Simultaneous enhancement of multiple functional properties using evolution-informed protein design.

A major challenge in protein design is to augment existing functional proteins with multiple property enhancements. Altering several properties likely necessitates numerous primary sequence changes, and novel methods are needed to accurately predict combinations of mutations that maintain or enhance function. Models of sequence co-variation (e.g., EVcouplings), which leverage extensive information about various protein properties and activities from homologous protein sequences, have proven effective for many applications including structure determination and mutation effect prediction. We apply EVcouplings to computationally design variants of the model protein TEM-1 ß-lactamase. Nearly all the 14 experimentally characterized designs were functional, including one with 84 mutations from the nearest natural homolog. The designs also had large increases in thermostability, increased activity on multiple substrates, and nearly identical structure to the wild type enzyme. This study highlights the efficacy of evolutionary models in guiding large sequence alterations to generate functional diversity for protein design applications.

Breaking New Ground in Interventional Pulmonology: Integrating Cone Beam CT and Robotic-Assisted Bronchoscopy for High-Risk Pneumothorax in Peripherally Located Solitary Pulmonary Nodules.

Lung cancer, a leading cause of global cancer-related deaths, necessitates the development of innovative diagnostic techniques. Traditional bronchoscopy, while useful, has limitations in diagnosing peripheral pulmonary lesions (PPLs) and carries a higher risk of complications such as pneumothorax. However, the field of interventional pulmonology has seen significant advancements, including the introduction of robotic-assisted bronchoscopy (RAB), cone-beam computed tomography (CBCT), radial endobronchial ultrasound (R-EBUS), and rapid on-site evaluation (ROSE). These advancements have greatly improved the precision of diagnosing high-risk PPLs. This report presents the case of a 60-year-old female smoker with chronic obstructive pulmonary disease and extensive centrilobular emphysema, who had a peripherally located high-risk pulmonary nodule. She was successfully diagnosed with metastatic adenocarcinoma using an integrated approach, despite the challenging location of the lesion and high risk of pneumothorax. The integration of RAB with CBCT and augmented fluoroscopy offers a groundbreaking approach for diagnosing and managing difficult-to-reach, high-risk pulmonary nodules, marking a significant stride in the field of interventional pulmonology.

Orthopaedic Hand Surgical Simulation Training: A Review.

In recent years, new orthopaedic surgical simulation and virtual reality (VR) training models have emerged to provide unlimited education medium to an unlimited number of trainees with no time limit, especially in response to trainee work-hour restrictions. Surgical simulators range from simple wooden boxes to animal and cadaver models to three-dimensional-printed and VR simulators. The coronavirus disease 2019 pandemic further highlighted the need for at-home learning tools for orthopaedic surgical trainees. Advancement in simulating shoulder and knee arthroscopies using VR simulators surpasses the other fields in orthopaedic surgery. Despite the high degree of precision needed to operate at a microscopic level involving vessels, nerves, and the small bones of the hand, the simulation tools have limited advancement in the field of orthopaedic hand surgery. This narrative review summarizes the status of surgical simulation and training techniques available to orthopaedic hand surgical trainees, factors affecting their application, and areas in hand surgery that still lag behind their surgical subspecialty counterparts.

Notice of retraction: Auraptene-induced cytotoxicity mechanisms in human malignant glioblastoma (U87) cells: role of reactive oxygen species (ROS).

[This retracts the article DOI: 10.17179/excli2019-1136.].

Anatomical determinants of occipitocervical fusion in skull base chordoma resection: a systematic review of the literature with illustrative cases.

