Preclinical Subjects Research Articles

Subclinical epileptiform activity in the Alzheimer continuum: association with disease, cognition and detection method

BackgroundEpileptic seizures are an established comorbidity of Alzheimer’s disease (AD). Subclinical epileptiform activity (SEA) as detected by 24-h electroencephalography (EEG) or magneto-encephalography (MEG) has been reported in temporal regions of clinically diagnosed AD patients. Although epileptic activity in AD probably arises in the mesial temporal lobe, electrical activity within this region might not propagate to EEG scalp electrodes and could remain undetected by standard EEG. However, SEA might lead to faster cognitive decline in AD.Aims1. To estimate the prevalence of SEA and interictal epileptic discharges (IEDs) in a well-defined cohort of participants belonging to the AD continuum, including preclinical AD subjects, as compared with cognitively healthy controls.2. To evaluate whether long-term-EEG (LTM-EEG), high-density-EEG (hd-EEG) or MEG is superior to detect SEA in AD.3. To characterise AD patients with SEA based on clinical, neuropsychological and neuroimaging parameters.MethodsSubjects (n = 49) belonging to the AD continuum were diagnosed according to the 2011 NIA-AA research criteria, with a high likelihood of underlying AD pathophysiology. Healthy volunteers (n = 24) scored normal on neuropsychological testing and were amyloid negative. None of the participants experienced a seizure before. Subjects underwent LTM-EEG and/or 50-min MEG and/or 50-min hd-EEG to detect IEDs.ResultsWe found an increased prevalence of SEA in AD subjects (31%) as compared to controls (8%) (p = 0.041; Fisher’s exact test), with increasing prevalence over the disease course (50% in dementia, 27% in MCI and 25% in preclinical AD). Although MEG (25%) did not withhold a higher prevalence of SEA in AD as compared to LTM-EEG (19%) and hd-EEG (19%), MEG was significantly superior to detect spikes per 50 min (p = 0.002; Kruskall–Wallis test). AD patients with SEA scored worse on the RBANS visuospatial and attention subset (p = 0.009 and p = 0.05, respectively; Mann–Whitney U test) and had higher left frontal, (left) temporal and (left and right) entorhinal cortex volumes than those without.ConclusionWe confirmed that SEA is increased in the AD continuum as compared to controls, with increasing prevalence with AD disease stage. In AD patients, SEA is associated with more severe visuospatial and attention deficits and with increased left frontal, (left) temporal and entorhinal cortex volumes.Trial registrationClinicaltrials.gov, NCT04131491. 12/02/2020.

A Prospective Interventional Study on Modified One-minute Preceptor Model: An Effective Teaching-learning Tool for Early Clinical Exposure in Biochemistry

Introduction: Early Clinical Exposure (ECE) was incorporated into the Competency-based Medical Education (CBME) curriculum in 2019. ECE in a classroom setting is conducted through Clinical Case Discussion (CCD) using paper-based clinical case scenarios. The assessment pattern of CBME and Maharashtra University of Health Sciences (MUHS) includes clinical case-based questions. Therefore, assessing and developing clinical reasoning skills and critical thinking has become the need of the hour. Aim: To measure the effectiveness of the modified One-minute Preceptor (OMP) model as a teaching-learning tool for CCD to enhance the knowledge and reasoning skills of Phase I Bachelor of Medicine Bachelor of Surgery (MBBS) students and to assess the perception of students and faculty towards the modified OMP model. Materials and Methods: This prospective interventional study was conducted in the Department of Biochemistry at Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India from February 2020 to May 2020. Out of 250 Phase I MBBS students, 180 who had given consent and participated in all the sessions were included. Eight faculty members voluntarily participated in the study. The faculty involved in CCD for the control and study groups were different and selected through randomisation. After a didactic lecture, a pretest was administered, and then students were divided into Control group A (n=90) and Study group B (n=90). For CCD, the modified OMP model was used for the study group and the traditional unstructured method for the control group. A post-test was given after CCD, and feedback was collected from faculty and students. Quantitative analysis of the feedback was done using a 5-point Likert scale, and open-ended questions were qualitatively assessed. Pretest and post-test scores were analysed using an unpaired t-test. Learning gain was measured, and program evaluation was conducted using Kirkpatrick’s model. Results: There was a statistically significant difference in the post-test scores obtained by the control group and study group (p-value <0.001). A higher normalised learning gain (0.83) was observed in the study group. The modified OMP model was perceived as an effective, interactive teaching-learning tool for CCD by both students and faculty. Conclusion: CCD using the modified OMP model significantly improved knowledge, critical thinking, and reasoning skills of students. Even after modifications to the original OMP model, the effectiveness of this model for preclinical subjects remains unaffected.

