Linking triphenylphosphonium cation to a bicyclic hydroquinone improves their antiplatelet effect via the regulation of mitochondrial function.

Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.

Using cryo-EM to understand the assembly pathway of respiratory complex I.

Complex I (proton-pumping NADH:ubiquinone oxidoreductase) is the first component of the mitochondrial respiratory chain. In recent years, high-resolution cryo-EM studies of complex I from various species have greatly enhanced the understanding of the structure and function of this important membrane-protein complex. Less well studied is the structural basis of complex I biogenesis. The assembly of this complex of more than 40 subunits, encoded by nuclear or mitochondrial DNA, is an intricate process that requires at least 20 different assembly factors in humans. These are proteins that are transiently associated with building blocks of the complex and are involved in the assembly process, but are not part of mature complex I. Although the assembly pathways have been studied extensively, there is limited information on the structure and molecular function of the assembly factors. Here, the insights that have been gained into the assembly process using cryo-EM are reviewed.

Postoperative Opioid Prescribing Practices and Patient Opioid Utilization in Pediatric Orthopaedic Surgery Patients.

INTRODUCTION: Amid a national opioid epidemic, it is essential to review the necessity of opioid prescriptions. Research in adults has demonstrated patients often do not use their entire postoperative opioid prescription. Limited data suggest that the trend is similar in children. This study investigated the prescription volume and postoperative utilization rate of opioids among pediatric orthopaedic surgery patients at our institution. METHODS: We identified pediatric patients (ages below 18 y old) who presented to our institution for operating room intervention from May 24, 2021, to December 13, 2021. Patient demographics and opioid prescription volume were recorded. Parents and guardians were surveyed by paper "opioid diary" or phone interview between postoperative days 10 to 15, assessing pain level, opioid use, and plans for remaining opioid doses. Wilcoxon rank-sum test, Independent t test, and Pearson correlation were used for the analysis of continuous variables. Multivariable logistic regression was used to control for patient demographic variables while analyzing opioid usage relationships. RESULTS: Prescription volume information was collected for 280 patients during the study period. We were able to collect utilization information for 102 patients (Group 1), whereas the remaining 178 patients contributed only prescription volume data (Group 2). Patients with upper extremity fractures received significantly fewer opioid doses at discharge compared with other procedure types ( P =0.036). Higher BMI was positively correlated with more prescribed opioid doses ( R2 =0.647, P <0.001). The mean opioid utilization rate was 22.37%. A total of 50.6% of patients prescribed opioids at discharge used zero doses. A total of 96.2% of patients used opioids for 5 days or less. Most families had not disposed of excess medication by postoperative day 10. CONCLUSIONS: We found significant differences in opioid prescribing practices based on patient and procedure-specific variables. In addition, although our pediatric orthopaedic surgery patients had low overall rates of postoperative opioid utilization, there was significant variation in opioid use among procedure types. These results provide insights that can guide opioid prescribing practices for pediatric orthopaedic patients and promote patient education to ensure safe opioid disposal.

Older age and smaller joint space width are associated with conversion to total hip arthroplasty following hip arthroscopy.

Purpose: The goal of this study was to define the outcomes of patients following hip arthroscopy and to identify potential factors, found during hip arthroscopy, that were associated with patients' eventual conversion to total hip arthroplasty (THA). Methods: Patients who had undergone hip arthroscopy from January 2010 to January 2015 were retrospectively reviewed and patients were reported if they had a THA in the same hip. Patients were followed up to December 2022 resulting in between 7 and 12 years of follow-up. Measures from the hip scope including joint space width and cartilage grades were reported. Differences in these measures and demographics were compared between patients who had THA after hip arthroscopy and those who did not with T-tests. Results: Patients who had hip arthroscopy and were then converted to THA were significantly older than those patients who did not have THA (50.3 vs 42.0 years) (p = 0.039). The average time of conversion to THA from index hip arthroscopy was 3.59 years with a range of 0.48-8.91 years. Joint space width in patients converted to THA was significantly less, 3.08 mm ± 1.93 mm, compared to non-THA converted patients, 3.62 mm ± 0.88 mm (p < 0.001). Conclusions: Older age and smaller joint space width of the hip was associated with patients who were converted to THA following hip arthroscopy. Level of evidence: Level III.