OBJECTIVE: Skull base chordomas are rare, locally osseo-destructive lesions that present unique surgical challenges due to their involvement of critical neurovascular and bony structures at the craniovertebral junction (CVJ). Radical cytoreductive surgery improves survival but also carries significant morbidity, including the potential for occipitocervical (OC) destabilization requiring instrumented fusion. The published experience on OC fusion after CVJ chordoma resection is limited, and the anatomical predictors of OC instability in this context remain unclear. METHODS: PubMed and Embase were systematically searched according to the PRISMA guidelines for studies describing skull base chordoma resection and OC fusion. The search strategy was predefined in the authors' PROSPERO protocol (CRD42024496158). RESULTS: The systematic review identified 11 surgical case series describing 209 skull base chordoma patients and 116 (55.5%) who underwent OC instrumented fusion. Most patients underwent lateral approaches (n = 82) for chordoma resection, followed by midline (n = 48) and combined (n = 6) approaches. OC fusion was most often performed as a second-stage procedure (n = 53), followed by single-stage resection and fusion (n = 38). The degree of occipital condyle resection associated with OC fusion was described in 9 studies: total unilateral condylectomy reliably predicted OC fusion regardless of surgical approach. After lateral transcranial approaches, 4 studies cited at least 50%-70% unilateral condylectomy as necessitating OC fusion. After midline approaches-most frequently the endoscopic endonasal approach (EEA)-at least 75% unilateral condylectomy (or 50% bilateral condylectomy) led to OC fusion. Additionally, resection of the medial atlantoaxial joint elements (the C1 anterior arch and tip of the dens), usually via EEA, reliably necessitated OC fusion. Two illustrative cases are subsequently presented, further exemplifying how the extent of CVJ bony elements removed via EEA to achieve complete chordoma resection predicts the need for OC fusion. CONCLUSIONS: Unilateral total condylectomy, 50% bilateral condylectomy, and resection of the medial atlantoaxial joint elements were the most frequently described independent predictors of OC fusion in skull base chordoma resection. Additionally, consistent with the occipital condyle harboring a significantly thicker joint capsule at its posterolateral aspect, an anterior midline approach seems to tolerate a greater degree of condylar resection (75%) than a lateral transcranial approach (50%-70%) prior to generating OC instability.

A quality and readability comparison of artificial intelligence and popular health website education materials for common hand surgery procedures.

INTRODUCTION: ChatGPT and its application in producing patient education materials for orthopedic hand disorders has not been extensively studied. This study evaluated the quality and readability of educational information pertaining to common hand surgeries from patient education websites and information produced by ChatGPT. METHODS: Patient education information for four hand surgeries (carpal tunnel release, trigger finger release, Dupuytren's contracture, and ganglion cyst surgery) was extracted from ChatGPT (at a scientific and fourth-grade reading level), WebMD, and Mayo Clinic. In a blinded and randomized fashion, five fellowship-trained orthopaedic hand surgeons evaluated the quality of information using a modified DISCERN criteria. Readability and reading grade level were assessed using Flesch Reading Ease (FRE) and Flesch-Kincaid Grade Level (FKGL) equations. RESULTS: The Mayo Clinic website scored higher in terms of quality for carpal tunnel release information (p = 0.004). WebMD scored higher for Dupuytren's contracture release (p < 0.001), ganglion cyst surgery (p = 0.003), and overall quality (p < 0.001). ChatGPT - 4th Grade Reading Level, ChatGPT - Scientific Reading Level, WebMD, and Mayo Clinic written materials on average exceeded recommended reading grade levels (4th-6th grade) by at least four grade levels (10th, 14th, 13th, and 11th grade, respectively). CONCLUSIONS: ChatGPT provides inferior education materials compared to patient-friendly websites. When prompted to provide more easily read materials, ChatGPT generates less robust information compared to patient-friendly websites and does not adequately simplify the educational information. ChatGPT has potential to improve the quality and readability of patient education materials but currently, patient-friendly websites provide superior quality at similar reading comprehension levels.

Harnessing the capacity of phytochemicals to enhance immune checkpoint inhibitor therapy of cancers: A focus on brain malignancies.

