Endometrial cancer and oral contraceptives : an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies.

BACKGROUND: Oral contraceptives are known to reduce the incidence rate of endometrial cancer, but it is uncertain how long this effect lasts after use ceases, or whether it is modified by other factors. METHODS: Individual participant datasets were sought from principal investigators and provided centrally for 27 276 women with endometrial cancer (cases) and 115 743 without endometrial cancer (controls) from 36 epidemiological studies. The relative risks (RRs) of endometrial cancer associated with oral contraceptive use were estimated using logistic regression, stratified by study, age, parity, body-mass index, smoking, and use of menopausal hormone therapy. FINDINGS: The median age of cases was 63 years (IQR 57-68) and the median year of cancer diagnosis was 2001 (IQR 1994-2005). 9459 (35%) of 27 276 cases and 45 625 (39%) of 115 743 controls had ever used oral contraceptives, for median durations of 3·0 years (IQR 1-7) and 4·4 years (IQR 2-9), respectively. The longer that women had used oral contraceptives, the greater the reduction in risk of endometrial cancer; every 5 years of use was associated with a risk ratio of 0·76 (95% CI 0·73-0·78; p<0·0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased, with no apparent decrease between the RRs for use during the 1960s, 1970s, and 1980s, despite higher oestrogen doses in pills used in the early years. However, the reduction in risk associated with ever having used oral contraceptives differed by tumour type, being stronger for carcinomas (RR 0·69, 95% CI 0·66-0·71) than sarcomas (0·83, 0·67-1·04; case-case comparison: p=0·02). In high-income countries, 10 years use of oral contraceptives was estimated to reduce the absolute risk of endometrial cancer arising before age 75 years from 2·3 to 1·3 per 100 women. INTERPRETATION: Use of oral contraceptives confers long-term protection against endometrial cancer. These results suggest that, in developed countries, about 400 000 cases of endometrial cancer before the age of 75 years have been prevented over the past 50 years (1965-2014) by oral contraceptives, including 200 000 in the past decade (2005-14). FUNDING: Medical Research Council, Cancer Research UK.

Epidemiology of multiple congenital anomalies in Europe: a EUROCAT population-based registry study.

BACKGROUND: This study describes the prevalence, associated anomalies, and demographic characteristics of cases of multiple congenital anomalies (MCA) in 19 population-based European registries (EUROCAT) covering 959,446 births in 2004 and 2010. METHODS: EUROCAT implemented a computer algorithm for classification of congenital anomaly cases followed by manual review of potential MCA cases by geneticists. MCA cases are defined as cases with two or more major anomalies of different organ systems, excluding sequences, chromosomal and monogenic syndromes. RESULTS: The combination of an epidemiological and clinical approach for classification of cases has improved the quality and accuracy of the MCA data. Total prevalence of MCA cases was 15.8 per 10,000 births. Fetal deaths and termination of pregnancy were significantly more frequent in MCA cases compared with isolated cases (p < 0.001) and MCA cases were more frequently prenatally diagnosed (p < 0.001). Live born infants with MCA were more often born preterm (p < 0.01) and with birth weight < 2500 grams (p < 0.01). Respiratory and ear, face, and neck anomalies were the most likely to occur with other anomalies (34% and 32%) and congenital heart defects and limb anomalies were the least likely to occur with other anomalies (13%) (p < 0.01). However, due to their high prevalence, congenital heart defects were present in half of all MCA cases. Among males with MCA, the frequency of genital anomalies was significantly greater than the frequency of genital anomalies among females with MCA (p < 0.001). CONCLUSION: Although rare, MCA cases are an important public health issue, because of their severity. The EUROCAT database of MCA cases will allow future investigation on the epidemiology of these conditions and related clinical and diagnostic problems.

GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins secreted in response to oral glucose ingestion by intestinal L and K cells, respectively. The molecular mechanisms responsible for intestinal cell glucose sensing are unknown but could be related to those described for beta-cells, brain and hepatoportal sensors. We determined the role of GLUT2, GLP-1 or GIP receptors in glucose-induced incretins secretion, in the corresponding knockout mice. GLP-1 secretion was reduced in all mutant mice, while GIP secretion did not require GLUT2. Intestinal GLP-1 content was reduced only in GIP and GLUT2 receptors knockout mice suggesting that this impairment could contribute to the phenotype. Intestinal GIP content was similar in all mice studied. Furthermore, the impaired incretins secretion was associated with a reduced glucose-stimulated insulin secretion and an impaired glucose tolerance in all mice. In conclusion, both incretins secretion depends on mechanisms involving their own receptors and GLP-1 further requires GLUT2.