Early clinical exposure as an adjunct in learning anatomy among first-year medical undergraduates

Abstract Introduction : Early clinical exposure (ECE) is a new teaching method introduced in the first year of medical school to bridge the gap between pre-clinical and clinical subjects. The impact of ECE on learning anatomy has not been extensively studied. Objectives: To examine the perceptions of first-year medical undergraduates towards ECE in learning anatomy. Methods: 197 first-year MBBS students who attended 30 hours of ECE sessions were surveyed through a Google form with closed and open-ended questions. Categorical data was represented by frequency and percentage, and continuous variables by mean ± SD. Results: 94.6% of the respondents agreed that ECE was an interesting method of learning anatomy compared to traditional lectures, while 5.4% disagreed. 95.1% of students agreed that ECE motivated them to read more on the topics covered, while 4.9% felt ECE showed no impact on their motivation to study. Students strongly believed that ECE helped them understand the topics taught in Anatomy better (36.5%, n=72), retain information (35.5%, n=70), correlate with clinical scenarios (48.2%, n=95) 95.6% students opined that the frequency of ECE sessions should be increased and incorporated along with regular lectures in Anatomy. Conclusion: ECE sessions were well appreciated and accepted by students. ECE helps in understanding concepts in anatomy better, makes correlation with clinical aspects easier, and retaining information learned through ECE sessions is possible. ECE may serve as a great tool in imparting quality medical education.

Plasma melatonin night‐time peak levels and 24‐hour area under the curve profile seem higher in AD patients with epileptiform activity than in those without

AbstractBackgroundPlasma melatonin levels drop in elderly, which might become more pronounced in Alzheimer’s disease (AD) as compared to controls.(1) Melatonin can serve as a potential biomarker for AD, given the inverse correlation between cerebrospinal fluid (CSF) melatonin levels and severity of neuropathology (Braak stages).(2) Due to suggested antiepileptic effects(6), melatonin can potentially slow down disease progression as epileptiform activity may contribute to AD disease progression.(3‐5). We here present a preliminary interim analysis of an ongoing study.Aims1. To evaluate melatonin’s potential as biomarker for AD by comparing blood melatonin levels between patients with mild cognitive impairment (MCI) and dementia due to AD and preclinical AD subjects.2. To study the link between melatonin levels and epileptiform activity in AD.MethodsAll subjects underwent a neuropsychological examination, and lumbar puncture for analysis of core AD CSF biomarkers or amyloid brain PET. Subjects belonging to the AD continuum (dementia [n = 7]; MCI [n = 4]; preclinical AD [n = 1]) were diagnosed according to the NIA‐AA research criteria. A subset of subjects (n = 6) underwent 50‐minute magnetoencephalography to detect epileptiform activity. Blood samples were taken multiple times during a 24‐hour period, in in‐hospital controlled circumstances, and were analysed by use of liquid chromatography‐mass spectrometry.ResultsAD patients with epileptiform activity (n = 2) tended to have a higher melatonin 24‐hour area under the curve (AUC) and peak concentration (AUC 517.9pg/ml.h [+/‐140.1pg/ml.h] versus 204.5pg/ml.h [+/‐115.5pg/ml.h]; peak 65.4pg/ml [+/‐14.6pg/ml] versus 25.8pg/ml [+/‐17.5pg/ml]) than AD patients without (n = 4) (p = 0.064 for both; MWU test). There was no statistical difference regarding the melatonin 24‐hour plasma AUC or peak levels between patients with dementia, MCI, preclinical AD subjects (p = 0.760 for both; Kruskall‐Wallis test). We have to interpret these data with caution since sample sizes are still small and more patients are being recruited.ConclusionOn the basis of very preliminary data, 24‐hour plasma melatonin profile and peak plasma melatonin concentration tended to be higher in AD patients with epileptiform activity than in those without. Whether this could be a potential compensatory mechanism against epileptiform activity in AD or whether melatonin could rather have pro‐epileptic effects, remains to be elucidated in future research.

