Statistical design and analysis of controlled human malaria infection trials.

BACKGROUND: Malaria is a potentially life-threatening disease caused by Plasmodium protozoa transmitted by infected Anopheles mosquitoes. Controlled human malaria infection (CHMI) trials are used to assess the efficacy of interventions for malaria elimination. The operating characteristics of statistical methods for assessing the ability of interventions to protect individuals from malaria is uncertain in small CHMI studies. This paper presents simulation studies comparing the performance of a variety of statistical methods for assessing efficacy of intervention in CHMI trials. METHODS: Two types of CHMI designs were investigated: the commonly used single high-dose design (SHD) and the repeated low-dose design (RLD), motivated by simian immunodeficiency virus (SIV) challenge studies. In the context of SHD, the primary efficacy endpoint is typically time to infection. Using a continuous time survival model, five statistical tests for assessing the extent to which an intervention confers partial or full protection under single dose CHMI designs were evaluated. For RLD, the primary efficacy endpoint is typically the binary infection status after a specific number of challenges. A discrete time survival model was used to study the characteristics of RLD versus SHD challenge studies. RESULTS: In a SHD study with the continuous time survival model, log-rank test and t-test are the most powerful and provide more interpretable results than Wilcoxon rank-sum tests and Lachenbruch tests, while the likelihood ratio test is uniformly most powerful but requires knowledge of the underlying probability model. In the discrete time survival model setting, SHDs are more powerful for assessing the efficacy of an intervention to prevent infection than RLDs. However, additional information can be inferred from RLD challenge designs, particularly using a likelihood ratio test. CONCLUSIONS: Different statistical methods can be used to analyze controlled human malaria infection (CHMI) experiments, and the choice of method depends on the specific characteristics of the experiment, such as the sample size allocation between the control and intervention groups, and the nature of the intervention. The simulation results provide guidance for the trade off in statistical power when choosing between different statistical methods and study designs.

Efficacy of autogenous platelet concentrates in immediate implant therapy: A systematic review and meta-analysis of prospective controlled clinical trials.

PURPOSE: To provide an overview of the outcomes of the use of autogenous platelet concentrates in immediate implant placement. MATERIALS AND METHODS: Based on an a priori protocol, a systematic search was performed of the National Library of Medicine (MEDLINE via PubMed), Embase and Scopus databases. Randomised and non-randomised controlled clinical trials on immediate implant placement including at least one study arm with use of platelet-rich fibrin or platelet-rich plasma as a gap filler between immediately placed implants and the alveolar bone were included. A random-effects meta-analysis model was built to assess the primary outcomes of marginal bone loss and probing pocket depths between test (platelet concentrates) and control (no graft or other graft materials) groups. A risk of bias assessment was performed and the Grading of Recommendations Assessment, Development and Evaluation approach was used to assess the certainty of evidence. RESULTS: A total of 20 trials (595 immediate implants placed in 454 individuals) were included in the meta-analytic model. Based on the data from studies with a minimum post-prosthetic loading period of 6 months after immediate implant placement, overall, the application of platelet concentrates was associated with significantly lower marginal bone loss and probing pocket depth compared to the control groups (mean difference -0.36 mm; P < 0.01 and mean difference -0.47 mm; P < 0.01, respectively). No additional benefit of application of platelet concentrates was detected regarding primary stability of immediate implants. Subgroup analysis revealed significantly lower marginal bone loss with xenogeneic bone alone compared to platelet concentrates alone as grafting material in immediate implant placement (mean difference 0.66 mm; P < 0.01). Evidence on soft tissue outcomes and aesthetic parameters was scarce. CONCLUSIONS: A low level of certainty based on the Grading of Recommendations Assessment, Development and Evaluation approach indicates superior outcomes in terms of marginal bone loss and probing pocket depth in immediate implant placement with the use of platelet concentrates versus no graft. Future research should be tailored towards a standardised protocol for preparation of platelet concentrates and inclusion of soft tissue and aesthetic outcomes as well.

