Search

Abstract Background There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer. Methods Chemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS. Results Mice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis. Conclusion Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors.

Low vision and blindness are increasing public health issues impacting individuals’ quality of life. During clinical low-vision services, vision rehabilitation is crucial for enhancing daily living skills and improving life quality. Low-vision and rehabilitation (LVR) services encompass comprehensive measures that aid visually disabled individuals in restoring function, autonomy, and social participation. Such holistic management requires a multidisciplinary approach, facilitating adaptation to environmental and sociocultural changes. However, the lack of awareness about the principles and practices of LVR services poses a major hindrance to setting up such a special clinic in the eye hospital. This article is about a consensus statement on the guidelines for establishing LVR services focusing on basic requirements, especially in low-resource countries. The present recommendation to set up an LVR clinic was made after group discussions and debates among various experts and stakeholders during the National Workshop on Strengthening Low-Vision and Rehabilitation Services organized at Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi. The event was participated by many ophthalmologists and optometrists coming from across the country. The recommendations required at the tertiary level are outlined under the four headings: Human resources and training: two ophthalmologists, that is, a low vision specialist or a well-experienced in low vision and one who has received one-week orientation and training, one optometrist, one rehabilitation supervisor, and two rehabilitation assistants; Assessment equipment: basic screening and diagnostic; Assistive devices for low vision, including, digital and non-digital; Assistive devices for rehabilitation, and methods for records maintenance. The institution may not follow strictly the present guidelines but will provide an idea on LVR services initiation.

The Descemet membrane (DM) is the basement membrane of corneal endothelial cells, which are responsible for maintaining corneal transparency. DM detachment (DMD) can occur due to various reasons, with the most common etiology being post-surgical. Older age, blunt instruments, and faulty surgical technique predispose to the intraoperative or postoperative occurrence of DMD, and one should have a high index of suspicion for DMD in cases with unexplained or an atypical pattern of corneal edema after surgery. Prompt intervention for DMD management is imperative to effect early visual rehabilitation, decrease corneal morbidity, and avoid permanent damage leading to scarring of the cornea. Various classifications of DMD and management protocols have been described. Anterior-segment optical coherence tomography (AS-OCT) imaging is the most effective imaging to detect DMD and quantify its extent. Desmetopexy with air/gas is the initial treatment of choice and could be aided by suture fixation. Non-responsive cases might need endothelial keratoplasty.

In Kenya, influenza virus circulates year-round, raising questions about optimum strategies for vaccination. Given national interest in introducing influenza vaccination for young children 6–23 months of age, we modeled total influenza-associated illnesses (inclusive of hospitalizations, outpatient illnesses, and non‒medically attended illnesses) averted by multiple potential vaccination strategies: year-round versus seasonal-campaign vaccination, and vaccination starting in April (Southern Hemisphere influenza vaccine availability) versus October (Northern Hemisphere availability). We modeled average vaccine effectiveness of 50% and annual vaccination coverage of 60%. In the introduction year, year-round vaccination averted 6,410 total illnesses when introduced in October and 7,202 illnesses when introduced in April, whereas seasonal-campaign vaccination averted 10,236 (October) to 11,612 (April) illnesses. In the year after introduction, both strategies averted comparable numbers of illnesses (10,831–10,868 for year-round, 10,175–11,282 for campaign). Campaign-style vaccination would likely have a greater effect during initial pediatric influenza vaccine introduction in Kenya; however, either strategy could achieve similar longer-term effects.

The precise control of tool offset in static shoulder friction stir welding (SSFSW) is vital for enhancing the mechanical properties and overall effectiveness of dissimilar metal joints. The present study investigates the impact of tool offset on the development of microstructural features, intermetallic compound formation, texture analysis, and mechanical characteristics of SSFSWed Al6061 to Ti6Al4V joints. The results demonstrate that a 2.5 mm tool offset results in an average grain size of 2.65 μm, compared to larger grains of about 4.76 μm and 7.31 μm observed at 2.0 mm and 1.5 mm offsets, respectively. The percentage of low-angle grain boundaries also varies, reaching up to 42.2% at a 2.5 mm offset compared to 48.6% at 2.0 mm and 64.1% at 1.5 mm, indicating enhanced homogeneity in the microstructural properties. Moreover, the ultimate tensile strength at the 2.5 mm tool offset reaches 279 MPa, which is 5.7% higher than at the 2.0 mm offset and 13.4% higher than at the 1.5 mm offset. This improvement is attributed to more uniform distribution of Ti particles over the stir zone. Texture analysis further supports these findings, with the development of alpha fibre at 2.5 mm offset enhancing ductility, thereby underscoring the critical role of tool offset in achieving sound dissimilar metal weldments.

Abstract Appendicitis, an infection and inflammation of the appendix is a prevalent condition in children that requires immediate treatment. Rupture of the appendix may lead to several complications, such as peritonitis and sepsis. Appendicitis is medically diagnosed using urine, blood, and imaging tests. In recent times, Artificial Intelligence and machine learning have been a boon for medicine. Hence, several supervised learning techniques have been utilized in this research to diagnose appendicitis in pediatric patients. Six heterogeneous searching techniques have been used to perform hyperparameter tuning and optimize predictions. These are Bayesian Optimization, Hybrid Bat Algorithm, Hybrid Self-adaptive Bat Algorithm, Firefly Algorithm, Grid Search, and Randomized Search. Further, nine classification metrics were utilized in this study. The Hybrid Bat Algorithm technique performed the best among the above algorithms, with an accuracy of 94% for the customized APPSTACK model. Five explainable artificial intelligence techniques have been tested to interpret the results made by the classifiers. According to the explainers, length of stay, means vermiform appendix detected on ultrasonography, white blood cells, and appendix diameter were the most crucial markers in detecting appendicitis. The proposed system can be used in hospitals for an early/quick diagnosis and to validate the results obtained by other diagnostic modalities.

