Pregnancy outcome following maternal exposure to statins: a multicenter prospective study

Introduction Statin use in women of childbearing age is increasingly common. However, published data on pregnancy outcome after exposure to statins are scarce and conflicting. This contribution addresses the safety of statin use during pregnancy.Materials and Methods In a multi-centre (n = 11), prospective study we compared the outcomes of 249 women exposed during the 1st trimester of pregnancy to simvastatin (n = 124), atorvastatin (n = 67), pravastatin (n = 32), rosuvastatin (n = 18), fl uvastatin (n = 7) or cerivastatin (n = 1) with a control group exposed to agents known to be non-teratogenic (n = 249). Data were collected by members of the European Network of Teratology Information Services during individual risk counselling.Results The difference in the rate of major birth defects between the statinexposed and the control group was statistically insignificant (4.0% versus 2.7% OR 1.5; 95% CI 0.5-4.5, p = 0.44). The crude rate of spontaneous abortions (12.8% versus 7.1%, OR 1.9, 95% CI 1.0-3.6, p = 0.04) was higher in the exposed group. However, after adjustment to maternal age and gestational age at initial contact, the difference became insignificant. The rate of elective pregnancy-termination (8.8% versus 4.4%, p = 0.05) was higher and the rate of live births was lower in the exposed group (77.9% versus 88.4%, p = 0.002). Prematurity was more frequent in exposed pregnancies (16.1% versus 8.5%; OR 2.1, 95% CI 1.1- 3.8, p = 0.02). Nonetheless, gestational age at birth (median 39 weeks, IQR 37-40 versus 39 weeks, IQR 38-40, p = 0.27) and birth weight (median 3280 g, IQR 2835-3590 versus 3250 g, IQR 2880- 3600, p = 0.95) did not differ between exposed and non-exposed pregnancies.Conclusion This study did not detect a teratogenic effect of statins. Its statistical power however is not sufficient to reverse the recommendation of treatment discontinuation during pregnancy.

The role of bile acid retention and a common polymorphism in the ABCB11 gene as host factors affecting antiviral treatment response in chronic hepatitis C.

Summary.  The outcome of hepatitis C virus (HCV) infection and the likelihood of a sustained virological response (SVR) to antiviral therapy depends on both viral and host characteristics. In vitro studies demonstrated that bile acids (BA) interfere with antiviral interferon effects. We investigate the influence of plasma BA concentrations and an ABCB11 polymorphism associated with lower transporter expression on viral load and SVR. Four hundred and fifty-one Caucasian HCV-patients treated with PEG-interferon and ribavirin were included in the study. ABCB11 1331T>C was genotyped, and plasma BA levels were determined. The 1331C allele was slightly overrepresented in HCV-patients compared to controls. In HCV-patients, a significant difference between patients achieving SVR vs non-SVR was observed for HCV-2/3 (5 vs 9 μm; P = 0.0001), while median BA levels in HCV-1 were marginally elevated. Normal BA levels <8 μm were significantly associated with SVR (58.3%vs 36.3%; OR 2.48; P = 0.0001). This difference was significant for HCV-2/3 (90.7%vs 67.6%; P = 0.002) but marginal in HCV-1 (38.7%vs 27.8%; P = 0.058). SVR rates were equivalent between ABCB11 genotypes for HCV-1, but increased for HCV-2/3 (TT 100%vs CC 78%; OR 2.01; P = 0.043). IL28B genotype had no influence on these associations. No correlation between BA levels and HCV RNA was detected for any HCV genotype. The higher allelic frequency of ABCB11 1331C in HCV-patients compared to controls may indirectly link increased BA to HCV chronicity. Our data support a role for BA as host factor affecting therapy response in HCV-2/3 patients, whereas a weaker association was found for HCV-1.

A CMR study of the effects of tissue edema and necrosis on left ventricular dyssynchrony in acute myocardial infarction: implications for cardiac resynchronization therapy.

