Effect of Combined Treatment with MLC601 (NeuroAiDTM) and Rehabilitation on Post-Stroke Recovery: The CHIMES and CHIMES-E Studies.

BACKGROUND AND PURPOSE: MLC601 has been shown in preclinical studies to enhance neurorestorative mechanisms after stroke. The aim of this post hoc analysis was to assess whether combining MLC601 and rehabilitation has an effect on improving functional outcomes after stroke. METHODS: Data from the CHInese Medicine NeuroAiD Efficacy on Stroke (CHIMES) and CHIMES-Extension (CHIMES-E) studies were analyzed. CHIMES-E was a 24-month follow-up study of subjects included in CHIMES, a multi-centre, double-blind placebo-controlled trial which randomized subjects with acute ischemic stroke, to either MLC601 or placebo for 3 months in addition to standard stroke treatment and rehabilitation. Subjects were stratified according to whether they received or did not receive persistent rehabilitation up to month (M)3 (non- randomized allocation) and by treatment group. The modified Rankin Scale (mRS) and Barthel Index were assessed at month (M) 3, M6, M12, M18, and M24. RESULTS: Of 880 subjects in CHIMES-E, data on rehabilitation at M3 were available in 807 (91.7%, mean age 61.8 ± 11.3 years, 36% female). After adjusting for prognostic factors of poor outcome (age, sex, pre-stroke mRS, baseline National Institute of Health Stroke Scale, and stroke onset-to-study-treatment time), subjects who received persistent rehabilitation showed consistently higher treatment effect in favor of MLC601 for all time points on mRS 0-1 dichotomy analysis (ORs 1.85 at M3, 2.18 at M6, 2.42 at M12, 1.94 at M18, 1.87 at M24), mRS ordinal analysis (ORs 1.37 at M3, 1.40 at M6, 1.53 at M12, 1.50 at M18, 1.38 at M24), and BI ≥95 dichotomy analysis (ORs 1.39 at M3, 1.95 at M6, 1.56 at M12, 1.56 at M18, 1.46 at M24) compared to those who did not receive persistent rehabilitation. CONCLUSIONS: More subjects on MLC601 improved to functional independence compared to placebo among subjects receiving persistent rehabilitation up to M3. The larger treatment effect of MLC601 was sustained over 2 years which supports the hypothesis that MLC601 combined with rehabilitation might have beneficial and sustained effects on neuro-repair processes after stroke. There is a need for more data on the effect of combining rehabilitation programs with stroke recovery treatments.

Prognostic Factors and Pattern of Long-Term Recovery with MLC601 (NeuroAiD™) in the Chinese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study.

BACKGROUND: The Chinese Medicine NeuroAiD Efficacy on Stroke recovery - Extension (CHIMES-E) study is among the few acute stroke trials with long-term outcome data. We aimed to evaluate the recovery pattern and the influence of prognostic factors on treatment effect of MLC601 over 2 years. METHODS: The CHIMES-E study evaluated the 2 years outcome of subjects aged ≥18 years with acute ischemic stroke, National Institutes of Health Stroke Scale (NIHSS) score 6-14, pre-stroke modified Rankin Scale (mRS) score ≤1 included in a multicenter, randomized, double-blind, placebo-controlled trial of MLC601 for 3 months. Standard stroke care and rehabilitation were allowed during follow-up with mRS score being assessed in-person at month (M) 3 and by telephone at M1, M6, M12, M18 and M24. RESULTS: Data from 880 subjects were analyzed. There was no difference in baseline characteristics between treatment groups. The proportion of subjects with mRS score 0-1 increased over time in favor of MLC601 most notably from M3 to M6, thereafter remaining stable up to M24, while the proportion deteriorating to mRS score ≥2 remained low at all time points. Older age (p < 0.01), female sex (p = 0.06), higher baseline NIHSS score (p < 0.01) and longer onset to treatment time (OTT; p < 0.01) were found to be predictors of poorer outcome at M3. Greater treatment effect, with more subjects improving on MLC601 than placebo, was seen among subjects with 2 or more prognostic factors (OR 1.65 at M3, 1.78 at M6, 1.90 at M12, 1.65 at M18, 1.39 at M24), especially in subjects with more severe stroke or longer OTT. CONCLUSIONS: The sustained benefits of MLC601 over 2 years were due to more subjects improving to functional independence at M6 and beyond compared to placebo. Selection of subjects with poorer prognosis, particularly those with more severe NIHSS score and longer OTT delay, as well as a long follow-up period, may improve the power of future trials investigating the treatment effect of neuroprotective or neurorestorative therapies.

