The Contribution of the Distal Oblique Band to Distal Radioulnar Joint Stability.

PURPOSE: The distal radioulnar joint (DRUJ) is supported by an array of dynamic and static stabilizers, of which the triangular fibrocartilage complex (TFCC) is the most important, and the distal interosseous ligament is next in importance. The distal oblique band (DOB) is an identifiable component of the distal interosseous ligament, found in a subset of the population. Our objective was to determine the contribution of the DOB to DRUJ stability in the presence of a disrupted TFCC. METHODS: Twenty-three above-elbow specimens were prepared by removing the TFCC and the DRUJ joint capsule, preserving the distal interosseous ligament and the pronator quadratus. Cadavers were stratified into two groups-those with, and those without a DOB. A bone plate and screws were attached to the ulna; then, a transverse load was applied to failure, creating a diastasis between the radius and ulna. RESULTS: The group with a DOB had a mean load at failure of 160.7 ± 46.5 N. The group without a DOB had a mean load at failure of 148.0 ± 26.3 N. Stiffness prior to failure was 16.9 N/mm in the group with a DOB and 12.4 N/mm in the group without a DOB. CONCLUSIONS: The current results indicate that the DOB may not substantially contribute to DRUJ stability in the presence of a disrupted TFCC. CLINICAL RELEVANCE: Stability of the DRUJ after TFCC injury may not be substantially improved by the presence of a DOB. Thus, the clinical importance of DOB reconstruction remains unclear.

Return to Play After Hook of Hamate Fracture: A Systematic Review and Meta-Analysis.

In athletes, a hook of hamate fracture is concerning in terms of time to return to sport and effect on performance upon return. This study aims to analyze the treatment of hook of hamate fractures in athletes to determine their rates of return to play, timelines of recovery, and performance level upon return to play. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to perform this analysis. The PubMed database was queried to perform the literature search. Data were pooled and analyzed. P values <.05 were considered significant. Data were analyzed using the Comprehensive Meta-Analysis software to determine heterogeneity. Twenty studies with 823 patients sustaining hook of hamate fractures that reported any competitive level of play were included in the analysis. Of the 823 patients, 778 (94.5%) were able to return to play with 91.2% (506/555) of patients demonstrating similar or improved performance. The mean time to return to play was 45 days (range: 21-168 days). Treatment included surgical excision for 787 patients (95.6%), open reduction and internal fixation for 18 patients (2.2%), stress reduction/casting for 13 patients (1.6%), and loss to follow-up or surgery refusal for 5 patients (0.6%). A very high number of athletes return to play following a hook of hamate fracture at the same or improved level of performance. In our study, the majority of injuries were treated with surgical excision of the fractured hook of hamate fragment. Most athletes returned to their sport at an average of 45 days.

Earliest known Gondwanan bird tracks: Wonthaggi Formation (Early Cretaceous), Victoria, Australia.

The fossil record for Cretaceous birds in Australia has been limited to rare skeletal material, feathers, and two tracks, a paucity shared with other Gondwanan landmasses. Hence the recent discovery of 27 avian footprints and other traces in the Early Cretaceous (Barremian-Aptian, 128-120 Ma) Wonthaggi Formation of Victoria, Australia amends their previous rarity there, while also confirming the earliest known presence of birds in Australia and the rest of Gondwana. The avian identity of these tracks is verified by their tridactyl forms, thin digits relative to track lengths, wide divarication angles, and sharp claws; three tracks also have hallux imprints. Track forms and sizes indicate a variety of birds as tracemakers, with some among the largest reported from the Early Cretaceous. Although continuous trackways are absent, close spacing and similar alignments of tracks on some bedding planes suggest gregariousness. The occurrence of this avian trace-fossil assemblage in circumpolar fluvial-floodplain facies further implies seasonal behavior, with trackmakers likely leaving their traces on floodplain surfaces during post-thaw summers.

Diversity of mitochondrial DNA in 3 species of great whales before and after modern whaling.

The 20th century commercial whaling industry severely reduced populations of great whales throughout the Southern Hemisphere. The effect of this exploitation on genetic diversity and population structure remains largely undescribed. Here, we compare pre- and post-whaling diversity of mitochondrial DNA (mtDNA) control region sequences for 3 great whales in the South Atlantic, such as the blue, humpback, and fin whale. Pre-whaling diversity is described from mtDNA extracted from bones collected near abandoned whaling stations, primarily from the South Atlantic island of South Georgia. These bones are known to represent the first stage of 20th century whaling and thus pre-whaling diversity of these populations. Post-whaling diversity is described from previously published studies reporting large-scale sampling of living whales in the Southern Hemisphere. Despite relatively high levels of surviving genetic diversity in the post-whaling populations, we found evidence of a probable loss of mtDNA lineages in all 3 species. This is evidenced by the detection of a large number of haplotypes found in the pre-whaling samples that are not present in the post-whaling samples. A rarefaction analysis further supports a loss of haplotypes in the South Atlantic humpback and Antarctic blue whale populations. The bones from former whaling stations in the South Atlantic represent a remarkable molecular archive for further investigation of the decline and ongoing recovery in the great whales of the Southern Hemisphere.

Covalent-reversible peptide-based protease inhibitors. Design, synthesis, and clinical success stories.

Dysregulated human peptidases are implicated in a large variety of diseases such as cancer, hypertension, and neurodegeneration. Viral proteases for their part are crucial for the pathogens' maturation and assembly. Several decades of research were devoted to exploring these precious therapeutic targets, often addressing them with synthetic substrate-based inhibitors to elucidate their biological roles and develop medications. The rational design of peptide-based inhibitors offered a rapid pathway to obtain a variety of research tools and drug candidates. Non-covalent modifiers were historically the first choice for protease inhibition due to their reversible enzyme binding mode and thus presumably safer profile. However, in recent years, covalent-irreversible inhibitors are having a resurgence with dramatic increase of their related publications, preclinical and clinical trials, and FDA-approved drugs. Depending on the context, covalent modifiers could provide more effective and selective drug candidates, hence requiring lower doses, thereby limiting off-target effects. Additionally, such molecules seem more suitable to tackle the crucial issue of cancer and viral drug resistances. At the frontier of reversible and irreversible based inhibitors, a new drug class, the covalent-reversible peptide-based inhibitors, has emerged with the FDA approval of Bortezomib in 2003, shortly followed by 4 other listings to date. The highlight in the field is the breathtakingly fast development of the first oral COVID-19 medication, Nirmatrelvir. Covalent-reversible inhibitors can hipothetically provide the safety of the reversible modifiers combined with the high potency and specificity of their irreversible counterparts. Herein, we will present the main groups of covalent-reversible peptide-based inhibitors, focusing on their design, synthesis, and successful drug development programs.

Negative Splenic Angiography in Blunt Trauma: Does Embolization Affect Splenic Salvage?

Angioembolization in blunt splenic trauma is used to maximize splenic preservation. Superiority of prophylactic embolization over expectant management in patients with a negative splenic angiography (SA) is debated. We hypothesized that embolization in negative SA would be associated with splenic salvage. Of 83 patients undergoing SA, 30 (36%) had a negative SA. Embolization was performed in 23 (77%). Grade of injury, contrast extravasation (CE) on computed tomography (CT) or embolization were not associated with splenectomy. In 20 patients with either a high-grade injury or CE on CT, 17 (85%) underwent embolization with a failure rate of 24%. In the remaining 10 without high-risk features, 6 underwent embolization with a 0% splenectomy rate. Despite embolization, the failure rate of nonoperative management (NOM) remains significant in those with high-grade injury or CE on CT. A low threshold for early splenectomy after prophylactic embolization is needed.

MCB-613 exploits a collateral sensitivity in drug resistant EGFR-mutant non-small cell lung cancer through covalent inhibition of KEAP1.

Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets EGFR-mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant, EGFR-mutant NSCLC cells.

Potentially Inappropriate Medications are Associated With Geriatric Trauma Recidivism.

INTRODUCTION: The American Geriatric Society has identified polypharmacy and categories of potentially inappropriate medication (PIM) that should be avoided in the elderly. These medications can potentially cause an increased risk of falls and traumatic events. MATERIALS AND METHODS: We conducted a retrospective study on elderly patients with traumatic injuries at a Level 1 trauma center. We compared patients having only one traumatic event and those with one or more traumatic events with the presence of prescriptions for PIMs. RESULTS: Identified high risk categories of anticoagulant and antiplatelet agents (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.08-1.28), psychiatric and neurologic agents (OR 1.32, 95% CI 1.22-1.43), as well as medication with anticholinergic properties (OR 1.14, 95% CI 1.03-1.27) were associated with an increased risk of recurrent trauma. CONCLUSIONS: We can quantify the risk of recurrent trauma with certain categories of PIM. Medication reconciliation and shared decision-making regarding the continued use of these medications may positively impact trauma recidivism.

