Progression of left atrial volume index in a population at risk for heart failure:a substudy of the STOP-HF (St Vincent's Screening TO Prevent Heart Failure) trial

AIMS: Limited data are available concerning the evolution of the left atrial volume index (LAVI) in pre-heart failure (HF) patients. The aim of this study was to investigate clinical characteristics and serological biomarkers in a cohort with risk factors for HF and evidence of serial atrial dilatation.

METHODS AND RESULTS: This was a prospective substudy within the framework of the STOP-HF cohort (NCT00921960) involving 518 patients with risk factors for HF electively undergoing serial clinical, echocardiographic, and natriuretic peptide assessment. Mean follow-up time between assessments was 15 ± 6 months. 'Progressors' (n = 39) were defined as those with serial LAVI change ≥3.5 mL/m(2) (and baseline LAVI between 20 and 34 mL/m(2)). This cut-off was derived from a calculated reference change value above the biological, analytical, and observer variability of serial LAVI measurement. Multivariate analysis identified significant baseline clinical associates of LAVI progression as increased age, beta-blocker usage, and left ventricular mass index (all P < 0.05). Serological biomarkers were measured in a randomly selected subcohort of 30 'Progressors' matched to 30 'Non-progressors'. For 'Progressors', relative changes in matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 1 (TIMP1), and the TIMP1/MMP9 ratio, markers of interstitial remodelling, tracked with changes in LAVI over time (all P < 0.05).

CONCLUSION: Accelerated LAVI increase was found to occur in up to 14% of all pre-HF patients undergoing serial echocardiograms over a relatively short follow-up period. In a randomly selected subcohort of 'Progressors', changes in LAVI were closely linked with alterations in MMP9, TIMP1, and the ratio of these enzymes, a potential aid in highlighting this at-risk group.

Antibody Signatures Reflect Different Disease Pathologies in Patients With Schistosomiasis Due to Schistosoma japonicum

Infection with Schistosoma japonicum causes high levels of pathology that is predominantly determined by the cellular and humoral response of the host. However, the specific antibody response that arises during the development of disease is largely undescribed in Asian schistosomiasis-endemic populations. A schistosome protein microarray was used to compare the antibody profiles of subjects with acute infection, with early or advanced disease associated with severe pathology, with chronic infection, and subjects exposed but stool negative for S. japonicum eggs to the antibody profiles of nonexposed controls. Twenty-five immunodominant antigens were identified, including vaccine candidates, tetraspanin-related proteins, transporter molecules, and unannotated proteins. Additionally, individuals with severe pathology had a limited specific antibody response, suggesting that individuals with mild disease may use a broad and strong antibody response, particularly against surface-exposed proteins, to control pathology and/or infection. Our study has identified specific antigens that can discriminate between S. japonicum-exposed groups with different pathologies and may also allow the host to control disease pathology and provide resistance to parasite infection.

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications.

We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele.

Future trends in cystic fibrosis demography in 34 European countries

Median survival has increased in people with cystic fibrosis (CF) during the past six decades, which has led to an increased number of adults with CF. The future impact of changes in CF demographics has not been evaluated. The aim of this study was to estimate the number of children and adults with CF in 34 European countries by 2025. Data were obtained from the European Cystic Fibrosis Society Patient Registry. Population forecasts were performed for countries that have extensive CF population coverage and at least 4 years of longitudinal data by modelling future entering and exiting flows in registry cohorts. For the other countries, population projections were performed based on assumptions from knowledge of current CF epidemiology. Western European countries' forecasts indicate that an increase in the overall number of CF patients by 2025, by approximately 50%, corresponds to an increase by 20% and by 75% in children and adults, respectively. In Eastern European countries the projections suggest a predominant increase in the CF child population, although the CF adult population would also increase.It was concluded that a large increase in the adult CF population is expected in the next decade. A significant increase in adult CF services throughout Europe is urgently required.

Utilization of analgesics, sedatives, and pain scores in infants with a prolonged hospitlaization: A prospective descriptive cohort study

Aim
Describe the utilization of analgesic and sedative medications and documentation of pain scores in a cohort of critically ill infants in a neonatal intensive care unit.

