Epidemiological Study in Antiviral Innate Immunity.

This chapter summarizes the epidemiological study design of natural immune epidemiology studies based on recent COVID-19-related research. The epidemiological studies on antiviral innate immunity have mainly included randomized controlled trials (RCTs) and observational studies. Importantly, this chapter will discuss how to use these methodologies to answer an epidemiological question of natural immunity in the viral infection process based on previous studies. An observational case- or cohort-based study of antiviral innate immunity may support this theoretical hypothesis but is not appropriate for clinical practice or treatment. RCTs are the gold standard for epidemiological studies and occupy a greater role in the hierarchy of evidence.

Dental applications of Punica granatum L. in the treatment of gingivitis: A review of ethnomedicinal uses, randomized clinical trials, and antibacterial potential against Porphyromonas gingivalis.

ETHNOPHARMACOLOGICAL RELEVANCE: Mouthwashes based on medicinal plants have demonstrated benefits in controlling plaque and inflammation, acting positively on the oral hygiene of patients with gingivitis. In traditional medicine, Punica granatum L. has been used to treat oral diseases in countries in Europe, Asia, North America, and Africa. AIM OF THE STUDY: The present study aimed to conduct a comprehensive review on the dental applications of Punica granatum L. for the treatment of gingivitis, including ethnomedicinal uses, analysis of randomized clinical trials, antibacterial activity against Porphyromonas gingivalis, mechanisms of action of phytochemicals isolated from this plant, and preclinical toxicity. MATERIALS AND METHODS: The literature was retrieved from Google Scholar, PubMed®, SciELO, and ScienceDirect®, since the first report published on the topic in 2001 until March 2024. RESULTS: Several clinical trials have demonstrated that mouthwashes containing P. granatum have equal or better efficacy than chlorhexidine in treating patients with gingivitis, confirming the indications for use of this plant by traditional communities. However, reports on the in vitro antibacterial activity of extracts from the fruits of this plant have not shown clinical relevance against the pathogen P. gingivalis. The ellagitannin punicalagin isolated from P. granatum has shown potential against several strains of Gram-positive and Gram-negative bacteria, but, to date, this compound has not yet been tested against P. gingivalis. It is likely that the mechanisms of action of flavonoids, such as quercetin, are involved in the inhibition of the activities of the RgpA, RgpB, and Kgp proteases of P. gingivalis. CONCLUSIONS: In summary, natural products obtained from P. granatum do not present toxic side effects and can be considered as possible substitutes of commercial products recommended for the treatment of gingivitis and other oral diseases.

Janus kinase inhibitors and adverse events of acne in dermatologic indications: a systematic review and network meta-analysis.

Background: The occurrence of acne in patients treated with Janus kinase (JAK) inhibitors for skin diseases is a potential issue, which may reduce treatment adherence.Purpose: To systematically analyzes randomized clinical trials (RCTs) of JAK inhibitors in dermatological indications for the risk of acne as an adverse event.Methods: A meta-analysis of odds ratios (ORs) for acne incidence was conducted. Data were quantitatively synthesized using random-effects meta-analysis. Surface under the cumulative ranking curve (SUCRA) values representing the relative ranking probabilities of treatments were obtained. Analyses were performed using R statistical software version 4.4.0.Results: A total of 11,396 patients were included from 24 studies. The incidence of acne for JAK inhibitors was ranked according to the SUCRA as follows: JAK1 inhibitors > TYK2 inhibitors > combined JAK1 and JAK2 inhibitors > combined JAK1 and TYK2 inhibitors > JAK3 + TEC inhibitors > pan-JAK inhibitors. ORs were higher for longer durations of drug use and larger dosages. Subgroup analyses by disease indication revealed increased ORs for psoriasis (5.52 [95% CI, 1.39-21.88]), vitiligo (4.15 [95% CI, 1.27-13.58]), alopecia areata (3.86 [95% CI, 1.58-9.42]), and atopic dermatitis (2.82 [95% CI, 1.75-4.54]). The use of JAK inhibitors in patients with systemic lupus erythematosus (SLE) may not significantly increase the incidence of acne.Conclusions: There are higher rates of acne following treatment with JAK inhibitors for dermatologic indications, particularly with longer durations and larger dosages. Pan-JAK inhibitors exhibit the lowest incidence of acne.

Mesenchymal stem cell therapy for liver fibrosis need "partner": Results based on a meta-analysis of preclinical studies.

