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Anna-Lena Klauser,1 Marc Hirschfeld,1– 3 Andrea Ritter,1,2 Gerta Rücker,1,4 Markus Jäger,1,2 Julia Gundarova,1 Daniela Weiss,1,2 Ingolf Juhasz-Böss,1,2 Kai Berner,1,2 Thalia Erbes,1,2 Jasmin Asberger1,2 1Faculty of Medicine, University of Freiburg, Freiburg, Germany; 2Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany; 3Institute of Veterinary Medicine, University of Göttingen, Göttingen, Germany; 4Institute of Medical Biometry and Statistics, Medical Center – University of Freiburg, Freiburg, GermanyCorrespondence: Jasmin AsbergerDepartment of Obstetrics and Gynecology, Faculty of Medicine and Medical Center – University of Freiburg, Hugstetterstr. 55, Freiburg, 79106, GermanyTel +49 761 270 30020Fax +49 761 270 30370Email jasmin.asberger@uniklinik-freiburg.dePurpose: In 2020, breast cancer still represents the most common type of cancer in women worldwide. Depending on the specific molecular subtype, clinical breast cancer management comprises surgery, radiotherapy, chemotherapy and targeted therapy. Furthermore, there are some therapeutic approaches from the field of complementary and alternative medicine. Current research focuses on the elucidation of new therapeutic targets for treatment development. Odorant substances affect apoptosis, proliferation and cell cycle in healthy and cancerous cells. Exact signalling pathways involved are not entirely clear. The present study aims to analyse their therapeutic potential in breast cancer.Methods: This study focuses on the effect of commonly used odorant substances (citral, citrathal R, cyclovertal, para-cymol, hexylacetat, herbavert, dihydromyrcerol and limonen) on the breast cancer cell lines MDA-MB-231, T47-D and BT474. Methodologically, this study applied cell culturing, MTT assay for detection of IC50 of the odorant substance, RNA purification followed by qRT-PCR, protein isolation and Western Blot, as well as immunocytochemistry. Further, this study investigates the role of transient receptor potential channel V1 (TRPV1), involved in the mechanisms of action for some odorant substances. Therefore, capsazepine, a TRPV1 antagonist, was used.Results: The odorant substances citral, citrathal R and cyclovertal have significant pro-apoptotic (p < 0.001), anti-proliferative (p < 0.001) and cell cycle-arresting effects measurable in RNA expression as well as in protein levels and immunocytochemical staining. The combination of citral and capsazepine no longer showed significant pro-apoptotic, antiproliferative, and cell cycle inhibitory effects compared to the compounds alone. This indicates that TRPV1 is necessary for the signal transduction of citral.Conclusion: This present study reveals three odorant substances with effects on cell viability, indicating their potential use in breast cancer therapy.Keywords: citral, citrathal R, cyclovertal, odorant substances, olfactory receptor and breast cancer

Summary: Postoperative nausea and vomiting is a common adverse effect of anaesthesia. Although dozens of different anti‐emetics are available for clinical practice, there is currently no comparative ranking of efficacy and safety of these drugs to inform clinical practice. We performed a systematic review with network meta‐analyses to compare, and rank in terms of efficacy and safety, single anti‐emetic drugs and their combinations, including 5‐hydroxytryptamine3, dopamine‐2 and neurokinin‐1 receptor antagonists; corticosteroids; antihistamines; and anticholinergics used to prevent postoperative nausea and vomiting in adults after general anaesthesia. We systematically searched for placebo‐controlled and head‐to‐head randomised controlled trials up to November 2017 (updated in April 2020). We assessed how trustworthy the evidence was using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Confidence In Network Meta‐Analysis (CINeMA) approaches for vomiting within 24 h postoperatively, serious adverse events, any adverse event and drug class‐specific side‐effects. We included 585 trials (97,516 participants, 83% women) testing 44 single drugs and 51 drug combinations. The studies' overall risk of bias was assessed as low in only 27% of the studies. In 282 trials, 29 out of 36 drug combinations and 10 out of 28 single drugs lowered the risk of vomiting at least 20% compared with placebo. In the ranking of treatments, combinations of drugs were generally more effective than single drugs. Single neurokinin‐1 receptor antagonists were as effective as other drug combinations. Out of the 10 effective single drugs, certainty of evidence was high for aprepitant, with risk ratio (95%CI) 0.26 (0.18–0.38); ramosetron, 0.44 (0.32–0.59); granisetron, 0.45 (0.38–0.54); dexamethasone, 0.51 (0.44–0.57); and ondansetron, 0.55 (0.51–0.60). It was