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1.
Orthop J Sports Med ; 12(7): 23259671241254795, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39100218

ABSTRACT

Background: Despite increasing use of quadriceps tendon (QT) autograft in anterior cruciate ligament (ACL) reconstruction (ACLR), limited data exist regarding its outcomes in high-risk adolescent athletes. Purpose: To (1) report the outcomes after QT ACLR in adolescent athletes and (2) identify patient-related and surgery-related factors that may influence failure rates after QT ACLR. Study Design: Case series; Level of evidence, 4. Methods: All patients aged 14 to 17 years who underwent primary anatomic, transphyseal, single-bundle QT ACLR between 2010 and 2021 with a minimum 2-year follow-up were included for analysis. Demographic and surgical data as well as preoperative International Knee Documentation Committee (IKDC) and Marx activity scores were collected retrospectively. All patients were also contacted to assess postoperative patient-reported outcomes (PROs), including IKDC and Marx activity scores, and return-to-sports (RTS) data. Outcomes of interest included rates of revision ACLR and ipsilateral complications, contralateral ACL tears, difference in pre- and postoperative PROs, and rates of RTS. Patient and surgical characteristics were compared between groups who required revision ACLR versus those who did not. Results: A total of 162 patients met inclusion criteria, of which 89 adolescent athletes (mean age 16.2 ± 1.1 years, 64% female) were included for analysis at mean follow-up of 4.0 years. Postoperative IKDC scores were significantly higher than preoperative scores (88.5 vs 37.5; P < .001), whereas Marx activity scores decreased postoperatively (14.3 vs 12.2; P = .011). Successful RTS occurred in 80% of patients at a mean time of 9.7 ± 6.9 months, and 85% of these patients returned to the same or higher level of sports. The most common reasons for failure to RTS included lack of time (n = 7, 70%) and fearing reinjury in the operative knee (n = 5, 50%). The overall revision ACLR rate was 10% (n = 9), and contralateral ACL tears occurred in 14% (n = 12) of patients. The overall ipsilateral knee reoperation rate was 22.5% (n = 20). No statistically significant differences in patient or surgical characteristics were observed between patients who underwent revision ACLR and those who did not. Conclusion: At a minimum 2-year follow-up after QT ACLR, adolescent athletes experienced significantly improved postoperative IKDC scores, high rates of RTS, and low rates of graft failure, despite a relatively high ipsilateral reoperation rate. Surgeons may utilize this information when identifying the optimal graft choice for adolescent athletes who have sustained an ACL injury and wish to return to high level of sporting activities.

2.
J ISAKOS ; : 100314, 2024 Aug 24.
Article in English | MEDLINE | ID: mdl-39187130

ABSTRACT

OBJECTIVES: To investigate the incidence and risk factors associated with loss of motion after anterior cruciate ligament reconstruction (ACLR) during the coronavirus disease 2019 pandemic (COVID-19). METHODS: A retrospective review of patients undergoing primary ACLR between March 2017-November 2022 by a senior high-volume orthopaedic surgeon was performed. Exclusion criteria included revision ACLR, multiligamentous knee surgery, and age <14 years. The COVID-19 group was categorized according to the United States Centers for Disease Control Public Health Emergency declaration dates (January 31, 2020-May 11, 2023). To minimize confounding variables associated with the early stages of COVID-19, patients who underwent ACLR between December 1, 2019 and February 29, 2020 were excluded. Loss of motion was defined using the International Knee Documentation Committee (IKDC) criteria for loss of motion of the knee (i.e. an extension deficit >5° or flexion deficit >15° compared to the contralateral knee) 3-12 months after ACLR, or surgery to restore motion within 12 months of ACLR. RESULTS: A total of 336 individuals that underwent 352 primary ACLRs (164 pre-COVID-19, 188 during COVID-19) were included (mean age 25.2 ± 10.6 years, 44% female). The overall rate of postoperative loss of motion was 15% (n=53) and 9% (n=31) required surgery to restore motion within 12 months of ACLR. More patients underwent surgery for loss of motion during COVID-19 compared to pre-COVID-19, which was statistically significant (12% (n=23) vs 5% (n=8) respectively, P=0.02). However, a statistically significant difference in the rate of loss of motion was not detected (18% (n=33) vs 12% (n=20) respectively, P=0.16). A statistically significant increased median time from injury to ACLR was observed during COVID-19 compared to pre-COVID-19 (55 vs 37 days, P<0.01). More patients were unable to achieve terminal extension (0°) at minimum 9 months postoperatively during COVID-19 compared to pre-COVID-19 (10% vs 3%, P=0.04) and motion was worse at this interval (0°-136° vs -2°-138°, P<0.01). CONCLUSION: Surgery for loss of motion following ACLR was more common during COVID-19. Decreased access to elective medical care, changed activity level, psychological effects, or COVID-19 itself, may explain the increased rate of surgery for loss of motion during COVID-19. LEVEL OF EVIDENCE: Case series; level IV.