Are There Differences Among Evidence-Based Psychotherapies for Treating Different DSM-5 PTSD Symptom Clusters? A Systematic Review and Meta-analysis of Controlled Clinical Trials.

ABSTRACT: Posttraumatic stress disorder (PTSD) is a heterogeneous disease defined by four Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) symptom clusters: reexperiencing, avoidance, negative alterations in cognitions and mood, and hyperarousal. There are effective evidence-based psychotherapies (EBPs) for PTSD. However, given the variety of PTSD clinical presentations, we conducted the first meta-analysis investigating whether DSM-5 PTSD symptom clusters show different responses to EBPs. We systematically reviewed the literature for controlled clinical trials in five databases, performed a meta-analysis, and evaluated the methodological quality of the studies. We screened 633 studies and included seven. Three showed high risk, two showed some concerns, and one showed a low risk of bias. The symptom clusters do not seem to respond differently to EBPs (SMD cluster B: -0.40; 95% confidence interval [CI], -0.87 to 0.08; cluster C: -0.49; 95% CI, -0.90 to -0.08; cluster D: -0.44; 95% CI, -0.94 to 0.05; cluster E: -0.54; 95% CI, -1.07 to -0.0), even when analyzed by the therapeutic focuses. The findings dovetail nicely with the network theory of PTSD symptom, as although it is a heterogeneous disorder, the EBPs seem to promote a kind of cascade of symptom improvement.

Cardiovascular benefits of GLP-1 receptor agonists in patients living with obesity or overweight: a meta-analysis of randomized controlled trials

BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) have emerged as an effective therapeutic class for weight loss. However, the efficacy of these agents in reducing cardiovascular endpoints among patients living with obesity or overweight is unclear. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing GLP-1 RAs versus placebo in patients with obesity or overweight. We searched PubMed, Cochrane, and Embase databases. A random-effects model was used to calculate risk ratios (RRs) and mean differences (MDs), with 95% confidence intervals (CIs). RESULTS: A total of 13 RCTs were included, with 30,512 patients. Compared with placebo, GLP-1 RAs reduced systolic blood pressure (MD - 4.76 mmHg; 95% CI - 6.03, - 3.50; p < 0.001; I2 = 100%) and diastolic blood pressure (MD - 1.41 mmHg; 95% CI - 2.64, - 0.17; p = 0.03; I2 = 100%). GLP-1 RA significantly reduced the occurrence of myocardial infarction (RR 0.72; 95% CI 0.61, 0.85; p < 0.001; I2 = 0%). There were no significant differences between groups in unstable angina (UA; RR 0.84; 95% CI 0.65, 1.07; p = 0.16; I2 = 0%), stroke (RR 0.91; 95% CI 0.74, 1.12; p = 0.38; I2 = 0%), atrial fibrillation (AF; RR 0.49; 95% CI 0.17, 1.43; p = 0.19; I2 = 22%), and deep vein thrombosis (RR 0.30; 95% CI 0.06, 1.40; p = 0.13; I2 = 0%). CONCLUSIONS: In patients living with obesity or overweight, GLP-1 RA reduced systolic and diastolic blood pressure and the occurrence of myocardial infarction, with a neutral effect on the occurrence of UA, stroke, AF, and deep vein thrombosis.

Effect of implementation strategies on the routine provision of antenatal care addressing smoking in pregnancy: study protocol for a non-randomised stepped-wedge cluster controlled trial.

