Safety and efficacy of umbilical cord-derived Wharton\u27s jelly compared to hyaluronic acid and saline for knee osteoarthritis: Study protocol for a randomized, controlled, single-blind, multi-center trial

BACKGROUND: Osteoarthritis (OA) is the most common joint disorder in the United States of America (USA) with a fast-rising prevalence. Current treatment modalities are limited, and total knee replacement surgeries have shown disadvantages, especially for grade II/III OA. The interest in the use of biologics, including umbilical cord (UC)-derived Wharton\u27s jelly (WJ), has grown in recent years. The results from a preliminary study demonstrated the presence of essential components of regenerative medicine, namely growth factors, cytokines, hyaluronic acid (HA), and extracellular vesicles, including exosomes, in WJ. The proposed study aims to evaluate the safety and efficacy of intra-articular injection of UC-derived WJ for the treatment of knee OA symptoms. METHODS: A randomized, controlled, single-blind, multi-center, prospective study will be conducted in which the safety and efficacy of intra-articular administration of UC-derived WJ are compared to HA (control) and saline (placebo control) in patients suffering from grade II/III knee OA. A total of 168 participants with grade II or III knee OA on the KL scale will be recruited across 53 sites in the USA with 56 participants in each arm and followed for 1 year post-injection. Patient satisfaction, Numeric Pain Rating Scale, Knee Injury and Osteoarthritis Outcome Score, 36-Item Short Form Survey (SF-36), and 7-point Likert Scale will be used to assess the participants. Physical exams, X-rays, and MRI with Magnetic Resonance Observation of Cartilage Repair Tissue score will be used to assess improvement in associated anatomy. DISCUSSION: The study results will provide valuable information into the safety and efficacy of intra-articular administration of Wharton\u27s jelly for grade II/III knee osteoarthritis. The results of this study will also add to the treatment options available for grade II/III OA as well as help facilitate the development of a more focused treatment strategy for patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04711304 . Registered on January 15, 2021

Riluzole attenuates glutamatergic tone and cognitive decline in AβPP/PS1 mice.

We have previously demonstrated hippocampal hyperglutamatergic signaling occurs prior to plaque accumulation in AβPP/PS1 mice. Here, we evaluate 2-Amino-6-(trifluoromethoxy) benzothiazole (riluzole) as an early intervention strategy for Alzheimer\u27s disease (AD), aimed at restoring glutamate neurotransmission prior to substantial Beta amyloid (Aβ) plaque accumulation and cognitive decline. Male AβPP/PS1 mice, a model of progressive cerebral amyloidosis, were treated with riluzole from 2-6 months of age. Morris water maze, in vivo electrochemistry, and immunofluorescence were performed to assess cognition, glutamatergic neurotransmission, and pathology, respectively, at 12 months. Four months of prodromal riluzole treatment in AβPP/PS1 mice resulted in long-lasting procognitive effects and attenuated glutamatergic tone that was observed six months after discontinuing riluzole treatment. Riluzole-treated AβPP/PS1 mice had significant improvement in long-term memory compared to vehicle-treated AβPP/PS1 mice that was similar to normal aging C57BL/6J control mice. Furthermore, basal glutamate concentration and evoked-glutamate release levels, which were elevated in vehicle-treated AβPP/PS1 mice, were restored to levels observed in age-matched C57BL/6J mice in AβPP/PS1 mice receiving prodromal riluzole treatment. Aβ plaque accumulation was not altered with riluzole treatment. This study supports that interventions targeting the glutamatergic system during the early stages of AD progression have long-term effects on disease outcome, and importantly may prevent cognitive decline. Our observations provide preclinical support for targeting glutamate neurotransmission in patients at risk for developing AD

Guidelines for reporting of statistics for clinical research in urology

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148242/1/bju14640.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148242/2/bju14640_am.pd

Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival

<p>Abstract</p> <p>Background</p> <p>Glioblastoma is a complex multifactorial disorder that has swift and devastating consequences. Few genes have been consistently identified as prognostic biomarkers of glioblastoma survival. The goal of this study was to identify general and clinical-dependent biomarker genes and biological processes of three complementary events: lifetime, overall and progression-free glioblastoma survival.</p> <p>Methods</p> <p>A novel analytical strategy was developed to identify general associations between the biomarkers and glioblastoma, and associations that depend on cohort groups, such as race, gender, and therapy. Gene network inference, cross-validation and functional analyses further supported the identified biomarkers.</p> <p>Results</p> <p>A total of 61, 47 and 60 gene expression profiles were significantly associated with lifetime, overall, and progression-free survival, respectively. The vast majority of these genes have been previously reported to be associated with glioblastoma (35, 24, and 35 genes, respectively) or with other cancers (10, 19, and 15 genes, respectively) and the rest (16, 4, and 10 genes, respectively) are novel associations. <it>Pik3r1</it>, <it>E2f3, Akr1c3</it>, <it>Csf1</it>, <it>Jag2</it>, <it>Plcg1</it>, <it>Rpl37a</it>, <it>Sod2</it>, <it>Topors</it>, <it>Hras</it>, <it>Mdm2, Camk2g</it>, <it>Fstl1</it>, <it>Il13ra1</it>, <it>Mtap </it>and <it>Tp53 </it>were associated with multiple survival events.</p> <p>Most genes (from 90 to 96%) were associated with survival in a general or cohort-independent manner and thus the same trend is observed across all clinical levels studied. The most extreme associations between profiles and survival were observed for <it>Syne1</it>, <it>Pdcd4</it>, <it>Ighg1</it>, <it>Tgfa</it>, <it>Pla2g7</it>, and <it>Paics</it>. Several genes were found to have a cohort-dependent association with survival and these associations are the basis for individualized prognostic and gene-based therapies. <it>C2</it>, <it>Egfr</it>, <it>Prkcb</it>, <it>Igf2bp3</it>, and <it>Gdf10 </it>had gender-dependent associations; <it>Sox10</it>, <it>Rps20</it>, <it>Rab31</it>, and <it>Vav3 </it>had race-dependent associations; <it>Chi3l1</it>, <it>Prkcb</it>, <it>Polr2d</it>, and <it>Apool </it>had therapy-dependent associations. Biological processes associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death.</p> <p>Conclusions</p> <p>Known biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme.</p

Identification and characterization of gene and microRNA networks associated with cancer survival and drug abuse

The study of the dysregulation of the transcriptome in diseases like cancer and drug abuse can offer insights into preventive and therapeutical remedies, as well as targets for future basic and applied research. The identification of reliable transcriptome biomarkers requires the simultaneous consideration of regulatory and target elements including microRNAs (miRNAs), transcription factors (TFs), and target genes. Previously, there has been limited validation of reported associations between these diseases and miRNAs, TFs, and target mRNA in independent studies. This may be due to several reasons. Few studies simultaneously analyze multiple miRNAs, TFs, and target mRNA. Also, most studies do not consider clinical or cohort-dependent factors when characterizing the associations between the transcriptome and disease. Lastly, most transcriptome studies tend to be small, and the individual analysis has limited statistical power to detect accurate and precise associations between transcripts and diseases. This thesis aims to address the previous limitations and identify replicable biomarkers of cancer and drug abuse. Functional and network analyses were performed to identify and study targets of microRNA biomarkers associated with glioblastoma multiforme survival within and across race, gender, recurrence, and therapy cohorts. A Cox survival model was applied to profiles from 253 individuals, 534 microRNAs, and the results were confirmed using cross-validation, discriminant analyses, and cross-study comparisons. All 45 microRNAs revealed were confirmed in independent cancer studies, and 25 of those were further confirmed in glioblastoma studies. Thirty-nine and six microRNAs were associated with one and multiple glioblastoma survival indicators, respectively. Nineteen and 26 microRNAs exhibited cohort-dependent and independent associations with glioblastoma, respectively. An approach integrating survival analysis, feature selection, and regulatory network visualization was used to identify reliable biomarkers of ovarian cancer survival and recurrence. Expression profiles of 799 miRNAs, 17,814 TFs and target genes and cohort clinical records on 272 patients diagnosed with ovarian cancer were simultaneously considered and results were validated on an independent group of 146 patients. This study confirmed 19 miRNAs previously associated with ovarian cancer and identified two miRNAs that have previously been associated with other cancer types. In total, the expression of 838 and 734 target genes and 12 and eight TFs were associated (FDR-adjusted P-value <0.05) with ovarian cancer survival and recurrence, respectively. The simultaneous analysis of co-expression profiles along with consideration of clinical characteristics of patients allowed reliable microRNA-transcription factor-target gene networks associated with ovarian cancer survival to be inferred. Illicit drug exposure brings about changes in the brain transcriptome that result in the dysregulation of pathways. To detect the progression of drug exposure pathways, meta-analysis of five individual microarray experiments measuring gene expression in the brain of mice under acute and chronic drug exposure was performed. Functional analysis and network visualization offered insights into the network changes across drug exposure levels. Meta-analyses uncovered 263 and 2,641 genes differentially expression (FDR-adjusted P-value <0.1) between control and acute and chronic exposure, respectively. Individual genes in these processes have been previously associated with drug exposure and reward-dependent behaviors. The MAPK signaling pathway and the molecular functions of protein dimerization and leucine zipper transcription factor were enriched in response to acute exposure. This study was able to detect the progression of drug exposure pathways using meta, functional, and network analyses

