Tag: clinical trial

Response to treatment in the Multiple Symptoms Study 3 trial

Letter:
Chistopher Burton and colleagues conducted an unblinded trial of a consultative intervention for 354 people with persistent physical symptoms but no identifiable “organic” cause. Patient Health Questionnaire-15 (PHQ-15) score, which is a brief, subjective, self-administered screen of severity of somatic complaints, was the primary outcome. This kind of trial design can be expected to produce modest positive outcomes, via expectation bias alone. No real-life, objective assessment of functioning was conducted.
The intervention involved up to four sessions with a general practitioner, offering patients “rational explanations” for their symptoms in the absence of known, falsifiable causes and helping patients to develop strategies for managing symptoms. Although the “rational explanations” are not described, they presumably did not include “organic” diseases or conditions.
Scores on the PHQ-15 range from 0 to 30. Recruited patients had scores from 10 to 20, indicating moderate severity. At the end of the study, the adjusted between-group difference of –1·82 did not reach the minimal clinically important difference of 2·3. The change is well within what would be expected from bias alone. The results therefore confirmed that the intervention was of limited, if any, practical benefit. However, the paper presents the findings as though they had shown the opposite.
Instead of the “rational explanations” promoted by the investigators, more straightforward and honest explanations—for example, we do not know what is causing symptoms—could easily have produced similar results. Patients desire resolution of symptoms and recovery of functions. The trial did not achieve this result. Post-intervention, participants continue to have an impaired quality of life and poor experiences of health care.
DT holds an academic position at the Center for Global Public Health at UC Berkeley, which is largely supported by crowdfunded donations directly to the university, many of them from patients with myalgic encephalomyelitis or chronic fatigue syndrome and related conditions that fall under the heading of persistent physical symptoms. JSC declares no competing interests.
Source: Joan S Crawford and David Tuller. Response to treatment in the Multiple Symptoms Study 3 trial.  The Lancet, Volume 405, Issue 10485, 1145 – 1146  https://link.springer.com/article/10.1007/s00421-025-05759-5 (Full text)

Assessing fatigue in myalgic encephalomyelitis/chronic fatigue syndrome patients before and after treatment with bright light therapy: A prospective randomized controlled crossover study

Abstract:

Objective: The aim of the current study was to test the effectiveness of treatment with bright light therapy (BLT) on fatigue and cognitive function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A randomized-controlled cross-over study design was chosen in order to provide all patients access to BLT treatment and account for placebo effects.

Methods: In this study, a total of 36 outpatients with a diagnosis of ME/CFS according to the criteria of the Institute of Medicine (2015) were randomly assigned to a cross-over design starting out either with BLT or waitlist for the course of 2 weeks with a washout phase in between. Portable light boxes emitting full-spectrum visible light with a luminance intensity of 10,000 lux were used by the participants at home. Primary outcome of the study was fatigue as assessed by Chalder Fatigue Score (CFQ) and the secondary outcome variable was cognitive function assessed per standardized test battery (Test of Attentional Performance – TAP).

Results: The primary outcome variable fatigue was not significantly improved after treatment with BLT compared to wait list in the full crossover design, although fatigue scores improved immediately after two weeks of BLT. Additionally, patients showed decreased reaction time after treatment with BLT in a subtest of TAP compared to wait list. Over 45 % of patients were diagnosed with postural tachycardia syndrome.

Conclusion: BLT for two weeks is not effective for the treatment of fatigue in ME/CFS, but it might have beneficial effects on attention in patients with ME/CFS. The clinical trial is registered with www.

Clinicaltrials: gov (NCT06635928).

