Use of a Clostridioides difficile Murine Immunization and Challenge Model to Evaluate Single and Combination Vaccine Adjuvants Consisting of Alum and NKT Cell-Activating Ligands

Adjuvant combinations may enhance or broaden the expression of immune responses to vaccine antigens. Information on whether established Alum type adjuvants can be combined with experimental CD1d ligand adjuvants is currently lacking. In this study, we used a murine Clostridioides difficile immunization and challenge model to evaluate Alum (Alhydrogel™), α-galactosylceramide (α-GC), and one of its analogs 7DW8-5 singly and in combination as vaccine adjuvants. We observed that the Alum/α-GC combination caused modest enhancement of vaccine antigen-specific IgG1 and IgG2b responses, and a broadening to include IgG2c that did not significantly impact overall protection. Similar observations were made using the Alum/7DW8-5 combination. Examination of the impact of adjuvants on NKT cells revealed expansion of invariant NKT (iNKT) cells with modest expansion of their iNKTfh subset and little effect on diverse NKT (dNKT) cells. Side effects of the adjuvants was determined and revealed transient hepatotoxicity when Alum/α-GC was used in combination but not singly. In summary these results showed that the Alum/α-GC or the Alum/7DW8-5 combination could exert distinct effects on the NKT cell compartment and on isotype switch to produce Th1-driven IgG subclasses in addition to Alum/Th2-driven subclasses. While Alum alone was efficacious in stimulating IgG-mediated protection, and α-GC offered no apparent additional benefit in the C. difficile challenge model, the work herein reveals immune response features that could be optimized and harnessed in other vaccine contexts.

Effects of 8-weeks of stable vs unstable surface destabilizing training on shot outcome in elite golfers (Efectos de 8 semanas de entrenamiento desestabilizador en superficies estables vs inestables sobre el resultado de los golpes en golfistas de élite)

Purpose: This research aimed to compare the effect of two intervention programs using stable or unstable surfaces on speed and hitting distance in golf stroke/swing. Methods: Twenty-five elite golfers (19.20 ± 1.77 years, height = 181.12 ± 4 cm, body mass = 75.35 ± 5.83; kg, BMI = 22.71 ± 1.76 kg.m2, handicap: 2.49 ± 2.56) were randomly assigned to two different 8-week training programs based on unstable surface (n = 12) or stable surface training (n=13). Measurements of carry distance and club head speed were performed using the Trackman Golf® system, with each participant executing five swings and obtaining the average and best distance. Results: No significant changes (p< 0.05) in the club head speed or carry distance were found after the intervention in the stable surface or the unstable surface training group. Conclusions: The proposed intervention using instability surfaces does not provide any additional benefit to training on stable surfaces in the specific performance of the stroke in elite golfers. Resumen. Objetivo: Esta investigación tuvo como objetivo comparar el efecto de dos programas de intervención que utilizan superficies estables o inestables sobre la velocidad y la distancia de golpeo en el golpeo/swing de golf. Métodos: Veinticinco golfistas de élite (19,20 ± 1,77 años, altura = 181,12 ± 4 cm, peso corporal = 75,35 ± 5,83; kg, IMC = 22,71 ± 1,76 kg.m2, hándicap: 2,49 ± 2,56) fueron asignados aleatoriamente a dos programas de entrenamiento diferentes de 8 semanas de duración basados en superficies inestables (n = 12) o en superficies estables (n = 13). Las mediciones de la distancia de golpeo y la velocidad de la cabeza del palo se realizaron con el sistema Trackman Golf®, ejecutando cada participante cinco swings y obteniendo la media y la mejor distancia. Resultados: No se encontraron cambios significativos (p< 0,05) en la velocidad de la cabeza del palo ni en la distancia de golpeo después de la intervención en el grupo de entrenamiento en superficie estable o en el de superficie inestable. Conclusiones: La intervención propuesta utilizando superficies de inestabilidad no aporta ningún beneficio adicional al entrenamiento en superficies estables en el rendimiento específico del golpe en golfistas de élite.

