Inclusion Of Randomized Controlled Trials Research Articles

Acupuncture for premature ejaculation: a systematic review and meta-analysis.

Although acupuncture is widely used to treat premature ejaculation (PE), its effectiveness remains highly controversial. To evaluate the efficacy and safety of acupuncture on PE. According to the relevant keywords, 11 major English and Chinese databases were searched for randomized controlled trials (RCTs) of acupuncture alone or in combination with other treatments for PE. The quality of evidence across studies was assessed by the GRADEpro tool. Study outcome measures included the intravaginal ejaculation latency time (IELT), the Premature Ejaculation Diagnostic Tool (PEDT), the Chinese Index of Premature Ejaculation-5 (CIPE-5), treatment success rate, and adverse events. Seven trials were included in this review for a total of 603 participants. A low quality of evidence suggests that it is not possible to determine whether acupuncture, as compared with a selective serotonin reuptake inhibitor, has an advantage in improving the IELT (standardized mean difference [SMD], -1.75; 95% CI, -6.12 to 2.63; P = .43, I2 = 98%), PEDT scores (SMD, 0.32; 95% CI, -0.68 to 1.32; P = .53, I2 = 85%), and treatment success rate (risk ratio, 0.69; 95% CI, 0.41-1.14; P = .15). However, participants receiving acupuncture had a lower CIPE-5 (SMD, -1.06; 95% CI, -1.68 to -0.44; P < .01). As compared with sham acupuncture, acupuncture significantly improved the IELT (SMD, 1.47; 95% CI, 1.01-1.92; P < .01, I2 = 0%) and PEDT scores (SMD, -1.23; 95% CI, -1.78 to -0.67; P < .01, I2 = 37%). When compared with other treatments alone, a combined treatment with acupuncture can significantly improve the IELT (SMD, 7.06; 95% CI, 2.53-11.59; P < .01, I2 = 97%), CIPE-5 (SMD, 0.84; 95% CI, 0.45-1.22; P < .01, I2 = 0%), and treatment success rate (SMD, 1.60; 95% CI, 1.18-2.16; P < .01, I2 = 53). The results suggest a significant effect of acupuncture in the treatment of certain important indicators of PE; however, this finding needs to be treated with caution because of the quality of the RCTs included. Comprehensive inclusion of available RCTs has been performed. However, limitations include a low number of studies and a lack of detailed information to allow subgroup analysis. The present systematic review and meta-analysis show that acupuncture has a significant effect on several subjective PE parameters, such as improving the feeling of control over ejaculation and distress, particularly when used in an integrated way. However, due to the low quality of evidence, acupuncture still needs larger well-designed RCTs to be confirmed.

Diet Therapy of Obstructive Sleep Apnea Syndrome Treated with Positive Airway Pressure: A Systematic Review of Randomized Controlled Trials

The positive airway pressure (PAP) is a gold standard in therapy for obstructive sleep apnea (OSA) patients, though weight loss is among the most effective supportive therapeutic methods. The aim of the study is to conduct a systematic review of randomized controlled trials (RCTs) of diet therapy interventions for OSA patients treated with PAP. The systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42023398374). The 1436 records were screened and five records were included identified as RCTs available within PubMed and Web of Science databases until 1 February 2023. Two researchers independently conducted identification, screening, inclusion, and evaluation of RCTs, using the revised Cochrane risk-of-bias tool for randomized trials. The studies were conducted in groups with patients treated or intended to be treated with CPAP, while patients with moderate-to-severe or severe OSA were included. Within all included studies, an experimental diet was compared with a control group; however, various interventions were applied, including dietary intervention, which was compared with no intervention, and dietary and physical activity intervention, which was only compared with general advice. The applied intervention included various dietary approaches, such as various energy deficits or dietary health-promoting behaviors. The monitored variables included apnea–hypopnea index (AHI), sleep time, sleep efficiency, sleep latency, oxygen desaturation episodes, oxygen saturation, OSA type, Epworth Sleepiness Scale score, Pittsburgh Sleep Quality Index, and quality of life. For the majority of studies, some concerns were defined for the risk of bias; however, for one study the risk was high. Three studies supported the positive influence of diet therapy, one study somewhat supported it and one study did not support it. It may be stated that for excessive body mass individuals, even if PAP is applied, the diet therapy should be included in order to reduce body mass, reduce the symptoms of OSA, and improve the quality of life. This therapeutic option should be applied, even if no effect on OSA is noted, as body mass reduction have multiple positive effects, which may also influence the quality of life.

