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Background: A previous clinical trial of training communication partners of people with traumatic brain injury (TBI) demonstrated positive outcomes [Togher, Power, McDonald, Tate, & Rietdijk (2009). Brain Impairment, 10(2), 188-204]. Adapting communication partner training for delivery via telehealth could improve access to this intervention.
Objectives: To compare outcomes across in-person communication partner training, telehealth communication partner training and a control group
Method: Protocol for a partially randomised controlled trial. People with moderate-severe TBI will be allocated to either an in-person or telehealth-based training program. Comparison data will be drawn from the original trial control group, which was recruited using the same eligibility criteria as this protocol. Outcomes after training will be compared between the in-person training group, the telehealth training group and the historical control group.
Discussion: This protocol uses specific design features with the aim of maximising the study’s power, including a partially randomised allocation process and a historical control group. The results will inform about the feasibility and effectiveness of delivering TBI rehabilitation via telehealth.
Trial registration: Australian and New Zealand Clinical Trials Registry: ACTRN12615001024538.
We aim to evaluate the effect of caloric restriction (CR) in cognition by comparing performance in neuropsychological tests for working memory between a group of non-obese healthy subjects doing CR for 2 years with another consuming ad libitum diet (AL).
This study was part of a larger multicenter trial called CALERIE that consisted of a randomized clinical trial with parallel-group comparing 2 years of 25% CR and AL in 220 volunteers with a BMI between 22 and 28 kg/m2, across 3 sites. The cognitive tests used were the Cambridge Neuropsychological Tests Automated Battery (CANTAB) for Spatial Working Memory (SWM) including the total number of errors (SWMTE) and strategy (SWMS). Included as possible moderators were sleep quality, mood states, perceived stress, and energy expenditure. Analyses were performed at baseline and months 12 and 24.
After adjustments, there was a significantly greater improvement in working memory assessed by the SWM for CR individuals, compared to AL. At month 24, it was related mostly to lower protein intake, compared to other macronutrients. Changes in SWM were moderated by changes in sleep quality, physical activity, and energy expenditure.
On the long term, CR in healthy individuals seems to have a slightly positive effect on working memory. The study of brain CR targets opens new possibilities to prevent and treat cognitive deficits.
Experimental studies indicate that lithium may facilitate neurotrophic/protective responses in the brain. Epidemiological and imaging studies in bipolar disorder, in addition to a few trials in Alzheimer's disease support the clinical translation of these findings. Nonetheless, there is limited controlled data about potential use of lithium to treat or prevent dementia.
To determine the benefits of lithium treatment in patients with amnestic mild cognitive impairment (MCI), a clinical condition associated with high risk for Alzheimer's disease.
A total of 61 community-dwelling, physically healthy, older adults with MCI were randomised to receive lithium or placebo (1:1) for 2 years (double-blind phase), and followed-up for an additional 24 months (single-blinded phase) (trial registration at clinicaltrials.gov: NCT01055392). Lithium carbonate was prescribed to yield subtherapeutic concentrations (0.25–0.5 mEq/L). Primary outcome variables were the cognitive (Alzheimer's Disease Assessment Scale – cognitive subscale) and functional (Clinical Dementia Rating – Sum of Boxes) parameters obtained at baseline and after 12 and 24 months. Secondary outcomes were neuropsychological test scores; cerebrospinal fluid (CSF) concentrations of Alzheimer's disease-related biomarkers determined at 0, 12 and 36 months; conversion rate from MCI to dementia (0–48 months).
Participants in the placebo group displayed cognitive and functional decline, whereas lithium-treated patients remained stable over 2 years. Lithium treatment was associated with better performance on memory and attention tests after 24 months, and with a significant increase in CSF amyloid-beta peptide (Aβ1−42) after 36 months.
Long-term lithium attenuates cognitive and functional decline in amnestic MCI, and modifies Alzheimer's disease-related CSF biomarkers. The present data reinforces the disease-modifying properties of lithium in the MCI–Alzheimer's disease continuum.
