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STUDY PROTOCOL
Safety and efficacy of human umbilical cord-derived mesenchymal stem cells in patients with Alzheimer's disease: study protocol for an open-label self-control trial
Jing-wen Niu, Bin Zhang, Hu Chen
January-March 2016, 1(1):1-8
Background: Animal model experiments have demonstrated the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in the treatment of Alzheimer's disease. However, the clinical efficacy of hUC-MSCs in the treatment of Alzheimer's disease in humans remains unclear. This study protocol for a phase I/II clinical trial was designed to investigate the clinical safety (primary outcome) and efficacy (secondary outcome) of hUC-MSCs in the clinical treatment of Alzheimer's disease. Methods/Design: This open-label, self-control, single-center prospective phase I/II clinical trial will be performed at the Department of Hematopoietic Stem Cell Transplantation, Cell and Gene Therapy Center, the 307 th Hospital of Chinese People's Liberation Army, China. Thirty patients with moderate to severe Alzheimer's disease will be included. The primary outcome is the number of patients who have adverse events at 10 weeks and 1 year after hUM-MSCs therapy. Secondary outcomes include cognitive function, overall clinical status, daily living activities, neuropsychiatric symptoms, blood biochemical Alzheimer's disease markers. Discussion: The findings from this trial will provide valuable evidence for the use of hUM-MSCs in the clinical treatment of Alzheimer's disease. Trial registration: ClinicalTrial.gov identifier: NCT01547689; registered on 5 March 2012. This study protocol was approved by the Ethics Committee of the 307 th Hospital of Chinese People's Liberation Army.
  1,721 265 -
Safety of intrathecal transplantation of human umbilical cord mesenchymal stem cells for treating hereditary cerebellar ataxia: study protocol for a randomized controlled trial
Yi-hua An
January-March 2016, 1(1):9-16
Background: Intrathecal transplantation of human umbilical cord mesenchymal stem cells (hUCMSCs) has been shown to be effective for treating spinocerebellar ataxia and can improve patient's neurological function to a certain degree without safety concerns. However, further validation by randomized controlled trials is needed. The present study aims to fill this gap. Methods/Design: A single-center, parallel group, open-label, randomized controlled trial will be performed at General Hospital of Chinese Armed Police Forces, China. A total of 100 patients with hereditary cerebellar ataxia will undergo hUCMSC transplantation in the subarachnoid space through lumbar puncture (hUCMSCs transplantation group) or not (control group). The outcome observation time will be designated within 1 week before transplantation, as well as 1, 3, 6, and 12 months after transplantation. Primary outcomes include neurological function evaluation (International Cooperative Ataxia Rating Scale, Modified Falls Efficacy Scale, Berg Balance Assessment, Tremor Rating Scale, and the Timed Up and Go test) and blood tests. Secondary outcomes include electrophysiology examination, mental state evaluation, and urine testing. Discussion: This trial protocol is designed to provide reference data for the safety and rational use of hUCMSC transplantation in the treatment of hereditary cerebellar ataxia. Trial registration: ClinicalTrials.gov identifier: NCT01489267; registered on 30 October 2011. The study protocol has been approved by the ethics committee of the General Hospital of Chinese Armed Police Forces, China (approval No. 201117).
  1,673 197 -
Transcutaneous electrical acupoint stimulation with different acupoint combinations on opioid consumption in patients undergoing off-pump coronary artery bypass grafting: study protocol for a randomized double-blind controlled trial
Hui Zhang, Chong Lei, Tao-yuan Zhang, Li-hong Hou, Qiang Wang, Hai-long Dong, Jian-ge Han, Li-ze Xiong
January-March 2016, 1(1):17-24
Background: The demand for improved anesthesia during off-pump coronary artery bypass grafting (OP-CABG) is continually increasing. Ensuring stable hemodynamics and balanced myocardial oxygen supply during OP-CABG are key issues that remain to be resolved. There is evidence that acupuncture anesthesia can decrease mortality after OP-CABG, while reducing the dose of anesthesia required, minimizing surgical complications, and decreasing medical costs. Acupuncture at distal-proximal acupoints in combination is the most commonly used method requiring acupoint compatibility. We hypothesize that electroacupuncture at distal-proximal and regional acupoints prior to OP-CABG will reduce the dosage of anesthesia required during OP-CABG, and minimize postoperative complications. Methods/Design: This prospective, randomized, double-blind, controlled trial will be performed at the Departments of Anesthesiology at Xijing Hospital, Fourth Military Medical University, and Tianjin Chest Hospital, China. A total of 186 patients scheduled for OP-CABG in these two hospitals will be included in the study. The patients will be divided into three groups: distal-proximal acupoints group (acupuncture at the Danzhong (CV17) and Hegu (LI4) acupoints); regional acupoints group (acupuncture at the Danzhong (CV17) and Juque (CV14) acupoints); and non-acupoint group (acupuncture at a site 2 cm lateral from the Danzhong (CV17) and Juque (CV14) acupoints). All interventions will start 30 minutes prior to anesthesia and continue until the beginning of anesthesia. The primary outcome is the dose of sufentanil used for anesthesia. Secondary outcomes are cardiac troponin I content, inotropic score, dose of propofol used for anesthesia, duration of mechanical ventilation, duration of stay in the intensive care unit, length of postoperative hospital stay, incidence of overall complications within 30 days of surgery, and incidence of overall mortality within 30 days of surgery. Adverse events will be also evaluated. Discussion: This trial protocol will determine whether acupuncture at distal-proximal or regional acupoints can reduce anesthetic dose and postoperative complications in OP-CABG surgery, with the purpose of ensuring patient safety in the perioperative phase. Trial registration: ClinicalTrals.gov identifier: NCT02443220; registered on 18 August 2014. Ethical approval: The protocol was approved by the Ethics Committee on Clinical Trials of Drugs, Xijing Hospital, and the Ethics Committee on Clinical Trials, Tianjin Chest Hospital, China. Written informed consent regarding trial procedure and treatment protocol will be obtained from each subject.
