Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis.

OBJECTIVE: To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS). METHODS: We long-listed licensed drugs with evidence of human safety, blood-brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review. RESULTS: From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine. CONCLUSIONS: We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.

Comparison of two formats of journal club for postgraduate students at two centers in developing critical appraisal skills.

Journal club (JC) is an integral part of postgraduate medical education. Although several innovations have been attempted to improve its effectiveness, the influence of the number of sessions remains unexplored. The current study investigated the effect of the number of sessions (one vs. four) of conduction of journal club on critical appraisal skills of postgraduate students at two institutions. A quasi-experimental study was conducted comparing the effectiveness of JC in a one- versus four-session JC format using two objective tests: Critical Appraisal Skills Test (CAST) and Population, Intervention, Comparison, Outcome (PICO) score. The degree of changes (pre-JC vs. post-JC session) after each format exposure, association of prescores to postscores, and correlation between the CAST and PICO scores were discerned. CAST score was higher in the four-session format (P = 0.03), whereas PICO score increased in the single-session format of JC (P = 0.03). Also, the change in CAST score was higher in the four-session versus single-session JC format (P = 0.04). We conclude that a four-session format of JC is more effective in augmenting critical appraisal skills of postgraduate students, whereas a single session is sufficient for improving factual knowledge.

The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability.

BACKGROUND: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. OBJECTIVES: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. METHODS: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. CONCLUSION: Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS ( http://www.cdisc.org/therapeutic#MS ) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.

The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis.

BACKGROUND: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function. OBJECTIVE: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment. METHODS: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm ( n = 215) data, we analyzed disability progression using a novel progression endpoint, "EDSS-Plus," defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT. RESULTS: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors' times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone. CONCLUSION: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.

Level of Mercury Manometer With Respect to Heart: Does it Affect Blood Pressure Measurement?

Measurement of blood pressure is an integral part of clinical examination. Over the years various types of instruments have been used to measure blood pressure but till date the mercury sphygmomanometer is regarded as the gold standard. However, there is a myth prevalent among health professionals regarding the level of the manometer in relation to heart at the time of measuring of blood pressure. Many professionals insist that it has to be placed at the level of the heart. We argue that the limb from which pressure is measured must be at the heart level rather than the manometer. We conducted a study in which we measured the blood pressure in adults by placing the manometer at three different levels with respect to the heart. The values of blood pressure obtained at all levels were similar and did not show any statistically significant difference. We therefore conclude that the level of sphygmomanometer per se does not affect blood pressure measurement.

Low myo-inositol indicating astrocytic damage in a case series of neuromyelitis optica.

Astrocytic necrosis is a prominent pathological feature of neuromyelitis optica (NMO) lesions and is clinically relevant. We report 5 NMO-related cases, all with longitudinally extensive lesions in the upper cervical cord, who underwent cervical cord (1) H-magnetic resonance spectroscopy. Lower myo-inositol/creatine values, suggesting astrocytic damage, were consistently found within the NMO lesions when compared with healthy controls and patients with multiple sclerosis (MS), who showed at least 1 demyelinating lesion at the same cord level. Therefore, the in vivo quantification of myo-inositol may distinguish NMO from MS. This is an important step toward developing imaging markers for clinical trials in NMO.

The Influence of Gender on Food Consumption Patterns Among National-Level Adolescent Cyclists.

Background and objective Adolescents in general make poor food choices due to a lack of awareness, social pressure, and other factors, leading to a faulty lifestyle. On the other hand, the adolescent athletic population is associated with a healthy eating pattern. In light of this, this study aimed to evaluate the eating behavior of adolescent cyclists competing at the national level. Methods A total of 50 national-level adolescent cyclists (26 males and 24 females) were assessed for eating behavior, daily food consumption patterns, and eating habits around exercise time by using a pre-tested validated questionnaire, Food Frequency Questionnaire (FFQ), and 24-hour Food Recall. Results The majority (82%) of the cyclists were non-vegetarians, followed by lacto-vegetarians (14%) and lacto-ovo vegetarians (14%). Of note, 72% of the cyclists consumed four meals consisting of breakfast, lunch, snacks, and dinner daily, while 28% skipped at least one of the meals. The preference for takeaways (52%) surpassed dine-outs (34%) and home-cooked (14%) food. Pre-training snack was consumed by 37% and post-training snack by 47%. Cyclists daily consumed breakfast cereals (76%), bread (94%), pulses (92%), fruits (100%), vegetables (62%), milk (84%), milk products (90%), egg (82%), poultry, fish, and meat (74%), dry fruits, nuts, and seeds (78%), and saturated fats (100%). Junk foods (94%) and sweetened beverages (70%) were consumed at least once a week. No significant difference was observed in eating behavior and daily food consumption pattern between male and female cyclists. Conclusion The eating behavior of adolescent cyclists was inclined towards the consumption of saturated fats, junk food, and sweetened beverages. Male and female athletes have similar food habits. There is a need for the implementation of behavior change-oriented nutrition strategies to inculcate healthy eating habits among adolescent cyclists.

Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS.

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.

Effect of Practicing Meditation, Pranayama, and Yoga on the Mental Health of Female Undergraduate Medical Students: An Interventional Study.

Background Medical education is a rigorous formal education with a vast syllabus. Burnout and stresses are common among medical students and more prominent in females. Female medical students suffer from a higher level of stress than male medical students. For the improvement of physical and mental health, meditation, pranayama, and yoga are some of the ancient techniques. Meditation is a technique of focusing the mind on a target like an object, activity, or any thought. Pranayama is an ancient yogic practice focusing on the breath. Yoga is a combination of physical, mental, and spiritual dimensions that has the potential to improve mental and physical health. Objective This study aimed to find the effect of meditation, pranayama, and yoga on the improvement of mental health among female undergraduate medical students. Materials and methods This was an interventional study. A total of 105 females with a median age of 19 years (first quartile - third quartile: 18-20) first-year undergraduate medical students were recruited for this study. They were randomly allocated to control, meditation, pranayama, and yoga groups. The control group did not practice any form of meditation, pranayama, or yoga. The rest of the group practiced a designated program for their group, six days a week for 12 weeks. The anxiety, depression, anger, and sense of well-being were assessed by a validated self-administered questionnaire developed by the Defence Institute of Physiology and Allied Sciences, New Delhi before starting the study, at six weeks, and at 12 weeks after the intervention. Inter-group levels of anxiety, depression, anger, and well-being were compared by the Kruskal-Wallis test with Dunn's posthoc test. Intra-group parameters at baseline, at six weeks, and at 12 weeks after the intervention was tested by Friedman's test. Result The age (years) (p = 0.07), height (cm) (p = 0.98), and weight (kg) (p = 0.26) of participants among groups were similar. Anxiety, depression, and anger significantly decreased after six weeks in all three intervention groups. A further decrement was seen after 12 weeks of meditation, pranayama, and yoga. The maximum effect was seen in the yoga group. A sense of well-being was improved after practicing all types of interventions. However, meditation was found to increase a sense of well-being to the highest level compared to pranayama and yoga. Conclusion Introduction and sustainment of meditation, pranayama, and yoga programs for first-year female undergraduate medical students may help reduce anxiety, depression, and anger and promote a sense of well-being. Although a six-week program helps to improve mental health, a 12-week program helps in further improvement. A yoga program is more effective for improving the mental health of the students in comparison with pranayama and meditation.

Utilization of over-ripened fruit (waste fruit) for the eco-friendly production of ethanol.

This research was carried out to produce ethanol for use as a sanitizer in today's COVID-19 pandemic situation, via cost-effective and eco-friendly techniques. The waste of seasonal fruit, i.e. apple, grape and Indian blueberry, was used in the study. Saccharomyces cerevisiae (baker's yeast) was used with KMnO4 (5%), sucrose (47 g) and urea (1.5 g) for the fermentation process. All the selected overripe fruits were analyzed for variations in parameters including specific gravity, pH, temperature and concentration during complete fermentation for ethanol production. After complete fermentation, it was clear that the use of Indian blueberry at a temperature of 33 °C, specific gravity of 0.875 and pH value of 5.2 yielded the highest ethanol concentration of 6.5%. The concentration of ethanol obtained from grape samples was 5.23% at 30 °C with specific gravity of 0.839 and pH 4.3. Lastly, the ethanol concentration obtained from apple waste was about 4.52% at 32 °C with specific gravity of 0.880 and pH of 4.7 pH. The FTIR curve of each sample shows an absorbance peak in a wave number range of 3000 cm-1 to 3500 cm-1, which indicates the absence of alcohol in the samples after fermentation.

Prominent oromandibular dystonia and pharyngeal telangiectasia in atypical ataxia telangiectasia.

Ataxia telangiectasia (A-T) typically presents with early-onset progressive cerebellar ataxia, oculomotor apraxia and later, oculo-cutaneous telangiectasia. Extrapyramidal symptoms, apart from chorea, are rare. In this paper, we report a case of A-T with an atypically mild and slowly progressive disease course. Although by history there was mild gait clumsiness in early childhood, the leading problem was that of dystonia with onset at age 15, in the absence of gross gait imbalance or ocular motor apraxia. Dystonia was generalized and with prominent oromandibular involvement. Unusually, a leash of telangiectasia was present on the posterior pharyngeal wall, while other features frequently associated with A-T were absent.

