An epidermal growth factor receptor-targeting immunotoxin based on IgG shows potent antitumor activity against head and neck cancer.

The epidermal growth factor receptor (EGFR) is an important target for cancer therapies. Many head and neck cancer (HNC) cells have been reported to overexpress EGFR; therefore, anti-EGFR therapies have been attempted in patients with HNC. However, its clinical efficacy is limited owing to the development of drug resistance. In this study, we developed an EGFR-targeting immunotoxin consisting of a clinically proven anti-EGFR IgG (cetuximab; CTX) and a toxin fragment (LR-LO10) derived from Pseudomonas exotoxin A (PE) using a novel site-specific conjugation technology (peptide-directed photo-crosslinking reaction), as an alternative option. The immunotoxin (CTX-LR-LO10) showed specific binding to EGFR and properties of a typical IgG, such as stability, interactions with receptors of immune cells, and pharmacokinetics, and inhibited protein synthesis via modification of elongation factor-2. Treatment of EGFR-positive HNC cells with the immunotoxin resulted in apoptotic cell death and the inhibition of cell migration and invasion. The efficacy of CTX-LR-LO10 was evaluated in xenograft mouse models, and the immunotoxin exhibited much stronger tumor suppression than CTX or LR-LO10. Transcriptome analyses revealed that the immunotoxins elicited immune responses and altered the expression of genes related to its mechanisms of action. These results support the notion that CTX-LR-LO10 may serve as a new therapeutic agent targeting EGFR-positive cancers.

Deciphering head and neck cancer microenvironment: Single-cell and spatial transcriptomics reveals human papillomavirus-associated differences.

Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV- associated HNSCC is increasing. The role of tumor microenvironment in viral infection and metastasis needs to be explored further. We studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status. Eight samples for single-cell RNA profiling and six samples for spatial transcriptomics (ST), composed of matched primary tumors (PT) and lymph node metastases (LNMT), were collected from both HPV- negative (HPV- ) and HPV-positive (HPV+ ) patients. Using the 10x Genomics Visium platform, integrative analyses with single-cell RNA sequencing were performed. Intracellular and intercellular alterations were analyzed, and the findings were confirmed using experimental validation and publicly available data set. The HPV+ tissues were composed of a substantial amount of lymphoid cells regardless of the presence or absence of metastasis, whereas the HPV- tissue exhibited remarkable changes in the number of macrophages and plasma cells, particularly in the LNMT. From both single-cell RNA and ST data set, we discovered a central gene, pyruvate kinase muscle isoform 1/2 (PKM2), which is closely associated with the stemness of cancer stem cell-like populations in LNMT of HPV- tissue. The consistent expression was observed in HPV- HNSCC cell line and the knockdown of PKM2 weakened spheroid formation ability. Furthermore, we found an ectopic lymphoid structure morphology and clinical effects of the structure in ST slide of the HPV+ patients and verified their presence in tumor tissue using immunohistochemistry. Finally, the ephrin-A (EPHA2) pathway was detected as important signals in angiogenesis for HPV- patients from single-cell RNA and ST profiles, and knockdown of EPHA2 declined the cell migration. Our study described the distinct cellular composition and molecular alterations in primary and metastatic sites in HNSCC patients based on their HPV status. These results provide insights into HNSCC biology in the context of HPV infection and its potential clinical implications.

Liquid plasma promotes angiogenesis through upregulation of endothelial nitric oxide synthase-induced extracellular matrix metabolism: potential applications of liquid plasma for vascular injuries.

BACKGROUND: Applications of nonthermal plasma have expanded beyond the biomedical field to include antibacterial, anti-inflammatory, wound healing, and tissue regeneration. Plasma enhances epithelial cell repair; however, the potential damage to deep tissues and vascular structures remains under investigation. RESULT: This study assessed whether liquid plasma (LP) increased nitric oxide (NO) production in human umbilical vein endothelial cells by modulating endothelial NO synthase (eNOS) phosphorylation and potential signaling pathways. First, we developed a liquid plasma product and confirmed the angiogenic effect of LP using the Matrigel plug assay. We found that the NO content increased in plasma-treated water. NO in plasma-treated water promoted cell migration and angiogenesis in scratch and tube formation assays via vascular endothelial growth factor mRNA expression. In addition to endothelial cell proliferation and migration, LP influenced extracellular matrix metabolism and matrix metalloproteinase activity. These effects were abolished by treatment with NG-L-monomethyl arginine, a specific inhibitor of NO synthase. Furthermore, we investigated the signaling pathways mediating the phosphorylation and activation of eNOS in LP-treated cells and the role of LKB1-adenosine monophosphate-activated protein kinase in signaling. Downregulation of adenosine monophosphate-activated protein kinase by siRNA partially inhibited LP-induced eNOS phosphorylation, angiogenesis, and migration. CONCLUSION: The present study suggests that LP treatment may be a novel strategy for promoting angiogenesis in vascular damage. Video Abstract.