Method
A prospective, longitudinal, cohort study of infants with a predicted length of stay =28 days. Dosages and routes of administration of analgesic and sedative medications and documentation of pain scores were collected on a daily basis.

Results
55 infants were enrolled into the study. Oral sucrose was administered to all 55 infants, 51 infants (93%) were administered enteral acetaminophen and 50 (91%) infants were administered morphine during their hospitalization. Sedatives were administered to 42 infants (76%); 36 (65%) were administered chloral hydrate and 32 (58%) were administered intravenous midazolam. With the exception of the first week of admission, when there was highest utilization of opioids and lower use of sucrose, acetaminophen and sedatives, the pattern of administration of analgesic and sedative agents remained relatively constant throughout the hospitalization. Pain scores were documented for 36 (65%) infants during their hospitalisation, however for these 36 infants, pain scores were infrequently recorded.

Conclusion
There was substantial and varied analgesic and sedative use in this cohort of infants, yet infrequent documentation of pain assessment scores. These practices highlight important clinical implications for sick infants requiring careful consideration of pain and distress management.

Maternal age at birth and childhood type 1 diabetes: a pooled analysis of 30 observational studies

OBJECTIVE - The aim if the study was to investigate whether children born to older mothers have an increased risk of type 1 diabetes by performing a pooled analysis of previous studies using individual patient data to adjust for recognized confounders.
RESEARCH DESIGN AND METHODS - Relevant studies published before June 2009 were identified from MEDLINE, Web of Science, and EMBASE. Authors of studies were contacted and asked to provide individual patient data or conduct prespecified analyses. Risk estimates of type 1 diabetes by maternal age were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were used to derive combined odds ratios and to investigate heterogeneity among studies.
RESULTS - Data were available for 5 cohort and 25 case-control studies, including 14,724 cases of type 1 diabetes. Overall, there was, on average, a 5% (95% CI 2-9) increase in childhood type 1 diabetes odds per 5-year increase in maternal age (P = 0.006), but there was heterogeneity among studies (heterogeneity I 2 = 70%). In studies with a low risk of bias, there was a more marked increase in diabetes odds of 10% per 5-year increase in maternal age. Adjustments for potential confounders little altered these estimates. CONCLUSIONS - There was evidence of a weak but significant linear increase in the risk of childhood type 1 diabetes across the range of maternal ages, but the magnitude of association varied between studies. A very small percentage of the increase in the incidence of childhood type 1 diabetes in recent years could be explained by increases in maternal age.

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data

Aims/hypothesis: We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes. Methods: Relevant studies published before February 2009 were identified from literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies. Results: Data were available for 29 predominantly European studies (five cohort, 24 case-control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 [95% CI 1.01-1.11]; p=0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 [95% CI 1.04-1.19]; p=0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 [95% CI 1.00-1.06]; p=0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings. Conclusions/interpretation: Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes. © 2010 Springer-Verlag.


--------------------------------------------------------------------------------

Reaxys Database Information|

--------------------------------------------------------------------------------

The genetics of coronary heart disease: The contribution of twin studies

Despite the decline in coronary heart disease in many European countries, the disease remains an enormous public health problem. Although we know a great deal about environmental risk factors for coronary heart disease, a heritable component was recognized a long time ago. The earliest and best known examples of how our genetic constitution may determine cardiovascular risk relate to lipoprotein(a), familial hypercholesterolaemia and apolipoprotein E. In the past 20 years a fair number of polymorphisms assessed singly have shown strong associations with the disease but most are subject to poor repeatability. Twins constitute a compelling natural experiment to establish the genetic contribution to coronary heart disease and its risk factors. GenomEUtwin, a recently funded Framework 5 Programme of the European Community, affords the opportunity of comparing the heritability of risk factors in different European Twin Registries. As an illustration we present the heritabilities of systolic and diastolic blood pressure, based on data from over 4000 twin pairs from six different European countries and Australia. Heritabilities for systolic blood pressure are between 52 and 66% and for diastolic blood pressure between 44 and 66%. There is no evidence of sex differences in heritability estimates and very little to no evidence for a significant contribution of shared family environment. A non-twin based prospective case/cohort study of coronary heart disease and stroke (MORGAM) will allow hypotheses relating to cardiovascular disease, generated in the twin cohorts, to be tested prospectively in adult populations. Twin studies have also contributed to our understanding of the life course hypothesis, and GenomEUtwin has the potential to add to this.