ABSTRACT: BACKGROUND: In acute myocardial infarction (AMI), both tissue necrosis and edema are present and both might be implicated in the development of intraventricular dyssynchrony. However, their relative contribution to transient dyssynchrony is not known. Cardiovascular magnetic resonance (CMR) can detect necrosis and edema with high spatial resolution and it can quantify dyssynchrony by tagging techniques. METHODS: Patients with a first AMI underwent percutaneous coronary interventions (PCI) of the infarct-related artery within 24 h of onset of chest pain. Within 5-7 days after the event and at 4 months, CMR was performed. The CMR protocol included the evaluation of intraventricular dyssynchrony by applying a novel 3D-tagging sequence to the left ventricle (LV) yielding the CURE index (circumferential uniformity ratio estimate; 1 = complete synchrony). On T2-weighted images, edema was measured as high-signal (>2 SD above remote tissue) along the LV mid-myocardial circumference on 3 short-axis images (% of circumference corresponding to the area-at-risk). In analogy, on late-gadolinium enhancement (LGE) images, necrosis was quantified manually as percentage of LV mid-myocardial circumference on 3 short-axis images. Necrosis was also quantified on LGE images covering the entire LV (expressed as %LV mass). Finally, salvaged myocardium was calculated as the area-at-risk minus necrosis (expressed as % of LV circumference). RESULTS: After successful PCI (n = 22, 2 female, mean age: 57 ± 12y), peak troponin T was 20 ± 36ug/l and the LV ejection fraction on CMR was 41 ± 8%. Necrosis mass was 30 ± 10% and CURE was 0.91 ± 0.05. Edema was measured as 58 ± 14% of the LV circumference. In the acute phase, the extent of edema correlated with dyssynchrony (r2 = -0.63, p < 0.01), while extent of necrosis showed borderline correlation (r2 = -0.19, p = 0.05). PCI resulted in salvaged myocardium of 27 ± 14%. LV dyssynchrony (=CURE) decreased at 4 months from 0.91 ± 0.05 to 0.94 ± 0.03 (p < 0.004, paired t-test). At 4 months, edema was absent and scar %LV slightly shrunk to 23.7 ± 10.0% (p < 0.002 vs baseline). Regression of LV dyssynchrony during the 4 months follow-up period was predicted by both, the extent of edema and its necrosis component in the acute phase. CONCLUSIONS: In the acute phase of infarction, LV dyssynchrony is closely related to the extent of edema, while necrosis is a poor predictor of acute LV dyssynchrony. Conversely, regression of intraventricular LV dyssynchrony during infarct healing is predicted by the extent of necrosis in the acute phase.

Antimicrobial resistance among Brazilian Corynebacterium diphtheriae strains

The increasing problems with multidrug resistance in relation to Corynebacterium, including C. diphtheriae, are examples of challenges confronting many countries. For this reason, Brazilian C. diphtheriae strains were evaluated by the E-Test for their susceptibility to nine antibacterial drugs used in therapy. Resistance (MIC < 0.002; 0.38 µg/ml) to penicillin G was found in 14.8% of the strains tested. Although erythromycin (MIC90 0.75 µg/ml) and azithromycin (MIC90 0.064 µg/ml) were active against C. diphtheriae in this study, 4.2% of the strains showed decreased susceptibility (MIC 1.0 µg/ml) to erythromycin. Multiple resistance profiles were determined by the disk diffusion method using 31 antibiotics. Most C. diphtheriae strains (95.74%) showed resistance to mupirocin, aztreonam, ceftazidime, and/or oxacillin, ampicillin, penicillin, tetracycline, clindamycin, lincomycin, and erythromycin. This study presents the antimicrobial susceptibility profiles of Brazilian C. diphtheriae isolates. The data are of value to practitioners, and suggest that some concern exists regarding the use of penicillin.

Validation of the instability shoulder index score in a multicenter reliability study in 114 consecutive cases.

