-
1.
Inflammation moderates the effects of lifestyle modification on neurocognition among individuals with resistant hypertension.
Avorgbedor, F, Blumenthal, JA, Hinderliter, A, Ingle, K, Lin, PH, Craighead, L, Tyson, C, Kraus, W, Sherwood, A, Smith, PJ
Journal of clinical hypertension (Greenwich, Conn.). 2023;25(1):106-110
-
-
-
Free full text
-
Plain language summary
Hypertension is one of the primary causes of cardiovascular disease, stroke, Alzheimer’s Disease, and Alzheimer’s Disease and related dementias (AD/ADRD). Among individuals with hypertension, those with resistant hypertension (RH) appear to have the greatest risk of cerebrovascular disease and associated cognitive impairment. The aim of this study was to investigate the potential influence of individual differences in pre-treatment inflammatory profiles on changes in cognition following lifestyle modification among RH participants in the TRIUMPH clinical trial. This study is a report based on the TRIUMPH study which was a randomised clinical trial. One hundred forty patients with RH were randomised with 2:1 allocation to either a 4-month Centre-based Lifestyle intervention or Standardized Education and Physician Advice. Results show that basal levels of elevated peripheral inflammation may represent an intermediate phenotype of risk for cognitive decline. In fact, individuals with higher levels of c-reactive protein at baseline demonstrated greater improvements in Executive Function/Learning following participation in an intensive lifestyle intervention. Authors conclude that their findings may help inform targeted treatments to reduce ADRD among middle-aged and older adults with cardiovascular disease risk factors.
Abstract
Individuals with resistant hypertension (RH) have the greatest risk of cerebrovascular disease and cognitive impairment among individuals with hypertension. Elevated levels of pro-inflammatory cytokines may represent a critical yet unexamined factor influencing the impact of healthy lifestyle changes on cognitive function. We explored the influence of inflammation on changes in cognition following lifestyle modification among individuals with RH participating in the TRIUMPH clinical trial. One hundred forty participants with RH completed a battery of neurocognitive tests along with the inflammatory marker C-reactive protein (hsCRP) and were subsequently randomized to an intensive 4-month lifestyle modification intervention or to education and physician advice control. Results indicated that the effects of lifestyle modification on Executive Function and Learning were moderated by pre-intervention hsCRP levels (P = .049), with treatment efficacy increasing across levels of baseline inflammation levels (low: d = 0.12; mild: d = 0.43; moderate: d = 0.81). We conclude that inflammatory profiles may help identify individuals more likely to improve executive functioning resulting from lifestyle modification.
-
2.
Effect of a multi-domain lifestyle intervention on cardiovascular risk in older people: the FINGER trial.
Lehtisalo, J, Rusanen, M, Solomon, A, Antikainen, R, Laatikainen, T, Peltonen, M, Strandberg, T, Tuomilehto, J, Soininen, H, Kivipelto, M, et al
European heart journal. 2022;43(21):2054-2061
-
-
-
Free full text
-
Plain language summary
Older people are at high risk of cardiovascular disease, and 90% of the risk factors can be modified, including an unhealthy diet, poor physical activity, obesity, smoking, and obesity-related comorbidities. This randomised controlled trial examined a multifactorial approach combining several lifestyle modifications in 1259 older adults between 60 and 77 years of age to reduce the risk of cardiovascular disease. Participants were randomly assigned to intensive multi-domain lifestyle intervention or regular health advice control groups. The multifactorial lifestyle intervention incorporated dietary counselling, exercise training, cognitive training, and managing CVD and metabolic risk factors. Dietary interventions included tailored strategies that considered increased consumption of fruits, berries, vegetables, whole grains, margarine, oil, and fish. Physical exercise interventions included strength training, balance exercises, and aerobic exercises. Cognitive interventions and intensive strategies to manage metabolic factors were also implemented. In the multifactorial lifestyle intervention group, cerebrovascular events were lower after two years than in the control group. In addition, cardiovascular disease and stroke incidence were lower in the elderly with a history of cardiovascular disease. Healthcare professionals can use the results from this study to understand the benefits of multifactorial lifestyle interventions on cardiovascular disease. However, there is a need for longer-term robust studies since the evidence is sparse.
