Methodological challenges and actionable recommendations in studying the health effects of high-concentration THC products.

In conducting a scoping review on the health effects of high-concentration cannabis products, we have uncovered pervasive methodological shortcomings within the cannabis literature. This paper begins by defining the 'causal effect' of interest for public health and delineating the desirable features of study design that can address crucial questions pertaining to public health and policy. We further delve into the methodological complexities inherent in studying the health effects of high-concentration cannabis products, describing challenges associated with the measurement of exposures and outcomes, confounding, selection bias, and the generalizability of findings. We introduce causal inference methods to mitigate potential biases in observational cannabis use studies. We identify specific areas that necessitate further development and investigation to deepen our understanding of this topic. Finally, this paper extends actionable recommendations, serving as a roadmap for upcoming research initiatives in this domain.

Silicone hydrogel versus hydrogel soft contact lenses for differences in patient-reported eye comfort and safety: A Cochrane systematic review summary.

SIGNIFICANCE: This work is significant because it is the first Cochrane systemic review that compares the comfort and safety of hydrogel and silicone hydrogel soft contact lenses (SCL). PURPOSE: This study aimed to conduct a systemic review of randomized trials comparing the comfort and safety of silicone hydrogel and hydrogel SCLs. METHODS: CENTRAL, MEDLINE Ovid, EMBASE.com, PubMed, LILACS, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform were searched on or before June 24, 2022, to identify randomized clinical trials that compared silicone hydrogel and hydrogel SCLs. RESULTS: Seven trials were identified and evaluated. One trial reported Ocular Surface Disease Index results, with the evidence being very uncertain about the effects of SCL material on Ocular Surface Disease Index scores (mean difference, -1.20; 95% confidence interval, -10.49 to 8.09). Three trials reported visual analog scale comfort score results, with no clear difference in comfort between materials, although results were of low certainty; trial results could not be combined because the three trials reported results at different time points. None of the included trials reported Contact Lens Dry Eye Questionnaire 8 or Standard Patient Evaluation of Eye Dryness scores. There was no evidence of a clinically meaningful difference (>0.5 unit) between daily disposable silicone hydrogel and hydrogel SCLs in corneal staining, conjunctival staining, or conjunctival redness (very low certainty evidence). CONCLUSIONS: The overall evidence for a difference between all included silicone hydrogel and hydrogel SCL trials was of very low certainty, with most trials judged as having a high overall risk of bias. There was insufficient evidence to support recommending one SCL material over the other. Future well-designed trials are needed to generate high certainty evidence to further clarify differences in SCL material comfort and safety.

Health Effects of High-Concentration Cannabis Products: Scoping Review and Evidence Map.

Background. The concentration of pharmacologically active tetrahydrocannabinol (THC) in cannabis products has been increasing over the past decade. Concerns about potential harmful health effects of using these increasingly higher-concentration products have led some states to consider regulation of cannabis product THC concentration. We conducted a scoping review of health effects of high-concentration cannabis products to inform policy on whether the THC concentrations of cannabis product should be regulated or limited. Objectives. We conducted a scoping review to (1) identify and describe human studies that explore the relationship of high-concentration cannabis products with any health outcomes in the literature and (2) create an interactive evidence map of the included studies to facilitate further analyses. Search Methods. An experienced medical information specialist designed a comprehensive search strategy of 7 electronic databases. Selection Criteria. We included human studies of any epidemiological design with no restrictions by age, sex, health status, country, or outcome measured that reported THC concentration or included a known high-concentration cannabis product. Data Collection and Analysis. We imported search results into Distiller SR, and trained coders conducted artificial intelligence‒assisted screening. We developed, piloted, and revised data abstraction forms. One person performed data abstraction, and a senior reviewer verified a subset. We provide a tabular description of study characteristics, including exposures and outcomes measured, for each included study. We interrogated the evidence map published in Tableau to answer specific questions and provide the results as text and visual displays. Main Results. We included 452 studies in the scoping review and evidence map. There was incomplete reporting of exposure characteristics including THC concentration, duration and frequency of use, and products used. The evidence map shows considerable heterogeneity among studies in exposures, outcomes, and populations studied. A limited number of reports provided data that would facilitate further quantitative synthesis of the results across studies. Conclusions. This scoping review and evidence map support strong conclusions concerning the utility of the literature for characterizing risks and benefits of the current cannabis marketplace and the research approaches followed in the studies identified. Relevance of the studies to today's products is limited. Public Health Implications. High-quality evidence to address the policy question of whether the THC concentration of cannabis products should be regulated is scarce. The publicly available interactive evidence map is a timely resource for other entities concerned with burgeoning access to high-concentration cannabis. (Am J Public Health. 2023;113(12):1332-1342. https://doi.org/10.2105/AJPH.2023.307414).