Télésurveillance des insuffisants cardiaques: de nouvelles technologies pour améliorer le suivi?: revue Cochrane pour le praticien

Cet article présente les résultats de la revue systématique: Inglis SC, Clark RA, McAlister FA, et al. Structured telephone support or telemonitoring programmes for patients with chronic heart failure. Cochrane Database Systematic Reviews 2010, Issue 8. Art. No.:CD007228. DOI:10.1002/14651858.CD007228.pub2. PMID: 20687083

Predicting positive food challenges in children sensitised to peanuts/tree nuts.

BACKGROUND: Children with atopic diseases in early life are frequently found with positive IgE tests to peanuts/tree nuts without a history of previous ingestion. We aimed to identify risk factors for reactions to nuts at first introduction. METHODS: A retrospective case-note and database analysis was performed. Recruitment criteria were: patients aged 3-16 yr who had a standardized food challenge to peanut and/or tree nuts due to sensitisation to the peanut/tree nut (positive spIgE or SPT) without previous consumption. A detailed assessment was performed of factors relating to food challenge outcome with univariate and multivariate logistic regression analysis. RESULTS: There were 98 food challenges (47 peanut, 51 tree nut) with 29 positive, 67 negative and 2 inconclusive outcomes. A positive maternal history of allergy and a specific IgE >5 kU/l were strongly associated with a significantly increased risk of a positive food challenge (OR 3.73; 95% CI 1.31-10.59; p = 0.013 and OR 3.35; 95% CI 1.23-9.11; p = 0.007, respectively). Adjusting for age, a three year-old with these criteria has a 67% probability of a positive challenge. There was no significant association between types of peanut/tree nut, other food allergies, atopic conditions or severity of previous food reactions and positive challenges. CONCLUSIONS: We have demonstrated an association between the presence of maternal atopic history and a specific IgE >5 kU/l, with a significant increase in the likelihood of a positive food challenge. Although requiring further prospective validation these easily identifiable components should be considered when deciding the need for a challenge.

The newly defined "Greenstone Unit'' of the Aiguilles Rouges massif (western Alps): remnant of an Early Palaeozoic oceanic island-arc ?

In the southwestern part of the Aiguilles Rouges massif (pre-Alpine basement of the Helvetic realm, western Alps), a metavolcanic sequence, newly defined as the ``Greenstone Unit'',is exposed in two NS trending belts of several 100 metres in thickness. It consists of epidote amphibolites, partly epidote and/or calcic amphibole-bearing greenschists, and small amounts of alkali feldspar-bearing greenschists, which underwent low- to medium-grade metamorphism during Visean oblique collision. Metamorphic calcic amphiboles and epidotes show strong chemical zoning, whereas metamorphic plagioclase is exclusively albitic in composition (An 1-3). The SiO2 content of the subalkaline tholeiitic to calc-alkaline suite ranges continuously from 44 wt% to 73 wt%,but andesitic rocks predominate. The majority of samples have chemical compositions close to recent subduction-related lavas; some are even restricted to recent oceanic arcs (extremely low Ta and Nb contents, high La/Nb and Th/Ta ratios). But several basaltic to basalto-andesitic samples resemble continental tholeiites (low Th/Ta, La/Nb ratio). As it is very probable that both lava types are to some extent contemporaneous, it is proposed that the Greenstone Unit represents a former oceanic volcanic are which temporarily underwent extension during which emplacement of continental tholeiite-like rocks occurred. The cause of the extension remains ambiguous. Considering palaeotectonic significance and age of other metavolcanic units in the Aiguilles Rouges massif, the Greenstone Unit most likely formed in the Early Palaeozoic.

Older persons' perceptions of general practitioner or specialist primary care physicians : same point of view?