Evaluating exercise challenge to validate cardiac autonomic dysfunction in lean PCOS phenotype.

Background Polycystic ovary syndrome (PCOS) is frequently associated with infertility, obesity, hypertension, and diabetes mellitus. Cardiac autonomic dysfunction is well documented in long-term patients of PCOS, with impairment being proportionate to disease duration. However, there is paucity of literature on cardiac autonomic tone in the "lean" phenotype of PCOS. We used exercise challenge to probe for autonomic dysfunction, as assessed by heart rate variability (HRV), an index of cardiac autonomic tone. Methods Our study population consisted of 27 newly diagnosed PCOS patients and 25 healthy females matched by age and body mass index. Short-term HRV was assessed using time and frequency domain indices. Moderate, isotonic exercise was used as an interventional tool. Indices of both groups were compared in three bins - at baseline, immediate, and late postexercise stages. Results The groups had comparable HRV indices at baseline. However, low-frequency (LF) power was significantly reduced in PCOS patients during immediate and late postexercise phases when compared with controls (p = 0.03 and 0.03, respectively). Time domain indices also exhibited a fall postexercise, although not statistically significant. Conclusions Although "lean" phenotype PCOS patients had comparable HRV parameters as controls at baseline, the administration of exercise challenge led to reduced sympathetic drive, evident by reduced LF power in patient group. This may be due to latent autonomic dysfunction in "lean" PCOS, which is unmasked on exposure to exercise challenge. We propose that the evaluation of HRV response to exercise may serve as a sensitive screening tool to detect early cardiovascular dysfunction in newly diagnosed lean PCOS patients.

Relationship of Emotional Intelligence, Intelligence Quotient, and Autonomic Reactivity Tests in Undergraduate Medical Students.

BACKGROUND: Emotional intelligence is emerging as a determinant of success of an individual in their professions. Therefore, this study was designed to decipher the association of emotional intelligence, intelligence quotient, and autonomic stress reactivity tests in undergraduate medical students. METHOD: Fifty-two undergraduate medical students were recruited in this study. Validated questionnaires for EI-self report and performance based-and IQ were filled by all the participants. Autonomic reactivity tests-lying to standing, deep breathing (DBT), Valsalva maneuver, cold pressor (CPT), and handgrip tests-were also performed. Correlational analysis was done using GraphPad Prism version 5.00. RESULTS: Performance-based EI had a positive correlation with DBT responses and an inverse relation with CPT response. Additionally, sub-grouping on the basis of emotional quotient (EQ) and IQ and comparing their autonomic profile revealed an important pattern of parasympathetic reactivity-wherein it was higher in both high > EQ high IQ low > EQ low IQ high > both low . CONCLUSIONS: Emotional intelligence is associated with autonomic reactivity responses. EQ has a positive relation to parasympathetic system while a negative relation to sympathetic system emphasizing the association of sympatho-vagal balance with the emotional intelligence of an individual. Also, parasympathetic responses in an individual differed significantly in groups based on EQ and IQ which again focuses on the strong relation between higher parasympathetic reactivity and emotional intelligence. This study highlights the probable role of emotional intelligence in medical students in deciphering not only their empathy towards patients, but also their physiological responses and cognitive capacity.

Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data.

OBJECTIVE: We report analyses of a pooled database by the Multiple Sclerosis Outcome Assessments Consortium to evaluate 4 proposed components of a multidimensional test battery. METHODS: Standardized data on 12,776 participants, comprising demographics, multiple sclerosis disease characteristics, Expanded Disability Status Scale (EDSS) score, performance measures, and Short Form-36 Physical Component Summary (SF-36 PCS), were pooled from control and treatment arms of 14 clinical trials. Analyses of Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), Low Contrast Letter Acuity (LCLA), and Symbol Digit Modalities Test (SDMT) included measurement properties; construct, convergent, and known group validity; and longitudinal performance of the measures individually and when combined into a multidimensional test battery relative to the EDSS and SF-36 to determine sensitivity and clinical meaningfulness. RESULTS: The performance measures had excellent test-retest reliability and showed expected differences between subgroups based on disease duration and EDSS level. Progression rates in detecting time to 3-month confirmed worsening were lower for T25FW and 9HPT compared to EDSS, while progression rates for LCLA and SDMT were similar to EDSS. When the 4 measures were analyzed as a multidimensional measure rather than as individual measures, progression on any one performance measure was more sensitive than the EDSS. Worsening on the performance measures analyzed individually or as a multidimensional test battery was associated with clinically meaningful SF-36 PCS score worsening, supporting clinical meaningfulness of designated performance test score worsening. CONCLUSION: These results support the use of the 4 proposed performance measures, individually or combined into a multidimensional test battery as study outcome measures.

Heart Rate Variability and Cardiovascular Reflex Tests for Assessment of Autonomic Functions in Preeclampsia.

Alterations in the autonomic cardiovascular control have been implicated to play an important etiologic role in preeclampsia. The present study was designed to evaluate autonomic functions in preeclamptic pregnant women and compare the values with normotensive pregnant and healthy nonpregnant controls. Assessment of autonomic functions was done by cardiovascular reflex tests and by analysis of heart rate variability (HRV). Cardiovascular reflex tests included deep breathing test (DBT) and lying to standing test (LST). HRV was analyzed in both time and frequency domain for quantifying the tone of autonomic nervous system to the heart. The time domain measures included standard deviation of normal R-R intervals (SDNN) and square root of mean squared differences of successive R-R intervals (RMSSD). In the frequency domain we measured total power (TP), high frequency (HF) power, low frequency (LF) power, and LF/HF ratio. Cardiovascular reflex tests showed a significant parasympathetic deficit in preeclamptic women. Among parameters of HRV, preeclamptic group had lower values of SDNN, RMSSD, TP, HF, and LF (ms2) and higher value of LF in normalised units along with high LF/HF ratio compared to normotensive pregnant and nonpregnant controls. Furthermore, normotensive pregnant women had lower values of SDNN, TP, and LF component in both absolute power and normalised units compared to nonpregnant females. The results confirm that normal pregnancy is associated with autonomic disturbances which get exaggerated in the state of preeclampsia.

Steps towards Collective Sustainability in Biomedical Research.

The optimism surrounding multistakeholder research initiatives does not match the clear view of policies that are needed to exploit the potential of these collaborations. Here we propose some action items that stem from the integration between research advancements with the perspectives of patient-advocacy organizations, academia, and industry.

A Pilot Study for Evaluation of Digital Systems as an Adjunct to Sphygmomanometry for Undergraduate Teaching.

OBJECTIVES:  Blood pressure estimation is a key skill for medical practitioners. It is routinely taught to undergraduate medical students using an aneroid sphygmomanometer. However, the conceptual understanding in the practical remains limited. We conducted the following study to evaluate the efficacy of digital data acquisition systems as an adjunct to the sphygmomanometer to teach blood pressure. METHODS:  Fifty-seven first-year medical students participated in the study. An MCQ test of 15 questions, consisting of 10 conceptual and five factual questions, was administered twice - pre- and post-demonstration of blood pressure measurement using a digital data acquisition system. In addition, qualitative feedback was also obtained. RESULTS:  Median scores were 7 (6 - 8) and 3 (1.5 - 4) in pre-test sessions for conceptual and factual questions, respectively. Post-test scores showed a significant improvement in both categories (10 (9 - 10) and 4 (4 - 4.5), respectively, Mann-Whitney U test, p < 0.0001). Student feedback also indicated that the digital system enhanced learning and student participation. CONCLUSIONS:  Student feedback regarding the demonstrations was uniformly positive, which was also reflected in significantly improved post-test scores. We conclude that parallel demonstration on digital systems and the sphygmomanometer will enhance student engagement and understanding of blood pressure measurement.

Effect of Isometric Exercise on QTc Interval.

INTRODUCTION: The QTc interval is affected by heart rate, autonomic nervous system and diseases like diabetes. However, the affect of exercise which alters autonomic nervous system activity, on QTc is not clear. On the other hand, the incidence of sudden cardiac death increases many fold post exercise. These events may be better explained by studying the effect of exercise on QTc. AIM: This study was designed with an aim to record the QTc interval changes in response to isometric exercise in a group of normal individuals with or without parental history of diabetes mellitus. Also the QTc duration was correlated with the LF-HF ratio. MATERIALS AND METHODS: Twenty nine, healthy medical students were subjected to isometric hand grip test for 5min. ECG was recorded pre-exercise and at various time intervals post-exercise. STATISTICAL ANALYSIS: All data are expressed in mean ± SD. Intra group comparison was done using paired t-test and unpaired t-test was used for comparison among group I and group II subjects, and among males and females. RESULT: The difference in the pre and post exercise QTc values both within and between groups was statistically significant with group I subjects recording lower values. The post exercise LF: HF values were significantly increased when compared to pre exercise values in both the groups. There was no correlation between LF: HF and QTc. CONCLUSION: A longer than normal QTc interval predisposes to arrhythmia. Exercise brings about detectable changes in the QTc interval after a period of isometric exercise in normal individuals which in high risk individuals may predispose to sudden cardiac death. In addition women may be more susceptible to post-exercise arrhythmia owing to a longer QTc even at rest.