Search

Nirodhini Narendran,1,2 Clare Bailey,3 Louise Downey,4 Richard Gale,5 Ajay Kotagiri,6 Ian Pearce,7 Christina A Rennie,8 Sobha Sivaprasad,9 James Talks,10 Peter Morgan-Warren,11 Jackie Napier,11 Carolyn O’Neil,11 Timothy Seeborne11 1The Royal Wolverhampton NHS Trust, Wolverhampton, UK; 2School of Life & Health Sciences, Aston University, Birmingham, UK; 3University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK; 4Hull University Teaching Hospitals NHS Trust, Hull, UK; 5York and Scarborough Teaching Hospitals NHS Foundation Trust, York, UK; 6South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK; 7Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK; 8University Hospital Southampton NHS Foundation Trust, Southampton, UK; 9NIHR Moorfields Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, London, UK; 10Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK; 11Bayer plc, Reading, UKCorrespondence: Nirodhini Narendran, Ophthalmology Department, New Cross Hospital (Part of the Royal Wolverhampton NHS Trust), Wolverhampton Road, Wolverhampton, WV10 0QP, UK, Email niro.narendran@nhs.netPurpose: The inclusion of ranibizumab biosimilars into National Health Service England commissioning recommendations published in 2022 created a need for expert guidance to optimize treatment outcomes in patients with neovascular age-related macular degeneration (nAMD) who otherwise may not have received first-line ranibizumab. This article provides a consensus treatment pathway supporting timely identification and management of a suboptimal response to these therapies, thereby aiming to facilitate clinically meaningful outcomes and efficient management of service capacity under specific circumstances where ranibizumab biosimilars may be initiated as a first-line treatment.Methods: Two structured round-table meetings of UK medical retina specialists were held in person and virtually on September 22 and November 3, 2022, respectively. These meetings were organized and funded by Bayer.Results: The panel provided guidance on the implementation of an early treatment optimization pathway in cases where ranibizumab biosimilars are used as a first-line treatment, including recommendations on patient suitability and capacity requirements, and criteria for identification and strategies for management of a suboptimal response. The panel discussed the role of aflibercept treatment and its potential benefits and outlined recommendations on switching ranibizumab biosimilar suboptimal responders to an aflibercept treat-and-extend regimen, where appropriate.Conclusion: Developed by a retinal expert panel, this early treatment optimization pathway provides guidance to facilitate optimal long-term patient outcomes while addressing capacity and resourcing constraints in circumstances of first-line ranibizumab biosimilar use for nAMD, including how aflibercept may be used in cases with a suboptimal response. Therefore, this fills an important gap in guidance on navigating the new treatment landscape.Keywords: anti-VEGF agents, capacity, consensus pathway, ranibizumab

Introduction: The Coronavirus Disease-2019 (COVID-19) pandemic has halted the progress of India made towards the ambition of achieving Tuberculosis (TB)-free status by 2025. Steps taken to control the disease have affected many national health programs, including those for TB. Aim: To understand the delays in diagnosing and initiating therapy among TB patients receiving Antitubercular Therapy (ATT) during the early COVID-19 pandemic period. Materials and Methods: This was a cross-sectional study conducted in the Sonepat District of Haryana state, India. The study was conducted among 20% of the total Nikshay Portal-notified TB patients who received treatment from the public sector in the second and third quarters of 2020. Data was collected using a pretested semistructured schedule consisting of variables related to demography, past medical history, symptoms leading to TB diagnosis, place of diagnosis, time between symptom onset and diagnosis, duration taken for initiating therapy, and reasons for delays. The Chi-square test and Fisher's exact test were used to test the significance of the differences. A p-value

