Immune Response and Risk of Decompensation following SARS-CoV-2 Infection in Outpatients with Advanced Chronic Liver Disease.

Advanced chronic liver disease (ACLD) is associated with a wide spectrum of immune dysfunction. The clinical impact of SARS-CoV-2 on the development of decompensation and immune response in unvaccinated outpatients has not as yet been clearly defined. This study aimed to evaluate the clinical and immunological impact of SARS-CoV-2 on outpatients with ACLD. This is an observational case-control study, in which ACLD outpatients were included prospectively and consecutively and classified into two groups: SARS-CoV-2 infected and non-infected. Patients' baseline characteristics and infection data were collected and analyzed. Immunoglobulin G (IgG) levels against Spike 1 were evaluated. The primary endpoint was risk of liver decompensation during follow-up, assessed after propensity score matching and adjusted by Cox regression. Between October 2020 and July 2021, ACLD outpatients (n = 580) were identified, and 174 patients with clinical follow-up were included. SARS-CoV-2 infection incidence was 7.6% (n = 44). Risk of liver decompensation was significantly higher after infection (HR = 2.43 [1.01-5.86], p = 0.048) vs. non-infection. The time of IgG evaluation was similar in all patients (n = 74); IgG concentrations were significantly higher in compensated vs. decompensated patients (1.02 ± 0.35 pg/mL vs. 0.34 ± 0.16 pg/mL, p < 0.0001) and correlated with hemoglobin levels. The dysregulation of the innate immune response in patients with decompensated liver disease increased the risk of further decompensation following SARS-CoV-2, mainly due to a worsening of ascites.

Peripheral macrophages contribute to nociceptor priming in mice with chronic intermittent hypoxia.

Obstructive sleep apnea (OSA) is a prevalent sleep disorder that is associated with increased incidence of chronic musculoskeletal pain. We investigated the mechanism of this association in a mouse model of chronic intermittent hypoxia (CIH) that mimics the repetitive hypoxemias of OSA. After 14 days of CIH, both male and female mice exhibited behaviors indicative of persistent pain, with biochemical markers in the spinal cord dorsal horn and sensory neurons of the dorsal root ganglia consistent with hyperalgesic priming. CIH, but not sleep fragmentation alone, induced an increase in macrophage recruitment to peripheral sensory tissues (sciatic nerve and dorsal root ganglia), an increase in inflammatory cytokines in the circulation, and nociceptor sensitization. Peripheral macrophage ablation blocked CIH-induced hyperalgesic priming. The findings suggest that correcting the hypoxia or targeting macrophage signaling might suppress persistent pain in patients with OSA.

Binge drinking at time of bariatric surgery is associated with liver disease, suicides, and increases long-term mortality.

BACKGROUND AND AIMS: Alcohol use disorder has been reported in patients undergoing bariatric procedures, but the pattern of alcohol consumption has not been evaluated. We investigated the prevalence, risk factors, and impact of binge drinking (BD) at the time of surgery and during follow-up. METHODS: A prospective, longitudinal study of subjects undergoing bariatric surgery was included in the LABS-2 registry between 2006 and 2009. Participants with AUDIT questionnaire at the time of surgery and a minimum of 12 months follow-up were included. BD was defined as consuming ≥5 drinks on at least 1 occasion in the previous month. Liver biopsies were obtained during bariatric procedures in not all cases. Survival analysis was performed with the adjusted Cox regression model and competing risk. RESULTS: A total of 2257 subjects were included, with a median follow-up of 79 months. The prevalence of BD at time of surgery was 12%, and it raised up to 23% during follow-up. Patients with BD predominantly had a binge eating disorder (OR=1.35 [95% CI: 1.04-1.76]), regularly consumed fast food [OR=1.4 (95% CI: 1.07-1.85)] and used other drugs (OR=2.65 [95% CI: 1.74-4.04]). Within liver biopsies evaluation, BD showed higher hepatic iron deposits (OR=3.00 [95% CI: 1.25-7.21]). BD at the time of surgery was associated with a higher risk of BD during follow-up (OR=10.49 [95% CI: 7.86-14.00]) and long-term mortality (HR: 3.21 [95% CI: 1.67-6.18]). Specific causes of death in these patients with BD were liver disease (p=0.020), suicide (p=0.015), neoplasms (p=0.034), and respiratory (p=0.025). CONCLUSIONS: The prevalence of BD in patients undergoing bariatric surgery is high and increases the risk of postoperative liver disease, suicides, and long-term mortality.