BACKGROUND: The efficacy of mesenchymal stem cells (MSCs) in treating liver fibrosis has been demonstrated in several clinical studies. However, their low survival and liver implantation rates remain problematic. In recent years, a large number of studies in animal models of liver fibrosis have shown that MSCs combined with drugs can improve the efficacy of MSCs in the treatment of liver fibrosis alone and inhibit its progression to end-stage liver disease. This has inspired new ways of thinking about treating liver fibrosis. AIM: To investigate the effectiveness and mechanisms of MSCs combined with drugs in treating liver fibrosis. METHODS: Data sources included four electronic databases and were constructed until January 2024. The subjects, interventions, comparators, outcomes, and study design principle were used to screen the literature, and the quality of the literature was evaluated to assess the risk of bias. Relevant randomised controlled trials were selected, and the final 13 studies were included in the final study. RESULTS: A total of 13 studies were included after screening. Pooled analysis showed that MSCs combined with drug therapy significantly improved liver function, promoted the repair of damaged liver tissues, reduced the level of liver fibrosis-related indexes, and effectively ameliorated hepatic fibrosis by modulating the hepatic inflammatory microenvironment, promoting the homing of MSCs, and regulating the relevant signaling pathways, and the treatment efficacy was superior to MSCs alone. However, the combined treatment statistics showed no ame-lioration in serum albumin levels (standardized mean difference = 0.77, 95% confidence interval: -0.13 to 1.68, P = 0.09). CONCLUSION: In conclusion, MSCs combined with drugs for treating liver fibrosis effectively make up for the shortcomings of MSCs in their therapeutic effects. However, due to the different drugs, the treatment mechanism and effect also differ. Therefore, more randomized controlled trials are needed to compare the therapeutic efficacy of different drugs in combination with MSCs, aiming to select the "best companion" of MSCs in treating hepatic fibrosis.

Intervention effect of exercise on working memory in patients with depression: a systematic review.

Background: This article aims to systematically evaluate the intervention effect of exercise on working memory in patients with depression. Methods: Six Chinese and English databases were searched for randomized controlled trials (RCTs) about exercise on working memory in patients with depression. PEDro scale was adopted to evaluate the methodological quality of the included articles, GRADEpro scale was employed to evaluate the level of evidence for outcomes, and the Metafor Package in R 4.4.1 was used to analyze the combined effect size, subgroup analyses and publication bias. Results: A total of 15 studies were included. The meta-analysis indicated that exercise had a statistically significant effect on working memory in patients with depression, with an effect size of 0.16 (95% CI [0.03-0.28], p = 0.02). Exercise type (F(3,34) = 1.99, p = 0.13), intervention content (F(1,36) = 1.60, p = 0.22), and exercise duration (F(1,36) = 0.05, p = 0.83) did not moderate the effect, whereas exercise intensity showed a moderating effect (F(2,35) = 8.83, p < 0.01). There was evidence of publication bias in the study results (t = 2.52, p = 0.02). Conclusion: Exercise can improve the working memory of patients with depression, and its moderating effect is the best when having low-intensity and moderate-intensity. Research plan was registered in international system evaluation platform PROSPERO (https://www.crd.york.ac.uk/PROSPERO/) (CRD42023475325).

Efficacy of arch contouring foot orthoses for midfoot osteoarthritis: Protocol for a randomised controlled trial.

INTRODUCTION: Midfoot osteoarthritis (OA) is a painful and disabling condition. Arch contouring foot orthoses have been recommended for midfoot OA, yet there is no high-quality evidence from randomised controlled trials to support their use. This clinical trial aims to evaluate the efficacy of arch contouring foot orthoses for midfoot OA. METHODS: This will be a parallel-group randomised controlled superiority trial. One-hundred and forty community-dwelling people with painful midfoot OA will be randomised to receive either arch contouring foot orthoses or flat sham inserts. Outcome measures will be obtained at baseline, 4, 8 and 12 weeks; the primary endpoint for assessing efficacy being 12 weeks. The primary outcome measure will be average midfoot pain whilst walking over the last 7 days on an 11-point numerical rating scale. Secondary outcome measures include function (walking/standing subscale of the Manchester-Oxford Foot Questionnaire), participants' perception of overall treatment effect (self-reported global rating of change on a 15-point Likert scale), physical activity (Incidental and Planned Exercise Questionnaire), general health-related quality of life (Short Form-12 Version® 2.0), use of co-interventions and adverse events. DISCUSSION: This trial will evaluate the efficacy of arch contouring foot orthoses for relieving pain and improving function, physical activity and health-related quality of life in people with midfoot OA. The findings will provide high-quality evidence as to whether arch contouring foot orthoses are efficacious and will help to inform clinical guidelines about the use of foot orthoses for midfoot OA. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry (ACTRN12623000953639).

