Effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis based on large randomized trials: A systematic review and network meta-analysis.

OBJECTIVE: To quantify the effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis (OA) through a systematic review and Bayesian random-effects network meta-analysis. DESIGN: We searched CENTRAL and regulatory agency websites (inception-2023) for large, English-language, randomized controlled trials (RCTs) (≥100 patients/group) examining any intra-articular intervention. PRIMARY OUTCOME: pain intensity. SECONDARY OUTCOMES: physical function and safety outcomes. Pain and function outcomes were analyzed at 2, 6, 12, 24, and 52 weeks post-randomization, and presented as standardized mean differences (SMDs) (95% credible intervals, 95% CrI). The prespecified minimal clinically important between-group difference (MID) was -0.37 SMD. Safety outcomes were presented as odds ratios (OR) (95% CrI). FINDINGS: Among 57 RCTs (22,795 participants) examining 18 intra-articular interventions, usual care or placebo, treatment effects were larger in 35 high-risk-of-bias trials than in 22 low/unclear-risk-of-bias trials. In the main analysis (excluding high-risk-of-bias trials), triamcinolone had the highest probabilities of reaching the MID at weeks 2 and 6 (75.3% and 90%, respectively) with corresponding SMDs of -0.48 (95% CrI,-0.85 to -0.10) and -0.53 (95% CrI,-0.79 to -0.27) compared to placebo (1 trial). The complex homeopathic products Tr14/Ze14 showed therapeutic potential at week 6 compared to placebo (SMD:-0.42, 95% CrI,-0.71 to -0.11, 63.5% probability of reaching the MID, 1 trial). Hyaluronic acid had no effect on pain (SMD:-0.04, 95% CrI,-0.19 to 0.11, 11 trials) but a higher risk of dropouts due to adverse events (OR: 2.01, 95% CrI,1.08 to 3.77) and serious adverse events (OR: 1.86, 95% CrI, 1.16 to 3.03) than placebo. CONCLUSION: Triamcinolone had the highest probabilities to have a treatment effect beyond the MID at weeks 2-6. Large RCTs with lower risk of bias indicate that the effects of 16 intra-articular interventions in knee or hip OA were smaller than the MID, and that most were consistent with placebo effects. Lack of evidence of long-term effectiveness underscores the need for further research beyond 24 weeks.

De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: a systematic review and individual patient-level meta-analysis of randomised trials.

BACKGROUND: Dual antiplatelet therapy (DAPT) for 12 months is the standard of care after coronary stenting in patients with acute coronary syndrome (ACS). The aim of this individual patient-level meta-analysis was to summarise the evidence comparing DAPT de-escalation to ticagrelor monotherapy versus continuing DAPT for 12 months after coronary drug-eluting stent implantation. METHODS: A systematic review and individual patient data (IPD)-level meta-analysis of randomised trials with centrally adjudicated endpoints was performed to evaluate the comparative efficacy and safety of ticagrelor monotherapy (90 mg twice a day) after short-term DAPT (from 2 weeks to 3 months) versus 12-month DAPT in patients undergoing percutaneous coronary intervention with a coronary drug-eluting stent. Randomised trials comparing P2Y12 inhibitor monotherapy with DAPT after coronary revascularisation were searched in Ovid MEDLINE, Embase, and two websites (www.tctmd.com and www.escardio.org) from database inception up to May 20, 2024. Trials that included patients with an indication for long-term oral anticoagulants were excluded. The risk of bias was assessed using the revised Cochrane risk-of-bias tool. The principal investigators of the eligible trials provided IPD by means of an anonymised electronic dataset. The three ranked coprimary endpoints were major adverse cardiovascular or cerebrovascular events (MACCE; a composite of all-cause death, myocardial infarction, or stroke) tested for non-inferiority in the per-protocol population; and Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding and all-cause death tested for superiority in the intention-to-treat population. All outcomes are reported as Kaplan-Meier estimates. The non-inferiority was tested using a one-sided α of 0·025 with the prespecified non-inferiority margin of 1·15 (hazard ratio [HR] scale), followed by the ranked superiority testing at a two-sided α of 0·05. This study is registered with PROSPERO (CRD42024506083). FINDINGS: A total of 8361 unique citations were screened, of which 610 records were considered potentially eligible during the screening of titles and abstracts. Of these, six trials that randomly assigned patients to ticagrelor monotherapy or DAPT were identified. De-escalation took place a median of 78 days (IQR 31-92) after intervention, with a median duration of treatment of 334 days (329-365). Among 23 256 patients in the per-protocol population, MACCE occurred in 297 (Kaplan-Meier estimate 2·8%) with ticagrelor monotherapy and 332 (Kaplan-Meier estimate 3·2%) with DAPT (HR 0·91 [95% CI 0·78-1·07]; p=0·0039 for non-inferiority; τ2<0·0001). Among 24 407 patients in the intention-to-treat population, the risks of BARC 3 or 5 bleeding (Kaplan-Meier estimate 0·9% vs 2·1%; HR 0·43 [95% CI 0·34-0·54]; p<0·0001 for superiority; τ2=0·079) and all-cause death (Kaplan-Meier estimate 0·9% vs 1·2%; 0·76 [0·59-0·98]; p=0·034 for superiority; τ2<0·0001) were lower with ticagrelor monotherapy. Trial sequential analysis showed strong evidence of non-inferiority for MACCE and superiority for bleeding among the overall and ACS populations (the z-curve crossed the monitoring boundaries or the required information size without crossing the futility boundaries or approaching the null). The treatment effects were heterogeneous by sex for MACCE (p interaction=0·041) and all-cause death (p interaction=0·050), indicating a possible benefit in women with ticagrelor monotherapy, and by clinical presentation for bleeding (p interaction=0·022), indicating a benefit in ACS with ticagrelor monotherapy. INTERPRETATION: Our study found robust evidence that, compared with 12 months of DAPT, de-escalation to ticagrelor monotherapy does not increase ischaemic risk and reduces the risk of major bleeding, especially in patients with ACS. Ticagrelor monotherapy might also be associated with a mortality benefit, particularly among women, which warrants further investigation. FUNDING: Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale.