Source: Ludwig B, Hauer L, Böck M, Schillerwein-Kral C, Weyer L, Moser D, Zehetmayer S, Trimmel K, Seidel S. Assessing fatigue in myalgic encephalomyelitis/chronic fatigue syndrome patients before and after treatment with bright light therapy: A prospective randomized controlled crossover study. Sleep Med. 2025 Mar 14;129:369-374. doi: 10.1016/j.sleep.2025.03.003. Epub ahead of print. PMID: 40120538. https://www.sciencedirect.com/science/article/pii/S1389945725001200 (Full text)

Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome

Abstract:

Background: Etiology remains elusive for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and no treatment exists. Antivirals had no efficacy in randomized clinical trials (RCT) for Epstein-Barr Virus and HHV-6. Enteroviruses (EV) have been implicated, but no antivirals are available. Many patients who received SARS–CoV-2-specific antiviral drugs for acute Covid-19 (COV19) infection experienced significant improvement of prior ME/CFS symptoms. This study summarizes their responses to antivirals for SARS-Cov-2.
Methods: Neutralizing Antibody (NA) for Coxsackievirus B (CVB)1-6 and Echovirus 6, 7, 9, 11, 30 were done by ARUP lab. Enterovirus Protein (EVP) of Peripheral Blood Leukocytes (PBL) was determined by Western Blot. ME/CFS patients fulfilled Canadian consensus criteria, and had either elevated NA for enteroviruses and/or positive EVP in PBL. ME/CFS patients hospitalized for acute COV19 infection and patients without COV19, were given 5-10 days of IV Remdesivir (Rem) +/- immune modulators. Controls: 20 ME/CFS patients seen concurrently without Remdesivir treatment. Other ME/CFS patients (non-COV19) were given Nirmaltrelvir/Ritonavir (PAX) daily for 10 days +/- one repeat. The energy index (EI) was monitored by the patients before, during and after treatment. Significant improvement was defined as > 30%.
Results: 15/20 (75%) ME/CFS patients – 10/12 hospitalized, 5/8 non-COV19 patients – responded to IV Rem 2-6 weeks after infusions; remission lasted 6-8 weeks to 6-9 months before relapse. Of Controls: 2/20 had mild improvement (< 0.001, X 2 ).

104/200 (52%) of PAX-treated ME/CFS patients improved, often within 2-3 days; all relapsed within days to weeks after treatment. 66%, 33% and 44% of CVB4+, CVB3+, non-CVB3,4+ patients responded to treatment, respectively. EVP decreased and increased with clinical response and relapse.

Conclusion: Rem and PAX demonstrated clinical efficacy in ME/CFS patients with chronic enterovirus infections. Placebo-controlled RCT will be needed to clarify the role of antivirals in ME/CFS.
Source: John K Chia, David Wang, P-2363. Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome, Open Forum Infectious Diseases, Volume 12, Issue Supplement_1, February 2025, ofae631.2514, https://doi.org/10.1093/ofid/ofae631.2514 https://academic.oup.com/ofid/article/12/Supplement_1/ofae631.2514/7988721?login=false 

Qigong and Tai Chi for ME/CFS: A Systematic Review of Randomized Controlled Trials

Abstract:

Objective: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating illness with symptoms such as post-exertional malaise and cognitive dysfunction that can be challenging for patients to manage independently. Randomized controlled trials (RCTs) have examined mind-body and psychological approaches that teach patients coping skills for mitigating ME/CFS symptoms, including emerging literature on Qigong or Tai Chi instruction programs. This systematic review aims to summarize the characteristics of these trials and highlight potential areas for future optimization and refinement.

Methods: Ovid MEDLINE, Embase.com, Web of Science Core Collection, Cochrane CENTRAL, PsycINFO via Ovid, and ClinicalTrials.gov were searched in April 2023 using controlled vocabulary and keywords for the following eligibility criteria: Sample (ME/CFS), Design (RCT), Behavioral Intervention (mind-body or psychological interventions). Data extraction and reporting followed Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results: “Qigong” and “Tai Chi” yielded 142 and 80 abstracts, respectively. Of the 222 abstracts, full texts were available for 5 RCTs of Qigong (k = 5; N = 481). Notably, no trials of Tai Chi utilized a randomized control design. Among the 5 Qigong RCTs, the publication range was from 2012 to 2023. Details regarding intervention components and effects were summarized. Qigong intervention sessions (median = 12, mode = 10, 12) tended to last between 1-2 hours and occur across 5-12 weeks (median = 7, mode = 5). The Qigong interventions were all delivered in groups and incorporated at-home practice. Daily practice was a requirement (k = 4) or an advisement (k = 1). Patient-reported outcomes suggest an emerging evidence base for diffuse benefits on physical and emotional health outcomes.