Silicone hydrogel versus hydrogel soft contact lenses for differences in patient-reported eye comfort and safety.

BACKGROUND: Ocular discomfort is the leading cause of permanent discontinuation of soft contact lens (SCL) wear. Silicone hydrogel and hydrogel materials are the two major categories of SCLs, with silicone hydrogel materials being newer and more breathable than hydrogel materials. Whether comfort is associated with SCL material is controversial despite numerous studies. Similarly, the difference between these materials in terms of safety outcomes (e.g. frequency of microbial keratitis) is unclear. OBJECTIVES: To evaluate the comparative effectiveness and safety of silicone hydrogel compared with hydrogel SCLs on self-reported comfort, dry eye test results, and adverse events in SCL-wearing adults 18 years of age or older. SEARCH METHODS: The Cochrane Eyes and Vision Information Specialist searched the electronic databases for randomized controlled trials (RCTs). There were no restrictions on language or date of publication. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, including the Cochrane Eyes and Vision Trials Register; 2022, Issue 6), MEDLINE Ovid, Embase.com, PubMed, LILACS (Latin American and Caribbean Health Science Information database), ClinicalTrials.gov, and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We also searched the reference lists of identified studies, review articles, and guidelines for information about relevant studies that may not have been identified by our search strategy. Furthermore, we contacted investigators regarding ongoing trials. The most recent database search was conducted on 24 June 2022. SELECTION CRITERIA: Our search selection criteria included RCTs, quasi-RCTs, and cross-over RCTs. DATA COLLECTION AND ANALYSIS: We applied standard Cochrane methodology. MAIN RESULTS: We included seven parallel-group RCTs conducted in the USA, the UK, Australia, Germany, India, and Turkey. A total of 1371 participants were randomized. The duration of SCL wear ranged from one to 52 weeks. Study characteristics and risk of bias The median number of participants per trial was 120 (interquartile range: 51 to 314), and the average age ranged from 20.7 to 33.0 years. Women represented the majority of participants (range 55% to 74.9%; 5 RCTs). Collectively, the included trials compared eight different silicone hydrogel SCLs with three different hydrogel SCLs. Five trials compared daily disposable SCLs, and two compared extended wear SCLs (worn for seven days and six nights). New SCL wearers were enrolled in three trials. Two trials included both new and established SCL wearers, and two trials did not report participants' history of SCL use. Five trials were sponsored by industry. We judged the overall risk of bias to be 'high' or 'some concerns' for the safety and efficacy outcomes. Findings One trial reported Ocular Surface Disease Index (OSDI) results, with the evidence being very uncertain about the effects of SCL material on OSDI scores (mean difference -1.20, 95% confidence interval [CI] -10.49 to 8.09; 1 RCT, 47 participants; very low certainty evidence). Three trials reported visual analog scale comfort score results, with no clear difference in comfort between materials, but the evidence was of very low certainty; trial results could not be combined because the three trials reported results at different time points. The evidence is very uncertain about the effect of SCL material on discontinuation of contact lens wear (risk ratio [RR] 0.64, 95% CI 0.11 to 3.74; 1 RCT, 248 participants). None of the included trials reported Contact Lens Dry Eye Questionnaire (CLDEQ-8) or Standard Patient Evaluation of Eye Dryness (SPEED) scores. There was no evidence of a clinically meaningful difference (> 0.5 unit) between daily disposable silicone hydrogel and hydrogel SCLs in corneal staining, conjunctival staining, or conjunctival redness (very low certainty evidence). Adverse events Very low certainty evidence from two trials comparing daily disposable SCLs suggested no evidence of a difference between lens materials in the risk of vision-threatening adverse events at one to four weeks (RR 0.68, 95% CI 0.08 to 5.51; 2 RCTs, 368 participants). Two trials comparing extended wear SCLs indicated that hydrogel SCLs may have a 2.03 times lower risk of adverse events at 52 weeks compared with silicone hydrogel SCLs (RR 2.03, 95% CI 1.38 to 2.99; 815 participants), but the certainty of evidence was very low. AUTHORS' CONCLUSIONS: The overall evidence for a difference between all included silicone hydrogel and hydrogel SCLs was of very low certainty, with most trials at high overall risk of bias. The majority of studies did not assess comfort using a validated instrument. There was insufficient evidence to support recommending one SCL material over the other. For extended wear, hydrogel SCL may have a lower risk of adverse events at 52 weeks compared to silicon hydrogel. Future well-designed trials are needed to generate high certainty evidence to further clarify differences in SCL material comfort and safety.