A systematic review on the impact of plant-based milk consumption on growth and nutrition in children and adolescents.

BACKGROUND: Children are increasingly consuming plant-based milks, yet the impact on their growth and nutrition is unclear. OBJECTIVE: This systematic review aimed to summarize the available evidence on the impact of plant-based milk consumption on growth and nutrition in children and adolescents. METHODS: MEDLINE, Embase (Excerpta Medica Database), EBM Reviews - Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Child Development and Adolescent Studies, and Scopus were comprehensively searched from 2000 to 2024 to identify studies evaluating the growth and nutritional effects of plant-based milk consumption in children aged 1-18 y. Two reviewers independently screened full-text articles, assessed their quality, and extracted data. RESULTS: A total of 6 studies were identified: 3 cross-sectional studies, 1 prospective cohort study, and 2 clinical trials (total n = 15,815). Observational studies found that consumption of plant-based milk was associated with lower childhood BMI, height, and lower serum vitamin D levels compared to cow milk. No association was found between soy milk consumption and BMI in adolescent girls. Low-quality clinical trials showed minimal effects on growth, and one study found that adolescent girls with low calcium intake who consumed fortified soy milk had higher bone density compared to those who did not consume soy milk. CONCLUSIONS: Available evidence suggests that children who consume plant-based milk may have lower BMI, height, and micronutrient intake compared to those who consume cow milk, while fortified soy milk may support bone health in adolescents who do not drink cow milk. Longitudinal studies and RCTs are needed to determine whether these associations persist over time, differ between children and adolescents or for those who consume soy milk, and to understand the potential underlying mechanisms. STUDY REGISTRATION: This systematic review was registered with PROSPERO (registration number: CRD42022367269).

Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: long-term follow-up of the AVATAR trial.

BACKGROUND AND AIMS: The question of when and how to treat truly asymptomatic patients with severe aortic stenosis (AS) and normal left ventricular (LV) systolic function is still subject to debate and ongoing research. Here, the results of extended follow-up of the AVATAR trial are reported (NCT02436655, clinical trials.gov). METHODS: The AVATAR trial randomly assigned patients with severe, asymptomatic AS and LV ejection fraction ≥50% to undergo either early surgical aortic valve replacement (AVR) or conservative treatment with watchful waiting strategy. All patients had negative exercise stress testing. The primary hypothesis was that early AVR will reduce a primary composite endpoint comprising all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure (HF), as compared to conservative treatment strategy. RESULTS: A total of 157 low-risk patients (mean age 67 years, 57% men, mean Society of Thoracic Surgeons score 1.7%) were randomly allocated to either early AVR group (n=78) or conservative treatment group (n=79). In an intention-to-treat analysis, after a median follow-up of 63 months, the primary composite endpoint outcome event occurred in 18/78 patients (23.1%) in the early surgery group and in 37/79 patients (46.8%) in the conservative treatment group (hazard ratio [HR] early surgery vs. conservative treatment 0.42; 95% confidence interval [CI] 0.24-0.73, p=0.002). The Kaplan-Meier estimates for individual endpoints of all-cause death and HF hospitalization were significantly lower in the early surgery compared with the conservative group (HR 0.44; 95% CI 0.23-0.85, p=0.012 for all-cause death, and HR 0.21; 95% CI 0.06-0.73, p=0.007 for HF hospitalizations). CONCLUSIONS: The extended follow-up of the AVATAR trial demonstrates better clinical outcomes with early surgical AVR in truly asymptomatic patients with severe AS and normal LV ejection fraction compared with patients treated with conservative management on watchful waiting. TRIAL REGISTRATION NUMBER: NCT02436655 (ClinicalTrials.gov).

