-
The Lancet. Gastroenterology &... Dec 2021Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease.
METHODS
We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (≥18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register of Controlled Trials, conference proceedings, trial registries, and unpublished data from inception to June 3, 2021, without any language restrictions. Summary estimates of the primary and secondary outcomes were extracted from the published reports; individual patient-level data were not sought. The primary endpoint was induction of clinical remission in patients with active disease (CDAI <150) and maintenance of remission in patients with response to induction therapy, with data extracted from published reports. A network meta-analysis with multivariate consistency model random-effects meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values.
FINDINGS
The search strategy yielded 18 382 citations, of which 31 trials were eligible for inclusion. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4·53 [95% CI 1·49-13·79]), infliximab combined with azathioprine (7·49 [2·04-27·49]), adalimumab (3·01 [1·25-7·27]), and ustekinumab (2·63 [1·10-6·28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol (all moderate confidence); infliximab and azathioprine combination therapy was also associated with significantly higher odds of inducing remission than vedolizumab (3·76 [1·01-14·03]; low confidence). On the basis of ten randomised controlled trials including 2479 patients with previous biologic exposure, adalimumab after loss of response to infliximab (OR 2·82 [95% CI 1·20-6·62]; low confidence), and risankizumab (2·10 [1·12-3·92]; moderate confidence), were associated with higher odds of inducing remission than vedolizumab. No differences between active interventions were observed in maintenance trials. Most trials were at low or uncertain risk of bias.
INTERPRETATION
Although biologic treatment choices in patients with moderate-to-severe Crohn's disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission.
FUNDING
None.
Topics: Adalimumab; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Benzene Derivatives; Biological Therapy; Carboxylic Acids; Case-Control Studies; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infliximab; Interleukin-12 Subunit p40; Interleukin-23 Subunit p19; Male; Network Meta-Analysis; Placebos; Randomized Controlled Trials as Topic; Remission Induction; Safety; Severity of Illness Index; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Ustekinumab
PubMed: 34688373
DOI: 10.1016/S2468-1253(21)00312-5 -
The Lancet. Gastroenterology &... Feb 2022There is a growing armamentarium for the treatment of moderate-to-severe ulcerative colitis. We aimed to compare the relative efficacy and safety of biologics and small... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There is a growing armamentarium for the treatment of moderate-to-severe ulcerative colitis. We aimed to compare the relative efficacy and safety of biologics and small molecule drugs for the treatment of patients with moderate-to-severe ulcerative colitis.
METHODS
In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials without language restrictions for articles published between Jan 1, 1990, and July 1, 2021. Major congresses' databases from Jan 1, 2018, to July 3, 2021, were reviewed manually. Phase 3, placebo-controlled or head-to-head randomised controlled trials (RCTs) assessing the efficacy and safety of biologics or small molecule drugs as induction or maintenance therapies for patients with moderate-to-severe ulcerative colitis were included. Phase 2 RCTs were excluded because of their small sample sizes and inclusion of doses not further explored in phase 3 RCTs. Summary data from intention-to-treat analyses were extracted from included reports by JSL and PAO. The primary outcome was the induction of clinical remission. A network meta-analysis was done under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% CIs. The surface under the cumulative ranking (SUCRA) was used to rank the included agents for each outcome. Higher SUCRA scores correlate with better efficacy, whereas lower SUCRA scores correlate with better safety. Maintenance data on efficacy for treat-straight-through and randomised responder trials are also presented. This study is registered with PROSPERO, CRD42021225329.
FINDINGS
Our search yielded 5904 results, from which 29 studies (four being head-to-head RCTs) fulfilled our inclusion criteria and were included. Of these, 23 studies assessed induction therapy with either a biologic or small molecule drug, comprising 10 061 patients with ulcerative colitis. A risk of bias assessment showed a low risk of bias for most of the included studies. Upadacitinib was significantly superior to all other interventions for the induction of clinical remission (infliximab [OR 2·70, 95% CI 1·18-6·20], adalimumab [4·64, 2·47-8·71], golimumab [3·00, 1·32-6·82], vedolizumab [3·56, 1·84-6·91], ustekinumab [2·92, 1·31-6·51], etrolizumab [4·91, 2·59-9·31], tofacitinib [2·84, 1·28-6·31], filgotinib 100 mg [6·15, 2·98-12·72], filgotinib 200 mg [4·49, 2·18-9·24], and ozanimod (2·70, 1·18-6·20), and ranked highest for the induction of clinical remission (SUCRA 0·996). No differences between active interventions were observed when assessing adverse events and serious adverse events. Vedolizumab ranked lowest for both adverse events (SUCRA 0·184) and serious adverse events (0·139), whereas upadacitinib ranked highest for adverse events (0·843) and ozanimod ranked highest for serious adverse events (0·831).
