very easy) compared with a median of 4 (easy) to undergo the other colonic investigations. CONCLUSIONS: Symptomatic patients can perform FIT with little difficulty, and often would have been happy to avoid conventional colonic investigations with a negative result. However, shared decision-making should be employed to identify those who would be dissatisfied with relying on FIT for further investigation decisions.

Metrics are required for diagnostic accuracy in acute medicine.

The article by Subbe et al raise important considerations as to what is deemed quality care in medicine. Throughput in acute medicine is highly prized. Prompt decision making, and action, is certainly required for several groups of unwell patients, but there is system-wide pressure to maintain this fast pace for all patients. It does not automatically follow that quicker medicine benefits all patients to some degree. 'Productivity' may come at the cost of too much medicine - characterised by overdiagnosis, overtreatment, and substantial resource utilisation.

Rhythmicity of patient flow in an acute medical unit: relationship to hospital occupancy, 7-day working and the effect of COVID-19.

BACKGROUND: The Acute Medical Unit (AMU) provides care for unscheduled hospital admissions. Seven-day consultant presence and morning AMU discharges have been advocated to improve hospital bed management. AIMS: To determine whether a later time of daily peak AMU occupancy correlates with measures of hospital stress; whether 7-day consultant presence, for COVID-19, abolished weekly periodicity of discharges. DESIGN: Retrospective cohort analysis. METHODS: : Anonymised AMU admission and discharge times were retrieved from the Profile Information Management System (PIMS), at a large, urban hospital from 14 April 2014 to 31 December 2018 and 20 March to 2 May 2020 (COVID-19 peak). Minute-by-minute admission and discharge times were combined to construct a running total of AMU bed occupancy. Fourier transforms were used to determine periodicity. We tested association between (i) average AMU occupancy and (ii) time of peak AMU occupancy, with measures of hospital stress (total medical bed occupancy and 'medical outliers' on non-medical wards). RESULTS: : Daily, weekly and seasonal patterns of AMU bed occupancy were evident. Timing of AMU peak occupancy was unrelated to each measure of hospital stress: total medical inpatients (Spearman's rho, rs = 0.04, P = 0.24); number of medical outliers (rs = -0.06, P = 0.05). During COVID-19, daily bed occupancy was similar, with continuation of greater Friday and Monday discharges than the weekend. CONCLUSIONS: : Timing of peak AMU occupancy did not alter with hospital stress. Efforts to increase morning AMU discharges are likely to have little effect on hospital performance. Seven-day consultant presence did not abolish weekly periodicity of discharges-other factors influence weekend discharges.

Childhood predictors of cardiovascular disease in adulthood. A systematic review and meta-analysis.

Childhood obesity predicts the risk of adult adiposity, which is associated with the earlier onset of cardiovascular disease [adult atherosclerotic cardiovascular disease, ACVD: hypertension, increased carotid intima media thickness (CIMT) stroke, ischemic heart disease (IHD)] and dysglycaemia. Because it is not known whether childhood obesity contributes to these diseases, we conducted a systematic review of studies that examine the ability of measures of obesity in childhood to predict dysglycaemia and ACVD. Data sources were Web of Science, MEDLINE, PubMed, CINAHL, Cochrane, SCOPUS, ProQuest and reference lists. Studies measuring body mass index (BMI), skin fold thickness and waist circumference were selected; of 1,954 studies, 18 met study criteria. Childhood BMI predicted CIMT: odds ratio (OR), 3.39 (95% confidence interval (CI), 2.02 to 5.67, P < 0.001) and risk of impaired glucose tolerance in adulthood, but its ability to predict ACVD events (stroke, IHD; OR, 1.04; 95% CI, 1.02 to 1.07; P < 0.001) and hypertension (OR, 1.17, 95% CI 1.06 to 1.27, P = 0.003) was weak-moderate. Body mass index was not predictive of systolic BP (r -0.57, P = 0.08) and weakly predicted diastolic BP (r 0.21, P = 0.002). Skin fold thickness in childhood weakly predicted CIMT in female adults only (rs 0.09, P < 0.05). Childhood BMI predicts the risk of dysglycaemia and abnormal CIMT in adulthood, but its ability to predict hypertension and ACVD events was weak and moderate, respectively. Skin fold thickness was a weak predictor of CIMT in female adults.

