Reduction of lower-limb edema in patients with chronic venous disease by micronized purified flavonoid fraction: a systematic literature review and meta-analysis.

INTRODUCTION: The prevalence of lower limb edema is high among patients with chronic venous disease (CVD). Several clinical studies with various designs have assessed the effect of micronized purified flavonoid fraction (MPFF) on edema. The aim of this work was to provide a comprehensive and accurate evaluation of the reduction in ankle and calf circumference as an indicator of lower limb edema reduction in patients with CVD treated with MPFF by combining studies that use different designs in a single group meta-analysis. EVIDENCE ACQUISITION: We conducted a systematic literature review in April 2022 based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria to identify prospective studies investigating the effect of oral MPFF treatment 1000 mg/day on ankle and calf circumference in patients with CVD. Studies with population including at least one patient with an ulcer were excluded. All prospective studies irrespectively of design (i.e., interventional and non-interventional studies, randomized controlled trials (RCTs), non-randomized studies, studies without a control or reference treatment) were eligible. The Medline, Embase and Cochrane databases were searched. Endpoints were ankle and calf circumference measurements and their overall mean change from baseline estimated with random-effects meta-analysis methods. The evaluation criterion feeling of swelling was also analyzed as a standardized mean change (SMC) with 95% confidence intervals after combination of quantitative scales. EVIDENCE SYNTHESIS: Among 861 articles identified, eight studies (five RCTs including one placebo-controlled, three non-comparative studies) met the criteria. The overall population consisted of 1635 patients, predominantly female (89% ranging from 64% to 94%) with a mean age of 47 years ranging from 41 to 48 years. Mean reduction in ankle circumference was 6.0 mm (95%CI: 3.6 to 8.4; P<0.001) and 7.0 mm (95%CI: 0.9 to 13.1; P=0.024) after two and at least six months of treatment respectively. The results were similar when considering the study type RCTs and non-RCTs. Mean reduction in calf circumference was 5.7 mm (95%CI: 2.8 to 8.6; P<0.001) and 6.7 mm (95%CI: 5.2 to 8.1; P<0.001), at two months and at the last post-baseline evaluation respectively. Heterogeneity among studies was statistically significant (degree of consistency I2=93.5%; P<0.001 and I2=81.1%, P<0.01 for ankle and calf circumference, respectively). In the three studies reporting the effect on feeling of swelling a significant standardized mean change (SMC) reduction of 2.2 (95%CI: 0.2 to 4.2; P=0.028) on a quantitative scale was observed after two months of treatment with MPFF. CONCLUSIONS: MPFF appeared to be effective in reducing ankle and calf circumference as well as feeling of swelling irrespective of study design. The circumference reduction is present at short and long term, suggesting that benefit occurs early and is maintained overtime. Despite the observed heterogeneity among included studies, this meta-analysis supports the significant therapeutic efficacy of MPFF in reducing lower-limb edema in patients with CVD. The complete video presentation of the work is available online at www.minervamedica.it (Supplementary Digital Material 1: Supplementary Video 1, 5 min, 192 MB).

Prenatal tetanus-diphtheria-acellular pertussis vaccine effectiveness at preventing infant pertussis.

OBJECTIVE: To evaluate the effectiveness of the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine containing five pertussis components (Tdap5; Adacel®, Sanofi) when given during pregnancy at preventing pertussis in infants less than 2 months of age. METHODS: The US Centers for Disease Control and Prevention (CDC), in collaboration with the Emerging Infections Program (EIP) Network, undertook a case-control study evaluating the effectiveness of Tdap vaccination in pregnancy against pertussis in infants less than 2 months of age based on data collected by the EIP Network from 2011 through 2014. The dataset from the CDC/EIP Network study was used to conduct this product-specific vaccine effectiveness analysis of Tdap5 vaccination in pregnancy to prevent disease in young infants. The main outcome of interest was vaccine effectiveness in infants whose pregnant parents were vaccinated with Tdap5 between 27 and 36 weeks' gestation, in accordance with the ideal timing for Tdap vaccination in pregnancy recommended by the US Advisory Committee on Immunization Practices. Odd ratios (ORs) and 95 % confidence intervals (CIs) were estimated using conditional logistic regression, and vaccine effectiveness was calculated as (1-OR) × 100 %. RESULTS: There were 160 infant pertussis cases and 302 matched controls included in this Tdap5-specific study. Tdap5 effectiveness in preventing pertussis in infants whose pregnant parents were vaccinated between 27 and 36 weeks' gestation was 92.5 % (95 % CI, 38.5 %-99.1 %). Effectiveness of Tdap5 against pertussis-related hospitalization in infants whose pregnant parents were vaccinated between 27 and 36 weeks' gestation could not be calculated due to lack of discordance among matched cases and controls. Vaccination of the parents after pregnancy or less than 14 days before delivery did not protect infants from pertussis. CONCLUSIONS: Tdap5 vaccination in pregnancy between 27 and 36 weeks' gestation is highly effective at protecting young infants from pertussis. STUDY REGISTRATION: ClinicalTrials.gov, NCT05040802.