Abstract Background Bilateral ocular surface disease resulting from Stevens Johnson Syndrome (SJS) and chemical injuries are visually debilitating and difficult to treat. Ocular surface reconstruction by various means has been reported with variable results. This study addresses an unmet need for a prospective clinical trial comparing the outcomes of transplanting autologous oral and conjunctival epithelial cell constructs on human amniotic membrane by ex vivo tissue engineering. Methods A prospective, randomized controlled clinical trial was prospectively applied for registration, with the clinical trial registry of India (CTRI), with the approval of the Institute Ethics Committee number IEC/NP-99/11.04.2014 and CTRI No. REF/2018/10/021791, the study also registered with the WHO-recognized trial registry, International Standard Randomised Controlled Trial Number (ISRCTN) registration reference number 45780. The study was conducted to compare clinical outcomes of two different tissue-engineered cell grafts, Cultivated Oral Mucosal Epithelial Transplantation (COMET) and Conjunctival Cultivated Epithelial Transplantation (CCET) for ocular surface reconstruction in patients with bilateral ocular surface disease due to Stevens-Johnson Syndrome or chemical injuries. Fifty patients were enrolled and randomized to either the COMET or CCET group. A uniform pre-op and post-op protocol using standard medications was followed for all patients Parameters assessed at baseline, day 1, 1 week, 2 weeks, 1 month, 2 months, 3 months and 6 months postoperatively included patient comfort, best corrected visual acuity (BCVA), ocular surface status and corneal clarity. The efficacy was measured in terms of improvement of vision, reduction in vascularization, symblepharon and corneal clarity. Results In the study, 50 patients (50 eyes; mean ages of 29 ± 15.86 years and 26.36 ± 10.85 years, respectively; range, 12–65 years) were enrolled, with 25 patients each in the COMET and CCET groups. Out of them, 36% were female and 64% were male; the causes were Steven Johnson syndrome (48), and chemical injury (2). Mean pre-operative BCVA was log MAR 1.73 ± 0.57 for COMET and 1.99 ± 0.33 for the CCET group. Pre-operatively all 50 enrolled patients had opaque corneas pre-operatively, symblepharon that extended to the cornea categorised as grade 3 and corneal vascularization that went beyond the pupil’s boundary into the central zone encluaching on the visual axis. The minimal follow-up time was six months. Following surgery postoperatively, the BCVA considerably improved in the COMET group by 1.51 ± 0.58 compared to the CCET group by 1.91 ± 0.33 at 3 months. BCVA at 6 months was 1.73 ± 0.56 in the COMET group and 1.99 ± 0.31 in the CCET group, which is not statistically significant and comparable to the BCVA before surgery. The corneal clarity was significantly improved in COMET group 25 eye (100%) at 2 month, 3month and 19 eye (76%), 6eye (24%) at 6 months when compared to CCET group 15 eye improved (60%), 9 eyes (36%) not improved and one eye with opaque cornea (4%) at 2 months. 22 eye (88%) had not improved, 2 eye (8%) opaque cornea and 1 eye (4%) improved at 3 months. At 6 months 21 eye (84%) were not improved, 4 eye (16%) eye became opaqued at 6 months. Compared to preoperative conditions, both groups had improved corneal clarity significantly (p > 0.005). Of the 50 patients with grade 3 symblepharon extended to the cornea, were completely resolved 19 (76%) in COMET group when compared to CCET group 22 eye (88%) not improved. Similarly, 19 eye (76%) had a improvement in corneal vascularization when compared to the CCET group not improved 25 eye (100%) at 6months. No adverse event was observed in any of either group during the follow up periods. Conclusion Both cell types are effective to restore the ocular surface integrity in bilateral ocular surface disease. Whereas COMET is safe and efficacious in terms of improvement of clinical parameters including, BCVA, corneal clarity, reduction in vascularization and preventing the recurrence of symblepharon postoperatively 3months and 6 months. In addition, the CCET group maintained the stability of the ocular surface and had improvement in corneal clarity and a decrease in vascularization at 3 months compared to their pre-operative characteristics.

Abstract Hypertension is a leading contributor to mortality in low‐middle income countries including Haiti, yet only 13% achieve blood pressure (BP) control. We evaluated the effectiveness of a community‐based hypertension management program delivered by community health workers (CHWs) and physicians among 100 adults with uncontrolled hypertension from the Haiti Cardiovascular Disease Cohort. The 12‐month intervention included: community follow‐up visits with CHWs (1 month if BP uncontrolled ≥140/90, 3 months otherwise) for BP measurement, lifestyle counseling, medication delivery, and dose adjustments. Primary outcome was mean change in systolic BP from enrollment to 12 months. Secondary outcomes were mean change in diastolic BP, BP control, acceptability, feasibility, and adverse events. We compared outcomes to 100 age, sex, and baseline BP matched controls with standard of care: clinic follow‐up visits with physicians every 3 months. We also conducted qualitative interviews with participants and providers. Among 200 adults, median age was 59 years, 59% were female. Baseline mean BP was 154/89 mmHg intervention versus 153/88 mmHg control. At 12 months, the difference in SBP change between groups was −12.8 mmHg (95%CI −6.9, −18.7) and for DBP −7.1 mmHg (95%CI −3.3, −11.0). BP control increased from 0% to 58.1% in intervention, and 28.4% in control group. Four participants reported mild adverse events. In mixed methods analysis, we found community‐based delivery addressed multiple participant barriers to care, and task‐shifting with strong teamwork enhanced medication adherence. Community‐based hypertension management using task‐shifting with CHWs and community‐based care was acceptable, and effective in reducing SBP, DBP, and increasing BP control.

Abstract Climate change is currently one of humanity’s greatest threats. To help scholars understand the psychology of climate change, we conducted an online quasi-experimental survey on 59,508 participants from 63 countries (collected between July 2022 and July 2023). In a between-subjects design, we tested 11 interventions designed to promote climate change mitigation across four outcomes: climate change belief, support for climate policies, willingness to share information on social media, and performance on an effortful pro-environmental behavioural task. Participants also reported their demographic information (e.g., age, gender) and several other independent variables (e.g., political orientation, perceptions about the scientific consensus). In the no-intervention control group, we also measured important additional variables, such as environmentalist identity and trust in climate science. We report the collaboration procedure, study design, raw and cleaned data, all survey materials, relevant analysis scripts, and data visualisations. This dataset can be used to further the understanding of psychological, demographic, and national-level factors related to individual-level climate action and how these differ across countries.

Abstract Background The characteristics of a tumor are largely determined by its interaction with the surrounding micro-environment (TME). TME consists of both cellular and non-cellular components. Cancer-associated fibroblasts (CAFs) are a major component of the TME. They are a source of many secreted factors that influence the survival and progression of tumors as well as their response to drugs. Identification of markers either overexpressed in CAFs or unique to CAFs would pave the way for novel therapeutic strategies that in combination with conventional chemotherapy are likely to have better patient outcome. Methods Fibroblasts have been derived from Benign Prostatic Hyperplasia (BPH) and prostate cancer. RNA from these has been used to perform a transcriptome analysis in order to get a comparative profile of normal and cancer-associated fibroblasts. Results The study has identified 818 differentially expressed mRNAs and 17 lincRNAs between normal and cancer-associated fibroblasts. Also, 15 potential lincRNA-miRNA-mRNA combinations have been identified which may be potential biomarkers. Conclusions This study identified differentially expressed markers between normal and cancer-associated fibroblasts that would help in targeted therapy against CAFs/derived factors, in combination with conventional therapy. However, this would in future need more experimental validation.