Longitudinal changes of self‐ and informant‐reported cognitive decline in elderly with regard to clinical progression and amyloid‐status

AbstractBackgroundSelf‐ and informant‐reports of cognitive decline have been previously associated with a higher risk of cognitive decline in elderly. Yet, few studies assessed their longitudinal changes over time with regard to both incident mild cognitive impairment (iMCI) and Alzheimer’s disease (AD) pathology. This study aims at describing these links to better understand which trajectories are indicative of higher AD‐risk.MethodWe used data from 501 participants followed‐up annually (2.51±1.35 years) in the DELCODE project. All were cognitively unimpaired, and had an amyloid measurement available, at inclusion. Among them, 145 were amyloid‐positive, and 65 progressed to iMCI during the follow‐up period (31 iMCI‐Aß+). The SCD‐Interview was used to measure (i) the number of cognitive domains in which the participants or its relative perceived a decline (i.e., self‐ and informant‐SCD‐I), and (ii) the number of fulfilled SCD‐plus criteria. Linear mixed‐effect models were used to assess SCD trajectories over time, according to four groups defined by amyloid status and clinical progression (Stable‐Aß‐, Stable‐Aß+, iMCI‐Aß‐ and iMCI‐Aß+). Analyses were adjusted for age, sex and education; and their interaction with time.ResultBoth self‐SCD‐I levels and SCD‐plus scores decreased significantly over time, without significant differences between groups (Figure 1A, 1B). Conversely, informant‐SCD‐I levels did not significantly change over time in the whole sample, although slopes significantly differed between groups. Compared to the Stable‐Aß‐ group, there was a greater increase over time of informant‐SCD‐I report only in iMCI‐Aß+ [est 0.16, SE 0.05, p<.001] (Figure 1C). The resulting discrepancy score (Self‐SCD‐I minus Informant‐SCD‐I) tended to decrease over time with significant differences between groups. Compared to the Stable‐Aß‐ group, the discrepancy score showed a faster decrease over time in iMCI‐Aß+ [est ‐0.21, SE 0.056 p<.001] (Figure 1D).ConclusionLongitudinal patterns in subjective reports of cognitive decline might help identify preclinical AD subjects at higher risk of clinical progression. Specifically, an increase of informant‐reported cognitive decline over time may indicate objective cognitive decline in amyloid‐positive subjects. Conversely, the decrease of self‐reported cognitive decline over time, regardless of the group, may reflect generally reduced concerns after inclusion, or result from current limitations in longitudinal SCD assessment.

Longitudinal changes of self‐ and informant‐reported cognitive decline in elderly with regard to clinical progression and amyloid‐status

AbstractBackgroundSelf‐ and informant‐reports of cognitive decline have been previously associated with a higher risk of cognitive decline in elderly. Yet, few studies assessed their longitudinal changes over time with regard to both incident mild cognitive impairment (iMCI) and Alzheimer’s disease (AD) pathology. This study aims at describing these links to better understand which trajectories are indicative of higher AD‐risk.MethodWe used data from 501 participants followed‐up annually (2.51±1.35 years) in the DELCODE project. All were cognitively unimpaired, and had an amyloid measurement available, at inclusion. Among them, 145 were amyloid‐positive, and 65 progressed to iMCI during the follow‐up period (31 iMCI‐Aß+). The SCD‐Interview was used to measure (i) the number of cognitive domains in which the participants or its relative perceived a decline (i.e., self‐ and informant‐SCD‐I), and (ii) the number of fulfilled SCD‐plus criteria. Linear mixed‐effect models were used to assess SCD trajectories over time, according to four groups defined by amyloid status and clinical progression (Stable‐Aß‐, Stable‐Aß+, iMCI‐Aß‐ and iMCI‐Aß+). Analyses were adjusted for age, sex and education; and their interaction with time.ResultsBoth self‐SCD‐I levels and SCD‐plus scores decreased significantly over time, without significant differences between groups (Figure 1A, 1B). Conversely, informant‐SCD‐I levels did not significantly change over time in the whole sample, although slopes significantly differed between groups. Compared to the Stable‐Aß‐ group, there was a greater increase over time of informant‐SCD‐I report only in iMCI‐Aß+ [est 0.16, SE 0.05, p<.001] (Figure 1C). The resulting discrepancy score (Self‐SCD‐I minus Informant‐SCD‐I) tended to decrease over time with significant differences between groups. Compared to the Stable‐Aß‐ group, the discrepancy score showed a faster decrease over time in iMCI‐Aß+ [est ‐0.21, SE 0.056 p<.001] (Figure 1D).ConclusionLongitudinal patterns in subjective reports of cognitive decline might help identify preclinical AD subjects at higher risk of clinical progression. Specifically, an increase of informant‐reported cognitive decline over time may indicate objective cognitive decline in amyloid‐positive subjects. Conversely, the decrease of self‐reported cognitive decline over time, regardless of the group, may reflect generally reduced concerns after inclusion, or result from current limitations in longitudinal SCD assessment.