Non-inferiority, randomised, open-label clinical trial on the effectiveness of transurethral microwave thermotherapy compared to prostatic artery embolisation in reducing severe lower urinary tract symptoms in men with benign prostatic hyperplasia: study protocol for the TUMT-PAE-1 trial.

BACKGROUND: One-fourth of men older than 70 years have lower urinary tract symptoms (LUTS) that impair their quality of life. Transurethral resection of the prostate (TURP) is considered the gold standard for surgical treatment of LUTS caused by benign prostatic hyperplasia (BPH) that cannot be managed conservatively or pharmacologically. However, TURP is only an option for patients fit for surgery and can result in complications. Transurethral microwave thermotherapy (TUMT) and prostatic artery embolisation (PAE) are alternative minimally invasive surgical therapies (MISTs) performed in an outpatient setting. Both treatments have shown to reduce LUTS with a similar post-procedure outcome in mean International Prostate Symptom Score (IPSS). It is however still unknown if TUMT and PAE perform equally well as they have never been directly compared in a randomised clinical trial. The objective of this clinical trial is to assess if PAE is non-inferior to TUMT in reducing LUTS secondary to BPH. METHODS: This study is designed as a multicentre, non-inferiority, open-label randomised clinical trial. Patients will be randomised with a 1:1 allocation ratio between treatments. The primary outcome is the IPSS of the two arms after 6 months. The primary outcome will be evaluated using a 95% confidence interval against the predefined non-inferiority margin of + 3 points in IPSS. Secondary objectives include the comparison of patient-reported and functional outcomes at short- and long-term follow-up. We will follow the patients for 5 years to track long-term effect. Assuming a difference in mean IPSS after treatment of 1 point with an SD of 5 and a non-inferiority margin set at the threshold for a clinically non-meaningful difference of + 3 points, the calculated sample size was 100 patients per arm. To compensate for 10% dropout, the study will include 223 patients. DISCUSSION: In this first randomised clinical trial to compare two MISTs, we expect non-inferiority of PAE to TUMT. The most prominent problems with MIST BPH treatments are the unknown long-term effect and the lack of proper selection of candidates for a specific procedure. With analysis of the secondary outcomes, we aspire to contribute to a better understanding of durability and provide knowledge to guide treatment decisions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05686525. Registered on January 17, 2023, https://clinicaltrials.gov/study/NCT05686525 .

SMSs as an alternative to provider-delivered care for unhealthy alcohol use: study protocol for Leseli, an open-label randomised controlled trial of mhGAP-Remote vs mhGAP-Standard in Lesotho.

BACKGROUND: The World Health Organization's (WHO) Mental Health Gap Action Programme (mhGAP) is a validated intervention that can be provided by non-specialised healthcare workers to individuals with unhealthy alcohol use. However, it typically requires several in-person sessions at a health facility, which may limit its feasibility and effectiveness in remote settings. This trial compares mhGAP-Standard, a 4 to 6 in-person session intervention, to mhGAP-Remote, a 1 in-person session intervention followed by 8 week of short message service (SMS) in Lesotho. We hypothesise that mhGAP-Remote is superior to mhGAP-Standard in reducing alcohol use (as detailed by the primary and secondary outcomes below). METHODS: This is a two-arm randomised open-label multicentre superiority trial. Participants allocated to mhGAP-Standard receive 4 in-person sessions using motivational interviewing, identifying triggers, and alternative behaviours, with the option of two additional booster sessions. Participants in the mhGAP-Remote arm receive 1 in-person session covering the same content, followed by standardised SMSs over 8 weeks that reinforce intervention content. Non-specialist providers deliver the intervention and receive weekly supervision. Adults (Nplanned = 248) attending participating health facilities for any reason and who meet criteria for unhealthy alcohol use based on the Alcohol Use Disorders Identification Test ([AUDIT] score ≥ 6 for women, ≥ 8 for men) are individually randomised to the two arms (1:1 allocation, stratified by participant sex and age (≥ 50 vs < 50 years old). Follow-up assessments occur at 8, 20, and 32 weeks post-randomisation. The primary outcome is change in self-reported alcohol use (continuous AUDIT score), from baseline to 8 weeks follow-up. Change in the AUDIT from baseline to 20 and 32 weeks follow-up is a secondary outcome. Change in the biomarker phosphatidylethanol (secondary), liver enzyme values in serum (exploratory), and HIV viral load (for people with HIV only; exploratory) are also evaluated from baseline throughout the entire follow-up period. A linear regression model will be conducted for the primary analysis, adjusted for the stratification factors. Three a priori sensitivity analyses for the primary outcome are planned based on per protocol treatment attendance, recovery from unhealthy alcohol use, and clinically significant and reliable change. DISCUSSION: This trial will provide insight into feasibility and effectiveness of a shortened and primarily SMS supported version of mhGAP, which is especially relevant for settings where regular clinic attendance is a major barrier. TRIAL REGISTRATION: clinicaltrials.gov NCT05925270 . Approved on June 29th, 2023.

