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1.
Cell ; 173(3): 792-803.e19, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29656897

RESUMO

Microscopy is a central method in life sciences. Many popular methods, such as antibody labeling, are used to add physical fluorescent labels to specific cellular constituents. However, these approaches have significant drawbacks, including inconsistency; limitations in the number of simultaneous labels because of spectral overlap; and necessary perturbations of the experiment, such as fixing the cells, to generate the measurement. Here, we show that a computational machine-learning approach, which we call "in silico labeling" (ISL), reliably predicts some fluorescent labels from transmitted-light images of unlabeled fixed or live biological samples. ISL predicts a range of labels, such as those for nuclei, cell type (e.g., neural), and cell state (e.g., cell death). Because prediction happens in silico, the method is consistent, is not limited by spectral overlap, and does not disturb the experiment. ISL generates biological measurements that would otherwise be problematic or impossible to acquire.


Assuntos
Corantes Fluorescentes/química , Processamento de Imagem Assistida por Computador/métodos , Microscopia de Fluorescência/métodos , Neurônios Motores/citologia , Algoritmos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Córtex Cerebral/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Aprendizado de Máquina , Redes Neurais de Computação , Neurociências , Ratos , Software , Células-Tronco/citologia
2.
Mol Cell ; 70(2): 211-227.e8, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29656925

RESUMO

Flux through kinase and ubiquitin-driven signaling systems depends on the modification kinetics, stoichiometry, primary site specificity, and target abundance within the pathway, yet we rarely understand these parameters and their spatial organization within cells. Here we develop temporal digital snapshots of ubiquitin signaling on the mitochondrial outer membrane in embryonic stem cell-derived neurons, and we model HeLa cell systems upon activation of the PINK1 kinase and PARKIN ubiquitin ligase by proteomic counting of ubiquitylation and phosphorylation events. We define the kinetics and site specificity of PARKIN-dependent target ubiquitylation, and we demonstrate the power of this approach to quantify pathway modulators and to mechanistically define the role of PARKIN UBL phosphorylation in pathway activation in induced neurons. Finally, through modulation of pS65-Ub on mitochondria, we demonstrate that Ub hyper-phosphorylation is inhibitory to mitophagy receptor recruitment, indicating that pS65-Ub stoichiometry in vivo is optimized to coordinate PARKIN recruitment via pS65-Ub and mitophagy receptors via unphosphorylated chains.


Assuntos
Células-Tronco Embrionárias Humanas/enzimologia , Membranas Mitocondriais/enzimologia , Células-Tronco Neurais/enzimologia , Neurogênese , Neurônios/enzimologia , Proteômica/métodos , Ubiquitina-Proteína Ligases/metabolismo , Ativação Enzimática , Células HeLa , Humanos , Cinética , Mitofagia , Fenótipo , Fosforilação , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Canal de Ânion 1 Dependente de Voltagem/genética , Canal de Ânion 1 Dependente de Voltagem/metabolismo
3.
J Arthroplasty ; 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38838962

RESUMO

BACKGROUND: Total hip arthroplasty (THA) is a common procedure that requires consideration of preexisting comorbidities. Factor V Leiden (FVL), an inherited thrombophilia, is one such condition that predisposes patients to venous thromboembolism (VTE, deep vein thrombosis, and pulmonary embolism). The present study aimed to characterize the risks associated with FVL patients undergoing THA and evaluate the effect of VTE chemoprophylactic agents on these risks. METHODS: A total of 544,022 adult patients who underwent primary THA for osteoarthritis indications between 2010 and October 2021 were identified in an administrative claims database. Of these, FVL was identified in 1,138 (0.21%). Patients who had and did not have FVL were matched at a 1:4 ratio (1,131 with FVL and 4,519 without FVL) based on age, sex, and Elixhauser comorbidity index. Univariable and multivariable analyses were assessed for 90-day complications. Implant survival at 5 years was assessed and compared with log-rank tests. The relative use of different chemoprophylactic agents, including aspirin, warfarin, heparin, or direct oral anticoagulant (DOAC), was assessed. Bleeding events and VTE were compared for those prescribed either aspirin or warfarin, heparin, or DOAC. A Bonferroni correction was applied. RESULTS: On multivariable analysis, FVL patients were found to have increased odds of 90-day deep vein thrombosis (odds ratio (OR) = 9.20), pulmonary embolism (OR = 6.89), and aggregated severe and all adverse events (OR = 4.74 and 1.98, respectively), but not elevated risk of other perioperative adverse events or 5-year reoperations. More potent chemoprophylactic agents (warfarin, heparin, DOAC) reduced, but did not completely eliminate, the increased VTE risks (without increasing bleeding events). CONCLUSIONS: This study quantified the significantly elevated VTE risk associated with FVL patients undergoing THA. The lack of difference in other specific adverse events and 5-year reoperations is reassuring. Clearly, chemoprophylactic agents are important in this population and may need further attention.

