Infraoccluded primary molars: New findings from the last 10 years - A systematic review.

BackgroundsSyntheses of non-randomized studies of interventions (NRSIs) and randomized controlled trials (RCTs) are increasingly used in decision-making. This study aimed to summarize when NRSIs are included in evidence syntheses of RCTs, with a particular focus on the methodological issues associated with combining NRSIs and RCTs.MethodsWe searched PubMed to identify clinical systematic reviews published between 9 December 2017 and 9 December 2022, randomly sampling reviews in a 1:1 ratio of Core and non-Core clinical journals. We included systematic reviews with RCTs and NRSIs for the same clinical question. Clinical scenarios for considering the inclusion of NRSIs in eligible studies were classified. We extracted the methodological characteristics of the included studies, assessed the concordance of estimates between RCTs and NRSIs, calculated the ratio of the relative effect estimate from NRSIs to that from RCTs, and evaluated the impact on the estimates of pooled estimates when NRSIs are included.ResultsTwo hundred twenty systematic reviews were included in the analysis. The clinical scenarios for including NRSIs were grouped into four main justifications: adverse outcomes (n = 140, 63.6%), long-term outcomes (n = 36, 16.4%), the applicability of RCT results to broader populations (n = 11, 5.0%), and other (n = 33, 15.0%). When conducting a meta-analysis, none of these reviews assessed the compatibility of the different types of evidence prior, 203 (92.3%) combined estimates from RCTs and NRSIs in the same meta-analysis. Of the 203 studies, 169 (76.8%) used crude estimates of NRSIs, and 28 (13.8%) combined RCTs and multiple types of NRSIs. Seventy-seven studies (35.5%) showed “qualitative disagree” between estimates from RCTs and NRSIs, and 101 studies (46.5%) found “important difference”. The integration of NRSIs changed the qualitative direction of estimates from RCTs in 72 out of 200 studies (36.0%).ConclusionsSystematic reviews typically include NRSIs in the context of assessing adverse or long-term outcomes. The inclusion of NRSIs in a meta-analysis of RCTs has a substantial impact on effect estimates, but discrepancies between RCTs and NRSIs are often ignored. Our proposed recommendations will help researchers to consider carefully when and how to synthesis evidence from RCTs and NRSIs.

Including non-randomized studies of interventions in meta-analyses of randomized controlled trials changed the estimates in more than a third of the studies: evidence from an empirical analysis.

