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1.
medRxiv ; 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38883733

ABSTRACT

Nonfatal suicidality is the most robust predictor of suicide death. However, only ~10% of those who survive an attempt go on to die by suicide. Moreover, ~50% of suicide deaths occur in the absence of prior known attempts, suggesting risks other than nonfatal suicide attempt need to be identified. We studied data from 4,000 population-ascertained suicide deaths and 26,191 population controls to improve understanding of risks leading to suicide death. This study included 2,253 suicide deaths and 3,375 controls with evidence of nonfatal suicidality (SUI_SI/SB and CTL_SI/SB) from diagnostic codes and natural language processing of electronic health records notes. Characteristics of these groups were compared to 1,669 suicides with no prior nonfatal SI/SB (SUI_None) and 22,816 controls with no lifetime suicidality (CTL_None). The SUI_None and CTL_None groups had fewer diagnoses and were older than SUI_SI/SB and CTL_SI/SB. Mental health diagnoses were far less common in both the SUI_None and CTL_None groups; mental health problems were less associated with suicide death than with presence of SI/SB. Physical health diagnoses were conversely more often associated with risk of suicide death than with presence of SI/SB. Pending replication, results indicate highly significant clinical differences among suicide deaths with versus without prior nonfatal SI/SB.

2.
Mol Psychiatry ; 28(9): 3909-3919, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37794117

ABSTRACT

Recent large-scale genome-wide association studies (GWAS) have started to identify potential genetic risk loci associated with risk of suicide; however, a large portion of suicide-associated genetic factors affecting gene expression remain elusive. Dysregulated gene expression, not assessed by GWAS, may play a significant role in increasing the risk of suicide death. We performed the first comprehensive genomic association analysis prioritizing brain expression quantitative trait loci (eQTLs) within regulatory regions in suicide deaths from the Utah Suicide Genetic Risk Study (USGRS). 440,324 brain-regulatory eQTLs were obtained by integrating brain eQTLs, histone modification ChIP-seq, ATAC-seq, DNase-seq, and Hi-C results from publicly available data. Subsequent genomic analyses were conducted in whole-genome sequencing (WGS) data from 986 suicide deaths of non-Finnish European (NFE) ancestry and 415 ancestrally matched controls. Additional independent USGRS suicide deaths with genotyping array data (n = 4657) and controls from the Genome Aggregation Database were explored for WGS result replication. One significant eQTL locus, rs926308 (p = 3.24e-06), was identified. The rs926308-T is associated with lower expression of RFPL3S, a gene important for neocortex development and implicated in arousal. Gene-based analyses performed using Sherlock Bayesian statistical integrative analysis also detected 20 genes with expression changes that may contribute to suicide risk. From analyzing publicly available transcriptomic data, ten of these genes have previous evidence of differential expression in suicide death or in psychiatric disorders that may be associated with suicide, including schizophrenia and autism (ZNF501, ZNF502, CNN3, IGF1R, KLHL36, NBL1, PDCD6IP, SNX19, BCAP29, and ARSA). Electronic health records (EHR) data was further merged to evaluate if there were clinically relevant subsets of suicide deaths associated with genetic variants. In summary, our study identified one risk locus and ten genes associated with suicide risk via gene expression, providing new insight into possible genetic and molecular mechanisms leading to suicide.


Subject(s)
Quantitative Trait Loci , Suicide , Humans , Quantitative Trait Loci/genetics , Genome-Wide Association Study/methods , Bayes Theorem , Brain , Polymorphism, Single Nucleotide/genetics , Genetic Predisposition to Disease/genetics , Membrane Proteins/genetics
3.
J Clin Oncol ; 41(2): 186-197, 2023 01 10.
Article in English | MEDLINE | ID: mdl-36166727

ABSTRACT

PURPOSE: Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. PATIENTS AND METHODS: In a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety. RESULTS: A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A (P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B (P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated. CONCLUSION: Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.


