Objective:The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought ...to fill this gap by conducting dose-response meta-analyses.Methods:A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.Results:Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.Conclusions:In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.
Over the last two decades, and in the wake of increases in recorded crime and other social changes, British criminal justice policy has become increasingly politicised as an index of governments' ...competence. New and worrying developments, such as the inexorable rise of the US prison population and the rising force of penal severity, seem unstoppable in the face of popular anxiety about crime. But is this inevitable? Nicola Lacey argues that harsh 'penal populism' is not the inevitable fate of all contemporary democracies. Notwithstanding a degree of convergence, globalisation has left many of the key institutional differences between national systems intact, and these help to explain the striking differences in the capacity for penal tolerance in otherwise relatively similar societies. Only by understanding the institutional preconditions for a tolerant criminal justice system can we think clearly about the possible options for reform within particular systems.
This study examines the toxicity of immunosuppressive regimens in renal-transplant recipients. A regimen containing mycophenolate mofetil, daclizumab, low-dose tacrolimus, and corticosteroids ...appeared to be the most effective with respect to the glomerular filtration rate, allograft survival, and acute rejection, as compared with regimens containing dacluzimab induction plus either low-dose cyclosporine or low-dose sirolimus and with standard-dose cyclosporine without induction.
A regimen containing mycophenolate mofetil, daclizumab, low-dose tacrolimus, and corticosteroids appeared to be the most effective with respect to the glomerular filtration rate, allograft survival, and acute rejection.
Despite improved short-term outcome in renal transplantation, 3 to 5% of allografts per year are still lost; the leading causes are long-term allograft nephropathy and death with a functioning allograft.
1
As patients have fewer acute rejection episodes, adverse events associated with long-term immunosuppression have become increasingly evident. Accordingly, reducing the toxic effects of immunosuppressive regimens has become a major goal in the treatment of transplant recipients.
Cyclosporine, a calcineurin inhibitor in use for many years, is still the basis of many immunosuppressive regimens because of its clinical success. However, standard recommended doses are associated with nephrotoxicity, resulting in long-term renal . . .
Summary Background Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which ...drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people. Methods We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. Findings We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference −0·51, 95% credible interval CrI −0·99 to −0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio OR 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I2 values were 33·21% for efficacy and 0% for tolerability. Interpretation When considering the risk–benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated. Funding National Basic Research Program of China (973 Program).
Over the last decade governments in Europe and North America have attempted to improve efficiency of public services through Information and Communication Technology, commonly branded as electronic ...government (e-government). Public Sector Transformation through E-Government explores the influence that e-government has on public sector organizations, the organizational complexities that result, and its impact on citizens and democratic society.
This book examines e-government's potential to transform public services from a theoretical perspective, and provides practical examples from leading public sector institutions that have utilized e-government as a basis to bring about change. It further investigates the relationship between citizens and government and how they are affected by e-government policies and programs. Aimed at students and researchers of public administration/management and information systems, this book serves as a welcome tool for examining and understanding e-government and transformational change.
The apparent shortfall in prevention of coronary heart disease (CHD) noted in early hypertension trials has been attributed to disadvantages of the diuretics and β blockers used. For a given ...reduction in blood pressure, some suggested that newer agents would confer advantages over diuretics and β blockers. Our aim, therefore, was to compare the effect on non-fatal myocardial infarction and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril.
We did a multicentre, prospective, randomised controlled trial in 19 257 patients with hypertension who were aged 40–79 years and had at least three other cardiovascular risk factors. Patients were assigned either amlodipine 5–10 mg adding perindopril 4–8 mg as required (amlodipine-based regimen; n=9639) or atenolol 50–100 mg adding bendroflumethiazide 1·25–2·5 mg and potassium as required (atenolol-based regimen; n=9618). Our primary endpoint was non-fatal myocardial infarction (including silent myocardial infaction) and fatal CHD. Analysis was by intention to treat.
The study was stopped prematurely after 5·5 years' median follow-up and accumulated in total 106 153 patient-years of observation. Though not significant, compared with the atenolol-based regimen, fewer individuals on the amlodipine-based regimen had a primary endpoint (429 vs 474; unadjusted HR 0·90, 95% CI 0·79–1·02, p=0·1052), fatal and non-fatal stroke (327 vs 422; 0·77, 0·66–0·89, p=0·0003), total cardiovascular events and procedures (1362 vs 1602; 0·84, 0·78–0·90, p<0·0001), and all-cause mortality (738 vs 820; 0·89, 0·81–0·99, p=0·025). The incidence of developing diabetes was less on the amlodipine-based regimen (567 vs 799; 0·70, 0·63–0·78, p<0·0001).
The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen. On the basis of previous trial evidence, these effects might not be entirely explained by better control of blood pressure, and this issue is addressed in the accompanying article. Nevertheless, the results have implications with respect to optimum combinations of antihypertensive agents.
Background
Vitamins and minerals play multiple functions within the central nervous system which may help to maintain brain health and optimal cognitive functioning. Supplementation of the diet with ...various vitamins and minerals has been suggested as a means of maintaining cognitive function, or even of preventing dementia, in later life.
Objectives
To evaluate the effects of vitamin and mineral supplementation on cognitive function in cognitively healthy people aged 40 years or more.
Search methods
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group’s (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov and the WHO Portal/ICTRP from inception to 26th January 2018.
Selection criteria
We included randomised controlled trials that evaluated the cognitive effects on people aged 40 years or more of any vitamin or mineral supplements taken by mouth for at least three months.
Data collection and analysis
Study selection, data extraction, and quality assessments were done in duplicate. Vitamins were considered broadly in the categories of B vitamins, antioxidant vitamins, and combinations of both. Minerals were considered separately, where possible. If interventions and outcomes were considered sufficiently similar, then data were pooled. In order to separate short‐term cognitive effects from possible longer‐term effects on the trajectory of cognitive decline, data were pooled for various treatment durations from 3 months to 12 months and up to 10 years or more.
Main results
In total, we included 28 studies with more than 83,000 participants. There were some general limitations of the evidence. Most participants were enrolled in studies which were not designed primarily to assess cognition. These studies often had no baseline cognitive assessment and used only brief cognitive assessments at follow‐up. Very few studies assessed the incidence of dementia. Most study reports did not mention adverse events or made only very general statements about them. Only 10 studies had a mean follow‐up > 5 years. Only two studies had participants whose mean age was < 60 years at baseline. The risk of bias in the included studies was generally low, other than a risk of attrition bias for longer‐term outcomes. We considered the certainty of the evidence behind almost all results to be moderate or low.
We included 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo. The majority of participants were aged over 60 years and had a history of cardio‐ or cerebrovascular disease. We found that giving B vitamin supplements to cognitively healthy adults, mainly in their 60s and 70s, probably has little or no effect on global cognitive function at any time point up to 5 years (SMD values from ‐0.03 to 0.06) and may also have no effect at 5‐10 years (SMD ‐0.01). There were very sparse data on adverse effects or on incidence of cognitive impairment or dementia.
We included 8 studies with 47,840 participants in which the active intervention was one or more of the antioxidant vitamins: ß‐carotene, vitamin C or vitamin E. Results were mixed. For overall cognitive function, there was low‐certainty evidence of benefit associated with ß‐carotene after a mean of 18 years of treatment (MD 0.18 TICS points, 95% CI 0.01 to 0.35) and of vitamin C after 5 years to 10 years (MD 0.46 TICS points, 95% CI 0.14 to 0.78), but not at earlier time points. From two studies which reported on dementia incidence, there was low‐certainty evidence of no effect of an antioxidant vitamin combination or of vitamin E, either alone or combined with selenium. One of the included studies had been designed to look for effects on the incidence of prostate cancer; it found a statistically significant increase in prostate cancer diagnoses among men taking vitamin E.
One trial with 4143 participants compared vitamin D3 (400 IU/day) and calcium supplements to placebo. We found low‐ to moderate‐certainty evidence of no effect of vitamin D3 and calcium supplements at any time‐point up to 10 years on overall cognitive function (MD after a mean of 7.8 years ‐0.1 MMSE points, 95% CI ‐0.81 to 0.61) or the incidence of dementia (HR 0.94, 95% CI 0.72 to 1.24). A pilot study with 60 participants used a higher dose of vitamin D3 (4000 IU on alternate days) and found preliminary evidence that this dose probably has no effect on cognitive function over six months.
We included data from one trial of zinc and copper supplementation with 1072 participants. There was moderate‐certainty evidence of little or no effect on overall cognitive function (MD 0.6 MMSE points, 95% CI ‐0.19 to 1.39) or on the incidence of cognitive impairment after 5 years to 10 years. A second smaller trial provided no usable data, but reported no cognitive effects of six months of supplementation with zinc gluconate.
From one study with 3711 participants, there was low‐certainty evidence of no effect of approximately five years of selenium supplementation on the incidence of dementia (HR 0.83, 95% CI 0.61 to 1.13).
Finally, we included three trials of complex supplements (combinations of B vitamins, antioxidant vitamins, and minerals) with 6306 participants. From the one trial which assessed overall cognitive function, there was low‐certainty evidence of little or no effect on the TICS (MD after a mean of 8.5 years 0.12, 95% CI ‐0.14 to 0.38).
Authors' conclusions
We did not find evidence that any vitamin or mineral supplementation strategy for cognitively healthy adults in mid or late life has a meaningful effect on cognitive decline or dementia, although the evidence does not permit definitive conclusions. There were very few data on supplementation starting in midlife (< 60 years); studies designed to assess cognitive outcomes tended to be too short to assess maintenance of cognitive function; longer studies often had other primary outcomes and used cognitive measures which may have lacked sensitivity. The only positive signals of effect came from studies of long‐term supplementation with antioxidant vitamins. These may be the most promising for further research.
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness ...from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.
The other invisible hand Le Grand, Julian
2008, 2007., 20090110, 2009, 2007, 2007-01-01, 20070101
eBook, Book
How can we ensure high-quality public services such as health care and education? Governments spend huge amounts of public money on public services such as health, education, and social care, and yet ...the services that are actually delivered are often low quality, inefficiently run, unresponsive to their users, and inequitable in their distribution. In this book, Julian Le Grand argues that the best solution is to offer choice to users and to encourage competition among providers. Le Grand has just completed a period as policy advisor working within the British government at the highest levels, and from this he has gained evidence to support his earlier theoretical work and has experienced the political reality of putting public policy theory into practice. He examines four ways of delivering public services: trust; targets and performance management; "voice"; and choice and competition. He argues that, although all of these have their merits, in most situations policies that rely on extending choice and competition among providers have the most potential for delivering high-quality, efficient, responsive, and equitable services. But it is important that the relevant policies be appropriately designed, and this book provides a detailed discussion of the principal features that these policies should have in the context of health care and education. It concludes with a discussion of the politics of choice.
Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for ...patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.
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