CHInese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study (CHIMES-E): A Multicenter Study of Long-Term Efficacy.

BACKGROUND: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. METHODS: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age ≥18, baseline National Institute of Health Stroke Scale of 6-14, and pre-stroke modified Rankin Scale (mRS) ≤1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. RESULTS: CHIMES-E included 880 subjects (mean age 61.8 ± 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy ≤1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy ≤1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy ≥95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. CONCLUSIONS: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS ≤1 was significantly increased at 6 months and persisted up to 18 months after a stroke.

The use of technology in cancer prehabilitation: a systematic review.

Aim: This review aimed to evaluate the effectiveness and feasibility of cancer prehabilitation programs delivered through technological enablers compared to conventional face-to-face interventions. Methods: A systematic review was conducted, searching PubMed, Embase, and CINAHL for studies published from inception to February 6, 2024. Studies were included if they involved adult cancer patients in primary research, utilized technology for prehabilitation, and assessed functional, psychological, and quality of life outcomes. Results: Sixteen studies were included, encompassing wearables, apps, teleprehabilitation, and virtual reality. All studies reported feasibility, but challenges included technical issues, lack of supervision, and non-compliance. Effectiveness depended on intervention rigor and technology type. Wearables offered objective monitoring but faced compliance issues. Videoconferencing provided supervision and could mitigate compliance concerns. Multimodal programs and intervention-specific outcome measures were recommended. Conclusion: Technology-based prehabilitation programs seem feasible, but effectiveness depends on intervention design and technology employed. Future research should focus on developing robust evidence to guide clinical practice and explore the potential of integrated technological solutions. Systematic review registration: PROSPERO, identifier CRD42022376028.

Use of large language model-based chatbots in managing the rehabilitation concerns and education needs of outpatient stroke survivors and caregivers.

Background: The utility of large language model-based (LLM) artificial intelligence (AI) chatbots in many aspects of healthcare is becoming apparent though their ability to address patient concerns remains unknown. We sought to evaluate the performance of two well-known, freely-accessible chatbots, ChatGPT and Google Bard, in responding to common questions about stroke rehabilitation posed by patients and their caregivers. Methods: We collected questions from outpatients and their caregivers through a survey, categorised them by theme, and created representative questions to be posed to both chatbots. We then evaluated the chatbots' responses based on accuracy, safety, relevance, and readability. Interrater agreement was also tracked. Results: Although both chatbots achieved similar overall scores, Google Bard performed slightly better in relevance and safety. Both provided readable responses with some general accuracy, but struggled with hallucinated responses, were often not specific, and lacked awareness of the possibility for emotional situations with the potential to turn dangerous. Additionally, interrater agreement was low, highlighting the variability in physician acceptance of their responses. Conclusions: AI chatbots show potential in patient-facing support roles, but issues remain regarding safety, accuracy, and relevance. Future chatbots should address these problems to ensure that they can reliably and independently manage the concerns and questions of stroke patients and their caregivers.

A Case Report of Becker Muscular Dystrophy and Stroke Who Successfully Regained Mobility With Robot-Assisted Gait Training.

ABSTRACT: A 30-yr-old patient with Becker muscular dystrophy presented with stroke. Background issues of proximal weakness, dilated cardiomyopathy, and reduced endurance challenged the usual goal-setting and formulation of a stroke rehabilitation plan. We discuss the holistic rehabilitation program that this patient underwent, with a focus on the utilization of robot-assisted gait training that eventually led him to successfully regain mobility.