moderate for fosaprepitant, 0.06 (0.02–0.21) and droperidol, 0.61 (0.54–0.69). Granisetron and amisulpride are likely to have little or no increase in any adverse event compared with placebo, while dimenhydrinate and scopolamine may increase the number of patients with any adverse event compared with placebo. So far, there is no convincing evidence that other single drugs effect the incidence of serious, or any, adverse events when compared with placebo. Among drug class specific side‐effects, evidence for single drugs is mostly not convincing. There is convincing evidence regarding the prophylactic effect of at least seven single drugs for postoperative vomiting such that future studies investigating these drugs will probably not change the estimated beneficial effect. However, there is still considerable lack of evidence regarding safety aspects that does warrant investigation. [ABSTRACT FROM AUTHOR]

Ravindra Gopaul,1 Robert A Waller,1 Ricci Kalayanamitra,2 Garrett Rucker,3 Andrew Foy4 1Department of Emergency Medicine, Penn State Hershey Medical Center, Hershey, PA, USA; 2Department of Emergency Medicine, Staten Island University Hospital, New York, NY, USA; 3Penn State Milton S. Hershey College of Medicine, Hershey, PA, USA; 4Department of Internal Medicine, Division of Cardiology, Penn State Hershey Medical Center, Hershey, PA, USACorrespondence: Ravindra Gopaul, Email rgopaul@pennstatehealth.psu.eduObjective: The HEART Score is a clinically validated risk stratification tool for patients with chest pain. Using five parameters (History, Electrocardiogram, Age, Risk factors, and Troponin), this instrument categorizes patients as low, moderate, or high risk for major adverse cardiac events within six weeks after evaluation. Of these parameters, History is the most subjective, as providers independently assign their level of clinical suspicion. Overestimation of history, and ultimately the HEART Score, can result in increased resource utilization, expense, and patient risk. We sought to evaluate bias in provider assessment of history when determining the HEART Score.Methods: Emergency medicine (EM) and Cardiology providers received surveys with one of two versions of clinical vignettes randomized at the question level and were asked to estimate the history component of the HEART Score. Vignettes differed by age, risk factors, sex, and socioeconomic status (SES), but both versions should have received the same score for history. Statistical analysis was then used to assess differences in history assessment between vignettes.Results: Of the 884 responses analyzed, most providers overestimated the historical portion of the HEART Score when assessing risk factors, patient distress, age, and lower SES. Many underestimated history with knowledge of a previous negative stress test. When controlling for specialty, the universal theme was overestimation by EM providers and underestimation by cardiologists. Despite the presence of hypertension, gender differences, and the appearance of mild distress, cardiologists were more likely to correctly estimate history compared to EM providers. SES consideration generally led to an underestimation of history by cardiologists. These findings were all statistically significant.Conclusion: Our study demonstrates that both EM and cardiology providers overestimate history when considering prognosticators that are frequently viewed as concerning. Further education on proper usage of the HEART Score is needed for more appropriate scoring of history and improved resource allocation for hospital systems.Keywords: HEART score, physician, provider, history

Quantifying the contributions, or weights, of comparisons or single studies to the estimates in a network meta-analysis (NMA) is an active area of research. We extend this work to include the contributions of paths of evidence. We present a general framework, based on the path-design matrix, that describes the problem of finding path contributions as a linear equation. The resulting solutions may have negative coefficients. We show that two known approaches, called shortestpath and randomwalk, are special solutions of this equation, and both meet an optimization criterion, as they minimize the sum of absolute path contributions. In general, there is an infinite set of solutions, which can be identified using the generalized inverse (Moore-Penrose pseudoinverse). We consider two further special approaches. For large networks we find that shortestpath is superior with respect to run time and variability, compared to the other approaches, and is thus recommended in practice. The path-weights framework also has the potential to answer more general research questions in NMA., (© 2024 The Author(s). Statistics in Medicine published by John Wiley & Sons Ltd.)

