Medical interventions for traumatic hyphema.

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.

Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

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, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 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.

Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate.

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.

Measuring Apathy in Alzheimer's Disease in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): A Comparison of Instruments.

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.

Spectacle correction versus no spectacles for prevention of strabismus in hyperopic children.

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.

Medical interventions for traumatic hyphema.

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.

Lessons learned conducting a multi-center trial with a military population: The Tinnitus Retraining Therapy Trial.

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.

Full publication of results initially presented in abstracts.

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.

Spectacle correction versus no spectacles for prevention of strabismus in hyperopic children.

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.

Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial.

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.

Terminology for Retinal Findings in Sickle Cell Disease Research: A Scoping Review.

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.

A survey of frameworks for best practices in weight-of-evidence analyses.

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.

Designing a trial to evaluate potential treatments for apathy in dementia: the apathy in dementia methylphenidate trial (ADMET).

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.

ClinicalTrials.gov registration can supplement information in abstracts for systematic reviews: a comparison study.

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.

Medical interventions for traumatic hyphema.

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.

What comparative effectiveness research is needed? A framework for using guidelines and systematic reviews to identify evidence gaps and research priorities.

The authors developed and tested a framework for identifying evidence gaps and prioritizing comparative effectiveness research by using a combination of clinical practice guidelines and systematic reviews. In phase 1 of the project, reported elsewhere, 45 clinical questions on the management of primary open-angle glaucoma were derived from practice guidelines and prioritized by using a 2-round Delphi survey of clinicians. On the basis of the clinicians' responses, 9 questions were classified as high-priority. In phase 2, reported here, systematic reviews that addressed the 45 clinical questions were identified. The reviews were classified as at low, high, or unclear risk of bias, and evidence gaps (in which no systematic review was at low risk of bias) were identified. The following comparative effectiveness research agenda is proposed: Two of the 9 high-priority questions require new primary research (such as a randomized, controlled trial) and 4 require a new systematic review. The utility and limitations of the framework and future adaptations are discussed.

Rationale for the tinnitus retraining therapy trial.

The Tinnitus Retraining Therapy Trial (TRTT) is a National Institutes of Health-sponsored, multi-centered, placebo-controlled, randomized trial evaluating the efficacy of tinnitus retraining therapy (TRT) and its component parts, directive counseling and sound therapy, as treatments for subjective debilitating tinnitus in the military. The TRTT will enroll 228 individuals at an allocation ratio of 1:1:1 to: (1) directive counseling and sound therapy using conventional sound generators; (2) directive counseling and placebo sound generators; or (3) standard of care as administered in the military. Study centers include a Study Chair's Office, a Data Coordinating Center, and six Military Clinical Centers with treatment and data collection standardized across all clinics. The primary outcome is change in Tinnitus Questionnaire (TQ) score assessed longitudinally at 3, 6, 12, and 18-month follow-up visits. Secondary outcomes include: Change in TQ sub-scales, Tinnitus Handicap Inventory, Tinnitus Functional Index, and TRT interview visual analog scale; audiometric and psychoacoustic measures; and change in quality of life. The TRTT will evaluate TRT efficacy by comparing TRT (directive counseling and conventional sound generators) with standard of care; directive counseling by comparing directive counseling plus placebo sound generators versus standard of care; and sound therapy by comparing conventional versus placebo sound generators. We hypothesize that full TRT will be more efficacious than standard of care, directive counseling and placebo sound generators more efficacious than standard of care, and conventional more efficacious than placebo sound generators in habituating the tinnitus awareness, annoyance, and impact on the study participant's life.

Predictors of Citations for Original Research in Ophthalmology.

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.

CONSORT Harms 2022 statement, explanation, and elaboration: updated guideline for the reporting of harms in randomized trials.

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.