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Triple-negative breast cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming especially fatty acid oxidation (FAO) has emerged as a major driver of breast cancer metastasis. Analyzing the expression of major FAO regulatory genes in breast cancer, we found selective overexpression of acyl-CoA synthetase 4 (ACSL4) in TNBC, which is primarily attributed to the absence of progesterone receptor. Loss of ACSL4 function, by genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity positively influences the gene expression related to TNBC migration and invasion. Mechanistically, ACSL4 modulates FAO and intracellular acetyl-CoA levels, leading to hyperacetylation of particularly H3K9ac and H3K27ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lung. Further, human TNBC metastasis exhibits positive correlation among ACSL4, H3K9ac, H3K27ac, and SNAIL expression. Altogether, our findings provide molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis, and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective . The present work shows the first extensive validation of the generalized stochastic microdosimetric model (GSM 2 ). This mechanistic and probabilistic model is trained and tested over cell survival experiments conducted with two cell lines (H460 and H1437), three different types of radiation (protons, helium, and carbon ions), spanning a very broad LET range from1 keVμm-1up to more than300 keVμm-1. Currently, the existing mechanistic radiation biophysical models show some limitations in describing cell killing without the addition of ad hoc corrections, especially in the high-LET regime, where the overkill effect is observed. Approach . The experimental irradiation conditions have been accurately reproduced with Monte Carlo simulations using the GEANT4-based TOPAS computational toolkit. We show the main and unique features of GSM2, i.e. how it can predict the biological response by considering the full information on the stochasticity of radiation through the microdosimetric spectrum, which is supposed to be the best descriptor of radiation quality. Main results . Well-matching results for different biological endpoints with the natural presence of the overkill effect fully display the predictive power of GSM 2 . Significance . This study shows the complete generality and flexibility of GSM 2 and its ability to successfully predict the cell survival probability from very different particle radiation fields. Consequently, we demonstrate the dependence of the relative biological effectiveness on the whole microdosimetric spectrum, which fully includes the stochasticity inherently given by radiation-matter interaction., (Creative Commons Attribution license.)

Introduction: Cancer is the primary cause of death globally, and despite the significant advancements in treatment and survival rates, it is still stigmatized in many parts of the world. However, there is limited public health research on cancer stigma among the general female population in Nepal. Therefore, this study aims to determine the prevalence of cancer stigma and its associated factors in this group., Methods: We conducted a cross-sectional study among 426 healthy women aged 30 to 60 years who were residents of Dhulikhel and Banepa in central Nepal. We measured cancer stigma using the Cancer Stigma Scale (CASS). CASS measures cancer stigma in six domains (awkwardness, avoidance, severity, personal responsibility, policy opposition, financial discrimination) on a 6-point Likert scale (strongly disagree to agree strongly) with higher mean stigma scores correlating with higher levels of stigma. We utilized Generalized Estimating Equations (GEE) with multivariable linear regression to identify the socio-demographic factors associated with the CASS score., Results: Overall, the level of cancer stigma was low, with a mean stigma score of 2.6 (0.6), but it was still present among participants. Stigma related to personal responsibility had the highest levels, with a mean score of 3.9 (1.3), followed by severity with a mean score of 3.2 (1.3), and financial discrimination with a mean score of 2.9 (1.6). There was a significant association between the mean CASS score and older age (mean difference in stigma score: 0.11 points; 95% CI: 0.02-0.20) as well as lower education (difference: -0.02 points; 95% CI: -0.03 to -0.003), after adjusting for age, ethnicity, education, marital status, religion, occupation, and parity., Conclusion: While overall cancer stigma was low, some domains of stigma were higher among women in a suburban area in central Nepal; thus, indicating that cancer stigma persists in this region despite its low overall prevalence., Competing Interests: The authors have declared that no competing interests exist, (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Amyloid-proteinopathy is observed in type 2 diabetes, where Islet amyloid polypeptide is secreted atypically and impedes cellular homeostasis. The thiazolidinediones family is reported to influence amyloid-beta aggregations. However, research on drug-based stimulation of insulin signaling to alleviate Islet amyloid aggregations is lacking. To understand the impact of pioglitazone on islet amyloid aggregation, we conducted an in vivo and in silico analysis. For in vivo analysis, we generated a transgenic Drosophila harboring the preproform of human Islet amyloid polypeptide (IAPP) that can be ectopically expressed in a spatio-temporal manner. We show that the unprocessed form of IAPP also has the propensity to form aggregates and cause degeneration. Pioglitazone feeding effectively reduces the burden of Islet amyloid aggregations in the larval brain. In silico analysis shows that there is a higher protein-ligand binding energy for IAPP with pioglitazone than amyloid-beta. These results suggests that pioglitazone might be repurposed as a drug to cure islet amyloidogenesis., Competing Interests: Declarations. Ethics approval: This work does not require ethical clearance. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The parapharyngeal space (PPS) is a pyramidal-shaped fat-filled space in the head and neck, between the base of the skull and the hyoid bone. It is a vital anatomic structure in head and neck imaging and serves as a path for the spread of infection or tumor, a critical landmark for diagnosing various lesions in this region, and a potential site of infections. The purpose of this pictorial review is to illustrate the anatomy of the PPS, the pathologies in and around PPS, and the distinguishing imaging characteristics of these lesions. It also explores the limitations and challenges of imaging techniques in certain scenarios as well as the surgical approaches for PPS masses, emphasizing their radiological relevance. The review aims to underscore the significance of a multidisciplinary approach, involving radiologists, otolaryngologists, and head and neck surgeons, in interpreting imaging findings and determining the most appropriate management strategies for PPS lesions for improved patient outcomes., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Oral cancer became a very common condition. WHO estimates that there are 4 cases of lip and oral cavity cancer for every 100,000 people worldwide. The early diagnosis of cancers is currently a top focus in the health sector. Recent systematic reviews and meta-analyses have identified promising biomarkers for early detection in several original research investigations. However, it is still unclear the quality of these evidence and which biomarker performs the best in terms of early detection. Therefore, the objective was, to map the methodological and reporting quality of available oral squamous cell carcinoma (OSCC) or head/neck squamous cell carcinoma (HNSCC) systematic reviews and meta-analysis. Secondly, to evaluate diagnostic accuracy of salivary biomarkers for common craniofacial cancers and to compare the diagnostic value of different salivary biomarkers. PubMed, Scopus, Web of Science, Embase and Cochrane Library electronic databases were used to map the methodological and reporting quality of the systematic reviews and meta-analysis conducted on the HNSCC, OSCC using the AMSTAR-2 checklist. The inclusion criteria were systematic reviews and meta-analysis published in the topic of HNSCC and OSCC biomarkers. Exclusion criteria were no animal studies; original primary studies, due to limitation of competency in other languages articles with language other than English were excluded. The sensitivity and specificity were calculated for salivary biomarkers and ranked according to network meta-analysis principles. A total of N = 5893 patients were included from four meta-analysis studies. All together, these included n = 37 primary studies. n = 94 biomarkers were pooled from these four meta-analyses and categorised into the stages at which they were detected (I-IV). In OSCC, Chemerin and MMP-9 displayed the highest sensitivity, registering 0.94 (95% CI 0.78, 1.00) and a balanced accuracy of 0.93. Phytosphingosine closely followed, with a sensitivity of 0.91 (95% CI 0.68, 0.99) and a balanced accuracy of 0.87. For HNSCC, the top three biomarkers are Actin, IL-1β Singleplex, and IL-8 ELISA. Actin leads with a sensitivity of 0.91 (95% CI 0.68-0.99), a specificity of 0.67, and an overall accuracy of 0.79. Subsequently, IL-1β Singleplex exhibits a sensitivity of 0.62 (95% CI 0.30-0.88), a specificity of 0.89, and an accuracy of 0.75, followed by IL-8 ELISA with a sensitivity of 0.81 (95% CI 0.54-0.97), a specificity of 0.59, and an accuracy of 0.70. In conclusion, there was highest sensitivity for MMP-9 and chemerin salivary biomarkers. There is need of further more studies to identify biomarkers for HNSCC and OSCC., (© 2023 The Authors.)