Radiomics-Based Detection of Radionecrosis Using Harmonized Multiparametric MRI

In this study, a radiomics analysis was conducted to provide insights into the differentiation of radionecrosis and tumor progression in multiparametric MRI in the context of a multicentric clinical trial. First, the sensitivity of radiomic features to the unwanted variability caused by different protocol settings was assessed for each modality. Then, the ability of image normalization and ComBat-based harmonization to reduce the scanner-related variability was evaluated. Finally, the performances of several radiomic models dedicated to the classification of MRI examinations were measured. Our results showed that using radiomic models trained on harmonized data achieved better predictive performance for the investigated clinical outcome (balanced accuracy of 0.61 with the model based on raw data and 0.72 with ComBat harmonization). A comparison of several models based on information extracted from different MR modalities showed that the best classification accuracy was achieved with a model based on MR perfusion features in conjunction with clinical observation (balanced accuracy of 0.76 using LASSO feature selection and a Random Forest classifier). Although multimodality did not provide additional benefit in predictive power, the model based on T1-weighted MRI before injection provided an accuracy close to the performance achieved with perfusion.

A Perspective on the Success and Failure of BCG

TB continues to be one of the major public health threats. BCG is the only available vaccine against TB and confers significant protection against the childhood disease. However, the protective efficacy of BCG against adult pulmonary TB, which represents a larger burden of disease, is highly variable. It has been suggested that prior exposure to environmental mycobacteria (EMb) mitigates the anti-TB efficacy of BCG by blocking its duplication or masking its immunogenicity. However, its effectiveness against childhood TB and failure of repeated administration to provide additional benefit against pulmonary TB, suggest of some other mechanisms for the variable efficacy of BCG against the pulmonary disease. Importantly, TB is a heterogeneous disease occurring in different forms and having distinct mechanisms of pathogenesis. While inability of the immune system to contain the bacilli is responsible for TB pathogenesis in infants, an aggravated immune response to Mtb has been blamed for the development of adult pulmonary TB. Available data suggest that EMb play a key role in heightening the immune response against Mtb. In this article, differential efficacy of BCG against childhood and adult TB is explained by taking into account the heterogeneity of TB, mechanisms of TB pathogenesis, and the effect of EMb on anti-Mtb immunity. It is believed that a refined understanding of the success and failure of BCG will help in the development of effective anti-TB vaccines.

AMNOG Arbitral Awards: Analysis of the Decisions of the Arbitration Board Ten Years after AMNOG Implementation

Aim The analysis investigates the arbitral awards of the last ten years with regards to the characteristics of pharmaceuticals, contractual details and decisions of the arbitration board. Method Arbitral awards until end of 2020 were considered for the analysis. Data were gathered from the arbitral awards, the corresponding G-BA resolutions and the Lauer-Taxe. Results Nearly 50 % of the arbitral awards were based on an additional benefit. Besides the reimbursement price the duration of the contract, sales volume and redemption of the manufacturer’s discount were most commonly set by the arbitration board. Rebates set by the arbitration board seem to be higher than overall AMNOG rebates and appear to vary depending on the extent of the additional benefit. Conclusion While the arbitral awards show a strong variability and individuality a few patterns can be identified.

A Multifunctional, Low-Volume Resuscitation Cocktail Improves Vital Organ Blood Flow and Hemostasis in a Pig Model of Polytrauma with Traumatic Brain Injury