Abstract Introduction LMNB1-related autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurodegenerative disorder caused by overexpression of LMNB1. We retrospectively reviewed charts of all ADLD patients seen at Mayo Clinic. Methods All available data from molecularly confirmed ADLD patients was reviewed. Results Of eight patients identified, three were male. Age at symptom onset ranged from 33 to 64 years. In males, the first symptom was erectile dysfunction (2/3) or neurogenic bladder (1/3) and, in females, weakness (3/5), bladder dysfunction (2/5), or depression (1/5). Diagnostic delay from symptom onset was a median of 6 (IQR 2.3–10) years. Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8). Family history was positive in 6. All eight patients had LMNB1 duplication. Eighteen brain MRIs were reviewed from 7 patients. All showed symmetric confluent T2W deep cerebral and periventricular white matter hyperintensities with involvement of the posterior limb of the internal capsule, corpus callosum, corticospinal tract in brain stem, and superior and middle cerebellar peduncles. Seven spine MRIs from six patients showed moderate diffuse atrophy of the spinal cord. Conclusion Typical clinical symptoms and characteristic MRI changes should prompt genetic testing for ADLD.

Background: With a call to action from the health-care industry and the Indian government, there are significant gaps in health-care professionals’ uptake and utilization of artificial intelligence (AI)-based tools. This study attempts to explore the current perceptions and readiness for AI among health-care workers. Methods: A web-based questionnaire comprising seven sections on descriptive educational and occupational data, AI familiarity level, role-specific training benefits, training advantages, implementation issues, driving factors, and perceived risks was designed from a literature search. Two additional domains of perception on professional impact and preparedness for AI in health care were estimated using a prevalidated Shinners AI Perception tool. Results: Of the 402 study participants, 192 (47.9%) were doctors from diverse specializations, and the remaining 209 (52.1%) were undergraduate medical and nursing students and affiliated health professionals. Although 79.8% of participants had never attended a course on AI, 82% agreed on the need for training in AI to explore new opportunities in their respective fields. 72.1% of participants agreed that data privacy and confidentiality posed the most significant challenge to AI implementation among the studied factors. Conclusion: This survey reveals awareness regarding AI, which is attributable to a lack of formal training received by health-care professionals. Most participants believed that AI could improve population health outcomes, and collective efforts are needed to make this belief a reality.

Children are seen as beings who exist from birth through puberty, while teenagers are regarded as existing from puberty until around the age of 20 years. For a number of legal processes, including child labor, employment, the age of majority, rape, adoption, marriage eligibility, and situations where the birth certificate is unavailable, age estimation in children and adolescents is crucial. Despite the wide range of methods available, dental age estimation techniques that take into account tooth maturation are thought to be the most reliable predictors of chronological age in subadults. This is because genetic factors predominate and environmental factors, particularly between birth and age ten, tend to have little impact on tooth maturation. The eruption of teeth holds greater significance in the deciduous dentition, where genetic factors predominantly govern the process, compared to the permanent dentition. Conversely, tooth calcification serves as a viable indicator for estimating dental age in both primary and permanent dentitions. Current dental age estimation methods are based on age-related changes in teeth, such as tooth growth and development, changes that occur after teeth form, and biochemical changes. Therefore, in this review article, we will explore the several methodologies used for dental age assessment in children and adolescents.

Introduction: Road traffic injuries are the eighth leading cause of death in India. The Law Commission of India report says that 50% of the victims who died of preventable injuries could have been saved had they received the medical care on time. To protect the people who help road accident victims, Good Samaritan Law was enacted. OBJECTIVES: To assess awareness and knowledge about Good Samaritan Law among the general literate population and to assess the impact of awareness session on awareness score. Methods: In this cross-sectional study, adult participants of either gender, literate enough to read and comprehend the material provided, were included in the study through either an electronic or written informed consent process. The participants were asked to complete a questionnaire, watch/read the awareness video/material provided, and then complete the post-awareness session questionnaire. The participants were divided into the aware and unaware groups for further assessment of pre-awareness scores. The pre- and post-awareness session scores were compared in the participants using paired-t-test. Results: In this study, 379 participants gave consent for participation; however, only 288 participants attempted the post-awareness questionnaire. The mean pre-awareness session score was significantly higher in the aware group (8.5) as compared to the unaware group (5.6). The pre-awareness scores were significantly high in doctors as compared to medical students in the aware group and as compared to medical students, graduates, teachers, and general public in the unaware group. Post-awareness session scores (9.2 ± 2.8) were observed to be significantly higher (p < 0.001) than pre-awareness session scores (6.4 ± 3.4). Conclusion: In this study, it was observed that the percentage of participants who were aware of the law was less. It demonstrated the impact of awareness session on increasing GSL awareness score in participants. These findings indicate the need of awareness programs to transform bystanders into good samaritans.

Abstract Proteins can be targeted for degradation by engineering biomolecules that direct them to the eukaryotic ubiquitination machinery. For instance, the fusion of an E3 ubiquitin ligase to a suitable target binding domain creates a ‘biological Proteolysis-Targeting Chimera’ (bioPROTAC). Here we employ an analogous approach where the target protein is recruited directly to a human E2 ubiquitin-conjugating enzyme via an attached target binding domain. Through rational design and screening we develop E2 bioPROTACs that induce the degradation of the human intracellular proteins SHP2 and KRAS. Using global proteomics, we characterise the target-specific and wider effects of E2 vs. VHL-based fusions. Taking SHP2 as a model target, we also employ a route to bioPROTAC discovery based on protein display libraries, yielding a degrader with comparatively weak affinity capable of suppressing SHP2-mediated signalling.