The purpose of this research was to understand the preferences of patients receiving integrative medicine services for return of aggregate study results.
A brief online survey (survey 1) was sent to 341 cancer patients receiving integrative medicine interventions; subsequently, a minimally revised survey (survey 2) was sent to 812 individuals with various medical conditions who had been either research participants in integrative medicine studies (n = 446) or patients (n = 346) of mind–body medicine.
Feedback to a model plain language summary was elicited from survey 1 and survey 2 respondents. Seventy-seven survey recipients (23%) responded to survey 1, and 134 survey recipients (17%) responded to survey 2. The majority of respondents to the surveys were female and 51–70 years of age. Ninety percent of responders to survey 1 and 89% of responders to survey 2 indicated that researchers should share overall results of a study with participants. In terms of the means of result distribution, 37%–47% preferred email, while 22%–27% indicated that, as long as the results are shared, it did not matter how this occurred. Of 38 survey 1 respondents who had previously participated in a clinical trial, 37% had received the results of their study. In survey 2, 63 individuals indicated that they previously participated in clinical trials, but only 16% recalled receiving results.
These results confirm that the majority (89%–90%) of integrative medicine patients are interested in receiving the results of clinical trials. The majority (82%–94%) of respondents felt the model plain language summary of results provided was helpful.
Two similarly designed extension studies evaluated the long-term safety and tolerability of desvenlafaxine for the treatment of children and adolescents with major depressive disorder (MDD). Efficacy was evaluated as a secondary objective.
Both 6-month, open-label, flexible-dose extension studies enrolled children and adolescents who had completed one of two double-blind, placebo-controlled, lead-in studies. One lead-in study included a 1-week transition period prior to the extension study. Patients received 26-week treatment with flexible-dose desvenlafaxine (20–50 mg/d). Safety assessments included comprehensive psychiatric evaluations, vital sign assessments, laboratory evaluations, 12-lead electrocardiogram, physical examination with Tanner assessment, and Columbia-Suicide Severity Rating Scale. Adverse events (AEs) were collected throughout the studies. Efficacy was assessed using the Children’s Depression Rating Scale–Revised (CDRS-R).
A total of 552 patients enrolled (completion rates: 66.4 and 69.1%). AEs were reported by 79.4 and 79.1% of patients in the two studies; 8.9 and 5.2% discontinued due to AEs. Treatment-emergent suicidal ideation or behavior was reported for 16.6 and 14.1% of patients in the two studies. Mean (SD) CDRS-R total score decreased from 33.83 (11.93) and 30.92 (10.20) at the extension study baseline to 24.31 (7.48) and 24.92 (8.45), respectively, at week 26.
Desvenlafaxine 20 to 50 mg/d was generally safe and well tolerated with no new safety signals identified in children and adolescents with MDD who received up to 6 months of treatment in these studies. Patients maintained the reduction in severity of depressive symptoms observed in all treatment groups at the end of the lead-in study.
This paper describes three case examples from a recent trial of family intervention specifically designed for people of African-Caribbean descent. These examples, told from the therapists’ perspectives, highlight key components of the intervention and issues that arose in working with this client group. Findings from the study suggest that it is possible to engage this client-group in family therapy similar to traditional evidenced-based family interventions, although as illustrated in the paper, it is important that therapists pay attention to themes that are likely to be particularly pertinent for this group, including experiences of discrimination and mistrust of services. The use of Family Support Members, consisting of members of the person's care team or volunteers recruited from the community, may also help support people to engage in therapy in the absence of biological relatives.