BACKGROUND: Anterior shoulder stabilization surgery with the arthroscopic Bankart procedure can have a high recurrence rate in certain patients. Identifying these patients to modify outcomes has become a focal point of research. PURPOSE: The Instability Shoulder Index Score (ISIS) was developed to predict the success of arthroscopic Bankart repair. Scores range from 0 to 10, with higher scores predicting a higher risk of recurrence after stabilization. The interobserver reliability of the score is not known. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: This is a prospective multicenter (North America and Europe) study of patients suffering from shoulder instability and waiting for stabilization surgery. Five pairs of independent evaluators were asked to score patient instability severity with the ISIS. Patients also completed functional scores (Western Ontario Shoulder Instability Index [WOSI], Disabilities of the Arm, Shoulder and Hand-short version [QuickDASH], and Walch-Duplay test). Data on age, sex, number of dislocations, and type of surgery were collected. The test-retest method and intraclass correlation coefficient (ICC: >0.75 = good, >0.85 = very good, and >0.9 = excellent) were used for analysis. RESULTS: A total of 114 patients with anterior shoulder instability were included, of whom 89 (78%) were men. The mean age was 28 years. The ISIS was very reliable, with an ICC of 0.933. The mean number of dislocations per patient was higher in patients who had an ISIS of ≥6 (25 vs 14; P = .05). Patients who underwent more complex arthroscopic procedures such as Hill-Sachs remplissage or open Latarjet had higher preoperative ISIS outcomes, with a mean score of 4.8 versus 3.4, respectively (P = .002). There was no correlation between the ISIS and the quality-of-life questionnaires, with Pearson correlations all >0.05 (WOSI = 0.39; QuickDASH = 0.97; Walch-Duplay = 0.08). CONCLUSION: Our results show that the ISIS is reliable when used in a multicenter study with anterior traumatic instability populations. There was no correlation between the ISIS and the quality-of-life questionnaires, but surgical decisions reflected its increased use.

Carcinoma verrugoso de vagina. Presentacion de un caso

Verrucous carcinoma of the vagina is a rare neoplasm. This entity is a slow-growing, locally invasive but generally nonmetastasizing neoplasm, with a characteristic gross and microscopic appearance. We report a case of verrucous carcinoma of the vagina in a postmenopausal woman diagnosed 4 years after transvaginal hysterectomy for grade 4 uterine prolapse. We also discuss the differential diagnosis and treatment.Verrucous carcinoma of the vagina is a rare neoplasm. The differential diagnosis includes typical squamous cell carcinoma, warty carcinoma, and condyloma acuminatum. Surgery remains the most effective treatment.

Effectiveness of a nurse-led case management home care model in Primary Health Care. A quasi-experimental, controlled, multi-centre study

Background Demand for home care services has increased considerably, along with the growing complexity of cases and variability among resources and providers. Designing services that guarantee co-ordination and integration for providers and levels of care is of paramount importance. The aim of this study is to determine the effectiveness of a new case-management based, home care delivery model which has been implemented in Andalusia (Spain). Methods Quasi-experimental, controlled, non-randomised, multi-centre study on the population receiving home care services comparing the outcomes of the new model, which included nurse-led case management, versus the conventional one. Primary endpoints: functional status, satisfaction and use of healthcare resources. Secondary endpoints: recruitment and caregiver burden, mortality, institutionalisation, quality of life and family function. Analyses were performed at base-line, and at two, six and twelve months. A bivariate analysis was conducted with the Student's t-test, Mann-Whitney's U, and the chi squared test. Kaplan-Meier and log-rank tests were performed to compare survival and institutionalisation. A multivariate analysis was performed to pinpoint factors that impact on improvement of functional ability. Results Base-line differences in functional capacity – significantly lower in the intervention group (RR: 1.52 95%CI: 1.05–2.21; p = 0.0016) – disappeared at six months (RR: 1.31 95%CI: 0.87–1.98; p = 0.178). At six months, caregiver burden showed a slight reduction in the intervention group, whereas it increased notably in the control group (base-line Zarit Test: 57.06 95%CI: 54.77–59.34 vs. 60.50 95%CI: 53.63–67.37; p = 0.264), (Zarit Test at six months: 53.79 95%CI: 49.67–57.92 vs. 66.26 95%CI: 60.66–71.86 p = 0.002). Patients in the intervention group received more physiotherapy (7.92 CI95%: 5.22–10.62 vs. 3.24 95%CI: 1.37–5.310; p = 0.0001) and, on average, required fewer home care visits (9.40 95%CI: 7.89–10.92 vs.11.30 95%CI: 9.10–14.54). No differences were found in terms of frequency of visits to A&E or hospital re-admissions. Furthermore, patients in the control group perceived higher levels of satisfaction (16.88; 95%CI: 16.32–17.43; range: 0–21, vs. 14.65 95%CI: 13.61–15.68; p = 0,001). Conclusion A home care service model that includes nurse-led case management streamlines access to healthcare services and resources, while impacting positively on patients' functional ability and caregiver burden, with increased levels of satisfaction.

