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Mas-related G protein-coupled receptor-X2 (MRGPRX2) expressed on mast cells (MCs) contributes to hypersensitivity reactions to cationic US-Food and Drug Administration (FDA) approved drugs such as the neuromuscular blocking agent, rocuronium. In addition, activation of MRGPRX2 by the neuropeptide substance P (SP) and the pro-adrenomedullin peptide (PAMP-12) is associated with a variety of cutaneous conditions such as neurogenic inflammation, pain, atopic dermatitis, urticaria, and itch. Thus, small molecules aimed at blocking MRGPRX2 constitute potential options for modulating IgE-independent MC-mediated disorders. Two inverse MRGPRX2 agonists, named C9 and C9-6, have recently been identified, which inhibit basal G protein activation and agonist-induced calcium mobilization in transfected HEK293 cells. Substance P serves as a balanced agonist for MRGPRX2 whereby it activates both G protein-mediated degranulation and β-arrestin-mediated receptor internalization. The purpose of this study was to determine if C9 blocks MRGPRX2's G protein and β-arrestin-mediated signaling and to determine its specificity. We found that C9, but not its inactive analog C7, inhibited degranulation in RBL-2H3 cells stably expressing MRGPRX2 in response to SP, PAMP-12 and rocuronium with an IC value of ~300 nM. C9 also inhibited degranulation as measured by cell surface expression of CD63, CD107a and β-hexosaminidase release in LAD2 cells and human skin-derived MCs in response to SP but not the anaphylatoxin, C3a or FcϵRI-aggregation. Furthermore, C9 inhibited β-arrestin recruitment and MRGPRX2 internalization in response to SP and PAMP-12. We found that a G protein-coupling defective missense MRGPRX2 variant (V282M) displays constitutive activity for β-arrestin recruitment, and that this response was significantly inhibited by C9. Rocuronium, SP and PAMP-12 caused degranulation in mouse peritoneal MCs and these responses were abolished in the absence of MrgprB2 or cells treated with pertussis toxin but C9 had no effect. These findings suggest that C9 could provide an important framework for developing novel therapeutic approaches for the treatment of IgE-independent MC-mediated drug hypersensitivity and cutaneous disorders.

Spinal Cord Injury (SCI) or Acquired Brain Injury (ABI) leads to disability, unemployment, loss of income, decreased quality of life and increased mortality. The impact is worse in Low-and Middle-Income Countries (LMICs) due to a lack of efficient long-term rehabilitative care. This study aims to explore the feasibility and acceptability of a telerehabilitation programme in Nepal.

Infection, trauma, and autoimmunity trigger tissue inflammation, often leading to pain and loss of function. Therefore, approaches to control inflammation based on nanotechnology principles are being developed in addition to available methods. The metal-based nanoparticles are particularly attractive due to the ease of synthesis, control over physicochemical properties, and facile surface modification with different types of molecules. Here, we report curcumin conjugated silver (Cur-Ag) nanoparticles synthesis, followed by their surface functionalization with isoniazid, tyrosine, and quercetin, leading to Cur-AgINH, Cur-AgTyr, and Cur-AgQrc nanoparticles, respectively. These nanoparticles possess radical scavenging capacity, haemocompatibility, and minimal cytotoxicity to macrophages. Furthermore, the nanoparticles inhibited the secretion of pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-α, and interleukin-1β from macrophages stimulated by lipopolysaccharide (LPS). The findings reveal that the careful design of surface corona of nanoparticles could be critical to increasing their efficacy in biomedical applications.

One-half of patients with newly diagnosed pancreatic cancer will have metastatic disease at the time of diagnosis, mainly due to its non-specific initial clinical presentation which includes abdominal pain, dyspepsia, weight loss, bowel habit changes, jaundice and pruritus. The signs, symptoms and stage of the disease at initial diagnosis depends on the origin of the primary tumor, with tumors of the head presenting earlier with obstructive symptoms while tumors of the body/tail are often diagnosed at an advanced stage due to their non-specific presentation. The most common sites of metastasis are the lymph nodes, liver, lung, and peritoneum. The presence of metastatic disease in the skeletal muscles is a rare manifestation of pancreatic cancer and has been described in a limited number of cases. We report the case of a pancreatic cancer patient with a solitary muscle lesion as the only site of extra-nodal metastasis upon initial presentation.

The emergence of potentially pandemic viruses has resulted in preparedness efforts to develop candidate vaccines and adjuvant formulations. We evaluated the dose-sparing effect and safety of two distinct squalene-based oil-in-water adjuvant emulsion formulations (IB160 and SE) with influenza A/H7N9 antigen. This phase I, randomized, double-blind, placebo-controlled, dose-finding trial (NCT03330899), enrolled 432 healthy volunteers aged 18 to 59. Participants were randomly allocated to 8 groups: 1A) IB160 + 15μg H7N9, 1B) IB160 + 7.5μg H7N9, 1C) IB160 + 3.75μg H7N9, 2A) SE + 15μg H7N9, 2B) SE + 7.5μg H7N9, 2C) SE + 3.75μg H7N9, 3) unadjuvanted vaccine 15μg H7N9 and 4) placebo. Immunogenicity was evaluated through haemagglutination inhibition (HI) and microneutralization (MN) tests. Safety was evaluated by monitoring local and systemic, solicited and unsolicited adverse events (AE) and reactions (AR) 7 and 28 days after each study injection, respectively, whereas serious adverse events (SAE) were monitored up to 194 days post-second dose. A greater increase in antibody geometric mean titers (GMT) was observed in groups receiving adjuvanted vaccines. Vaccinees receiving IB160-adjuvanted formulations showed the greatest response in group 1B, which induced an HI GMT increase of 4.7 times, HI titers ≥40 in 45.2% of participants (MN titers ≥40 in 80.8%). Vaccinees receiving SE-adjuvanted vaccines showed the greatest response in group 2A, with an HI GMT increase of 2.5 times, HI titers ≥40 in 22.9% of participants (MN titers ≥40 in 65.7%). Frequencies of AE and AR were similar among groups. Pain at the administration site and headache were the most frequent local and systemic solicited ARs. The vaccine candidates were safe and the adjuvanted formulations have a potential dose-sparing effect on immunogenicity against influenza A/H7N9. The magnitude of this effect could be further explored.