Efficacy and safety of total neoadjuvant therapy in locally advanced rectal cancer: a meta-analysis.

The standard of care for locally advanced rectal cancer (LARC) has changed from a single radical surgical treatment to the current multimodality treatment (standard chemoradiotherapy (CRT) and total neoadjuvant therapy (TNT)). The efficacy and safety of both TNT and standard CRT are evaluated in randomized controlled trials (RCTs). RCTs were comprehensively searched in Chinese and English electronic databases. The experimental and control groups were TNT and the standard CRT, respectively, included in this meta-analysis. The outcomes were assessed through a fixed-effect or random-effect model of pooled odds (OR) or hazard ratios (HR). Eleven RCTs, involving 3,101 patients were included in the final analysis. TNT showed increase in the pathological complete response (pCR) (OR = 1.95, 95% confidence interval (CI): 1.57-2.41; P < 0.05) and the R0 resection (OR = 1.19, 95% CI: 0.99-1.43; P = 0.062). There was no significant difference in local recurrence-free survival (LRFS) (HR = 0.97, P = 0.803), but TNT had better 3-year disease-free survival (DFS) (HR = 0.82, 95% CI: 0.72-0.93, P < 0.05), overall survival (OS) (HR = 0.87, 95% CI: 0.74-1.02, P = 0.08) and distant metastasis-free survival (DMFS) (HR = 0.79, 95% CI: 0.67-0.93, P < 0.05) than standard CRT. TNT was safe and feasible as it improved pCR and survival outcomes, and reduced the risk of distant metastasis compared with standard CRT. TNT may be a superior strategy for LARC, but more RCTs are needed to prove it. PROSPERO CRD42022327697. We added the Chinese database after registration because of the inclusion of fewer RCTs www.crd.york.ac.uk/PROSPERO/ .

Lack of attention to sex and gender in periodontitis-related randomized clinical trials: A meta-research study.

This meta-research study aimed to investigate the level of compliance with the Sex and Gender Equity in Research (SAGER) Guidelines for the inclusion, analysis, and reporting of sex/gender, in periodontitis-related randomized controlled trials (RCTs). Following the inclusion of RCTs related to the treatment of periodontitis published between 2018 and 2019, we applied the SAGER checklist to assess the adherence to sex/gender reporting guidelines. We used non-parametric descriptive statistics and correlation models to test the association of the dependent outcome with other variables. One hundred and one articles were included in the analysis. The female enrolment ranged between 30% and 94%. Twenty-six studies enrolled less than 50% of female participants. The overall SAGER score (OSS) of item fulfilment ranged between 0 and 7 items with an average of 1.9 items signifying poor guideline adherence to the SAGER guidelines. These findings were not associated with the corresponding author gender (p= .623), publication year (p= .947), and funding source (p= .133). However, a significant but negative correlation with journal impact factor (r= -0.253, p= .026) was observed. Sex and gender were frequently disregarded in clinical trial reporting. This oversight might limit the understanding of sex/gender differences in periodontitis-related clinical trials.

Meta-analysis of clinical trials focusing on hypertonic dextrose prolotherapy (HDP) for knee osteoarthritis.