INTRODUCTION: Globally, guideline-recommended antenatal care for smoking cessation is not routinely delivered by antenatal care providers. Implementation strategies have been shown to improve the delivery of clinical practices across a variety of clinical services but there is an absence of evidence in applying such strategies to support improvements to antenatal care for smoking cessation in pregnancy. This study aims to determine the effectiveness and cost effectiveness of implementation strategies in increasing the routine provision of recommended antenatal care for smoking cessation in public maternity services. METHODS AND ANALYSIS: A non-randomised stepped-wedge cluster-controlled trial will be conducted in maternity services across three health sectors in New South Wales, Australia. Implementation strategies including guidelines and procedures, reminders and prompts, leadership support, champions, training and monitoring and feedback will be delivered sequentially to each sector over 4 months. Primary outcome measures will be the proportion of: (1) pregnant women who report receiving a carbon monoxide breath test; (2) smokers or recent quitters who report receiving quit/relapse advice; and (3) smokers who report offer of help to quit smoking (Quitline referral or nicotine replacement therapy). Outcomes will be measured via cross-sectional telephone surveys with a random sample of women who attend antenatal appointments each week. Economic analyses will be undertaken to assess the cost effectiveness of the implementation intervention. Process measures including acceptability, adoption, fidelity and reach will be reported. ETHICS AND DISSEMINATION: Ethics approval was obtained through the Hunter New England Human Research Ethics Committee (16/11/16/4.07; 16/10/19/5.15) and the Aboriginal Health and Medical Research Council (1236/16). Trial findings will be disseminated to health policy-makers and health services to inform best practice processes for effective guideline implementation. Findings will also be disseminated at scientific conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry-ACTRN12622001010785.

Overcoming Methodological Challenges for Advancing Stem Cell Therapies in Parkinson's Disease.

The quest for new and improved therapies for Parkinson's disease (PD) remains of paramount importance, despite previous trial failures. There is a current debate regarding the potential of stem cell research as a therapeutic approach for PD. The studies of dopaminergic fetal stem cells for PD treatment, their design, and the results of the initial surgical placebo-controlled trials were reviewed in this study. Some of the fundamental methodological challenges and possible strategies to resolve them were proposed. In this article, we argue that the most important impact lies in the proof-of-principle demonstrated by clinical trials for cell replacement strategies in reconstructing the human brain. While some researchers argue that the considerable technical challenges associated with cell therapies for PD warrant the discontinuation of further development using stem cells, we believe that the opposing viewpoints are instrumental in identifying a series of methodological misunderstandings. Here, we propose to expose key challenges to ensure the advancement of the field and unlock the potential of stem cell therapies in PD treatment. Overall, this review underscores the need for further research and innovation to overcome the hurdles in realizing the potential of stem cell-based therapies for PD.

A systematic review of the efficacy of group social skills interventions on social functioning and social participation in children with acquired brain injury or cerebral palsy.

AIM: The aim of this study was to evaluate the efficacy of Group social skills interventions (GSSIs) versus any comparator on social functioning in children aged 5-12 years with acquired brain injury or cerebral palsy. BACKGROUND: GSSIs are an evidence-based approach to foster social skills development in children with autism spectrum disorder. Currently, limited literature exploring GSSIs in children with acquired brain injury and cerebral palsy is available. RESULTS: MEDLINE, SCOPUS, Embase, CINAHL, Cochrane Library, PsycINFO, clinicaltrials.gov, ICTRP and ProQuest Dissertations and Theses were systematically searched. Study screening, risk-of-bias, Grading of Recommendations Assessment, Development and Evaluation and data extraction were performed in duplicate. Six studies were included in the narrative synthesis (one randomised controlled trial and five nonrandomised studies). Results indicate that GSSIs may increase children's social skills as measured on the Social Skills Rating System and Social Skills Questionnaire. Very low certainty evidence was found for improvements in social functioning and competence. CONCLUSIONS: There is low certainty evidence that participation in GSSI may lead to gains in social functioning for children with acquired brain injury or cerebral palsy. Given the certainty of the evidence, these results must be interpreted with caution. Only one randomised controlled trial of GSSIs for children with acquired brain injury was identified, underscoring the need for additional high-quality studies.

Efficacy of pulpotomy in managing irreversible pulpitis in mature permanent teeth: A systematic review and meta-analysis.