3.
J Med Chem ; 2024 Aug 22.
Article in English | MEDLINE | ID: mdl-39172133

ABSTRACT

Acinetobacter baumannii, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential A. baumannii lipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with 1 (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against A. baumannii in murine septicemia and lung infection models.

4.
Orthop J Sports Med ; 12(8): 23259671241263883, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39165328

ABSTRACT

Background: Smaller intercondylar notch sizes have been consistently associated with a predisposition for primary anterior cruciate ligament tears. Purpose: To evaluate the association between intercondylar notch size, graft size, and postoperative complications, including knee stiffness and return to the operating room, after primary anatomic anterior cruciate ligament reconstruction (ACLR). Study Design: Case-control study; Level of evidence, 3. Methods: This was a retrospective analysis of prospectively collected data from consecutive patients who underwent anatomic single-bundle primary ACLR using a bone-patellar tendon-bone or quadriceps tendon autograft performed by fellowship-trained orthopaedic sports medicine surgeons between April 2009 and August 2019. Graft failure was defined as patient report of instability, pathologic laxity on clinical examination, or graft rerupture confirmed by magnetic resonance imaging and/or subsequent arthroscopy. To ensure the purposeful selection of covariates, univariate analyses were conducted on the list of potential confounders selected a priori, and those with a significance value of P < .10 were considered for the multivariate regression model. Covariates found to be statistically significant with univariate analysis were patient age, notch size, and graft type. After validating all potential covariates, they were added to the regression model and then eliminated in a stepwise fashion. Results: In total, 252 patients were included for analysis (99 bone-patellar tendon-bone and 153 quadriceps tendon autograft; age, 22.2 ± 7.0 years; graft size, 9.8 ± 1.0 mm; time to follow-up, 50.4 ± 28.9 months). Knee stiffness developed in 23 patients (9.1%), and 15 grafts failed (6.0%). Smaller notch size on magnetic resonance imaging was significantly associated with graft failure (P = .005). There was a significantly higher risk of graft failure with notch size <16 versus ≥16 mm (17.6% vs 2.3%; P = .005) with an odds ratio (OR) of 5.0 (95% CI, 1.7-15.1; P = .004). Notch size <15 mm was associated with the highest risk of graft failure (22.2%; OR, 5.8; 95% CI, 1.6-20.6; P = .006). There was no significant association between notch size or graft-notch size ratio and knee stiffness, meniscal injury, or cartilage damage at the time of ACLR, regardless of graft type. Conclusion: Intercondylar notch size <16 mm was associated with a 5-fold increased risk of graft failure after primary anatomic ACLR.

5.
Sports Biomech ; : 1-18, 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38990167

ABSTRACT

This study aimed to compare the agreement between three-dimensional motion capture and vertical ground reaction force (vGRF) in identifying the point of dumbbell (DB) release during a countermovement jump with accentuated eccentric loading (CMJAEL), and to examine the influence of the vGRF analysis method on the reliability and magnitude of CMJAEL variables. Twenty participants (10 male, 10 female) completed five maximal effort CMJAEL at 20% and 30% of body mass (CMJAEL20 and CMJAEL30, respectively) using DBs. There was large variability between methods in both loading conditions, as indicated by the wide limits of agreement (CMJAEL20 = -0.22 to 0.07 s; CMJAEL30 = -0.29 to 0.14 s). Variables were calculated from the vGRF data, and compared between four methods (forward integration (FI), backward integration (BI), FI adjusted at bottom position (BP), FI adjusted at DB release point (DR)). Greater absolute reliability was observed for variables from DR (CV% ≤ 7.28) compared to BP (CV% ≤ 13.74), although relative reliability was superior following the BP method (ICC ≥ 0.781 vs ≥ 0.606, respectively). The vGRF method shows promise in pinpointing the DB release point when only force platforms are accessible, and a combination of FI and BI analyses is advised to understand CMJAEL dynamics.

6.
Bone Rep ; 22: 101787, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39071944

ABSTRACT

Background: Recently, we developed the machine learning (ML)-based Progressive CKD Risk Classifier (PCRC), which accurately predicts CKD progression within 5 years. While its performance is robust, it is unknown whether PCRC categorization is associated with CKD-mineral bone disorder (CKD-MBD), a critical, yet under-recognized, downstream consequence. Therefore, we aimed to 1) survey real-world testing utilization data for CKD-MBD and 2) evaluate ML-based PCRC categorization with CKD-MBD. Methods: The cohort study utilized deidentified data from a US laboratory outpatient network, composed of 330,238 outpatients, over 5 years. The main outcomes were: 1) Laboratory testing utilization of eGFR, urine albumin creatinine ratio (UACR), parathyroid hormone (PTH), calcium, phosphate; and 2) PCRC categorization and biochemical abnormalities associated with CKD-MBD over 5 years. Results: We identified significant under-utilization of laboratory testing for UACR, phosphate and PTH, which ranged from -40 % to -100 % against the minimum standard-of-care. At five years, the CKD progression group, as predicted by the PCRC, was associated with 15.5 % increase in phosphate (P value <<0.01) and 94.9 % increase in PTH (P value <<0.01), consistent with CKD-MBD. Conclusions: We identified significant under-utilization of laboratory testing for CKD-MBD. Moreover, we demonstrated that CKD progression, as predicted by the PCRC, is associated with CKD-MBD, several years in advance of disease. To our knowledge, this investigation is the first to examine the role of predictive analytics for CKD progression on mineral bone disorder. While further studies are required, these findings have the potential to advance AI/ML-based risk stratification and treatment of CKD and CKD-MBD.

7.
J Bone Joint Surg Am ; 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39066689

ABSTRACT

➤ Posterior tibial slope (PTS) of ≥12° represents an important risk factor for both anterior cruciate ligament (ACL) injury and ACL reconstruction failure.➤ PTS measurements can significantly differ on the basis of the imaging modality and the measurement technique used. PTS should be measured on strictly lateral radiographs, with a recommended proximal tibial length of 15 cm in the image. The PTS measurement can be made by placing 2 circles to define the proximal tibial axis, 1 just below the tibial tubercle and another 10 cm below it. PTS measurements are underestimated when made on magnetic resonance imaging and computed tomography.➤ Slope-reducing osteotomies can be performed using a (1) supratuberosity, (2) tubercle-reflecting transtuberosity, or (3) infratuberosity method. The correction target remains a topic of debate. Although it is controversial, some authors recommend overcorrecting the tibial slope slightly to a range of 4° to 6°. For instance, if the initial slope is 12°, a correction of 6° to 8° should be performed, given the target tibial slope of 4° to 6°.➤ Clinical outcomes following slope-reducing osteotomies have been favorable. However, potential complications, limited data with regard to the impact of slope-reducing osteotomies on osteoarthritis, and uncertainty with regard to the effects on the patellofemoral joint are notable concerns.➤ Patients with complex deformities may need biplanar osteotomies to comprehensively address the condition.

