TLR-4 Agonist Induces IFN-γ Production Selectively in Proinflammatory Human M1 Macrophages through the PI3K-mTOR- and JNK-MAPK-Activated p70S6K Pathway.

IFN-γ, a proinflammatory cytokine produced primarily by T cells and NK cells, activates macrophages and engages mechanisms to control pathogens. Although there is evidence of IFN-γ production by murine macrophages, IFN-γ production by normal human macrophages and their subsets remains unknown. Herein, we show that human M1 macrophages generated by IFN-γ and IL-12- and IL-18-stimulated monocyte-derived macrophages (M0) produce significant levels of IFN-γ. Further stimulation of IL-12/IL-18-primed macrophages or M1 macrophages with agonists for TLR-2, TLR-3, or TLR-4 significantly enhanced IFN-γ production in contrast to the similarly stimulated M0, M2a, M2b, and M2c macrophages. Similarly, M1 macrophages generated from COVID-19-infected patients' macrophages produced IFN-γ that was enhanced following LPS stimulation. The inhibition of M1 differentiation by Jak inhibitors reversed LPS-induced IFN-γ production, suggesting that differentiation with IFN-γ plays a key role in IFN-γ induction. We subsequently investigated the signaling pathway(s) responsible for TLR-4-induced IFN-γ production in M1 macrophages. Our results show that TLR-4-induced IFN-γ production is regulated by the ribosomal protein S6 kinase (p70S6K) through the activation of PI3K, the mammalian target of rapamycin complex 1/2 (mTORC1/2), and the JNK MAPK pathways. These results suggest that M1-derived IFN-γ may play a key role in inflammation that may be augmented following bacterial/viral infections. Moreover, blocking the mTORC1/2, PI3K, and JNK MAPKs in macrophages may be of potential translational significance in preventing macrophage-mediated inflammatory diseases.

Quantifying Surgeon Intuition Using a Judgment Analysis Model: Surgeon Accuracy of Predicting Patient-Reported Outcomes in Patients Undergoing Hip Arthroscopy for Femoroacetabular Impingement Is Moderate at Best.

Purpose: To quantify surgeon intuition, determine whether a surgeon's prediction of outcomes after hip arthroscopy correlates with actual patient-reported outcomes (PRO), and identify differences in clinical judgment between expert and novice examiners. Methods: This prospective, longitudinal study was conducted at an academic medical center on adults undergoing primary hip arthroscopy for treatment of femoroacetabular impingement. A Surgeon Intuition and Prediction (SIP) score was completed preoperatively by an attending surgeon (expert) and physician assistant (novice). Baseline and postoperative outcome measures included legacy hip scores (e.g., Modified Harris Hip score) and Patient-Reported Outcomes Information System tools. Mean differences were assessed using t-tests. Generalized estimating equations assessed longitudinal changes. Pearson correlation coefficients (r) evaluated associations between SIP score and PRO scores. Results: Data from 98 patients (mean age 36 years, 67% female) with complete data sets at 12-month follow-up were analyzed. Weak-to-moderate strength correlations were seen between SIP score and PRO scores (r = 0.36 to r = 0.53) for pain, activity and physical function. Significant improvements were seen in all primary outcome measures at 6 and 12 months postoperatively when compared to baseline scores (P < .05), with about 50% to 80% of patients achieving the minimum clinically important difference and patient acceptable symptomatic state thresholds postoperatively. Conclusions: An experienced, high-volume hip arthroscopist had only weak-to-moderate ability to intuitively predict PRO. Surgical intuition and judgment were not superior in an expert examiner compared to a novice. Level of Evidence: Level III, retrospective comparative prognostic trial.

Solvent-free production of thermoplastic lignocellulose from wood pulp by reactive extrusion.

