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Background: With prevalence estimates between 50% and 90% of people with cancer, cancer-related fatigue is one of the most common morbidities related to cancer and its treatment. Exercise is beneficial for the treatment of cancer-related fatigue. However, the efficacy of different types of exercise (i.e. cardiovascular training and resistance training) have not yet been investigated systematically and compared directly in a meta-analysis., Objectives: To compare the benefits and harms of cardiovascular training versus resistance training for treatment or prevention of cancer-related fatigue in people with cancer., Search Methods: We searched CENTRAL, MEDLINE, Embase, and five other databases in January 2023. We searched ClinicalTrials.gov and the International Clinical Trials Registry Platform for ongoing trials. We integrated results from update searches of previously published Cochrane reviews. In total, our searches included trials from inception to October 2023., Selection Criteria: We included randomised controlled trials investigating cardiovascular training compared with resistance training, with exercise as the main component. We included studies on adults with cancer (aged 18 years and older), with or without a diagnosis of cancer-related fatigue, for any type of cancer and any type of cancer treatment, with the intervention starting before, during, or after treatment. We included trials evaluating at least one of our primary outcomes (cancer-related fatigue or quality of life). We excluded combined cardiovascular and resistance interventions, yoga, and mindfulness-based interventions. Our primary outcomes were cancer-related fatigue and quality of life. Our secondary outcomes were adverse events, anxiety, and depression., Data Collection and Analysis: We used standard Cochrane methodology. For analyses, we pooled results within the same period of outcome assessment (i.e. short term (up to and including 12 weeks' follow-up), medium term (more than 12 weeks' to less than six months' follow-up), and long term (six months' follow-up or longer)). We assessed risk of bias using the Cochrane RoB 1 tool, and certainty of the evidence using GRADE., Main Results: We included six studies with 447 participants with prostate, breast, or lung cancer who received radiotherapy or chemotherapy, had surgery, or a combination of these. All studies had a high risk of bias due to lack of blinding. Three studies had an additional high risk of bias domain; one study for attrition bias, and two studies for selection bias. Interventions in the cardiovascular training groups included training on a cycle ergometer, treadmill, an elliptical trainer, or indoor bike. Interventions in the resistance training group included a varying number of exercises using bodyweight, weights, or resistance bands. Interventions varied in frequency, intensity, and duration. None of the included studies reported including participants with a confirmed cancer-related fatigue diagnosis. The interventions in four studies started during cancer treatment and in two studies after cancer treatment. Before treatment No studies reported interventions starting before cancer treatment. During treatment The evidence was very uncertain about the effect of cardiovascular training compared with resistance training for short-term cancer-related fatigue (mean difference (MD) -0.29, 95% confidence interval (CI) -2.52 to 1.84; 4 studies, 311 participants; Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) scale where higher values indicate better outcome; very low-certainty evidence) and long-term cancer-related fatigue (MD 1.30, 95% CI -2.17 to 4.77; 1 study, 141 participants; FACIT-Fatigue scale; very low-certainty evidence). The evidence was very uncertain about the effect of cardiovascular training compared with resistance training for short-term quality of life (MD 1.47, 95% CI -1.47 to 4.42; 4 studies, 319 participants; Functional Assessment of Cancer Therapy - General scale where higher values indicate better outcome; very low-certainty evidence) and for long-term quality of life (MD 3.40, 95% CI -4.85 to 11.65; 1 study, 141 participants; Functional Assessment of Cancer Therapy - Anemia scale where higher values indicate better outcome; very low-certainty evidence). The evidence is very uncertain about the effect of cardiovascular training compared with resistance training on the occurrence of adverse events at any follow-up (risk ratio (RR) 2.00, 95% CI 0.19 to 21.18; 2 studies, 128 participants; very low-certainty evidence). No studies reported medium-term cancer-related fatigue or quality of life. After treatment The evidence was very uncertain about the effect of cardiovascular training compared with resistance training for short-term cancer-related fatigue (MD 1.47, 95% CI -0.09 to 3.03; 1 study, 95 participants; Multidimensional Fatigue Inventory-20 General Fatigue subscale where higher values indicate worse outcome; very low-certainty evidence). Resistance training may improve short-term quality of life compared to cardiovascular training, but the evidence is very uncertain (MD -10.96, 95% CI -17.77 to -4.15; 1 study, 95 participants; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 Global Health subscale where higher values indicate better outcome; very low-certainty evidence). No studies reported outcomes at medium-term or long-term follow-up., Authors' Conclusions: The evidence is very uncertain about the effects of cardiovascular training compared with resistance training on treatment of cancer-related fatigue in people with cancer. Larger, well-conducted studies including people with different cancer types receiving different treatments are needed to increase the certainty in the evidence and to better understand who may benefit most from cardiovascular or resistance training. Moreover, studies comparing the effects of cardiovascular and resistance training initiated before as well as after cancer treatment are needed to understand the prophylactic and rehabilitative effects of these exercise types on cancer-related fatigue., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: To review the current sickle cell disease (SCD) literature to assess how "retinopathy" has been defined and to identify ocular outcomes that have been measured and described., Design: A systematic scoping review of SCD literature was completed regarding ocular manifestations of SCD and vision outcomes across all medical specialties., Subjects: Participants with SCD and control patients were included in our data extraction., Methods: We reviewed English-language literature from 2000 to 2021 for eligible studies by searching PubMed, Google Scholar, Embase, and the Cochrane library using terms to encompass SCD and ocular findings., Main Outcome Measures: Data collection included study information, patient characteristics, vision-related findings (inclusion criteria and/or study outcomes), and retinopathy characteristics (definition, when, how and by whom diagnosed)., Results: We identified 4006 unique citations and 111 were included in the analysis. Ophthalmologists were senior authors of about half (59/111; 53.2%) of the articles; most articles were published between 2016 and 2021 (71/111; 70.0%). The studies had been conducted primarily in North America (54/111; 48.6%) or Europe (23/111; 20.7%); designs were cross-sectional (51/111; 45.9%), prospective cohort (28/111; 25.2%), retrospective cohort (27/111; 24.3%), and case-control (4/111; 3.6%). Among studies reporting any retinopathy, it was commonly defined as a combination of nonproliferative sickle cell retinopathy and proliferative sickle cell retinopathy (PSR; 52/87; 59.8%), infrequently as PSR only (6/87; 6.9%), or not defined at all (23/87; 26.4%). The Goldberg classification was used to grade retinopathy in almost half of the studies (41/87; 47.1%). Investigators reporting diagnostic methods used clinical fundus examination (56/111; 50.4%), OCT (24/111; 21.6%), fluorescein angiography (20/111; 18.0%), ultrawidefield fundus photographs (15/111; 13.5%), and OCT angiography (10/111; 9.0%), or did not report methods (28/111; 25.2%)., Conclusions: There are inconsistencies in documentation of methods and outcomes in studies of SCD ophthalmic findings. Particularly concerning is the lack of documentation of ophthalmic examination methods, qualifications of examiners, and clarity and specificity of sickle cell retinopathy definitions. With the increase in SCD treatment research and novel systemic therapies available, it is important to adopt clear and consistent descriptions and rigorous data collection and reporting of ophthalmic outcomes in SCD studies., Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive., Methods: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors., Results: Costs were not significantly different between groups whether the cost of methylphenidate was excluded ( F (2,330) = 0.626, η p 2 = 0.004, p = 0.535) or included ( F (2,330) = 0.629, η p 2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction ( F (2,330) = 7.525, η p 2 = 0.044, p < 0.001)., Discussion: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer's disease while considering the burden on the healthcare system.

Randomized controlled trials remain the reference standard for healthcare research on effects of interventions, and the need to report both benefits and harms is essential. The Consolidated Standards of Reporting Trials (the main CONSORT) statement includes one item on reporting harms (i.e., all important harms or unintended effects in each group). In 2004, the CONSORT group developed the CONSORT Harms extension; however, it has not been consistently applied and needs to be updated. Here, we describe CONSORT Harms 2022, which replaces the CONSORT Harms 2004 checklist, and shows how CONSORT Harms 2022 items could be incorporated into the main CONSORT checklist. Thirteen items from the main CONSORT were modified to improve harms reporting. Three new items were added. In this article, we describe CONSORT Harms 2022 and how it was integrated into the main CONSORT checklist and elaborate on each item relevant to complete reporting of harms in randomized controlled trials. Until future work from the CONSORT group produces an updated checklist, authors, journal reviewers, and editors of randomized controlled trials should use the integrated checklist presented in this paper., (Copyright © 2023. Published by Elsevier Inc.)

There is a dearth of literature on factors associated with citation of publications in ophthalmology. We investigated predictors of citations for original ophthalmologic research articles based on author, study, and journal characteristics. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), we extracted articles that studied the leading cause of vision impairment in the United States (cataract, diabetic retinopathy, age-related macular degeneration, and glaucoma) and were published in the top fifteen ophthalmology journals with the highest impact factors that accepted original research. Descriptive statistics, one-way analysis of variance (ANOVA) tests, and negative binomial regression were used to compare citation counts based on author, study, and journal characteristics. In this study, author research productivity, journal impact factor, study funding, and location in high-income countries were predictors of increased citation in ophthalmology.