Radiographic Outcomes following K-Wire Augmentation of Dorsal Spanning Plate Fixation for Intra-Articular Fractures of the Distal Radius.

Background Restoration of articular surface alignment is critical in treating intra-articular distal radius fractures. Dorsal spanning plate fixation functions as an internal distraction mechanism and can be advantageous in the setting of highly comminuted fracture patterns, polytrauma patients, and patients with radiocarpal instability. The addition of K-wires to support articular surface reduction potentially augments fracture repair stability. Questions/Purposes We examined the radiographic outcomes and maintenance of reduction in patients with comminuted intra-articular distal radius fractures treated with K-wire fixation of articular fragments followed by dorsal spanning plate application. Patients and Methods We reviewed 35 consecutive patients with complex intra-articular distal radius fractures treated with dorsal spanning plate and K-wire fixation between April 2016 and October 2019. AO classification was recorded: B1 (3), B3 (2), C2 (2), C3 (28). A two-tailed paired t -test was used to compare findings immediately post-dorsal spanning plate surgery and at final follow-up after dorsal spanning plate removal. Results Mean patient age was 43.3 years (19-78 years). Mean follow-up was 7.8 months (SD 4.3 months) from surgery and 2.5 months from pin removal (SD 2.6 months). All patients achieved radiographic union. Radial height (mean interval change (MIC) 0.2 mm, SD 2.2, p = 0.63), articular step-off (MIC 0.1 mm, SD 0.6 mm, p = 0.88), and radial inclination (MIC -1.1 degrees, SD 3.7 degrees, p = 0.10) did not change from post-surgery to final follow-up. Ulnar variance (MIC -0.9 mm, SD 2.0 mm, p = 0.02) and volar tilt (MIC -1.5 degrees, SD 4.4 degrees, p = 0.05) were found to have decreased. Conclusion Dorsal spanning plate augmented with K-wire fixation for comminuted intra-articular distal radius fractures in polytrauma patients allows for immediate weightbearing and maintains articular surface alignment at radiographic union and may provide better articular restoration than treatment with dorsal spanning plate alone. Level of Evidence This is a Level IV , therapeutic study.

The Unexpected Helical Supramolecular Assembly of a Simple Achiral Acetamide Tecton Generates Selective Water Channels.

Invited for the cover of this issue is the collaborative research team coordinated by Arie van der Lee at the University of Montpellier. The image depicts chiral channels with highly mobile water molecules resulting from the robust self-organization of a simple achiral acetamide. Fully reversible release and re-uptake of water molecules takes place near ambient conditions, with efficient water transport and a good selectivity against NaCl suggesting it to be an efficient candidate for desalination processes. Read the full text of the article at 10.1002/chem.20200383.

The Unexpected Helical Supramolecular Assembly of a Simple Achiral Acetamide Tecton Generates Selective Water Channels.

Achiral 2-hydroxy-N-(diphenylmethyl)acetamide (HNDPA) crystallizes in the P61 chiral space group as a hydrate, building up permeable chiral crystalline helical water channels. The crystallization-driven chiral self-resolution process is highly robust, with the same air-stable crystalline form readily obtained under a variety of conditions. Interestingly, the HNDPA supramolecular helix inner pore is filled by a helical water wire. The whole edifice is mainly stabilized by robust hydrogen bonds involving the HNDPA amide bonds and CH… π interactions between the HNDPA phenyl groups. The crystalline structure shows breathing behavior, with completely reversible release and re-uptake of water inside the chiral channel under ambient conditions. Importantly, the HNDPA channel is able to transport water very efficiently and selectively under biomimetic conditions. With a permeability per channel of 3.3 million water molecules per second in large unilamellar vesicles (LUV) and total selectivity against NaCl, the HNDPA channel is a very promising functional nanomaterial for future applications.

External validation of a pediatric decision rule for blunt abdominal trauma.

