Meningitis in children in Fiji: etiology, epidemiology, and neurological sequelae.

OBJECTIVES: To describe the etiology, epidemiology, neurological sequelae, and quality of life of children aged 1 month to less than 5 years admitted with meningitis to the Colonial War Memorial Hospital (CWMH), Suva, Fiji. METHODS: Over a 3-year period, all eligible children with suspected meningitis admitted to CWMH had blood drawn for culture. Of these children, those for whom is was possible were tested for a four-fold rise in antibody titers to Haemophilus influenzae type b (Hib) and pneumococcal surface adhesin A (PsaA). Cerebrospinal fluid (CSF) was taken for bacteriological culture and antigen testing. CSF was also tested by PCR for Streptococcus species, Neisseria meningitidis, Hib, Mycobacterium tuberculosis, and enterovirus. Pneumococcal isolates were serotyped using multiplex-PCR reverse-line blot hybridization. Following discharge, cases underwent a neurological assessment, audiometry, and quality of life assessment (Pediatric Quality of Life Inventory (PedsQL) tool). RESULTS: There were 70 meningitis cases. Meningitis was more common in indigenous Fijian than Indo-Fijian children. Enterovirus was the most common etiological agent and appeared to be outbreak-associated. Streptococcus pneumoniae was the most common bacterial cause of meningitis with an annual incidence of 9.9 per 100 000 under 5 years old (95% confidence interval 4.9-17.7) and a case fatality rate of 36%. With the exception of deafness, neurological sequelae were more frequent in cases of bacterial meningitis than in viral meningitis (18.5% vs. 0%, p=0.04). Quality of life at follow-up was significantly lower in patients with bacterial meningitis than in those with viral meningitis (p=0.003) or meningitis of unknown etiology (p=0.004). CONCLUSIONS: During the study period an outbreak of enterovirus occurred making it the most common etiological agent identified. However in the absence of this outbreak, S. pneumoniae was the most common cause of childhood meningitis in Fiji. Bacterial meningitis is associated with serious sequelae and a reduced quality of life

Predicting potential spawning areas of European bass, Dicentrarchus labrax, in the Irish and Celtic seas

© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Marine fish species that form spawning aggregations are often vulnerable to exploitation, such as the European bass (Dicentrarchus labrax). Information on bass spawning aggregations is not well resolved temporally and spatially. Otolith daily growth increment (DGI) counts were conducted on 0-group bass collected in July-August 2014 & 2019 from seven settlement estuaries in the Irish and Celtic seas, to estimate the timing of spawning. These timings parameterised three-dimensional hydrodynamic and Lagrangian particle tracking models, run in reverse, to identify probable spawning locations. Estimated spawning occurred between April-May (inshore and offshore) < 200 km from each settlement area. At least two broad spawning areas were predicted: the central Irish Sea that led to post-larval recruitment in north Wales and northwest England, and the southern Irish Sea/Celtic Sea that led to post-larval recruitment in south Wales. Results indicate the current seasonal closure for northern stock bass may not protect spawning events that drive recruitment into settlement sites in Wales and northwest England. Surface temperatures and wind- and tide-driven surface currents determined the connectivity between spawning and settlement sites. Atmospheric drivers are expected to change in the future and management needs to account for potential regional shifts in spawning times and locations.This research was funded by the Bluefish Project (Grant Agreement No. 80991, part-funded by the European Regional Development Fund (ERDF) through the Ireland Wales Co-operation Programme), the European Fisheries Fund, and the European Maritime Fisheries Fund (Fisher-Scientist Project, 81920).Peer reviewe

Modelled larval dispersal and measured gene flow: seascape genetics of the common cockle Cerastoderma edule in the southern Irish Sea:Conservation Genetics

The role of marine currents in shaping population connectivity in the common cockle Cerastoderma edule was investigated in the southern Irish Sea. C. edule is one of the most valuable and exploited shellfish species in the area, yet very little is known about its population dynamics. In the present study, coupled hydrodynamic and particle tracking models are used in conjunction with genetic data collected at twelve microsatellite loci to estimate the influence of the Celtic Sea front on larval transport between the coasts of Britain and Ireland. Genetic analysis highlights the presence of at least three genetic clusters partitioned within locations, suggesting a contact zone between separate subpopulations. Samples collected from the Irish coast are most similar to each other. On the British coast, the Burry Inlet appears genetically isolated while samples collected from the coast of Pembrokeshire show evidence of connectivity between Britain and Ireland. These results agree with the model’s predictions: away from the coastal zone, residual baroclinic currents develop along tidal mixing fronts and act as conduit systems, transporting larvae great distances. Larvae spawned in south Wales are capable of travelling west towards Ireland due to the Celtic Sea front residual current, confirming the action of the Celtic Sea front on larval transport. Sheltered, flood-dominant estuaries such as the Burry Inlet promote self-recruitment. The validation of the model using genetic data represents progress towards a sustainable future for the common cockle, and paves the way for a more effective approach to management of all Irish Sea shellfisheries

An improved synthesis of n-(4-[18 f]fluorobenzoyl)-interleukin-2 for the preclinical pet imaging of tumour-infiltrating t-cells in ct26 and mc38 colon cancer models

10.3390/molecules26061728Molecules266172

Granzyme B PET Imaging in Response to In Situ Vaccine Therapy Combined with &alpha;PD1 in a Murine Colon Cancer Model

Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with &alpha;PD1. [18F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [18F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting

Imaging Effector Memory T-Cells Predicts Response to PD1-Chemotherapy Combinations in Colon Cancer

Often, patients fail to respond to immune checkpoint inhibitor (ICI) treatment despite favourable biomarker status. Numerous chemotherapeutic agents have been shown to promote tumour immunogenicity when used in conjunction with ICIs; however, little is known about whether such combination therapies lead to a lasting immune response. Given the potential toxicity of ICI&ndash;chemotherapy combinations, identification of biomarkers that accurately predict how individuals respond to specific treatment combinations and whether these responses will be long lasting is of paramount importance. In this study, we explored [18F]AlF-NOTA-KCNA3P, a peptide radiopharmaceutical that targets the Kv1.3 potassium channel overexpressed on T-effector memory (TEM) cells as a PET imaging biomarker for lasting immunological memory response. The first-line colon cancer chemotherapies oxaliplatin and 5-fluorouracil were assessed in a syngeneic colon cancer model, either as monotherapies or in combination with PD1, comparing radiopharmaceutical uptake to memory-associated immune cells in the tumour. [18F]AlF-NOTA-KCNA3P reliably separated tumours with immunological memory responses from non-responding tumours and could be used to measure Kv1.3-expressing TEM cells responsible for durable immunological memory response to combination therapy in vivo

Imaging Memory T-Cells Stratifies Response to Adjuvant Metformin Combined with &alpha;PD-1 Therapy

The low response rates associated with immune checkpoint inhibitor (ICI) use has led to a surge in research investigating adjuvant combination strategies in an attempt to enhance efficacy. Repurposing existing drugs as adjuvants accelerates the pace of cancer immune therapy research; however, many combinations exacerbate the immunogenic response elicited by ICIs and can lead to adverse immune-related events. Metformin, a widely used type 2 diabetes drug is an ideal candidate to repurpose as it has a good safety profile and studies suggest that metformin can modulate the tumour microenvironment, promoting a favourable environment for T cell activation but has no direct action on T cell activation on its own. In the current study we used PET imaging with [18F]AlF-NOTA-KCNA3P, a radiopharmaceutical specifically targeting KV1.3 the potassium channel over-expressed on active effector memory T-cells, to determine whether combining PD1 with metformin leads to an enhanced immunological memory response in a preclinical colorectal cancer model. Flow cytometry was used to assess which immune cell populations infiltrate the tumours in response to the treatment combination. Imaging with [18F]AlF-NOTA-KCNA3P demonstrated that adjuvant metformin significantly improved anti-PD1 efficacy and led to a robust anti-tumour immunological memory response in a syngeneic colon cancer model through changes in tumour infiltrating effector memory T-cells

Granzyme B PET Imaging Stratifies Immune Checkpoint Inhibitor Response in Hepatocellular Carcinoma

10.1155/2021/9305277Molecular Imaging2021930527

Arginine-Selective Bioconjugation Reagent for Effective ¹⁸F‑labeling of Native Proteins

Protein-based 18F-PET tracers offer new possibilities in early disease detection and personalized medicine. Their development relies heavily on the availability and effectiveness of 18F-prosthetic groups. We prepared and evaluated a novel arginine-selective prosthetic group, 4-[18F]fluorophenylglyoxal ([18F]FPG). [18F]FPG was radiosynthesized by a one-pot, two-step procedure with a non-decay-corrected (n.d.c.) isolated radiochemical yield (RCY) of 41 ± 8% (n = 10). [18F]FPG constitutes a generic tool for 18F-labeling of various proteins, including human serum albumin (HSA), ubiquitin, interleukin-2, and interleukin-4 in ∼30–60% n.d.c. isolated RCYs. [18F]FPG conjugation with arginine residues is highly selective, even in the presence of a large excess of lysine, cysteine, and histidine. [18F]FPG protein conjugates are able to preserve the binding affinity of the native proteins while also demonstrating excellent in vivo stability. The [18F]FPG-HSA conjugate has prolonged blood retention, which can be applied as a potential blood pool PET imaging agent. Thus, [18F]FPG is an arginine-selective bioconjugation reagent that can be effectively used for the development of 18F-labeled protein radiopharmaceuticals

Imaging Kv1.3 Expressing Memory T Cells as a Marker of Immunotherapy Response

Immune checkpoint inhibitors have shown great promise, emerging as a new pillar of treatment for cancer; however, only a relatively small proportion of recipients show a durable response to treatment. Strategies that reliably differentiate durably-responding tumours from non-responsive tumours are a critical unmet need. Persistent and durable immunological responses are associated with the generation of memory T cells. Effector memory T cells associated with tumour response to immune therapies are characterized by substantial upregulation of the potassium channel Kv1.3 after repeated antigen stimulation. We have developed a new Kv1.3 targeting radiopharmaceutical, [18F]AlF-NOTA-KCNA3P, and evaluated whether it can reliably differentiate tumours successfully responding to immune checkpoint inhibitor (ICI) therapy targeting PD-1 alone or combined with CLTA4. In a syngeneic colon cancer model, we compared tumour retention of [18F]AlF-NOTA-KCNA3P with changes in the tumour immune microenvironment determined by flow cytometry. Imaging with [18F]AlF-NOTA-KCNA3P reliably differentiated tumours responding to ICI therapy from non-responding tumours and was associated with substantial tumour infiltration of T cells, especially Kv1.3-expressing CD8+ effector memory T cells