Background: Traumatic hyphema is the entry of blood into the anterior chamber, the space between the cornea and iris, following significant injury to the eye. Hyphema may be associated with significant complications that uncommonly cause permanent vision loss. Complications include elevated intraocular pressure, corneal blood staining, anterior and posterior synechiae, and optic nerve atrophy. People with sickle cell trait or disease may be particularly susceptible to increases in intraocular pressure and optic atrophy. Rebleeding is associated with an increase in the rate and severity of complications., Objectives: To assess the effectiveness of various medical interventions in the management of traumatic hyphema., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 3); MEDLINE Ovid; Embase.com; PubMed (1948 to March 2022); the ISRCTN registry; ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The last date of the search was 22 March 2022., Selection Criteria: Two review authors independently assessed the titles and abstracts of all reports identified by the electronic and manual searches. We included randomized and quasi-randomized trials that compared various medical (non-surgical) interventions versus other medical interventions or control groups for the treatment of traumatic hyphema following closed-globe trauma. We applied no restrictions on age, gender, severity of the closed-globe trauma, or level of visual acuity at time of enrollment., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane and assessed the certainty of evidence using GRADE., Main Results: We included 23 randomized and seven quasi-randomized studies with a total of 2969 participants. Interventions included antifibrinolytic agents (systemic and topical aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid), corticosteroids (systemic and topical), cycloplegics, miotics, aspirin, conjugated estrogens, traditional Chinese medicine, monocular versus bilateral patching, elevation of the head, and bed rest. We found no evidence of an effect on visual acuity for any intervention, whether measured within two weeks (short term) or for longer periods. In a meta-analysis of two trials, we found no evidence of an effect of aminocaproic acid on long-term visual acuity (RR 1.03, 95% confidence interval (CI) 0.82 to 1.29) or final visual acuity measured up to three years after the hyphema (RR 1.05, 95% CI 0.93 to 1.18). Oral tranexamic acid appeared to provide little to no benefit on visual acuity in four trials (RR 1.12, 95% CI 1.00 to 1.25). The remaining trials evaluated the effects of various interventions on short-term visual acuity; none of these interventions was measured in more than one trial. No intervention showed a statistically significant effect (RRs ranged from 0.75 to 1.10). Similarly, visual acuity measured for longer periods in four trials evaluating different interventions was also not statistically significant (RRs ranged from 0.82 to 1.02). The evidence supporting these findings was of low or very low certainty. Systemic aminocaproic acid reduced the rate of recurrent hemorrhage (RR 0.28, 95% CI 0.13 to 0.60), as assessed in six trials with 330 participants. A sensitivity analysis omitting two studies not using an intention-to-treat analysis reduced the strength of the evidence (RR 0.43, 95% CI 0.17 to 1.08). We obtained similar results for topical aminocaproic acid (RR 0.48, 95% CI 0.20 to 1.10) in two trials with 131 participants. We assessed the certainty of the evidence as low. Systemic tranexamic acid had a significant effect in reducing the rate of secondary hemorrhage (RR 0.33, 95% CI 0.21 to 0.53) in seven trials with 754 participants, as did aminomethylbenzoic acid (RR 0.10, 95% CI 0.02 to 0.41), as reported in one study. Evidence to support an associated reduction in risk of complications from secondary hemorrhage (i.e. corneal blood staining, peripheral anterior synechiae, elevated intraocular pressure, and development of optic atrophy) by antifibrinolytics was limited by the small number of these events. Use of aminocaproic acid was associated with increased nausea, vomiting, and other adverse events compared with placebo. We found no evidence of an effect on the number of adverse events with the use of systemic versus topical aminocaproic acid or with standard versus lower drug dose.  The number of days for the primary hyphema to resolve appeared to be longer with the use of systemic aminocaproic acid compared with no use, but this outcome was not altered by any other intervention. The available evidence on usage of systemic or topical corticosteroids, cycloplegics, or aspirin in traumatic hyphema was limited due to the small numbers of participants and events in the trials. We found no evidence of an effect between a single versus binocular patch on the risk of secondary hemorrhage or time to rebleed. We also found no evidence of an effect on the risk of secondary hemorrhage between ambulation and complete bed rest., Authors' Conclusions: We found no evidence of an effect on visual acuity of any of the interventions evaluated in this review. Although the evidence was limited, people with traumatic hyphema who receive aminocaproic acid or tranexamic acid are less likely to experience secondary hemorrhage. However, hyphema took longer to clear in people treated with systemic aminocaproic acid. There is no good evidence to support the use of antifibrinolytic agents in the management of traumatic hyphema, other than possibly to reduce the rate of secondary hemorrhage. The potentially long-term deleterious effects of secondary hemorrhage are unknown. Similarly, there is no evidence to support the use of corticosteroids, cycloplegics, or non-drug interventions (such as patching, bed rest, or head elevation) in the management of traumatic hyphema. As these multiple interventions are rarely used in isolation, further research to assess the additive effect of these interventions might be of value., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: The National Institutes of Health (NIH) announced a revised, expanded definition of "clinical trial" in 2014 to improve trial identification and administrative compliance. Some stakeholders voiced concerns that the policy added administrative burden potentially slowing research progress., Methods: This quasi-experimental study examined the difference-in-differences impact of the new NIH clinical trial definition policy on participant recruitment progress in grants funded by the National Institute of Mental Health (NIMH)., Results: 132 funded clinical trial grants were identified. While more grants were identified as clinical trials under the revised definition, the difference-in-differences in recruitment progress before and after the policy change was not statistically significant., Conclusions: The revised NIH clinical trial definition had no clear effect on recruitment progress in newly-identified NIMH-funded clinical trials as compared to traditionally-identified clinical trials. Concerns that administrative delays and burden could impact study progress may be alleviated by these initial results., Competing Interests: Disclosures: The views expressed in this article do not necessarily represent the views of the National Institutes of Health, the Department of Health and Human Services, or the United States Government. This article reflects the views of Dr. Fain and should not be construed to represent FDA’s views or policies. The authors thank Dr. Brendan Saloner for his contributions in reviewing this manuscript.

Purpose: Tinnitus retraining therapy (TRT) has been widely used for 30 years, but its efficacy and the component contributions from counseling and sound therapy remain controversial. The purpose of this secondary analysis from the Tinnitus Retraining Therapy Trial (TRTT) was to compare treatment response dynamics for TRT (counseling and conventional sound generators) with partial TRT (pTRT; counseling and placebo sound generators) and standard of care (SOC; a patient-centered counseling control)., Method: The TRTT randomized 151 participants with primary tinnitus ( no significant hearing or sound tolerance problems ) to TRT, pTRT, or SOC, each of which encouraged use of enriched environmental sound. The primary outcome, mean change in Tinnitus Questionnaire score assessed at baseline and follow-up across 18 months, was normalized for a common baseline and fitted with an exponential model. Time constants were estimated to quantify and compare the treatment response dynamics, which were evaluated for statistical significance using bootstrap analyses., Results: The change in response to TRT took less time to achieve than that for either pTRT or SOC, as demonstrated by time for normalized Tinnitus Questionnaire scores to decline to 63% and 99% of baseline TRT values: 1.2 months (95% CI [0.2, 1.9]) and 5.7 months (95% CI [0.9, 9.0]), respectively. Corresponding SOC values were 2.7 months (95% CI [1.5, 4.1]) and 12.4 months (95% CI [6.9, 19.0]), while those for pTRT were 2.2 months (95% CI [1.2, 3.4]) and 10.1 months (95% CI [5.7, 15.9]). The differences were significant for TRT versus SOC ( p = .020), borderline significant for TRT versus pTRT ( p = .057), but nonsignificant for pTRT versus SOC ( p = .285). The magnitude of the asymptotic treatment response did not differ significantly among groups., Conclusion: Sound generator use in TRT increases treatment efficiency (beyond any advantage from enriched environmental sound) without affecting treatment efficacy (determined by counseling).

Importance: Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality., Objective: To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease., Design, Setting, and Participants: This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included., Interventions: Ten milligrams of methylphenidate, twice daily, vs matching placebo., Main Outcomes and Measures: The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life., Results: Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups., Conclusions and Relevance: This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease., Trial Registration: ClinicalTrials.gov Identifier: NCT02346201.

Background/aims: The National Institutes of Health (NIH) implemented a recruitment milestone and progress reporting policy in fiscal year 2019. While too recent to evaluate, the National Institute of Mental Health (NIMH) previously implemented a similar policy in fiscal year 2006 which may forecast likely effects of the NIH-wide policy., Methods: An observational, single-group, pre/post evaluation of the association between the NIMH policy and the Relative Citation Ratio was conducted for non-fellowship, competing clinical trial grants funded from fiscal years 2004-2007., Results: 124 clinical trial grants were identified. After adjusting for covariates, the clinical trial grants subject to the NIMH recruitment monitoring policy were associated with a statistically significant mean-per-grant citation ratio (citations relative to the field norm) 1.98 times that of the clinical trial grants that were not subject to the policy (p = 0.005; 95% CI: [1.23, 3.20]). The clinical trial grants subject to the policy were also associated with a non-statistically significant 1.58 times maximum-per-grant citation ratio compared to the clinical trial grants not covered by the policy (p = 0.24; 95% CI: [0.73, 3.44])., Conclusions: The NIMH recruitment monitoring and reporting policy was associated with a statistically significant increase in the mean-per-grant Relative Citation Ratio. NIMH-specific results suggest that the NIH-wide policy might also be positively associated with improved Relative Citation Ratio., (Copyright © 2021. Published by Elsevier Inc.)

The National Institutes of Health (NIH) and the National Institute of Mental Health (NIMH) have implemented numerous clinical trial policies in recent years. These policies have well-intended goals but concerns of undue burden have been raised by professional societies. This study identified the new and revised NIH and NIMH clinical trial policies from 2005 to 2019 and summarized the publicly-identified potential benefits and burdens of those policies. Five new/revised NIH-wide and four NIMH-only clinical trial policies were identified. Potential benefits were improved identification, review, conduct, and reporting of publicly-funded clinical trials. Potential burdens were loss of researcher time, potential loss of future research funding opportunities for basic behavioral researchers, and researcher confusion resulting from perceived definition overlap between clinical trials and basic science. Future clinical trial policy development may benefit from early engagement of researchers as stakeholders. Policymakers may benefit from publicly incorporating benefit/burden analyses and outcome evaluations into future policy development., (Copyright © 2021. Published by Elsevier Inc.)

