Medicine and Health Sciences Commons^™

Biological Treatment Usage In Patients With Hiv And Rheumatic Disease, 2003-2021: Long-Term Safety And Follow-Up, Benjamin Sornrung Naovarat, Gloria Salazar, Mariko Ishimori, Francis M Williams, John D Reveille

Faculty, Staff and Student Publications

OBJECTIVE: This study examined the safety and efficacy of biological agents, especially tumour necrosis factor (TNF) inhibitors, for HIV-positive rheumatology patients refractory to standard therapy.

METHODS: This study is a retrospective case series including patients derived from a community HIV clinic as well as from two academic centres. Initial visit data collected included: sociodemographic characteristics, CD4 counts, HIV viral load and medication use. Patients with persistent disease activity despite standard conservative therapy were begun on biological agents.The main outcomes were patient and physician global assessment of treatment response and medication side effects in patients with rheumatological disorders treated with biological …

Inflammation Subtypes In Psychosis And Their Relationships With Genetic Risk For Psychiatric And Cardiometabolic Disorders, Lusi Zhang, Paulo Lizano, Bin Guo, Yanxun Xu, Leah H. Rubin, S. Kristian Hill, Ney Alliey-Rodriguez, Adam M. Lee, Baolin Wu, Sarah K. Keedy

School of Medicine Publications

Cardiometabolic disorders have known inflammatory implications, and peripheral measures of inflammation and cardiometabolic disorders are common in persons with psychotic disorders. Inflammatory signatures are also related to neurobiological and behavioral changes in psychosis. Relationships between systemic inflammation and cardiometabolic genetic risk in persons with psychosis have not been examined. Thirteen peripheral inflammatory markers and genome-wide genotyping were assessed in 122 participants (n = 86 psychosis, n = 36 healthy controls) of European ancestry. Cluster analyses of inflammatory markers classified higher and lower inflammation subgroups. Single-trait genetic risk scores (GRS) were constructed for each participant using previously reported GWAS summary statistics …

Non-Alcoholic Fatty Liver Disease And Depression: Evidence For Genotype × Environment Interaction In Mexican Americans, Eron G. Manusov, Vincent P. Diego, Khalid Sheikh, Sandra Laston, John Blangero, Sarah Williams-Blangero

School of Medicine Publications

This study examines the impact of G × E interaction effects on non-alcoholic fatty liver disease (NAFLD) among Mexican Americans in the Rio Grande Valley (RGV) of South Texas. We examined potential G × E interaction using variance components models and likelihood-based statistical inference in the phenotypic expression of NAFLD, including hepatic steatosis and hepatic fibrosis (identified using vibration controlled transient elastography and controlled attenuation parameter measured by the FibroScan Device). We screened for depression using the Beck Depression Inventory-II (BDI-II). We identified significant G × E interactions for hepatic fibrosis × BDI-II. These findings provide evidence that genetic factors …

Acute Otitis Media: Tympanostomy Antibiotics, Children's Mercy Kansas City

Clinical Critically Appraised Topics

No abstract provided.

Impact Of Covid-19 On Otolaryngology Literature, Yeshwant R. Chillakuru, Eleanor F. Gerhard, Timothy Shim, Samuel H. Selesnick, Lawrence R. Lustig, John H. Krouse, Ehab Y. Hanna, Timothy L. Smith, Edward W. Fisher, Joseph E. Kerschner, Ashkan Monfared

School of Medicine Publications

Objective

To understand the effect of the COVID-19 pandemic on the volume, quality, and impact of otolaryngology publications.

Methods

Fifteen of the top peer-reviewed otolaryngology journals were queried on PubMed for COVID and non-COVID related articles from April 1, 2020 - March 31, 2021 (pandemic period) and pre-COVID articles from the year prior. Information on total number of submissions and rate of acceptance were collected from seven top-ranked journals.