Evidence-based hierarchy of pain outcome measures for osteoarthritis clinical trials and meta-analyses.

OBJECTIVE: To rank commonly used patient-reported outcome measures (PROMs) for assessing pain in osteoarthritis trials according to their assay sensitivity, defined as the ability of a PROM to distinguish an effective from a less effective intervention or placebo, proposing a hierarchy for PROM selection in trials and data-extraction in meta-analyses. DESIGN: Analysis of trials with placebo, sham, or non-intervention control that included ≥100 patients per arm with knee/hip osteoarthritis, reporting treatment effects on ≥2 pain PROMs. Treatment effects from all PROMs were standardized on a 0-100 scale. Negative mean differences indicated a larger effect of the experimental treatment compared to control. We ranked PROMs by assay sensitivity using a Bayesian multi-outcome synthesis random-effects model. RESULTS: 135 trials comprising 57,141 participants were included. The ranking of PROMs from highest to lowest assay sensitivity was as follows: pain overall, pain on stairs, pain at night, pain on walking, pain at rest, WOMAC pain, WOMAC global, Lequesne index. Pain overall, the highest-ranked PROM, had a pooled mean difference of -6.96 (95%CrI -7.94, -6.02), while WOMAC pain, the most reported PROM in our study, had a pooled mean difference of -4.90 (95%CrI -5.55, -4.26). The pooled ratio of mean differences between pain overall and WOMAC pain was 1.42 (95%CrI 1.30, 1.55), representing a 42% larger effect size with pain overall. CONCLUSIONS: Pain overall has better assay sensitivity than other pain PROMs. Investigators should consider the hierarchy proposed in this study to guide PROM selection in osteoarthritis clinical trials and data extraction in osteoarthritis meta-analyses.

Influence of Pathophysiologic Patterns of Coronary Artery Disease on Immediate Percutaneous Coronary Intervention Outcomes.

BACKGROUND: Diffuse coronary artery disease affects the safety and efficacy of percutaneous coronary intervention (PCI). Pathophysiologic coronary artery disease patterns can be quantified using fractional flow reserve (FFR) pullbacks incorporating the pullback pressure gradient (PPG) calculation. This study aimed to establish the capacity of PPG to predict optimal revascularization and procedural outcomes. METHODS: This prospective, investigator-initiated, single-arm, multicenter study enrolled patients with at least one epicardial lesion with an FFR ≤0.80 scheduled for PCI. Manual FFR pullbacks were used to calculate PPG. The primary outcome of optimal revascularization was defined as an FFR ≥0.88 after PCI. RESULTS: A total of 993 patients with 1044 vessels were included. The mean FFR was 0.68±0.12, PPG 0.62±0.17, and the post-PCI FFR was 0.87±0.07. PPG was significantly correlated with the change in FFR after PCI (r=0.65 [95% CI, 0.61-0.69]; P<0.001) and demonstrated excellent predictive capacity for optimal revascularization (area under the receiver operating characteristic curve, 0.82 [95% CI, 0.79-0.84]; P<0.001). FFR alone did not predict revascularization outcomes (area under the receiver operating characteristic curve, 0.54 [95% CI, 0.50-0.57]). PPG influenced treatment decisions in 14% of patients, redirecting them from PCI to alternative treatment modalities. Periprocedural myocardial infarction occurred more frequently in patients with low PPG (<0.62) compared with those with focal disease (odds ratio, 1.71 [95% CI, 1.00-2.97]). CONCLUSIONS: Pathophysiologic coronary artery disease patterns distinctly affect the safety and effectiveness of PCI. PPG showed an excellent predictive capacity for optimal revascularization and demonstrated added value compared with an FFR measurement. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04789317.

Factors Associated With Loss to Follow-Up in Surgical Trials: A Systematic Review and Meta-Analysis.

INTRODUCTION: Loss to follow-up (LTFU) distorts results of randomized controlled trials (RCTs). Understanding trial characteristics that contribute to LTFU may enable investigators to anticipate the extent of LTFU and plan retention strategies. The objective of this systematic review and meta-analysis was to investigate the extent of LTFU in surgical RCTs and evaluate associations between trial characteristics and LTFU. METHODS: MEDLINE, Embase, and PubMed Central were searched for surgical RCTs published between January 2002 and December 2021 in the 30 highest impact factor surgical journals. Two-hundred eligible RCTs were randomly selected. The pooled LTFU rate was estimated using random intercept Poisson regression. Associations between trial characteristics and LTFU were assessed using metaregression. RESULTS: The 200 RCTs included 37,914 participants and 1307 LTFU events. The pooled LTFU rate was 3.10 participants per 100 patient-years (95% confidence interval [CI] 1.85-5.17). Trial characteristics associated with reduced LTFU were standard-of-care outcome assessments (rate ratio [RR] 0.17; 95% CI 0.06-0.48), surgery for transplantation (RR 0.08; 95% CI 0.01-0.43), and surgery for cancer (RR 0.10; 95% CI 0.02-0.53). Increased LTFU was associated with patient-reported outcomes (RR 14.21; 95% CI 4.82-41.91) and follow-up duration ≥ three months (odds ratio 10.09; 95% CI 4.79-21.28). CONCLUSIONS: LTFU in surgical RCTs is uncommon. Participants may be at increased risk of LTFU in trials with outcomes assessed beyond the standard of care, surgical indications other than cancer or transplant, patient-reported outcomes, and longer follow-up. Investigators should consider the impact of design on LTFU and plan retention strategies accordingly.

