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  • 1
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-08-11)
    Abstract: Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2553671-0
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  • 2
    In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 73, No. 8 ( 2021-10-20), p. 1459-1468
    Abstract: Influenza vaccine effectiveness (VE) against a spectrum of severe disease, including critical illness and death, remains poorly characterized. Methods We conducted a test-negative study in an intensive care unit (ICU) network at 10 US hospitals to evaluate VE for preventing influenza-associated severe acute respiratory infection (SARI) during the 2019–2020 season, which was characterized by circulation of drifted A/H1N1 and B-lineage viruses. Cases were adults hospitalized in the ICU and a targeted number outside the ICU (to capture a spectrum of severity) with laboratory-confirmed, influenza-associated SARI. Test-negative controls were frequency-matched based on hospital, timing of admission, and care location (ICU vs non-ICU). Estimates were adjusted for age, comorbidities, and other confounders. Results Among 638 patients, the median (interquartile) age was 57 (44–68) years; 286 (44.8%) patients were treated in the ICU and 42 (6.6%) died during hospitalization. Forty-five percent of cases and 61% of controls were vaccinated, which resulted in an overall VE of 32% (95% CI: 2–53%), including 28% (−9% to 52%) against influenza A and 52% (13–74%) against influenza B. VE was higher in adults 18–49 years old (62%; 95% CI: 27–81%) than those aged 50–64 years (20%; −48% to 57%) and ≥65 years old (−3%; 95% CI: −97% to 46%) (P = .0789 for interaction). VE was significantly higher against influenza-associated death (80%; 95% CI: 4–96%) than nonfatal influenza illness. Conclusions During a season with drifted viruses, vaccination reduced severe influenza-associated illness among adults by 32%. VE was high among young adults.
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2002229-3
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  • 3
    In: The American Journal of Sports Medicine, SAGE Publications, Vol. 47, No. 10 ( 2019-08), p. 2394-2401
    Abstract: Patient-reported outcomes (PROs) are a valid measure of results after revision anterior cruciate ligament (ACL) reconstruction. Revision ACL reconstruction has been documented to have worse outcomes when compared with primary ACL reconstruction. Understanding positive and negative predictors of PROs will allow surgeons to modify and potentially improve outcome for patients. Purpose/Hypothesis: The purpose was to describe PROs after revision ACL reconstruction and test the hypothesis that patient- and technique-specific variables are associated with these outcomes. Study Design: Cohort study; Level of evidence, 2. Methods: Patients undergoing revision ACL reconstruction were identified and prospectively enrolled by 83 surgeons over 52 sites. Data included baseline demographics, surgical technique and pathology, and a series of validated PRO instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index, and Marx Activity Rating Scale. Patients were followed up at 2 years and asked to complete the identical set of outcome instruments. Multivariate regression models were used to control for a variety of demographic and surgical factors to determine the positive and negative predictors of PRO scores at 2 years after revision surgery. Results: A total of 1205 patients met the inclusion criteria and were successfully enrolled: 697 (58%) were male, with a median cohort age of 26 years. The median time since their most recent previous ACL reconstruction was 3.4 years. Two-year questionnaire follow-up was obtained from 989 patients (82%). The most significant positive predictors of 2-year IKDC scores were a high baseline IKDC score, high baseline Marx activity level, male sex, and having a longer time since the most recent previous ACL reconstruction, while negative predictors included having a lateral meniscectomy before the revision ACL reconstruction or having grade 3/4 chondrosis in either the trochlear groove or the medial tibial plateau at the time of the revision surgery. For KOOS, having a high baseline score and having a longer time between the most recent previous ACL reconstruction and revision surgery were significant positive predictors for having a better (ie, higher) 2-year KOOS, while having a lateral meniscectomy before the revision ACL reconstruction was a consistent predictor for having a significantly worse (ie, lower) 2-year KOOS. Statistically significant positive predictors for 2-year Marx activity levels included higher baseline Marx activity levels, younger age, male sex, and being a nonsmoker. Negative 2-year activity level predictors included having an allograft or a biologic enhancement at the time of revision surgery. Conclusion: PROs after revision ACL reconstruction are associated with a variety of patient- and surgeon-related variables. Understanding positive and negative predictors of PROs will allow surgeons to guide patient expectations as well as potentially improve outcomes.