Chinese medicine NeuroAiD efficacy stroke recovery-extension study (CHIMES-E study): an observational multicenter study to investigate the longer-term efficacy of NeuroAiD in stroke recovery.

BACKGROUND: Stroke carries a poor long-term prognosis for death and disability. There are few acute treatments that reduce death and disability after stroke. The ongoing international, multicenter, randomized, placebo-controlled, double-blind CHIMES trial is currently testing the hypothesis that a 3-month course of the traditional Chinese medicine MLC601 (NeuroAiD) is superior to placebo in reducing neurological deficit and improving functional outcome after acute ischemic stroke in patients receiving standard stroke care. This extension study tests the hypothesis that at 2 years, an initial 3-month administration of NeuroAiD is superior to placebo in reducing neurological deficit and improving functional outcome in patients with cerebral infarction of an intermediate range of severity. METHODS: Study subjects will be those who are already participants in CHIMES - aged above 21 years, had signs and symptoms of acute stroke, 6 ≤ NIHSS ≤ 14, neuroimaging consistent with ischemic stroke, and received study medication within 72 h of stroke onset. A subject will not be eligible for inclusion in CHIMES-E if they have withdrawn consent from all participation and follow-up for CHIMES. Subjects will be contacted at 6, 12, 18 and 24 months after CHIMES enrollment. After verbal consent is obtained, subjects will be assessed for functional state by the modified Rankin scale (mRS) and Barthel Index (BI), and a history of recurrent vascular events as well as medical events. The primary outcome measure will be the mRS at month 24. Secondary outcome measures will be mRS and BI at 6, 12 and 18 months, and BI at 24 months. Analysis will be based on the intention-to-treat principle. If the number of patients lost to follow-up is substantial, a sensitivity analysis based on the last observation carried forward method will be carried out, to compare the results with those from the main analysis without imputation. Based on a cumulative odds ratio of 1.5 for the NeuroAiD group, a two-sided test of 5% type I error and an expected 30% dropout rate after 2 years of follow-up for the 1,100 patients recruited into CHIMES, the 770 subjects with mRS data expected to be available at year 2 yields an 89% power to detect a difference in efficacy between NeuroAiD and placebo. CONCLUSIONS: This study will provide evidence for the longer-term efficacy of an initial course of a neurorestorative therapy after acute ischemic stroke of intermediate severity.

The effects of toe spreader in people with overactive toe flexors post stroke: a randomized controlled pilot study.

OBJECTIVES: To investigate the long-term effects of the toe spreader on gait characteristics, pain, activity level and balance in individuals with chronic stroke who exhibited tonic toe flexion reflex. The secondary objectives were to determine the sample size for future studies and to assess compliance to the use of the toe spreader. DESIGN: Single-blind, randomized controlled pilot trial. SETTING: Outpatient clinic of a tertiary hospital in Singapore. SUBJECTS: Nine ambulatory participants with tonic toe flexion reflex more than six months post stroke. INTERVENTION: Control or customized toe spreader groups for six months. The toe spreader was made of Rolyan Ezemix elastomer putty and worn with sport sandals during ambulation. MAIN MEASURES: Gait speed and plantar surface contact area, pain visual analogue scale (VAS), Berg Balance Scale, Modified Ashworth Scale, activity level measured on pedometer and compliance via logbook. RESULTS: There were no significant differences between the groups. Both groups showed non-significant improvements in gait speed (toe spreader 0.34 (0.26) versus 0.37 (0.29) m/s; control 0.40 (0.27) versus 0.50 (0.17) m/s), activity level, step length of the hemiplegic leg and stride length at six months. All participants in the intervention group used the toe spreader less than 50% of the days, indicating suboptimal compliance. CONCLUSION: The use of the toe spreader did not result in significant improvements in any outcomes. Studies with sample sizes of at least 56 participants and strategies to increase compliance to the use of the toe spreader are recommended.