Limited fasciectomy with versus without autologous adipose tissue grafting for treatment of Dupuytren's contracture (REMEDY): study protocol for a multicentre randomised controlled trial.

BACKGROUND: Dupuytren's contracture is a hereditary disorder which causes progressive fibrosis of the palmar aponeurosis of the hand, resulting in digital flexion contractures of the affected rays. Limited fasciectomy is a standard surgical treatment for Dupuytren's, and the one with the lowest recurrence rate; however, the recurrence is still relatively high (2-39%). Adipose-derived stem cells have been shown to inhibit Dupuytren's myofibroblasts proliferation and contractility in vitro, as well as to improve scar quality and skin regeneration in different types of surgeries. Autologous adipose tissue grafting has already been investigated as an adjuvant treatment to percutaneous needle fasciotomy for Dupuytren's contracture with good results, but it was only recently associated with limited fasciectomy. The purpose of REMEDY trial is to investigate if limited fasciectomy with autologous adipose tissue grafting would decrease recurrence compared to limited fasciectomy alone. METHODS: The REMEDY trial is a multi-centre open-label randomised controlled trial (RCT) with 1:1 allocation ratio. Participants (n = 150) will be randomised into two groups, limited fasciectomy with autologous adipose tissue grafting versus limited fasciectomy alone. The primary outcome is the recurrence of Dupuytren's contracture on any of the treated rays at 2 years postoperatively. The secondary outcomes are recurrence at 3 and 5 years, scar quality, complications, occurrence of algodystrophy (complex regional pain syndrome), patient-reported hand function, and hypodermal adipose tissue loss at 1 year postoperatively in a small subset of patients. DISCUSSION: The REMEDY trial is one of the first studies investigating limited fasciectomy associated with autologous adipose tissue grafting for Dupuytren's contracture, and, to our knowledge, the first one investigating long-term outcomes of this treatment. It will provide insight into possible benefits of combining adipose tissue grafting with limited fasciectomy, such as lower recurrence rate and improvement of scar quality. TRIAL REGISTRATION: ClinicalTrials.gov NCT05067764, June 13, 2022.

Efficacy and safety of compound glycyrrhizin combined with topical minoxidil for alopecia areata: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Alopecia areata (AA) is a common autoimmune skin disease. Our study aimed to systematically evaluate the efficacy and safety of compound glycyrrhizin (CG) combined with topical minoxidil therapy in treating AA. METHODS: We searched the PubMed, EMBASE, Cochrane Library, Web of Science, CNKI, Wanfang, and VIP databases. Randomized controlled trials (RCTs) on CG combined with topical minoxidil therapy compared with topical minoxidil therapy alone for AA were included. The Cochrane Collaborative Network Tool was used to assess the risk of bias. Statistical analysis was completed using RevMan5.3 software and Stata 15.0 software. The GRADE system was used to evaluate the quality of evidence for outcomes. RESULT: 11 RCTs and 1189 patients were included. Compared with topical minoxidil therapy alone, CG combined with topical minoxidil therapy was more effective at improving the clinical efficacy (RR = 1.36, 95% CI [1.27, 1.45], p < 0.00001). The SALT score (MD = -10.09, 95% CI [-12.89, -7.30], p < 0.00001), serum TNF-α levels (MD = -0.99, 95% CI [-1.19, -0.39], p < 0.00001), serum IL-12 levels (MD = -8.84, 95% CI [-11.20, -6.47], p < 0.00001) and serum IFN-γ levels (MD = -7.44, 95% CI [-11.51, -3.37], p = 0.0003) were reduced, and the serum TGF-ß1 levels (MD = 2.40, 95% CI [1.24, 3.57], p < 0.0001) were increased. There were no significant differences in reported adverse events, including irritant contact dermatitis (RR = 0.51, 95% CI [0.25, 1.01], p = 0.05),' gastrointestinal reactions (RR = 2.47, 95% CI [0.49, 12.55], p = 0.28), lower limb edema (RR = 2.60, 95% CI [0.61, 11.06], p = 0.20), facial edema (RR = 2.33, 95% CI [0.61, 8.93], p = 0.22), or localized itching (RR = 0.56, 95% CI [0.18, 1.75], p = 0.32), between the two groups. CONCLUSION: The current evidence indicates that CG combined with topical minoxidil therapy is effective and safe for AA. However, owing to the suboptimal quality of the included studies, more high-quality and large-scale RCTs are needed for comprehensive analysis and further validation.

