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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.

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

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.

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.

Abstract Introduction The study aimed to evaluate comparability in terms of efficacy, safety and immunogenicity of Sun’s ranibizumab biosimilar with reference ranibizumab in patients with neovascular age-related macular degeneration (nAMD). Methods This prospective, randomised, double-blind, two-group, parallel-arm, multicentre, phase 3 comparative study included patients with nAMD ≥ 50 years, randomised (in a 2:1 ratio) in a double-blind manner to receive 0.5 mg (0.05 mL) intravitreal injection of either Sun’s ranibizumab or reference ranibizumab in the study eye every 4 weeks until week 16 (total of four doses). Results Primary endpoint results demonstrated equivalence in the proportion of patients who lost fewer than 15 letters from baseline best-corrected visual acuity (BCVA) to the end of week 16 (99% of patients in Sun’s ranibizumab and 100% in reference ranibizumab; p > 0.9999), with the proportional difference (90% confidence interval) at −1% (−2.51, +0.61) lying within a pre-specified equivalence margin. Visual acuity improved by 15 or more letters in 43% of Sun’s ranibizumab group and 37% of the reference ranibizumab group (p = 0.4267). The mean increase in BCVA was 15.7 letters in Sun’s ranibizumab group and 14.6 letters in the reference ranibizumab group (p

Abstract Background/Objectives Rare genetic disorders causing specific congenital developmental abnormalities often manifest in single families. Investigation of disease-causing molecular features are most times lacking, although these investigations may open novel therapeutic options for patients. In this study, we aimed to identify the genetic cause in an Iranian patient with severe skeletal dysplasia and to model its molecular function in zebrafish embryos. Results The proband displays short stature and multiple skeletal abnormalities, including mesomelic dysplasia of the arms with complete humero-radio-ulna synostosis, arched clavicles, pelvic dysplasia, short and thin fibulae, proportionally short vertebrae, hyperlordosis and mild kyphosis. Exome sequencing of the patient revealed a novel homozygous c.374G > T, p.(Arg125Leu) missense variant in MSGN1 (NM_001105569). MSGN1, a basic-Helix–Loop–Helix transcription factor, plays a crucial role in formation of presomitic mesoderm progenitor cells/mesodermal stem cells during early developmental processes in vertebrates. Initial in vitro experiments show protein stability and correct intracellular localization of the novel variant in the nucleus and imply retained transcription factor function. To test the pathogenicity of the detected variant, we overexpressed wild-type and mutant msgn1 mRNA in zebrafish embryos and analyzed tbxta (T/brachyury/ntl). Overexpression of wild-type or mutant msgn1 mRNA significantly reduces tbxta expression in the tailbud compared to control embryos. Mutant msgn1 mRNA injected embryos depict a more severe effect, implying a gain-of-function mechanism. In vivo analysis on embryonic development was performed by clonal msgn1 overexpression in zebrafish embryos further demonstrated altered cell compartments in the presomitic mesoderm, notochord and pectoral fin buds. Detection of ectopic tbx6 and bmp2 expression in these embryos hint to affected downstream signals due to Msgn1 gain-of-function. Conclusion In contrast to loss-of-function effects described in animal knockdown models, gain-of-function of MSGN1 explains the only mildly affected axial skeleton of the proband and rather normal vertebrae. In this context we observed notochord bending and potentially disruption of pectoral fin buds/upper extremity after overexpression of msgn1 in zebrafish embryos. The latter might result from Msgn1 function on mesenchymal stem cells or on chondrogenesis in these regions. In addition, we detected ectopic tbx6 and bmp2a expression after gain of Msgn1 function in zebrafish, which are interconnected to short stature, congenital scoliosis, limb shortening and prominent skeletal malformations in patients. Our findings highlight a rare, so far undescribed skeletal dysplasia syndrome associated with a gain-of-function mutation in MSGN1 and hint to its molecular downstream effectors.

Abstract The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.

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.

Slit lamp biomicroscope is the right hand of an Ophthalmologist. Even though precise, its bulky design and complex working process are limiting constraints, making it difficult for screening at outreach camps, which are an integral part of this field for the purpose of eliminating needless blindness. The torchlight is the main tool used for screening. Recently, the integration of smartphones with instruments and the digitization of slit lamp has been explored, to provide simple and easy hacks. By bringing the slit of the slit lamp to traditional torchlight, we have created “The Slitscope”. It combines the best of both worlds as a simple innovative do-it-yourself novel technique for precise cataract screening. It is especially useful in peripheral centers, vision centers, and outreach camps. We present two prototypes which can also be 3D printed.