Ticagrelor or Clopidogrel Monotherapy vs Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: A Systematic Review and Patient-Level Meta-Analysis.

Importance: Among patients undergoing percutaneous coronary intervention (PCI), it remains unclear whether the treatment efficacy of P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) depends on the type of P2Y12 inhibitor. Objective: To assess the risks and benefits of ticagrelor monotherapy or clopidogrel monotherapy compared with standard DAPT after PCI. Data Sources: MEDLINE, Embase, TCTMD, and the European Society of Cardiology website were searched from inception to September 10, 2023, without language restriction. Study Selection: Included studies were randomized clinical trials comparing P2Y12 inhibitor monotherapy with DAPT on adjudicated end points in patients without indication to oral anticoagulation undergoing PCI. Data Extraction and Synthesis: Patient-level data provided by each trial were synthesized into a pooled dataset and analyzed using a 1-step mixed-effects model. The study is reported following the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data. Main Outcomes and Measures: The primary objective was to determine noninferiority of ticagrelor or clopidogrel monotherapy vs DAPT on the composite of death, myocardial infarction (MI), or stroke in the per-protocol analysis with a 1.15 margin for the hazard ratio (HR). Key secondary end points were major bleeding and net adverse clinical events (NACE), including the primary end point and major bleeding. Results: Analyses included 6 randomized trials including 25 960 patients undergoing PCI, of whom 24 394 patients (12 403 patients receiving DAPT; 8292 patients receiving ticagrelor monotherapy; 3654 patients receiving clopidogrel monotherapy; 45 patients receiving prasugrel monotherapy) were retained in the per-protocol analysis. Trials of ticagrelor monotherapy were conducted in Asia, Europe, and North America; trials of clopidogrel monotherapy were all conducted in Asia. Ticagrelor was noninferior to DAPT for the primary end point (HR, 0.89; 95% CI, 0.74-1.06; P for noninferiority = .004), but clopidogrel was not noninferior (HR, 1.37; 95% CI, 1.01-1.87; P for noninferiority > .99), with this finding driven by noncardiovascular death. The risk of major bleeding was lower with both ticagrelor (HR, 0.47; 95% CI, 0.36-0.62; P < .001) and clopidogrel monotherapy (HR, 0.49; 95% CI, 0.30-0.81; P = .006; P for interaction = 0.88). NACE were lower with ticagrelor (HR, 0.74; 95% CI, 0.64-0.86, P < .001) but not with clopidogrel monotherapy (HR, 1.00; 95% CI, 0.78-1.28; P = .99; P for interaction = .04). Conclusions and Relevance: This systematic review and meta-analysis found that ticagrelor monotherapy was noninferior to DAPT for all-cause death, MI, or stroke and superior for major bleeding and NACE. Clopidogrel monotherapy was similarly associated with reduced bleeding but was not noninferior to DAPT for all-cause death, MI, or stroke, largely because of risk observed in 1 trial that exclusively included East Asian patients and a hazard that was driven by an excess of noncardiovascular death.

Veterinarians exposed to inhaled anesthetic present chromosome damage, apoptosis and cell cycle changes.

This cross-sectional study evaluated, for the first time, DNA damage, viability, and cell death of lymphocytes and cell cycle phases of mononuclear and polymorphonuclear cells in veterinarians exposed to the volatile anesthetic isoflurane. Veterinarians who were occupationally exposed to isoflurane (exposed group; n = 20) and matched-unexposed individuals (volunteers without occupational exposure; n = 20) were enrolled in the study. DNA damage was assessed in lymphocytes by micronucleus (MN) and phosphorylated histone gamma-H2AX (γ-H2AX). Cell viability, cytotoxicity, and the cell cycle were evaluated by flow cytometry. Isoflurane was detected in urine samples by headspace gas chromatography-mass spectrometry. Compared with unexposed subjects, veterinarians occupationally exposed to isoflurane (25.7 ± 23.7 µg/L urine) presented statistically higher MN frequencies, lymphocytic apoptosis rates, and numbers of polymorphonuclear cells in the G0/G1 stage. Additionally, the exposed group presented statistically lower proportions of viable lymphocytes and G2/M polymorphonuclear cells. Our findings indicate that veterinarians who are frequently exposed to inhaled anesthetic exhibit chromosomal and cell damage in addition to changes in peripheral blood cell proliferation.

