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Clozapine-induced gastrointestinal hypomotility (CIGH) affects some 75% of patients treated with clozapine.
Aims
To document the incidence of potentially harmful CIGH in the UK.
Method
We studied spontaneous UK pharmacovigilance reports recorded as clozapine-related gastrointestinal adverse drug reactions, 1992–2017.
Results
There were 527 patients reported with potentially harmful CIGH; 33% (n = 172) died. Deaths averaged 1 per year 1992–1999, 5 per year 2000–2009 and 15 per year 2010–2017. Those who died were older (median 52 years v. 49 years) and had been prescribed clozapine for longer than those who recovered (median 11.3 years v. 4.8 years), but there was no difference in prescribed dose. Within the first 4 years of clozapine treatment, there were 169 reports of CIGH, of which 3% (n = 5) were fatal. At 10–14 years there were 63 reports of CIGH, of which 25% (n = 16) were fatal. Among the deaths, males were younger (median 51, range 22–89 v. median 57, range 24–89 years) with higher clozapine doses (median 450, range 100–900 v. median 300, range 12.5–800 mg/d) than females. In non-fatal CIGH, surgery was the most frequent outcome (n = 92). The procedures included appendectomy, ileostomy, total/partial colectomy, colostomy/stoma and proctosigmoidectomy. Clozapine dosage was reduced in 6 patients, stopped and restarted in 23, ‘continued’ in 6 and discontinued permanently in at least 76 patients.
Conclusions
The risk of serious morbidity/mortality from CIGH is substantial. The need to actively monitor bowel function and give laxatives to patients treated with clozapine is clear.
Quasi-periodic plasmoid formation at the tip of magnetic streamer structures is observed to occur in experiments on the Big Red Ball as well as in simulations of these experiments performed with the extended magnetohydrodynamics code, NIMROD. This plasmoid formation is found to occur on a characteristic time scale dependent on pressure gradients and magnetic curvature in both experiment and simulation. Single mode, or laminar, plasmoids exist when the pressure gradient is modest, but give way to turbulent plasmoid ejection when the system drive is higher, which produces plasmoids of many sizes. However, a critical pressure gradient is also observed, below which plasmoids are never formed. A simple heuristic model of this plasmoid formation process is presented and suggested to be a consequence of a dynamic loss of equilibrium in the high-$\beta$ region of the helmet streamer. This model is capable of explaining the periodicity of plasmoids observed in the experiment and simulations, and produces plasmoid periods of 90 minutes when applied to two-dimensional models of solar streamers with a height of $3R_\odot$. This is consistent with the location and frequency at which periodic plasma blobs have been observed to form by Large Angle and Spectrometric Coronograph and Sun Earth Connection Coronal and Heliospheric Investigation instruments.
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)
There are several situations of practical importance where it is essential to maintain a satellite in a fixed orientation relative to the earth. Of the numerous methods proposed for such station keeping, gravity gradient stabilisation has gained considerable attention primarily due to the passive nature of the system. The pioneering work for pure gravity orientated satellites was carried out by Klemperer who obtained the exact solution for planar librations of a dumbbell satellite in circular orbit, and by Baker who found periodic solutions of the problem for small orbit eccentricity. Schechter attempted, with limited success, to extend Klemperer's solution to non-circular orbital motion by perturbation methods. Zlatousov et al and, more recently, Brereton and Modi successfully employed numerical methods, involving the use of the stroboscopic phase plane, to analyse motion in the large for orbits of arbitrary eccentricity.
In addition to direct solar radiation, this paper includes the effect of direct earth radiation, its albedo and shadow on the attitude dynamics of gravity orientated systems, thus extending the analysis of Part I down to the earth's effective atmosphere. The importance of these radiations was indicated by a preliminary force analysis, which revealed that they can exert a force comparable to that of direct solar radiation for close earth satellites. Thus, the need for a rigorous investigation including the effect of earth radiations on satellite attitude dynamics is evident.
Earth radiation forces were obtained in integral form by Clancy and Mitchell using elementary radiation principles. However, in a test on an IBM-7044 digital computer, it was found that the time required to evaluate these integrals renders a study of satellite attitude dynamics virtually impossible.
For many space applications, it is necessary to maintain a satellite in a fixed orientation relative to the earth. Unfortunately, a correctly positioned satellite deviates with time from this preferred orientation due to perturbing environmental forces. This explains considerable interest librational stability study in recent times.
Among the numerous methods developed for librational control, a passive technique depending on the gradient of the gravitational field has gained attention. Depending on the orbital distance, environmental effects, such as, aerodynamic, radiation, and magnetic torques become significant compared to the gravity-gradient restoring moment. A need to determine the influence of these disturbing forces is thus evident.
For many space applications, such as communication, weather, military, and scientific experiment satellites scanning precise regions, it is necessary to maintain a satellite in a fixed orientation relative to the earth. Unfortunately, a correctly positioned satellite deviates with time from this preferred orientation due to perturbing environmental forces. This explains considerable interest in libra-tional stability study in recent times.
Among the numerous methods developed for librational control, a passive technique depending on the gradient of the gravitational field has gained attention. Depending on the orbital distance, environmental effects, such as, aerodynamic, radiation, and magnetic torques, become significant compared to the gravity-gradient restoring moment. A need to determine the influence of these disturbing forces is thus evident.
For satellites that have part or all of their orbits extending into the earth's effective atmosphere, i.e. less than 500 miles, it is necessary to consider the contribution of the aerodynamic force in attitude dynamic studies. The importance of the aerodynamic torque is revealed by the fact that it is comparable to earth radiation at 500 miles, direct solar radiation at 400 miles, and depending on satellite geometry, can be as large as gravity gradient torque at 200-300 miles. Hence, in addition to solar and earth radiation torques, this paper includes the effect of the rarefied atmosphere on the response of gravity gradient satellites, thus covering the entire altitude range.
High iron concentrations have been reported in the brains of multiple sclerosis victims. To determine if there are abnormalities in general iron metabolism indicative of iron overload in MS, measurements of transferrin saturation, serum ferritin and red cell ferritin in 31 female and 18 male patients were compared to the results in 49 age- and sex-matched healthy controls. Compared to controls, mean serum ferritin in MS was high, whereas transferrin saturation and red cell ferritin were similar. High values in one or more individual test results were observed in eleven MS patients. They were prevalent in patients who required bilateral assistance to walk or were confined to a chair, and appeared to be related to the severity of the disease. An investigation was made into the relationship of the high serum ferritin values in MS to the HLA-A3 histocompatibility antigen, a marker of the hemochromatosis gene which is prevalent in MS. A statistically significant interaction was not found between serum ferritin and the presence of HLA-A3.
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 $10~\text{m}^{3}$, fully ionized, magnetic-field-free plasma in a spherical geometry. Plasma parameters of $T_{e}\approx 5$ to $20~\text{eV}$ and $n_{e}\approx 10^{11}$ to $5\times 10^{12}~\text{cm}^{-3}$ 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.
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.
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.