Reduced pro-inflammatory responses to Staphylococcus aureus bloodstream infection and low prevalence of enterotoxin genes in isolates from patients on haemodialysis.

Patients with end-stage renal failure undergo regular haemodialysis (HD) and often develop episodes of Staphylococcus aureus bloodstream infection (BSI), which can re-occur. However, clinically, patients on HD, with S. aureus BSI, respond well to treatment, rarely developing overt signs of sepsis. We investigated the contributions of bacterial virulence and cytokine responses to the clinical course of S. aureus BSI in HD and non-HD patients. Seventy patients were recruited, including 27 (38.6 %) patients on HD. Isolates were spa-typed and virulence and antimicrobial resistance gene carriage was investigated using DNA microarray analysis. Four inflammatory cytokines, IL-6, RANTES, GROγ and leptin, were measured in patient plasma on the day of diagnosis and after 7 days. There was no significant difference in the prevalence of genotypes or antimicrobial resistance genes in S. aureus isolates from HD compared to non-HD patients. The enterotoxin gene cluster (containing staphylococcal enterotoxins seg, sei, sem, sen, seo and seu) was significantly less prevalent among BSI isolates from HD patients compared to non-HD patients. Comparing inflammatory cytokine response to S. aureus BSI in HD patients to non-HD patients, IL-6 and GROγ were significantly lower (p = 0.021 and p = 0.001, respectively) in HD patients compared to other patients on the day of diagnosis and RANTES levels were significantly lower (p = 0.025) in HD patients on day 7 following diagnosis. Lowered cytokine responses in HD patients and a reduced potential for super-antigen production by infecting isolates may partly explain the favourable clinical responses to episodes of S. aureus BSI in HD patients that we noted clinically.

Tunable terahertz wave generation through a bimodal laser diode and plasmonic photomixer.

We demonstrate a compact, robust, and stable terahertz source based on a novel two section digital distributed feedback laser diode and plasmonic photomixer. Terahertz wave generation is achieved through difference frequency generation by pumping the plasmonic photomixer with two output optical beams of the two section digital distributed feedback laser diode. The laser is designed to offer an adjustable terahertz frequency difference between the emitted wavelengths by varying the applied currents to the laser sections. The plasmonic photomixer is comprised of an ultrafast photoconductor with plasmonic contact electrodes integrated with a logarithmic spiral antenna. We demonstrate terahertz wave generation with 0.15-3 THz frequency tunability, 2 MHz linewidth, and less than 5 MHz frequency stability over 1 minute, at useful power levels for practical imaging and sensing applications.

Large and prolonged food-borne multistate hepatitis A outbreak in Europe associated with consumption of frozen berries, 2013 to 2014.

In May 2013, Italy declared a national outbreak of hepatitis A, which also affected several foreign tourists who had recently visited the country. Molecular investigations identified some cases as infected with an identical strain of hepatitis A virus subgenotype IA. After additional European Union/European Economic Area (EU/EEA) countries reported locally acquired and travel-related cases associated with the same outbreak, an international outbreak investigation team was convened, a European outbreak case definition was issued and harmonisation of the national epidemiological and microbiological investigations was encouraged. From January 2013 to August 2014, 1,589 hepatitis A cases were reported associated with the multistate outbreak; 1,102 (70%) of the cases were hospitalised for a median time of six days; two related deaths were reported. Epidemiological and microbiological investigations implicated mixed frozen berries as the vehicle of infection of the outbreak. In order to control the spread of the outbreak, suspected or contaminated food batches were recalled, the public was recommended to heat-treat berries, and post-exposure prophylaxis of contacts was performed. The outbreak highlighted how large food-borne hepatitis A outbreaks may affect the increasingly susceptible EU/EEA general population and how, with the growing international food trade, frozen berries are a potential high-risk food.

The Dan Young Neonatal Surgical Unit audit: an audit of admissions and mortality rates pre- and post-amalgamation.

BACKGROUND AND AIMS: (1) To record the number of Index Surgical Cases (ISCs) admitted to the Royal Hospital for Sick Children (RHSC) Yorkill in 2012-2014. (2) To investigate if the amalgamation of the neonatal intensive care unit with the Dan Young Neonatal Surgical Unit in 2008 has impacted on the number of admissions and deaths. METHOD AND RESULTS: Data were collected from the ward admission books and the BadgerNet UK database. Reason for admission and outcome was recorded. Nonsurgical cases were categorised as 'miscellaneous'.The total number of admissions per year and the number of miscellaneous cases have been increasing since the amalgamation. There were no clinically significant differences in the number of babies with each ISC. The death rate was 1.8% in 2012, 2.9% in 2013 and 2.6% 2014. CONCLUSIONS: The unit now admits more miscellaneous babies and this has caused an increase in total admissions. Although the total number of deaths has increased, the death rates as a percentage of total admissions have now plateaued after an initial rise at the time of union. There has been no significant increase in the number of ISC deaths. Thus, it appears that the amalgamation has affected survival outcomes in the short term only.