Feasibility of Noninvasive Assessment of Cardiac Output during Exercise in Healthy Adults by a Novel Elaboration on Systolic Time Intervals.

BACKGROUND: Although assessment of cardiovascular hemodynamics during exercise can provide clinical insights, it is challenging to acquire it in clinical settings. OBJECTIVES: Accordingly, this preliminary study was to determine whether a novel elaboration on systolic time interval measures (eSTICO) method of quantifying cardiac output and stroke volume was comparable to those obtained using a validated soluble gas (open circuit CO measure [OpCircCO]) method or calculation based on oxygen consumption (oxygen consumption-based CO [VO2CO]) during exercise. METHODS: For the present study, 14 healthy subjects (male: n = 12, female: n = 2) performed incremental exercise on a recumbent cycle ergometer. At rest and during exercise, cardiac output (CO) was obtained via the eSTICO method, while the OpenCircCO and VO2CO measures were obtained at the last minute of each workload. RESULTS: At peak, there was no difference between eSTICO and OpCircCO (12.39 ± 3.06 vs. 13.96 ± 2.47 L/min, p > 0.05), while there was a slight difference between eSTICO and VO2CO (12.39 ± 3.06 vs. 14.28 ± 2.55 L/min, p < 0.05). When we performed correlation analysis with all subjects and all measures of CO at all WL, between eSTICO and OpenCircCO, there was a good relationship (r = 0.707, p < 0.001) with a Bland and Altman agreement analysis demonstrating a -1.6 difference (95% LoA: -6.3-3.5). Between eSTICO and VO2CO, we observed an r = 0.865 (p < 0.001) and a Bland and Altman agreement analysis with a -1.2 difference (95% LoA: -4.8-2.4). CONCLUSION: A novel exploitation of cardiac hemodynamics using systolic timing intervals may allow a relatively good assessment of CO during exercise in healthy adults.

The effect of teriparatide on fracture healing after atypical femoral fracture: A systematic review and meta-analysis.

This meta-analysis demonstrated that a greater prevalence of delayed union and nonunion and a longer time to fracture healing in the group that did not receive TPTD treatment after AFFs than in the group that received TPTD treatment. PURPOSE: To date, there is no hard evidence for medical management after atypical femoral fracture (AFF), even though weak data indicate faster healing with teriparatide (TPTD). Herein, we aimed to investigate the effect of postfracture TPTD treatment on AFF healing using a pairwise meta-analysis focusing on delayed union, nonunion, and fracture healing time. METHODS: A systematic search of the MEDLINE (PUBMED), Embase, and Cochrane Library databases was performed for studies investigating the effect of TPTD after AFF up to October 11, 2022. We compared the incidence of delayed union and nonunion and the time of fracture healing between the TPTD ( +) and TPTD (-) groups. RESULTS: The 6 studies analyzed a total of 214 AFF patients, including 93 who received TPTD therapy after AFF and 121 who did not. The pooled analysis showed a significantly higher rate of delayed union in the TPTD (-) group than in the TPTD ( +) group (OR, 0.24; 95% CI, 0.11-0.52; P < 0.01; I2 = 0%), and a higher nonunion rate was observed in the TPTD (-) group than in the TPTD ( +) group with low heterogeneity (OR, 0.21; 95% CI, 0.06-0.78; P = 0.02; I2 = 0%). The TPTD (-) group required 1.69 months longer to achieve fracture union than the TPTD ( +) group, with statistical significance (MD = - 1.69, 95% CI: - 2.44 to - 0.95, P < 0.01; I2 = 13%). Subgroup analysis for patients with complete AFF showed that the TPTD (-) group had a higher rate of delayed union with low heterogeneity (OR, 0.22; 95% CI, 0.10-0.51; P < 0.01; I2 = 0%), but there was no significant difference in the nonunion rate between TPTD ( +) and TPTD (-) groups (OR, 0.35; 95% CI, 0.06-2.21; P = 0.25; I2 = 0%). Fracture healing took significantly longer in the TPTD (-) group (MD = - 1.81, 95% CI: - 2.55 to - 1.08; P < 0.01; I2 = 48%). The reoperation rate showed no significant difference between the two groups (OR, 0.29; 95% CI, 0.07-1.20; P = 0.09; I2 = 0%). CONCLUSIONS: The current meta-analysis supported the hypothesis that TPTD treatment following AFF might benefit fracture healing, lowering the rate of delayed union and nonunion and shortening the fracture healing time.