Purpose This clinical focus article is a companion to the work of Erdman et al. (2019), in which we described the rationale, development, and implementation of the standard-of-care protocol used in the Tinnitus Retraining Therapy Trial (TRTT), a multicenter, placebo-controlled, randomized, definitive efficacy trial of tinnitus retraining therapy (TRT). We now describe the historical background, development, and standardized implementation and delivery of the TRT counseling protocol (tinnitus counseling [TC]) used in the TRTT. TC is conjectured to be the key component in the TRT protocol for initiating the habituation process that reduces the response to the tinnitus signal and, ultimately, reduces its impact. In the TRTT, participants assigned to receive TC achieved > 30% reduction in the impact of tinnitus. Method and Results The design and implementation of standardized treatments in multisite randomized controlled trials presents many challenges for investigators. Here, subsequent to presenting the background, rationale, and the TRT protocol model, we describe the development, refinement, and training/certification for standardized delivery of TC in the TRTT. The primary challenges encountered while distilling and streamlining TC for standardized delivery across multiple clinicians and their replacements at six participating military treatment centers in the TRTT are considered, and the resulting counseling protocol is detailed. Conclusions The standardized and streamlined TC used in the TRTT was successful for treating debilitating tinnitus among persons with functionally adequate unaided hearing sensitivity. The structured TC protocol described here appears to be the main determinant of the significant and sizable TRT treatment effects measured in the TRTT, thus bolstering the merits of this standardized counseling approach as one model for the clinical implementation of TRT for the treatment of primary tinnitus.

Background: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver., Objective: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored., Methods: ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation., Results: Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%)., Conclusion: The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Treatment fidelity, defined as ensuring that the recipient receives the intended intervention, is a critical component for accurate estimation of treatment efficacy. Ensuring fidelity and protocol adherence in behavioral trials requires careful planning during the design phase and implementation during the trial. The Tinnitus Retraining Therapy Trial (TRTT) randomized individuals with severe tinnitus to tinnitus retraining therapy (TRT, comprised of tinnitus-specific educational counseling (TC) and sound therapy (ST) using conventional sound generators (SGs)); Partial TRT (TC and placebo SGs); or standard of care (SOC), using a patient-centered care approach. Study audiologists administered both types of counseling in the TRTT, creating a challenge for managing protocol adherence., Methods: We developed methods to enhance treatment fidelity including training, competency assessment, scripts, visual aids, and fidelity monitoring. Protocol monitors identified critical topics and content to be addressed for each type of counseling session, prepared corresponding scripts, and developed training aids and treatment-specific checklists covering those topics. Study audiologists' competency assessment required submission and review by the protocol monitors of an audiotape of one TC and one SOC counseling session. Treatment-specific aids included scripts, a 3-D model of the ear, handouts, and for TC, an illustrated flip-chart with talking points that followed the scripted content. During the trial, audiologists completed treatment-specific checklists during each counseling session, indicating topics covered/discussed and submitted audiotapes of counseling sessions. Protocol monitors reviewed audiotapes using corresponding treatment-specific checklists. Results for individual checklist items were tabulated and proportions calculated., Results: Twenty-five audiologists were certified for TC and/or SOC counseling and 24 completed at least one counseling session. Adherence to each of 33 critical items on the TC checklist as assessed by the protocol monitor ranged from 70 to 100% across 37 counseling sessions (median 97%), with no difference between adherence for TRT (median, 97%) and partial TRT (median, 100%). Adherence to each of 44 critical items on the SOC checklist across 30 SOC counseling sessions ranged from 42 to 100% (median, 87.5%)., Conclusion: The TRTT used multiple methods to address treatment fidelity. The close adherence to each treatment type was critical for evaluating the efficacy of the study interventions in this randomized trial., Trial Registration: clinicaltrials.gov NCT01177137 . Registered on 5 August 2010.

Importance: Conference proceedings are platforms for early communication and dissemination of relevant and timely topics of interest. More than half of abstracts presented at biomedical conferences fail to be published in full, resulting in wasted time and resources., Objective: To systematically review reports evaluating the proportion of abstracts presented at eye and vision conferences that are subsequently published in full and investigate factors associated with publication., Data Sources: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and reference lists of included reports were systematically searched from inception to January 11, 2019., Study Selection: Reports that examined the proportion of abstracts presented at eye and vision conferences and subsequently published in peer-reviewed journals 24 or more months later., Data Extraction and Synthesis: Two reviewers independently assessed study eligibility, abstracted data, and evaluated the risk of bias. A meta-analysis was conducted to determine the proportion of abstracts published in full and assess factors associated with subsequent full publication., Main Outcomes and Measures: Proportion of abstracts presented at eye and vision conferences subsequently published in full., Results: There were 19 reports covering 12 261 abstracts presented at 11 unique eye and vision conferences. The overall risk of bias of the reports was low. The weighted proportion of abstracts published in full was 38.0% (95% CI, 31.7%-44.3%) and 54.9% (95% CI, 34.6%-73.7%) among reports restricted to abstracts describing randomized clinical trials. Nine reports (47.4%) investigated the proportion of abstracts subsequently published by ophthalmic subspecialties, ranging from 28.3% (oculoplastics: 95% CI, 17.2%-42.9%) to 42.7% (glaucoma: 95% CI, 34.7%-51.0%). Oral presentation (risk ratio, 1.45; 95% CI, 1.20-1.76) and basic science (risk ratio, 1.25; 95% CI, 1.05-1.47) were significantly associated with higher full publication; factors not significantly associated with full publication included positive results, randomized clinical trial vs other study design, multicenter study, and industry funding., Conclusion and Relevance: More than 60% of abstracts presented at eye and vision conferences were not published in full within 2 years of conference presentation. Failure to disseminate research studies in peer-reviewed journals is not desired, especially when involving human participants.

Background: Hyperopia in infancy requires accommodative effort to bring images into focus. Prolonged accommodative effort has been associated with an increased risk of strabismus. Strabismus may result in asthenopia and intermittent diplopia, and makes near work tasks difficult to complete. Spectacles to correct hyperopic refractive error is believed to prevent the development of strabismus., Objectives: To assess the effectiveness of prescription spectacles compared with no intervention for the prevention of strabismus in infants and children with hyperopia., Search Methods: We searched CENTRAL (2018, Issue 12; which contains the Cochrane Eyes and Vision Trials Register); Ovid MEDLINE; Embase.com; three other databases; and two trial registries. We used no date or language restrictions in the electronic search for trials. We last searched the electronic databases on 4 December 2018., Selection Criteria: We included randomized controlled trials and quasi-randomized trials investigating spectacle intervention or no treatment for children with hyperopia. We required hyperopia to be at least greater than +2.00 diopters (D)., Data Collection and Analysis: We used standard Cochrane methodological procedures. The primary outcome was the proportion of children with manifest strabismus, as defined by study investigators. Other outcomes included the amblyopia, stereoacuity, and the effect of spectacle use of strabismus and visual acuity. We also collected information on change in refractive error as a measurement of the interference of emmetropization., Main Results: We identified four randomized controlled trials (985 children enrolled who were aged six months to less than 36 months) in this review. Three trials were in the UK with follow-up periods ranging from one to 3.5 years and one in the US with three years' follow-up. Investigators reported both incidence and final status regarding strabismus. Evidence of the incidence of strabismus, measured in 804 children over three to four years in four trials was uncertain although suggestive of a benefit with spectacle use (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.41 to 1.02). We have very low confidence in these results due to high risk of bias, inconsistency, and imprecision. When assessed as the proportion of children with strabismus at the end of three years' follow-up, we found a similar level of evidence for an effect of spectacles on strabismus as reported in one study (RR 1.00, 95% CI 0.31 to 3.25; 106 children). We have very low confidence in these results because of low sample size and risk of bias. One trial reported on the risk for developing amblyopia and inadequate stereoacuity after three years in 106 children. There was unclear evidence for a decreased risk of developing amblyopia (RR 0.78, 95% CI 0.31 to 1.93), and limited evidence for a benefit of spectacles for prevention of inadequate stereoacuity (RR 0.38, 95% CI 0.16 to 0.88). We have very low confidence in these findings due to imprecision and risk of bias. The risk of not developing emmetropization is unclear. One trial reported on the proportion of children not achieving emmetropization at three years' follow-up (RR 0.75, 95% CI 0.18 to 3.19). One trial suggested spectacles impede emmetropization, and one trial reported no difference. These two trials could not be combined because the methods for assessing emmetropization were different. With the high risk of bias and inconsistency, the certainty of evidence for a risk for impeding or benefiting emmetropization is very low. Based on a meta-analysis of four trials (770 children), the risk of having visual acuity worse than 20/30 measured up to three years of age or at the end of three years of follow-up was uncertain for children with spectacle correction compared with those without correction (RR 0.87, 95% CI 0.64 to 1.18; very low confidence due to risk of bias and imprecision)., Authors' Conclusions: The effect of spectacle correction for prevention of strabismus is still unclear. In addition, the use of spectacle on the risk of visual acuity worse than 20/30, amblyopia, and inadequate emmetropization is also unclear. There may be a benefit on prevention of inadequate stereoacuity. However, these effects may have been chance findings or due to bias., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Importance: Patient care and clinical practice guidelines should be informed by evidence from reliable systematic reviews. The reliability of systematic reviews related to forthcoming guidelines for retina and vitreous conditions is unknown., Objectives: To summarize the reliability of systematic reviews on interventions for 7 retina and vitreous conditions, describe characteristics of reliable and unreliable systematic reviews, and examine the primary area in which they appeared to be lacking., Design, Setting, and Participants: A cross-sectional study of systematic reviews was conducted. Systematic reviews of interventions for retina- and vitreous-related conditions in a database maintained by the Cochrane Eyes and Vision United States Satellite were identified. Databases that the reviewers searched, whether any date or language restrictions were applied, and bibliographic information, such as year and journal of publication, were documented. The initial search was conducted in March 2007, and the final update was performed in July 2018. The conditions of interest were age-related macular degeneration; diabetic retinopathy; idiopathic epiretinal membrane and vitreomacular traction; idiopathic macular hole; posterior vitreous detachment, retinal breaks, and lattice degeneration; retinal and ophthalmic artery occlusions; and retinal vein occlusions. The reliability of each review was evaluated using prespecified criteria. Data were extracted by 2 research assistants working independently, with disagreements resolved through discussion or by 1 research assistant with verification by a senior team member., Main Outcomes and Measures: Proportion of reviews that meet all of the following criteria: (1) defined eligibility criteria for study selection, (2) described conducting a comprehensive literature search, (3) reported assessing risk of bias in included studies, (4) described using appropriate methods for any meta-analysis performed, and (5) provided conclusions consistent with review findings., Results: A total of 327 systematic reviews that addressed retina and vitreous conditions were identified; of these, 131 reviews (40.1%) were classified as reliable and 196 reviews (59.9%) were classified as not reliable. At least 1 reliable review was found for each of the 7 retina and vitreous conditions. The most common reason that a review was classified as not reliable was lack of evidence that a comprehensive literature search for relevant studies had been conducted (149 of 196 reviews [76.0%])., Conclusion and Relevance: The findings of this study suggest that most systematic reviews that addressed interventions for retina and vitreous conditions were not reliable. Systematic review teams and guideline developers should work with information professionals who can help navigate sophisticated and varied syntaxes required to search different resources.

