Western Hospital

Jack Jumper ant (JJA) venom immunotherapy (VIT) is highly efficacious but the lowest effective dose is unknown. Delta-inulin adjuvant (Advax) is known to enhance honeybee VIT immunogenicity. This phase 1/2 single-blind, randomised controlled trial aimed to compare the efficacy and safety of JJA VIT with different doses of venom ± Advax. Adults aged 18-65 with a history of immediate systemic reaction (SR) to JJA stings were randomised to receive JJA VIT at a maintenance dose of 25 mcg or 50 mcg ± Advax; participants were blinded to treatment allocation. Primary outcomes were the response to sting challenges after 12 months and venom-specific IgE and IgG4 responses to treatment. Forty-nine of 50 screened subjects met inclusion criteria and were randomised; 44 started treatment (25 mcg n = 12; 25 mcg + Advax n = 13; 50mcg n = 12, 50 mcg + Advax n = 12). Subsequently, two withdrew due to SRs to treatment, and two withdrew due to unrelated factors. The higher JJA venom maintenance dose was associated with reduced likelihood of SRs (OR 0.53 (95% CI, 0.28-0.98)), while Advax did not have an effect (OR 1.17 (95% CI, 0.59-2.32)). Forty proceeded to sting challenge, with six developing SRs. There was no difference between groups for sting challenge outcome (p = 0.98), and the ORs for 25 mcg vs. 50 mcg venom dose (0.89, 95% CI, 0.38-2.09) and Advax vs. no Advax (0.99, 95% CI 0.42-2.33) indicated no effect. There were no differences between groups for venom sIgE (p = 0.78), sIgG4 (p = 0.25), sIgE/IgG4 ratio (p = 0.42), intradermal (p = 0.77), and basophil activation test (BAT) (p = 0.69) responses to treatment. Subjects with high baseline BAT sensitivity, which reduced markedly in response to treatment, were less likely to have a positive sting challenge (p = 0.006). Challenge outcomes were similar for all groups, with no significant difference found between 25 and 50 mcg maintenance dose or between treatment with and without Advax. Further research of low dose JJA VIT is warranted to confirm its efficacy and tolerability. NCT03066986.

Corticobasal syndrome (CBS) is a rare, clinically heterogeneous form of atypical Parkinsonism. Hyperkinetic movements, aside from myoclonus and dystonia, have rarely been reported in CBS. We present two patients with CBS, one with pathologically confirmed corticobasal degeneration (CBD) and generalized chorea, and another with probable CBS and Levodopa-induced dyskinesia (LID). Case 1 exhibited late-onset generalized chorea, which was preceded by several years of dystonia, rigidity and apraxia affecting the right upper limb. Case 2 presented with dystonia, cortical sensory loss, and apraxia in the left upper limb, while LID affected the face and the right side of the body. A systematic review of published cases of chorea or levodopa-induced dyskinesia (LID) in CBS was performed. The literature search was executed in PubMed from its inception for cases of chorea or LID associated with CBS. Twelve patients were identified across eight studies. Only five cases of pathologically confirmed CBD with chorea were found; chorea developed after 4 years of disease progression. Chorea and LID are rare but may represent late manifestations of CBS. The exact mechanisms are unclear; they may relate to variability in anatomical involvement, particularly relative sparing of the GPi. Greater understanding of topographical disease progression may improve diagnostic precision and phenotypic classification in CBS and related tauopathies.

