Canagliflozin shares common mTOR and MAPK signaling mechanisms with other lifespan extension treatments.

Long-lived mouse models and treatments that extend lifespan, such as Rapamycin, acarbose and 17α- -estradiol, lead to reduction in mTORC1 activity, declines in cap-dependent translation and increases in cap-independent translation. In addition, these treatments reduce the MEK-ERK-MNK (ERK1-2) signaling cascade, leading to reduction in eIF4E phosphorylation, which also regulates mRNA translation. Here, we report that Canagliflozin, a drug that extends lifespan only in male mice reduces mTORC1 and ERK1-2 signaling in male mice only. The data suggest reduction in mTORC1 and ERK pathways are common mechanisms shared by both genetic and pharmacological models of slowed aging in mice. Our data also reveal a significant sexual dimorphism in the ERK1-2 signaling pathway which might help to explain why some drugs can extend lifespan in males but have no effects in female mice.

Evaluation of a modified emergency surgical acuity score in predicting operative and non-operative mortality and morbidity in an acute surgical unit.

BACKGROUND: Emergency general surgery (EGS) patients have an increased risk of mortality and morbidity compared to other surgical patients. Limited risk assessment tools exist for use in both operative and non-operative EGS patients. We assessed the accuracy of a modified Emergency Surgical Acuity Score (mESAS) in EGS patients at our institution. METHODS: A retrospective cohort study from an acute surgical unit at a tertiary referral hospital was performed. Primary endpoints assessed included death before discharge, length of stay (LOS) >5 days and unplanned readmission within 28 days. Operative and non-operative patients were analysed separately. Validation was performed using the area under the receiver operating characteristic (AUROC), Brier score and Hosmer-Lemeshow test. RESULTS: A total of 1763 admissions between March 2018 and June 2021 were included for analysis. The mESAS was an accurate predictor of both death before discharge (AUROC 0.979, Brier score 0.007, Hosmer-Lemeshow P = 0.981) and LOS >5 days (0.787, 0.104, and 0.253, respectively). The mESAS was less accurate in predicting readmission within 28 days (0.639, 0.040, and 0.887, respectively). The mESAS retained its predictive ability for death before discharge and LOS >5 days in the split cohort analysis. CONCLUSION: This study is the first to validate a modified ESAS in a non-operatively managed EGS population internationally and the first to validate the mESAS in Australia. The mESAS accurately predicts death before discharge and prolonged LOS for all EGS patients, providing a highly useful tool for surgeons and EGS units worldwide.

Trends in management of adult tarsometatarsal joint injuries in a contemporary Australian context: a nationwide study of claims data over 20 years.

BACKGROUND: Traumatic tarsometatarsal joint (TMTJ) injuries are uncommon, but can cause significant morbidity due to delayed or missed diagnosis. Recent evidence highlights the importance of achieving anatomical reduction via operative management. This study aims to analyse trends in rates of open reduction internal fixation (ORIF) for Lisfranc injuries in Australia according to Nationwide claims data. METHODS: Claims according to the Medicare Benefits Schedule (MBS) on ORIF of traumatic TMTJ injuries were collated for the period from January 2000 to December 2020. Paediatric patients were excluded. Two negative binomial models were utilized to analyse the trends in TMTJ injuries over time after controlling for sex, age group and population changes. Results were absolute and per 100 000 population. RESULTS: 7840 patients underwent TMTJ ORIF over the period studied. There was a mean yearly increase of 12% (P < 0.001). Age group (P < 0.001) and year (P < 0.001) were significant predictors for TMTJ fixation, whilst sex was not (P = 0.48). Patients older than 65 years were noted to have a 53% lower rate of TMTJ ORIF per person, when compared to the reference group of 25-34 year-olds (P < 0.001). Five-year block analysis revealed increases in rate of fixation for all age groups. CONCLUSION: Rates of operative fixation for TMTJ injuries are increasing in Australia. This is likely due to improved diagnostics, understanding of optimal treatment goals, and increased orthopaedic subspecialisation. Further studies with clinical and patient reported outcomes, as well as comparing rates of operative intervention to incidence, will be useful.

Surgical management of clavicle fractures in Australia: an analysis of Australian Medicare Benefits Schedule database from 2001 to 2020.

BACKGROUND: There is no consensus on the optimal management of clavicle fractures, with advocates of both operative and non-operative management. The objective of this study is to assess the trends in the management of clavicle fractures in Australia over the past two decades. METHODS: The incidence of surgical fixation of clavicle fractures from 2001 to 2020 was analysed using the Australian Medicare Benefits Schedule database, reflective of operations performed on privately insured patients, thus excluding public patients and compensable cases. An offset term was utilized with data from the Australian Bureau of Statistics to account for population changes over the study period. RESULTS: A total of 17 089 procedures for the management of clavicle fractures were performed from 2001 to 2020. The incidence of operative intervention increased from 1.87 per 100 000 in 2001 to a peak of 6.63 per 100 000 in 2016. An overall increase was seen in males (310%) and females (347%) over the study period, as well as across all age groups. A greater proportion of operative interventions was performed on males (n = 14 075, 82%) than females (n = 3014, 18%, P < 0.001). The greatest increase in intervention was noted in those aged 65 or older (14% increase per year, 95% CI 11%-17%, P < 0.05). In 2020, the incidence of operative intervention decreased to a level last seen in 2013. CONCLUSIONS: The incidence of operative interventions for clavicle fractures has increased in Australia over the 20-year study period. This increase is in keeping with recent evidence suggesting several advantages when displaced mid-shaft clavicle fractures are operatively managed.

The impact of COVID-19 on spinal cord injuries and trauma at a tertiary referral centre in Sydney.

Background: The coronavirus disease 2019 (COVID-19) pandemic has yielded far-reaching consequences for individual health systems as well as society. Although several studies have investigated epidemiological trends due to the pandemic-associated restrictions in patients requiring surgery for general surgical, trauma and orthopaedic aetiologies, there has been no assessment of the impact on spinal trauma and surgery in Australia. Thus, the aim of this study was to examine these changes at an Australian level one tertiary referral spinal cord injury (SCI) centre. Methods: We performed a retrospective cohort study of patients presenting to this institution with spinal injuries requiring surgery, from two time periods [one prior to the pandemic, and one during]. We analysed demographics, injury mechanism and characteristics, and surgical factors to identify significant differences between the cohorts. Results: There were 7.3% fewer spinal operations performed in the COVID-19 affected period. Although patient demographics were unchanged, the total number of emergency operations performed for injuries sustained in a motor vehicle accident decreased by 44% compared to the pre-COVID cohort (P=0.049). The median number of spinal levels affected by injury decreased, and there was a 30% decrease in American Spinal Injury Association (ASIA) type A injuries during the pandemic (P=0.006), with a corresponding increase in ASIA B injuries (P=0.032). Conclusions: The pandemic (and its associated social restrictions) has influenced the patterns of spinal injuries treated at this tertiary level institute during this time. We observed an overall reduction in the volume of emergency procedures performed during the pandemic. There was no change in the proportion of spinal cord injuries when compared to the pre-pandemic period; however, the severity of spinal cord injuries was diminished during the pandemic.

Scapulothoracic Dyskinesis: A Concept Review.

PURPOSE OF REVIEW: Scapulothoracic dyskinesis (SD) occurs when there is a noticeable disruption in typical position and motion of the scapula, which can result in debilitating pain. The purpose of this review is to describe the current knowledge regarding the diagnosis and management of scapulothoracic dyskinesis by providing an evidence-based overview of clinical exams and treatment modalities available for orthopedic surgeons and provide insight into which treatment modalities require further investigation. RECENT FINDINGS: SD is highly prevalent in athletes, particularly those participating in overhead activities (e.g., baseball, tennis, and swimming) and can coexist with several shoulder pathologies. A holistic approach in the diagnosis of SD has been supported in the literature; however, it is important to recognize that diagnosis is currently limited to the absence of a quantitative SD clinical assessment. The main goal of the treatment of SD is to regain proper scapular positioning and dynamics. The standard of care for the management of SD is conservative interventions aimed at optimizing scapular kinematics. Surgical intervention is only considered in the presence of concomitant pathology requiring surgery. Due to the complexity of coordinated movement of the shoulder girdle, recent literature has begun to move away from the use of traditional orthopedic tests, in favor of a more system-based approach for the diagnosis of SD. We present a concise review of clinical exams and treatment modalities available for orthopedic surgeons in the management of SD.

Failures, Reoperations, and Improvement in Knee Symptoms Following Matrix-Assisted Autologous Chondrocyte Transplantation: A Meta-Analysis of Prospective Comparative Trials.

OBJECTIVE: Though multiple high-level comparative studies have been performed for matrix-assisted autologous chondrocyte transplantation (MACT), quantitative reviews synthesizing best-available clinical evidence on the topic are lacking. DESIGN: A meta-analysis was performed of prospective randomized or nonrandomized comparative studies utilizing MACT. A total of 13 studies reporting 13 prospective trials (9 randomized, 5 nonrandomized) were included (658 total study participants at weighted mean 3.1 years follow-up, range 1-7.5 years). RESULTS: Reporting and methodological quality was moderate according to mean Coleman (59.4 SD 7.6), Delphi (3.0 SD 2.1), and MINORS (Methodological Index For Non-Randomized Studies) scores (20.2 SD 1.6). There was no evidence of small study or reporting bias. Effect sizes were not correlated with reporting quality, financial conflict of interest, sample size, year of publication, or length of follow-up (P > 0.05). Compared to microfracture, MACT had greater improvement in International Knee Documentation Committee (IKDC)-subjective and Knee Injury and Osteoarthritis Outcome Pain Subscale Score (KOOS)-pain scores in randomized studies (P < 0.05). Accelerated weight-bearing protocols (6 or 8 weeks) resulted in greater improvements in IKDC-subjective and KOOS-pain scores than standard protocols (8 or 11 weeks) for MACT in randomized studies (P < 0.05) with insufficient nonrandomized studies for pooled analysis. CONCLUSIONS: Compared to microfracture, MACT has no increased risk of clinical failure and superior improvement in patient-reported outcome scores. Compared to MACT with standardized postoperative weight-bearing protocols, accelerated weight-bearing protocols have no increased risk of clinical failure and show superior improvement in patient-reported outcome scores. There is limited evidence regarding MACT compared to first-generation autologous chondrocyte implantation, mosaicplasty, and mesenchymal stem cell therapy without compelling differences in outcomes.

Orthopedic Oncology Experience During Residency.

The objective of this study was to determine the characteristics and logistics of orthopedic oncology rotations at various residency programs across the USA and determine the effect of orthopedic oncology rotations on Orthopedic In-Training Examination (OITE) scores. An eight-question survey was sent to 162 orthopedic surgery residency programs obtained from the Accreditation Council for Graduate Medical Education public database. Pre-oncology rotation and post-oncology rotation OITE scores for 24 residents at a major academic medical center were collected and analyzed. The response rate was 43.8%. Survey results were as follows: 90.1% responded positively to having a dedicated orthopedic oncology rotation in their curriculum; 49.3% carried out their oncology rotation at a hospital outside of their home institution; 70.4% of programs had only one dedicated orthopedic oncology rotation throughout residency; 42.3% indicated that residents experience 6-10 weeks of dedicated orthopedic oncology training during the 5-year residency program; 42.2% indicated that residents experience oncology rotations during post-graduate year 4; and 80.3% of programs had orthopedic oncology trained surgeons on their faculty. The mean increase in OITE oncology scores after the rotation was 12.1% (p = 0.005). There are variations in orthopedic oncology curricula across residency programs, most notably in the number of weeks residents participate in a dedicated oncology rotation, the post-graduate year that residents rotate on an oncology service, and the location where residents obtain their orthopedic oncology training. Participating in a dedicated orthopedic oncology rotation resulted in significant improvement in scores on the oncology domain of the OITE.

Biomechanical Properties of Posterior Meniscal Root Repairs: A Systematic Review.

PURPOSE: To systematically review the literature regarding the biomechanical properties of various meniscal root repair techniques. METHODS: A systematic review of multiple databases was performed. The inclusion criteria included English language, studies relevant to meniscal root repairs, studies comparing 2 or more different discrete techniques, posterior root repairs, controlled laboratory studies, and human cadaveric or animal studies. Abstracts, case reports, cohort studies, case-control studies, systematic reviews and meta-analyses, and studies of meniscal body repairs were excluded. RESULTS: Seventeen controlled laboratory studies were included for final analysis. There is no consensus on biomechanical superiority between transtibial pullout repair (TPR) and suture anchor repair. For TPR, there is no significant difference between 1 and 2 tibial tunnels. Nonanatomic repairs result in significantly lower joint surface contact areas and higher contact pressures, but suture placement farther from the root results in higher maximum load to failure. Two-suture repair has a greater maximum load to failure than 1-suture repair. Use of more than 2 sutures has diminishing returns. The modified Mason-Allen suture configuration is superior to a simple suture configuration, but there is no consensus regarding the superiority or feasibility of more complex sutures. There is no consensus on the superiority of a single suture material or shape. CONCLUSIONS: Anatomic meniscal root repairs with either TPR or suture anchor repair have better joint surface contact pressures and contact surface areas than nonanatomic repairs. The use of 2 sutures results in better fixation than 1 suture. There is evidence that the modified Mason-Allen suture configuration is superior to a simple suture configuration in a TPR, although the benefits of more complicated configurations are unclear. CLINICAL RELEVANCE: This study suggests that, in general, more complex sutures exhibit higher maximum loads. Increasing the number of sutures to up to 2 of the same configuration also increases the maximum load.

Enhanced Survival with Implantable Scaffolds That Capture Metastatic Breast Cancer Cells In Vivo.

The onset of distant organ metastasis from primary breast cancer marks the transition to a stage IV diagnosis. Standard imaging modalities often detect distant metastasis when the burden of disease is high, underscoring the need for improved methods of detection to allow for interventions that would impede disease progression. Here, microporous poly(ε-caprolactone) scaffolds were developed that capture early metastatic cells and thus serve as a sentinel for early detection. These scaffolds were used to characterize the dynamic immune response to the implant spanning the acute and chronic foreign body response. The immune cell composition had stabilized at the scaffold after approximately 1 month and changed dramatically within days to weeks after tumor inoculation, with CD11b(+)Gr1(hi)Ly6C(-) cells having the greatest increase in abundance. Implanted scaffolds recruited metastatic cancer cells that were inoculated into the mammary fat pad in vivo, which also significantly reduced tumor burden in the liver and brain. Additionally, cancer cells could be detected using a label-free imaging modality termed inverse spectroscopic optical coherence tomography, and we tested the hypothesis that subsequent removal of the primary tumor after early detection would enhance survival. Surgical removal of the primary tumor following cancer cell detection in the scaffold significantly improved disease-specific survival. The enhanced disease-specific survival was associated with a systemic reduction in the CD11b(+)Gr1(hi)Ly6C(-) cells as a consequence of the implant, which was further supported by Gr-1 depletion studies. Implementation of the scaffold may provide diagnostic and therapeutic options for cancer patients in both the high-risk and adjuvant treatment settings. Cancer Res; 76(18); 5209-18. ©2016 AACR.

In vivo capture and label-free detection of early metastatic cells.

Breast cancer is a leading cause of death for women, with mortality resulting from metastasis. Metastases are often detected once tumour cells affect the function of solid organs, with a high disease burden limiting effective treatment. Here we report a method for the early detection of metastasis using an implanted scaffold to recruit and capture metastatic cells in vivo, which achieves high cell densities and reduces the tumour burden within solid organs 10-fold. Recruitment is associated with infiltration of immune cells, which include Gr1(hi)CD11b(+) cells. We identify metastatic cells in the scaffold through a label-free detection system using inverse spectroscopic optical coherence tomography, which identifies changes to nanoscale tissue architecture associated with the presence of tumour cells. For patients at risk of recurrence, scaffold implantation following completion of primary therapy has the potential to identify metastatic disease at the earliest stage, enabling initiation of therapy while the disease burden is low.