INTERPRETATION
Upadacitinib was the best performing agent for the induction of clinical remission (the primary outcome) but the worst performing agent in terms of adverse events in patients with moderate-to-severe ulcerative colitis. Vedolizumab was the best performing agent for safety outcomes. With the paucity of direct comparisons in the published literature, our results might help clinicians to position drugs in treatment algorithms.
FUNDING
None.
Topics: Biological Products; Colitis, Ulcerative; Humans; Severity of Illness Index
PubMed: 34856198
DOI: 10.1016/S2468-1253(21)00377-0 -
Gut Feb 2023There are numerous biological therapies and small molecules licensed for luminal Crohn's disease (CD), but these are often studied in placebo-controlled trials, meaning... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
There are numerous biological therapies and small molecules licensed for luminal Crohn's disease (CD), but these are often studied in placebo-controlled trials, meaning relative efficacy is uncertain. We examined this in a network meta-analysis.
DESIGN
We searched the literature to 1 July 2022, judging efficacy according to induction of clinical remission, clinical response and maintenance of clinical remission, and according to previous exposure or non-exposure to biologics. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs, ranking drugs according to p-score.
RESULTS
We identified 25 induction of remission trials (8720 patients). Based on failure to achieve clinical remission, infliximab 5 mg/kg ranked first versus placebo (RR=0.67, 95% CI 0.56 to 0.79, p-score 0.95), with risankizumab 600 mg second and upadacitinib 45 mg once daily third. However, risankizumab 600 mg ranked first for clinical remission in biologic-naïve (RR=0.66, 95% CI 0.52 to 0.85, p-score 0.78) and in biologic-exposed patients (RR=0.74, 95% CI 0.67 to 0.82, p-score 0.92). In 15 maintenance of remission trials (4016 patients), based on relapse of disease activity, upadacitinib 30 mg once daily ranked first (RR=0.61, 95% CI 0.52 to 0.72, p-score 0.93) with adalimumab 40 mg weekly second, and infliximab 10 mg/kg 8-weekly third. Adalimumab 40 mg weekly ranked first in biologic-naïve patients (RR=0.59, 95% CI 0.48 to 0.73, p-score 0.86), and vedolizumab 108 mg 2-weekly first in biologic-exposed (RR=0.70, 95% CI 0.57 to 0.86, p-score 0.82).
CONCLUSION
In a network meta-analysis, infliximab 5 mg/kg ranked first for induction of clinical remission in all patients with luminal CD, but risankizumab 600 mg was first in biologic-naïve and biologic-exposed patients. Upadacitinib 30 mg once daily ranked first for maintenance of remission.
Topics: Humans; Crohn Disease; Adalimumab; Infliximab; Network Meta-Analysis; Biological Therapy; Remission Induction
PubMed: 35907636
DOI: 10.1136/gutjnl-2022-328052 -
Archives of Physical Medicine and... Nov 2023To Identify evidence-based rehabilitation interventions for persons with non-specific low back pain (LBP) with and without radiculopathy and to develop recommendations... (Review)
Review
A Systematic Review of Clinical Practice Guidelines for Persons With Non-specific Low Back Pain With and Without Radiculopathy: Identification of Best Evidence for Rehabilitation to Develop the WHO's Package of Interventions for Rehabilitation.
OBJECTIVE
To Identify evidence-based rehabilitation interventions for persons with non-specific low back pain (LBP) with and without radiculopathy and to develop recommendations from high-quality clinical practice guidelines (CPGs) to inform the World Health Organization's (WHO) Package of Interventions for Rehabilitation (PIR).
DATA SOURCE
We searched MEDLINE, EMBASE, CINAHL, PsycINFO, National Health Services Economic Evaluation Database, Health Technology Assessment Database, PEDro, the Trip Database, the Index to Chiropractic Literature and the gray literature.
STUDY SELECTION
Eligible guidelines were (1) published between 2009 and 2019 in English, French, Italian, or Swedish; (2) included adults or children with non-specific LBP with or without radiculopathy; and (3) assessed the benefits of rehabilitation interventions on functioning. Pairs of independent reviewers assessed the quality of the CPGs using AGREE II.