Abstract
AIMS: Joint prevention of cardiovascular disease (CVD) and dementia could reduce the burden of both conditions. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) demonstrated a beneficial effect on cognition (primary outcome) and we assessed the effect of this lifestyle intervention on incident CVD (pre-specified secondary outcome). METHODS AND RESULTS FINGER enrolled 1259 individuals aged 60-77 years (ClinicalTrials.gov NCT01041989). They were randomized (1:1) to a 2-year multi-domain intervention with diet, physical and cognitive activity, and vascular monitoring (n = 631), or general health advice (n = 628). National registries provided data on CVD including stroke, transient ischaemic attack (TIA), or coronary heart event. During an average of 7.4 years, 229 participants (18%) had at least one CVD diagnosis: 107 in the intervention group and 122 in the control group. The incidence of cerebrovascular events was lower in the intervention than the control group: hazard ratio (HR) for combined stroke/TIA was 0.71 [95% confidence interval (CI): 0.51-0.99] after adjusting for background characteristics. Hazard ratio for coronary events was 0.84 (CI: 0.56-1.26) and total CVD events 0.80 (95% CI: 0.61-1.04). Among those with history of CVD (n = 145), the incidence of both total CVD events (HR: 0.50, 95% CI: 0.28-0.90) and stroke/TIA (HR: 0.40, 95% CI: 0.20-0.81) was lower in the intervention than the control group. CONCLUSION A 2-year multi-domain lifestyle intervention among older adults was effective in preventing cerebrovascular events and also total CVD events among those who had history of CVD.
-
3.
Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders.
Nay, K, Smiles, WJ, Kaiser, J, McAloon, LM, Loh, K, Galic, S, Oakhill, JS, Gundlach, AL, Scott, JW
International journal of molecular sciences. 2021;22(8)
-
-
-
Free full text
Plain language summary
Exercise as therapy for mental health disorders has become common due to its reported benefits and low cost. There are many biological ways in which exercise may help mood disorders and diseases associated with brain degeneration and this review article aimed to highlight these. The authors first highlighted the research indicating that exercise may be protective in mood disorders with studies showing reduction of symptoms of depression, anxiety, schizophrenia, autism, and bipolar disorder. Exercise may also be of benefit in several brain degenerative disorders with studies indicating a positive impact in individuals with Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Multiple Sclerosis. Studies have also indicated that individuals with brain injuries, such as stroke may also benefit. Several reasons for this were highlighted. When muscle is stimulated during exercise a key brain signalling molecule may be produced, known as brain-derived neurotrophic factor (BDNF). BDNF may have the effect of preventing brain degeneration and promoting regeneration. Exercise may also increase gut microbial diversity and increase beneficial bacteria which may benefit the brain in several ways. It was concluded that exercise may have beneficial effects for individuals with brain disorders. This study could be used by healthcare professionals to understand how exercise may be of benefit to individuals with mood disorders, brain degenerative diseases and brain injuries as part of a holistic treatment plan.
Abstract
As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle-brain, liver-brain and gut-brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise-brain communication and their benefits for physiology and brain function.
-
4.
Coenzyme Q10 for heart failure.