Abstract Groundwater arsenic poisoning has posed serious health hazards in the exposed population. The objective of the study is to evaluate the arsenic ingestion from breastmilk among pediatric population in Bihar. In the present study, the total women selected were n = 513. Out of which n = 378 women after consent provided their breastmilk for the study, n = 58 subjects were non-lactating but had some type of disease in them and n = 77 subjects denied for the breastmilk sample. Hence, they were selected for the women health study. In addition, urine samples from n = 184 infants’ urine were collected for human arsenic exposure study. The study reveals that the arsenic content in the exposed women (in 55%) was significantly high in the breast milk against the WHO permissible limit 0.64 µg/L followed by their urine and blood samples as biological marker. Moreover, the child’s urine also had arsenic content greater than the permissible limit (

Abstract Most clinical information is encoded as free text, not accessible for quantitative analysis. This study presents an open-source pipeline using the local large language model (LLM) “Llama 2” to extract quantitative information from clinical text and evaluates its performance in identifying features of decompensated liver cirrhosis. The LLM identified five key clinical features in a zero- and one-shot manner from 500 patient medical histories in the MIMIC IV dataset. We compared LLMs of three sizes and various prompt engineering approaches, with predictions compared against ground truth from three blinded medical experts. Our pipeline achieved high accuracy, detecting liver cirrhosis with 100% sensitivity and 96% specificity. High sensitivities and specificities were also yielded for detecting ascites (95%, 95%), confusion (76%, 94%), abdominal pain (84%, 97%), and shortness of breath (87%, 97%) using the 70 billion parameter model, which outperformed smaller versions. Our study successfully demonstrates the capability of locally deployed LLMs to extract clinical information from free text with low hardware requirements.

Abstract Many parts of the world face severe and prolonged drought conditions, stressing the sustainability of water resources and agriculture. Transitioning to water-efficient crops is one strategy that can help adapt to water scarcity. An emerging drought-tolerant crop of interest is chia (Salvia hispanica). Yet, no study has compared its large-scale water use dynamics to those of widely established crops across the globe. Here, we use satellite data over multiple years to assess the water use efficiency of chia, alfalfa, corn, and soybean globally. Results show that chia consumed 13-38% less water than alfalfa, corn, and soy and assimilated 14-20% more carbon per amount of water used. Substituting 10% of Southwest United States alfalfa cultivation with chia would save 184 million liters of water per growing season, equivalent to the annual water consumption of 1,300 households. Future research shall explore the economic, societal, and environmental ramifications of substituting alfalfa with chia in dry areas worldwide. These insights can guide decision-makers in promoting sustainable agriculture and water resource management.

Abstract Background Owing to their peculiar location, cavernous sinuses communicate with numerous head and neck structures via fissures and foramen which provide an easy access for pathologies to traverse to and from the cavernous sinuses to these vital structures. On routine brain imaging, diseases involving the cavernous sinuses can be easily missed if we are not vigilant to examine cavernous sinuses using dedicated thin sections of sellar and parasellar region. Main body of the abstract The various pathologic conditions involving cavernous sinuses either primarily or secondarily include neoplasms, vascular conditions, cystic/fat-containing lesions and infective/inflammatory conditions. Due to considerable overlap in clinical symptoms of numerous diseases affecting cavernous sinuses, timely and effective imaging evaluation of cavernous sinuses using multimodality approach with dedicated imaging sequences can help in formulating a clinically relevant differential diagnosis and alter patient management. Thin T1- and T2-weighted axial and coronal images with appropriately timed MR angiography and venography should be performed for diagnosis of cavernous sinus pathologies and delineation of pathologies arising from closely placed neurovascular structures in this region of middle cranial fossa. In this review article, we aim to discuss how to best image the cavernous sinuses for detection of cavernous sinus pathologies and imaging appearance of various pathologies involving cavernous sinuses. Conclusion Cavernous sinuses form an important pathway for spread of numerous pathologies to and from the intracranial compartment to nearby vital structures. A variety of conditions can affect these small paired venous structures including benign and malignant neoplasms, vascular lesions, and infective/inflammatory pathologies. It is therefore important that besides routine brain imaging, dedicated thin axial and coronal images along with contrast-enhanced imaging should be performed for diagnosis of cavernous sinus pathologies.

Abstract In this research work, optimized nebivolol-loaded lecithin-chitosan hybrid nanoparticles (NEB-LCNPs) were prepared using sequential screening and optimization designs. The design of experiments software (DoE) was used to obtain a robust formulation that can improve ocular delivery of the NEB in the treatment of glaucoma. The optimized NEB-LCNPs had a mean particle size of 170.5 ± 5.3 nm and drug loading of 10.5 ± 1.2%. These were further loaded in a dual-responsive in situ gel, designed and reported previously by our group. The NEB-LCNPs loaded in situ gel (NEB-LCNPs-ISG) was characterized for physicochemical properties, rheological behavior, stability, in vitro dissolution, and ocular in vivo studies. The ocular pharmacokinetics showed that NEB-LCNPs-ISG had two-fold higher aqueous humor exposure with AUC0–tlast of 375.4 ng × h/mL and sustained drug concentrations for longer durations (1.7-folds higher duration with a mean residence time of 10.6 h) in comparison to a conventional aqueous suspension of NEB (NEB-Susp). Similarly, the pharmacodynamic study showed that NEB-LCNPs-ISG resulted in a higher percentage reduction in intraocular pressure (% ΔIOP) of 28.1 ± 1.8% × h, which was 2.2-times higher reduction compared to NEB-Susp (74.2 ± 3.2% × h). In addition, the pharmacodynamic effect was more sustained with a mean response time of 11.3 ± 0.2 h, a 2.8-times higher response time compared to NEB-Susp (4.06 ± 0.3 h). These results suggest that NEB-LCNPs-ISG was more effective than the conventional aqueous suspension of NEB in the treatment of glaucoma.

Abstract Background The healthcare system in India is tiered and has primary, secondary and tertiary levels of facilities depending on the complexity and severity of health challenges at these facilities. Evidence suggests that emergency services in the country is fragmented. This study aims to identify the barriers and facilitators of emergency care delivery for patients with time-sensitive conditions, and develop and implement a contextually relevant model, and measure its impact using implementation research outcomes. Methods We will study 85 healthcare facilities across five zones of the country and focus on emergency care delivery for 11 time-sensitive conditions. This implementation research will include seven phases: the preparatory phase, formative assessment, co-design of Model “Zero”, co-implementation, model optimization, end-line evaluation and consolidation phase. The “preparatory phase” will involve stakeholder meetings, approval from health authorities and the establishment of a research ecosystem. The “formative assessment” will include quantitative and qualitative evaluations of the existing healthcare facilities and personnel to identify gaps, barriers and facilitators of emergency care services for time-sensitive conditions. On the basis of the results of the formative assessment, context-specific implementation strategies will be developed through meetings with stakeholders, providers and experts. The “co-design of Model ‘Zero’” phase will help develop the initial Model “Zero”, which will be pilot tested on a small scale (co-implementation). In the “model optimization” phase, iterative feedback loops of meetings and testing various strategies will help develop and implement the final context-specific model. End-line evaluation will assess implementation research outcomes such as acceptability, adoption, fidelity and penetration. The consolidation phase will include planning for the sustenance of the interventions. Discussion In a country such as India, where resources are scarce, this study will identify the barriers and facilitators to delivering emergency care services for time-sensitive conditions across five varied zones of the country. Stakeholder and provider participation in developing consensus-based implementation strategies, along with iterative cycles of meetings and testing, will help adapt these strategies to local needs. This approach will ensure that the developed models are practical, feasible and tailored to the specific challenges and requirements of each region.

