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To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up.
Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo.
Community settings and care homes in 26 UK centers.
People with probable or possible Alzheimer’s disease and agitation.
Primary outcome included incremental cost of participants’ health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants’ and unpaid carers’ gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives.
One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment.
On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.
Women with underlying cardiac conditions have an increased risk of adverse pregnancy outcomes. Counselling reproductive age women with heart disease is important to assist them in deciding whether to pursue pregnancy, to ensure their best cardiovascular status prior to pregnancy, and that they understand the risks of pregnancy for them and baby. This also provides an opportunity to explore management strategies to reduce risks. For this growing cohort of women, there is a great need for pre-conceptual counselling.
This retrospective comparative audit assessed new referrals and pre-conceptual counselling of women attending a joint obstetric–cardiology clinic at a tertiary maternity centre in a 12-month period of 2015–2016 compared with 2018–2019. This reflected the timing of the introduction of a multidisciplinary meeting prior to clinics and assessed the impact on referrals with the introduction of the European Society of Cardiology guidelines.
Data were reviewed from 56 and 67 patients in respective audit periods. Patient’s risk was stratified using modified World Health Organization classification.
Less than 50% of women with pre-existing cardiac conditions had received pre-conceptual counselling, although half of them had risks clearly documented. The majority of patients had a recent electrocardiograph and echocardiogram performed prior to counselling, and there was a modest improvement in the number of appropriate functional tests performed between time points. One-third of patients in both cohorts were taking cardiac medications during pregnancy.
There was a significant increase in the number of pregnant women with cardiac disease and in complexity according to modified World Health Organization risk classification. While there have been improvements, it is clear that further work to improve availability and documentation of pre-pregnancy counselling is needed.
OBJECTIVES/GOALS: To evaluate whether the default mode network experiences age-related changes in functional connectivity and to identify these patterns of progression across seven decades of life. The overall goal is to evaluate whether quantifying these functional changes can serve as potential neurobiomarkers of aging for further quantitative genetic analyses. METHODS/STUDY POPULATION: Scans were performed at the RII on a 3T Siemens Trio scanner with an 8-channel head coil. Whole-brain, rsfMR imaging was performed using a gradient-echo EPI sequence sensitive to the BOLD effect (TE/TR = 30/3000 ms; flip angle = 90°; isotropic 1.72 mm2). Subjects were instructed to lie in dimmed light with their eyes open and try not to fall asleep. Image analysis was performed with FMRIB’s Software Library tools (www.fmrib.ox.ac.uk/fsl). Preprocessing of resting state data includes motion correction, brain extraction, spatial smoothing, and high-pass temporal filtering. Time series data was extracted from 9 DMN ROIs using FSL’s Featquery tool with 6mm radius spherical ROI masks created in Mango. After extraction, DMN connectivity was assess using structural equation modeling implemented in Amos 22.0 (IBM, Inc.). RESULTS/ANTICIPATED RESULTS: The exploratory SEM (eSEM) default mode network (DMN) model used consists of 9 regions of interest and 13 functional connectivity paths. The eSEM DMN model exhibited exceptional model fit to a primary resting state data set of 1169 subjects from the Genetics of Brain Structure project (1R01MH078111-01, David Glahn PI) with an RMSEA of 0.037. This model also had excellent model fit in 7 cohorts that were grouped by decade age (10s – RMSEA: 0.058, 20s – 0.051, 30s – 0.045, 40s – 0.048, 50s – 0.043, 60s – 0.035, 70s – 0.037). Analysis of the decade group-wise path coefficients identified 7 of the 13 paths (pC -> LMTG, pC -> PCC, PCC -> MPFG, PCC -> vACC, MPFG -> vACC, LIPL -> RIPL, LMTG -> RMTG) significantly negatively correlated with age-related changes. As early as the 1st decade of life, the functional connectivity within the DMN decreases. DISCUSSION/SIGNIFICANCE OF IMPACT: The DMN experiences progressive age-related decreases in connectivity, beginning in the first decade of life. Our results suggest that DMN path coefficients can serve as biomarkers of cognitive aging, which can then be used as quantitative traits for genetic analyses to identify genes associated with normal aging and age-related cognitive diseases.