  1,639 146 -
RESEARCH ARTICLE
Pain treatment with cooled radiofrequency in osteoarthritis and total knee arthroplasty: case series in Hospital Universitario de Son Espases
Andres Camprodon Alberca, José Andrés López-Riquelme, María del Pilar Sanchis Cortés
October-December 2017, 2(4):77-83
DOI:10.4103/2542-3975.222178  
Background and objectives: Cooled radiofrequency (RF) for neurotomy of genicular nerves has been proved to be efficient in short-term (12 weeks) to relieve the knee pain in severe osteoarthritis (OA) and total knee arthroplasty (TKA). This study is aimed to analyze the results of cooled radiofrequency in patients with chronic knee pain after one year of follow-up. Design: A retrospective case-series study. Methods: Forty patients underwent cooled RF of genicular nerves. We evaluated results of 36-Item Short Form Survey (SF-36), Knee Society Score (KSS) and Visual Analogue Scale (VAS) preoperatively and after one-year follow-up. Results: Regarding SF-36, a significant improvement in pain, general health and overall outcome was obtained. Preoperative average VAS score was 8.5; 1 year after surgery this score was 5.3. Significant differences were found at the knee score (KS) in KSS but not in the function score (FS) in KSS. Conclusion: Cooled RF for neurotomy of genicular nerves is still effective after 1 year of the procedure in the treatment of chronic knee pain due to osteoarthritis. The rate of conversion to arthroplasty is low. This technique could be a good alternative for chronic pain management in patients in whom TKA is not the first option of treatment.
  1,391 317 -
STUDY PROTOCOL
Skill-building through Task-Oriented Motor Practice (STOMP) intervention for activities of daily living in dementia: study protocol for a randomized controlled clinical trial
Carrie A Ciro, Julie A Stoner, Calin Prodan, Linda Hershey
April-June 2016, 1(2):45-50
DOI:10.4103/2468-5658.184743  
Background: Progressive disability in activities of daily living (ADL) is inevitable for people with Alzheimer's disease and related dementias (ADRD). Attempts to slow or prevent ADL disability have been unsuccessful despite making progress in behavioral training methods. Missing from this research is an emphasis on how we maximize a patient's engagement during training and the rigorous examination of implementation protocols (dosing and training methods) which may advantage learning in people with ADRD. Our team addressed this gap with the development of the Skill-building through Task-Oriented Motor Practice (STOMP) intervention which creates methods for obtaining ADL goals that support "personhood" and tests high-intensity protocols that appear to advantage learning and sustained learning over time. Through this study, we aim to evaluate differential outcomes in activities of daily living by two different dose levels of the STOMP intervention. Secondarily, we will assess the moderating effects of participant attention to task during training. Methods/Design: A randomized, single blinded, controlled trial with 32 eligible patients with dementia assigned to either the original, intensive STOMP protocol (3 hours per day, 5 days per week for 2 weeks) or a less-intensive STOMP protocol (1 hour per day, 2 days per week for 2 weeks) delivered by an occupational therapy assistant in the home. ADL training is delivered using motor learning theory techniques of blocked practice, continuous verbal praise, errorless learning and intense dosing schedules. Blinded occupational therapists will complete baseline, post-intervention and 3-month follow-up assessments in the home. Primary outcomes will be examiner and caregiver rated ADL performance. Secondary outcomes will be the amount of time the participant is engaged in the task (e.g., attention to training). Discussion: Through this protocol, we will examine differential ADL outcomes by dose for the STOMP ADL intervention. Our results will inform dosing parameters for future intervention studies for people with ADRD. Trial registration: ClinicalTrials.gov identifier: NCT02356055 Ethics: This study protocol was approved by the University of Oklahoma Health Sciences Center Institutional Review Board (#4648) and will be performed in accordance with the Declaration of Helsinki. Informed consent: Written consent will be obtained by the participant's legally-authorized representative as older adults with dementia are considered a vulnerable population. However, in all cases, assent of the participant will also be obtained at the time of consent.
  1,497 194 -
Chinese medicine packet plus wax therapy for periarthritis of the shoulder: study protocol for a multi-center, randomized controlled trial
Ye Wang
January-March 2016, 1(1):25-31
Background: Periarthritis of the shoulder clinically manifests as pain and functional disorder of the shoulder joint. Although there is a tendency to self-heal, results are unsatisfactory. Nonsurgical treatments often used for clinical treatment of periarthritis, including simple closure, massage and acupuncture, do not improve symptoms. Chinese medicine packets and wax treatment effectively improves the local micro-circulation and regulates body functions. Therefore, this study aims to develop a new Chinese medicine wax treatment for periarthritis of the shoulder using these two techniques, and to observe its safety and efficacy. Methods/Design: A prospective, multi-center randomized, double-blind, placebo-controlled clinical trial will enroll patients with periarthritis of the shoulder who will be randomized into treatment and control groups. In the treatment group, packets will be immersed in a decoction of Chinese medicine. Prepared packets will be placed onto the shoulder joint followed by warm paraffin cake, once a day for 20 minutes, for 4 weeks. In the control group, Chinese medicine packets will be replaced by placebo; all other procedures will be identical. Outcome measures will be assessed at baseline and 1, 2, and 4 weeks after treatment. Primary outcome is the McGill Pain Questionnaire score. Secondary outcomes include shoulder disability questionnaire score, Oxford shoulder score, American Shoulder and Elbow Surgeons score, University of California, Los Angeles shoulder score, the efficacy in treating Traditional Chinese Medicine syndromes, visual analog scale score, and Constant-Murley shoulder score. Discussion: This trial will provide a quantitative basis to establish therapeutic guidelines and technical standards for Chinese medicine packet plus wax therapy for the treatment of periarthritis of the shoulder. Trial registration: Chictr.org.cn identifier: ChiCTR-IOR-15006149; registered on 11 March 2015. Written approval for this protocol was obtained from the Ethics Committee of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine in China (approval No. 2014ZX (KT)-010-02).