Background: While identifying and cataloging unpublished studies from conference proceedings is generally recognized as a good practice during systematic reviews, controversy remains whether to include study results that are reported in conference abstracts. Existing guidelines provide conflicting recommendations., Main Body: The main argument for including conference abstracts in systematic reviews is that abstracts with positive results are preferentially published, and published sooner, as full-length articles compared with other abstracts. Arguments against including conference abstracts are that (1) searching for abstracts is resource-intensive, (2) abstracts may not contain adequate information, and (3) the information in abstracts may not be dependable. However, studies comparing conference abstracts and fully published articles of the same study find only minor differences, usually with conference abstracts presenting preliminary results. Other studies that have examined differences in treatment estimates of meta-analyses with and without conference abstracts report changes in precision, but usually not in the treatment effect estimate. However, in some cases, including conference abstracts has made a difference in the estimate of the treatment effect, not just its precision. Instead of arbitrarily deciding to include or exclude conference abstracts in systematic reviews, we suggest that systematic reviewers should consider the availability of evidence informing the review. If available evidence is sparse or conflicting, it may be worthwhile to search for conference abstracts. Further, attempts to contact authors of abstracts or search for protocols or trial registers to supplement the information presented in conference abstracts is prudent. If unique information from conference abstracts is included in a meta-analysis, a sensitivity analysis with and without the unique results should be conducted., Conclusions: Under given circumstances, it is worthwhile to search for and include results from conference abstracts in systematic reviews.

Purpose The selection and design of control conditions are critical factors in minimizing the influence of unwanted variables in randomized controlled trials (RCTs). This article describes the rationale, design, and content of a standard of care control condition in a Phase III RCT of tinnitus retraining therapy. Method Existing tinnitus practices at military hospitals were identified and aligned with the American Speech-Language-Hearing Association's (2006) preferred practice patterns for tinnitus management and counseling and embedded in a patient-centered protocol to ensure uniformity and treatment fidelity. Results For those involved in the design of behavioral RCTs, the article identifies options and methods to consider in the selection and design of control conditions. Conclusion For those who provide tinnitus services, the standard of care protocol developed for the tinnitus retraining therapy trial constitutes a patient-centered approach to intervention that can be implemented clinically. Supplemental Material https://doi.org/10.23641/asha.9342503.

Importance: Tinnitus retraining therapy (TRT) is an internationally recognized, but controversial, protocol of uncertain efficacy that uses tinnitus-specific educational counseling (TC) and sound therapy (ST) to reduce the patient's tinnitus-evoked negative reaction to, and awareness of, tinnitus., Objective: To compare the efficacy of TRT and its components, ST and TC, with the standard of care (SoC) in reducing the negative effect of tinnitus on quality of life., Design, Setting, and Participants: A randomized, placebo-controlled, multicenter phase 3 trial was conducted from August 4, 2011, to June 20, 2017, at 6 US military hospitals, the study chairs' office, and a data coordinating center, among 151 active-duty and retired military personnel and dependents with functionally adequate hearing sensitivity and moderate to severe subjective tinnitus. All analyses were based on intention to treat., Interventions: Central randomized allocation to TRT (TC and ST with conventional sound generators), partial TRT (TC with placebo sound generators), or SoC., Main Outcomes and Measures: The primary outcome was mean change on the Tinnitus Questionnaire (TQ), assessed longitudinally between baseline and 18 months after start of therapy. The secondary outcomes were changes in TQ subscales, Tinnitus Functional Index (TFI), and Tinnitus Handicap Inventory (THI) total and subscales, as well as a 10-point visual analog scale (VAS)., Results: Among the 151 participants in the study (44 women and 107 men; mean [SD] age, 50.6 [11.3] years), 51 were randomized to receive TRT, 51 to receive partial TRT, and 49 to receive standard of care. Longitudinal analyses showed no difference between partial TRT or TRT compared with SoC, or partial TRT compared with TRT, on TQ, TFI, or THI total scores. Comparison of changes in mean score from baseline to the 18-month visit also showed no difference between treatment groups. Significant improvement was observed at 18 months in all treatment groups on TQ scores for TRT (effect size, -1.32; 95% CI, -1.78 to -0.85), partial TRT (effect size, -1.16; 95% CI, -1.56 to -0.76), and SoC (effect size, -1.01; 95% CI, -1.41 to -0.61). Compared with baseline scores, at 18 months there were reductions in scores by 7 points or more on the TQ score for 86 of 111 participants (77.55%; 95% CI, 69.7%-85.2%), 13 points or more on the TFI for 52 of 111 participants (46.8%; 95% CI, 37.6%-56.1%), 7 points or more on the THI for 63 of 111 participants (56.8%; 95% CI, 47.5%-66.0%), and 2 points or more on the VAS for 45 of 93 participants (48.4%; 95% CI, 38.2%-58.5%)., Conclusions and Relevance: There were few differences between treatment groups. About half of participants showed clinically meaningful reductions in the effect of tinnitus., Trial Registration: ClinicalTrials.gov identifier: NCT01177137.

Evidence shows that the quality of reporting of randomised controlled trials (RCTs) is not optimal. The lack of transparent reporting impedes readers from judging the reliability and validity of trial findings and researchers from extracting information for systematic reviews and results in research waste. The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve the reporting of RCTs. Within person trials are used for conditions that can affect two or more body sites, and are a useful and efficient tool because the comparisons between interventions are within people. Such trials are most commonly conducted in ophthalmology, dentistry, and dermatology. The reporting of within person trials has, however, been variable and incomplete, hindering their use in clinical decision making and by future researchers. This document presents the CONSORT extension to within person trials. It aims to facilitate the reporting of these trials. It extends 16 items of the CONSORT 2010 checklist and introduces a modified flowchart and baseline table to enhance transparency. Examples of good reporting and evidence based rationale for CONSORT within person checklist items are provided., (© 2017 The BMJ.)

Background: Traumatic hyphema is the entry of blood into the anterior chamber (the space between the cornea and iris) subsequent to a blow or a projectile striking the eye. Hyphema uncommonly causes permanent loss of vision. Associated trauma (e.g. corneal staining, traumatic cataract, angle recession glaucoma, optic atrophy, etc.) may seriously affect vision. Such complications can lead to permanent impairment of vision. People with sickle cell trait/disease may be particularly susceptible to increases of elevated intraocular pressure. If rebleeding occurs, the rates and severity of complications increase., Objectives: To assess the effectiveness of various medical interventions in the management of traumatic hyphema., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 6); MEDLINE Ovid; Embase.com; PubMed (1948 to June 2018); the ISRCTN registry; ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the search was 28 June 2018., Selection Criteria: Two review authors independently assessed the titles and abstracts of all reports identified by the electronic and manual searches. In this review, we included randomized and quasi-randomized trials that compared various medical (non-surgical) interventions versus other medical intervention or control groups for the treatment of traumatic hyphema following closed-globe trauma. We applied no restrictions regarding age, gender, severity of the closed-globe trauma, or level of visual acuity at the time of enrollment., Data Collection and Analysis: Two review authors independently extracted the data for the primary outcomes, visual acuity and time to resolution of primary hemorrhage, and secondary outcomes including: secondary hemorrhage and time to rebleed; risk of corneal blood staining, glaucoma or elevated intraocular pressure, optic atrophy, or peripheral anterior synechiae; adverse events; and duration of hospitalization. We entered and analyzed data using Review Manager 5. We performed meta-analyses using a fixed-effect model and reported dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD)., Main Results: We included 20 randomized and seven quasi-randomized studies with a total of 2643 participants. Interventions included antifibrinolytic agents (systemic and topical aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid), corticosteroids (systemic and topical), cycloplegics, miotics, aspirin, conjugated estrogens, traditional Chinese medicine, monocular versus bilateral patching, elevation of the head, and bed rest.We found no evidence of an effect on visual acuity for any intervention, whether measured within two weeks (short term) or for longer periods. In a meta-analysis of two trials, we found no evidence of an effect of aminocaproic acid on long-term visual acuity (RR 1.03, 95% confidence interval (CI) 0.82 to 1.29) or final visual acuity measured up to three years after the hyphema (RR 1.05, 95% CI 0.93 to 1.18). Eight trials evaluated the effects of various interventions on short-term visual acuity; none of these interventions was measured in more than one trial. No intervention showed a statistically significant effect (RRs ranged from 0.75 to 1.10). Similarly, visual acuity measured for longer periods in four trials evaluating different interventions was also not statistically significant (RRs ranged from 0.82 to 1.02). The evidence supporting these findings was of low or very low certainty.Systemic aminocaproic acid reduced the rate of recurrent hemorrhage (RR 0.28, 95% CI 0.13 to 0.60) as assessed in six trials with 330 participants. A sensitivity analysis omitting two studies not using an intention-to-treat analysis reduced the strength of the evidence (RR 0.43, 95% CI 0.17 to 1.08). We obtained similar results for topical aminocaproic acid (RR 0.48, 95% CI 0.20 to 1.10) in two studies with 121 participants. We assessed the certainty of these findings as low and very low, respectively. Systemic tranexamic acid had a significant effect in reducing the rate of secondary hemorrhage (RR 0.31, 95% CI 0.17 to 0.55) in five trials with 578 participants, as did aminomethylbenzoic acid as reported in one study (RR 0.10, 95% CI 0.02 to 0.41). The evidence to support an associated reduction in the risk of complications from secondary hemorrhage (i.e. corneal blood staining, peripheral anterior synechiae, elevated intraocular pressure, and development of optic atrophy) by antifibrinolytics was limited by the small number of these events. Use of aminocaproic acid was associated with increased nausea, vomiting, and other adverse events compared with placebo. We found no evidence of an effect in the number of adverse events with the use of systemic versus topical aminocaproic acid or with standard versus lower drug dose. The number of days for the primary hyphema to resolve appeared to be longer with the use of systemic aminocaproic acid compared with no use, but this outcome was not altered by any other intervention.The available evidence on usage of systemic or topical corticosteroids, cycloplegics, or aspirin in traumatic hyphema was limited due to the small numbers of participants and events in the trials.We found no evidence of an effect between a single versus binocular patch or ambulation versus complete bed rest on the risk of secondary hemorrhage or time to rebleed., Authors' Conclusions: We found no evidence of an effect on visual acuity by any of the interventions evaluated in this review. Although evidence was limited, it appears that people with traumatic hyphema who receive aminocaproic acid or tranexamic acid are less likely to experience secondary hemorrhaging. However, hyphema took longer clear in people treated with systemic aminocaproic acid.There is no good evidence to support the use of antifibrinolytic agents in the management of traumatic hyphema other than possibly to reduce the rate of secondary hemorrhage. Similarly, there is no evidence to support the use of corticosteroids, cycloplegics, or non-drug interventions (such as binocular patching, bed rest, or head elevation) in the management of traumatic hyphema. As these multiple interventions are rarely used in isolation, further research to assess the additive effect of these interventions might be of value.

