A Dimerization Function in the Intrinsically Disordered N-Terminal Region of Src.

The mode of regulation of Src kinases has been elucidated by crystallographic studies identifying conserved structured protein modules involved in an orderly set of intramolecular associations and ligand interactions. Despite these detailed insights, much of the complex behavior and diversity in the Src family remains unexplained. A key missing piece is the function of the unstructured N-terminal region. We report here the function of the N-terminal region in binding within a hydrophobic pocket in the kinase domain of a dimerization partner. Dimerization substantially enhances autophosphorylation and phosphorylation of selected substrates, and interfering with dimerization is disruptive to these functions. Dimerization and Y419 phosphorylation are codependent events creating a bistable switch. Given the versatility inherent in this intrinsically disordered region, its multisite phosphorylations, and its divergence within the family, the unique domain likely functions as a central signaling hub overseeing much of the activities and unique functions of Src family kinases

A Dimerization Function in the Intrinsically Disordered N-Terminal Region of Src

Summary: The mode of regulation of Src kinases has been elucidated by crystallographic studies identifying conserved structured protein modules involved in an orderly set of intramolecular associations and ligand interactions. Despite these detailed insights, much of the complex behavior and diversity in the Src family remains unexplained. A key missing piece is the function of the unstructured N-terminal region. We report here the function of the N-terminal region in binding within a hydrophobic pocket in the kinase domain of a dimerization partner. Dimerization substantially enhances autophosphorylation and phosphorylation of selected substrates, and interfering with dimerization is disruptive to these functions. Dimerization and Y419 phosphorylation are codependent events creating a bistable switch. Given the versatility inherent in this intrinsically disordered region, its multisite phosphorylations, and its divergence within the family, the unique domain likely functions as a central signaling hub overseeing much of the activities and unique functions of Src family kinases. : Spassov et al. report that Src exists in cells and functions as a dimer and that dimerization and autophosphorylation are codependent events. Through a comprehensive structure-function analysis, they show that the dimer is an asymmetric dimer held through the interaction of the myristoylated N-terminal unique domain of one partner with a hydrophobic pocket in the kinase domain of another. Keywords: Src, dimerization, dimer, unique domain, intrinsically disordered protein, tyrosine 416, tyrosine 419, myristoyl, kinase domai

Duloxetine for Postoperative Pain Control Following Knee or Hip Replacement: A Systematic Review and Meta-Analysis

BackgroundDuloxetine is a Food and Drug Administration-approved selective norepinephrine reuptake inhibitor for treating depression, anxiety, fibromyalgia, and neuropathic and chronic musculoskeletal pain. This meta-analysis aims to evaluate the efficacy of duloxetine in reducing pain and postoperative opioid use following lower extremity total joint arthroplasty.MethodsA literature search was performed, identifying randomized controlled trials investigating duloxetine for pain management after total hip and total knee arthroplasty. Data from the visual analog scale (VAS) for pain during movement and at rest were extracted for postoperative days (PODs) 1, 3, 7, and 14, as well as postoperative week 6 and postoperative month 3. Opioid use data were obtained at 24, 48 and 72 hours. All data were analyzed using inverse variance with random effects and presented as weighted mean difference.ResultsEight unique studies were identified and included, 7 of which were analyzed quantitatively. Duloxetine decreased postoperative opioid consumption at 48 and 72 hours. For VAS for pain at rest, significantly reduced pain was reported by duloxetine-treated patients at POD 3, POD 7, and postoperative week 6. For VAS for pain at movement, significantly reduced pain was reported by duloxetine-treated patients at POD1, POD 3, POD 7, POD 14, postoperative week 6, and postoperative month 3.ConclusionsDuloxetine appears to decrease postoperative pain and opioid consumption following total joint arthroplasty. However, definitive conclusions are limited by small sample size and study heterogeneity. While there is a need for follow-up studies to determine the optimal dose, duration, and patient population, strong preliminary data provide robust support for future large-scale efficacy studies

Prevalence of primary malignant tumours, rates of pathological fracture, and mortality in the setting of metastatic bone disease

Aims: The modern prevalence of primary tumours causing metastatic bone disease is ill-defined in the oncological literature. Therefore, the purpose of this study is to identify the prevalence of primary tumours in the setting of metastatic bone disease, as well as reported rates of pathological fracture, postoperative complications, 90-day mortality, and 360-day mortality for each primary tumour subtype. Methods: The Premier Healthcare Database was queried to identify all patients who were diagnosed with metastatic bone disease from January 2015 to December 2020. The prevalence of all primary tumour subtypes was tabulated. Rates of long bone pathological fracture, 90-day mortality, and 360-day mortality following surgical treatment of pathological fracture were assessed for each primary tumour subtype. Patient characteristics and postoperative outcomes were analyzed based upon whether patients had impending fractures treated prophylactically versus treated completed fractures. Results: In total, 407,893 unique patients with metastatic bone disease were identified. Of the 14 primary tumours assessed, metastatic bone disease most frequently originated from lung (24.8%), prostatic (19.4%), breast (19.3%), gastrointestinal (9.4%), and urological (6.5%) malignancies. The top five malignant tumours resulting in long bone pathological fracture were renal (5.8%), myeloma (3.4%), female reproductive (3.2%), lung (2.8%), and breast (2.7%). Following treatment of pathological fractures of long bones, 90-day mortality rates were greatest for lung (12.1%), central nervous system (10.5%), lymphoma (10.4%), gastrointestinal (10.1%), and non-renal urinary (10.0%) malignancies. Finally, our study demonstrates improved 90-day and 360-day survival in patients treated for impending pathological fracture compared to completed fracture, as well as significantly lower rates of deep vein thrombosis, pulmonary embolism, urinary tract infection, and blood transfusion. Conclusion: This study defines the contemporary characteristics of primary malignancies resulting in metastatic bone disease. These data should be considered by surgeons when prognosticating patient outcomes during treatment of their metastatic bone disease. Cite this article: Bone Jt Open 2023;4(6):424–431

Pyogenic spinal infections warrant a total spine MRI.

Study design: retrospective case series. Objective: the presenting clinical symptoms of spinal infections are often nonspecific and a delay in diagnosis can lead to adverse patient outcomes. The morbidity and mortality of patients with multifocal spinal infections is significantly higher compared to unifocal infections. The purpose of the current study was to analyse the risk factors for multifocal spinal infections. Methods: we conducted a retrospective review of all pyogenic non-tuberculous spinal infections treated surgically at a single tertiary care medical center from 2006-2020. The medical records, imaging studies, and laboratory data of 43 patients during this time period were reviewed and analysed after receiving Institutional Review Board approval. Univariate and multivariate analyses were performed to identify factors associated with a multifocal spinal infection. Results: 15 patients (35 %) had multifocal infections. In univariate analysis, there was a significant association with chronic kidney disease ( p = 0.040 ), gender ( p = 0.003 ), a white blood cell count ( p = 0.011 ), and cervical ( p < 0.001 ) or thoracic ( p < 0 .001) involvement. In multivariate analysis, both cervical and thoracic involvement remained statistically significant ( p = 0.001 and p < 0.001 , respectively). Conclusions: patients with infections in the thoracic or cervical region are more likely to have a multifocal infection. Multifocal pyogenic spinal infections remain a common entity and a total spine MRI should be performed to aid in prompt diagnosis

Duloxetine for Postoperative Pain Control Following Knee or Hip Replacement: A Systematic Review and Meta-Analysis

Background: Duloxetine is a Food and Drug Administration–approved selective norepinephrine reuptake inhibitor for treating depression, anxiety, fibromyalgia, and neuropathic and chronic musculoskeletal pain. This meta-analysis aims to evaluate the efficacy of duloxetine in reducing pain and postoperative opioid use following lower extremity total joint arthroplasty. Methods: A literature search was performed, identifying randomized controlled trials investigating duloxetine for pain management after total hip and total knee arthroplasty. Data from the visual analog scale (VAS) for pain during movement and at rest were extracted for postoperative days (PODs) 1, 3, 7, and 14, as well as postoperative week 6 and postoperative month 3. Opioid use data were obtained at 24, 48 and 72 hours. All data were analyzed using inverse variance with random effects and presented as weighted mean difference. Results: Eight unique studies were identified and included, 7 of which were analyzed quantitatively. Duloxetine decreased postoperative opioid consumption at 48 and 72 hours. For VAS for pain at rest, significantly reduced pain was reported by duloxetine-treated patients at POD 3, POD 7, and postoperative week 6. For VAS for pain at movement, significantly reduced pain was reported by duloxetine-treated patients at POD1, POD 3, POD 7, POD 14, postoperative week 6, and postoperative month 3. Conclusions: Duloxetine appears to decrease postoperative pain and opioid consumption following total joint arthroplasty. However, definitive conclusions are limited by small sample size and study heterogeneity. While there is a need for follow-up studies to determine the optimal dose, duration, and patient population, strong preliminary data provide robust support for future large-scale efficacy studies

Characteristics of Very Young Patients Undergoing Total Hip Arthroplasty: A Contemporary Assessment

Background: This study aims to compare indications, patient characteristics, hospital factors, and complication rates between total hip arthroplasty (THA) patients aged 30 years or younger and those older than 30 years using a large national database. Methods: The Premier Healthcare Database was utilized to identify primary THA patients from 2015 to 2021 who were aged ≤30 or >30 years. Patient demographics, hospital factors, and primary indications were compared for each cohort. Rates of complications and readmissions were assessed for each cohort by primary indication. Differences were assessed through univariate analysis. Results: Overall, 539,173 primary THA patients were identified (age ≤30: 1849; >30: 537,234). Compared to the >30 cohort, the ≤30 cohort was more likely to be male (56.5% vs 44.9%, P 30 cohort, they were osteoarthritis (77.0%), other arthritis (11.3%), and osteonecrosis (5.4%). Patients aged ≤30 years had lower rates of respiratory failure (0.16% vs 0.57%, P 30 years, but higher rates of wound dehiscence (0.59% vs 0.29%, P = .015) and transfusion (3.68% vs 2.21%, P < .001). There were no differences in 90-day readmission rates (P = .811) or 90-day in-hospital death (P = .173) between cohorts. Conclusions: Younger patients undergoing THA differed significantly in indication, patient characteristics, and hospital factors compared to the older population on univariate analysis. Despite differences in indications, the cohorts did not differ markedly with regard to complication rates in this study

Peripheral Nerve Block Utilization is Associated With Decreased Postoperative Opioid Consumption and Shorter Length of Stay Following Total Knee Arthroplasty

Background: This study aims to examine differences in postoperative complications and opioid consumption associated with perioperative peripheral nerve block (PNB) utilization during primary total knee arthroplasty (TKA). Methods: The Premier Healthcare Database was queried for adult patients who underwent primary, elective TKA from 2015 to 2020. Patients who received a femoral or adductor canal PNB were compared to patients who did not. PNB utilization was trended from 2015 to 2020. Univariate and multivariate regression analyses were performed to assess differences in the 90-day risk of postoperative complications between groups. The average inpatient opioid consumption in morphine milligram equivalents was assessed as a function of length of stay. Results: Overall, 609,991 patients were included. PNB utilization increased from 9.29% in 2015 to 30.3% in 2020. After controlling for confounders, the PNB cohort was more likely to have same-day discharge (adjusted odds ratio [aOR] 1.88) and had a decreased risk of periprosthetic joint infection (aOR 0.87), pulmonary embolism (aOR 0.81), and respiratory failure (aOR 0.78). However, there was an increased risk of seroma (aOR 1.75) and hematoma (aOR 1.22) associated with PNB utilization. Lower average overall opioid exposure was seen in the PNB cohort vs no-PNB cohort (82.1 ± 194.7 vs 89.4 ± 214.1 morphine milligram equivalents, P < .001). Conclusions: PNB utilization during primary TKA is associated with a shorter length of stay and decreased risk of multiple postoperative complications, as well as reduced postoperative opioid consumption. These data provide evidence in support of the safety and efficacy of this emerging practice. However, the clinical relevance of an increased risk of seroma and hematoma formation may warrant further investigation

An Updated Estimate of Total Hip and Total Knee Arthroplasty Inpatient Case Volume During the 2020 COVID-19 Pandemic in the United States

Background: Inpatient total hip arthroplasty (THA) and total knee arthroplasty (TKA) practices were dramatically affected in the United States in 2020 as elective surgeries were paused in response to the COVID-19 pandemic. This study sought to provide an updated estimate of inpatient total joint arthroplasty (TJA) case volumes in the United States in 2020. Methods: A retrospective cohort study was performed by identifying all adult patients who underwent primary, elective TJA from January 1st, 2017 to December 31st, 2020, using the National Inpatient Sample. Monthly and annual case volumes were reported with descriptive statistics. Baseline case volumes were established by taking the average number of monthly cases performed in 2017, 2018, and 2019. These monthly averages were compared to 2020 values. Results: From 2017 to 2019, the average case volume was 1,056,669 cases per year (41.0% THA, 59.0% TKA) and 88,055 cases per month. In 2020, 535,441 cases were identified (45.4% THA, 54.6% TKA), corresponding to a 49.3% reduction from the 2017-2019 annual average. Monthly cases decreased to 4515 in April during the “first wave” of COVID-19, corresponding to a 94.8% decrease from prior years. In June, cases rebounded to 55,520 before decreasing again in July to 50,100 during the “second wave” of COVID-19. During the “third wave,” COVID-19 cases decreased month-over-month from October through December (56.5% decrease). Conclusions: This updated estimate identified a 49.3% decrease in inpatient TJA cases in 2020 compared to prior years. This is similar to the 46.5-47.7% decrease in case volume previously reported