  1,457 168 -
REVIEW
An update on clinical trials targeting human tauopathies
Monica Javidnia, Bahjat T Kurd-Misto, Charbel E-H Moussa
July-September 2017, 2(3):66-76
DOI:10.4103/2542-3975.216580  
The microtubule-associated protein 'tau' is primarily expressed within axons in the central nervous system where it stabilizes microtubules and aids in cargo transport. While basal phosphorylation of tau is normal, tau modifications, predominantly hyperphosphorylation, are critical in the pathogenesis of numerous neurodegenerative disorders known as the tauopathies. Over the years, tau has been shown to be a valuable and elusive target for the treatment of neurodegenerative diseases. Targeting tau via genetic, biological, and pharmacological approaches in vitro and in vivo may prevent degenerative pathologies. However, to date none of these approaches have been successful in human studies, albeit some promising studies are currently underway. This review aims to briefly discuss the biology and pathology of tau and summarize current treatment strategies in clinical trials.
  1,223 196 -
STUDY PROTOCOL
Coronary artery disease as a cause of morbidity and mortality in patients suffering from schizophrenia: protocol for a prospective cohort study with long-term follow-up
Jørgen Aagaard, Pirathiv Kugathasan, Svend Eggert Jensen
October-December 2016, 1(4):141-148
DOI:10.4103/2468-5658.196979  
  988 357 -
REVIEW
Medication for management of pregnancy-induced hypertension
Yi Lin, Ying Zhang, Yi-Nong Jiang, Wei Song
April-June 2018, 3(2):83-87
DOI:10.4103/2542-3975.235153  
Hypertension refers to increased arterial blood pressure and can be divided into two categories: primary and secondary. Primary hypertension caused by angiogenic degenerative changes is a degenerative disease. With liberalization of China’s reproduction policy and increases in maternal age, the prevalence of pregnancy-induced hypertension (PIH) in China has increased gradually. PIH is not a type of primary hypertension, but there are differences in the treatment of these two types of hypertension. Here, we review the choice and use of drugs for PIH management using drugs for the management of primary hypertension as a reference. First-line drugs such as labetalol, nifedipine, or methyldopa should be taken via the oral route if blood pressure is ≥ 150/90 mmHg. For chronic hypertension, other drugs should be added after the first drug at the highest concentration has been revealed to be ineffective. If the blood pressure of patients with acute hypertension is ≥ 160/110 mmHg, maternal stroke or eclampsia can result. If PIH patients are about to deliver, they can be given labetalol (i.v.), hydralazine (i.v.) or nifedipine (p.o.). Moreover, all anti-hypertensive treatments should be based on considerations of maternal and fetal safety.
  1,086 250 -
STUDY PROTOCOL
Long-term effects of Enterprise self-expanding intracranial stent implantation in the treatment of carotid artery stenosis in patients with ischemic stroke: study protocol for a randomized controlled trial
Meng Ji, Wei Wang, Wen-li Hu
April-June 2016, 1(2):38-44
DOI:10.4103/2468-5658.184742  
Background: The Enterprise stent system (Johnson & Johnson (Shanghai) Medical Equipment Co., Ltd., China) is a closed-loop, recoverable self-expanding stent that is effective in the treatment of intracranial aneurysm. However, most studies on the treatment of intracranial aneurysm after ischemic stroke are case series or case reports. Methods/Design: We will perform a single-center, double-blind, randomized parallel-controlled trial at the Department of Neurology, Beijing Chao-yang Hospital, Capital Medical University, China. A cohort of 100 patients with atherosclerotic ischemic stroke will be randomly allocated to undergo either Enterprise self-expanding intracranial stent implantation in combination with antiplatelet medication (stent implantation group, n = 50) or only antiplatelet medication (drug group, n = 50) for treatment of carotid artery stenosis. Four time points (0.5, 1, 2, and 3 years after stent implantation or antiplatelet medication) will be selected for outcome observation and evaluation. The primary outcome will be the National Institutes of Health Stroke Scale score, which is used to evaluate neurologic deficits. The secondary outcomes will be the Barthel index and carotid stenosis rate. Discussion: There is a lack of randomized controlled studies addressing the long-term effects of the Enterprise self-expanding intracranial stent system for carotid artery stenosis in patients with ischemic stroke. This study will investigate and further confirm the clinical significance of the Enterprise stent system in the treatment of carotid artery stenosis in patients with ischemic stroke. Trial registration: This trial was registered at ClinicalTrial.gov (NCT02802072). Ethics: The study protocol has been approved by the Ethics Committee of Beijing Chao-yang Hospital, Captical Medical University, China (approval number: GJCY16012) and will be performed in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association. Informed consent: Written informed consent will be obtained from participants or their guardians prior to inclusion in this study.