BACKGROUND: Identification of a Primary Care Physician (PCP) by older patients is considered as essential for the coordination of care, but the extent to which identified PCPs are general practitioners or specialists is unknown. This study described older patients' experiences with their PCP and tested the hypothesis of differences between patients who identify a specialist as their PCP (SP PCP) and those who turn to a general practitioner (GP PCP). METHODS: In 2012, a cross-sectional postal survey on care was conducted in the 68+ year old population of the canton of Vaud. Data was provided by 2,276 participants in the ongoing Lausanne cohort 65+ (Lc65+), a study of those born between 1934 and 1943, and by 998 persons from an additional sample drawn to include the population outside of Lausanne or born before 1934. RESULTS: Participants expressed favourable perceptions, at rates exceeding 75% for most items. However, only 38% to 51% responded positively for out-of-hours availability, easy access and at home visits, likelihood of prescribing expensive medication if needed, and doctors' awareness of over-the-counter drugs. 12.0% had an SP PCP, in 95.9% specialised in a discipline implying training in internal medicine. Bivariate and multivariate analyses did not result in significant differences between GP and SP PCPs regarding perceptions of accessibility/availability, doctor-patient relationship, information and continuity of care, prevention, spontaneous use of the emergency department or ambulatory care utilisation. CONCLUSIONS: Experiences of old patients were mostly positive despite some lack in reported hearing, memory testing, and colorectal cancer screening. We found no differences between GP and SP PCP groups.

Personality traits and behavioral and psychological symptoms in patients at an early stage of Alzheimer's disease.

OBJECTIVE: The origins of behavioral and psychological symptoms (BPS) in Alzheimer's disease (AD) are still poorly understood. Focusing on individual personality structure, we explored the relationship between premorbid personality and its changes over 5 years, and BPS in patients at an early stage of AD. METHOD: A total of 54 patients at an early stage of AD according to ICD-10 and NINCDS-ADRDA criteria and 64 control subjects were included. Family members filled in the Neuropsychiatric Inventory Questionnaire to evaluate their proxies' current BPS and the NEO Personality Inventory Revised twice, the first time to evaluate the participants' current personality and the second time to assess personality traits as they were remembered to be 5 years earlier. RESULTS: Behavioral and psychological symptoms, in particular apathy, depression, anxiety, and agitation, are frequent occurrences in early stage AD. Premorbid personality differed between AD patients and normal control, but it was not predictive of BPS in patients with AD. Personality traits clearly change in the course of beginning AD, and this change seems to develop in parallel with BPS as early signs of AD. CONCLUSIONS: Premorbid personality was not associated with BPS in early stage of AD, although complex and non-linear relationships between the two are not excluded. However, both personality and behavioral changes occur early in the course of AD, and recognizing them as possible, early warning signs of neurodegeneration may prove to be a key factor for early detection and intervention. Copyright © 2012 John Wiley & Sons, Ltd.

A robust genomic signature for the detection of colorectal cancer patients with microsatellite instability phenotype and high mutation frequency.

Microsatellite instability (MSI) occurs in 10-20% of colorectal tumours and is associated with good prognosis. Here we describe the development and validation of a genomic signature that identifies colorectal cancer patients with MSI caused by DNA mismatch repair deficiency with high accuracy. Microsatellite status for 276 stage II and III colorectal tumours has been determined. Full-genome expression data was used to identify genes that correlate with MSI status. A subset of these samples (n = 73) had sequencing data for 615 genes available. An MSI gene signature of 64 genes was developed and validated in two independent validation sets: the first consisting of frozen samples from 132 stage II patients; and the second consisting of FFPE samples from the PETACC-3 trial (n = 625). The 64-gene MSI signature identified MSI patients in the first validation set with a sensitivity of 90.3% and an overall accuracy of 84.8%, with an AUC of 0.942 (95% CI, 0.888-0.975). In the second validation, the signature also showed excellent performance, with a sensitivity 94.3% and an overall accuracy of 90.6%, with an AUC of 0.965 (95% CI, 0.943-0.988). Besides correct identification of MSI patients, the gene signature identified a group of MSI-like patients that were MSS by standard assessment but MSI by signature assessment. The MSI-signature could be linked to a deficient MMR phenotype, as both MSI and MSI-like patients showed a high mutation frequency (8.2% and 6.4% of 615 genes assayed, respectively) as compared to patients classified as MSS (1.6% mutation frequency). The MSI signature showed prognostic power in stage II patients (n = 215) with a hazard ratio of 0.252 (p = 0.0145). Patients with an MSI-like phenotype had also an improved survival when compared to MSS patients. The MSI signature was translated to a diagnostic microarray and technically and clinically validated in FFPE and frozen samples.

Bihippocampal damage with emotional dysfunction: impaired auditory recognition of fear.

