Impact of plant-based nanoparticles synthesized from Carica papaya and Bryophyllum pinnatum against selected microorganisms

Plant-based nanoparticles offer sustainable, eco-friendly alternatives to conventional methods, promising antibacterial properties in the face of antibiotic resistance and addressing global health concerns. Five urine and stool samples were collected from the Benin Medical Centre in Benin City, Edo State, and sent to the Wellspring University Research Laboratory for microbiological analysis. Carica papaya and Bryophyllum pinnatum were used for fresh utilization by washing, weighing, and crushing their leaves, then mixing them with distilled water and heating at 85 °C and 60 °C for 60 minutes. Silver and copper nanoparticles (AgNPs and CuNPs) were synthesized using standard procedures. The NPs were preliminary validated by visual detection of color changes and characterized using a UV-visible spectrophotometer at 300 nm and Fourier transform infrared. The in vitro antimicrobial activity of plant-mediated NPs was investigated using five isolates: S. aureus, B. alvei, H. pylori, P. aeruginosa, and E. coli. The in vitro antimicrobial activity of plant-mediated NPs was investigated using five clinical strains displaying multiple resistance to antibiotics: S. aureus, B. alvei, H. pylori, P. aeruginosa, and E. coli. The agar-well diffusion method showed inhibition of the isolates by plant-mediated NPs but no inhibition by the plant extract alone. The study indicates that plant-mediated NPs exhibit promising antimicrobial activity, promoting sustainability and eco-friendliness, but further research is needed to assess their safety and efficacy in clinical settings. Article history: Received 24 November 2023; Revised 19 February 2024; Accepted 16 May 2024; Available online 30 June 2024

Health and criminal justice system involvement among African American siblings

Importance: Health disparities between African Americans and Whites have persisted in the United States. Researchers have recently hypothesized that the relatively poor health of African Americans may be caused, in part, by African American overrepresentation in the criminal justice system. Objectives: To test the hypothesis that criminal justice system involvement is associated with poor health and greater health risk when controlling for unobserved family factors through a discordant sibling design. Methods: Subjects were drawn from the Carolina African American Twin Study of Aging (CAATSA). Criminal conviction records were extracted from North Carolina\u27s Department of Public Safety. Six measures of health and one measure of health risk were analyzed. The health of convicted respondents was compared to that of unrelated non-convicted respondents matched on childhood and demographic factors (“matched sample”). Convicted respondents were also compared to non-convicted siblings (“discordant sibling sample”). Results: The matched sample included 134 CAATSA respondents. On average, convicted CAATSA respondents, compared to matched non-convicted respondents, were in worse health. Convicted respondents had worse mean self-reported health, worse lung function, more depressive symptoms, and smoked more. The discordant sibling sample included 74 respondents. Convicted siblings and non-convicted siblings had similar self-reported health, depressive symptoms, and smoking. In general, non-convicted siblings were in worse health than non-convicted respondents from the matched sample, implying that poor health runs in families. Conclusions: This study provided preliminary evidence that some of the association between a criminal record and poor health is confounded by family factors. Though more research is needed to support these results, the study suggests that criminal involvement may not be associated with the surfeit of health problems observed among African Americans. The criminal justice system, nonetheless, could be used to decrease the health disparity

Locoregional and systemic therapy for hepatocellular carcinoma

The management of hepatocellular carcinoma (HCC) remains challenging due to late presentation and the presence of accompanying liver dysfunction. As such, most patients are not eligible for curative resection and liver transplant. Management in this scenario depends on a number of factors including hepatic function, tumor burden, patency of hepatic vasculature and patients' functional status. Based on these, patients can be offered catheter based intra-arterial therapy for intermediate stage disease and in more advanced disease, sorafenib. Given recent data, regorafenib is now an option following failure of sorafenib. Catheter directed intra-arterial therapy takes advantage of tumor hypervascularity and the unique dual blood supply of the liver, as hepatic tumors receive arterial perfusion via the hepatic artery while the rest of the liver is supplied by the portal vein. This allows selective embolization and delivery of chemotherapeutic agents to the tumor. Compared to best supportive care, intra-arterial therapy offers a survival benefit in intermediate stage HCC and is the recommended approach for treatment. None of the catheter based approaches; including bland embolization, conventional trans-arterial chemoembolization (cTACE), drug eluting bead trans-arterial chemoembolization (DEB-TACE) or trans-arterial radioembolization (TARE) offers a clear advantage over the other, although DEB-TACE may be characterized by less systemic toxicity. All of these approaches are contraindicated in patients with portal vein thrombosis (PVT). On the other hand, intra-arterial, radio embolization, with Yttrium-90 (Y90) can be offered to patients with PVT. The place of this modality in management of HCC is still being investigated. The role of sorafenib in advanced HCC is not in doubt, as until recently, it was the only systemic therapy approved for the management in this setting. This is despite multiple trials evaluating other agents. The addition of sorafenib to catheter-based therapy in intermediate stage disease has also failed to show any benefit. The modest survival benefit with sorafenib and the failure of other targeted agents suggest that it is important to look beyond inhibition of angiogenesis in advanced HCC. Identification of key drivers and mediators of HCC remains paramount for successful drug development. In line with this, it is refreshing that the excitement that has followed developments in cancer immunotherapy is finding its way to HCC with early trials of anti-PD1 monoclonal antibodies showing sufficient activity that phase III trials are now ongoing for Pembrolizumab and Nivolumab in advanced HCC. Future drug development efforts will focus on defining the feasibility of combining different treatment approaches targeting multiple important modulators of HCC

