An Overview of Ethical Issues Raised by Medicolegal Challenges to Death by Neurologic Criteria in the United Kingdom and a Comparison to Management of These Challenges in the USA.

Although medicolegal challenges to the use of neurologic criteria to declare death in the USA have been well-described, the management of court cases in the United Kingdom about objections to the use of neurologic criteria to declare death has not been explored in the bioethics or medical literature. This article (1) reviews conceptual, medical and legal differences between death by neurologic criteria (DNC) in the United Kingdom and the rest of the world to contextualize medicolegal challenges to DNC; (2) summarizes highly publicized legal cases related to DNC in the United Kingdom, including the nuanced 2022 case of Archie Battersbee, who was transiently considered dead by neurologic criteria, but ultimately determined to be in a vegetative state/unresponsive-wakeful state; and (3) provides an overview of ethical issues raised by medicolegal challenges to DNC in the United Kingdom and a comparison to the management of these challenges in the USA.

Deep brain stimulation in disorders of consciousness: 10 years of a single center experience.

Disorders of consciousness (DoC), namely unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), represent severe conditions with significant consequences for patients and their families. Several studies have reported the regaining of consciousness in such patients using deep brain stimulation (DBS) of subcortical structures or brainstem nuclei. Our study aims to present the 10 years' experience of a single center using DBS as a therapy on a cohort of patients with DoC. Eighty Three consecutive patients were evaluated between 2011 and 2022; entry criteria consisted of neurophysiological and neurological evaluations and neuroimaging examinations. Out of 83, 36 patients were considered candidates for DBS implantation, and 32 patients were implanted: 27 patients had UWS, and five had MCS. The stimulation target was the centromedian-parafascicular complex in the left hemisphere in hypoxic brain lesion or the one better preserved in patients with traumatic brain injury. The level of consciousness was improved in seven patients. Three out of five MCS patients emerged to full awareness, with the ability to interact and communicate. Two of them can live largely independently. Four out of 27 UWS patients showed consciousness improvement with two patients emerging to full awareness, and the other two reaching MCS. In patients with DoC lasting longer than 12 months following traumatic brain injury or 6 months following anoxic-ischemic brain lesion, spontaneous recovery is rare. Thus, DBS of certain thalamic nuclei could be recommended as a treatment option for patients who meet neurological, neurophysiological and neuroimaging criteria, especially in earlier phases, before occurrence of irreversible musculoskeletal changes. Furthermore, we emphasize the importance of cooperation between centers worldwide in studies on the potentials of DBS in treating patients with DoC.

Sham-controlled randomized multicentre trial of transcranial direct current stimulation for prolonged disorders of consciousness.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation (tDCS) has been shown to improve signs of consciousness in a subset of patients with disorders of consciousness (DoC). However, no multicentre study confirmed its efficacy when applied during rehabilitation. In this randomized controlled double-blind study, the effects of tDCS whilst patients were in rehabilitation were tested at the group level and according to their diagnosis and aetiology to better target DoC patients who might repond to tDCS. METHODS: Patients received 2 mA tDCS or sham applied over the left prefrontal cortex for 4 weeks. Behavioural assessments were performed weekly and up to 3 months' follow-up. Analyses were conducted at the group and subgroup levels based on the diagnosis (minimally conscious state [MCS] and unresponsive wakefulness syndrome) and the aetiology (traumatic or non-traumatic). Interim analyses were planned to continue or stop the trial. RESULTS: The trial was stopped for futility when 62 patients from 10 centres were enrolled (44 ± 14 years, 37 ± 24.5 weeks post-injury, 18 women, 32 MCS, 39 non-traumatic). Whilst, at the group level, no treatment effect was found, the subgroup analyses at 3 months' follow-up revealed a significant improvement for patients in MCS and with traumatic aetiology. CONCLUSIONS: Transcranial direct current stimulation during rehabilitation does not seem to enhance patients' recovery. However, diagnosis and aetiology appear to be important factors leading to a response to the treatment. These findings bring novel insights into possible cortical plasticity changes in DoC patients given these differential results according to the subgroups of patients.

Trigeminal nerve stimulation for prolonged disorders of consciousness: A randomized double-blind sham-controlled study.