Ocean fronts are an important submesoscale feature, yet frontogenesis theory often neglects turbulence – even parameterized turbulence – leaving theory lacking in comparison with observations and models. A perturbation analysis is used to include the effects of eddy viscosity and diffusivity as a first-order correction to existing strain-induced inviscid, adiabatic frontogenesis theory. A modified solution is obtained by using potential vorticity and surface conditions to quantify turbulent fluxes. It is found that horizontal viscosity and diffusivity tend to be readily frontolytic – reducing frontal tendency to negative values under weakly non-conservative perturbations and opposing or reversing front sharpening, whereas vertical viscosity and diffusivity tend to only weaken frontogenesis by slowing the rate of sharpening of the front even under strong perturbations. During late frontogenesis, vertical diffusivity enhances the rate of frontogenesis, although perturbation theory may be inaccurate at this stage. Surface quasi-geostrophic theory – neglecting all injected interior potential vorticity – is able to describe the first-order correction to the along-front velocity and ageostrophic overturning circulation in most cases. Furthermore, local conditions near the front maximum are sufficient to reconstruct the modified solution of both these fields.
OBJECTIVES/SPECIFIC AIMS: The development of new anti-cancer agents for children requires an inherently longer timeline than in adults. The 3+3 study design for Phase 1 dose escalation trials is commonly used to estimate the maximum tolerated dose and assess safety. The Rolling 6 study design was developed to shorten the study conduct timeline. METHODS/STUDY POPULATION: This study compares twenty Phase 1 COG Pilot and Phase 1 Consortium trials that employed the Rolling 6 design with hypothetical results under the assumption that a 3+3 design had been executed. The number of evaluable patients required to complete the study, number of DLTs, number of inevaluable patients, overall study duration, time suspended to enrollment (i.e., waiting for DLT evaluation), and DLT risk are compared between study designs using Wilcoxon’s signed rank test. RESULTS/ANTICIPATED RESULTS: The Rolling 6 study design required less time to complete the studies compared with 3+3 design (median 273 vs. 297 days, P = 0.01). In general, the Rolling 6 study design required more patients, had more inevaluable patients, and there were more dose limiting toxicity (DLT) events. However, there was no significant difference in DLT risk (median 0.15 vs. 0.17, P = 0.72). DISCUSSION/SIGNIFICANCE OF IMPACT: The Rolling 6 study design effectively shortens the study conduct timeline compared with the traditional 3+3 design for Phase 1 COG Pilot and Phase 1 Consortium trials without increasing the risk of toxicity.
OBJECTIVES/SPECIFIC AIMS: Our objective is to understand the influence of the features comprising metabolic syndrome (central obesity, raised fasting plasma glucose, triglycerides, blood pressure, and decreased HDL cholesterol) on brain structure in men and women. With the understanding that MetS is a strong predictor of gray matter volume loss in specific brain regions, in this study we sought to quantify the influence of each of the metabolic syndrome biometric variables on the structures involved in the neural signature of metabolic syndrome. METHODS/STUDY POPULATION: We conducted multiple linear regression analyses on a cross-sectional sample of 800 individuals from the Genetics of Brian Structure (GOBS) image archive (352 men and 448 women). GOBS is an offshoot of the San Antonio Heart Study involving an extended pedigree of Mexican Americans from the greater San Antonio area. Its goal is to localize, identify, and characterize genes/quantitative trait loci associated with variations in brain structure and function (Winkler, 2010). The archive has continuously added participants from approximately 40 families since 2006. Neuroanatomic (T1-weighted MRI scans obtained on a Siemens 3T scanner and processed using FSL), neurocognitive, and biometric phenotypes have been obtained for each subject (including blood lipids). Linear regressions were run using SPSS and incorporated biometric and gray matter volume values obtained from 800 GOBS participants. RESULTS/ANTICIPATED RESULTS: Linear regressions incorporating metabolic syndrome variables as dependent variables and gray matter volume from regions involved in the neural signature of metabolic syndrome as predictors show significant predictive patterns that are largely similar between men and women, with some differences. Another linear regression conducted with gray matter volume from the neural signature of metabolic syndrome as the dependent variable and metabolic syndrome variables as predictors show that waist circumference and triglycerides are the greatest predictors of gray matter volume loss in men, and fasting plasma glucose and waist circumference are the greatest predictors of gray matter volume loss in women. DISCUSSION/SIGNIFICANCE OF IMPACT: Significant sex differences in the relationships between metabolic syndrome variables and gray matter volume changes between brain regions comprising the neural signature of metabolic syndrome were identified. waist circumference, fasting plasma glucose, and triglycerides are the most reliable predictors of gray matter volume loss. The variance in gray matter volume of the neural signature of metabolic syndrome in men is more significantly explained by waist circumference and triglycerides (when accounting for age) and in women is more significantly explained by waist circumference and fasting plasma glucose (when accounting for age). A model of metabolic syndrome that emphasizes a risk of neurodegeneration should focus on waist circumference for both men and women and weigh the remaining variables accordingly by sex (triglycerides in men and fasting plasma glucose in women).