Cognitive dysfunction is common in many psychiatric disorders. While it has long been described as a core feature in schizophrenia, more recent data suggest qualitatively similar impairments in patients with bipolar disorder and major depressive disorder. There is compelling evidence to suggest that cognitive impairment contributes directly to functional disability and reduced quality of like across these disorders. As current treatments focus heavily on “primary” symptoms of mood and psychosis, the standard of care typically leaves cognitive deficits unmanaged. With this in mind, the field has recently begun to consider intervening directly on this important symptom domain, with several ongoing trials in schizophrenia. Fewer studies have targeted cognition in bipolar disorder and still fewer in MDD. With progress toward considering this domain as a target for treatment comes the need for consensus guidelines and methodological recommendations on cognitive trial design. In this manuscript, we first summarize the work conducted to date in this area for schizophrenia and for bipolar disorder. We then begin to address these same issues in MDD and emphasize the need for additional work in this area.
This study aimed to explore effects of adjunctive treatment with N-acetyl cysteine (NAC) on markers of inflammation and neurogenesis in bipolar depression.
This is a secondary analysis of a placebo-controlled randomised trial. Serum samples were collected at baseline, week 8, and week 32 of the open-label and maintenance phases of the clinical trial to determine changes in interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-α (TNF-α), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following adjunctive NAC treatment, and to explore mediation and moderator effects of the listed markers.
Levels of brain-derived neurotrophic factor (BDNF), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukins (IL) -6, 8, or 10 were not significantly changed during the course of the trial or specifically in the open-label and maintenance phases. There were no mediation or moderation effects of the biological factors on the clinical parameters.
The results suggest that these particular biological parameters may not be directly involved in the therapeutic mechanism of action of adjunctive NAC in bipolar depression.
High-quality placebo-controlled evidence for food, nutrient or dietary advice interventions is vital for verifying the role of diet in optimising health or for the management of disease. This could be argued to be especially important where the benefits of dietary intervention are coupled with potential risks such as compromising nutrient intake, particularly in the case of exclusion diets. The objective of the present paper is to explore the challenges associated with clinical trials in dietary research, review the types of controls used and present the advantages and disadvantages of each, including issues regarding placebos and blinding. Placebo-controlled trials in nutrient interventions are relatively straightforward, as in general placebos can be easily produced. However, the challenges associated with conducting placebo-controlled food interventions and dietary advice interventions are protean, and this has led to a paucity of placebo-controlled food and dietary advice trials compared with drug trials. This review appraises the types of controls used in dietary intervention trials and provides recommendations and nine essential criteria for the design and development of sham diets for use in studies evaluating the effect of dietary advice, along with practical guidance regarding their evaluation. The rationale for these criteria predominantly relate to avoiding altering the outcome of interest in those delivered the sham intervention in these types of studies, while not compromising blinding.
Knowledge regarding association of dietary branched-chain amino acid (BCAA) and type 2 diabetes (T2D), and the contribution of BCAA from meat to the risk of T2D are scarce. We evaluated associations between dietary BCAA intake, meat intake, interaction between BCAA and meat intake and risk of T2D. Data analyses were performed for 74 155 participants aged 50−79 years at baseline from the Women’s Health Initiative for up to 15 years of follow-up. We excluded from analysis participants with treated T2D, and factors potentially associated with T2D or missing covariate data. The BCAA and total meat intake was estimated from FFQ. Using Cox proportional hazards models, we assessed the relationship between BCAA intake, meat intake, and T2D, adjusting for confounders. A 20 % increment in total BCAA intake (g/d and %energy) was associated with a 7 % higher risk for T2D (hazard ratio (HR) 1·07; 95 % CI 1·05, 1·09). For total meat intake, a 20 % increment was associated with a 4 % higher risk of T2D (HR 1·04; 95 % CI 1·03, 1·05). The associations between BCAA intake and T2D were attenuated but remained significant after adjustment for total meat intake. These relations did not materially differ with or without adjustment for BMI. Our results suggest that dietary BCAA and meat intake are positively associated with T2D among postmenopausal women. The association of BCAA and diabetes risk was attenuated but remained positive after adjustment for meat intake suggesting that BCAA intake in part but not in full is contributing to the association of meat with T2D risk.