Birth order and childhood type 1 diabetes risk: A pooled analysis of 31 observational studies

Background: The incidence rates of childhood onset type 1 diabetes are almost universally increasing across the globe but the aetiology of the disease remains largely unknown. We investigated whether birth order is associated with the risk of childhood diabetes by performing a pooled analysis of previous studies. Methods: Relevant studies published before January 2010 were identified from MEDLINE, Web of Science and EMBASE. Authors of studies provided individual patient data or conducted pre-specified analyses. Meta-analysis techniques were used to derive combined odds ratios (ORs), before and after adjustment for confounders, and investigate heterogeneity. Results: Data were available for 6 cohort and 25 case-control studies, including 11 955 cases of type 1 diabetes. Overall, there was no evidence of an association prior to adjustment for confounders. After adjustment for maternal age at birth and other confounders, a reduction in the risk of diabetes in second-or later born children became apparent [fully adjusted OR=0.90 95% confidence interval (CI) 0.83-0.98; P=0.02] but this association varied markedly between studies (I 2=67%). An a priori subgroup analysis showed that the association was stronger and more consistent in children <5years of age (n=25 studies, maternal age adjusted OR=0.84 95% CI 0.75, 0.93; I 2=23%). Conclusion: Although the association varied between studies, there was some evidence of a lower risk of childhood onset type 1 diabetes with increasing birth order, particularly in children aged <5 years. This finding could reflect increased exposure to infections in early life in later born children. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2010; all rights reserved.

Levels of Neonatal Thyroid Hormone in Preterm Infants and Neurodevelopmental Outcome at 51/2 Years: Millennium Cohort Study

Context: Transient hypothyroxinemia is the commonest thyroid dysfunction of premature infants, and recent studies have found adverse associations with neurodevelopment. The validity of these associations is unclear because the studies adjusted for a differing range of factors likely to influence neurodevelopment. Objective: The aim was to describe the association of transient hypothyroxinemia with neurodevelopment at 5.5 yr corrected age. Design: We conducted a follow-up study of a cohort of infants born in Scotland from 1999 to 2001 =34 wk gestation. Main Outcome Measures: We measured scores on the McCarthy scale adjusted for 26 influences of neurodevelopment including parental intellect, home environment, breast or formula fed, growth retardation, and use of postnatal drugs. Results: A total of 442 infants =34 wk gestation who had serum T4 measurements on postnatal d 7, 14, or 28 and 100 term infants who had serum T4 measured in cord blood were followed up at 5.5 yr. Infants with hypothyroxinemia (T4 level = 10th percentile on d 7, 14, or 28 corrected for gestational age) scored significantly lower than euthyroid infants (T4 level greater than the 10th percentile and less than the 90th percentile on all days) on all McCarthy scales, except the quantitative. After adjustment for confounders of neurodevelopment, hypothyroxinemic infants scored significantly lower than euthyroid infants on the general cognitive and verbal scales. Conclusions: Our findings do not support the view that the hypothyroxinemic state, in the context of this analysis, is harmless in preterm infants. Many factors contribute both to the etiology of hypothyroxinemia and neurodevelopment; strategies for correction of hypothyroxinemia should acknowledge its complex etiology and not rely solely on one approach.

Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria:an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort

Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes mellitus. Long-term outcomes after the development of microalbuminuria are variable.

Nuclear magnetic resonance-determined lipoprotein subclass profile in the DCCT/EDIC cohort:associations with carotid intima-media thickness

To relate nuclear magnetic resonance lipoprotein subclass profiles (NMR-LSP) and other lipoprotein-related factors with carotid intima-media thickness (IMT) in Type 1 diabetes.