Subject(s)
Melanoma , Skin Neoplasms , Humans , Ipilimumab , Nivolumab/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Prospective Studies , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Pyridones , Oximes , Disease Progression , Mitogen-Activated Protein Kinase Kinases , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Mutation
4.
J Ultrasound Med ; 41(12): 3003-3012, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35560254

ABSTRACT

OBJECTIVES: To test if a deep learning (DL) model trained on echocardiography images could accurately segment the left ventricle (LV) and predict ejection fraction on apical 4-chamber images acquired by point-of-care ultrasound (POCUS). METHODS: We created a dataset of 333 videos from cardiac POCUS exams acquired in the emergency department. For each video we derived two ground-truth labels. First, we segmented the LV from one image frame and second, we classified the EF as normal, reduced, or severely reduced. We then classified the media's quality as optimal, adequate, or inadequate. With this dataset we tested the accuracy of automated LV segmentation and EF classification by the best-in-class echocardiography trained DL model EchoNet-Dynamic. RESULTS: The mean Dice similarity coefficient for LV segmentation was 0.72 (N = 333; 95% CI 0.70-0.74). Cohen's kappa coefficient for agreement between predicted and ground-truth EF classification was 0.16 (N = 333). The area under the receiver-operating curve for the diagnosis of heart failure was 0.74 (N = 333). Model performance improved with video quality for the tasks of LV segmentation and diagnosis of heart failure, but was unchanged with EF classification. For all tasks the model was less accurate than the published benchmarks for EchoNet-Dynamic. CONCLUSIONS: Performance of a DL model trained on formal echocardiography worsened when challenged with images captured during resuscitations. DL models intended for assessing bedside ultrasound should be trained on datasets composed of POCUS images. Such datasets have yet to be made publicly available.


Subject(s)
Deep Learning , Heart Failure , Humans , Artificial Intelligence , Exercise Test , Point-of-Care Systems , Echocardiography/methods
5.
Am J Med Genet B Neuropsychiatr Genet ; 189(3-4): 60-73, 2022 04.
Article in English | MEDLINE | ID: mdl-35212135

ABSTRACT

Suicide accounts for >800,000 deaths annually worldwide; prevention is an urgent public health issue. Identification of risk factors remains challenging due to complexity and heterogeneity. The study of suicide deaths with increased extended familial risk provides an avenue to reduce etiological heterogeneity and explore traits associated with increased genetic liability. Using extensive genealogical records, we identified high-risk families where distant relatedness of suicides implicates genetic risk. We compared phenotypic and polygenic risk score (PRS) data between suicides in high-risk extended families (high familial risk (HFR), n = 1,634), suicides linked to genealogical data not in any high-risk families (low familial risk (LFR), n = 147), and suicides not linked to genealogical data with unknown familial risk (UFR, n = 1,865). HFR suicides were associated with lower age at death (mean = 39.34 years), more suicide attempts, and more PTSD and trauma diagnoses. For PRS tests, we included only suicides with >90% European ancestry and adjusted for residual ancestry effects. HFR suicides showed markedly higher PRS of suicide death (calculated using cross-validation), supporting specific elevation of genetic risk of suicide in this subgroup, and also showed increased PRS of PTSD, suicide attempt, and risk taking. LFR suicides were substantially older at death (mean = 49.10 years), had fewer psychiatric diagnoses of depression and pain, and significantly lower PRS of depression. Results suggest extended familiality and trauma/PTSD may provide specificity in identifying individuals at genetic risk for suicide death, especially among younger ages, and that LFR of suicide warrants further study regarding the contribution of demographic and medical risks.


Subject(s)
Genetic Predisposition to Disease , Mental Disorders , Family , Humans , Multifactorial Inheritance/genetics , Suicide, Attempted/psychology
6.
Pediatr Ann ; 50(7): e282-e285, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34264794

ABSTRACT

Symptoms of thyroid nodules and differentiated thyroid cancer include those of hypo- or hyperthyroidism, voice changes, difficulty breathing when supine, globus sensation, dysphagia, and cervical adenopathy. Surgery has been the first-line mainstay treatment option for large thyroid nodules and thyroid carcinomas. This article highlights thyroid carcinoma in the pediatric population and reviews the current testing and management options. [Pediatr Ann. 2020;50(7):e282-e285.].