Introduction: Since its discovery in the early 1900s, sickle cell disease (SCD) has contributed significantly to the scientific understanding of hemoglobin and hemoglobinopathies. Despite this, now almost a century later, optimal medical management and even curative options remain limited. Encouragingly, in the last decade, there has been a push toward advancing the care for individuals with SCD and a diversifying interest in options to manage this disorder., Areas Covered: Here, we review the current state of disease modifying therapies for SCD including fetal hemoglobin inducers, monoclonal antibodies, anti-inflammatory modulators, and enzyme activators. We also discuss current curative strategies with specific interest in transformative gene therapies., Expert Opinion: SCD is a chronic, progressive disease that despite a century of clinical description, only now is seeing a growth and advance in therapeutic options to improve the lifespan and quality of life for individuals with SCD. We anticipate newly designed and even repurposed therapies that may work as a single agent or combination agents to tackle the progression of SCD. The vast majority of individuals living with SCD are unlikely to receive gene therapy, therefore improved disease management is critical even for those that may ultimately chose to pursue a potentially curative strategy.

Nutrition is the critical nongenetic factor that has a major influence on the health status of an organism. The nutritional status of the mother during gestation and lactation plays a vital role in defining the offspring's health. Undernutrition during these critical periods may induce chronic metabolic disorders like obesity and cardiovascular diseases in mothers as well as in offspring. The present study aims to evaluate the impact of undernutrition during gestational and lactational periods on the plasma metabolic profile of dams. Additionally, we investigated the potential synergistic mitigating effects of astaxanthin and docosahexaenoic acid (DHA) on dysregulated plasma metabolic profiles. Evaluation of plasma lipid profile revealed that undernourishment resulted in elevated levels of total cholesterol, triglycerides, low density and very low-density lipoproteins in dams. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based untargeted metabolomics illustrated that pathways related to lipid metabolism, such as cholesterol metabolism, steroid biosynthesis and metabolism of amine-derived hormones, were dysregulated by undernourishment. Additionally, pathway enrichment analysis predicted that there is a high incidence of development of desmosterolosis, hypercholesterolaemia, lysosomal acid lipase deficiency and Smith-Lemli-Opitz syndrome in the offspring, reflecting predisposition in mothers. However, synergistic supplementation of astaxanthin and DHA ameliorated these adverse effects by regulating a separate set of metabolic pathways associated with lipid metabolism. They included branched chain amino acid degradation such as valine, leucine and isoleucine, metabolism of alpha-linolenic acid, lipoic acid, lysine degradation, biosynthesis, elongation and degradation of fatty acids.

Erdheim-Chester Disease (ECD) is a rare, multisystem histiocytic disorder characterized by its variable clinical presentations. Central Nervous System (CNS) involvement is observed in approximately half of ECD patients (up to 76% in some series), and often carries a poorer prognosis. While CNS involvement may remain asymptomatic, others may experience a range of neurological symptoms, including cognitive decline, neuropsychiatric disturbances, motor deficits, cranial or peripheral neuropathies, and endocrine abnormalities.Neuroimaging findings in CNS-ECD are diverse, including neurodegeneration manifesting as cerebral or cerebellar volume loss, solitary or multifocal variably enhancing intraparenchymal lesions along the neuroaxis, meningeal infiltration, involvement of the Hypothalamo-pituitary axis, perivascular sheathing or basal ganglia lesions. Other well documented sites of involvement include the craniofacial region, orbits and spine. Awareness of these findings is relevant, not only because of the non-specific nature of these findings, but also given the high proportion of CNS involvement in ECD as well as the higher mortality associated with CNS involvement.This review provides an in-depth overview of the various manifestations of CNS involvement in ECD and their imaging features, along with a brief overview of the differential considerations which include other histiocytic and non-histiocytic processes.ABBREVIATIONS: ECD＝Erdheim-Chester Disease; RDD＝Rosai-Dorfman Disease; LCH= Langerhans cell histiocytosis., (© 2024 by American Journal of Neuroradiology.)

Nitric oxide (NO) is one of the byproducts of nitrogen metabolism. Excess amount of NO is scavenged by phytoglobins. The role of phytoglobin mediated NO homoeostasis in modulation of nitrate transporters was investigated using NO scavenger cPTIO, phytoglobin overexpressing rice and Arabidopsis. Growing plants under low nitrate leads to generation of reduced levels of NO accompanied by elevated expression of high affinity transporters (HATs) such as NRT2.1, NRT2.3 and NRT2.4. Scavenging of NO by cPTIO under optimal nitrate caused enhanced HATs expression. Phytoglobin overexpressing Arabidopsis showed improved growth and enhanced expression of HATs under low nitrogen in comparison to WT. Pretreatment of optimal nitrate grown plants with NO scavenger cPTIO enhanced HATs expression and shifting of these primed plants from optimal to low nitrate leads to further elevation of HATs expression accompanied by enhanced nitrogen uptake and its accumulation with positive effect on growth. Phytoglobin overexpression in rice leads to enhanced HATs expression, improved growth, nitrogen accumulation under low nitrate. Pgb OE lines showed enhanced accumulation of amino acids. Taken together our results suggest an important role of phytoglobins in nitrogen uptake and assimilation., (© 2024 John Wiley & Sons Ltd.)

Introduction:  White matter tracts that connect different parts of the brain comprise the structural connectome, which is essential to its operation. Assessing behavioral changes and brain health requires an understanding of these tracts. Diffusion tensor imaging (DTI), in particular, allows for the thorough viewing and characterization of these routes in tractography. In order to assess the impact of aging on white matter integrity, this study examines the 10 main white matter tracts in men, paying particular attention to volume, fractional anisotropy (FA), and mean diffusivity (MD)., Materials and Methods:  A cohort of 49 men aged 18-50 years was examined using a Philips Multiva 1.5T MRI. DTI scans were performed after obtaining informed consent. Participants with neuronal disorders were excluded. Ten tracts were assessed: inferior fronto-occipital fasciculus (IFOF), superior fronto-occipital fasciculus (SFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), cingulum, corticospinal tract (CST), forceps major, forceps minor, uncinate fasciculus, and anterior thalamic radiation (ATR). Statistical analysis employed Kruskal-Wallis tests to compare age groups., Results:  Significant age-related differences were observed in the IFOF, which exhibited notable changes in both volume and MD. Specifically, the IFOF's volume peaked in the 31-40 age group (14.42 ± 6.05) and declined in the 41-50 age group (8.71 ± 5.07), with a statistically significant p-value of 0.019. In parallel, MD increased significantly with age, moving from 0.86 ± 0.08 in the 18-30 group to 1.09 ± 0.13 in the 31-40 group and stabilizing at 0.96 ± 0.12 in the 41-50 group (p < 0.001). Notably, while the FA values remained relatively stable across age groups (p = 0.063), the increase in MD suggests a decline in neural efficiency or potential myelin degradation. Other tracts, including the SFOF and SLF, displayed stability in volume, FA, and MD across age groups, indicating a degree of resilience in certain neural pathways., Conclusion:  This study highlights the utility of tractography in understanding age-related changes in white matter, such as in Alzheimer's disease, age- and sex-related abnormalities, and dementia, particularly emphasizing the IFOF's sensitivity. Findings offer insights into brain connectivity and neurological health, indicating a need for further contribution to inform interventions aimed at cognitive preservation., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Ethics Committee of MMIMSR issued approval IEC-2206. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sharma et al.)