We aimed to assess the performance of Ag-RDT and RT-qPCR with regard to detecting infectious SARS-CoV-2 in cell cultures, as their diagnostic test accuracy (DTA) compared to virus isolation remains largely unknown. We searched three databases up to 15 December 2021 for DTA studies. The bivariate model was used to synthesise the estimates. Risk of bias was assessed using QUADAS-2/C. Twenty studies (2605 respiratory samples) using cell culture and at least one molecular test were identified. All studies were at high or unclear risk of bias in at least one domain. Three comparative DTA studies reported results on Ag-RDT and RT-qPCR against cell culture. Two studies evaluated RT-qPCR against cell culture only. Fifteen studies evaluated Ag-RDT against cell culture as reference standard in RT-qPCR-positive samples. For Ag-RDT, summary sensitivity was 93% (95% CI 78; 98%) and specificity 87% (95% CI 70; 95%). For RT-qPCR, summary sensitivity (continuity-corrected) was 98% (95% CI 95; 99%) and specificity 45% (95% CI 28; 63%). In studies relying on RT-qPCR-positive subsamples (n = 15), the summary sensitivity of Ag-RDT was 93% (95% CI 92; 93%) and specificity 63% (95% CI 63; 63%). Ag-RDT show moderately high sensitivity, detecting most but not all samples demonstrated to be infectious based on virus isolation. Although RT-qPCR exhibits high sensitivity across studies, its low specificity to indicate infectivity raises the question of its general superiority in all clinical settings. Study findings should be interpreted with caution due to the risk of bias, heterogeneity and the imperfect reference standard for infectivity., (© 2024 The Author(s). Reviews in Medical Virology published by John Wiley & Sons Ltd.)

The LFK index has been promoted as an improved method to detect bias in meta-analysis. Putatively, its performance does not depend on the number of studies in the meta-analysis. We conducted a simulation study, comparing the LFK index test to three standard tests for funnel plot asymmetry in settings with smaller or larger group sample sizes. In general, false positive rates of the LFK index test markedly depended on the number and size of studies as well as the between-study heterogeneity with values between 0% and almost 30%. Egger's test adhered well to the pre-specified significance level of 5% under homogeneity, but was too liberal (smaller groups) or conservative (larger groups) under heterogeneity. The rank test was too conservative for most simulation scenarios. The Thompson-Sharp test was too conservative under homogeneity, but adhered well to the significance level in case of heterogeneity. The true positive rate of the LFK index test was only larger compared with classic tests if the false positive rate was inflated. The power of classic tests was similar or larger than the LFK index test if the false positive rate of the LFK index test was used as significance level for the classic tests. Under ideal conditions, the false positive rate of the LFK index test markedly and unpredictably depends on the number and sample size of studies as well as the extent of between-study heterogeneity. The LFK index test in its current implementation should not be used to assess funnel plot asymmetry in meta-analysis., (© 2024 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and "symptomatic" etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The placebo effect is the 'effect of the simulation of treatment that occurs due to a participant's belief or expectation that a treatment is effective'. Although the effect might be of little importance for some conditions, it can have a great role in others, mostly when the evaluated symptoms are subjective. Several characteristics that include informed consent, number of arms in a study, the occurrence of adverse events and quality of blinding may influence response to placebo and possibly bias the results of randomised controlled trials. Such a bias is inherited in systematic reviews of evidence and their quantitative components, pairwise meta-analysis (when two treatments are compared) and network meta-analysis (when more than two treatments are compared). In this paper, we aim to provide red flags as to when a placebo effect is likely to bias pairwise and network meta-analysis treatment effects. The classic paradigm has been that placebo-controlled randomised trials are focused on estimating the treatment effect. However, the magnitude of placebo effect itself may also in some instances be of interest and has also lately received attention. We use component network meta-analysis to estimate placebo effects. We apply these methods to a published network meta-analysis, examining the relative effectiveness of four psychotherapies and four control treatments for depression in 123 studies., Competing Interests: Competing interests: TAF reports personal fees from Boehringer Ingelheim, DT Axis, Kyoto University Original, Shionogi and