Subject(s)
Thyroid Neoplasms , Thyroid Nodule , Child , Deglutition Disorders/etiology , Humans , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/surgery , Thyroid Nodule/diagnosis , Thyroid Nodule/surgery
7.
Neurosci Res ; 172: 99-109, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34023358

ABSTRACT

Within the brain, traumatic brain injury (TBI) alters synaptic plasticity and increases neuroinflammation and neuronal death. Yet, there lacks effective TBI treatments providing pleiotropic beneficial effects on these diverse cellular processes necessary for functional recovery. Here, we show the diabetes drug, metformin, significantly improves cognitive functions after controlled cortical impact (CCI) injury in mice, showing improved spatial learning and nest building. Furthermore, injured animals treated with metformin exhibit increased ramification of microglia processes, indicating reduced neuroinflammation. Finally, metformin treatment in vitro increased neuronal activation of partitioning defective 1 (Par1), a family of Ser/Thr kinases playing a key role in synaptic plasticity and neuroinflammation. These results suggest metformin is a promising therapeutic agent for targeting multiple cellular processes necessary for functional TBI recovery.


Subject(s)
Brain Injuries, Traumatic , Metformin , Animals , Brain , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/drug therapy , Cognition , Disease Models, Animal , Metformin/pharmacology , Mice , Mice, Inbred C57BL , Microglia
8.
Biomolecules ; 10(7)2020 06 29.
Article in English | MEDLINE | ID: mdl-32610618

ABSTRACT

Traumatic brain injury (TBI) is a relatively common occurrence following accidents or violence, and often results in long-term cognitive or motor disability. Despite the high health cost associated with this type of injury, presently there are no effective treatments for many neurological symptoms resulting from TBI. This is due in part to our limited understanding of the mechanisms underlying brain dysfunction after injury. In this study, we used the mouse controlled cortical impact (CCI) model to investigate the effects of TBI, and focused on Reelin, an extracellular protein that critically regulates brain development and modulates synaptic activity in the adult brain. We found that Reelin expression decreases in forebrain regions after TBI, and that the number of Reelin-expressing cells decrease specifically in the hippocampus, an area of the brain that plays an important role in learning and memory. We also conducted in vitro experiments using mouse neuronal cultures and discovered that Reelin protects hippocampal neuronal cells from glutamate-induced neurotoxicity, a well-known secondary effect of TBI. Together our findings suggest that the loss of Reelin expression may contribute to neuronal death in the hippocampus after TBI, and raise the possibility that increasing Reelin levels or signaling activity may promote functional recovery.


Subject(s)
Brain Injuries, Traumatic/metabolism , Cell Adhesion Molecules, Neuronal/genetics , Cell Adhesion Molecules, Neuronal/metabolism , Down-Regulation , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Hippocampus/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Animals , Brain Injuries, Traumatic/etiology , Brain Injuries, Traumatic/genetics , Cells, Cultured , Disease Models, Animal , Glutamic Acid/adverse effects , Male , Mice , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Reelin Protein , Signal Transduction
9.
J Neuroinflammation ; 16(1): 11, 2019 Jan 17.
Article in English | MEDLINE | ID: mdl-30654821

ABSTRACT

BACKGROUND: Microglia, the resident immune cells of the brain, exhibit various morphologies that correlate with their functions under physiological and pathological conditions. In conditions such as aging and stress, microglia priming occurs, which leads to altered morphology and lower threshold for activation upon further insult. However, the molecular mechanisms that lead to microglia priming are unclear. METHODS: To understand the role of Par1b/MARK2 in microglia, we first expressed shRNA targeting luciferase or Par1b/MARK2 in primary microglial cells and imaged the cells using fluorescent microscopy to analyze for morphological changes. A phagocytosis assay was then used to assess functional changes. We then moved in vivo and used a Par1b/MARK2 knockout mouse model to assess for changes in microglia density, morphology, and phagocytosis using immunohistochemistry, confocal imaging, and 3D image reconstruction. Next, we used two-photon in vivo imaging in live Par1b/MARK2 deficient mice to examine microglia dynamics. In addition, a controlled-cortical impact injury was performed on wild-type and Par1b/MARK2-deficient mice and microglial response was determined by confocal imaging. Finally, to help rule out non-cell autonomous effects, we analyzed apoptosis by confocal imaging, cytokine levels by multiplex ELISA, and blood-brain barrier permeability using Evans Blue assay. RESULTS: Here, we show that loss of the cell polarity protein Par1b/MARK2 facilitates the activation of primary microglia in culture. We next found that microglia in Par1b/MARK2 deficient mice show increased density and a hypertrophic morphology. These morphological changes are accompanied with alterations in microglia functional responses including increased phagocytosis of neuronal particles early in development and decreased surveillance of the brain parenchyma, all reminiscent of a primed phenotype. Consistent with this, we found that microglia in Par1b/MARK2 deficient mice have a significantly lower threshold for activation upon injury. CONCLUSIONS: Together, our studies show that loss of Par1b/MARK2 switches microglia from a surveillant to a primed state during development, resulting in an increased neuroinflammatory response to insults.