Outbreak of hepatitis A infection associated with the consumption of frozen berries, Ireland, 2013--linked to an international outbreak.

In May 2013, a European alert was issued regarding a hepatitis A virus (HAV) outbreak in Italy. In June 2013, HAV subgenotype IA with an identical sequence was identified in Ireland in three cases who had not travelled to Italy. The investigation consisted of descriptive epidemiology, a case-control study, microbiological testing of human and food specimens, molecular typing of positive specimens and food traceback. We identified 21 outbreak cases (14 confirmed primary cases) with symptom onset between 31 January and 11 October 2013. For the case-control study, we recruited 11 confirmed primary cases and 42 matched controls. Cases were more likely than controls to have eaten berry cheesecake (matched odds ratio (mOR): 12; 95% confidence interval (CI): 1.3-114), whole frozen berries (mOR: 9.5; 95% CI: 1.0-89), yoghurt containing frozen berries (mOR: 6.6, 95% CI: 1.2-37) or raw celery (mOR: 4; 95% CI: 1.2-16). Among cases, 91% had consumed at least one of four products containing frozen berries (mOR: 12; 95% CI: 1.5-94). Sixteen food samples tested were all negative for HAV. As products containing frozen berries were implicated in the outbreak, the public were advised to heat-treat frozen berries before consumption.

A Statistical Framework for Assessing the Relationship between Biomarkers and Clinical Endpoints in Alzheimer's Disease.

Changes in biomarker levels of Alzheimer's disease (AD) reflect underlying pathophysiological changes in the brain and can provide evidence of direct and downstream treatment effects linked to disease modification. Recent results from clinical trials of anti-amyloid ß (Aß) treatments have raised the question of how to best characterize the relationship between AD biomarkers and clinical endpoints. Consensus methodology for assessing such relationships is lacking, leading to inconsistent evaluation and reporting. In this review, we provide a statistical framework for reporting treatment effects on early and late accelerating AD biomarkers and assessing their relationship with clinical endpoints at the subject and group levels. Amyloid positron emission tomography (PET), plasma p-tau, and tau PET follow specific trajectories during AD and are used as exemplar cases to contrast biomarkers with early and late progression. Subject-level correlation was assessed using change from baseline in biomarkers versus change from baseline in clinical endpoints, and interpretation of the correlation is dependent on the biomarker and disease stage. Group-level correlation was assessed using the placebo-adjusted treatment effects on biomarkers versus those on clinical endpoints in each trial. This correlation leverages the fundamental advantages of randomized placebo-controlled trials and assesses the predictivity of a treatment effect on a biomarker or clinical benefit. Harmonization in the assessment of treatment effects on biomarkers and their relationship to clinical endpoints will provide a wealth of comparable data across clinical trials and may yield new insights for the treatment of AD.

Implementation of a cost-effective optical comb source in a WDM-PON with 10.7 Gb/s data to each ONU and 50 km reach.

The performance of a cost-effective optical comb source using commercial off the shelf (COTS) components in a WDM passive optical network is demonstrated. Eight comb modes are individually modulated at 10.7 Gb/s and transmitted over 50 km of single mode fiber for downlink transmission. Error free performance is obtained for each comb line and a maximum performance difference of 1.4 dB is experienced between the eight channels. Colorless operation of the optical network unit is achieved by utilizing an integrated module consisting of a tunable laser and an electro-absorption modulator as an uplink transmitter. Finally the predicted downstream performance of the system, when all the channels are transmitted simultaneously, is numerically simulated.

Circulating rotavirus genotypes in the Irish paediatric population prior to the introduction of the vaccination programme.

