Substrate stiffness promotes vascular smooth muscle cell calcification by reducing the levels of nuclear actin monomers.

BACKGROUND: Vascular calcification (VC) is a prevalent independent risk factor for adverse cardiovascular events and is associated with diabetes, hypertension, chronic kidney disease, and atherosclerosis. However, the mechanisms regulating the osteogenic differentiation of vascular smooth muscle cells (VSMC) are not fully understood. METHODS: Using hydrogels of tuneable stiffness and lysyl oxidase-mediated stiffening of human saphenous vein ex vivo, we investigated the role of substrate stiffness in the regulation of VSMC calcification. RESULTS: We demonstrate that increased substrate stiffness enhances VSMC osteogenic differentiation and VSMC calcification. We show that the effects of substrate stiffness are mediated via a reduction in the level of actin monomer within the nucleus. We show that in cells interacting with soft substrate, elevated levels of nuclear actin monomer repress osteogenic differentiation and calcification by repressing YAP-mediated activation of both TEA Domain transcription factor (TEAD) and RUNX Family Transcription factor 2 (RUNX2). CONCLUSION: This work highlights for the first time the role of nuclear actin in mediating substrate stiffness-dependent VSMC calcification and the dual role of YAP-TEAD and YAP-RUNX2 transcriptional complexes.

Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (Aß) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that Aß is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e., microglia), which culminates in neuronal damage and cognitive decline. To test this hypothesis, many in vitro systems have been established to study Aß-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale. METHODS: We used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic Aß or LPS and INFγ. RESULTS: We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell model that best resembles primary microglia. Surprisingly, synthetic Aß does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of Aß formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INFγ activate microglia and induce transcriptional changes that resemble many, but not all, aspects of the transcriptomic profiles of disease associated microglia (DAM) present in the AD brain. CONCLUSIONS: These results suggest that synthetic Aß treatment of innate immune cell cultures does not recapitulate transcriptional profiles observed in microglia from AD brains. In contrast, treating IMGL with LPS and INFγ induces transcriptional changes similar to those observed in microglia detected in AD brains.

Determination of the baseline tritium concentrations (HTO, TFWT and OBT) in soil and plants in Ontario, Canada.

Tritiated water (HTO), tissue free water tritium (TFWT) and organically bound tritium (OBT) activity concentrations in soil and plant leaves, collected at background areas in Ontario, were measured to quantify the current tritium baseline. Five representative background sites, based on their geological characteristics and residential populations, have been selected for this study. Undisturbed soils, plant leaves and surface water samples were collected at 5 sites (London, Kapuskasing, Thunder Bay, Elliot Lake and Cornwall areas) in 2015. Water sample HTO activity concentrations were measured using Liquid Scintillation Counting (LSC, ALOKA), and HTO activity concentrations for soil and TFWT for plant leaves were measured by LSC (Quantulus 1220) on water extracted from frozen samples using a freeze-drying vacuum system equipped with a liquid nitrogen trap. Plant leaf OBT levels were obtained by combustion of rinsed freeze-dried samples using a Parr combustion system, while soil OBT values were obtained using a tube furnace combustion system. Combustion water was distilled before being counted by LSC (Quantulus 1220). HTO activity concentrations were found to range between 1.4 and 2.0 Bq/L (MDA = 0.5 Bq/L) in surface water and soil samples. TFWT values were less than the minimum detectable activity (MDA = 3.5 Bq/L) in plant leaves. In contrast, OBT activity concentrations (MDA = 5 Bq/L) ranged from 5.7 to 17.1 Bq/L in plant leaves and 8.3-20.7 Bq/L in surface soil (0-5 cm depth). The overall OBT activity concentrations were higher in the London and the Cornwall areas. Lower levels were measured near Thunder Bay, Kapuskasing and Elliot Lake. There was no obvious relationship between soil OBT activity concentrations and soil types. The results provide the current tritium (HTO, TFWT and OBT) baseline values in Ontario. These values will be helpful for use as background locations for the evaluation of past and future environmental tritium inputs associated with nuclear facilities, and will be taken into account when evaluating the environmental impact of nuclear facilities in Ontario. Since samples in this study were primarily taken in wooded areas, some questions remain regarding the possibility that soil samples in open, non-wooded areas could show different HTO and OBT contents than those presented in this study.