The clinical and cost-effectiveness of sertraline in preventing depression in adults following a traumatic brain injury (STOP-D): study protocol for a multi-centre randomised controlled trial

Background: Traumatic brain injury (TBI) is a common presentation in emergency departments worldwide. Approximately 1.4 million adults present with TBI in England and Wales annually. Post-TBI depression (PTD) is a common neuropsychiatric consequence, affecting up to 50% of patients within two years, and is associated with adverse functional outcomes. PTD remains underdiagnosed and undertreated. Sertraline, a selective serotonin reuptake inhibitor (SSRI), has shown potential in reducing PTD incidence, yet evidence of its effectiveness in preventing depression from adequately powered trials is lacking. This randomised controlled trial aims to compare the clinical and cost-effectiveness of sertraline in reducing the risk of PTD in adults compared to usual care. Methods: The design is a multi-centre, double-blind, placebo-controlled, randomised controlled trial (RCT) aiming to recruit 514 participants. Eligible adults (aged ≥ 18 years) with possible, mild or moderate-severe TBI within eight weeks of injury and without current major depressive disorder (MDD) are randomly assigned to receive sertraline (100 mg daily) or placebo for 12 months. The primary outcome is depressive symptom severity at 12 months, measured using the Patient Health Questionnaire-9. Secondary outcomes include incidence rates of major depressive disorder, psychiatric comorbidities, cognitive impairment, substance use, carer burden, productivity and cost-effectiveness at 6, 12 and 18 months. Discussion: This is the first adequately powered RCT to investigate sertraline as a preventive intervention for PTD. Findings will help inform whether prescribing an SSRI soon after a TBI may reduce the risk of depression and improve functional outcomes. Trial registration: This study is registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT no. 2022–000072-18, date: 7 January 2022) and the ISRCTN – The UK’s Clinical Study Registry (ISRCTN no. 17518945, date: 23 December 2022, https://www.isrctn.com/ISRCTN17518945)

Paediatric meningitis in the conjugate vaccine era and a novel clinical decision model to predict bacterial aetiology

Objectives The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes. Methods Children aged <16 years hospitalised with suspected meningitis/encephalitis were included, and prospectively recruited at 31 UK hospitals. Meningitis was defined as identification of bacteria/viruses from cerebrospinal fluid (CSF) and/or a raised CSF white blood cell count. New clinical decision rules were developed to distinguish bacterial from viral meningitis and those of alternative aetiology. Results The cohort included 3002 children (median age 2·4 months); 1101/3002 (36·7%) had meningitis, including 180 bacterial, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged <6 months and 10–16 years, with Neisseria meningitidis and/or Streptococcus pneumoniae commonest at age 6 months to 9 years. The Bacterial Meningitis Score had a negative predictive value of 95·3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after lumbar puncture (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis. Conclusions Bacterial meningitis comprised 6% of children with suspected meningitis/encephalitis. Our clinical decision rules provide potential novel approaches to assist with identifying children with bacterial meningitis. Funding This study was funded by the Meningitis Research Foundation, Pfizer and the NIHR Programme Grants for Applied Research

45th Annual Larval Fish Conference & 13th International Larval Biology Symposium San Diego, California 29 August – 1 September, 2022

INDITU

Estimating the Economic Value of Automated Virtual Reality Cognitive Therapy for Treating Agoraphobic Avoidance in Patients With Psychosis: Findings From the gameChange Randomized Controlled Clinical Trial

Background:An automated virtual reality cognitive therapy (gameChange) has demonstrated its effectiveness to treat agoraphobia in patients with psychosis, especially for high or severe anxious avoidance. Its economic value to the health care system is not yet established.Objective:In this study, we aimed to estimate the potential economic value of gameChange for the UK National Health Service (NHS) and establish the maximum cost-effective price per patient.Methods:Using data from a randomized controlled trial with 346 patients with psychosis (ISRCTN17308399), we estimated differences in health-related quality of life, health and social care costs, and wider societal costs for patients receiving virtual reality therapy in addition to treatment as usual compared with treatment as usual alone. The maximum cost-effective prices of gameChange were calculated based on UK cost-effectiveness thresholds. The sensitivity of the results to analytical assumptions was tested.Results:Patients allocated to gameChange reported higher quality-adjusted life years (0.008 QALYs, 95% CI –0.010 to 0.026) and lower NHS and social care costs (–£105, 95% CI –£1135 to £924) compared with treatment as usual (£1=US $1.28); however, these differences were not statistically significant. gameChange was estimated to be worth up to £341 per patient from an NHS and social care (NHS and personal social services) perspective or £1967 per patient from a wider societal perspective. In patients with high or severe anxious avoidance, maximum cost-effective prices rose to £877 and £3073 per patient from an NHS and personal social services perspective and societal perspective, respectively.Conclusions:gameChange is a promising, cost-effective intervention for the UK NHS and is particularly valuable for patients with high or severe anxious avoidance. This presents an opportunity to expand cost-effective psychological treatment coverage for a population with significant health needs.Trial Registration:ISRCTN Registry ISRCTN17308399; https://www.isrctn.com/ISRCTN1730839

Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study

Background: Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues. // Methods: We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109 T4+ T-cells, administered without prior lymphodepletion. // Results: Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product. // Conclusions: These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC