Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to ...developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.
We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT.
Most studies concerning the potentially positive effect ...of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently "sterilize" regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful.
Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups.
One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P=0.007), but not in the multimodality arm (hazard ratio 1.00; P=0.98).
The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.
To assess the impact of duloxetine dose escalation on tolerability and efficacy, 516 women with stress urinary incontinence were randomized to receive placebo or duloxetine in one of three regimens: ...40 mg BID for 8 weeks, 40 mg QD for 2 weeks escalating to 40 mg BID for 6 weeks or 20 mg BID for 2 weeks escalating to 40 mg BID for 6 weeks. A non-inferiority analysis confirmed that the 20 mg BID starting dose was significantly better than the other two duloxetine regimens for nausea reduction (16.5% vs 25.2% and 29.4%). There were also significant differences in the discontinuation rates (7.5% vs 11.8% and 16.2%). The efficacy after 4 weeks was significantly better with duloxetine than with placebo. Starting duloxetine at 20 mg BID for 2 weeks before increasing to 40 mg BID significantly improved tolerability but did not impact duloxetine efficacy after all the subjects had been on 40 mg BID for at least 2 weeks.
We present the final combination of CDF and D0 measurements of cross sections for single-top-quark production in proton-antiproton collisions at a center-of-mass energy of 1.96 TeV. The data ...correspond to total integrated luminosities of up to 9.7 fb−1 per experiment. The t-channel cross section is measured to be σt=2.25+0.29−0.31 pb. We also present the combinations of the two-dimensional measurements of the s- vs. t-channel cross sections and of the s+t channel cross section measurement resulting in σs+t=3.30+0.52−0.40 pb, without assuming the standard-model value for the ratio σs/σt. The resulting value of the magnitude of the top-to-bottom quark coupling is |Vtb| = 1.02+0.06−0.05, corresponding to |Vtb|>0.92 at the 95% C.L.
We report the observation of B{sub s}{sup 0}-B{sub s}{sup 0} oscillations from a time-dependent measurement of the B{sub s}{sup 0}-B{sub s}{sup 0} oscillation frequency {delta}m{sub s}. Using a data ...sample of 1 fb{sup -1} of pp collisions at {radical}(s)=1.96 TeV collected with the CDF II detector at the Fermilab Tevatron, we find signals of 5600 fully reconstructed hadronic B{sub s} decays, 3100 partially reconstructed hadronic B{sub s} decays, and 61 500 partially reconstructed semileptonic B{sub s} decays. We measure the probability as a function of proper decay time that the B{sub s} decays with the same, or opposite, flavor as the flavor at production, and we find a signal for B{sub s}{sup 0}-B{sub s}{sup 0} oscillations. The probability that random fluctuations could produce a comparable signal is 8x10{sup -8}, which exceeds 5{sigma} significance. We measure {delta}m{sub s}=17.77{+-}0.10(stat){+-}0.07(syst) ps{sup -1} and extract vertical bar V{sub td}/V{sub ts} vertical bar =0.2060{+-}0.0007({delta}m{sub s}){sub -0.0060}{sup +0.0081}({delta}m{sub d}+theor)
Patients who undergo major vascular surgery are at increased risk of perioperative cardiac complications. High-risk patients can be identified by clinical factors and noninvasive cardiac testing, ...such as dobutamine stress echocardiography (DSE); however, such noninvasive imaging techniques carry significant disadvantages. A recent study found that perioperative beta-blocker therapy reduces complication rates in high-risk individuals.
To examine the relationship of clinical characteristics, DSE results, beta-blocker therapy, and cardiac events in patients undergoing major vascular surgery.
Cohort study conducted in 1996-1999 in the following 8 centers: Erasmus Medical Centre and Sint Clara Ziekenhuis, Rotterdam, Twee Steden Ziekenhuis, Tilburg, Academisch Ziekenhuis Utrecht, Utrecht, and Medisch Centrum Alkmaar, Alkmaar, the Netherlands; Ziekenhuis Middelheim, Antwerp, Belgium; and San Gerardo Hospital, Monza, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.
A total of 1351 consecutive patients scheduled for major vascular surgery; DSE was performed in 1097 patients (81%), and 360 (27%) received beta-blocker therapy.
Cardiac death or nonfatal myocardial infarction within 30 days after surgery, compared by clinical characteristics, DSE results, and beta-blocker use.
Forty-five patients (3.3%) had perioperative cardiac death or nonfatal myocardial infarction. In multivariable analysis, important clinical determinants of adverse outcome were age 70 years or older; current or prior angina pectoris; and prior myocardial infarction, heart failure, or cerebrovascular accident. Eighty-three percent of patients had less than 3 clinical risk factors. Among this subgroup, patients receiving beta-blockers had a lower risk of cardiac complications (0.8% 2/263) than those not receiving beta-blockers (2.3% 20/855), and DSE had minimal additional prognostic value. In patients with 3 or more risk factors (17%), DSE provided additional prognostic information, for patients without stress-induced ischemia had much lower risk of events than those with stress-induced ischemia (among those receiving beta-blockers, 2.0% 1/50 vs 10.6% 5/47). Moreover, patients with limited stress-induced ischemia (1-4 segments) experienced fewer cardiac events (2.8% 1/36) than those with more extensive ischemia (>/=5 segments, 36% 4/11).
The additional predictive value of DSE is limited in clinically low-risk patients receiving beta-blockers. In clinical practice, DSE may be avoided in a large number of patients who can proceed safely for surgery without delay. In clinically intermediate- and high-risk patients receiving beta-blockers, DSE may help identify those in whom surgery can still be performed and those in whom cardiac revascularization should be considered.
Aims To assess the efficacy of an angiotensin converting enzyme (ACE) inhibitor (perindopril), a dihydropyridine calcium channel blocker (sustained release nifedipine) and placebo in preventing the ...progression of albuminuria and decline in glomerular filtration rate (GFR) in patients with Type 2 diabetes and microalbuminaria.
Methods A prospective, randomized, open, blinded end point study of 77 patients allocated to three treatment groups (23 perindopril, 27 nifedipine, 27 placebo). Drug doses were adjusted to achieve a decrease in diastolic blood pressure (DBP) of 5 mmHg in the first 3 months and additional therapy was given if hypertension developed (supine DBP > 90 mmHg and/or systolic blood pressure (SBP) > 140 mmHg if ≤ 40 years; supine DBP > 90 mmHg and/or SBP > 160 mmHg if > 40 years). Median follow‐up was 66 months, with 37 patients being followed for at least 6 years.
Results Blood pressure remained within the non‐hypertensive range in 83% of perindopril‐, 95% of nifedipine‐ and 30% of placebo‐treated patients (P < 0.01). In the first 12 months albumin excretion rate (AER) decreased by 47% only in the perindopril group (P = 0.04). From 12 to 72 months, AER gradients increased by 27% per year only in the placebo group (P < 0.01). After 6 years, macroalbuminuria had developed in 7/15 placebo compared with 2/11 in perindopril and 1/11 nifedipine‐treated patients (P = 0.05). GFR did not change in the first 12 months, but thereafter the median GFR gradient (ml/min/1.73 m2 per year) was −2.4 (P < 0.01) for perindopril‐, −1.3 (P = 0.26) for nifedipine‐ and −4.2 (P = 0.01) for placebo‐treated patients. The rate of decline in GFR for the study group as a whole from 12 months to the end of follow‐up correlated negatively with mean arterial pressure (MAP) (r = −0.38, P < 0.01). During a 3‐month treatment pause in 29 patients AER tended to increase only in the perindopril group (P < 0.07).
Conclusions Long‐term control of blood pressure with perindopril or nifedipine stabilizes AER and attenuates GFR decline in proportion to MAP in non‐hypertensive patients with Type 2 diabetes and microalbuminuria.
Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, increases rhabdosphincter contractility via the stimulation of pudendal motor neuron α-1 adrenergic and 5-hydroxytryptamine-2 ...receptors. In this first phase 3 study we assessed the efficacy and safety of duloxetine in women with stress urinary incontinence (SUI).
A total of 683 North American women 22 to 84 years old were enrolled in this double-blind, placebo controlled study. The case definition included a predominant symptom of SUI with a weekly incontinence episode frequency (IEF) of 7 or greater, the absence of predominant symptoms of urge incontinence, normal diurnal and nocturnal frequency, a bladder capacity of 400 ml or greater, and a positive cough stress test and stress pad test. After a 2-week placebo lead-in period subjects were randomly assigned to receive placebo (339) or 80 mg duloxetine daily (344) as 40 mg twice daily for 12 weeks. Primary outcome variables included IEF and an incontinence quality of life questionnaire. Van Elteren’s test was used to analyze percent changes in IEF with a stratification variable of weekly baseline IEF (less than 14 and 14 or greater). ANCOVA was used to analyze incontinence quality of life scores.
Mean baseline IEF was 18 weekly and 436 subjects (64%) had a baseline IEF of 14 or greater. There was a significant decrease in IEF with duloxetine compared with placebo (50% vs 27%, p <0.001) with comparably significant improvements in quality of life (11.0 vs 6.8, p <0.001). Of subjects on duloxetine 51% had a 50% to 100% decrease in IEF compared with 34% of those on placebo (p <0.001). These improvements with duloxetine were associated with a significant increases in the voiding interval compared with placebo (20 vs 2 minutes, p <0.001) and they were observed across the spectrum of incontinence severity. The discontinuation rate for adverse events was 4% for placebo and 24% for duloxetine (p <0.001) with nausea the most common reason for discontinuation (6.4%). Nausea, which was also the most common side effect, tended to be mild to moderate and transient, usually resolving after 1 week to 1 month. Of the 78 women who experienced treatment emergent nausea while taking duloxetine 58 (74%) completed the trial.
These phase 3 data are consistent with phase 2 data and they provide further evidence for the safety and efficacy of duloxetine as a pharmacological agent for the treatment of women with SUI.
Background. There is limited information on the association between colonization density of upper respiratory tract colonizers and pathogen-specific pneumonia. We assessed this association for ...Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii. Methods. In 7 low- and middle-income countries, nasopharyngeal/oropharyngeal swabs from children with severe pneumonia and age-frequency matched community controls were tested using quantitative polymerase chain reaction (PCR). Differences in median colonization density were evaluated using the Wilcoxon rank-sum test. Density cutoffs were determined using receiver operating characteristic curves. Cases with a pathogen identified from lung aspirate culture or PCR, pleural fluid culture or PCR, blood culture, and immunofluorescence for P. jirovecii defined microbiologically confirmed cases for the given pathogens. Results. Higher densities of H. influenzae were observed in both microbiologically confirmed cases and chest radiograph (CXR)–positive cases compared to controls. Staphylococcus aureus and P. jirovecii had higher densities in CXR-positive cases vs controls. A 5.9 log10 copies/mL density cutoff for H. influenzae yielded 86% sensitivity and 77% specificity for detecting microbiologically confirmed cases; however, densities overlapped between cases and controls and positive predictive values were poor (<3%). Informative density cutoffs were not found for S. aureus and M. catarrhalis, and a lack of confirmed case data limited the cutoff identification for P. jirovecii. Conclusions. There is evidence for an association between H. influenzae colonization density and H. influenzae–confirmed pneumonia in children; the association may be particularly informative in epidemiologic studies. Colonization densities of M. catarrhalis, S. aureus, and P. jirovecii are unlikely to be of diagnostic value in clinical settings.
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