BACKGROUND: Trigeminal nerve stimulation (TNS) has been proposed as a promising intervention for coma awakening. However, the effect of TNS on patients with prolonged disorders of consciousness (pDoC) is still unclear. OBJECTIVE: This study aimed to investigate the therapeutic effects of TNS in pDoC caused by stroke, trauma, and anoxia. METHODS: A total of 60 patients (male =25, female =35) aged over 18 who were in a vegetative state or minimally conscious state were randomly assigned to the TNS (N = 30) or sham TNS (N = 30) groups. 4 weeks of intervention and a followed up for 8 weeks were performed. The Glasgow Coma Scale (GCS) and Coma Recovery Scale-Revised (CRS-R) scores as primary outcomes were assessed at baseline and at 2, 4, 8, and 12 weeks. RESULTS: The score changes in the TNS group over time for CRS-R (2-week: mean difference = 0.9, 95% CI = [0.3, 1.5], P = 0.006; 4-week: 1.6, 95% CI = [0.8, 2.5], P < 0.001; 8-week: mean difference = 2.4, 95% CI = [1.3, 3.5], P < 0.001; 12-week: mean difference = 2.3, 95% CI = [1.1, 3.4], P < 0.001) and GCS (4-week: mean difference = 0.7, 95% CI = [0.3, 1.2], P = 0.002; 8-week: mean difference = 1.1, 95% CI = [0.6, 1.7], P < 0.001; 12-week: 1.1, 95% CI = [0.5, 1.7], P = 0.003) were higher than those in the sham group. 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) revealed that the metabolism of the right parahippocampal cortex, right precuneus, and bilateral middle cingulate cortex was significantly increased in TNS group. CONCLUSION: The results of this study indicate that TNS could increase local brain metabolism and may promote functional recovery in patients with prolonged disorders of consciousness. REGISTRATION INFORMATION: Name of the registry: Chinese Clinical Trial Registry. REGISTRATION NUMBER: ChiCTR1900025573. The date that the study was submitted to a registry: 2019-09-01. The date when the first patient was enrolled was 2021-01-20.

Effect of Transcranial Direct Current Stimulation on Patients With Disorders of Consciousness: A Systematic Review and Meta-analysis.

OBJECTIVES: The aims of this study are to evaluate the efficacy of transcranial direct current stimulation for improving disorders of consciousness and to compare efficacy of the different etiologies of disorders of consciousness. DESIGN: Randomized controlled trials or crossover trials examining effects of transcranial direct current stimulation in patients with disorders of consciousness were searched in PubMed, Embase, Cochrane Library, and Web of Science. The sample characteristics, etiology, transcranial direct current stimulation treatment characteristics, and outcomes were extracted. Meta-analysis was performed using the RevMan software. RESULTS: We included nine trials providing data with 331 participants and found that transcranial direct current stimulation improved the Coma Recovery Scale-Revised score of disorders of consciousness patients. We found a significant improvement of Coma Recovery Scale-Revised score in the minimally conscious state group (weighted mean difference = 0.77, 95% confidence interval = 0.30-1.23, P = 0.001), but not in the vegetative state or unresponsive wakefulness syndrome group. The effects of transcranial direct current stimulation are related to etiology, as the Coma Recovery Scale-Revised score was improved in the traumatic brain injury group (weighted mean difference = 1.18, 95% confidence interval = 0.60-1.75, P < 0.001), but not in vascular accident and anoxia groups. CONCLUSIONS: This meta-analysis revealed the evidence for positive effects of transcranial direct current stimulation on disorders of consciousness without adverse effects observed in minimally conscious state patients. In particular, transcranial direct current stimulation may be an effective treatment in rehabilitating cognitive functions in people with traumatic brain injury.

Effect of high-frequency repetitive transcranial magnetic stimulation over M1 for consciousness recovery after traumatic brain injury.