BACKGROUND: Rotavirus is the leading cause of viral gastroenteritis in children, and it is anticipated that the introduction of the Rotarix™ vaccine (GlaxoSmithKline Biologicals S.A., Rixensart, Belgium) into the Irish immunisation schedule will result in a significant reduction of rotavirus-associated disease. In the pre- and post-vaccination eras, it is important to determine circulating strains of rotavirus to assess vaccine effectiveness, to monitor vaccine failures, and to detect potential emerging strains. AIM: This study was a collaboration between the Temple Street Children's University Hospital (TSCUH), Dublin, and the National Virus Reference Laboratory (NVRL), Dublin, to determine the then circulating rotavirus strains in a paediatric hospital. METHOD: In the 2015/2016 period (July 2015-June 2016) 89 faecal samples from paediatric patients (53 from TSCUH, 36 from other hospitals) were characterised. RESULTS: The results showed G1P[8] to be the predominant genotype (57%), followed by G9P[8] (34%), G4P[8] (6%), G2P[4] (2%), and G12P[8] (1%). CONCLUSION: This distribution of genotypes is comparable to those found in other European countries prior to vaccination suggesting that the vaccine should be highly efficacious in the Irish population.

Clinical Development of Aducanumab, an Anti-Aß Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease.

The amyloid hypothesis has been the dominant framework for Alzheimer's disease (AD) research, including the development of anti-AD therapies. However, none of the phase III clinical trials conducted to date that targeted amyloid ß (Aß) production, aggregation, or clearance demonstrated a statistically significant treatment effect in patients with AD. This includes the approach of using monoclonal antibodies that recognize various Aß epitopes and display different binding selectivity. While some monoclonal antibodies have failed in phase III trials, several are still in development. Aducanumab (BIIB037) is a human antibody that selectively targets aggregated forms of Aß, including soluble oligomers and insoluble fibrils. In PRIME (NCT01677572), an ongoing phase Ib trial (N=196 patients dosed), aducanumab was shown to reduce Aß plaques and slow decline in clinical measures in patients with prodromal or mild AD, with acceptable safety and tolerability. The main safety finding was amyloid-related imaging abnormalities (ARIA), a side effect associated with removal of Aß, which was dose-dependent and occurred more often in ApoE ε4 carriers than non-carriers. ENGAGE (NCT02477800) and EMERGE (NCT02484547), the ongoing phase III trials of aducanumab in early AD, have been designed based on the outcomes of PRIME and on lessons from past clinical trials in patients with AD. Those study design features include patient selection with confirmed Aß pathology, ensuring sufficient target engagement, and conducting clinical trials in patients at earlier symptomatic stages of AD.

Digitized mammography: a clinical trial of postmenopausal women randomly assigned to receive raloxifene, estrogen, or placebo.

BACKGROUND: High mammographic density is associated with increased breast cancer risk. Previous studies have shown that estrogens increase breast density on mammograms, but the effect on mammographic density of selective estrogen receptor modulators, such as raloxifene, is unknown. We assessed changes in mammographic density among women receiving placebo, raloxifene, or conjugated equine estrogens in an osteoporosis prevention trial. METHODS: In a 5-year multicenter, double-blind, randomized, placebo-controlled osteoporosis prevention trial, healthy postmenopausal women who had undergone hysterectomy less than 15 years before the study and had no history of breast cancer received placebo, raloxifene (at one of two doses), or conjugated estrogens (ERT). Women from English-speaking investigative sites who had baseline and 2-year craniocaudal mammograms with comparable positioning (n = 168) were eligible for this analysis. Changes in mammographic density were determined by digital scanning and computer-assisted segmentation of mammograms and were analyzed with the use of analysis of variance. All statistical tests were two-sided. RESULTS: Among the four treatment groups after 2 years on study, the mean breast density (craniocaudal view) was statistically significantly greater in the ERT group than it was in the other three groups (P<0.01 for all three comparisons). Within treatment groups, the mean breast density from baseline to 2 years decreased statistically significantly in women receiving the placebo or either the higher or lower raloxifene dose (P = 0.003, P = 0.002, and P<0.001, respectively) and showed a nonstatistically significant increase in women receiving ERT. CONCLUSIONS: In an osteoporosis prevention trial, raloxifene did not increase breast density after 2 years of treatment. Raloxifene administration should not interfere with, and could even enhance, mammographic detection of new breast cancers.

Chronic hormone replacement therapy alters thermoregulatory and vasomotor function in postmenopausal women.