Plant-Based Milk Consumption and Growth in Children 1-10 Years of Age.

BACKGROUND: The effects of plant-based milk consumption on the growth of children are unclear. OBJECTIVES: We aimed to evaluate the relationship between plant-based milk consumption and BMI in childhood. Secondary objectives were to examine the association with height and whether these relationships are mediated by dairy milk intake and modified by age or the type of plant-based milk consumed. METHODS: A prospective cohort study was conducted in healthy children aged 1-10 y through the TARGet Kids! primary care research network in Toronto, Canada. Linear mixed-effect modeling and logistic generalized estimating equations were used to evaluate the association between plant-based milk consumption (number of 250 mL cups/d) and BMI. A mediation analysis was conducted to examine whether dairy milk intake mediated these relationships. Effect modification by age and type of plant-based milk was explored. RESULTS: Among 7195 children (mean age: 3.1 y; 52.3% male), higher plant-based milk consumption was associated with lower BMI (P = 0.0002) and height (P = 0.005). No association was found with BMI categories. Lower dairy milk intake partially mediated these relationships. A child aged 5 y who consumed 3 cups of plant-based milk compared with 3 cups of dairy milk had a lower weight of 0.5 kg and lower height of 0.8 cm. Associations did not change over time and were similar for children who consumed soy milk compared with other plant-based milks. CONCLUSIONS: Plant-based milk consumption was associated with lower BMI and height, but both were within the normal range on average. Future longitudinal studies are needed to determine whether these associations persist over time.

Treatment outcomes of regenerative endodontic therapy in immature permanent teeth with pulpal necrosis: A systematic review and network meta-analysis.

AIM: The aim of this study was to assess which treatment modality regarding scaffold selection for immature permanent teeth with pulpal necrosis will be the most successful for regenerative endodontic treatment (RET). METHODOLOGY: PubMed, Cochrane, Web of Science and Embase, and additional records until August 2022 were searched providing a total of 3021 articles, and nine of these articles were included for quantitative synthesis. The reviewers selected eligible randomized controlled trials and extracted pertinent data. Network meta-analysis was conducted to estimate treatment effects for primary outcomes (clinical and radiographic healing) and secondary outcomes (apical closure, root length and root wall thickness increase) following RET [mean difference (MD); 95% credible interval (CrI) and surface under the cumulative ranking curve (SUCRA)]. The quality of the included studies was appraised by the revised Cochrane risk of bias tool, and the quality of evidence was assessed using the GRADE approach. RESULTS: Six interventions from nine included studies were identified: blood clot scaffold (BC), blood clot scaffold with basic fibroblast growth factor, blood clot scaffold with collagen, platelet pellet, platelet-rich plasma (PRP) and platelet-rich fibrin (PRF). The PRP scaffold showed the greatest increase in root lengthening at 6-12 months (MD = 4.2; 95% CrI, 1.2 to 6.8; SUCRA = 89.0%, very low confidence). PRP or PRF achieved the highest level of success for primary and secondary outcomes at 1-6 and 6-12 months. Blood clot scaffold (with collagen or combined with basic fibroblast growth factor (bFGF)) achieved the highest level of success for secondary outcomes beyond 12 months follow-up. A very low to low quality of evidence suggests that both PRP and PRF exhibit the greatest success evaluating primary and secondary outcomes within 12 months postoperatively compared to the traditional blood clot scaffold protocol. CONCLUSION: Limited evidence suggests both PRP and PRF exhibit success in the short-term, not long-term. The value of this information stems in its recommendation for future randomized trials prioritizing both of these materials in their protocol.

Initiation of continuous renal replacement therapy versus intermittent hemodialysis in critically ill patients with severe acute kidney injury: a secondary analysis of STARRT-AKI trial.

BACKGROUND: There is controversy regarding the optimal renal-replacement therapy (RRT) modality for critically ill patients with acute kidney injury (AKI). METHODS: We conducted a secondary analysis of the STandard versus Accelerated Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial to compare outcomes among patients who initiated RRT with either continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD). We generated a propensity score for the likelihood of receiving CRRT and used inverse probability of treatment with overlap-weighting to address baseline inter-group differences. The primary outcome was a composite of death or RRT dependence at 90-days after randomization. RESULTS: We identified 1590 trial participants who initially received CRRT and 606 who initially received IHD. The composite outcome of death or RRT dependence at 90-days occurred in 823 (51.8%) patients who commenced CRRT and 329 (54.3%) patients who commenced IHD (unadjusted odds ratio (OR) 0.90; 95% confidence interval (CI) 0.75-1.09). After balancing baseline characteristics with overlap weighting, initial receipt of CRRT was associated with a lower risk of death or RRT dependence at 90-days compared with initial receipt of IHD (OR 0.81; 95% CI 0.66-0.99). This association was predominantly driven by a lower risk of RRT dependence at 90-days (OR 0.61; 95% CI 0.39-0.94). CONCLUSIONS: In critically ill patients with severe AKI, initiation of CRRT, as compared to IHD, was associated with a significant reduction in the composite outcome of death or RRT dependence at 90-days.

