Cameron Rink

This study sought to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on orthopedic surgery residency training across the United States. A 26-question online survey was created and sent to all orthopedic surgery residency programs across the United States. Areas of emphasis in the survey included the pandemic's effect on work hours, operative experience, didactics, and medical student recruitment. There were 142 respondents to the survey. One hundred seventeen (82.4%) respondents stated that their residency changed to an alternative/surge schedule during the pandemic. Regarding the degree to which the pandemic affected their training, 77 (54.2%) respondents gave a rating of 8 to 10 on a scale of 0 to 10. Similarly, 94 (66.2%) residents indicated that their operative experience had decreased significantly. Twenty-two (15.5%) residents expected that their next year clinical abilities would not be affected. One hundred thirty-seven (96.5%) residents stated their program transitioned to online didactics. Responses regarding the effectiveness of online didactics were mixed. One hundred twenty-six (88.7%) respondents stated the pandemic would negatively affect the 2021 National Residency Matching Program match. This study demonstrated that the COVID-19 pandemic greatly affected orthopedic surgery residency training in the United States. Resident operative experience decreased significantly, and most respondents indicated a switch to online didactics. Effects were also felt to extend to fourth-year scheduling and the 2021 National Residency Matching Program match. [ Orthopedics . 2023;46(5):315–319.]

The purpose of this study was to characterize the effects of tocotrienol form of vitamin E (TCT) on platelet function in patients with stroke or transient ischemic attack (TIA). A double blind, randomized, single center phase II clinical trial was conducted comparing placebo (PBO) and 400 and 800 mg TCT daily for a year in 150 patients with a sentinel ischemic stroke or TIA event in the prior 6 months. Platelet function was measured at baseline and then, at 3 month intervals for a year, using light transmission aggregometry. The incidence of aspirin resistance in aspirin‐treated patients or platelet inhibition in patients on clopidogrel alone was compared between the three treatment groups. Results showed that in patients taking aspirin and clopidogrel, the incidence of aspirin resistance was significantly decreased from 40% in PBO‐treated patients to 9% in the 400 mg TCT group and 25% in the TCT 800 mg group ( P = .03). In conclusion, patients on aspirin and clopidogrel had a higher incidence of aspirin resistance than all patients treated with aspirin alone and TCT decreased the frequency of aspirin resistance in this group.

Introduction: While recombinant tissue plasminogen activator (rTPA) is the mainstay of ischemic stroke treatment, recanalization is only achieved in 25-50% of patients. With a significant risk of intracranial hemorrhage, its use has been limited to within 4.5 hours of symptom onset. Previous work has demonstrated that aptamer inhibition of Von Willebrand Factor (VWF) effectively restores reperfusion following murine carotid artery occlusion. Hypothesis: We tested the hypothesis that VWF aptamer would promote recanalization following thrombotic middle cerebral artery (MCA) occlusion, ameliorating stroke burden with greater efficacy than rTPA. Methods: Adult wild-type (C57BL/6J) mice were anesthetized, and the right carotid artery was exposed. A 32-gauge intracranial catheter was advanced within the carotid artery. Murine autologous blood was then mixed with 10 μL 0.9% normal saline and 1 μL murine thrombin and was allowed to stabilize at 37 °C for 15 minutes, after which it was injected through the catheter into the MCA. Laser-doppler flowmetry monitoring measured decreased flow following injection of the embolus. Treatment (vehicle, platelet binding buffer, n=5; VWF aptamer, n=6; rTPA, n=7) was initiated 20 minutes after thrombus injection. An MRI was obtained at 24 hours to assess ischemic stroke volumes. Results: None of the mice receiving rTPA survived to 24 hours, while all mice treated with VWF aptamer and vehicle survived to 24 hours and received an MRI. Ischemic stroke volume was significantly decreased in mice treated with VWF aptamer (5.49 ± 5.01 mm ³ ) compared to vehicle (35.34 ± 9.57 mm ³ , pConclusions: Treatment with VWF aptamer decreases stroke volume on MRI in a murine model of embolic stroke without the risk of hemorrhagic conversion seen in patients treated rTPA. VWF inhibition represents a promising therapy in stroke treatment.