Abstract Background To explore intraocular lens (IOL) preferences of United Kingdom-based (UK) refractive surgeons in cataract and refractive lens exchange (RLE) surgery. Methods An online survey on IOL preferences (and reasons for their choice) in cataract and RLE surgery was distributed. It also enquired about implementing mini-monovision with extended depth of field (EDoF) IOLs, about utilising IOL mix-and-match (different IOL types in each eye), and at what level of corneal astigmatism they prefer toric lenses. Results Following an 81.6% response rate, thirty responses were analysed; median years of refractive surgery experience was 12.5. The most popular IOL choices for cataract surgery were EDoF lenses (30%), monofocals (20%), and trifocals (20%). The most cited reason for each was better overall visual outcomes (88.9%), fewer unwanted symptoms (66.7%) and best spectacle independence (66.7%), respectively. For RLE, EDoF remained most popular (36.7%), followed by trifocals (30%), and multifocals (16.7%) with the same reasons for choice cited above. Mini-monovision with EDoF lenses was well-regarded (83% recommend for most/select patients), unlike utilising IOL mix-and-match (60% did not recommend). 40% prefer toric IOLs for astigmatism of 1 dioptre (D) or higher, whilst 30% opt for them at

Continuously Reinforced Concrete Pavement (CRCP) is a preferred choice in highway and roadway construction due to its durability and reduced maintenance needs. This study employs Finite Element Analysis (FEA) to investigate CRCP's static behavior, shedding light on its structural response. A comprehensive numerical model within a commercial software package is utilized, considering complex interactions among concrete, longitudinal reinforcement, and subgrade layers. This model accounts for nonlinear material behavior by incorporating concrete and steel reinforcement constitutive models. Various loading scenarios, including wheel loads and temperature variations, are simulated to assess their impact on CRCP's static behavior. The analysis focuses on essential performance metrics such as load-carrying capacity, stress distribution, and deflection patterns. It systematically examines variable parameters like reinforcement spacing, concrete strength, and slab thickness. The results are compared against experimental data and design guidelines to validate the numerical model's accuracy and applicability. This research enhances our understanding of CRCP's static behavior, emphasizing its sensitivity to different parameters. The findings underscore the significance of proper reinforcement spacing, concrete strength, and slab thickness in optimizing CRCP performance and longevity. The implications of this study extend to pavement designers, engineers, and transportation agencies involved in CRCP construction and maintenance. The validated numerical model serves as a valuable tool for optimizing designs, assessing structural integrity, and predicting long-term performance.

In this research paper, we present an innovative investigation into a novel two parameter semicircular distribution, termed the “stereographic semicircular Erlang distribution,” which is constructed using the inverse stereographic projection (ISP) technique. This distribution serves as advancement over the existing stereographic semicircular exponential distribution. We delve into essential mathematical properties of this distribution and execute a simulation study to estimate its parameter values. Furthermore, we perform an empirical analysis utilizing a dataset comprising posterior corneal curvature measurements extracted from the eyes of 23 patients. This empirical assessment is designed to evaluate the adaptability and potential applicability of the proposed distribution within the realm of ophthalmology in medical science.

Abstract The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D: IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimer’s disease, notably apolipoprotein-e. Using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 (ZBP1) as a target of IRF3 that is relevant across various neuroinflammatory disorders. Lastly, we show IRF3 phosphorylation and IRF3-dependent ZBP1 induction in response to Aβ in primary microglia cultures. Together, our results identify IRF3 as an important regulator of LPS and Aβ -mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases.

Abstract Objectives This study compared the whitening effect, microhardness, and enamel surface alterations of over-the-counter (OTC) tooth bleaching products with those of a dentist-prescribed at-home bleaching agent. Materials and methods The products available on a popular online marketplace were comprehensively searched and then rated using a specific formula. The effects of the lowest-rated OTC agent (LRA) and the highest-rated OTC agent (HRA) were compared with those of a dentist-prescribed bleaching agent (DPA) on the enamel of extracted human teeth. The bleaching efficacy, post-bleaching microhardness changes, and morphological alterations were assessed by spectrophotometric analysis, Vickers hardness testing, and scanning electron microscopy (SEM) respectively. Statistical analyses included one-way ANOVA and post hoc tests, maintaining a significance level of P

Although heart disease stands as a prominent contributor to worldwide deaths, not all individuals affected by it ultimately fall prey to its effects. Timely diagnosis and effective treatment can offer those with heart conditions a high-quality life in their later years. Consequently, early disease detection using accessible medical data has been a central goal for researchers in recent decades. Traditionally, researchers relied on statistical tools for this purpose. However, machine learning algorithms, especially classification models, have gained prominence with the growing accumulated data. These algorithms have shown promise in predicting heart disease based on individual data. Our study employed various classification algorithms to predict heart disease incidence using the available dataset. We prioritized model reliability by incorporating the conformal classifier. Our results have shown that boosting algorithms, such as XGBoost and CatBoost, demonstrated exceptional performance with promising metrics. These models identified chest pain type and ST segment slope as crucial indicators of heart disease. Boosting algorithms exhibited a compelling combination of broad coverage and a small prediction set size, making them well-suited for heart disease prediction. Furthermore, we employed explainable artificial intelligence-boosting algorithms to enhance the interpretability of our predictions.

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used for stroke prevention in atrial fibrillation. At the Asia Pacific Advancing Patient care with EdoXaban 2023 meeting, experts shared insights on gastrointestinal bleeding with NOACs for stroke prevention in atrial fibrillation in Asian clinical practice, where NOACs have gained widespread acceptance due to their favourable profiles. Gastrointestinal bleeding risk varies amongst NOACs, emphasizing the importance of diligent patient assessment, dosage selection and vigilant monitoring. Edoxaban emerged as a viable option with a low gastrointestinal bleeding risk profile in Asian compared with non-Asian patients, supporting its continued clinical utilization for appropriate patients.

