Travel-related Zika virus cases in Canada: October 2015-June 2017.

BACKGROUND: Zika virus (ZIKV) is an emerging mosquito-borne disease that can cause severe birth defects if contracted congenitally. Since late 2015, there has been a large increase in the number of travel-related cases of Zika virus infection in Canada. OBJECTIVE: The objective of this study was to describe the epidemiology of travel-related Zika cases in Canada from October 2015 to June 2017 and review them in the context of the international outbreak in the Americas. METHODS: Zika virus infections were confirmed by polymerase chain reaction (PCR) detection of viral RNA and/or the serological identification of ZIKV-specific antibodies in serum. Cases of ZIKV infection were identified by provincial and territorial health authorities, and reported on a regular basis to the Public Health Agency of Canada (PHAC). Case information requested included date of illness onset, age category, sex, pregnancy status, and location(s) and dates of travel. Estimates for the monthly number of Canadians travelling outside of Canada to other countries in the Americas were obtained from Statistics Canada and the International Air Transport Association (IATA). Data to produce the epidemic curves of autochthonous cases for each region of the Americas were extracted from country-specific epidemic curves on the Pan American Health Organization website. RESULTS: As of June 7, 2017, 513 laboratory confirmed cases and two Zika-related birth/fetal anomalies were reported across all 10 provinces. Illness in Canadian travellers generally coincided with outbreak intensity in the country of exposure rather than travel volume. There has been no evidence of autochthonous (local) transmission in Canada. Currently, cases are on the decline both in Canada and internationally. CONCLUSION: The surge in Canadian ZIKV infections in 2016 was directly related to the incursion and spread of ZIKV into the Americas. Although cases are now on the decline worldwide, it remains to be seen whether a resurgence of cases in previously affected or new areas will occur. Both outbreak intensity and seasonality of ZIKV transmission should be monitored over time in order to inform the timing of public health education campaigns, as some may turn out to be more effective in the off-peak travel season when the risk of disease transmission may be higher. Ongoing education and awareness among travellers, particularly for pregnant women and those planning pregnancies, is still indicated.

Brief Report: Social Functioning Predicts Externalizing Problem Behaviors in Autism Spectrum Disorder.

Individuals with ASD often display externalizing behaviors, which have been associated with lower quality of life in adulthood. Social difficulties have been hypothesized to underlie externalizing problems among individuals with ASD (Klin and Volkmar in Asperger Syndrome, 340-366, 2000), but this has never been tested empirically. We examined whether socialization abilities predicted externalizing problems assessed by parent report in a group of 29 individuals with ASD (age range 7-16 years) and 29 TD individuals matched for IQ, age, and gender. Socialization scores accounted for 50% of the variance in externalizing behaviors among individuals with ASD, but not in TD children. These findings have implications for intervention, and suggest that targeting social difficulties might provide a better means to addressing externalizing problems.

Allocating effort and anticipating pleasure in schizophrenia: Relationship with real world functioning.

BACKGROUND: Poor motivation to engage in goal-oriented behavior has been recognized as a hallmark feature of schizophrenia spectrum disorders (SZ). Low drive in SZ may be related to anticipating rewards as well as to poor working memory. However, few studies to date have examined beliefs about self-efficacy and satisfaction for future rewards (anticipatory pleasure). Additionally, few studies to date have examined how these deficits may impact SZ patients' real world functioning. METHOD: The present study examined SZ patients' (n=57) anticipatory pleasure, working memory, self-efficacy and real world functioning in relation to their negative symptom severity. RESULTS: Results revealed that SZ patients' negative symptom severity was related to decisions in effort allocation and reward probability, working memory deficits, self-efficacy and anticipatory pleasure for future reward. Effort allocation deficits also predicted patients' daily functioning skills. CONCLUSIONS: SZ patients with high levels of negative symptoms are not merely effort averse, but have more difficulty effectively allocating effort and anticipating pleasure engaging in effortful activities. It may be the case that continuously failing to achieve reinforcement from engagement and participation may lead SZ patients to form certain negative beliefs about their abilities which contributes to amotivation and cognitive deficits. Lastly, our findings provide further support for a link between SZ patients functional daily living skills their effort allocation.