A right-handed man developed a sudden transient, amnestic syndrome associated with bilateral hemorrhage of the hippocampi, probably due to Urbach-Wiethe disease. In the 3rd month, despite significant hippocampal structural damage on imaging, only a milder degree of retrograde and anterograde amnesia persisted on detailed neuropsychological examination. On systematic testing of recognition of facial and vocal expression of emotion, we found an impairment of the vocal perception of fear, but not that of other emotions, such as joy, sadness and anger. Such selective impairment of fear perception was not present in the recognition of facial expression of emotion. Thus emotional perception varies according to the different aspects of emotions and the different modality of presentation (faces versus voices). This is consistent with the idea that there may be multiple emotion systems. The study of emotional perception in this unique case of bilateral involvement of hippocampus suggests that this structure may play a critical role in the recognition of fear in vocal expression, possibly dissociated from that of other emotions and from that of fear in facial expression. In regard of recent data suggesting that the amygdala is playing a role in the recognition of fear in the auditory as well as in the visual modality this could suggest that the hippocampus may be part of the auditory pathway of fear recognition.

Prognostic importance of anaemia in patients with acute pulmonary embolism.

Although associated with adverse outcomes in other cardiopulmonary diseases, limited evidence exists on the prognostic value of anaemia in patients with acute pulmonary embolism (PE). We sought to examine the associations between anaemia and mortality and length of hospital stay in patients with PE. We evaluated 14,276 patients with a primary diagnosis of PE from 186 hospitals in Pennsylvania, USA. We used random-intercept logistic regression to assess the association between anaemia at the time of presentation and 30-day mortality and discrete-time logistic hazard models to assess the association between anaemia and time to hospital discharge, adjusting for patient (age, gender, race, insurance type, clinical and laboratory variables) and hospital (region, size, teaching status) factors. Anaemia was present in 38.7% of patients at admission. Patients with anaemia had a higher 30-day mortality (13.7% vs. 6.3%; p <0.001) and a longer length of stay (geometric mean, 6.9 vs. 6.6 days; p <0.001) compared to patients without anaemia. In multivariable analyses, anaemia remained associated with an increased odds of death (OR 1.82, 95% CI: 1.60-2.06) and a decreased odds of discharge (OR 0.85, 95% CI: 0.82-0.89). Anaemia is very common in patients presenting with PE and is independently associated with an increased short-term mortality and length of stay.

Interaction between calcium intake and menarcheal age on bone mass gain: an eight-year follow-up study from prepuberty to postmenarche.

Both late menarcheal age and low calcium intake (Ca intake) during growth are risk factors for osteoporosis, probably by impairing peak bone mass. We investigated whether lasting gain in areal bone mineral density (aBMD) in response to increased Ca intake varies according to menarcheal age and, conversely, whether Ca intake could influence menarcheal age. In an initial study, 144 prepubertal girls were randomized in a double-blind controlled trial to receive either a Ca supplement (Ca-suppl.) of 850 mg/d or placebo from age 7.9-8.9 yr. Mean aBMD gain determined by dual energy x-ray absorptiometry at six sites (radius metaphysis, radius diaphysis, femoral neck, trochanter, femoral diaphysis, and L2-L4) was significantly (P = 0.004) greater in the Ca-suppl. than in the placebo group (27 vs. 21 mg/cm(2)). In 122 girls followed up, menarcheal age was recorded, and aBMD was determined at 16.4 yr of age. Menarcheal age was lower in the Ca-suppl. than in the placebo group (P = 0.048). Menarcheal age and Ca intake were negatively correlated (r = -0.35; P < 0.001), as were aBMD gains from age 7.9-16.4 yr and menarcheal age at all skeletal sites (range: r = -0.41 to r = -0.22; P < 0.001 to P = 0.016). The positive effect of Ca-suppl. on the mean aBMD gain from baseline remained significantly greater in girls below, but not in those above, the median of menarcheal age (13.0 yr). Early menarcheal age (12.1 +/- 0.5 yr): placebo, 286 +/- 36 mg/cm(2); Ca-suppl., 317 +/- 46 (P = 0.009); late menarcheal age (13.9 +/- 0.5 yr): placebo, 284 +/- 58; Ca-suppl., 276 +/- 50 (P > 0.05). The level of Ca intake during prepuberty may influence the timing of menarche, which, in turn, could influence long-term bone mass gain in response to Ca supplementation. Thus, both determinants of early menarcheal age and high Ca intake may positively interact on bone mineral mass accrual.