The area between ROC curves, a non-parametric method to evaluate a biomarker for patient treatment selection.

Treatment selection markers are generally sought for when the benefit of an innovative treatment in comparison with a reference treatment is considered, and this benefit is suspected to vary according to the characteristics of the patients. Classically, such quantitative markers are detected through testing a marker-by-treatment interaction in a parametric regression model. Most alternative methods rely on modeling the risk of event occurrence in each treatment arm or the benefit of the innovative treatment over the marker values, but with assumptions that may be difficult to verify. Herein, a simple non-parametric approach is proposed to detect and assess the general capacity of a quantitative marker for treatment selection when no overall difference in efficacy could be demonstrated between two treatments in a clinical trial. This graphical method relies on the area between treatment-arm-specific receiver operating characteristic curves (ABC), which reflects the treatment selection capacity of the marker. A simulation study assessed the inference properties of the ABC estimator and compared them with other parametric and non-parametric indicators. The simulations showed that the estimate of the ABC had low bias, power comparable to parametric indicators, and that its confidence interval had a good coverage probability (better than the other non-parametric indicator in some cases). Thus, the ABC is a good alternative to parametric indicators. The ABC method was applied to data of the PETACC-8 trial that investigated FOLFOX4 versus FOLFOX4 + cetuximab in stage III colon adenocarcinoma. It enabled the detection of a treatment selection marker: the DDR2 gene.

A Bayesian method to estimate the optimal threshold of a marker used to select patients' treatment.

The use of a quantitative treatment selection marker to choose between two treatment options requires the estimate of an optimal threshold above which one of these two treatments is preferred. Herein, the optimal threshold expression is based on the definition of a utility function which aims to quantify the expected utility of the population (e.g. life expectancy, quality of life) by taking into account both efficacy (success or failure) and toxicity of each treatment option. Therefore, the optimal threshold is the marker value that maximizes the expected utility of the population. A method modelling the marker distribution in patient subgroups defined by the received treatment and the outcome is proposed to calculate the parameters of the utility function so as to estimate the optimal threshold and its 95% credible interval using the Bayesian inference. The simulation study found that the method had low bias and coverage probability close to 95% in multiple settings, but also the need of large sample size to estimate the optimal threshold in some settings. The method is then applied to the PETACC-8 trial that compares the efficacy of chemotherapy with a combined chemotherapy + anti-epidermal growth factor receptor in stage III colorectal cancer.

A comparative study about the incidence of dislocation and peri-prosthetic fracture between dual mobility versus standard cups after primary total hip arthroplasty.

PURPOSE: Dislocation and peri-prosthetic fracture (PPF) are major reasons for revision THA (total hip arthroplasty). The main advantage of dual mobility (DM) cups is to minimize the incidence of dislocation compared to single mobility (SM) cups. We hypothesized that the use of DM would lead to an increased risk of PPF because of its greater stability. In contrast, standard cups would be at higher risk of dislocation. METHODS: A retrospective comparative study was performed in our institution including 126 revision THAs between January 2013 and December 2017. Collected data included gender, age, BMI, Parker score, ASA score, the etiology for primary THA, type of cup (SM or DM), cortical index, Noble index, and the stem fixation. RESULTS: Overall, 53 standard and 73 DM cups were included for study. In the dislocation group, 29 had standard cups (83%) and 6 had DM cups (17%). Dislocation was 12-fold higher in SM cups (p < 0.001). In the PPF group, 24 had standard cups (26%) and 67 had DM cups (74%). PFF was 12-fold higher for DM cups (p < 0.001). A higher Parker score and a higher cortical index had a protective effect on the risk of PPF (OR = 0.76 (p = 0.03), OR = 0.57 (p = 0.048)). CONCLUSION: The use of DM increased hip stability but led to a higher rate of PPF by load transfer on the femur. Further studies with larger cohort and follow-up are needed to confirm these findings and measure the incidence of these complications.