Parasitism, personality and cognition in fish.

It is well established that parasites can have profound effects on the behaviour of host organisms, and that individual differences in behaviour can influence susceptibility to parasite infections. Recently, two major themes of research have developed. First, there has been a growing interest in the proximate, mechanistic processes underpinning parasite-associated behaviour change, and the interactive roles of the neuro-, immune, and other physiological systems in determining relationships between behaviour and infection susceptibility. Secondly, as the study of behaviour has shifted away from one-off measurements of single behaviours and towards a behavioural syndromes/personality framework, research is starting to focus on the consequences of parasite infection for temporal and contextual consistency of behaviour, and on the implications of different personality types for infection susceptibility. In addition, there is increasing interest in the potential for relationships between cognition and personality to also have implications for host-parasite interactions. As models well-suited to both the laboratory study of behaviour and experimental parasitology, teleost fish have been used as hosts in many of these studies. In this review we provide a broad overview of the range of mechanisms that potentially generate links between fish behaviour, personality, and parasitism, and illustrate these using examples drawn from the recent literature. In addition, we examine the potential interactions between cognition, personality and parasitism, and identify questions that may be usefully investigated with fish models.

Evidence of horsemanship and dogmanship and their application in veterinary contexts.

This review collates peer-reviewed evidence for desirable attributes for those who work with dogs and horses. It is written with a particular focus on the veterinary profession. Although veterinarians and veterinary nurses (VNs) occupy variable roles when interacting with their patients, several behavioural attributes emerge as helpful across the range of such roles. In light of recent research on the value of considering animals' arousal and affective state as predictors of behaviour and welfare, best practice in human-horse and human-dog-interactions is outlined. The attributes of affiliation, safety and positive reinforcement seem to contribute greatly to the development and maintenance of moderate arousal and positive affect in animals. The information in this review article is offered in an attempt to show why veterinary professionals with good horsemanship are likely to remain safe, and to introduce the concept of dogmanship. In the light of the peer-reviewed evidence assembled here, it is arguable that veterinary teams, comprising both veterinarians and VNs, can become scholars in these areas. The benefits of this approach for practitioner safety, animal welfare and client satisfaction are likely to be significant.

Chlamydia and lymphogranuloma venereum in Canada: 2003-2012 Summary Report.

BACKGROUND: Chlamydia continues to be the most commonly reported sexually transmitted infection in Canada. Lymphogranuloma venereum (LGV), caused by certain serovars of Chlamydia trachomatis, is becoming established in some populations in a number of Western countries. OBJECTIVE: To identify trends in reported cases of chlamydia and LGV in Canada from January 1, 2003 to December 31, 2012. METHODS: Notifiable disease data on chlamydia were submitted to the Public Health Agency of Canada by provincial and territorial epidemiological units and summarized at the national level by age and sex. Confirmatory testing for suspected LGV cases and serovar subtyping were performed by the National Microbiology Laboratory (NML). Where possible, provincial/territorial health authorities use a standardized national case report form to collect enhanced epidemiological data on each case and to submit the data to the Agency. RESULTS: Rates of reported cases of chlamydia increased by 57.6%, from 189.6 to 298.7 per 100,000 between 2003 and 2012. The rate of reported cases of chlamydia among females (383.5 per 100,000) was almost twice as high as that among males (212.0 per 100,000), although the highest relative rate increase occurred among males. In both males and females, the rates of chlamydia were highest in those aged 20 to 24 years. From 2004 to 2012, 170 cases of LGV were reported to the Agency by provincial health authorities (including 104 confirmed and 66 probable cases). In 2012, case reports were received on 12 confirmed and probable cases, compared to 38 laboratory-positive cases confirmed by the NML. CONCLUSION: In Canada, as in many countries, chlamydia rates have markedly increased over the last 10 years, in part due to improved diagnosis through nucleic acid amplification (NAAT) testing. Consistent with trends in Europe and other countries, LGV is emerging in Canada among men who have sex with men (MSM).

Gonorrhea in Canada: 2003-2012.