Background: The incidence of obesity in patients with inflammatory bowel disease (IBD) is increasing and there are limited data on the impact of obesity on perianal fistulas in Crohn's disease (CD)., Aims: We aim to examine the relationship between obesity and the prevalence and complications of Crohn's perianal fistulas., Methods: We conducted a cross-sectional study of CD patients treated at a tertiary care center from 2012 to 2022. Obesity was defined as maximum BMI > 30 kg/m 2 and further subdivided into 5 BMI categories. The prevalence of perianal fistulas was defined by any history of perianal fistula. The complications of perianal fistulas were measured by five variables including complex fistulas, history of perianal fistula surgery, number of perianal surgeries, history of fecal diversion, and median time to first anal surgery., Results: In all, 704 patients with CD were included; 31.1% were obese. There was no significant association between obesity and prevalence of perianal fistulas (p = 0.719), complex fistulas (p = 0.144), history of perianal surgery (p = 0.146), ≥ 1 perianal surgeries (p = 0.220), fecal diversion (p = 0.705), or median time to first perianal surgery (p = 0.192). Increasing BMI category was not associated with the prevalence of perianal fistulas (p = 0.944), complex fistulas (p = 0.089), perianal surgery (p = 0.583), ≥ 1 perianal surgeries (p = 0.114), fecal diversion (p = 0.542), or median time to first perianal surgery (p = 0.486). When comparing those with perianal fistulas to those without, there was no significant difference in rates of obesity (p = 0.876)., Conclusion: There was no association between obesity and the prevalence and complications of Crohn's perianal fistulas., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The epidemiology of cleft lip (CL) and cleft palate (CLP) has not previously been described in the context of the Bhutan and Bhutanese populations. Using National Birth Defects Surveillance Data and other vital statistics, we present the comprehensive epidemiology of the cleft lip and palate in Bhutan., Methodology: The National Birth Defects Surveillance Data Registry from 2015 to 2022 is reviewed retrospectively, covering 8 years of birth defect surveillance in the country from records maintained with three referral hospitals in the country. The baseline prevalence and incidence of cleft lip and palate have been presented over the years. The incidence of cleft lip and palate was defined as the number of cases per 1000 live births. We used Poisson's regression to compute the incidence of cleft lip and palate. Pearson chi-square tests (χ2) were used to examine the associations of maternal and child characteristics with cleft lip and palate., Results: A total of 1401 newborns with various birth defects were born among the 89,078 live births from 2015 to 2022 in Bhutan. Of these, 122 (8.7%) constituted orofacial clefts. The prevalence of orofacial clefts tended to increase, with a period prevalence of 1.37 per 1000 live births. There were more cases in males (72) than in females (50). The incidence rate ratio ranged from 1.2 to 2.0 compared with the 2015 baseline year, indicating increased rates over time., Conclusion: Orofacial clefts constituted 8.7% of total birth defects and 1.37 per 1000 live births over the years. The increasing prevalence trends and incidence rate ratios over the years underscore the importance of ongoing surveillance and interventions to address the burden of orofacial clefts in Bhutan., Clinical Trial Number: Not applicable., Competing Interests: Declarations Ethics approval and consent to participate The study received a waiver for ethics approval from the Research Ethics Board of Health (REBH), Ministry of Health, Royal Government of Bhutan. Since the research utilized routine surveillance data without any identifiable personal information, the requirement for informed consent was also waived by the REBH. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Hypertrophic olivary degeneration (HOD) is a rare form of transsynaptic degeneration, caused by injury to the dentato-rubro-olivary pathway (DROP). Radiologically, this manifests as T2 hyperintensity, with or without enlargement of the inferior olivary nucleus. The purpose of the study was to evaluate the incidence, associated imaging characteristics, potential etiologies, latency period, and temporal progression of HOD in patients undergoing surgical resection of posterior fossa tumors (PFTs)., Methods: A retrospective analysis of patients with PFTs and postsurgical magnetic resonance imaging scans was conducted. HOD was diagnosed based on inferior olivary nucleus signal abnormalities and size changes. Demographics, tumor characteristics, time to HOD onset, involved DROP components, and clinical symptoms were recorded., Results: HOD was seen in 40 (6.2%) patients following PFT surgery. Twenty six patients were aged 17 years or less, while the rest were aged more than 17 years. Medulloblastoma was the most frequently diagnosed tumor type (n = 25), followed by pilocytic astrocytoma (n = 8), ependymoma (n = 6), and high-grade glioma (n = 1). No statistical association was found between the development of HOD and tumor grade (P = 0.882). Ataxia was the most commonly reported clinical symptom (n = 15). The time elapsed between surgery and the diagnosis of HOD varied, with median intervals of 1 month, 5 months, and 37 months for different stages. Dentate nucleus was the most commonly affected component of the DROP (n = 36)., Conclusions: HOD is a frequently overlooked postoperative complication following PFT resection. Increased recognition of HOD by neuroradiologists is essential for timely diagnosis and avoidance of unnecessary diagnostic procedures., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: One of the key steps in arthroscopic Anterior Cruciate Ligament Reconstruction (ACLR) is getting the femoral tunnel at the right position to attach the graft. While the correct position has been described as a low and posterior position behind the bifurcate ridge on the medial surface of lateral femoral condyle, to reproducibly achieve it more than one technique is being used by surgeons. There are no randomized studies in literature which have evaluated the efficacy of these in a surgeon's hand. This study attempts to do that., Methods: This randomized study was performed at a military sports injury centre by a single surgical team led by two sports fellowship-trained surgeons. One hundred fifty patients undergoing ACLR surgery were randomized to Anteromedial Portal technique e (AMP)group, Far Anteromedial portal technique (FAMP) group and Outside in drilling (OI) group. We used postoperative three-dimensional Computed Tomogram (3D CT) to study tunnel position (Magnussen method), length and orientation (Basdekis method)., Results: 80 % of femoral entry points were in satisfactory position using all three techniques. The ideal position was achieved more often using FAMP & OI technique which was better than AMP, however it was not below level of significance set at P < 0.025 (18, 13 & 5 respectively using FAMP, OI and AMP techniques, p-value 0.08 OI vs AMP & 0.07 AMP vs FAMP). The average femoral tunnel length was longest in OI group 34.72 ± 2.41 mm. The mean FAMP tunnel lengths were significantly smaller than the mean tunnel length of AMP and OI groups. (p-value <0.01 FAMP vs OI and p-value <0.01 FAMP vs AMP)., Conclusion: Our study showed that all three techniques achieved acceptable femoral tunnel placement in 80 % cases. However, FAMP and OI technique further improved accuracy of achieving ideal tunnel location and OI technique predictably achieved longer tunnel length preventing risk of lateral blow out while using suspensory fixation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Delhi Orthopedic Association. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Competing Interests: The authors declare no conflicts of interest.