To evaluate the effects of levomilnacipran extended-release (ER) on suicidal ideation and behavior in adults with major depressive disorder (MDD).
Post hoc analyses were conducted in patients from 4 randomized, double-blind, placebo-controlled trials and a long-term, open-label extension study of levomilnacipran ER (40-120 mg/d) in adults with MDD. Analyses included incidence of suicide-related treatment-emergent adverse events (TEAEs); incidence of Columbia–Suicide Severity Rating Scale (C-SSRS) suicidal ideation (score=1–5) and behavior (score=6-10); percent of patients who shifted from no C-SSRS suicidal ideation/behavior at baseline to suicidal ideation during treatment (worsened from score=0 to score=1–5), or vice-versa (improved from score=1-5 to score=0).
Suicide-related TEAEs occurred in<1% of patients in the levomilnacipran ER studies. The incidence of C-SSRS suicidal ideation was 22.2%, 23.9%, and 21.7% for placebo, short-term levomilnacipran ER, and long-term levomilnacipran ER, respectively; C-SSRS suicidal behavior was<1% in all of these groups. In the short-term studies, the percentage of patients with C-SSRS shifts were as follows: worsening from score=0 to score=1–5 (placebo, 8.6%; levomilnacipran ER, 11.0%); improvement from score=1–5 to score=0 (placebo, 24.0%; levomilnacipran ER, 27.7%).
In adult MDD patients, the incidence of suicidal ideation and behavior was similar between placebo and short-term levomilnacipran ER as indicated by TEAE reports and C-SSRS scores. Worsening in C-SSRS scores was also similar between placebo and levomilnacipran ER. There was no indication of increased suicidality during longer courses of continued therapy. Together, these findings suggest that this medication is not associated with increased risks of suicidal ideation or behavior.
This study aimed to explore effects of adjunctive N-acetylcysteine (NAC) treatment on inflammatory and neurogenesis markers in unipolar depression.
We embarked on a 12-week clinical trial of NAC (2000 mg/day compared with placebo) as an adjunctive treatment for unipolar depression. A follow-up visit was conducted 4 weeks following the completion of treatment. We collected serum samples at baseline and the end of the treatment phase (week 12) to determine changes in interleukin-6 (IL6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following NAC treatment.
NAC treatment significantly improved depressive symptoms on the Montgomery–Asberg Depression Rating Scale (MADRS) over 16 weeks of the trial. Serum levels of IL6 were associated with reductions of MADRS scores independent of treatment response. However, we found no significant changes in IL6, CRP and BDNF levels following NAC treatment.
Overall, this suggests that our results failed to support the hypothesis that IL6, CRP and BDNF are directly involved in the therapeutic mechanism of NAC in depression. IL6 may be a useful marker for future exploration of treatment response.
Sodium nitroprusside (SNP) has been reported to rapidly reduce psychotic symptoms in patients with schizophrenia. This has the potential to revolutionize treatment for schizophrenia. In this study, we tested the hypothesis that SNP leads to a reduction in psychotic symptoms and an improvement in spatial working memory (SWM) performance in patients with schizophrenia.
This was a single-centre, randomized, double-blind, placebo-controlled trial performed from 27 August 2014 to 10 February 2016 (clinicaltrials.gov identifier: NCT02176044). Twenty patients with schizophrenia aged 18–60 years with a diagnosis of schizophrenia or schizoaffective disorder were recruited from psychiatric outpatient clinics in the South London and Maudsley NHS Trust, London, UK. Baseline symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18), and SWM was assessed using the CANTAB computerized test. Participants received either an infusion of SNP (0.5 μg/kg per min for 4 h) or placebo and were re-assessed for symptoms and SWM performance immediately after the infusion, and 4 weeks later.
SNP did not lead to any reduction in psychotic symptoms or improvement in SWM performance compared to placebo.
Although this study was negative, it is possible that the beneficial effects of SNP may occur in patients with a shorter history of illness, or with more acute exacerbation of symptoms.