Hypertonic dextrose prolotherapy (HDP) is an injection of a concentrated dextrose solution for the purpose of local treatment of musculoskeletal pain and possible enhancement of repair mechanisms. This systematic review and meta-analysis examines the clinical utility of HDP injection for treatment of knee osteoarthritis (OA). Randomized controlled trials (RCTs) utilizing HDP to treat knee OA were retrieved from MEDLINE, EMBASE, and Cochrane Library (CENTRAL). Identification and inclusion of RCTs utilizing intra-articular and extra-articular administration of HDP vs administration of other injectate or physical therapy as control for knee OA were included. Primary clinical outcomes were changes in knee WOMAC, pain and function score. Secondary outcomes were adverse events related to HDP. For continuous outcomes with same or different measurements, we calculated, respectively the weighted mean difference (WMD) or the standardized mean difference (SMD), respectively. Results were pooled using DerSimonian and Laird random effect models across the included studies and heterogeneity between studies was estimated using the I2 index. Five studies comprising a total of 319 treated patients met inclusion criteria and were included in the final analysis. At a mean of 22.8weeks follow-up, HDP treatment significantly improved total WOMAC score (WMD = 13.77, 95% CI: 6.75-20.78; p < 0.001; I2 = 90%), pain (SMD = 1.33, 95% CI: 0.49-2.17; p < 0.001; I2 = 91%) and knee function (SMD = 1.30, 95% CI: 0.45-2.14; p < 0.001; I2 = 91%) compared with control group. There were nosevere adverse events related to dextrose injection reported in all the included studies. HDP is a promising treatment for knee OA with a reasonable safety profile. Further research in mechanism of HDP activity and long-term follow-up study will be needed for exploring this novel therapy modality.

Temporal Trends and Clinical Trial Characteristics Associated With the Inclusion of Women in Heart Failure Trial Steering Committees: A Systematic Review.

Trial steering committees (TSCs) steer the conduct of randomized controlled trials (RCTs). We examined the gender composition of TSCs in impactful heart failure RCTs and explored whether trial leadership by a woman was independently associated with the inclusion of women in TSCs. We systematically searched MEDLINE, EMBASE, and CINAHL for heart failure RCTs published in journals with impact factor ≥10 between January 2000 and May 2019. We used the Jonckheere-Terpstra test to assess temporal trends and multivariable logistic regression to explore trial characteristics associated with TSC inclusion of women. Of 403 RCTs that met inclusion criteria, 127 (31.5%) reported having a TSC but 20 of these (15.7%) did not identify members. Among 107 TSCs that listed members, 56 (52.3%) included women and 6 of these (10.7%) restricted women members to the RCT leaders. Of 1213 TSC members, 11.1% (95% CI, 9.4%-13.0%) were women, with no change in temporal trends (P=0.55). Women had greater odds of TSC inclusion in RCTs led by women (adjusted odds ratio, 2.48 [95% CI, 1.05-8.72], P=0.042); this association was nonsignificant when analysis excluded TSCs that restricted women to the RCT leaders (adjusted odds ratio 1.46 [95% CI, 0.43-4.91], P=0.36). Women were included in 52.3% of TSCs and represented 11.1% of TSC members in 107 heart failure RCTs, with no change in trends since 2000. RCTs led by women had higher adjusted odds of including women in TSCs, partly due to the self-inclusion of RCT leaders in TSCs.

PNS318 NETWORK META-ANALYSES COMBINING RANDOMIZED AND NON-RANDOMIZED EVIDENCE; A NICE HTA REVIEW

Randomized controlled trials (RCTs) are considered the most reliable sources of information for evidence synthesis in network meta-analyses (NMAs). However, interest in including non-randomized studies (NRSs) in NMAs is growing. NRSs may complement evidence provided by RCTs and they can be used to connect disconnected evidence networks of RCTs. Statistical techniques including Bayesian hierarchical models have been developed to account for potential bias from including RCTs and NRSs in NMAs. This review aims to assess NICE technology appraisals which included NMAs combining RCTs and NRSs and to evaluate how the risk of bias has been addressed in these NMAs. A NICE health technology assessment (HTA) review was conducted on submissions appraised between 2001-2019. NMAs combining both RCT and NRS evidence were included. NMAs constructed using indirect treatment comparison techniques to connect a single-arm pivotal trial with other comparators are excluded if they don’t include RCT evidence in the network. Two relevant submissions were identified. Unavailability of RCTs was the reason for including NRSs in the NMAs. The sources of NRSs were evidence from other indirect treatment comparisons and observational studies. Risk of bias for RCTs was evaluated using CRD's guidance for undertaking reviews in health care and the NICE user guide. For the NRSs evidence; no formal quality assessment was done in one submission, but the second submission used ROBINS-I tool. In both submissions, specific methodologies for adjusting the bias that is introduced by combining different study designs in NMAs were not implemented. Inclusion of RCTs and NRSs in NMAs submitted to NICE is limited and differences in the risk of bias was not well addressed in the included NMAs. Available methodologies for incorporating RCTs and NRSs in NMAs can benefit future submissions which would require combining RCT and NRS evidence in NMAs.

The road from intermittently scanned continuous glucose monitoring to hybrid closed-loop systems. Part B: results from randomized controlled trials.

Background:Advances in diabetes technology have been exponential in the last few decades. With evolution in continuous glucose monitoring (CGM) systems and its progressive automation in control of insulin delivery, these advances have changed type 1 diabetes mellitus (T1DM) management. These novel technologies have the potential to improve glycated haemoglobin (HbA1c), reduce hypoglycaemic events, increase time spent in range and improve quality of life (QoL). Our aim was to evaluate the sustained effects in free-living unsupervised conditions of CGM systems (intermittently scanned and real time) and insulin delivery [from multiple daily injections, via sensor-augmented pump therapy and (predictive) low-glucose insulin suspension to hybrid closed-loop systems] on glucose control and QoL in adults and children with T1DM.Methods:We performed a systematic review of randomized controlled trials (RCTs), using PubMed and the Cochrane library up to 30 May 2019. Inclusion of RCTs was based on type of intervention (comparing glucose-monitoring devices and insulin-delivery devices), population (nonpregnant adults and children with T1DM), follow-up (outpatient setting for at least 8 weeks) and relevant outcomes [HbA1c, time in range (TIR), time in target, time in hypoglycaemia and QoL]. Exclusion of RCTs was based on intervention (exercise, only overnight use). The Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were used to score the quality of the papers and for the final selection of the articles.Results:Our search resulted in 214 articles, of which 19 were eligible. Studies on advanced use in adults and children with T1DM reported increased TIR (all 9 studies); decreased time in hypoglycaemia (13 out of 15 studies); lowered HbA1c levels (5 out of 15 studies); improved QoL (10 of 16 studies) and treatment satisfaction (7 studies).Conclusions:Recent technologies have dramatically changed the course of T1DM. They are proving useful in controlling glycaemia in patients with T1DM, without increasing the treatment burden.

Non-steroidal anti-inflammatory drugs for chronic low back pain.

Chronic back pain is an important health problem. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat people with low back pain, especially people with acute back pain. Short term NSAID use is also recommended for pain relief in people with chronic back pain. Two types of NSAIDs are available and used to treat back pain: non-selective NSAIDs and selective COX-2 NSAIDs. In 2008, a Cochrane review identified a small but significant effect from NSAIDs compared to placebo in people with chronic back pain. This is an update of the Cochrane review published in 2008 and focuses on people with chronic low back pain. To determine if NSAIDs are more efficacious than various comparison treatments for non-specific chronic low back pain and if so, which type of NSAID is most efficacious. We searched CENTRAL, MEDLINE, EMBASE, PubMed and two clinical trials registry databases up to 24 June 2015 for randomized controlled trials (RCTs) published in English, German or Dutch. We also screened references cited in relevant reviews. We included RCTs (double-blind and single-blind) of NSAIDs used to treat people with chronic low back pain. Two review authors independently screened trials for inclusion in this Cochrane review according to the inclusion criteria. One review author extracted the data, and a second review author checked the data. Two review authors independently evaluated the risk of bias of all included trials. If data were clinically homogeneous, we performed a meta-analysis and assessed the quality of evidence using the GRADE approach. We included 13 trials in this Cochrane review. Ten studies were at 'low' risk of bias. Six studies compared NSAIDs with placebo, and included 1354 participants in total. There is low quality evidence that NSAIDs are more effective than placebo, with a mean difference in pain intensity score from baseline of -3.30 (95% CI -5.33 to -1.27) on a 0 to 100 visual analogue scale (VAS) with a median follow-up of 56 days (interquartile range (IQR) 13 to 91 days). Four studies measured disability using the Roland Morris Disability Questionnaire. There is low quality evidence that NSAIDs are more effective than placebo on disability, with a mean difference from baseline of -0.85 (95% CI -1.30 to -0.40) on a scale from 0 to 24 with a median follow-up of 84 days (IQR 42 to 105 days). All six placebo controlled studies also reported adverse events, and suggested that adverse events are not statistically significant more frequent in participants using NSAIDs compared to placebo (RR 1.04, 95% CI 0.92 to 1.17). Due to the relatively small sample size and relatively short follow-up in most included trials, it is likely that the proportion of patients experiencing an adverse event is underestimated.Two studies compared different types of non-selective NSAIDs, namely ibuprofen versus diclofenac and piroxicam versus indomethacin. The trials did not find any differences between these NSAID types, but both trials had small sample sizes. One trial reported no differences in pain intensity between treatment groups that used selective or non-selective NSAIDs. One other trial compared diflunisal with paracetamol and showed no difference in improvement from baseline on pain intensity score. One trial showed a better global improvement in favour of celecoxib versus tramadol.One included trial compared NSAIDs with 'home-based exercise'. Disability improved more in participants who did exercises versus participants receiving NSAIDs, but pain scores were similar. Six of the 13 included RCTs showed that NSAIDs are more effective than placebo regarding pain intensity. NSAIDs are slightly more effective than placebo regarding disability. However, the magnitude of the effects is small, and the level of evidence was low. When we only included RCTs at low risk of bias, differences in effect between NSAIDs and placebo were reduced. We identified no difference in efficacy between different NSAID types, including selective versus non-selective NSAIDs. Due to inclusion of RCTs only, the relatively small sample sizes and relatively short follow-up in most included trials, we cannot make firm statements about the occurrence of adverse events or whether NSAIDs are safe for long-term use.

Network meta-analysis incorporating randomized controlled trials and non-randomized comparative cohort studies for assessing the safety and effectiveness of medical treatments: challenges and opportunities.

Network meta-analysis is increasingly used to allow comparison of multiple treatment alternatives simultaneously, some of which may not have been compared directly in primary research studies. The majority of network meta-analyses published to date have incorporated data from randomized controlled trials (RCTs) only; however, inclusion of non-randomized studies may sometimes be considered. Non-randomized studies can complement RCTs or address some of their limitations, such as short follow-up time, small sample size, highly selected population, high cost, and ethical restrictions. In this paper, we discuss the challenges and opportunities of incorporating both RCTs and non-randomized comparative cohort studies into network meta-analysis for assessing the safety and effectiveness of medical treatments. Non-randomized studies with inadequate control of biases such as confounding may threaten the validity of the entire network meta-analysis. Therefore, identification and inclusion of non-randomized studies must balance their strengths with their limitations. Inclusion of both RCTs and non-randomized studies in network meta-analysis will likely increase in the future due to the growing need to assess multiple treatments simultaneously, the availability of higher quality non-randomized data and more valid methods, and the increased use of progressive licensing and product listing agreements requiring collection of data over the life cycle of medical products. Inappropriate inclusion of non-randomized studies could perpetuate the biases that are unknown, unmeasured, or uncontrolled. However, thoughtful integration of randomized and non-randomized studies may offer opportunities to provide more timely, comprehensive, and generalizable evidence about the comparative safety and effectiveness of medical treatments.

Chemotherapy for advanced non-small cell lung cancer in the elderly population.

Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC) are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs). As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted. To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV) NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life. Search methods: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to 31 October 2014), EMBASE (1974 to 31 October 2014), and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 31 October 2014). In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database.Selection criteria: We included only RCTs that compared non-platinum single-agent therapy versus non-platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses.Data collection and analysis: Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS), one-year survival rate (1yOS), progression-free survival (PFS), objective response rate (ORR), major adverse events, and quality of life (QoL). We included 51 trials in the review: non-platinum single-agent therapy versus non-platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials).Non-platinum single-agent versus non-platinum combination therapyLow-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single-agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low-quality evidence).Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data.Non-platinum therapy versus platinum combination therapyPlatinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate-quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non-platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs).Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data. In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making.

Chemotherapy for advanced non-small cell lung cancer in the elderly population.

Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC) are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs). As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted. To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV) NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life. We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to 31 October 2014), EMBASE (1974 to 31 October 2014), and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 31 October 2014). In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database. We included only RCTs that compared non-platinum single-agent therapy versus non-platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses. Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS), one-year survival rate (1yOS), progression-free survival (PFS), objective response rate (ORR), major adverse events, and quality of life (QoL). We included 51 trials in the review: non-platinum single-agent therapy versus non-platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials). Non-platinum single-agent versus non-platinum combination therapy Low-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single-agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low-quality evidence).Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data. Non-platinum therapy versus platinum combination therapy Platinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate-quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non-platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs).Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data. In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making.

Connective Tissue Disease-associated Interstitial Lung Diseases (CTD-ILD) - Report from OMERACT CTD-ILD Working Group.

Interstitial lung disease (ILD) is common in connective tissue disease (CTD) and is the leading cause of mortality. Investigators have used certain outcome measures in randomized controlled trials (RCT) in CTD-ILD, but the lack of a systematically developed, CTD-specific index that captures all measures relevant and meaningful to patients with CTD-ILD has left a large and conspicuous gap in CTD-ILD research. The CTD-ILD working group, under the aegis of the Outcome Measures in Rheumatology (OMERACT) initiative, has completed a consensus group exercise to reach harmony on core domains and items for inclusion in RCT in CTD-ILD. During the OMERACT 12 meeting, consensus was sought on domains and core items for inclusion in RCT. In addition, consensus was pursued on a definition of response in RCT. Consensus was defined as ≥ 75% agreement among the participants. OMERACT 12 participants endorsed the domains with minimal modifications. Clinically meaningful progression for CTD-ILD was proposed as ≥ 10% relative decline in forced vital capacity (FVC) or ≥ 5% to < 10% relative decline in FVC and ≥ 15% relative decline in DLCO. There is consensus on domains for inclusion in RCT in CTD-ILD and on a definition of clinically meaningful progression. Data-driven approaches to validate these results in different cohorts and RCT are needed.

Validation of a prognostic score for early mortality in severe head injury cases.

Traumatic brain injury (TBI) represents a large health and economic burden. Because of the inability of previous randomized controlled trials (RCTs) on TBI to demonstrate the expected benefit of reducing unfavorable outcomes, the IMPACT (International Mission on Prognosis and Analysis of Clinical Trials in TBI) and CRASH (Corticosteroid Randomisation After Significant Head Injury) studies provided new methods for performing prognostic studies of TBI. This study aimed to develop and externally validate a prognostic model for early death (within 48 hours). The secondary aim was to identify patients who were more likely to succumb to an early death to limit their inclusion in RCTs and to improve the efficiency of RCTs. The derivation cohort was recruited at 1 center, Hospital 12 de Octubre, Madrid (1990-2003, 925 patients). The validation cohort was recruited in 2004-2006 from 7 study centers (374 patients). The eligible patients had suffered closed severe TBIs. The study outcome was early death (within 48 hours post-TBI). The predictors were selected using logistic regression modeling with bootstrapping techniques, and a penalized reduction was used. A risk score was developed based on the regression coefficients of the variables included in the final model. In the validation set, the final model showed a predictive ability of 50% (Nagelkerke R(2)), with an area under the receiver operating characteristic curve of 89% and an acceptable calibration (goodness-of-fit test, p = 0.32). The final model included 7 variables, and it was used to develop a risk score with a range from 0 to 20 points. Age provided 0, 1, 2, or 3 points depending on the age group; motor score provided 0 points, 2 (untestable), or 3 (no response); pupillary reactivity, 0, 2 (1 pupil reacted), or 6 (no pupil reacted); shock, 0 (no) or 2 (yes); subarachnoid hemorrhage, 0 or 1 (severe deposit); cisternal status, 0 or 3 (compressed/absent); and epidural hematoma, 0 (yes) or 2 (no). Based on the risk of early death estimated with the model, 4 risk of early death groups were established: low risk, sum score 0-3 (< 1% predicted mortality); moderate risk, sum score 4-8 (predicted mortality between 1% and 10%); high risk, sum score 9-12 (probability of early death between 10% and 50%); and very high risk, sum score 13-20 (early mortality probability > 50%). This score could be used for selecting patients for clinical studies. For example, if patients with very high risk scores were excluded from our study sample, the patients included (eligibility score < 13) would represent 80% of the original sample and only 23% of the patients who died early. The combination of Glasgow Coma Scale score, CT scanning results, and secondary insult data into a prognostic score improved the prediction of early death and the classification of TBI patients.

