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Treatment resistant schizophrenia (TRS) is one of the most disabling of psychiatric disorders, affecting about 1/3 of patients. First-line treatments include both atypical and typical antipsychotics. The original atypical, clozapine, is a final option, and although it has been shown to be the only effective treatment for TRS, many patients do not respond well to clozapine. Clozapine use is related to adverse events, most notably agranulocytosis, a potentially fatal blood disorder which affects about 1% of those prescribed clozapine and requires regular blood monitoring. This as a barrier to prescription and there is a long delay in access for TRS patients, of five or more years, from first antipsychotic prescription. Better tools to predict treatment resistance and to identify risk of adverse events would allow faster and safer access to clozapine for patients who are likely to benefit from it. The CRESTAR project (www.crestar-project.eu) is a European Framework 7 collaborative project that aims to develop tools to predict i) treatment response, particularly patients who are less likely to respond to usual antipsychotics, indicating treatment with clozapine as early as possible, ii) patients who are at high or low risk of adverse events and side effects, iii) extreme TRS patients so that they can be stratified in clinical trials for novel treatments. CRESTAR has addressed these questions by examining genome-wide association data, genome sequence, epigenetic biomarkers and epidemiological data in European patient cohorts characterized for treatment response, and adverse drug reaction using data from clozapine therapeutic drug monitoring and linked National population medical and pharmacy databases, to identify predictive factors. In parallel CRESTAR will perform health economic research on potential benefits, and ethics and patient-centred research with stakeholders.
To date, Ireland has been a leading light in the provision of youth mental health services. However, cognisant of the efforts of governmental and non-governmental agencies working in youth mental health, there is much to be done. Barriers into care as well as discontinuity of care across the spectrum of services remain key challenges. This editorial provides guidance for the next stage of development in youth mental care and support that will require significant national engagement and resource investment.
Objectives: With comparable baseline performance on executive functions (EF) and memory between Alzheimer’s disease (AD) and behavioral-variant frontotemporal dementia (bvFTD), it is currently unclear if both diseases can be distinguished longitudinally on these measures reliably. Methods: A total of 111 participants (33 AD, 31 bvFTD, and 47 controls) were followed-up annually over a 4-year period and tested on measures of EF, memory, and orientation. Linear mixed-effect models were constructed using disease severity as a nuisance variable to examine profiles of neuropsychological performance decline. Results: At baseline, overlap in terms of cognitive impairment between bvFTD and AD on multiple EF, memory, and orientation measures was present. Longitudinally, only disinhibition (Hayling total errors) appeared sensitive to discriminating AD from bvFTD; however, only after the first annual follow-up. Subgroup analyses on smaller samples revealed comparable profiles on EF tasks at baseline and over time between bvFTD and AD who presented with impaired EF at presentation, and on memory and orientation tasks between AD and bvFTD who presented with severe amnesia. Conclusions: Our results replicate previous findings showing only moderate discriminability between AD and bvFTD at clinical presentation on EF and memory measures. More importantly, we also show that longitudinal trajectories strongly overlap for both dementias on these measures. Disinhibition emerged as the sole measure that in the long run was significantly more impaired in bvFTD. Future studies should use tests designed to target cortical regions that are specifically impaired in bvFTD, such as the ventromedial prefrontal cortex, to improve the accurate discrimination of these diseases. (JINS, 2017, 23, 34–43)
The Wisconsin Plasma Astrophysics Laboratory (WiPAL) is a flexible user facility designed to study a range of astrophysically relevant plasma processes as well as novel geometries that mimic astrophysical systems. A multi-cusp magnetic bucket constructed from strong samarium cobalt permanent magnets now confines a
, fully ionized, magnetic-field-free plasma in a spherical geometry. Plasma parameters of
provide an ideal testbed for a range of astrophysical experiments, including self-exciting dynamos, collisionless magnetic reconnection, jet stability, stellar winds and more. This article describes the capabilities of WiPAL, along with several experiments, in both operating and planning stages, that illustrate the range of possibilities for future users.