  1,151 160 -
Can early counselling and support for Alzheimer's disease caregivers reduce burden? Study protocol for a multicenter randomized controlled trial
Serena Amici, Pamela Iannizzi, Alessandra Di Pucchio, Iosief Abraha, Alessandro Montedori, Rabih Chattat, Nicola Vanacore
July-September 2016, 1(3):99-106
DOI:10.4103/2468-5658.191352  
Background: The activity of "caregiving" for people affected with Alzheimer's disease (AD) is associated with an augmentation in health problems (anxiety, depression, stress, increased mortality), as well as in social and financial problems. Different methods of counselling, to reduce caregiver anxiety and depression, have been shown to be effective. Methods/Design: This study will be a multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) controlled superiority trial with two parallel groups. Two hundred and sixty-four caregivers of AD patients will be randomly allocated to the modified Mittelmann psychosocial intervention or an educational intervention. The treatment will consist of 6 hours of counselling and psychosocial support to caregivers, administered by psychologists, along with a specific telephone support service, whereas the active control treatment will be 6 hours of general information about AD. The primary endpoint is change in caregiver burden measured with the Zarit Burden Interview. Secondary endpoints comprise caregiver depression, anxiety and quality of life. All endpoints will be measured at baseline, 6, 12 and 24 months post treatment. Discussion: The results of this trial will be helpful to supply the efficacy of early counselling and psychosocial support for AD caregivers and offer in-depth useful information for stakholders and policy makers to implement strategies for caregivers. Trial registration: Clinical Trials.gov identifier: NCT02685787; registered on 6 February 2016. Ethics: This trial has been approved by Umbria Ethical Review Committee, Italy and will be performed in accordance with the norms on Good Clinical Practice and the Helsinki Declaration. Informed consent: Written informed consent will be obtained from the caregivers.
  1,162 143 2
Neurologic Stem Cell Treatment Study (NEST) using bone marrow derived stem cells for the treatment of neurological disorders and injuries: study protocol for a nonrandomized efficacy trial
Jeffrey N Weiss, Steven Levy
October-December 2016, 1(4):176-180
DOI:10.4103/2468-5658.196984  
Background: A large number of approximately 600 known neurological diseases have no or limited medical interventions; many treatments are temporizing or only marginally effective and have changed little over decades. The Neurologic Stem Cell Treatment Study (NEST) utilizes bone marrow derived stem cells (BMSCs) for neurological diseases and injuries to nervous tissue. Methods/Design: Administration of BMSCs is an established approach for the treatment of neurological diseases and injury with its effectiveness verified in the pre-clinical and clinical studies. BMSCs and the associated bone marrow fraction are posited to have a number of different mechanisms by which they may potentially improve neurological function. The circumventricular organs which lie in the wall of the third ventricle are noteworthy for a minimized or absent blood-brain barrier (BBB) facilitating entry of intravenously provided BMSCs. There is documentation in the literature that intranasal delivery of BMSCs may follow the pathways of the trigeminal nerves, facilitating their entry into the pons, brain parenchyma and cerebral spinal fluid (CSF) for effects on the CNS. The NEST is an open label, non-randomized, efficacy study with two arms. Arm 1 consists of intravenous autologous BMSCs alone; Arm 2 combines intravenous with intranasal application of BMSCs to the lower 1/3 of the nasal mucosa. There will be a total of 300 patients in the study. Endpoints include at least a 10% improvement in neurological function. Discussion: There have been a number of preclinical studies establishing the utility of intravenous and intranasal methods in providing access to the CNS for certain drugs, proteins and cellular elements. Preclinical and clinical studies utilizing BMSCs have shown positive effects in various neurological diseases. It is anticipated that combining these two administration methods for BMSCs delivery to the brain may provide a greater therapeutic response. Trial registration: ClinicalTrials.gov identifier NCT02795052; registered on June 6, 2016. Ethics: This study protocol has been Institutional Review Board (IRB) approved and will be performed in accordance with principles of research ethics set forth in the Belmont Report. Informed consent: Signed informed consent will be obtained from the patients or their guardians.
  1,195 81 1
Local administration of enriched mononuclear cells, platelets and zoledronic acid for preventing collapse of the femoral head in the early stage of osteonecrosis: study protocol for a prospective randomized parallel-controlled clinical trial
Ning Ma, Jiang Peng, Quan-yi Guo
January-March 2016, 1(1):32-37
Background: Although there are many treatments for osteonecrosis of the femoral head, conservative treatment is often ineffective. Once collapse of the femoral head occurs, the damage is irreversible. Our previous animal studies have shown that local administration of zoledronic acid prevents collapse of the osteonecrotic femoral head. Additionally, bone marrow mononuclear cell therapy has a good short-term clinical effect on osteonecrosis of the femoral head. Currently, it is unclear whether a combination of bone marrow mononuclear cells and platelet-rich plasma may have efficacy in preventing early-stage collapse of the osteonecrotic femoral head. Methods/Design: A prospective, randomized, parallel-controlled, single-center clinical trial will be completed at the Chinese PLA General Hospital, China. One hundred patients with Ficat I-II osteonecrosis of the femoral head will be recruited and equally randomized into treatment and control groups. The treatment group will be given injection of enriched autologous mononuclear cells and zoledronic acid into the necrotic area following core decompression by drilling. In the control group, core decompression by drilling will be done, but no treatment will be given. Patients will be followed up at 3, 6, 12 and 18 months. Dynamic perfusion MR imaging, three-dimensional CT reconstruction, and anteroposterior and lateral X-ray observations of the hip joint will be performed to observe blood supply, bone formation and femoral appearance in the necrotic area. Harris score of the hip joint and a numeric rating scale score will be used to evaluate hip function and pain. These indicators will be used as primary outcome measures. Scores from the 36-Item Short-Form Health Survey and activity of daily living scale will be used as secondary outcome measures. Discussion: The outcomes of this trial will provide quantitative data and related information for evaluating the efficacy of local administration of enriched bone marrow mononuclear cells, platelets and zoledronic acid for the clinical prevention of collapse of the early-stage osteonecrotic femoral head. Trial registration: ClinicalTrial.gov identifier: NCT02721940. Written approval for this protocol was obtained from the ethics committee of the Chinese PLA General Hospital in China (approval No. S2015-082-01).
