Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analysis.

Given the lack of head-to-head studies of systemic therapies in moderate-to-severe atopic dermatitis (AD), network meta-analyses (NMAs) can provide comparative efficacy and safety data to inform clinical decision-making. In this NMA, eligible randomized controlled trials (RCTs) published before 24 October 2019 were identified by a systematic literature review. Short-term (12-16 weeks) efficacy (Investigator's Global Assessment [IGA] and Eczema Area and Severity Index [EASI] responses), patient-reported outcomes (PROs) and safety data from each trial were abstracted and analysed separately for monotherapy and combination therapy (systemic plus topical anti-inflammatory therapy). RCTs were analysed in fixed-effects and random-effects Bayesian NMA models. Overall, 19 phase 2 and phase 3 RCTs of abrocitinib, baricitinib, dupilumab, lebrikizumab, nemolizumab, tralokinumab and upadacitinib were included. In monotherapy RCTs, upadacitinib 30 mg once daily (QD) had the numerically highest efficacy (83.6% achieved ≥50% improvement in EASI [EASI-50 response]), followed by abrocitinib 200 mg QD (74.6%), upadacitinib 15 mg QD (70.5%), dupilumab 300 mg every 2 weeks (Q2W) (63.4%) and abrocitinib 100 mg QD (56.7%). Similar trends in EASI-75 and EASI-90 response were observed. In combination therapy RCTs, abrocitinib 200 mg QD had the highest EASI-50 (86.6%), followed by dupilumab 300 mg Q2W (82.4%) and abrocitinib 100 mg QD (79.7%). Similar findings were observed for IGA response and PROs. In monotherapy and combination therapy RCTs, the probability of treatment-emergent adverse events (TEAEs) was higher among all active treatments than with placebo (except for dupilumab 300 mg Q2W [odds ratio (OR), 0.96; 95% credible interval (CrI), 0.45-2.18] and abrocitinib 100 mg QD [OR, 0.95; 95% CrI, 0.35-2.66] in combination therapy RCTs), although active treatments did not significantly differ from one another. Abrocitinib, dupilumab and upadacitinib were consistently the most effective systemic therapies in adult and adolescent patients with AD, with no significant TEAE differences in short-term RCTs.

Comparison of major bleeding risk in patients with non-valvular atrial fibrillation receiving direct oral anticoagulants in the real-world setting: a network meta-analysis.

OBJECTIVE: To conduct a systematic literature review (SLR) and network meta-analysis (NMA) of real-world studies comparing major bleeding risk among patients with non-valvular atrial fibrillation (NVAF) on direct oral anticoagulants (DOACs) or warfarin. METHODS: Systematic searches were conducted in MEDLINE and Embase for full-text articles published between January 1, 2003 and March 18, 2017. Eligible studies compared at least two of the following in a real-world setting: warfarin, apixaban, dabigatran, rivaroxaban, or edoxaban. A Bayesian NMA was conducted to estimate hazard ratios (HRs) for major bleeding using a random-effects model. RESULTS: Eleven studies were included in the NMA. Nine studies included DOACs vs Warfarin comparisons, and four studies included DOACs vs DOACs comparisons (two studies included both comparisons). Median follow-up duration ranged from 2.6-31.2 months. No evidence was identified for edoxaban. Apixaban was associated with a significantly lower risk of major bleeding compared to other oral anticoagulants (warfarin HR = 0.58; 95% credible interval [CrI] = 0.48-0.69; dabigatran = 0.73; 0.61-0.87; rivaroxaban = 0.55; 0.46-0.66). Dabigatran was associated with a significantly lower risk than warfarin (0.79; 0.71-0.88) and rivaroxaban (0.76; 0.67-0.85), and rivaroxaban was not statistically different from warfarin (1.05; 0.91-1.19). Sensitivity analyses with standard dose and sponsorship showed consistent results. CONCLUSION: DOACs were associated with lower or similar risk of major bleeding compared with warfarin in NVAF patients. Apixaban was associated with a significantly lower risk of major bleeding than other DOACs. Dabigatran was associated with a significantly lower risk of major bleeding compared to rivaroxaban and warfarin.

Correlations between MRI and Information Processing Speed in MS: A Meta-Analysis.

Objectives. To examine relationships between conventional MRI measures and the paced auditory serial addition test (PASAT) and symbol digit modalities test (SDMT). Methods. A systematic literature review was conducted. Included studies had ≥30 multiple sclerosis (MS) patients, administered the SDMT or PASAT, and measured T2LV or brain atrophy. Meta-analysis of MRI/information processing speed (IPS) correlations, analysis of MRI/IPS significance tests to account for reporting bias, and binomial testing to detect trends when comparing correlation strengths of SDMT versus PASAT and T2LV versus atrophy were conducted. Results. The 39 studies identified frequently reported only significant correlations, suggesting reporting bias. Direct meta-analysis was only feasible for correlations between SDMT and T2LV (r = -0.45, P < 0.001) and atrophy in patients with mixed-MS subtypes (r = -0.54, P < 0.001). Familywise Holm-Bonferroni testing found that selective reporting was not the source of at least half of significant results reported. Binomial tests (P = 0.006) favored SDMT over PASAT in strength of MRI correlations. Conclusions. A moderate-to-strong correlation exists between impaired IPS and MRI in mixed MS populations. Correlations with MRI were stronger for SDMT than for PASAT. Neither heterogeneity among populations nor reporting bias appeared to be responsible for these findings.