Results

Our PubMed query returned 759 COVID articles, 4885 non-COVID articles, and 4200 pre-COVID articles, corresponding to a 34% increase in ENT publications during the pandemic period. Meta-analysis/reviews and miscellaneous publication …

Appropriateness Of Indirect Markers Of Muscle Damage Following Lower Limbs Eccentric-Biased Exercises: A Systematic Review With Meta-Analysis, Emeric Chalchat, Anne Fleur Gaston, Keyne Charlot, Luis Peñailillo, Omar Valdés, Pierre Emmanuel Tardo-Dino, Kazunori Nosaka, Vincent Martin, Sebastian Garcia-Vicencio, Julien Siracusa

Research outputs 2022 to 2026

Purpose The aim of this review was to (1) characterize the time-course of markers of exercise-induced muscle damage (EIMD) based on the level of maximal voluntary contraction torque loss at 24-48h post-exercise (MVCloss24-48h), (2) identify factors (e.g., exercise and population characteristics) affecting the level of MVCloss24-48h, and (3) evaluate the appropriateness of EIMD markers as indicators of MVCloss24-48h. Methods Magnitude of change of each EIMD markers was normalized using the standardized mean differences method to compare the results from different studies. Time-course of EIMD markers were characterized according to three levels of MVCloss24-48h based on a clustering analysis of the …

Genomic Epidemiology Of Salmonella Typhi In Central Division, Fiji, 2012 To 2016, Mark R. Davies, Sebastian Duchene, Mary Valcanis, Aaron P. Jenkins, Adam Jenney, Varanisese Rosa, Andrew J. Hayes, Aneley Getahun Strobel, Liam Mcintyre, Jake A. Lacey, Elizabeth J. Klemm, Vanessa K. Wong, Aalisha Sahukhan, Helen Thomson, Andrew Page, Dianna Hocking, Nancy Wang, Litia Tudravu, Eric Rafai, Gordon Dougan, Benjamin P. Howden, John A. Crump, Kim Mulholland, Richard A. Strugnell

Research outputs 2022 to 2026

Background: Typhoid fever is endemic in some Pacific Island Countries including Fiji and Samoa yet genomic surveillance is not routine in such settings. Previous studies suggested imports of the global H58 clade of Salmonella enterica var Typhi (Salmonella Typhi) contribute to disease in these countries which, given the MDR potential of H58, does not auger well for treatment. The objective of the study was to define the genomic epidemiology of Salmonella Typhi in Fiji. Methods: Genomic sequencing approaches were implemented to study the distribution of 255 Salmonella Typhi isolates from the Central Division of Fiji. We augmented epidemiological surveillance and …

Offspring Conceived Through Art Have Normal Thyroid Function In Adolescence And As Young Adults, L. A. Wijs, D. A. Doherty, J. A. Keelan, V. Panicker, P. Burton, J. L. Yovich, R. J. Hart

Research outputs 2022 to 2026

STUDY QUESTION: Are there differences in thyroid function between adolescents and young adults conceived with and without ART? SUMMARY ANSWER: This study demonstrated no evidence of clinically relevant differences in thyroid function between adolescents and young adults conceived with and without ART. WHAT IS KNOWN ALREADY: Studies to date have reported an increase in subclinical hypothyroidism in offspring conceived after ART. It has been suggested that the increase in maternal estrogen (E2) after fresh embryo transfers could affect thyroid function of the offspring. Suboptimal thyroid function at a young age can cause irreversible damage to the central nervous system, which …

Prospective Dietary Polyunsaturated Fatty Acid Intake Is Associated With Trajectories Of Fatty Liver Disease: An 8 Year Follow-Up Study From Adolescence To Young Adulthood, Fuzhen Wan, Feng Pan, Oyekoya Ayonrinde, Leon A. Adams, Trevor A. Mori, Lawrence J. Beilin, Therese A. O’Sullivan, John K. Olynyk, Wendy H. Oddy

Research outputs 2022 to 2026

Background and aim:

Dietary fat intake has long been associated with fatty liver. Our study aimed to determine the effect of dietary fats on longitudinal fatty liver index (FLI) trajectories from adolescence to young adulthood.