INTRODUCTION: Blunt traumatic injuries are a leading cause of morbidity and mortality in the pediatric population. Contrast-enhanced multidetector computed tomography is the best imaging tool for screening patients at risk of blunt abdominal injury. The Pediatric Emergency Care Applied Research Network (PECARN) abdominal rule was derived to identify patients at low risk for significant abdominal injury who do not require imaging. METHODS: We conducted a retrospective review of pediatric patients with blunt trauma to validate the PECARN rule in a non-pediatric specialized hospital from February 3, 2013, through December 31, 2019. We excluded those with penetrating or mild isolated head injury. The PECARN decision rule was retrospectively applied for the presence of a therapeutic intervention, defined as a laparotomy, angiographic embolization, blood transfusion, or administration of intravenous fluids for pancreatic or gastrointestinal injury. Sensitivity and specificity analysis were conducted along with the negative and positive predictive values. RESULTS: A total of 794 patients were included in the final analysis; 23 patients met the primary outcome for an acute intervention. The PECARN clinical decision rule (CDR) had a sensitivity of 91.3%, a negative predictive value of 99.5, and a negative likelihood ration of 0.16. CONCLUSION: In a non-pediatric specialty hospital, the PECARN blunt abdominal CDR performed with comparable sensitivity and negative predictive value to the derivation and external validation study performed at specialized children's hospitals.

Open Abdomen after Two Trauma Laparotomies: Do Diuretics Help?

Data are lacking regarding the use of diuretics in facilitating closure of the open abdomen (OA). For patients with an OA after 2 laparotomies, we hypothesized that diuretic use was associated with a higher rate of primary fascial closure than no diuretic use. A retrospective review of patients with trauma laparotomies over 7 years was performed. Primary fascial closure (PFC) was defined as apposition of fascial edges without interposition mesh. Of 321 patients, 30 (9%) remained with an OA after 2 laparotomies. Prior to the third laparotomy, median cumulative fluid balance was +12.6 L. Thirteen (43%) received diuretics. Primary fascial closure rates were similar for diuretic use vs no diuretic (38% vs 59%, P = .46). Primary fascial closure was not associated with age (P = .2), gender (P = 0.7), cumulative fluid balance (P = .3), or units of packed cells (P = .4). Diuretic use in trauma patients with an OA after 2 laparotomies was not associated with successful PFC.

Tracheostomy dislodgement: Are obese patients at increased risk?

BACKGROUND: Obesity is a risk factor for tracheostomy-related complications. We aimed to investigate whether obesity was associated with a risk of unplanned tracheostomy dislodgement or decannulation (DD). METHODS: Retrospective review of patients undergoing tracheostomy at a single institution from 2013 to 2019 was performed. The primary outcome was unplanned DD within 42 days. Obesity was assessed by body mass index (BMI) and skin-to-trachea distance (STT) measured on computed tomographic images. RESULTS: 25 (12%) episodes of unplanned DD occurred in 213 patients within 42 days. BMI ≥35 kg/m2 was associated with STT ≥80 mm (p < 0.0001). On multivariate analysis, STT ≥80 mm but not BMI was an independent predictor of unplanned DD (hazard ratio = 8.34 [95% confidence interval 2.85-24.4]). CONCLUSIONS: STT ≥80 mm was a better predictor of unplanned DD than BMI. Assessment of STT in addition to BMI may be useful to identify patients that would benefit from extended length tracheostomy tubes.

Ultrasound-assisted one-pot three-component synthesis of new isoxazolines bearing sulfonamides and their evaluation against hematological malignancies.

In the present study, following a one-pot two-step protocol, we have synthesized novel sulfonamides-isoxazolines hybrids (3a-r) via a highly regioselective 1,3-dipolar cycloaddition. The present methodology capitalized on trichloroisocyanuric acid (TCCA) as a safe and ecological oxidant and chlorinating agent for the in-situ conversion of aldehydes to nitrile oxides in the presence of hydroxylamine hydrochloride, under ultrasound activation. These nitrile oxides could be engaged in 1,3-dipolar cycloaddition reactions with various alkene to afford the targeted sulfonamides-isoxazolines hybrids (3a-r). The latter were assessed for their antineoplastic activity against model leukemia cell lines (Chronic Myeloid Leukemia, K562 and Promyelocytic Leukemia, HL-60).

Gut microbiota mediate the FGF21 adaptive stress response to chronic dietary protein-restriction in mice.

Chronic dietary protein-restriction can create essential amino acid deficiencies and induce metabolic adaptation through the hepatic FGF21 pathway which serves to maintain host fitness during prolonged states of nutritional imbalance. Similarly, the gut microbiome undergoes metabolic adaptations when dietary nutrients are added or withdrawn. Here we confirm previous reports that dietary protein-restriction triggers the hepatic FGF21 adaptive metabolic pathway and further demonstrate that this response is mediated by the gut microbiome and can be tuned through dietary supplementation of fibers that alter the gut microbiome. In the absence of a gut microbiome, we discover that FGF21 is de-sensitized to the effect of protein-restriction. These data suggest that host-intrinsic adaptive pathways to chronic dietary protein-restriction, such as the hepatic FGF21 pathway, may in-fact be responding first to adaptive metabolic changes in the gut microbiome.