Cerebral Small Vessel Disease Burden and Futile Reperfusion after Endovascular Treatment for Patients with Acute Ischemic Stroke.

INTRODUCTION: Cerebral small vessel disease (SVD) burden includes increased risk of poor functional outcomes after acute ischemic stroke (AIS). We aimed to investigate the impact of cerebral SVD on 3-month functional outcomes in patients with AIS who received endovascular treatment (EVT) and to determine whether SVD is associated with futile reperfusion (FR). METHODS: Using a multicenter stroke registry, we analyzed consecutive patients with AIS with either intracranial and/or extracranial anterior circulation large artery occlusion, who were treated with EVT and achieved successful reperfusion (thrombolysis in cerebral infarction grade 2b-3). The cerebral SVD burden was evaluated using baseline brain magnetic resonance imaging using a modified Fazekas score (mFS). The main outcome variable was FR, defined as poor functional outcomes (modified Rankin scale 3-6) at 3 months after stroke, despite successful recanalization. Secondary outcomes included stroke progression/recurrence and any hemorrhagic transformation. RESULTS: Among 10,890 patients with AIS, 577 (5.3%) received EVT within 12 h of onset, including 354 who met study eligibility criteria. FR was observed in 191 patients (53.5%) and was positively associated with SVD burden. After adjustment for covariates including age, sex, stroke etiology, initial stroke severity, collateral status, Alberta stroke program early CT score, initial serum glucose, systemic blood pressure, and vascular risk factors, mFS grade 3 was significantly associated with FR (odds ratio: 3.93, 95% confidence interval: 1.602-9.619; p = 0.003). CONCLUSIONS: We demonstrated that cerebral SVD assessed with baseline brain MRI is associated with the futility of successful recanalization after EVT and any hemorrhagic transformation but not with early stroke progression or recurrence. Nevertheless, our findings do not justify withholding EVT in otherwise eligible patients with AIS based on the presence of severe SVD.

Production of highly pure R,R-2,3-butanediol for biological plant growth promoting agent using carbon feeding control of Paenibacillus polymyxa MDBDO.

BACKGROUND: Chemical fertilizers have greatly contributed to the development of agriculture, but alternative fertilizers are needed for the sustainable development of agriculture. 2,3-butanediol (2,3-BDO) is a promising biological plant growth promoter. RESULTS: In this study, we attempted to develop an effective strategy for the biological production of highly pure R,R-2,3-butanediol (R,R-2,3-BDO) by Paenibacillus polymyxa fermentation. First, gamma-ray mutagenesis was performed to obtain P. polymyxa MDBDO, a strain that grew faster than the parent strain and had high production of R,R-2,3-BDO. The activities of R,R-2,3-butanediol dehydrogenase and diacetyl reductase of the mutant strain were increased by 33% and decreased by 60%, respectively. In addition, it was confirmed that the carbon source depletion of the fermentation broth affects the purity of R,R-2,3-BDO through batch fermentation. Fed-batch fermentation using controlled carbon feeding led to production of 77.3 g/L of R,R-2,3-BDO with high optical purity (> 99% of C4 products) at 48 h. Additionally, fed-batch culture using corn steep liquor as an alternative nitrogen source led to production of 70.3 g/L of R,R-2,3-BDO at 60 h. The fed-batch fermentation broth of P. polymyxa MDBDO, which contained highly pure R,R-2,3-BDO, significantly stimulated the growth of soybean and strawberry seedlings. CONCLUSIONS: This study suggests that P. polymyxa MDBDO has potential for use in biological plant growth promoting agent applications. In addition, our fermentation strategy demonstrated that high-purity R,R-2,3-BDO can be produced at high concentrations using P. polymyxa.

One-year change in handgrip strength in patients with hip fracture: a prospective comparison with hip disease.