Kinetics of IFNγ-Induced Cytokines and Development of Immune-Related Adverse Events in Patients Receiving PD-(L)1 Inhibitors.

Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFß) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFß levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study's findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity.

PACAP38/mast-cell-specific receptor axis mediates repetitive stress-induced headache in mice.

BACKGROUND: Pain, an evolutionarily conserved warning system, lets us recognize threats and motivates us to adapt to those threats. Headache pain from migraine affects approximately 15% of the global population. However, the identity of any putative threat that migraine or headache warns us to avoid is unknown because migraine pathogenesis is poorly understood. Here, we show that a stress-induced increase in pituitary adenylate cyclase-activating polypeptide-38 (PACAP38), known as an initiator of allosteric load inducing unbalanced homeostasis, causes headache-like behaviour in male mice via mas-related G protein-coupled receptor B2 (MrgprB2) in mast cells. METHODS: The repetitive stress model and dural injection of PACAP38 were performed to induce headache behaviours. We assessed headache behaviours using the facial von Frey test and the grimace scale in wild-type and MrgprB2-deficient mice. We further examined the activities of trigeminal ganglion neurons using in vivo Pirt-GCaMP Ca2+ imaging of intact trigeminal ganglion (TG). RESULTS: Repetitive stress and dural injection of PACAP38 induced MrgprB2-dependent headache behaviours. Blood levels of PACAP38 were increased after repetitive stress. PACAP38/MrgprB2-induced mast cell degranulation sensitizes the trigeminovascular system in dura mater. Moreover, using in vivo intact TG Pirt-GCaMP Ca2+ imaging, we show that stress or/and elevation of PACAP38 sensitized the TG neurons via MrgprB2. MrgprB2-deficient mice showed no sensitization of TG neurons or mast cell activation. We found that repetitive stress and dural injection of PACAP38 induced headache behaviour through TNF-a and TRPV1 pathways. CONCLUSIONS: Our findings highlight the PACAP38-MrgprB2 pathway as a new target for the treatment of stress-related migraine headache. Furthermore, our results pertaining to stress interoception via the MrgprB2/PACAP38 axis suggests that migraine headache warns us of stress-induced homeostatic imbalance.

Potential Role of Circulating PD-L1+ Leukocytes as a Predictor of Response to Anti-PD-(L)1 Therapy in NSCLC Patients.

PD-(L)1 inhibitors are part of the treatment strategy for non-small cell lung cancer (NSCLC) although its efficacy is limited to certain patients. Our study aimed to identify patients who might benefit from anti-PD-(L)1 inhibitors by analyzing the PD-L1 expression on circulating leukocytes and its evolution during treatment. One hundred thirteen NSCLC patients, according to their radiological response after 10-12 weeks of treatment, were classified into responders, stable, and progressive disease. Percentages of circulating PD-L1+ leukocytes, PD-L1+ platelets (PLTs), and leukocyte-PLT complexes were assessed using flow cytometry, and plasma concentrations of soluble immunomodulatory factors were quantified by ELISA. Responders exhibited significantly higher pre-treatment percentages of PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs than progressors. The percentages of these populations decreased in responders post-treatment, contrasting with stables and progressors. PLTs notably contributed to PD-L1 expression in CD14+ cells and neutrophils. Plasma cytokine analysis revealed baseline differences only in IL-17 concentration among groups, whereas network analyses highlighted distinct association patterns between plasma molecules and PD-L1+ leukocytes after 10-12 weeks of treatment. Our findings suggest that pre-treatment assessment of circulating PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs may be helpful in identifying NSCLC patients who are potential candidates for anti-PD-(L)1 therapy.