Blended Learning in Obstetrics and Gynecology Resident Education: Impact on Resident Clinical Performance

Problem Effects of residents’ blended learning on their clinical performance have rarely been reported. A blended learning pilot program was instituted at Southern Illinois University School of Medicine's Obstetrics and Gynecology program. One of the modules was chronic hypertension in pregnancy. We sought to evaluate if the resident blended learning was transferred to their clinical performance six months after the module. Intervention A review of patient charts demonstrated inadequate documentation of history, evaluation, and counseling of patients with chronic hypertension at the first prenatal visit by Obstetrics and Gynecology (OB/GYN) residents. A blended learning module on chronic hypertension in pregnancy was then provided to the residents. A retrospective chart review was then performed to assess behavioral changes in the OB/GYN residents. Context This intervention was carried out at the Department of Obstetrics and Gynecology, Southern Illinois University. All 16 OB/GYN residents were enrolled in this module as part of their educational curriculum. A query of all prenatal patients diagnosed with chronic hypertension presenting to the OB/GYN resident clinics four months prior to the implementation of the blended learning module (March 2015–June 2015) and six months after (July 20, 2015–February 2016) was performed. Data were collected from outpatient charts utilizing the electronic medical record. Data were abstracted from resident documentation at the first prenatal visit. Outcome The residents thought that the blended learning module was applicable to performance improvement in the real-world setting. Patients evaluated before ( n = 10) and after ( n = 7) the intervention were compared. After the intervention, there was an increase in assessment of baseline liver enzymes, referral for electrocardiogram, and early assessment for diabetes in the obese patients. More patients were provided a blood pressure cuff after the module (71.4% vs. 20%). Data were provided to the residents in an informal setting. Discussion during this session suggested that inconsistent use of the algorithm and incomplete documentation were reasons for the findings. Lessons Learned This study suggests that blended learning may be a viable tool to support sustained changes in the performance of OB/GYN residents. Scheduled follow-up should be employed to facilitate and ensure continued learning and behavioral changes

A Blended Approach to Learning in an Obstetrics and Gynecology Residency Program: Proof of Concept