BACKGROUND: Gonorrhea is the second most commonly reported sexually transmitted infection in Canada. Between 1991 and 1997, Canada experienced a sharp decline in the rates of reported cases of gonorrhea, followed by a steady incline. OBJECTIVE: To identify trends in reported cases of gonorrhea in Canada from January 1, 2003 to December 31, 2012. METHODS: Notifiable disease reports were submitted to the Public Health Agency of Canada by provincial and territorial epidemiological units and data were summarized by age and sex. RESULTS: Between 2003 and 2012, the rate of reported cases of gonorrhea increased by 38.9%, from 26.0 to 36.2 per 100,000. Over this time frame, a greater relative rate increase was observed in females, though rates of gonorrhea increased in both sexes and across all age groups. In 2012, as in previous years, the rate of reported cases of gonorrhea was higher in males than females (41.4 vs. 31.0 per 100,000). Females between the ages of 15 and 24 years and males between the ages of 20 and 29 years accounted for the highest rates of gonorrhea in 2012. CONCLUSION: In Canada, as in many countries, gonorrhea is on the rise, especially in young adults. This increase in rates of reported cases is in part due to improved diagnosis through nucleic acid amplification (NAAT) testing and may also be affected by growing gonococcal resistance to many available treatments.

Infectious syphilis in Canada: 2003-2012.

BACKGROUND: In the 1990s, rates of reported cases of infectious syphilis were relatively low and were similar among males and females. In 2001, rates began to increase, particularly among males. OBJECTIVE: To identify trends in reported cases of infectious syphilis in Canada from January 1, 2003 to December 31, 2012. METHODS: Notifiable disease reports were submitted to the Public Health Agency of Canada by provincial and territorial epidemiological units and data were summarized by age and sex. RESULTS: Rates of reported cases of infectious syphilis increased by 101.0% between 2003 and 2012, from 2.9 to 5.8 per 100,000. Over this time frame, rates increased among males by 128.3% and decreased among females by 40.9%. In males, rates of infectious syphilis were highest among those aged 25 to 29; in females, rates were highest among those aged 20 to 24. CONCLUSION: In Canada, as in many countries, rates of reported infectious syphilis cases in males have markedly increased over the last 10 years.

Hepatitis B surveillance in Canada: 2005-2012.

OBJECTIVE: To describe surveillance trends by age, sex and infection status of Hepatitis B (HB) virus in Canada between 2005 and 2012. METHODS: Data on acute and chronic HB cases reported to the Canadian Notifiable Disease Surveillance System were compiled at the national level to examine trends by age and sex over time. Time trends are presented from 2005 to 2012, corresponding to the availability of data differentiated by acute and chronic infection status. RESULTS: The rate of reported acute HB infections decreased from 1.0 to 0.6 per 100,000 between 2005 and 2012. Both sexes showed rate decreases over this time, although acute HB rates were consistently higher among males than females. The rate of reported chronic HB infections decreased from 14.1 to 12.0 per 100,000 between 2009 and 2012. These results are based on data in which infection status was specified. The proportion of unspecified cases in any given year may somewhat alter the results. CONCLUSION: This is the first time that trends in reported cases and corresponding rates of HB in Canada have been examined by acute and chronic infection status using national surveillance data. Canada continues to have a downward trend in HB rates across Canada, most notably in acute HB cases. Increasing national capacity to differentiate between acute and chronic HB will facilitate a more thorough understanding of trends in transmission and of the burden of HB infection in Canada.

Hepatitis C surveillance in Canada.