An unlinked anonymous study was conducted to estimate the prevalence of hepatitis C virus (HCV) infection in emergency department (ED) attendees at a London Hospital. Nine hundred and ninety-seven samples collected over a 12-day period were tested for HCV antibody (Ab) and reactive samples were further tested for HCV RNA. The HCV seroprevalence was 2·6% (26/997) with 1·2% (12/997) HCV RNA positive. A peak HCV RNA-positive prevalence of 4·8% (3/63) was found in males aged 35–44 years, this was compared to 0% (0/136) in males aged <35 years (P = 0·0614) and 1·4% (4/278) in males aged ⩾45 years (P = 0·2415). Assuming the cost for HCV Ab is £6 and HCV RNA is £40 per test, screening ED attendees aged 25–54 years would cost £360 per viraemic infection and identify 82% of those who were HCV RNA positive, yielding the most favourable cost/benefit ratio. HCV screening of ED attendees aged 25–54 years in this population could be an effective way of identifying patients and limit onward transmission.
Objectives: The aim of this study was to develop a decision support tool to assess the potential benefits and costs of new healthcare interventions.
Methods: The Canadian Partnership Against Cancer (CPAC) commissioned the development of a Cancer Risk Management Model (CRMM)—a computer microsimulation model that simulates individual lives one at a time, from birth to death, taking account of Canadian demographic and labor force characteristics, risk factor exposures, and health histories. Information from all the simulated lives is combined to produce aggregate measures of health outcomes for the population or for particular subpopulations.
Results: The CRMM can project the population health and economic impacts of cancer control programs in Canada and the impacts of major risk factors, cancer prevention, and screening programs and new cancer treatments on population health and costs to the healthcare system. It estimates both the direct costs of medical care, as well as lost earnings and impacts on tax revenues. The lung and colorectal modules are available through the CPAC Web site (www.cancerview.ca/cancerrriskmanagement) to registered users where structured scenarios can be explored for their projected impacts. Advanced users will be able to specify new scenarios or change existing modules by varying input parameters or by accessing open source code. Model development is now being extended to cervical and breast cancers.
Sheep infected with the triclabendazole-susceptible, Cullompton isolate of Fasciola hepatica were dosed with 15 mg/kg of compound alpha at 12 weeks post-infection. Adult flukes were recovered from the bile ducts at 24, 48 and 72 h post-treatment (p.t.). Ultrastructural changes to the flukes were assessed using transmission electron microscopy (TEM), with a view to gathering information on the mechanism(s) of action for compound alpha and on the possible route of its entry into F. hepatica. The tegumental syncytium was more severely affected than the gut at all time-points p.t. with compound alpha, suggesting a predominantly trans-tegumental route of uptake. Disruption to the tegumental system became increasingly severe over time. A stress response was observed at 24 h p.t. and took the form of blebbing and increases in the production and transport of secretory bodies. By 72 h p.t., extensive tegumental loss and degeneration of the tegumental cell bodies had occurred. Degeneration of subtegumental tissues and internal flooding were also observed. Changes in the gastrodermal cells were slow to develop: reduced secretory activity was evident at 72 h p.t.. There was progressive disruption to the somatic muscle layers, with disorganization of the muscle blocks and loss of muscle fibres.
Polycaprolactone is a bioresorbable polymer that has potential for tissue engineering of bone and cartilage. In this work, we report on the computational design and freeform fabrication of porous polycaprolactone scaffolds using selective laser sintering, a rapid prototyping technique. The microstructure and mechanical properties of the fabricated scaffolds were assessed and compared to designed porous architectures and computationally predicted properties. Compressive modulus and yield strength were within the lower range of reported properties for human trabecular bone. Finite element analysis showed that mechanical properties of scaffold designs and of fabricated scaffolds can be computationally predicted. Scaffolds were seeded with BMP-7 transduced fibroblasts and implanted subcutaneously in immunocompromised mice. Histological evaluation and micro-computed tomography (μCT) analysis confirmed that bone was generated in vivo. Finally, we have demonstrated the clinical application of this technology by producing a prototype mandibular condyle scaffold based on an actual pig condyle.
Breast cancer is a leading cause of cancer death in women. It is estimated that 1 in 12 women will develop breast cancer in their lifetime. Risk factors for breast cancer include: age, early menarche, late menopause, obesity (particularly in postmenopausal women), oestrogen replacement therapy and a positive family history.