Outcomes of a Multi-Modal Hospital-Associated Home-Based Cancer Prehabilitation Program.

OBJECTIVE: To assess the impact of a "one-stop", multi-modal, hospital-associated-home-based prehabilitation model, helmed by a small core team, on newly diagnosed gastrointestinal and urological cancer patients planned for surgery. METHODS: This is a retrospective study in a tertiary public hospital, involving all newly diagnosed gastrointestinal and urological cancer patients planned for surgery. The primary outcome measure was the 6-minute walk test (6MWT). Other outcomes included physical, psychological and quality-of-life measures, and patient satisfaction surveys, taken at baseline, pre-operatively (post-prehabilitation), and at 3 months post-operatively. RESULTS: When comparing the baseline to pre-operatively (post-prehabilitation), there was a statistically significant improvement in the 6MWT (21.52 m, p<0.001), 30-Second Sit to Stand test (STS) (1.08 repetitions, p<0.001), Timed Up and Go test (TUG) (0.83 seconds, p=0.014) and Hospital Anxiety and Depression Scale (HADS) (total score 1.77, p<0.001). These were sustained (6MWT: 0.22, p=0.964; STS: 0.08 repetitions, p=0.863; TUG: 0.04 seconds, p=0.939) or further improved (HADS total score 2.06, p=0.003) at 3 months post-operatively. There was also a statistically significant improvement in the EuroQol-5 dimension health score (health-related quality-of-life measure) from baseline to 3 months post-operatively (7.04 points, p=0.001), with more than 90% overall patient satisfaction reported. CONCLUSION: Prehabilitation applied via our model resulted in significant improvements in functional capacity, psychological and quality-of-life outcomes, sustained at 3 months post-operatively, and is a feasible and effective approach that is well-received by our patients.

Novel use of robot-assisted gait rehabilitation in a patient with stroke and blindness.

Robot-assisted gait training (RAGT) is an effective adjunctive treatment for patients with stroke that helps to regain functional mobility and is applied in many rehabilitation units for poststroke neurorecovery. We discuss our successful attempt to apply RAGT in a patient with blindness that impeded his ability to maintain balance during gait training. He initially required two assistants to walk, but after undergoing conventional therapy with adjunctive RAGT, he improved to standby assistance for ambulation. There were also improvements in balance, activity tolerance and quality of life. Low-or-no vision states can affect the pace of recovery poststroke, but RAGT and conventional physiotherapy can possibly be combined in such patients to improve balance and motor outcomes. The Andago robot's safety features of weight support, harnessed suspension and walking mode selection supported our decision and enabled us to apply it safely for this patient.

Factors Predicting Return to Work After Inpatient Stroke Rehabilitation: A Retrospective Follow-up Study.

Objective: To determine the proportion of patients who return to work after inpatient stroke rehabilitation and to identify demographic, clinical, and functional predictive factors for its success. Design: A retrospective follow-up study of patients with stroke who were premorbidly working and had completed inpatient rehabilitation in a large metropolitan hospital between January 2016 and December 2017. They underwent a telephone interview at 2 years post discharge. Setting: Inpatient rehabilitation and follow-up post discharge. Participants: A total of 314 patients with stroke (73.9% male) with mean age of 58.9 at time of stroke (N=314). Results: A total of 46% of 314 participants returned to work. In multivariable logistic regression analysis, viewing return to work as important (odds ratio [OR], 11.90; 95% confidence interval [CI], 5.15-27.52), absence of language impairment (OR, 9.39; 95% CI, 3.01-29.34), ambulation FIM≥5 (supervision to independence level) on discharge (OR, 4.93; 95% CI, 2.44-9.98), cognitive FIM on discharge ≥25 (OR, 2.77; 95% CI, 1.19-6.47), employment in premorbid office work (OR, 2.67; 95% CI, 1.26-5.64), and a lower Charlson Comorbidity Index (CCI) score at discharge (OR, 0.83; 95% CI, 0.68-1.00) were associated with successful return to work. Conclusions: Viewing return to work as important, absence of language impairments on discharge, discharge ambulation FIM≥5, discharge cognitive FIM≥25, employment in premorbid office work, and a lower discharge CCI score were positive predictors of successful return to work.