Strongyloidiasis is a neglected tropical disease caused by the roundworm Strongyloides stercoralis affecting 30–100 million people worldwide. Many Southeast-Asian countries report a high prevalence of S. stercoralis infection, but there are little data from Vietnam. Here, we evaluated the seroprevalence of S. stercoralis related to geography, sex and age in Vietnam through serological testing of anonymized sera. Sera (n = 1710, 1340 adults and 270 children) from an anonymized age-stratified serum bank from four regions in Vietnam between 2012 and 2013 were tested using a commercial Strongyloides ratti immunoglobulin G ELISA. Seroreactivity was found in 29·1% (390/1340) of adults and 5·5% (15/270) of children. Male adults were more frequently seroreactive than females (33·3% vs. 24·9%, P = 0·001). The rural central highlands had the highest seroprevalence (42·4% of adults). Seroreactivity in the other regions was 29·9% (Hue) and 26·0% and 18·2% in the large urban centres of Hanoi and Ho Chi Minh City, respectively. We conclude that seroprevalence of S. stercoralis was high in the Vietnamese adult population, especially in rural areas.
Most mid-life and older adults are not achieving recommended physical activity (PA) targets and effective interventions are needed to increase and maintain PA long-term for health benefits. The Pedometer And Consultation Evaluation (PACE-UP) trial, a three-armed primary care pedometer-based walking intervention in those aged 45–75 years, demonstrated increased PA levels at 12 months. A three-year follow-up was conducted to evaluate long-term PA maintenance, including a qualitative component.
To examine facilitators and barriers to PA maintenance in mid-life and older adults previously involved in a PA trial.
Semi-structured telephone interviews were conducted with 60 PACE-UP participants across all study arms. Interviews were audio-recorded, transcribed verbatim and coded independently by researchers, prior to thematic analysis.
Two-thirds of participants felt since the PACE-UP trial they had an awareness of PA, with the pedometer reported as ‘kick-starting’ regular activity, and then helped them to maintain regular activity. PA facilitators included: maintaining good health, self-motivation, social support and good weather. Lack of time was the most frequently cited barrier. Other barriers were often the inverse of the facilitators; for example, poor health and bad weather. Participants described the type of ‘top-up’ intervention they would find beneficial to aid PA maintenance (eg, text messages, online resources and walking groups).
A challenge for future PA interventions is to transform barriers into facilitators; for example, educating trial participants about the value of PA for many chronic health conditions to change this from inhibiting to promoting PA. Participants provided ideas for encouraging PA maintenance which could be incorporated into future interventions.