Background: Abstracts of presentations at scientific meetings are usually available only in conference proceedings. If subsequent full publication of results reported in these abstracts is based on the magnitude or direction of the results, publication bias may result. Publication bias creates problems for those conducting systematic reviews or relying on the published literature for evidence about health and social care., Objectives: To systematically review reports of studies that have examined the proportion of meeting abstracts and other summaries that are subsequently published in full, the time between meeting presentation and full publication, and factors associated with full publication., Search Methods: We searched MEDLINE, Embase, the Cochrane Library, Science Citation Index, reference lists, and author files. The most recent search was done in February 2016 for this substantial update to our earlier Cochrane Methodology Review (published in 2007)., Selection Criteria: We included reports of methodology research that examined the proportion of biomedical results initially presented as abstracts or in summary form that were subsequently published. Searches for full publications had to be at least two years after meeting presentation., Data Collection and Analysis: Two review authors extracted data and assessed risk of bias. We calculated the proportion of abstracts published in full using a random-effects model. Dichotomous variables were analyzed using risk ratio (RR), with multivariable models taking into account various characteristics of the reports. We assessed time to publication using Kaplan-Meier survival analyses., Main Results: Combining data from 425 reports (307,028 abstracts) resulted in an overall full publication proportion of 37.3% (95% confidence interval (CI), 35.3% to 39.3%) with varying lengths of follow-up. This is significantly lower than that found in our 2007 review (44.5%. 95% CI, 43.9% to 45.1%). Using a survival analyses to estimate the proportion of abstracts that would be published in full by 10 years produced proportions of 46.4% for all studies; 68.7% for randomized and controlled trials and 44.9% for other studies. Three hundred and fifty-three reports were at high risk of bias on one or more items, but only 32 reports were considered at high risk of bias overall.Forty-five reports (15,783 abstracts) with 'positive' results (defined as any 'significant' result) showed an association with full publication (RR = 1.31; 95% CI 1.23 to 1.40), as did 'positive' results defined as a result favoring the experimental treatment (RR =1.17; 95% CI 1.07 to 1.28) in 34 reports (8794 abstracts). Results emanating from randomized or controlled trials showed the same pattern for both definitions (RR = 1.21; 95% CI 1.10 to 1.32 (15 reports and 2616 abstracts) and RR = 1.17; 95% CI, 1.04 to 1.32 (13 reports and 2307 abstracts), respectively.Other factors associated with full publication include oral presentation (RR = 1.46; 95% CI 1.40 to 1.52; studied in 143 reports with 115,910 abstracts); acceptance for meeting presentation (RR = 1.65; 95% CI 1.48 to 1.85; 22 reports with 22,319 abstracts); randomized trial design (RR = 1.51; 95% CI 1.36 to 1.67; 47 reports with 28,928 abstracts); and basic research (RR = 0.78; 95% CI 0.74 to 0.82; 92 reports with 97,372 abstracts). Abstracts originating at an academic setting were associated with full publication (RR = 1.60; 95% CI 1.34 to 1.92; 34 reports with 16,913 abstracts), as were those considered to be of higher quality (RR = 1.46; 95% CI 1.23 to 1.73; 12 reports with 3364 abstracts), or having high impact (RR = 1.60; 95% CI 1.41 to 1.82; 11 reports with 6982 abstracts). Sensitivity analyses excluding reports that were abstracts themselves or classified as having a high risk of bias did not change these findings in any important way.In considering the reports of the methodology research that we included in this review, we found that reports published in English or from a native English-speaking country found significantly higher proportions of studies published in full, but that there was no association with year of report publication. The findings correspond to a proportion of abstracts published in full of 31.9% for all reports, 40.5% for reports in English, 42.9% for reports from native English-speaking countries, and 52.2% for both these covariates combined., Authors' Conclusions: More than half of results from abstracts, and almost a third of randomized trial results initially presented as abstracts fail to be published in full and this problem does not appear to be decreasing over time. Publication bias is present in that 'positive' results were more frequently published than 'not positive' results. Reports of methodology research written in English showed that a higher proportion of abstracts had been published in full, as did those from native English-speaking countries, suggesting that studies from non-native English-speaking countries may be underrepresented in the scientific literature. After the considerable work involved in adding in the more than 300 additional studies found by the February 2016 searches, we chose not to update the search again because additional searches are unlikely to change these overall conclusions in any important way.

Background The Tinnitus Retraining Therapy Trial (TRTT), a randomized, placebo-controlled, multi-center trial, evaluated the efficacy of tinnitus retraining therapy and its individual components, tinnitus-specific educational counseling and sound therapy versus the standard of care, in military practice to improve study participants' quality of life. The trial was conducted at six US military hospitals to take advantage of the greater prevalence of tinnitus in the military population. Methods During the trial, various challenges arose that were uniquely related to the military setting. To convey these challenges to investigators planning future multi-center trials in military hospitals, we itemized various challenges that arose during the trial, interviewed clinic directors and coordinators to elicit their viewpoints, and then collated and organized their responses, together with those challenges presented while conducting the Tinnitus Retraining Therapy Trial. Results We encountered challenges in site selection, the approval process, administrative issues, study personnel training and retention, participant recruitment methods and issues, adherence to protocol, reimbursement issues, and military security. Site selection involved visiting 20 military hospitals to identify six sites that enrolled and followed study participants. We found that commitment for the trial must be obtained from the full military chain of command, but with ongoing changes in staff or military priorities, initial commitments were insufficient to sustain support throughout the entire trial. More time is required to obtain necessary administrative approvals by various military authorities and institutional review boards than is typically experienced in civilian settings. Recruitment strategies must be flexible due to changing military regulations regarding display of materials. Protracted periods of inactivity were due to sequestration and delays in institutional review board approval of required study personnel or protocol amendments. While mostly adherent to the protocol, study staff had difficulties in integrating study visits into the military clinical schedule. Unexpected study expenses revolved around hiring civilian study staff and obtaining associated security clearance while maintaining a consistent flow of funds to each site. The added expense negated cost savings realized by conducting the National Institutes of Health-funded trial at federal institutions, whose personnel could not be reimbursed for their efforts. Military security concerns impacted the use of web-based data systems and led to increased time and effort required for site visits. Conclusion Overall, US military hospitals provide a unique setting to conduct multi-center trials. Challenges arise mainly due to ever-changing authority personnel and military priorities. Pre-planning and flexibility are keys in overcoming these challenges. Multi-center trials conducted in the military will likely take longer to initiate and complete than those in the civilian sector due to multiple levels of command and administrative approvals.

Background: Alzheimer's disease (AD) is characterized not only by cognitive and functional decline, but also often by the presence of neuropsychiatric symptoms. Apathy, which can be defined as a lack of motivation, is one of the most prevalent neuropsychiatric symptoms in AD and typically leads to a worse quality of life and greater burden for caregivers. Treatment options for apathy in AD are limited, but studies have examined the use of the amphetamine, methylphenidate. The Apathy in Dementia Methylphenidate Trial (ADMET) found that treatment of apathy in AD with methylphenidate was associated with significant improvement in apathy in two of three outcome measures, some evidence of improvement in global cognition, and minimal adverse events. However, the trial only enrolled 60 participants who were followed for only 6 weeks. A larger, longer-lasting trial is required to confirm these promising findings., Methods: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is a phase III, placebo-controlled, masked, 6-month, multi-center, randomized clinical trial targeted to enroll 200 participants with AD and apathy. Participants are randomly assigned 1:1 to 20 mg methylphenidate per day prepared as four over-encapsulated tablets or to matching placebo. The primary outcomes include (1) the mean difference in the Neuropsychiatric Inventory Apathy subscale scores measured as change from baseline to 6 months, and (2) the odds of having a given rating or better on the modified AD Cooperative Study Clinical Global Impression of Change ratings at month 6 compared with the baseline rating. Other outcomes include change in cognition, safety, and cost-effectiveness measured at monthly follow-up visits up to 6 months., Discussion: Given the prevalence of apathy in AD and its impact on both patients and caregivers, an intervention to alleviate apathy would be of great benefit to society. ADMET 2 follows on the promising results from the original ADMET to evaluate the efficacy of methylphenidate as a treatment for apathy in AD. With a larger sample size and longer follow up, ADMET 2 is poised to confirm or refute the original ADMET findings., Trial Registration: ClinicalTrials.gov, NCT02346201 . Registered on 26 January 2015.