BACKGROUND: Hepatitis C is a highly transmissible virus that can lead to chronic liver disease. It continues to be a major public health concern in Canada. OBJECTIVE: To describe surveillance trends of reported cases of Hepatitis C virus (HCV) in Canada by age and sex from 1991-2012. METHODS: Cases of HCV reported to the Canadian Notifiable Disease Surveillance System were compiled at the national level. As most reported cases are not differentiated by acute or chronic HCV infection status, presented results are based on total HCV cases. Time trends are provided from 1991-2012, with a more detailed examination of age and sex patterns from 2005-2012. RESULTS: The rate of reported HCV infection increased sharply from 1991 (the year it was first notifiable) until 1998, when the highest overall rate of 66.9 per 100,000 was observed. From that time until 2012, rates of reported cases decreased in both sexes, but remained consistently higher among males than females. In 2012, the overall rate of reported HCV infection was 29.3 per 100,000. In younger age groups, rates among females were marginally higher, while males in older age groups (30 and above) exhibited substantially higher rates. CONCLUSION: This surveillance summary presents the longer-term trends in reported cases and corresponding rates of HCV in Canada using national surveillance data. Canada continues to experience a downward trend in HCV rates; however, the burden of infection will continue to increase as chronically infected individuals develop severe illness.

Pre-exposure prophylaxis for conception (PrEP-C) as a risk reduction strategy in HIV-positive men and HIV-negative women in the UK.

Couples wishing to have biological children when one partner is HIV positive and the other is HIV negative present clinicians with complex clinical, social and ethical considerations. We established two multidisciplinary pre-conception services for HIV-positive individuals and their partners. We report the first UK use of pre-exposure prophylaxis for conception (PrEP-C) as part of an overall risk reduction strategy. Couples were counselled and written informed consent for PrEP-C was obtained. Patient demographics, HIV and medical histories were recorded. Males underwent baseline semen analysis and seminal HIV viral load testing. Females had full fertility screens. Both partners were screened for sexually transmitted infections. All couples used timed ovulatory intercourse (TOI). Tenofovir±emtricitabine was taken by the female at protocol designated times before±after TOI. Thirty-two male positive/female negative couples used the services. Thirteen couples have used PrEP-C (median age of male 41 years (range 32-56), female 31 (28-43); median CD4 533 (236-1194); all male plasma and seminal HIV viral loads were undetectable). Eleven pregnancies in 10 couples have resulted in 7 live births, 1 ongoing pregnancy and 4 miscarriages (5/40, 6/40, 10/40 and 1 twin 17/40) after a median of 2.5 attempts (range 1-5). PrEP-C was well tolerated with no discontinuations and no HIV transmissions. These data suggest that PrEP-C is a safe and effective option for serodiscordant couples wishing to conceive; a standardised protocol has been developed; data collection via a central database is under way.

Zebrafish microRNA-126 determines hematopoietic cell fate through c-Myb.

Precise regulatory mechanisms are required to appropriately modulate the cellular levels of transcription factors controlling cell fate decisions during blood cell development. In this study, we show that miR-126 is a novel physiological regulator of the proto-oncogene c-myb during definitive hematopoiesis. We show that knockdown of miR-126 results in increased c-Myb levels and promotes erythropoiesis at the expense of thrombopoiesis in vivo. We further provide evidence that specification of thrombocyte versus erythrocyte cell lineages is altered by the concerted activities of the microRNAs (miRNAs) miR-126 and miR-150. Both miRNAs are required but not sufficient individually to precisely regulate the cell fate decision between erythroid and megakaryocytic lineages during definitive hematopoiesis in vivo. These results support the notion that miRNAs not only function to provide precision to developmental programs but also are essential determinants in the control of variable potential functions of a single gene during hematopoiesis.

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs.

RNA interference (RNAi)-based gene silencing is widely used in laboratories for gene function studies and also holds a great promise for developing treatments for diseases. However, in vivo delivery of RNAi therapy remains a key issue. Lentiviral vectors have been employed for stable gene transfer and gene therapy and therefore are expected to deliver a stable and durable RNAi therapy. But this does not seem to be true in some disease models. Here, we showed that lentivirus delivered short-hairpin RNA (shRNA) against human papillomavirus (HPV) E6/E7 oncogenes were effective for only 2 weeks in a cervical cancer model. However, using this vector to carry two copies of the same shRNA or two shRNAs targeting at two different but closely related genes (HPV E6 and vascular endothelial growth factor) was more effective at silencing the gene targets and inhibiting cell or even tumor growth than their single shRNA counterparts. The cancer cells treated with dual shRNA were also more sensitive to chemotherapeutic drugs than single shRNA-treated cells. These results suggest that a multi-shRNA strategy may be a more attractive approach for developing an RNAi therapy for this cancer.