4.
J Arthroplasty ; 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38462141

RESUMO

BACKGROUND: Von Willebrand disease (VWD) is the most common congenital bleeding disorder. This autosomal dominant condition arises from quantitative or qualitative defects of Von Willebrand factor. To our knowledge, this study leveraged a national database to characterize the largest VWD cohort of total hip arthroplasty (THA) patients to date, assessing 90-day postoperative adverse events and 5-year revision-free survival. METHODS: Adult patients who underwent primary THA for osteoarthritis were identified from January 2010 to October 2021 in a nationwide database. Patients who had and did not have VWD were matched (4:1) on age, sex, and Elixhauser Comorbidity Index and compared with multivariable logistic regression. Patients were then categorized based upon venous thromboembolism (VTE) chemoprophylaxis prescription patterns to compare bleeding and thrombotic adverse events. RESULTS: Of 544,851 THA patients, VWD was identified in 309 patients (0.06%). The matched cohorts contained 1,221 patients who did not have VWD and 306 patients who have VWD. On multivariable analysis, VWD patients had increased odds of 90-day VTE (odds ratio [OR] = 1.86) and hematoma (OR = 3.40) (P < .05 for all). No difference in 5-year revision-free survival was found. The VWD patients receiving aspirin or no prescriptions had greater odds of VTE (OR = 2.39, P = .048). Those on other chemoprophylaxis agents had greater odds of hematoma (OR = 4.84, P = .006). CONCLUSIONS: Patients with VWD undergoing THA had increased odds of 90-day VTE if using aspirin or no prescriptions, or hematoma if using other chemoprophylaxis. There is a delicate balancing act of clotting versus bleeding that must be considered in managing such patients, but it was reassuring that no difference in overall 5-year revision-free survival was found.

5.
Cell ; 132(4): 549-52, 2008 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-18295572

RESUMO

Much of the attention focused on stem cells relates to their use in cell replacement therapy; however, stem cells may also transform the way in which therapeutics are discovered and validated.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Células-Tronco Embrionárias/citologia , Animais , Técnicas de Cultura de Células , Diferenciação Celular , Camundongos
6.
J Arthroplasty ; 38(3): 525-529, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36272511

RESUMO

BACKGROUND: Many previous studies of total hip arthroplasty (THA) have focused on adverse events occurring within 30 days of surgery. Studies examining 90-day postoperative adverse events have typically not focused on the timing of adverse events within that period. The current study evaluated the rate and timing of adverse events within 90 days of THA. METHODS: Adult THA patients between 2010 and 2020 Q3 were identified from a large administrative dataset. Rates and timing of 90-day adverse events were determined. The median, interquartile range, and middle 80% were calculated based on the time of diagnosis for each adverse event. These were also dichotomized as occurring before or after 30 days and predictive factors for later adverse events were determined. RESULTS: Overall, 81,158 adverse events were noted, of which 56,500 (69.0%) were diagnosed within 30 days of surgery and 25,355 (31.0%) were diagnosed 31-90 days after surgery. The proportion of adverse events occurring 31-90 days after surgery ranged from 6% (transfusion) to 45% (wound dehiscence). Patients experiencing a later adverse event were more likely to be women and to have higher Elixhauser Comorbidity Index (ECI) scores. CONCLUSION: Almost one-third of adverse events following THA were diagnosed between postoperative days 31 and 90, highlighting the importance of looking beyond 30 days when estimating patients' risk of postoperative adverse events. These data may inform future research, patient counseling, and prevention strategies.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Adulto , Humanos , Feminino , Masculino , Artroplastia de Quadril/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/diagnóstico , Transfusão de Sangue , Bases de Dados Factuais , Artroplastia do Joelho/efeitos adversos , Fatores de Risco , Estudos Retrospectivos
7.
J Arthroplasty ; 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-37952742

RESUMO

BACKGROUND: Marfan syndrome is a rare inherited connective tissue disease, which may be present in patients who have advanced hip pathologies that may require total hip arthroplasty (THA). The postoperative course of patients who have Marfan syndrome following THA has not yet been defined. METHODS: Adult patients who have and do not have Marfan syndrome and underwent THA were identified in a national database. Patients diagnosed who had infection, trauma, or neoplasms within the 90 days prior to surgery were excluded. Those who have versus those who did not have Marfan syndrome were matched 1:10 based on age, sex, and a comorbidity index. After matching, 144 patients who have Marfan syndrome and 1,440 who do not have Marfan syndrome were identified. The 90-day postoperative adverse events and 5-year revisions were assessed and compared with multivariable analyses and log rank tests, respectively. RESULTS: Multivariable analyses demonstrated that Marfan syndrome was independently associated with greater odds of 90-day adverse events: venous thromboembolic events (odds ratio [OR]: 2.9, P = .001), cardiac events (OR: 4.5, P = .034), pneumonia (OR: 3.5, P < .001), and urinary tract infections (OR: 5.2, P < .001). There was no significant difference in 5-year rates of revision. CONCLUSIONS: Following THA, Marfan syndrome was independently associated with greater rates of several 90-day adverse events, but not higher 5-year rates of revision. The identified at-risk adverse events may help guide surgeons to improve perioperative care pathways, while having confidence regarding joint survival of THA in this rare disease population.

8.
J Arthroplasty ; 38(11): 2259-2263, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37279847

RESUMO

BACKGROUND: Total knee arthroplasty (TKA) is commonly considered to address symptomatically limiting knee osteoarthritis. With increasing utilization, understanding the variability and related drivers may help the healthcare system optimize delivery to the large numbers of patient to whom it is offered. METHODS: A total of 1,066,327 TKA patients who underwent primary TKA were isolated from a 2010 to 2021 PearlDiver national dataset. Exclusion criteria included patients less than 18 years old and traumatic, infectious, or oncologic indications. Overall, 90-day reimbursements and variables associated with the patient, surgical procedure, region, and perioperative period were abstracted. Multivariable linear regressions were performed to determine independent drivers of reimbursement. RESULTS: The 90-day postoperative reimbursements had an average (standard deviation) of $11,212.99 ($15,000.62), a median (interquartile range) of $4,472.00 ($13,101.00), and a total of $11,946,962,912. Variables independently associated with the greatest increase in overall 90-day reimbursement were related to admission (in-patient index-procedure [+$5,695.26] or hospital readmission [+$18,495.03]). Further drivers were region (Midwest +$8,826.21, West +$4,578.55, South +$3,709.40; relative to Northeast), insurance (commercial +$4,492.34, Medicaid +$1,187.65; relative to Medicare), postoperative emergency department visits (+$3,574.57), postoperative adverse events (+$1,309.35), (P < .0001 for each). CONCLUSION: The current study assessed over a million TKA patients and found large variations in reimbursement/cost. The largest increases in reimbursement were associated with admission (readmission or index procedure). This was followed by region, insurance, and other postoperative events. These results underscore the necessity to balance performing out-patient surgeries in appropriate patients versus the risk of readmissions and defined other areas for cost containment strategies.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Humanos , Estados Unidos , Idoso , Adolescente , Artroplastia do Joelho/efeitos adversos , Medicare , Medicaid , Readmissão do Paciente , Artroplastia de Quadril/efeitos adversos
9.
J Arthroplasty ; 38(5): 862-867, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36529197

RESUMO

BACKGROUND: Computer navigation is an increasingly utilized technology that is considered with total hip arthroplasty (THA). However, the evidence to support this practice is mixed. The current study leveraged a large national administrative database to compare 90-day adverse events as well as 5-year all-cause revision and dislocation rates following THA performed with and without imageless navigation. METHODS: From 2010 to 2020, a large national database was queried for THA cases performed for osteoarthritis. Cases with or without imageless navigation were matched at 1:4 based on age, sex, and Elixhauser Comorbidity Index (ECI) score. Ninety-day adverse events were assessed and compared with multivariate analyses. Five-year incidence of revision and dislocation were also assessed between cohorts. RESULTS: Use of THA imageless navigation increased from 2010 (2.5% of cases) to 2020 (5.5% of cases; P < .001). After matching, 11,990 THA patients with navigation and 47,948 without navigation were identified. Overall, 90-day adverse events were observed in 7.0% of the population. Multivariate analysis controlling for age, sex, and ECI demonstrated a difference in only one 90-day adverse event; wound dehiscence, which had higher odds in the navigation group (odds ratio, 1.60, P < .001). At 5 years, revisions for the navigated group were higher (4.4 versus 3.6%: P = .006), while dislocations were not significantly different. CONCLUSION: THA imageless navigation was not found to be associated with improved 90-day postoperative adverse events or differences in the 5-year rates of revision or dislocation. The current data were unable to identify clear advantages of this evolving technology for primary THA.


Assuntos
Artroplastia de Quadril , Luxações Articulares , Osteoartrite , Humanos , Artroplastia de Quadril/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Luxações Articulares/etiologia , Razão de Chances , Estudos Retrospectivos
10.
J Arthroplasty ; 38(11): 2361-2365, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37196730

RESUMO

BACKGROUND: Following total hip arthroplasty (THA), readmissions and emergency department (ED) visits have been studied. Urgent care utilization is not well-characterized and may represent an overlooked avenue to facilitate lesser acuity patient needs. METHODS: Primary THAs performed for osteoarthritis indications were identified from 2010 to April of 2021 from a large national database. The incidence and timing of 90-day postoperative ED and urgent care visits were determined. Univariable and multivariable analyses assessed factors associated with urgent care relative to ED utilization. Reasons and acuity of diagnoses for these visits were determined. For 213,189 THA patients, 90-day ED visits were identified for 37,692 (17.7%) and urgent care visits for 2,083 (1.0%). The greatest incidence of both ED and urgent care visits were in the first two postoperative weeks. RESULTS: Independent predictors of urgent care utilization relative to ED utilization were: procedures being performed in the Northeast or South, insurance plan being Commercial, women, and lesser comorbidity burden (P < .0001). Reason for visits to the ED was directly related to the surgical site for 25.6% but for urgent care were just 4.8% (P < .0001). Reasons for visits to the ED were classified as low-acuity for 57.4% and for urgent care 96.9% (P < .0001). CONCLUSION: Following THA, patients may need urgent evaluation. While many issues can be addressed through the office, urgent care visits may represent a viable and underused resource relative to the ED for a large percentage of patients who have lower acuity diagnoses.


Assuntos
Artroplastia de Quadril , Osteoartrite , Humanos , Feminino , Readmissão do Paciente , Assistência Ambulatorial , Comorbidade , Serviço Hospitalar de Emergência , Estudos Retrospectivos
11.
Reprod Biomed Online ; 45(1): 69-80, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35570176

RESUMO

Patients undergoing IVF experience high levels of IVF-related state anxiety. Non-pharmacological interventions such as acupuncture may provide support, but its effect on IVF-related anxiety is unclear. This was a systematic review and meta-analysis to examine the effect of acupuncture on IVF-related state anxiety. The primary outcome was state anxiety after embryo transfer or oocyte retrieval as assessed by the State-Trait Anxiety Inventory, Hamilton Anxiety Scale, visual analogue scale or Standard Form 36. Eight trials with 2253 participants were reviewed, and 1785 participants completed an anxiety assessment. Using the random effects model, the meta-analysis found small but significant effects on state anxiety with acupuncture versus any control (standardized mean difference -0.21, 95% confidence interval -0.39 to -0.04, representing very low certainty evidence). Evidence was limited by the moderate number of included studies of an intermediate median sample size (n = 191). There was also a high risk of performance bias and substantial heterogeneity across trials. Acupuncture is a drug-free and safe treatment that may benefit those who are burdened with IVF-related anxiety, but more investigation is needed for confirmation.


Assuntos
Terapia por Acupuntura , Ansiedade/terapia , Transferência Embrionária , Fertilização in vitro , Humanos , Recuperação de Oócitos
12.
J Arthroplasty ; 37(9): 1822-1826, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35447277

RESUMO

BACKGROUND: Patients with postpolio syndrome (PPS) may be afflicted by hip arthritis in either the paralytic or contralateral limb. Total hip arthroplasty (THA) may be considered in these patients. However, short-term and long-term outcomes following THA in PPS patients remain poorly characterized. METHODS: The PearlDiver MHip administrative database was queried for patients undergoing THA. Patients with a diagnosis of PPS were matched 1:4 with control patients on the basis of age, gender, and comorbidity burden. Incidence of postoperative adverse events and readmission in the 90 days following surgery and occurrence of revision arthroplasty in the five-year postoperative period were assessed between the two cohorts. RESULTS: In total, 1,519 PPS patients were matched to 6,076 control patients without PPS. After controlling for patient demographics and comorbidities, PPS patients demonstrated higher 90-day odds of urinary tract infection (odds ratio [OR] = 1.34, P = .016), pneumonia (OR = 2.07, P < .001), prosthetic dislocation (OR = 1.63, P = .018), and readmission (OR = 1.49, P = .002). Five years following surgery, 94.7% of the PPS cohort remained revision-free, compared to 96.7% of the control cohort (P = .001). CONCLUSION: Compared to patients without PPS, patients with PPS demonstrated a higher incidence of urinary tract infection, pneumonia, prosthetic dislocation, and hospital readmission. In addition, five-year incidence of revision arthroplasty was significantly higher among the PPS cohort. In light of these increased risks, special considerations should be made in both preoperative planning and postoperative surveillance of PPS patients undergoing THA. LEVEL OF EVIDENCE: Level III.


Assuntos
Artroplastia de Quadril , Luxações Articulares , Artroplastia de Quadril/efeitos adversos , Estudos de Coortes , Humanos , Luxações Articulares/etiologia , Razão de Chances , Readmissão do Paciente , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco
13.
J Arthroplasty ; 37(7): 1333-1337, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35257821

RESUMO

BACKGROUND: Patients with classic hemophilia can develop joint hemarthroses, degenerative changes, and eventually require total hip arthroplasty (THA). Little data exist concerning THA outcomes in this population, and evidence-based guidelines specifically addressing venous thromboembolism (VTE) prophylaxis in this population are lacking. METHODS: A retrospective study was conducted using the 2010-2020 PearlDiver MHip database. Patients undergoing primary THA were identified, and those with classic hemophilia were matched 1:10 with non-hemophilia patients based on age, gender, and Elixhauser Comorbidity Index. Ninety-day serious adverse events, minor adverse events, and any adverse events were compared with multivariate analysis. Reoperation at 5 years was assessed using Kaplan-Meier analysis. RESULTS: Five hundred eighteen classic hemophilia THA patients were matched 1:10 with 5,193 non-hemophilia patients. On multivariate analysis, those with classic hemophilia had greater odds of aggregated any adverse events (odds ratio [OR] 1.76), serious adverse events (OR 2.30), and minor adverse events (OR 1.52) (P < .001 for each). Patients with classic hemophilia had greater odds of bleeding issues (transfusion, OR 1.98; hematoma, OR 4.23; P < .001 for both), VTE (deep vein thrombosis, OR 2.67; pulmonary embolism, OR 4.01; P < .001 for both), and acute kidney injury (OR 1.63; P = .03). Five-year implant survival was lower in hemophilia patients (91.9%) relative to matched controls (95.3%; P = .009). CONCLUSION: Hemophilia patients undergoing THA had elevated risks of both 90-day bleeding complications (transfusion and hematoma) and VTE (deep vein thrombosis and pulmonary embolism) relative to matched controls. These findings emphasize the need to balance factor replacement and VTE prophylaxis. Although the 5-year implant survival was lower in hemophilia patients, this represented a difference of 3.4% at 5 years, suggesting that THA remains effective in this cohort.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Hemofilia A , Embolia Pulmonar , Tromboembolia Venosa , Trombose Venosa , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Hematoma , Hemofilia A/complicações , Hemofilia A/cirurgia , Humanos , Complicações Pós-Operatórias/etiologia , Embolia Pulmonar/etiologia , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Trombose Venosa/etiologia
14.
J Arthroplasty ; 37(3): 425-430, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34871749

RESUMO

BACKGROUND: Patients with hip and knee arthritis often undergo bilateral total hip arthroplasty (THA) and total knee arthroplasty (TKA) in a staged or simultaneous fashion. However, when staged, the incidence and factors associated with having both procedures performed by the same surgeon or different surgeon are not well studied. METHODS: All patients undergoing nonsimultaneous bilateral THA or TKA for osteoarthritis were abstracted from the 2010 to 2020 PearlDiver Mariner administrative database. The National Provider Identifier number was used to determine whether the same surgeon performed both surgeries. Demographics, comorbidities, and 90-day complications after the first joint replacement were assessed as possible independent predictors of utilizing a different surgeon for the contralateral joint. RESULTS: Of 87,593 staged bilateral THAs, the same surgeon performed 40,707 (46.5%) arthroplasties. Of 147,938 staged bilateral TKAs, the same surgeon performed 77,072 (52.1%) arthroplasties. Notably, older cohorts of patients had independent, stepwise, and significantly greater odds of changing surgeons for the contralateral THA and TKA. Those patients who were insured by Medicare and Medicaid had significantly lower odds of changing surgeons. For both THA and TKA, surgical and implant-related adverse events (surgical site infection/periprosthetic joint infection, periprosthetic fracture, dislocation, manipulation) carried the greatest odds of undergoing the contralateral replacement with a different surgeon. CONCLUSION: Patients covered by Medicaid and sicker patients were significancy less likely to switch surgeons for their contralateral THA or TKA. Additionally, patients experiencing a surgery-related adverse event within 90 days of their first THA or TKA had significantly, increased odds of switching surgeons for their subsequent TJA.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Cirurgiões , Idoso , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Humanos , Medicaid , Medicare , Estudos Retrospectivos , Fatores de Risco , Estados Unidos
15.
BMC Neurol ; 21(1): 201, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006233

RESUMO

BACKGROUND: Characterization of prediagnostic Parkinson's Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting. METHODS: We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window. RESULTS: We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300 days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles. CONCLUSIONS: Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.


Assuntos
Doença de Parkinson/diagnóstico , Marcha/fisiologia , Análise da Marcha , Humanos , Aprendizado de Máquina , Estudos Retrospectivos , Medição de Risco , Tremor
16.
Proc Natl Acad Sci U S A ; 115(36): E8368-E8377, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30120125

RESUMO

Variations in a multitude of material microenvironmental properties have been observed across tissues in vivo, and these have profound effects on cell phenotype. Phenomenological experiments have suggested that certain of these features of the physical microenvironment, such as stiffness, could sensitize cells to other features; meanwhile, mechanistic studies have detailed a number of biophysical mechanisms for this sensing. However, the broad molecular consequences of these potentially complex and nonlinear interactions bridging from biophysical sensing to phenotype have not been systematically characterized, limiting the overall understanding and rational deployment of these biophysical cues. Here, we explore these interactions by employing a 3D cell culture system that allows for the independent control of culture substrate stiffness, stress relaxation, and adhesion ligand density to systematically explore the transcriptional programs affected by distinct combinations of biophysical parameters using RNA-seq. In mouse mesenchymal stem cells and human cortical neuron progenitors, we find dramatic coupling among these substrate properties, and that the relative contribution of each property to changes in gene expression varies with cell type. Motivated by the bioinformatic analysis, the stiffness of hydrogels encapsulating mouse mesenchymal stem cells was found to regulate the secretion of a wide range of cytokines, and to accordingly influence hematopoietic stem cell differentiation in a Transwell coculture model. These results give insights into how biophysical features are integrated by cells across distinct tissues and offer strategies to synthetic biologists and bioengineers for designing responses to a cell's biophysical environment.


Assuntos
Alginatos , Técnicas de Cultura de Células/métodos , Células-Tronco Hematopoéticas/metabolismo , Hidrogéis , Células-Tronco Mesenquimais/metabolismo , Nicho de Células-Tronco , Transcrição Gênica/efeitos dos fármacos , Alginatos/química , Alginatos/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Ácido Glucurônico/química , Ácido Glucurônico/farmacologia , Células-Tronco Hematopoéticas/citologia , Ácidos Hexurônicos/química , Ácidos Hexurônicos/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Células-Tronco Mesenquimais/citologia , Camundongos
17.
BMC Biol ; 18(1): 127, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938453

RESUMO

BACKGROUND: Understanding the genetic modifiers of neurodegenerative diseases can provide insight into the mechanisms underlying these disorders. Here, we examine the relationship between the motor neuron disease spinal muscular atrophy (SMA), which is caused by reduced levels of the survival of motor neuron (SMN) protein, and the actin-bundling protein Plastin 3 (PLS3). Increased PLS3 levels suppress symptoms in a subset of SMA patients and ameliorate defects in SMA disease models, but the functional connection between PLS3 and SMN is poorly understood. RESULTS: We provide immunohistochemical and biochemical evidence for large protein complexes localized in vertebrate motor neuron processes that contain PLS3, SMN, and members of the hnRNP F/H family of proteins. Using a Caenorhabditis elegans (C. elegans) SMA model, we determine that overexpression of PLS3 or loss of the C. elegans hnRNP F/H ortholog SYM-2 enhances endocytic function and ameliorates neuromuscular defects caused by decreased SMN-1 levels. Furthermore, either increasing PLS3 or decreasing SYM-2 levels suppresses defects in a C. elegans ALS model. CONCLUSIONS: We propose that hnRNP F/H act in the same protein complex as PLS3 and SMN and that the function of this complex is critical for endocytic pathways, suggesting that hnRNP F/H proteins could be potential targets for therapy development.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Glicoproteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Atrofia Muscular Espinal/genética , Proteínas de Ligação a RNA/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Animais , Animais Geneticamente Modificados/fisiologia , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Endocitose/genética , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo
18.
J Arthroplasty ; 36(10): 3534-3537, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34176692

RESUMO

BACKGROUND: People with cerebral palsy (CP) may be considered for total hip arthroplasty (THA). However, short- and long-term outcomes after THA in this population remain poorly characterized. METHODS: Data from patients undergoing THA were abstracted from the 2010-2018 PearlDiver Mariner administrative database. Those with CP were matched to those without CP based on demographic and comorbid factors (1:4 matching). Ninety-day incidence of postoperative complications and hospital readmission was identified and compared. Five-year implant survival (based on need for revision) was also assessed and compared. Perioperative adverse events were then compared using multivariate logistic regression to adjust for any potential residual differences in demographic and comorbid factors after matching. Implant survival over time was compared with Kaplan-Meier plots with a log-rank test. Significance was set at P < .05 for all comparisons. RESULTS: In total, 864 patients with CP were matched to 3448 patients without CP. After adjusting for differences in demographics and comorbidities, multivariate analyses demonstrated patients with CP had higher odds of urinary tract infection (odds ratio [OR] = 2.42, P = .007), pneumonia (OR = 3.77, P = .001), and periprosthetic fracture (OR = 2.55, P = .001). Rates of the other studied adverse events, including readmissions, were not significantly different between groups. At five years, 94.2% of the CP cohort and 95.2% of the non-CP cohort THAs remained unrevised (no difference by log rank, P = .195). CONCLUSION: Compared with patients without CP, patients with CP undergoing THA were found to have higher odds of perioperative urinary tract infection, pneumonia, and periprosthetic fracture but not other perioperative complications or difference in five-year implant survival.


Assuntos
Artroplastia de Quadril , Paralisia Cerebral , Artroplastia de Quadril/efeitos adversos , Paralisia Cerebral/complicações , Paralisia Cerebral/epidemiologia , Paralisia Cerebral/cirurgia , Humanos , Reoperação , Estudos Retrospectivos , Fatores de Risco
19.
Instr Course Lect ; 69: 25-34, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32017716

RESUMO

Acetabular implant revision is commonly performed during revision total hip arthroplasty (THA).1 With recent significant increase in the utilization of direct anterior approach for primary THA,2,3 many surgeons familiar with this approach are exploring the direct anterior for revision THA (r-THA) applications. This chapter will specifically address acetabular implant revision via direct anterior approach. The exposure techniques for the acetabulum are described elsewhere in this lecture series. Instead, attention to the mechanics and techniques of acetabular implant revision via direct anterior approach will be stressed.


Assuntos
Acetábulo , Artroplastia de Quadril , Prótese de Quadril , Humanos , Reoperação , Cirurgiões
20.
J Arthroplasty ; 35(11): 3188-3194, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32654940

RESUMO

BACKGROUND: Geriatric femoral neck fracture is a common injury for which hemiarthroplasty (HA) or total hip arthroplasty (THA) may be considered in select patients. As prior database studies comparing these have not used propensity matching, which is a robust statistical method of controlling for potentially confounding variables, unmatched and matched methodologies are contrasted in the present study. METHODS: Patients aged ≥70 years who underwent HA or THA for hip fractures were identified from the 2012-2015 National Surgical Quality Improvement database. Propensity score 1:1 matching was performed. Differences in rates of 30-day postoperative adverse outcomes were compared using multivariate logistic regression for unmatched and matched cohorts. RESULTS: In total, 15,558 patients (14,403 HA and 1155 THA) were evaluated. Although multivariate outcomes for the unmatched populations were different for blood transfusion, mortality, minor adverse events, major adverse events, and reoperation, multivariate outcomes for matched populations only differed for blood transfusion (odds ratio 0.6 for HA vs THA, P < .001). Of note, although readmissions were similar for the two groups, patients undergoing THA had a 5.4% greater rate of perioperative readmission due to dislocation. CONCLUSION: Geriatric patients undergoing HA and THA for hip fracture were compared with and without propensity matching. Once matching was performed, the only differences in outcomes between the two groups were a lower transfusion rate among the HA group and a greater readmission rate due to dislocation among the THA group. This suggests that either procedure can be safely considered if found to be advantageous from a longer-term outcome perspective. LEVEL OF EVIDENCE: Level III, retrospective comparative study.


Assuntos
Artroplastia de Quadril , Fraturas do Colo Femoral , Hemiartroplastia , Fraturas do Quadril , Idoso , Artroplastia de Quadril/efeitos adversos , Fraturas do Colo Femoral/epidemiologia , Fraturas do Colo Femoral/cirurgia , Hemiartroplastia/efeitos adversos , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/cirurgia , Humanos , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos
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