SONY, and a grant from Shionogi, outside the submitted work. In addition, TAF has patents 2020-548587 and 2022-082495 pending, and intellectual properties for Kokoro-app licensed to Mitsubishi Tanabe., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Shivering is a common side effect after general anesthesia. Risk factors are hypothermia, young age and postoperative pain. Severe complications of shivering are rare but can occur due to increased oxygen consumption. Previous systematic reviews are outdated and have summarized the evidence on the topic using only pairwise comparisons. The objective of this manuscript was a quantitative synthesis of evidence on pharmacological interventions to treat postanesthetic shivering., Evidence Acqusition: Systematic review and frequentist network meta-analysis using the R package netmeta. Endpoints were the risk ratio (RR) of persistent shivering at one, five and 10 minutes after treatment with saline/placebo as the comparator. Data were retrieved from Medline, Embase, Central and Web of Science up to January 2022. Eligibility criteria were: randomized, controlled, and blinded trials comparing pharmacological interventions to treat shivering after general anesthesia. Studies on shivering during or after any type of regional anesthesia were excluded as well as sedated patients after cardiac surgery., Evidence Synthesis: Thirty-two trials were eligible for data synthesis, including 28 pharmacological interventions. The largest network included 1431 patients. The network geometry was two-centered with most comparisons linked to saline/placebo or pethidine. The best interventions were after one minute: doxapram 2 mg/kg, tramadol 2 mg/kg and nefopam 10 mg, after 5 minutes: tramadol 2 mg/kg, nefopam 10 mg and clonidine 150 µg and after 10 minutes: nefopam 10 mg, methylphenidate 20 mg and tramadol 1 mg/kg, all reaching statistical significance. Pethidine 25 mg and clonidine 75 µg also performed well and with statistical significance in all networks., Conclusions: Nefopam, tramadol, pethidine and clonidine are the most effective treatments to stop postanesthetic shivering. The efficacy of doxapram is uncertain since different doses showed contradictory effects and the evidence for methylphenidate is based on a single comparison in only one network. Furthermore, both lack data on side effects. Further studies are needed to clarify the efficacy of dexmedetomidine to treat postanesthetic shivering.

Poisoning of children requires quick and rational action. It is crucial to recognize a poisoning, to interpret the symptoms correctly, and to assess the severity of the poisoning as precisely as possible. This is the best way to find the optimal therapy for each patient.Cases of suspected poisoning are common in childhood. The risk of a potential poisoning must be recognized and interpreted correctly. Based on this, symptomatic and specific therapy can be carried out. The poisons information centres have a great experience in the diagnosis and treatment of poisonings and can help the attending physicians to plan the further therapeutic steps.Both the hazard of a toxic substance and a realistic exposure assessment must be considered. This is especially crucial in cases of suspected poisoning of (still) mostly asymptomatic patients. This is the way to prevent overtreatment without overlooking dangerous poisonings., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: nein; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Network meta-analysis (NMA) allows estimating and ranking the effects of several interventions for a clinical condition. Component network meta-analysis (CNMA) is an extension of NMA which considers the individual components of multicomponent interventions. CNMA allows to "reconnect" a disconnected network with common components in subnetworks. An additive CNMA assumes that component effects are additive. This assumption can be relaxed by including interaction terms in the CNMA., Methods: We evaluate a forward model selection strategy for component network meta-analysis to relax the additivity assumption that can be used in connected or disconnected networks. In addition, we describe a procedure to create disconnected networks in order to evaluate the properties of the model selection in connected and disconnected networks. We apply the methods to simulated data and a Cochrane review on interventions for postoperative nausea and vomiting in adults after general anaesthesia. Model performance is compared using average mean squared errors and coverage probabilities., Results: CNMA models provide good performance for connected networks and can be an alternative to standard NMA if additivity holds. For disconnected networks, we recommend to use additive CNMA only if strong clinical arguments for additivity exist., Conclusions: CNMA methods are feasible for connected networks but questionable for disconnected networks., (© 2023. The Author(s).)