In the pathophysiologic setting of cerebral ischemia, excitotoxic levels of glutamate contribute to neuronal cell death. Our previous work demonstrated the ability of glutamate oxaloacetate transaminase (GOT) to metabolize neurotoxic glutamate in the stroke‐affected brain. Here, we seek to identify small‐molecule inducers of GOT expression to mitigate ischemic stroke injury. From a panel of phytoestrogen isoflavones, biochanin A (BCA) was identified as the most potent inducer of GOT gene expression in neural cells. BCA significantly increased GOT mRNA and protein expression at 24 h and protected against glutamate‐induced cell death. Of note, this protection was lost when GOT was knocked down. To validate outcomes in vivo , C57BL/6 mice were intraperitoneally injected with BCA (5 and 10 mg/kg) for 4 wk and subjected to ischemic stroke. BCA levels were significantly increased in plasma and brain of mice. Immunohistochemistry demonstrated increased GOT protein expression in the brain. BCA attenuated stroke lesion volume as measured by 9.4T MRI and improved sensorimotor function—this protection was lost with GOT knockdown. BCA increased luciferase activity in cells that were transfected with the pERRE ₃ tk‐LUC plasmid, which demonstrated transactivation of GOT. This increase was lost when estrogen‐related receptor response element sites were mutated. Taken together, BCA represents a natural phytoestrogen that mitigates stroke‐induced injury by inducing GOT expression.—Khanna, S., Stewart, R., Gnyawali, S., Harris, H., Balch, M., Spieldenner, J., Sen, C. K., Rink, C. Phytoestrogen isoflavone intervention to engage the neuroprotective effect of glutamate oxaloacetate transaminase against stroke. FASEB J. 31, 4533–4544 (2017). www.fasebj.org

Arrayed nanochannels can be used to controllably transfect and reprogram tissues in vivo for applications in regenerative medicine and cell-based therapies. Although cellular therapies represent a promising strategy for a number of conditions, current approaches face major translational hurdles, including limited cell sources and the need for cumbersome pre-processing steps (for example, isolation, induced pluripotency)1,2,3,4,5,6. In vivo cell reprogramming has the potential to enable more-effective cell-based therapies by using readily available cell sources (for example, fibroblasts) and circumventing the need for ex vivo pre-processing7,8. Existing reprogramming methodologies, however, are fraught with caveats, including a heavy reliance on viral transfection9,10. Moreover, capsid size constraints and/or the stochastic nature of status quo approaches (viral and non-viral) pose additional limitations, thus highlighting the need for safer and more deterministic in vivo reprogramming methods11,12. Here, we report a novel yet simple-to-implement non-viral approach to topically reprogram tissues through a nanochannelled device validated with well-established and newly developed reprogramming models of induced neurons and endothelium, respectively. We demonstrate the simplicity and utility of this approach by rescuing necrotizing tissues and whole limbs using two murine models of injury-induced ischaemia.

Objective: (1) Develop a standardized approach to quantitatively measure residual limb skin health. (2) Report reference residual limb skin health values in people with transtibial and transfemoral amputation. Approach: Residual limb health outcomes in individuals with transtibial (n = 5) and transfemoral (n = 5) amputation were compared to able-limb controls (n = 4) using noninvasive imaging (hyperspectral imaging and laser speckle flowmetry) and probe-based approaches (laser doppler flowmetry, transcutaneous oxygen, transepidermal water loss, surface electrical capacitance). Results: A standardized methodology that employs noninvasive imaging and probe-based approaches to measure residual limb skin health are described. Compared to able-limb controls, individuals with transtibial and transfemoral amputation have significantly lower transcutaneous oxygen tension, higher transepidermal water loss, and higher surface electrical capacitance in the residual limb. Innovation: Residual limb health as a critical component of prosthesis rehabilitation for individuals with lower limb amputation is understudied in part due to a lack of clinical measures. Here, we present a standardized approach to measure residual limb health in people with transtibial and transfemoral amputation. Conclusion: Technology advances in noninvasive imaging and probe-based measures are leveraged to develop a standardized approach to quantitatively measure residual limb health in individuals with lower limb loss. Compared to able-limb controls, resting residual limb physiology in people that have had transfemoral or transtibial amputation is characterized by lower transcutaneous oxygen tension and poorer skin barrier function.

Ischemic stroke results in excessive release of glutamate, which contributes to neuronal cell death. Here, we test the hypothesis that otherwise neurotoxic glutamate can be productively metabolized by glutamate oxaloacetate transaminase (GOT) to maintain cellular energetics and protect the brain from ischemic stroke injury. The GOT‐dependent metabolism of glutamate was studied in primary neural cells and in stroke‐affected C57‐BL6 mice using magnetic resonance spectroscopy and GC‐MS. Extracellular Glu sustained cell viability under hypoglycemic conditions and increased GOT‐mediated metabolism in vitro . Correction of stroke‐induced hypoxia using sup‐plemental oxygen in vivo lowered Glu levels as measured by ¹ H magnetic resonance spectroscopy. GOT knock‐down abrogated this effect and caused ATP loss in the stroke‐affected brain. GOT overexpression increased anaplerotic refilling of tricarboxylic acid cycle intermediates in mouse brain during ischemic stroke. Furthermore, GOT overexpression not only reduced ischemic stroke lesion volume but also attenuated neurodegeneration and improved poststroke sensorimotor function. Taken together, our results support a new paradigm that GOT enables metabolism of otherwise neurotoxic extracellular Glu through a truncated tricarboxylic acid cycle under hypoglycemic conditions. —Rink, C., Gnyawali, S., Stewart, R., Teplitsky, S., Harris, H., Roy, S., Sen, C. K., Khanna, S. Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke‐affected brain. FASEB J . 31, 1709–1718 (2017) www.fasebj.org

The efficacy and optimization of poststroke physical therapy paradigms is challenged in part by a lack of objective tools available to researchers for systematic preclinical testing. This work represents a maiden effort to develop a robot‐assisted mechanical therapy (RAMT) device to objectively address the significance of mechanical physiotherapy on poststroke outcomes. Wistar rats were subjected to right hemisphere middle‐cerebral artery occlusion and reperfusion. After 24 h, rats were split into control (RAMT ⁻ )or RAMT ⁺ groups (30 min daily RAMT over the stroke‐affected gastrocnemius) and were followed up to poststroke d 14. RAMT ⁺ increased perfusion 1.5‐fold in stroke‐affected gastrocnemius as compared to RAMT ⁻ controls. Furthermore, RAMT ⁺ rats demonstrated improved poststroke track width (11% wider), stride length (21% longer), and travel distance (61% greater), as objectively measured using software‐automated testing platforms. Stroke injury acutely increased myostatin (3‐fold) and lowered brain‐derived neurotrophic factor (BDNF) expression (0.6‐fold) in the stroke‐affected gastrocnemius, as compared to the contralateral one. RAMT attenuated the stroke‐induced increase in myostatin and increased BDNF expression in skeletal muscle. Additional RAMT‐sensitive myokine targets in skeletal muscle (IL‐1ra and IP‐10/CXCL10) were identified from a cytokine array. Taken together, outcomes suggest stroke acutely influences signal transduction in hindlimb skeletal muscle. Regimens based on mechanical therapy have the clear potential to protect hindlimb function from such adverse influence.—Sen, C. K., Khanna, S., Harris, H., Stewart, R., Balch, M., Heigel, M., Teplitsky, S., Gnyawali, S., Rink, C. Robot‐assisted mechanical therapy attenuates stroke‐induced limb skeletal muscle injury. FASEB J. 31, 927–936 (2017). www.fasebj.org

Individuals living outside the tropics need to adjust their behavioral and physiological repertoires throughout the year to adapt to the changing seasons. White-footed mice (Peromyscus leucopus) reduce hippocampal volumes, hippocampal-dependent memory function, long-term potentiation, and alter neurogenesis in response to short (winter-like) day lengths (photoperiods). During winter, these mice putatively shunt energy away from the brain to maximize peripheral thermogenesis, immune function, and survival. We hypothesized that these changes in brain function are accompanied by alterations in brain vasculature. We maintained white-footed mice in short (8 h light/16 h dark) or long (16 h light/8 h dark) photoperiods for 8–9 weeks. Mice were then perfused with fluorescein isothiocyanate (FITC)-conjugated tomato (Lycopersicon esculentum) lectin to visualize the perfused cerebrovasculature. Short-day mice reduced hippocampal and cortical capillary density (FITC⁺area); vessels isolated from short day-exposed mice expressed higher mRNA levels of the gelatinase matrix metalloproteinase 2 (MMP2). Additionally, short-day mice reduced cerebral blood flow ∼15% compared with their long-day counterparts, as assessed by laser speckle flowmetry. Immunohistochemistry revealed higher levels of MMP2 in the hippocampus of mice maintained in short days compared with long days, potentially contributing to the observed vascular remodeling. These data demonstrate that a discrete environmental signal (i.e., day length) can substantially alter cerebral blood flow in adult mammals.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of hemorrhagic stroke with 30-day mortality between 33 and 45%. Delayed cerebral ischemia (DCI) is the chief cause of morbidity and mortality in patients who survive the initial aSAH. DCI accounts for almost 50% of deaths in patients surviving to treatment of the ruptured aneurysm. The mechanisms for brain injury after aSAH and the brain's response to this injury are not fully understood in humans. MicroRNAs (miRs) are 22- to 25-nucleotide single-stranded RNA molecules that inhibit the expression of specific messenger RNA targets. In this work, miR profiling of human cerebrospinal fluid from eight patients after aSAH was performed daily for 10 days with the goal of identifying changes in miR abundance. Using the nanoString nCounter Expression Assay, we identified two specific clusters of miR that were differentially regulated over time. Quantitative RT-PCR was performed on select miRs from each cluster. The first cluster contained miRs known to be present in blood and decreased in abundance over time. miRs in this group include miR-92a and let-7b. The second cluster contained several poorly characterized miRs that increased in abundance over time. miRs in this group included miR-491. This second cluster of miRs may be released into the CSF by the brain itself as a result of the initial SAH. Temporal changes in the abundance of specific miRs in human CSF after aSAH may provide novel insight into the role of miRs in brain injury and the brain's response.