Mechanical compliance has been demonstrated to be a key determinant of cell behavior, directing processes such as spreading, migration, and differentiation. Durotaxis, directional migration from ...softer to more stiff regions of a substrate, has been observed for a variety of cell types. Recent stiffness mapping experiments have shown that local changes in tissue stiffness in disease are often accompanied by an altered ECM composition in vivo. However, the importance of ECM composition in durotaxis has not yet been explored. To address this question, we have developed and characterized a polyacrylamide hydrogel culture platform featuring highly tunable gradients in mechanical stiffness. This feature, together with the ability to control ECM composition, allows us to isolate the effects of mechanical and biological signals on cell migratory behavior. Using this system, we have tracked vascular smooth muscle cell migration in vitro and quantitatively analyzed differences in cell migration as a function of ECM composition. Our results show that vascular smooth muscle cells undergo durotaxis on mechanical gradients coated with fibronectin but not on those coated with laminin. These findings indicate that the composition of the adhesion ligand is a critical determinant of a cell’s migratory response to mechanical gradients.
MicroRNA (miRNA)-deficient helper T cells exhibit abnormal IFN-γ production and decreased proliferation. However, the contributions of individual miRNAs to this phenotype remain poorly understood. We ...conducted a screen for miRNA function in primary T cells and identified individual miRNAs that rescue the defects associated with miRNA deficiency. Multiple members of the miR-17 and miR-92 families enhanced miRNA-deficient T cell proliferation whereas miR-29 largely corrected their aberrant interferon-γ (IFN-γ) expression. Repression of IFN-γ production by miR-29 involved direct targeting of both T-bet and Eomes, two transcription factors known to induce IFN-γ production. Although not usually expressed at functionally relevant amounts in helper T cells, Eomes was abundant in miRNA-deficient cells and was upregulated after miR-29 inhibition in wild-type cells. These results demonstrate that miR-29 regulates helper T cell differentiation by repressing multiple target genes, including at least two that are independently capable of inducing the T helper 1 (Th1) cell gene expression program.
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► miRNA -deficient T cells exhibit cell-intrinsic defects in IFN-γ signaling ► Individual miRNAs independently rescue specific defects of miRNA-deficient T cells ► miR-29 negatively regulates IFN-γ production in helper T cells ► IFN-γ repression by miR-29 involves regulation of both T-bet and Eomes
Retear rates after arthroscopic rotator cuff repair continue to be unacceptably high. Of the known risk factors for failure of rotator cuff repair, many are nonmodifiable. Poor glycemic control in ...patients with diabetes in the first 3 to 6 months after arthroscopic rotator cuff repair is associated with a lower healing rate. This represents a modifiable risk factor that we should routinely address in patients postoperative rotator cuff repair.
The impact of surgical timing on outcomes involving traumatic rotator cuff tears (RCTs) remains uncertain. The purpose of this study was to determine how functional outcomes are affected by surgical ...timing in traumatic RCTs.
We performed a retrospective review of patients with repair of traumatic full-thickness RCTs. Preoperative magnetic resonance imaging scans were evaluated by 2 blinded reviewers to measure RCT area and muscular atrophy. Functional outcomes were assessed via the American Shoulder and Elbow Surgeons (ASES) score, Single Assessment Numeric Evaluation (SANE) score, Simple Shoulder Test score, and visual analog scale (VAS) pain score. Patients were divided into 4 groups based on the time from injury to surgery: 0-2 months (group 1), 2-4 months (group 2), 4-6 months (group 3), and 6-12 months (group 4). Multivariate analysis was performed to assess the impact of surgical timing on functional outcomes. A subanalysis was performed to assess outcomes in patients who underwent surgery within 3 weeks of injury.
The study included 206 patients (150 men and 56 women) with a mean age of 60.0 ± 9.7 years and a minimum of 24 months’ clinical follow-up (mean, 35.5 months; range, 24-54.4 months). The average tear area was 8.4 ± 6.3 cm2 in group 1 (66 patients), 5.8 ± 5.1 cm2 in group 2 (76 patients), 5.1 ± 4.6 cm2 in group 3 (29 patients), and 3.7 ± 3.1 cm2 in group 4 (35 patients) (P < .001). There were significant differences between the 4 cohorts in the final postoperative ASES score (P = .030) and VAS pain score (P = .032). The multivariate regression demonstrated that patients who underwent surgery within 4 months of injury had estimated improvements of 10.3 points in the ASES score (P = .008), 1.8 points in the Simple Shoulder Test score (P = .001), 8.6 points in the SANE score (P = .033), and 0.93 points in the VAS pain score (P = .028) compared with patients who underwent surgery later. The subanalysis demonstrated that patients who underwent surgery within 3 weeks of injury (n = 13) had significantly better VAS (P = .003), ASES (P = .008), and SANE (P = .019) scores than patients who underwent surgery at between 3 weeks and 4 months after injury (n = 129).
This study demonstrates that surgical repair of traumatic RCTs results in significant improvements in functional outcomes for all patients; however, patients who undergo surgery within 3 weeks can expect the best functional outcomes, with a drop in function in patients who undergo surgery >4 months after injury.
Poor compliance with multi-dose vaccine schedules by adults for whom hepatitis (Hep) A and B vaccines are recommended contributes to major Hep A and B disease burdens among high-risk U.S. adults. ...Evidence on hepatitis vaccine series adherence, completion, timeliness of completion, and factors associated with these outcomes, is limited and not readily generalizable for U.S. adults. This retrospective, observational study examined adherence, completion, its timeliness, and the impact of sociodemographic and clinical factors on these outcomes among a large, geographically representative sample of U.S. adults. We analyzed the Optum Clinformatics SES administrative claims database (1/1/2010-6/30/2020) for recipients of 2-dose (HepA, HepB2) or 3-dose (HepB3, HepAB) hepatitis vaccines. Adherence was defined as receipt of booster doses within specified assessment periods, per label-recommended schedules. Completion (receipt of all doses) was assessed at 6, 12, 18, and 24 months.The study included 356,828 adults ≥19 years old who were continuously enrolled in a medical benefit plan for one (HepB2), six (HepB3; HepAB), or 18 months (HepA) prior to and following the index date (first observed vaccine dose). Adherence and 24-month completion rates were: HepA (27.0%, 28.4%), HepB2 (32.2%, 44.8%), HepB3 (14.3%, 37.3%), HepAB, (15.3%, 33.8%). Kaplan-Meier completion curves plateaued after about 6 months for HepB2 and about 12 months for HepA, HepB3, and HepAB vaccines. Logistic regression analyses showed risk for low adherence/completion was generally associated with male gender, younger age, Black or Hispanic race/ethnicity, lower educational or household income attainment, and more comorbidities. Adherence and completion rates for all hepatitis vaccine series are low, especially for males, younger adults, those with lower socio-economic status and more comorbidities. To our knowledge, this is the largest claims-based analysis of adherence and completion rates for U.S. adults initiating all currently available HepA and HepB vaccines. Findings may inform hepatitis vaccination programming.
Acute Fractures of the Glenoid Seidl, Adam J; Joyce, Christopher D
Journal of the American Academy of Orthopaedic Surgeons,
2020-Nov-15, Letnik:
28, Številka:
22
Journal Article
Recenzirano
Glenoid fractures are unique in which they span the fields of orthopaedic traumatology and sports medicine. Treatment of glenoid fractures, whether surgical or nonsurgical, may be challenging and ...have long-term implications on pain and shoulder function. Plain radiographs are always indicated, and most glenoid fractures will require advanced imaging in the form of CT scan. Two general categories of glenoid fractures exist and differ in mechanism of injury, fracture morphology, and treatment. The first category is glenoid fractures with extension into the scapular neck and body. These fractures are typically from high-energy trauma and are often associated with other orthopaedic and nonorthopaedic injuries. The second category includes glenoid rim fractures, which are typically consequent of lower energy mechanisms and are associated with shoulder instability events. Treatment of glenoid rim fractures is dictated by the size and displacement of the fracture fragment and may be nonsurgical or surgical with either open and arthroscopic techniques. The purpose of this review was to discuss the current evidence on glenoid fractures regarding diagnosis, classification, management, and outcomes.
Extracellular matrix composition and stiffness are known to be critical determinants of cell behavior, modulating processes including differentiation, traction generation, and migration. Recent ...studies have demonstrated that the ECM composition can modulate how cells migrate in response to gradients in environmental stiffness, altering a cell's ability to undergo durotaxis. These observations were limited to single varieties of extracellular matrix, but typically cells are exposed to environments containing complex mixtures of extracellular matrix proteins. Here, we investigate migration of NIH 3T3 fibroblasts on mechanical gradients coated with one or more type of extracellular matrix protein. Our results show that NIH 3T3 fibroblasts exhibit durotaxis on fibronectin-coated mechanical gradients but not on those coated with laminin, demonstrating that extracellular matrix type can act as a regulator of cell response to mechanical gradients. Interestingly, NIH 3T3 fibroblasts were also observed to migrate randomly on gradients coated with a mixture of both fibronectin and laminin, suggesting that there may be a complex interplay in the cellular response to mechanical gradients in the presence of multiple extracellular matrix signals. These findings indicate that specific composition of available adhesion ligands is a critical determinant of a cell's migratory response to mechanical gradients.
•Fibroblasts undergo durotaxis on gradients coated with fibronectin but not laminin.•Migration on gradients coated with a mixture of fibronectin and laminin is random.•Soluble laminin prevents durotaxis on fibronectin-coated mechanical gradients.•ECM type is a key determinant of a cell's response to mechanical gradients.
Children who require chronic mechanical ventilation via tracheostomy are medically complex and require prolonged hospitalization, placing a heavy burden on caregivers and hospital systems. We ...developed an interdisciplinary Ventilator Care Program to relieve this burden, through improved communication and standardized care. We hypothesized that a standardized team approach to the discharge of tracheostomy- and ventilator-dependent children would decrease length of stay (LOS), reduce patient costs, and improve safety.
We used process mapping to standardize the discharge process for children requiring chronic ventilation. Interventions included developing education materials, a Chronic Ventilation Road Map for caregivers, utilization of the electronic medical record to track discharge readiness, team-based care coordination, and timely case management to arrange home nursing. We aimed to decrease overall and pediatric respiratory care unit LOS as the primary outcomes. We also analyzed secondary outcomes (mortality, emergency department visits, unplanned readmissions), and per-patient hospital costs during 2-year "preintervention" and "postintervention" periods (n = 18 and 30, respectively).
Patient demographics were not different between groups. As compared with the preintervention cohort, the overall LOS decreased 42% (P = .002). Pediatric respiratory care unit LOS decreased 56% (P = .001). As a result, unplanned readmissions, emergency department visits, and mortality were not increased. Direct costs per hospitalization were decreased by an average of 43% (P = .01).
Although LOS remained high, a standardized discharge process for chronically ventilated children by an interdisciplinary Ventilator Care Program team resulted in decreased LOS and costs without a negative impact on patient safety.
Background
This study aimed to investigate the association of acute kidney injury (AKI) with change in estimated glomerular filtration rate (eGFR) in children with advanced chronic kidney disease ...(CKD).
Methods
Single centre, retrospective longitudinal study including all prevalent children aged 1–18 years with nondialysis CKD stages 3–5. Variables associated with CKD were analysed for their potential effect on annualised eGFR change (ΔGFR/year) following multiple regression analysis. Composite end-point including 25% reduction in eGFR or progression to kidney replacement therapy was evaluated.
Results
Of 147 children, 116 had at least 1-year follow-up in a dedicated CKD clinic with mean age 7.3 ± 4.9 years with 91 (78.4%) and 77 (66.4%) with 2- and 3-year follow-up respectively. Mean eGFR at baseline was 29.8 ± 11.9 ml/min/1.73 m
2
with 79 (68%) boys and 82 (71%) with congenital abnormalities of kidneys and urinary tract (CAKUT). Thirty-nine (33.6%) had at least one episode of AKI. Mean ΔGFR/year for all patients was − 1.08 ± 5.64 ml/min/1.73 m
2
but reduced significantly from 2.03 ± 5.82 to − 3.99 ± 5.78 ml/min/1.73 m
2
from youngest to oldest age tertiles (
P
< 0.001). There was a significant difference in primary kidney disease (PKD) (77% versus 59%, with CAKUT,
P
= 0.048) but no difference in AKI incidence (37% versus 31%,
P
= 0.85) between age tertiles. Multiple regression analysis identified age (
β
= − 0.53,
P
< 0.001) and AKI (
β
= − 3.2,
P
= 0.001) as independent predictors of ΔGFR/year. 48.7% versus 22.1% with and without AKI reached composite end-point (
P
= 0.01).
Conclusions
We report AKI in established CKD as a predictor of accelerated kidney disease progression and highlight this as an additional modifiable risk factor to reduce progression of kidney dysfunction.
Graphical abstract
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