This investigation examined effects of chronic (>/=2 yr) hormone replacement therapy (HRT), both estrogen replacement therapy (ERT) and estrogen plus progesterone therapy (E+P), on core temperature and skin blood flow responses of postmenopausal women. Twenty-five postmenopausal women [9 not on HRT (NO), 8 on ERT, 8 on E+P] exercised on a cycle ergometer for 1 h at an ambient temperature of 36 degrees C. Cutaneous vascular conductance (CVC) was monitored by laser-Doppler flowmetry, and forearm vascular conductance (FVC) was measured by using venous occlusion plethysmography. Iontophoresis of bretylium tosylate was performed before exercise to block local vasoconstrictor (VC) activity at one skin site on the forearm. Rectal temperature (Tre) was approximately 0.5 degrees C lower for the ERT group (P < 0.01) compared with E+P and NO groups at rest and throughout exercise. FVC: mean body temperature (Tb) and CVC: Tb curves were shifted approximately 0.5 degrees C leftward for the ERT group (P < 0.0001). Baseline CVC was significantly higher in the ERT group (P < 0.05), but there was no interaction between bretylium treatment and groups once exercise was initiated. These results suggest that 1) chronic ERT likely acts centrally to decrease Tre, 2) ERT lowers the Tre at which heat-loss effector mechanisms are initiated, primarily by actions on active cutaneous vasodilation, and 3) addition of exogenous progestins in HRT effectively blocks these effects.

Effect of raloxifene on serum triglycerides in postmenopausal women: influence of predisposing factors for hypertriglyceridemia.

BACKGROUND: Estrogen increases serum triglyceride (TG) levels and induces hypertriglyceridemia in susceptible women. The effect of raloxifene (RLX), a selective estrogen-receptor modulator, on serum TG has not been studied in detail. OBJECTIVE: The purpose of this study was to examine the effect of RLX on serum TG levels in postmenopausal women with and without osteoporosis, including those with predisposing factors for hypertriglyceridemia. METHODS: Fasting serum TG levels were assessed over 36 months in 2738 osteoporotic postmenopausal women (mean age, 67 years) assigned to placebo or RLX (60 or 120 mg/d) in an osteoporosis treatment trial and over 24 months in 1318 postmenopausal women without osteoporosis (mean age, 54 years) assigned to placebo or RLX (60 or 150 mg/d) in 3 osteoporosis prevention trials. RESULTS: In the osteoporosis treatment trial, the median serum TG concentration decreased in all groups, but significantly more in the placebo group (placebo, -3.4%; RLX 60 mg/d, -1.4%; RLX 120 mg/d, -1.3%; P = 0.002). In the osteoporosis prevention trials, the percentage change in median serum TG concentration was not significantly different among treatments (P = 0.22). Among women with varying degrees of hypertriglyceridemia at baseline (>2.82, >3.39, and >4.51 mmol/L), the median serum TG level at the end of the study decreased from baseline in all groups, with no significant differences among treatments (P > or = 0.13). The effect of RLX on serum TG level was not influenced by age, smoking status, use of alcohol, or presence of diabetes (P > or = 0.10 for all interactions). Among women in the highest tertile of body mass index (>26.4 kg/m2), RLX increased serum TG levels significantly compared with placebo (placebo, -3%; RLX 60 mg/d, 6%: RLX 120 mg/d, 4%; P < 0.05); the absolute increase from baseline with RLX in this subgroup was 0.05 mmol/L (4.4 mg/dL). CONCLUSIONS: RLX did not increase serum TG in postmenopausal women overall or among women with elevated TG levels or evidence of diabetes at baseline. TG levels increased slightly but statistically significantly in women in the upper tertile of body mass index who were treated with RLX.

Extraversion and the EEG: I. An evaluation of Gale's hypothesis.

The hypothesis of A. Gale that extraverts differ from introverts in EEG defined arousal only under moderately arousing conditions is examined. It is argued that the hypothesis is not entirely internally consistent and lacks empirical support. A re-analysis of the literature on which it was based points to problems in the measurement of extraversion as a more significant source of confounding than variation in conditions of testing.

Individual differences in habituation of human physiological responses: a review of theory, method, and findings in the study of personality correlates in non-clinical populations.