Abstract Several COVID-19 vaccines, some more efficacious than others, are now available and deployed, including multiple mRNA- and viral vector-based vaccines. With the focus on creating cost-effective solutions that can reach the low- and medium- income world, GreenLight Biosciences has developed an mRNA vaccine candidate, GLB-COV2-043, encoding for the full-length SARS-CoV-2 Wuhan wild-type spike protein. In pre-clinical studies in mice, GLB-COV2-043 induced robust antigen-specific binding and virus-neutralizing antibody responses targeting homologous and heterologous SARS-CoV-2 variants and a TH1-biased immune response. Boosting mice with monovalent or bivalent mRNA-LNPs provided rapid recall and long-lasting neutralizing antibody titers, an increase in antibody avidity and breadth that was held over time and generation of antigen-specific memory B- and T- cells. In hamsters, vaccination with GLB-COV2-043 led to lower viral loads, reduced incidence of SARS-CoV-2-related microscopic findings in lungs, and protection against weight loss after heterologous challenge with Omicron BA.1 live virus. Altogether, these data indicate that GLB-COV2-043 mRNA-LNP vaccine candidate elicits robust protective humoral and cellular immune responses and establishes our mRNA-LNP platform for subsequent clinical evaluations.

The growth of IoT (Internet of Things) devices has revolutionized several industries and brought about novel security threats. Recognizing network anomalies that may point to malicious activity or system flaws is a major issue. Traditional anomalous identification methods frequently need to catch up when dealing with the special traits of IoT environments, including resource limitations and changing network behavior. This paper introduces an innovative approach, the Bat-optimized CNN-BiLSTM model, to enhance the security and efficiency of IoT environments. This model combines the strengths of Convolutional Neural Networks (CNNs) for spatial analysis and Bidirectional Long Short-Term Memory (BiLSTM) networks for capturing temporal patterns, thus effectively representing time and space trends in IoT data. To optimize its performance further, researchers have leveraged the Bat algorithm, inspired by natural behaviors, to fine-tune the model. This program effectively searches for the best network anomaly detection parameters by imitating the echo activity of bats. Researchers want to increase detection accuracy by lowering false positives and false negatives using the Bat algorithm to enhance the CNN-BiLSTM model. The experimental findings show that the Bat-optimised CNN-BiLSTM model beats the state-of-the-art anomaly detection methods with 99.43% accuracy and efficiency.

Introduction: The global increase in Diabetes Mellitus (DM) is a recognised re-emerging risk and challenge to Tuberculosis (TB) control. The bidirectional association between TB and DM is currently one of the major concerns for clinicians. India has the highest prevalence of TB and the second highest prevalence of DM worldwide. Aim: To estimate the prevalence of DM and its associated risk factors among TB patients in District Sonipat, Haryana, India. Materials and Methods: A cross-sectional study was conducted to determine the prevalence and factors associated with Diabetes among TB patients registered at the Nikshay portal. A total of 400 patients were interviewed using consecutive sampling technique from eight randomly selected Designated Microscopy Centres (DMCs) in District Sonipat, Haryana , India. To identify associations, a multivariable logistic regression model was applied. Results: The prevalence of diabetes among TB patients was found to be 16.25% (65/400). The mean age of the study subjects was 39.9±17.3 years. DM was significantly associated with increasing age, literacy, marital status, occupation, smoking, second-hand smoking, duration of smoking, sputum status at the time of initiation of treatment, pulmonary TB, and other chronic diseases such as hypertension and cardiovascular disease. Conclusion: The present study found a higher prevalence of diabetes among TB patients than in the general population. Therefore, it is recommended to strengthen early bidirectional screening and timely management of TB/DM co-morbidity.

Blood–brain barrier (BBB) injury and dysfunction following infection with the human immunodeficiency virus (HIV) enables viral entry into the brain, infection of resident brain cells, neuronal injury and subsequent neurodegeneration leading to HIV-associated neurocognitive disorders (HAND). Although combination antiretroviral therapy has significantly reduced the incidence and prevalence of acquired immunodeficiency syndrome and increased the life expectancy of people living with HIV, the prevalence of HAND remains high. With aging of people living with HIV associated with increased comorbidities, the prevalence of HIV-related central nervous system (CNS) complications is expected to remain high. Considering the principal role of the brain endothelium in HIV infection of the CNS and HAND, the purpose of this manuscript is to review the current literature on the pathobiology of the brain endothelium structural and functional dysregulation in HIV infection, including in the presence of HIV-1 and viral proteins (gp120, Tat, Nef, and Vpr). We summarize evidence from human and animal studies, in vitro studies, and associated mechanisms. We further summarize evidence of synergy or lack thereof between commonly abused substances (cocaine, methamphetamine, alcohol, tobacco, opioids, and cannabinoids) and HIV- or viral protein-induced BBB injury and dysfunction.