Problem Graduate medical education programs are expected to educate residents to be able to manage critically ill patients. Most obstetrics and gynecology (OB/GYN) graduate medical education programs provide education primarily in a didactic format in a traditional face-to-face setting. Busy clinical responsibilities tend to limit resident engagement during these educational sessions. The revision of the training paradigm to a more learner-centered approach is suggested. Intervention A blended learning education program was designed and implemented to facilitate the teaching and learning of obstetric emergencies, specifically diabetic ketoacidosis and acute-onset severe hypertension in pregnancy. The program incorporated tools to foster a community of inquiry. Multimedia presentations were also utilized as the main modality to provide instruction. The blended learning course was designed in accordance with the cognitive theory of multimedia learning. Context This intervention was carried out in the Department of Obstetrics and Gynecology, Southern Illinois University. All 15 OB/GYN residents were enrolled in this course as part of their educational curriculum. First, face-to-face instructions were given in detail about the blended learning process, course content, and online website. The residents were then assigned tasks related to completing the online component of the course, including watching multimedia presentations, reading the resources placed online, and participating in online asynchronous discussions. The course culminated with a face-to-face session to clarify misconceptions. Pre- and postcourse quizzes were administered to the residents to assess their retention and understanding. Outcome Objective analysis demonstrated significant improvements in retention and understanding after participating in the course. The blended learning format was well received by the residents. Resident perception of social presence in the asynchronous online discussions was demonstrative of low scores relating to peer-to-peer interaction. The multimedia presentations and the availability of learning resources were well received. Lessons Learned Outcomes of this study suggest that blended learning is a viable tool to support teaching and learning of obstetric emergencies in an OB/GYN residency program

Transcription Factor-MicroRNA-Target Gene Networks Associated with Ovarian Cancer Survival and Recurrence

<div><p>The identification of reliable transcriptome biomarkers requires the simultaneous consideration of regulatory and target elements including microRNAs (miRNAs), transcription factors (TFs), and target genes. A novel approach that integrates multivariate survival analysis, feature selection, and regulatory network visualization was used to identify reliable biomarkers of ovarian cancer survival and recurrence. Expression profiles of 799 miRNAs, 17,814 TFs and target genes and cohort clinical records on 272 patients diagnosed with ovarian cancer were simultaneously considered and results were validated on an independent group of 146 patients. Three miRNAs (hsa-miR-16, hsa-miR-22*, and ebv-miR-BHRF1-2*) were associated with both ovarian cancer survival and recurrence and 27 miRNAs were associated with either one hazard. Two miRNAs (hsa-miR-521 and hsa-miR-497) were cohort-dependent, while 28 were cohort-independent. This study confirmed 19 miRNAs previously associated with ovarian cancer and identified two miRNAs that have previously been associated with other cancer types. In total, the expression of 838 and 734 target genes and 12 and eight TFs were associated (FDR-adjusted P-value <0.05) with ovarian cancer survival and recurrence, respectively. Functional analysis highlighted the association between cellular and nucleotide metabolic processes and ovarian cancer. The more direct connections and higher centrality of the miRNAs, TFs and target genes in the survival network studied suggest that network-based approaches to prognosticate or predict ovarian cancer survival may be more effective than those for ovarian cancer recurrence. This study demonstrated the feasibility to infer reliable miRNA-TF-target gene networks associated with survival and recurrence of ovarian cancer based on the simultaneous analysis of co-expression profiles and consideration of the clinical characteristics of the patients.</p> </div

Characteristics of Chronic Pain among Head and Neck Cancer Patients Treated with Radiation Therapy: A Retrospective Study

Pain is common among patients with head and neck cancer (HNC). However, there are very limited data on chronic pain among HNC patients treated with radiation therapy (XRT). In this retrospective study, we focused on the characteristics of chronic post-XRT pain in such patients. Post-XRT pain is common among HNC patients; however, we found discrepancy between frequency of treatment and frequency of chronic pain, suggesting poor documentation of pain in the medical records. Among patients who reported to have chronic post-XRT pain, most of them described having severe pain and used descriptors of neuropathic pain. Pharynx was the commonest site of cancer as well as the commonest site of cancer-related chronic pain; squamous cell carcinoma was the most frequent histological pattern, and opioids were used most often to treat such chronic pain. There was a significant association between chronic pain and number of sites of pain, and chronic pain was also associated with use of opioids