Insights into complex I assembly: Function of NDUFAF1 and a link with cardiolipin remodeling.

Respiratory complex I is a ~1-MDa proton pump in mitochondria. Its structure has been revealed in great detail, but the structural basis of its assembly, in humans involving at least 15 assembly factors, is essentially unknown. We determined cryo-electron microscopy structures of assembly intermediates associated with assembly factor NDUFAF1 in a yeast model system. Subunits ND2 and NDUFC2 together with assembly factors NDUFAF1 and CIA84 form the nucleation point of the NDUFAF1-dependent assembly pathway. Unexpectedly, the cardiolipin remodeling enzyme tafazzin is an integral component of this core complex. In a later intermediate, all 12 subunits of the proximal proton pump module have assembled. NDUFAF1 locks the central ND3 subunit in an assembly-competent conformation, and major rearrangements of central subunits are required for complex I maturation.

Binding of Natural Inhibitors to Respiratory Complex I.

NADH:ubiquinone oxidoreductase (respiratory complex I) is a redox-driven proton pump with a central role in mitochondrial oxidative phosphorylation. The ubiquinone reduction site of complex I is located in the matrix arm of this large protein complex and connected to the membrane via a tunnel. A variety of chemically diverse compounds are known to inhibit ubiquinone reduction by complex I. Rotenone, piericidin A, and annonaceous acetogenins are representatives of complex I inhibitors from biological sources. The structure of complex I is determined at high resolution, and inhibitor binding sites are described in detail. In this review, we summarize the state of knowledge of how natural inhibitors bind in the Q reduction site and the Q access pathway and how their inhibitory mechanisms compare with that of a synthetic anti-cancer agent.

Ubiquinone Binding and Reduction by Complex I-Open Questions and Mechanistic Implications.

NADH: ubiquinone oxidoreductase (complex I) is the first enzyme complex of the respiratory chain. Complex I is a redox-driven proton pump that contributes to the proton motive force that drives ATP synthase. The structure of complex I has been analyzed by x-ray crystallography and electron cryo-microscopy and is now well-described. The ubiquinone (Q) reduction site of complex I is buried in the peripheral arm and a tunnel-like structure is thought to provide access for the hydrophobic substrate from the membrane. Several intermediate binding positions for Q in the tunnel were identified in molecular simulations. Structural data showed the binding of native Q molecules and short chain analogs and inhibitors in the access pathway and in the Q reduction site, respectively. We here review the current knowledge on the interaction of complex I with Q and discuss recent hypothetical models for the coupling mechanism.

Patient comprehension of hip arthroscopy: an investigation of health literacy.

Several studies have demonstrated that patients have significant impairments in understanding their injury and appropriate course of management in orthopedic surgery. The purpose of this investigation is to determine if patients are able to obtain a fundamental understanding of the requisite care associated with hip arthroscopy. Any patient who elected to have hip arthroscopy was prospectively recruited to participate in the study. All patients were told they would be asked to complete a questionnaire about their surgery and post-operative instructions. The answers to each question of the questionnaire they would receive at the first post-operative visit were verbally given to each patient during the pre-operative visit. They were also given a post-operative instruction sheet on the day of surgery that contained answers to the questionnaire. At the first post-operative visit, all patients were then asked to complete a multiple-choice questionnaire prior to seeing the surgeon. A total of 56 patients (14 males, 42 females) were enrolled. All patients reported they had read the post-operative instruction sheet. The average number of correct answers was 6.5 ± 0.6 (95% CI 6 - 7) out of 11 questions (59% correct response rate ±18% [95% CI 52 - 66%]). Although we made significant pre-operative oral and written efforts to help patients achieve an elementary level of health literacy regarding their forthcoming hip arthroscopy, many patients did not achieve satisfactory comprehension. Even with instruction and information given verbally and physically (via post-operative instruction sheet) patients did not obtain satisfactory comprehension of their surgical procedure. New ways (through video, simplified cartoons or verbal explanations) must be considered in educating patients concerning surgical procedures to increase comprehension and health literacy.