8.
Vasc Endovascular Surg ; : 15385744241264791, 2024 Jul 21.
Article in English | MEDLINE | ID: mdl-39033397

ABSTRACT

The current state of the literature for a bullet embolization to the heart and/or pulmonary vasculature indicates the occurrence is rare but could increase due to the rise in civilian low-kinetic-energy firearm acquisition and use. We present the case of an older teenage male who sustained a gunshot wound to the left flank. The bullet entered the iliac vein, travelled through the heart and lodged in the pulmonary artery. Successful relocation of the bullet to the internal iliac vein was performed by the interventional radiologist. This article highlights the advancement of interventional radiology as a successful non-invasive endovascular technique for bullet embolus removal.

9.
Article in English | MEDLINE | ID: mdl-38966516

ABSTRACT

The impact of a pharmacist has been evaluated within the primary care setting but not within a resident-managed internal medicine clinic. This retrospective study found that the integration of a clinical pharmacist within a resident clinic improved the mean HbA1c of a high-risk patient group by 3% in 3 months and 2.6% in 6 months. None of the residents surveyed reported that the presence of a clinical pharmacist hindered their learning experience. The study also found the residents perceived the clinical pharmacist to be helpful with co-management of diabetes. This data supports the addition of a clinical pharmacist into a resident clinic and continues to support the benefits in the primary care setting.

10.
Arch Bone Jt Surg ; 12(6): 400-406, 2024.
Article in English | MEDLINE | ID: mdl-38919741

ABSTRACT

Objectives: This study aimed to compare short-term outcomes following Total Shoulder Arthroplasty (TSA) and Humeral Head Resurfacing (HHR) in patients with glenohumeral osteoarthritis (GHOA). Methods: A retrospective analysis included patients who had undergone either TSA or HHR for GHOA at a single institution. Baseline demographics, complications, range of motion (active forward flexion, FF and active external rotation, ER), visual analog scores (VAS), and Subjective Shoulder Values (SSV) were collected. Results: A total of 69 TSA and 56 HHR patients were analyzed. More HHR patients were laborers (44% versus 21%, P=0.01). There were more smokers in the TSA group (25% versus 11%, P=0.04) and more cardiovascular disease in the HHR cohort (64% versus. 6%, p<0.0001). Postoperative FF was similar, but ER was greater in the HHR (47° ± 15°) vs. TSA group (40° ± 12°, P = 0.01). VAS was lower after TSA vs. HHR (median 0, IQR 1 versus median 3.7, IQR 6.9, p<0.0001), and SSV was higher after TSA (89% ± 13% vs. 75% ± 20% after HHR; p<0.0001). Post-operative impingement was more common after HHR (32% vs. 3% for TSA, p<0.0001). All other complications were equivalent. Conclusion: While younger patients and heavy laborers had improved ER following HHR, their pain relief was greater after TSA. Decisions on surgical technique should be based on patient-specific demographic and anatomic factors.

11.
J Vet Intern Med ; 38(4): 2214-2220, 2024.
Article in English | MEDLINE | ID: mdl-38932495

ABSTRACT

BACKGROUND: The information relating to the outcome specifically for juvenile dogs with meningoencephalitis of unknown etiology (MUE) is lacking. OBJECTIVES: To describe the clinical presentation, diagnostic findings, treatment, and outcome in a cohort of dogs with MUE <52 weeks old. ANIMALS: Thirty-four client-owned dogs. METHODS: Multicenter retrospective case series. Records from 5 referral centers were searched. Data was extracted from the medical records and referring veterinarians were contacted for survival data if this was not available from the record. RESULTS: The mean age was 31 weeks; the youngest dog was 11 weeks and 3 dogs were <16 weeks old. Altered mentation (71%), ataxia (44%), seizures (29%), and circling (26%) were the most common presenting complaints. Neuroanatomical localization was to the forebrain (38%), multifocal (35%), brainstem (18%), and cerebellum (12%). Corticosteroid monotherapy (n = 15) and corticosteroid plus cytosine arabinoside (n = 15) were used in equal proportions. Outcome data was available for 26 dogs, 8 (31%) were alive at the time of data collection with a follow-up range of 135 to 2944 days. Death or euthanasia was related to MUE in 17/18 dogs that died during the study period. Kaplan-Meier survival analysis demonstrated a median survival time for all-cause death of 84 days. CONCLUSION: The prognosis for MUE in this subset of dogs was considered poor.


Subject(s)
Dog Diseases , Meningoencephalitis , Animals , Dogs , Dog Diseases/drug therapy , Meningoencephalitis/veterinary , Meningoencephalitis/drug therapy , Meningoencephalitis/mortality , Retrospective Studies , Female , Male , Treatment Outcome , Adrenal Cortex Hormones/therapeutic use , Cytarabine/therapeutic use , Cytarabine/administration & dosage
12.
Article in English | MEDLINE | ID: mdl-38866213

ABSTRACT

PURPOSE: Patients with locally advanced rectal cancer often require neoadjuvant chemoradiation therapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiation therapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target. METHODS AND MATERIALS: Immunohistochemical analysis of a tissue microarray (TMA) for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using small interfering RNA, a small molecular inhibitor (wj460), and a CRISPR-Cas9 knockout cell line. Radiosensitization after treatment was assessed using 2-dimensional clonogenic assays, 3-dimensional spheroid models, and patient-derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence, and immunoblotting. RESULTS: Analysis of both the diagnostic biopsy and tumor resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant long-course chemoradiation therapy. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (P = .01; hazard ratio, 3.5; 95% CI, 1.27-10.04). This was externally validated using the Stratification in Colorectal Cancer database. Quantification of myoferlin using immunoblotting in immortalized colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacologic manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2-dimensional and 3-dimensional models. After irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double-strand breaks. This appeared to be mediated via nonhomologous end-joining. CONCLUSIONS: We have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of patients with rectal cancer to radiation therapy, and further work is required.

13.
Article in English | MEDLINE | ID: mdl-38842025

ABSTRACT

PURPOSE: The purpose of this study was to identify risk factors for subsequent meniscal surgery following anterior cruciate ligament (ACL) reconstruction (ACLR) in patients without recurrent ACL injury. METHODS: Patients aged ≥14 years who underwent primary ACLR with minimum 1-year follow-up and without recurrent ACL injury were retrospectively reviewed. Patient demographics and surgical data at the time of ACLR were collected. Postoperative radiographs were used to measure femoral and tibial tunnel position, and posterior tibial slope. Univariate and multivariate analyses were performed to identify risk factors for subsequent meniscal surgery. RESULTS: Of 629 ACLRs that fulfilled the inclusion criteria, subsequent meniscal surgery was performed in 65 [10.3%] patients. Multivariate analysis revealed that medial meniscal repair at the time of ACLR, younger age, anterior femoral tunnel position and distal femoral tunnel position were significantly associated with subsequent meniscal surgery (p < 0.001, p = 0.016, p = 0.015, p = 0.035, respectively). The frequency of femoral tunnel placement >10% outside of the literature-established anatomic position was significantly higher in those who underwent subsequent meniscal surgery compared to those who did not (38.3% vs. 20.3%, p = 0.006). Posterior tibial slope and ACL graft type were not significantly associated with subsequent meniscal surgery. CONCLUSION: Medial meniscal repair at the time of ACLR, younger age and nonanatomic femoral tunnel placement were risk factors for subsequent meniscal surgery in patients without recurrent ACL injury. Femoral tunnel placement <10% outside of the native anatomic position is important to reduce the risk of subsequent meniscal surgery. LEVEL OF EVIDENCE: Level IV.