Objective: To determine equianalgesic potency ratios for opioids with an -evidence-based approach without the use of pre-existing potency tables., Design: Frequentist network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing opioids in patient-controlled analgesia (PCA)., Setting: A systematic review., Data Sources: A systematic search of MEDLINE, EMBASE, the Cochrane Library (CENTRAL), and Web of Science identified relevant RCTs from start of recording to 2019., Eligibility Criteria: RCTs comparing opioids via intravenous PCA in acute pain, with comparable resulting pain scores and identical treatment with coanalgesics at study level. The quality of studies was assessed using the Cochrane risk of bias tool with six items., Results: 52 RCTs were identified with data for 16 opioids. Primary endpoint was the inverted ratio of means of the total consumption administered via PCA, which resembles the analgesic potency. The calculated analgesic potencies were sufentanil 423 [95 percent CI 334.99; 532.96], fentanyl 58 [48.22; 68.60], buprenorphine 37 [26.66; 50.81], remifentanil 13 [9.37; 19.13], alfentanil 7 [4.02; 11.01], hydromorphone 6 [4.96; 8.43], oxymorphone 6 [4.46; 8.84], butorphanol 4.5 [3.05; 6.73], diamorphine 2.2 [1.16; 4.10], morphine 1, oxycodone 0.9 [0.65; 1.34], piritramide 0.9 [0.55; 1.56], nalbuphine 0.7 [0.54; 0.95], pethidine 0.12 [0.10; 0.15], meptazinol 0.08 [0.03; 0.20], and tramadol 0.08 [0.07; 0.10]., Conclusions: The results in part contradict the values from the literature, which have been criticized for their imprecision. From clinical experience however, our findings seem very plausible. Short-acting opioids are less potent compared to longer acting drugs, eg, morphine, probably due to shorter intervals for -readministration.

The cornerstone of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is reverse-transcription polymerase chain reaction (RT-PCR) of viral RNA. As a surrogate assay SARS-CoV-2 RNA detection does not necessarily imply infectivity. Only virus isolation in permissive cell culture systems can indicate infectivity. Here, we review the evidence on RT-PCR performance in detecting infectious SARS-CoV-2. We searched for any studies that used RT-PCR and cell culture to determine infectious SARS-CoV-2 in respiratory samples. We assessed (i) diagnostic accuracy of RT-PCR compared to cell culture as reference test, (ii) performed meta-analysis of positive predictive values (PPV) and (iii) determined the virus isolation probabilities depending on cycle threshold (Ct) or log 10 genome copies/ml using logistic regression. We included 55 studies. There is substantial statistical and clinical heterogeneity. Seven studies were included for diagnostic accuracy. Sensitivity ranged from 90% to 99% and specificity from 29% to 92%. In meta-analysis, the PPVs varied across subgroups with different sampling times after symptom onset, with 1% (95% confidence interval [CI], 0%-7%) in sampling beyond 10 days and 27% (CI, 19%-36%) to 46% (CI, 33%-60%) in subgroups that also included earlier samples. Estimates of virus isolation probability varied between 6% (CI, 0%-100%) and 50% (CI, 0%-100%) at a Ct value of 30 and between 0% (CI, 0%-22%) and 63% (CI, 0%-100%) at 5 log 10 genome copies/ml. Evidence on RT-PCR performance in detecting infectious SARS-CoV-2 in respiratory samples was limited. Major limitations were heterogeneity and poor reporting. RT-PCR and cell culture protocols need further standardisation., (© 2022 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.)

