Digoxin treatment is associated with an increased incidence of breast cancer: a population-based case-control study

INTRODUCTION. Laboratory and epidemiologic studies have suggested a modifying effect of cardiac glycosides (for example, digoxin and digitoxin) on cancer risk. We explored the association between digoxin treatment and invasive breast cancer incidence among postmenopausal Danish women. METHODS. We used Danish registries to identify 5,565 postmenopausal women diagnosed with incident invasive breast carcinoma between 1 January 1991 and 31 December 2007, and 55,650 matched population controls. Cardiac glycoside prescriptions were ascertained from county prescription registries. All subjects had at least 2 years of recorded prescription drug and medical history data. We estimated the odds ratio associating digoxin use with breast cancer in conditional logistic regression models adjusted for age, county of residence, and use of anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, and hormone replacement therapy. We also explored the impact of confounding by indication and detection bias. RESULTS. Digoxin was the sole cardiac glycoside prescribed to subjects during the study period. There were 324 breast cancer cases (5.8%) and 2,546 controls (4.6%) with a history of digoxin use at least 1 year before their index date (adjusted odds ratio (OR): 1.30; 95% confidence interval: 1.14 to 1.48). The breast cancer OR increased modestly with increasing duration of digoxin exposure (adjusted OR for 7 to 18 years of digoxin use: 1.39; 95% confidence interval: 1.10 to 1.74). The association was robust to adjustment for age, receipt of hormone replacement therapy, coprescribed drugs, and confounding by indication. A comparison of screening mammography rates between cases and controls showed no evidence of detection bias. CONCLUSIONS. Our results suggest that digoxin treatment increases the risk of invasive breast cancer among postmenopausal women.Congressionaly Directed Medical Research Programs (BC073012); Karen Elise Jensen Foundation; Western Danish Research Forum for Health Science

Potential misinterpretations caused by collapsing upper categories of comorbidity indices: An illustration from a cohort of older breast cancer survivors

BACKGROUND: Comorbidity indices summarize complex medical histories into concise ordinal scales, facilitating stratification and regression in epidemiologic analyses. Low subject prevalence in the highest strata of a comorbidity index often prompts combination of upper categories into a single stratum (\u27collapsing\u27). OBJECTIVE: We use data from a breast cancer cohort to illustrate potential inferential errors resulting from collapsing a comorbidity index. METHODS: Starting from a full index (0, 1, 2, 3, and \u3e/=4 comorbidities), we sequentially collapsed upper categories to yield three collapsed categorizations. The full and collapsed categorizations were applied to analyses of (1) the association between comorbidity and all-cause mortality, wherein comorbidity was the exposure; (2) the association between older age and all-cause mortality, wherein comorbidity was a candidate confounder or effect modifier. RESULTS: Collapsing the index attenuated the association between comorbidity and mortality (risk ratio, full versus dichotomized categorization: 4.6 vs 2.1), reduced the apparent magnitude of confounding by comorbidity of the age/mortality association (relative risk due to confounding, full versus dichotomized categorization: 1.14 vs 1.09), and obscured modification of the association between age and mortality on both the absolute and relative scales. CONCLUSIONS: Collapsing categories of a comorbidity index can alter inferences concerning comorbidity as an exposure, confounder and effect modifier

Identification of the Pr1 Gene Product Completes the Anthocyanin Biosynthesis Pathway of Maize