Impact of Post-PCI FFR Stratified by Coronary Artery.

BACKGROUND: Low fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) has been associated with adverse clinical outcomes. Hitherto, this assessment has been independent of the epicardial vessel interrogated. OBJECTIVES: This study sought to assess the predictive capacity of post-PCI FFR for target vessel failure (TVF) stratified by coronary artery. METHODS: We performed a systematic review and individual patient-level data meta-analysis of randomized clinical trials and observational studies with protocol-recommended post-PCI FFR assessment. The difference in post-PCI FFR between left anterior descending (LAD) and non-LAD arteries was assessed using a random-effect models meta-analysis of mean differences. TVF was defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization. RESULTS: Overall, 3,336 vessels (n = 2,760 patients) with post-PCI FFR measurements were included in 9 studies. The weighted mean post-PCI FFR was 0.89 (95% CI: 0.87-0.90) and differed significantly between coronary vessels (LAD = 0.86; 95% CI: 0.85 to 0.88 vs non-LAD = 0.93; 95% CI: 0.91-0.94; P < 0.001). Post-PCI FFR was an independent predictor of TVF, with its risk increasing by 52% for every reduction of 0.10 FFR units, and this was mainly driven by TVR. The predictive capacity for TVF was poor for LAD arteries (AUC: 0.52; 95% CI: 0.47-0.58) and moderate for non-LAD arteries (AUC: 0.66; 95% CI: 0.59-0.73; LAD vs non-LAD arteries, P = 0.005). CONCLUSIONS: The LAD is associated with a lower post-PCI FFR than non-LAD arteries, emphasizing the importance of interpreting post-PCI FFR on a vessel-specific basis. Although a higher post-PCI FFR was associated with improved prognosis, its predictive capacity for events differs between the LAD and non-LAD arteries, being poor in the LAD and moderate in the non-LAD vessels.

Intracluster correlation coefficients in osteoarthritis cluster randomized trials: A systematic review.

OBJECTIVES: The design, analysis, and interpretation of cluster randomized clinical trials (RCTs) require accounting for potential correlation of observations on individuals within the same cluster. Reporting of observed intracluster correlation coefficients (ICCs) in cluster RCTs, as recommended by Consolidated Standards of Reporting Trials (CONSORT), facilitates sample size calculation of future cluster RCTs and understanding of the trial statistical power. Our objective was to summarize observed ICCs in osteoarthritis (OA) cluster RCTs. DESIGN: Systematic review of knee/hip OA cluster RCTs. We searched Cochrane Central Register of Controlled Trials for trials published from 2012, when CONSORT cluster RCTs extension was published, to September 2022. We calculated the proportion of cluster RCTs that reported observed ICCs. Of those that did, we extracted observed ICCs. PROSPERO: CRD42022365660. RESULTS: We screened 1121 references and included 20 cluster RCTs. Only 5 trials (25%) reported the observed ICC for at least one outcome variable. ICC values for pain outcomes were: 0, 0.01, 0.18; for physical function outcomes were: 0, 0.06, 0.13 (knee)/0.27 (hip); Western Ontario and McMaster Universities Arthritis Index (WOMAC) total: 0.02, 0.02; symptoms of anxiety/depression: 0.22; disability: 0; and global change: 0. One out of four (25%) trials reported an ICC that was larger than the ICC used for sample size calculation and thus was underpowered. CONCLUSIONS: Despite CONSORT statement recommendations for reporting cluster RCTs, few OA trials reported the observed ICC. Given the importance of the ICC to interpretation of trial results and future trial design, this reporting gap warrants attention.

Rationale and design of the pullback pressure gradient (PPG) global registry.

INTRODUCTION: Diffuse disease has been identified as one of the main reasons leading to low post-PCI fractional flow reserve (FFR) and residual angina after PCI. Coronary pressure pullbacks allow for the evaluation of hemodynamic coronary artery disease (CAD) patterns. The pullback pressure gradient (PPG) is a novel metric that quantifies the distribution and magnitude of pressure losses along the coronary artery in a focal-to-diffuse continuum. AIM: The primary objective is to determine the predictive capacity of the PPG for post-PCI FFR. METHODS: This prospective, large-scale, controlled, investigator-initiated, multicenter study is enrolling patients with at least 1 lesion in a major epicardial vessel with a distal FFR ≤ 0.80 intended to be treated by PCI. The study will include 982 subjects. A standardized physiological assessment will be performed pre-PCI, including the online calculation of PPG from FFR pullbacks performed manually. PPG quantifies the CAD pattern by combining several parameters from the FFR pullback curve. Post-PCI physiology will be recorded using a standardized protocol with FFR pullbacks. We hypothesize that PPG will predict optimal PCI results (post-PCI FFR ≥ 0.88) with an area under the ROC curve (AUC) ≥ 0.80. Secondary objectives include patient-reported and clinical outcomes in patients with focal vs. diffuse CAD defined by the PPG. Clinical follow-up will be collected for up to 36 months, and an independent clinical event committee will adjudicate events. RESULTS: Recruitment is ongoing and is expected to be completed in the second half of 2023. CONCLUSION: This international, large-scale, prospective study with pre-specified powered hypotheses will determine the ability of the preprocedural PPG index to predict optimal revascularization assessed by post-PCI FFR. In addition, it will evaluate the impact of PPG on treatment decisions and the predictive performance of PPG for angina relief and clinical outcomes.