Functional and structural changes of cholinergic basal forebrain in asymptomatic PSEN1 E280A mutation carriers compared with non‐mutation carriers from the API ADAD Colombia cohort

AbstractBackgroundImaging studies showed early atrophy of the cholinergic basal forebrain in prodromal sporadic Alzheimer’s disease (AD) and alterations of the posterior basal forebrain functional connectivity in amyloid positive, but cognitively normal people. Similar investigations in familial cases of AD are still lacking. Here we investigated whether basal forebrain volume, metabolism, and posterior connectivity were already reduced in preclinical stages of autosomal dominant AD.MethodWe analyzed baseline data from 242 cognitively unimpaired subjects (69% PSEN1 E280A mutation carriers; mean age = 38 years; 62% female; mean education = 9 years) enrolled in the API ADAD Colombia Trial including available MRI, FDG‐PET and cognitive measures. We determined volume and metabolism of the basal forebrain, and of the hippocampus as a comparison region. In addition, we created connectivity maps from resting state fMRI data using anterior and posterior BF seed regions. We carried out Bayesian ANCOVA to determine evidence in favor or against an effect of carriers’ status on volumes, metabolism, functional connectivity and cognitive scores.ResultWe found inconclusive to moderate evidence in favor of no effect of carrier status on basal forebrain (BF10 = 0.884) and hippocampal volumes (BF10 = 0.964) or metabolism (BF10 = 0.187) (see Figure) in preclinical (CDR = 0) and prodromal (CDR = 0.5) subjects. However, we found extreme evidence that delayed memory was decreased already in preclinical mutation carriers (BF10 = 4066.73). Yet, we found no conclusive evidence that this subtle memory impairment was associated with basal forebrain (BF10 = 0.582) or hippocampal (BF10 = 0.906) atrophy.ConclusionOur findings indicate absence of basal forebrain and hippocampus atrophy or metabolic impairment in preclinical mutation carriers. Interestingly, memory impairment was already present in preclinical mutation carriers. This is consistent with results of the Dominantly Inherited Alzheimer Network (DIAN) cohort showing early cognitive impairment in mutation carriers, but no significant group differences in hippocampal volume until later stages of the disease. These previous and our findings may suggest that different brain regions and networks are affected in preclinical stages of familial AD than in preclinical sporadic AD, which should be investigated in future studies.

Distinct CSF biomarker‐associated DNA methylation in Alzheimer’s disease and cognitively normal subjects

AbstractBackgroundGrowing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer’s disease and that DNAm differences can be detected in the blood of AD subjects. Because access to human brain tissues is primarily limited to postmortem samples, most studies have correlated blood DNAm with clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Thus, the association of blood DNAm with changes in AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis.MethodCSF biomarkers are well‐established AD endophenotypes and correlate significantly with neuropathology scores measured on postmortem brain samples. In this study, we performed a comprehensive analysis to identify blood DNA methylation associated with CSF pathological biomarkers for AD in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Our study included matched samples of whole blood DNA methylation, CSF Aβ42, phosphorylated tau181 (pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 cognitively normal, 79 AD cases).ResultWe identified a number of novel associations between blood DNAm and CSF Aβ42, pTau181, and total tau biomarkers, demonstrating that changes in various pathological processes in the CSF are also reflected in the blood epigenome. Overall, the CSF biomarker‐associated DNAm is relatively distinct in cognitively normal (CN) and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our pathway analysis of CSF biomarker associated‐DNAm from CN subjects revealed that biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood.ConclusionOur study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.