Effect of using a kinetic wedge during the hallux dorsiflexion resistance test in asymptomatic individuals.

BACKGROUND: The hallux dorsiflexion resistance test is a frequently employed clinical maneuver for assessing the initiation of the windlass mechanism This maneuver involves dorsiflexion of the phalanx of the hallux, thereby evaluating plantarflexion of the first metatarsal, elevation of the medial longitudinal arch, and supination of the rearfoot. The windlass mechanism plays a crucial role in gait, and orthopedic devices, such as a kinetic wedge, which aims to facilitate its activation by increasing the hallux dorsiflexion. Although it is believed that facilitating the windlass mechanism with the kinetic wedge should be directly correlated with a decrease in hallux dorsiflexion resistance, its effects have yet to be characterized. Thus, this study aimed to determine the influence of a kinetic wedge on hallux dorsiflexion resistance in asymptomatic individuals. METHODS: The sample comprised thirty participants (14 women and 16 men). A digital force gauge measured the force required to perform the hallux dorsiflexion resistance test during two conditions: barefoot and with a kinetic wedge. The Wilcoxon signed-rank test was used to compare the hallux dorsiflexion resistance between conditions. RESULTS: A statistically significant reduction in force (10.54 ± 3.16N vs. 19.62 ± 5.18N, p < 0.001) was observed when using the kinetic wedge compared to the barefoot condition during the hallux dorsiflexion resistance test. CONCLUSION: The use of a kinetic wedge reduces the required force for performing the passive hallux dorsiflexion resistance test in asymptomatic individuals. Future studies should determine to what extent the kinetic wedge can attenuate the required force to dorsiflex the hallux in individuals with musculoskeletal disorders such as plantar fasciopathy and functional hallux limitus.

Levels of Lysozyme and SLPI in Bronchoalveolar Lavage: Exploring Their Role in Interstitial Lung Disease.

Interstitial lung diseases (ILDs) are characterized by inflammation or fibrosis of the pulmonary parenchyma. Despite the involvement of immune cells and soluble mediators in pulmonary fibrosis, the influence of antimicrobial peptides (AMPs) remains underexplored. These effector molecules display a range of activities, which include immunomodulation and wound repair. Here, we investigate the role of AMPs in the development of fibrosis in ILD. We compare the concentration of different AMPs and different cytokines in 46 fibrotic (F-ILD) and 17 non-fibrotic (NF-ILD) patients by ELISA and using peripheral blood mononuclear cells from in vitro stimulation in the presence of lysozyme or secretory leukocyte protease inhibitor (SLPI) from 10 healthy donors. We observed that bronchoalveolar lavage (BAL) levels of AMPs were decreased in F-ILD patients (lysozyme: p < 0.001; SLPI: p < 0.001; LL-37: p < 0.001; lactoferrin: p = 0.47) and were negatively correlated with levels of TGF-ß (lysozyme: p = 0.02; SLPI: p < 0.001) and IL-17 (lysozyme: p < 0.001; SLPI: p < 0.001). We observed that lysozyme increased the percentage of CD86+ macrophages (p < 0.001) and the production of TNF-α (p < 0.001). We showed that lysozyme and SLPI were associated with clinical parameters (lysozyme: p < 0.001; SLPI: p < 0.001) and disease progression (lysozyme: p < 0.001; SLPI: p = 0.01). These results suggest that AMPs may play an important role in the anti-fibrotic response, regulating the effect of pro-fibrotic cytokines. In addition, levels of lysozyme in BAL may be a potential biomarker to predict the progression in F-ILD patients.

Effects of Myofascial Release Technique along with Cognitive Behavior Therapy in University Students with Chronic Neck Pain and Forward Head Posture: A Randomized Clinical Trial.