Topical ophthalmic anesthetics for corneal abrasions.

BACKGROUND: Despite potential analgesic benefits from topical ophthalmic amides and esters, their outpatient use has become of concern because of the potential for abuse and ophthalmic complications. OBJECTIVES: To assess the effectiveness and safety of topical ophthalmic anesthetics compared with placebo or other treatments in persons with corneal abrasions. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase.com; Latin American and Caribbean Health Sciences (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), without restriction on language or year of publication. The search was performed on 10 February 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of topical ophthalmic anesthetics alone or in combination with another treatment (e.g. nonsteroidal anti-inflammatory drugs (NSAIDs)) versus a non-anesthetic control group (e.g. placebo, non-treatment, or alternative treatment). We included trials that enrolled participants of all ages who had corneal abrasions within 48 hours of presentation. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: We included nine parallel-group RCTs with a total of 556 participants (median number of participants per study: 45, interquartile range (IQR) 44 to 74), conducted in eight countries: Australia, Canada, France, South Korea, Turkey, New Zealand, UK, and USA. Study characteristics and risk of bias Four RCTs (314 participants) investigated post-traumatic corneal abrasions diagnosed in the emergency department setting. Five trials described 242 participants from ophthalmology surgery centers with post-surgical corneal defects: four from photorefractive keratectomy (PRK) and one from pterygium surgery. Study duration ranged from two days to six months, the most common being one week (four RCTs). Treatment duration ranged from three hours to one week (nine RCTs); the majority were between 24 and 48 hours (five RCTs). The age of participants was reported in eight studies, ranging from 17 to 74 years of age. Only one participant in one trial was under 18 years of age. Of four studies that reported funding sources, none was industry-sponsored. We judged a high risk of bias in one trial with respect to the outcome pain control by 48 hours, and in five of seven trials with respect to the outcome complications at the furthest time point. The domain for which we assessed studies to be at the highest risk of bias was missing or selective reporting of outcome data. Findings The treatments investigated included topical anesthetics compared with placebo, topical anesthetic compared with NSAID (post-surgical cases), and topical anesthetics plus NSAID compared with placebo (post-surgical cases). Pain control by 24 hours In all studies, self-reported pain outcomes were on a 10-point scale, where lower numbers represent less pain. In post-surgical trials, topical anesthetics provided a moderate reduction in self-reported pain at 24 hours compared with placebo of 1.28 points on a 10-point scale (mean difference (MD) -1.28, 95% confidence interval (CI) -1.76 to -0.80; 3 RCTs, 119 participants). In the post-trauma participants, there may be little or no difference in effect (MD -0.04, 95% CI -0.10 to 0.02; 1 RCT, 76 participants). Compared with NSAID in post-surgical participants, topical anesthetics resulted in a slight increase in pain at 24 hours (MD 0.82, 95% CI 0.01 to 1.63; 1 RCT, 74 participants). One RCT compared topical anesthetics plus NSAID to placebo. There may be a large reduction in pain at 24 hours with topical anesthetics plus NSAID in post-surgical participants, but the evidence to support this large effect is very uncertain (MD -5.72, 95% CI -7.35 to -4.09; 1 RCT, 30 participants; very low-certainty evidence). Pain control by 48 hours Compared with placebo, topical anesthetics reduced post-trauma pain substantially by 48 hours (MD -5.68, 95% CI -6.38 to -4.98; 1 RCT, 111 participants) but had little to no effect on post-surgical pain (MD 0.41, 95% CI -0.45 to 1.27; 1 RCT, 44 participants), although the evidence is very uncertain. Pain control by 72 hours One post-surgical RCT showed little or no effect of topical anesthetics compared with placebo by 72 hours (MD 0.49, 95% CI -0.06 to 1.04; 44 participants; very low-certainty evidence). Proportion of participants with unresolved epithelial defects When compared with placebo or NSAID, topical anesthetics increased the number of participants without complete resolution of defects in trials of post-trauma participants (risk ratio (RR) 1.37, 95% CI 0.78 to 2.42; 3 RCTs, 221 participants; very low-certainty evidence). The proportion of placebo-treated post-surgical participants with unresolved epithelial defects at 24 to 72 hours was lower when compared with those assigned to topical anesthetics (RR 0.14, 95% CI 0.01 to 2.55; 1 RCT, 30 participants; very low-certainty evidence) or topical anesthetics plus NSAID (RR 0.33, 95% CI 0.04 to 2.85; 1 RCT, 30 participants; very low-certainty evidence). Proportion of participants with complications at the longest follow-up When compared with placebo or NSAID, topical anesthetics resulted in a higher proportion of post-trauma participants with complications at up to two weeks (RR 1.13, 95% CI 0.23 to 5.46; 3 RCTs, 242 participants) and post-surgical participants with complications at up to one week (RR 7.00, 95% CI 0.38 to 128.02; 1 RCT, 44 participants). When topical anesthetic plus NSAID was compared with placebo, no complications were reported in either treatment arm up to one week post-surgery (risk difference (RD) 0.00, 95% CI -0.12 to 0.12; 1 RCT, 30 participants). The evidence is very uncertain for safety outcomes. Quality of life None of the included trials assessed quality of life outcomes. AUTHORS' CONCLUSIONS: Despite topical anesthetics providing excellent pain control in the intraoperative setting, the currently available evidence provides little or no certainty about their efficacy for reducing ocular pain in the initial 24 to 72 hours after a corneal abrasion, whether from unintentional trauma or surgery. We have very low confidence in this evidence as a basis to recommend topical anesthetics as an efficacious treatment modality to relieve pain from corneal abrasions. We also found no evidence of a substantial effect on epithelial healing up to 72 hours or a reduction in ocular complications when we compared anesthetics alone or with NSAIDs versus placebo.