Psychedelic-assisted therapy for treating anxiety, depression, and existential distress in people with life-threatening diseases.

BACKGROUND: Psychedelic-assisted therapy refers to a group of therapeutic practices involving psychedelics taken under therapeutic supervision from physicians, psychologists, and others. It has been hypothesised that psychedelic-assisted therapy may reduce symptoms of anxiety, depression, and existential distress in patients facing life-threatening diseases (e.g. cancer). However, these substances are illegal in most countries and have been associated with potential risks. OBJECTIVES: To assess the benefits and harms of psychedelic-assisted therapy compared to placebo or active comparators (e.g. antidepressants) for treatment of anxiety, depression, and existential distress in people with life-threatening diseases. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registers on 30 March 2024. In addition, we undertook reference checking, citation searching, and contact with study authors to identify additional studies. We used no language or date restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs), with no restrictions regarding comorbidity, sex, or ethnicity. Interventions comprised a substance-induced psychedelic experience preceded by preparatory therapeutic sessions and followed by integrative therapeutic sessions. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included six studies in the review, which evaluated two different interventions: psychedelic-assisted therapy with classical psychedelics (psilocybin ('magic mushrooms') and lysergic acid diethylamide (LSD)), and psychedelic-assisted therapy with 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'). The studies randomised 149 participants with life-threatening diseases and analysed data for 140 of them. The age range of participants was 36 to 64 years. The studies lasted between 6 and 12 months, and were conducted in outpatient settings in the USA and in Switzerland. Drug companies were not involved in study funding, but funding was provided by organisations that promote psychedelic-assisted therapy. Primary outcomes (at 1 to 12 weeks) Anxiety Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) may result in a reduction in anxiety when compared to active placebo (or low-dose psychedelic): State Trait Anxiety Inventory (STAI-Trait, scale 20 to 80) mean difference (MD) -8.41, 95% CI -12.92 to -3.89; STAI-State (scale 20 to 80) MD -9.04, 95% CI -13.87 to -4.21; 5 studies, 122 participants; low-certainty evidence. The effect of psychedelic-assisted therapy using MDMA on anxiety, compared to placebo, is very uncertain: STAI-T MD -14.70, 95% CI -29.45 to 0.05; STAI-S MD -16.10, 95% CI -33.03 to 0.83; 1 study, 18 participants; very low certainty evidence. Depression Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) may result in a reduction in depression when compared to active placebo (or low-dose psychedelic): Beck Depression Inventory (BDI, scale 0 to 63) MD -4.92, 95% CI -8.97 to -0.87; 4 studies, 112 participants; standardised mean difference (SMD) -0.43, 95% CI -0.79 to -0.06; 5 studies, 122 participants; low-certainty evidence. The effect of psychedelic-assisted therapy using MDMA on depression, compared to placebo, is very uncertain: BDI-II (scale: 0 to 63) MD -6.30, 95% CI -16.93 to 4.33; 1 study, 18 participants; very low certainty evidence. Existential distress Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) compared to active placebo (or low-dose psychedelic) may result in a reduction in demoralisation, one of the most common measures of existential distress, but the evidence is very uncertain (Demoralisation Scale, 1 study, 28 participants): post treatment scores, placebo group 39.6 (SEM 3.4), psilocybin group 18.8 (3.6), P ≤ 0.01). Evidence from other measures of existential distress was mixed. Existential distress was not measured in people receiving psychedelic-assisted therapy with MDMA. Secondary outcomes (at 1 to 12 weeks) Quality of life When classical psychedelics were used, one study had inconclusive results and two reported improved quality of life, but the evidence is very uncertain. MDMA did not improve quality of life measures, but the evidence is also very uncertain. Spirituality Participants receiving psychedelic-assisted therapy with classical psychedelics rated their experience as being spiritually significant (2 studies), but the evidence is very uncertain. Spirituality was not assessed in participants receiving MDMA. Adverse events No treatment-related serious adverse events or adverse events grade 3/4 were reported. Common minor to moderate adverse events for classical psychedelics were elevated blood pressure, nausea, anxiety, emotional distress, and psychotic-like symptoms (e.g. pseudo-hallucination where the participant is aware they are hallucinating); for MDMA, common minor to moderate adverse events were anxiety, dry mouth, jaw clenching, and headaches. Symptoms subsided when drug effects wore off or up to one week later. Certainty of the evidence Although all six studies had intended to blind participants, personnel, and assessors, blinding could not be achieved as this is very difficult in studies investigating psychedelics. Using GRADE criteria, we judged the certainty of evidence to be low to very low, mainly due to high risk of bias and imprecision (small sample size). AUTHORS' CONCLUSIONS: Implications for practice Psychedelic-assisted therapy with classical psychedelics (psilocybin, LSD) may be effective for treating anxiety, depression, and possibly existential distress, in people facing a life-threatening disease. Psychedelic-assisted therapy seemed to be well tolerated, with no treatment-emergent serious adverse events reported in the studies included in this review. However, the certainty of evidence is low to very low, which means that we cannot be sure about these results, and they might be changed by future research. At the time of this review (2024), psychedelic drugs are illegal in many countries. Implications for research The risk of bias due to 'unblinding' (participants being aware of which intervention they are receiving) could be reduced by measuring expectation bias, checking blinding has been maintained before cross-over, and using active placebos. More studies with larger sample sizes are needed to reduce imprecision. As the US Drug Enforcement Administration (DEA) currently classifies psychedelics as Schedule I substances (i.e. having no accepted medical use and a high potential for abuse), research involving these drugs is restricted, but is steadily increasing.