Al Saadi, T, Assaf, Y, Farwati, M, Turkmani, K, Al-Mouakeh, A, Shebli, B, Khoja, M, Essali, A, Madmani, ME
The Cochrane database of systematic reviews. 2021;(2):CD008684
-
-
-
Free full text
-
Plain language summary
As per the definition given by the NHS, heart failure happens when the heart fails to pump blood around the body due to stiffness or weakness of the heart muscle. Coenzyme Q10 reduces oxidative stress and toxic effects in the body by acting as a fat-soluble antioxidant nutrient. Due to these beneficial effects, CoQ10 may effectively reduce damage to cardiac cells and disruption to cellular signalling. CoQ10 is also a cell membrane stabiliser, and previous studies have shown a correlation between the severity of heart failure and CoQ10 deficiency. In addition, dietary absorption of CoQ10 is relatively slow and ineffective; therefore, supplementation is effective and safe with no side effects. This review included eleven randomised controlled studies to compare the beneficial effects of Coenzyme Q10 for the treatment of people with heart disease. This review showed that Coenzyme Q10 might reduce all-cause mortality and hospitalisation due to heart failure. In addition, CoQ10 may stabilise myocardial calcium‐dependent ion channels and encourage adenosine‐5'‐triphosphate (ATP) synthesis. However, the effectiveness of CoQ10 in lowering the risk of myocardial infarction or stroke, left ventricular ejection fraction and exercise capacity is inconclusive. Healthcare professionals can use this study's results to understand the potential beneficial effects of CoQ10 supplementation on maintaining heart health. However, due to the high heterogeneity in the current research, further robust long-term studies are required to evaluate the therapeutic value of Coenzyme Q10 in managing heart disease.
Abstract
BACKGROUND Coenzyme Q10, or ubiquinone, is a non-prescription nutritional supplement. It is a fat-soluble molecule that acts as an electron carrier in mitochondria, and as a coenzyme for mitochondrial enzymes. Coenzyme Q10 deficiency may be associated with a multitude of diseases, including heart failure. The severity of heart failure correlates with the severity of coenzyme Q10 deficiency. Emerging data suggest that the harmful effects of reactive oxygen species are increased in people with heart failure, and coenzyme Q10 may help to reduce these toxic effects because of its antioxidant activity. Coenzyme Q10 may also have a role in stabilising myocardial calcium-dependent ion channels, and in preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis. Coenzyme Q10, although not a primary recommended treatment, could be beneficial to people with heart failure. Several randomised controlled trials have compared coenzyme Q10 to other therapeutic modalities, but no systematic review of existing randomised trials was conducted prior to the original version of this Cochrane Review, in 2014. OBJECTIVES To review the safety and efficacy of coenzyme Q10 in heart failure. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Web of Science, CINAHL Plus, and AMED on 16 October 2020; ClinicalTrials.gov on 16 July 2020, and the ISRCTN Registry on 11 November 2019. We applied no language restrictions. SELECTION CRITERIA We included randomised controlled trials of either parallel or cross-over design that assessed the beneficial and harmful effects of coenzyme Q10 in people with heart failure. When we identified cross-over studies, we considered data only from the first phase. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods, assessed study risk of bias using the Cochrane 'Risk of bias' tool, and GRADE methods to assess the quality of the evidence. For dichotomous data, we calculated the risk ratio (RR); for continuous data, the mean difference (MD), both with 95% confidence intervals (CI). Where appropriate data were available, we conducted meta-analysis. When meta-analysis was not possible, we wrote a narrative synthesis. We provided a PRISMA flow chart to show the flow of study selection. MAIN RESULTS We included eleven studies, with 1573 participants, comparing coenzyme Q10 to placebo or conventional therapy (control). In the majority of the studies, sample size was relatively small. There were important differences among studies in daily coenzyme Q10 dose, follow-up period, and the measures of treatment effect. All studies had unclear, or high risk of bias, or both, in one or more bias domains. We were only able to conduct meta-analysis for some of