Dual Covalent Inhibition of PKM and IMPDH Targets Metabolism in Cutaneous Metastatic Melanoma.

Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of patients with BRAFV600E cutaneous metastatic melanoma (CMM) eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming that profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase, the rate-limiting enzyme of de novo guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafenib-sensitive and vemurafenib-resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines in vitro. Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers. SIGNIFICANCE: Glycolytic and purine synthesis pathways are often deregulated in therapy-resistant tumors and can be targeted by the covalent inhibitor described in this study, suggesting its broad application for overcoming resistance in cancer.

Nanofibrous hyaluronic acid scaffolds delivering TGF-ß3 and SDF-1α for articular cartilage repair in a large animal model.

Focal cartilage injuries have poor intrinsic healing potential and often progress to osteoarthritis, a costly disease affecting almost a third of adults in the United States. To treat these patients, cartilage repair therapies often use cell-seeded scaffolds, which are limited by donor site morbidity, high costs, and poor efficacy. To address these limitations, we developed an electrospun cell-free fibrous hyaluronic acid (HA) scaffold that delivers factors specifically designed to enhance cartilage repair: Stromal Cell-Derived Factor-1α (SDF-1α; SDF) to increase the recruitment and infiltration of mesenchymal stem cells (MSCs) and Transforming Growth Factor-ß3 (TGF-ß3; TGF) to enhance cartilage tissue formation. Scaffolds were characterized in vitro and then deployed in a large animal model of full-thickness cartilage defect repair. The bioactivity of both factors was verified in vitro, with both SDF and TGF increasing cell migration, and TGF increasing matrix formation by MSCs. In vivo, however, scaffolds releasing SDF resulted in an inferior cartilage healing response (lower mechanics, lower ICRS II histology score) compared to scaffolds releasing TGF alone. These results highlight the importance of translation into large animal models to appropriately screen scaffolds and therapies, and will guide investigators towards alternative growth factor combinations. STATEMENT OF SIGNIFICANCE: This study addresses an area of orthopaedic medicine in which treatment options are limited and new biomaterials stand to improve patient outcomes. Those suffering from articular cartilage injuries are often destined to have early onset osteoarthritis. We have created a cell-free nanofibrous hyaluronic acid (HA) scaffold that delivers factors specifically designed to enhance cartilage repair: Stromal Cell-Derived Factor-1α (SDF-1α; SDF) to increase the recruitment and infiltration of mesenchymal stem cells (MSCs) and Transforming Growth Factor-ß3 (TGF-ß3; TGF) to enhance cartilage tissue formation. To our knowledge, this study is the first to evaluate such a bioactive scaffold in a large animal model and demonstrates the capacity for dual growth factor release.

Resorbable Pins to Enhance Scaffold Retention in a Porcine Chondral Defect Model.

OBJECTIVE: Cartilage repair strategies have seen improvement in recent years, especially with the use of scaffolds that serve as a template for cartilage formation. However, current fixation strategies are inconsistent with regards to retention, may be technically challenging, or may damage adjacent tissues or the implant itself. Therefore, the goal of this study was to evaluate the retention and repair potential of cartilage scaffolds fixed with an easy-to-implement bioresorbable pin. DESIGN: Electrospun hyaluronic acid scaffolds were implanted into trochlear groove defects in 3 juvenile and 3 adult pigs to evaluate short-term retention (2 weeks; pin fixation vs. press-fit and fibrin fixation) and long-term repair (8 months; scaffold vs. microfracture), respectively. RESULTS: For the retention study, press-fit and fibrin fixation resulted in short-term scaffold dislodgment (n = 2 each), whereas pin fixation retained all scaffolds that were implanted (n = 6). Pin fixation did not cause any damage to the opposing patellar surface, and only minor changes in the subchondral bone were observed. For long-term repair, no differences were observed between microfracture and scaffold groups, in terms of second-look arthroscopy and indentation testing. On closer visualization with micro computed tomography and histology, a high degree of variability was observed between animals with regard to subchondral bone changes and cartilage repair quality, yet each Scaffold repair displayed similar properties to its matched microfracture control. CONCLUSIONS: In this study, pin fixation did not cause adverse events in either the short- or the long-term relative to controls, indicating that pin fixation successfully retained scaffolds within defects without inhibiting repair.