Validity and severity thresholds for the depression subscale of the affective self rating scale: An equipercentile equating study using classical test theory.

BACKGROUND: The Affective Symptoms Scale (ASRS) is a unique instrument designed to separately measure depressive and manic symptoms in mood disorders. We validated the ASRS against the Patient Health Questionnaire (PHQ-9) and the Quick Inventory of Depressive Symptomatology (QIDS-16). METHODS: A retrospective study of 258 patients who completed the PHQ-9, QIDS-16 and ASRS as part of routine clinical care. To establish meaningful clinical thresholds for the depression subscale of the ASRS, it was equated with the QIDS and the PHQ-9. RESULTS: The depression subscale of the ASRS had significant positive correlations with the QIDS-16 and the PHQ-9 (respectively, r= 0.8, t[253] = 19.8, p < 0.001, and r= 0.8, t[245] = 28.2, p < 0.001). The equipercentile equating method with the PHQ-9 indicated that the thresholds corresponded to ASRS depression subscale scores of 5.4, 10.6, 16.1, and 23. Equating with the QIDS indicated that thresholds corresponded to ASRS depression subscale scores of 5.1, 11, 18.4, and 27.5. LIMITATIONS: Limitations include a small sample size that did not allow more detailed statistical analysis, such as Item Response Theory. The population is a heterogenous population at a university outpatient setting. CONCLUSIONS: The ASRS depression subscale significantly correlated with the PHQ-9 and QIDS-16. Our proposed threshold scores for the ASRS are 5, 11, 16 and 23 to indicated mild, moderate, severe and very severe depression respectively.

Sociability increases survival of adult female giraffes.

Studies increasingly show that social connectedness plays a key role in determining survival, in addition to natural and anthropogenic environmental factors. Few studies, however, integrated social, non-social and demographic data to elucidate what components of an animal's socio-ecological environment are most important to their survival. Female giraffes (Giraffa camelopardalis) form structured societies with highly dynamic group membership but stable long-term associations. We examined the relative contributions of sociability (relationship strength, gregariousness and betweenness), together with those of the natural (food sources and vegetation types) and anthropogenic environment (distance from human settlements), to adult female giraffe survival. We tested predictions about the influence of sociability and natural and human factors at two social levels: the individual and the social community. Survival was primarily driven by individual- rather than community-level social factors. Gregariousness (the number of other females each individual was observed with on average) was most important in explaining variation in female adult survival, more than other social traits and any natural or anthropogenic environmental factors. For adult female giraffes, grouping with more other females, even as group membership frequently changes, is correlated with better survival, and this sociability appears to be more important than several attributes of their non-social environment.

Genome-Wide Association Study Identifies Single Nucleotide Polymorphism Markers Associated with Mycelial Growth (at 15, 20, and 25°C), Mefenoxam Resistance, and Mating Type in Phytophthora infestans.

Phenotypic diversity among individuals defines the potential for evolutionary selection in a species. Phytophthora infestans epidemics are generally thought to be favored by moderate to low temperatures, but temperatures in many locations worldwide are expected to rise as a result of global climate change. Thus, we investigated variation among individuals of P. infestans for relative growth at different temperatures. Isolates of P. infestans came from three collections: (i) individual genotypes recently dominant in the United States, (ii) recently collected individuals from Central Mexico, and (iii) progeny of a recent sexual recombination event in the northeastern United States. In general, these isolates had optimal mycelial growth rates at 15 or 20°C. However, two individuals from Central Mexico grew better at higher temperatures than did most others and two individuals grew relatively less at higher temperatures than did most others. The isolates were also assessed for mefenoxam sensitivity and mating type. Each collection contained individuals of diverse sensitivities to mefenoxam and individuals of the A1 and A2 mating type. We then searched for genomic regions associated with phenotypic diversity using genotyping-by-sequencing. We found one single nucleotide polymorphism (SNP) associated with variability in mycelial growth at 20°C, two associated with variability in mycelial growth at 25°C, two associated with sensitivity to mefenoxam, and one associated with mating type. Interestingly, the SNPs associated with mefenoxam sensitivity were found in a gene-sparse region, whereas the SNPs associated with growth at the two temperatures and mating type were found both at more gene-dense regions.