Common mental disorders (CMDs) are highly prevalent in the working population, and are associated with long-term sickness absence and disability. Workers on sick leave with CMDs would benefit from interventions that enable them to successfully return to work (RTW). However, the effectiveness of RTW interventions for workers with a CMD is not well studied. The objective of this review is to assess the effectiveness of existing workplace and clinical interventions that were aimed at enhancing RTW. A systematic review of studies of interventions for improving RTW in workers with a CMD was conducted. The main outcomes were proportion of RTW and sick-leave duration until RTW. Randomized controlled trials (RCTs) were identified from Medline/PubMed, PsycINFO, EMBASE, SocINDEX, and Human resource and management databases from January 1995 to 2016. Two authors independently selected studies, assessed risk of bias and extracted data. We pooled studies that we deemed sufficiently homogeneous in different comparison groups and assessed the overall quality of the evidence. We reviewed 2347 abstracts from which 136 full-text articles were reviewed and 16 RCTs were included in the analysis. Combined results from these studies suggested that the available interventions did not lead to improved RTW rates over the control group [pooled risk ratio 1.05, 95% confidence interval (CI) 0.97–1.12], but reduced the number of sick-leave days in the intervention group compared to the control group, with a mean difference of −13.38 days (95% CI −24.07 to −2.69).
Introduction: Background: A single-agent approach to children’s moderate to severe pain is often inadequate. To date, no studies have evaluated the combined use of oral morphine and ibuprofen for optimal pain management of children presenting to an Emergency Department (ED) for musculoskeletal (MSK) trauma. Objective: To assess the efficacy of a combination of oral morphine and ibuprofen for pain management in children with MSK trauma in the ED. Methods: A double-blind, placebo-controlled, multi-centered, three-arm, randomized clinical trial of 500 patients was conducted at three pediatric tertiary care EDs. Patients 6 to 17 years of age, who presented to the ED with a MSK trauma, and a score >30 mm on the 100 mm Visual Analogue Scale were eligible to participate. Patients were randomized (in a 2:1:1 ratio) to receive (orally): (a) morphine (0.2mg/kg) + ibuprofen (10mg/kg) (Group MOR + IBU) or (b) morphine (0.2 mg/kg) + placebo (Group MOR) or (c) ibuprofen (10mg/kg) + placebo (Group IBU). Primary outcome was pain intensity score under 30 mm (mild pain) at 60-minutes (T-60) after treatment administration. Results: A total of 456 patients were included in analyses: 177 (MOR + IBU), 188 (MOR), 91 (IBU). Mean age was 11.9 + 2.7 years, with a majority of boys (55.3%) and soft tissue injuries (62%). There were no differences in baseline characteristics in the three groups. Baseline mean pain score was 60.9 + 16.2 mm. Only 30% (MOR + IBU), 29% (MOR) and 30% (IBU) of patients reached a pain score under 30 mm at T-60 (p=0.83). Mean pain scores at T-60 were 42.3 + 23.2 mm (MOR + IBU), 43.8 + 23.1 mm (MOR) and 42.3 + 23.3 mm (IBU) (p=0.83). No severe adverse events were observed in any of the groups, at any of the study measurement points. Conclusion: Combination of morphine with ibuprofen did not provide any additional pain relief for children with MSK injuries, in the ED. None of the study medication provided optimal pain management, as the majority of children did not reach the WHO definition of mild pain. Alternative analgesic combinations should be investigated to optimize pain relief of children who present to the ED with MSK injuries.
Objectives: This study aims to analyze the key factors considered for the first application of the National Committee for the Evaluation of Medical Devices (CNEDiMTS) for achieving reimbursement through registration in the list of products and services qualifying for reimbursement (LPPR).
Methods: All the appraisals studied on medical devices (MD) for first inclusion in the LPPR during 2011 and 2012 were retrieved from the French National Authority for Health or Haute Autorité de santé (HAS) Web site. A list of relevant factors was analyzed for each included opinion, followed by univariate and multivariate analyses to highlight the key factors that impacted the expected benefit (EB) provided by HAS.
