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.

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.

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.

Application of copper to prevent and control infection. Where are we now?

BACKGROUND: The antimicrobial effect of copper has long been recognized and has a potential application in the healthcare setting as a mechanism to reduce environmental contamination and thus prevent healthcare-associated infection (HCAI). AIM: To review the rationale for copper use, the mechanism of its antimicrobial effect, and the evidence for its efficacy. METHODS: A PubMed search of the published literature was performed. FINDINGS: Extensive laboratory investigations have been carried out to investigate the biocidal activity of copper incorporated into contact surfaces and when impregnated into textiles and liquids. A limited number of clinical trials have been performed, which, although promising, leave significant questions unanswered. In particular there is a lack of consensus on minimum percentage copper alloys required for effectiveness, the impact of organic soiling on the biocidal effect of copper, and the best approach to routine cleaning of such surfaces. Limited information is available on the ability of copper surfaces to eradicate spores of Clostridium difficile. CONCLUSION: Additional studies to demonstrate that installing copper surfaces reduces the incidence of HCAI are required and the cost-effectiveness of such intervention needs to be assessed. Further research in a number of key areas is required before the potential benefits of using copper routinely in the clinical setting to prevent and control infection can be confirmed and recommended.

A 12-year review of Staphylococcus aureus bloodstream infections in haemodialysis patients: more work to be done.

Staphylococcus aureus bloodstream infections (BSI) are a significant cause of morbidity and mortality in haemodialysis patients. This study describes a 12-year retrospective review of S. aureus BSI in a large haemodialysis centre in a tertiary referral hospital. The overall rate of S. aureus BSI was 17.9 per 100 patient-years (range 9.7-36.8). The rate of meticillin-resistant S. aureus (MRSA) BSI was 5.6 per 100 patient-years (range 0.9-13.8). Infective complications occurred in 11% of episodes, the most common being infective endocarditis (7.6%). Ten percent of patients died within 30 days of S. aureus being isolated from blood. Most cases of S. aureus BSI (83%) were related to vascular catheters. The provision of lower-risk vascular access, such as arteriovenous fistulae, and reduced use of intravascular catheters should be priorities in all haemodialysis units. Where alternative vascular access cannot be established, interventions to reduce the risk of catheter-related infections should be implemented to reduce morbidity and mortality in this vulnerable patient group.

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.

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.

Nonparametric models and methods for designs with dependent censored data: part I.

We consider a nonparametric (NP) approach to the analysis of repeated measures designs with censored data. Using the NP model of Akritas and Arnold (1994, Journal of the American Statistical Association 89, 336-343) for marginal distributions, we present test procedures for the NP hypotheses of no main effects, no interaction, and no simple effects. This extends the existing NP methodology for such designs (Wei and Lachin, 1984, Journal of the American Statistical Association 79, 653-661). The procedures do not require any modeling assumptions and should be useful in cases where the assumptions of proportional hazards or location shift fail to be satisfied. The large-sample distribution of the test statistics is based on an i.i.d. representation for Kaplan-Meier integrals. The testing procedures apply also to ordinal data and to data with ties. Useful small-sample approximations are presented, and their performance is examined in a simulation study. Finally, the methodology is illustrated with two real life examples, one with censored and one with missing data. It is indicated that one of the data sets does not conform to any set of assumptions underlying the available methods and also that the present method provides a useful additional analysis even when data sets conform to modeling assumptions.

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.

Effects of severe traumatic brain injury on visual memory.

The study aimed to clarify the effects of severe traumatic brain injury (TBI) on visual memory. Three groups of participants (14 late-recovery and 14 early-recovery TBI individuals and 18 controls) were administered the following: The Shum Visual Learning Test (SVLT), a test that measures the ability to remember visual patterns, an electronic maze test, a test that measures the ability to remember spatial positions, and the Rey Auditory Verbal Learning Test (RAVLT), a test of verbal memory and learning. The individuals with TBI (late- and early-recovery) were found to be impaired on the SVLT and the RAVLT but not on the electronic maze. Specifically, on the SVLT, they were found to learn at a slower rate and make more false-positive errors than the controls. The advantages of the SVLT over visual memory tests used in previous studies and the significance of findings of the present study were discussed.

Neuropathic gait shows only trends towards increased variability of sagittal plane kinematics during treadmill locomotion.

Patients with diabetes mellitus (DM) and peripheral neuropathy (PN) are at greater risk of falling and of suffering injuries during falls. It has been hypothesized that PN leads to changes in gait variability that may account for this increased risk. The purpose of this investigation was to analyze the variability of the sagittal plane kinematics of diabetic neuropathic (NP), diabetic non-neuropathic (NNP) and age- and weight-matched control subjects (Control) during motorized treadmill walking at constant speed. While there were distinct trends towards increased variability within the three diagnostic groups (NP > NNP > Control) for several measures of gait variability, most of these trends were not statistically significant. We hypothesize that motorized treadmill walking may be inherently less variable than overground walking and that statistical measures of variability may not be sufficient to fully characterize stride-to-stride variability in human locomotion.

Normative data for a new memory test: the Shum Visual Learning Test.

This study reports normative data and test-retest reliabilities for a visuo-spatial memory test, the Shum Visual Learning Test (SVLT). Participants were 146 Caucasians (70 males and 76 females, age range between 17-83 years). The test was administered to 116 participants once and 30 participants twice (1 month apart). Age (but not gender and education) was found to affect SVLT test performance. The norms, therefore, were presented according to seven age groups (viz., 17-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70+ years). Three indices (learning, retention after interference, and delayed retention) were derived for descriptive and clinical purposes. The test-retest reliabilities for all trials of the SVLT (except Trial 6) were found to be significant (rs ranged from .63 to .82). Normative data reported allow neuropsychologists to compare patient performances with those of appropriate controls and are important for fostering clinical application of this test.