Methods:

Nine hundred eighty-five participants in the Raine Study, Perth, Western Australia, Australia, had cross-sectional assessments at ages 14, 17, 20 and 22 years, during which anthropometric measurements and blood tests were obtained. FLI trajectories were derived from the longitudinal FLI results. Dietary fat intake was measured with a semi-quantitative food frequency questionnaire at 14 years and log multinominal regression analyses were used to estimate …

The Nutritional Quality Of Kids’ Menus From Cafés And Restaurants: An Australian Cross‐Sectional Study, Gina S. A. Trapp, Claire E. Pulker, Miriam Hurworth, Kristy K. Law, Sally Brinkman, Christina M. Pollard, Amelia J. Harray, Ros Sambell, Joelie Mandzufas, Stephanie Anzman‐Frasca, Siobhan Hickling

Research outputs 2022 to 2026

Australian families increasingly rely on eating foods from outside the home, which in-creases intake of energy‐dense nutrient‐poor foods. ‘Kids’ Menus’ are designed to appeal to families and typically lack healthy options. However, the nutritional quality of Kids’ Menus from cafes and full‐service restaurants (as opposed to fast‐food outlets) has not been investigated in Australia. The aim of this study was to evaluate the nutritional quality of Kids’ Menus in restaurants and cafés in metropolitan Perth, Western Australia. All 787 cafes and restaurants located within the East Metropolitan Health Service area were contacted and 33% had a separate Kids’ Menu. The …

Assessment Of A Comparative Bayesian-Enhanced Population-Based Decision Model For Covid-19 Critical Care Prediction In The Dominican Republic Social Security Affiliates, Amado A. Baez, Oscar J. Lopez, Maria Martinez, Colyn White, Pedro Ramirez-Slaibe, Leticia Martinez, Pedro L. Castellanos

School of Medicine Publications

Introduction: The novel coronavirus disease 2019 (COVID-19) has been a major health concern worldwide. This study aims to develop a Bayesian model to predict critical outcomes in patients with COVID-19.

Methods: Sensitivity and specificity were obtained from previous meta-analysis studies. The complex vulnerability index (IVC-COV2 index for its abbreviation in Spanish) was used to set the pretest probability. Likelihood ratios were integrated into a Fagan nomogram for posttest probabilities, and IVC-COV2 + National Early Warning Score (NEWS) values and CURB-65 scores were generated. Absolute and relative diagnostic gains (RDGs) were calculated based on pretest and posttest differences.

Results: The IVC-COV2 …

Modelo De Predicción De La Demencia En Adultos Mayores De 60 Años [Dementia Prediction Model In Adults Over 60 Years Old], Maria Del Pilar Santacruz-Ortega, Maria Fernanda Cobo-Charry, Bertha Lucia Avendaño-Prieto, Silvia Mejia-Arango

School of Medicine Publications

In order to determine the contribution of the sociodemographic, psychosocial and health variables to a prediction model of dementia in the elderly population, a secondary analysis was carried out with the data from the “Health, Well-being and Aging. Bogotá, 2012”, with 2000 men and women over 60 years of age from urban and rural areas of Bogotá. To select the sample, a probabilistic, multistage, conglomerate and stratified sampling was carried out, based on the 2005 National Census. The SABE questionnaire adapted for Colombia was used. According to the level of measurement of each variable and the distribution of the data, …

A Neonatal Surgeon’S Concern – Review On Neonatal Gastric Perforation, Anoush Sardesai Sadat, Mahisha Virdiana, Raj Parag Gohil, Sundeep Payyanur Thotan, Ranjani Rammohan

Manipal Journal of Medical Sciences

NGP is an uncommon phenomenon that requires skilled tackling and apt management. The pathology itself is multifactorial with prematurity as a significant risk factor. NGP may present with marked abdominal distention, respiratory distress, vomiting, failure to feed, and lethargy. The diagnosis of a pneumoperitoneum can be made by plain abdominal radiographs and management usually includes an emergency laparotomy with gastrorrhaphy. Percutaneous drainage has also shown good results and may be considered in those patients who cannot be taken up for surgery. LBW and prematurity are known to affect the prognosis and it is important to have an eagle’s eye to …

Interim Outcomes Of Mechanical Thrombectomy For Deep Vein Thrombosis From The All-Comer Clout Registry, David J Dexter, Luis Sanchez, Et Al.