Very low-certainty evidence suggested that it is unclear whether gluten intake is associated with all-cause mortality. Our findings also indicate that low-certainty evidence may show little or no association between gluten intake and cardiovascular mortality and non-fatal myocardial infarction. Low-certainty evidence suggested that a lower compared with a higher gluten intake may be associated with a slightly increased risk to develop type 2 diabetes - a major cardiovascular risk factor. For other cardiovascular risk factors it is unclear whether there is a difference between a gluten-free and normal diet. Given the limited findings from this review predominantly based on observational studies, no recommendations for practice can be made.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital malformations syndrome caused by defective cholesterol biosynthesis. Affected individuals show cholesterol deficiency and accumulation of various precursor molecules, mainly 7-dehydrocholesterol and 8-dehydrocholesterol. There is currently no cure for SLOS, with cholesterol supplementation being primarily a biochemical therapy of limited evidence. However, several anecdotal reports and preclinical studies have highlighted statins as a potential therapy for SLOS. To evaluate the effects of statins, either alone or in combination with other non-statin therapies (e.g. cholesterol, bile acid, or vitamin co-supplementation), compared to cholesterol supplementation alone or in combination with other non-statin therapies (e.g. bile acid or vitamin supplementation) on several important outcomes including overall survival, neurobehavioral features, and adverse effects in individuals with SLOS. We searched CENTRAL, MEDLINE, Embase, five other databases and three trials registers on 15 February 2022, together with reference checking, citation searching and contact with study authors to identify additional studies. Randomized controlled trials (RCTs) and quasi-RCTs with parallel or cross-over designs, and non-randomized studies of interventions (NRSIs) including non-randomized trials, cohort studies, and controlled before-and-after studies, were eligible for inclusion in this review if they met our prespecified inclusion criteria, i.e. involved human participants with biochemically or genetically diagnosed SLOS receiving statin therapy or cholesterol supplementation, or both. Two authors screened titles and abstracts and subsequently full-texts for all potentially-relevant references. Both authors independently extracted relevant data from included studies and assessed the risks of bias. We analyzed the data extracted from the included NRSIs and cohort studies separately from the data extracted from the single included RCT. We used a random-effects model to account for the inherent heterogeneity and methodological variation between these different study designs. We used GRADE to assess the certainty of evidence. We included six studies (61 participants with SLOS); one RCT (N = 18), three prospective NRSIs (N = 20), and two retrospective NRSIs (N = 22). Five studies included only children, and two limited their participant inclusion by disease severity. Overall, there were nearly twice as many males as females. All six studies compared add-on statin therapy to cholesterol supplementation alone. However, the dosages, formulations, and durations of treatment were highly variable across studies. We judged the RCT as having a high risk of bias due to missing data and selective reporting. All included NRSIs had a serious or critical overall risk of bias assessed by the Risk Of Bias In Non-randomized Studies of Interventions tool (ROBINS-I). None of the included studies evaluated survival or reported quality of life (QoL). Only the included RCT formally assessed changes in the neurobehavioral manifestations of SLOS, and we are uncertain whether statin therapy improves this outcome (very low-certainty evidence). We are also uncertain whether the adverse events reported in the RCT were statin-related (very low-certainty evidence). In contrast, the adverse events reported in the NRSIs seem to be possibly due to statin therapy (risk ratio 13.00, 95% confidence interval 1.85 to 91.49; P = 0.01; low-certainty evidence), with only one of the NRSIs retrospectively mentioning changes in the irritability of two of their participants. We are uncertain whether statins affect growth based on the RCT or NRSI results (very low-certainty evidence). The RCT showed that statins may make little or no difference to plasma biomarker levels (low-certainty evidence), while we are uncertain of their effects on such parameters in the NRSIs (very low-certainty evidence). Currently, there is no evidence on the potential effects of statin therapy in people with SLOS regarding survival or QoL, and very limited evidence on the effects on neurobehavioral manifestations. Likewise, current evidence is insufficient and of very low certainty regarding the effects of statins on growth parameters in children with SLOS and plasma or cerebrospinal fluid (CSF) levels of various disease biomarkers. Despite these limitations, current evidence seemingly suggests that statins may increase the risk of adverse reactions in individuals with SLOS receiving statins compared to those who are not. Given the insufficient evidence on potential benefits of statins in individuals with SLOS, and their potential for causing adverse reactions, anyone considering this therapy should take these findings into consideration. Future studies should address the highlighted gaps in evidence on the use of statins in individuals with SLOS by collecting prospective data on survival and performing serial standardized assessments of neurobehavioral features, QoL, anthropometric measures, and plasma and CSF biomarker levels after statin introduction. Future studies should also attempt to use consistent dosages, formulations and durations of cholesterol and statin therapy.

IntroductionAlthough interest in including non-randomised studies of interventions (NRSIs) in meta-analysis of randomised controlled trials (RCTs) is growing, estimates of effectiveness obtained from NRSIs are vulnerable to greater bias than...

We found low-certainty evidence that early tracheostomy may result in little to no difference in overall mortality in critically ill COVID-19 patients requiring prolonged mechanical ventilation compared with late tracheostomy. In terms of clinical improvement, early tracheostomy may result in little to no difference in duration to liberation from mechanical ventilation compared with late tracheostomy. We are not certain about the impact of early tracheostomy on clinical worsening in terms of the incidence of adverse events, need for renal replacement therapy, ventilator-associated pneumonia, or the length of stay in the ICU. Future RCTs should provide additional data on the benefits and harms of early tracheostomy for defined main outcomes of COVID-19 research, as well as of comparable diseases, especially for different population subgroups to reduce clinical heterogeneity, and report a longer observation period. Then it would be possible to draw conclusions regarding which patient groups might benefit from early intervention. Furthermore, validated scoring systems for more accurate predictions of the need for prolonged mechanical ventilation should be developed and used in new RCTs to ensure safer indication and patient safety. High-quality (prospectively registered) NRSIs should be conducted in the future to provide valuable answers to clinical questions. This could enable us to draw more reliable conclusions about the potential benefits and harms of early tracheostomy in critically ill COVID-19 patients.