[Bitcoin, Libra and Central Bank Digital Currencies - Elements of a New Monetary System?] / Bitcoin, Libra und digitale Zentralbankwährungen ­ ein Geldsystem der Zukunft?

After the launch of Bitcoin in 2008 and the subsequent introduction of more than 6,600 cryptocurrencies, a new wave of innovative payment projects is currently on its way, including innovations like Libra - designed as a supranational stable coin - and central bank digital currencies (CBDCs). Various interrelations link these private and public projects. Contrary to the original intentions, Bitcoin has not developed into a widespread means of payments, not the least due to its considerable price volatility. Its most significant contribution could be the "proof of concept" for an innovative, private means of payment outside the conventional monetary system. In contrast, Libra is designed as a rather conventional means of payment with close relations with the existing banking sector, which raises numerous policy questions concerning monetary and financial stability. Central bank digital currencies could be viewed as a public sector response to these private projects to secure central banks' predominant role in the monetary system of the future.

Patient Comprehension of Carpal Tunnel Surgery: An Investigation of Health Literacy.

Background: Health literacy is the ability of a patient to understand their medical condition. The purpose of this investigation is to determine whether patients are able to obtain an elementary understanding of the fundamental principles of carpal tunnel release and the postoperative instructions after going through the process of informed consent and being provided an additional standardized postoperative instruction document. Our hypothesis is that patients will lack an understanding of these principles and, therefore, will be at risk for being noncompliant in their postoperative care. Methods: Fifty patients with a diagnosis of carpal tunnel surgery who elected to undergo carpal tunnel release alone were enrolled. A standardized education process was performed. Patients completed the questionnaire at their postoperative visit. Results: The average percentage of correct answers was 75.8% (8.34 out of 11 correct). Fisher exact test analysis demonstrated that patients with a lower education level were less likely to know how long it takes for their preoperative symptoms to resolve (P = .0071), and they were less likely to correctly choose all of the important elements of postoperative care during the first week after surgery (P = .022). Conclusions: Although we made efforts to help patients achieve health literacy in carpal tunnel surgery, we found that patients continued to lack comprehension of pertinent components of carpal tunnel surgery, particularly understanding the involved anatomy.

Lower Extremity Avulsion Fractures in the Pediatric and Adolescent Athlete.

Lower extremity avulsion fractures are uncommon in the pediatric population and can be misdiagnosed without proper imaging and/or clinical suspicion for these injuries. The most common locations of avulsion injuries are the ischial tuberosity, anterior superior iliac spine, and anterior inferior iliac spine. Less often, avulsion fractures occur in the tibial tubercle, calcaneus, and greater and lesser trochanters. When treated properly with rest and altered weight bearing, most of these injuries heal without complication. Although surgical intervention is rarely necessary, it has a high degree of success when it is used. However, avulsion injuries are often misdiagnosed as muscle strains or apophysitis and are mistakenly treated with early range of motion. An error in diagnosis and/or management can cause nonunion or further displacement, which may require surgery. Improper identification of these injuries can also lead to nerve irritation, chronic pain, and gait dysfunction. Awareness of these injuries and their natural history is important because healed avulsion fractures may resemble neoplastic bone on radiographs.

Preliminary Report-The Long Leg Cast With a Pelvic Band: A Novel Approach to Treatment of Pediatric Femur Fractures.