Dietary Carbohydrate Intake, Glycemic Index, and Glycemic Load and Endometrial Cancer Risk: A Prospective Cohort Study

Endometrial cancer risk has been directly associated with glycemic load. However, few studies have investigated this link, and the etiological role of specific dietary carbohydrate components remains unclear. Our aim was to investigate associations of carbohydrate intake, glycemic index, and glycemic load with endometrial cancer risk in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Recruitment took place in 1993-2001. Over a median of 9.0 years of follow-up through 2009, 386 women developed endometrial cancer among 36,115 considered in the analysis. Dietary intakes were assessed using a 124-item diet history questionnaire. Cox proportional hazards models were applied to calculate hazard ratios and 95% confidence intervals. Significant inverse associations were detected between endometrial cancer risk and total available carbohydrate intake (hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.49, 0.90), total sugars intake (HR = 0.71, 95% CI: 0.52, 0.96), and glycemic load (HR = 0.63, 95% CI: 0.46, 0.84) when women in the highest quartile of intake were compared with those in the lowest. These inverse associations were strongest among overweight and obese women. No associations with endometrial cancer risk were observed for glycemic index or dietary fiber. Our findings contrast with previous evidence and suggest that high carbohydrate intakes and glycemic loads are protective against endometrial cancer development. Further clarification of these associations is warranted.

Incidence of colorectal cancer in a population-based cohort of patients with Barrett's oesophagus

Objective. Previous studies have shown a positive association between colorectal cancer and Barrett's oesophagus, but this association is disputed. No population-based studies have examined the incidence of this cancer in patients with Barrett's oesophagus. Material and methods. The present study comprised a population-based cohort of patients with Barrett's oesophagus (constructed using pathology reports of all oesophageal biopsies in Northern Ireland 1993-99; cohort subclassified according to whether specialized intestinal metaplasia (SIM) was present, absent, or not commented on in biopsies). Cases of colorectal cancer were identified by linking with the Northern Ireland Cancer Registry. The comparison group used was the general population in Northern Ireland. Results. A total of 2969 patients with Barrett's oesophagus were followed for a total of 14,014 person-years (mean 4.7 years). SIM was present in 1670 patients (56.2%), absent in 545 (18.4%) and not commented on in 754 (25.4%). Colorectal cancer was diagnosed in 39 patients; 22 patients had cancer diagnosed at least 6 months after diagnosis of Barrett's oesophagus. There was no increased risk of colorectal cancer: the standardized incidence ratio (SIR) for cancer diagnosed at least 6 months after entry into the cohort was 0.82 (95% CI, 0.48-1.17); this risk did not alter with SIM status or gender. To assess a possible effect of diagnostic bias, we calculated SIRs for cancers occurring after at least 3 months, after at least 1 month and at any time after diagnosis of Barrett's oesophagus. These were 0.94 (0.57-1.30), 1.09 (0.69-1.48) and 1.46 (1.00-1.92), respectively. Conclusions. The incidence of colorectal cancer was not elevated in patients with Barrett's oesophagus. Diagnostic bias may explain why previous studies have found an association. © 2005 Taylor & Francis.

Beta-blocker usage and breast cancer survival: a nested case-control study within a UK clinical practice research datalink cohort.

Background: To investigate the association between post-diagnostic beta-blocker usage and risk of cancer-specific mortality in a large population-based cohort of female breast cancer patients.

Methods: A nested case-control study was conducted within a cohort of breast cancer patients identified from cancer registries in England(using the National Cancer Data repository) and diagnosed between 1998 and 2007. Patients who had a breast cancer-specific death(ascertained from Office of National Statistics death registration data) were each matched to four alive controls by year and age at diagnosis. Prescription data for these patients were available through the Clinical Practice Research Datalink. Conditional logistic regression models were used to investigate the association between breast cancer-specific death and beta-blocker usage.

Results: Post-diagnostic use of beta-blockers was identified in 18.9% of 1435 breast cancer-specific deaths and 19.4% of their 5697 matched controls,indicating little evidence of association between beta-blocker use and breast cancer-specific mortality [odds ratio (OR) = 0.97,95% confidence interval (CI) 0.83, 1.13]. There was also little evidence of an association when analyses were restricted to cardio non-selective beta-blockers (OR = 0.90, 95% CI 0.69, 1.17). Similar results were observed in analyses of drug dosage frequency and duration, and beta-blocker type.

Conclusions: In this large UK population-based cohort of breast cancer patients,there was little evidence of an association between post-diagnostic beta-blocker usage and breast cancer progression. Further studies which include information on tumour receptor status are warranted to determine whether response to beta-blockers varies by tumour subtypes.