Abstract Background Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by destruction of pancreatic islet beta-cells. There is significant residual beta-cell function, measured through circulating C-peptide, present at the time of T1D diagnosis but this subsequently decreases with time. Higher residual beta-cell function at diagnosis associates with better glycaemic control and less glucose variability, and later in the disease course with less hypoglycaemia, lower glucose variability and fewer microvascular complications. There is therefore value in preserving residual beta cell function in new onset T1D Immunotherapeutic agents can protect residual beta-cell function in type 1 diabetes. However, clinical trials of such agents, whilst demonstrating C-peptide preservation in short term studies, have yet to be taken forward into routine clinical care due to concerns around safety and long-term efficacy. Here we report the case of a gentleman with newly diagnosed T1D whose glycaemic control and insulin requirement improved whilst on a five year infusion programme of infliximab, a monoclonal antibody against TNF-alpha, for colitis. Case presentation A 52-year-old White Caucasian man was diagnosed with T1D in August 2018. Glucose was 25.6 mmol/L, HbA1c was 98mmol/mol and GAD antibodies were strongly positive. HbA1c marginally improved to 91mmol/mol following initiation of insulin detemir 5 units at night and 1:10 g of insulin aspart (November 2018). In June 2019, he developed rectal bleeding and abdominal pain. Following colonoscopy, he was diagnosed with “indeterminate colitis” and commenced on 6-weekly infusions of 400-450 mg infliximab. Thus far, he has received 32 doses and achieved colitis remission. Following infliximab initiation there was increased frequency of mild-moderate hypoglycaemia and he was gradually weaned off and discontinued detemir in June 2020. Since then, HbA1c improved from 57mmol/mol in August 2019 to 52mmol/mol in April 2022, remaining stable at 51mmol/mol. His most recent HbA1c is 54mmol/mol in February 2024. His c-peptide was 550pmol/L in October 2022 and 442pmol/L in February 2024, suggesting well-preserved beta-cell function almost 6 years post-diagnosis. Conclusions Our patient’s improvement in glycaemic control can be explained by immunomodulation and C peptide preservation from infliximab. With the growing focus on type 1 diabetes disease modulation and working towards an ‘insulin free T1D’, our findings strengthen the evidence base for the repurposing of and long-term treatment with anti-TNF-α agents to preserve beta-cell function in new onset T1D.

Purpose: To assess the incidence and clinical profile of hemifacial spasm (HFS) and the association between HFS and systemic diseases. Methods: This retrospective study was carried out on 85 patients with HFS, presenting at a tertiary eye care center in South India. Demographic and clinical details were recorded for all patients. Of these, the patients who had undergone magnetic resonance imaging (MRI) of the brain were analyzed for primary and secondary HFS. Results: The mean age of the patients was 56.11 ± 12.51 years. The age at onset of HFS was 54.9 ± 12.7 years. The disease duration was 9.51 ± 7.28 years. Male:female ratio was 1:1.17. The right side was involved in 31 patients (36.47%) and the left side in 54 patients (63.52%). MRI was performed in 54 (63.52%) patients and showed neurovascular conflict in 22 (40.74%) patients and space-occupying lesions in 2 (3.70%) patients. Forty-nine (57.64%) patients had primary HFS, while five (5.88%) patients had secondary HFS due to old facial palsy in 3 and space-occupying lesions in two patients. Twenty (23.52%) patients received botulinum toxin A with a good response. Type of HFS had a significant association with hypertension (P = 0.046) while no significant association was present between laterality of HFS and systemic diseases (P > 0.05 each). Multivariate analysis showed a marginally significant association between type of HFS and hypertension (P = 0.057). Conclusions: Primary HFS was the main type of HFS with female dominance and predilection for the left side. Hypertension had a relationship with HFS that needs to be investigated further for its causal nature.

There are significant variations in discharge post-diabetes-related ketoacidosis (DKA) hospitalisation, yet there is a paucity of research to understand or minimise the reasons. This quality improvement project (QIP) aimed to identify reasons for post-DKA discharge delays and assess intervention efficacy. Utilising the Digital Evaluation of Ketosis and Other Diabetes-related Emergencies (DEKODE) model, data from 177 DKA episodes from January 2021 to September 2023 across three hospitals were analysed. Factors affecting discharge were investigated through a plan, do, study, act (PDSA) methodology. While interventions focused on optimising data collection and refining discharge guidelines, no significant reduction in DKA duration or length of stay was observed. Findings highlight post-DKA hospitalisation's multifaceted nature and the limited impact of simple interventions. Collaborative efforts and further research are necessary to develop effective strategies for expedited discharge and improved patient care. This study's comprehensive tracking and analysis tool offers valuable insights for future interventions in managing DKA-related hospitalisations.