  1,134 114 -
Oxidative stress response in patients with severe aortic stenosis undergoing transcatheter or surgical aortic valve replacement: protocol for a prospective observational study
Gabriel Maluenda, Nick Curzen, Michael Mahmoudi
October-December 2016, 1(4):149-153
DOI:10.4103/2468-5658.196983  
Background: Myocardial ischemia and reperfusion injury mediated by reactive oxygen species (ROS) related to cardiopulmonary bypass has been linked to adverse clinical outcomes following cardiac surgery. The generation of ROS and its clinical impact in patients undergoing transcatheter aortic valve replacement (TAVR) have not been studied. Methods/Design: This is a prospective observational study that will compare the generation of ROS between 12 consecutive patients undergoing TAVR and 12 patients undergoing isolated surgical aortic valve replacement (SAVR) and will determine whether any potential differences are related to the 3-month composite endpoints of cardiovascular mortality, myocardial infarction, stroke, major bleeding or life threatening bleeding. Peripheral blood will be taken immediately before aortic intervention, at the completion of the procedure, 6-8 hours after the procedure, and 24 hours after the procedure for measurements of ROS. Clinical follow-up at 3 months post discharge will be undertaken either in the outpatient clinic or by telephone. Discussion: This study will determine changes in the levels of ROS in patients undergoing TAVR and identify whether any potential changes are correlated with clinical outcomes. Trial registration: ClinicalTrials.gov identifier: NCT02841917; registered on December 29, 2015. Ethics: The study protocol has been approved by the RES Committee North West Liverpool East (IRAS Project ID: 206946). Informed consent: Signed informed consent will be obtained from each patient who wishes to participate in this study.
  931 257 -
Cortical physiology as a therapeutic target in Parkinson's disease related dementia and cognitive dysfunction: study protocol for a randomized controlled trial
Isabelle Buard, Christine S Martin, Benzi M Kluger
July-September 2016, 1(3):91-98
DOI:10.4103/2468-5658.191351  
Background: Dementia is the leading cause of nursing home placement in Parkinson's disease (PD), yet little is known about the causes of cognitive dysfunction in PD and there are no effective treatments. Our preliminary data and other published studies suggest that abnormalities in brain activity involving networks important for normal thinking and memory may contribute to cognitive dysfunction in PD and may represent a target for treatment. Methods/Design: A randomized control trial will be conducted to assess the therapeutic potential of bifrontal repetitive transcranial magnetic stimulation (rTMS) in modulating cortical activity related to cognitive dysfunction in PD. This study will be performed at the University of Colorado Denver, Anschutz Campus, in Aurora, Colorado. Fifty-five PD patients (> 40 years of age) with mild cognitive impairment or mild dementia will be included and randomized in a 1:1 ratio to sham or real rTMS groups. Primary outcome measurement is the total score of the Mattis Dementia Rating Scale. Secondary outcome measurements are domain specific ratings of executive function, memory, language, attention, and visuospatial abilities. Discussion: If bifrontal rTMS results in positive changes to cognitive function in PD patients with mild cognitive impairment, this may represent a new and effective treatment for PD-related cognitive dysfunction. Secondly, evaluation of any bifrontal rTMS-induced changes to cognitive function will improve the current understanding of the mechanisms behind the causes of cognitive dysfunction in PD. Trial registration: Clinical Trials.gov identifier: NCT02346708; registered on 9 January 2015. Ethics: This study protocol was approved by the Colorado Multiple Institutional Review Board (COMIRB) (approval No. 13-2474) and will be performed in accordance with the Declaration of Helsinki. Informed consent: Signed informed consent will be obtained from the patients or their guardians.
  1,024 106 1
REVIEW
Remarkable achievements in multiple sclerosis
Selvarasu Vaitheeshvaran, Manickam Agaath Hedina
April-June 2016, 1(2):77-83
DOI:10.4103/2468-5658.184748  
Multiple sclerosis as a demyelinating disease is characterized by divergent clinical symptoms in the central nervous system. To date, its etiology is still indefinite. Out of the human leukocyte antigen (HLA) region, there are different aspects contributing to multiple sclerosis. Some genome-wide association studies have shown several non-HLA genes play a major role in multiple sclerosis. Additionally, a few single nucleotide polymorphisms in non-HLA genes are likely to be predisposing markers for multiple sclerosis, including rs6897932 in IL7RA, and rs2104286, rs12044852 in IL2RA and CD58 genes, respectively. However, the exact region in the mitochondria is still now indefinite. Given that relevant studies are mostly from Europe, further investigation in different cohorts throughout the world is warranted.
  1,009 87 -
STUDY PROTOCOL
Efficacy of Qingxin Huatan therapy in regulating cardiac autonomic nerve function in patients with chronic stable angina: study protocol for a randomized controlled trial
Ping Li, Hong-hao Ma
April-June 2016, 1(2):51-57
DOI:10.4103/2468-5658.184744  
Background: Coronary heart disease is a chronic degenerative disease of the coronary arteries characterized by atherosclerosis. Lianxia Ningxin granules, a traditional Chinese medicine, is a representative preparation of Qingxin Huatan therapy, which has been confirmed to be effective in improving autonomic nerve dysfunction in patients with coronary heart disease. Methods/Design: We herein describe a prospective, single-center, randomized, double-blind, placebo-controlled trial to be performed by the Department of Cardiovascular Medicine, Third Affiliated Hospital of Beijing University of Chinese Medicine, China. Eighty patients with chronic stable angina will be randomly assigned to receive 4 weeks of treatment with either Western medicine plus Lianxia Ningxin granules (traditional Chinese medicine group) or Western medicine plus placebo (control group). All patients will be followed up for 8 weeks. The primary outcome is frequency of angina attacks. The secondary outcomes include heart rate variability, plasma catecholamine concentrations, nitroglycerin consumption, duration of angina, severity of angina pain, efficacy of traditional Chinese medicine treatment, and quality of life. Discussion: This study is designed to assess the efficacy of Qingxin Huatan therapy in treating chronic stable angina, and simultaneously investigate the regulatory effects of this therapy on cardiac autonomic nerve function and related neurotransmitter concentrations. The outcomes will provide information concerning the clinical use of Qingxin Huatan therapy to treat chronic stable angina and its ability to regulate cardiac autonomic nervous function. Trial registration : This protocol was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR-TRC-14004699). Ethics: Written approval has been obtained from the Medical Ethical Committee, Third Affiliated Hospital of Beijing University of Chinese Medicine, China (approval number: KTPJ-BZYSY-2003-003). Informed consent: Written informed consent will be obtained from patients or their guardians prior to inclusion in this study.