In vitro kinetic properties of the Thr201Met variant of human aromatase gene CYP19A1: functional responses to substrate and product inhibition and enzyme inhibitors.

CONTEXT: The T(201)M variant (rs28757184) within exon 5 of the human aromatase gene CYP19A1, present in up to 20% of some populations, has been reported to reduce prostate cancer progression. OBJECTIVE: We hypothesized that the T(201)M variant would alter the structure of the enzyme and thus would also affect function compared to wild-type human aromatase. DESIGN: HEK293 cells were transiently transfected with CYP19A1 wild-type or T(201)M variant gene transcripts made by site-directed mutagenesis and enzyme activity measured using tritiated androstenedione as the substrate. The effects of differing concentrations of substrate and product (E1 and E2) and four aromatase inhibitors were assessed. RESULTS: At all substrate concentrations tested, the T(201)M variant showed substantially increased activity compared to the wild-type (Vmax: variant, 738 +/- 36 pmol/h . mg; wild-type, 189 +/- 17 pmol/h . mg, P < 0.0001; Km: variant, 64.4 +/- 19.3 nm; wild-type, 46.6 +/- 9.1 nm, P = 0.04). Kinetic analysis showed evidence of substrate inhibition for the wild-type, but no product inhibition was demonstrated for either transcript. Formestane, chrysin, and letrozole had no differential inhibitory effect on the two transcripts, but aminoglutethimide inhibition was substantially reduced in the variant compared to wild-type (IC(50): wild-type, 1.3 +/- 0.2 nm; variant, 45 +/- 14.2 nm, P = 0.002; and Ki: wild-type, 0.7 +/- 0.2 nm; variant, 29.6 +/- 9.7 nm, P = 0.0001). CONCLUSIONS: In addition to loss of function mutations previously described, a new naturally occurring relatively common alteration of enzyme structure at T(201)M increases enzyme activity and reduces the inhibitory effect of aminoglutethimide. These findings identify the T(201)M site, distant from the substrate-binding site and not previously considered to play a role in enzyme activity, as a functionally important area of the enzyme that may play a role in the propensity to disease. Common to other cytochrome P450 enzymes, wild-type aromatase demonstrates substrate but not product inhibition.

Gene expression profiling in human skeletal muscle during recovery from eccentric exercise.

We used cDNA microarrays to screen for differentially expressed genes during recovery from exercise-induced muscle damage in humans. Male subjects (n = 4) performed 300 maximal eccentric contractions, and skeletal muscle biopsy samples were analyzed at 3 h and 48 h after exercise. In total, 113 genes increased 3 h postexercise, and 34 decreased. At 48 h postexercise, 59 genes increased and 29 decreased. On the basis of these data, we chose 19 gene changes and conducted secondary analyses using real-time RT-PCR from muscle biopsy samples taken from 11 additional subjects who performed an identical bout of exercise. Real-time RT-PCR analyses confirmed that exercise-induced muscle damage led to a rapid (3 h) increase in sterol response element binding protein 2 (SREBP-2), followed by a delayed (48 h) increase in the SREBP-2 gene targets Acyl CoA:cholesterol acyltransferase (ACAT)-2 and insulin-induced gene 1 (insig-1). The expression of the IL-1 receptor, a known regulator of SREBP-2, was also elevated after exercise. Taken together, these expression changes suggest a transcriptional program for increasing cholesterol and lipid synthesis and/or modification. Additionally, damaging exercise induced the expression of protein kinase H11, capping protein Z alpha (capZalpha), and modulatory calcineurin-interacting protein 1 (MCIP1), as well as cardiac ankryin repeat protein 1 (CARP1), DNAJB2, c-myc, and junD, each of which are likely involved in skeletal muscle growth, remodeling, and stress management. In summary, using DNA microarrays and RT-PCR, we have identified novel genes that respond to skeletal muscle damage, which, given the known biological functions, are likely involved in recovery from and/or adaptation to damaging exercise.

Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers.