Autologous Serum Eye Drops for Dry Eye: Systematic Review.

BACKGROUND: Dry eye is a common condition with serious implications worldwide. The unique composition of autologous serum (AS) eye drops has been hypothesized as a possible treatment. OBJECTIVES: This study aimed to review the effectiveness and safety of AS. DATA SOURCES: We searched five databases and three registries up to September 30, 2022. STUDY ELIGIBILITY: We included randomized controlled trials (RCTs) comparing AS with artificial tears, saline, or placebo for participants with dry eye. STUDY APPRAISAL AND SYNTHESIS METHODS: We adhered to Cochrane methods for study selection, data extraction, risk-of-bias assessment, and synthesis. We used the Grading of Recommendations Assessment, Development and Evaluation framework to evaluate the certainty of evidence. RESULTS: We included six RCTs with 116 participants. Four trials compared AS with artificial tears. We found low-certainty evidence that AS may improve symptoms (0- to 100-point pain scale) after 2 weeks of treatment compared with saline (mean difference, -12.00; 95% confidence interval, -20.16 to -3.84; 1 RCT, 20 participants). Ocular surface outcomes (corneal staining, conjunctival staining, tear breakup time, Schirmer test) were inconclusive. Two trials compared AS with saline. Very low-certainty evidence suggested that Rose Bengal staining (0- to 9-point scale) may be slightly improved after 4 weeks of treatment compared with saline (mean difference, -0.60; 95% confidence interval, -1.11 to -0.09; 35 eyes). None of the trials reported outcomes of corneal topography, conjunctival biopsy, quality of life, economic outcomes, or adverse events. LIMITATIONS: We were unable to use all data because of unclear reporting. CONCLUSIONS: The effectiveness of AS is uncertain based on current data. Symptoms improved slightly with AS compared with artificial tears for 2 weeks. Staining scores improved slightly with AS compared with saline, with no benefit identified for other measures. IMPLICATIONS OF KEY FINDINGS: High-quality, large trials enrolling diverse participants with varying severity are needed. A core outcome set would allow for evidence-based treatment decisions consistent with current knowledge and patient values.

Non-biologic, steroid-sparing therapies for non-infectious intermediate, posterior, and panuveitis in adults.