BackgroundHip fractures are common in older people and are associated with high perioperative mortality. Prompt surgical intervention within the first 48 h of fraction reduces complications; however, surgical urgency often precludes a comprehensive preoperative cardiac evaluation. Preliminary data suggests that performing a focused cardiac ultrasound (FCU) before surgery may reduce postoperative complications. We therefore propose to test the primary hypothesis that FCU reduces a 30-day composite of mortality and serious complications.MethodsWe plan a definitive multicenter pragmatic randomized trial that will enroll 2000 adults with hip fractures. Participants will be randomized before surgery to either receive FCU as part of their preoperative assessment or to routine care without FCU. FCU is a brief, 10-min, goal-directed echocardiography performed at the patient’s bedside. FCU will be conducted by physicians trained in FCU and the information gathered will be shared immediately with all clinicians involved in the patient’s care (anesthesiologists, orthopedic surgeons, geriatricians). The primary outcome will be a 30-day composite of all-cause mortality, hospital readmission, acute kidney injury, cardiac failure, and myocardial injury after noncardiac surgery. Secondary and exploratory outcomes include hospital length of stay, days to return to original residence, postoperative recovery, and quality of life. Additionally, a health cost analysis will be conducted to weigh costs against benefits.DiscussionOur large RCT aims to determine whether preoperative focused ultrasound examinations of hip fracture patients reduce serious postoperative complications, improves the quality of recovery, improves life quality, and is cost-effective.Trial registrationRegistration number: ACTRN12622001546741. Date registered 14/12/2022.

To examine how well fracture risk predicts subchondral bone and cartilage morphometry independently of osteoarthritis (OA) clinical risk factors. Male and female participants in the Osteoarthritis Initiative (OAI) at visit 5 (36months) were evaluated for fracture risk using FRAX and categorized into low-, moderate-, or high-risk groups. These groups were compared for bone marrow lesion (BML) size, number and effusion, subchondral bone structure, density, and cartilage morphometry in the most affected knee at either same time point, 1 or 2years later, using general linear models. Sex interactions were examined in each case and probed if significant. Among 1240 participants (58.8% female, age: 63.7 ± 8.8years, and BMI: 30.1 ± 4.9kg/m2), 20.32% had moderate or high FRAX and showed lower subchondral bone density (- 0.12 to - 0.25g/cm2), less intact trabeculae, and thinner cartilage (- 0.14 to - 0.47mm) compared to low FRAX (p < 0.05). Males showed larger positive FRAX correlations with bone density, and females had protective effects of FRAX against BML numbers, although the effects were small (sex interaction, p < 0.05). All FRAX models adjusting for OA risk factors yielded better model fit than OA risk factors alone. Having moderate/high versus low FRAX at baseline predicted a 1.36 (1.00, 1.86)-fold higher odds of reaching a Kellgren-Lawrence score of 3 or 4 within a year. High FRAX predicts thinner cartilage and weaker subchondral bone within a year. Complementing standard OA clinical risk factors with FRAX calculation could help identify individuals likely to develop worse knee OA radiologic outcomes.

Introduction and Purpose: Melanoma, an aggressive malignancy from melanocytes, has a poor prognosis. Despite advances in targeted therapies and immunotherapies, drug resistance remains a challenge. This review examines the molecular pathways involved in melanoma and therapeutic strategies targeting them, aiming to improve patient outcomes and overcome treatment resistance by understanding genetic alterations and signaling cascades driving melanoma progression. State of Knowledge: Melanoma arises from genetic predisposition and UV radiation exposure, involving mutations in pathways like RAS/RAF/MAPK and PI3K/AKT. Targeted therapies, such as BRAF and MEK inhibitors, are effective, especially in BRAF-mutant patients. However, resistance mechanisms, including alternative pathway activation and immune evasion, limit their long-term success. Combination therapies with immunotherapies show promise in overcoming resistance. Emerging targets like NRAS, c-KIT, and c-MET offer new treatment possibilities. Ongoing challenges include identifying biomarkers for patient stratification and managing treatment-related toxicity. Conclusions: Understanding the molecular mechanisms of melanoma is crucial for advancing therapies. Targeted therapies and combination approaches have improved outcomes, especially in advanced cases. However, challenges like treatment resistance and toxicity require ongoing research. By exploring signaling pathways and new targets, treatment efficacy and durability can be enhanced. Continued research and clinical trials are essential to translate these advancements into practice, improving survival rates and quality of life for melanoma patients.