Perception of Indian medical students regarding introduction of early clinical exposure

The Medical Council of India (MCI) has stressed the necessity of Early Clinical Exposure (ECE) for a better understanding of preclinical medical subjects. However, its implementation at the medical college level in the current Indian scenario is a big challenge due to the large classroom strength and smaller number of faculty in preclinical subjects. The aim of this study to introduce ECE in physiology at our medical college, we planned an ECE session on anaemia and recorded the students' perceptions regarding the same. We conducted an ECE session on Anemia designed by the subject experts of the Physiology and Medical Education Unit (MEU) faculty of our institute. We conducted a cross-sectional survey among MBBS students of 2019 batch using a pre-validated questionnaire via online Google form to capture their perceptions regarding the ECE session. After exclusion, a total of 127 responses from medical students were included for data analysis. The majority of the students responded that the overall format of the ECE session was appropriate and that the session was helpful to them in the clinical application of their knowledge about Anemia. More than 75% of students opined that the ECE session made basic science learning more interesting and they felt motivated to read further on the topic. About 80% of students preferred ECE over traditional teaching. In conclusion, Students find ECE to be interesting, motivating, and helpful for the clinical application of basic science knowledge into clinical practice. Hence, ECE should be conducted more frequently and more topics should be taught by ECE at all medical colleges.

Differences in medical education before, during, and in the post-peak period of the COVID-19 pandemic—exploring senior medical students’ attitudes

BackgroundThe burden that COVID-19 has brought to the economy, healthcare systems, and education is unmatched. Public health and social measures were implemented to halt transmission. Thus, social gathering and in-person learning, core aspects of medical education, were interrupted. Studies have documented the detrimental impact students graduating during the pandemic have had on their confidence and skills. However, data comparing pre-pandemic, pandemic, and post-peak students still lack. This study aimed to identify senior medical students' attitudes regarding their education and compare them according to the three previously described periods.MethodsIn this cross-sectional study, the survey employed was designed based on a previous questionnaire and applied to senior medical students before graduating between January 2018 and June 2022. Answers were collected using a three-point Likert scale and Yes/No questions. Associations between variables were examined using Chi-squared, Fisher’s Exact tests, and ANOVA, employing logistic regression to calculate odds ratio (OR) when appropriate.ResultsA total of 679 responses were analyzed. Most students (59%) were women. Up to 383, 241, and 55 senior medical students answered the survey before, during, and in the post-peak period of the COVID-19 pandemic, respectively. There was a staggering decrease in the percentage of students in the post-peak compared to the pre-pandemic period that considered certain factors such as being taught about the doctor-patient relationship (62% vs 75%), practicing teamwork (33% vs 54%), preclinical & clinical subjects (44% vs 63%), and being taught to conduct research (22% vs 32%) as “very useful” to their professional traineeship. There was a significant difference between pre-pandemic, pandemic, and post-peak students when asked if the study curriculum accomplished the goal of training a professional with integrity (89% vs 66% vs 64%, p < 0.001), respectively. In a multivariate analysis graduating during the pandemic (OR 3.92; 95% CI, 2.58–5.94) and in the post-peak period (OR 4.24; 95% CI, 2.23–8.07) were independent factors for the appreciation that the study curriculum did not meet its objective.ConclusionsThe pandemic has hindered medical education. Students’ appreciation of their instruction has deteriorated. Urgent interventions that halt the negative impact on training, ensure readiness for future problems and improve schooling worldwide are needed.

English Language Difficulties of Pre-Clinical Medical Students and the Contributing Role of Foundation-Year English Language Course at a Medical College in Saudi Arabia

The study investigates the pre-clinical medical students' perceptions about their English language difficulties and lack at King Khalid University in Saudi Arabia. The Saudi medical students study an English language course at the pre-university level (Foundation Year) to train and prepare for their future extensive medical study in medical college. The English language program comprises reading, writing, listening, and speaking skills and targets enhancing students' language skills. The study aims: (a) to examine the pre-clinical medical students' level of difficulties related to their listening, speaking, reading, and writing skills. (b) To determine the pre-medical students' language lacks and the students' general proficiency. A mixed-method approach, including quantitative and qualitative research methods was used. Data from questionnaires of 67 pre-clinical medical students has been used with representative interviews from the faculty members teaching pre-clinical subjects in the medical college. The findings revealed that the students experience significant difficulties in the use of English language skills, and the skill-wise average is worth considering such as writing (27.95%), reading (25.36%), speaking (24.86%), and listening (12.73%). The findings indicated that writing skills were the most difficult among all the language skills for pre-clinical medical students. Finally, the recommendations were made to revise the English language course, improve the teaching methodology, and address the students' insufficient English language proficiency.

Curriculum for Undergraduate Medical Sciences: Traditional, Integrated or Both

The traditional curriculum for undergraduate medical students ensures discipline-based learning. In a traditional curriculum, students get ample time to get a detailed understanding and undergraduate-level knowledge which is elaborative and sufficient for each subject. Although the students gain ample knowledge of the subject, they lack in correlating the gained information with other subjects. This is not the students’ fault; instead, it is due to the lack of scope of correlation in the traditional curriculum. In this curriculum, students are not taught about the applicability of the gained information. Consequently, basic science or pre-clinical subjects seem irrelevant to the students as if the clinical subjects are independent of these subjects, whereas the reality is the opposite (Watmough et al., 2009). The knowledge of the basic subjects serves as the targeted goal of clinical manoeuvre. Traditional curriculum receives criticism for demotivating students to learn basic subjects to practice as a doctor. Moreover, the traditional curriculum is a more lecture-dependent one-way teaching method devoid of a student-oriented approach (Christianson et al., 2007). There is no scope for problem-solving or critical thinking rather than pedagogical learning. Another disadvantage of the traditional curriculum is that students need to wait until clinical years to have experience with patients. Therefore, there is no opportunity for clinical skill development earlier in this curriculum (Rahman, 2022).

Tissue-Specific Vulnerability to Apoptosis in Machado-Joseph Disease.

Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD and to evaluate if expression alterations of specific apoptosis genes/proteins can be used as transcriptional biomarkers of disease, the expression levels of BCL2, BAX and TP53 and the BCL2/BAX ratio (an indicator of susceptibility to apoptosis) were assessed in blood and post-mortem brain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of blood BCL2 transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of blood BAX transcripts and decreased BCL2/BAX ratio are associated with earlier onset of disease, indicating a possible association with MJD pathogenesis. Post-mortem MJD brains show increased BCL2/BAX transcript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that blood BCL2 and TP53 transcript levels increase over time in MJD patients. Furthermore, while the similar levels of blood BCL2, BAX, and TP53 transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue-dependent behavior is partially replicated in a MJD mouse model.

Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects

BackgroundGrowing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer’s disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis.MethodsWe performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aβ42, phosphorylated tau181 (pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset.ResultsWe identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau181 in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker.ConclusionsOur study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.

The Early Impact of Deciding to Take the United States Medical Licensing Examination Step 1 for Osteopathic Medical Students in the Pass/Fail Era.

The United States Medical Licensing Examination (USMLE) Step 1 recently shifted from a three-digit scoring format to a pass/fail scoring rubric. Lake Erie College of Osteopathic Medicine (LECOM) is among a number of osteopathic medical schools that traditionally included passing Step 1 as a graduation requirement. However, LECOM removed this requirement following the change in scoring format. National Board of Medical Examiners (NBME) subject examinations have a significant impact on the clerkship grades of third-year medical students. Therefore, our pilot study compared NBME subject examination scores among third-year LECOM medical students that did and did not take and pass Step 1. We anticipate that both high pre-clinical grade point average (GPA) and having passed Step 1 will be associated with higher subject exam scores, but passing Step 1 will have a relationship with higher subject exam scores that is independent of pre-clinical GPA. Using voluntary response sampling, 201 osteopathic medical students from LECOM completed an online survey through Google Forms regarding their pre-clinical GPA, subject exam scores, whether they took and passed USMLE Step 1, and their study resources used throughout clerkships. Results: There was a positive correlation (p < 0.05) found between pre-clinical GPA and exam scores across all subjects among students that took Step 1. There was no relationship between pre-clinical GPA andexam scores across all subjects among students that did not take Step 1 (p> 0.05). Students that took Step 1 had a higher pre-clinical GPA than those that did not. Students that took and passed Step 1 scored higher on subject exams. Fifty-nine percent of respondents indicated they would have studied more for Step 1 if these exams were scored on the three-digit format, while zero respondents indicated they would have studied less. Although higher pre-clinical GPA and taking Step 1 were associated with higher scores on subject exams, taking Step 1 appears to have an independent influence on subject exams because there was no relationship found between pre-clinical GPA and subject exam scores among students that did not take Step 1. Therefore, there may be features related to preparing for this exam that better equip osteopathic medical students to perform well on subject exams.

Synthesis, Cannabinoid Receptor Targeted Molecular Docking of Some New Pyrazole Derivatives as Hypolipidemic and Anti- Obesity Agents

Obesity is a serious health problem of 21st century. Around 1 billion adults are overweight and more than 300 million people are found to be obese globally. In fact 2.6 million people die per year due to obesity and thus it has now become a major reason of morbidity and mortality. In line to this few novel pyrazole derivatives (Z)-3-(4-subtituted phenyl)-2-(3, 5-dimethyl-1H-pyrazol-1-yl)-1-phenylprop-2-en-1-one (4a-f) were synthesized from 3, 5 dimethyl pyrazole by a simple inexpensive, rapid method. All compounds were authenticated using different physical and analytical techniques such as Infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance and mass spectrometry. Hypolipidemic activity was carried out for all the compounds using Triton WR 1339 induced hyperlipidemia model in rodents. Further, molecular docking was performed to understand the receptor-ligand interactions of synthesized compounds with cannabinoid receptor (protein data bank code: 5TGZ) using Argus lab 4.0, followed by anti-obesity studies of the selected compound (Z)-3-(4-chlorophenyl)-2-(3, 5-dimethyl-1H-pyrazol-1-yl)-1-phenylprop-2-en-1-one (4b). Amongst six compounds four compounds showed significant reduction in cholesterol levels in along with triglyceride levels in hyperlipidemic rats. Compound 4b also caused significant elevation in % high density lipoprotein levels of rats comparable to the standard Gemfibrozil. All these compounds showed good interactions with the target protein. Compound 4b (5 mg/kg and 10 mg/kg orally), caused notable reduction in body weight of high fat diet rats. Compound 4b i.e. (Z)-3-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1- yl)-1-phenylprop-2-en-1-one has ability to reduce body weight and improve lipid profile in rats and requires further studies to establish its safety and efficacy in preclinical and clinical subjects.

Nternal Assessment in Phase I of Medical Undergraduates as per the New Competency-based Medical Education Curriculum

The new Competency-Based Medical Education (CBME) curriculum was introduced in August 2019. Phase-I of the CBME curriculum encompasses preclinical subjects, each with its own set of competencies to be assessed according to the new CBME guidelines. Internal Assessment (IA) serves as the foundation of the CBME curriculum and is an essential component of medical education. It is included in Module three of the CBME curriculum and aids in the assessment of various competencies. IA consists of both formative and summative assessments, and employing multiple methods can enhance its effectiveness. The incorporation of regular feedback and remedial measures is crucial within the IA framework. The purpose of present review is to provide a review of the IA in Phase I based on CBME and previous research papers.

Impact of Blue Light Therapy on Wound Healing in Preclinical and Clinical Subjects: A Systematic Review.

Introduction: While a wound caused by a minor cutaneous incision routinely heals in a short time, wounds from major surgical operations might need numerous days to heal and may leave an obvious cicatrix. The use of blue light therapy (BLT) to destroy infectious microorganisms and disrupt biofilm formation could be an efficient method for healing ulcers. This systematic review focused on the effects of BLT in different preclinical in vivo studies and clinical models of skin wound healing. Furthermore, this study attempted to determine what main light parameters should be tested in preclinical and clinical studies. Methods: The online databases PubMed.gov, Google Scholar, Scopus, Web of Science, and Cochrane were searched using the keywords "blue light" and "wound healing" according to PRISMA guidelines. No publication time limit was enforced. Results: A total of 858 articles were identified, and 17 articles in three distinct categories were included for review. They comprised two articles on humans, fourteen articles on healthy animals, and one article on diabetic animals. Conclusion: Some studies have shown that the application of BLT on preclinical and clinical models of wound healing in vivo is able to significantly accelerate the healing process. Few studies, however, have explored the bactericidal effect of BLT on skin injury repair in burn patients. Further preclinical investigations designed to provide a better understanding of the bactericidal effect of BLT using standardized protocols, different BLT wavelengths, and different stages of the wound healing process of infected wounds and ulcers in healthy and diabetic animals should be carried out before clinical trials can be considered. BLT could eventually be a good option for treating infected chronic wounds, including those in diabetic patients.