In maize, mutations in the pr1 locus lead to the accumulation of pelargonidin (red) rather than cyanidin (purple) pigments in aleurone cells where the anthocyanin biosynthetic pathway is active. We characterized pr1 mutation and isolated a putative F3′H encoding gene (Zmf3′h1) and showed by segregation analysis that the red kernel phenotype is linked to this gene. Genetic mapping using SNP markers confirms its position on chromosome 5L. Furthermore, genetic complementation experiments using a CaMV 35S::ZmF3′H1 promoter–gene construct established that the encoded protein product was sufficient to perform a 3′-hydroxylation reaction. The Zmf3′h1-specific transcripts were detected in floral and vegetative tissues of Pr1 plants and were absent in pr1. Four pr1 alleles were characterized: two carry a 24 TA dinucleotide repeat insertion in the 5′-upstream promoter region, a third has a 17-bp deletion near the TATA box, and a fourth contains a Ds insertion in exon1. Genetic and transcription assays demonstrated that the pr1 gene is under the regulatory control of anthocyanin transcription factors red1 and colorless1. The cloning and characterization of pr1 completes the molecular identification of all genes encoding structural enzymes of the anthocyanin pathway of maize

Flexion Relaxation and Its Relation to Pain and Function over the Duration of a Back Pain Episode

BACKGROUND: Relaxation of the erector spinae often occurs in healthy individuals as full trunk flexion is achieved when bending forward from standing. This phenomenon, referred to as flexion relaxation is often absent or disrupted (EMG activity persists) in individuals reporting low back pain (LBP). METHODS AND RESULTS: Self-reported pain and disability scores were compared to EMG measures related to the flexion relaxation (FR) phenomenon by 33 participants with LBP at up to eight sessions over a study period of up to eight weeks. Fourteen participants served as a control group. In the protocol, starting from standing participants bent forward to a fully flexed posture, and then extended the trunk to return to standing position. A thoracic inclinometer was used to measure trunk posture. Surface electrodes located at the L2 and L5 levels recorded EMG amplitudes of the erector spinae. Ratios of EMG amplitudes recorded during forward bending to amplitudes at full flexion, and ratios of extension to full flexion were calculated. EMG amplitudes and their ratios were compared between control and LBP groups at the initial visit. No significant differences between groups were found except at the L5 location at full flexion. Correlations of the ratios to pain and function scores recorded in repeated sessions over the LBP episode also were compared between LBP group participants classified as having transient, recurrent or chronic symptoms. In another analysis participants were grouped by whether their symptoms resolved over the study period. CONCLUSIONS: The transient LBP group had significantly stronger correlations between pain and function to both ratios, than did those with more chronic LBP symptoms. Participants who experienced symptom resolution generally had stronger correlations of ratios to both pain and function than those with partial or no resolution. Improved understanding of these relationships may provide insight in clinical management of LBP

Effectiveness and cost-effectiveness of referral to a commercial open group behavioural weight management programme in adults with overweight and obesity: 5-year follow-up of the WRAP randomised controlled trial

Background There is evidence that commercially available behavioural weight management programmes can lead to short-term weight loss and reductions in glycaemia. Here, we aimed to provide the 5-year impact and cost-effectiveness of these interventions compared with a brief intervention. Methods WRAP was a non-blinded, parallel-group randomised controlled trial (RCT). We recruited from primary care practices in England and randomly assigned participants to one of three interventions (brief intervention, 12-week open-group behavioural programme [WW, formerly Weight Watchers], or a 52-week open-group WW behavioural programme) in an uneven (2:5:5) allocation. Participants were followed up 5 years after randomisation using data from measurement visits at primary care practices or a research centre, review of primary care electronic medical notes, and self-report questionnaires. The primary outcome was change in weight at 5 years follow-up, assessed using analysis of covariance. We also estimated cost-effectiveness of the intervention. This study is registered at Current Controlled Trials, ISRCTN64986150. Findings Between Oct 18, 2012, and Feb 10, 2014, we recruited 1269 eligible participants (two participants were randomly assigned but not eligible and therefore excluded) and 1040 (82%) consented to be approached about additional follow-up and to have their medical notes reviewed at 5 years. The primary outcome (weight) was ascertained for 871 (69%) of 1267 eligible participants. Mean duration of follow-up was 5·1 (SD 0·3) years. Mean weight change from baseline to 5 years was −0·46 (SD 8·31) kg in the brief intervention group, −1·95 (9·55) kg in the 12-week programme group, and −2·67 (9·81) kg in the 52-week programme. The adjusted difference in weight change was –1·76 (95% CI –3·68 to 0·17) kg between the 52-week programme and the brief intervention; –0·80 (–2·13 to 0·54) kg between the 52-week and the 12-week programme; and –0·96 (–2·90 to 0·97) kg between the 12-week programme and the brief intervention. During the trial, the 12-week programme incurred the lowest cost and produced the highest quality-adjusted life-years (QALY). Simulations beyond 5 years suggested that the 52-week programme would deliver the highest QALYs at the lowest cost and would be the most cost-effective. No participants reported adverse events related to the intervention. Interpretation Although the difference in weight change between groups was not statistically significant, some weight loss was maintained at 5 years after an open-group behavioural weight management programme. Health economic modelling suggests that this could have important implications to reduce the incidence of weight-related disease and these interventions might be cost-saving. Funding The UK National Institute for Health and Care Research Programme Grants for Applied Research and the Medical Research Council