2020-Current year OA Pubs

OBJECTIVES: The multicenter, prospective, single arm CLOUT registry assesses the safety and effectiveness of the ClotTriever System (Inari Medical, Irvine, CA) for the treatment of acute and nonacute lower extremity deep vein thrombosis (DVT) in all-comer patients. Reported here are the outcomes of the first 250 patients.

METHODS: All-comer patients with lower extremity DVT were enrolled, including those with bilateral DVT, those with previously failed DVT treatment, and regardless of symptom duration. The primary effectiveness end point is complete or near-complete (≥75%) thrombus removal determined by independent core laboratory-adjudicated Marder scores. Safety outcomes include serious adverse events through 30 days …

Longitudinal Morphological And Functional Characterization Of Human Heart Organoids Using Optical Coherence Tomography, Yixuan Ming, Senyue Hao, Fei Wang, Yonatan R. Lewis-Israeli, Brett D. Volmert, Zhiyao Xu, Anna Goestenkors, Aitor Aguirre, Chao Zhou

2020-Current year OA Pubs

Organoids play an increasingly important role as in vitro models for studying organ development, disease mechanisms, and drug discovery. Organoids are self-organizing, organ-like three-dimensional (3D) cell cultures developing organ-specific cell types and functions. Recently, three groups independently developed self-assembling human heart organoids (hHOs) from human pluripotent stem cells (hPSCs). In this study, we utilized a customized spectral-domain optical coherence tomography (SD-OCT) system to characterize the growth of hHOs. Development of chamber structures and beating patterns of the hHOs were observed via OCT and calcium imaging. We demonstrated the capability of OCT to produce 3D images in a fast, label-free, and …

Accuracy And Reliability Of Diffusion Imaging Models, Nicole A. Seider, Babatunde Adeyemo, Ryland Miller, Dillan J. Newbold, Jacqueline M. Hampton, Kristen M. Scheidter, Jerrel Rutlin, Timothy O. Laumann, Jarod L. Roland, David F. Montez, Andrew N. Van, Annie Zheng, Scott Marek, Benjamin P. Kay, G. Larry Bretthorst, Yong Wang, Steven E. Petersen, Deanna M. Barch, Evan M. Gordon, Abraham Z. Snyder, Joshua S. Shimony, Nico U. F. Dosenbach

2020-Current year OA Pubs

Diffusion imaging aims to non-invasively characterize the anatomy and integrity of the brain's white matter fibers. We evaluated the accuracy and reliability of commonly used diffusion imaging methods as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (927-1442 diffusion weighted images [DWIs] per individual). Diffusion imaging methods that allow for crossing fibers (FSL's BedpostX [BPX], DSI Studio's Constant Solid Angle Q-Ball Imaging [CSA-QBI], MRtrix3's Constrained Spherical Deconvolution [CSD]) estimated excess fibers when insufficient data were present and/or when the data did not match the model priors. To reduce such overfitting, we developed …

Surgical Perspectives Of Primary Liver Tumors In Children: A Series Of 76 Consecutive Cases, Pailin Arunsopha, Kanokrat Thaiwatcharamas, Sinobol Chusilp, Patchareeporn Tanming, Pongserath Sirichindakul, Nimmita Srisan, Katawaetee Decharun, Soottiporn Chittmittrapap, Paisarn Vejchapipat