Introduction: Randomized controlled trials (RCTs) are the gold standard to evaluate the efficacy of interventions (e.g., drugs and vaccines), yet the sample size of RCTs is often limited for safety assessment. Non-randomized studies of interventions (NRSIs) had been proposed as an important alternative source for safety assessment. In this study, we aimed to investigate whether there is any difference between RCTs and NRSIs in the evaluation of adverse events.Methods: We used the dataset of systematic reviews with at least one meta-analysis including both RCTs and NRSIs and collected the 2 × 2 table information (i.e., numbers of cases and sample sizes in intervention and control groups) of each study in the meta-analysis. We matched RCTs and NRSIs by their sample sizes (ratio: 0.85/1 to 1/0.85) within a meta-analysis. We estimated the ratio of the odds ratios (RORs) of an NRSI against an RCT in each pair and used the inverse variance as the weight to combine the natural logarithm of ROR (lnROR).Results: We included systematic reviews with 178 meta analyses, from which we confirmed 119 pairs of RCTs and NRSIs. The pooled ROR of NRSIs compared to that of RCTs was estimated to be 0.96 (95% confidence interval: 0.87 and 1.07). Similar results were obtained with different sample size subgroups and treatment subgroups. With the increase in sample size, the difference in ROR between RCTs and NRSIs decreased, although not significantly.Discussion: There was no substantial difference in the effects between RCTs and NRSIs in safety assessment when they have similar sample sizes. Evidence from NRSIs might be considered a supplement to RCTs for safety assessment.

For preventing relapses in relapsing MS, rituximab as 'first choice' and as 'switching' may compare favourably with a wide range of approved DMTs. A protective effect of rituximab against disability worsening is uncertain. There is limited information to determine the effect of rituximab for progressive MS. The evidence is uncertain about the effect of rituximab on SAEs. They are relatively rare in people with MS, thus difficult to study, and they were not well reported in studies. There is an increased risk of common infections with rituximab, but absolute risk is small. Rituximab is widely used as off-label treatment in people with MS; however, randomised evidence is weak. In the absence of randomised evidence, remaining uncertainties on beneficial and adverse effects of rituximab for MS might be clarified by making real-world data available.

Midshaft clavicle fractures are among the most common shoulder girdle injuries and have traditionally been managed conservatively. Over the past two decades, evidence comparing operative and non-operative approaches has expanded, and this systematic review aimed to evaluate functional outcomes, union rates, complications, and temporal trends in management between 2005 and 2025. A comprehensive literature search was performed across PubMed, Embase, CINAHL, Web of Science, the Cochrane Library, and Ovid MEDLINE for studies published during this period. Randomised controlled trials (RCTs), cohort studies, comparative observational studies, and systematic reviews or meta-analyses directly comparing operative and non-operative management in adults were included. Two reviewers independently screened titles, abstracts, and full texts in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and study quality was assessed using the Cochrane Risk of Bias 2 (RoB-2) tool for RCTs and the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool for non-randomised studies. Grey literature and non-peer-reviewed reports were excluded to ensure methodological rigour.A total of 28 studies met the inclusion criteria (15 RCTs and 13 cohort or observational studies), enrolling 3,094 patients. Additional systematic reviews and meta-analyses were examined to contextualise and support primary findings. The mean age ranged from 20 to 45 years, with a 70-80% male predominance. Road traffic accidents and sports injuries were the most frequent mechanisms, and follow-up duration ranged from 6 to 53 months. Operative management (n = 1,572) primarily involved plate fixation, whereas non-operative care (n = 1,522) utilised slings or figure-of-eight harnesses. Surgical fixation was consistently associated with shorter union times (16-18 vs. 24-30 weeks) and lower rates of non-union (0.8-2.4% vs. 11-23%) and malunion (0-4.5%, occurring only in conservative groups). Early and intermediate functional outcomes generally favoured surgery, but long-term results often converged with conservative treatment. Conservative management avoided implant-related complications but showed higher risks of non-union and malunion, whereas surgical complications were more frequent (16-40%), most commonly hardware irritation or infection. A temporal trend was observed - earlier studies (2007-2015) strongly supported surgical fixation, while more recent evidence (2020-2025) emphasises selective indications and shared decision-making.Overall, evidence from 2005 to 2025 demonstrates a clear temporal evolution in the management of midshaft clavicle fractures. Surgical fixation provides faster recovery, earlier union, and lower non-union and malunion rates, particularly in young, active patients with displaced fractures. However, long-term functional outcomes frequently align with conservative care, which remains appropriate for low-demand patients. Current findings highlight the importance of an individualised, patient-centred approach informed by fracture pattern, activity level, and patient preference.