BACKGROUND: Handgrip strength (HGS) has been adopted as one of the diagnostic tools for sarcopenia and is gaining attention because of its association with osteoporotic hip fractures. Longitudinal data of HGS at multiple follow-up intervals in older hip fractures are lacking. We aimed to investigate and compare the HGS changes in patients with hip fracture within 1-year with those in patients with hip diseases. METHODS: This prospective study was conducted between June 2018 and July 2020. The HGS was measured preoperatively, at predischarge, and at 3, 6, and 12 months postoperatively. We prospectively compared the number of patients with low muscle strength (LMS) as well as the HGS changes over time between the two groups. RESULTS: A total of 115 consecutive patients with hip fracture (n = 58) and hip disease (57) were enrolled. The rate of preoperative LMS was higher in the hip fracture group than control (P = 0.005), but there was no significant difference in the postoperative period (P = 0.343). The mean HGS was lower in the hip fracture group at all measured time periods. The preoperative HGS increased right before discharge (15.2 kg to 17.0 kg), and plateaued thereafter 1-year in the fracture group, whereas there were no statistically significant changes in serial follow-up trends in the control group. CONCLUSIONS: The preoperative HGS in fracture patients may have been underestimated, due to different position of the arm, insufficient practice, or pain. Subsequently, HGS was rather constant during 1-year indicating no development of general sarcopenia after treatment for hip fracture. Therefore, in hip fracture patients, the predischarge HGS might be more reliable than preoperative HGS.

Plasma Surface Modification of 3Y-TZP at Low and Atmospheric Pressures with Different Treatment Times.

The efficiency of plasma surface modifications depends on the operating conditions. This study investigated the effect of chamber pressure and plasma exposure time on the surface properties of 3Y-TZP with N2/Ar gas. Plate-shaped zirconia specimens were randomly divided into two categories: vacuum plasma and atmospheric plasma. Each group was subdivided into five subgroups according to the treatment time: 1, 5, 10, 15, and 20 min. Following the plasma treatments, we characterized the surface properties, including wettability, chemical composition, crystal structure, surface morphology, and zeta potential. These were analyzed through various techniques, such as contact angle measurement, XPS, XRD, SEM, FIB, CLSM, and electrokinetic measurements. The atmospheric plasma treatments increased zirconia's electron donation (γ-) capacity, while the vacuum plasma treatments decreased γ- parameter with increasing times. The highest concentration of the basic hydroxyl OH(b) groups was identified after a 5 min exposure to atmospheric plasmas. With longer exposure times, the vacuum plasmas induce electrical damage. Both plasma systems increased the zeta potential of 3Y-TZP, showing positive values in a vacuum. In the atmosphere, the zeta potential rapidly increased after 1 min. Atmospheric plasma treatments would be beneficial for the adsorption of oxygen and nitrogen from ambient air and the generation of various active species on the zirconia surface.

Impact of concomitant upper-extremity injuries in patients with hip fractures: a systematic review and meta-analysis.

INTRODUCTION: Combined hip and upper-extremity fractures raise clinical concerns because upper-extremity fractures may hinder early mobilization, thereby affecting rehabilitation and mortality. This systematic review and meta-analysis aimed to evaluate the effects of combined upper-extremity and hip fractures on rehabilitation and mortality. MATERIALS AND METHODS: We systematically searched MEDLINE, Embase, and the Cochrane Library for studies published before March 20, 2022, that evaluated the impact of concomitant upper-extremity injuries in geriatric patients with hip fractures. The pooled analysis identified differences in the (1) length of hospital stay, (2) discharge destination, and (3) mortality rates between the isolated and combined hip fracture groups. RESULTS: A total of 217,233 patients with isolated hip fractures (n = 203,816) and combined hip and upper-extremity fractures (n = 13,417) from 12 studies were analyzed. The average length of hospital stay was significantly longer in the combined upper-extremity fracture group than in the isolated hip fracture group (mean difference = 1.67 days; 95% confidence interval [CI] 0.63-2.70; P = 0.002). Patients in the combined upper limb fracture group were less likely to be discharged directly home (odds ratio [OR] = 0.64; 95% CI 0.52-0.80; P < 0.001) and showed significantly higher 30-day mortality (OR = 1.44; 95% CI 1.32-1.58; P < 0.001). The mortality rate after 30 days was not significantly different between the two groups. CONCLUSIONS: Concomitant upper-extremity fractures have debilitating effects on rehabilitation and early mortality in geriatric patients with hip fractures. Therefore, more focus should be placed on the early ambulation of patients with hip fractures and simultaneous upper limb fractures to promote rehabilitation and alleviate the public health burden. LEVEL OF EVIDENCE: III meta-analysis.