the outcomes. None of the included trials considered quality of life, measured on a validated scale, exercise variables (exercise haemodynamics), or cost-effectiveness. Coenzyme Q10 probably reduces the risk of all-cause mortality more than control (RR 0.58, 95% CI 0.35 to 0.95; 1 study, 420 participants; number needed to treat for an additional beneficial outcome (NNTB) 13.3; moderate-quality evidence). There was low-quality evidence of inconclusive results between the coenzyme Q10 and control groups for the risk of myocardial infarction (RR 1.62, 95% CI 0.27 to 9.59; 1 study, 420 participants), and stroke (RR 0.18, 95% CI 0.02 to 1.48; 1 study, 420 participants). Coenzyme Q10 probably reduces hospitalisation related to heart failure (RR 0.62, 95% CI 0.49 to 0.78; 2 studies, 1061 participants; NNTB 9.7; moderate-quality evidence). Very low-quality evidence suggests that coenzyme Q10 may improve the left ventricular ejection fraction (MD 1.77, 95% CI 0.09 to 3.44; 7 studies, 650 participants), but the results are inconclusive for exercise capacity (MD 48.23, 95% CI -24.75 to 121.20; 3 studies, 91 participants); and the risk of developing adverse events (RR 0.70, 95% CI 0.45 to 1.10; 2 studies, 568 participants). We downgraded the quality of the evidence mainly due to high risk of bias and imprecision. AUTHORS' CONCLUSIONS The included studies provide moderate-quality evidence that coenzyme Q10 probably reduces all-cause mortality and hospitalisation for heart failure. There is low-quality evidence of inconclusive results as to whether coenzyme Q10 has an effect on the risk of myocardial infarction, or stroke. Because of very low-quality evidence, it is very uncertain whether coenzyme Q10 has an effect on either left ventricular ejection fraction or exercise capacity. There is low-quality evidence that coenzyme Q10 may increase the risk of adverse effects, or have little to no difference. There is currently no convincing evidence to support or refute the use of coenzyme Q10 for heart failure. Future trials are needed to confirm our findings.
-
5.
6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records.
Taquet, M, Geddes, JR, Husain, M, Luciano, S, Harrison, PJ
The lancet. Psychiatry. 2021;8(5):416-427
-
-
-
Free full text
Plain language summary
Recent literature shows that COVID-19 survivors might be at an increased risk of neurological and psychiatric disorders. The aim of this study was to investigate the incidence of neurological and psychiatric diagnoses in survivors in the 6 months after documented clinical COVID-19 infection. This study is a retrospective cohort study with the primary cohort comprised of 236,379 patients diagnosed with COVID-19 and two propensity-score-matched control cohorts. The primary cohort was divided into one of the four subgroups. Results indicate that the severity of COVID-19 had a clear effect on subsequent neurological diagnoses. In fact, COVID-19 was associated with an increased risk of neurological and psychiatric outcomes. However, the incidences and hazard ratio of these were greater in patients who had required hospitalisation, and particularly those who required ITU admission or developed encephalopathy, even after extensive propensity score matching for other factors. Authors conclude that COVID-19 is followed by significant rates of neurological and psychiatric diagnoses over the subsequent 6 months.
Abstract
BACKGROUND Neurological and psychiatric sequelae of COVID-19 have been reported, but more data are needed to adequately assess the effects of COVID-19 on brain health. We aimed to provide robust estimates of incidence rates and relative risks of neurological and psychiatric diagnoses in patients in the 6 months following a COVID-19 diagnosis. METHODS For this retrospective cohort study and time-to-event analysis, we used data obtained from the TriNetX electronic health records network (with over 81 million patients). Our primary cohort comprised patients who had a COVID-19 diagnosis; one matched control cohort included patients diagnosed with influenza, and the other matched control cohort included patients diagnosed with any respiratory tract infection including influenza in the same period. Patients with a diagnosis of COVID-19 or a positive test for SARS-CoV-2 were excluded from the control cohorts. All cohorts included patients older than 10 years who had an index event on or after Jan 20, 2020, and who were still alive on Dec 13, 2020. We estimated the incidence of 14 neurological and psychiatric