Abstract In this work, the impact of physicochemical modifications on pharmacokinetics and in vivo targeting of a small molecule fibroblast activation protein inhibitor (FAPI) imaging ligand in a murine model of rheumatoid arthritis was evaluated. While similar ligands have been well-reported in oncology for molecular imaging and radiotherapy, there are limited reports of FAPI derivatives in targeted applications in immunology. As inflammation may increase both specific and non-specific delivery of targeted agents in general, we sought to identify the optimal targeted molecular imaging probe characteristics for efficient cell surface engagement. A series of FAPI derivatives were synthesized and their physicochemical properties modified via conjugation of fluorescent dyes and/or an albumin-binding small molecule. The impact of these modifications on cell surface binding affinity was assessed using an overexpressing cell line. Additionally, a thorough mechanistic characterization of fibroblast activation protein (FAP) cell surface internalization was evaluated in both overexpressing and endogenously expressing cells. Lastly, the pharmacokinetics and in vivo uptake in inflamed arthritic paws were characterized via near-infrared (NIR) imaging. All targeted molecular imaging agents tested maintained strong nanomolar binding affinity to cell surface FAP independent of chemical modification. The murine fibroblast-like synoviocytes expressed lower absolute cell-surface FAP compared to a transfected line, and the net internalization half-life measured for the transfected cells via flow cytometry was 7.2 h. The unmodified FAPI ligand exhibited the poorest in vivo targeting, likely resulting from its large apparent volume of distribution (62.7 ml) and rapid systemic clearance (t 1/2 = 0.5 h). Conjugation of a charged, hydrophilic AF647 fluorophore decreased systemic clearance (t 1/2 = 2.1 h) and demonstrated a 2-fold improvement in blocking FAPI-800CW engagement of FAP in vivo when compared to blocking of FAPI-800CW with FAPI with up to 2.8-fold improvements noted for the equivalent albumin binding construct comparison.

Abstract This study focused on strategically employing the carboxylesterase enzyme Ha006a, derived from the pesticide-resistant microorganism Helicoverpa armigera, to detect atrazine. A comprehensive analysis through biochemical, biophysical and bioinformatics approaches was conducted to determine the interaction between the Ha006a protein and the herbicide atrazine. These experimental findings elucidated the potential of leveraging the inherent pesticide sequestration mechanism of the Ha006a enzyme for sensor fabrication. Numerous optimizations were undertaken to ensure the precision, reproducibility and convenient storage of the resulting electrochemical sensor, Ha006a/MCPE. This biosensor exhibited exceptional performance in detecting atrazine, demonstrating outstanding selectivity with a lower limit of detection of 5.4 µM. The developed biosensor has emerged as a reliable and cost-effective green tool for the detection of atrazine from diverse environmental samples. The Ha006a-based biosensor fabrication has expanded the possibilities for the efficient integration of insect enzymes as analytical tools, paving the way for the design of cost-effective biosensors capable of detecting and quantifying pesticides.

Introduction: Urinary cytology (UrCy) is highly sensitive to diagnosing high-grade urothelial carcinoma (HGUC) but cannot predict muscularis propria invasion. Further, the atypical urothelial cell category (AUC) may have variable outcomes. Image morphometry (IM) may be a valuable adjunct technique in this setting. Hence, we evaluated IM in the AUC and HGUC categories to improve the diagnostic performance. Materials and Methods: The following six nuclear parameters were evaluated by IM on 3150 cells: nucleo-cytoplasmic (N:C) ratio, nuclear area, diameter, perimeter, standard deviation of the nuclear area (SDNA; pleomorphism) and integrated density (ID; nuclear chromasia), using the ImageJ software, in three cohorts based on the histopathology outcome: 20 cases of AUC – benign non-neoplastic outcome (AUC-B); 22 cases of HGUC Muscle invasive (HGUC-MI) and 21 cases of HGUC non-muscle invasive (HGUC-MF). Results: A retrospective analysis of urine cytology. The patient’s ages ranged from 36 to 85 years, with a mean age of 60.6. The male-to-female ratio was 5.4:1. A total of 20 cases of AUC-B and 43 cases of HGUC were selected for IM analysis. HGUC cases had higher nuclear parameters than AUC-B, and HGUC-MI had higher SDNA, ID, diameter, and area than HGUC-MF. SDNA and ID predict muscularis propria invasion in HGUC. Conclusions: Image morphometry successfully differentiates HGUC cases from benign non-neoplastic ones and might help to identify muscularis propria invasion in HGUC using a combination of nuclear parameters.

Vesical calculi are unusual in females, and giant calculi (weighing >100 g) are even more uncommon, considering the advances in contemporary diagnostic modalities. The entity is associated with a variety of pestering symptoms—frequency, dysuria, and hematuria, to name a few—causing serious effects on patients’ quality of life. This report cites the case of an elderly female with a giant vesical calculus weighing 1.28 kg (12.5 cm in diameter). Our patient had no past surgical history or symptoms suggestive of bladder outlet obstruction or neurogenic bladder. As per our literature search, a stone as large as that of our patient has not yet been found in females. She underwent an uneventful open suprapubic cystolithotomy. A biopsy from a suspicious lesion during the surgery revealed squamous cell carcinoma. Given that such a large stone was found in an elderly female without any predisposing causative factors, it is worthwhile looking into the etiopathogenesis and management of giant vesical calculi.

Abstract Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018-2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20–0.43) and TCEs (aHR = 0.62, 95%CI = 0.43–0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18–0.44) and TCEs (aHR = 0.60, 95%CI = 0.39–0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable.

Abstract Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.

Abstract Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation. Here, we present a patient with a 46,XY karyotype, born with undervirilized genitalia, age-appropriate testosterone levels and no uterus, characteristic for AIS. Diagnostic whole exome sequencing (WES) showed a maternally inherited LINE1 (L1) retrotransposon insertion in the 5′ untranslated region (5′UTR) of the AR gene. Long-read nanopore sequencing confirmed this as an insertion of a truncated L1 element of ≈ 2.7 kb and showed an increased DNA methylation at the L1 insertion site in patient-derived genital skin fibroblasts (GSFs) compared to healthy controls. The insertion coincided with reduced AR transcript and protein levels in patient-derived GSFs confirming the clinical diagnosis AIS. Our results underline the relevance of retrotransposons in human disease, and expand the growing list of human diseases associated with them.

Abstract Background Rural African people living with HIV face significant challenges in entering and remaining in HIV care. In rural Uganda, for example, there is a threefold higher prevalence of HIV compared to the national average and lower engagement throughout the HIV continuum of care. There is an urgent need for appropriate interventions to improve entry and retention in HIV care for rural Ugandans with HIV. Though many adults living with HIV in rural areas prioritize seeking care services from traditional healers over formal clinical services, healers have not been integrated into HIV care programs. The Omuyambi trial is investigating the effectiveness of psychosocial support delivered by traditional healers as an adjunct to standard HIV care versus standard clinic-based HIV care alone. Additionally, we are evaluating the implementation process and outcomes, following the Consolidated Framework for Implementation Research. Methods This cluster randomized hybrid type 1 effectiveness-implementation trial will be conducted among 44 traditional healers in two districts of southwestern Uganda. Healers were randomized 1:1 into study arms, where healers in the intervention arm will provide 12 months of psychosocial support to adults with unsuppressed HIV viral loads receiving care at their practices. A total of 650 adults with unsuppressed HIV viral loads will be recruited from healer clusters in the Mbarara and Rwampara districts. The primary study outcome is HIV viral load measured at 12 months after enrollment, which will be analyzed by intention-to-treat. Secondary clinical outcome measures include (re)initiation of HIV care, antiretroviral therapy adherence, and retention in care. The implementation outcomes of adoption, fidelity, appropriateness, and acceptability will be evaluated through key informant interviews and structured surveys at baseline, 3, 9, 12, and 24 months. Sustainability will be measured through HIV viral load measurements at 24 months following enrollment. Discussion The Omuyambi trial is evaluating an approach that could improve HIV outcomes by incorporating previously overlooked community lay supporters into the HIV cascade of care. These findings could provide effectiveness and implementation evidence to guide the development of policies and programs aimed at improving HIV outcomes in rural Uganda and other countries where healers play an essential role in community health. Trial registration ClinicalTrials.gov NCT05943548. Registered on July 5, 2023. The current protocol version is 4.0 (September 29, 2023).

Trematode granuloma has been reported as one of the common causes of infectious uveitis in paediatric age group in recent times in Tamil Nadu. These granulomas occur after exposure to the trematode-infested water resources. Studies from South India have established the cause of granuloma as trematode by histopathological and molecular diagnostics. The smaller granulomas responded to topical and oral steroids while larger lesions needed surgical excision. Untreated cases develop retro corneal membrane, cataract, glaucoma and even phthisis in the long run. Early identification and prompt treatment are needed to prevent visual morbidity in these children.

Aim: To evaluate the role of combined Mantoux test and serum angiotensin-converting enzyme (ACE) levels in the diagnosis of ocular tuberculosis (TB) and ocular sarcoidosis. Materials and Methods: A prospective and observational study including patients with bilateral granulomatous uveitis diagnosed both radiologically and clinically as ocular TB or ocular sarcoidosis within a six-month period. CT Thorax/CT abdomen was done, and findings were noted. Mantoux test and serum ACE levels were recorded, and findings were correlated. Results: The study included a total of 60 patients: 32 patients with ocular TB and 28 patients with ocular sarcoidosis. Using Mantoux test, 84.4% in the TB group tested positive and were correctly identified (sensitivity), and 96.4% in the sarcoid group tested negative and were correctly identified as sarcoidosis. Hence, the association between Mantoux test and diagnoses was statistically significant (P < 0.001). In the TB group, 25 subjects had normal and seven had elevated serum ACE levels. In the sarcoidosis group, 22 subjects had elevated and six had normal serum ACE levels. Hence, 78.1% were correctly identified with normal serum ACE levels (sensitivity) in the TB group and 78.6% were identified with elevated serum ACE levels in the sarcoidosis group, and the proportion difference was statistically significant (P < 0.001). Conclusion: Mantoux test and serum ACE levels are cost-effective investigations and can be used for the diagnosis of ocular TB and sarcoidosis when combined with clinical and radiological evidence. The combined use of serum ACE and Mantoux test is useful in differentiating between sarcoidosis and TB.

Abstract Background Burnout syndrome attributable to cumulative stressors is highly prevalent among teachers. Despite this, knowledge of burnout syndrome among schoolteachers in lower-middle-income countries are limited, therefore we aimed to investigate self-reported occupational burnout syndrome and associated factors among schoolteachers in Nepal. Methods A survey was conducted among randomly selected 37 community schools in Kathmandu, Nepal in 2022, with a total sample of 218 schoolteachers (70% male). Occupational burnout was assessed using the Nepali version of the validated Maslach Burnout Inventory (MBI-ES). MBI-ES consists of 22 items assessing occupational burnout, which were classified into emotional exhaustion (EE, 9 items, score range: 0–45), depersonalization (DP, 5 items, 0–23), and personal accomplishment (PA, 8 items; 3–48). The greater score in EE and DP and the lower score in PA indicate a higher level of burnout. Various socio-demographic, lifestyle, and work-related factors were examined as determinants of occupational burnout using ANOVA and multivariable linear regression models. Results The mean scores of EE, DP, and PA were 14.99 (Standard Deviation, SD = 9.79), 4.18 (SD = 4.57), and 42.11 (SD = 6.82) respectively. Poor/moderate work ability contributed to poorer ratings of all three dimensions. Teaching special needs students contributed to EE and DP, whereas low physical activity and alcohol intake were associated with PA only. Younger age, being married, language of teaching, having a disability, sub-optimal physical fitness, poor sleep quality, and ever smoking contributed to EE only. Conclusion Occupational burnout among schoolteachers was relatively high. Marital status, lifestyle behavioral, and work-related factors were associated especially with EE and workability was a strong determinant of all three dimensions. Clinical trial registration number NCT05626543.

Purpose: To evaluate the effect of topical carbonic anhydrase inhibitor (brinzolamide) versus placebo on visual function and waveforms in infantile nystagmus syndrome (INS). Design: Prospective, placebo-controlled, double-blind, cross-over study. Methods: Setting- A tertiary eye care center. Patients- Cases of idiopathic INS with and without abnormal head posture aged ≥10 years who had not received previous treatment for nystagmus. Intervention- Patients were randomized into two groups. Group 1 was given placebo for 3 months, and after a washout period of 7 days started on topical brinzolamide for the next 3 months. In group 2, the order was reversed. The drops were administered topically three times (every 8 hours) in both eyes. Outcome measure- Binocular best corrected visual acuity (BCVA) using the ETDRS chart, eXpanded nystagmus acuity function (NAFX) score and INS waveforms obtained from eye movement recordings, intraocular pressure (IOP) by Goldmann applanation tonometer, near stereopsis by TNO stereo test, and change in abnormal head posture before and after intervention in the null position. Results: A total of 29 cases completed the study (23 with abnormal head posture; 6 without abnormal head posture) . A significant improvement was noted in INS waveform characteristics, mean NAFX score (P < 0.001), and mean binocular visual acuity (P < 0.001) with topical brinzolamide in comparison to baseline as well as placebo. No significant change in head position and stereopsis was noted. No side effects were reported with 3 months of brinzolamide therapy. Conclusions: While brinzolamide shows improvement in visual acuity and NAFX score in idiopathic INS, its clinical significance needs further evidence.