Background: Discrepancies between information in conference abstracts and full publications describing the same randomized controlled trial have been reported. The association between author conflicts of interest and the publication of randomized controlled trials is unclear. The objective of this study was to use randomized controlled trials in ophthalmology to evaluate (1) the agreement in the reported main outcome results by comparing abstracts and corresponding publications and (2) the association between the author conflicts of interest and publication of the results presented in the abstracts., Methods: We considered abstracts describing results of randomized controlled trials presented at the 2001-2004 Association for Research in Vision and Ophthalmology conferences as eligible for our study. Through electronic searching and by emailing abstract authors, we identified the earliest publication (journal article) containing results of each abstract's main outcome through November 2013. We categorized the discordance between the main outcome results in the abstract and its paired publication as qualitative (a difference in the direction of the estimated effect) or as quantitative. We used the Association for Research in Vision and Ophthalmology categories for conflicts of interest: financial interest, employee of business with interest, consultant to business with interest, inventor/developer with patent, and receiving ≥ 1 gift from industry in the past year. We calculated the relative risks (RRs) of publication associated with the categories of conflicts of interest for abstracts with results that were statistically significant, not statistically significant, or not reported., Results: We included 513 abstracts, 230 (44.8 %) of which reached publication. Among the 86 pairs with the same main outcome domain at the same time point, 47 pairs (54.7 %) had discordant results: qualitative discordance in 7 pairs and quantitative discordance in 40 pairs. Quantitative discordance was indicated as < 10, 10-20, > 20 %, and unclear in 14, 5, 14, and 7 pairs, respectively. First authors reporting of one or more conflicts of interest was associated with a greater likelihood of publication (RR = 1.31; 95 % CI = 1.04 to 1.64) and a shorter time-to-publication (log-rank p = 0.026). First author conflicts of interests that were associated with publication were financial support (RR = 1.50; 95 % CI = 1.19 to 1.90) and one or more gifts (RR = 1.42; 95 % CI = 1.05 to 1.92). The association between conflicts of interest and publication remained, irrespective of the statistical significance of the results., Conclusions: More than half the abstract/publication pairs exhibited some amount of discordance in the main outcome results, calling into question the dependability of conference abstracts. Regardless of the main outcome results, the conflicts of interests of the abstract's first author were associated with publication.

Objectives: To systematically review reports that queried abstract authors about reasons for not subsequently publishing abstract results as full-length articles., Study Design and Setting: Systematic review of MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science, and study bibliographies for empirical studies in which investigators examined subsequent full publication of results presented at a biomedical conference and reasons for nonpublication., Results: The mean full publication rate was 55.9% [95% confidence interval (CI): 54.8%, 56.9%] for 24 of 27 eligible reports providing this information and 73.0% (95% CI: 71.2%, 74.7%) for seven reports of abstracts describing clinical trials. Twenty-four studies itemized 1,831 reasons for nonpublication, and six itemized 428 reasons considered the most important reason. "Lack of time" was the most frequently reported reason [weighted average = 30.2% (95% CI: 27.9%, 32.4%)] and the most important reason [weighted average = 38.4% (95% CI: 33.7%, 43.2%)]. Other commonly stated reasons were "lack of time and/or resources," "publication not an aim," "low priority," "incomplete study," and "trouble with co-authors.", Conclusions: Across medical specialties, the main reasons for not subsequently publishing an abstract in full lie with factors related to the abstract author rather than with journals., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Including results from unpublished randomized controlled trials (RCTs) in a systematic review may ameliorate the effect of publication bias in systematic review results. Unpublished RCTs are sometimes described in abstracts presented at conferences, included in trials registers, or both. Trial results may not be available in a trials register and abstracts describing RCT results often lack study design information. Complementary information from a trials register record may be sufficient to allow reliable inclusion of an unpublished RCT only available as an abstract in a systematic review., Methods: We identified 496 abstracts describing RCTs presented at the 2007 to 2009 Association for Research in Vision and Ophthalmology (ARVO) meetings; 154 RCTs were registered in ClinicalTrials.gov. Two persons extracted verbatim primary and non-primary outcomes reported in the abstract and ClinicalTrials.gov record. We compared each abstract outcome with all ClinicalTrials.gov outcomes and coded matches as complete, partial, or no match., Results: We identified 800 outcomes in 152 abstracts (95 primary [51 abstracts] and 705 [141 abstracts] non-primary outcomes). No outcomes were reported in 2 abstracts. Of 95 primary outcomes, 17 (18%) agreed completely, 53 (56%) partially, and 25 (26%) had no match with a ClinicalTrials.gov primary or non-primary outcome. Among 705 non-primary outcomes, 56 (8%) agreed completely, 205 (29%) agreed partially, and 444 (63%) had no match with a ClinicalTrials.gov primary or non-primary outcome. Among the 258 outcomes partially agreeing, we found additional information on the time when the outcome was measured more often in ClinicalTrials.gov than in the abstract (141/258 (55%) versus 55/258 (21%)). We found no association between the presence of non-matching "new" outcomes and year of registration, time to registry update, industry sponsorship, or multi-center status., Conclusion: Conference abstracts may be a valuable source of information about results for outcomes of unpublished RCTs that have been registered in ClinicalTrials.gov. Complementary additional descriptive information may be present for outcomes reported in both sources. However, ARVO abstract authors also present outcomes not reported in ClinicalTrials.gov and these may represent analyses not originally planned.

Aim: To review the experience on depot-dose, and daily low-dose gonadotropin releasing hormone agonist (GnRHa) long protocols and identify prognostic factors., Setting and Design: A chart review was conducted on 2106 depot and 1299 daily low-dose cycles at a university hospital., Methods: Clinical parameters were summarized, and prognostic factors of clinical pregnancy for each protocol were identified by logistic regressions. Missing data were imputed using multiple imputations (MI) and the regression models were rerun after MI., Results: Clinical pregnancy rate was 57.5% and 46.9% in the depot and daily low-dose groups, respectively. Logistic regressions with MI identified age (odds ratio [OR]: 0.95, 95% confidence interval [CI]: 0.92-0.98), serum progesterone (OR: 0.62, 95% CI: 0.45-0.84) and endometrial thickness (OR: 1.06, 95% CI: 1.02-1.12) on human chorionic gonadotropin (hCG) day, number of oocytes retrieved (OR: 1.04, 95% CI: 1.01-1.06), fertilization rate (OR: 2.66, 95% CI: 1.46-4.87) and ratio of good-quality D3 embryos (OR: 4.31, 95% CI: 2.79-6.67) as prognostic factors in the depot group. Age (OR: 0.95, 95% CI: 0.92-0.98), endometrial thickness on hCG day (OR: 1.09, 95% CI: 1.03-1.15), ratio of good quality D3 embryos (OR: 2.56, 95% CI: 1.59-4.13) and the number of cryopreserved embryos (OR: 1.07, 95% CI: 1.003-1.15) are prognostic for the daily low-dose protocol. Some regression coefficients that are significant under model-wise deletion become nonsignificant after MI., Conclusions: Age, embryo quality and endometrial thickness on hCG day are important prognostic factors for both 1.0/1.3 mg depot and 0.05/0.1 mg daily low-dose luteal phase GnRHa long protocols. MI is a valuable tool to gauge and address bias caused by missing data in reproductive medicine.

Purpose/objectives: To evaluate the effectiveness of exercise interventions on overall health-related quality of life (HRQOL) and its domains among adults scheduled to, or actively undergoing, cancer treatment., Data Sources: 11 electronic databases were searched through November 2011. In addition, the authors searched PubMed's related article feature, trial registries, and reference lists of included trials and related reviews., Data Synthesis: 56 trials with 4,826 participants met the inclusion criteria. At 12 weeks, people exposed to exercise interventions had greater improvement in overall HRQOL, physical functioning, role functioning, social functioning, and fatigue. Improvement in HRQOL was associated with moderate-to-vigorous intensity exercise interventions., Conclusions: Exercise can be a useful tool for managing HRQOL and HRQOL domains for people scheduled to, or actively undergoing, cancer treatment. More methodologically rigorous trials are needed to examine the attributes of exercise programs most effective for improving HRQOL., Implications for Nursing: Evidence from this review supports the incorporation of exercise programs of moderate-to-vigorous intensity for the management of HRQOL among people scheduled to, or actively undergoing, cancer treatment into clinical guidelines through the Oncology Nursing Society's Putting Evidence Into Practice resources.