OBJECTIVES: To assess the clinical effectiveness of positron emission tomography (PET) using 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) in breast, colorectal, head and neck, lung, lymphoma, melanoma, oesophageal and thyroid cancers. Management decisions relating to diagnosis, staging/restaging, recurrence, treatment response and radiotherapy (RT) planning were evaluated separately. DATA SOURCES: Major electronic databases were searched up to August 2005 and a survey of UK PET facilities was performed in February 2006. REVIEW METHODS: This assessment augments the systematic search undertaken in a previous review. Studies were limited to those using commercial dedicated PET or PET/computed tomography (CT) devices with FDG, in one of the eight cancers. RESULTS: The new search identified six systematic reviews and 158 primary studies. An economic model for England showed that in non-small cell lung cancer (NSCLC) FDG-PET was cost-effective in CT node-negative patients, but not in CT node-positive patients. A less robust model also showed that FDG-PET was cost-effective in RT planning for NSCLC. A model for Scotland showed that in late-stage Hodgkin's lymphoma (HL), FDG-PET was cost-effective for restaging after induction therapy. For staging/restaging colorectal cancer, FDG-PET changed patient management in a way that can impact on curative therapy. For detection of solitary pulmonary nodule (SPN) there was also impact on patient management, but the resulting effect on patient outcomes was unclear. FDG-PET had an impact on patient management across paediatric lymphoma decisions, but further study of individual management decisions is required. For other cancer management decisions, the evidence on patient management is weak. FDG-PET was accurate in detecting distant metastases across several sites, but sensitivity was variable for detection of lymph-node metastases and poor in early stage disease where sentinel lymph-node biopsy would be used and for small lesions. There were 61 studies of treatment response. These were generally small and covered all cancers except melanoma. They showed that FDG-PET imaging could be correlated with response, in some cases, but the impact on patient management was not documented. There were 17 small studies of RT planning in four cancers; here, FDG-PET led to alteration of RT volumes and doses, but the impact on patient outcomes was not studied. FDG-PET improved diagnostic accuracy compared with alternatives in a number of other cancer management decisions, but more comparative evidence is needed. There were 23 studies of PET/CT in six cancers (excluding breast and melanoma). In these FDG-PET/CT generally improved accuracy by 10-15% over PET, resolving some equivocal images. The survey of PET facilities in the UK showed that PET and PET/CT are being used for a variety of cancer indications. PET facilities are not distributed evenly across the UK and use is inconsistent. Various research studies are underway in most centres, but only a few of these are collaborative studies. There is major variation in throughput and cost per scan (635-1300 pounds). CONCLUSIONS: The strongest evidence for the clinical effectiveness of FDG-PET is in staging NSCLC, restaging HL, staging/restaging colorectal cancer and detection of SPN. Some of these may still require clinical audit to augment the evidence base. Other management decisions require further research to show the impact of FDG-PET on patient management or added value in the diagnostic pathway. It is likely that capital investment will be in the newer PET/CT technology, for which there is less evidence. However, as this technology appears to be slightly more accurate than PET/CT, the PET clinical effectiveness results presented here can be extrapolated to cover PET/CT. PET research could be undertaken on FDG-PET or FDG-PET/CT, using a standard cancer work-up process on typical patients who are seen within the NHS in England. For treatment response and RT planning, the need for larger studies using consistent methods across the UK is highlighted as a priority for all cancers. For all studies, consideration should be given to collaboration across sites nationally and internationally, taking cognisance of the work of the National Cancer Research Institute.

The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease.

