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A common adverse effect of Parkinson's disease (PD) treatment is L-dopa-induced dyskinesia (LID). This condition results from both dopamine (DA)-dependent and DA-independent mechanisms, as glutamate inputs from corticostriatal projection neurons impact DA-responsive medium spiny neurons in the striatum to cause the dyskinetic behaviors. In this study, we explored whether suppression of presynaptic corticostriatal glutamate inputs might affect the behavioral and biochemical outcomes associated with LID. We first established an animal model in which 6-hydroxydopamine (6-OHDA)-lesioned mice were treated daily with L-dopa (10 mg/kg, i.p.) for 2 weeks; these mice developed stereotypical abnormal involuntary movements (AIMs). When the mice were pretreated with the NMDA antagonist, amantadine, we observed suppression of AIMs and reductions of phosphorylated ERK1/2 and NR2B in the striatum. We then took an optogenetic approach to manipulate glutamatergic activity. Slc17a6 (vGluT2)-Cre mice were injected with pAAV5-Ef1a-DIO-eNpHR3.0-mCherry and received optic fiber implants in either the M1 motor cortex or dorsolateral striatum. Optogenetic inactivation at either optic fiber implant location could successfully reduce the intensity of AIMs after 6-OHDA lesioning and L-dopa treatment. Both optical manipulation strategies also suppressed phospho-ERK1/2 and phospho-NR2B signals in the striatum. Finally, we performed intrastriatal injections of LDN 212320 in the dyskenesic mice to enhance expression of glutamate uptake transporter GLT-1. Sixteen hours after the LDN 212320 treatment, L-dopa-induced AIMs were reduced along with the levels of striatal phospho-ERK1/2 and phospho-NR2B. Together, our results affirm a critical role of corticostriatal glutamate neurons in LID and strongly suggest that diminishing synaptic glutamate, either by suppression of neuronal activity or by upregulation of GLT-1, could be an effective approach for managing LID.
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Discinesias , Doença de Parkinson , Ratos , Camundongos , Animais , Levodopa/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Oxidopamina/toxicidade , Ácido Glutâmico/metabolismo , Ratos Sprague-Dawley , Dopamina/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Antiparkinsonianos/efeitos adversosRESUMO
STUDY OBJECTIVE: Prior studies have suggested potential racial differences in receiving imaging tests in emergency departments (EDs), but the results remain inconclusive. In addition, most prior studies may only have limited racial groups for minority patients. This study aimed to investigate racial differences in head computed tomography (CT) administration rates in EDs among patients with head injuries. METHODS: Patients with head injuries who visited EDs were examined. The primary outcome was patients receiving head CT during ED visits, and the primary exposure was patient race/ethnicity, including Asian, Hispanic, Non-Hispanic Black (Black), and Non-Hispanic White (White). Multivariable logistic regression analyses were performed using the National Hospital Ambulatory Medical Care Survey database, adjusting for patients and hospital characteristics. RESULTS: Among 6130 patients, 51.9% received a head CT scan. Asian head injury patients were more likely to receive head CT than White patients (59.1% versus 54.0%, difference 5.1%, p < 0.001). This difference persisted in adjusted results (odds ratio, 1.52; 95% CI, 1.06-2.16, p = 0.022). In contrast, Black and Hispanic patients have no significant difference in receiving head CT than White patients after the adjustment. CONCLUSIONS: Asian head injury patients were more likely to receive head CT than White patients. This difference may be attributed to the limited English proficiency among Asian individuals and the fact that there is a wide variety of different languages spoken by Asian patients. Future studies should examine rates of receiving other diagnostic imaging modalities among different racial groups and possible interventions to address this difference.