BACKGROUND: Non-infectious intermediate, posterior, and panuveitis (NIIPPU) represent a heterogenous collection of autoimmune and inflammatory disorders isolated to or concentrated in the posterior structures of the eye. Because NIIPPU is typically a chronic condition, people with NIIPPU frequently require treatment with steroid-sparing immunosuppressive therapy. Methotrexate, mycophenolate, cyclosporine, azathioprine, and tacrolimus are non-biologic, disease-modifying antirheumatic drugs (DMARDs) which have been used to treat people with NIIPPU. OBJECTIVES: To compare the effectiveness and safety of selected DMARDs (methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine, and azathioprine) in the treatment of NIIPPU in adults. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), MEDLINE, Embase, the Latin American and Caribbean Health Sciences database, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform, most recently on 16 April 2021. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing selected DMARDs (methotrexate, mycophenolate, tacrolimus, cyclosporine, and azathioprine) with placebo, standard of care (topical steroids, with or without oral steroids), or with each other. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 11 RCTs with a total of 601 participants in this review. DMARDs versus control Two studies compared an experimental DMARD (cyclosporine A or enteric-coated mycophenolate [EC-MPS]) plus oral steroid with steroid monotherapy. We did not pool these results into a meta-analysis because the dose of cyclosporine used was much higher than that used in current clinical practice. The evidence is very uncertain about whether EC-MPS plus low-dose oral steroid results in a higher proportion of participants achieving control of inflammation over steroid monotherapy (risk ratio [RR] 2.81, 95% confidence interval [CI] 1.10 to 7.17; 1 study, 41 participants; very low-certainty evidence). The change in best-corrected visual acuity (BCVA) was reported separately for right and left eyes. The evidence for improvement (lower logarithm of the minimum angle of resolution (logMAR) indicates better vision) between the groups is very uncertain (mean difference [MD] -0.03 and -0.10, 95% CI -0.96 to 0.90 and -0.27 to 0.07 for right and left, respectively; 1 study, 82 eyes; very low-certainty evidence). No data were available for the following outcomes: proportion of participants achieving a 2-line improvement in visual acuity, with confirmed macular edema, or achieving steroid-sparing control. The evidence for the proportion of participants requiring cessation of medication in the DMARD versus control group is very uncertain (RR 2.61, 95% CI 0.11 to 60.51; 1 study, 41 participants; very low-certainty evidence). Methotrexate versus mycophenolate We were able to combine two studies into a meta-analysis comparing methotrexate versus mycophenolate mofetil. Methotrexate probably results in a slight increase in the proportion of participants achieving control of inflammation, including steroid-sparing control, compared to mycophenolate at six months (RR 1.23, 95% CI 1.01 to 1.50; 2 studies, 261 participants; moderate-certainty evidence). Change in BCVA was reported per eye and the treatments likely result in little to no difference in change in vision (MD 0.01 logMAR higher [worse] for methotrexate versus mycophenolate; 2 studies, 490 eyes; moderate-certainty evidence). No data were available for the proportion of participants achieving a 2-line improvement in visual acuity. The evidence is very uncertain regarding the proportion of participants with confirmed macular edema between methotrexate versus mycophenolate (RR 0.49, 95% CI 0.19 to 1.30; 2 studies, 35 eyes; very low-certainty). Methotrexate versus mycophenolate may result in little to no difference in the proportion of participants requiring cessation of medication (RR 0.99, 95% CI 0.43 to 2.27; 2 studies, 296 participants; low-certainty evidence). Steroids with or without azathioprine versus cyclosporine A Four studies compared steroids with or without azathioprine (oral steroids, intravenous [IV] steroids, or azathioprine) to cyclosporine A. We excluded two studies from the meta-analysis because the participants were treated with 8 mg to 15 mg/kg/day of cyclosporine A, a significantly higher dose than is utilized today because of concerns for nephrotoxicity. The remaining two studies were conducted in all Vogt-Koyanagi-Harada disease (VKH) populations and compared cyclosporine A to azathioprine or IV pulse-dose steroids. The evidence is very uncertain for whether the steroids with or without azathioprine or cyclosporine A influenced the proportion of participants achieving control of inflammation (RR 0.84, 95% CI 0.70 to 1.02; 2 studies, 112 participants; very low-certainty evidence), achieving steroid-sparing control (RR 0.64, 95% CI 0.33 to 1.25; 1 study, 21 participants; very low-certainty evidence), or requiring cessation of medication (RR 0.85, 95% 0.21 to 3.45; 2 studies, 91 participants; very low-certainty evidence). The evidence is uncertain for improvement in BCVA (MD 0.04 logMAR lower [better] with the steroids with or without azathioprine versus cyclosporine A; 2 studies, 91 eyes; very low-certainty evidence). There were no data available (with current cyclosporine A dosing) for the proportion of participants achieving a 2-line improvement in visual acuity or with confirmed macular edema. Studies not included in synthesis We were unable to include three studies in any of the comparisons (in addition to the aforementioned studies excluded based on historic doses of cyclosporine A). One was a dose-response study comparing cyclosporine A to cyclosporine G, a formulation which was never licensed and is not clinically available. We excluded another study from meta-analysis because it compared cyclosporine A and tacrolimus, considered to be of the same class (calcineurin inhibitors). We were unable to combine the third study, which examined tacrolimus monotherapy versus tacrolimus plus oral steroid, with any group. AUTHORS' CONCLUSIONS: There is a paucity of data regarding which DMARD is most effective or safe in NIIPPU. Studies in general were small, heterogenous in terms of their design and outcome measures, and often did not compare different classes of DMARD with each other. Methotrexate is probably slightly more efficacious than mycophenolate in achieving control of inflammation, including steroid-sparing control (moderate-certainty evidence), although there was insufficient evidence to prefer one medication over the other in the VKH subgroup (very low-certainty evidence). Methotrexate may result in little to no difference in safety outcomes compared to mycophenolate.