Brain cancers, particularly glioblastoma multiforme (GBM), are challenging health issues with frequent unmet aspects. Today, discovering safe and effective therapeutic modalities for brain tumors is among the top research interests. Immunotherapy is an emerging area of investigation in cancer treatment. Since immune checkpoints play fundamental roles in repressing anti-cancer immunity, diverse immune checkpoint inhibitors (ICIs) have been developed, and some monoclonal antibodies have been approved clinically for particular cancers; nevertheless, there are significant concerns regarding their efficacy and safety in brain tumors. Among the various tools to modify the immune checkpoints, phytochemicals show good effectiveness and excellent safety, making them suitable candidates for developing better ICIs. Phytochemicals regulate multiple immunological checkpoint-related signaling pathways in cancer biology; however, their efficacy for clinical cancer immunotherapy remains to be established. Here, we discussed the involvement of immune checkpoints in cancer pathology and summarized recent advancements in applying phytochemicals in modulating immune checkpoints in brain tumors to highlight the state-of-the-art and give constructive prospects for future research.

One-Point Technique in Brainstem Cavernous Malformation Surgery: Evaluation of Approaches and Outcomes From a Different Perspective.

BACKGROUND AND OBJECTIVES: Brainstem cavernous malformations (BCMs) are a distinct clinical entity that carry a high risk of patient morbidity because of location and risk of hemorrhage. Surgical management of these lesions requires intimate knowledge of surgical anatomy and skull base approaches. This article is intended to highlight a modern approach for the treatment of BCMs, with an emphasis on the use of the one-point technique to guide resection. METHODS: We describe a case series of BCMs treated through a variety of skull base approaches, describing our decision-making strategy. We review the concept of the one-point technique focusing on the safest access to the malformation through 2 representative cases and also perform a retrospective review of 32 consecutive patients who underwent BCM resection to present outcomes and the comparison of two-point vs one-point techniques. RESULTS: Consecutive series of 32 patients in whom the one-point technique was used is presented. In 8 patients (25%), the traditional two-point technique would suggest a different trajectory than the one-point technique. Postoperative MRI confirmed complete resection in 30 patients (95%), and 29 patients (91%) had modified Rankin Scale (0-2) at follow-up. All patients in whom the one-point technique guided a different trajectory had gross total removal of the cavernous malformation, with one patient having long-term new neurological impairment from the surgery. There were no mortalities. CONCLUSION: Despite surgical advances in recent decades and more widespread understanding of surgical anatomy and safe entry zones, surgical resection of BCMs remains a formidable challenge. While not necessarily the shortest access, the one-point technique offers a safe approach considering all the different modalities in our armamentarium and can be used as part of a strategy to determine the optimal approach to resect BCMs.

Unique presentation of an endemic opportunistic fungal infection: Disseminated coccidioidomycosis mimicking metastatic lung cancer with endotracheal and endobronchial involvement.

Coccidioidomycosis is a fungal infection primarily Endemic in the Southwest United States. Disseminated Coccidioidomycosis is a life-threatening variant that mainly occurs in an immunocompromised host. This report describes an unusual presentation of disseminated Coccidioidomycosis in an immunocompetent individual. The patient was admitted with a subacute cough, progressively worsening shortness of breath, significant weight loss, nodular skin lesions in upper extremities, and acute hypoxemic respiratory failure. Chest imaging revealed extensive nodularity and mass-like lesions. What sets this case apart is the significant endotracheal and endobronchial involvement, which mimicked metastatic lung cancer. The diagnosis was confirmed through serology and bronchoscopy biopsy. This case underscores the critical importance of considering detailed travel history and maintaining a high index of suspicion for fungal infections in patients with endobronchial lesions, particularly in regions where Coccidioidomycosis is endemic.

The role of surgical disconnection for posterior fossa pial arteriovenous fistulas and dural fistulas with pial supply: an illustrative case series.