Effectiveness and safety of isoniazid chemoprophylaxis for HIV-1 infected patients from Rio de Janeiro

The clinical and epidemiological characteristics, adverse events, treatment adherence and effectiveness of isoniazid chemoprophylaxis were analyzed in a cohort of 138 tuberculosis/HIV-coinfected patients. An open, non-randomized, pragmatic prophylactic trial was conducted on adult patients with a normal chest X-ray and positive tuberculin skin test (> 5 mm) who received isoniazid chemoprophylaxis (300 mg/day) for six months. The mean of follow up was 2.8 years (SD 1.3). Adherence to chemoprophylaxis was 87.7% (121/138). Only one patient presented tuberculosis after the end of chemoprophylaxis, corresponding to 0.3 cases per 100 persons per year. The relative risk of some adverse effects was 4.6 times higher (95% CI: 1.9-11.5) in patients with positive anti-HCV serology (4/9, 44.4%) compared to those with negative serology (12/129, 9.6%) (p = 0.002). This study provides evidence regarding the effectiveness and safety of a short and self-administered isoniazid regimen. We recommend the implementation of this routine by health service practitioners.

Disparate activation of the coronary sinus and inferior left atrium during atrial tachycardia after persistent atrial fibrillation ablation: prevalence, pitfalls, and impact on mapping.

INTRODUCTION: Persistent atrial fibrillation (AF) ablation may lead to partial disconnection of the coronary sinus (CS). As a result, disparate activation sequences of the local CS versus contiguous left atrium (LA) may be observed during atrial tachycardia (AT). We aimed to evaluate the prevalence of this phenomenon and its impact on activation mapping. METHODS: AT occurring after persistent AF ablation were investigated in 74 consecutive patients. Partial CS disconnection during AT was suspected when double potentials with disparate activation sequences were observed on the CS catheter. Endocardial mapping facing CS bipoles was performed to differentiate LA far-field from local CS potentials. RESULTS: A total of 149 ATs were observed. Disparate LA-CS activations were apparent in 20 ATs after magnifying the recording scale (13%). The most common pattern (90%) was distal to proximal endocardial LA activation against proximal to distal CS activation, the latter involving the whole CS or its distal part. Perimitral macroreentry was more common when disparate LA-CS activations were observed (67% vs 29%; P = 0.002). Partial CS disconnection also resulted in "pseudo" mitral isthmus (MI) block during LA appendage pacing in 20% of patients as local CS activation was proximal to distal despite distal to proximal activation of the contiguous LA. CONCLUSION: Careful analysis of CS recordings during AT following persistent AF ablation often reveals disparate patterns of activation. Recognizing when endocardial LA activation occurs in the opposite direction to the more obvious local CS signals is critical to avoid misleading interpretations during mapping of AT and evaluation of MI block.

Central corneal thickness, intraocular pressure, and degree of myopia in an adult myopic population aged 20 to 40 years in southeast Spain: determination and relationships

Objective: To determine the values of, and study the relationships among, central corneal thickness (CCT), intraocular pressure (IOP), and degree of myopia (DM) in an adult myopic population aged 20 to 40 years in Almeria (southeast Spain). To our knowledge this is first study of this kind in this region. Methods: An observational, descriptive, cross-sectional study was done in which a sample of 310 myopic patients (620 eyes) aged 20 to 40 years was selected by gender- and age-stratified sampling, which was proportionally fixed to the size of the population strata for which a 20% prevalence of myopia, 5% epsilon, and a 95% confidence interval were hypothesized. We studied IOP, CCT, and DM and their relationships by calculating the mean, standard deviation, 95% confidence interval for the mean, median, Fisher’s asymmetry coefficient, range (maximum, minimum), and the Brown-Forsythe’s robust test for each variable (IOP, CCT, and DM). Results: In the adult myopic population of Almeria aged 20 to 40 years (mean of 29.8), the mean overall CCT was 550.12 μm. The corneas of men were thicker than those of women (P = 0.014). CCT was stable as no significant differences were seen in the 20- to 40-year-old subjects’ CCT values. The mean overall IOP was 13.60 mmHg. Men had a higher IOP than women (P = 0.002). Subjects over 30 years (13.83) had a higher IOP than those under 30 (13.38) (P = 0.04). The mean overall DM was −4.18 diopters. Men had less myopia than women (P < 0.001). Myopia was stable in the 20- to 40-year-old study population (P = 0.089). A linear relationship was found between CCT and IOP (R2 = 0.152, P ≤ 0.001). CCT influenced the IOP value by 15.2%. However no linear relationship between DM and IOP, or between CCT and DM, was found. Conclusions: CCT was found to be similar to that reported in other studies in different populations. IOP tends to increase after the age of 30 and is not accounted for by alterations in CCT values.

Bulky DNA adducts, 4-aminobiphenyl-haemoglobin adducts and diet in the European Prospective Investigation into Cancer and Nutrition (EPIC) prospective study

In contrast to some extensively examined food mutagens, for example, aflatoxins, N-nitrosamines and heterocyclic amines, some other food contaminants, in particular polycyclic aromatic hydrocarbons (PAH) and other aromatic compounds, have received less attention. Therefore, exploring the relationships between dietary habits and the levels of biomarkers related to exposure to aromatic compounds is highly relevant. We have investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort the association between dietary items (food groups and nutrients) and aromatic DNA adducts and 4-aminobiphenyl-Hb adducts. Both types of adducts are biomarkers of carcinogen exposure and possibly of cancer risk, and were measured, respectively, in leucocytes and erythrocytes of 1086 (DNA adducts) and 190 (Hb adducts) non-smokers. An inverse, statistically significant, association has been found between DNA adduct levels and dietary fibre intake (P = 0·02), vitamin E (P = 0·04) and alcohol (P = 0·03) but not with other nutrients or food groups. Also, an inverse association between fibre and fruit intake, and BMI and 4-aminobiphenyl-Hb adducts (P = 0·03, 0·04, and 0·03 respectively) was observed. After multivariate regression analysis these inverse correlations remained statistically significant, except for the correlation adducts v. fruit intake. The present study suggests that fibre intake in the usual range can modify the level of DNA or Hb aromatic adducts, but such role seems to be quantitatively modest. Fibres could reduce the formation of DNA adducts in different manners, by diluting potential food mutagens and carcinogens in the gastrointestinal tract, by speeding their transit through the colon and by binding carcinogenic substances.

Three-year multicenter surveillance of community-acquired Listeria monocytogenes meningitis in adults

BACKGROUND. Listeria monocytogenes is the third most frequent cause of bacterial meningitis. The aim of this study is to know the incidence and risk factors associated with development of acute community-acquired Lm meningitis in adult patients and to evaluate the clinical features, management, and outcome in this prospective case series. METHODS. A descriptive, prospective, and multicentric study carried out in 9 hospitals in the Spanish Network for Research in Infectious Diseases (REIPI) over a 39-month period. All adults patients admitted to the participating hospitals with the diagnosis of acute community-acquired bacterial meningitis (Ac-ABM) were included in this study. All these cases were diagnosed on the basis of a compatible clinical picture and a positive cerebrospinal fluid (CSF) culture or blood culture. The patients were followed up until death or discharge from hospital. RESULTS. Two hundred and seventy-eight patients with Ac-ABM were included. Forty-six episodes of Lm meningitis were identified in 46 adult patients. In the multivariate analysis only age (OR 1.026; 95% CI 1.00-1.05; p = 0.042), immunosuppression (OR 2.520; 95% CI 1.05-6.00; p = 0.037), and CSF/blood glucose ratio (OR 39.42; 95% CI 4.01-387.50; p = 0.002) were independently associated with a Lm meningitis. The classic triad of fever, neck stiffness and altered mental status was present in 21 (49%) patients, 32% had focal neurological findings at presentation, 12% presented cerebellum dysfunction, and 9% had seizures. Twenty-nine (68%) patients were immunocompromised. Empirical antimicrobial therapy was intravenous ampicillin for 34 (79%) of 43 patients, in 11 (32%) of them associated to aminoglycosides. Definitive ampicillin plus gentamicin therapy was significantly associated with unfavourable outcome (67% vs 28%; p = 0.024) and a higher mortality (67% vs 32%; p = 0.040).The mortality rate was 28% (12 of 43 patients) and 5 of 31 (16.1%) surviving patients developed adverse clinical outcome. CONCLUSIONS Elderly or immunocompromised patients, and a higher CSF/blood glucose ratio in patients with Ac-ABM must alert clinicians about Lm aetiology. Furthermore, we observed a high incidence of acute community-acquired Lm meningitis in adults and the addition of aminoglycosides to treatment should be avoid in order to improve the patients' outcome. Nevertheless, despite developments in intensive care and antimicrobial therapy, this entity is still a serious disease that carries high morbidity and mortality rates.

CD40: Novel Association with Crohn's Disease and Replication in Multiple Sclerosis Susceptibility

Background: A functional polymorphism located at 21 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves’ disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves’ disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn’s disease (CD) lesions. Methodology: Genotyping of rs1883832C.T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry. Principal Findings: The observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p= 0.025; OR (95% CI)= 1.12 (1.01–1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p= 0.002; OR (95% CI)= 1.19 (1.06–1.33)]. This increased predisposition was not detected in UC patients [p= 0.5; OR (95% CI)= 1.04 (0.93–1.17)]. Conclusion: The impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions

Clinical presentation and time-course of postoperative venous thromboembolism: Results from the RIETE Registry

There is little literature about the clinical presentation and time-course of postoperative venous thromboembolism (VTE) in different surgical procedures. RIETE is an ongoing, prospective registry of consecutive patients with objectively confirmed, symptomatic acute VTE. In this analysis, we analysed the baseline characteristics, thromboprophylaxis and therapeutic patterns, time-course, and three-month outcome of all patients with postoperative VTE. As of January 2006, there were 1,602 patients with postoperative VTE in RIETE: 393 (25%) after major orthopaedic surgery (145 elective hip arthroplasty, 126 knee arthroplasty, 122 hip fracture); 207 (13%) after cancer surgery; 1,002 (63%) after other procedures. The percentage of patients presenting with clinically overt pulmonary embolism (PE) (48%, 48%, and 50% respectively), the average time elapsed from surgery to VTE (22 +/- 16, 24 +/- 16, and 21 +/- 15 days, respectively), and the three-month incidence of fatal PE (1.3%, 1.4%, and 0.8%, respectively), fatal bleeding (0.8%, 1.0%, and 0.2%, respectively), or major bleeding (2.3%, 2.9%, and 2.8%, respectively) were similar in the three groups. However, the percentage of patients who had received thromboprophylaxis (96%, 76% and 52%, respectively), the duration of prophylaxis (17 +/- 9.6, 13 +/- 8.9, and 12 +/- 11 days, respectively) and the mean daily doses of low-molecular-weight heparin (4,252 +/- 1,016, 3,260 +/- 1,141, and 3,769 +/- 1,650 IU, respectively), were significantly lower in those undergoing cancer surgery or other procedures. In conclusion, the clinical presentation, time-course, and three-month outcome of VTE was similar among the different subgroups of patients, but the use of prophylaxis in patients undergoing cancer surgery or other procedures was suboptimal.