The purpose of this randomized controlled trial was to evaluate the effectiveness of the Myofascial Release Technique (MRT) along with Cognitive Behavioral Therapy (CBT) on pain, craniovertebral angle (CVA), and neck disability in university students with chronic neck pain and forward head posture. A total of sixty-six eligible participants with chronic neck pain and forward head posture were randomized into the Myofascial Release Therapy (MRT) group (n = 33) and MRT and Cognitive Behavior Therapy (CBT) group (n = 33). Clinical outcomes included neck pain measured using the numerical pain rating scale, neck disability measured through the neck disability index, and forward head posture measured through the cranial vertebral angle. The outcomes were assessed at baseline and the four and eight weeks after the intervention. Both groups showed significant improvement in pain intensity, CVA, and neck disability after the intervention. However, the CBT group demonstrated greater improvements than the MRT group. The difference in outcomes between the groups was statistically significant. Myofascial Release Therapy combined with CBT is an effective treatment method for patients with chronic neck pain and forward head posture.

Gender Differences among Nurses in Managing Arterial Puncture-Related Pain: A Multicenter Cross-Sectional Study.

There is evidence that healthcare can be executed differentially depending on the gender of patients, researchers, and clinicians. The aim was to analyze the possible existence of nursing gender differences in pain management produced by arterial puncture for blood gas analysis. A cross-sectional, multicenter study designed was conducted in Castilla-la Mancha (Spain). Variables of interest were collected from nurses in the public health system of a European region through a questionnaire. Data were collected for four months; the primary outcome was the use of any intervention to reduce pain and the explanatory variable was the nurse's gender. Bivariate analysis was carried out to assess associations between gender and pain-reducing interventions and a multivariate model was created with those factors that were relevant using logistic regression. A significantly higher proportion of men reported using some form of intervention (45% vs. 30%) and had more specific training (45.9% vs. 32.4%). The adjusted probability of using pain-reducing interventions by men was 71% higher than women. Thus, we found gender differences in the management of pain caused by arterial punctures performed by nurses as the main healthcare providers.

Clinical Relevance of Tumour-Infiltrating Immune Cells in HER2-Negative Breast Cancer Treated with Neoadjuvant Therapy.

Currently, therapy response cannot be accurately predicted in HER2-negative breast cancer (BC). Measuring stromal tumour-infiltrating lymphocytes (sTILs) and mediators of the tumour microenvironment and characterizing tumour-infiltrating immune cells (TIICs) may improve treatment response in the neoadjuvant setting. Tumour tissue and peripheral blood samples were retrospectively collected from 118 patients, and sTILs were evaluated. Circulating exosomes and myeloid-derived suppressor cells were determined by flow cytometry. TIICs markers (CD4, CD8, CD20, CD1a, and CD68) were assessed immunohistochemically. High sTILs were significantly associated with pathological complete response (pCR; p = 0.048) and event-free survival (EFS; p = 0.027). High-CD68 cells were significantly associated with pCR in triple-negative (TN, p = 0.027) and high-CD1a cells with EFS in luminal-B (p = 0.012) BC. Cluster analyses of TIICs revealed two groups of tumours (C1 and C2) that had different immune patterns and clinical outcomes. An immunoscore based on clinicopathological variables was developed to identify high risk (C1) or low-risk (C2) patients. Additionally, cluster analyses revealed two groups of tumours for both luminal-B and TNBC. Our findings support the association of sTILs with pCR and show an immunological component in a subset of patients with HER2-negative BC. Our immunoscore may be useful for future escalation or de-escalation treatments.

Biomechanical Effect on Jack's Test on Barefoot Position, Regular Socks, and Biomechanics Socks.