BACKGROUND: The brain area stimulated during repetitive transcranial magnetic stimulation (rTMS) treatment is important in altered states of consciousness. However, the functional contribution of the M1 region during the treatment of high-frequency rTMS remains unclear. OBJECTIVE: The aim of this study was to examine the clinical [the Glasgow coma scale (GCS) and the coma recovery scale-revised (CRS-R)] and neurophysiological (EEG reactivity and SSEP) responses in vegetative state (VS) patients following traumatic brain injury (TBI) before and after a protocol of high-frequency rTMS over the M1 region. METHODS: Ninety-nine patients in a VS following TBI were recruited so that their clinical and neurophysiological responses could be evaluated in this study. These patients were randomly allocated into three experimental groups: rTMS over the M1 region (test group; n = 33), rTMS over the left dorsolateral prefrontal cortex (DLPFC) (control group; n = 33) and placebo rTMS over the M1 region (placebo group; n = 33). Each rTMS treatment lasted 20 min and was carried out once a day. The duration of this protocol was a month with 20 treatments (5 times per week) occurring with that time. RESULTS: We found that the clinical and neurophysiological responses improved after treatment in the test, control, and placebo groups; the improvement was highest in the test group compared to that in the control and placebo groups. CONCLUSIONS: Our results demonstrate an effective method of high-frequency rTMS over the M1 region for consciousness recovery after severe brain injury.

Long-term functional outcomes improved with deep brain stimulation in patients with disorders of consciousness.

BACKGROUND: Deep brain stimulation (DBS) has been preliminarily applied to treat patients with disorders of consciousness (DoCs). The study aimed to determine whether DBS was effective for treating patients with DoC and identify factors related to patients' outcomes. METHODS: Data from 365 patients with DoCs who were consecutively admitted from 15 July 2011 to 31 December 2021 were retrospectively analysed. Multivariate regression and subgroup analysis were performed to adjust for potential confounders. The primary outcome was improvement in consciousness at 1 year. RESULTS: An overall improvement in consciousness at 1 year was achieved in 32.4% (12/37) of the DBS group compared with 4.3% (14/328) of the conservative group. After full adjustment, DBS significantly improved consciousness at 1 year (adjusted OR 11.90, 95% CI 3.65-38.46, p<0.001). There was a significant treatment×follow up interaction (H=14.99, p<0.001). DBS had significantly better effects in patients with minimally conscious state (MCS) compared with patients with vegetative state/unresponsive wakefulness syndrome (p for interaction <0.001). A nomogram based on age, state of consciousness, pathogeny and duration of DoCs indicated excellent predictive performance (c-index=0.882). CONCLUSIONS: DBS was associated with better outcomes in patients with DoC, and the effect was likely to be significantly greater in patients with MCS. DBS should be cautiously evaluated by nomogram preoperatively, and randomised controlled trials are still needed.

Food as Love: Ethical and Moral Dilemmas in Withdrawal of Artificial Nutrition and Hydration in the Minimally Conscious State.

Supportive Palliative Care and Hospice professionals frequently attend to Minimally Conscious State (MCS) patients near the end of life and in so doing, face decisions over maintenance or withdrawal of artificial nutrition and hydration. Although both withholding and withdrawal of artificial nutrition and hydration (ANH) in such circumstances are considered by experts in ethics and law to be acceptable, not all families nor health care professionals agree. This paper will explore basic aspects of serious brain injuries, especially MCS, the psychological role of food in interpersonal relationships, and lessons from clinical ethics that can help in goals of care discussions about withdrawal of ANH.

Deep brain stimulation improves electroencephalogram functional connectivity of patients with minimally conscious state.

AIM: Deep brain stimulation (DBS) is a potential neuromodulatory therapy that enhances recovery from disorders of consciousness, especially minimally conscious state (MCS). This study measured the effects of DBS on the brain and explored the underlying mechanisms of DBS on MCS. METHODS: Nine patients with MCS were recruited for this study. The neuromodulation effects of 100 Hz DBS were explored via cross-control experiments. Coma Recovery Scale-Revised (CRS-R) and EEG were recorded, and corresponding functional connectivity and network parameters were calculated. RESULTS: Our results showed that 100 Hz DBS could improve the functional connectivity of the whole, local and local-local brain regions, while no significant change in EEG functional connectivity was observed in sham DBS. The whole brain's network parameters (clustering coefficient, path length, and small world characteristic) were significantly improved. In addition, a significant increase in the CRS-R and functional connectivity of three MCS patients who received 100 Hz DBS for 6 months were observed. CONCLUSION: This study showed that DBS improved EEG functional connectivity and brain networks, indicating that the long-term use of DBS could improve the level of consciousness of MCS patients.