Results: A total of 151 appraisals were included in the study. Of them, 94 (62 percent) were granted with sufficient EB. The manufacturers were mostly from the United States (36 percent), while most of the applicants were from France (84 percent). After adjusting for other retrieved factors, it was observed that MDs complying with the technical standards, requests supported by opinion(s) from previous generation of MD, and the presence of recommendations or guidelines had more probability to obtain a sufficient EB. A lower probability was related to MDs supported by low-quality studies and with no specific health public benefit.
Conclusions: Our results confirmed that manufacturers seeking reimbursement should be aware of the expectations of the health authorities (level of evidence, technical standard, etc.) and foresee their plan of sending requests for funding so that they can provide evidence of good quality.
The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD.
We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013.
We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of “clinically significant A/A.” There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials.
This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.
The generalized Pólya urn has been extensively studied and is widely applied in many disciplines. An important application of urn models is in the development of randomized treatment allocation schemes in clinical studies. The randomly reinforced urn was recently proposed, but, although the model has some intuitively desirable properties, it lacks theoretical justification. In this paper we obtain important asymptotic properties for multicolor reinforced urn models. We derive results for the rate of convergence of the number of patients assigned to each treatment under a set of minimum required conditions and provide the distributions of the limits. Furthermore, we study the asymptotic behavior for the nonhomogeneous case.
Background: A large body of research has identified that many therapists do not use research to inform their practice, but few studies investigate the reasons behind this. Aims: The current study seeks to understand what sources therapists use to inform their practice and why they are chosen. Method: Thirty-three interviews with psychological therapists in the UK were undertaken. These were transcribed and analysed using Interpretative Phenomenological Analysis. Results: Two superordinate themes emerged. The former focused on the nature of evidence and the latter described why certain sources were used to make clinical decisions. When discussing evidence, participants felt that research studies, specifically Randomized Controlled Trials (RCTs), used unrepresentative samples. Therapists felt that research other than RCTs, particularly qualitative research, was important. Therapist specific factors were felt to be as, or more, important than the technique used to treat patients. When discussing the sources they used, therapists preferred to use their clinical experience or their patients’ experience to make clinical decisions. Theoretical or practical information was preferred to empirical research. The presentation of information was felt to be important to encourage the implementation of research, and therapists also felt tools such as outcome measures and manuals were too rigid to be useful. Finally, patients’ choice of treatment was felt to be important in treatment decisions. Conclusions: The views of therapists were heterogeneous, but this study highlighted some of the barriers to closing the gap between science and practice. This knowledge can be used to increase the translation of science into practice.
Objectives: The use of value of information methods to inform trial design has been widely advocated but there have been few empirical applications of these methods and there is little evidence they are widely used in decision making. This study considers the usefulness of value of information models in the context of a real clinical decision problem relating to alternative diagnostic strategies for patients with a recent non-ST elevated myocardial infarction.
Methods: A pretrial economic model is constructed to consider the cost-effectiveness of two competing strategies: coronary angiography alone or in conjunction with fractional flow reserve measurement. A closed-form solution to the expected benefits of information is used with optimal sample size estimated for a range of models reflecting increasingly realistic assumptions and alternative decision contexts.
Results: Fractional flow reserve measurement is expected to be cost-effective with an incremental cost-effectiveness ratio of GBP 1,621, however, there is considerable uncertainty in this estimate and consequently a large expected value to reducing this uncertainty via a trial. The recommended sample size is strongly affected by the reality of the assumptions of the expected value of information (EVI) model and the decision context.
Conclusions: Value of information models can provide a simple and flexible approach to clinical trial design and are more consistent with the constraints and objectives of the healthcare system than traditional frequentist approaches. However, the variation in sample size estimates demonstrates that it is essential that appropriate model parameters and decision contexts are used in their application.