Top predators induce habitat shifts in prey within marine protected areas.

Emerging conservation efforts for the world's large predators may, if successful, restore natural predator-prey interactions. Marine reserves, where large predators tend to be relatively common, offer an experimental manipulation to investigate interactions between large-bodied marine predators and their prey. We hypothesized that southern stingrays-large, long-lived and highly interactive mesopredators-would invest in anti-predator behavior in marine reserves where predatory large sharks, the primary predator of stingrays, are more abundant. Specifically, we predicted southern stingrays in marine reserves would reduce the use of deep forereef habitats in the favor of shallow flats where the risk of shark encounters is lower. Baited remote underwater video was used to survey stingrays and reef sharks in flats and forereef habitats of two reserves and two fished sites in Belize. The interaction between "protection status" and "habitat" was the most important factor determining stingray presence. As predicted, southern stingrays spent more time interacting with baited remote underwater videos in the safer flats habitats, were more likely to have predator-inflicted damage inside reserves, and were less abundant in marine reserves but only in the forereef habitat. These results are consistent with a predation-sensitive habitat shift rather than southern stingray populations being reduced by direct predation from reef sharks. Our study provides evidence that roving predators can induce pronounced habitat shifts in prey that rely on crypsis and refuging, rather than active escape, in high-visibility, heterogeneous marine habitats. Given documented impacts of stingrays on benthic communities it is possible restoration of reef shark populations with reserves could induce reef ecosystem changes through behavior-mediated trophic cascades.

Effects of vitamin supplementation on inflammatory markers and psychological wellbeing among distressed women: a randomized controlled trial.

BACKGROUND: Multivitamins are a popular supplement taken to promote physical and mental health. During periods of stress, they may have a protective role for health and wellbeing, although the current evidence of their efficacy is mixed. OBJECTIVE: To determine whether multivitamin supplementation impacts psychological and inflammatory markers of women who are experiencing psychological distress. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: An 8-week randomized controlled trial was conducted to assess changes in both psychological state and pro-inflammatory markers of patients receiving multivitamins or placebo. The sample comprised women who reported elevated psychological distress in the previous 4 weeks. MAIN OUTCOME MEASURES: Psychological state was assessed using Spielberger's State-Trait Personality Inventory to assess anxiety, curiosity, depression and anger. Pro-inflammatory markers comprised interleukin (IL)-1ß, IL-5, IL-6, tumour necrosis factor (TNF)-α and TNF-ß. RESULTS: Improvements across time were observed for all psychological measures and cytokines, except IL-5, but were independent of the active intervention. Only TNF-ß demonstrated a significant differential change between groups over the course of the intervention, in favour of multivitamin supplementation (active group mean rank decreased from 11.1 to 7.1; placebo group mean rank decreased from 8.9 to 7.8). CONCLUSION: The results suggest that administration of multivitamins was not effective in improving psychological state. However, some evidence supported the positive impact of multivitamin supplementation on pro-inflammatory cytokine profiles of women currently experiencing stress.

Occurrence and habitat use of the critically endangered smalltooth sawfish Pristis pectinata in the Bahamas.

This study documents and discusses recent (2002-2015) sightings and captures of smalltooth sawfish Pristis pectinata in the Bahamas. Movement patterns and habitat preferences of five P. pectinata are examined: two tracked with acoustic telemetry in Bimini and three tagged with pop-up archival transmitting tags in Andros. Historically, P. pectinata may have been distributed throughout the Bahamas; however, since 2002 only 61 encounters were recorded including: Andros (30), Bimini (19) and a handful across other Islands (12). In Bimini, all P. pectinata were >225 cm (stretched total length, LST) suggesting that it is not used as a nursery area. Pristis pectinata in Andros ranged from c. 80 to 450 cm (LST) indicating that this island might be an important nursery and breeding habitat. Pristis pectinata tracked in both islands remained at depths <3 m, often adjacent to mangrove habitats, displaying residency from 42 days (Bimini) to 180 days (Andros). These preliminary findings confirm the Bahamas as an important habitat for P. pectinata and emphasize the urgent need for national protection and management of this population.

Evaluation of Potential Pharmacokinetic Drug-Drug Interaction between Armodafinil and Aripiprazole in Healthy Adults.