BACKGROUND: Pial arteriovenous fistulas (pAVFs) are rare vascular malformations characterized by high-flow arteriovenous shunting involving a cortical arterial supply directly connecting to venous drainage without an intermediate nidus. Dural arteriovenous fistulas (dAVFs) can infrequently involve additional pial feeders which can introduce higher flow shunting and increase the associated treatment risk. In the posterior fossa, arteriovenous fistula (AVF) angioarchitecture tends to be particularly complex, involving either multiple arterial feeders-sometimes from both dural and pial origins-or small caliber vessels that are difficult to catheterize and tend to be intimately involved with functionally critical brainstem or upper cervical cord structures. Given their rarity, published experience on microsurgical or endovascular treatment strategies for posterior fossa pAVFs and dAVFs with pial supply remains limited. METHODS: Retrospective chart review from 2019-2023 at a high-volume center identified six adult patients with posterior fossa pAVFs that were unable to be fully treated endovascularly and required microsurgical disconnection. These cases are individually presented with a technical emphasis and supported by comprehensive angiographic and intraoperative images. RESULTS: One vermian (Case 1), three cerebellopontine angle (Cases 2-4) and two craniovertebral junction (Cases 5-6) posterior fossa pAVFs or dAVFs with pial supply are presented. Three cases involved mixed dural and pial arterial supply (Cases 1, 4, and 6), and one case involved a concomitant microAVM (Case 2). Endovascular embolization was attempted in four cases (Cases 1-4): The small caliber and tortuosity of the main arterial feeder prevented catheterization in two cases (Cases 1 and 3). Partial embolization was achieved in Cases 2 and 4. In Cases 5 and 6, involvement of the lateral spinal artery or anterior spinal artery created a prohibitive risk for endovascular embolization, and surgical clip ligation was pursued as primary management. In all cases, microsurgical disconnection resulted in complete fistula obliteration without evidence of recurrence on follow-up imaging (mean follow-up 27.1 months). Two patients experienced persistent post-treatment sensory deficits without significant functional limitation. CONCLUSIONS: This illustrative case series highlights the technical difficulties and anatomical limitations of endovascular management for posterior fossa pAVFs and dAVFs with pial supply and emphasizes the relative safety and utility of microsurgical disconnection in this context. A combined approach involving partial preoperative embolization-when the angioarchitecture is permissive-can potentially decrease surgical morbidity. Larger studies are warranted to better define the role for multimodal intervention and to assess associated long-term AVF obliteration rates in the setting of pial arterial involvement.

Experimental exploration of fracture behavior (pure mode III) in eco-friendly steel fiber-reinforced self-compacting concrete with waste tempered glass as coarse aggregates.

To aid in the creation of sustainable structures, scientists have utilized waste materials found in the environment to serve as alternatives for traditional resources in the construction sector. They have undertaken extensive investigations pertaining to this matter. In this particular study, tempered glass as waste glass coarse aggregate (WGCA) was substituted for natural coarse aggregate (NCA) at varying proportions of 15%, 30%, and 45% in the formulation of eco-friendly self-compacting concrete (SCC), combined with hooked-end steel fibers (SFs) at various volumes. The study assessed concrete's flowability, permeability, compressive strength, and fracture parameters at 28 and 56 days. A total of 240 edge-notched disc bending samples (ENDB) and 60 cubic samples (150 × 150 mm) were tested to assess fracture resilience and compressive strength, respectively. The results showed that increasing SF and WGCA content reduced slump flow diameter and blockage ratio, particularly at higher levels. The solidified characteristics of all specimens incorporating SF and WGCA displayed heightened attributes when contrasted with the reference sample. Among the entire array of specimens, WG15SF0.5 and WG30SF0.5 exhibited the most superior performance, demonstrating an average percentage elevation of 20.29 and 27.63 in both compressive strength and fracture toughness assessments across the different curing periods. SF had the most significant impact on post-cracking behavior by enhancing load-bearing capacity through a bridging fiber mechanism. Through a comparison of the influence of SFs and WGCA on the fracture toughness of pure mode III, it was observed that the inclusion of SF in samples with a 30% replacement of WGCA resulted in an average increase of approximately 15.48% and 11.1% in this mode at the ages of 28 and 56 days, respectively, compared to the control sample.

Application of RNA-based therapeutics in glioma: A review.