Clinical and neurophysiological effects of central thalamic deep brain stimulation in the minimally conscious state after severe brain injury.

Deep brain stimulation (DBS) of the central thalamus is an experimental treatment for restoration of impaired consciousness in patients with severe acquired brain injury. Previous results of experimental DBS are heterogeneous, but significant improvements in consciousness have been reported. However, the mechanism of action of DBS remains unknown. We used magnetoencephalography to study the direct effects of DBS of the central thalamus on oscillatory activity and functional connectivity throughout the brain in a patient with a prolonged minimally conscious state. Different DBS settings were used to improve consciousness, including two different stimulation frequencies (50 Hz and 130 Hz) with different effective volumes of tissue activation within the central thalamus. While both types of DBS resulted in a direct increase in arousal, we found that DBS with a lower frequency (50 Hz) and larger volume of tissue activation was associated with a stronger increase in functional connectivity and neural variability throughout the brain. Moreover, this form of DBS was associated with improvements in visual pursuit, a reduction in spasticity, and improvement of swallowing, eight years after loss of consciousness. However, after DBS, all neurophysiological markers remained significantly lower than in healthy controls and objective increases in consciousness remained limited. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of DBS of the central thalamus in humans and suggest that DBS can re-activate dormant functional brain networks, but that the severely injured stimulated brain still lacks the ability to serve cognitive demands.

The minimally conscious state: an analysis of current clinical trials registered in ClinicalTrials.gov.

The minimally conscious state (MCS) is a disorder of consciousness described in recent years for patients who have behavioral responses to stimuli that do not meet the classification of chronic vegetative state (CVS) or coma. This distinction is valuable in clinical practice, as minimally conscious patients may require different treatments and may have different long-term outcomes when compared to vegetative states or coma. In this report, we analyzed the ClinicalTrials.gov database to systematically assess all clinical trials regarding MCS. The database was queried using the term "minimally conscious state" in the "condition or disease" search parameter. Of the studies identified, those that had suspended, terminated, or otherwise unknown statuses were excluded. In total, 41 studies were analyzed. The included studies were initiated between 2008 and 2020, with the majority (63%) beginning in 2015 or later. Of the primary intervention modalities included, 15 (37%) evaluated stimulation modalities such as transcranial magnetic stimulation, transcranial direct current stimulation, implantable neurostimulation, vagus nerve stimulation, focused ultrasound and median nerve stimulation. Additionally, 5 (12%) used some form of behavioral therapy. A total of 4 (10%) studies involved pharmaceutical intervention, including dopamine agonists, analgesics and sedatives. Finally, 4 (10%) studies sought to determine the validity of current diagnostic methods and systems used to assess the status of patients in MCSs. Since the definition and criteria for CVS and MCS have been established, these two conditions remain closely associated despite evidence of different patient outcomes and treatment options. Many clinical trials are underway assessing interventions with stimulation. However, the trials are lacking with respect to diagnostic methods and pharmaceutical treatment.

Long-term functional prognosis and related factors of spinal cord stimulation in patients with disorders of consciousness.

INTRODUCTION: The treatment of patients with disorders of consciousness (DoC) remains a challenging issue, and spinal cord stimulation (SCS) has been reported to be a promising treatment for DoC in some studies. AIMS: This study explores the efficiency of SCS in treating patients with DoC at different consciousness levels, including the vegetative state/unresponsive wakefulness syndrome (VS/UWS) and the minimally conscious state (MCS) and summarizes and analyzes the long-term effect and related factors of SCS in patients with DoC. RESULTS: An overall positive outcome was reached in 35 of 110 patients (31.8%). Among patients with positive outcomes, the MCS group improved 45.53% more than VS/UWS group, and this difference was statistically significant. In terms of the recommendation standard, positive outcomes occurred in 33 patients (94.3%) in the highly recommended group and 2 patients (5.7%) in the weakly recommended group (p < 0.001). After adjustment for potential covariables, young age (age ≤ 19 years old) (p = 0.045) and MCS (p < 0.001) were significantly correlated with positive outcome. A nomogram based on age, state of consciousness, and pathogeny showed good predictive performance, with a c-index of 0.794. The Hosmer-Lemeshow goodness-of-fit test showed that the model was well calibrated (χ2  = 3.846, p = 0.871). CONCLUSIONS: SCS is one of the most feasible treatments for patients with DoC, especially for patients with MCS. Younger age is significantly associated with better outcomes and could therefore serve as a basis for preoperative screening. However, more evidence-based randomized controlled trials are needed to confirm the efficacy of the treatment.

Consciousness, Conflations, and Disability Rights: Denials of Care for Children in the "Minimally Conscious State".

This essay critiques the fiercely utilitarian allocation scheme of Cameron et al. Children have no hope of recovery if their lives are cut short based on administrative protocols that misrepresent the nature of their conditions. Unilateral futility judgements - especially those based on a false predicate - are discriminatory. When considering the best interests of children, we should see possibility in disability and not advance ill-informed utilitarianism.

P300 correlates with tDCS response in minimally conscious state patients.

BACKGROUND: Several recent studies indicated that transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex (DLPFC) showed promising results in patients in a minimally conscious state (MCS). However, the neurological characteristics of patients in MCS considered to be tDCS responders have not been firmly established. OBJECTIVES: In the current study, we aimed to explore a reliable electrophysiological biomarker of tDCS response before the patients' inclusion in a tDCS protocol. METHOD: A hierarchical auditory event-related potential (ERP) pattern was applied to thirty-one MCS patients who subsequently received 20 anodal tDCS sessions of the left DLPFC over 10 consecutive working days. The patients were divided into responders and non-responders according to the Coma Recovery Scale-Revised (CRS-R) behavioral evaluation, and the differences in cortical information processing were compared using the P300 component in the ERP pattern. RESULTS: For the Tone-SON (TO) paradigm, CRS-R score (OR = 2.229, 95% CI: 1.241-4.005, P = 0.007) at admission was independently associated with tDCS response, while in the SDN-SON (DO) paradigm, CRS-R score at admission (OR = 2.369, 95% CI: 1.143-4.908, P = 0.020) and P300 (OR = 22.795, 95% CI: 1.823-285.038, P = 0.015) were independently associated with tDCS response in MCS patients. CONCLUSION: Our findings showed that higher total CRS-R score and presence of P300 in the hierarchical auditory ERP pattern, especially P300 in the DO paradigm, are associated with tDCS response in MCS patients. We speculate that P300 in the DO paradigm indicates patients with more preserved semantic processing abilities, and a priority to recover. The results provide important information for guidelines on the use of tDCS in MCS patients.

Prognostication, Ethical Issues, and Palliative Care in Disorders of Consciousness.

Research advances in recent years have shown that some individuals with vegetative state or minimally conscious state can emerge to higher states of consciousness even years after injury. A minority of behaviorally unresponsive patients with vegetative state have also been shown to follow commands, or even communicate, using neuroimaging or electrophysiological techniques. These advances raise ethical questions that have important implications for clinical care. In this article, the authors argue that adopting a neuropalliative care approach can help clinicians provide ethical, compassionate care to these patients and their caregivers.

[Xingnao Kaiqiao acupuncture on promoting wake-up of vegetative state after brain injury].

OBJECTIVE: To observe the clinical effect of Xingnao Kaiqiao acupuncture on promoting wake-up of vegetative state after brain injury on the basis of comprehensive rehabilitation training. METHODS: A total of 100 patients with vegetative state after brain injury were randomly divided into an observation group (50 cases, 2 cases dropped off) and a control group (50 cases). Both groups were treated with routine clinical treatment. The patients in the control group were treated with rehabilitation and hyperbaric oxygen; on the basis of the control group treatment, the patients in the observation group were treated with Xingnao Kaiqiao acupuncture at Neiguan (PC 6), Shuigou (GV 26), Sanyinjiao (SP 6), Chize (LU 5), Weizhong (BL 40), Hegu (LI 4) and Taichong (LR 3). The acupuncture was given once a day, 5 days per week, for continuous 30 days. The Glasgow coma scale (GCS) and coma recovery scale-revised (CRS-R) scores were observed before treatment and 10, 20 and 30 days into treatment. The wake-up rate of the two groups was compared after treatment. RESULTS: On 10, 20 and 30 days into treatment, the GCS and CRS-R scores in the two groups were higher than those before treatment (P<0.01), and the scores in the observation group were higher than those in the control group (P<0.01). After treatment, the wake-up rate was 16.7% (8/48) in the observation group, which was higher than 12.0% (6/50) in the control group (P<0.01). CONCLUSION: On the basis of comprehensive rehabilitation and wake-up promotion therapy, the Xingnao Kaiqiao acupuncture could promote the recovery of consciousness level in patients with vegetative state after brain injury.