Background: Estimation of the risk of future atherosclerotic cardiovascular (CV) events is an important step in the primary prevention of CV events. However, the relative accuracy of the various currently available CV risk scores is not validated in Indians. Aims and Objectives: The study was done to compare the accuracy of three clinically relevant CV risk assessment algorithms in the South Indian population and to validate the risk scores by correlating with the measures of subclinical atherosclerosis. Materials and Methods: This cross-sectional study was conducted among patients attending a chest pain clinic at a Tertiary care center in South India. The study included subjects ≥30 years of age, with no previous coronary artery disease (CAD) and major cardiac illness. Totally 110 subjects were included in the study. Detailed clinical evaluation and routine investigations were done. The 10-year CV risk for each subject was calculated using the three risk scores – Framingham, American College of Cardiology/American Heart Association (ACC/AHA), and Q risk score. The risk scores of all patients were then correlated with their corresponding carotid intima-media thickness (CIMT) measured using carotid Doppler and coronary angiography results. Results: The mean age of the study population was 51.45±9.01 years and the majority of them were females (57.2%). CAD patients demonstrated significantly increased CIMT. There was a significant positive correlation (P

CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ SCID patient's HSPCs resulted in a 71.2% ± 7.85% (n = 3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate the preclinical efficacy of ABE in HSPCs for the treatment of CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.

Introduction We describe the identification and management of general population screen-detected type 1 diabetes (T1D) and share learnings for best practice.Research design and methods Children diagnosed with T1D through a general population screening initiative, the EarLy Surveillance for Autoimmune diabetes (ELSA) study, were reviewed and described.Parents provided written, informed consent for inclusion in the case series.Results 14 children with insulin requiring (stage 3) T1D are described. These cases offer unique insights into the features of screen-detected T1D. T1D is identified sooner through screening programs, characterized by absent/short symptom duration, median presenting glycated hemoglobin 6.6% (49 mmol/mol) and insulin requirements

Type 1 diabetes (T1D) is a chronic autoimmune disease in which the adaptive immune system targets insulin-producing β-cells of pancreatic islets, leading to dependence on exogenous insulin therapy. Cytotoxic (CD8+) T-cells specific for islet antigens are major players in T1D autoimmunity. Data indicate that regular exercise may preserve β-cell function in people recently diagnosed with T1D, but the role of islet-reactive CD8+ T-cells is unclear. In a randomised crossover design, this study will determine the impact of a 12-week exercise programme on the frequency and proliferative state of islet-reactive CD8+ T-cells in the peripheral blood of 20 adults diagnosed with T1D within the past 3 years. The exercise intervention will consist of three high-intensity interval training sessions per week (6–10 1 min intervals >80% maximum heart rate, with 1 min rest), the duration of which will incrementally increase from 14 to 22 min. Habitual physical activity and diet will be maintained during control and washout periods. At weeks 0, 12, 24 and 36, a fasting blood sample will be collected to quantify the frequency, phenotype and proliferative activity of islet-reactive CD8+ T-cells (primary outcome) and various clinical parameters. Glycaemic control will also be evaluated using 14-day continuous glucose monitoring at the start and end of each study arm. Findings may provide a rationale for conducting large-scale trials to evaluate the implementation of exercise into routine clinical care, particularly for people recently diagnosed with T1D when maintenance of β-cell function is critical to counteract disease progression.Trial registration number: ISRCTN79006041.

ABSTRACT Introduction This work describes a secondary analysis of a qualitative data set originally used to understand parent participants' preferences for the design and implementation of a screening programme for paediatric Type 1 diabetes (T1D). From this, their spontaneous preferences for peer support emerged, described here in the context of existing peer support programmes for the newly diagnosed alongside suggestions for their incorporation into screening programmes for T1D and a range of other conditions. Methods Data were collected from semi‐structured interviews conducted with parents of children aged 3–13 years to explore their expectations, perceptions and preferences of a T1D paediatric screening programme. A secondary analysis of interviews from participants who spontaneously raised preferences for peer support was used to populate a novel framework informed by NHS England's key principles for the same, namely, Shared experiences and reciprocated support, Accessibility and inclusivity and Person‐centred and integrated peer support. Results Parents in 29 of 33 interviews spontaneously described the potential value of peer support if receiving a result indicating a positive (presymptomatic T1D result) from a screening programme. Specifically, the value of ‘Shared experiences and reciprocated support’ in terms of emotional support and reassurance, and access to more directly interpretable and relevant information related to the condition; ‘Accessibility and inclusivity’ relating to access to a community of similar individuals, whether in person or online; ‘Person‐centred and integrated peer‐support’ and the need for support reflecting the changing need of the child and the integration of peer support with clinical care. Conclusions The needs of peer support described by parents involved in T1D paediatric screening appear to be shared with those of families with children diagnosed with a range of life‐altering conditions. Although the needs of peer support for paediatric screening may differ across conditions, our findings are a valuable starting point for its design both in T1D and other examples of similar population screening programmes. Patient or Public Contribution Patients and the public have been involved throughout the design of the ELSA study and have worked with us to inform the study process. They contributed to the design and content of patient‐facing materials, the content of our topic guides and the analysis and interpretation of our findings.

Recent advancements in the field of photoresponsive-based mercury (II) sensors have witnessed a surge in research focused on enhancing detection capabilities. Leveraging innovations in materials science, particularly with quantum dots, nanomaterials, and organic semiconductors, these sensors exhibit improved selectivity and sensitivity. Beyond traditional applications, such as environmental monitoring, the integration of photoresponsive principles with emerging technologies like the internet of things (IoT) and wearable promises real-time and remote mercury (II) ion detection. The on-going efforts also explore multifunctional sensors and miniaturization for on-site applications, addressing current challenges and paving the way for broader commercialization. This dynamic landscape underscores the potential for these sensors to play a crucial role in ensuring the effective monitoring and management of mercury (II) levels in diverse settings.

ABSTRACT Contemporary antifungal therapies utilized to treat filamentous fungal infections are inhibited by intrinsic and emerging drug resistance. Consequently, there is an urgent need to develop novel antifungal compounds that are effective against drug-resistant filamentous fungi. Here, we utilized an Aspergillus fumigatus cell-based high-throughput screen to identify small molecules with antifungal activity that also potentiated triazole activity. The screen identified 16 hits with promising activity against A. fumigatus. A nonspirocyclic piperidine, herein named MBX-7591, exhibited synergy with triazole antifungal drugs and activity against pan-azole-resistant A. fumigatus isolates. MBX-7591 has additional potent activity against Rhizopus species and CO2-dependent activity against Cryptococcus neoformans. Chemical, genetic, and biochemical mode of action analyses revealed that MBX-7591 increases cell membrane saturation by decreasing oleic acid content. MBX-7591 has low toxicity in vivo and shows good efficacy in decreasing fungal burden in a murine model of invasive pulmonary aspergillosis. Taken together, our results suggest MBX-7591 is a promising hit with a novel mode of action for further antifungal drug development to combat the rising incidence of triazole-resistant filamentous fungal infections.IMPORTANCEThe incidence of infections caused by fungi continues to increase with advances in medical therapies. Unfortunately, antifungal drug development has not kept pace with the incidence and importance of fungal infections, with only three major classes of antifungal drugs currently available for use in the clinic. Filamentous fungi, also called molds, are particularly recalcitrant to contemporary antifungal therapies. Here, a recently developed Aspergillus fumigatus cell reporter strain was utilized to conduct a high-throughput screen to identify small molecules with antifungal activity. An emphasis was placed on small molecules that potentiated the activity of contemporary triazole antifungals and led to the discovery of MBX-7591. MBX-7591 potentiates triazole activity against drug-resistant molds such as A. fumigatus and has activity against Mucorales fungi. MBX-7591’s mode of action involves inhibiting the conversion of saturated to unsaturated fatty acids, thereby impacting fungal membrane integrity. MBX-7591 is a novel small molecule with antifungal activity poised for lead development.