Abstract FN-doped carbon dots were synthesized using powdered leaves of Moringa oleifera L./Chromolaena odorata L./Tridax procumbens L./Tinospora cordifolia L./ and Lantana camara L., along with a precursor called 4,5-difluoro-1,2-benzenediamine (DFBD) and compared against the drug zaltoprofen derived carbon dots. They were assessed for their optical and structural characteristics using photoluminescence (optimal emission λ of 600 nm), vibrational (FTIR) spectroscopy (characteristic wave numbers of 1156 and 1269 cm−1 for C–F), as well as X-ray diffraction (XRD) (highest intensity at 27.56°) and high-resolution transmission electron microscopy (HR-TEM) (particles in the size range of 15–20 nm). Further, field emission scanning electron microscopy (FESEM) / energy dispersive spectroscopy (EDX) indicated FN doping of oval/oblong carbon dots. Membrane protection in percent is found to be 55.3 and 80.4 for FN-CDs and Z-FN-CDs respectively. The DPPH-free radical scavenging activity by FN-CDs was 69.4%, while with Z-FN-CDs, it was 54.2%. When tested on six bacterial strains (three each for gram-positive and gram-negative), the FN-CDs displayed a halo (ZOI) between 9 and 19 mm, whereas the Z-FN-CDs displayed a clearance zone between 9 and 17 mm. The FN-CDs showed significant emission-red-shift effects and demonstrated concentration-dependent biocompatibility and viability in neuroblastoma and beta-TC6-cell lines.

Abstract A short prokaryotic Argonaute (pAgo) TIR-APAZ (SPARTA) defense system, activated by invading DNA to unleash its TIR domain for NAD(P)+ hydrolysis, was recently identified in bacteria. We report the crystal structure of SPARTA heterodimer in the absence of guide-RNA/target-ssDNA (2.66 Å) and a cryo-EM structure of the SPARTA oligomer (tetramer of heterodimers) bound to guide-RNA/target-ssDNA at nominal 3.15–3.35 Å resolution. The crystal structure provides a high-resolution view of SPARTA, revealing the APAZ domain as equivalent to the N, L1, and L2 regions of long pAgos and the MID domain containing a unique insertion (insert57). Cryo-EM structure reveals regions of the PIWI (loop10-9) and APAZ (helix αN) domains that reconfigure for nucleic-acid binding and decrypts regions/residues that reorganize to expose a positively charged pocket for higher-order assembly. The TIR domains amass in a parallel-strands arrangement for catalysis. We visualize SPARTA before and after RNA/ssDNA binding and uncover the basis of its active assembly leading to abortive infection.

Abstract Engaging young people in research is a promising approach to tackling issues like chronic disease prevention. Our involvement as youth advisors provided valuable experiences, including being at the forefront of change and learning to work within a research team. Furthermore, our experience provides greater insight and learnings for future youth engagement in research.

Background: Neonatal sepsis is a leading cause of neonatal morbidity and mortality globally, with variations in causative bacteria and treatment efficacy across health-care facilities. Aims and Objectives: The aims and objectives of the study are to analyze the bacterial pathogens causing neonatal sepsis and the effectiveness of their treatment in diverse hospital environments. By highlighting the differences in treatment success rates, antibiotic resistance profiles, and the pathogens involved, this study demonstrate the impact of health-care practices and infrastructure on the management of neonatal sepsis. Materials and Methods: The study encompassed 100 neonates with sepsis, evenly distributed across the three hospital types. It involved identifying bacterial pathogens through blood cultures, assessing antibiotic sensitivity, and examining treatment outcomes such as success rate, mortality, hospital stay duration, and complication rates. Statistical methods were employed to evaluate differences in outcomes among the settings. Results: Seventy percent of neonates tested positive for bacterial pathogens, with a 60% predominance of Gram-positive over Gram-negative bacteria (40%). Staphylococcus aureus (22%) and Streptococcus agalactiae (18%) were the leading pathogens. Notably, resistance was high against ampicillin (65%) and gentamicin (40%) but lower for cephalosporins and vancomycin. The overall success rate of treatments was 80%, with the tertiary care hospital achieving an 88% success rate, significantly outperforming the private hospitals (72%). The mortality rate was 10%, and 30% of the cases developed complications, predominantly respiratory distress syndrome. Conclusion: Hospital setting significantly influences the management and outcomes of neonatal sepsis, with tertiary care centers showing better results. These findings highlight the need for focused antimicrobial stewardship and the adoption of sophisticated care protocols in less advanced settings to improve neonatal sepsis outcomes.

Background: Laparoscopic cholecystectomy (LC) is a common surgical procedure, the difficulty of which can vary significantly based on pre-operative factors. Identifying these factors can improve surgical planning, patient counseling, and outcomes. Aims and Objectives: To develop a predictive scoring system for assessing the difficulty of LC preoperatively based on individual patient parameters. To employ operative time and intra-operative events to validate the accuracy of the scoring system in reflecting the technical difficulty of LCs. Materials and Methods: This prospective study enrolled 104 patients scheduled for LC, assessing them with a pre-operative scoring system to predict operative difficulty. Patients were categorized into groups indicating expected levels of difficulty: Easy, difficult, and very difficult. Demographic information, clinical characteristics, and operative outcomes were analyzed to validate the scoring system’s predictive accuracy. Results: Of the patients assessed, 68.3% were predicted to have an easy LC (scores 0–5), whereas 31.7% were anticipated to face a difficult LC (scores 6–10). Key predictors of operative difficulty included age, sex, history of previous hospitalization for acute cholecystitis, body mass index (BMI), the presence of an abdominal scar, palpable gallbladder (GB), thickened GB wall, pericholecystic collection, and impacted stone. The study found that operative outcomes closely aligned with pre-operative predictions, confirming the scoring system’s moderate predictive accuracy (area under the curve of 0.798). Conclusion: The pre-operative scoring system demonstrated moderate effectiveness in predicting LC difficulty, with significant predictors including a history of hospitalization, BMI, palpable GB, and thickened GB wall. These findings can aid in pre-operative planning and optimizing patient outcomes.