The Impact of Simulation-Based Teaching Module Involving Virtual Dissection on Anatomy Curriculum Delivery

Background: Knowledge of anatomy, one of the core preclinical subjects, is very important for medical undergraduates to have a thorough understanding of various clinical conditions. The traditional method of learning anatomy involves dissection of human cadavers. Medical education system is entering an era in which the traditional teaching methods are being supplemented by newer technological teaching techniques. Simulation based teaching like virtual dissection table “Anatomage” can enhance the understanding and retaining capacity of the subject. The aim of the study is to determine the perception of virtual dissection, among students and staff and to compare the knowledge acquired through simulation based teaching and traditional teaching method. Material and Method: The study comprised of 150 first-year MBBS students who attended regular theory class on ‘joints of musculoskeletal system’ and answered pre-test. The students were divided into two groups, based on teaching method, one which involved the use of a virtual dissection table, and the other, involving the use of cadaveric dissection. The students were made to attempt the post-test. The students were then assessed based on their responses to the pre- and post-tests. Feedback on the overall utility of the table from both students and staff was taken. Results: The mean post-test scores were significantly higher than the mean pre-test scores, irrespective of the teaching method used. (p&lt;0.001) However, the students who were exposed to the virtual dissection table scored comparatively better in the post-test than those exposed to cadaveric dissection. (p&lt;0.001) 100% of the faculty and 93.3% of the students agreed that three-dimensional visualization improves understanding of anatomical structures. Conclusion: The findings of this study suggest that though cadaveric dissection and virtual dissection enhance learning, the students tend to perform better with virtual dissection. The incorporation of simulation-based teaching into the Anatomy curriculum is essential to supplement traditional cadaveric dissection and ensure engaging as well as high impact delivery of the curriculum. KEY WORDS: Simulation, Virtual dissection, Musculoskeletal, Anatomage, Cadaver, Dissection, Anatomy, MBBS, Teaching Methodologies.

Preclinical Detection and Monitoring of Alzheimer’s Disease Using a Multi‐Disease Diagnostic Platform Employing Autoantibodies as Blood‐based Biomarkers

AbstractBackgroundEvidence for the universal presence of serum autoantibodies and their potential diagnostic utility for detection of Alzheimer’s disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. It is well known that AD‐related pathological changes in the brain can begin up to a decade before patients experience telltale symptoms, yet preclinical detection remains an unmet goal. In the present study, we demonstrate the utility of a panel of AD‐related autoantibodies capable of detecting AD at the earliest points along the AD continuum, including preclinical AD, years before the onset of symptoms, and prodromal AD (mild cognitive impairment, MCI).MethodUsing a customized panel of AD‐specific autoantibody biomarkers and Luminex xMAP® technology, sera from ADNI subjects with preclinical AD or MCI were screened to demonstrate both preclinical and prodromal AD detection. A panel of eight autoantibodies with increased titer in MCI and preclinical AD relative to controls was evaluated using both Random Forest and Receiver Characteristic Operating curves for their ability to distinguish diseased subjects from age‐ and sex‐matched controls, as well as from individuals with other neurodegenerative and non‐neurodegenerative diseases.ResultResults showed that the panel of eight autoantibody biomarkers was capable of differentiating patients with MCI from corresponding age‐ and sex‐matched controls with high overall accuracy, sensitivity, and specificity. These biomarkers were also capable of identifying cognitively normal subjects who later converted to MCI and AD, years before the clinical onset of their symptoms. This autoantibody biomarker panel readily distinguished MCI and preclinical AD subjects from Parkinson’s disease and breast cancer subjects, demonstrating excellent disease specificity.ConclusionResults demonstrate the utility of our custom Luminex xMAP® blood‐based autoantibody biomarker panel as an accurate, non‐invasive, and inexpensive diagnostic screener, not only for the detection of prodromal AD, but also the earlier stages of pathology, several years before the first onset of telltale clinical symptoms. This appears to be a multi‐disease diagnostic and disease‐staging strategy, since it has been demonstrated to be useful for a multitude of neurodegenerative diseases including both early‐stage AD and PD, as well as Multiple Sclerosis, with other disease applications currently underway