Topical pharmacologic interventions versus placebo for epidemic keratoconjunctivitis.

BACKGROUND: Viruses cause about 80% of all cases of acute conjunctivitis. Human adenoviruses are believed to account for 65% to 90% of cases of viral conjunctivitis, or 20% to 75% of all causes of infectious keratoconjunctivitis worldwide. Epidemic keratoconjunctivitis (EKC) is a highly contagious subset of adenoviral conjunctivitis that has been associated with large outbreaks at military installations and at medical facilities. It is accompanied by severe conjunctival inflammation, watery discharge, and light sensitivity, and can lead to chronic complications such as corneal and conjunctival scarring with discomfort and poor quality of vision. Due to a lack of consensus on the efficacy of any pharmacotherapy to alter the clinical course of EKC, no standard of care exists, therefore many clinicians offer only supportive care. OBJECTIVES: To assess the efficacy and safety of topical pharmacological therapies versus placebo, an active control, or no treatment for adults with EKC. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 4); Ovid MEDLINE; Ovid Embase; Latin American and Caribbean Health Sciences database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), with no restrictions on language or year of publication. The date of the last search was 27 April 2021. SELECTION CRITERIA: We included randomized controlled trials in which antiseptic agents, virustatic agents, or topical immune-modulating therapy was compared with placebo, an active control, or no treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: We identified 10 studies conducted in Asia, Europe, the Middle East, and North Africa with a total of 892 participants who were treated for 7 days to 6 months and followed for 7 days up to 1.5 years. Study characteristics and risk of bias In most studies participants were predominantly men (range: 44% to 90%), with an age range from 9 to 82 years. Three studies reported information on trial registration, but we found no published study protocol. The majority of trials had small sample sizes, ranging from 18 to 90 participants enrolled per study; the only exception was a trial that enrolled 350 participants. We judged most studies to be at high or unclear risk of bias across risk of bias domains. Findings We included 10 studies of 892 EKC participants and estimated combined intervention effects in analyses stratified by steroid-containing control treatment or artificial tears. Six trials contributed to the comparisons of topical interventions (povidone-iodine [PVP-I], trifluridine, ganciclovir, dexamethasone plus neomycin) with artificial tears (or saline). Very low certainty evidence from two trials comparing trifluridine or ganciclovir with artificial tears showed inconsistent effects on shortening the mean duration of cardinal symptoms or signs of EKC. Low certainty evidence based on two studies (409 participants) indicated that participants treated with PVP-I alone more often experienced resolution of symptoms (risk ratio (RR) 1.15, 95% confidence interval (CI) 1.07 to 1.24) and signs (RR 3.19, 95% CI 2.29 to 4.45) during the first week of treatment compared with those treated with artificial tears. Very low certainty evidence from two studies (77 participants) suggested that PVP-I or ganciclovir prevented the development of subepithelial infiltrates (SEI) when compared with artificial tears within 30 days of treatment (RR 0.24, 95% CI 0.10 to 0.56). Four studies compared topical interventions (tacrolimus, cyclosporin A [CsA], trifluridine, PVP-I + dexamethasone) with topical steroids, and one trial compared fluorometholone (FML) plus polyvinyl alcohol iodine (PVA-I) with FML plus levofloxacin. Evidence from one trial showed that more eyes receiving PVP-I 1.0% plus dexamethasone 0.1% had symptoms resolved by day seven compared with those receiving dexamethasone alone (RR 9.00, 95% CI 1.23 to 66.05; 52 eyes). In two trials, fewer eyes treated with PVP-I or PVA-I plus steroid developed SEI within 15 days of treatment compared with steroid alone or steroid plus levofloxacin (RR 0.08, 95% CI 0.01 to 0.55; 69 eyes). One study found that CsA was no more effective than steroid for resolving SEI within four weeks of treatment (RR 0.84, 95% CI 0.67 to 1.06; N = 88). The evidence from trials comparing topical interventions with steroids was overall of very low level certainty. Adverse effects Antiviral or antimicrobial agents plus steroid did not differ from artificial tears in terms of ocular discomfort upon instillation (RR 9.23, 95% CI 0.61 to 140.67; N = 19). CsA and tacrolimus eye drops were associated with more cases of severe ocular discomfort, and sometimes intolerance, when compared with steroids (RR 4.64, 95% CI 1.15 to 18.71; 2 studies; N = 141). Compared with steroids, tacrolimus did not increase the risk of elevated intraocular pressure (RR 0.07, 95% CI 0 to 1.13; 1 study; N = 80), while trifluridine conferred no additional risk compared to tear substitute (RR 5.50, 95% CI 0.31 to 96.49; 1 study; N = 97). Overall, bacterial superinfection was rare (one in 23 CsA users) and not associated with use of the intervention steroid (RR 3.63, 95% CI 0.15 to 84.98; N = 51). The evidence for all estimates was of low or very low certainty. AUTHORS' CONCLUSIONS: The evidence for the seven specified outcomes was of low or very low certainty due to imprecision and high risk of bias. The evidence that antiviral agents shorten the duration of symptoms or signs when compared with artificial tears was inconclusive. Low certainty evidence suggests that PVP-I alone resolves signs and symptoms by seven days relative to artificial tears. PVP-I or PVA-I, alone or with steroid, is associated with lower risks of SEI development than artificial tears or steroid (very low certainty evidence). The currently available evidence is insufficient to determine whether any of the evaluated interventions confers an advantage over steroids or artificial tears with respect to virus eradication or its spread to initially uninvolved fellow eyes. Future updates of this review should provide evidence of high-level certainty from trials with larger sample sizes, enrollment of participants with similar durations of signs and symptoms, and validated methods to assess short- and long-term outcomes.