Forte ceramic-on-delta ceramic cementless total hip arthroplasty: an 8- to 15-year follow-up study.

INTRODUCTION: Forte ceramic head on delta ceramic liner articulation showed satisfactory midterm results without ceramic-related complication. We aimed to investigate the clinical and radiological outcomes of cementless total hip arthroplasty (THA) with forte ceramic head on delta ceramic liner articulation. MATERIALS AND METHODS: Overall, 107 patients (57 men, 50 women; 138 hips) who underwent cementless THA with forte ceramic head on delta ceramic liner articulation were enrolled. The mean follow-up duration was 11.6 years. For the clinical assessments, Harris hip score (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), presence of thigh pain, and presence of squeaking were evaluated. Radiographs were assessed to search for osteolysis, stem subsidence, loosening of implants. Kaplan-Meier survival curves were evaluated. RESULTS: The mean HHS and WOMAC improved from 57.1 and 28.1 preoperatively to 81.4 and 13.1 at the final follow-up, respectively. Nine revisions (6.5%) were performed; 5 hips for stem loosening, 1 hip for ceramic liner fracture, 2 hips for periprosthetic fracture, and 1 hip for progressive osteolysis around cup and stem. Thirty-two patients (37 hips) complained squeaking, in which 4 cases (2.9%) were identified as ceramic-related noises. After a mean follow-up period of 11.6 years, 91% (95% CI 87.8-94.2) were free from revision of both femoral and acetabular components due to any reason. CONCLUSIONS: Cementless THA with forte ceramic-on-delta ceramic articulation showed acceptable clinical and radiological results. Serial surveillance of these patients should be performed due to the possibility of cerami- related complications such as squeaking, osteolysis, and ceramic liner fracture.

Is Nail-Canal Diameter Discordance a Risk Factor for the Excessive Sliding of Cephalomedullary Nails in Geriatric Intertrochanteric Fracture Surgery?

Background and Objectives:: There were limited studies which investigated nail diameter as a predictor for cephalomedullary nail (CMN) failure in intertrochanteric fracture (ITF). We aimed to evaluate the surgical outcomes of CMN in fragility ITF following nail-canal (N-C) diameter discordance. Materials and Methods: From November 2010 to March 2022, we retrospectively reviewed 120 consecutive patients who underwent CMN surgeries due to fragility ITF. We included patients with acceptable reduction and a tip-apex distance ≤ 25 mm. The N-C diameter differences both in anterior-posterior (AP) and lateral-view X-rays were measured, and we compared the number of excessive sliding instances and the rate of implant failure between the N-C concordance (≤3 mm) and discordance (>3 mm) group. Simple linear regression was used to determine the strength of the relationship between the N-C difference and sliding distance. Results: The sliding distance showed no differences between the groups in the AP (3.6 vs. 3.3 mm, p = 0.75) and lateral view (3.5 vs. 3.4 mm, p = 0.91). For analyses in the AP view, the AP-concordance and AP-discordance groups had 14 (25%) and 14 patients (22%) with a sliding distance of >5 mm (p = 0.69), while treatment failure occurred in 3 (5%) and 3 (3%) patients, respectively (p = 0.66). For analyses in the lateral view, the lat-concordance and lat-discordance groups had 8 (27%) and 20 patients (22%) with a sliding distance of >5 mm (p = 0.62), while treatment failure occurred in 1 (3%) and 4 (4%) patients, respectively (p = 1.00). Linear regression analyses showed that the N-C difference in either views was not a significant predictor of sliding distance in both the AP (R2 = 0.002, p = 0.60) and lateral views (R2 = 0.007, p = 0.35). Conclusions: If appropriate fracture reduction and fixation are achieved, the N-C discordance of short CMN does not affect treatment outcomes in ITF.

Revision Total Hip Arthroplasty Utilizing an Acetabular Reinforcement Ring with a Metal Augment: A Minimum Eight-Year Follow-Up Study.