The CA1 region of the hippocampus is one of the most studied regions of the rodent brain, thought to play an important role in cognitive functions such as memory and spatial navigation. Despite a wealth of experimental data on its structure and function, it has been challenging to integrate information obtained from diverse experimental approaches. To address this challenge, we present a community-based, full-scale in silico model of the rat CA1 that integrates a broad range of experimental data, from synapse to network, including the reconstruction of its principal afferents, the Schaffer collaterals, and a model of the effects that acetylcholine has on the system. We tested and validated each model component and the final network model, and made input data, assumptions, and strategies explicit and transparent. The unique flexibility of the model allows scientists to potentially address a range of scientific questions. In this article, we describe the methods used to set up simulations to reproduce in vitro and in vivo experiments. Among several applications in the article, we focus on theta rhythm, a prominent hippocampal oscillation associated with various behavioral correlates and use our computer model to reproduce experimental findings. Finally, we make data, code, and model available through the hippocampushub.eu portal, which also provides an extensive set of analyses of the model and a user-friendly interface to facilitate adoption and usage. This community-based model represents a valuable tool for integrating diverse experimental data and provides a foundation for further research into the complex workings of the hippocampal CA1 region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Romani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: The aim was to investigate the relationship between metabolic indices and abnormal bone mass (ABM), analyse the association between osteoprotegerin (OPG) gene mutations and ABM, and explore the interaction effect of type 2 diabetes mellitus (T2DM) and OPG gene mutations on bone mineral density (BMD) in postmenopausal women to provide a new supplementary index and a reliable basis for the early identification of osteoporosis (OP) in postmenopausal women in the clinical setting., Methods: Postmenopausal women hospitalized within the Department of Endocrinology of the First Affiliated Sanatorium of Shihezi University from June 2021 to March 2023 were retrospectively analysed, and the bone mineral density of lumbar vertebrae 1-4 (BMD (L1-4)) of the studied subjects was measured once via twin-energy X-ray absorptiometry. The studied subjects were divided into a normal bone mass (NBM) group and an ABM group according to their bone mineral density, and the general data of the studied subjects were recorded once. Blood biochemical indices were determined, and genotyping of the rs4355801 locus of the OPG gene was performed. Differences in the overall data and biochemical indices of the two groups were evaluated via the rank-sum test, and the relationship between blood glucose levels and mutations of the rs4355801 locus of the OPG gene and ABM or BMD (L1-4) was evaluated via binary logistic regression analysis or linear regression analysis. A bootstrap test was performed to test whether uric acid (UA) levels mediate the association between blood glucose levels and BMD (L1-4). Simple effect analysis was performed to analyse the interaction between T2DM and mutations at the rs4355801 locus of the OPG gene on BMD (L1-4)., Results: ① After adjusting for confounding factors, the risk of ABM increased by 50% (95% CI 21-85%) for each unit increase in fasting plasma glucose (FPG) levels and 31% (95% CI 2-69%) for each unit increase in glycosylated haemoglobin (HbA1c) levels (both P < 0.05). FPG levels were negatively correlated with BMD (L1-4) (both P < 0.05), and uric acid in blood sugar and BMD (L1-4) played a significant mediating role in the model; this mediation accounted for 21% of the variance. ② After adjusting for confounding factors, women with the mutant genotypes GA and GG + GA of the OPG gene rs4355801 locus had a lower risk of ABM than did those with the wild-type genotype AA (OR = 0.71, 95% CI = 0.52-1.00; OR = 0.51, 95% CI = 0.28-0.92, P < 0.05). The mutant genotypes GG, GA and GG + GA were positively correlated with BMD (L1-4) (all P < 0.05). The interaction between T2DM and mutations in the OPG gene rs4355801 locus had an effect on BMD (L1-4), and this site mutation weakened the increase in blood glucose levels and led to an increase in the risk of ABM (P < 0.05)., Conclusion: Elevated blood glucose levels in postmenopausal women were associated with an increased risk of ABM, and UA played a mediating role in the relationship FPG levels and BMD (L1-4), accounting for 21% of the variance. Mutations at the rs4355801 locus of the OPG gene were associated with a reduced risk of ABM in postmenopausal women. The interaction between T2DM and mutations at the rs4355801 locus of the OPG gene in postmenopausal women affects BMD (L1-4), and mutations at this locus attenuate the increased risk of ABM due to elevated blood glucose levels., (© 2024. The Author(s).)

Objective: Prior studies using global cognitive measures have shown that social connectedness is linked with cognitive performance. We investigate the role of different social network dimensions on performance across distinct cognitive domains among dementia-free middle-aged and older rural Indians., Method: We utilized baseline assessment data of 2,525 participants (≥45 years) of an ongoing, prospective, aging cohort in rural India (Srinivaspura Aging, Neuro Senescence, and COGnition) for this study. We evaluated social networks using Cohen's Social Network Index on three dimensions: network diversity, network size, and network embeddedness. We measured cognitive performance on memory (narrative recall), visuospatial ability (geometric figure spatial recognition, visuospatial span), language (verbal fluency, semantic association, word comprehension, reading comprehension), and attention domains of a culturally adapted, computerized, neurocognitive test battery. Linear regression models, adjusted for age and sex, were used for statistical analysis., Results: In the linear regression model adjusted for age and sex, we found that greater network diversity was significantly associated with better performance in narrative recall, geometric figure spatial recognition, reading comprehension, semantic association, and attention tests. Participants with a larger network size had significantly better performance in verbal fluency and semantic association tests. Further, participants with greater network embeddedness had better visuospatial span and verbal fluency., Conclusions: Individuals having a greater network diversity, larger network size, and greater network embeddedness had better cognitive performance in multiple distinct cognitive domains. Following up these participants with serial cognitive monitoring can help understand if social networks play a role in delaying cognitive decline and protecting against dementia. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Chikungunya virus (CHIKV) and Mayaro virus (MAYV) are emerging/re-emerging alphaviruses transmitted by Aedes spp. mosquitoes and responsible for recent disease outbreaks in the Americas. The capacity of these viruses to cause epidemics is frequently associated with increased mosquito transmission, which in turn is governed by virus-host-vector interactions. Although many studies have explored virus-vector interactions, significant gaps remain in understanding how vertebrate host factors influence alphavirus transmission by mosquitoes. We previously showed that obesity, a ubiquitous vertebrate host biological factor, reduces alphavirus transmission potential in mosquitoes. We hypothesized that alphavirus-infected obese bloodmeals altered immune genes and/or pathways in mosquitoes, thereby inhibiting virus transmission. To test this, we conducted RNA sequencing (RNA-seq) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) on midgut RNA from mosquitoes fed on alphavirus-infected lean and obese mice. This approach aimed to identify potential antiviral or proviral genes and pathways altered in mosquitoes after consuming infected obese bloodmeals. We found upregulation of the Toll pathway and downregulation of several metabolic and other genes in mosquitoes fed on alphavirus-infected obese bloodmeals. Through gene knockdown studies, we demonstrated the antiviral role of Toll pathway and proviral roles of AAEL009965 and fatty acid synthase (FASN) in the transmission of alphaviruses by mosquitoes. Therefore, this study utilized obesity to identify factors influencing alphavirus transmission by mosquitoes and this research approach may pave the way for designing broadly effective antiviral measures to combat mosquito-borne viruses, such as releasing transgenic mosquitoes deficient in the identified genes., (Journal of Medical Virology© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