DATA SYNTHESIS
We identified 4 high-quality CPGs. Recommended interventions included (1) education about recovery expectations, self-management strategies, and maintenance of usual activities; (2) multimodal approaches incorporating education, exercise, and spinal manipulation; (3) nonsteroidal anti-inflammatory drugs combined with education in the acute stage; and (4) intensive interdisciplinary rehabilitation that includes exercise and cognitive/behavioral interventions for persistent pain. We did not identify high-quality CPGs for people younger than 16 years of age.
CONCLUSION
We developed evidence-based recommendations from high-quality CPGs to inform the WHO PIR for people with LBP with and without radiculopathy. These recommendations emphasize the potential benefits of education, exercise, manual therapy, and cognitive/behavioral interventions.
Topics: Adult; Child; Humans; Radiculopathy; Low Back Pain; Musculoskeletal Manipulations; World Health Organization
PubMed: 36963709
DOI: 10.1016/j.apmr.2023.02.022 -
Phytomedicine : International Journal... Jul 2022Cancer-related insomnia is a highly prevalent complaint in cancer patients. However, there is no meta-analytic synthesis explored the efficacy of acupuncture for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cancer-related insomnia is a highly prevalent complaint in cancer patients. However, there is no meta-analytic synthesis explored the efficacy of acupuncture for cancer-related insomnia among cancer patients undergoing active cancer treatments.
OBJECTIVE
This systematic review and meta-analysis were performed to explore the efficacy and safety of acupuncture for insomnia in people diagnosed with cancer.
STUDY DESIGN
Systematic review and meta-analysis of existing randomized controlled trials on acupuncture in the treatment of cancer-related insomnia.
METHODS
According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement, we identified and extracted the trials through November 2021 from ten databases and two trials record platforms (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PUBMED, Web of Science, PsycINFO, Allied and Complementary Medicine, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, Wanfang Digital Journals, ClinicalTrials, World Health Organization International Clinical Trials Registry Platform). The quality of the trials was assessed using Jadad score and Risk of Bias (2.0). A meta-analysis was synthesized using the random-effects model if the included studies were in high methodological quality.
RESULTS
A total of 690 studies were identified, with 22 were included in the review, and 6 of them were included in the quantitative synthesis. Studies were highly heterogeneous in terms of participant characteristics and study methodologies. Most studies recruited patients diagnosed with a specific cancer type, and breast cancer patients were the subgroup most represented. The qualitative review of available evidence suggested a beneficial efficacy of acupuncture on sleep without serious adverse events in several studies (55%). The meta-analysis revealed that acupuncture produced a significant improvement in the total Pittsburgh Sleep Quality Index (PSQI) score relative to the wait-list control among breast cancer patients undergoing active cancer treatments (MD -1.92, 95% CI -3.25 to -0.59, p = 0.005). Similar improvement of real and sham acupuncture on PSQI score change post-intervention was found (MD: -0.68, 95% CI: -2.44 to 1.07, p = 0.44). Manual acupuncture had similar effective rate as compared to estazolam immediately post-intervention (RR: 0.94, 95% CI: 0.87 to 1.01, p = 0.09), and had significantly better effective rate than estazolam at 1-week post-intervention follow-up (RR: 1.25, 95% CI: 1.10 to 1.43, p = 0.0009). All reported acupuncture related adverse events were mild or moderate in severity.
CONCLUSION
Acupuncture has great potential to be used to manage cancer-related insomnia for cancer patients or survivors. More studies with rigorous designs and larger sample size are warranted to verify the efficacy and safety of acupuncture for insomnia among people diagnosed with cancer, in particular among those with clinically significant insomnia.
REGISTRATION
PROSPERO (ID: CRD42021285844).
