Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ’s exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics

Investigating the biological properties of carbohydrate derived fulvic acid (CHD-FA) as a potential novel therapy for the management of oral biofilm infections.

Background: A number of oral diseases, including periodontitis, derive from microbial biofilms and are associated with increased antimicrobial resistance. Despite the widespread use of mouthwashes being used as adjunctive measures to control these biofilms, their prolonged use is not recommended due to various side effects. Therefore, alternative broad-spectrum antimicrobials that minimise these effects are highly sought after. Carbohydrate derived fulvic acid (CHD-FA) is an organic acid which has previously demonstrated to be microbiocidal against Candida albicans biofilms, therefore, the aims of this study were to evaluate the antibacterial activity of CHD-FA against orally derived biofilms and to investigate adjunctive biological effects.<p></p> Methods: Minimum inhibitory concentrations were evaluated for CHD-FA and chlorhexidine (CHX) against a range of oral bacteria using standardised microdilution testing for planktonic and sessile. Scanning electron microscopy was also employed to visualise changes in oral biofilms after antimicrobial treatment. Cytotoxicity of these compounds was assessed against oral epithelial cells, and the effect of CHD-FA on host inflammatory markers was assessed by measuring mRNA and protein expression.<p></p> Results: CHD-FA was highly active against all of the oral bacteria tested, including Porphyromonas gingivalis, with a sessile minimum inhibitory concentration of 0.5%. This concentration was shown to kill multi-species biofilms by approximately 90%, levels comparable to that of chlorhexidine (CHX). In a mammalian cell culture model, pretreatment of epithelial cells with buffered CHD-FA was shown to significantly down-regulate key inflammatory mediators, including interleukin-8 (IL-8), after stimulation with a multi-species biofilm.<p></p> Conclusions: Overall, CHD-FA was shown to possess broad-spectrum antibacterial activity, with a supplementary function of being able to down-regulate inflammation. These properties offer an attractive spectrum of function from a naturally derived compound, which could be used as an alternative topical treatment strategy for oral biofilm diseases. Further studies in vitro and in vivo are required to determine the precise mechanism by which CHD-FA modulates the host immune response.<p></p&gt

“She’s been a rock”: the function and importance of ‘holding’ by social prescribing link workers in primary care in England: findings from a realist evaluation.

Social prescribing link workers are new roles in English primary care. One of their intended functions is to address the increasing number of patients with conditions influenced by the wider, social determinants of health. Their main purpose is to connect people to community resources to meet their non-medical needs. However, our research reveals that link workers provide not only connections, but also what we have described as ‘holding’ for patients who have complex needs, who lack informal networks of support or who are waiting to access services. We explore the concept of holding, its meaning and significance in this context and its consequences.As part of a realist evaluation, we observed seven link workers in GP practices in England during focussed ethnographies over a three-week period. We took field notes and interviewed 61 patients and 93 healthcare professionals. Nine to twelve months later we carried out follow-up interviews with 41 patients, seven link workers and a link worker manager. We identified four functions of holding: supporting patients waiting for services, sustaining patients as they prepare for change, reducing the emotional burden of primary healthcare professionals, and bearing witness to patients’ distress. Holding appears to be a vital, but often overlooked aspect of social prescribing. Patients benefit from having a reliable and consistent person to support their emotional needs. However, similar to the impact of holding on other primary care professionals, there are unintended consequences: some link workers exceed their capacity, become over-burdened, experience burnout, and leave their job. Recognizing the importance of holding and understanding its role in link workers' primary care responsibilities are critical. If holding work is accepted as a role for link workers, providing training and support for them should be prioritized to ensure successful implementation and positive outcomes for patients, link workers and primary healthcare

Evaluating a pre-surgical health optimisation programme: a feasibility study

BACKGROUND: Health optimisation programmes are increasingly popular and aim to support patients to lose weight or stop smoking ahead of surgery, yet there is little published evidence about their impact. This study aimed to assess the feasibility of evaluating a programme introduced by a National Health Service (NHS) clinical commissioning group offering support to smokers/obese patients in an extra 3 months prior to the elective hip/knee surgery pathway. METHODS: Feasibility study mapping routinely collected data sources, availability and completeness for 502 patients referred to the hip/knee pathway in February–July 2018. RESULTS: Data collation across seven sources was complex. Data completeness for smoking and ethnicity was poor. While 37% (184) of patients were eligible for health optimisation, only 28% of this comparatively deprived patient group accepted referral to the support offered. Patients who accepted referral to support and completed the programme had a larger median reduction in BMI than those who did not accept referral (− 1.8 BMI points vs. − 0.5). Forty-nine per cent of patients who accepted support were subsequently referred to surgery, compared to 61% who did not accept referral to support. CONCLUSIONS: Use of routinely collected data to evaluate health optimisation programmes is feasible though demanding. Indications of the positive effects of health optimisation interventions from this study and existing literature suggest that the challenge of programme evaluation should be prioritised; longer-term evaluation of costs and outcomes is warranted to inform health optimisation policy development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13741-022-00255-2

Integration of research and practice to improve public health and healthcare delivery through a collaborative 'Health Integration Team' model - A qualitative investigation

© 2016 The Author(s). Background: Economic considerations and the requirement to ensure the quality, safety and integration of research with health and social care provision have given rise to local developments of collaborative organisational forms and strategies to span the translational gaps. One such model - the Health Integration Team (HIT) model in Bristol in the United Kingdom (UK) - brings together National Health Service (NHS) organisations, universities, local authorities, patients and the public to facilitate the systematic application of evidence to promote integration across healthcare pathways. This study aimed to (1) provide empirical evidence documenting the evolution of the model; (2) to identify the social and organisational processes and theory of change underlying healthcare knowledge and practice; and (3) elucidate the key aspects of the HIT model for future development and translation to other localities. Methods: Contemporaneous documents were analysed, using procedures associated with Framework Analysis to produce summarised data for descriptive accounts. In-depth interviews were undertaken with key informants and analysed thematically. Comparative methods were applied to further analyse the two data sets. Results: One hundred forty documents were analysed and 10 interviews conducted with individuals in leadership positions in the universities, NHS commissioning and provider organisations involved in the design and implementation of the HIT model. Data coalesced around four overarching themes: 'Whole system' engagement, requiring the active recruitment of all those who have a stake in the area of practice being considered, and 'collaboration' to enable coproduction were identified as 'process' themes. System-level integration and innovation were identified as potential 'outcomes' with far-reaching impacts on population health and service delivery. Conclusion: The HIT model emerged as a particular response to the perceived need for integration of research and practice to improve public health and healthcare delivery at a time of considerable organisational turmoil and financial constraints. The concept gained momentum and will likely be of interest to those involved in setting up similar arrangements, and researchers in the social and implementation sciences with an interest in their evaluation

Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries

BACKGROUND: Childhood tuberculosis remains a major cause of morbidity and mortality in part due to missed diagnosis. Diagnostic methods with enhanced sensitivity using easy-to-obtain specimens are needed. We aimed to assess the diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR), a candidate test measuring a three-gene transcriptomic signature from fingerstick blood, in children with presumptive tuberculosis disease. METHODS: RaPaed-TB was a prospective diagnostic accuracy study conducted at four sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and one site in India. Children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30, 2021. MTB-HR was performed at baseline and at 1 month in all children and was repeated at 3 months and 6 months in children on tuberculosis treatment. Accuracy was compared with tuberculosis status based on standardised microbiological, radiological, and clinical data. FINDINGS: 5313 potentially eligible children were screened, of whom 975 were eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic classification and were included in the analysis. MTB-HR differentiated children with culture-confirmed tuberculosis from those with unlikely tuberculosis with a sensitivity of 59·8% (95% CI 50·8–68·4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7–48·7), and using a composite clinical reference standard, sensitivity was 29·6% (25·4–34·2). Specificity for all three reference standards was 90·3% (95% CI 85·5–94·0). Performance was similar in different age groups and by malnutrition status. Among children living with HIV, accuracy against the strict reference standard tended to be lower (sensitivity 50·0%, 15·7–84·3) compared with those without HIV (61·0%, 51·6–69·9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71·2% of children with microbiologically confirmed tuberculosis. INTERPRETATION: MTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung; German Center for Infection Research (DZIF)

Burden and associated phenotypic characteristics of tuberculosis infection in adult Africans with diabetes: a systematic review.

Diabetes mellitus (DM) increases the risk of developing tuberculosis infection (TBI). However, the evidence on the burden and phenotypic characteristics of TBI in African patients with DM is limited. This study aimed to determine the prevalence and characterisation of TBI in native African patients living with DM. We searched PubMed, EMBASE, and African Journals Online for original studies reporting information on the prevalence and characteristics of TBI in adult Africans with DM. A forest plot was used to describe the pooled prevalence estimate of TBI and the corresponding 95% confidence intervals (CI). Six studies conducted in four African countries involving 721 participants with DM were included in this systematic review. The pooled prevalence estimate of TBI was 40% (95% CI 20-60%, I2 = 98.52%, p < 0.001). Age ≥ 40 years and glycated haemoglobin levels independently predicted TBI positivity in patients with DM in three studies. Africans with DM have a high prevalence of TBI, especially those who are older or with poorly controlled diabetes. This justifies the need for studies to explore how to screen and manage TBI to avert the progression to active TB disease