BackgroundThere is an increasing number of meta-analyses including data from non-randomized studies for therapeutic evaluation. We aimed to systematically assess the methods used in meta-analyses including non-randomized studies evaluating therapeutic interventions.MethodsFor this methodological review, we searched MEDLINE via PubMed, from January 1, 2013 to December 31, 2013 for meta-analyses including at least one non-randomized study evaluating therapeutic interventions. Etiological assessments and meta-analyses with no comparison group were excluded. Two reviewers independently assessed the general characteristics and key methodological components of the systematic review process and meta-analysis methods.ResultsOne hundred eighty eight meta-analyses were selected: 119 included both randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSI) and 69 only NRSI. Half of the meta-analyses (n = 92, 49 %) evaluated non-pharmacological interventions. “Grey literature” was searched for 72 meta-analyses (38 %). An assessment of methodological quality or risk of bias was reported in 135 meta-analyses (72 %) but this assessment considered the risk of confounding bias in only 33 meta-analyses (18 %). In 130 meta-analyses (69 %), the design of each NRSI was not clearly specified. In 131 (70 %), whether crude or adjusted estimates of treatment effect for NRSI were combined was unclear or not reported. Heterogeneity across studies was assessed in 182 meta-analyses (97 %) and further explored in 157 (84 %). Reporting bias was assessed in 127 (68 %).ConclusionsSome key methodological components of the systematic review process—search for grey literature, description of the type of NRSI included, assessment of risk of confounding bias and reporting of whether crude or adjusted estimates were combined—are not adequately carried out or reported in meta-analyses including NRSI.

Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia (Review)

ABSTRACTWe performed an update (last search: 24 July 2023) of a systematic review on relative efficacy/effectiveness (rVE) and safety of newer/enhanced seasonal influenza vaccines in comparison with standard influenza vaccine or in head‐to‐head comparison. Eligible studies investigated adults aged ≥ 18 years, analysed the MF59‐adjuvanted or high‐dose or cell‐based or recombinant or mRNA‐based influenza vaccine and reported rVE or safety in randomised controlled trials (RCT) or non‐randomised studies of interventions (NRSI). Of 1561 new entries identified, 17 studies were included. Together with 42 studies identified in the previous primary review they added up to 59 studies, all comparing newer/enhanced with standard seasonal influenza vaccines. Relative VE against laboratory‐confirmed influenza was −30% (95%CI: −146% to 31%) to 88% (51%–100%; 7 NRSI) for the MF59‐adjuvanted vaccine (low certainty of evidence, CoE); 24.2% (9.7%–36.5%; 1 RCT) and −9% (−158% to 54%) to 19% (−27% to 48%; 1 NRSI) for the high‐dose vaccine (moderate CoE); −5.8% (−36.1% to 17.7%) to 21.4% (−7.3% to 42.4%; 2 NRSI) for the cell‐based vaccine (low CoE); 30% (10%–47%; 1 RCT) and 3% (−31% to 28%) to 19% (−27% to 48%; 1 NRSI) for the recombinant vaccine (moderate CoE), respectively. Relative VE against laboratory‐confirmed influenza‐related hospitalisation was 59.2% (14.6%–80.5%; 1 NRSI) for the MF59‐adjuvanted (moderate CoE); 27% (−1 to 48%; 1 NRSI) for the high‐dose (low CoE); 8.5% (−75.9% to 52.3%; 1 NRSI) for the cell‐based (low CoE); −7.3% (−52.1% to 24.4%) to 16.3% (−8.7% to 35.5%; 1 RCT) for the recombinant vaccine. No increased risk of serious adverse events was detected for any vaccine (12 RCT, 7 NRSI; low CoE). While all have a favourable safety profile, evidence on rVE of newer/enhanced vaccines is still limited, warranting further studies.

