Heat-killed Mycobacterium tuberculosis induces trained immunity in vitro and in vivo administered systemically or intranasally.

Trained immunity (TI) represents a memory-like process of innate immune cells. TI can be initiated with various compounds such as fungal ß-glucan or the tuberculosis vaccine, Bacillus Calmette-Guérin. Nevertheless, considering the clinical applications of harnessing TI against infections and cancer, there is a growing need for new, simple, and easy-to-use TI inducers. Here, we demonstrate that heat-killed Mycobacterium tuberculosis (HKMtb) induces TI both in vitro and in vivo. In human monocytes, this effect represents a truly trained process, as HKMtb confers boosted inflammatory responses against various heterologous challenges, such as lipopolysaccharide (Toll-like receptor [TLR] 4 ligand) and R848 (TLR7/8 ligand). Mechanistically, HKMtb-induced TI relies on epigenetic mechanisms in a Syk/HIF-1α-dependent manner. In vivo, HKMtb induced TI when administered both systemically and intranasally, with the latter generating a more robust TI response. Summarizing, our research has demonstrated that HKMtb has the potential to act as a mucosal immunotherapy that can successfully induce trained responses.

mRNA-1273 boost after BNT162b2 vaccination generates comparable SARS-CoV-2-specific functional responses in naïve and COVID-19-recovered individuals.

Introduction: COVID-19 vaccines based on mRNA have represented a revolution in the biomedical research field. The initial two-dose vaccination schedule generates potent humoral and cellular responses, with a massive protective effect against severe COVID-19 and death. Months after this vaccination, levels of antibodies against SARS-CoV-2 waned, and this promoted the recommendation of a third vaccination dose. Methods: We have performed an integral and longitudinal study of the immunological responses triggered by the booster mRNA-1273 vaccination, in a cohort of health workers previously vaccinated with two doses of the BNT162b2 vaccine at University Hospital La Paz located in Madrid, Spain. Circulating humoral responses and SARS-CoV-2-specific cellular reactions, after ex vivo restimulation of both T and B cells (cytokines production, proliferation, class switching), have been analyzed. Importantly, all along these studies, the analyses have been performed comparing naïve and subjects recovered from COVID-19, addressing the influence of a previous infection by SARS-CoV-2. Furthermore, as the injection of the third vaccination dose was contemporary to the rise of the Omicron BA.1 variant of concern, T- and B-cell-mediated cellular responses have been comparatively analyzed in response to this variant. Results: All these analyses indicated that differential responses to vaccination due to a previous SARS-CoV-2 infection were balanced following the boost. The increase in circulating humoral responses due to this booster dropped after 6 months, whereas T-cell-mediated responses were more stable along the time. Finally, all the analyzed immunological features were dampened in response to the Omicron variant of concern, particularly late after the booster vaccination. Conclusion: This work represents a follow-up longitudinal study for almost 1.5 years, analyzing in an integral manner the immunological responses triggered by the prime-boost mRNA-based vaccination schedule against COVID-19.

Combined Anterior Cruciate Ligament Reconstruction and Modified Lemaire Lateral Extra-articular Tenodesis Better Restores Knee Stability and Reduces Failure Rates Than Isolated Anterior Cruciate Ligament Reconstruction in Skeletally Immature Patients.