outcomes in the 6 months after a confirmed diagnosis of COVID-19: intracranial haemorrhage; ischaemic stroke; parkinsonism; Guillain-Barré syndrome; nerve, nerve root, and plexus disorders; myoneural junction and muscle disease; encephalitis; dementia; psychotic, mood, and anxiety disorders (grouped and separately); substance use disorder; and insomnia. Using a Cox model, we compared incidences with those in propensity score-matched cohorts of patients with influenza or other respiratory tract infections. We investigated how these estimates were affected by COVID-19 severity, as proxied by hospitalisation, intensive therapy unit (ITU) admission, and encephalopathy (delirium and related disorders). We assessed the robustness of the differences in outcomes between cohorts by repeating the analysis in different scenarios. To provide benchmarking for the incidence and risk of neurological and psychiatric sequelae, we compared our primary cohort with four cohorts of patients diagnosed in the same period with additional index events: skin infection, urolithiasis, fracture of a large bone, and pulmonary embolism. FINDINGS Among 236 379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33·62% (95% CI 33·17-34·07), with 12·84% (12·36-13·33) receiving their first such diagnosis. For patients who had been admitted to an ITU, the estimated incidence of a diagnosis was 46·42% (44·78-48·09) and for a first diagnosis was 25·79% (23·50-28·25). Regarding individual diagnoses of the study outcomes, the whole COVID-19 cohort had estimated incidences of 0·56% (0·50-0·63) for intracranial haemorrhage, 2·10% (1·97-2·23) for ischaemic stroke, 0·11% (0·08-0·14) for parkinsonism, 0·67% (0·59-0·75) for dementia, 17·39% (17·04-17·74) for anxiety disorder, and 1·40% (1·30-1·51) for psychotic disorder, among others. In the group with ITU admission, estimated incidences were 2·66% (2·24-3·16) for intracranial haemorrhage, 6·92% (6·17-7·76) for ischaemic stroke, 0·26% (0·15-0·45) for parkinsonism, 1·74% (1·31-2·30) for dementia, 19·15% (17·90-20·48) for anxiety disorder, and 2·77% (2·31-3·33) for psychotic disorder. Most diagnostic categories were more common in patients who had COVID-19 than in those who had influenza (hazard ratio [HR] 1·44, 95% CI 1·40-1·47, for any diagnosis; 1·78, 1·68-1·89, for any first diagnosis) and those who had other respiratory tract infections (1·16, 1·14-1·17, for any diagnosis; 1·32, 1·27-1·36, for any first diagnosis). As with incidences, HRs were higher in patients who had more severe COVID-19 (eg, those admitted to ITU compared with those who were not: 1·58, 1·50-1·67, for any diagnosis; 2·87, 2·45-3·35, for any first diagnosis). Results were robust to various sensitivity analyses and benchmarking against the four additional index health events. INTERPRETATION Our study provides evidence for substantial neurological and psychiatric morbidity in the 6 months after COVID-19 infection. Risks were greatest in, but not limited to, patients who had severe COVID-19. This information could help in service planning and identification of research priorities. Complementary study designs, including prospective cohorts, are needed to corroborate and explain these findings. FUNDING National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre.
-
6.
Pilot trial of a group cognitive behavioural therapy program for comorbid depression and obesity.
Lores, T, Musker, M, Collins, K, Burke, A, Perry, SW, Wong, ML, Licinio, J
BMC psychology. 2020;8(1):34
-
-
-
Free full text
Plain language summary
Depression and obesity are significant global health concerns. Depression can significantly impact physical health and reduced immune function. The aim of this study was to examine the potential benefits of a novel group psychological intervention program. The study is a preliminary quasi-experimental (single-arm) before-after pilot trial of a newly developed group-based psychological intervention program for people with depression and comorbid obesity. The program consisted of 10 two-hour group sessions held weekly. A total of 24 participants were recruited to the program across two pilot groups. Results indicate that there was a significant reduction in participants’ depression and anxiety scores by program-end. Some evidence also shows improvements in weight-related negative cognitions. Authors conclude that the group therapy program therefore has considerable potential to be effective in helping people enjoy better mental health and improve health outcomes.