Inadequate Reporting of Cointerventions, Other Methodological Factors, and Treatment Estimates in Cardiovascular Trials: A Meta-Epidemiological Study.

Objective: To assess how inadequate reporting of cointerventions influences estimated treatment effects in recent cardiovascular trials. Methods: Medline/Embase were systematically searched from January 1, 2011 to July 1, 2021 for trials evaluating pharmacologic interventions on clinical cardiovascular outcomes published in 5 high-impact journals. Information on adequate vs inadequate reporting of cointerventions, blinding, risk of bias due to deviations of intended interventions (low vs high/some concerns), funding (nonindustry vs industry), design (superiority vs noninferiority), and results were assessed by 2 reviewers. The association with effect sizes was assessed using meta-regression random-effect analysis, expressed as ratios of odds ratios (ROR). RORs of >1.0 indicated that trials with the methodological factor pointing to lower quality report larger treatment estimates. Results: In total, 164 trials were included. Of the 164 trials, 124 (74%) did not adequately report cointerventions; 89 of the 164 trials (54%) provided no information regarding cointerventions, and 70 of the 164 (43%) were at risk of bias due to inadequate blinding. Moreover, 86 of the 164 (53%) were at risk of bias due to deviation of intended interventions. Of the 164 trials, 144 (88%) were funded by the industries. Trials with inadequate reporting of cointerventions had larger treatment estimates for the primary end point (ROR, 1.08; 95% CI, 1.01-1.15; I2=0%). No significant association with results for blinding (ROR, 0.97; 95% CI, 0.91-1.03; I2=66%), deviation of intended interventions (ROR, 0.98; 95% CI, 0.92-1.04; I2=0%), or funding (ROR, 1.01; 95% CI, 0.93-1.09; I2=0%) was found. Conclusion: We conclude that trials with inadequate reporting of cointerventions showed larger treatment effect estimates, potentially indicating overestimation of therapeutic benefit. Trial Registration: Prospero Identifier: CRD42017072522.

Nebivolol versus placebo in patients undergoing anthracyclines (CONTROL Trial): rationale and study design.

AIMS: Anthracyclines are the chemotherapeutic agents most frequently associated with cardiotoxicity, while remaining widely used. Different neurohormonal blockers have been tested as a primary prevention strategy to prevent or attenuate the onset of cardiotoxicity, with mixed results. However, prior studies were often limited by a nonblinded design and an assessment of cardiac function based only on echocardiographic imaging. Moreover, on the basis of an improved mechanistic understanding of anthracycline cardiotoxicity mechanisms, new therapeutic strategies have been proposed. Among cardioprotective drugs, nebivolol might be able to prevent the cardiotoxic effects of anthracyclines, through its protective properties towards the myocardium, endothelium, and cardiac mitochondria. This study aims to evaluate the cardioprotective effects of the beta blocker nebivolol in a prospective, placebo-controlled, superiority randomized trial in patients with breast cancer or diffuse large B cell lymphoma (DLBCL) who have a normal cardiac function and will receive anthracyclines as part of their first-line chemotherapy programme. METHODS: The CONTROL trial is a randomized, placebo-controlled, double-blinded, superiority trial. Patients with breast cancer or a DLBCL, with a normal cardiac function as assessed by echocardiography, scheduled for treatment with anthracyclines as part of their first-line chemotherapy programme will be randomized 1 : 1 to nebivolol 5 mg once daily (o.d.) or placebo. Patients will be examined with cardiological assessment, echocardiography and cardiac biomarkers at baseline, 1 month, 6 months and 12 months. A cardiac magnetic resonance (CMR) assessment will be performed at baseline and at 12 months. The primary end point is defined as left ventricular ejection fraction reduction assessed by CMR at 12 months of follow-up. CONCLUSION: The CONTROL trial is designed to provide evidence to assess the cardioprotective role of nebivolol in patients undergoing chemotherapy with anthracyclines. CLINICAL TRIAL REGISTRATION: The study is registered in the EudraCT registry (number: 2017-004618-24) and in the ClinicalTrials.gov registry (identifier: NCT05728632).

Effect of plant milk consumption on childhood growth: protocol for a systematic review.