The 2020 EU biodiversity strategy aims to halt the loss of biodiversity and ecosystem services, but this requires effective monitoring to determine whether these aims are achieved. Common bird monitoring continuously assesses changes in the avian community, providing a powerful tool for monitoring temporal changes in the abundance and distribution of these upper trophic level consumers. Two-thirds of Denmark’s land area is intensively farmed, so agricultural habitats make a major contribution to Danish biodiversity. We looked for changes in abundance amongst farmland birds in Denmark during 1987–2014 to test for reductions in declines and to predict whether the 2020-target can be expected to be achieved. Sixteen specialist farmland species were those showing the most rapid declines amongst 102 common breeding species in Denmark. Of these, those species nesting on the ground showed significant long-term declines, which was not the case for those that nest elsewhere, i.e. in hedgerows, trees and buildings. There was no evidence to suggest that these trends were attributable to widespread declines in long-distance migrant species (as reported elsewhere), which may be affected by conditions at other times in the annual cycle. We therefore conclude that continued declines in specialist farmland breeding bird species are due to contemporary agricultural changes within Denmark and urge habitat- and species-specific analysis to identify the core causes of these changes and halt the declines.
Between August 25 and September 25, 2003 seven patients with West Nile virus neurological manifestations were identified through the hospital neurology consultation services in Calgary, Alberta, Canada. Three of the seven patients were treated with interferon alpha-2b (IFN alpha-2b). In this report we document the clinical characteristics of these seven cases.
Clinical and laboratory information was obtained from a retrospective review of patient hospital and clinic charts. Patients were included if they had serological evidence of West Nile virus infection and had clinical evidence of aseptic meningitis, encephalomyelitis, cerebellar syndrome or motor neuronopathy. Three patients received a treatment course of three million units IFN alpha-2b, administered by subcutaneous injection once per day for 14 days.
Four patients had cerebellar signs without change in consciousness, two had both encephalitis and neuromuscular weakness, and one patient had focal lower motor neuron arm weakness. The mean age was 52 (range 24 - 73). All patients had flu-like illness and fever as presenting symptoms and six had severe headaches. Two patients were immunocompromised prior to infection. Two patients with cerebellar signs (one with opsoclonus-myoclonus) improved spontaneously and exhibited only mild residual deficits on discharge. The other two patients with cerebellar findings developed brainstem involvement, one coinciding with and one subsequent to the cerebellar symptoms. Within one week of treatment with IFN alpha-2b these latter two patients showed marked improvement. One patient with encephalitis and neuromuscular weakness, was treated with IFN alpha-2b and subsequently recovered.
In this case review of seven patients, multiple neurological symptoms occurred in each patient and the neurological presentation was varied. Four patients had predominant cerebellar findings and one patient had opsoclonus-myoclonus, not previously reported. The marked improvement in three patients who received IFN alpha-2b raises preliminary optimism towards this potential treatment.
The granting of legal-deposit status in 1801 and the arrival of the Fagel collection the following year transformed the Library both in size and status. The impact of the legal-deposit legislation would be a gradual one; the impact of acquiring the Fagel library, on the other hand, was immediate. The size of the College Library was increased by about 40 per cent at a stroke, and a collection that was essentially secular in nature and continental in origin was added to a library that had grown over the previous two centuries principally on the basis of books acquired by or for Protestant clergy.
The process of buying the Fagel collection began formally on 31 May 1798, when the governors of the Erasmus Smith Schools, meeting in the Committee Room of the Irish House of Lords, decided ‘that the surplus money now in hand belonging to the Charity may be well applied in purchasing the library of the Greffier Faghel of The Hague, for the use of Trinity College’.
On 7 February 1852, Wall resigned as Librarian, though he was allowed to retain a set of Library keys and have exclusive use of the Librarian's Room for a further 5 years. He remained a Senior Fellow and, until his death 10 years later, continued as Vice-Provost, an office he had held simultaneously with that of Librarian since 1847. There could be only one successor – the man who had effectively run the Library for the previous 20 years. James Henthorn Todd, elected Librarian for an initial period of 5 years from the date of Wall's resignation, was then 47 and the Professor of Hebrew and Senior Lecturer at Trinity, as well as Secretary of the Royal Irish Academy and a founder of both St Columba's College, Dublin, and the Irish Archaeological Society. (See Figure 11.)