Meta‐analysis of the studies of bleeding complications of platelets pathogen‐reduced with the Intercept system

The eligibility criteria of a previously reported meta-analysis (Transfusion 2011;51:1058-1071) of randomized controlled trials (RCTs) of pathogen reduction of platelets in patients with hypoproliferative thrombocytopenia were modified to examine the impact on the findings of: (1) inclusion of a (previously excluded) RCT; (2) restriction of eligibility to RCTs of the Intercept (amotosalen-HCl/ultraviolet-A-light) system; and (3) differences in the methods used to assess bleeding complications. Five RCTs comparing the risk of all, clinically significant (grades 2 through 4) and/or severe (grades 3 and 4) bleeding complications between recipients of platelets treated with Intercept vs. standard unmanipulated platelets were included. Odds ratios (ORs) of bleeding complications of similar severity recorded during similar periods of observation were calculated across all studies and across homogeneous subsets of studies by random-effects methods. Treatment with Intercept increased all bleeding complications when four RCTs meeting the eligibility criteria of the previous meta-analysis were integrated, but not across all the five currently available studies [summary OR=1·24; 95% confidence interval (CI), 0·79-1·93]. Clinically significant bleeding complications increased when the results of the SPRINT RCT were based on the expanded safety analysis (summary OR=1·52; 95% CI, 1·09-2·12)--but not the initial report (summary OR=1·30; 95% CI, 0·54-3·14)--of that study. Treatment with Intercept may increase the risk of all and clinically significant (albeit not severe) bleeding complications in RCTs maintaining a platelet count of ≥10×10(9) or ≥20×10(9)/l through increased platelet transfusions.

Is there a role for real life observational studies in integrating knowledge provided by randomized clinical trials?

Randomized controlled trials (RCTs) are the gold standard for determining the efficacy of treatment agents, because they represent the only secure method of attributing causality in observed associations between treatments and outcomes. The main strengths of RCTs are well known to researchers. In particular: 1. they reduce the risk of selection bias. The random allocation of patients to treatment or control groups balances their measured and unmeasured characteristics; 2. they allow assessment of the cause-effect association. The impact of treatment is compared with the impact of placebo in the control group. But researchers are also aware of some important limitations of RCTs. In particular: 1. strict inclusion and exclusion criteria for patient selection are always applied, in order to eliminate factors which may confound or obscure treatment effects. However, patient selection limits the generalizability of results, and clinicians recognize that many of the patients they see in routine clinical practice, and for whom they must make therapeutic decisions, would not be eligible for inclusion in RCTs. Therefore, the main issue raised is the applicability of trial results to ordinary patients; 2. most RCTs involve younger adults, and treatment decisions in elderly patients are derived from them. The benefit-to-risk ratio of any given intervention may be quite different in frail older patients with significant comorbidities, and the applicability of study Is there a role for real life observational studies in integrating knowledge provided by randomized clinical trials?

Abstract reporting in randomized clinical trials of acute lung injury: An audit and assessment of a quality of reporting score*

To evaluate the quality of reporting among abstracts of randomized controlled trials (RCTs) in acute lung injury and to highlight important trial information for abstract inclusion. Audit of published RCT abstracts. A total of 56 RCTs, identified in MEDLINE, EMBASE, HEALTHSTAR, CINAHL, and the Cochrane Central Register of Controlled Trials. We used a research focus group and published literature on suggested content for abstracts of original articles to generate a list of 32 recommended items. The focus group reduced this list to a 20-item long form list of highly relevant criteria and a 12-item short form list of essential criteria for inclusion in abstracts of RCTs in acute lung injury. After pilot testing the abstract appraisal form, we evaluated abstracts independently and in duplicate. We scored the quality of reporting of each abstract by dividing the number of criteria fulfilled by the number applicable. Although abstracts described the study objectives and interventions well and the participants, outcomes, and conclusions to an intermediate extent, key deficiencies were noted in reporting the study methods, setting, and results. Mean quality of reporting scores were significantly higher for structured compared with unstructured abstracts using the 32-item, 20-item, and 12-item lists (p = .008, .014, and <.0001, respectively), especially for abstracts published after 1990 (p = .004, .017, and .001, respectively). The 20-item and 12-item lists correlated well with the 32-item list (r = .89 and .62, respectively) and with one another (r = .73). Key design features and results are frequently under-reported in RCT abstracts, particularly among unstructured abstracts. Checklists may aid authors and editors in prioritizing important criteria for inclusion in RCT abstracts.