  982 92 1
RESEARCH ARTICLES
Wharton’s jelly derived allogeneic mesenchymal stromal cells for treatment of type 1 diabetes: Study protocol for a double-blinded, randomized, parallel, placebo-controlled trial
Per-Ola Carlsson, Mathias G Svahn
April-June 2018, 3(2):32-37
DOI:10.4103/2542-3975.235141  
Background and objectives: The Wharton’s jelly of the umbilical cord tissue contains a high density of mesenchymal stromal cells (MSCs). Wharton’s jelly derived mesenchymal stromal cells have immunosuppressive potential that can be utilized for treatment of autoimmune diseases such as type 1 diabetes (T1D). The objectives of this study are to assess the safety and efficacy of allogeneic Wharton’s Jelly derived MSCs (WJMSCs) in the treatment of T1D from the viewpoints of changes in beta-cell function, metabolic control, and diabetes treatment satisfaction during one year study period. Design: A two stage design. An open, non-randomized, dose-escalation scheme will be used in the first stage of the study, and a randomized, double-blinded, parallel, placebo-controlled scheme in the second stage of the study. Methods: The study population will consist of adult patients with T1D for < 2 years, 18–40 years of age (inclusive at both ends), only male in the first stage and both sexes in the second stage. In the first stage, a dose-escalation scheme with three doses will be evaluated for safety. The second stage will not be started until all patients in the first stage will have completed the 1-month follow-up visit. The second stage will recruit 15 patients who will be randomized to active treatment or placebo (2:1 ratio). Both patients and investigators will be blinded to the study protocol used in the second stage. Outcome measures: The primary outcome measure of this study will be safety. The secondary outcome measure will be efficacy of treatment, i.e., preservation of endogenous insulin production. This will be evaluated as delta change in C-peptide concentration in response to a mixed meal tolerance test, compared with before treatment. Discussion: By combining the first part (dose-escalation scheme) with the second part (double-blinded, parallel, placebo-controlled scheme), this study will provide both safety and efficacy data for the use of WJMSCs in the treatment of T1D. Obtained findings will guide on how to pursue this concept and indicate what dose of cells will be optimal for future trials. Ethics and dissemination: This study protocol was approved by the Ethics Committee Stockholm (approval number: 2017/1533-31/2) and the Swedish Medicinal Product Agency (EudraCT number: 2017-002766-50), and will be performed in accordance with the Declaration of Helsinki. Dissemination plans include presentations at scientific conferences and scientific publications. Patient recruitment was initiated in January 2018, and the first stage of the trial, the dose escalation, is expected to be completed for 1-month follow-up safety data, in the fourth quarter of 2018. Primary outcome measure will be estimated in 2020. Trial registration: ClinicalTrials.gov identifier: NCT03406585.
  920 144 -
STUDY PROTOCOL
Shared decision making between Chinese medical staff members and patients with coronary heart disease: study protocol for a multicenter, large sample, cross-sectional, open-label, clinical survey
Rong-chong Huang, Shu-mei Ma, Xian-tao Song, Ping Yang, Bin Liang, Min Sun, Jia-ying Xu, Qi Li, Xiao-fu Teng, Dong-feng Zhang, Yue Liu, Bing Li, Yan Yan, Zhi Li, Kasey R Boehmer, Henry H Ting, Victor M Montori
October-December 2016, 1(4):166-175
DOI:10.4103/2468-5658.196985  
Background: Shared decision making is an emerging approach through which physicians and patients can reach health care decisions based on mutual agreement. Scientific physician-patient shared decision making can facilitate selection of optimized treatments, improvement in curative effects, postoperative prognosis, and short-term and long-term rehabilitation in patients with coronary heart disease. However, there have been no studies on Chinese physicians' and patients' attitude to shared decision making. Methods/Design: This is a multicenter, large sample, cross-sectional, open-label, clinical survey. Participants are 1,000 Chinese patients with coronary heart disease and 200 medical staff members of both sexes over 18 years old. The primary survey index is the satisfaction of medical staff members and coronary heart disease patients with shared decision making. The secondary survey indices include staff and patient satisfaction with a clinical decision-making aid, patients' awareness of disease risk and curative benefits, and physician-patient trust. Discussion: This study is the first to investigate the attitude of Chinese medical staff members and coronary heart disease patients to clinical shared decision making and to examine the feasibility of using this approach. This study provides an evidence-based foundation for investigating the problems and solutions of clinical shared decision making and strengthening the adherence to statin medication in patients with coronary heart disease. Trial registration: This study protocol was registered at Chinese Clinical Trial Registry (registration number: ChiCTR-OCS-14004646). Ethics: This study protocol has been approved by Ethics Committee, The First Affiliated Hospital of Dalian Medical University (approval number: LCKY2014-14) and will be performed in strict accordance with the Declaration of Helsinki, formulated by the World Medical Association. Informed consent: Signed informed consent will be obtained from each included subject.