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Traumatismos Craniocerebrais , Serviço Hospitalar de Emergência , Tomografia Computadorizada por Raios X , População Branca , Humanos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Feminino , Masculino , Traumatismos Craniocerebrais/diagnóstico por imagem , Traumatismos Craniocerebrais/etnologia , Adulto , Pessoa de Meia-Idade , População Branca/estatística & dados numéricos , Estados Unidos , Idoso , Adolescente , Negro ou Afro-Americano/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Adulto Jovem , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Modelos LogísticosRESUMO
BACKGROUND: Recent studies have focused on the safety and efficacy of performing primary total knee arthroplasty (TKA) in an outpatient setting. Despite being associated with greater costs, much less is known about the accompanying impact on revision TKA (rTKA). The purpose of this study was to describe the trends in costs and outcomes of patients undergoing inpatient and outpatient rTKA. METHODS: An observational cohort study was conducted using commercial claims databases. Patients who underwent 1-component and 2-component rTKA in an inpatient setting, hospital outpatient department (HOPD), or ambulatory surgery center (ASC) from 2018 to 2020 were included. The primary outcome was the 30-day episode-of-care costs following rTKA. Secondary outcomes included surgical cost, 90-day readmission rate, and emergency department visit rate. Covariates for analyses included patient demographics, surgery type, and indication for revision. RESULTS: There were 6,515 patients who were identified, with 17.0% of rTKAs taking place in an outpatient setting. On adjusted analysis, patients in the highest quartile of 30-day postoperative costs were more likely to be those whose rTKA was performed in an inpatient setting. One-component revisions were more common in an outpatient setting (HOPD, 50.7%; ASC, 62.0%) compared to an inpatient setting (39.6%). The 90-day readmission rates were higher (P = .003) for rTKAs performed in inpatient (+9.2%) and HOPD (+8.6%) settings compared to those in an ASC. CONCLUSIONS: The ASC may be a suitable setting for simpler revisions performed for less severe indications and is associated with lower costs and 90-day readmission and emergency department visit rates.
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Background: The clinic-pathological boundary between poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) is unclear due to a wide spectrum of histopathological features and the rarity of the disease. In addition to that, with the highest mortality rate and non-standard treatment modality, the PDTC/ATC population has not been subjected to comprehensive description and comparison with the extent of histological characteristics, therapeutic response, prognostic factors, and death attribution analysis. Method: A total of 4,947 PDTC/ATC patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival curve estimation and Cox proportional hazard regression were applied. Results: Overall, the 5- and 10-year DSS for PDTC were 71.9% and 68.0%, respectively, whereas the 5- and 10-year OS are 59.3% and 51.2%, respectively. The median survival time for ATC patients was 3 months with 1-year OS being 26.9% and 1-year DSS being 31.2%. During the follow-up period, 68.1% of the PDTC/ATC cohort were dead, 51.6% of which were attributed to thyroid malignancies and 16.5% to non-thyroid causes. The top three common non-thyroid causes of death were miscellaneous cancers, lower respiratory system disease, and heart disease. The histological feature of papillary thyroid cancer (PTC) was the leading pathological category for PDTC patients (51.7%), whereas 76.7% of ATC patients' pathological feature was characterized as unidentifiable. Sarcoma histological characteristics found in ATC cases suffer the highest overall mortality (vs. PTC, HR = 2.61, 95% CI 1.68-4.06, P < 0.001). Older age unidentifiable histology feature, more advanced AJCC N1b, AJCC M1, and SEER stage, tumor size larger than 5 cm, and more invasive tumor extension were independent bad outcome predictors. Conclusion: The populational analysis of the PDTC/ATC cohort has provided reliable support for better understanding of the difference between PDTC and ATC cases and the guidance of clinical practice and further studies.
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Adenocarcinoma , Prolina/análogos & derivados , Tiocarbamatos , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/patologia , Prognóstico , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/epidemiologia , Câncer Papilífero da TireoideRESUMO
BACKGROUND: Oncocytic carcinoma of the thyroid (OCA) is an independent type of thyroid cancer. Radioactive iodine (RAI) therapy was frequently administered to OCA patients, but its contribution to improving survival is indefinite. METHODS: 4641 OCA patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazard regression and competing risk analysis were applied. RESULTS: Tumor size, SEER stage, primary surgery, and neck dissection were prognostic factors for cancer-specific survival. The results of competing risk analysis demonstrated that age over 55 years dramatically increased non-OCA death risks. Treatments that improve non-OCA survival (including total thyroidectomy, RAI therapy, and systemic therapy) should be recommended in OCA patients older than 55 years of age. Neck lymphadenectomy should not be recommended for OCA, since the metastatic lymph node ratio was low (about 3%). CONCLUSIONS: RAI therapy can improve survival in OCA by reducing noncancer death risks.