Despite the extensive advancements made in the field of cancer therapy, the outlook of individuals suffering from glioblastoma multiforme remains highly detrimental. The absence of specific treatments for cancerous cells significantly hinders the effectiveness of conventional anticancer techniques. Multiple research studies have demonstrated that the suppression of specific genes or the augmentation of therapeutic proteins through RNA-based therapeutics may represent a valuable approach when combined with chemotherapy or immunotherapy. In recent years, there has been a significant increase in the application of RNA therapeutics in conjunction with chemotherapy and immunotherapy. This emerging field has become a prominent area of research for advancing various types of cancer treatments. The present investigation provides an in-depth overview of the classification and application of RNA therapy, focusing on the mechanisms of RNA antitumor treatment and the current status of clinical studies on RNA drugs.

Advances in liposome-based delivery of RNA therapeutics for cancer treatment.

Liposomal drug delivery systems stand as versatile therapeutic platforms for precisely targeting related elements in cancerous tissues owing to their intrinsic passive and acquired active targeting capabilities and exceptional compatibility with physiologic environments. When the capacity of liposomes as nanocarriers is combined with the revolutionary potential of RNA therapies in affecting undruggable targets, the outcome would be promising drug candidates as game-changers in the cancer treatment arena. However, optimizing liposome composition, physicochemical properties, and surface chemistry is paramount to maximizing their pharmacokinetic and pharmacodynamic attributes. This review highlighted the potential of liposomes as nanovehicles for RNA therapeutics through a literature review and looked at the most recent preclinical and clinical advancements in utilizing liposomal RNA therapeutics for cancer management. Notably, the discovery of novel targets, advancements in liposome engineering, and organizing well-planned clinical trials would help uncover the incredible potential of these nanotherapeutics in cancer patients.

Impact of Cerebral Revascularization on Pial Collateral Flow in Patients With Unilateral Moyamoya Disease Using Quantitative Magnetic Resonance Angiography.

BACKGROUND AND OBJECTIVES: Moyamoya disease (MMD) is a chronic steno-occlusive disease of the intracranial circulation that depends on neoangiogenesis of collateral vessels to maintain cerebral perfusion and is primarily managed with cerebral revascularization surgery. A quantitative assessment of preoperative and postoperative collateral flow using quantitative magnetic resonance angiography with noninvasive optimal vessel analysis (NOVA) was used to illustrate the impact of revascularization on cerebral flow distribution. METHODS: A retrospective review of patients with unilateral MMD who underwent direct, indirect, or combined direct/indirect cerebral revascularization surgery was conducted between 2011 and 2020. Using NOVA, flow was measured at the anterior cerebral artery (ACA), ACA distal to the anterior communicating artery (A2), middle cerebral artery (MCA), posterior cerebral artery (PCA), and PCA distal to the posterior communicating artery (P2). Pial flow (A2 + P2) and collateral flow (ipsilateral [A2 + P2])-(contralateral [A2 + P2]) were measured and compared before and after revascularization surgery. Total hemispheric flow (MCA + A2 + P2) with the addition of the bypass graft flow postoperatively was likewise measured. RESULTS: Thirty-four patients with unilateral MMD underwent cerebral revascularization. Median collateral flow significantly decreased from 68 to 39.5 mL/min (P = .007) after bypass. Hemispheres with maintained measurable bypass signal on postoperative NOVA demonstrated significant reduction in median collateral flow after bypass (P = .002). Median total hemispheric flow significantly increased from 227 mL/min to 247 mL/min (P = .007) after bypass. Only one patient suffered an ipsilateral ischemic stroke, and no patients suffered a hemorrhage during follow-up. CONCLUSION: NOVA measurements demonstrate a reduction in pial collateral flow and an increase in total hemispheric flow after bypass for MMD, likely representing a decrease in leptomeningeal collateral stress on the distal ACA and PCA territories. Further studies with these measures in larger cohorts may elucidate a role for NOVA in predicting the risk of ischemic and hemorrhagic events in MMD.