Acupuncture and Escitalopram for Treating Major Depression Clinical Study (AE-TMDCS): protocol for a factorial randomised controlled trial.

INTRODUCTION: Major depressive disorder (MDD), the second leading cause of disability globally, is considered to be associated with a consequent deterioration in the quality of life and can lead to a major economic burden on medical service and suicide-related costs. Previous research has shown that acupuncture may be beneficial for treating MDD. However, there is a lack of rigorous evidence from previous studies comparing acupuncture with antidepressant medications. This study aims to assess the therapeutic potential of acupuncture in the management of depressive disorders. METHODS AND ANALYSIS: A multicentre, randomised, participant-blind, sham-controlled, 2×2 factorial clinical trial, Acupuncture and Escitalopram for Treating Major Depression Clinical Study, aims to compare the efficacy of acupuncture versus escitalopram in treating depression. This study will be conducted at three hospitals in China, enrolling 260 patients with moderate-to-severe major depression, as defined by DSM-5 criteria and Hamilton Depression Rating Scale (HDRS-17) Scores above 17. Participants will be randomly assigned in equal proportions to one of four groups (acupuncture/escitalopram, sham acupuncture/escitalopram, acupuncture/placebo and sham acupuncture/placebo) and undergo 30 sessions across 10 weeks. The primary outcome is change in HDRS-17 Score and secondary outcomes include BDI, Clinical Global Impression, Generalised Anxiety Disorder-7 and Mini-Mental State Examination Scores, alongside potential biological markers. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the Ethics Committees of the Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine (2023-7th-HIRB-020), Shanghai Mental Health Centre (2022-86) and Shanghai Pudong New Area Hospital of Traditional Chinese Medicine (2023-003). Informed consent will be obtained from all participants. The study's findings are intended for publication in a scholarly journal. TRIAL REGISTRATION: NCT05901571.

Comparative effects of sacubitril/valsartan and ACEI/ARB on endothelial function and arterial stiffness in patients with heart failure: a protocol for systematic review and meta-analysis.

INTRODUCTION: Heart failure (HF) is a complex syndrome that affects millions of people worldwide and leads to significant morbidity and mortality. Sacubitril/valsartan, a combination drug consisting of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), has shown a greater improvement in the prognosis of HF than ACE inhibitors (ACEI) or ARB. Recent studies have found that ACEI/ARB or sacubitril/valsartan can increase flow-mediated dilation (FMD) and reduce pulse wave velocity (PWV), which are independent predictors of cardiovascular events and HF prognosis. The purpose of this study is to assess and compare the effect of sacubitril/valsartan and ACEI/ARB on FMD and PWV using meta-analysis and further provide a reference for the role of sacubitril/valsartan in the treatment of HF. METHODS AND ANALYSIS: Clinical randomised controlled trials investigating the effect of sacubitril/valsartan and/or ACEI/ARB on FMD and PWV in patients with HF will be searched in the relevant database, including PubMed, Web of Science, Embase, Cochrane Library and China's National Knowledge Infrastructure up to January 2024. The outcomes of interest are changes in endothelial function assessed by FMD and changes in arterial stiffness assessed by PWV. The risk of bias was evaluated using the revised Cochrane risk of bias tool for randomised trials (RoB2.0). Review Manager V.5.3 software is used for meta-analysis data synthesis, sensitivity analysis, meta-regression analysis, subgroup analysis and risk of bias assessment. The reporting bias of studies will be evaluated using the funnel plot, in which symmetry will be assessed by Begg's and Egger's tests. The evidence quality of the included studies will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation. ETHICS AND DISSEMINATION: This study only analyses research data from the published literature and therefore does not require ethical approval. We will submit the systematic review to a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42024538148.