OBJECTIVES: This paper evaluated the success rates of pulpotomy, compared its efficacy with non-surgical root canal treatment (NSRCT), evaluated different pulpotomy techniques, and analyzed the effectiveness of contemporary bioactive materials in managing irreversible pulpitis in mature permanent teeth. DATA SOURCES: A comprehensive literature search was conducted across multiple databases including PubMed, Web of Science, Scopus, and the Cochrane Library. Search was conducted from the inception of each database to the present, adhering to PRISMA 2020 guidelines. STUDY SELECTION: Studies were selected through a multi-step screening process, focusing on adult populations, randomized controlled trials, and single-arm trials. DATA: Fifteen randomized controlled trials and eight single-arm trials were included. For a follow-up period of more than 24 months, pooled clinical success rate of pulpotomy was 92.9 % (95 %CI;82.1-99.0 %), whereas pooled radiographic success rate was 78.5 % (95 %CI;66.7-88.4 %). Meta-analyses showed that there was no significant difference in success rates between pulpotomy and NSRCT, between full and partial pulpotomy techniques, or between Mineral Trioxide Aggregate pulpotomy and Calcium Enriched Mixture pulpotomy. The results indicated comparable efficacy across these variables. CONCLUSIONS: The study highlights the potential of less invasive treatments. Pulpotomy may be a viable alternative to NSRCT for managing irreversible pulpitis in mature permanent teeth. Limitations such as the low quality of some single-arm trials and the high risk of bias in some randomized controlled trials highlight the need for further research to standardize methodologies and broaden literature inclusion for a more comprehensive understanding of the efficacy of pulpotomy, considering the high success rates reported. Clinical Significance This quantitative systematic review recognizes the potential of full or partial pulpotomy as a viable treatment alternative to root canal therapy for managing irreversible pulpitis in mature permanent teeth. Future studies should aim for standardized protocols to validate these findings and improve patient treatment outcomes.

DO ORAL CARE AND REHABILITATION IMPROVE COGNITIVE FUNCTION? A SYSTEMATIC REVIEW OF CLINICAL STUDIES.

OBJECTIVES: An increasing number of studies have identified an association between oral health status and cognitive function. However, the effect of oral interventions, including oral health care, dental treatment and oral motor exercises, on cognitive function remains unclear. This systematic review examined whether oral interventions contribute to the long-term improvement of cognitive status. METHODS: Four databases were searched (MEDLINE, Web of Science, Cochrane Library, and ICHUSHI Web) to identify randomized and nonrandomized controlled trial studies and prospective cohort studies from inception until 1 September 2023, published in English or Japanese. The Cochrane risk of bias tool for randomized controlled trials and the risk of bias assessment tool for nonrandomized studies were used to assess bias risk. RESULTS: A total of 20 articles were included in the qualitative analysis; 13 articles were published in English, and 7 were published in Japanese. The implemented interventions were oral care in 8 studies, dental treatment in 8 studies, and oral motor exercise in 4 studies. One study found a significant effect on attention following oral care intervention. Some dental treatments influenced cognitive function, although a clear positive effect was not determined. In 1 study, attention and working memory improved in the chewing exercise group. CONCLUSIONS: Several studies verified the improvement effects of oral interventions, such as oral care, dental treatment, and oral motor exercise, on cognitive function or impairment. However, there was still a lack of conclusive evidence that such an intervention clearly improved cognitive function. To clarify the effects of oral interventions on cognitive function, it is necessary to examine participants, interventions, and outcome measures in detail.

A person-centred care transition support for people with stroke/TIA: A study protocol for effect and process evaluation using a non-randomised controlled design.