Renal Effects of SGLT-2 Inhibitors and Other Anti-diabetic Drugs: Clinical Relevance and Potential Risks.

Type 2 diabetes mellitus (T2DM) is a metabolic disease affecting an increasing percentage of general population worldwide. Patients with T2DM are frequently characterized by impaired renal function, primarily as a result of diabetic kidney injury, but also by other contributing factors, such as hypertension, atherosclerosis, and medications. Sodium-glucose cotransporter (SGLT)-2 inhibitors have emerged as a new, promising class of antidiabetic agents with actions that seem to extend beyond their hypoglycemic effect.

Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism.

Hypoxia and bacterial infection frequently co-exist, in both acute and chronic clinical settings, and typically result in adverse clinical outcomes. To ameliorate this morbidity, we investigated the interaction between hypoxia and the host response. In the context of acute hypoxia, both S. aureus and S. pneumoniae infections rapidly induced progressive neutrophil mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, prior to infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes. Specifically, perturbation of HIF pathway and glycolysis genes by hypoxic preconditioning was associated with reduced leukocyte glucose utilisation, resulting in systemic rescue from a global negative energy state and myocardial protection. Thus we demonstrate that hypoxia preconditions the innate immune response and determines survival outcomes following bacterial infection through suppression of HIF-1α and neutrophil metabolism. The therapeutic implications of this work are that in the context of systemic or tissue hypoxia therapies that target the host response could improve infection associated morbidity and mortality.

Perspectives on Perspective Taking: How Children Think About the Minds of Others.

Perspective taking, or "theory of mind," involves reasoning about the mental states of others (e.g., their intentions, desires, knowledge, beliefs) and is called upon in virtually every aspect of human interaction. Our goals in writing this chapter were to provide an overview of (a) the research questions developmental psychologists ask to shed light on how children think about the inner workings of the mind, and (b) why such research is invaluable in understanding human nature and our ability to interact with, and learn from, one another. We begin with a brief review of early research in this field that culminated in the so-called litmus test for a theory of mind (i.e., false-belief tasks). Next, we describe research with infants and young children that created a puzzle for many researchers, and briefly mention an intriguing approach researchers have used to attempt to "solve" this puzzle. We then turn to research examining children's understanding of a much broader range of mental states (beyond false beliefs). We briefly discuss the value of studying individual differences by highlighting their important implications for social well-being and ways to improve perspective taking. Next, we review work illustrating the value of capitalizing on children's proclivity for selective social learning to reveal their understanding of others' mental states. We close by highlighting one line of research that we believe will be an especially fruitful avenue for future research and serves to emphasize the complex interplay between our perspective-taking abilities and other cognitive processes.

Periodontal Defects in the A116T Knock-in Murine Model of Odontohypophosphatasia.

Mutations in ALPL result in hypophosphatasia (HPP), a disease causing defective skeletal mineralization. ALPL encodes tissue nonspecific alkaline phosphatase (ALP), an enzyme that promotes mineralization by reducing inorganic pyrophosphate, a mineralization inhibitor. In addition to skeletal defects, HPP causes dental defects, and a mild clinical form of HPP, odontohypophosphatasia, features only a dental phenotype. The Alpl knockout (Alpl (-/-)) mouse phenocopies severe infantile HPP, including profound skeletal and dental defects. However, the severity of disease in Alpl (-/-) mice prevents analysis at advanced ages, including studies to target rescue of dental tissues. We aimed to generate a knock-in mouse model of odontohypophosphatasia with a primarily dental phenotype, based on a mutation (c.346G>A) identified in a human kindred with autosomal dominant odontohypophosphatasia. Biochemical, skeletal, and dental analyses were performed on the resulting Alpl(+/A116T) mice to validate this model. Alpl(+/A116T) mice featured 50% reduction in plasma ALP activity compared with wild-type controls. No differences in litter size, survival, or body weight were observed in Alpl(+/A116T) versus wild-type mice. The postcranial skeleton of Alpl(+/A116T) mice was normal by radiography, with no differences in femur length, cortical/trabecular structure or mineral density, or mechanical properties. Parietal bone trabecular compartment was mildly altered. Alpl(+/A116T) mice featured alterations in the alveolar bone, including radiolucencies and resorptive lesions, osteoid accumulation on the alveolar bone crest, and significant differences in several bone properties measured by micro-computed tomography. Nonsignificant changes in acellular cementum did not appear to affect periodontal attachment or function, although circulating ALP activity was correlated significantly with incisor cementum thickness. The Alpl(+/A116T) mouse is the first model of odontohypophosphatasia, providing insights on dentoalveolar development and function under reduced ALP, bringing attention to direct effects of HPP on alveolar bone, and offering a new model for testing potential dental-targeted therapies in future studies.