Topics: Acupuncture Therapy; Breast Neoplasms; China; Estazolam; Female; Humans; Sleep Initiation and Maintenance Disorders
PubMed: 35636168
DOI: 10.1016/j.phymed.2022.154160 -
Journal of Sleep Research Dec 2023In the management of insomnia, physicians and patients are seeking alternative therapeutics to sleeping pills, in addition to sleep hygiene and cognitive behavioural... (Meta-Analysis)
Meta-Analysis Review
In the management of insomnia, physicians and patients are seeking alternative therapeutics to sleeping pills, in addition to sleep hygiene and cognitive behavioural therapy. Bright light therapy (LT) has proven its efficacy in circadian and mood disorders. We conducted a systematic literature review and meta-analysis according to Cochrane and PRISMA guidelines and using the databases Medline, Cochrane, and Web of Science, with a special focus on light therapy and insomnia. Twenty-two studies with a total of 685 participants were included, five of which with a high level of proof. Meta-analysis was performed with 13 of them: light therapy for insomnia compared with control conditions significantly improved wake after sleep onset (WASO: SMD = -0.61 [-1.11, -0.11]; p = 0.017; weighted difference of 11.2 min ±11.5 based on actigraphy, and SMD = -1.09 [-1.43, -0.74] (p < 0.001) weighted difference of -36.4 min ±15.05) based on sleep diary, but no other sleep measures such as sleep latency, total sleep time (TST), or sleep efficiency. Qualitative analysis of the review showed some improvement mainly in subjective measures. Morning light exposure advanced sleep-wake rhythms and evening exposure led to a delay. No worsening was observed in objective nor subjective measures, except for TST in one study with evening exposure. A light dose-response may exist but the studies' heterogeneity and publication bias limit the interpretation. To conclude, light therapy shows some effectiveness for sleep maintenance in insomnia disorders, but further research is needed to refine the light parameters to be chosen according to the type of insomnia, in the hope of developing personalised therapeutics.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Sleep; Phototherapy; Cognitive Behavioral Therapy; Polysomnography; Treatment Outcome
PubMed: 37002704
DOI: 10.1111/jsr.13895 -
Resuscitation Oct 2021To perform a systematic review and meta-analysis on targeted temperature management in adult cardiac arrest patients. (Meta-Analysis)
Meta-Analysis Review
AIM
To perform a systematic review and meta-analysis on targeted temperature management in adult cardiac arrest patients.
METHODS
PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched on June 17, 2021 for clinical trials. The population included adult patients with cardiac arrest. The review included all aspects of targeted temperature management including timing, temperature, duration, method of induction and maintenance, and rewarming. Two investigators reviewed trials for relevance, extracted data, and assessed risk of bias. Data were pooled using random-effects models. Certainty of evidence was evaluated using GRADE.
RESULTS
The systematic search identified 32 trials. Risk of bias was assessed as intermediate for most of the outcomes. For targeted temperature management with a target of 32-34 °C vs. normothermia (which often required active cooling), 9 trials were identified, with six trials included in meta-analyses. Targeted temperature management with a target of 32-34 °C did not result in an improvement in survival (risk ratio: 1.08 [95%CI: 0.89, 1.30]) or favorable neurologic outcome (risk ratio: 1.21 [95%CI: 0.91, 1.61]) at 90 to 180 days after the cardiac arrest (low certainty of evidence). Three trials assessed different hypothermic temperature targets and found no difference in outcomes (low certainty of evidence). Ten trials were identified comparing prehospital cooling vs. no prehospital cooling with no improvement in survival (risk ratio: 1.01 [95%CI: 0.92, 1.11]) or favorable neurologic outcome (risk ratio: 1.00 [95%CI: 0.90, 1.11]) at hospital discharge (moderate certainty of evidence).
CONCLUSIONS
Among adult patients with cardiac arrest, the use of targeted temperature management at 32-34 °C, when compared to normothermia, did not result in improved outcomes in this meta-analysis. There was no effect of initiating targeted temperature management prior to hospital arrival. These findings warrant an update of international cardiac arrest guidelines.
Topics: Adult; Cardiopulmonary Resuscitation; Cold Temperature; Heart Arrest; Humans; Hypothermia, Induced
PubMed: 34474143
DOI: 10.1016/j.resuscitation.2021.08.040 -
Intensive Care Medicine Dec 2022Intravenous maintenance fluid therapy (IV-MFT) prescribing in acute and critically ill children is very variable among pediatric health care professionals. In order to... (Meta-Analysis)
Meta-Analysis
PURPOSE
Intravenous maintenance fluid therapy (IV-MFT) prescribing in acute and critically ill children is very variable among pediatric health care professionals. In order to provide up to date IV-MFT guidelines, the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) undertook a systematic review to answer the following five main questions about IV-MFT: (i) the indications for use (ii) the role of isotonic fluid (iii) the role of balanced solutions (iv) IV fluid composition (calcium, magnesium, potassium, glucose and micronutrients) and v) and the optimal amount of fluid.
METHODS
A multidisciplinary expert group within ESPNIC conducted this systematic review using the Scottish Intercollegiate Guidelines Network (SIGN) grading method. Five databases were searched for studies that answered these questions, in acute and critically children (from 37 weeks gestational age to 18 years), published until November 2020. The quality of evidence and risk of bias were assessed, and meta-analyses were undertaken when appropriate. A series of recommendations was derived and voted on by the expert group to achieve consensus through two voting rounds.