INTRODUCTION: Care transitions following a stroke call for integrated care approaches to reduce death and disability. The proposed research described in this study protocol aims to evaluate the effectiveness of a person-centred multicomponent care transition support and the process in terms of contextual moderators, implementation aspects and mechanisms of impact. METHODS: A non-randomized controlled trial design will be used. The intervention includes person-centred dialogue intended to permeate all patient-provider communication, various pedagogical modes of information, a person-centred care and rehabilitation plan, and a bridging e-meeting to prepare patients for homecoming. Patients with stroke or TIA who are to be discharged from the participating hospitals to home and referred to a neurorehabilitation team for continued rehabilitation will be included. Follow-ups will be conducted at one week, 3 months and 12 months. Data will be collected on the primary outcome of perceived quality of the care transition, and on the secondary outcomes of health literacy, medication adherence, and perceived person-centeredness. Data for process evaluation will be collected through semi-structured interviews, focus groups, participatory observations, and the Normalisation Measure Development Questionnaire. DISCUSSION: The study will provide insights on implementation, mechanisms of impact, contextual moderators, and effectiveness of a care transition support, targeting a poorly functioning part of the care trajectory for people with stroke and TIA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05646589.

Effects of n-3 polyunsaturated fatty acid supplementation on appetite: a systematic review and meta-analysis of controlled clinical trials.

BACKGROUND: The current studies explore the effect of omega-3 polyunsaturated fatty acids (PUFAs) on appetite. OBJECTIVE: To examine the effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on appetite using a systematic review and meta-analysis of controlled clinical trials (CTs). PATIENTS AND METHODS: Online databases including PubMed, Scopus, ISI Web of Science, and Google Scholar were searched up to January 2022. A random-effects model was used to compare the overall standardized mean difference in appetite scores between n-3 PUFAs supplemented and control individuals. RESULTS: Fifteen eligible CTs with 1504 participants (872 for n-3 PUFA supplementation and 632 for placebo groups) were included in our systematic review. The meta-analysis showed no significant difference in overall appetite score between n-3 PUFAs supplemented and control groups (standardized mean difference [SMD] = 0.458, 95% confidence interval [CI] - 0.327, 1.242, P value = 0.25). However, the n-3 PUFA supplementation significantly increased the desire to eat (SMD = 1.07, 95% CI 0.116, 2.029, P = 0.02) compared to control. CONCLUSION: Although we found no effect of omega-3 supplementation on overall appetite score, it modestly increases the desire to eat. Further CTs evaluating the effect of PUFAs on appetite are still needed to confirm these findings.

Psychological and attentional outcomes following acute mindfulness induction among high anxiety individuals: A systematic review and meta-analysis.

BACKGROUND: Training outcomes of mindfulness interventions for anxiety have been extensively researched. Less is known about the acute effects of mindfulness induction and associated mechanisms. This systematic review aimed to identify 1) the effect of mindfulness induction on pre-post measures of state anxiety and attention among adults experiencing high levels of anxiety; and 2) the impact of predictors, mediators and moderators on post-induction changes in anxiety and attention. State distress and mindfulness were included as secondary outcomes. METHODS: A systematic search was conducted in November 2021 in electronic databases using relevant search terms. Five studies (four randomised controlled trials and one non-randomised controlled trial) were included, comprising a total of 277 participants with elevated trait/generalised anxiety. Each study used a brief audio-based mindfulness induction exercise. RESULTS: The meta-analysis indicated mindfulness induction had medium and large effects on state anxiety (k = 3, n = 100, g = -0.60, 95%CI [-1.04, -0.16]; p = .008) and state mindfulness (k = 2, n = 110, g = 0.91, 95%CI [0.52, 1.30], p < .001), respectively, when compared with non-therapeutic control conditions. Furthermore, two studies showed small and moderate effects of mindfulness on state anxiety when compared to therapeutic active controls, but were not pooled in a meta-analysis. While results could not be pooled for attention, there was limited evidence of behavioural improvements on tasks measuring aspects of attention following mindfulness induction. However, one study found an increase in Low Beta to High Beta ratio and a reduction in Beta activity in the Anterior Cingulate Cortex following mindfulness induction. Moreover, another study found aspects of state mindfulness mediated reductions in state anxiety. LIMITATIONS: A small number of studies were included in the review, with high risk of bias and low certainty of evidence present. CONCLUSION: The findings support the use of mindfulness induction to reduce state anxiety in anxious individuals but suggest gains in state mindfulness may be a more realistic expected outcome. Further controlled trials are needed to delineate the relative effects of objectively assessed anxiety outcomes from mindfulness induction in clinically defined samples.