Studies up to 1976 of the relationship between psychometrically defined dimensions of personality and individual differences in habituation of EEG and autonomic responses were examined. Attention was confined to reports employing persons who were not diagnosed as suffering from mental disorder, institutionalized for this reason of for delinquent or criminal behaviour. The dimensions of extraversion and anxiety were most frequently found to be implicated in predictions about individual differences in response habituation, though no consistent rationale for these predictions was identified. Methodological problems involved in studying the predictions were considered, and a number of factors relating to measurement of personality and habituation and the experimental conditions under which response habituation is studied were suggested as possible sources of confounding. A survey of the empirical literature led to the conclusions that anxiety as defined by the Manifest Anxiety Scale is related to habituation of the finger vasomotor response but probably not to habituation of the electrodermal response, while extraversion, as defined by Eysenck's scale, is related to habituation of the electrodermal response. For other scales and other dimensions, including cognitive factors, the available data are inconsistent or too meagre to permit conclusions being drawn. It is suggested that future research be directed to a systematic investigation of the conditions under which personality factors contribute significantly to individual differences in response habituation, rather than seek to identify general relationships.

Consistency of individual differences in non-specific electrodermal activity.

The study sought to determine whether, as implied by a trait interpretation of individual differences in non-specific electrodermal responding, the frequency of NSRs is a consistent characteristic of subjects across conditions. 40 male subjects completed two 1-hour sessions spaced at an interval of 2 weeks. In each session, three 12-min conditions were administered: relaxation, vigilance, and mental arithmetic. Continuous recordings were made throughout each condition of electrodermal and respiratory activity, and at the end of each condition subjects completed an Adjective Checklist (ACL). Counts were made of the total number of 10-sec intervals during each condition in which at least one NSR was recorded. Separate counts were made for large amplitude (equal to or greater than 1% of baseline) and for small amplitude (less than 1%) responses. Analyses of variance performed on the NSR data indicated that the major component of variance was that due to subjects, and that the interactions between subjects and conditions and subjects and sessions, which would contradict a trait interpretation, were negligible. Consistency in subject's responding was estimated by intraclass correlations across conditions and sessions. For NSR large, the coefficient was 0.58 and for NSR small 0.50. The data were interpreted as support for a trait interpretation of NSR frequency.

Extraversion and the EEG: II. A test of Gale's hypothesis.

The study sought to test A. Gale's hypothesis that only under moderately arousing conditions will introverts be shown to differ from extraverts in EEG defined arousal. Alpha activity was recorded for 45 subjects under each of six conditions, and extravert and introvert groups formed on the basis of subject's score on the E scale of the Eysenck Personality Questionnaire (EPQ). Contrary to the hypothesis, extraverts showed more prestimulus alpha activity than introverts under all conditions except opening and closing eyes on instruction where the reverse was the case. It is argued that the failure to confirm the hypothesis is not due to faults in design or execution of the study, and that future research may profit more from ignoring interactions of the sort demonstrated.

Methods and mechanisms in electrodermal studies of omission responding.

Barry and O'Gorman (1987) employed a response-averaging technique to investigate the electrodermal orienting response (OR) to stimulus omission. We obtained reliable evidence of increased response latency to stimulus omission, supporting an explanation of the missing-stimulus effect in terms of Maltzman's voluntary OR. Wilson's (1989) commentary on our article addresses both methodological and theoretical aspects. This response first examines his methodological difficulties, and provides simulation exercises which serve as a validation of our procedure. We then examine Wilson's theoretical points. His alternative theoretical explanation of the missing-stimulus effect, in terms of a systematic bias in the time-keeper of the stimulus-comparator process, is shown to be untenable. His remaining problem, concerning what he terms "assessment of stimulus significance", appears to have arisen through misinterpretation of our theory. A clarification of our theoretical position indicates the internal consistency of our use of "significance" and "voluntary OR".

Stimulus omission and the orienting response: latency differences suggest different mechanisms.

Following response habituation to a regularly-presented innocuous stimulus, omission of that stimulus may elicit a response. The missing-stimulus effect has been of some importance in the development of Orienting Response (OR) theory, particularly Sokolov's neuronal model/stimulus comparator mechanism. Western work on this effect has been somewhat equivocal, with only some subjects emitting small responses at stimulus omission. Barry (1984b) proposed that the fragility of the data might reflect the elicitation of a voluntary OR (Maltzman, 1979) rather than the more robust (reflexive) involuntary OR commonly emphasised in OR work. A prediction generated from this hypothesis, that the OR to stimulus omission has a longer latency than that associated with physical stimuli, was tested here. The first experiment found such an effect in the electrodermal responses to simple visual stimuli and their omission. This was replicated in a second experiment with both significant and indifferent visual stimuli. These latency delays (group mean differences ranged from 1.15 to 1.65 s) imply an intervening process in the elicitation of the electrodermal response to stimulus omission, compatible with it being viewed as a voluntary OR. An implication of these results for the conceptualization of other ORs to stimulus change is discussed.