Far Lateral Approach With C1 Hemilaminotomy for Excision of a Ruptured Fusiform Lateral Spinal Artery Aneurysm: 2-Dimensional Operative Video.

The lateral spinal artery (LSA) represents the most rostral extent of the posterolateral arterial axis of the spinal cord and supplies both the posterior and lateral aspects of the spinal cord.1 The LSA originates from either the intradural segment of vertebral artery or the lateral segment of the posterior inferior cerebellar artery.1,2 It terminates at the level of C5 because it anastomoses with the posterior spinal artery. Although the LSA is in communication with the subarachnoid space, subarachnoid hemorrhage (SAH) due to an LSA aneurysm is rare.3-6 Moreover, accurate diagnosis of vascular pathologies involving the LSA is challenging because the LSA is typically too small to be visualized with conventional angiography.2 Here, we present the case of a 74-year-old woman who presented to our institution with headache, nausea, and confusion due to posterior fossa SAH without any visible vascular malformation on initial diagnostic cerebral angiography. A right frontal external ventricular drain was placed for communicating hydrocephalus. Immediate cerebral angiogram was within normal limits. Two-week follow-up angiogram demonstrated a fusiform right LSA aneurysm. The endovascular treatment was not an option because of the risk of occlusion of proximal perforators of the right posterior spinal artery, resulting in a long segment ischemia. The patient underwent a right far lateral transcondylar approach with C1 hemilaminotomy and excision of the LSA aneurysm. The postoperative course was uneventful. The patient was neurologically intact. Six-month follow-up angiogram showed no evidence of residual aneurysm. LSA pathologies should be kept in mind with posterior fossa SAH. Surgical excision is an effective treatment option in carefully selected patients. The patient consented to the procedure.

Effectiveness of Arthroscopic Debridement, Trapeziectomy, and Joint Replacement for Trapeziometacarpal Joint Osteoarthritis: A Meta-Analysis of Pre and Postoperative Pain Scores.

Trapeziometacarpal joint osteoarthritis (TMJO) affects up to 33% of postmenopausal women, leading to pain, reduced mobility, and grip strength, with initial treatments focusing on non-surgical options like injections, orthoses, and exercises before considering surgery. A major challenge in managing TMJO involves selecting the optimal surgical strategy that is customized to individual clinical conditions. This study aimed to compare the effectiveness of three common surgical interventions for TMJO in relieving pain, including arthroscopic debridement (AD), trapeziectomy (TRAP), and joint replacement (JR). PubMed, Cochrane, Embase, and MEDLINE databases were queried according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for studies that presented pain outcomes following intervention for TMJO. Pain scores were reported preoperatively and postoperatively using the visual analog scale (VAS). Inclusion criteria included studies published in Q1 and Q2 journals and those with a follow-up of > six months. The final selection comprised 18 studies with 763 patients treated with AD (n = 102, 13%), TRAP (n = 428, 56%), and JR (n = 233, 31%) between 2010 and 2023, with a mean follow-up period of 38 ± 28 months. The studies included a total of 24 groups, five of which received AD, 13 of which received TRAP, and six of which received JR. The mean preoperative VAS was 6.7 ± 1.7, and the mean postoperative VAS was 1.7 ± 1.3 for all groups (P < 0.001). The meta-analysis demonstrated a mean preoperative pain score of 5.8 (95% CI, 4.1-7.5) for AD, 6.6 (95% CI, 5.7-7.5) for TRAP, and 7.8 (95% CI, 7.0-8.7) for JR. Postoperatively, there was a mean pain score of 2.2 (95% CI, 0.1-4.2) for AD, 1.4 (95% CI, 1.1-1.7) for TRAP, and 0.9 (95% CI, 0.6-1.2) for JR. This study showed that, if appropriately indicated, joint preservation with AD may be as effective as TRAP and JR for reducing pain associated with TMJO in the short term. However, the rate of conversion or revision should be assessed in future studies.