The proper dorsal flexion movement of the first metatarsophalangeal joint (MTPJ) is crucial for an accurate gait. Restricted movement can disrupt the windlass mechanism, and Jack's test is a tool to assess such alterations. Although running socks are commonly used, their influence on the windlass mechanism remains unclear. Therefore, the aim of this study was to measure the resistance to passive dorsal flexion of the first metatarsophalangeal joint (MTPJ) under three different conditions: barefoot, wearing regular socks, and wearing biomechanical socks, using a digital force gauge. METHODS: The research involved a sample size of 30 subjects (14 men and 16 women), and Jack's test was conducted using a digital force gauge and a lever system. Three conditions were measured, barefoot, with a regular sock, and with the biomechanical socks. RESULTS: Statistically significant differences were observed when using biomechanical socks with orthopedic corrections during Jack's test, as measured with the digital force gauge (13.33 N ± 3.54, p < 0.001). CONCLUSIONS: The utilization of biomechanical socks with a kinetic wedge, reinforced mesh in the medial longitudinal arch, and padding in the heel area results in a reduction of the force required, measured in newtons, to perform dorsal flexion of the first metatarsophalangeal joint (MTPJ) during Jack's test compared to being barefoot or wearing regular socks.

Pilates versus Zumba training effects on postural control under conflicting sensory conditions in postmenopausal women.

The current study aimed to compare the effects of Pilates versus Zumba training on postural performance in middle-aged postmenopausal women. Fifty-seven eligible women, aged between 50 and 60 years, were randomized into three groups: Zumba (ZG) group, Pilates (PG) group or control (CG) group. Postural control was assessed using a force platform under 4 sensory manipulation conditions: on firm and foam surfaces with eyes opened (EO) and closed (EC). Our results showed more marked adaptations in favor of ZG concerning postural performance compared to PG. For the PG, postural control was significantly improved only in simple postural conditions on the firm surface with EO (p < 0.1) and EC (p < 0.05) conditions. However, postural control of the ZG significantly improved in both the simple and complex postural conditions, even under conflicting sensory situations (firm surface/EO (p < 0.001; 95 % CI: [1.34, 4.46]), EC (p < 0.001; 95 % CI: [2.13, 5.24])); foam surface/EO (p < 0.01; 95 % CI: [0.70, 8.57]), EC (p < 0.01; 95 % CI: [0.65, 8.52])). In conclusion, Zumba training seems to be more effective and a better strategy to promote postural control in daily living activities and autonomy in postmenopausal women than Pilates training. These findings are useful for public health practitioners in designing physical interventions for balance disorders.

Elucidation of neuronal activity in mouse models of TMJ injury by in vivo GCaMP Ca 2+ imaging of intact trigeminal ganglion neurons.

Patients with temporomandibular disorders (TMD) typically experience facial pain and discomfort or tenderness in the temporomandibular joint (TMJ), causing disability in daily life. Unfortunately, existing treatments for TMD are not always effective, creating a need for more advanced, mechanism-based therapies. In this study, we used in vivo GCaMP3 Ca 2+ imaging of intact trigeminal ganglia (TG) to characterize functional activity of the TG neurons in vivo , specifically in TMJ animal models. This system allows us to observe neuronal activity in intact anatomical, physiological, and clinical conditions and to assess neuronal function and response to various stimuli. We observed a significant increase in spontaneously and transiently activated neurons responding to mechanical, thermal, and chemical stimuli in the TG of forced mouth open (FMO) mice. An inhibitor of the CGRP receptor significantly attenuated FMO-induced facial hypersensitivity. In addition, we confirmed the attenuating effect of CGRP antagonist on FMO-induced sensitization by in vivo GCaMP3 Ca 2+ imaging of intact TG. Our results contribute to unraveling the role and activity of TG neurons in the TMJ pain animal models of TMD, bringing us closer understanding the pathophysiological processes underlying TMD. Our study also illustrates the utility of in vivo GCaMP3 Ca 2+ imaging of intact TG for studies aimed at developing more targeted and effective treatments for TMD.

The effect of varus rearfoot wedges on hallux dorsiflexion resistance.