14.
Cell Death Discov ; 10(1): 282, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38866739

ABSTRACT

Ionising radiation (IR) is widely used in cancer treatment, including for head and neck squamous cell carcinoma (HNSCC), where it induces significant DNA damage leading ultimately to tumour cell death. Among these lesions, DNA double strand breaks (DSBs) are the most threatening lesion to cell survival. The two main repair mechanisms that detect and repair DSBs are non-homologous end joining (NHEJ) and homologous recombination (HR). Among these pathways, the protein kinases ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR) and the DNA dependent protein kinase catalytic subunit (DNA-Pkcs) play key roles in the sensing of the DSB and subsequent coordination of the downstream repair events. Consequently, targeting these kinases with potent and specific inhibitors is considered an approach to enhance the radiosensitivity of tumour cells. Here, we have investigated the impact of inhibition of ATM, ATR and DNA-Pkcs on the survival and growth of six radioresistant HPV-negative HNSCC cell lines in combination with either X-ray irradiation or proton beam therapy, and confirmed the mechanistic pathway leading to cell radiosensitisation. Using inhibitors targeting ATM (AZD1390), ATR (AZD6738) and DNA-Pkcs (AZD7648), we observed that this led to significantly decreased clonogenic survival of HNSCC cell lines following both X-ray and proton irradiation. Radiosensitisation of HNSCC cells grown as 3D spheroids was also observed, particularly following ATM and DNA-Pkcs inhibition. We confirmed that the inhibitors in combination with X-rays and protons led to DSB persistence, and increased micronuclei formation. Cumulatively, our data suggest that targeting DSB repair, particularly via ATM and DNA-Pkcs inhibition, can exacerbate the impact of ionising radiation in sensitising HNSCC cell models.

15.
J Hered ; 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38833450

ABSTRACT

The XX/XY sex chromosome system is deeply conserved in therian mammals, as is the role of Sry in testis determination, giving the impression of stasis relative to other taxa. However, the long tradition of cytogenetic studies in mammals documents sex chromosome karyotypes that break this norm in myriad ways, ranging from fusions between sex chromosomes and autosomes to Y chromosome loss. Evolutionary conflict, in the form of sexual antagonism or meiotic drive, is the primary predicted driver of sex chromosome transformation and turnover. Yet conflict-based hypotheses are less considered in mammals, perhaps because of the perceived stability of the sex chromosome system. To address this gap, we catalogue and characterize all described sex chromosome variants in mammals, test for family-specific rates of accumulation, and consider the role of conflict between the sexes or within the genome in the evolution of these systems. We identify 152 species with sex chromosomes that differ from the ancestral state and find evidence for different rates of ancestral to derived transitions among families. Sex chromosome-autosome fusions account for 80% of all variants whereas documented sex chromosome fissions are limited to three species. We propose that meiotic drive and drive suppression provide viable explanations for the evolution of many of these variant systems, particularly those involving autosomal fusions. We highlight taxa particularly worthy of further study and provide experimental predictions for testing the role of conflict and its alternatives in generating observed sex chromosome diversity.