Perspectives on the Direction of Cancer Prehabilitation in the Pandemic and Beyond.

Growing attention has been placed on cancer prehabilitation in the recent years as the number of publications increase. The real-world application of prehabilitation remains heterogeneous and its implementation has been challenging during the COVID-19 pandemic. However, the pandemic has also provided impetus for change-leveraging technology and digitalization. This paper will discuss the pre-existing models of care, adaptations that had taken place in the pandemic, the model of care in the author's institution, and the future direction of cancer prehabilitation.

Hydrodissection for Carpal Tunnel Syndrome: A Systematic Review.

ABSTRACT: Hydrodissection is an ultrasound-guided technique that has received more attention recently for its role in nerve entrapment syndromes. The purposes of this systematic review were to evaluate the safety and effectiveness of hydrodissection in carpal tunnel syndrome and to investigate the ideal parameters for injectate type, dosage, volume, and frequency; injection approach and technique; as well as operator experience and training required. We searched the Embase, MEDLINE, and PubMed databases with supplemental searches in the CINAHL, Web of Science, and Google Scholar databases for relevant randomized controlled trials. Primary outcome measures were adverse outcomes and clinical effectiveness. Six randomized controlled trials involving 356 wrists were included. All studies used ultrasound guidance in their interventions. No safety-related adverse outcomes were found, although not all studies declared this. Only one study was placebo controlled and revealed symptomatic as well as functional improvements at 6 mos, whereas the rest investigated hydrodissection with different injectate types. We concluded that nerve hydrodissection for carpal tunnel syndrome can be safely performed under ultrasound guidance. However, it is unclear whether the hydrodissection mechanism truly causes improvements in clinical outcomes. We were also unable to draw conclusions regarding the ideal procedure-related parameters. We recommend that future work should not only investigate safety and clinical effectiveness but also attempt to clarify the ideal procedure-related parameters.

Effectiveness of Adjunct Robotic Therapy With a Patient-Guided Suspension System for Stroke Rehabilitation Using a 7-Days-a-Week Model of Care: A Comparison With Conventional Rehabilitation.

OBJECTIVE: To determine and compare the effectiveness of robotic therapy with a patient-guided suspension system for stroke rehabilitation using a 7-days-a-week model of care with that of conventional rehabilitation. DESIGN: Retrospective cohort study. SETTING: Inpatient rehabilitation unit of an acute general hospital. PARTICIPANTS: A total of 100 consecutive patients with stroke (N=100) admitted within a 7-month period who fulfilled the criteria to undergo robotic therapy with a patient-guided suspension system were enrolled in this study. INTERVENTIONS: Patients either underwent robotic therapy in addition to conventional therapy (robotic group) or conventional therapy only (control group). There were 50 patients in each cohort. MAIN OUTCOME MEASURES: FIM and its derivatives (FIM gain and FIM efficiency); Berg Balance Scale (BBS), functional ambulation category (FAC); modified Rankin Scale (mRS); and National Institutes of Health Stroke Scale. RESULTS: The average FIM gains in both groups were statistically significant (P<.01). The robotic group had greater improvement in FAC scores (1.24 vs 0.78, P=.007). However, other measurements such as FIM efficiency, BBS, and mRS were not significantly different between the 2 groups. The robotics group reported high patient satisfaction rates, with most patients finding the intervention both beneficial and desirable. CONCLUSIONS: Adjunct robotic therapy has the potential to increase the efficacy of stroke rehabilitation. However, further studies are needed to strengthen the evidence.

Results from a prospective acute inpatient rehabilitation database: clinical characteristics and functional outcomes using the Functional Independence Measure.