The human IRGM gene has been linked to inflammatory diseases including sepsis and Crohn's disease. Decreased expression of human IRGM, or the mouse orthologues Irgm1 and Irgm2, leads to increased production of a number of inflammatory chemokines and cytokines in vivo and/or in cultured macrophages. Prior work has indicated that increased cytokine production is instigated by metabolic alterations and changes in mitochondrial homeostasis; however, a comprehensive mechanism has not been elucidated. In the studies presented here, RNA deep sequencing and quantitative PCR were used to show that increases in cytokine production, as well as most changes in the transcriptional profile of Irgm1 -/- bone marrow-derived macrophages (BMM), are dependent on increased type I IFN production seen in those cells. Metabolic alterations that drive increased cytokines in Irgm1 -/- BMM - specifically increases in glycolysis and increased accumulation of acyl-carnitines - were unaffected by quenching type I IFN signaling. Dysregulation of peroxisomal homeostasis was identified as a novel upstream pathway that governs type I IFN production and inflammatory cytokine production. Collectively, these results enhance our understanding of the complex biochemical changes that are triggered by lack of Irgm1 and contribute to inflammatory disease seen with Irgm1-deficiency., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Aims: To prospectively determine whether extrinsic warming of the low-osmolality CT contrast media (Iohexol 350, Iodixanol 320, Iopromide 300, and Iopamidol 300) to 37°C prior to intravenous administration affects extravasation and allergic-like reaction rates., Materials and Methods: This large scale prospective case control study of adverse events included all the patients between the age group of 15-80 years undergoing routine contrast-enhanced computed tomographic (CECT) examinations from April 2018 to March 2020 at our institute. Ex vivo experiments were also performed to demonstrate change in contrast viscosity and fluid dynamics in relation to temperature., Results: A total of 24,379 CECTs were conducted during the study period. Extrinsic warming showed a significant decrease in extravasation rates for Iohexol 350 at flow rates <3.5 mL/sec (P=0.037). No significant difference was observed with Iopromide 300 (P=0.432). Overall, a significant decrease in allergic reactions and overall contrast-related reactions (excluding physiologic reactions) was noted (P<0.001), with Iohexol 350. However, no significant difference was found with Iopromide 300. The most common physiological reaction was a sense of warmth, more prevalent in the warmed group, aligning with ex-vivo experiments demonstrating decreased viscosity with contrast warming., Conclusions: Extrinsic warming of contrast helps reduce the incidence of allergic-like reactions and extravasations for Iohexol 350, but no significant difference was noted with Iopromide 300 even at low injection rates (<3.5 mL/sec)., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the outcomes of aqueous shunt exposure repair and to identify risk factors for recurrent exposure after surgical repair., Methods: This is a retrospective interventional case series of consecutive patients who underwent repair of an exposed aqueous shunt. Demographic and clinical data were extracted from the patients' records and survival analysis was employed to determine the probability of survival of the repair without further exposure. Cox proportional regression analysis was utilised to identify potential risk factors for failure of the repair surgery., Results: Seventy-six eyes of 76 patients were included in the study. The probability of survival without further exposure was 76.2% (CI 66.9-86.8%), 72.7% (CI 62.8-84.1%) and 54.7% (40.5-73.7%) at 1,2 and 4 years, respectively. No eye in which the tube was repositioned in the anterior chamber or in the sulcus (n = 9; 11.8%) developed a recurrence of the exposure. A shorter interval from the time of tube insertion to the repair surgery (HR 2.87 [CI 1.11-7.39]; p = 0.03; reference longer interval), a history of previous surgical revision (HR 3.06 [1.15-8.12]; p = 0.02; reference no prior revision) and the use of a human pericardial donor patch at the time of revision (HR 3.43 [1.16-10.13]; p = 0.03; reference other than pericardium) was associated with an increased risk of exposure recurrence., Conclusion: Aqueous shunt exposure revision is associated with reasonable mid and long term success. A shorter interval from tube insertion to exposure revision, previous revisions and the use of a human pericardium patch were associated with increased risk of failure., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Maternal nutrition was recognized as a significant part of brain growth and maturation in most mammalian species. Timely intervention with suitable nutraceuticals would provide long-term health benefits. We aim to unravel the molecular mechanisms of perinatal undernutrition-induced impairments in cognition and synaptic plasticity, employing animal model based on dietary nutraceutical supplementation. We treated undernourished dams at their gestational, lactational, and at both the time point with Astaxanthin (AsX) and Docosahexaenoic acid (DHA), and their pups were used as experimental animals. We evaluated the cognitive function by subjecting the pups to behavioral tests in their adult life. In addition, we assessed the expression of genes in the hippocampus related to cognitive function and synaptic plasticity. Our results showed downregulation of Brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), cAMP response-element-binding protein (CREB), and uncoupling protein-2 (UCP2) gene expression in pups born to undernourished dams in their adult life, which AsX and DHA modulated. Maternal AsX and DHA supplementation ameliorated the undernutrition-induced learning impairment in novel object recognition (NOR) tests and partially baited radial arm maze (RAM) tasks in offspring's. The expressions of Synapsin-1 and PSD-95 decreased in perinatally undernourished groups compared to control and AsX-DHA treated groups at CA1, CA2, CA3, and DG. AsX and DHA supplementation upregulated BDNF, NT-3, CREB, and UCP2 gene expressions in perinatally undernourished rats, which are involved in intracellular signaling cascades like Ras, PI3K, and PLC. The results of our study give new insights into neuronal differentiation, survival, and plasticity, indicating that the perinatal period is the critical time for reversing maternal undernutrition-induced cognitive impairment in offspring's., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Extrahepatic portal vein thrombosis (EHPVO) is an uncommon cause of portal hypertension. In the long term, patients may develop portal cavernoma cholangiopathy (PCC). Up to 30%-40% of patients with EHPVO may not have shuntable veins and are often difficult to manage surgically. Interventional treatment including portal vein recanalisation-trans jugular intrahepatic portosystemic shunt (PVRecan-TIPS) has been used for patients with EHPVO. However, PV reconstruction-trans jugular intrahepatic portosystemic shunt (PVRecon-TIPS) and portal vein stenting are novel techniques for managing such patients with EHPVO with non-shuntable venous anatomy. In contrast to PVRecan-TIPS, PV reconstruction-TIPS (PVRecon-TIPS) is performed through intrahepatic collaterals. Here we present six cases of PCC who presented with recurrent acute variceal bleeding (AVB) and or refractory biliary stricture. They did not have any shuntable veins. PVRecon-TIPS was performed for five patients whilst PV stenting was done in one. Amongst the six patients, one died of sepsis whilst one who developed hyponatremia and hepatic encephalopathy was salvaged with conservative management. Following the procedure, they were started on anti-coagulation. Decompression of cavernoma was documented in all other patients. Biliary changes improved completely in 40% of patients., (© 2024 Indian National Association for Study of the Liver. Published by Elsevier B.V.)

RT-PCR is the gold standard for diagnosis of COVID-19. All RT-PCR kits are based on RNA extraction from the clinical sample. There was a sudden increase in demand of these kits, both RNA extraction and COVID-19 RT-PCR kits during the pandemic. This sudden spurt in global demand created a situation of shortage of consumables, especially the RNA extraction kits. Hence, this study was carried out to evaluate and compare COVID-19 RT-PCR without RNA extraction step using buffer R3. Sensitivity, specificity and accuracy of RT-PCR kit without RNA extraction were 89.16 %, 100% and 89.6% respectively. This approach saved more than 50 % time compared to the RT-PCR kit with RNA extraction approach allowing enhanced daily sample processing capability. RT-PCR kit without RNA extraction help in managing a greater number of samples, reduces cost and turnaround time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Light-chain deposition disease (LCDD) is a rare CNS disorder characterized by the extracellular accumulation of monoclonal immunoglobulin light chains in various organs. LCDD typically arises secondary to an underlying plasma cell dyscrasia, such as monoclonal gammopathy of undetermined significance or multiple myeloma. However, rare cases can occur in the absence of a demonstrable plasma cell disorder. The kidneys, liver, lungs, and heart are the most affected organs. Intracerebral LCDD, particularly without an underlying plasma cell neoplasm, represents an exceedingly uncommon entity with limited documented cases in the literature. This review article explores the pathogenesis, histopathologic features, and characteristic neuroimaging findings of intracerebral LCDD. We emphasize the diverse imaging presentations of this disease, which can closely resemble other neurologic pathologies. Recognizing these potential mimics is crucial for avoiding misdiagnosis, especially in the absence of a known underlying plasma cell disorder. This article aims to provide a comprehensive overview from a neuroradiologic perspective, facilitating the recognition and differentiation of this challenging entity., (© 2025 by American Journal of Neuroradiology.)

Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second-leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. Here, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared to their castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer (CSPC) populations, the obligate sGC heterodimer was repressed via methylation of its beta subunit. Genetically abrogating sGC complex formation in CSPC cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and co-treatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy.

Temporal lobe epilepsy (TLE) can present in a variety of ways and is challenging to diagnose. While MRIs are the gold standard for detecting structural lesions and EEGs can identify epileptiform discharges, relying solely on these diagnostic methods can result in underdiagnosis or misdiagnosis of the condition. Seizures with motor components may manifest as unusual behavior; anxiety, psychosis, and other psychiatric conditions can occur in conjunction with or independently of seizure activity. In cases where diagnostic testing yields negative results but the history strongly suggests seizure-like activity, practitioners should not hesitate to initiate antiepileptic medications. Here, we present the case of a patient who exhibited behavioral problems, including shouting religious slogans and experiencing recurrent loss of consciousness, either occurring together or separately, while lacking awareness. The patient had a history of type 2 diabetes and no relevant family history. An extensive multidisciplinary evaluation was performed, including EEG and MRI, all of which returned normal results. Given the high clinical suspicion of TLE, the patient was started on the antiepileptic medication divalproex sodium. After six months of treatment, there was a significant improvement in all symptoms. This case highlights the importance of considering TLE in patients with suggestive clinical features even when initial diagnostic tests are normal and underscores the potential efficacy of early antiepileptic treatment in managing symptoms effectively., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Khan et al.)