BACKGROUND: The first metatarsophalangeal joint (MTPJ), which includes the first metatarsal and proximal phalanx, plays a crucial role in gait and impacts the windlass mechanism. Disruptions to this mechanism are implicated in various foot pathologies. Jack's Test serves as a valuable tool for clinicians to assess the functionality of the MTPJ. Varus rearfoot wedges (VRFWs) are a common treatment employed in the management of lower limb pathologies. The impact of VRFWs on the resistance of the first MTPJ during Jack´s Test is currently unknown. This study aimed to measure the influence of VRFWs on the resistance of the first MTPJ during Jack´s Test. The secondary objective was to validate a new measurement method using a digital force gauge. METHODS: Thirty participants (17 women and 13 men) were enrolled. A digital force gauge measured the weight-bearing force needed for Jack's Test, thereby evaluating the effects of VRFWs of different angulations. The Kolmogorov-Smirnov test confirmed that the data followed a normal distribution (p > 0.05). The nonparametric Friedman test (p < 0.001) showed that there were significant differences among all VRFWs, while the Wilcoxon test (p < 0.001) showed that there were differences between barefoot conditions and 3°, 5°, and 8° VRFWs. RESULTS: The use of 8° VRFWs yielded a statistically significant reduction in the passive dorsiflexion force of hallux during Jack's Test (12.51 N ± 4.12, p < 0.001). CONCLUSIONS: The use of VRFWs has been observed to reduce dorsiflexion resistance in the proximal phalanx of the first MTPJ during Jack's Test. Additionally, the digital force gauge was proven to be a valid tool for conducting Jack's Test, thus offering a reliable measurement method.

Strengthening the relationship between intractable plantar keratosis and human papillomavirus.

The aim of the study was to determine the presence of human papillomavirus (HPV) in patients with intractable plantar keratosis (IPK) by comparing the histopathological findings of biopsies. A prospective, observational, and concordance study was carried out. Three different specimens were taken from each IPK. A first punch was sent for histopathological examination, and a second punch and a superficial skin scraping were both sent for HPV  polymerase chain reaction (PCR) and type determination. A total of 51 patients were included. From the histopathological examination, it was determined that 35 (68.6%) samples were diagnosed as warts and 16 (31.3%) as keratosis. However, the presence of HPV was confirmed by PCR in 49 (96.1%) and in 42 (82.4%) samples obtained by punch and superficial scraping, respectively. In the 49 PCR-positive samples, the most common HPV types were HPV1, HPV2, HPV27, HPV57, and HPV65, accounting for 81.6% of the samples. In conclusion, this study demonstrates that HPV infection and IPK lesions are very closely related. Although we cannot confirm that HPV is the cause of the development of IPK, the high prevalence of HPV observed in these lesions calls for a change to the procedures for managing IPK.

Mast-cell-specific receptor mediates alcohol-withdrawal-associated headache in male mice.

Rehabilitation from alcohol addiction or abuse is hampered by withdrawal symptoms including severe headaches, which often lead to rehabilitation failure. There is no appropriate therapeutic option available for alcohol-withdrawal-induced headaches. Here, we show the role of the mast-cell-specific receptor MrgprB2 in the development of alcohol-withdrawal-induced headache. Withdrawing alcohol from alcohol-acclimated mice induces headache behaviors, including facial allodynia, facial pain expressions, and reduced movement, which are symptoms often observed in humans. Those behaviors were absent in MrgprB2-deficient mice during alcohol withdrawal. We observed in vivo spontaneous activation and hypersensitization of trigeminal ganglia (TG) neurons in alcohol-withdrawal WT mice, but not in alcohol-withdrawal MrgprB2-deficient mice. Increased mast cell degranulation by alcohol withdrawal in dura mater was dependent on the presence of MrgprB2. The results indicate that alcohol withdrawal causes headache via MrgprB2 of mast cells in dura mater, suggesting that MrgprB2 is a potential target for treating alcohol-withdrawal-related headaches.