How to use implantable loop recorders in clinical trials and hybrid therapy

Epidemiological studies show that atrial fibrillation (AF) is associated with a doubling of mortality, even after adjustment for confounders. AF can be asymptomatic, but this does not decrease the thromboembolic risk of the patient. Office ECGs, occasional 24-h Holter recordings and long-term ECG event recording might not be sensitive and accurate enough in patients with AF, especially in those with paroxysmal episodes. In one study, 7 days of continuous monitoring with event recorders detected paroxysmal AF in 20 of 65 patients with a previous negative 24-h Holter recording. Over the last decade, enormous improvements have been made in the technology of implantable devices, which can now store significant information regarding heart rhythm. The first subcutaneous implantable monitor (Reveal XT, Medtronic) was validated for continuous AF monitoring by the XPECT study. The dedicated AF detection algorithm uses irregularity and incoherence of R–R intervals to identify and classify patterns in ventricular conduction. Its sensitivity in identifying patients with AF is >96%. Numerous clinical data from continuous monitoring of AF have recently been published. The first applications of this technology have been in the field of surgical and catheter AF ablation. With regard to cryptogenic stroke, an international randomized trial is ongoing to compare standard care with standard care plus the implantable cardiac monitor for AF detection in patients discharged with the diagnosis of cryptogenic stroke: the Crystal AF trial. Continuous AF monitoring provides an optimal picture of daily AF burden, both symptomatic and asymptomatic. Implantable cardiac monitors have high sensitivity, enable better assessment of therapy success and may guide further AF therapy

A failed RCT to determine if antibiotics prevent mastitis: Cracked nipples colonized with Staphylococcus aureus: A randomized treatment trial [ISRCTN65289389]

BACKGROUND: A small, non-blinded, RCT (randomised controlled trial) had reported that oral antibiotics reduced the incidence of mastitis in lactating women with Staphylococcus aureus (S. aureus)- colonized cracked nipples. We aimed to replicate the study with a more rigorous design and adequate sample size. METHODS: Our intention was to conduct a double-blind placebo-controlled trial to determine if an antibiotic (flucloxacillin) could prevent mastitis in lactating women with S. aureus-colonized cracked nipples. We planned to recruit two groups of 133 women with S. aureus-colonized cracked nipples. RESULTS: We spent over twelve months submitting applications to five hospital ethics committees and seven funding bodies, before commencing the trial. Recruitment to the trial was very slow and only ten women were randomized to the trial after twelve months, and therefore the trial was stopped early. CONCLUSIONS: In retrospect we should have conducted a feasibility study, which would have revealed the low number of women in these Melbourne hospitals (maternity wards and breastfeeding clinics) with damaged nipples. The appropriate use of antibiotics for breastfeeding women with cracked nipples still needs to be tested

Effect of atorvastatin on C-reactive protein and benefits for cardiovascular disease in patients with type 2 diabetes: analyses from the Collaborative Atorvastatin Diabetes Trial

CARDS was partially funded by Diabetes UK and the National Health Service Research and Development Forum (England)

A case-control study of mastitis: nasal carriage of Staphylococcus aureus

BACKGROUND: Mastitis is a common problem for breastfeeding women. Researchers have called for an investigation into the possible role of maternal nasal carriage of S. aureus in the causation of mastitis in breastfeeding women. METHODS: The aim of the study was to investigate the role of maternal S. aureus nasal carriage in mastitis. Other factors such as infant nasal S. aureus carriage, nipple damage, maternal fatigue and oversupply of milk were also investigated. A case-control design was used. Women with mastitis (cases, n = 100) were recruited from two maternity hospitals in Melbourne, Australia (emergency departments, breastfeeding clinics and postnatal wards). Breastfeeding women without mastitis (controls, n = 99) were recruited from maternal and child health (community) centres and the rooms of a private obstetrician. Women completed a questionnaire and nasal specimens were collected from mother and baby and placed in charcoal transport medium. Women also collected a small sample of milk in a sterile jar. RESULTS: There was no difference between nasal carriage of S. aureus in breastfeeding women with mastitis (42/98, 43%) and control women (45/98, 46%). However, significantly more infants of mothers with mastitis were nasal carriers of S. aureus (72/88, 82%) than controls (52/93, 56%). The association was strong (adjusted OR 3.23, 95%CI 1.30, 8.27) after adjustment for the following confounding factors: income, private health insurance, difficulty with breastfeeding, nipple damage and tight bra. There was also a strong association between nipple damage and mastitis (adjusted OR 9.34, 95%CI 2.99, 29.20). CONCLUSION: We found no association between maternal nasal carriage of S. aureus and mastitis, but nasal carriage in the infant was associated with breast infections. As in other studies of mastitis, we found a strong association between nipple damage and mastitis. Prevention of nipple damage is likely to reduce the incidence of infectious mastitis. Mothers need good advice about optimal attachment of the baby to the breast and access to skilled help in the early postpartum days and weeks