Chulalongkorn Medical Journal

Background: Primary liver tumors in children are rare. The objective of this study was to review cases of primary liver tumors in children who underwent tumor removal. Methods: Children (0 - 15 years old) who underwent surgery for primary liver tumors between 2006 and 2019 were studied. Their clinical data and pathological reports were reviewed. Demographic data, types of procedures, operative time, and post-operative complications were described. Data are expressed as mean  standard deviation. Results: There were 76 children (male/female = 39/37), who underwent resection for primary liver tumors. Their average age was 27.9  32.0 months. Asymptomatic abdominal …

Marital Satisfaction In Patients With Breast Cancer Who Have Undergone Mastectomy At King Chulalongkorn Memorial Hospital, Chatchadaporn Pornleegalearn, Chutima Roomruangwong

Chulalongkorn Medical Journal

Background: Breast is an organ that affects sexual symbol and sexual satisfaction. The patients with mastectomy may suffer from both physical and psychological effects. The reaction from their close relatives can lead negative effects to the patients, especially, in term of body image. Previous studies in Thailand focused on depression, body image, coping style, and quality of life in breast cancer patients who had undergone mastectomy. However, there are few studies on marital satisfaction and sexual satisfaction. Objectives: To investigate marital satisfaction and related factors in breast cancer patients who had undergone mastectomy at King Chulalongkorn Memorial Hospital. Methods: A …

School Bullying Behaviors And Victimization In Thai Children And Adolescents With Comorbid Attention Deficit Hyperactivity Disorder, Anxiety Disorders, And Oppositional Defiant Disorder, Jirada Prasartpornsirichoke, Nuttorn Pityaratstian, Warunya Pongparadorn

Chulalongkorn Medical Journal

Background: Bullying in school is a chronic social problem which has life-time impact. The prevalence of school bullying in Thai children and adolescents with attention deficit hyperactivity disorder (ADHD) is significantly higher than other groups. However, there is no research work has been done on the association and impact of the comorbidity of ADHD, anxiety disorder, and oppositional defiant disorder (ODD) on bullying in school. Objectives: This study aimed to examine the prevalence of school bullying in Thai children and adolescents with comorbid ADHD, anxiety disorders, and ODD at King Chulalongkorn Memorial Hospital and to investigate associations and effects of …

Depression In Male Patients With Schizophrenia Residing In Half-Way House For Protection And Development Of Mental Disabilities, Pathum Thani Province, Soraya Nabun, Chavit Tunvirachaisakul

Chulalongkorn Medical Journal

Background: Schizophrenia is a mental disorder with prominently impaired cognitive ability and daily life functioning, resulting in institutionalization for some patients A common comorbidity of patients with schizophrenia is depression that could further reduce patients quality of life. Objectives: The current study aimed to examine the prevalence of depression and associated factors in male patients with schizophrenia residing at Half-way House for Protection and Development of Mental Disabilities, Pathum Thani Province. Methods: This cross-sectional descriptive study was conducted among patients with schizophrenia who was residing at the half-way house. The data collection period for all eligible patients was from September …

Cranial Thickness In Relation To Age, Gender And Head Circumference In Thai Population, Sumas Ruenhuns, Vijarn Vachirawongsakorn

Chulalongkorn Medical Journal

Background: The skull is one of the most studied materials of the human bone. To date, several studies have investigated the range of cranial vault thickness variation in modern human. Objective: To investigate the average thickness of cranial vaults in different positions and their relation to individual variables in the Thai population. Methods: Cranial vaults of 118 male and 59 female cadavers aged over 20 years were eligible for the study. The measurement of the cranial vault was conducted as described: frontal cranial thickness (FCT), occipital cranial thickness (OCT), left and right lateral cranial thickness (LCT). The relationship between the …

A Comparison Of Dilatation Of The Right Atrium On Post Mortem Ct Between Asphyxial Death And Non-Asphyxial Death, Irada Jhunthasiriyakorn, Koravik Meesilpavikkai, Udomsak Hoonvijit, Rathachai Kaewlai, Raksachai Nathongchai

Chulalongkorn Medical Journal

Background: The dilatation of the right atrium and the great vein is one of classical Sign of asphyxial death. The diagnosis of dilatation of the right atrium from the autopsy is difficult due to the unclear criteria and unavailability of measuring the organ size while it is still in the body. Post-mortem computed tomography (PMCT) is useful for the study on the dilatation of the right atrium before autopsy. Objective: This study aimed to compare the size of right atrium measuring with PMCT between the asphyxial and non-asphyxial death. Methods: The samples of this observational analytic research were a total …

Meaning Of Life And Its Association With Perspective Towards Life And Way Of Living: A Qualitative Study In Palliative Care Professionals, Soonthorn Limluck, Wiraporn Pothisiri, Teerayuth Rungnirundorn

Chulalongkorn Medical Journal

Background: Having the meaning of life plays an essential part in human life. It is shown to affect one’s perspective towards life and way of living, and is positively correlated with physical and mental health status. However, the meaning of life in palliative care staff was not yet explored. Objectives: This study aimed to uncover the meaning of life among the palliative care professionals, and to determine factors contributing to the meanings. The associations between the meaning of life and their professions and the way of life were also studied. Methods: Qualitative descriptive method was employed. Twelve palliative care professionals …

Prediction Of Patient Outcomes Through Social Determinants Of Health: The Pulmonary Hypertension Association Registry (Phar) Evaluation, Dan Grinnan, Murali Chakinala, Et Al.

2020-Current year OA Pubs

Outcomes of patients with pulmonary arterial hypertension (PAH) may be associated with social determinants of health (SDOH) and other baseline patient characteristics. At present, there is no prognostic model to predict important patient outcomes in PAH based on SDOH. Utilizing information from the Pulmonary Hypertension Association Registry (PHAR), we derive a model (PHAR Evaluation or PHARE) to predict an important composite patient outcomes based on SDOH and other patient characteristics. Baseline data regarding SDOH from adult patients with PAH enrolled in the PHAR between 2015 and March 23, 2020, were included for analysis. We performed repeated measures logistic regression modeling …

Management Of Histoplasmosis By Infectious Disease Physicians, Patrick B Mazi, Sandra R Arnold, John W Baddley, Nathan C Bahr, Susan E Beekmann, Todd P Mccarty, Philip M Polgreen, Adriana M Rauseo, Andrej Spec

2020-Current year OA Pubs

BACKGROUND: The Infectious Diseases Society of America (IDSA) guidelines for the management of histoplasmosis were last revised 15 years ago. Since those guidelines were compiled, new antifungal treatment options have been developed. Furthermore, the ongoing development of immunomodulatory therapies has increased the population at increased risk to develop histoplasmosis.

METHODS: An electronic survey about the management practices of histoplasmosis was distributed to the adult infectious disease (ID) physician members of the IDSA's Emerging Infections Network.

RESULTS: The survey response rate was 37% (551/1477). Only 46% (253/551) of respondents reported seeing patients with histoplasmosis. Regions considered endemic had 82% (158/193) of …

Online Learning For Infectious Disease Fellows-A Needs Assessment, Miguel A Chavez, Nathanial S Nolan, Emily Gleason, Saman Nematollahi, Emily Abdoler, Gerome Escota

2020-Current year OA Pubs

BACKGROUND: Online resources and social media have become increasingly ubiquitous in medical education. Little is known about the need for educational resources aimed at infectious disease (ID) fellows.

METHODS: We conducted an educational needs assessment through a survey that aimed to describe ID fellows' current use of online and social media tools, assess the value of online learning, and identify the educational content preferred by ID fellows. We subsequently convened focus groups with ID fellows to explore how digital tools contribute to fellow learning.