Enhanced cellular responses and environmental sampling within inner foreskin explants: implications for the foreskin's role in HIV transmission.

The decrease in HIV acquisition after circumcision suggests a role for the foreskin in HIV transmission. However, the mechanism leading to protection remains undefined. Using tissue explant cultures we found that Langerhans cells (LCs) in foreskin alter their cellular protein expression in response to external stimuli. Furthermore, we observe that upon treatment with TNF-alpha, tissue-resident LCs became activated and that stimulatory cytokines can specifically cause an influx of CD4+ T-cells into the epithelial layer. Importantly, both of these changes are significant in the inner, but not outer, foreskin. In addition, we find that LCs in the inner foreskin have increased ability to sample environmental proteins. These results suggest differences in permeability between the inner and outer foreskin and indicate that HIV target cells in the inner foreskin have increased interaction with external factors. This increased responsiveness and sampling provides novel insights into the underlying mechanism of how circumcision can decrease HIV transmission.

Intermediate and long-term outcomes of total ankle arthroplasty and ankle arthrodesis. A systematic review of the literature.

BACKGROUND: The efficacy of total ankle replacement compared with that of ankle fusion continues to be one of the most debated topics in foot and ankle surgery. The purpose of this study was to determine whether there are sufficient objective cumulative data in the literature to compare the two procedures. A systematic review of the literature addressing the intermediate and long-term outcomes of interest in total ankle arthroplasty and ankle arthrodesis was performed. METHODS: A comprehensive search of MEDLINE for all relevant articles published in English from January 1, 1990, to March 2005 was conducted. Additionally, relevant abstracts from the 2003 and 2004 annual proceedings of major orthopaedic meetings were eligible. Two reviewers evaluated each study to determine whether it was eligible for inclusion and collected the data of interest. Meta-analytic pooling of group results across studies was performed for the two procedures. The analysis of the outcomes focused on second-generation ankle implants. RESULTS: The systematic review identified forty-nine primary studies, ten of which evaluated total ankle arthroplasty in a total of 852 patients and thirty-nine of which evaluated ankle arthrodesis in a total of 1262 patients. The mean AOFAS (American Orthopaedic Foot and Ankle Society) Ankle-Hindfoot Scale score was 78.2 points (95% confidence interval, 71.9 to 84.5) for the patients treated with total ankle arthroplasty and 75.6 points (95% confidence interval, 71.6 to 79.6) for those treated with arthrodesis. Meta-analytic mean results showed 38% of the patients treated with total ankle arthroplasty had an excellent result, 30.5% had a good result, 5.5% had a fair result, and 24% had a poor result. In the arthrodesis group, the corresponding values were 31%, 37%, 13%, and 13%. The five-year implant survival rate was 78% (95% confidence interval, 69.0% to 87.6%) and the ten-year survival rate was 77% (95% confidence interval, 63.3% to 90.8%). The revision rate following total ankle arthroplasty was 7% (95% confidence interval, 3.5% to 10.9%) with the primary reason for the revisions being loosening and/or subsidence (28%). The revision rate following ankle arthrodesis was 9% (95% confidence interval, 5.5% to 11.6%), with the main reason for the revisions being nonunion (65%). One percent of the patients who had undergone total ankle arthroplasty required a below-the-knee amputation compared with 5% in the ankle arthrodesis group. CONCLUSIONS: On the basis of these findings, the intermediate outcome of total ankle arthroplasty appears to be similar to that of ankle arthrodesis; however, data were sparse. Comparative studies are needed to strengthen this conclusion.

Adverse events in coronary artery bypass graft (CABG) trials: a systematic review and analysis.