Cleft lip and palate are common congenital defects with multifactorial complex etiology characterized by complete or incomplete cleft of lip, alveolus, and hard and soft palate. In infants, the main problem lies in the difficulty of suckling with frequent nasal regurgitation leading to respiratory and middle ear infections. This article presents a case report of an 8-day-old female with complete cleft of hard and soft palate who was given a novel self-retentive type feeding obturator. This obturator eliminated the need for supplementary aids to help in retention and has a simple design, is cost-effective, and easy to use., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The No Surprises Act (NSA) went into effect on January 1, 2022. This federal law is designed to minimize surprise bills for emergency care, out of network (OON) care, and care for uninsured or self-pay individuals. To achieve these goals, the NSA relies heavily on physicians providing cost estimates to patients prior to administering care. Because healthcare is often price-opaque, this study was conducted to assess physician and patient attitudes toward price transparency in plastic surgery and aesthetic/self-pay medicine., Methods: Two cohorts of providers received a survey asking whether and how their practice offers pricing information prior to a consultation and their views regarding the NSA. Patients who had previously used an online price estimator tool also received a survey regarding their experience and accuracy of estimates received online., Results: Most surveyed providers do not share the costs of their services online, whereas patients had a positive experience when receiving estimates of medical services before consultation. Although many providers cited the inaccuracy of price estimator tools as a reason not to incorporate them into their website, most patients reported that their final cost of service was close to (or even less than) the estimate received online prior to the consultation., Conclusions: This study suggests that price transparency is a patient satisfier. Therefore, plastic surgeons should exercise price transparency to be compliant with federal law and to gain a competitive advantage in the market, as the decision to implement price transparency can be mutually beneficial to patients and providers., Competing Interests: The senior author has equity interest in KP Innovations LLC. The other authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Protein aggregation is a common pathological occurrence in neurodegenerative diseases. This often leads to neuroinflammation, which exacerbates the aggregation and progression of diseases like Parkinson's and Alzheimer's. Here, we focus on immune responses and neurotoxicity in a Parkinson's disease model in Drosophila . Mutations in the SNCA gene that encodes the alpha (α)-Synuclein protein have been linked to familial Parkinson's disease, disrupting autophagy regulation in neuronal cells and promoting the formation of Lewy bodies, a hallmark of Parkinson's pathology. This results in the loss of dopaminergic neurons, manifesting as movement disorders. α-Synuclein aggregation triggers innate immune responses by activating microglial cells, leading to phagocytic activity and the expression of neuroprotective antimicrobial peptides (AMPs). However, sustained AMP expression or chronic inflammation resulting from inadequate microglial phagocytosis can induce neuronal toxicity and apoptosis, leading to severe dopaminergic neuron loss. This review underscores the mechanistic connection between immune response pathways and α-Synuclein-mediated neurodegeneration using Drosophila models. Furthermore, we extensively explore factors influencing neuroinflammation and key immune signaling pathways implicated in neurodegenerative diseases, particularly Parkinson's disease. Given the limited success of traditional treatments, recent research has focused on therapies targeting inflammatory signaling pathways. Some of these approaches have shown promising results in animal models and clinical trials. We provide an overview of current therapeutic strategies showing potential in treating neurodegenerative diseases, offering new avenues for future research and treatment development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rai and Bergmann.)

Endoscopic ultrasound (EUS) has evolved from a diagnostic to an interventional modality, allowing precise vascular access and therapy. EUS-guided vascular access of the portal vein has received increasing attention in recent years as a diagnostic and therapeutic tool. EUS-guided portal pressure gradient directly measures the hepatic vein portal pressure gradient and is crucial for understanding of liver function and prognostication of liver disease. EUS facilitates the sampling of portal venous blood to obtain circulating tumor cells (CTCs) in pancreatobiliary malignancies. This technique aids in the diagnosis and staging of cancers. EUS-guided interventions have a substantial potential for diagnosing portal vein tumor thrombus (PVTT) in patients with hepatocellular carcinoma. EUS-guided coil and glue embolization have higher efficacy for the treatment of gastric varices than direct endoscopic glue. Pseudoaneurysm (PsA), a rare vascular complication of acute and chronic pancreatitis, is typically managed with interventional radiology (IR)-guided embolization and surgery. EUS is increasingly used in specialized centers for non-variceal gastrointestinal bleeding, particularly for pseudoaneurysm-related bleeding. There is limited data on EUS-guided intervention for bleeding ectopic varices, rectal varices and Dieulafoy lesions, but it is becoming more widely accepted. In this extensive review, we evaluated both current and potential future applications of EUS-guided vascular interventions, including EUS-guided gastric variceal bleed therapy, rectal and ectopic varices, pseudoaneurysmal bleeding, splenic artery embolization, portal pressure gradient measurement, portal vein sampling for CTCs, fine needle aspiration of PVTT, intrahepatic portosystemic shunt placement, liver tumor ablation and EUS-guided cardiac intervention., (© 2024. Indian Society of Gastroenterology.)

Seed priming by nitric oxide (NO) and hydrogen sulphide (H 2 S) in combating against abiotic stress in plants is well documented. However, knowledge of fundamental mechanisms of their crosstalk is scrambled. Therefore, the reported study examined the probable role of NO and H 2 S in the mitigation of arsenate toxicity (As(V)) in rice seedlings and whether their potential signalling routes crossover. Results report that As(V) toxicity limited shoot and root length growth with more As accumulation in roots. As(V) further caused elevated reactive oxygen species levels, inhibited ascorbate-glutathione cycle enzymes and relative gene expression of its enzymes and thus, causing lipid and protein oxidation. These results correlate with reduced nitric oxide synthase-like and L -cysteine desulfhydrase activity along with endogenous NO and H 2 S. While, L-NAME or PAG augmented As(V) toxicity, and addition of SNP or NaHS effectively reversed their respective effects. Furthermore, SNP under PAG or NaHS under L-NAME were able to pacify As(V) stress, implicating that endogenous NO and H 2 S efficiently ameliorate As(V) toxicity but without their shared signaling in rice seedlings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background and Aims: The appropriate length of esophageal myotomy in peroral endoscopic myotomy (POEM) for achalasia cardia remains unclear. This study aimed to compare the outcome of short (≤3 cm) and long (≥6 cm) esophageal myotomy in patients with type I and II achalasia cardia., Methods: This single-blinded, randomized controlled noninferiority trial was conducted at a tertiary center between July 2021 and December 2021. Patients with achalasia types I and II were randomized into short (≤3 cm) and long (≥6 cm) esophageal myotomy groups. The primary outcome of the study was clinical success (Eckardt score ≤3) 1 year after the procedure. The secondary outcomes included a comparison of technical success, operating duration, occurrence of intraoperative adverse events, alterations in integrated relaxation pressure (IRP), change in barium column height after 5 minutes (1 mo), and gastroesophageal reflux disease (3 mo) between the groups., Results: Fifty-four patients were randomized into the short (n=27) or long (n=27) esophageal myotomy groups. Technical success rates were 100% (27/27) and 96.3% (26/27) in short myotomy (SM) and long myotomy (LM) groups, respectively. The clinical success rates were 96.3% (26/27) and 96.2% (25/26) in the SM and LM groups, respectively ( P =0.998). The mean (±SD) length of the esophageal myotomy was 2.75±0.36 cm in the SM and 6.69±1.35 cm in the LM groups ( P <0.001). The mean (±SD) procedure time for the SM and LM groups was 61.22±8.44 and 82.42±14.70 minutes ( P <0.001), respectively. The mean integrated relaxation pressure (IRP), Eckardt score, adverse events, reflux esophagitis, symptomatic gastroesophageal reflux disease, and esophageal acid exposure (>6%) did not differ significantly between the 2 groups following POEM treatment., Conclusions: Short myotomy is noninferior to long myotomy in terms of clinical success, gastroesophageal reflux disease, and intraoperative adverse events at the short-term follow-up ( P >0.05). Short myotomy resulted in a reduced operative time ( P <0.05)., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Compelling evidence has strongly linked unregulated sugar levels to developing Alzheimer's disease, suggesting Alzheimer's to be 'diabetes of the brain or 'type 3 diabetes. Insulin resistance contributes to the pathogenesis of Alzheimer's disease due to uncontrolled and unchecked blood glucose, though the interrelatedness between Alzheimer's disease and type 2 diabetes is debatable. Here we describe the consequences of inducing type 3 diabetes by feeding Drosophila on a high sucrose diet, which effectively mimics the pathophysiology of diabetes. A high sucrose diet increases glycogen and lipid accumulation. Inducing type 3 diabetes worsened neurodegeneration and accelerated disease progression in Drosophila expressing the Alzheimer's Familial Arctic mutation. High sucrose milieu also negatively affected locomotor ability and reduced the lifespan in the Alzheimer's disease model of Drosophila. The results showed that creating diabetic conditions by using insulin receptor (InR) knockdown in the eyes of Drosophila led to a degenerative phenotype, indicating a genetic interaction between the insulin signaling pathway and Alzheimer's disease. The expression of PERK reflects disruption in the endoplasmic reticulum homeostasis due to amyloid-β (Aβ) under a high sucrose diet. These observations demonstrated an association between type 3 diabetes and Alzheimer's disease, and that a high sucrose environment has a degenerating effect on Alzheimer's disease condition., Competing Interests: Declaration of competing interest All the authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Mastalgia, a common complaint among women, denotes breast discomfort that can manifest as cyclical or non-cyclical. Reassurance, mechanical support and various non-pharmacological treatments, like flaxseeds, have been seen to have a good effect in treating mastalgia. Thus, the aim of this study was to investigates the efficacy of flaxseed in alleviating pain associated with mastalgia and its impact on the overall health-related quality of life among female patients., Materials and Methods: Conducted at a tertiary care center in Northern India over 18 months, it employed a single-arm interventional design. The participants included females aged 18 years and older presenting with breast pain at the Department of General Surgery. The intervention involved daily consumption of 30 g of milled flaxseed for each participant, administered over a period of six months. Pain severity was assessed using the visual analogue scale (VAS) before supplementation and at follow-up intervals up to six months. Concurrently, the Short Form-12 (SF-12) items Health Survey measured health-related quality of life, encompassing both physical and mental health domains. Statistical analysis employed parametric (paired t-test) and non-parametric tests (chi-square, McNemar) where appropriate, with statistical significance set at p <0.05., Results: Two hundred women with mastalgia were included with a significant reduction in mean VAS scores from 6.03±0.83 at baseline to 2.19±0.66 at six months post-intervention ( p = 0.0001). This reduction in pain intensity demonstrated a positive correlation with duration of flaxseed supplementation, notably declining after the initial three months. The mean difference in physical and mental SF-12 score at first visit and at 6 months after intervention was significant ( p = 0.0001)., Conclusion: This study underscores the potential of flaxseed as a therapeutic option for managing mastalgia and enhancing health-related quality of life among affected individuals., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (©Copyright 2024 by the Turkish Federation of Breast Diseases Societies / European Journal of Breast Health published by Galenos Publishing House.)