BACKGROUND: The increase in anterior cruciate ligament (ACL) injuries in pediatric patients and the high failure rate reported in the literature in this population are driving surgeons to search for specific techniques to better restore knee stability. Recent literature has reported that the combination of lateral extra-articular tenodesis (LET) and ACL reconstruction improves outcomes in high-risk patients. However, such advantages in pediatric patients have been infrequently evaluated. PURPOSE: To assess whether adding LET to ACL reconstruction can significantly improve knee stability, clinical outcomes, and failure rates in pediatric patients. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A multicentric study involving 3 orthopaedic teaching centers was conducted to evaluate pediatric patients aged between 12 and 16 years who had undergone primary ACL reconstruction using a physeal-sparing femoral tunnel drilling technique. A minimum 2-year follow-up evaluation was required. Based on the surgical technique performed, the patients were divided into 2 group. The patients in group 1 underwent an isolated arthroscopic ACL reconstruction, while the patients in group 2 had an arthroscopic ACL reconstruction in combination with a modified Lemaire LET procedure. Group 1 was a historical control cohort of patients, whereas group 2 was prospectively enrolled. All the patients included in the present study were clinically evaluated using the Pediatric International Knee Documentation Committee (Pedi-IKDC) subjective score and the Pediatric Functional Activity Brief Scale (Pedi-FABS) score. Anteroposterior knee stability was measured using the KT-1000 knee ligament arthrometer, and the objective pivot-shift evaluation was documented using a triaxial accelerometer (Kinematic Rapid Assessment [KiRA]). The included patients also underwent a standardized radiological protocol to evaluate leg-length discrepancies, axial deviation, and degenerative signs preoperatively and at last follow-up. RESULTS: This study included 66 pediatric patients with an anatomic hybrid ACL reconstruction using an autologous 4-strand hamstring graft. In group 1, there were 34 patients (mean age, 13.5 ± 1.2 years), while 32 patients (mean age, 13.8 ± 1.4 years) were included in group 2. The clinical outcome scores showed no difference between the 2 groups (Pedi-IKDC, P = .072; Pedi-FABS, P = .180). Nevertheless, the patients in group 2 had better anteroposterior stability measured using a KT-1000 arthrometer (1.9 ± 1.1 mm in group 1 vs 0.8 ± 0.8 mm in group 2; P = .031), as well as better rotational stability measured using the KiRA (-0.59 ± 1.05 m/s2 in group 2 vs 0.98 ± 1.12 m/s2 in group 1; P = .012). The patients in group 1 returned to sports at the same competitive level at a rate of 82.4%, while patients included in group 2 returned at the same competitive level in 90.6% of the cases without a significant difference between the 2 groups (P = .059). No leg-length discrepancies were found between the 2 groups at last follow-up (P = .881). Two patients displayed an increased valgus deformity of 3° on the operated limb at last follow-up (1 patient in group 1 and 1 patient in group 2). Group 1 had a significatively higher cumulative failure rate (14.7% vs 6.3%; P = .021). No intra- or postoperative complications was observed between the 2 groups. CONCLUSION: Performing a modified Lemaire LET along with an ACL reconstruction with hamstring graft in pediatric patients reduced the cumulative failure rate and improved objective stability with no increase in intra- or postoperative complications. No significant difference was found between the 2 groups in terms of patient-reported outcomes or in the return-to-sports activity.

Specialized Proresolving Mediators Protect Against Experimental Autoimmune Myocarditis by Modulating Ca2+ Handling and NRF2 Activation.

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.

Intertwined leukocyte balances in tumours and peripheral blood as robust predictors of right and left colorectal cancer survival.