Background: The synthesis of published research in systematic reviews is essential when providing evidence to inform clinical and health policy decision-making. However, the validity of systematic reviews is threatened if journal publications represent a biased selection of all studies that have been conducted (dissemination bias). To investigate the extent of dissemination bias we conducted a systematic review that determined the proportion of studies published as peer-reviewed journal articles and investigated factors associated with full publication in cohorts of studies (i) approved by research ethics committees (RECs) or (ii) included in trial registries., Methods and Findings: Four bibliographic databases were searched for methodological research projects (MRPs) without limitations for publication year, language or study location. The searches were supplemented by handsearching the references of included MRPs. We estimated the proportion of studies published using prediction intervals (PI) and a random effects meta-analysis. Pooled odds ratios (OR) were used to express associations between study characteristics and journal publication. Seventeen MRPs (23 publications) evaluated cohorts of studies approved by RECs; the proportion of published studies had a PI between 22% and 72% and the weighted pooled proportion when combining estimates would be 46.2% (95% CI 40.2%-52.4%, I2 = 94.4%). Twenty-two MRPs (22 publications) evaluated cohorts of studies included in trial registries; the PI of the proportion published ranged from 13% to 90% and the weighted pooled proportion would be 54.2% (95% CI 42.0%-65.9%, I2 = 98.9%). REC-approved studies with statistically significant results (compared with those without statistically significant results) were more likely to be published (pooled OR 2.8; 95% CI 2.2-3.5). Phase-III trials were also more likely to be published than phase II trials (pooled OR 2.0; 95% CI 1.6-2.5). The probability of publication within two years after study completion ranged from 7% to 30%., Conclusions: A substantial part of the studies approved by RECs or included in trial registries remains unpublished. Due to the large heterogeneity a prediction of the publication probability for a future study is very uncertain. Non-publication of research is not a random process, e.g., it is associated with the direction of study findings. Our findings suggest that the dissemination of research findings is biased.

Purpose/objectives: To evaluate the effectiveness of exercise interventions on overall health-related quality of life (HRQOL) and its domains among cancer survivors who have completed primary treatment., Data Sources: 11 electronic databases were searched from inception (dates varied) to October 2011. The authors also identified eligible trials through a search of additional sources., Data Synthesis: 40 trials with 3,694 participants met the inclusion criteria. At 12 weeks, cancer survivors exposed to exercise interventions had greater positive improvement in overall HRQOL (standardized mean difference [SMD] 0.48; 95% confidence interval [CI] [0.16, 0.81]), emotional well-being (SMD 0.33; 95% CI [0.05, 0.61]), and social functioning (SMD 0.45; 95% CI [0.02, 0.87]); and had a significant reduction in anxiety (SMD -0.26; 95% CI [-0.44, -0.07]) and fatigue (SMD -0.82; 95% CI [-1.5, -0.14])., Conclusions: Exercise programs have a beneficial effect on HRQOL and most of its domains and can be integrated into the management plans for cancer survivors who have completed treatment. Future research is needed to help understand specific attributes of exercise programs that are beneficial for improving HRQOL within and across cancer types., Implications for Nursing: Evidence presented in this review supports the inclusion of exercise programs in clinical guidelines for the management of cancer survivors who have completed treatment, such as the Oncology Nursing Society's Putting Evidence Into Practice resource.

Background: Subjective tinnitus is the perception of sound in the absence of a corresponding external sound for which there is no known medical etiology. For a minority of individuals with tinnitus, the condition impacts their ability to lead a normal lifestyle and is severely debilitating. There is no known cure for tinnitus, so current therapy focuses on reducing the effect of tinnitus on the patient's quality of life. Tinnitus retraining therapy (TRT) uses nonpsychiatric tinnitus-specific educational counseling and sound therapy in a habituation-based protocol to reduce the patient's tinnitus-evoked negative reaction to, and awareness of, the tinnitus, with the ultimate goal of reducing the tinnitus impact on the patient's quality of life. Some studies support the efficacy of TRT, but no trial to date has compared TRT with the current standard of care or evaluated the separate contributions of TRT counseling and sound therapy. The Tinnitus Retraining Therapy Trial (TRTT) is a randomized, double-blind, placebo-controlled, multicenter trial for individuals with intolerable tinnitus., Methods/design: The TRTT is enrolling active-duty and retired military personnel and their dependents with functionally adequate hearing sensitivity and severe tinnitus at US Air Force, Navy, and Army medical centers. Eligible study participants are randomized to TRT, partial TRT, or standard care to determine the efficacy of TRT and its components (TRT counseling and sound therapy). The primary outcome is change in score on the Tinnitus Questionnaire assessed longitudinally between baseline and follow-up (3, 6, 12, and 18 months following treatment). Secondary outcomes include subscale score changes in the Tinnitus Questionnaire, overall and subscale score changes in the Tinnitus Functional Index and Tinnitus Handicap Inventory, and change in the visual analog scale of the TRT Interview Form. Audiological outcomes include tinnitus pitch and loudness match and measures of loudness discomfort levels. The incidence of depression as a safety measure is assessed at each visit using the Beck Depression Inventory Fast Screen., Trial Registration: Clinicaltrials.gov NCT01177137.

Background: Hyperopia (far-sightedness) in infancy requires accommodative effort to bring images into focus. Prolonged accommodative effort has been associated with an increased risk of strabismus (eye misalignment). Strabismus makes it difficult for the eyes to work together and may result in symptoms of asthenopia (eye strain) and intermittent diplopia (double vision), and makes near work tasks difficult to complete. Untreated strabismus may result in the development of amblyopia (lazy eye). The prescription of spectacles to correct hyperopic refractive error is believed to prevent the development of strabismus., Objectives: To assess the effectiveness of prescription spectacles compared with no intervention for the prevention of strabismus in infants and children with hyperopia., Search Methods: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), PubMed (1966 to April 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 April 2014. We also searched the Science Citation Index database in September 2013., Selection Criteria: We included randomized controlled trials and quasi-randomized trials investigating the assignment to spectacle intervention or no treatment for children with hyperopia. The definition of hyperopia remains subjective, but we required it to be at least greater than +2.00 diopters (D) of hyperopia., Data Collection and Analysis: Two review authors independently extracted data using the standard methodologic procedures expected by The Cochrane Collaboration. One review author entered data into Review Manager and a second review author verified the data entered. The two review authors resolved discrepancies at all stages of the review process., Main Results: We identified three randomized controlled trials (855 children enrolled) in this review. These trials were all conducted in the UK with follow-up periods ranging from one to 3.5 years. We judged the included studies to be at high risk of bias, due to use of quasi-random methods for assigning children to treatment, no masking of outcomes assessors, and high proportions of drop-outs. None of the three trials accounted for missing data and analyses were limited to the available-case data (674 (79%) of 855 children enrolled for the primary outcome). These factors impair our ability to assess the effectiveness of treatment.Analyses incorporating the three trials we identified in this review (674 children) suggested the effect of spectacle correction initiated prior to the age of one year in hyperopic children between three and four years of age is uncertain with respect to preventing strabismus (risk ratio (RR) 0.71; 95% confidence interval (CI) 0.44 to 1.15; very low quality evidence). Based on a meta-analysis of three trials (664 children), the risk of having visual acuity worse than 20/30 at three years of age was also uncertain for children with spectacles compared with those without spectacle correction irrespective of compliance (RR 0.87; 95% CI 0.60 to 1.26; very low quality evidence).Emmetropization was reported in two trials: one trial suggested that spectacles impede emmetropization, and the second trial reported no difference in the rate of refractive error change., Authors' Conclusions: Although children who were allocated to the spectacle group were less likely to develop strabismus and less likely to have visual acuity worse than 20/30 children allocated to no spectacles, these effects may have been chance findings, or due to bias. Due to the high risk of bias and poor reporting of included trials, the true effect of spectacle correction for hyperopia on strabismus is still uncertain.

Background: Little is known about the effect of methylphenidate (MPH) on attention in Alzheimer's disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses., Methods: MPH (10 mg PO twice daily) or placebo was administered for six weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory (NPI) Apathy ≥ 4). Attention was measured with the Wechsler Adult Intelligence Scale--Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as δ (MPH (DS week 6-DS baseline)) - (placebo (DS week 6-DS baseline))., Results: In 60 patients (37 females, age = 76 ± 8, Mini-Mental State Examination (MMSE) = 20 ± 5, NPI Apathy = 7 ± 2), the change in DS forward (δ = 0.87 (95% CI: 0.06-1.68), p = 0.03) and DS total (δ = 1.01 (95% CI: 0.09-1.93), p = 0.03) favored MPH over placebo. Of 57 completers, 17 patients had improved apathy (≥3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder, or non-responder groups. DS scores did not predict apathy response to MPH treatment., Conclusion: These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population.

Background: Traumatic hyphema is the entry of blood into the anterior chamber (the space between the cornea and iris) subsequent to a blow or a projectile striking the eye. Hyphema uncommonly causes permanent loss of vision. Associated trauma (e.g. corneal staining, traumatic cataract, angle recession glaucoma, optic atrophy, etc.) may seriously affect vision. Such complications may lead to permanent impairment of vision. Patients with sickle cell trait/disease may be particularly susceptible to increases of elevated intraocular pressure. If rebleeding occurs, the rates and severity of complications increase., Objectives: To assess the effectiveness of various medical interventions in the management of traumatic hyphema., Search Methods: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 8), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2013), EMBASE (January 1980 to August 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 30 August 2013., Selection Criteria: Two authors independently assessed the titles and abstracts of all reports identified by the electronic and manual searches. In this review, we included randomized and quasi-randomized trials that compared various medical interventions versus other medical interventions or control groups for the treatment of traumatic hyphema following closed globe trauma. We applied no restrictions regarding age, gender, severity of the closed globe trauma, or level of visual acuity at the time of enrolment., Data Collection and Analysis: Two authors independently extracted the data for the primary and secondary outcomes. We entered and analyzed data using Review Manager 5. We performed meta-analyses using a fixed-effect model and reported dichotomous outcomes as odds ratios and continuous outcomes as mean differences., Main Results: We included 20 randomized and seven quasi-randomized studies with 2643 participants in this review. Interventions included antifibrinolytic agents (oral and systemic aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid), corticosteroids (systemic and topical), cycloplegics, miotics, aspirin, conjugated estrogens, traditional Chinese medicine, monocular versus bilateral patching, elevation of the head, and bed rest. No intervention had a significant effect on visual acuity whether measured at two weeks or less after the trauma or at longer time periods. The number of days for the primary hyphema to resolve appeared to be longer with the use of aminocaproic acid compared with no use, but was not altered by any other intervention.Systemic aminocaproic acid reduced the rate of recurrent hemorrhage (odds ratio (OR) 0.25, 95% confidence interval (CI) 0.11 to 0.57), but a sensitivity analysis omitting studies not using an intention-to-treat (ITT) analysis reduced the strength of the evidence (OR 0.41, 95% CI 0.16 to 1.09). We obtained similar results for topical aminocaproic acid (OR 0.42, 95% CI 0.16 to 1.10). We found tranexamic acid had a significant effect in reducing the rate of secondary hemorrhage (OR 0.25, 95% CI 0.13 to 0.49), as did aminomethylbenzoic acid as reported in one study (OR 0.07, 95% CI 0.01 to 0.32). The evidence to support an associated reduction in the risk of complications from secondary hemorrhage (i.e. corneal bloodstaining, peripheral anterior synechiae, elevated intraocular pressure, and development of optic atrophy) by antifibrinolytics was limited by the small number of these events. Use of aminocaproic acid was associated with increased nausea, vomiting, and other adverse events compared with placebo. We found no difference in the number of adverse events with the use of systemic versus topical aminocaproic acid or with standard versus lower drug dose. The available evidence on usage of corticosteroids, cycloplegics, or aspirin in traumatic hyphema was limited due to the small numbers of participants and events in the trials.We found no difference in effect between a single versus binocular patch or ambulation versus complete bed rest on the risk of secondary hemorrhage or time to rebleed., Authors' Conclusions: Traumatic hyphema in the absence of other intraocular injuries uncommonly leads to permanent loss of vision. Complications resulting from secondary hemorrhage could lead to permanent impairment of vision, especially in patients with sickle cell trait/disease. We found no evidence to show an effect on visual acuity by any of the interventions evaluated in this review. Although evidence was limited, it appears that patients with traumatic hyphema who receive aminocaproic acid or tranexamic acid are less likely to experience secondary hemorrhaging. However, hyphema in patients treated with aminocaproic acid take longer to clear.Other than the possible benefits of antifibrinolytic usage to reduce the rate of secondary hemorrhage, the decision to use corticosteroids, cycloplegics, or nondrug interventions (such as binocular patching, bed rest, or head elevation) should remain individualized because no solid scientific evidence supports a benefit. As these multiple interventions are rarely used in isolation, further research to assess the additive effect of these interventions might be of value.

The National Academy of Sciences (NAS) Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde proposed a "roadmap" for reform and improvement of the Agency's risk assessment process. Specifically, it called for development of a transparent and defensible methodology for weight-of-evidence (WoE) assessments. To facilitate development of an improved process, we developed a white paper that reviewed approximately 50 existing WoE frameworks, seeking insights from their variations and nominating best practices for WoE analyses of causation of chemical risks. Four phases of WoE analysis were identified and evaluated in each framework: (1) defining the causal question and developing criteria for study selection, (2) developing and applying criteria for review of individual studies, (3) evaluating and integrating evidence and (4) drawing conclusions based on inferences. We circulated the draft white paper to stakeholders and then held a facilitated, multi-disciplinary invited stakeholder workshop to broaden and deepen the discussion on methods, rationales, utility and limitations among the surveyed WoE frameworks. The workshop developed recommendations for improving the conduct of WoE evaluations. Based on the analysis of the 50 frameworks and discussions at the workshop, best practices in conducting WoE analyses were identified for each of the four phases. Many of these best practices noted from the analysis and workshop could be implemented immediately, while others may require additional refinement as part of the ongoing discussions for improving the scientific basis of chemical risk assessments.

Objective: In a recent crossover trial, methylphenidate treatment decreased apathy in Alzheimer's disease. We further assessed this finding in the Apathy in Dementia Methylphenidate Trial (ADMET)., Method: Six-week, randomized, double-blind, placebo-controlled multicenter trial enrolling Alzheimer's disease participants (NINCDS-ADRDA criteria) with apathy assigned to methylphenidate 20 mg daily or placebo, conducted from June 2010 to December 2011. Primary outcomes were change in Apathy Evaluation Scale (AES) score and modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGI-C). Secondary outcomes included change in Neuropsychiatric Inventory (NPI) apathy score, Mini-Mental State Examination (MMSE) score, and safety., Results: 60 participants were randomly assigned (29 methylphenidate, 31 placebo). At baseline, mean (SD) age = 76 (8) years, MMSE score = 20 (5), AES score = 51 (12), NPI total score = 16 (8), and 62% of the participants (n = 37) were female. After 6 weeks' treatment, mean (SD) change in AES score was -1.9 (1.5) for methylphenidate and 0.6 (1.4) for placebo (P = .23). Odds ratio for improvement in ADCS-CGI-C was 3.7 (95% CI, 1.3 to 10.8) (P = .02), with 21% of methylphenidate versus 3% of placebo rated as moderately or markedly improved. NPI apathy score improvement was 1.8 points (95% CI, 0.3 to 3.4) greater on methylphenidate than on placebo (P = .02). MMSE trended toward improvement on methylphenidate (P = .06). There were trends toward greater anxiety and weight loss > 2% in the methylphenidate-treated group., Conclusions: Methylphenidate treatment of apathy in Alzheimer's disease was associated with significant improvement in 2 of 3 efficacy outcomes and a trend toward improved global cognition with minimal adverse events, supporting the safety and efficacy of methylphenidate treatment for apathy in Alzheimer's disease., Trial Registration: ClinicalTrials.gov identifier: NCT01117181., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Background: The inclusion of randomized controlled trials (RCTs) reported in conference abstracts in systematic reviews is controversial, partly because study design information and risk of bias is often not fully reported in the abstract. The Association for Research in Vision and Ophthalmology (ARVO) requires trial registration of abstracts submitted for their annual conference as of 2007. Our goal was to assess the feasibility of obtaining study design information critical to systematic reviews, but not typically included in conference abstracts, from the trial registration record., Methods: We reviewed all conference abstracts presented at the ARVO meetings from 2007 through 2009, and identified 496 RCTs; 154 had a single matching registration record in ClinicalTrials.gov. Two individuals independently extracted information from the abstract and the ClinicalTrials.gov record, including study design, sample size, inclusion criteria, masking, interventions, outcomes, funder, and investigator name and contact information. Discrepancies were resolved by consensus. We assessed the frequencies of reporting variables appearing in the abstract and the trial register and assessed agreement of information reported in both sources., Results: We found a substantial amount of study design information in the ClinicalTrials.gov record that was unavailable in the corresponding conference abstract, including eligibility criteria associated with gender (83%; 128/154); masking or blinding of study participants (53%, 82/154), persons administering treatment (30%, 46/154), and persons measuring the outcomes (40%, 61/154)); and number of study centers (58%; 90/154). Only 34% (52/154) of abstracts explicitly described a primary outcome, but a primary outcome was included in the "Primary Outcome" field in the ClinicalTrials.gov record for 82% (126/154) of studies. One or more study interventions were reported in each abstract, but agreed exactly with those reported in ClinicalTrials.gov only slightly more than half the time (88/154, 56%). We found no contact information for study investigators in the abstract, but this information was available in less than one quarter of ClinicalTrial.gov records (17%; 26/154)., Conclusion: RCT design information not reported in conference abstracts is often available in the corresponding ClinicalTrials.gov registration record. Sometimes there is conflicting information reported in the two sources and further contact with the trial investigators may still be required.

Background: Research on efficacious treatments for apathy in Alzheimer disease has been hindered by a lack of consensus diagnosis, difficulties in measurement, and studies with small sample sizes., Methods: In designing the Apathy in Dementia Methylphenidate Trial (ADMET), a trial to evaluate the efficacy and safety of methylphenidate for the treatment of apathy in Alzheimer disease, we encountered the following issues: defining and measuring apathy, distinguishing apathy and depression, determining an appropriate test treatment, selecting relevant secondary outcomes, recruiting participants, and deciding on a suitable method for treatment unmasking. ADMET is a 6-week randomized, double-masked, placebo-controlled multicenter clinical trial with two parallel treatment groups assigned in a 1:1 ratio with randomization stratified by clinical center. The recruitment goal is 60 randomized participants over 2 years. The primary outcomes are change in apathy severity as measured by the Apathy Evaluation Scale and the Alzheimer Disease Cooperative Study-Clinical Global Impression of Change., Conclusion: The design decisions made for ADMET are important elements to be considered in trials assessing the safety and efficacy of medications for clinically significant apathy in Alzheimer disease., (Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Methodological research has found that non-published studies often have different results than those that are published, a phenomenon known as publication bias. When results are not published, or are published selectively based on the direction or the strength of the findings, healthcare professionals and consumers of healthcare cannot base their decision-making on the full body of current evidence., Methods: As part of the OPEN project (http://www.open-project.eu) we will conduct a systematic review with the following objectives:1. To determine the proportion and/or rate of non-publication of studies by systematically reviewing methodological research projects that followed up a cohort of studies that a. received research ethics committee (REC) approval,b. were registered in trial registries, orc. were presented as abstracts at conferences.2. To assess the association of study characteristics (for example, direction and/or strength of findings) with likelihood of full publication.To identify reports of relevant methodological research projects we will conduct electronic database searches, check reference lists, and contact experts. Published and unpublished projects will be included. The inclusion criteria are as follows:a. RECs: methodological research projects that examined the subsequent proportion and/or rate of publication of studies that received approval from RECs;b. Trial registries: methodological research projects that examine the subsequent proportion and/or rate of publication of studies registered in trial registries;c. Conference abstracts: methodological research projects that examine the subsequent proportion and/or rate of full publication of studies which were initially presented at conferences as abstracts., Primary Outcomes: Proportion/rate of published studies; time to full publication (mean/median; cumulative publication rate by time)., Secondary Outcomes: Association of study characteristics with full publication.The different questions (a, b, and c) will be investigated separately. Data synthesis will involve a combination of descriptive and statistical summaries of the included methodological research projects., Discussion: Results are expected to be publicly available in mid 2013.