Subject(s)
Brain Injuries, Traumatic/pathology , Brain/growth & development , Brain/pathology , Cell Cycle Proteins/deficiency , Microglia/metabolism , Protein Serine-Threonine Kinases/deficiency , Adenosine Triphosphate/pharmacology , Animals , Animals, Newborn , Apoptosis/physiology , Brain Injuries, Traumatic/physiopathology , CX3C Chemokine Receptor 1/deficiency , CX3C Chemokine Receptor 1/genetics , Cell Cycle Proteins/genetics , Cells, Cultured , Computer Simulation , Disease Models, Animal , Gene Expression Regulation, Developmental/genetics , Mice , Mice, Transgenic , Models, Neurological , Phagocytosis/genetics , Protein Serine-Threonine Kinases/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Rats , Rats, Sprague-Dawley , Synapsins/metabolism
12.
Oncol Res ; 26(3): 515-518, 2018 Apr 10.
Article in English | MEDLINE | ID: mdl-29229020

ABSTRACT

Solid tumors involving glandular organs express mucin glycoprotein that is eventually shed into the circulation. As a result, these proteins can easily be measured in the serum and be used as potential tumor markers. The most commonly used tumor markers for breast cancer are CA27-29 and CA15-3, which both measure the glycoprotein product of the mucin-1 (MUC1) gene. CA27-29 has been approved by the US Food and Drug Administration for monitoring disease activity in breast cancer patients. Most oncology clinical practice guidelines do not recommend the use of tumor markers for routine surveillance of early stage disease but recognize their utility in the metastatic setting. We present a patient with stage IIIA breast cancer and preexisting hypersensitivity pneumonitis who was found to have an elevated serum tumor marker CA27-29. After successful curative intent treatment of her early stage breast cancer, she developed gradual and progressive worsening of her lung disease with eventual development of severe pulmonary fibrosis requiring bilateral lung transplantation. As part of the pretransplant evaluation, she was found to have an elevation of serum tumor marker CA27-29. While the diagnostic evaluation, including imaging studies, was negative for the presence of recurrent disease, the serial serum tumor marker CA27-29 levels remained persistently elevated. The decision was made for her to undergo bilateral lung transplantation. Shortly after surgery, her CA27-29 tumor marker level returned to normal range, and it has continued to remain in the normal range with no evidence of breast cancer recurrence.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/blood , Biomarkers, Tumor/blood , Breast Neoplasms/blood , Idiopathic Pulmonary Fibrosis/blood , Lung Transplantation/methods , Breast Neoplasms/complications , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Female , Humans , Idiopathic Pulmonary Fibrosis/complications , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/surgery , Prognosis
16.
Brain Inj ; 30(1): 48-65, 2016.
Article in English | MEDLINE | ID: mdl-26579945