Pulmonary Arterial Hypertension Affects the Rat Gut Microbiome

We have analysed whether pulmonary arterial hypertension (PAH) alters the rat faecal microbiota. Wistar rats were injected with the VEGF receptor antagonist SU5416 (20 mg/kg s.c.) and followed for 2 weeks kept in hypoxia (10% O2, PAH) or injected with vehicle and kept in normoxia (controls). Faecal samples were obtained and microbiome composition was determined by 16S rRNA gene sequencing and bioinformatic analysis. No effect of PAH on the global microbiome was found (α- or β-diversity). However, PAH-exposed rats showed gut dysbiosis as indicated by a taxonomy-based analysis. Specifically, PAH rats had a three-fold increase in Firmicutes-to-Bacteroidetes ratio. Within the Firmicutes phylum, there were no large changes in the relative abundance of the bacterial families in PAH. Among Bacteroidetes, all families were less abundant in PAH. A clear separation was observed between the control and PAH clusters based on short chain fatty acid producing bacterial genera. Moreover, acetate was reduced in the serum of PAH rats. In conclusion, faecal microbiota composition is altered as a result of PAH. This misbalanced bacterial ecosystem might in turn play a pathophysiological role in PAH by altering the immunologic, hormonal and metabolic homeostasis.This study is supported by grants from Mineco (SAF2014-55399-R, SAF2014-55523-R, SAF2016-77222 and SAF2017-84494-C2-1R), Instituto de Salud Carlos III (PI15/01100), with funds from the European Union (Fondo Europeo de Desarrollo Regional FEDER). M.C., G.M-P. and S.E-R. are funded by Universidad Complutense, Fondo de Garantía Juvenil (Comunidad de Madrid) and Ciberes grant with funds from Fundación Contra la Hipertensión Pulmonar, a FPU grant from Ministerio de Educación, respectively. J.L.I.G is a CNIC IPP COFUND Fellow and has received funding from the People Programme (Marie Curie Actions) of the FP7/2007-2013 under REA grant agreement n° 600396. The CNIC is supported by MEIC-AEI and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505)

Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Statins are a class of medications that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Whether statins can benefit patients with dementia remains unclear because of conflicting results. We hypothesized that some of the confusion in the literature might arise from differences in efficacy of different statins. We used a large database to compare the action of several different statins to investigate whether some statins might be differentially associated with a reduction in the incidence of dementia and Parkinson's disease.</p> <p>Methods</p> <p>We analyzed data from the decision support system of the US Veterans Affairs database, which contains diagnostic, medication and demographic information on 4.5 million subjects. The association of lovastatin, simvastatin and atorvastatin with dementia was examined with Cox proportional hazard models for subjects taking statins compared with subjects taking cardiovascular medications other than statins, after adjusting for covariates associated with dementia or Parkinson's disease.</p> <p>Results</p> <p>We observed that simvastatin is associated with a significant reduction in the incidence of dementia in subjects ≥65 years, using any of three models. The first model incorporated adjustment for age, the second model included adjusted for three known risk factors for dementia, hypertension, cardiovascular disease or diabetes, and the third model incorporated adjustment for the Charlson index, which is an index that provides a broad assessment of chronic disease. Data were obtained for over 700000 subjects taking simvastatin and over 50000 subjects taking atorvastatin who were aged >64 years. Using model 3, the hazard ratio for incident dementia for simvastatin and atorvastatin are 0.46 (CI 0.44–0.48, <it>p </it>< 0.0001) and 0.91 (CI 0.80–1.02, <it>p </it>= 0.11), respectively. Lovastatin was not associated with a reduction in the incidence of dementia. Simvastatin also exhibited a reduced hazard ratio for newly acquired Parkinson's disease (HR 0.51, CI 0.4–0.55, <it>p </it>< 0.0001).</p> <p>Conclusion</p> <p>Simvastatin is associated with a strong reduction in the incidence of dementia and Parkinson's disease, whereas atorvastatin is associated with a modest reduction in incident dementia and Parkinson's disease, which shows only a trend towards significance.</p

Up-regulation of endothelin type B receptors in the human internal mammary artery in culture is dependent on protein kinase C and mitogen-activated kinase signaling pathways

<p>Abstract</p> <p>Background</p> <p>Up-regulation of vascular endothelin type B (ET_B) receptors is implicated in the pathogenesis of cardiovascular disease. Culture of intact arteries has been shown to induce similar receptor alterations and has therefore been suggested as a suitable method for, <it>ex vivo</it>, in detail delineation of the regulation of endothelin receptors. We hypothesize that mitogen-activated kinases (MAPK) and protein kinase C (PKC) are involved in the regulation of endothelin ET_Breceptors in human internal mammary arteries.</p> <p>Methods</p> <p>Human internal mammary arteries were obtained during coronary artery bypass graft surgery and were studied before and after 24 hours of organ culture, using <it>in vitro </it>pharmacology, real time PCR and Western blot techniques. Sarafotoxin 6c and endothelin-1 were used to examine the endothelin ET_Aand ET_Breceptor effects, respectively. The involvement of PKC and MAPK in the endothelin receptor regulation was examined by culture in the presence of antagonists.</p> <p>Results</p> <p>The endohtelin-1-induced contraction (after endothelin ET_Breceptor desensitization) and the endothelin ET_Areceptor mRNA expression levels were not altered by culture. The sarafotoxin 6c contraction, endothelin ET_Breceptor protein and mRNA expression levels were increased after organ culture. This increase was antagonized by; (1) PKC inhibitors (10 μM bisindolylmaleimide I and 10 μM Ro-32-0432), and (2) inhibitors of the p38, extracellular signal related kinases 1 and 2 (ERK1/2) and C-jun terminal kinase (JNK) MAPK pathways (10 μM SB203580, 10 μM PD98059 and 10 μM SP600125, respectively).</p> <p>Conclusion</p> <p>In conclusion, PKC and MAPK seem to be involved in the up-regulation of endothelin ET_Breceptor expression in human internal mammary arteries. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the development of vascular endothelin ET_Breceptor changes in cardiovascular disease.</p