Assessing the effect of anthocyanins through diet and supplementation on cognitive function in older adults at risk for dementia: protocol for a randomised controlled trial.

INTRODUCTION: Promising evidence is emerging for the procognitive, anti-inflammatory and neuroprotective properties of dietary flavonoids, particularly anthocyanins that provide red, purple and blue plant pigments. METHODS AND ANALYSIS: The 'Food for Thought' study is a multicentre, 6-month randomised, parallel 3-arm clinical trial. Its primary aim is to investigate whether anthocyanin consumption, either through diet or supplementation, can prevent memory loss progression and improve inflammatory and cardiovascular health in older adults at risk for dementia. Eligible participants will include those aged 60-85 years with a diagnosis of amnestic mild cognitive impairment or with a self-referral of memory concerns and scoring ≤13 on the Memory Index Score within the Telephone Montreal Cognitive Assessment screening test. Participants will be randomised to one of three arms: High anthocyanin ('purple foods') diet (aiming for a target of 250 mg anthocyanins/day); freeze-dried product derived from blackcurrants (250 mg anthocyanins/day); or control (coloured maltose powder). The primary outcome is auditory anterograde memory functioning assessed by the Buschke and Grober Free and Cued Selective Reminding Test-Immediate Recall. Secondary outcomes are additional cognitive functions including processing speed, working memory, aspects of executive functioning (attentional shifting and word generativity) and premorbid estimate as well as subjective memory problems and self-reported depression symptoms. Additional secondary outcomes are blood pressure, inflammatory biomarkers, brain-derived neurotrophic factor, fatty acid profile, apolipoprotein E and polyphenol metabolites, gut microbiota composition and function and vascular and microvascular endothelial function tests. Repeated measures analysis of variance and/or mixed linear modelling will evaluate changes over time, with the inclusion of covariates. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Greater Western Human Research Ethics Committee (2021/ETH12083). A Consumer Advisory Group was established to guide and review the protocol and dissemination strategy. The results of this trial are intended to be published in a peer-reviewed journal. TRIAL SPONSOR: National Health and Medical Research Centre Dementia Collaborative Research Centre.Start date of clinical trial: 02 September 2022.Expected end date: 11 October 2024. TRIAL REGISTRATION NUMBER: ACTRN12622000065796.

Rotation or change of biotherapy after TNF blocker treatment failure for axial spondyloarthritis: the ROC-SpA study, a randomised controlled study protocol.

INTRODUCTION: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease characterised by inflammatory low back pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as a first treatment in axSpA. In case of inadequate response to NSAIDs, biological disease-modifying antirheumatic drugs (bDMARDs) should be introduced according to the recommendations of the European League Against Rheumatism (EULAR) and the American College of Rheumatology. Until 2015, only bDMARD was recommended for axSpA in case of failure to anti-tumour necrosis factor (TNF). The 2022 Assessment of SpondyloArthritis International Society (ASAS)-EULAR recommendation proposed to start an alternative bDMARD but without advocating a switch in mode of action as proposed in rheumatoid arthritis. Since 2015, the inhibition of interleukin (IL)-17 has demonstrated efficacy in axSpA. Then, we designed a randomised multicentre clinical trial to identify the more effective treatment after a first anti-TNF failure in axSpA, comparing an anti-IL-17 to a second anti-TNF. METHODS AND ANALYSIS: The ROC-SpA (Rotation Or Change of biotherapy after first anti-TNF treatment failure in axSpA patients) study is a prospective, randomised, multicentre, superiority open-label phase IV trial comparing an anti-IL-17 strategy (secukinumab or ixekizumab) to a second TNF blocker in a 1:1 ratio. Patients with an active axSpA (Bath Ankylosing Spondylitis Disease Activity Index >4 or ankylosing spondylitis disease activity score (ASDAS) >3.5) with inadequate 3 months response to a first anti-TNF and with a stable dose of conventional synthetic DMARDs, oral corticosteroids and/or NSAIDs for at least 1 month are included in 31 hospital centres in France and Monaco. The primary outcome is the ASAS40 response at week 24. The secondary outcomes are ASAS40 at weeks 12 and 52, other clinical scores (ASAS20, partial remission rate, ASDAS major improvement rate) at weeks 12, 24 and 52 with the drugs and anti-drugs concentrations at baseline, weeks 12, 24 and 52. The primary analysis is performed at the end of the study according to the intent-to-treat principle. ETHICS AND DISSEMINATION: Ethics approval was obtained from the committee for the protection of persons (Comité de protection des personnes Ouest IV #12/18_1, 6 February 2018) and registered in ClinicalTrials.gov and in EudraCT. Results of this study, whether positive or negative, will be presented at national and international congresses, to national axSpA patient associations and published in a peer-reviewed journal. It could also impact the international recommendation to manage patients with axSpA. TRIAL REGISTRATION NUMBER: NCT03445845 and EudraCT2017-004700-22.