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Relationship between apelin and new-onset atrial fibrillation after coronary artery bypass grafting: a prospective cohort study and retrospective case-control clinical trial
Shu Xu, Zhi Li, Hui Jiang, Hai-bo Wu, Deng-shun Tao, Jin-song Han, Peng Hou, Hui-shan Wang
April-June 2016, 1(2):58-63
DOI:10.4103/2468-5658.184745  
Background: Coronary atherosclerotic heart disease as a chronic degenerative disease is the most common type of organ damage caused by atherosclerosis. Coronary artery bypass grafting is an internationally accepted treatment for coronary atherosclerotic heart disease. However, new-onset atrial fibrillation is a common complication after grafting, and its initiation and maintenance might be associated with levels of the peptide apelin. Methods/Design: A prospective cohort study and retrospective case-control clinical trial will be performed at the Department of Cardiac Surgery, General Hospital of Shenyang Military Region, China. We will recruit 120 patients without a history of atrial fibrillation and scheduled to undergo coronary artery bypass grafting. (1) Cohort study: patients will be assigned to two groups according to preoperative plasma apelin levels: high apelin (> 250 pg/mL) and low apelin (≤ 250 pg/mL). Seven days after surgery, the incidence of new-onset atrial fibrillation will be compared between the two groups. (2) Case-control study: those patients with new-onset atrial fibrillation will comprise the atrial fibrillation group, and those without will form the control group. MRI findings, and levels of plasma apelin, brain natriuretic peptide, and hypersensitive C-reactive protein, will be compared between the two groups 7 days postoperatively. Discussion: This trial is designed to investigate whether apelin can be used as an indicator to predict postoperative atrial fibrillation in patients with coronary atherosclerotic heart disease, and to provide an objective basis for the clinical selection of a preventive intervention program for atrial fibrillation. Trial registration: This trial was registered at ClinicalTrial.gov (NCT02807532). Ethics: The study protocol has acquired written approval from the Chinese Ethics Committee of Registering Clinical Trials (approval No. ChiECRCT-20150011), and will be performed in accordance with the Declaration of Helsinki formulated by the World Medical Association. Informed consent: Written informed consent will be obtained from each subject.
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RESEARCH ARTICLES
Metastatic adenocarcinoma of the lung presenting as deep vein thrombosis: an evidence of anchoring bias
Walid Ibrahim, Hossam Abubakar, Lubna Osman, Muhammad Sheikh
April-June 2017, 2(2):36-39
DOI:10.4103/2542-3975.209685  
Background: Non-small cell lung cancer is the most common type of lung cancer and it is often diagnosed at the advanced stages of this disease. Although skeletal metastasis is a common manifestation of lung cancer, distal appendicular skeletal metastasis, especially distal to the knee and elbow joints, is relatively rare. Case representation: We described a 51-year-old female patient who had been admitted with a classical presentation and diagnosis of lower-extremity deep vein thrombosis that cannot be cured using conventional treatment. Further workup revealed a mass arising from the head of the fibula compressing the adjacent vasculature that was found to be metastatic pulmonary adenocarcinoma. Conclusion: Identifying such uncommon presentations may be delayed or missed due to cognitive errors including anchoring bias. Knowledge and insight of such errors may possibly reduce their incidence and their consequent preventable patient injury.
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STUDY PROTOCOL
Use of the Smart nitinol stent system for the treatment of severe atherosclerotic carotid stenosis: study protocol for a retrospective, non-randomized, long-term parallel controlled trial
Zhi-gang Ma, Yu-heng Sun, Xiao-xin Peng, Hong-tao Hu
April-June 2016, 1(2):64-70
DOI:10.4103/2468-5658.184746  
Background: The carotid artery should be stented in patients with 70-90% stenosis owing to the high risk of stroke. The self-expanding Smart nitinol stent system is a popular treatment for carotid artery stenosis, because it is easy to manipulate and deploy, and endothelialization is rapid. Methods/Design: We conducted a retrospective, single-center, non-randomized, parallel controlled trial at Beijing Jishuitan Hospital, China. A cohort of 103 patients with severe atherosclerotic carotid stenosis was included in the analysis. Treatment was undertaken according to each patient's wishes after weighing the options: a Smart nitinol stent system (Cordis Corporation, Miami, FL, USA) was used in 40 patients, while 63 were managed conservatively with antiplatelet drugs. The primary outcome is the degree of disability and dependence 2 years after treatment, assessed by the modified Rankin Scale (mRS). The secondary outcomes are mRS score 90 days and 1 year after treatment, recurrence of cerebrovascular events, and severity of neurologic deficit measured using the National Institutes of Health Stroke Scale 1 and 2 years after treatment. Discussion: Previous studies of the Smart nitinol stent system for the treatment of carotid stenosis are mostly self-controlled case series or small cohort studies with short follow-up periods. Consequently, the long-term influence of Smart nitinol stent deployment on the risk of cerebrovascular events and long-term outcomes are not known. This trial illuminates the therapeutic benefits of the Smart nitinol stent system in a 2-year follow-up study of a large cohort of patients with severe atherosclerotic carotid stenosis. Trial registration: This trial was registered at ClinicalTrial.gov (NCT02800174). Ethics: The study protocol was approved by the Ethics Committee of Beijing Jishuitan Hospital, China (approval number: 201605-01) and conducted in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association. Informed consent: Written informed consent was obtained from participants or their guardians.