Topical Ophthalmic Anesthetics for CornealAbrasions: Findings from a Cochrane SystematicReview and Meta-Analysis.

Background: Despite potential benefit, outpatient use of topical ophthalmic anesthetics can result in poor healing, infection, scar, and blindness. An unbiased analysis of randomized controlled trials (RCTs) is needed to examine their effectiveness and safety compared with placebo or other treatments for corneal abrasions. Methods: Cochrane Central Register of Controlled Trials, MEDLINE, Embase.com, Latin American and Caribbean Health Sciences, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched on February 10, 2023, without restriction on language or publication date. Results: Systematic review and meta-analysis of nine RCTs describing 314 participants with post-traumatic abrasions and 242 participants with post-surgical abrasions, with a median study length of 7 days (interquartile range, 7-14), show no evidence of a difference in pain control between anesthetics and placebo at 24 hours in post-trauma cases. Self-reported pain at 24 hours is reduced with anesthetics plus topical nonsteroid anti-inflammatory drug in post-surgical participants (mean difference [MD], -5.72 on a 10-point scale; 95% CI, -7.35 to -4.09; 1 RCT; 30 participants) and at 48 hours with anesthetics alone in post-trauma participants (MD, -5.68; 95% CI, -6.38 to -4.98; 1 RCT; 111 participants). Anesthetics are associated with 37% increased risk of non-healing defects (risk ratio, 1.37; 95% CI, 0.78 to 2.42; 3 RCTs; 221 post-trauma participants). All evidence is of very low certainty. Over 50% of trials have an overall high risk of bias. Conclusions: Available evidence is insufficient to support outpatient use of topical anesthetics for corneal abrasions with respect to pain, re-epithelialization, and complication risk.

Social Determinants of Dry Eye in the United States: A Systematic Review.

PURPOSE: To conduct a systematic review to summarize current evidence on associations between social determinants of health (SDOH) indicators and dry eye in the United States. DESIGN: Systematic review. METHODS: We followed a protocol registered on Open Science Framework to include studies that examined associations between SDOH indicators and dry eye. We mapped SDOH indicators to 1 of the 5 domains following the Healthy People 2030 framework and categorized dry eye measures into "dry eye diagnosis and care," "dry eye symptoms," or "ocular surface parameters." We summarized the direction of association between SDOH indicators and dry eye as worsening, beneficial, or null. We used items from the Newcastle Ottawa Scale to assess risk of bias. RESULTS: Eighteen studies reporting 51 SDOH indicators, mostly mapped to the neighborhood and built environment domain, were included. Thirteen studies were judged at high risk of bias. Fifteen of 19 (79%) associations revealed an increase in the diagnosis of dry eye or delayed specialty care for it. Thirty-four of 56 (61%) associations unveiled exacerbated dry eye symptoms. Fifteen of 23 (65%) found null associations with corneal fluorescein staining. Ten of 22 (45%) associations revealed an increased tear break up time (45%) whereas another 10 (45%) showed null associations. CONCLUSIONS: Most SDOH indicators studied were associated with unfavorable dry eye measures, such as a higher disease burden, worse symptoms, or delayed referral, in the United States. Future investigations between SDOH and dry eye should use standardized instruments and address the domains in which there is an evidence gap.

Topical Pharmacologic Interventions Versus Active Control, Placebo, or No Treatment for Epidemic Keratoconjunctivitis: Findings From a Cochrane Systematic Review.