16.
J Cell Mol Med ; 28(12): e18482, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38899556

ABSTRACT

Hypoxia poses a significant challenge to the effectiveness of radiotherapy in head and neck squamous cell carcinoma (HNSCC) patients, and it is imperative to discover novel approaches to overcome this. In this study, we investigated the underlying mechanisms contributing to x-ray radioresistance in HPV-negative HNSCC cells under mild hypoxic conditions (1% oxygen) and explored the potential for autophagy modulation as a promising therapeutic strategy. Our findings show that HNSCC cells exposed to mild hypoxic conditions exhibit increased radioresistance, which is largely mediated by the hypoxia-inducible factor (HIF) pathway. We demonstrate that siRNA knockdown of HIF-1α and HIF-1ß leads to increased radiosensitivity in HNSCC cells under hypoxia. Hypoxia-induced radioresistance was not attributed to differences in DNA double strand break repair kinetics, as these remain largely unchanged under normoxic and hypoxic conditions. Rather, we identify autophagy as a critical protective mechanism in HNSCC cells following irradiation under mild hypoxia conditions. Targeting key autophagy genes, such as BECLIN1 and BNIP3/3L, using siRNA sensitizes these cells to irradiation. Whilst autophagy's role in hypoxic radioresistance remains controversial, this study highlights the importance of autophagy modulation as a potential therapeutic approach to enhance the effectiveness of radiotherapy in HNSCC.


Subject(s)
Autophagy , Cell Hypoxia , Radiation Tolerance , Squamous Cell Carcinoma of Head and Neck , Humans , Autophagy/radiation effects , Autophagy/genetics , Radiation Tolerance/genetics , Cell Line, Tumor , Squamous Cell Carcinoma of Head and Neck/radiotherapy , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/metabolism , Cell Hypoxia/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Beclin-1/metabolism , Beclin-1/genetics , Head and Neck Neoplasms/radiotherapy , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , DNA Repair/radiation effects , DNA Repair/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , X-Rays , DNA Breaks, Double-Stranded/radiation effects , Tumor Suppressor Proteins
17.
Clin Sports Med ; 43(3): 449-464, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38811121

ABSTRACT

Failure of anterior cruciate ligament reconstruction (ACLR) is a common yet devastating complication due to inferior clinical outcomes associated with revision ACLR. Identifying the cause and associated risk factors for failure is the most important consideration during preoperative planning. Special attention to tunnel quality, concomitant injuries, and modifiable risk factors will help determine the optimal approach and staging for revision ACLR. Additional procedures including lateral extra-articular tenodesis and osteotomy may be considered for at-risk populations. The purpose of this review is to explore causes of ACLR failure, clinical indications and appropriate patient evaluation, and technical considerations when performing revision ACLR.


Subject(s)
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Reoperation , Humans , Anterior Cruciate Ligament Reconstruction/methods , Anterior Cruciate Ligament Injuries/surgery , Risk Factors , Treatment Failure , Tenodesis/methods , Osteotomy/methods
18.
Br J Sports Med ; 58(12): 649-654, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38760154

ABSTRACT

OBJECTIVES: To investigate the impact of demographic and socioeconomic factors on the management of isolated meniscus tears in young patients and to identify trends in surgical management of meniscus tears based on surgeon volume. METHODS: Data from a large healthcare system on patients aged 14-44 years who underwent isolated meniscus surgery between 2016 and 2022 were analysed. Patient demographics, socioeconomic factors and surgeon volume were recorded. Patient age was categorised as 14-29 years and 30-44 years old. Area Deprivation Index (ADI), a measure of neighbourhood disadvantage with increased ADI corresponding to more disadvantage, was grouped as <25th, 25-75th and >75th percentile. Multivariate comparisons were made between procedure groups while univariate comparisons were made between surgeon groups. RESULTS: The study included 1552 patients treated by 84 orthopaedic surgeons. Older age and higher ADI were associated with higher odds of undergoing meniscectomy. Patients of older age and with non-private insurance were more likely to undergo treatment by a lower-volume knee surgeon. Apart from the year 2022, higher-volume knee surgeons performed significantly higher rates of meniscus repair compared with lower-volume knee surgeons. When controlling for surgeon volume, higher ADI remained a significant predictor of undergoing meniscectomy over meniscus repair. CONCLUSION: Significant associations exist between patient factors and surgical choices for isolated meniscus tears in younger patients. Patients of older age and with increased neighbourhood disadvantage were more likely to undergo meniscectomy versus meniscus repair. While higher-volume knee surgeons favoured meniscus repair, a growing trend of meniscus repair rates was observed among lower-volume knee surgeons. LEVEL OF EVIDENCE: Retrospective cohort study, level III.


Subject(s)
Meniscectomy , Socioeconomic Factors , Tibial Meniscus Injuries , Humans , Adolescent , Tibial Meniscus Injuries/surgery , Young Adult , Meniscectomy/statistics & numerical data , Male , Adult , Female , Age Factors , Retrospective Studies , Residence Characteristics
19.
Clin Sports Med ; 43(3): 399-412, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38811118

ABSTRACT

The ideal anterior cruciate ligament reconstruction (ACLR) is an individualized anatomic approach aimed at restoring the native structure and function of the knee. Surgeons are tasked with difficult decisions during operative planning, including the optimal graft choice for the patient and appropriate anatomic tunnel placement. Special considerations should additionally be given for skeletally immature patients and those at high-risk for failure, including younger, active patients participating in pivoting sports. The purpose of this review is to provide an overview of the individualized approach to ACLR, including the necessary preoperative and operative considerations to optimize patient outcomes.


Subject(s)
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Humans , Anterior Cruciate Ligament Reconstruction/methods , Anterior Cruciate Ligament Injuries/surgery
20.
J ISAKOS ; 9(4): 689-698, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38604570

ABSTRACT

IMPORTANCE: Anterolateral augmentation during primary anterior cruciate ligament (ACL) reconstruction (ACLR) may lower rates of ACL graft failure. However, differences in costs between two techniques, lateral extra-articular tenodesis (LET) and anterolateral ligament reconstruction (ALLR), are unclear. OBJECTIVE: To perform a systematic review and subsequent cost-effectiveness analysis comparing LET versus ALLR in the setting of primary ACLR. The hypothesis was that LET is more cost-effective than ALLR. EVIDENCE REVIEW: A systematic review was conducted on studies in which patients underwent primary ACLR with a concomitant LET or ALLR with minimum 24 months follow-up published between January 2013 and July 2023. Primary outcomes included ACL graft failure rates and Knee Injury and Osteoarthritis Outcome Survey-Quality of Life (KOOS-QoL) subscale scores, which were used to determine health utilities measured by quality-adjusted life years (QALYs) gained. A decision tree model with one-way and two-way sensitivity analyses compared the cost of primary ACLR with a concomitant LET, independent autograft ALLR, or independent allograft ALLR. Costs were estimated using a combination of QALYs, institution prices, literature references, and a survey sent to 49 internationally recognized high-volume knee surgeons. FINDINGS: A total of 2505 knees undergoing primary ACLR with concomitant LET (n=1162) or ALLR (n=1343) were identified from 22 studies. There were 77 total ACL graft failures with comparable failure rates between patients receiving LET versus ALLR (2.9% vs. 3.2%, P=0.690). The average QALYs gained was slightly higher for those who received LET (0.77) compared to ALLR (0.75). Survey results revealed a 5 minute longer median self-reported operative time for ALLR (20 â€‹min) than LET (15 â€‹min). The estimated costs for LET, autograft ALLR, and allograft ALLR were $1,015, $1,295, and $3,068, respectively. CONCLUSIONS AND RELEVANCE: Anterolateral augmentation during primary ACLR with LET is more cost-effective than independent autograft and allograft ALLR given the lower costs and comparable clinical outcomes. Surgeons may utilize this information when determining the optimal approach to anterolateral augmentation during primary ACLR, although differences in preferred technique and health care systems may influence operative efficiency and material costs. LEVEL OF EVIDENCE: Systematic review; Level of evidence, IV.


Subject(s)
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Cost-Benefit Analysis , Tenodesis , Humans , Anterior Cruciate Ligament Reconstruction/methods , Anterior Cruciate Ligament Reconstruction/economics , Tenodesis/methods , Tenodesis/economics , Anterior Cruciate Ligament Injuries/surgery , Quality-Adjusted Life Years , Quality of Life , Anterior Cruciate Ligament/surgery
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