Importance of cannulated prolactin test in the definition of hyperprolactinaemia.

PURPOSE: Recent guidelines suggest that a single prolactin measurement is adequate to confirm hyperprolactinaemia. This may lead to unnecessary investigation of artefactual hyperprolactinaemia. Prolactin measurement drawn from an indwelling cannula after rest removes stress as a confounding variable. The objective was to determine the frequency of true hyperprolactinaemia amongst patients referred following a single prolactin measurement. METHODS: A cannulated study was considered if prolactin on referral ('Referral Prolactin') was <5,500 mU/L (260 ng/mL) but >410 mU/L (19 ng/mL) in males or >510 mU/L (24 ng/mL) in females, irrespective of clinical context. Case-notes of 267 patients undergoing cannulated prolactin measurement over a 10-year period (2000-2010) were reviewed. Pre-existing pituitary disease, dopamine antagonist use, and macroprolactinaemia were excluded. Morning ante-cubital vein cannulation was followed immediately by withdrawal of 'Repeat Prolactin' sample. After 120-min bed-rest, 'Resting Prolactin' was withdrawn through the cannula. RESULTS: 235 patients were included for analysis. 64 (27%) were within normal range; following Repeat Prolactin in 41 (17%) and Resting Prolactin in 23 (9%) cases. Referral Prolactin was higher in patients with true hyperprolactinaemia, 1,637 ± 100 mU/L (77.2 ± 4.7 ng/mL) than with artefactual hyperprolactinaemia, 1,122 ± 68 mU/L (52.9 ± 3.2 ng/mL; P < 0.001) but there was substantial overlap. 21 out of 171 cases (12%) with true hyperprolactinaemia had a macroadenoma. Presenting symptoms did not predict true hyperprolactinaemia. Referral Prolactin of 2,000 mU/L (94 ng/mL) had 97% specificity to identify true hyperprolactinaemia. CONCLUSIONS: Reliance on a single, non-rested prolactin value may lead to over-diagnosis of hyperprolactinaemia. A resting sample should be considered with random values <2,000 mU/L (94 ng/mL).

Disease severity and staging of obesity: a rational approach to patient selection.

The increasing prevalence of obesity places ever-increasing cost demands on healthcare systems. One million individuals are eligible for bariatric surgery in the UK, and yet less than 6000 bariatric procedures are performed annually. Bariatric surgery reverses or improves almost all the medical and psychosocial co-morbidities associated with obesity. Although the BMI is a simple method to estimate adiposity at a population level, it is relatively inaccurate within an individual and provides little-to-no indication of overall health status or disease severity. Staging systems overcome the inherent limitations of BMI and allow highly informed decision-making for an individual. At a societal level, this helps to identify those most likely to gain and maximise economic benefit. This review summarises the co-morbidities associated with obesity and the evidence for their improvement following surgery. The rationale for new staging criteria and appropriate patient selection are discussed.

Pregnancy after diabetes obesity surgery (PADOS): Qualitative study of pre-pregnancy care.