Antagonist enamel tooth wear produced by different dental ceramic systems: A systematic review and network meta-analysis of controlled clinical trials.

OBJECTIVES: The aim of this study was to evaluate the amount of enamel tooth wear induced by different antagonistic ceramic crown materials in the posterior area within a follow-up period up to 24 months in function. A network meta-analysis was performed to assess the effect of the materials on the mean vertical loss (MVL) of the antagonist enamel tooth surface. DATA: Main search terms used in combination: ceramic, dental materials, metal ceramic, tooth wear and dental enamel. SOURCES: An electronic search was conducted in PubMed/Medline, Embase, and Cochrane CENTRAL plus hand-searching. STUDY SELECTION: Eligibility criteria included clinical studies reporting on MVL on antagonist's tooth up to 24 months following the permanent crown placement. From a total of 5697 articles, 7 studies reporting on 261 crowns for 177 subjects with 3 ceramic materials (Lithium disilicate, metal-ceramic, monolithic zirconia) were included. Among all, metal-ceramic and zirconia caused significantly higher enamel tooth wear on antagonist teeth, representing 82.5 µm [54.4; 110.6]) and 40.1 µm [22.2; 58.0]) more MVL than natural teeth group. In contrast, lithium disilicate showed only 5.0 µm [-48.2; 58.1]) more MVL than occurs on opposing natural teeth. CONCLUSIONS: This systematic review demonstrated that prosthodontic ceramic materials produced significantly more antagonist enamel tooth wear than opposing natural enamel tooth wear, and ceramic material type was correlated to the degree of enamel tooth wear. Additional well-conducted, randomized controlled trials with homogeneous specimens are required due to inadequate sample size and number of the clinical studies included in the analyses. CLINICAL SIGNIFICANCE: The amount of wear caused by different restorative materials has a high influence on the antagonistic natural teeth and should therefore be evaluated intensively by the dentist.

Percutaneous electrical nerve field stimulation for adolescents with irritable bowel syndrome: Cost-benefit and cost-minimization analysis.

Abdominal pain drives significant cost for adolescents with irritable bowel syndrome (IBS). We performed an economic analysis to estimate cost-savings for patients' families and healthcare insurance, and health outcomes, based on abdominal pain improvement with percutaneous electrical nerve field stimulation (PENFS) with IB-Stim® (Neuraxis). We constructed a Markov model with a 1-year time horizon comparing outcomes and costs with PENFS versus usual care without PENFS. Clinical outcomes were derived from a sham-controlled double-blind trial of PENFS for adolescents with IBS. Costs/work-productivity impact for parents were derived from appropriate observational cohorts. PENFS was associated with 18 added healthy days over 1 year of follow-up, increased annual parental wages of $5,802 due to fewer missed work days to care for the child, and $4744 in cost-savings to insurance. Percutaneous electrical field nerve stimulation for adolescents with IBS appears to yield significant cost-savings to patients' families and insurance.

Self-reported MeasUrement of Physical and PsychosOcial Symptoms Response Tool (SUPPORT-dialysis): systematic symptom assessment and management in patients on in-centre haemodialysis - a parallel arm, non-randomised feasibility pilot study protocol.