Background:The benefit of loco-regional treatments such as hepatic arterial infusion (HAI) in terms of survival and response rate is unclear. The aim of this work is to quantitatively summarize the results of both randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) comparing fluoropyrimidine-HAI (F-HAI) to systemic chemotherapy (SCT) for the treatment of colorectal liver metastases (CRLMs).Methods:We searched the Cochrane Library, PubMed, EMBASE, and Web of Science up to July 1, 2021. The outcome measures were tumor response rate and overall survival (OS). Both RCTs and NRSIs comparing HAI to SCT for patients with unresectable CRLMs were included. The outcome measures were tumor response rate and OS. Two reviewers assessed trial quality and extracted data independently. All statistical analyses were performed using standard statistical procedures provided in Review Manager 5.2.Results:A total of 16 studies including 11 RCTs and 5 NRSIs were identified for the present meta-analysis. Nine RCTs compared F-HAI to SCT for patients with unresectable CRLMs and the pooled result indicated that patients who received F-HAI experienced more than twofold response rate than SCT, with a pooled risk ratio of 2.10 (95%CI 1.59–2.79; P < .00001). In addition, the pooled result based on RCTs showed that F-HAI had a significant benefit regarding OS, with a pooled HR of 0.83 (95% CI 0.70–0.99; P = .04). Similarly, the benefit of F-HAI in terms of OS was also observed in the results of NRSIs.Conclusions:Our results indicated that the F-HAI regimen had a greater tumor response rate and survival advantage than SCT for patients with unresectable CRLMs. Future propensity score-matched analyses with a large sample size should be conducted to support the evidence of our results based on RCTs and NRSIs.

ObjectiveTo investigate the relationship between radiographic JIA disease course in the TMJs and mandibular growth rotation, compared with growth in healthy individuals.MethodsFrom a larger series of JIA patients followed from childhood to adulthood, 26 were included; 11 without and 15 with bilateral radiographic TMJ involvement. Joint morphology and function were assessed at baseline, 2-, 4-, 6- and 27 years follow-up. Mandibular growth rotation (anterior, posterior or none) was assessed from cephalometric evaluations at childhood and adulthood, with observations from 16 healthy individuals as controls. TMJ disease course and mandibular growth rotation were assessed independently and their relationship analysed. Non-parametric statistical methods were applied to test differences between groups.ResultsIn the normal TMJ group of JIA patients the joint morphology was similar at the follow-ups and all patients had good function both in childhood and in adulthood. The mandibular growth rotation was similar to that of healthy controls, i.e. predominantly in anterior direction. In the abnormal TMJ group different JIA TMJ disease courses were observed and associated with changes in the mandibular growth rotation (p = 0.007).Progressing JIA TMJ disease course was related to posterior mandibular growth rotation and improving disease course to anterior mandibular growth rotation.ConclusionA relationship was found between JIA disease course in the TMJs and mandibular growth rotation, suggesting that a favourable growth could be regained in patients with improvement in TMJ morphology and/or TMJ function. To confirm this, further research on larger patient series is needed.

Antidepressants for people with epilepsy and depression.