ABSTRACT

PRIMARY OBJECTIVE: Neurotrophin levels are elevated after TBI, yet there is minimal regeneration. It was hypothesized that the pro-neurotrophin/p75NTR pathway is induced more than the mature neurotrophin/Trk pathway and that interfering with p75 signalling improves recovery following TBI. RESEARCH DESIGN: Lateral Fluid Percussion (LFP) injury was performed on wildtype and p75 mutant mice. In addition, TrkB agonist 7,8 Dihydroxyflavone or p75 antagonist TAT-Pep5 were tested. Western blot and immunohistochemistry revealed biochemical and cellular changes. Morris Water Maze and Rotarod tests demonstrated cognitive and vestibulomotor function. MAIN OUTCOMES AND RESULTS: p75 was up-regulated and TrkB was down-regulated 1 day post-LFP. p75 mutant mice as well as mice treated with the p75 antagonist or the TrkB agonist exhibited reduced neuronal death and degeneration and less astrocytosis. The cells undergoing apoptosis appear to be neurons rather than glia. There was improved motor function and spatial learning in p75 mutant mice and mice treated with the p75 antagonist. CONCLUSIONS: Many of the pathological and behavioural consequences of TBI might be due to activation of the pro-neurotrophin/p75 toxic pathway overriding the protective mechanisms of the mature neurotrophin/Trk pathway. Targeting p75 can be a novel strategy to counteract the damaging effects of TBI.


Subject(s)
Brain Injuries, Traumatic/drug therapy , Brain Injuries, Traumatic/metabolism , Receptor, trkB/metabolism , Receptors, Nerve Growth Factor/metabolism , Animals , Apoptosis/physiology , Astrocytes/metabolism , Astrocytes/pathology , Brain Injuries, Traumatic/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cognition/physiology , Flavones/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Nerve Growth Factors/metabolism , Receptor, trkB/agonists , Receptor, trkB/genetics , Receptors, Nerve Growth Factor/antagonists & inhibitors , Receptors, Nerve Growth Factor/genetics , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/pathology
17.
Curr Hematol Malig Rep ; 10(3): 192-8, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26104908

ABSTRACT

The use of large databases has provided advancements in the understanding of racial, ethnic, and socioeconomic disparities in the field of adult hematopoietic cell transplants (HCT). Disparities exist on individual, institutional, and systemic levels for both allogeneic and autologous HCT. We reviewed the most recent publications that utilized large databases to elucidate disparities in HCT and placed them into historical context of the other major studies in the field. Two emerging themes were identified. These themes are persistent inequalities in both allogeneic HCT and autologous HCT for myeloma and the importance of improving homogeneity of care in HCT. Minimization of inequalities can be achieved only with an understanding of the persistent barriers that exist in the field.


Subject(s)
Healthcare Disparities/statistics & numerical data , Hematopoietic Stem Cell Transplantation , Adult , Databases, Factual , Humans , Multiple Myeloma/epidemiology , Multiple Myeloma/therapy , Public Health Surveillance , Transplantation, Autologous , Transplantation, Homologous
18.
Facial Plast Surg Clin North Am ; 22(4): 573-86, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25444729

ABSTRACT

Cleft lip with or without cleft palate is the most common congenital malformation of the head and neck. Orofacial clefting could significantly affect the quality of life of the child and requires multiple steps of care to obtain an optimal outcome. Each patient should be evaluated for congenital anomalies, developmental delay, neurologic disorders, and psychosocial concerns. A multidisciplinary team is necessary to ensure that every aspect of the child's care is appropriately treated and coordination between providers is achieved. This article discusses the assessment and treatment recommendations for children born with cleft lip and/or cleft palate.


Subject(s)
Cleft Lip/surgery , Cleft Palate/surgery , Orthognathic Surgical Procedures/methods , Child , Cleft Lip/diagnosis , Cleft Palate/diagnosis , Humans , Patient Positioning , Perioperative Care , Postoperative Complications/diagnosis , Postoperative Complications/therapy , Rhinoplasty , Surgical Flaps
19.
Clin Sarcoma Res ; 4: 8, 2014.
Article in English | MEDLINE | ID: mdl-25276339

ABSTRACT

Dermatofibrosarcoma Protuberans (DFSP) is a rare skin tumor, characterized by frequent local recurrence but is seldom metastatic. It is histologically characterized by storiform arrangement of spindle cells. Cytogenetically, most tumors are characterized by translocation 17:22 leading to overexpression of tyrosine kinase PDGFB which can be targeted with tyrosine kinase inhibitor, Imatinib. We describe the first case of unresectable pancreatic metastases from DFSP treated with neoadjuvant Imatinib and subsequently R0 metastectomy. Additionally, a comprehensive systematic review of DFSP pancreatic metastases and the current published data on the use of Imatinib in DFSP is summarized.

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