INTRODUCTION: Patients with kidney failure experience symptoms that are often under-recognised and undermanaged. These symptoms negatively impact health-related quality of life and are associated with adverse clinical outcomes. Regular symptom assessment, using electronic patient reported outcomes measure (ePROMs) linked to systematic symptom management, could improve such outcomes. Clinical implementation of ePROMs have been successful in routine oncology care, but not used for patients on dialysis. In this study, we describe a pilot study of ePROM-based systematic symptom monitoring and management intervention in patients treated with in-centre haemodialysis. METHODS AND ANALYSIS: This is a parallel-arm, controlled pilot of adult patients receiving in-centre maintenance haemodialysis. Participants in the intervention arm will complete ePROMs once a month for 6 months. ePROMs will be scored real time and the results will be shared with participants and with the clinical team. Moderate-severe symptoms will be flagged using established cut-off scores. Referral options for those symptoms will be shared with the clinical team, and additional symptom management resources will also be provided for both participants and clinicians. Participants in the control arm will be recruited at a different dialysis unit, to prevent contamination. They will receive usual care, except that they will complete ePROMs without the presentation of results to participants of the clinical team. The primary objectives of the pilot are to assess (1) the feasibility of a larger, randomised clinical effectiveness trial and (2) the acceptability of the intervention. Interviews conducted with participants and staff will be assessed using a content analysis approach. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the University Health Network (REB#21-5199) and the William Osler Health System (#23-0005). All study procedures will be conducted in accordance with the standards of University Health Network research ethics board and with the 1964 Helsinki declaration and its later amendments. Results of this study will be shared with participants, patients on dialysis and other stakeholders using lay language summaries, oral presentations to patients and nephrology professionals. We will also be publishing the results in a peer-reviewed journal and at scientific meetings. PROTOCOL VERSION: 4 (16 November 2022). TRIAL REGISTRATION NUMBER: NCT05515991.

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective, real-world experience with 200 cases outside of controlled clinical trials.

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Tezepelumab decreases airway epithelial IL-33 and T2-inflammation in response to viral stimulation in patients with asthma.

BACKGROUND: Respiratory virus infections are main triggers of asthma exacerbations. Tezepelumab, an anti-TSLP mAb, reduces exacerbations in patients with asthma, but the effect of blocking TSLP on host epithelial resistance and tolerance to virus infection is not known. AIM: To examine effects of blocking TSLP in patients with asthma on host resistance (IFNß, IFNλ, and viral load) and on the airway epithelial inflammatory response to viral challenge. METHODS: Bronchoalveolar lavage fluid (BALF, n = 39) and bronchial epithelial cells (BECs) were obtained from patients with uncontrolled asthma before and after 12 weeks of tezepelumab treatment (n = 13) or placebo (n = 13). BECs were cultured in vitro and exposed to the viral infection mimic poly(I:C) or infected by rhinovirus (RV). Alarmins, T2- and pro-inflammatory cytokines, IFNß IFNλ, and viral load were analyzed by RT-qPCR and multiplex ELISA before and after stimulation. RESULTS: IL-33 expression in unstimulated BECs and IL-33 protein levels in BALF were reduced after 12 weeks of tezepelumab. Further, IL-33 gene and protein levels decreased in BECs challenged with poly(I:C) after tezepelumab whereas TSLP gene expression remained unaffected. Poly(I:C)-induced IL-4, IL-13, and IL-17A release from BECs was also reduced with tezepelumab whereas IFNß and IFNλ expression and viral load were unchanged. CONCLUSION: Blocking TSLP with tezepelumab in vivo in asthma reduced the airway epithelial inflammatory response including IL-33 and T2 cytokines to viral challenge without affecting anti-viral host resistance. Our results suggest that blocking TSLP stabilizes the bronchial epithelial immune response to respiratory viruses.

Urate-Lowering Drugs and Muscle Injury: A Systematic Review and Network Meta-Analysis.