Investigating combined acupuncture and transcranial direct current stimulation in patients with poststroke shoulder pain from China: protocol for a randomised controlled trial.

INTRODUCTION: Poststroke shoulder pain is a common complication that severely affects the recovery of upper limb motor function. Acupuncture has positive analgesic effects in treating poststroke shoulder pain, and studies have demonstrated the efficacy of transcranial direct current stimulation (tDCS) in treating patients with this pain. However, whether acupuncture combined with tDCS has a superior rehabilitation effect on poststroke shoulder pain is currently unknown. We aimed to observe the effect of the combined intervention on poststroke shoulder pain and explore its possible central analgesic mechanism. METHODS AND ANALYSIS: This study describes a randomised controlled trial using assessor blinding. A total of 135 poststroke patients with shoulder pain will be randomly assigned in a 1:1:1 ratio to the tDCS group, acupuncture group and combined group (acupuncture plus tDCS). All three groups will undergo conventional rehabilitation treatment. Participants in the tDCS group will receive tDCS stimulation on the M1 area for 20 min, while the acupuncture group will receive 20 min of acupuncture. The combined treatment group will receive both. All treatments will be performed five times per week for 4 weeks. The primary outcome indicator in this study is the Visual Analogue Scale pain score. Secondary outcome indicators include shoulder mobility, Shoulder Pain and Disability Index, Fugl-Meyer Motor Function Scale, Modified Barthel Index Scale, Self-Rating Anxiety and Depression Scale and functional MRI. All scale results will be assessed at baseline and at 2 weeks and 4 weeks, and during follow-up at 1 month, 3 months and 6 months postdischarge. A repeated analysis of variance will be conducted to observe the group×time interaction effects of the combined intervention. Moreover, functional MRI will be applied to explore the central analgesic mechanism. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the Affiliated Rehabilitation Hospital of Fujian University of Traditional Chinese Medicine (2023KY-039-001). The results of the study will be published in a peer-reviewed journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300078270.

Data collection methods for patient-reported outcome measures in cancer randomised controlled trials: a protocol for a rapid scoping review.

BACKGROUND: There are different modes and ways to assess patient-reported outcomes (PROs) in clinical trials. However, there is little systematic information on how often different modes of assessment (MOA) are used in cancer clinical trials and how exactly assessments are conducted. The goal of this scoping review is to gain an understanding of the MOA and data management of PROs in cancer randomised controlled trials (RCTs) and the reporting quality thereof. METHODS AND ANALYSIS: This scoping review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant trials will be identified via their indexed publications. We will search PubMed for RCTs conducted in cancer populations that evaluate a biomedical treatment with a PRO endpoint. Trials with publications published between January 2019 and November 2023 will be included. Two independent reviewers will review the references for both the abstract and full-text screening. We will extract data from the publications from a trial and the trial protocol if a protocol can be traced. Data will be summarised at the trial level. We will focus on a descriptive analysis of the MOA of PROs and on the relative frequencies of the different MOA. We will also evaluate the quality of reporting for the relevant SPIRIT and CONSORT guidelines that refer to the assessment of PROs in trials. Due to the scoping nature of our review, we will not perform a dedicated quality assessment of all trials. ETHICS AND DISSEMINATION: The proposed review is based on secondary, published data. Hence, no ethics review is necessary. The review is part of an ongoing project on the use of electronic data capture methods in cancer clinical trials. The findings from the review will support the project and contribute to synthesising guidance to ultimately improve the (electronic) measurement of patient-reported outcome measures in clinical trials.