Though the Library had been without Todd's involvement for only 2 years, it was already showing signs of a lack of direction, and the report that he produced for the Board during his second year in office was a depressing one. The books in the gallery were ‘in very great disorder’; there was a substantial backlog of cataloguing (though the appointment of an additional Library clerk had already started to reduce this); the shelf-lists were not properly written up and contained ‘perplexing irregularities’; one of the Library clerks had been dismissed for neglect of duty; one of the cleaners had stolen some books; and, finally, a ‘want of room’ was being felt, because the carpenters had been slow in installing bookcases in the gallery – and even when those were completed they would provide space for only about a further 4 years’ intake. Cataloguing and space were to dominate Todd's tenure of office.
When Todd responded to the enquiries of the Royal Commission in 1852 he was able to show that the Library was generally well run and, though not heavily used, could meet the needs of its readers. The same could not be reported a century later by Herbert Parke, Smyly's successor as the College Librarian. (See Figure 24.)
In 1950, the Library officially occupied two buildings: the 1937 Reading Room and what was to become known as the Old Library. Books stored in the latter were transferred to the Reading Room for readers’ use by means of a conveyor belt through a tunnel from the West Pavilion. The annual number of reader visits was about 73,000, a figure that was showing a steady increase each year and was almost three times that in 1912 when the size of the Reading Room had been determined. As a result, the room was overcrowded, even though seats for an additional 32 readers had been added in 1949 after complaints from the students. It was open from 10 a.m. until 10 p.m. on Mondays to Fridays, except during July and August when it closed at 6 p.m., and on Saturdays throughout the year from 10 a.m. until 1 p.m. Because of the pressure on space, some first-year undergraduates were given ‘restricted admission’, which meant that they could use the Reading Room only after 6 p.m. and in the vacation. The Catacombs in the basement were used for storage, but the area was prone to damp.
The reforms that had been initiated by Parke continued under his successors. John Hurst was appointed as Librarian from 12 July 1965, but the Board, which had previously shown generosity in placing him on the professorial salary scale as the Deputy Librarian, remarkably saw no need to increase his salary or change his conditions when he became the Librarian. William Dieneman replaced him as the Deputy Librarian in April 1966. For the first time in its history the College not only had a professionally qualified Librarian but also one whose appointment was full-time and not held in conjunction with teaching or other offices. However, the Board found itself unable to relinquish academic control completely. It created for Parke a new honorary office of Curator of the Library, which had no clear terms of reference except to chair the Library Committee. Parke remained as Curator throughout the tenure of Hurst and his successor, Denis Roberts, and relinquished the title only in 1972, shortly before his retirement from the Vice-Provostship and Chair of Ancient History. Hurst's tenure as Librarian was brief and uncomfortable.
As the completion date for the New Library approached, it became ever clearer that the building would be inadequate to meet the demands about to be placed upon it. Whilst he was the Deputy Librarian, Hurst had been closely involved with the planning and was aware of the new building's shortcomings. He sought to reduce their impact, but he received little support from the academic community in the College. The divergence of views between the Librarian and some of the Fellows came to a head at a contentious Board meeting in November 1966 when the Board refused to overturn its earlier decision to use part of the basement of the New Library as an exhibition hall, despite Hurst's pleading that he needed the space to transfer books from their various stores around the College.
The death of Peter Brown and the start of the present writer's incumbency of the Librarianship might seem an appropriate point to end this narrative. The final years of the twentieth century, however, saw such dramatic changes in universities and their libraries that to conclude in 1983 seems premature. This final section must inevitably be less analytical than previous chapters, but it seeks to chronicle as objectively as possible the main development of the Library up to the formal opening of the Ussher Library in 2003.
During these two decades the Library was served by three Librarians: Peter Fox from 1984 until 1994, when he was appointed Librarian of the University of Cambridge; Bill Simpson, who had been the Librarian of the University of London and was at Trinity from 1994 until 2002, when he moved to Manchester as University Librarian and Director of the John Rylands Library; and Robin Adams, who had been the College's Deputy Librarian since 1991 and was appointed Librarian in 2002.