INTRODUCTION: There has been considerable debate about whether plant milks can support the nutritional requirements of growing children. The proposed systematic review aims to assess the evidence on the relationship between plant milk consumption and growth and nutritional status in childhood. METHODS AND ANALYSIS: Ovid MEDLINE ALL (1946-present), Ovid EMBASE Classic (1947-present), CINAHL Complete (Cumulative Index to Nursing and Allied Health Literature), Scopus, the Cochrane Library and grey literature will be searched comprehensively (from 2000 to present; English language) to find studies that describe the association between plant milk consumption and growth or nutrition in children 1-18 years of age. Two reviewers will identify eligible articles, extract data and assess the risk of bias in individual studies. If a meta-analyses is not conducted, the evidence will be synthesised narratively and the overall certainty of evidence will be rated using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: Ethical approval is not required for this study since no data will be collected. Results of the systematic review will be published in a peer-reviewed journal. Findings from this study may be useful in informing future evidence-based recommendations about plant milk consumption in children. PROSPERO REGISTRATION NUMBER: CRD42022367269.

Parent and physician beliefs, perceptions and knowledge of plant milks for children.

Background: Parent and physician perceptions of plant milk are unclear. Aim: To explore parent and physician perceptions of plant milk for children and to gain a better understanding of why parents and physicians might choose plant milk for children. Methods: A mixed methods study was conducted using a questionnaire and interviews with parents and physicians participating in the TARGet Kids! cohort study. Questionnaire data were analyzed using descriptive statistics. Interview transcripts were analyzed using thematic analysis. Results: Parents reported a variety of reasons for choosing plant milk for their children including concerns around allergies, the environment, animal welfare, plant-based diet, health benefits, taste and hormones in cow's milk. Parents gave their children various types of plant milks and physicians provided various recommendations to parents of children not consuming cow's milk. Our study identified that 79% of parents and 51% of physicians were unaware that soy milk is the recommended cow's milk substitute for children. Additionally, 26% of parents did not know some plant milks are not fortified and can contain added sugar. Three main themes were identified from interviews about why parents and physicians may choose plant milk for children: (i) healthiness of plant milk; (ii) concerns about hormones; and (iii) environmental impacts. Conclusions: Parents and physicians choose the milk that they believe is healthiest for their child or patient. However, a lack of clarity on the effects of plant milk consumption on children's health resulted in conflicting views on whether plant milk or cow's milk is healthier for children.

Prognostic Features of Preoperative OCT in Retinal Detachments: A Systematic Review and Meta-analysis.

TOPIC: To evaluate the prognostic association between preoperative features seen on OCT imaging and postoperative visual acuity (VA) outcomes in rhegmatogenous retinal detachments (RRDs). CLINICAL RELEVANCE: Currently, there is limited literature on the prognostic value of preoperative RRD OCT features. METHODS: A literature search was conducted on Ovid MEDLINE, Ovid Embase, and Cochrane CENTRAL from inception to September 15, 2022. A meta-analysis was performed using a random-effects model. Quality of studies and evidence were assessed using the Joanna Briggs Institute tools and the Grading of Recommendations, Assessment, Development and Evaluation framework, respectively. RESULTS: A total of 1671 eyes of 1670 patients from 29 observational studies were included. Of these, 89% of eyes had a macula-off RRD at presentation. The mean average duration of detachment was 15 ± 10 days. Most eyes (62%) underwent pars plana vitrectomy. Six preoperative OCT features were analyzed: height of retinal detachment (HRD) at the fovea, central macular thickness (CMT), disruption of the ellipsoid zone (EZ) and/or external limiting membrane (ELM), intraretinal cystic cavities (ICCs), outer retinal corrugations (ORCs), and macular detachment. A greater HRD was weakly associated with postoperative VA (Pearson correlation r = 0.35; 95% confidence interval [CI], 0.20-0.48; P < 0.01), and there was no change in this association throughout the postoperative follow-up period. The CMT was not associated with postoperative VA. Eyes with disruption of the EZ and/or ELM had a postoperative VA worse by 0.35 logarithm of the minimum angle of resolution (logMAR) (95% CI, 0.15-0.54; P < 0.01) or 3 Snellen lines. Eyes with ICCs had a postoperative VA worse by 0.14 logMAR (95% CI, 0.01-0.26; P < 0.01) or 2 Snellen lines. Eyes with ORCs did not have a significantly different postoperative VA than eyes without ORCs. Eyes with macular detachment had a postoperative VA worse by 0.15 logMAR (95% CI, -0.31 to 0.00; P = 0.02) or 2 Snellen lines. Overall, the quality of studies ranged from moderate to good (73%-100%). All associations had a low quality of evidence, with CMT being of very low quality. CONCLUSION: Despite the low quality of evidence, a greater HRD, disruption of the EZ and/or ELM, presence of ICCs, and macular detachment were associated with a poor postoperative VA. We propose a standardized nomenclature for consistency and accuracy in reporting preoperative RRD OCT features for future studies. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.