OBJECTIVES: The aim of the study was to describe the long leg cast with a pelvic band (LLCPB), a novel alternative to spica casting for treating femur fractures in patients aged 6 months to 6 years which requires no casting above the waist, allows for hip flexion adjustments after it is applied, and does not require an operating room for placement. METHODS: Seven children aged 7.9 months to 3.7 years with femur fractures treated with the LLCPB at a single institution were retrospectively studied. All children were casted in the emergency department under conscious sedation. Radiographic and subjective outcomes were recorded. RESULTS: All 7 children achieved acceptable reduction of their fractures without the need for re-reduction or cast wedging. Five of the 7 children were discharged from the emergency department; 1 child required 1 night of hospitalization and another child required 2 nights of hospitalization. There were no complications. The cost of placing an LLCPB at our institution was $430.46. The cost of placing a spica cast in the operating room was $5427.54 to $6465.00. CONCLUSIONS: The long leg cast with a pelvic band seems to be an acceptable treatment for children aged 8 months to 4 years with spiral femur fractures. This technique has significant advantages over traditional and modified spica casts including allowing for uninhibited toileting, weight bearing on the unaffected leg, adjustment of hip flexion at any point after placement, and easier access to the perineum, abdomen, and chest for hygienic and medical purposes. Furthermore, treatment with an LLCPB presents significant potential for cost savings.

Understanding Athletic Pubalgia: A Review.

Athletic Pubalgia, more commonly known as sports hernia, is defined as chronic lower abdominal and groin pain without the presence of a true hernia. It is increasingly recognized in athletes as a source of groin pain and is often associated with other pathology. A comprehensive approach to the physical exam and a strong understanding of hip and pelvic anatomy are critical in making the appropriate diagnosis. Various management options are available. We review the basic anatomy, patholophysiology, diagnostic approach and treatment of athletic pubalgia as well as discuss associated conditions such as femoroacetabular impingement. [Full article available at http://rimed.org/rimedicaljournal-2016-10.asp].

Three-Dimensional Carpal Kinematics after Carpal Tunnel Release.

BACKGROUND: Carpal tunnel release (CTR) has been shown to change carpal arch morphology. However, the effect of CTR on the three-dimensional kinematics of the carpal bones has not been demonstrated. PURPOSE: This study examined whether release of the transverse carpal ligament (TCL) would alter the three-dimensional kinematics of the carpus, specifically the bony attachments of the TCL. METHODS: The in vitro kinematics of the carpus was studied in five fresh-frozen cadaveric wrists before and after CTR using three-dimensional computed tomography. The specimens were evaluated in three positions: neutral, 60 degrees of flexion, and 60 degrees of extension. RESULTS: The data indicate that carpal arch width increases significantly in all positions after CTR as measured between the trapezium and hamate. Second, the trapezium-hamate distance increases in both a translational and rotational component after CTR. Additionally, the pisiform rotates away from the triquetrum after CTR. CONCLUSIONS: Carpal kinematics is significantly altered with a CTR, especially on the ulnar side of the wrist. CLINICAL RELEVANCE: Although the kinematic changes are small, they may be clinically significant and potentially responsible for pillar pain or postoperative loss of grip strength.

Orthopaedic Management of Spasticity.

Spasticity is a common manifestation of many neurological conditions including multiple sclerosis, stroke, cerebral palsy, traumatic brain injury, and spinal cord injuries. Management of spasticity seeks to reduce its burden on patients and to limit secondary complications. Non-operative interventions including stretching/splinting, postural management, physical therapy/strengthening, anti-spasticity medications, and botulinum toxin injections may help patients with spasticity. Surgical management of these conditions, however, is often necessary to improve quality of life and prevent complications. Orthopaedic surgeons manage numerous sequelae of spasticity, including joint contractures, hip dislocations, scoliosis, and deformed extremities. When combined with the efforts of rehabilitation specialists, neurologists, and physical/occupational therapists, the orthopaedic management of spasticity can help patients maintain and regain function and independence as well as reduce the risk of long-tem complications.

Femoroacetabular impingement: a review of current concepts.