    Type of Medium: Online Resource
    ISSN: 0363-5465 , 1552-3365
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2019
    detail.hit.zdb_id: 2063945-4
    SSG: 31
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  • 4
    In: The American Journal of Sports Medicine, SAGE Publications, Vol. 48, No. 12 ( 2020-10), p. 2978-2985
    Abstract: Meniscal preservation has been demonstrated to contribute to long-term knee health. This has been a successful intervention in patients with isolated tears and tears associated with anterior cruciate ligament (ACL) reconstruction. However, the results of meniscal repair in the setting of revision ACL reconstruction have not been documented. Purpose: To examine the prevalence and 2-year operative success rate of meniscal repairs in the revision ACL setting. Study Design: Case-control study; Level of evidence, 3. Methods: All cases of revision ACL reconstruction with concomitant meniscal repair from a multicenter group between 2006 and 2011 were selected. Two-year follow-up was obtained by phone and email to determine whether any subsequent surgery had occurred to either knee since the initial revision ACL reconstruction. If so, operative reports were obtained, whenever possible, to verify the pathologic condition and subsequent treatment. Results: In total, 218 patients (18%) from 1205 revision ACL reconstructions underwent concurrent meniscal repairs. There were 235 repairs performed: 153 medial, 48 lateral, and 17 medial and lateral. The majority of these repairs (n = 178; 76%) were performed with all-inside techniques. Two-year surgical follow-up was obtained on 90% (197/218) of the cohort. Overall, the meniscal repair failure rate was 8.6% (17/197) at 2 years. Of the 17 failures, 15 were medial (13 all-inside, 2 inside-out) and 2 were lateral (both all-inside). Four medial failures were treated in conjunction with a subsequent repeat revision ACL reconstruction. Conclusion: Meniscal repair in the revision ACL reconstruction setting does not have a high failure rate at 2-year follow-up. Failure rates for medial and lateral repairs were both 〈 10% and consistent with success rates of primary ACL reconstruction meniscal repair. Medial tears underwent reoperation for failure at a significantly higher rate than lateral tears.
    Type of Medium: Online Resource
    ISSN: 0363-5465 , 1552-3365
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2020
    detail.hit.zdb_id: 2063945-4
    SSG: 31
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  • 5
    In: The American Journal of Sports Medicine, SAGE Publications, Vol. 43, No. 7 ( 2015-07), p. 1616-1622
    Abstract: Knees undergoing revision anterior cruciate ligament reconstruction (rACLR) have a high prevalence of articular cartilage lesions. Hypothesis: The prevalence of chondrosis at the time of rACLR is associated with meniscal status and lower extremity alignment. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Data from the prospective Multicenter ACL Revision Study (MARS) cohort were reviewed to identify patients with preoperative lower extremity alignment films. Lower extremity alignment was defined by the weightbearing line (WBL) as a percentage of the tibial plateau width, while the chondral and meniscal status of each weightbearing compartment was recorded at the time of surgery. Multivariable proportional odds models were constructed and adjusted for relevant factors to examine which risk factors were independently associated with the degree of medial and lateral compartment chondrosis. Results: The cohort included 246 patients with lower extremity alignment films at the time of rACLR. Mean (±SD) patient age was 26.9 ± 9.5 years and body mass index (BMI) was 26.4 ± 4.6. The medial compartment had more chondrosis (grade 2/3, 42%; grade 4, 6.5%) than did the lateral compartment (grade 2/3, 26%; grade 4, 6.5%). Disruption of the meniscus was noted in 35% of patients on the medial side and 16% in the lateral side. The mean WBL was 0.43 ± 0.13. Medial compartment chondrosis was associated with BMI ( P = .025), alignment ( P = .002), and medial meniscal status ( P = .001). None of the knees with the WBL lateral to 0.625 had grade 4 chondrosis in the medial compartment. Lateral compartment chondrosis was significantly associated with age ( P = .013) and lateral meniscal status ( P 〈 .001). Subjects with “intact” menisci were found to decrease their odds of having chondrosis by 64% to 84%. Conclusion: The status of articular cartilage in the tibiofemoral compartments at the time of rACLR is related to meniscal status. Lower extremity alignment and BMI are associated with medial compartment chondrosis.
    Type of Medium: Online Resource
    ISSN: 0363-5465 , 1552-3365
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2015
    detail.hit.zdb_id: 2063945-4
    SSG: 31
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  • 6
    In: The American Journal of Sports Medicine, SAGE Publications, Vol. 42, No. 5 ( 2014-05), p. 1058-1067
    Abstract: Identifying risk factors for inferior outcomes after anterior cruciate ligament reconstruction (ACLR) is important for prognosis and future treatment. Hypothesis: Articular cartilage lesions and meniscus tears/treatment would predict International Knee Documentation Committee (IKDC) score, Knee injury and Osteoarthritis Outcome Score (KOOS) (all 5 subscales), and Marx activity level at 6 years after ACLR. Study Design: Cohort study (prognosis); Level of evidence, 1. Methods: Between 2002 and 2004, a total of 1512 ACLR patients were prospectively enrolled and followed longitudinally, with the IKDC, KOOS, and Marx activity score completed at entry, 2 years, and 6 years. A logistic regression model was built incorporating variables from patient demographics, surgical technique, articular cartilage injuries, and meniscus tears/treatment to determine the predictors (risk factors) of IKDC and KOOS scores and Marx activity level at 6 years. Results: A minimum follow-up on 86% (1307/1512) of the cohort was completed at 6 years. The cohort was 56% male and had a median age of 23 years at the time of enrollment, with 76% reporting a noncontact injury mechanism. Incidence of concomitant injury at the time of surgery consisted of the following: articular cartilage (medial femoral condyle [MFC], 25%; lateral femoral condyle [LFC] 20%; medial tibial plateau [MTP], 6%; lateral tibial plateau [LTP] , 12%; patella, 20%; trochlear, 9%) and meniscus (medial, 38%; lateral, 46%). Both articular cartilage lesions and meniscus tears were significant predictors of 6-year outcomes on the IKDC and KOOS. Grade 3 or 4 articular cartilage lesions (excluding patella) significantly reduced IKDC and KOOS scores at 6 years. The IKDC demonstrated worse outcomes with the presence of a grade 3 or 4 chondral lesion on the MFC, MTP, and LFC. Likewise, the KOOS score was negatively affected by cartilage injury. The sole significant predictor of reduced Marx activity level was the presence of a grade 4 lesion on the MFC. Lateral meniscus repairs did not correlate with inferior results, but medial meniscus repairs predicted worse IKDC and KOOS scores. Lateral meniscus tears left alone significantly improved prognosis. Small partial meniscectomies ( 〈 33%) on the medial meniscus fared worse; conversely, larger excisions ( 〉 50%) on either the medial or lateral menisci improved prognosis. Analogous to previous studies, other significant predictors of lower outcome scores were lower baseline scores, higher body mass index, lower education level, smoking, and anterior cruciate ligament revisions. Conclusion: Both articular cartilage injury and meniscus tears/treatment at the time of ACLR were significant predictors of IKDC and KOOS scores 6 years after ACLR. Similarly, having a grade 4 MFC lesion significantly reduced a patient’s Marx activity level score at 6 years.
    Type of Medium: Online Resource
    ISSN: 0363-5465 , 1552-3365
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2014
    detail.hit.zdb_id: 2063945-4
    SSG: 31
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  • 7
    In: Obesity, Wiley, Vol. 27, No. 7 ( 2019-07), p. 1184-1189
    Abstract: The aim of this study is to define the association between a genetic risk score (GRS) that combined the effect of multiple BMI‐associated variants and gestational weight trajectory. Because pregnancy is a state of sympathetic activation, the association between gestational weight trajectory and variants in adrenergic pathways previously associated with weight was examined. Methods In a previously defined cohort of pregnant women with ( n  = 1,504) and without gestational diabetes (GDM) ( n  = 435), weight trajectory was calculated using all weights during pregnancy. A GRS for BMI (GRS BMI ) was calculated using 31 common variants associated with BMI, and 10 variants in the adrenergic pathways were genotyped. Clinical and genetic factors were studied using generalized linear models. Results Prepregnancy BMI was associated with the GRS BMI ( P  = 9.3 × 10 −11 ) and parity ( P  = 4.54 × 10 −17 ). The GRS BMI was associated with gestational weight trajectory in women with and without GDM ( P  = 0.041 and P   〈  0.0001, respectively); however, when prepregnancy BMI was included in the models, the associations disappeared ( P   〉  0.05). Variants in adrenergic genes were not associated with gestational weight trajectory. Conclusions A GRS for BMI was associated with prepregnancy BMI but was not independently associated with gestational weight trajectory in women with and without GDM. Selected variants in adrenergic genes were not associated with gestational weight trajectory.
    Type of Medium: Online Resource
    ISSN: 1930-7381 , 1930-739X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2027211-X
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  • 8
    In: Journal of Clinical Orthopaedics and Trauma, Elsevier BV, Vol. 6, No. 4 ( 2015-12), p. 220-226
    Type of Medium: Online Resource
    ISSN: 0976-5662
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 2596956-0
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  • 9
    In: Advances in Orthopedics, Hindawi Limited, Vol. 2014 ( 2014), p. 1-7
    Abstract: As our healthcare system moves towards bundling payments, it is vital to understand the potential financial implications associated with treatment of surgical complications. Considering that surgical treatment of ankle fractures is common, there remains minimal data relating costs to postsurgical intervention. We aimed to identify costs associated with ankle fracture complications through case-control analysis. Using retrospective analysis at a level I trauma center, 28 patients with isolated ankle fractures who developed complications (cases) were matched with 28 isolated ankle fracture patients without complications (controls) based on ASA score, age, surgery type, and fracture type. Patient charts were reviewed for demographics and complications leading to readmission/reoperation and costs were obtained from the financial department. Wilcoxon tests measured differences in the costs between the cases and controls. 28 out of 439 patients (6.4%) developed complications. Length of stay and median costs were significantly higher for cases than controls. Specifically, differences in total costs existed for infection and hardware-related pain. This is the first study to highlight the considerable costs associated with the treatment of complications due to isolated ankle fractures. Physicians must therefore emphasize methods to control surgical and nonsurgical factors that may impact postoperative complications, especially under a global payment system.
    Type of Medium: Online Resource
    ISSN: 2090-3464 , 2090-3472
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2014
    detail.hit.zdb_id: 2621436-2
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  • 10
    In: BMJ Open Quality, BMJ, Vol. 11, No. 1 ( 2022-02), p. e001315-
    Abstract: Based on clinical staff safety within a learning healthcare system, the purpose of this study was to test an innovative model of care for addressing disruptive behaviour in hospitalised patients to determine whether it should be scaled up at the system level. Methods The Disruptive bEhaviour manageMEnt ANd prevention in hospitalised patients using a behaviOuRal (DEMEANOR) intervention team was a pragmatic, cluster, cross-over trial. A behavioural intervention team (BIT) with a psychiatric mental health advanced practice nurse and a social worker, with psychiatrist consultation, switched between units each month and occurrences of disruptive behaviours (eg, documented violence control measures, violence risk) compared. Nursing surveys assessed self-perceived efficacy and comfort managing disruptive patient behaviour. Results A total of 3800 patients hospitalised on the two units met the criteria for inclusion. Of those, 1841 (48.4%) were exposed to the BIT intervention and 1959 (51.6%) were in the control group. A total of 11 132 individual behavioural issues associated with 203 patient encounters were documented. There were no differences in the use of behavioural interventions, violence risk or injurious behaviour or sitter use between patients exposed to BIT and those in the control group. Tracking these data did rely on nursing documentation of such events. Nurses (82 pre and 48 post) rated BIT as the most beneficial support they received to manage patients exhibiting disruptive, threatening or acting out behaviour. Conclusions The BIT intervention was perceived as beneficial by nurses in preparing them to provide care for patients exhibiting disruptive, threatening or acting out behaviour, but documented patient behaviour was not observed to change. Trial registration number NCT03777241 .
    Type of Medium: Online Resource
    ISSN: 2399-6641
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2952859-8
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