Background and Objectives: An acetabular reinforcement ring (ARR) with a structural allograft is conventionally used to treat large acetabular bone defects or discontinuity during revision hip arthroplasty. However, ARR is prone to failure due to bone resorption and lack of incorporation. Here, we investigated the surgical outcomes of the patients who underwent revision total hip arthroplasty (THA) using ARR combined with a metal augment (MA). Materials and Methods: We retrospectively reviewed data from 10 consecutive patients who had a minimum 8-year follow-up after revision hip arthroplasty using ARR with MA in Paprosky type III acetabular defect. We collected patient demographics, surgical details, clinical scores (including Harris Hip Score (HHS)), postoperative complications, and 8-year survival rates. Results: Six male and four female patients were included. The mean age was 64.3 years, and the mean follow-up duration was 104.3 months (96.0-112.0 months). Trauma-related diagnosis was the most common reason for index surgery. Three patients underwent all component revision, and seven underwent cup revision. Six were confirmed as Paprosky type IIIA and four as type IIIB. The mean HHS at the final follow-up was 81.5 (72-91). One patient was diagnosed with prosthetic joint infection at the 3-month follow-up; therefore, the minimum 8-year survival rate with our technique was 90.0% (95% confidence interval, 90.3-118.5%). Conclusions: The satisfactory mid- to long-term results of revision THA suggest that ARR combined with tantalum MA is a viable revision option for treating severe acetabular defects with pelvic discontinuity.

Comparing the Anterior-Based Muscle-Sparing Approach with the Direct Anterior Approach in Hip Arthroplasty: A Systematic Review and Pairwise Meta-Analysis.

Background and Objectives: The anterior-based muscle-sparing (ABMS) approach, which utilizes the interval between the tensor fasciae latae posteriorly, offers several advantages, such as the reduced risk of nerve injury and the freedom to choose various implants. Herein, we aimed to compare the outcome of ABMS to the direct anterior (DA) approach using pairwise meta-analysis techniques. Materials and Methods: A systematic search of the MEDLINE (PUBMED), Embase, and Cochrane Library databases was performed for studies published up to 7 June 2023, which compared the ABMS approach with the DA approach for hip arthroplasty. We compared (1) perioperative outcomes (operation time, visual analog scale (VAS) score, total opioid consumption, length of hospital stay (LOS), and the number of patients discharged to their homes); (2) postoperative complications (neuropraxia/nerve injury, dislocation, surgical site infection, intraoperative fracture, and reoperation rate); and (3) implant position (cup inclination, cup anteversion, and stem alignment). Results: Ten studies were eligible for meta-analysis, including 1737 patients who underwent hip arthroplasty with the ABMS approach and 1979 with the DA approach. The pooled analysis showed no differences in all outcome variables, including perioperative outcomes, postoperative complications, and the implant position between the two surgical approaches. Conclusions: In current meta-analysis, the ABMS approach demonstrated comparable results to the conventional DA approach in terms of both clinical and radiologic outcomes as well as postoperative complications. Furthermore, the ABMS approach has the advantage of a broader indication and fewer limitations in terms of the surgical position compared to the DA approach. Therefore, the ABMS approach can be even more beneficial as an option within MSA, surpassing the utility of the DA approach.

Effectiveness of Intravenous Non-Opioid Analgesics for Postoperative Pain Management of in Patients Undergoing Hip Surgery: A Systematic Review and Meta-Analysis.

Background and Objectives: Intravenous (IV) non-opioid analgesics (NOAs) have been extensively investigated as a multimodal analgesic strategy for the management of acute pain after hip surgery. This pair-wise meta-analysis examined IV NOA effects following hip surgery. Materials and Methods: A systematic search of the MEDLINE (PUBMED), Embase, and Cochrane Library databases was performed for studies investigating the effect of IV NOA for postoperative pain management following hip surgery up to 7 June 2023. We compared in-admission opioid use, postoperative VAS (visual analogue scale) score, hospital stay duration, and opioid-related adverse events between IV NOA and control groups. Results: Seven studies were included with a total of 953 patients who underwent hip surgery. Of these, 478 underwent IV NOA treatment, and 475 did not. The IV NOA groups had lower opioid use within 24-h following hip surgery (SMD, -0.48; 95% CI, -0.66 to -0.30; p < 0.01), lower VAS score (SMD, -0.47; 95% CI, -0.79 to -0.16; p < 0.01), shorter hospital stay (SMD, -0.28; 95% CI, -0.44 to -0.12; p < 0.01), and lower incidence of nausea and vomiting (OR, 0.32; 95% CI, 0.15 to 0.67; p < 0.01) compared with the control groups. Conclusions: This meta-analysis demonstrated that IV NOA administration following hip surgery may have more favorable postoperative outcomes than those in control groups.

The Correlation between Carotid Artery Corrected Flow Time and Velocity Time Integral during Central Blood Volume Loss and Resuscitation.

Background: Doppler ultrasound of the common carotid artery is used to infer central hemodynamics. For example, change in the common carotid artery corrected flow time (ccFT) and velocity time integral (VTI) are proposed surrogates of changing stroke volume. However, conflicting data exist which may be due to inadequate beat sample size and measurement variability - both intrinsic to handheld systems. In this brief communication, we determined the correlation between changing ccFT and carotid VTI during progressively severe central blood volume loss and resuscitation. Methods: Measurements were obtained through a novel, wireless, wearable Doppler ultrasound system. Sixteen participants (ages of 18-40 years with no previous medical history) were studied across 25 lower body-negative pressure protocols. Relationships were assessed using repeated-measures correlation regression models. Results: In total, 33,110 cardiac cycles comprise this analysis; repeated-measures correlation showed a strong, linear relationship between ccFT and VTI. The strength of the ccFT-VTI relationship was dependent on the number of consecutively averaged cardiac cycles (R1 cycle = 0.70, R2 cycles = 0.74, and R10 cycles = 0.81). Conclusions: These results positively support future clinical investigations employing common carotid artery Doppler as a surrogate for central hemodynamics.

Antibody-mediated delivery of a viral MHC-I epitope into the cytosol of target tumor cells repurposes virus-specific CD8+ T cells for cancer immunotherapy.

BACKGROUND: Redirecting pre-existing virus-specific cytotoxic CD8+ T lymphocytes (CTLs) to tumors by simulating a viral infection of the tumor cells has great potential for cancer immunotherapy. However, this strategy is limited by lack of amenable method for viral antigen delivery into the cytosol of target tumors. Here, we addressed the limit by developing a CD8+ T cell epitope-delivering antibody, termed a TEDbody, which was engineered to deliver a viral MHC-I epitope peptide into the cytosol of target tumor cells by fusion with a tumor-specific cytosol-penetrating antibody. METHODS: To direct human cytomegalovirus (CMV)-specific CTLs against tumors, we designed a series of TEDbodies carrying various CMV pp65 antigen-derived peptides. CMV-specific CTLs from blood of CMV-seropositive healthy donors were expanded for use in in vitro and in vivo experiments. Comprehensive cellular assays were performed to determine the presentation mechanism of TEDbody-mediated CMV peptide-MHC-I complex (CMV-pMHCI) on the surface of target tumor cells and the recognition and lysis by CMV-specific CTLs. In vivo CMV-pMHCI presentation and antitumor efficacy of TEDbody were evaluated in immunodeficient mice bearing human tumors. RESULTS: TEDbody delivered the fused epitope peptides into target tumor cells to be intracellularly processed and surface displayed in the form of CMV-pMHCI, leading to disguise target tumor cells as virally infected cells for recognition and lysis by CMV-specific CTLs. When systemically injected into tumor-bearing immunodeficient mice, TEDbody efficiently marked tumor cells with CMV-pMHCI to augment the proliferation and cytotoxic property of tumor-infiltrated CMV-specific CTLs, resulting in significant inhibition of the in vivo tumor growth by redirecting adoptively transferred CMV-specific CTLs. Further, combination of TEDbody with anti-OX40 agonistic antibody substantially enhanced the in vivo antitumor activity. CONCLUSION: Our study offers an effective technology for MHC-I antigen cytosolic delivery. TEDbody may thus have utility as a therapeutic cancer vaccine to redirect pre-existing anti-viral CTLs arising from previously exposed viral infections to attack tumors.