INTRODUCTION: Rehabilitation improves functional outcomes, but there is little data on the profiles and outcomes of patients undergoing inpatient rehabilitation in Singapore. The aims of this paper were to document the clinical characteristics and functional outcomes, using the Functional Independence Measure (FIM), of all patients admitted to an inpatient rehabilitation unit in a tertiary teaching hospital, and to identify and analyse factors significantly associated with better discharge functional scores and higher functional gains. MATERIALS AND METHODS: In this prospective cohort study over a 4-year period, clinical and functional data for 1502 patients admitted consecutively to the Singapore General Hospital inpatient rehabilitation unit were charted into a custom-designed rehabilitation database. The primary outcome measures were the discharge total FIM scores, FIM gain and FIM efficiency. Multiple linear regression analysis was used to identify independent variables associated with better discharge FIM scores and FIM gain. RESULTS: The mean age was 61.3 +/- 15.0 years and 57.2% of the patients were male. Stroke (57.9%) followed by spinal cord injury (9.7%) were the most common diagnoses. The average rehabilitation length of stay was 21.5 +/- 19.0 days. The mean admission total FIM score was 70.3 +/- 23.2 and the mean discharge total FIM score was 87.3 +/- 23.0, with this gain being highly significant (P <0.001). The mean FIM gain was 17.0 +/- 13.4 and FIM efficiency was 0.95 +/- 0.90 points/day. Factors associated with better functional outcomes were higher admission motor and cognitive FIM scores, male gender, a longer rehabilitation length of stay and the use of acupuncture. Factors associated with poorer functional outcomes were older age, clinical deconditioning, ischaemic heart disease, depression, pressure sores and the presence of a domestic worker as a caregiver. CONCLUSIONS: The FIM is an easy-to-use, standardised and robust general measure of functional disability. Multiple demographic, clinical and socio-cultural variables are associated with the primary functional outcomes and should be taken into account in rehabilitation and discharge planning. Nevertheless, rehabilitation improves functional outcomes across a wide range of diagnoses. Further research should be aimed at evaluating long-term disability postdischarge from inpatient rehabilitation and translating these findings into improving rehabilitation and healthcare resource utilisation.

Functional outcomes of cancer patients in an inpatient rehabilitation setting.

INTRODUCTION: Cancer is the leading cause of death and the second most common cause of hospitalisation in Singapore. Significant functional gains are achievable with cancer rehabilitation yet there are no formal cancer rehabilitation programmes in Singapore. This study aims to describe the demographics, clinical characteristics, complications and functional outcomes of cancer patients undergoing comprehensive inpatient rehabilitation at our unit and compare these with non-cancer patients. It also seeks to compare these data within sub-groups of the cancer cohort. MATERIALS AND METHODS: This is a prospective cohort study. The Department of Rehabilitation Medicine database was reviewed for the period between 1 July 2002 and 31 December 2006. One thousand seven hundred and fifty patients had complete records, of which 58 are cancer patients. The primary outcome measures were the discharge total Functional Independence Measure (FIM), FIM gain and FIM efficiency. Other outcome measures included the length of rehabilitation stay, discharge destination, complication rates, rate of transfer back to the referring unit, the length of survival of the cancer patients upon discharge and the durability of the functional improvement made. RESULTS: The mean age of the cancer patients was 57.4 +/- 16.1 years and 62% were male. The mean admission total FIM was 70.9 +/- 18.0 and the total discharge FIM was 86.2 +/- 18.3. The average FIM gain was 15.3 +/- 11.6 and the mean efficiency was 0.867 +/- 0.806. This improvement is highly significant, and there is no statistical difference in FIM gain or efficiency between the cancer and non-cancer cohort, or between the cancer subgroups. The length of stay was similar in cancer and non-cancer cohorts but cancer patients with spinal metastasis and those who underwent concomitant radiotherapy stayed longer. There were good rates of discharge home, transfer back, survivorship and durability in functional gains. CONCLUSION: Cancer patients benefit as much as non-cancer patients in undergoing a rehabilitation programme. More patients should be admitted to such programmes and these programmes should be better structured and refined.