OBJECTIVES: To provide an update review of the best quality evidence for the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine for mild to moderately severe Alzheimer's disease (AD) and of memantine for moderately severe to severe AD. DATA SOURCES: Electronic databases, experts in the field and manufacturer submissions to the National Institute for Health and Clinical Excellence (NICE). REVIEW METHODS: A systematic review of the literature and an economic evaluation were undertaken. The quality of included randomised controlled trials (RCTs) was assessed using criteria developed by the NHS Centre for Reviews and Dissemination. An outline assessment of economic evaluations was undertaken using a standard checklist. The clinical and cost-effectiveness data were synthesised through a narrative review with full tabulation of the results of included studies. Where appropriate, meta-analysis of data was undertaken. RESULTS: For mild to moderately severe AD, the results of the study suggested that all three treatments were beneficial when assessed using cognitive outcome measures. Global outcome measures were positive for donepezil and rivastigmine, but mixed for galantamine. Results for measures of function were mixed for donepezil and rivastigmine, but positive for galantamine. Behaviour and mood measures were mixed for donepezil and galantamine, but showed no benefit for rivastigmine. For memantine, two published RCTs were included; in one of these trials the participants were already being treated with donepezil. The results suggest that memantine is beneficial when assessed using functional and global measurements. The effect of memantine on cognitive and behaviour and mood outcomes is, however, less clear. Literature on the cost-effectiveness of donepezil, rivastigmine and galantamine was dominated by industry-sponsored studies, and studies varied in methods and results. Of the three UK studies, two report donepezil as not cost-effective, whereas a third study reports an additional cost (1996 pounds sterling) of between 1200 pounds sterling and 7000 pounds sterling per year in a non-severe AD health state (concerns over these estimates are raised, suggesting that they may underestimate the true cost-effectiveness of donepezil). Cost-effectiveness analysis undertaken in this review suggests that donepezil treatment has a cost per quality-adjusted life-year (QALY) in excess of 80,000 pounds sterling, with donepezil treatment reducing the mean time spent in full-time care (delays progression of AD) by 1.42-1.59 months (over a 5-year period). From four published cost-effectiveness studies, two UK studies report additional costs associated with rivastigmine treatment. Cost-effectiveness analysis undertaken in the current review suggests that rivastigmine treatment has a cost per QALY in excess of 57,000 pounds sterling, with rivastigmine treatment reducing the mean time spent in full-time care (delays progression) by 1.43-1.63 months (over a 5-year period). From five published cost-effectiveness studies, one UK study reports a cost per QALY of 8693 pounds sterling for 16-mg galantamine treatment and 10,051 pounds sterling for 24-mg galantamine treatment (concerns raised suggest that this may underestimate the true cost-effectiveness of galantamine). Cost-effectiveness analysis undertaken in the present review suggests that galantamine treatment has a cost per QALY in excess of 68,000 pounds sterling, with galantamine reducing the time spent in full-time care (delays progression) by 1.42-1.73 months (over a 5-year period). From two published cost-effectiveness studies, one reports analysis for the UK, finding that memantine treatment results in cost savings and benefits in terms of delaying disease progression (concerns raised suggest that this may underestimate the true cost-effectiveness of memantine). In the current review, the cost-effectiveness of memantine has not been modelled separately, but where alternative parameter inputs on the cost structure and utility values have been used in a reanalysis using the industry model, the cost-effectiveness is reported at between 37,000 pounds sterling and 52,000 pounds sterling per QALY, with this alternative analysis still based on what is regarded as an optimistic or favourable effectiveness profile for memantine. CONCLUSIONS: Although results from the clinical effectiveness review suggest that these treatments may be beneficial, a number of issues need to be considered when assessing the results of the present review, such as the characteristics of the participants included in the individual trials, the outcome measures used, the length of study duration, the effects of attrition and the relationship between statistical significance and clinical significance. Many included trials were sponsored by industry. For donepezil, rivastigmine and galantamine, the cost savings associated with reducing the mean time spent in full-time care do not offset the cost of treatment sufficiently to bring estimated cost-effectiveness to levels generally considered acceptable by NHS policy makers. It is difficult to draw conclusions on the cost-effectiveness of memantine; it is suggested that further amendments to the potentially optimistic industry model (measure of effect) would offer higher cost per QALY estimates. Future research should include: information on the quality of the outcome measures used; development of quality of life instruments for patients and carers; studies assessing the effects of these interventions of durations longer than 12 months; comparisons of benefits between interventions; and research on the prediction of disease progression.

A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease.