Exercise training attenuates pulmonary inflammation and mitochondrial dysfunction in a mouse model of high-fat high-carbohydrate-induced NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) can lead to pulmonary dysfunction that is associated with pulmonary inflammation. Moreover, little is known regarding the therapeutic role of exercise training on pulmonary pathophysiology in NAFLD. The present study aimed to investigate the effect of exercise training on high-fat high-carbohydrate (HFHC)-induced pulmonary dysfunction in C57BL/6 mice. METHODS: Male C57BL/6 mice (N = 40) were fed a standard Chow (n = 20) or an HFHC (n = 20) diet for 15 weeks. After 8 weeks of dietary treatment, they were further assigned to 4 subgroups for the remaining 7 weeks: Chow (n = 10), Chow plus exercise (Chow+EX, n = 10), HFHC (n = 10), or HFHC plus exercise (HFHC+EX, n = 10). Both Chow+EX and HFHC+EX mice were subjected to treadmill running. RESULTS: Chronic exposure to the HFHC diet resulted in obesity with hepatic steatosis, impaired glucose tolerance, and elevated liver enzymes. The HFHC significantly increased fibrotic area (p < 0.001), increased the mRNA expression of TNF-α (4.1-fold, p < 0.001), IL-1ß (5.0-fold, p < 0.001), col1a1 (8.1-fold, p < 0.001), and Timp1 (6.0-fold, p < 0.001) in the lung tissue. In addition, the HFHC significantly altered mitochondrial function (p < 0.05) along with decreased Mfn1 protein levels (1.8-fold, p < 0.01) and increased Fis1 protein levels (1.9-fold, p < 0.001). However, aerobic exercise training significantly attenuated these pathophysiologies in the lungs in terms of ameliorating inflammatory and fibrogenic effects by enhancing mitochondrial function in lung tissue (p < 0.001). CONCLUSIONS: The current findings suggest that exercise training has a beneficial effect against pulmonary abnormalities in HFHC-induced NAFLD through improved mitochondrial function.

Association of atypical femoral fracture location and lower limb mechanical axis: a computed tomography-based finite element analysis.

Atypical femoral fractures (AFFs) are categorized as low-energy fractures of the femoral shaft or subtrochanteric region. The use of computed tomography-based finite element analysis demonstrated that the femoral weakest point against tensile stress coincided with AFF location, which was determined by the lower limb axis and femoral bowing. INTRODUCTION: This study aimed to assess the relationship between the femoral weakest point against tensile stress and the lower limb axis and geometry, including femoral bowing, using a computed tomography (CT)-based finite element analysis (FEA) model. METHODS: We retrospectively reviewed 19 patients with AFFs and analyzed their CT images of the contralateral intact femur. We performed FEA to find the maximum principal stress (MPS) and maximal tensile stress loading area (femoral weakest point, FWP) of each patient and matched the FWP with the real location of AFF. We applied mechanical axes differently, as neutral, varus, and valgus, in the FEA model, when we analyzed the change in MPS and FWP based on lower limb alignment. We compared the degree of agreement between the real fracture location and FWP before and after knee mechanical axis adjustment. RESULTS: The average participant age was 75.9 (range, 61-87) years, and all participants were women. In the 19 patients included, we observed 20 and 7 shaft and subtrochanteric AFFs, respectively. The average mechanical axis at the knee joint level was 22.6 mm (range, 0-70 mm) of the varus. All the patients showed an increasing trend of MPS and a distal movement of FWP when the mechanical axis of the knee was applied from the valgus to varus alignment. The root mean square errors between the FWP and real fracture location were 14.58% and 10.87% before and after adjustment, respectively, implying that the degree of agreement was better in patients who underwent mechanical adjustment. CONCLUSION: The use of CT/FEA demonstrated that the FWP against tensile stress coincided with AFF location, which was determined by the lower limb axis and femoral bowing.

Crosstalk between head and neck cancer cells and lymphatic endothelial cells promotes tumor metastasis via CXCL5-CXCR2 signaling.

Head and neck squamous cell carcinoma (HNSCC) metastasizes to the locoregional lymph nodes at high rates and is related to poor clinical outcomes. However, the mechanism by which cancer cells migrate to the lymph nodes is unclear. To address this, we established a conditioned medium culture system for HNSCC cells and lymphatic endothelial cells (LECs) and investigated their crosstalk. Stimulation with tumor-conditioned medium (TCM) activated LECs, resulting in a robust increase in cell proliferation to induce lymphatic hyperplasia. Further, stimulation of HNSCC cells with activated LEC Conditioned media (TCM-LEC CM) induced cell invasion. Among various chemokines, CXCL5 promoted the invasion of TCM-LEC CM-treated HNSCC cells. The level of CXCL5 protein was higher in cancer tissues than those in normal tissues from HNSCC patients. Furthermore, treatment with SB225002, a CXCR2 (CXCL5 receptor) inhibitor, resulted in decreased lymph node metastasis in vivo. In conclusion, inhibition of CXCL5-CXCR2 signaling between cancer cells and LECs suppresses cancer cell invasion and metastasis in vitro and in vivo. This novel therapeutic strategy might be a practical approach to the clinical management of HNSCC.