Post-COVID19 patients suffer from persistent respiratory, cardiovascular, neurological, and musculoskeletal health complaints such as dyspnea, chest pain/discomfort, and fatigue. In Tunisia, the potential benefits of a cardiorespiratory rehabilitation program (CRRP) after COVID19 remain unclear. The main aim of this study was to evaluate the impact of a CRRP on submaximal exercise capacity, evaluated through the 6-min walk test (6MWT) data in post-COVID19 Tunisian patients. This was a cross-sectional study including 14 moderate to severe COVID19 patients aged from 50 to 70 years. CRRP was performed after the end of patients' hospitalization in COVID19 units for extensive or severe extents of COVID19. Dyspnea (modified medical research council), spirometry data, handgrip strength values, 6MWT data, and 6-min walk work (i.e., 6-min walk distance x weight) were evaluated 1-week pre-CRRP, and 1-week post-CRRP. CRRP included 12 sessions [3 sessions (70 min each)/week for 4 weeks]. Exercise-training included aerobic cycle endurance, strength training, and educational sessions. Comparing pre- and post- CRRP results showed significant improvements in the means±standard deviations of dyspnea by 1.79 ± 0.80 points ( < 0.001), forced expiratory volume in one second by 110 ± 180 ml ( = 0.04), 6-min walk distance by 35 ± 42 m ( = 0.01), 6-min walk work by 2,448 ± 3,925 mkg ( = 0.048), resting heart-rate by 7 ± 9 bpm ( = 0.02) and resting diastolic blood pressure by 6 ± 10 mmHg ( = 0.045). In Tunisia, CRRP seems to improve the submaximal exercise capacity of post-COVID19 patients, mainly the 6-min walk distance and work.

Hemorrhage in vestibular schwannoma (VS) is a rare but potentially devastating complication, owing to the proximity to the brainstem and small space in the posterior fossa.

Following the surge of coronavirus disease 2019 (COVID-19) cases in the epicenter of East Java Province, this study aimed to determine the clinical characteristics of patients with COVID-19 at one of the emergency field hospitals in Indonesia. This was a single-centered, retrospective descriptive study of 763 patients admitted to the COVID-19 Emergency Field Hospital of Bangkalan from July 5 2021 to September 30 2021. The demographic data, clinical signs and symptoms, pre-existing comorbidities, therapy, and clinical outcomes of the patients were analyzed using SPSS. The clinical characteristics of patients with COVID-19 at the emergency hospital were varied. A total of 763 patients were included. The most common age was between 40 and 49 years (31.1%), a slight majority were women (51.5%), and most had travelled abroad in the last 14 days (99.1%). Of the 763 patients, 70.9% had no comorbidities. Half of the patients were asymptomatic (49.4%), 46% were mild cases, 4.1% were moderate, and 0.5% severe. The most common symptoms were productive cough (15.7%) and headache (15.3%). Supportive and comorbidity therapy were given which showed excellent clinical outcomes. The majority of COVID-19 patients were asymptomatic, female, middle aged and had recently been overseas. Therapy without antibiotics or antivirals showed positive outcomes in COVID-19 patients.

Structural approaches to promoting health focus on policies and practices affecting health at the community level and concentrate on systems and forces of society, including distribution of power, that foster disadvantage and diminish health and well-being. In this paper we advocate consideration of structural approaches to explore macro level influences on the burden of persistent pain on society. We argue that health promotion is an appropriate discipline to ameliorate painogenic environments and that a "settings approach" offers a crucial vehicle to do this. We encourage consideration of socio-ecological frameworks to explore factors affecting human development at individual, interpersonal, organizational, societal, and environmental levels because persistent pain is multifaceted and complex and unlikely to be understood from a single level of analysis. We acknowledge criticisms that the structural approach may appear unachievable due to its heavy reliance on inter-sectoral collaboration. We argue that a settings approach may offer solutions because it straddles "practical" and cross-sectorial forces impacting on the health of people. A healthy settings approach invests in social systems where health is not the primary remit and utilises synergistic action between settings to promote greater health gains. We offer the example of obesogenic environments being a useful concept to develop strategies to tackle childhood obesity in school-settings, community-settings, shops, and sports clubs; and that this settings approach has been more effective than one organisation tackling the issue in isolation. We argue that a settings approach should prove useful for understanding painogenic environments and tackling the burden of persistent pain.

This study aimed to explore the clinical efficacy of Chaihu Shugan powder combined with acupoint stimulation on the acute pancreatitis of liver and qi stagnation syndromes, the protection of intestinal barrier function, the prevention of severe tendency, and safety evaluation.