Conclusions: Qigong interventions are promising, yet relatively understudied, in improving ME/CFS symptom severity and frequency. Future trials must implement standardized eligibility criteria for ME/CFS history, integrate Qigong or Tai Chi with other empirically supported mind-body and psychological practices, and assess long-term resiliency outcomes relevant to ME/CFS survivorship.

Source: Markwart M, Felsenstein D, Mehta DH, Sethi S, Tsuchiyose E, Lydson M, Yeh GY, Hall DL. Qigong and Tai Chi for ME/CFS: A Systematic Review of Randomized Controlled Trials. Glob Adv Integr Med Health. 2024 Nov 7;13:27536130241275607. doi: 10.1177/27536130241275607. PMID: 39524182; PMCID: PMC11544658. https://pmc.ncbi.nlm.nih.gov/articles/PMC11544658/ (Full text)

Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Objectives: In this six-year follow-up study, we used patient-reported outcome measures (PROMs) to compare values at baseline, at 18 months, and at six-year follow up from the CycloME and the RituxME trials.

Methods: Based on the hypothesis that ME/CFS in a subgroup of patients is a variant of an autoimmune disease, we performed two clinical trials between 2014 and 2017. The RituxME trial was a randomized, double-blind and placebo-controlled phase III trial of 151 patients, assessing the B-cell depleting antibody rituximab. The CycloME trial was an open-label phase II trial of 40 patients using intravenous cyclophosphamide. Here we report six-year follow-up from both trials, using the Short Form 36 Physical Function (SF-36 PF) and DePaul short form (DSQ-SF) questionnaires.

Result: Of the patients available after six years, 75.7% of RituxME and 94.4% of CycloME patients participated. In the RituxME rituximab group, the mean SF-36 PF scores were 32.9 at baseline, 42.4 at 18 months and 45.5 at six years. In the placebo group, the mean SF-36 PF scores were 32.3 at baseline, 45.5 at 18 months and 43.1 at six years. In the CycloME trial, mean SF-36 PF increased from 35.4 at baseline to 54.4 at 18 months, and 56.7 at six years. At six-year follow-up, 44.1% of cyclophosphamide-, 27.6% of rituximab- and 20.4% of placebo-treated patients had an SF-36 PF ≥ 70, and further, 17.6%, 8.6% and 7.4% of the corresponding patient groups had an SF-36 PF ≥ 90, which is within normal range. In terms of worsening at six years, 5.9% of cyclophosphamide-treated, 10.3% of rituximab-, and 14.8% of placebo-treated patients had a drop in SF-36 PF of 20 points or more from baseline. There were no serious unexpected adverse reactions.

Conclusions: After six years, 44.1% of the cyclophosphamide group scored an SF-36 PF of at least 70, and 17.6% of at least 90, suggesting that cyclophosphamide in a subgroup may modulate the disease course in a beneficial way. However, cyclophosphamide carries toxicity concerns and should not be used for ME/CFS patients outside clinical trials. Rather, these data should encourage efforts to better understand the disease mechanisms and to search for targeted and less toxic immune modulatory treatment for this patient group.

Source: Rekeland IG, Sørland K, Neteland LL, Fosså A, Alme K, Risa K, Dahl O, Tronstad KJ, Mella O, Fluge Ø. Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PLoS One. 2024 Jul 23;19(7):e0307484. doi: 10.1371/journal.pone.0307484. PMID: 39042627; PMCID: PMC11265720. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265720/ (Full text)

Exploring the central mechanism of mind-regulation electroacupuncture in treatment of chronic fatigue syndrome with anxiety and depression comorbidity based on functional magnetic resonance imaging

Abstract:

in English, Chinese

Objectives: To observe the changes in the regional homogeneity (ReHo) and functional brain network in treatment of chronic fatigue syndrome (CFS) with anxiety and depression comorbidity with the mind-regulation electroacupuncture (EA), using resting-state functional magnetic resonance imaging (rs-fMRI).

Methods: Thirty CFS patients with anxiety and depression comorbidity were enrolled from medical staffs as the observation group. The other 30 healthy subjects were recruited from medical university students as the control group, matching gender, age and education years with the observation group. No any acupuncture intervention was delivered in the control group, and EA for regulating the mind was operated in the observation group. Main points were the emotional area of Sun‘s scalp acupuncture, the regions 1 and 8 of Sun‘s abdominal acupuncture. Supplementary acupoints included Baihui (GV 20), Guanyuan (CV 4) and bilateral.

Results: The scores of the five domains in MFI-20 (i.e. general fatigue, physical fatigue, mental fatigue, reduced motivation and reduced activity), the total score of MFI-20, and the scores of SDS, SAS and PSQI in the observation group before treatment were higher than those of the control group (P<0.05). Except the score of reduced motivation in MFI-20, the scores of the other domains and the total score of MFI-20, as well as the scores of SDS, SAS and PSQI after treatment were lower than those before treatment in the observation group (P<0.05).

Compared with the values before treatment, ReHo value was increased in the the right precuneus and decreased in the left inferior temporal gyrus and the left angular gyrus of the brain in the observation group after treatment. In the observation group, when compared with the control group, ReHo values were increased in the left inferior cerebral lobe, the interhemispheric region, the right occipital lobe and the thalamus; and it was reduced in the left middle temporal gyrus, the right posterior central gyrus, the right middle temporal gyrus, the right orbital middle frontal gyrus, the paracentral lobule and the right fusiform gyrus before treatment.

In the observation group, the functional connectivity was decreased between the right thalamus and the left posterior central gyrus, the right hippocampus and the right fusiform gyrus before treatment, respectively; it was re-constructed after treatment between the right thalamus and the left posterior central gyrus, and the right fusiform gyrus.

Compared with the control group, the functional connectivity between the right thalamus and the left posterior central gyrus, the right hippocampus, and the right fusiform gyrus was reduced before treatment; while after treatment, the functional connectivity was reduced between the right thalamus and the hippocampus in the observation group. With Spearman correlation analysis between the differential brain regions and the scores of MFI-20, SAS, SDS and PSQI, it was found that the left middle temporal gyrus, the paracentral lobule, the right precuneus, and the left inferior temporal gyrus had a partial positive correlation with the above clinical scales; and the interhemispheric region, the thalamus, the right fusiform gyrus, and the right middle temporal gyrus showed a partial negative correlation.

Conclusions: There is the decrease of ReHo in many brain regions and the numbers of the local brain functional network connectivity in CFS patients with anxiety and depression comorbidity. The mind-regulation electroacupuncture therapy may relieve the clinical symptoms of the patients through adjusting the abnormal brain regions and activating emotion-related brain regions.

Source: Zeng X, Feng C, Zhang M, Cheng W, Sun Z, Yang T. Exploring the central mechanism of mind-regulation electroacupuncture in treatment of chronic fatigue syndrome with anxiety and depression comorbidity based on functional magnetic resonance imaging. Zhongguo Zhen Jiu. 2023 Jan 12;44(1):3-11. English, Chinese. doi: 10.13703/j.0255-2930.20230603-k0003. PMID: 38191152. https://pubmed.ncbi.nlm.nih.gov/38191152/

Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating, and multi-faceted illness. Heterogenous onset and clinical presentation with additional comorbidities make it difficult to diagnose, characterize, and successfully treat. Current treatment guidelines focus on symptom management, but with no clear target or causative mechanism, remission rates are low, and fewer than 5% of patients return to their pre-morbid activity levels. Therefore, there is an urgent need to undertake robust clinical trials to identify effective treatments.
This review synthesizes insights from clinical trials exploring pharmacological interventions and dietary supplements targeting immunological, metabolic, gastrointestinal, neurological, and neuroendocrine dysfunction in ME/CFS patients which require further exploration. Additionally, the trialling of alternative interventions in ME/CFS based on reported efficacy in the treatment of illnesses with overlapping symptomology is also discussed. Finally, we provide important considerations and make recommendations, focusing on outcome measures, to ensure the execution of future high-quality clinical trials to establish clinical efficacy of evidence-based interventions that are needed for adoption in clinical practice.
Source: Seton KA, Espejo-Oltra JA, Giménez-Orenga K, Haagmans R, Ramadan DJ, Mehlsen J on behalf of the European ME Research Group for Early Career Researchers (Young EMERG). Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives. Journal of Clinical Medicine. 2024; 13(2):325. https://doi.org/10.3390/jcm13020325 https://www.mdpi.com/2077-0383/13/2/325 (Full text)

Yeast Beta-Glucan Supplementation with Multivitamins Attenuates Cognitive Impairments in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract:

This research aimed to examine the potential alleviative effects of beta-glucan administration on fatigue, unrefreshing sleep, anxiety/depression symptoms and health-related quality of life in ME/CFS. A 36-week unicenter, randomized, double-blind, placebo-controlled trial was conducted in 65 ME/CFS patients, who were randomly allocated to one of two arms to receive four capsules each one of 250 mg beta-glucan, 3.75 µg vitamin D3, 1.05 mg vitamin B6, and 7.5 mg zinc (n = 35), or matching placebo including only microcrystalline cellulose as an excipient (n = 30) once daily.

The findings showed that the beta-glucan supplementation significantly improved cognitive fatigue (assessed with FIS-40 scores) after the 36-week treatment compared to the baseline (p = 0.0338). Taken together, this study presents the novel finding that yeast-derived beta-glucan may alleviate cognitive fatigue symptoms in ME/CFS. Thus, it offers valuable scientific insights into the potential use of yeast beta-glucan as a nutritional supplement and/or functional food to prevent or reduce cognitive dysfunction in patients with ME/CFS. Further interventions are warranted to validate these findings and also to delve deeper into the possible immunometabolic pathomechanisms of beta-glucans in ME/CFS.

Source: Lacasa M, Alegre-Martin J, Sentañes RS, Varela-Sende L, Jurek J, Castro-Marrero J. Yeast Beta-Glucan Supplementation with Multivitamins Attenuates Cognitive Impairments in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2023 Oct 24;15(21):4504. doi: 10.3390/nu15214504. PMID: 37960157. https://www.mdpi.com/2072-6643/15/21/4504 (Full text)

Randomized, double-blinded, placebo-controlled pilot study: Efficacy of faecal microbiota transplantation on chronic fatigue syndrome

Abstract:

Background: Chronic fatigue syndrome (CFS) is a disabling illness of unknown aetiology. Disruption of gut microbiota may play a role in several neurological disorders. In this study, the effect of faecal microbiota transplantation (FMT) on fatigue severity and health-related quality of life (HRQOL) in patients with CFS was evaluated

Methods: Randomized, placebo-controlled pilot trial. Patients and researchers were blinded to treatment assignment. 11 patients with CFS (10 female and 1 male, mean age 42.2 years and mean duration of CFS 6.3 years) were randomly assigned to receive either FMT from a universal donor (n = 5) or autologous FMT (n = 6) via colonoscopy. Patients’ HRQOL was assessed by using visual analog scale (VAS) and self-reporting questionnaires Modified Fatigue Impact Scale (MFIS), 15D and EQ-5D-3L. Patients’ HRQOL was evaluated at baseline, and 1 and 6 months after the FMT.

Results: The baseline VAS scores in the FMT and placebo groups were 62.4 and 76.0 (p = 0.29). 1-month scores were 60.0 and 73.7 and 6-months scores 72.8 and 69.5, respectively. Total MFIS scores in the FMT and placebo groups were 59.6 and 61.0 at the baseline (p = 0.80), 53.5 and 62.0 at 1 month and 58.6 and 56.2 at 6 months. Compared to the baseline scores, differences at 1 and 6 months were statistically insignificant both in VAS and in MFIS. The 15D and EQ-5D-3L profiles did not change after the FMT or placebo. FMT-related adverse events were not reported.

Conclusion: FMT was safe but did not relieve symptoms or improve the HRQOL of patients with CFS. Small number of study subjects limits the generalizability of these results

Trial registration: ClinicalTrials.gov Identifier NCT04158427, https://register.clinicaltrials.gov, date of registration 08/08/2019

Source: Salonen TE, Jokinen E, Satokari R, Lahtinen P. Randomized, double-blinded, placebo-controlled pilot study: Efficacy of faecal microbiota transplantation on chronic fatigue syndrome. ResearchSquare [Preprint] April 25, 2023. https://doi.org/10.21203/rs.3.rs-2805527/v1 https://www.researchsquare.com/article/rs-2805527/v1 (Full text)

Clinical effects of wasabi extract containing 6-MSITC on myalgic encephalomyelitis/chronic fatigue syndrome: an open-label trial

Abstract:

Background: Wasabi (Eutrema japonicum) is a common pungent spice used in Japan. 6-Methylsulfinylhexyl isothiocyanate (6-MSITC) found in the rhizome of wasabi has been shown to have anti-inflammatory and antioxidant effects, as well as improve neuroinflammation and memory. Therefore, we hypothesized that these effects would be beneficial for treating myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The present study was conducted to investigate the effectiveness of wasabi extract containing 6-MSITC on ME/CFS in an open-label trial.

Methods: Fifteen patients (3 males, 12 females, 20-58 years old) were orally administered wasabi extract (9.6 mg of 6-MSITC/day) for 12 weeks. The following parameters and test results were compared pre- and post-treatment: performance status (PS), self-rating questionnaires, pressure pain threshold (PPT) on the occiput, Trail Making test-A (TMT-A), and hemodynamic patterns determined by an active standing test.

Results: After treatment with 6-MSITC, PS improved significantly (p = 0.001). Although the scores on the 11-item Chalder Fatigue scale (CFS-11) and numerical rating scale (NRS) of fatigue did not show significant changes, subjective symptoms improved significantly, including headache frequency (4.1 to 3.0 times/week, p = 0.001) and myalgia (4.1 to 2.4 times/week, p = 0.019), NRS brain fog scores (5.7 to 4.5, p = 0.011), difficulty finding appropriate words (4.8 to 3.7, p = 0.015), photophobia (4.8 to 3.5, p = 0.008), and the Profile of Mood Status vigor score (46.9 to 50.0, p = 0.045). The PPT of the right occiput (17.3 to 21.3 kPa, p = 0.01) and TMT-A scores (53.0 to 38.1 s, p = 0.007) also changed, suggesting reduced pain sensitivity, and improved cognitive function, respectively. Orthostatic patterns determined by a standing test did not show remarkable changes. There were no serious adverse reactions.

Conclusion: This study suggests that 6-MSITC improves PS as well as subjective symptoms such as pain and cognitive dysfunction, and psychological vitality of patients with ME/CFS. It also improved cognitive performance and increased pain thresholds in these patients. 6-MSITC may be a promising therapeutic option especially for improving cognitive dysfunction associated with ME/CFS.

Source: Oka T, Yamada Y, Lkhagvasuren B, Nakao M, Nakajima R, Kanou M, Hiramatsu R, Nabeshima YI. Clinical effects of wasabi extract containing 6-MSITC on myalgic encephalomyelitis/chronic fatigue syndrome: an open-label trial. Biopsychosoc Med. 2022 Dec 12;16(1):26. doi: 10.1186/s13030-022-00255-0. PMID: 36510244. https://bpsmedicine.biomedcentral.com/articles/10.1186/s13030-022-00255-0 (Full text)