Voltage-Dependent Gating in a “Voltage Sensor-Less” Ion Channel

An unusual mechanism of ion channel regulation generates voltage-dependent gating in the absence of a canonical voltage-sensing domain

Internet of Things for Sustainable Human Health

The sustainable health IoT has the strong potential to bring tremendous improvements in human health and well-being through sensing, and monitoring of health impacts across the whole spectrum of climate change. The sustainable health IoT enables development of a systems approach in the area of human health and ecosystem. It allows integration of broader health sub-areas in a bigger archetype for improving sustainability in health in the realm of social, economic, and environmental sectors. This integration provides a powerful health IoT framework for sustainable health and community goals in the wake of changing climate. In this chapter, a detailed description of climate-related health impacts on human health is provided. The sensing, communications, and monitoring technologies are discussed. The impact of key environmental and human health factors on the development of new IoT technologies also analyzed

Acid-evoked Ca2+ signalling in rat sensory neurones: effects of anoxia and aglycaemia

Ischaemia excites sensory neurones (generating pain) and promotes calcitonin gene-related peptide release from nerve endings. Acidosis is thought to play a key role in mediating excitation via the activation of proton-sensitive cation channels. In this study, we investigated the effects of acidosis upon Ca2+ signalling in sensory neurones from rat dorsal root ganglia. Both hypercapnic (pHo 6.8) and metabolic–hypercapnic (pHo 6.2) acidosis caused a biphasic increase in cytosolic calcium concentration ([Ca2+]i). This comprised a brief Ca2+ transient (half-time approximately 30 s) caused by Ca2+ influx followed by a sustained rise in [Ca2+]i due to Ca2+ release from caffeine and cyclopiazonic acid-sensitive internal stores. Acid-evoked Ca2+ influx was unaffected by voltage-gated Ca2+-channel inhibition with nickel and acid sensing ion channel (ASIC) inhibition with amiloride but was blocked by inhibition of transient receptor potential vanilloid receptors (TRPV1) with (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide (AMG 9810; 1 μM) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl) tetrahydropryazine-1(2H)-carbox-amide (BCTC; 1 μM). Combining acidosis with anoxia and aglycaemia increased the amplitude of both phases of Ca2+ elevation and prolonged the Ca2+ transient. The Ca2+ transient evoked by combined acidosis, aglycaemia and anoxia was also substantially blocked by AMG 9810 and BCTC and, to a lesser extent, by amiloride. In summary, the principle mechanisms mediating increase in [Ca2+]i in response to acidosis are a brief Ca2+ influx through TRPV1 followed by sustained Ca2+ release from internal stores. These effects are potentiated by anoxia and aglycaemia, conditions also prevalent in ischaemia. The effects of anoxia and aglycaemia are suggested to be largely due to the inhibition of Ca2+-clearance mechanisms and possible increase in the role of ASICs

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability