Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective ...studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
To conduct the first meta-analysis evaluating the internal and external validity of the sluggish cognitive tempo (SCT) construct as related to or distinct from attention-deficit/hyperactivity ...disorder (ADHD) and as associated with functional impairment and neuropsychological functioning.
Electronic databases were searched through September 2015 for studies examining the factor structure and/or correlates of SCT in children or adults. The search procedures identified 73 papers. The core SCT behaviors included across studies, as well as factor loadings and reliability estimates, were reviewed to evaluate internal validity. Pooled correlation effect sizes using random effects models were used to evaluate SCT in relation to external validity domains (i.e., demographics, other psychopathologies, functional impairment, and neuropsychological functioning).
Strong support was found for the internal validity of the SCT construct. Specifically, across factor analytic studies including more than 19,000 individuals, 13 SCT items loaded consistently on an SCT factor as opposed to an ADHD factor. Findings also support the reliability (i.e., internal consistency, test-retest reliability, interrater reliability) of SCT. In terms of external validity, there is some indication that SCT may increase with age (r = 0.11) and be associated with lower socioeconomic status (r = 0.10). Modest (potentially negligible) support was found for SCT symptoms being higher in males than females in children (r = 0.05) but not in adults. SCT is more strongly associated with ADHD inattention (r = 0.63 in children, r = 0.72 in adults) than with ADHD hyperactivity-impulsivity (r = 0.32 in children, r = 0.46 in adults), and it likewise appears that SCT is more strongly associated with internalizing symptoms than with externalizing symptoms. SCT is associated with significant global, social, and academic impairment (r = 0.38-0.44). Effects for neuropsychological functioning are mixed, although there is initial support for SCT being associated with processing speed, sustained attention, and metacognitive deficits.
This meta-analytic review provides strong support for the internal validity of SCT and preliminary support for the external validity of SCT. In terms of diagnostic validity, there is currently not enough evidence to describe SCT in diagnostic terms. Key directions for future research are discussed, including evaluating the conceptualization of SCT as a transdiagnostic construct and the need for longitudinal research.
Summary Background Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test ...characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS). Methods GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children. Findings We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli (ST-ETEC around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3% (95% CI 83·2–96·0) at the population level, compared with 51·5% (48·0–55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8% (74·6–80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. Interpretation A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised. Funding Bill & Melinda Gates Foundation.
Allergen measurements are used extensively in the formulation of allergy diagnostics and vaccines, yet no purified international allergen standards are available for calibration purposes. The aims of ...the European Union CREATE project were to develop international standards with verifiable allergen content. Purified natural and recombinant allergens were analyzed by means of SDS-PAGE, mass spectrometry, circular dichroism spectra, and small-angle x-ray scattering. IgE reactivity was assessed by means of direct RAST, RAST inhibition, immunoblotting, and basophil histamine release with sera from 961 allergic patients. Three recombinant allergens, rBet v 1, rPhl p 5a, and rDer p 2, were structurally indistinguishable from their natural counterparts and showed excellent IgE reactivity suitable for use as certified reference materials. A second tier of allergens (rPhl p 5b, rOle e1, rDer p 1, rDer f 1, and rDer f 2) was identified that could provide suitable candidates for certified reference materials with minor improvements to the recombinant proteins. Only rPhl p 1 was considered unsuitable as a reference material. Quantitative ELISAs were identified that accurately measured each allergen, except for rPhl p 1. The CREATE project has provided a major step forward in allergen standardization and provides a model for the development of a comprehensive panel of international reference preparations that will harmonize allergen measurements worldwide.
Background and purpose More than 50% of patients with acute intracerebral hemorrhage (ICH) are taking antihypertensive drugs before ictus. Although antihypertensive therapy should be given long term ...for secondary prevention, whether to continue or stop such treatment during the acute phase of ICH remains unclear, a question that was addressed in the Efficacy of Nitric Oxide in Stroke (ENOS) trial. Methods ENOS was an international multicenter, prospective, randomized, blinded endpoint trial. Among 629 patients with ICH and systolic blood pressure between 140 and 220 mmHg, 246 patients who were taking antihypertensive drugs were assigned to continue (n = 119) or to stop (n = 127) taking drugs temporarily for 7 days. The primary outcome was the modified Rankin Score at 90 days. Secondary outcomes included death, length of stay in hospital, discharge destination, activities of daily living, mood, cognition, and quality of life. Results Blood pressure level (baseline 171/92 mmHg) fell in both groups but was significantly lower at 7 days in those patients assigned to continue antihypertensive drugs (difference 9.4/3.5 mmHg, P < .01). At 90 days, the primary outcome did not differ between the groups; the adjusted common odds ratio (OR) for worse outcome with continue versus stop drugs was .92 (95% confidence interval, .45-1.89; P = .83). There was no difference between the treatment groups for any secondary outcome measure, or rates of death or serious adverse events. Conclusions Among patients with acute ICH, immediate continuation of antihypertensive drugs during the first week did not reduce death or major disability in comparison to stopping treatment temporarily.
Objectives We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared to clopidogrel. Background Ticagrelor reduced ...cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. Methods PLATO randomized 18,624 subjects with acute coronary syndrome (ACS) to ticagrelor vs. clopidogrel. The primary efficacy endpoint was cardiovascular death/myocardial infarction/stroke and the primary safety endpoint was major bleeding. The use of GPI was at the physician’s discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours. Results A total of 4020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, male, and undergo multi-vessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety endpoints. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared to clopidogrel (p<0.05), whereas there was no such difference with GPI (p-interaction<0.05). Conclusions In patients with ACS undergoing early PCI the efficacy and safety of ticagrelor as compared with clopidogrel was not modified by GPI use according to the primary efficacy and safety endpoint of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs. with) GPI treatment.
Objectives The goal of this study was to evaluate the prevalence and clinical characteristics of mental stress–induced myocardial ischemia. Background Mental stress–induced myocardial ischemia is ...prevalent and a risk factor for poor prognosis in patients with coronary heart disease, but past studies mainly studied patients with exercise-induced myocardial ischemia. Methods Eligible patients with clinically stable coronary heart disease, regardless of exercise stress testing status, underwent a battery of 3 mental stress tests followed by a treadmill test. Stress-induced ischemia, assessed by echocardiography and electrocardiography, was defined as: 1) development or worsening of regional wall motion abnormality; 2) left ventricular ejection fraction reduction ≥8%; and/or 3) horizontal or downsloping ST-segment depression ≥1 mm in 2 or more leads lasting for ≥3 consecutive beats during at least 1 mental test or during the exercise test. Results Mental stress–induced ischemia occurred in 43.45%, whereas exercise-induced ischemia occurred in 33.79% (p = 0.002) of the study population (N = 310). Women (odds ratio OR: 1.88), patients who were not married (OR: 1.99), and patients who lived alone (OR: 2.24) were more likely to have mental stress–induced ischemia (all p < 0.05). Multivariate analysis showed that compared with married men or men living with someone, unmarried men (OR: 2.57) and married women (OR: 3.18), or living alone (male OR: 2.25 and female OR: 2.72, respectively) had higher risk for mental stress–induced ischemia (all p < 0.05). Conclusions Mental stress–induced ischemia is more common than exercise-induced ischemia in patients with clinically stable coronary heart disease. Women, unmarried men, and individuals living alone are at higher risk for mental stress–induced ischemia. (Responses of Myocardial Ischemia to Escitalopram Treatment REMIT; NCT00574847 )
Abstract Background Although emotional stress is associated with ischemic heart disease (IHD) and related clinical events, sex-specific differences in the psychobiological response to mental stress ...have not been clearly identified. Objectives We aimed to study the differential psychological and cardiovascular responses to mental stress between male and female patients with stable IHD. Methods Patients with stable IHD enrolled in the REMIT (Responses of Mental Stress–Induced Myocardial Ischemia to Escitalopram) study underwent psychometric assessments, transthoracic echocardiography, and platelet aggregation studies at baseline and after 3 mental stress tasks. Mental stress–induced myocardial ischemia (MSIMI) was defined as the development or worsening of regional wall motion abnormality, reduction of left ventricular ejection fraction (LVEF) ≥8% by transthoracic echocardiography, and/or ischemic ST-segment change on electrocardiogram during 1 or more of the 3 mental stress tasks. Results In the 310 participants with known IHD (18% women, 82% men), most baseline characteristics were similar between women and men (including heart rate, blood pressure, and LVEF), although women were more likely to be nonwhite, living alone (p < 0.001), and unmarried (p < 0.001); they also had higher baseline depression and anxiety (p < 0.05). At rest, women had heightened platelet aggregation responses to serotonin (p = 0.007) and epinephrine (p = 0.004) compared with men. Following mental stress, women had more MSIMI (57% vs. 41%; p < 0.04), expressed more negative (p = 0.02) and less positive emotion (p < 0.001), and demonstrated higher collagen-stimulated platelet aggregation responses (p = 0.04) than men. Men were more likely than women to show changes in traditional physiological measures, such as blood pressure (p < 0.05) and double product. Conclusions In this exploratory analysis, we identified clear, measurable, and differential responses to mental stress in women and men. Further studies should test the association of sex differences in cardiovascular and platelet reactivity in response to mental stress and long-term outcomes. (Responses of Myocardial Ischemia to Escitalopram Treatment REMIT; NCT00574847 )
Background Mental stress-induced myocardial ischemia (MSIMI) is common in patients with ischemic heart disease (IHD) and associated with a poorer cardiovascular prognosis. Platelet hyperactivity is ...an important factor in acute coronary syndrome. This study examined associations between MSIMI and resting and mental stress-induced platelet activity. Methods Eligible patients with clinically stable IHD underwent a battery of 3 mental stress tests during the recruitment phase of REMIT study. MSIMI was assessed by echocardiography and electrocardiography. Ex vivo platelet aggregation in response to ADP, epinephrine, collagen, serotonin, and combinations of serotonin plus ADP, epinephrine, and collagen were evaluated as was platelet serotonin transporter expression. Results Of the 270 participants who completed mental stress testing, and had both resting and post-stress platelet aggregation evaluation , 43.33% (n = 117) met criteria for MSIMI and 18.15% (n = 49) had normal left ventricular response to stress (NLVR). The MSIMI group, relative to the NLVR groups, demonstrated heightened mental stress-induced aggregation responses, as measured by area under the curve, to collagen 10 μM (6.955.54 vs. -14.238.75.; P = 0.045), epinephrine 10 μM (12.844.84 vs. -6.407.61.; P = 0.037) and to serotonin 10 μM plus ADP 1 μM (6.645.29 vs. -27.348.34; P < .001). The resting platelet aggregation and serotonin transporter expression, however, were not different between the two groups. Conclusions These findings suggest that the dynamic change of platelet aggregation caused by mental stress may underlie MSIMI. While the importance of these findings requires additional investigation, they raise concern given the recognized relationship between mental stress-induced platelet hyperactivity and cardiovascular events in patients with IHD.
Falls are common in nursing homes and cause a high burden of injuries. The objective of this study was to analyze factors associated with serious consequences of falls in nursing home residents.
...Prospective observational study.
Falls were recorded over 1 year, covering all residents from 528 nursing homes in Bavaria, Germany.
The database consisted of 70,196 falls.
The standardized form included information about date, time, sex, age, functional status, location of fall, activity leading to the fall, footwear, and about potential consequences, such as transfer to hospital or a suspected fracture. Transfer to hospital was the main outcome and served as surrogate for a serious fall. The association of potential risk factors with hospital transfer after a fall was estimated in multiple logistic regression models.
Serious falls were associated with increasing age, being female, and less restricted functional status. Walking compared with transferring, and particularly the morning hours were also associated with a serious fall. Compared with midday, for example, the time period between 6 am and 8 am was associated with a more than 60% increased chance of transfer to hospital. Inappropriate footwear and weekends were associated with serious falls only in women.
Some observed factors or indicators associated with transfer to hospital are modifiable and targeted interventions may reduce injuries or costs after a fall.
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