Half of all bariatric surgical procedures are in women of childbearing age. Surgery may improve fertility yet exacerbate nutritional deficiencies, that may be disadvantageous to the fetus. A frequently encountered subgroup of obese women have type 2 diabetes. The health risks, to both mother and child, of diabetes in pregnancy are well described including 4.7× risk of stillbirth and 2× risk of congenital abnormality. What is not clear is whether bariatric surgery mitigates or complicates the health consequences of women with obesity and diabetes in pregnancy. In addition the influence of the type of surgery, the optimal interval between surgery and conception and evidence based preconception recommendations are unknown. This study complements wider research aiming to inform optimal management of this patient population. Obese diabetic women require clear guidance regarding pregnancy planning after surgery. This study will develop an understanding of the barriers and facilitators (psychological, behavioural, attitudinal and nutritional) to achieving effective pre-pregnancy health and care in women with type 2 diabetes who have undergone metabolic surgery. Currently women's perception of fertility issues and risks after bariatric surgery is unknown and thus a qualitative interpretive paradigm was chosen. Interviews with the target population will explore decision-making processes; experience regarding metabolic surgery and perceived pregnancy risk. Interviews with a broad range of health professionals involved in bariatric care will include rationale for selected surgical procedure and post surgery referral processes e.g. contraceptive care. This will advance understanding of how to provide targeted support and monitoring.

Pregnancy after diabetes obesity surgery (PADOS): Incidence and outcomes.

Half of all bariatric surgical procedures are in women of childbearing age but it remains unclear whether surgery is suitable for women who subsequently conceive: specifically the relative risks and benefits of potential nutrient deficiencies versus weight reduction. We will present data collected from Clinical Practice Research Databases on the maternal and fetal outcomes of pregnancies complicated either by obesity or previous bariatric surgery (BS). Two groups, matched to obese controls for BMI pre-BS and post-BS (at the time of ante-natal booking) will be compared. In this way, the effect of BS on pregnancy outcomes may be examined, independent of its effect on weight. A sub-group of women with antecedent Type 2 diabetes (T2DM) will allow for investigation of the additional impact and persistence of this co-morbidity. This builds upon pilot data collected from a retrospective cohort of women (18-45years) undergoing laparoscopic roux-en-Y (RYGB) surgery over a 24-month period (n=218). After exclusions and loss to follow up, data from 111 patients were analysed; 81 (73%) had conceived prior to RYGB, 20 (18%) became pregnant post RYGB and a further 22 patients (20%) were trying to conceive at the time of data collection. Three women had T2DM which resolved post BS. A suggestion of greater miscarriage risk prior to surgery in this sub-group will be confirmed as more women are recruited. Pregnancy is a frequent desire/occurrence after BS. This database study will advance understanding of the maternal and fetal outcomes of such pregnancies and inform antenatal care.

Succinate is an inflammatory signal that induces IL-1ß through HIF-1α.

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1ß but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1ß as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1ß production during inflammation.

Emergency slaughter of casualty cattle increases the prevalence of anthelmintic drug residues in muscle.

The ProSafeBeef project studied the prevalence of residues of anthelmintic drugs used to control parasitic worms and fluke in beef cattle in Ireland. Injured (casualty) cattle may enter the human food chain under certain conditions, verified by an attending veterinarian and the livestock keeper. An analytical survey was conducted to determine if muscle from casualty cattle contained a higher prevalence of anthelmintic drug residues than healthy (full slaughter weight) cattle as a result of possible non-observance of complete drug withdrawal periods. A validated analytical method based on matrix solid-phase dispersive extraction (QuEChERS) and ultra-performance liquid chromatography-tandem mass spectrometry was used to quantify 37 anthelmintic drugs and metabolites in muscle (assay decision limits, CCα, 0.15-10.2 µg kg⁻¹). Of 199 control samples of beef purchased in Irish shops, 7% contained detectable anthelmintic drug residues but all were compliant with European Union Maximum Residue Limits (MRL). Of 305 muscle samples from injured cattle submitted to abattoirs in Northern Ireland, 17% contained detectable residues and 2% were non-compliant (containing either residues at concentrations above the MRL or residues of a compound unlicensed for use in cattle). Closantel and ivermectin were the most common residues, but a wider range of drugs was detected in muscle of casualty cattle than in retail beef. These data suggest that specific targeting of casualty cattle for testing for anthelmintic residues may be warranted in a manner similar to the targeted testing for antimicrobial compounds often applied in European National Residues Surveillance Schemes.