RESULTS
56 papers met the inclusion criteria, and 16 recommendations were produced. Outcome reporting was inconsistent among studies. Recommendations generated were based on a heterogeneous level of evidence, but consensus within the expert group was high. "Strong consensus" was reached for 11/16 (69%) and "consensus" for 5/16 (31%) of the recommendations.
CONCLUSIONS
Key recommendations are to use isotonic balanced solutions providing glucose to restrict IV-MFT infusion volumes in most hospitalized children and to regularly monitor plasma electrolyte levels, serum glucose and fluid balance.
Topics: Infant, Newborn; Child; Humans; Critical Illness; Fluid Therapy; Isotonic Solutions; Infusions, Intravenous; Glucose
PubMed: 36289081
DOI: 10.1007/s00134-022-06882-z -
Journal of Evidence-based Integrative... 2020Sleep problems are widely prevalent and associated with various comorbidities including anxiety. Valerian ( L.) is a popular herbal medicine used as a sleep aid, however... (Meta-Analysis)
Meta-Analysis
Sleep problems are widely prevalent and associated with various comorbidities including anxiety. Valerian ( L.) is a popular herbal medicine used as a sleep aid, however the outcomes of previous clinical studies are inconsistent. This study was conducted to update and re-evaluate the available data in order to understand the reason behind the inconsistent outcomes and to provide a broader view of the use of valerian for associated disorders. PubMed, ScienceDirect, and Cochrane Library were searched to retrieve publications relevant to the effectiveness of valerian as a treatment of sleep problems and associated disorders. A total of 60 studies (n=6,894) were included in this review, and meta-analyses were performed to evaluate the effectiveness to improve subjective sleep quality (10 studies, n=1,065) and to reduce anxiety (8 studies, n=535). Results suggested that inconsistent outcomes were possibly due to the variable quality of herbal extracts and that more reliable effects could be expected from the whole root/rhizome. In addition, therapeutic benefits could be optimized when it was combined with appropriate herbal partners. There were no severe adverse events associated with valerian intake in subjects aged between 7 and 80 years. In conclusion, valerian could be a safe and effective herb to promote sleep and prevent associated disorders. However, due to the presence of multiple active constituents and relatively unstable nature of some of the active constituents, it may be necessary to revise the quality control processes, including standardization methods and shelf life.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anxiety; Anxiety Disorders; Child; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Phytotherapy; Plant Extracts; Plant Roots; Rhizome; Sleep; Sleep Initiation and Maintenance Disorders; Valerian; Young Adult
PubMed: 33086877
DOI: 10.1177/2515690X20967323 -
The Journal of Allergy and Clinical... Apr 2023A growing number of studies have shown encouraging results with omalizumab (OMA) as monotherapy and as an adjunct to oral immunotherapy (OMA+OIT) in patients with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A growing number of studies have shown encouraging results with omalizumab (OMA) as monotherapy and as an adjunct to oral immunotherapy (OMA+OIT) in patients with single/multiple food allergies.
OBJECTIVES
To evaluate the efficacy and safety of OMA or OMA+OIT in patients with immunoglobulin E (IgE)-mediated food allergy.
METHODS
An extensive literature search (inception to December 31, 2020) was performed to identify randomized, controlled, and observational studies that assessed OMA as monotherapy or OMA+OIT in patients with IgE-mediated food allergy. The outcomes were an increase in tolerated dose of foods, successful desensitization, sustained unresponsiveness, immunological biomarkers, severity of allergic reactions to food, quality of life (QoL), and safety. A P less than .05 was considered significant.
RESULTS
In total, 36 studies were included. The OMA monotherapy (vs pre-OMA) significantly increased the tolerated dose of multiple foods; increased the threshold of tolerated dose for milk, egg, wheat, and baked milk; improved QoL; and reduced food-induced allergic reactions (all P < .01). The OMA+OIT significantly increased the tolerated dose of multiple foods (vs placebo and pre-OMA), desensitization (vs placebo+OIT and pre-OMA) (all P ≤ .01), and improved QoL (vs pre-OMA) and immunoglobulin G4 levels (both P < .01). No major safety concerns were identified.
CONCLUSIONS
In IgE-mediated food allergy, OMA can help patients consume multiple foods and allow for food dose escalation. As an adjunct to OIT, OMA can also support high-dose desensitization and higher maintenance doses. Further studies are warranted to empirically evaluate the effect of OMA and confirm these findings.
Topics: Humans; Animals; Omalizumab; Quality of Life; Immunoglobulin E; Desensitization, Immunologic; Administration, Oral; Food Hypersensitivity; Allergens; Milk
PubMed: 36529441
DOI: 10.1016/j.jaip.2022.11.036