BACKGROUND: Colorectal cancer (CRC) accounts for 9.4% of overall cancer deaths, ranking second after lung cancer. Despite the large number of factors tested to predict their outcome, most patients with similar variables show big differences in survival. Moreover, right-sided CRC (RCRC) and left-sided CRC (LCRC) patients exhibit large differences in outcome after surgical intervention as assessed by preoperative blood leukocyte status. We hypothesised that stronger indexes than circulating (blood) leukocyte ratios to predict RCRC and LCRC patient outcomes will result from combining both circulating and infiltrated (tumour/peritumour fixed tissues) concentrations of leukocytes. AIM: To seek variables involving leukocyte balances in peripheral blood and tumour tissues and to predict the outcome of CRC patients. METHODS: Sixty-five patients diagnosed with colon adenocarcinoma by the Digestive Surgery Service of the La Paz University Hospital (Madrid, Spain) were enrolled in this study: 43 with RCRC and 22 with LCRC. Patients were followed-up from January 2017 to March 2021 to record overall survival (OS) and recurrence-free survival (RFS) after surgical interventions. Leukocyte concentrations in peripheral blood were determined by routine laboratory protocols. Paraffin-fixed samples of tumour and peritumoural tissues were assessed for leukocyte concentrations by immunohistochemical detection of CD4, CD8, and CD14 marker expression. Ratios of leukocyte concentration in blood and tissues were calculated and evaluated for their predictor values for OS and RFS with Spearman correlations and Cox univariate and multivariate proportional hazards regression, followed by the calculation of the receiver-operating characteristic and area under the curve (AUC) and the determination of Youden's optimal cutoff values for those variables that significantly correlated with either RCRC or LCRC patient outcomes. RCRC patients from the cohort were randomly assigned to modelling and validation sets, and clinician-friendly nomograms were developed to predict OS and RFS from the respective significant indexes. The accuracy of the model was evaluated using calibration and validation plots. RESULTS: The relationship of leukocyte ratios in blood and peritumour resulted in six robust predictors of worse OS in RCRC: CD8+ lymphocyte content in peritumour (CD8pt, AUC = 0.585, cutoff < 8.250, P = 0.0077); total lymphocyte content in peritumour (CD4CD8pt, AUC = 0.550, cutoff < 10.160, P = 0.0188); lymphocyte-to-monocyte ratio in peritumour (LMRpt, AUC = 0.807, cutoff < 3.185, P = 0.0028); CD8+ LMR in peritumour (CD8MRpt, AUC = 0.757, cutoff < 1.650, P = 0.0007); the ratio of blood LMR to LMR in peritumour (LMRb/LMRpt, AUC = 0.672, cutoff > 0.985, P = 0.0244); and the ratio of blood LMR to CD8+ LMR in peritumour (LMRb/CD8MRpt, AUC = 0.601, cutoff > 1.485, P = 0.0101). In addition, three robust predictors of worse RFS in RCRC were found: LMRpt (AUC = 0.737, cutoff < 3.185, P = 0.0046); LMRb/LMRpt (AUC = 0.678, cutoff > 0.985, P = 0.0155) and LMRb/CD8MRpt (AUC = 0.615, cutoff > 1.485, P = 0.0141). Furthermore, the ratio of blood LMR to CD4+ LMR in peritumour (LMRb/CD4MRpt, AUC = 0.786, cutoff > 10.570, P = 0.0416) was found to robustly predict poorer OS in LCRC patients. The nomograms showed moderate accuracy in predicting OS and RFS in RCRC patients, with concordance index of 0.600 and 0.605, respectively. CONCLUSION: Easily obtainable variables at preoperative consultation, defining the status of leukocyte balances between peripheral blood and peritumoural tissues, are robust predictors for OS and RFS of both RCRC and LCRC patients.

Potential Role of the Galectin-9/TIM-3 Axis in the Disparate Progression of SARS-CoV-2 in a Married Couple: A Case Report.

We report the disparate clinical progression of a couple infected by SARS-CoV-2 based on their immune checkpoint (IC) levels and immune cell distribution in blood from admission to exitus in patient 1 and from admission to discharge and recovery in patient 2. A detailed clinical follow-up accompanied by a longitudinal analysis of immune phenotypes and IC levels is shown. The continuous increase in the soluble IC ligand galectin-9 (Gal-9) and the increment in T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) protein in T cells in patient 1 suggests an activation of the Gal-9/TIM-3 axis and, subsequently, a potential cell exhaustion in this patient that did not occur in patient 2. Our data indicate that the Gal-9/TIM-3 axis could be a potential target in this clinical setting, along with a patent effector memory T-cell reduction.

Do we really improve life quality after total knee arthroplasty in patients with Parkinson's disease?

INTRODUCTION: The knee in Parkinson's disease (PD) patients is a problematic joint due to pain, stiffness and gait instability. The aim of this study is to evaluate the functional outcome and degree of pain relief achieved after total knee arthroplasty (TKA) in PD patients. MATERIALS AND METHODS: This is a retrospective review of 26 PD patients (32 knees) with osteoarthritis who underwent a TKA between 1994 and 2013. Comorbidities, anesthetic procedures and complications were recorded. Patient functional status was assessed with the Knee Society Function Score (KFS) and the Knee Society Score (KSS). PD stage was classified with the Hoehn and Yahr Scale. RESULTS: The mean follow-up was 3.5 years (range 2-9). The mean age was 71 years (range 61-83) with a mean time since PD diagnosis of 11.8 years (range 4-24). PD severity on the Hoehn and Yahr Scale was 1.5 points before surgery and 2 points postoperatively. Pain on the visual analogic scale improved from 8 points preoperatively to 5 points at 1-year follow-up; function improved from 32 (range 20-45) to 71 (range 50-81) and from 34 (range 28-52) to 59 (range 25-76) on the KSS and KFS, respectively. The mean postoperative hospital stay was 9.8 days (range 5-21). Confusion and flexion contracture were the most frequent perioperative complications. CONCLUSION: TKA successfully provided pain relief in PD patients. However, the functional outcome is related to disease progression and, therefore, variable. Perioperative complications are difficult to avoid and manage.