RESULTS: A total of 110 ID fellows responded to the survey. Over half were second-year fellows …

Recurrent Transcriptional Responses In Aml And Mds Patients Treated With Decitabine, Pawan Upadhyay, Jeremy Beales, Nakul M Shah, Agata Gruszczynska, Christopher A Miller, Allegra A Petti, Sai Mukund Ramakrishnan, Daniel C Link, Timothy J Ley, John S Welch

2020-Current year OA Pubs

The molecular events responsible for decitabine responses in myelodysplastic syndrome and acute myeloid leukemia patients are poorly understood. Decitabine has a short serum half-life and limited stability in tissue culture. Therefore, theoretical pharmacologic differences may exist between patient molecular changes in vitro and the consequences of in vivo treatment. To systematically identify the global genomic and transcriptomic alterations induced by decitabine in vivo, we evaluated primary bone marrow samples that were collected during patient treatment and applied whole-genome bisulfite sequencing, RNA-sequencing, and single-cell RNA sequencing. Decitabine induced global, reversible hypomethylation after 10 days of therapy in all patients, which was …

Is Combined Surgical Dislocation And Proximal Femoral Osteotomy A Safe Procedure For Correction Of Complex Hip Deformities?, Frank W Parilla, Jeffrey J Nepple, Gail E Pashos, Perry L Schoenecker, John C Clohisy

2020-Current year OA Pubs

Complex deformities of the hip requiring intra-articular and proximal femoral correction are challenging with regard to surgical access and complication risk. Combined surgical dislocation and proximal femoral osteotomy (SD/PFO) is a surgical strategy that provides unrestricted access to the joint with the capability for adjunctive PFO. Although providing excellent surgical access, concerns over a potentially high risk of postoperative complications remain, and published information on the safety of this technique remain scarce. In this study, we defined the early complication profile of combined surgery across 48 hips with a variety of complex deformities using a standardized, validated complication grading scheme …

Gan Training Acceleration Using Frechet Descriptor-Based Coreset, Yanzhe Xu, Teresa Wu, Jennifer R. Charlton, Kevin M. Bennett

2020-Current year OA Pubs

No abstract provided.

Single-Dose Intrathecal Dorsal Root Ganglia Toxicity Of Onasemnogene Abeparvovec In Cynomolgus Monkeys, Francis Fonyuy Tukov, Keith Mansfield, Mark Milton, Emily Meseck, Kelley Penraat, Deepa Chand, Andreas Hartmann

2020-Current year OA Pubs

Intravenous onasemnogene abeparvovec is approved for the treatment of spinal muscular atrophy in children < 2 years. For later-onset patients, intrathecal onasemnogene abeparvovec may be advantageous over intravenous administration. Recently, microscopic dorsal root ganglion (DRG) changes were observed in nonhuman primates (NHPs) following intrathecal onasemnogene abeparvovec administration. To characterize these DRG findings, two NHP studies evaluating intrathecal onasemnogene abeparvovec administration were conducted: a 12-month study with a 6-week interim cohort and a 13-week study with a 2-week interim cohort. The latter investigated the potential impact of prednisolone or rituximab plus everolimus on DRG toxicity. An additional 6-month, single-dose, intravenous NHP study conducted in parallel evaluated onasemnogene abeparvovec safety (including DRG toxicity) with or without prednisolone coadministration. Intrathecal onasemnogene abeparvovec administration was well tolerated and not associated with clinical observations. Microscopic onasemnogene abeparvovec-related changes were observed in the DRG and trigeminal ganglion (TG) and included mononuclear cell inflammation and/or neuronal degeneration, which was colocalized with high vector transcript expression at 6 weeks postdose. Incidence and severity of DRG changes were generally decreased after 52 weeks compared with 6 weeks postdose. Other onasemnogene abeparvovec-related microscopic findings of axonal degeneration, mononuclear cell infiltrates and/or gliosis in the spinal cord, dorsal spinal nerve root/spinal nerves, and/or peripheral nerves were absent or found at decreased incidences and/or severities after 52 weeks. DRG and/or TG microscopic findings following intravenous onasemnogene abeparvovec dosing included minimal to slight neuronal degeneration and mononuclear cell inflammation at 6 weeks and 6 months postdose. Nervous system microscopic findings following intrathecal onasemnogene abeparvovec (≥1.2 × 10