Various important medicines make use of secondary metabolites that are produced by plants. Medicinal plants, such as Withania somnifera and Tinospora cordifolia , are rich sources of chemically active compounds and are reported to have numerous therapeutic applications. The therapeutic use of medicinal plants is widely mentioned in Ayurveda and has folkloric importance in different parts of the world. The aim of this review is to summarize the phytochemical profiles, folkloric importance, and primary pharmacological activity of W. somnifera and T. cordifolia with emphasis on their action against the novel coronavirus., Competing Interests: Conflict-of-interest statement: No competing interests or conflicts to declare., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS) that is predominantly characterized by mood symptoms, and debilitating physical and cognitive symptoms, which have a direct or indirect impact on work efficiency, social and personal relationships, and overall quality of life. This study was conducted to determine the prevalence of moderate to severe PMS and PMDD among young women in India and investigate sociodemographic and other associated factors., Materials and Methods: We conducted a cross-sectional study that included 198 young women between 17 and 30 years of age who were medical students or nursing staff from a medical college in Eastern India. Data were collected regarding sociodemographic information, menstrual patterns, age of menarche, sexually active status, body mass index, and level of physical activity, which were analyzed to find correlations with moderate to severe PMS or PMDD. The Premenstrual Symptoms Screening Tool was used for diagnosing moderate to severe PMS or PMDD. The data were analyzed using Statistical Product and Service Solutions (SPSS, version 24.0; IBM SPSS Statistics for Windows, Armonk, NY) software., Results: Forty-six (23.5%) respondents were diagnosed with moderate-to-severe PMS, of which four (2%) were diagnosed with PMDD. Among those diagnosed with moderate-to-severe PMS/PMDD, 39 (27.3%) were of the age group 17-24 years, and seven (13.2%) were of the age group 25-30 years, which was a statistically significant difference (p=0.05). Thirty-eight (30.6%) students were diagnosed with moderate-to-severe PMS, as compared to eight (11.1%) working professionals, which was also a statistically significant difference., Conclusion: Moderate-to-severe PMS significantly impacts quality of life. Considering its prevalence among young subjects, it is important to make young girls aware of the condition and educate them regarding various ways to manage their symptoms., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. All India Institute of Medical Sciences, Deoghar, issued approval 2021-13-IND-02. IEC - Full committee approved this proposal. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Vineeta et al.)

The development of drug resistance in cancer cells poses a significant challenge for treatment, with nearly 90% of cancer-related deaths attributed to it. Over 50% of ovarian cancer patients and 30-40% of breast cancer patients exhibit resistance to therapies such as Taxol. Previous literature has shown that cytotoxic cancer therapies and ionizing radiation damage tumors, prompting cancer cells to exploit the autotaxin (ATX)-lysophosphatidic acid (LPA)-lysophosphatidic acid receptor (LPAR) signaling axis to enhance survival pathways, thus reducing treatment efficacy. Therefore, targeting this signaling axis has become a crucial strategy to overcome some forms of cancer resistance. Addressing this challenge, we identified and assessed ATX-1d, a novel compound targeting ATX, through computational methods and in vitro assays. ATX-1d exhibited an IC 50 of 1.8 ± 0.3 μM for ATX inhibition and demonstrated a significant binding affinity for ATX, as confirmed by MM-GBSA, QM/MM-GBSA, and SAPT in silico methods. ATX-1d significantly amplified the potency of paclitaxel, increasing its effectiveness tenfold in 4T1 murine breast carcinoma cells and fourfold in A375 human melanoma cells without inducing cytotoxic effects as a single agent.

Purpose: Anti-PD-1/PD(L)1-based combination therapy is the standard of care in first line (1L) for metastatic nonsquamous non-small cell lung cancer (mnsqNSCLC) without driver alterations. This study aimed to evaluate real-world clinical outcomes in this population., Methods: Eligible physicians in the United States, Europe, and Japan abstracted information from medical charts of eligible adult patients with mnsqNSCLC (without EGFR / ALK , no known ROS1 alterations) who initiated 1L anti-PD(L)1-based combination therapy for mnsqNSCLC between 2017 and 2021. Kaplan-Meier analyses were used to assess overall survival (OS), time-to-treatment discontinuation (TTD), and real-world progression-free survival (rwPFS) after 1L initiation., Results: Overall, 142 physicians contributed deidentified data from 430 patients' medical charts. The distribution of PD-L1 expression levels was 31.2% with tumor proportion score (TPS) <1%, 42.3% with TPS 1%-49%, and 26.5% with TPS ≥50%. In 1L, patients received anti-PD(L)1 + chemotherapy (84.6%), anti-PD(L)1 + anti-CTLA4 with or without chemotherapy (11.9%), and anti-PD(L)1 + chemotherapy + anti-vascular endothelial growth factor receptor (3.5%). The median OS was 21.7 months (TPS <1%: 18.3 months; TPS 1%-49%: 21.6 months; TPS ≥50%: 24.0 months). The median TTD was 11.0 months (TPS <1%: 9.1 months; TPS 1%-49%: 10.9 months; TPS ≥50%: 12.2 months). The median rwPFS was 11.2 months (TPS <1%: 9.3 months; TPS 1%-49%: 11.1 months; TPS ≥50%: 13.2 months)., Conclusion: This study assessed the real-world clinical effectiveness of 1L anti-PD(L)1-based combination therapy for mnsqNSCLC. Results from this study were generally consistent with previous clinical trials and published real-world evidence in 1L mnsqNSCLC.

Skin cancer is a widespread worldwide health concern, manifesting in many subtypes such as squamous cell carcinoma, basal cell carcinoma, and melanoma. Although all these types occur frequently, they generally lack the possibility of being cured, emphasizing the importance of early discovery and treatment. This comprehensive study explores the role of programmed cell death protein 1 (PD-1) in skin cancer, focusing on its molecular mechanisms in immune regulation and its critical role in tumor immune evasion, while also clarifying the complexities of immune checkpoints in cancer pathogenesis. It critically evaluates the clinical applications of PD-1 inhibitors, spotlighting their therapeutic potential in treating skin cancer, while also addressing the significant challenge of resistance. This work further discusses the evolution of resistance mechanisms against PD-1 inhibitors and suggests potential approaches to mitigate these issues, thereby enhancing the effectiveness of these therapies. The study further highlights the current state of PD-1 targeted therapies and sets the stage for future research aimed at optimizing these treatments for better clinical outcomes in skin cancer., (© 2024 John Wiley & Sons Ltd.)

Background: In clinical trials, frontline pembrolizumab for advanced NSCLC has demonstrated durable, clinically meaningful, long-term survival benefits over chemotherapy. Our objective was to evaluate 5-year survival rates outside the idealized setting of clinical trials for advanced/metastatic NSCLC treated with frontline pembrolizumab monotherapy., Methods: Using a nationwide, electronic health record-derived, deidentified database in the United States, we studied adult patients with advanced/metastatic NSCLC (unresectable stage IIIB/IIIC, or stage IV), with PD-L1 expression ≥ 50%, no documented EGFR, ALK, or ROS1 genomic alteration, and ECOG performance status of 0-1 initiating frontline pembrolizumab monotherapy from November 1, 2016, through March 31, 2020, excluding those in clinical trials. Kaplan-Meier was used to determine overall survival (OS). Data cutoff was May 31, 2023., Results: A total of 804 patients were eligible for the study, including 404 women (50%); median age was 72 years (range, 38-85 years), with 310 patients (39%) ≥ 75 years old. Median follow-up time from pembrolizumab initiation to data cutoff was 60.5 months (range, 38.0-78.7). At data cutoff, 549 patients (68%) had died. Median OS was 19.2 months (95% CI, 16.6-21.4), and survival rate at 5 years was 25.1% (95% CI, 21.7-28.7). Overall, 266 patients (33%) received 1 or more subsequent regimens, most commonly an anti-PD-(L)1 agent (as monotherapy or combination therapy) or platinum-based chemotherapy., Conclusions: With 5-year follow-up in a real-world population, frontline pembrolizumab monotherapy continues to demonstrate long-term effectiveness, with survival outcomes consistent with those of pivotal clinical trials, for treating patients with advanced NSCLC with PD-L1 expression of ≥ 50% and no EGFR, ALK, or ROS1 genomic alteration., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

In recent years, a growing number of roles have been identified for mitochondria in innate immunity. One principal mechanism is that translocation of mitochondrial nucleic acid species from the mitochondrial matrix to the cytosol and endolysosomal lumen in response to an array of microbial and non-microbial environmental stressors has been found to serve as a second messenger event in the cell signaling of the innate immune response. Thus, mitochondrial DNA and RNA have been shown to access the cytosol through several regulated mechanisms involving remodeling of the mitochondrial inner and outer membranes and to access lysosomes via vesicular transport, thereby activating cytosolic (e.g., cyclic GMP-AMP synthase [cGAS]; retinoic acid-inducible gene-I [RIG-I]-like receptors) and endolysosomal (Toll-like Receptor [TLR]7, -9) nucleic acid receptors that induce type I interferons and pro-inflammatory cytokines. In this mini-review, we discuss these molecular mechanisms of mitochondrial nucleic acid mislocalization and their roles in host defense, autoimmunity, and auto-inflammatory disorders. The emergent paradigm is one in which host-derived DNA interestingly serves as a signal amplifier in the innate immune response and also as an alarm signal for disturbances in organellar homeostasis. The apparent vast excess of mitochondria and mitochondrial DNA nucleoids per cell may thus serve to sensitize the cell response to stressors while ensuring an underlying reserve of intact mitochondria to sustain cellular metabolism. An improved understanding of these molecular mechanisms will hopefully afford future opportunities for therapeutic intervention in human disease., (Published by Oxford University Press on behalf of The Japanese Society for Immunology 2024.)

Background: Remission of early type 2 diabetes (T2D) is possible; however, diet programmes proven effective are unaffordable in many southeast Asian populations where T2D is more frequent and more aggressive at lower body weight and younger age. We evaluate an entirely food-based service., Methods: This study employed a single-arm intervention and follow-up design for intervention evaluation in existing hospital people with T2D of under 5 years known duration. Individuals attending a diabetes clinic in Kathmandu with early T2D (<5 years) aged 30-70 years, BMI ≥23 kg/m 2 , were offered a low-cost nutritionally complete diet-programme, using traditional Nepali foods to provide 8-weeks ∼850 kcal/day weight loss induction, and then weight maintenance. The participants received 4-weekly dietetic appointments (30-45 min) and verbo-pictorial leaflets using household measures. Glucose-lowering medications (49/70 at baseline) were stopped at baseline or soon after. The study was registered as ISRCTN10671396, testing a traditional food-based intervention for weight loss and T2D remission., Findings: For 70 individuals (45 female) invited between March 19, 2022 and September 19, 2023, baseline mean (SD) age was 48.6 (9.9) years, bodyweight 74.6 (9.5) kg, BMI 29.7 (3.6) kg/m 2 , known diabetes duration 2.5 (1.9) years, HbA1c on treatment 8.1 (1.6) %. At 12, 24 and 52 weeks respectively, evaluating n = 44, 46, 45, bodyweight was 70.1 (8.5), 69.8 (8.9), 70.0 (8.8) kg, HbA1c 6.8 (0.9), 6.9 (1.5), 7.1 (1.3) %; HbA1c <6.5% was recorded for 46%, 48% and 36% and remission of T2D (HbA1c <6.5% off medication >3 months) in 43%, 39% and 29%. The main reported adherence barriers were fears of weakness, hunger, and inconvenience during travel. Incentives were ease of the diet, reduced doses and costs of medications, and improved appearance., Interpretation: Traditional food-based weight management can valuably improve control, reduce medication needs, and generate remissions of established T2D, but adherence barriers must be overcome to optimise outcomes., Funding: All Saints Educational Trust, England., Competing Interests: All authors declare no conflicts of interest., (© 2024 The Author(s).)

Germination is an essential phenomenon in the life cycle of plants, and a variety of external and internal factors influence it. Fire and the produced smoke have been vital environmental stimulants for the germination of seeds in many plant species, like Leucospermum cordifolium and Serruria florida. These plants do not germinate at all if fire and smoke are not present. This phenomenon of germination in plant species has existed in the ecosystem since ancient times. Various studies to study the response of seeds to smoke and its extracts have been undertaken for stimulation of germination by burning various plant materials and bubbling the smoke produced through water. The application of plant-derived smoke and smoke water is well known for promoting germination, breaking dormancy, and checking abiotic stress. This significantly indicates that plant-derived smoke contains some bioactive metabolites responsible for the physiological metabolism of seed germination and is involved in enhancing seed vigor. The present review deals with the ancient use of smoke and smoke extracts for seed priming, the cost-efficient method of its preparation, the mode of action of karrikins relating to its perception by plants, and its significant effects on various crops, including its ability to check biotic and abiotic stresses., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Peptic ulcer disease (PUD) affects ~4 million people globally. Peptic ulcer perforation (PUP) is a serious complication of PUD associated with high mortality and morbidity. Hence, a high index of clinical suspicion is crucial in diagnosing such cases. Here, we present a case of a 19-year-old male who presented with 4 days of severe abdominal pain, fever, and vomiting. On examination, signs of acute abdomen were evident, and an erect chest X-ray confirmed free air under the diaphragm. The patient underwent an emergency midline laparotomy, during which 1000 ml of purulent fluid was evacuated. A perforation measuring 8 × 8 mm 2 was repaired using the falciform ligament due to the unavailability of adequate healthy omentum. His postoperative recovery was uneventful. This case report underscores the importance of considering the falciform ligament as a viable and effective alternative for the closure of PUP when the omentum is unavailable., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)