The resuscitation of polytrauma with hemorrhagic shock and traumatic brain injury (TBI) is a balance between permissive hypotension and maintaining vital organ perfusion. There is no current optimal solution. This study tested whether a multifunctional resuscitation cocktail supporting hemostasis and perfusion could mitigate blood loss while improving vital organ blood flow during prolonged limited resuscitation. Anesthetized Yorkshire swine were subjected to fluid percussion TBI, femur fracture, catheter hemorrhage, and aortic tear. Fluid resuscitation was started when lactate concentration reached 3–4 mmol/L. Animals were randomized to one of five groups. All groups received hydroxyethyl starch solution and vasopressin. Low- and high-dose fibrinogen (FBG) groups additionally received 100 and 200 mg/kg FBG, respectively. A third group received TXA and low-dose FBG. Two control groups received albumin, with one also including TXA. Animals were monitored for up to 6 h. Blood loss was decreased and vital organ blood flow was improved with low- and high-dose fibrinogen compared to albumin controls, but survival was not improved. There was no additional benefit of high- vs. low-dose FBG on blood loss or survival. TXA alone decreased blood loss but had no effect on survival, and combining TXA with FBG provided no additional benefit. Pooled analysis of all groups containing fibrinogen vs. albumin controls found improved survival, decreased blood loss, and improved vital organ blood flow with fibrinogen delivery. In conclusion, a low-volume resuscitation cocktail consisting of hydroxyethyl starch, vasopressin, and fibrinogen concentrate improved outcomes compare to controls during limited resuscitation of polytrauma.

Median Nerve Neural Mobilization Adds No Additional Benefit When Combined with Cervical Lateral Glide in the Treatment of Neck Pain: A Randomized Clinical Trial

Background: This study aimed to compare the effectiveness of cervical lateral glide (CLG) added to median nerve neural mobilization (MNNM) in patients with neck pain (NP). Methods: A single-blinded randomized controlled clinical trial was carried out in a Pain Management Unit from a Hospital. A total sample of 72 patients with NP was recruited from a hospital. Patients were randomized to receive isolated CLG (n = 36) or CLG + MNNM (n = 36). Bilateral elbow extension range of motion (ROM) on upper limb neurodynamic test 1 (ULNT1), bilateral pressure pain thresholds (PPT) on the median nerve at elbow joint, C6 zygapophyseal joint and tibialis anterior, Visual analogue scale (VAS), body chart distribution of pain, active cervical ROM (CROM), Neck Disability Index (NDI), and Tampa Scale of Kinesiophobia (TSK-11) were measured at baseline as well as immediately, 15 days, and 1 month after treatment. Results: There were no statistically significant interactions (p > 0.05) between treatment and time for median nerve mechanosensitivity outcomes, pain intensity, symptom distribution, and PPT of the widespread pain assessment, as well as cervical function, and kinesiophobia. Conclusions: MNNM gave no additional benefit to CLG in patients with NP regarding pain intensity, symptom distribution, mechanosensitivity, functionality, and kinesiophobia. Only two treatment sessions and the short follow-up are important issues, therefore, justifying further studies to answer the research question with better methodology.

Real Assessment of Maximum Oxygen Uptake as a Verification After an Incremental Test Versus Without a Test

The study was conducted to compare peak oxygen uptake (VO2peak) measured with the incremental graded test (GXT) (VO2peak) and two tests to verify maximum oxygen uptake, performed 15 min after the incremental test (VO2peak1) and on a separate day (VO2peak2). The aim was to determine which of the verification tests is more accurate and, more generally, to validate the VO2max obtained in the incremental graded test on cycle ergometer. The study involved 23 participants with varying levels of physical activity. Analysis of variance showed no statistically significant differences for repeated measurements (F = 2.28, p = 0.118, η2 = 0.12). Bland–Altman analysis revealed a small bias of the VO2peak1 results compared to the VO2peak (0.4 ml⋅min–1⋅kg–1) and VO2peak2 results compared to the VO2peak (−0.76 ml⋅min–1⋅kg–1). In isolated cases, it was observed that VO2peak1 and VO2peak2 differed by more than 5% from VO2peak. Considering the above, it can be stated that among young people, there are no statistically significant differences between the values of VO2peak measured in the following tests. However, in individual cases, the need to verify the maximum oxygen uptake is stated, but performing a second verification test on a separate day has no additional benefit.