PURPOSE: To summarize key findings from a Cochrane systematic review of the effectiveness and safety of topical pharmacologic interventions compared with active control or placebo for epidemic keratoconjunctivitis (EKC). DESIGN: Systematic review. METHODS: We included randomized controlled trials that compared antiseptic agents, virustatic agents, or immune-modulating topical therapies with placebo or an active control. We adhered to Cochrane methods for trial selection, data extraction, risk of bias evaluation, and data synthesis. RESULTS: Ten randomized controlled trials with 892 participants with acute or chronic EKC were included. Eight trials compared interventions with artificial tears or saline (n = 4) or with steroids (n = 4); two 3-arm trials contributed data to both comparisons. Estimates suggested that compared with tears, after povidone-iodine (PVP-I) alone (2 studies, 409 participants) more participants with acute EKC had resolution of symptoms (risk ratio [RR] 1.15 [95% confidence interval {CI} 1.07-1.24]) and signs (RR 3.19 [95% CI 2.29-4.45]) within 10 days. In 2 trials comparing treatments with steroid alone or steroid with levofloxacin, fewer eyes treated with PVP-I or polyvinyl alcohol iodine (PVA-I) plus steroid developed subepithelial infiltrates within 21 days (RR 0.08 [95% CI 0.01-0.55]; 69 eyes). No treatment was shown to improve resolution of infiltrates. CONCLUSIONS: Low- to very low-level certainty of evidence suggested that PVP-I or PVA-I with steroid may confer some benefit in acute EKC, but imprecision from small sample sizes, the potential risk of bias from inadequate reporting or trial design, and variability in participant selection, outcome measurement, and reporting limit the amount and quality of evidence.

Cross-sectional study of preprints and final journal publications from COVID-19 studies: discrepancies in results reporting and spin in interpretation.

OBJECTIVE: To compare results reporting and the presence of spin in COVID-19 study preprints with their finalised journal publications. DESIGN: Cross-sectional study. SETTING: International medical literature. PARTICIPANTS: Preprints and final journal publications of 67 interventional and observational studies of COVID-19 treatment or prevention from the Cochrane COVID-19 Study Register published between 1 March 2020 and 30 October 2020. MAIN OUTCOME MEASURES: Study characteristics and discrepancies in (1) results reporting (number of outcomes, outcome descriptor, measure, metric, assessment time point, data reported, reported statistical significance of result, type of statistical analysis, subgroup analyses (if any), whether outcome was identified as primary or secondary) and (2) spin (reporting practices that distort the interpretation of results so they are viewed more favourably). RESULTS: Of 67 included studies, 23 (34%) had no discrepancies in results reporting between preprints and journal publications. Fifteen (22%) studies had at least one outcome that was included in the journal publication, but not the preprint; eight (12%) had at least one outcome that was reported in the preprint only. For outcomes that were reported in both preprints and journals, common discrepancies were differences in numerical values and statistical significance, additional statistical tests and subgroup analyses and longer follow-up times for outcome assessment in journal publications.At least one instance of spin occurred in both preprints and journals in 23/67 (34%) studies, the preprint only in 5 (7%), and the journal publications only in 2 (3%). Spin was removed between the preprint and journal publication in 5/67 (7%) studies; but added in 1/67 (1%) study. CONCLUSIONS: The COVID-19 preprints and their subsequent journal publications were largely similar in reporting of study characteristics, outcomes and spin. All COVID-19 studies published as preprints and journal publications should be critically evaluated for discrepancies and spin.

Domains of quality for clinical ethics case consultation: a mixed-method systematic review.

BACKGROUND: "Clinical ethics consultation" (CEC) is the provision of consultative services by an individual or team with the aim of helping health professionals, patients, and their families grapple with difficult ethical issues arising during health care. There are almost 25,000 articles in the worldwide literature on CEC, but very few explicitly address measuring the quality of CEC. Many more address quality implicitly, however. This article describes a rigorous protocol for compiling the diverse literature on CEC, analyzing it with a quality measurement lens, and seeking a set of potential quality domains for CEC based on areas of existing, but hitherto unrecognized, consensus in the literature. METHODS/DESIGN: This mixed-method systematic review will follow a sequential pattern: scoping review, qualitative synthesis, and then a quantitative synthesis. The scoping review will include categorizing all quality measures for CEC discussed in the literature, both quantitative and qualitative. The qualitative synthesis will generate a comprehensive analytic framework for understanding the quality of CEC and is expected to inform the quantitative synthesis, which will be a meta-analysis of studies reporting the effects of CEC on pre-specified clinical outcomes. DISCUSSION: The literature on CEC is broad and diverse and has never been examined with specific regard to quality measurement. We propose a novel mixed-methods approach to compile and synthesize this literature and to derive a framework for assessing quality in CEC. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015023282.