INTRODUCTION: Armodafinil, a moderate inducer of cytochrome P450 (CYP) 3A4, has been studied as adjunctive therapy to maintenance medications for major depressive episodes associated with bipolar I disorder. We evaluated the effect of daily dosing with armodafinil on the pharmacokinetics and safety of the CYP3A4 substrate aripiprazole, an atypical antipsychotic used to treat bipolar I disorder. METHODS: Healthy adults received 15 mg aripiprazole alone and after armodafinil (250 mg/day) pretreatment. Pharmacokinetic parameters were derived from plasma concentrations of aripiprazole and its active metabolite, dehydro-aripiprazole, obtained over 16 days after each aripiprazole administration. Steady-state pharmacokinetics of armodafinil and its 2 circulating metabolites was assessed. RESULTS: Of 36 subjects enrolled, 24 were evaluable for pharmacokinetic analysis. Armodafinil reduced systemic exposure to aripiprazole (Cmax, - 8%; AUC0-∞, -34%) and dehydro-aripiprazole, which is both formed and eliminated in part via CYP3A4 (Cmax, - 10%; AUC0-∞, - 32%). Adverse events were generally consistent with known safety profiles of each agent. DISCUSSION: Systemic exposure to aripiprazole and dehydro-aripiprazole was moderately reduced following armodafinil pretreatment. The combination was generally well tolerated under the conditions studied.

An investigation of the support needs of men and partners throughout the prostate cancer journey.

OBJECTIVE: Prostate cancer is one of the mostly commonly diagnosed cancers in men. Unfortunately, the treatment for this cancer can have a number of negative side effects, both for the man himself and his partner. This study investigated the support needs of both men and partners throughout the prostate cancer journey and how this journey may be optimally managed. METHODS: Thirty-one men who had undergone prostate cancer treatment within the last 6 years and 31 partners answered a questionnaire, which explored support care issues as identified in the literature and from focus groups. RESULTS: Men and partners were moderately satisfied with information given regarding diagnosis, treatment and side effects, but partners were more satisfied with information relating to the particular chosen treatment. Men's understanding of their chosen treatment's potential side effects was significantly different from their understanding of diagnosis, cancer outcome, treatment options and selected treatment. Timing of information delivery was preferred by men at diagnosis, whereas partners preferred after the diagnosis. Men wanted more time to think about the diagnosis and treatment, whereas partners wanted an opportunity to discuss the diagnosis. The management of common side effects such as emotional changes, incontinence and erectile dysfunction was rated as 'somewhat' satisfactory. CONCLUSION: Men and partners may have different educational and supportive needs throughout the prostate cancer journey that require attention and tailored management.

Differential growth in estuarine and freshwater habitats indicated by plasma IGF1 concentrations and otolith chemistry in Dolly Varden Salvelinus malma.

This study employed a combination of otolith microchemistry to indicate the recent habitat use, and plasma concentrations of the hormone insulin-like growth factor 1 (IGF1) as an index of recent growth rate, to demonstrate differences in growth and habitat use by Dolly Varden Salvelinus malma occupying both freshwater and estuarine habitats in south-west Alaska. Extensive sampling in all habitats revealed that fish had higher IGF1 levels in estuarine compared to lake habitats throughout the summer, and that the growth rates in different habitats within the estuary varied seasonally. In addition, otolith microchemistry indicated differentiation in estuarine habitat use among individual S. malma throughout summer months. Although growth in the estuary was higher than in fresh water in nearly all sites and months, the benefits and use of the estuarine habitats varied on finer spatial scales. Therefore, this study further illustrates the diverse life histories of S. malma and indicates an evaluation of the benefits of marine waters needs to include sub-estuary scale habitat use.

Systematic review of the psychological consequences of false-positive screening mammograms.