Osteotomía percutánea de la falange distal del hallux. Indicaciones y técnica / Percutaneous osteotomy of the distal phalanx of the hallux. Indications and technique

Introducción: Las técnicas para corregir las deformidades del hallux incluyen osteotomías metatarsianas y falángicas. Las osteo-tomías sobre la falange proximal corrigen el DASA y el ángulo interfalángico. Sin embargo, no se han publicado las indicaciones para la osteotomía de la falange distal. El objetivo de este artículo es comunicar la técnica y las indicaciones de la osteotomía percutánea de la falange distal del hallux, y evaluar los resultados de una serie de casos. materiales y métodos: Se analizaron 14 pies en los que se realizó una osteotomía de la falange distal del hallux para corregir una deformidad. Se midieron el DASA, la oblicuidad interfalángica y el ángulo falange distal-interfalángico en las radiografías. La técnica quirúrgica fue percutánea con control fluoroscópico. Los resultados se evaluaron mediante las escalas analógica visual de dolor y AOFAS. Seguimiento medio: 52 meses. Resultados: 13 pies de mujeres y un pie de hombre. Edad promedio: 58 años. Los resultados clínico y estético fueron excelentes, con alivio del dolor. Mejoría de la escala AOFAS: promedio 37 puntos. Análisis comparativo de ángulos preoperatorios y posoperatorios: DASA (p = 0,01), excepto cuando se aisló de la muestra a los pacientes con osteotomía tipo Akin (p = 0,33); ángulos F2-IF y F2-MTF (p <0,00001). Se registraron las complicaciones. Conclusiones: En la deformidad en valgo de la falange distal del hallux sintomática, se debe considerar una osteotomía correctora sola o asociada a osteotomía de la falange proximal. La osteotomía percutánea de la falange distal es un método eficaz, seguro y rápido. Nivel de Evidencia: IV

Introduction. There are many techniques to correct the hallux deformity. Most of them include metatarsal and/or phalanx osteotomies. The Akin osteotomy of the proximal phalanx is used to correct the distal articular set angle (DASA), or the interphalangeal angle. However, indications for the distal phalanx osteotomy remain unpublished. The aim of this study is to communicate the technique of performing and the indications for percutaneous osteotomy of the distal phalanx of the hallux, and evaluate the results of a cases series. Materials and methods. We report 14 cases in which distal phalangeal osteotomy was performed. Radiographic measurements were performed on dorsal-plantar view foot, to analyze distal articular set angle (DASA), interphalangeal obliquity, and F2-IP angle. Surgical technique was performed by minimally incision surgery. The clinical and functional results were evaluate by the visual analogue scale pain, and the AOFAS score. Mean follow-up was 52 months. Results. The clinical result for all the patients was excellent, pain was relieved and deformities corrected. Pre- and post-operative comparative angles: DASA (p: 0.01), except when isolated from the sample for Akin-type osteotomy (p: 0.33). Angle F2-IF and angle F2-MTF (p: <0.00001). The patients where highly satisfied with both the aesthetic and functional results. Complications were registered. Conclusion. In the symptomatic hallux´s distal phalanx deformity a corrective distal phalanx osteotomy should be considered alone, or associated with the osteotomy of the proximal phalanx. Percutaneous distal phalanx osteotomy is an effective, safe, and fast procedure. Level of Evidence: IV

Proteins from SARS-CoV-2 reduce T cell proliferation: A mirror image of sepsis.

Increased cytokine levels, acute phase reactants and immune checkpoint expression changes have been described in patients with Coronavirus Disease 2019 (COVID-19). Here, we have reported a monocyte polarization towards a low HLA-DR and high PD-L1 expression after long exposure to proteins from SARS-CoV-2. Moreover, CD86 expression was also reduced over SARS-CoV-2 proteins exposure. Additionally, T-cells proliferation was significantly reduced after stimulation with these proteins. Eventually, patients with long-term SARS-CoV-2 infection also exhibited a significant blockade of T-cells proliferation.