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Background: Medullary thyroid cancer (MTC) is a challenging malignancy. The survival outcome of MTC based on AJCC staging system does not render a discriminant classifier among early stages. Methods: 3601 MTC patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Smooth curve fitting, Cox proportional hazard regression and competing risk analysis were applied. Results: A linear correlation between age and log RR (relative risk of overall death) was detected. Overlaps were observed between K-M curves representing patients aged 45-50, 50-55, and 55-60. The study cohort was divided into 3 subgroups with 2 age cutoffs set at 45 and 60. Each further advanced age cutoff population resulted in a roughly "5%" increase in MTC-specific death risks and an approximately "3 times" increase in non-MTC-specific death risks. Conclusions: The survival outcome disparity across age cutoffs at 45 and 60 for MTC has been well defined.
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Carcinoma Neuroendócrino , Programa de SEER , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Pessoa de Meia-Idade , Masculino , Feminino , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Estudos Retrospectivos , Fatores Etários , Taxa de Sobrevida , Idoso , Prognóstico , Adulto , Estudos de Coortes , SeguimentosRESUMO
STUDY DESIGN: Observational cohort study. OBJECTIVE: To describe the postoperative costs associated with both anterior cervical discectomy and fusion (ACDF) and cervical disc arthroplasty (CDA) in the two-year period following surgery. SUMMARY OF BACKGROUND DATA: CDA has become an increasingly common alternative to ACDF for the treatment of cervical disc disorders. Although a number of studies have compared clinical outcomes between both procedures, much less is known about the postoperative economic burden of each procedure. MATERIALS AND METHODS: By analyzing a commercial insurance claims database (Marketscan, Merative), patients who underwent one-level or two-level ACDF and CDA procedures between January 1, 2017 and December 31, 2017 were identified and included in the study. The primary outcome was the cost of payments for postoperative management in the two-year period following ACDF or CDA. Identified postoperative interventions included in the study were: (i) physical therapy, (ii) pain medication, (iii) injections, (iv) psychological treatment, and (iv) subsequent spine surgeries. RESULTS: Totally, 2304 patients (age: 49.0±9.4 yr; male, 50.1%) were included in the study. In all, 1723 (74.8%) patients underwent ACDF, while 581 (25.2%) underwent CDA. The cost of surgery was similar between both groups (ACDF: $26,819±23,449; CDA: $25,954±20,620; P =0.429). Thirty-day, 90-day, and two-year global costs were all lower for patients who underwent CDA compared with ACDF ($31,024 vs. $34,411, $33,064 vs. $37,517, and $55,723 vs. $68,113, respectively). CONCLUSION: Lower two-year health care costs were found for patients undergoing CDA compared with ACDF. Further work is necessary to determine the drivers of these findings and the associated longer-term outcomes.
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Degeneração do Disco Intervertebral , Fusão Vertebral , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Artroplastia/métodos , Vértebras Cervicais/cirurgia , Discotomia/métodos , Custos de Cuidados de Saúde , Degeneração do Disco Intervertebral/cirurgia , Fusão Vertebral/métodos , Resultado do Tratamento , FemininoRESUMO
STUDY DESIGN: Observational cohort study. OBJECTIVE: Cauda equina syndrome (CES) is a rare neurologic condition with potentially devastating consequences. The objective of this study was to compare the 2-year postoperative cost-associated treatments after posterior spinal decompression between patients with and without CES. METHODS: By analyzing a commercial insurance claims database, patients who underwent posterior spinal decompression with a concurrent diagnosis of lumbar spinal stenosis, radiculopathy, or disk herniation in 2017 were identified and included in the study. The primary outcome was the cost of payments for identified treatments in the 2-year period after surgery. Treatments included were (1) physical therapy (PT), (2) pain medication, (3) injections, (4) bladder management, (5) bowel management, (6) sexual dysfunction treatment, and (7) psychological treatment. RESULTS: In total, 3,140 patients (age, 55.3 ± 12.0 years; male, 62.2%) were included in the study. The average total cost of treatments identified was $2,996 ± 6,368 per patient. The overall cost of identified procedures was $2,969 ± 6,356 in non-CES patients, compared with $4,535 ± 6,898 in patients with CES ( P = 0.079). Among identified treatments, only PT and bladder management costs were significantly higher for patients with CES (PT: +115%, P < 0.001; bladder management: +697%, P < 0.001). The difference in overall cost was significant between patients (non-CES: $1,824 ± 3,667; CES: $3,022 ± 4,679; P = 0.020) in the first year. No difference was found in the second year. DISCUSSION: A short-term difference was observed in costs occurring in the first postoperative year. Cost of treatments was similar between patients apart from PT and bladder management.