A novel closed-loop EEG-tDCS approach to promote responsiveness of patients in minimally conscious state: A study protocol.

Transcranial direct current stimulation (tDCS) applied over the prefrontal cortex has been shown to improve behavioral responsiveness in patients with disorders of consciousness following severe brain injury, especially those in minimally conscious state (MCS). However, one potential barrier of clinical response to tDCS is the timing of stimulation with regard to the fluctuations of vigilance that characterize this population. Indeed, a previous study showed that the vigilance of MCS patients has periodic average cycles of 70 min (range 57-80 min), potentially preventing them to be in an optimal neural state to benefit from tDCS when applied randomly. To tackle this issue, we propose a new protocol to optimize the application of tDCS by selectively stimulating at high and low vigilance states. Electroencephalography (EEG) real-time spectral entropy will be used as a marker of vigilance and to trigger tDCS, in a closed-loop fashion. We will conduct a randomized controlled crossover clinical trial on 16 patients in prolonged MCS who will undergo three EEG-tDCS sessions 5 days apart (1. tDCS applied at high vigilance; 2. tDCS applied at low vigilance; 3. tDCS applied at a random moment). Behavioral effects will be assessed using the Coma Recovery Scale-Revised at baseline and right after the stimulations. EEG will be recorded throughout the session and for 30 min after the end of the stimulation. This unique and novel approach will provide patients' tailored treatment options, currently lacking in the field of disorders of consciousness.

Nursing, Caregiving and Psychological support in Chronic Disorders of Consciousness: a scoping review.

BACKGROUND AND AIMS: The major disorders of consciousness include Coma, Vegetative State, and Minimally Conscious State. The care and the management of patients with Disorders of Consciousness (DOC) have raised several important ethical, social and medical issues. Aim of this review is to evaluate the role of nursing and psychological support in DOC management, in order to improve the quality of life of both patients and their caregivers. METHODS: Studies dealing with DOC, nursing and caregiving pubblished in the last 20 years (from January 2000 to June 2020) were identified by searching on PubMed, Web of Science and Cochrane databases. RESULTS: This review highlights the important role of DOC carevigers in the complex management of these frail patients, as well as the need for a specific support and counselling of caregivers. This psychological support may be given by nurses, as they are the healthcare professionals more involved in DOC care and cure. DISCUSSION: Over the last years, specific recommendations for the assessment and rehabilitation of patients with DOC have been promulgated by neurorehabilitation organizations to provide some guidelines for the care and cure of such frail patients. Indeed, DOC patients need a multidisciplinary approach in which both caregivers and nurses have a pivotal role. CONCLUSIONS: As the family is a critical and fundamental aspect in the management of DOC patients, it should be considered an integral part of care in the future guidelines.

Effect of acupuncture method of removing-stasisand resuscitating on the consciousness of patients with severe traumatic brain injury: A randomized clinical trial.

INTRODUCTION: With the development of social economy, transportation and various infrastructures have also developed, but it has objectively increased the number of patients with head injury. Although the current craniocerebral medicine technology continues to advance, long-term bed rest and other complications have led to an insignificant decrease in the mortality rate of coma patients. It is not uncommon for patients with disturbance of consciousness caused by head injury in major hospitals. METHODS/DESIGN: This will be a retrospective, single-blind clinical observational study. We will select 50 cases that meet the subject's selection criteria. According to whether they received acupuncture treatment or not, they will be randomly divided into 2 groups, namely treatment group and control group. The control group will be given conventional Western medicine treatment, and the treatment group will be given acupuncture method of removing-stasis and resuscitating treatment on the basis of the control group. DISCUSSION: Our purpose is to observe the role of acupuncture method of removing-stasis and resuscitating in promoting the recovery of patients with severe head injury. We aim to provide more evidence-based medical evidence for acupuncture treatment of this disease. TRIAL REGISTRATION: ClinicalTrials.gov, ChiCTR2000034732, Registered on 19 July 2020.