BACKGROUND: In the UK, women aged 50-73 years are invited for screening by mammography every 3 years. In 2009-10, more than 2.24 million women in this age group in England were invited to take part in the programme, of whom 73% attended a screening clinic. Of these, 64,104 women were recalled for assessment. Of those recalled, 81% did not have breast cancer; these women are described as having a false-positive mammogram. OBJECTIVE: The aim of this systematic review was to identify the psychological impact on women of false-positive screening mammograms and any evidence for the effectiveness of interventions designed to reduce this impact. We were also looking for evidence of effects in subgroups of women. DATA SOURCES: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Health Management Information Consortium, Cochrane Central Register for Controlled Trials, Cochrane Database of Systematic Reviews, Centre for Reviews and Dissemination (CRD) Database of Abstracts of Reviews of Effects, CRD Health Technology Assessment (HTA), Cochrane Methodology, Web of Science, Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index-Science, Conference Proceeding Citation Index-Social Science and Humanities, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Sociological Abstracts, the International Bibliography of the Social Sciences, the British Library's Electronic Table of Contents and others. Initial searches were carried out between 8 October 2010 and 25 January 2011. Update searches were carried out on 26 October 2011 and 23 March 2012. REVIEW METHODS: Based on the inclusion criteria, titles and abstracts were screened independently by two reviewers. Retrieved papers were reviewed and selected using the same independent process. Data were extracted by one reviewer and checked by another. Each included study was assessed for risk of bias. RESULTS: Eleven studies were found from 4423 titles and abstracts. Studies that used disease-specific measures found a negative psychological impact lasting up to 3 years. Distress increased with the level of invasiveness of the assessment procedure. Studies using instruments designed to detect clinical levels of morbidity did not find this effect. Women with false-positive mammograms were less likely to return for the next round of screening [relative risk (RR) 0.97; 95% confidence interval (CI) 0.96 to 0.98] than those with normal mammograms, were more likely to have interval cancer [odds ratio (OR) 3.19 (95% CI 2.34 to 4.35)] and were more likely to have cancer detected at the next screening round [OR 2.15 (95% CI 1.55 to 2.98)]. LIMITATIONS: This study was limited to UK research and by the robustness of the included studies, which frequently failed to report quality indicators, for example failure to consider the risk of bias or confounding, or failure to report participants' demographic characteristics. CONCLUSIONS: We conclude that the experience of having a false-positive screening mammogram can cause breast cancer-specific psychological distress that may endure for up to 3 years, and reduce the likelihood that women will return for their next round of mammography screening. These results should be treated cautiously owing to inherent weakness of observational designs and weaknesses in reporting. Future research should include a qualitative interview study and observational studies that compare generic and disease-specific measures, collect demographic data and include women from different social and ethnic groups.

A systematic review of the effectiveness and cost-effectiveness of bilateral multichannel cochlear implants in adults with severe-to-profound hearing loss.

BACKGROUND: In the UK, approximately 10 000 people have cochlear implants, more than 99% with a unilateral implant. Evidence shows that adults implanted bilaterally may benefit from binaural advantages; however, systematic review evidence is limited. OBJECTIVES OF THE REVIEW: To conduct a systematic review to discover the evidence for effectiveness and cost-effectiveness of using bilateral cochlear implants in adults with severe-to-profound hearing loss by comparing their effectiveness with unilateral cochlear implantation or unilateral cochlear implantation and acoustic hearing aid in the contralateral ear. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: This examined 16 electronic databases, plus bibliographies and references for published and unpublished studies. EVALUATION METHOD: Abstracts were independently assessed against inclusion criteria by two researchers, and disagreements were resolved. Selected papers were then retrieved and further independently assessed in a similar way. Included studies had their data extracted by one reviewer and checked by another. RESULTS: Searches yielded 2892 abstracts producing 19 includable studies. Heterogeneity between studies precluded meta-analysis. However, all studies reported that bilateral cochlear implants improved hearing and speech perception: one randomised controlled trial found a significant binaural benefit over the first ear alone for speech and noise from the front (12.6 ± 5.4%, P < 0.001) and when noise was ipsilateral to the first ear (21 ± 6%, P < 0.001); and another found a significant benefit for spatial hearing at 3 and 9 months post-implantation compared with pre-implantation [mean difference (sd) scores: 3 months = 1.46 (0.83-2.09), P < 0.01].Quality of life results varied, showing bilateral implantation may improve quality of life in the absence of worsening tinnitus. Limited cost-effectiveness evidence showed that bilateral implantation is probably only cost-effective at a willingness-to-pay threshold above £62 000 per quality adjusted life year. CONCLUSIONS: Despite inconsistency in the quality of available evidence, the robustness of systematic review methods gives weight to the positive findings of included studies demonstrating that bilateral implantation is clinically effective in adults but unlikely to be cost-effective.

The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model.

BACKGROUND: Alzheimer's disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. OBJECTIVES: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). DATA SOURCES: Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. REVIEW METHODS: The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). INTERVENTIONS: mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities. RESULTS: Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £'30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £'30,000 per QALY (27% at a WTP of £'20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£'69,592 vs £'69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £'30,000 per QALY is 38% (and 28% at a WTP of £'20,000 per QALY). The deterministic ICER for memantine is £'32,100 per/QALY and the probabilistic ICER is £'36,700 per/QALY. LIMITATIONS: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. CONCLUSIONS: The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug's use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Responsiveness of the OARSI-OMERACT osteoarthritis pain and function measures.

OBJECTIVE: To assess the responsiveness of the Intermittent and Constant Osteoarthritis Pain (ICOAP) measure, Hip Disability and Osteoarthritis Outcome Score Physical Function Short Form (HOOS-PS), and the Knee Disability and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS) in a pharmacological trial. METHODS: Data were obtained from a randomized double-blind trial comparing naproxcinod with naproxen and ibuprofen in individuals with hip or knee osteoarthritis (OA) (NCT00662896). Participants completed the ICOAP, HOOS-PS/KOOS-PS, and Western Ontario and McMaster Universities OA Index (WOMAC) Likert version 3.0 before and 13 weeks after treatment. In hip and knee OA participants separately, the mean pre-post treatment change in scores, effect size (ES) and standardized response mean (SRM) were determined for each measure by treatment arm, and for all arms combined. RESULTS: Of 349 trial participants, 156 with knee OA and 48 with hip OA completed all measures at both time-points and were included (mean age 61 years; two-thirds female). Although there was both within treatment and between treatment variability in response, among knee OA participants, ICOAP intermittent, constant, and total scores and KOOS-PS scores showed, on average, moderate effects, with ESs ranging from 0.46 to 0.54 and SRMs from 0.49 to 0.56. Similar changes were seen for the WOMAC pain and function subscales (0.58 and 0.58, respectively). In those with hip OA, no significant improvement in symptoms was seen for any measure. CONCLUSION: Responsiveness to pharmaceutical intervention was demonstrated for ICOAP and KOOS-PS among participants with knee OA. Absence of treatment response precluded assessment of responsiveness in hip OA.

Addressing policy barriers to paternal involvement during pregnancy.

Efforts to reduce infant mortality in the United States have failed to incorporate paternal involvement. Research suggests that paternal involvement, which has been recognized as contributing to child development and health for many decades, is likely to affect infant mortality through the mother's well-being, primarily her access to resources and support. In spite of that, systemic barriers facing the father and the influence on his involvement in the pregnancy have received little attention. The Commission on Paternal Involvement in Pregnancy Outcomes (CPIPO) has identified the most important social barriers to paternal involvement during pregnancy and outlined a set of key policy priorities aimed at fostering paternal involvement. This article summarizes the key recommendations, including equitable paternity leave, elimination of marriage as a tax and public assistance penalty, integration of fatherhood initiatives in MCH programs, support of low-income fathers through employment training, father inclusion in family planning services, and expansion of birth data collection to include father information.

Systematic review of the effectiveness of weight management schemes for the under fives.

Overweight and obesity in pre-school children are an increasing problem, with poor diet and exercise habits laying the foundation for serious health risks in later life. Yet most research into childhood obesity has focused on school-age children. Two previous systematic reviews of pre-school children have included uncontrolled designs and self-report outcomes potentially biasing the results in favour of the interventions. We have conducted a systematic review of the effectiveness and cost-effectiveness of weight management schemes for the under fives restricting the inclusion criteria to controlled trials with objective measures. We found four effectiveness randomized controlled trials of prevention. No treatment or cost-effectiveness studies were found. Only one study in a Latino community showed a statistically significant advantage from the intervention in a slower rate of increase in body mass index. However, trends in decrease in body mass index and weight loss favoured the intervention groups in other studies. From the studies characteristics we hypothesize that important features to include in future interventions may be; cultural sensitivity, sustained moderate to vigorous exercise, active engagement of the parents in the programme and as role models of healthy living and active engagement of the children in nutrition education. Further randomized controlled trials are needed in this population.