Abstract
BACKGROUND Depression and obesity are significant global health concerns that commonly occur together. An integrated group cognitive behavioural therapy program was therefore developed to simultaneously address comorbid depression and obesity. METHODS Twenty-four participants (63% women, mean age 46 years) who screened positively for depression with a body mass index ≥25 were recruited from a self-referred general population sample. The group therapy program (10 two-hour weekly sessions) was examined in a single-arm, before-after pilot trial, conducted in a behavioural health clinic in Adelaide, Australia. Primary outcomes included survey and assessment-based analyses of depression, anxiety, body image, self-esteem, and weight (kg), assessed at four time-points: baseline, post-intervention, three-months and 12-months post program. Eighteen participants (75%) completed the program and all assessments. RESULTS Significant improvements in depression, anxiety, self-esteem and body shape concern scores, several quality of life domains, eating behaviours and total physical activity (among others) - but not weight - were observed over the course of the trial. CONCLUSIONS Results from this pilot trial suggest that combining interventions for depression and obesity may be useful. Further development of the program, particularly regarding the potential for physical health benefits, and a randomised controlled trial, are warranted. TRIAL REGISTRATION Trial registration: ANZCTR, ACTRN12617001079336, 13 July 2017. Retrospectively registered after date of the first consent (6 July 2017), but before the date of the first intervention session (20 July 2017).
-
7.
Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial.
Ohsawa, Y, Hagiwara, H, Nishimatsu, SI, Hirakawa, A, Kamimura, N, Ohtsubo, H, Fukai, Y, Murakami, T, Koga, Y, Goto, YI, et al
Journal of neurology, neurosurgery, and psychiatry. 2019;90(5):529-536
-
-
-
Free full text
Plain language summary
Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a major clinical entity encompassing mitochondrial diseases resulting from mitochondrial dysfunction. Stroke-like episodes, the most critical symptom of MELAS, are characterised by an abrupt onset of cortical neurological deficits with typical MRI abnormalities not conforming to the distribution of main arteries. The aim of this study was to evaluate the efficacy and safety of high-dose taurine supplementation for prevention of stroke-like episodes. This study is a multicentre, open-label, phase III trial with a total of 291 patients with MELAS. Results show that oral supplementation with high-dose taurine was effective in preventing stroke-like episodes. Furthermore, the 50% responder rate reached 80%, and the annual relapse rate of stroke-like episodes significantly decreased with concomitant increases in blood and cerebrospinal fluid taurine levels. Adverse events associated with taurine were observed among the participants, but no serious adverse events associated with taurine supplementation were reported. Authors conclude that oral high-dose taurine supplementation was effective and safe for the prevention of stroke-like episodes in patients with MELAS by ameliorating the modification defect in the first anticodon nucleotide of mitochondrial tRNA [transfer RNA – a small RNA molecule].
Abstract
OBJECTIVE The aim of this study was to evaluate the efficacy and safety of high-dose taurine supplementation for prevention of stroke-like episodes of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), a rare genetic disorder caused by point mutations in the mitochondrial DNA that lead to a taurine modification defect at the first anticodon nucleotide of mitochondrial tRNALeu(UUR), resulting in failure to decode codons accurately. METHODS After the nationwide survey of MELAS, we conducted a multicentre, open-label, phase III trial in which 10 patients with recurrent stroke-like episodes received high-dose taurine (9 g or 12 g per day) for 52 weeks. The primary endpoint was the complete prevention of stroke-like episodes during the evaluation period. The taurine modification rate of mitochondrial tRNALeu(UUR) was measured before and after the trial. RESULTS The proportion of patients who reached the primary endpoint (100% responder rate) was 60% (95% CI 26.2% to 87.8%). The 50% responder rate, that is, the number of patients achieving a 50% or greater reduction in frequency of stroke-like episodes, was 80% (95% CI 44.4% to 97.5%). Taurine reduced the annual relapse rate of stroke-like episodes from 2.22 to 0.72 (P=0.001). Five patients showed a significant increase in the taurine modification of mitochondrial tRNALeu(UUR) from peripheral blood leukocytes (P<0.05). No severe adverse events were associated with taurine. CONCLUSIONS The current study demonstrates that oral taurine supplementation can effectively reduce the recurrence of stroke-like episodes and increase taurine modification in mitochondrial tRNALeu(UUR) in MELAS. TRIAL REGISTRATION NUMBER UMIN000011908.