Several urate-lowering drugs have been linked to muscle injury. This study investigated the association of oral urate-lowering drugs with the risk of muscle injury by performing a network meta-analysis of randomized and non-randomized controlled trials. A systematic search of MEDLINE, via PubMed, the ClinicalTrials.gov website, and the Cochrane Central Register of Controlled Trials was conducted to identify relevant studies with a primary outcome of "all muscle injuries." A random-effects model was used to perform a frequentist network meta-analysis to estimate whether there was significant heterogeneity among the studies. In total, 32 studies including 28,327 participants with 2694 (9.5%) "all muscle injuries" were assessed, and the overall risk of bias was judged to be low to moderate. No statistically significant differences were found between placebo and 6 urate-lowering therapies: allopurinol (risk ratio, RR, 1.05; 95% confidence interval, 95%CI, 0.63-1.73), febuxostat (RR 1.10, 95%CI 0.71-1.70), lesinurad (RR 7.00, 95%CI 0.31-160.36), lesinurad concomitant with allopurinol (RR 0.85, 95%CI 0.34-2.11), lesinurad concomitant with febuxostat (RR 1.97, 95%CI 0.55-7.03), and topiroxostat (RR 0.99, 95%CI 0.37-2.65). The findings suggest that there is little need to consider the risk of muscle injury when using urate-lowering drugs in the clinical setting.

Implementation outcomes in psychosocial intervention studies for children and adolescents living in low- and middle-income countries: A systematic review.

Psychosocial interventions play a key role in addressing mental health and substance use needs for children and adolescents living in low- and middle-income countries (LMICs). While research efforts have primarily focused on their effectiveness, implementation outcomes also require examining. We conducted a systematic review of qualitative, quantitative, and mixed-methods studies (PROSPERO: CRD42022335997) to synthesize the literature on implementation outcomes for psychosocial interventions for children and adolescents in LMICs. We searched Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, PsychINFO, and Global Health through April 2023. Data were extracted and quality appraised through the Mixed Methods Appraisal Tool (MMAT) independently by two reviewers. A total of 13,380 records were screened, and 87 studies met inclusion criteria. Feasibility was the most reported implementation outcome (69, 79%), followed by acceptability (60, 69%), and fidelity (32, 37%). Appropriateness was assessed in 11 studies (13%), implementation costs in 10 (11%), and sustainability in one (1%). None of the included studies reported on penetration or adoption. Despite a growing body of evidence for implementation research in child and adolescent global mental health, most research focused on earlier-stage implementation outcomes, assessing them in research-controlled settings. To overcome this, future efforts should focus on assessing interventions in routine care, assessing later-stage implementation outcomes through standardized tools.

Evaluation of antimicrobial photodynamic therapy and minimal intervention associated with deproteinisation in permanent teeth with molar incisor hypomineralisation: study protocol for a clinical, controlled, blinded trial.

INTRODUCTION: Molar incisor hypomineralisation (MIH) is a qualitative defect of enamel development that occurs in the mineralisation phase. MIH affects one or more permanent molars and, occasionally, permanent incisors. The aim of the proposed study is to evaluate the clinical effect of antimicrobial photodynamic therapy (aPDT) on permanent teeth with MIH through decontamination and sensitivity control. METHODS AND ANALYSIS: Patients from 8 to 12 years of age with permanent molars will be randomly allocated to three groups. Group 1: selective chemical-mechanical removal of carious dentinal tissue around the walls of the cavity with Papacárie Duo and a curette followed by the application of aPDT and deproteinisation with Papacárie Duo; group 2: selective removal of carious dentinal tissue around the walls of the cavity with a curette, followed by the application of aPDT and deproteinisation with a 5% sodium hypochlorite solution; group 3: selective removal of carious dentinal tissue using a curette. The selected teeth must have a carious lesion in the dentin and posteruptive enamel breakdown on one or more surfaces with an indication for clinical restorative treatment. The teeth will subsequently be restored using a mixed technique with resin-modified glass ionomer cement and bulk-fill composite resin. The data will be submitted to descriptive statistical analysis. Associations with age and sex will be tested using either the χ2 test or Fisher's exact test. Pearson's correlation coefficients will be calculated to determine the strength of correlations between variables. Comparisons of the microbiological results (colony-forming units) will be performed using analysis of variance and the Kruskal-Wallis test. Kaplan-Meier survival analysis will be performed to assess the performance of the restorations. ETHICS AND DISSEMINATION: This protocol has been approved by the Human Research Ethics Committee of Nove de Julho University (certificate number: 61027522.0.0000.5511/approval date: 23 August 2022). The findings will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05443035.