Femoroacetabular impingement is becoming an increasingly more common diagnosis in the orthopaedic community for hip pain in the younger population. Variations in the femoral head and acetabulum can lead to a sequelae of changes to the cartilage that can lead to osteoarthritis. Diagnosis is made through a combination of patient history, physical examination, and diagnostic imaging. Plain radiographs are a very useful tool for evaluating the bony anatomy, while CT scan and MRI have roles for surgical planning and more definitive diagnosis. Most patients should trial physical therapy prior to consideration for any arthroscopic or open procedures. Long-term outcome studies are being performed to determine if surgical intervention has any impact on quality of life and development of osteoarthritis.

Acute pediatric leg compartment syndrome in chronic myeloid leukemia.

Acute compartment syndrome is an orthopedic surgical emergency and may result in devastating complications in the setting of delayed or missed diagnosis. Compartment syndrome has a variety of causes, including posttraumatic or postoperative swelling, external compression, burns, bleeding disorders, and ischemia-reperfusion injury. Rare cases of pediatric acute compartment syndrome in the setting of acute myeloid leukemia and, even less commonly, chronic myeloid leukemia have been reported. The authors report the first known case of pediatric acute compartment syndrome in a patient without a previously known diagnosis of chronic myeloid leukemia. On initial examination, an 11-year-old boy presented with a 2-week history of progressive left calf pain and swelling after playing soccer. Magnetic resonance imaging scan showed a hematoma in the left superficial posterior compartment. The patient had unrelenting pain, intermittent lateral foot parethesias, and inability to bear weight. Subsequently, he was diagnosed with acute compartment syndrome and underwent fasciotomy and evacuation of a hematoma. Laboratory results showed an abnormal white blood cell count of 440×10(9)/L (normal, 4.4-11×10(9)) and international normalized ratio of 1.3 (normal, 0.8-1.2). Further testing included the BCR-ABL1 fusion gene located on the Philadelphia chromosome, leading to a diagnosis of chronic myeloid leukemia. Monotherapy with imatinib mesylate (Gleevec) was initiated. This report adds another unique case to the growing literature on compartment syndrome in the pediatric population and reinforces the need to consider compartment syndrome, even in unlikely clinical scenarios.

The Effect of C-Arm Position on Radiation Exposure During Fixation of Pediatric Supracondylar Fractures of the Humerus.

BACKGROUND: Closed reduction and percutaneous pinning of a pediatric supracondylar fracture of the humerus requires operating directly next to the C-arm to hold reduction and perform fixation under direct imaging. This study was designed to compare radiation exposure from two C-arm configurations: with the image intensifier serving as the operating surface, and with a radiolucent hand table serving as the operating surface and the image intensifier positioned above the table. METHODS: We used a cadaveric specimen in this study to determine radiation exposure to the operative elbow and to the surgeon at the waist and neck levels during simulated closed reduction and percutaneous pinning of a pediatric supracondylar fracture of the humerus. Radiation exposure measurements were made (1) with the C-arm image intensifier serving as the operating surface, with the emitter positioned above the operative elbow; and (2) with the image intensifier positioned above a hand table, with the emitter below the table. RESULTS: When the image intensifier was used as the operating surface, we noted 16% less scatter radiation at the waist level of the surgeon but 53% more neck-level scatter radiation compared with when the hand table was used as the operating surface and the image intensifier was positioned above the table. In terms of direct radiation exposure to the operative elbow, use of the image intensifier as the operating surface resulted in 21% more radiation exposure than from use of the other configuration. The direct radiation exposure was also more than two orders of magnitude greater than the neck and waist-level scatter radiation exposure. CONCLUSIONS: Traditionally, there has been concern over increased radiation exposure when the C-arm image intensifier is used as an operating surface, with the emitter above, compared with when the image intensifier is positioned above the operating surface, with the emitter below. We determined that, although there was a statistically significant difference in radiation exposure between the two configurations, neither was safer than the other at all tested levels. CLINICAL RELEVANCE: In contrast to traditional teaching regarding radiation exposure, neither C-arm configuration-with the image intensifier serving as the operating surface or with the image intensifier positioned above a radiolucent hand table-was shown to be clearly safer for pediatric supracondylar humeral fracture fixation.