OBJECTIVES: To quantify the incidence of major adverse events (AEs) occurring in hospital or within 30 days after surgery in patients undergoing coronary artery bypass graft (CABG) surgery and to identify risk factors for these AEs. METHODS: Systematic review and analysis of studies published in English since 1990. Studies of isolated standard CABG reporting postoperative incidence of myocardial infarction (MI), stroke, gastrointestinal bleeding, renal failure, or death in hospital or within 30 days were eligible for inclusion. Incidence of these events was calculated overall and for selected patient groups defined by all elective CABG versus mixed (some non-elective); mean ejection fraction < or = 50% versus > 50%; mean age < or= 60 versus > 60 years; primary CABG versus some reoperations; randomised controlled trials versus cohort studies; and single centre versus multicentre studies. Odds ratios of selected AEs were computed according to group risk factors. RESULTS: 176 studies (205 717 patients) met all inclusion criteria. The average incidence of major AEs occurring in-hospital was death (1.7%); non-fatal MI (2.4%); non-fatal stroke (1.3%); gastrointestinal bleeding (1.5%); and renal failure (0.8%). Thirty day mortality was 2.1%. Meta-analyses show that age > 70, female sex, low ejection fraction, history of stroke, MI, or heart surgery, and presence of diabetes or hypertension are all associated with increased 30 day mortality after CABG. CONCLUSION: The incidence of major AEs in patients after CABG varies widely across studies and patient populations, and this heterogeneity must be controlled when using the literature to benchmark safety.

Overexpression of simian virus 40 small-T antigen blocks centrosome function and mitotic progression in human fibroblasts.

Recombinant adenoviruses that express high levels of the simian virus 40 (SV40) small-t (ST) antigen have been used to study the requirement for ST to drive cell cycle proliferation of confluent human diploid fibroblasts. This occurs when either large-T (LT) antigen or serum is added to provide a second signal. While cells readily completed S phase in these experiments, they were found to accumulate with 4N DNA content. Cellular and nuclear morphology, as well as the biochemical status of cyclin B complexes, showed that these cells entered mitosis but were blocked prior to mitotic metaphase. The defect appears to reflect an inability of cells overexpressing ST to form organized centrosomes that duplicate and separate normally during the cell cycle and, therefore, the absence of a mitotic spindle. The ability of ST to bind protein phosphatase 2A was required for this pattern, suggesting that altered phosphorylation of key centrosomal components may occur when ST is overexpressed. Although the possible significance of ST effects on the centrosome cycle is not fully understood, these findings suggest that ST could influence chromosomal instability patterns that are a hallmark of SV40-transformed cells and LT expression.

Facilitating interorganizational collaboration: the contributions of interorganizational alliances.

In an attempt to promote service delivery integration and improve interorganizational collaboration, many recent human service delivery initiatives have included the development of interorganizational alliances such as coalitions and coordinating councils. Despite their popularity, little is known about how these alliances influence interorganizational collaboration, specifically the extent to which they alter the interactions among human service delivery organizations. The present study examined the interorganizational interactions, specifically the exchange relationships, within one county that was implementing two interorganizational alliances--a countywide coordinating council and interagency service delivery teams. Membership on both alliances was associated with broader interorganizational exchange networks. Organizations involved in a coordinating council were more likely to be included in client, information, and resource exchanges, and participate in joint ventures with a broader range of organizations. Providers involved in interagency teams also exchanged clients and information with a broader sector of service delivery organizations than nonparticipating providers. Observational data suggested that both alliances created structures and processes intended to facilitate interorganizational exchanges. Together, these results suggest that the development of opportunities for and encouragement of staff and leader involvement in these types of alliances may be an important part of our attempt to create a more integrated social service delivery system. The implications of these findings for researchers and practitioners are discussed.

The relation of self-efficacy measures to sport performance: a meta-analytic review.

This meta-analysis examined the relationship between self-efficacy and performance in sport. Based on 45 studies (102 correlations), the average correlation between self-efficacy and sport performance was .38. Given the heterogeneity of findings, follow-up univariate and multivariate moderator analyses were conducted. Results indicated that the most important moderator was concordance, thereby highlighting the importance of matching the self-efficacy and performance measures. Additional moderators we examined included the types of self-efficacy measures, the types of performance measures, the nature of the task, and the time of assessments. These variables accounted for approximately 44% of the variance in the self-efficacy-performance relationship. Practical implications of the findings are discussed.

Ecological factors impacting provider attitudes towards human service delivery reform.

Although reform efforts are substantially altering the structural operations and guiding ideological framework of the human service delivery system, little empirical work has been done to systematically examine these transformations. This study examines providers' attitudes regarding two reform elements that are being widely implemented: an increased emphasis on interagency collaboration and a shift from a medical model service delivery philosophy, that focuses on client deficits, to one that emphasizes consumer strengths. Through survey data collected from 186 providers from 32 human service agencies in one county, the relationship between providers' perceptions of contextual support for human service delivery reform and providers' attitudes towards these initiatives is explored. The findings from this study support the importance of attending to the ecology in which we initiate system reform efforts. For both reform elements, working within contexts that are perceived as providing ideological and functional support for change was associated with positive provider attitudes towards those changes. Staffs' perceptions of the external environment played the most critical role in shaping staff attitudes. Interestingly, unique aspects of providers' work environments were related to positive attitudes towards the two different reforms. The implications of these findings for the success of human service delivery reform are discussed.