A novel acylation approach suited to rapid bulk thermoplasticization of lignocellulose without solvents was previously demonstrated by the authors in benchtop batch studies. The method relies upon a benzethonium chloride/sulfuric acid functionalizing agent at low concentrations to act as a wetting agent for the wood pulp, similar to an ionic liquid, yet binds to the lignocellulose ester as a flow aid in the final thermoplastic. The present investigation evaluates the approach in a residence time-limited (45-90 s) continuous twin-screw reactor, where intensive mixing and heat were found to yield high acylation. The modified lignocellulose exhibited desired thermoplasticity by being melt moldable without the need for plasticizers and maintained much of the excellent stiffness of cellulose, demonstrating a maximum flexural modulus of 5.4 GPa and tensile modulus of 1.8 GPa. The influence of extrusion conditions on thermoplasticity was examined by a Design of Experiments (DOE) analysis.

Threshold Values for Success After Hip Arthroscopy Using the Patient-Reported Outcomes Measurement Information System Assessment: Determining the Minimum Clinically Important Difference and Patient Acceptable Symptomatic State.

BACKGROUND: Threshold values for patient-reported outcome measures, such as the minimum clinically important difference (MCID) and patient acceptable symptomatic state (PASS), are important for relating postoperative outcomes to meaningful functional improvement. PURPOSE: To determine the PASS and MCID after hip arthroscopy for femoroacetabular impingement using the Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: A consecutive series of patients undergoing primary hip arthroscopy for femoroacetabular impingement were administered preoperative and minimum 1-year postoperative PROMIS surveys focusing on physical function (PF) and pain interference (PI). External anchor questions for the MCID and PASS were given with the postoperative PROMIS survey. Receiver operator curves were constructed to determine the threshold values for the MCID and PASS. Curves were generated for the study population as well as separate cohorts segregated by median baseline PF or PI scores and preoperative athletic participation. A multivariate post hoc analysis was then constructed to evaluate factors associated with achieving the PASS or MCID. RESULTS: There were 113 patients (35% male; mean ± SD age, 32.8 ± 12.5 years; body mass index, 25.8 ± 4.8 kg/m2), with 60 (53%) reporting preoperative athletic participation. Survey time averaged 77.5 ± 49.2 seconds. Anchor-based MCID values were 5.1 and 10.9 for the PF and PI domains, respectively. PASS thresholds were 51.8 and 51.9 for the PF and PI, respectively. PASS values were not affected by baseline scores, but athletic patients had a higher PASS threshold than did those not participating in a sport (53.1 vs 44.7). MCID values were affected by preoperative baseline scores but were largely independent of sports participation. A post hoc analysis found that 94 (83%) patients attained the MCID PF while 66 (58%) attained the PASS PF. A multivariate nominal logistic regression found that younger patients (P = .01) and athletic patients (P = .003) were more likely to attain the PASS. CONCLUSION: The PROMIS survey is an efficient metric to evaluate preoperative disability and postoperative function after primary hip arthroscopy for femoroacetabular impingement. The MCID and PASS provide surgeons with threshold values to help determine PROMIS scores that are clinically meaningful to patients, and they can assist with therapeutic decision making as well as expectation setting.

The failure of Haemonchus contortus excretory/secretory products to stimulate gastrin secretion in vitro.

Excretory/secretory (ES) products collected from exsheathed L3 or parasitic stages of Haemonchus contortus were tested in vitro for gastrin stimulatory properties using an ovine abomasal antral mucosal preparation. In addition, the motility of exsheathed L3 and parasites recovered on weeks 2, 6 and 8 post-infection was studied in water, saline, saline with glucose or ovine blood and in HBSS pH 2.5-7.4. Parasitic stages became immotile rapidly in water and HBSS pH 2.5, more slowly in HBSS pH 3.5, but nearly 100% remained motile for 48 h when blood was included in the medium. Exsheathed L3 motility was reduced only by water and HBSS pH 2.5, and then only in the second week of incubation. Gastrin secretion was not consistently increased by any of the parasite ES products tested in vitro, therefore, they probably do not stimulate the G cell directly to produce the hypergastrinaemia seen in parasitised sheep.