The majority of breast cancer (95%) is sporadic in nature and only a small proportion, in particular those diagnosed in young women, is due to a hereditary predisposition. This predisposition is transmitted as a highly penetrant autosomal dominant trait. Over the last 5–10 years, there has been considerable progress in the identification and localization of the genes responsible for hereditary breast cancer. In particular, two have attracted the most attention – BRCA1 and BRCA2 (Miki et al., 1994; Wooster et al., 1995).
The BRCA1 gene is located on chromosome 17q21 and encodes for a protein of 1863 amino acids (Miki et al., 1994). The protein includes a zinc finger motif, which suggests a possible role in transcription. Evidence is also accumulating for a role in DNA repair. Mutations in the BRCA1 gene are associated with a risk of breast cancer of approximately 80% and a risk of ovarian cancer of approximately 40% by the age of 70 years (Ford et al., 1994; Easton et al., 1995). The BRCA1 gene accounts for approximately 45% of all hereditary breast-cancer-prone families. Patients with mutations in the BRCA1 gene also have a slightly increased risk of colon and prostate cancer (Ford et al., 1994).
Psychopharmacology is rapidly becoming an adjuvant treatment to traditional rehabilitation strategies for patients with stroke or brain injury because it helps to facilitate recovery in a time-efficient manner. Norepinephrine, dopamine, acetylcholine, and serotonin appear to play important roles in recovery from stroke or brain injury. Animal models have shown that blockade of these neurotransmitters inhibits recovery, whereas recovery is promoted by drugs that promote norepinephrine, dopamine, acetylcholine, and serotonin activity. Preliminary evidence from human trials supports these finding. Further study is needed, but expanded use of pharmacologic agents for stroke and brain-injured patients appears imminent.
Radio-wave scattering in the Vela supernova remnant acts as an imperfect lens to resolve the pulsar’s radio emission region. We use this lens to measure the pulsar’s emission region. We suggest that refraction of radiation within the pulsar’s magnetosphere is responsible for the observed size.
As-cast, arc-melted Pd-Ni alloys are inhomogeneous and the H2 isotherms for these differ from their homogeneous counterparts in the two phase, (dilute + hydride), regions but not in the dilute phase regions. Pd-Ni alloys, which become inhomogeneous via a ternary (Pd + Ni + H) equilibrium phase change, have H2 isotherms which differ from those of the homogeneous alloy in both the two-phase and the dilute phase regions. These results are discussed with respect to the expected type of inhomogeneities.
The cross-sectional area of the common carotid artery bulb was measured using a 5 MHz pulse wave Doppler probe in a patient undergoing general anaesthesia using a laryngeal mask airway (LMA). A simultaneous measurement of blood velocity was performed to allow determination of the blood flow. Following inflation of the cuff on the LMA, the cross-sectional area of the right carotid artery bulb decreased from 1.09 to 0.89 cm2, flow velocity increased 120 to 176 cm s−1 and the blood flow increased from 130.8 to 156.6 cm3 s−1. On the left the cross-sectional area decreased from 1.16 to 1.13 cm2, the velocity increased 136 to 151 cm s−1 and the blood flow increased from 157·8 to 170·6 cm3 s−1 . While a reduction in cross-sectional area was observed in the carotid bulb in this patient, this was accompanied by an increase in the velocity and a consequent increase in blood flow. In patients with atheromatous disease involving the carotid arteries this decrease in cross-sectional area may prove clinically significant. The use of the LMA may not be suitable for this population.
The λ model suggests that detailed kinematics arise from changes in control variables and need not be explicitly planned. However, we have shown that when moving a grasped object, grip force is precisely modulated in phase with acceleration-dependent inertial load. This suggests that the motor system can predict detailed kinematics. This prediction may be based on a forward model of the dynamics of the loaded limb.
Many bacterial species are closely associated with epithelial surfaces of the gastrointestinal tract. The physicochemical interactions between bacteria and the intestinal surface are complex and include both stereospecific and chemotactic effects. Such mechanisms of interaction and attachment of bacteria to the gut have received considerable attention over the last decade as they have been recognised as an important initial event in colonisation and the pathogenesis of enteric infections. Many disease-causing bacteria possess surface fimbriae or fibrillae with lectin-like adhesins which interact with peptides or carbohydrates present on surface glycosphingolipids and/or glycoproteins. Research on the structural features of fimbrial receptors and on their expression on the surfaces of the mammalian intestine has led to new ideas for nutritional therapy and/or prophylaxis based on the prevention of adherence of pathogenic bacteria.