BACKGROUND: The use of cholinesterase inhibitors for Alzheimer's disease (AD) is currently being appraised by the National Institute for Clinical Evidence (NICE). This article provides the latest evidence that NICE will be using as part of this appraisal process. OBJECTIVE: To provide a systematic review of the best quality evidence of the effects of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in people with mild to moderately-severe AD. DESIGN: Electronic databases were searched, references of all retrieved articles were checked, and experts were contacted for advice, peer review and to identify additional references. Randomised controlled trials (RCTs) were included if they fulfilled pre-specified criteria. Data were synthesised through a narrative review. RESULTS: Twenty-six RCTs that compared any one of the cholinesterase inhibitors with either a control group or with another cholinesterase inhibitor were included. The quality of reporting and methodology was varied. Treatment with donepezil, rivastigmine or galantamine resulted in significantly better cognitive performance using the ADAS-cog scale when compared with placebo. These findings were generally supported using the MMSE scale. Results from head to head comparisons were limited by the low number of studies and the study quality; generally showing no robust support for any one drug. Few studies evaluated quality of life. Adverse events were generally related to the gastrointestinal system, with a tendency for these to be more common in the treatment arms. CONCLUSIONS: The cholinesterase inhibitors donepezil, rivastigmine, and galantamine can delay cognitive impairment in patients with mild to moderately-severe AD for at least 6 months duration.

The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

OBJECTIVES: To estimate the effectiveness and cost-effectiveness of dual-chamber pacemakers versus single-chamber atrial or single-chamber ventricular pacemakers in the treatment of bradycardia due to sick sinus syndrome (SSS) or atrioventricular block (AVB). DATA SOURCES: Electronic databases and relevant Internet sites. Contact with device manufacturers and experts in the field. REVIEW METHODS: A systematic review was carried out of randomised controlled trials (RCTs). The quality of selected studies was appraised using standard frameworks. Meta-analyses, using random effects models, were carried out where appropriate. Limited exploration of heterogeneity was possible. Critical appraisal of economic evaluations was carried out using two frameworks. A decision-analytic model was developed using a Markov approach, to estimate the cost-effectiveness of dual-chamber versus ventricular or atrial pacing over 5 and 10 years as cost per quality-adjusted life-year (QALY). Uncertainty was explored using one-way and probabilistic sensitivity analyses. RESULTS: The searches retrieved a systematic review of effectiveness and cost-effectiveness published in 2002, four parallel group RCTs and 28 cross-over trials. Dual-chamber pacing was associated with lower rates of atrial fibrillation, particularly in SSS, than ventricular pacing, and prevents pacemaker syndrome. Higher rates of atrial fibrillation were seen with dual-chamber pacing than with atrial pacing. Complications occurred more frequently in dual-chamber pacemaker insertion. The cost of a dual-chamber system, over 5 years, including cost of complications and subsequent clinical events in the population, was estimated to be around 7400 pounds. The overall cost difference between single and dual systems is not large over this period: around 700 pounds more for dual-chamber devices. The cost-effectiveness of dual-chamber compared with ventricular pacing was estimated to be around 8500 pounds per QALY in AVB and 9500 pounds in SSS over 5 years, and around 5500 pounds per QALY in both populations over 10 years. Under more conservative assumptions, the cost-effectiveness of dual-chamber pacing is around 30,000 pounds per QALY. The probabilistic sensitivity analysis showed that, under the base-case assumptions, dual-chamber pacing is likely to be considered cost-effective at levels of willingness to pay that are generally considered acceptable by policy makers. In contrast, atrial pacing may be cost-effective compared with dual-chamber pacing. CONCLUSIONS: Dual-chamber pacing results in small but potentially important benefits in populations with SSS and/or AVB compared with ventricular pacemakers. Pacemaker syndrome is a crucial factor in determining cost-effectiveness; however, difficulties in standardising diagnosis and measurement of severity make it difficult to quantify. Dual-chamber pacing is in common usage in the UK. Recipients are more likely to be younger. Insufficient evidence is currently available to inform policy on specific groups who may benefit most from pacing with dual-chamber devices. Further important research is underway. Outstanding research priorities include the economic evaluation of UKPACE studies of the classification, diagnosis and utility associated with pacemaker syndrome and evidence on the effectiveness of pacemakers in children.