Purpose: Ovarian cancer is the seventh most frequent form of malignant diseases in women worldwide and over 150,000 women die from it every year. More than 70 percent of all ovarian cancer patients are diagnosed at a late-stage disease with poor prognosis necessitating the development of sufficient screening biomarkers. MicroRNAs displayed promising potential as early diagnostics in various malignant diseases including ovarian cancer. The presented study aimed at identifying single microRNAs and microRNA combinations detecting ovarian cancer in vitro and in vivo., Methods: Intracellular, extracellular and urinary microRNA expression levels of twelve microRNAs (let-7a, let-7d, miR-10a, miR-15a, miR-15b, miR-19b, miR-20a, miR-21, miR-100, miR-125b, miR-155, miR-222) were quantified performing quantitative real-time-PCR. Therefore, the three ovarian cancer cell lines SK-OV-3, OAW-42, EFO-27 as well as urine samples of ovarian cancer patients and healthy controls were analyzed., Results: MiR-15a, miR-20a and miR-222 showed expression level alterations extracellularly, whereas miR-125b did intracellularly across the analyzed cell lines. MicroRNA expression alterations in single cell lines suggest subtype specificity in both compartments. Hypoxia and acidosis showed scarce effects on single miRNA expression levels only. Furthermore, we were able to demonstrate the feasibility to clearly detect the 12 miRNAs in urine samples. In urine, miR-15a was upregulated whereas let-7a was down-regulated in ovarian cancer patients., Conclusion: Intracellular, extracellular and urinary microRNA expression alterations emphasize their great potential as biomarkers in liquid biopsies. Especially, miR-15a and let-7a qualify for possible circulating biomarkers in liquid biopsies of ovarian cancer patients., (© 2021. The Author(s).)

Network meta-analysis can synthesize evidence from studies comparing multiple treatments for the same disease. Sometimes the treatments of a network are complex interventions, comprising several independent components in different combinations. A component network meta-analysis (CNMA) can be used to analyze such data and can in principle disentangle the individual effect of each component. However, components may interact with each other, either synergistically or antagonistically. Deciding which interactions, if any, to include in a CNMA model may be difficult, especially for large networks with many components. In this article, we present two Bayesian CNMA models that can be used to identify prominent interactions between components. Our models utilize Bayesian variable selection methods, namely the stochastic search variable selection and the Bayesian LASSO, and can benefit from the inclusion of prior information about important interactions. Moreover, we extend these models to combine data from studies providing aggregate information and studies providing individual patient data (IPD). We illustrate our models in practice using three real datasets, from studies in panic disorder, depression, and multiple myeloma. Finally, we describe methods for developing web-applications that can utilize results from an IPD-CNMA, to allow for personalized estimates of relative treatment effects given a patient's characteristics., (© 2022 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Introduction: Patients with inflammatory bowel diseases (IBD) often report psychological problems, unemployment, disability, sick leave and compromised quality of life. The effect of psychological interventions on health-related outcomes in IBD is controversial as previous reviews faced the obstacle of high heterogeneity among provided multimodular interventions. The heterogeneity can be addressed with network meta-analysis (NMA) and (multi)component NMA (CNMA). We aim to investigate whether psychological interventions can improve quality of life, clinical and social outcomes in IBD using NMA and CNMA. This is the study protocol., Methods and Analysis: We will consider randomised, quasi-randomised and non-randomised controlled trials, including cluster randomised and cross-over trials with 2 months of minimum follow-up. The conditions to be studied comprise Crohn's disease and ulcerative colitis in children, adolescents and adults. We will include any psychological intervention aiming to change the health status of the study participant.We will search Medline, Embase, Web of Science, CENTRAL, LILACS, Psyndex, PsycINFO, Google Scholar and trial registries from inception (the search will be updated before the review completion). Two authors will independently screen all references based on titles and abstracts. For data extraction, standard forms are developed and tested before extraction. All information will be assessed independently by at least two reviewers, and disagreements solved by consensus discussion or a third rater if necessary.The data synthesis will include a pairwise meta-analysis supported by meta-regression. We will conduct NMA (all treatments will constitute single nodes of the network) and CNMA (we will define all treatments as sums of core components, eg, cognitive +behaviour, or cognitive +behaviour + relaxation, and additionally consider interactions) using the R Package netmeta., Ethics and Dissemination: No ethical approval is required. Reports will include the final report to the funder, conference presentation, peer-reviewed publication and a patient report., Prospero Registration Number: CRD42021250446., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)