Operative treatment of type II supracondylar humerus fractures: does time to surgery affect complications?

BACKGROUND: Because of the changing referral patterns, operative pediatric supracondylar humerus fractures are increasingly being treated at tertiary referral centers. To expedite patient flow, type II fractures are sometimes pinned in a delayed manner. We sought to determine if delay in surgical treatment of modified Gartland type II supracondylar humerus fractures would affect the rate of complications following closed reduction and percutaneous pinning. METHODS: We performed a retrospective review of a consecutive series of 399 modified Gartland type II supracondylar fractures treated operatively at a tertiary referral center over 4 years. Mean patient age in the type II group was 5 years (range, 1 to 15 y). A total of 48% were pinned within 24 hours, 52% pinned >24 hours after the injury. RESULTS: No difference was in detected in rates of major complications between the early and delayed treatment group. Four percent of patients sustained a complication (16 patients). There were no compartment syndromes, vascular injuries, or permanent nerve injuries. Complications included nerve injury (3), physical therapy referral for stiffness (3), pin site infection (2 treated with oral antibiotics, 4 treated with debridement), refracture (2), and loss of fixation or broken hardware (2). Of the 3 patients who sustained nerve injuries, all underwent surgery within 24 hours of injury. One patient developed an ulnar motor and sensory nerve palsy after fixation with crossed K-wires. This resolved by 7 weeks postoperatively. Two patients presented with an anterior interosseous nerve palsy-1 resolved 1 week after surgery, the other by 8 weeks postoperatively. CONCLUSIONS: Delay in surgery did not result in an increased rate of major complications following closed reduction and percutaneous pinning of type II supracondylar humerus fractures in children. Further prospective work is necessary to determine if there are subtle treatment benefits from emergent treatment of type II supracondylar humerus fractures. LEVEL OF EVIDENCE: Level III-retrospective comparative series.

Clinical characteristics of severe supracondylar humerus fractures in children.

BACKGROUND: The safety of delayed surgical treatment of severe supracondylar elbow fractures in children remains debated. No large studies have evaluated complications of injury and surgery evaluating only type 3 fractures. Our aim was to review the results of our experience treating children with severe supracondylar elbow fractures at various time points after injury. METHODS: All children treated operatively for supracondylar humerus fractures from 2004 to 2007 at a single pediatric trauma center were identified. A total of 1296 children had operative treatment, of which 872 had type 3 fractures. Clinical records were reviewed to identify time to surgery from presentation at our institution. Patients were grouped into 4 cohorts [<6 h (n=325), 6 to 12 h (n=224), 12 to 24 h (n=295), and >24 h (n=28)]. Emergency, operative, inpatient, and outpatient records were reviewed to determine morbidity at presentation as well as operative and postoperative complications. RESULTS: There was no difference in sex, age, or energy mechanism between children in the various time groups. An absent pulse was found in 54 children (6%) at presentation, of which only 5 ultimately required a vascular intervention. Nerve injury occurred in 105 patients (12%). Use of a medial entry pin was not associated with ulnar nerve injury. Increased time from presentation to surgery was not associated with increased morbidity from the injury or treatment complications. In contrast, there was a trend to steady decrease in morbidity and complication rates with increased time to surgery. CONCLUSIONS: This is the largest single-center study of severe supracondylar humerus fractures and describes rates of vascular compromise, nerve injury, infection, and other complications of these injuries. Most children with type 3 supracondylar humerus fractures can be treated safely in a delayed manner. Appropriate clinical judgment is imperative to optimize outcomes. LEVEL OF EVIDENCE: Level III--retrospective comparative study.