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Post-market surveillance study of FLXfit TLIF interbody fusion device: protocol for a prospective case series study
Fady Y Hijji, Ankur S Narain, Kelly H Yom, Krishna T Kudaravalli, Kern Singh
October-December 2016, 1(4):181-186
DOI:10.4103/2468-5658.196981  
Background: Minimally invasive (MIS) lumbar fusion is a frequently utilized treatment for lumbar degenerative pathology. Interbody cages have been the preferred fusion construct in these procedures due to their ability to facilitate fusion and provide structural stability. However, due to the anatomic small access corridor of minimally invasive lumbar fusion procedures, the interbody cages used in these techniques are often limited in size, increasing the risk for pseudarthrosis and subsidence. Expandable interbody cages have been developed to overcome these risks in limitations. However, few clinical studies have been developed and initiated to describe the fusion rates, clinical outcomes, and complication rates in patients receiving these expandable cages. Methods/Design: A prospective case series of 30 patients receiving the FLXFit expandable interbody cage device is currently underway. Patients to undergo MIS transforaminal lumbar interbody fusion (TLIF) for degenerative pathology will be recruited based on their meeting of inclusion criteria and eligibility to receive the expandable cage device. Patient follow-up will occur at 6 weeks, 3 months, 6 months, 1 year, and 2 years. The primary outcome will be fusion status at 1-year, as measured by computed tomography (CT) scan. Patient reported outcomes and radiographic measurements will be obtained preoperatively and at all postoperative time points. All complications, reoperations, and hospital readmissions occurring during follow up will also be recorded. Discussion: This protocol is designed to better describe the outcomes and complications following the utilization of the FLXFit expandable interbody cage device following MIS TLIF. The present manuscript provides the process for patient selection, intervention, and follow-up. Trial registration: ClinicalTrials.gov identifier NCT02805985; registered on June 15, 2016. Ethics: The study protocol has been approved by the Rush University Institutional Review Board (IRB), and will be performed under the ethical standards of the IRB. Informed consent: Signed informed consent will be obtained from each patient.
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REVIEWS
Impact of incretin-related agents on endothelial cell function
Hiroshi Nomoto, Hideaki Miyoshi, Akinobu Nakamura, Tatsuya Atsumi, Naoki Manda, Yoshio Kurihara, Shin Aoki, on behalf of SAIS Study Group
January-March 2017, 2(1):7-11
DOI:10.4103/2542-3975.202726  
Incretin-related drugs, such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, have been clinically available and widely used to treat patients with type 2 diabetes mellitus. Accumulating evidence indicates that these agents exert glycemic control and have various other favorable effects, including prevention of atherosclerosis. It is important to assess and manage early-phase atherosclerosis, but whether diabetic therapeutics including incretin-related drugs improve or maintain vascular endothelial cell function has not been fully determined. We previously published prospective clinical trials focused on flow-mediated dilation in patients with type 2 diabetes, who did not have severe atherosclerosis, using two different incretin-related drugs: a DPP-4 inhibitor and a GLP-1 analogue. These trials showed that these therapeutic agents did not improve endothelial cell function. In this article, we discuss how incretin-related drugs contribute, if at all, to vascular endothelial cell function, atherosclerosis, and beta-cell function, based on our clinical trials and previous evidence.
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STUDY PROTOCOL
Effect of a long-term modified Tai Chi-based intervention in attenuating bone mineral density in postmenopausal women in southeast China: study protocol for a randomized controlled trial
Li-ye Zou, Chao-yi Wang, Hui-ru Wang
July-September 2017, 2(3):46-52
DOI:10.4103/2542-3975.216581  
Background and objectives: According to Chinese White Paper on Osteoporosis Prevention (2009), an estimated number of 69 million Chinese people are experiencing osteoporosis caused by loss and deterioration of bone mineral density (BMD). Middle-aged women have a greater possibility in developing osteoporosis in comparison with men because of a decreased estrogen level and degeneration in physical fitness level. A Tai Chi-based intervention in the present study will be created based on four components consisting of fall-prevention/balance training, stretching/flexibility training, resistance training (Tai Chi push hand), and strength training. Design: A prospective three-arm parallel randomized controlled trial. Methods: This study will take place in ten community centers in southeast China, and postmenopausal women aged 50–65 years and without menses for 6–12 months will be recruited and randomly assigned into three groups with the allocation ratio of 1:1:1 (n = 50 for each group), including two experimental groups (a traditional Tai Chi group and a modified Tai Chi-based intervention group) and a control group. Participants in the control group will be asked to maintain their original lifestyle during the 12-month intervention period. Participants in the traditional Tai Chi and modified Tai Chi-based intervention groups will experience the traditional Yang-style Tai Chi and receive the modified Tai Chi-based intervention, respectively. The modified Tai Chi-based intervention contains four components: 1) eight Tai Chi based fall-prevention movements; 2) ten Qigong-based stretching/flexibility movements; 3) eight resistance training-based Tai Chi push hand movements; 4) eight Chen style-based Tai Chi movements. For both the experimental groups, study participants will experience four 60-minute Tai Chi training sessions weekly for 12 months. Outcome measures: BMD at multiple musculoskeletal regions is primary outcome measure. Secondary outcome measures include low limb muscle strength, physical function, and reaction time at both upper and low limbs, which will be measured at baseline and 12 months (at the end of the intervention). Discussion: Results of this study will provide preliminary evidence regarding the value of Tai Chi movement as an intervention for attenuating BMD loss in postmenopausal women. Ethics and dissemination: This study protocol was approved by the Institution Review Board of Shanghai Sports University (approval No. 11290502800) and will be performed in accordance with the principles of the Declaration of Helsinki. Patient recruitment started in August 2017. The analysis of primary outcome measures will be completed in October 2018. The estimated study completion date is June 2019. Dissemination plans include presentations at scientific conferences and scientific publications. Trial registration: This trial was registered with the Chinese Clinical Trial Registry (registration No. ChiCTR-IOR-15005887) on 27 January 2015.
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