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Síndrome da Cauda Equina , Descompressão Cirúrgica , Humanos , Síndrome da Cauda Equina/cirurgia , Síndrome da Cauda Equina/economia , Masculino , Pessoa de Meia-Idade , Feminino , Descompressão Cirúrgica/economia , Idoso , Adulto , Efeitos Psicossociais da Doença , Estenose Espinal/cirurgia , Estenose Espinal/economia , Estudos de Coortes , Custos de Cuidados de Saúde , Deslocamento do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/economia , Vértebras Lombares/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: As total knee arthroplasty (TKA) further transitions toward an outpatient procedure, it becomes important to identify the resource utilization after TKAs at different outpatient facilities. The objective of this study was to determine the 90-day cost of patients who underwent TKAs at an ambulatory surgical center (ASC) or a hospital outpatient department (HOPD). METHODS: An observational cohort study was conducted using the Marketscan database with patients who had a TKA at an ASC or HOPD between January 1st, 2019, and October 2nd, 2021. The primary outcome was cost in a 90-day period (including the day of surgery), with inpatient admissions and ED visits as secondary outcomes. Multivariable regression analyses were conducted, adjusting for patient characteristics. RESULTS: The study population consisted of 47,261 patients with 7,874 ASC patients and 39,387 HOPD patients. 90-day costs for ASC patients were lower compared with HOPD patients ($35,634 ± 19,030 vs. $38,096 ± 24,389, P < 0.001). 90-day inpatient admission rates were lower for ASC than HOPD patients (2.5% vs. 4.8%, P < 0.001). 90-day ED visits for ASC patients were lesser compared with HOPD patients (8.9% vs. 12.7%, P < 0.001). CONCLUSION: Patients with TKAs at an ASC had an overall lower cost, inpatient admissions, and ED visits over a 90-day period compared with HOPD patients. Future consideration for which outpatient facilities patients have their TKA at is necessary as TKAs shift toward bundle payments and outpatient procedures.
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The canine anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibody is a potential therapeutic option for treating canine arthritis. The current treatments for arthritis in dogs have limitations due to side effects, emphasizing the need for safer and more effective therapies. The crystal structure of canine TNF-α (cTNF-α) was successfully determined at a resolution of 1.85 Å, and the protein was shown to assemble as a trimer, with high similarity to the functional quaternary structure of human TNF-α (hTNF-α). Adalimumab (Humira), a known TNF-α inhibitor, effectively targets and neutralizes TNF-α to reduce inflammation and has been used to manage autoimmune conditions such as rheumatoid arthritis. By comparing the structure of cTNF-α with the complex structure of hTNF-α and adalimumab-Fab, the epitope of adalimumab on cTNF-α was identified. The significant structural similarities of epitopes in cTNF-α and hTNF-α indicate the potential of using adalimumab to target cTNF-α. Therefore, a canine/human chimeric antibody, Humivet-R1, was created by grafting the variable domain of adalimumab onto a canine antibody framework derived from ranevetmab. Humivet-R1 exhibits potent neutralizing ability (IC50 = 0.05 nM) and high binding affinity (EC50 = 0.416 nM) to cTNF-α, comparable to that of adalimumab for both hTNF-α and cTNF-α. These results strongly suggest that Humivet-R1 has the potential to provide effective treatment for canine arthritis with reduced side effects. Here, we propose a structure-guided antibody design for the use of a chimeric antibody to treat canine inflammatory disease. Our successful development strategy can speed up therapeutic antibody discovery for animals and has the potential to revolutionize veterinary medicine.
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Artrite Reumatoide , Fator de Necrose Tumoral alfa , Cães , Animais , Humanos , Adalimumab/farmacologia , Adalimumab/uso terapêutico , Anticorpos Monoclonais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologiaRESUMO
Background: Treatment strategies for meniscal tears range from nonoperative management to surgical intervention. However, national trends in cost-related outcomes and patient factors related to the failure of nonoperative management remain poorly understood. Purpose: To describe the costs associated with nonoperative versus operative management of meniscal tears in the 2 years after diagnosis and examine the relationship between patient characteristics and timing of surgery. Study Design: Cross-sectional study; Level of evidence, 3. Methods: This study was conducted using the MarketScan databases. Patients diagnosed with a meniscal tear without concomitant knee osteoarthritis between January 1 and December 31, 2017, were included. The primary outcome was the total cost of meniscal tear-related procedures-including insurance deductibles, coinsurance, and net insurance payments-in the 2 years after diagnosis. Procedures included were as follows: (1) surgery-including meniscectomy or meniscal repair; (2) physical therapy; (3) medication-including nonsteroidal anti-inflammatories, opioids, and acetaminophen; (4) intra-articular injections-including professional fee, hyaluronic acid, and corticosteroids; (5) imaging; and (6) clinic visits to orthopaedic specialists. Patients were grouped as having undergone early surgery (ES) (≤3 months of diagnosis), late surgery (LS) (>3 months after diagnosis), or no surgery (NS). Multivariate logistic regression was performed to determine the likelihood of undergoing surgery early and failing nonoperative treatment. Results: The study population included 29,924 patients with a mean age of 43.9 ± 12.9 years (ES: n = 9507 (31.8%); LS: n = 2021 (6.8%); NS: n = 18,396 (61.5%)). Complex (36.6%) and medial (58.8%) meniscal tears were the most common type and location of injuries, respectively. The mean cost of management per patient was $3835 ± $4795. Costs were lower in the NS group ($1905 ± $3175) compared with the ES group ($6759 ± $5155), while the highest costs were observed in the LS group ($7649 ± $5913) (P < .001). Patients who were men, >40 years, and with a bucket-handle or lateral meniscal tear were more likely to undergo surgery early. Patients who were men, <30 years, and with a complex tear or tear to the lateral meniscus were more likely to fail nonoperative management. Conclusion: Nonoperative management had the lowest cost burden and should be recommended for patients with appropriate indications. However, if surgery is necessary, it should be performed earlier.
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INTRODUCTION: The function of the vocal folds (VFs) is determined by the phenotype, abundance, and distribution of differentiated cells within specific microenvironments. Identifying this histologic framework is crucial in understanding laryngeal disease. A paucity of studies investigating VF cellular heterogeneity has been undertaken. Here, we examined the cellular landscape of human VFs by utilizing single-nuclei RNA-sequencing. METHODS: Normal true VF tissue was excised from five patients undergoing pitch elevation surgery. Tissue was snap frozen in liquid nitrogen and subjected to cellular digestion and nuclear extraction. Nuclei were processed for single-nucleus sequencing using the 10X Genomics Chromium platform. Sequencing reads were assembled using cellranger and analyzed with the scanpy package in python. RESULTS: RNA sequencing revealed 18 global cell clusters. While many were of epithelial origin, expected cell types, such as fibroblasts, immune cells, muscle cells, and endothelial cells were present. Subcluster analysis defined unique epithelial, immune, and fibroblast subpopulations. CONCLUSION: This study evaluated the cellular heterogeneity of normal human VFs by utilizing single-nuclei RNA-sequencing. With further confirmation through additional spatial sequencing and microscopic imaging, a novel cellular map of the VFs may provide insight into new cellular targets for VF disease. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3193-3200, 2024.
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Análise de Sequência de RNA , Prega Vocal , Humanos , Prega Vocal/patologia , Análise de Sequência de RNA/métodos , Masculino , Núcleo Celular/genética , Análise de Célula Única/métodos , Pessoa de Meia-Idade , FemininoRESUMO
The induction of tissue-specific vessels in in vitro living tissue systems remains challenging. Here, we directly differentiated human pluripotent stem cells into CD32b+ putative liver sinusoidal progenitors (iLSEP) by dictating developmental pathways. By devising an inverted multilayered air-liquid interface (IMALI) culture, hepatic endoderm, septum mesenchyme, arterial and sinusoidal quadruple progenitors self-organized to generate and sustain hepatocyte-like cells neighbored by divergent endothelial subsets composed of CD32blowCD31high, LYVE1+STAB1+CD32bhighCD31lowTHBD-vWF-, and LYVE1-THBD+vWF+ cells. Wnt2 mediated sinusoidal-to-hepatic intercellular crosstalk potentiates hepatocyte differentiation and branched endothelial network formation. Intravital imaging revealed iLSEP developed fully patent human vessels with functional sinusoid-like features. Organoid-derived hepatocyte- and sinusoid-derived coagulation factors enabled correction of in vitro clotting time with Factor V, VIII, IX, and XI deficient patients' plasma and rescued the severe bleeding phenotype in hemophilia A mice upon transplantation. Advanced organoid vascularization technology allows for interrogating key insights governing organ-specific vessel development, paving the way for coagulation disorder therapeutics.
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Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1-2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome c release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant N-Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway.
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Autonomic parasympathetic neurons (parasymNs) control unconscious body responses, including "rest-and-digest." ParasymN innervation is important for organ development, and parasymN dysfunction is a hallmark of autonomic neuropathy. However, parasymN function and dysfunction in humans are vastly understudied due to the lack of a model system. Human pluripotent stem cell (hPSC)-derived neurons can fill this void as a versatile platform. Here, we developed a differentiation paradigm detailing the derivation of functional human parasymNs from Schwann cell progenitors. We employ these neurons (1) to assess human autonomic nervous system (ANS) development, (2) to model neuropathy in the genetic disorder familial dysautonomia (FD), (3) to show parasymN dysfunction during SARS-CoV-2 infection, (4) to model the autoimmune disease Sjögren's syndrome (SS), and (5) to show that parasymNs innervate white adipocytes (WATs) during development and promote WAT maturation. Our model system could become instrumental for future disease modeling and drug discovery studies, as well as for human developmental studies.
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Diferenciação Celular , Disautonomia Familiar , Células-Tronco Pluripotentes , Humanos , Células-Tronco Pluripotentes/citologia , Disautonomia Familiar/patologia , Neurônios , Síndrome de Sjogren/patologia , COVID-19/virologia , COVID-19/patologia , Animais , Sistema Nervoso Parassimpático , Células de Schwann , Camundongos , SARS-CoV-2/fisiologiaRESUMO
To investigate the co-development of vasculature, mesenchyme, and epithelium crucial for organogenesis and the acquisition of organ-specific characteristics, we constructed a human pluripotent stem cell-derived organoid system comprising lung or intestinal epithelium surrounded by organotypic mesenchyme and vasculature. We demonstrated the pivotal role of co-differentiating mesoderm and endoderm via precise BMP regulation in generating multilineage organoids and gut tube patterning. Single-cell RNA-seq analysis revealed organ specificity in endothelium and mesenchyme, and uncovered key ligands driving endothelial specification in the lung (e.g., WNT2B and Semaphorins) or intestine (e.g., GDF15). Upon transplantation under the kidney capsule in mice, these organoids further matured and developed perfusable human-specific sub-epithelial capillaries. Additionally, our model recapitulated the abnormal endothelial-epithelial crosstalk in patients with FOXF1 deletion or mutations. Multilineage organoids provide a unique platform to study developmental cues guiding endothelial and mesenchymal cell fate determination, and investigate intricate cell-cell communications in human organogenesis and disease. Highlights: BMP signaling fine-tunes the co-differentiation of mesoderm and endoderm.The cellular composition in multilineage organoids resembles that of human fetal organs.Mesenchyme and endothelium co-developed within the organoids adopt organ-specific characteristics.Multilineage organoids recapitulate abnormal endothelial-epithelial crosstalk in FOXF1-associated disorders.
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Purpose: To describe the different types of arthroscopic procedures that patients undergo in the year prior to total knee arthroplasty (TKA), reveal the cost associated with these procedures, and understand the relationship between preoperative arthroscopy and clinical outcomes after TKA. Methods: An observational cohort study was conducted using the IBM Watson Health MarketScan databases. Patients with knee osteoarthritis who underwent unilateral isolated primary TKA between January 1, 2018, and September 30, 2019, were included. Knee arthroscopic procedures performed in the 1-year period before a primary TKA was identified. The primary outcomes of interest were cost of these procedures and the risk of 90-day postoperative complications. Results: In total, 2,904 patients, representing 5.2% of the analyzed cohort, underwent arthroscopic procedures in the year prior to TKA. The most common procedure and diagnosis were meniscectomy and meniscal tear, respectively, with procedures performed an average of 7.2 ± 3.0 months before TKA. Average per patient costs were $9,716 ± $5,500 in the highest payment quartile vs $1,789 ± 636 in the lowest payment quartile. Patients with a history of arthroscopy were more likely to develop postoperative stiffness (P = .001), while no difference was found in the risk of 90-day periprosthetic joint infection (PJI). Conclusions: Of the patients, 5.2% underwent knee arthroscopy in the year prior to TKA. While no association was seen with PJI risk, the costs associated with these procedures are high and may increase the overall cost of management of knee osteoarthritis. Level of Evidence: Level III, retrospective comparative study.